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This study using contralateral teeth from human cadavers assessed the amount of unprepared wall surface areas (USA), accumulated hard tissue debris (AHTD), and dentinal crack formation after root canal preparation using either reciprocating or rotary instruments. Incisors with a single root canal from 11 human mandibles had their root canals prepared with Reciproc or Mtwo. Each contralateral tooth was treated with one of the test instruments in order to create matched pairs. Micro-CT scans were taken before and after preparation to instrument sizes 40 and 50 in both groups. USA and AHTD were evaluated in the full canal length or the apical portion only. Crack formation was also evaluated in the full root length. After size 40, no significant differences in USA and AHTD were observed in the full canal length (P > .05). Separate analysis of the apical 4-mm canal revealed no difference in AHTD, but significantly more USA with Mtwo than Reciproc (P .05). More AHTD were observed in the full canal after using Mtwo size 50 (P .05). Intragroup analyses showed a significant decrease of USA and a significant increase of AHTD when preparation size increased from 40 to 50 (P < .05). In teeth without any pre-existing detectable dentinal defect (n = 38), crack formation occurred in 4 teeth, 2 from each preparation system. Reciproc instrument size 40 resulted in more prepared areas in the apical canal than Mtwo instrument of the same size. However, the amount of AHTD did not differ between them at this file size. Canal enlargement to size 50 prepared more walls but created more debris. Dentinal defects were produced after preparation with both systems.

Neurological research and practice 3(1), 17 (2021). doi:10.1186/s42466-021-00116-1, Published by BioMed Central, [London]

Objectives To assess focused cardiac ultrasound impact on clinician hemodynamic characterization of patients with suspected septic shock as well as expert-generated focused cardiac ultrasound algorithm performance. Design Retrospective, observational study. Setting Single-center, noncardiac PICU. Patients Less than 18 years old receiving focused cardiac ultrasound study within 72 hours of sepsis pathway initiation from January 2014 to December 2016. Interventions Hemodynamics of patients with suspected septic shock were characterized as fluid responsive, myocardial dysfunction, obstructive physiology, and/or reduced systemic vascular resistance by a bedside clinician before and immediately following focused cardiac ultrasound performance. The clinician's post-focused cardiac ultrasound hemodynamic assessments were compared with an expert-derived focused cardiac ultrasound algorithmic hemodynamic interpretation. Subsequent clinical management was assessed for alignment with focused cardiac ultrasound characterization and association with patient outcomes. Measurements and main results Seventy-one patients with suspected septic shock (median, 4.7 yr; interquartile range, 1.6-8.1) received clinician performed focused cardiac ultrasound study within 72 hours of sepsis pathway initiation (median, 2.1 hr; interquartile range, -1.5 to 11.8 hr). Two patients did not have pre-focused cardiac ultrasound and 23 patients did not have post-focused cardiac ultrasound hemodynamic characterization by clinicians resulting in exclusion from related analyses. Post-focused cardiac ultrasound clinician hemodynamic characterization differed from pre-focused cardiac ultrasound characterization in 67% of patients (31/46). There was substantial concordance between clinician's post-focused cardiac ultrasound and algorithm hemodynamic characterization (33/48; κ = 0.66; CI, 0.51-0.80). Fluid responsive (κ = 0.62; CI, 0.40-0.84), obstructive physiology (к = 0.87; CI, 0.64-1.00), and myocardial dysfunction (1.00; CI, 1.00-1.00) demonstrated substantial to perfect concordance. Management within 4 hours of focused cardiac ultrasound aligned with algorithm characterization in 53 of 71 patients (75%). Patients with aligned management were less likely to have a complicated course (14/52, 27%) compared with misaligned management (8/19, 42%; p = 0.25). Conclusions Incorporation of focused cardiac ultrasound in the evaluation of patients with suspected septic shock frequently changed a clinician's characterization of hemodynamics. An expert-developed algorithm had substantial concordance with a clinician's post-focused cardiac ultrasound hemodynamic characterization. Management aligned with algorithm characterization may improve outcomes in children with suspected septic shock.

The use of three-dimensional printing in chemistry education has expanded greatly in the past 10 years. The technique has been used to demonstrate a range of concepts including molecular structure,...

Introduction Sepsis-associated encephalopathy (SAE) and septic encephalitis (SE) are associated with increased mortality, long-term cognitive impairment, and focal neurological deficits. Areas covered The PUBMED database was searched 2016-2020. The clinical manifestation of SAE is delirium, SE additionally is characterized by focal neurological symptoms. SAE is caused by inflammation with endothelial/microglial activation, increase of permeability of the blood-brain-barrier, hypoxia, imbalance of neurotransmitters, glial activation, axonal, and neuronal loss. Septic-embolic (SEE) and septic-metastatic encephalitis (SME) are characterized by focal ischemia (SEE) and small abscesses (SME). The continuum between SAE, SME, and SEE is documented by imaging techniques and autopsies. The backbone of treatment is rapid optimum antibiotic therapy. Experimental approaches focus on modulation of inflammation, stabilization of the blood-brain barrier, and restoration of membrane/mitochondrial function. Expert opinion The most promising diagnostic approaches are new imaging techniques. The most important measure to fight delirium remains establishment of daily structure and adequate sensory stimuli. Dexmedetomidine and melatonin appear to reduce the frequency of delirium, their efficacy in SAE and SE remains to be established. Drugs already licensed for other indications or available as food supplements which may be effective in SAE are statins, L-DOPA/benserazide, β-hydroxybutyrate, palmitoylethanolamide, and tetracyclines or other bactericidal non-lytic antibiotics.

Background The susceptibility of patients with chronic plaque psoriasis and the risks or benefits related to the use of biological therapies for COVID-19 are unknown. Few data about prevalence, clinical course and outcomes of COVID-19 among psoriatic patients were reported. The aims of this study were 1) to assess the prevalence and severity of COVID-19 in psoriatic patients treated with biologic agents during the first phase of the emergency (22 February to 22 April 2020) in Italy, and 2) to report the clinical outcomes of patients who have been exposed to individuals with confirmed SARS-CoV-2 infection. Methods Patients with moderate-to-severe chronic plaque psoriasis, aged ≥18 years and undergoing treatment with biologic agents as of 22 February 2020, were eligible to be included in PSO-BIO-COVID study. Demographic and clinical characteristics of patients using any biologic for psoriasis treatment between 22 February and 22 April 2020 were registered. For all confirmed or suspected cases of COVID-19, data about concomitant disease, ongoing therapies, and comorbidities were also reported. Results A total of 12,807 psoriatic patients were included in the PSO-BIO-COVID study. In this cohort twenty-six patients (0.2%) had a swab confirmation of SARS-CoV-2 infection. Eleven patients required hospitalization and two died. 125 of 12807 patients (1.0%) with exposure to a patient with COVID-19 under quarantine or active health surveillance, were reported. Conclusion The incidence of COVID-19 observed in our cohort of psoriatic patients (0.2%) is similar to that seen in the general population (0.31%) in Italy. However, the course of the disease was mild in most patients. Biological therapies may likely lessen "cytokine storm" of COVID-19, which sometimes lead to multiple organ failure, ARDS, and death.

Background: Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. Objectives: To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. Methods: Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg kg −1 intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). Results: Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10 mg kg −1 and 13 of 15 (87%) patients receiving 25 mg kg −1, with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0·26 mg kg −1 per day (range 0·06–0·48) led to complete clinical remission in 14 of 22 (64%) patients within 2–41 weeks. Conclusions: Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus.

To improve the therapy of neonatal central nervous system infections, well-characterized animal models are urgently needed. The present study analyzes neuropathological alterations with particular focus on neural injury and repair in brains of neonatal mice with Listeria monocytogenes (LM) meningitis/meningoencephalitis using a novel nasal infection model. The hippocampal formation and frontal cortex of 14 neonatal mice with LM meningitis/meningoencephalitis and 14 uninfected controls were analyzed by histology, immunohistochemistry, and in situ tailing for morphological alterations. In the dentate gyrus of the hippocampal formation of mice with LM meningitis/meningoencephalitis, an increased density of apoptotic neurons visualized by in situ tailing (p = 0.04) and in situ tailing plus immunohistochemistry for activated Caspase-3 (p

In 2020-2021, elearning became essential at all levels of education due to the COVID-19 pandemic. This editorial provides a year in review for eLearn Magazine. A common theme was the challenges of the COVID-19 pandemic in online education and opportunities for overcoming these challenges.

In IVF/ICSI treatment, the FSH starting dose is often increased in predicted low responders from the belief that it improves the chance of having a baby by maximizing the number of retrieved oocytes. This intervention has been evaluated in several randomized controlled trials, and despite a slight increase in the number of oocytes—on average one to two more oocytes in the high versus standard dose group—no beneficial impact on the probability of a live birth has been demonstrated (risk difference, −0.02; 95% CI, −0.11 to 0.06). Still, many clinicians and researchers maintain a highly ingrained belief in ‘the more oocytes, the better’. This is mainly based on cross-sectional studies, where the positive correlation between the number of retrieved oocytes and the probability of a live birth is interpreted as a direct causal relation. If the latter would be present, indeed, maximizing the oocyte number would benefit our patients. The current paper argues that the use of high FSH doses may not actually improve the probability of a live birth for predicted low responders undergoing IVF/ICSI treatment and exemplifies the flaws of directly using cross-sectional data to guide FSH dosing in clinical practice. Also, difficulties in the de-implementation of the increased FSH dosing strategy are discussed, which include the prioritization of intermediate outcomes (such as cycle cancellations) and the potential biases in the interpretation of study findings (such as confirmation or rescue bias).

Women experience challenges engaging with the healthcare system, but frequently utilize hair salons; these are promising venues for family planning and HIV prevention services. Our objective was to assess the acceptability of nurse-offered contraceptive and PrEP services at hair salons in Durban, South Africa. We interviewed salon owners (N = 10) and clients (N = 42) and conducted focus groups with hair stylists (N = 43 stylists; 6 focus groups across five hair salons) to explore barriers and facilitators to providing contraception and PrEP in salons. After developing a codebook, we performed content analysis to identify themes within each conceptual area; 10% of transcripts were coded by two coders to ensure reliability. Content was analyzed according to the following categories: (1) facilitators of and (2) barriers to utilizing these services, and (3) factors to consider for program implementation. Participants identified convenience and female-oriented, supportive atmosphere as facilitators to offering HIV and contraceptive services in salons. Owners and stylists noted that establishing legitimacy was important for program success, including providing promotional pamphlets and employing nurses. Clients cited privacy concerns surrounding HIV testing in a public space as a significant barrier to using these services. Overall, participants were enthusiastic about the program. Convenience and a conducive environment were noted as facilitators to receiving health services in the hair salon; attention will have to be directed to establishing privacy and program legitimacy. Hair salons represent an innovative venue for reaching young women at high-risk for unintended pregnancy and HIV infection.

STUDY QUESTION: Do cumulative live birth rates (CLBRs) over multiple IVF/ICSI cycles confirm the low prognosis in women stratified according to the POSEIDON criteria? SUMMARY ANSWER: The CLBR of low-prognosis women is ~56% over 18 months of IVF/ICSI treatment and varies between the POSEIDON groups, which is primarily attributable to the impact of female age. WHAT IS KNOWN ALREADY: The POSEIDON group recently proposed a new stratification for low-prognosis women in IVF/ICSI treatment, with the aim to define more homogenous populations for clinical trials and stimulate a patient-tailored therapeutic approach. These new criteria combine qualitative and quantitative parameters to create four groups of low-prognosis women with supposedly similar biologic characteristics. STUDY DESIGN, SIZE, DURATION: This study analyzed the data of a Dutch multicenter observational cohort study including 551 low-prognosis women, aged

Summary Background New point-of-care (POC) assays for early infant HIV diagnosis are costlier than conventional total nucleic acid assays, but could increase access to testing, shorten time to results, and expedite initiation of antiretroviral therapy. We aimed to assess the clinical benefits and cost-effectiveness of incorporating these POC assays into early infant diagnosis programmes in Zimbabwe. Methods We used the Cost Effectiveness of Preventing AIDS Complications (CEPAC)—Pediatric model to examine the clinical benefits, costs, and cost-effectiveness of replacing conventional assays for early infant HIV diagnosis with POC assays at age 6 weeks in Zimbabwe. We simulated two strategies for early infant HIV diagnosis: conventional and POC. Modelled assays differed in sensitivity; specificity; time to, and probability of, return of results; and cost. Model outcomes included survival, life expectancy, and mean lifetime per-person treatment cost, which were reported separately for all HIV-exposed infants and all infants with HIV. We calculated incremental cost-effectiveness ratios with discounted (3% per year) costs and life expectancy from a health-care system perspective for all HIV-exposed infants. We judged incremental cost-effectiveness ratios of $1010 (Zimbabwe's annual gross domestic product per person) or less per year of life saved to be cost-effective. Findings When conventional assays were used for early infant diagnosis, projected undiscounted life expectancy was 22·7 years for infants with HIV and 62·5 years for all HIV-exposed infants, at a cost of $610 per HIV-exposed infant. Use of POC assays for early infant HIV diagnosis improved projected undiscounted life expectancy to 25·5 years among infants with HIV and 62·6 years among HIV-exposed infants at a cost of $690 per HIV-exposed infant. At age 12 weeks, survival among all infants with HIV was 76·1% with the conventional testing strategy and 83·5% with the POC testing strategy. The incremental cost-effectiveness ratio of POC assays versus conventional assays for early infant diagnosis was $680 per year of life saved. When conventional assay characteristics remained constant, this ratio remained under the cost-effectiveness threshold as long as the specificity and sensitivity of the POC assay were greater than 92% and 65%, respectively. Our results were robust to plausible variations in POC assay cost, the probability of ART initiation, and probability of return of the results of POC testing. Interpretation Compared with conventional assays, POC assays for early infant HIV diagnosis in Zimbabwe will improve survival, extend life expectancy, and be cost-effective for HIV-exposed infants. Funding Elizabeth Glaser Pediatric AIDS Foundation, US National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Unitaid.

Zusammenfassung. Das nephrotische Syndrom wird durch einen renalen Proteinverlust definiert – damit einhergehend finden sich eine Hypalbuminämie im Serum und Ödeme. Nicht zu den Diagnosekriterien gehörend, aber als häufige Begleiterscheinungen werden eine Hyperlipoproteinämie und eine Thrombophilie beobachtet. Zudem besteht eine erhöhte Infektneigung. Differenziert werden die primären Ursachen eines nephrotischen Syndroms von sekundären Glomerulopathien als Folge einer systemischen Grunderkrankung. Zur Diagnosesicherung und Abschätzung der Prognose wird in den meisten Fällen eine Nierenbiopsie durchgeführt. Primäre Formen werden in der Regel mit Steroiden und/oder anderen Immunsuppressiva behandelt. Bei sekundären Formen steht die Behandlung der Grunderkrankung im Vordergrund. Meist wird eine RAAS-Blockade mittels ACE-Hemmer oder AT-II-Rezeptorblocker etabliert. Zur Kontrolle der Ödeme werden Schleifendiuretika eingesetzt. Zusätzlich muss die Notwendigkeit der Antikoagulation und einer Statintherapie evaluiert werden.

Introduction Prior studies suggest overuse of nonrecommended lung cancer screening tests in U.S. community practice and underuse of recommended tests. Methods Data from the 2010 and 2015 National Health Interview Surveys was analyzed from 2016 to 2018. Prevalence, populations, and number of chest computed tomography (CT) and chest x-ray tests were estimated for people who did and did not meet U.S. Preventive Services Task Force (USPSTF) criteria for lung cancer screening, among people aged ≥40 years without lung cancer. Results In 2015, among those who met USPSTF criteria, 4.4% (95% CI=3.0%, 6.6%), or 360,000 (95% CI=240,000, 535,000) people reported lung cancer screening with a chest CT; and 8.5% (95% CI=6.5%, 11.1%), or 689,000 (95% CI=526,000, 898,000) people reported a chest x ray. Among those who did not meet USPSTF criteria, 2.3% (95% CI=2.0%, 2.6%), or 3,259,000 (95% CI=2,850,000, 3,724,000) people reported a chest x ray; and 1.3% (95% CI=1.1%, 1.5%), or 1,806,000 (95% CI=1,495,000, 2,173,000) people reported a chest CT. The estimated population meeting USPSTF criteria for lung cancer screening in 2015 was 8,098,000 (95% CI=7,533,000, 8,702,000), which was smaller than the 9,620,000 people (95% CI=8,960,000, 10,325,000) in 2010. Conclusions The number of adults inappropriately screened for lung cancer greatly exceeds the number screened according to USPSTF recommendations, the prevalence of appropriate lung cancer screening is low, and the population meeting USPSTF criteria is shrinking. To realize the potential benefits of screening, better processes to appropriately triage eligible individuals to screening, plus screening with a USPSTF-recommended test, would be beneficial.

Evaluation of the dose distribution delivered in a radiosurgery treatment of an acoustic neuroma using an adapted Alderson phantom and radiochromic film to assess absolute dose. A system was developed to perform the dose measurements, using the Alderson Rando phantom´s head carrying a modified slice, where a material reproducing the tumor was inserted. The phantom’s head with the modified slice was irradiated in a medical linear accelerator, using a procedure similar to that adopted in real cases, and radiochromic films were used to assess dose values. The suitability of the dose distribution delivered in the treatment was evaluated by comparing the Dose Volume Histograms, obtained from the Treatment Planning System (TPS) and by radiochromic film measurements. An agreement around 3% between experimental data and TPS´s calculations, showing an acceptable concordance with the planning results. T he established approach of transforming 2D arrays of dose in a 3D one is satisfactory, validating it. T he developed method shows to be an excellent alternative to quality control in radiosurgery using the radiochromic film to assess absolute dose.

An autonomous car is a driverless vehicle for the purpose of navigating autonomously and safely over the earth's surface. Interest in this type of transport has increased significantly in recent years and it is possible that the number of these vehicles on the streets will increase, changing the daily lives of cities. In this context, this work aims to understand the technological limitations and impacts of using autonomous cars, observing the feasibility, adaptation, traffic legislation, and perceived benefits. Following the method of systematic literature review proposed by Kitchenham, 69 primary studies from relevant bases in the area of Technology were analyzed. These studies showed some evidence by indicating, for example, that there will be a change in the way people relate to cars, particularly in terms of sharing them, in addition to impacts on urban mobility.

Adiponectin, an adipokine that circulates as multiple multimeric complexes at high levels in serum, has antidiabetic, anti-inflammatory, antiatherogenic, and cardioprotective properties. Understanding the mechanisms regulating adiponectin’s physiological effects is likely to provide critical insight into the development of adiponectin-based therapeutics to treat various metabolic-related diseases. In this review, we summarize our current understanding on adiponectin action in its various target tissues and in cellular models. We also focus on recent advances in two particular regulatory aspects; namely, the regulation of adiponectin gene expression, multimerization, and secretion, as well as extravasation of circulating adiponectin to the interstitial space and its degradation. Finally, we discuss some potential therapeutic approaches using adiponectin as a target and the current challenges facing adiponectin-based therapeutic interventions.

Introduction Little is known about perceived health status and behavioral risk factors among prostate cancer survivors. The objective of this study was to describe racial and ethnic differences in self-reported health status, chronic conditions, and selected behavioral risk factors among prostate cancer survivors in the US. Methods We used data from the 2015 National Health Interview Survey to calculate the prevalence of various levels of health status, chronic conditions, behavioral risk factors, and sociodemographic characteristics among prostate cancer survivors aged 50 years or older. We stratified results by race and ethnicity. Results Of the 317 prostate cancer survivors in our sample, 33.1% reported no physical activity, 64.2% reported being current drinkers, 26.1% characterized their drinking as moderate/heavy, 42.3% reported being former smokers, and 8.7% were current smokers. Nearly one-third (29.1%) of survivors were obese (body mass index ≥30), and 15.1% had 3 to 6 chronic conditions. A greater percentage of White (29.7%) than Black (14.2%) or Hispanic (16.3%) survivors were moderate/heavy drinkers. A greater percentage of Black (16.2%) than White (7.5%) or Hispanic (7.3%) survivors were current smokers. A greater percentage of Black (25.1%) or Hispanic (27.7%) than White (11.4%) survivors had 3 to 6 chronic conditions. Conclusion As the population of older men increases, prostate cancer diagnoses and those surviving the disease will also increase. Significant racial and ethnic group differences in behavioral risk factors and chronic conditions exist among prostate cancer survivors. Public health could prioritize efforts to improve health behaviors among prostate cancer survivors and use targeted interventions to address disparities.

Bayesian network modelling is applied to health psychology data in order to obtain more insight into the determinants of physical activity. This preliminary study discusses some challenges to apply general machine learning methods to this application domain, and Bayesian networks in particular. We investigate several suitable methods for dealing with missing data, and determine which method obtains good results in terms of fitting the data. Furthermore, we present the learnt Bayesian network model for this e-health intervention case study, and conclusions are drawn about determinants of physical activity behaviour change and how the intervention affects physical activity behaviour and its determinants. We also evaluate the contributions of Bayesian network analysis compared to traditional statistical analyses in this field. Finally, possible extensions on the performed analyses are proposed.

Topical treatment is the mainstay for mild or moderate psoriasis, but patients are generally little satisfied. Calcipotriol/betamethasone dipropionate (Cal/BD) cutaneous foam has shown to improve signs and symptoms in plaque psoriasis patients. This study assessed patient's satisfaction with Cal/BD foam in a real-life Italian dermatological clinical practice. A multicenter, 4-week observational prospective cohort study enrolled, in 17 Italian dermatology clinics, adult patients with plaque psoriasis on the body and/or scalp. Treatment satisfaction was assessed by 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9), preference over previous treatments by Patient Preference Questionnaire (PPQ), and change in disease state by Psoriasis Area Severity Index (PASI). Overall 256 patients were eligible, with a mean (SD) age of 55.6 (15.4) years, 59.4% were males. Psoriasis severity was mild in 52.0% of patients, moderate in 43.3%, and severe in 4.7%. Scalp involvement was present in 36.7% of patients. Previous antipsoriatic treatments had been received by 80.5% of patients. TSQM-9 median (25th-75th percentile) scores were 83.3 (66.7-88.9) for effectiveness, 77.8 (66.7-88.9) for convenience, and 78.6 (64.3-92.9) for global satisfaction. Mean (SD) PASI value decreased from 7.3 (4.8) to 2.1 (2.7) after 4 weeks. More than 90% of patients previously treated for psoriasis evaluated the Cal/BD foam more effective, easier to use and better tolerated compared to previous topical treatments at PPQ. This observational study provides real-life evidence of a high level of satisfaction with effectiveness and convenience of the Cal/BD foam in a cohort of plaque psoriasis patients, with an objective improvement in PASI.

“Gaining Insight into Determinants of Physical Activity Using Bayesian Network Learning” was previously published non-open access. It has now been changed to open access under a CC BY 4.0 license and the copyright holder updated to ‘The Author(s)’. The book has also been updated with this change.

State and local health departments have been tasked with promoting the use of face coverings to decrease the spread of COVID-19 in their respective communities. However, little is known about motivations and barriers to wearing face coverings in the context of COVID-19 prevention, particularly among communities of color who are at an increased risk of serious illness from the disease. The purpose of this study was to identify common motivations and barriers to face covering use, as well as explore perceptions of messages encouraging the use of face coverings among a racially and ethnically diverse sample. A survey was distributed electronically to North Carolina (NC) residents through NC Department of Health and Human Services listservs in July 2020. Participants self-categorized as Latino/a (33.5%), Black (39.1%), or white or another race (27.5%). The most commonly endorsed motivations for wearing face coverings were to avoid spreading COVID-19 (77%), as well as to protect people who are vulnerable (76%) and one’s community (72%). Being uncomfortable (40%) was the most commonly endorsed barrier. Messages that included a clear request (ex. please wear a face covering) and a direct benefit (ex. keep community safe) were more commonly endorsed than those that did not. Commonly endorsed motivations, behaviors, and messages differed by race and ethnicity. Increased attention to message content, message structure, and access to information and resources may aid local officials in increasing consistent use of face coverings.

Background: Psoriasis (Ps) is a chronic systemic autoimmune disease associated with pruritus in 64–98% of patients. However, few modestly sized studies assess factors associated with psoriatic pruritus. Objective: To investigate factors associated with Ps pruritus intensity. Methods: Psoriasis patients 18years or older seen in one of 155 centres in Italy between September 2005 and 2009 were identified from the Italian PsoCare registry. Patients without cutaneous psoriasis and those with missed information on pruritus were excluded. Results: We identified 10802 patients, with a mean age 48.8±14.3years. Mild itch was present in 33.2% of patients, moderate in 34.4%, severe in 18.7% and very severe in 13.7%. Higher itch intensity was associated with female gender, lower educational attainment compared to university degree, pustular psoriasis, psoriasis on the head, face, palmoplantar areas, folds and genitalia, more severe disease, disease duration

Recent studies have shown that biological drugs approved for treating psoriasis and psoriatic arthritis are not effective in all patients, and that variations in the genome have been associated with different clinical responses or side effects. HLA-Cw6 gene is associated with more severe and early-onset psoriasis. Recent reports have shown that HLA-Cw6 status predicts efficacy of some biologic treatments in psoriasis patients. The Phase 3b SUPREME study (NCT02394561) demonstrated the efficacy of secukinumab in patients with moderate-to-severe plaque-type psoriasis, irrespective of HLA-Cw6 status at week 24. This article is protected by copyright. All rights reserved.

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Lambert-Eaton myasthenic syndrome (LEMS) is a rare, autoimmune or paraneoplastic condition characterized by muscle weakness and fatigability. In cancer therapy, immune checkpoint inhibitors (ICI) sensitize the immune system for tumor antigens.We report a 62-year-old, female patient with paraneoplastic LEMS as first manifestation of Merkel cell carcinoma. Under avelumab, the LEMS exacerbated with worsening of limb weakness and a severely reduced vital capacity (This is the first description of paraneoplastic LEMS, avelumab, and Merkel cell carcinoma. We conclude that immunoglobulins are an option to control an ICI-associated deterioration of paraneoplastic symptoms.

Widespread use of face coverings is a key public health strategy to prevent the spread of COVID-19. However, few studies have examined why Americans use or do not use face coverings, and little is known about the most effective messaging strategies. This study explored perceptions of face coverings, including motivations and barriers for use, and examined reactions to messaging promoting the use of face coverings. Six virtual focus groups were conducted with 34 North Carolina residents in July 2020. Participants reported high compliance with face covering recommendations but often did not wear them around family, friends, and colleagues. The most prevalent motivation for the use of face coverings was to protect or respect other people, including high-risk populations and individuals. Other motivators were self-protection, responsibility, desire for control, requirements, and expert advice. Barriers included physical and social discomfort, confusion or misinformation, low perceived susceptibility to COVID-19, and perceptions of identity and autonomy. Even among individuals who frequently wear face coverings, there are opportunities to improve compliance. Messaging should highlight how face coverings protect the wearer and others around them, normalize the use of face coverings in social settings, and emphasize requirements. Positive messages that focus on unity, personal experiences and the rationale for face coverings are recommended.

Cervical cancer, which main etiologic factor is Human Papillomavirus (HPV) infection, continues to be a burden for public health systems in developing countries. Our laboratory has been working with the hypothesis that signals generated in the tumor microenvironment can modulate local and systemic immune responses. In this context, it would be reasonable to think that tumors create pro-tumoral bias in immune cells, even before they are recruited to the tumor microenvironment. To understand if and how signaling started in the tumor microenvironment can influence cells within the tumor and systemically, we investigated the expression of key proteins in signaling pathways important for cell proliferation, viability, immune responses and tolerance. Besides, we used detection of specific phosphorylated residues, which are indicative of activation for Akt, CREB, p65 NFκB, and STAT3. Our findings included the observation of a significant STAT3 expression increase and p65 NFκB decrease in circulating leukocytes in correlation with lesion grade. In light of those observations, we started investigating the result of the inhibition of STAT3 in a tumor experimental model. STAT3 inhibition impaired tumor growth, increased anti-tumor T cell responses and decreased the accumulation of myeloid cells in the spleen. The concomitant inhibition of NFκB partially reversed these effects. This study indicates that STAT3 and NFκB are involved in immunomodulatory tumor effects and STAT3 inhibition could be considered as therapy for patients with cervical cancer.

Nowadays, smartphones and tablet computers are very common in European families. Consequently, such devices are frequently available for young children from a very early age. Engaging with these new technologies at home or at a childcare center offers a range of opportunities to promote children’s literacy competencies using e-books and storybook apps. In this chapter, we aim to outline how the use of digital media can address and motivate children, and in particular, children in need of literacy support. To this end, we review the current literature and results of relevant studies. First, we try to identify reasons why children differ consistently in their reading comprehension skills, how such differences develop in early childhood, and which groups are in additional need of support. Then, we discuss children’s digital home learning environments and the possibilities of reading with digital media in early childhood. Finally, we conclude by discussing practical implications for the use of digital media with children in educational contexts.

Galvanized steel's hardwares used by Brazilian utilities at networks close to coastal area historically has an average life of approximately four years against the estimated 20 years when used in non-corrosive environments. Low average life of such hardware is justified by the salty air and the leakage current from the degradation of insulators. The last factor causes a greatly accelerated and could be considered the main causative agent of low durability of such hardware. This paper presents studies' results conducted for alternative materials' selection in order to have an average life in the field at least 10 years. This studies are done using a new accelerated aging test methodology in a controlled environment which can produce major aggressiveness of the ambient and the stimuli to which the CELESC's overhead networks hardware experience in field (simplified model), including electric field' presence which results in their development are also presented herein.

This clinical study reports on the antibacterial effects and outcome of endodontic treatment using either a single-file or a multifile system, associated with calcium hydroxide interappointment medication. The root canals of single-rooted teeth with apical periodontitis were treated by using either Reciproc or BioRaCe instrument systems, 2.5% NaOCl irrigation, and calcium hydroxide medication. Bacteriological samples taken before preparation and immediately before obturation were evaluated for total bacterial counts by quantitative real-time polymerase chain reaction (qPCR). Patients were followed up and the treatment outcome was assessed by clinical and radiographic criteria. Decreasing lesions were classified as success in a lenient criterion or failure in a rigid one. Bacteria were detected in all initial samples (47 cases) and were significantly reduced after treatment in both groups (p0.05). Quantitative bacterial reduction was similar between groups (p>0.05). The success rate in the BioRaCe group was 95.5% and 77% in the loose and rigid criterion, respectively. In the Reciproc group, corresponding figures were 88% and 76%. Differences in outcome were not significant (p>0.05). No diseased case showed negative qPCR results for bacteria. A difference of >1 Log10 counts was observed between healed and diseased cases. Root canal treatments of teeth with apical periodontitis using a single-file or a multifile system for preparation, associated with NaOCl irrigation and calcium hydroxide interappointment medication, showed similar antibacterial effectiveness and success rate.

Enterprise Architecture has been growing as an approach used to add value to the sectors of organizations, providing the necessary support to the planning and integration of the business and Information Technology areas. Thus, the required actions are directed towards the achievement of the strategic goals defined by senior management. Hence, this article presents the state-of-the-art of Enterprise Architecture in which, through some defined research questions, we have explored the studies obtained in a systematic mapping of the literature. The proposed secondary study has selected and analyzed the necessary evidence to identify definitions of the term, countries that use it most, corporate segments, frameworks used, as well as the benefits and challenges reported by these companies.

Checkpoint blockade immunotherapy relies on the empowerment of the immune system to fight cancer. Why some patients fail to achieve durable clinical responses is not well understood, but unique individual factors such as diet, obesity, and related metabolic syndrome could play a role. The link between obesity and patient outcomes remains controversial and has been mired by conflicting reports and limited mechanistic insight. We addressed this in a C57BL/6 mouse model of diet-induced obesity using a Western diet high in both fats and sugars. Obese mice bearing B16 melanoma or MC38 carcinoma tumors had impaired immune responses to immunotherapy and a reduced capacity to control tumor progression. Unexpectedly, these compromised therapeutic outcomes were independent of body mass and, instead, were directly attributed to dietary fructose. Melanoma tumors in mice on the high-fructose diet were resistant to immunotherapy and showed increased expression of the cytoprotective enzyme heme oxygenase-1 (HO-1). This increase in HO-1 protein was recapitulated in human A375 melanoma cells exposed to fructose in culture. Induced expression of HO-1 shielded tumor cells from immune-mediated killing and was critical for resistance to checkpoint blockade immunotherapy, which could be overcome in vivo using a small-molecule inhibitor of HO-1. This study reveals dietary fructose as a driver of tumor immune evasion, identifying HO-1 expression as a mechanism of resistance and a promising molecular target for combination cancer immunotherapy. See article by Khojandi et al., p. 214

Introduction Uptake of early infant HIV diagnosis (EID) varies widely across sub-Saharan African settings. We evaluated the potential clinical impact and cost-effectiveness of universal maternal HIV screening at infant immunization visits, with referral to EID and maternal antiretroviral therapy (ART) initiation. Methods Using the CEPAC-Pediatric model, we compared two strategies for infants born in 2017 in Cote d'Ivoire (CI), South Africa (SA), and Zimbabwe: (1) existing EID programmes offering six-week nucleic acid testing (NAT) for infants with known HIV exposure (EID), and (2) EID plus universal maternal HIV screening at six-week infant immunization visits, leading to referral for infant NAT and maternal ART initiation (screen-and-test). Model inputs included published Ivoirian/South African/Zimbabwean data: maternal HIV prevalence (4.8/30.8/16.1%), current uptake of EID (40/95/65%) and six-week immunization attendance (99/74/94%). Referral rates for infant NAT and maternal ART initiation after screen-and-test were 80%. Costs included NAT ($24/infant), maternal screening ($10/mother-infant pair), ART ($5 to 31/month) and HIV care ($15 to 190/month). Model outcomes included mother-to-child transmission of HIV (MTCT) among HIV-exposed infants, and life expectancy (LE) and mean lifetime per-person costs for children with HIV (CWH) and all children born in 2017. We calculated incremental cost-effectiveness ratios (ICERs) using discounted (3%/year) lifetime costs and LE for all children. We considered two cost-effectiveness thresholds in each country: (1) the per-capita GDP ($1720/6380/2150) per year-of-life saved (YLS), and (2) the CEPAC-generated ICER of offering 2 versus 1 lifetime ART regimens (e.g. offering second-line ART; $520/500/580/YLS). Results With EID, projected six-week MTCT was 9.3% (CI), 4.2% (SA) and 5.2% (Zimbabwe). Screen-and-test decreased total MTCT by 0.2% to 0.5%, improved LE by 2.0 to 3.5 years for CWH and 0.03 to 0.07 years for all children, and increased discounted costs by $17 to 22/child (all children). The ICER of screen-and-test compared to EID was $1340/YLS (CI), $650/YLS (SA) and $670/YLS (Zimbabwe), below the per-capita GDP but above the ICER of 2 versus 1 lifetime ART regimens in all countries. Conclusions Universal maternal HIV screening at immunization visits with referral to EID and maternal ART initiation may reduce MTCT, improve paediatric LE, and be of comparable value to current HIV-related interventions in high maternal HIV prevalence settings like SA and Zimbabwe.

Measles was declared eliminated in the United States in 2000, but the risk of outbreaks owing to international importations remains. An outbreak of measles in New York City began when one unvaccinated child returned home from Israel with measles; onset of rash occurred on September 30, 2018, 9 days after the child returned home.We investigated suspected cases of measles by conducting interviews, reviewing medical and immunization records, identifying exposed persons, and performing diagnostic testing. Measles-mumps-rubella (MMR) vaccine (given as either MMR or measles-mumps-rubella-varicella vaccine and collectively referred to as MMR vaccine) uptake was monitored with the use of the Citywide Immunization Registry. The total direct cost to the New York City Department of Health and Mental Hygiene was calculated.A total of 649 cases of measles were confirmed, with onsets of rash occurring between September 30, 2018, and July 15, 2019. A majority of the patients (93.4%) were part of the Orthodox Jewish community, and 473 of the patients (72.9%) resided in the Williamsburg area of Brooklyn, New York. The median age was 3 years; 81.2% of the patients were 18 years of age or younger, and 85.8% of the patients with a known vaccination history were unvaccinated. Serious complications included pneumonia (in 37 patients [5.7%]) and hospitalization (in 49 patients [7.6%]); among the patients who were hospitalized, 20 (40.8%) were admitted to an intensive care unit. As a result of efforts to promote vaccination, the percentage of children in Williamsburg who received at least one dose of MMR vaccine increased from 79.5% to 91.1% among children 12 to 59 months of age. As of September 9, 2019, a total of 559 staff members at the Department of Health and Mental Hygiene (7% of the agency) had been involved in the measles response. The cost of the Department of Health and Mental Hygiene response was $8.4 million.Importation of measles and vaccination delays among young children led to an outbreak of measles in New York City. The outbreak response was resource intensive and caused serious illness, particularly among unvaccinated children.

Introduction: Hidradenitis suppurativa is a complex, chronic, difficult to treat condition belonging to the spectrum of cutaneous immune-mediated inflammatory diseases. Systemic treatment options for moderate-severe disease are limited to TNF-alpha antagonists and other biologic agents, with limited clinical evidence. Patient concerns: We report two adult patients with severe hidradenitis suppurativa presenting concomitant psoriatic arthritis and multiple medical comorbidities. Both were ineligible or resistant to adalimumab, the only biologic drug approved for the treatment of hidradenitis. Diagnosis: Both patients were diagnosed with severe Hurley III-stage disease and psoriatic arthritis, showing resistance to first-line systemic treatments and a complex comorbidity profile. Interventions: Patients underwent treatment with apremilast, an oral phosphodiesterase-4 inhibitor, approved for the treatment of psoriatic arthritis. Outcomes: After 16 weeks of treatment, a clinically relevant improvement of inflammatory lesions, skin- and arthritis-related pain, and patient-reported outcomes was achieved in both patients. Apremilast was well tolerated and continued up to 48 weeks of treatment. Conclusion: We report the “real-life” use of apremilast in the treatment of multimorbid patients with hidradenitis suppurativa and review its potential role in the management of this severe condition.

BACKGROUND: Fecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of feces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council.OBJECTIVE: Several European and international consensus statements concerning fecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document.METHODS: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about fecal microbiota transplantation.RESULTS: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening.CONCLUSION: The implementation of fecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor feces preparations for patients.

OBJECTIVE To compare presenting characteristics of patients with adductor spasmodic dysphonia (ADSD), ADSD with laryngeal tremor (ADSD + LT), and laryngeal tremor without ADSD (LT). DESIGN Cross-sectional analysis. METHODS Patients treated for laryngeal movement disorders (1990-2016) were included. Analysis of variance and chi square tests measured differences in patient characteristics across the three disease groups. Using ADSD as the referent, multivariable logistic regression models were used to determine whether potential risk factors including patient demographics, family history, presence of potential inciting events prior to disease onset, and coprevalent movement disorders were associated with ADSD + LT or LT. RESULTS In all, 652 patients with ADSD (n = 377), ADSD + LT (n = 98), and LT (n = 177) were included. ADSD patients were significantly younger than those with ADSD + LT and LT (52.5 ± 13.4, 63.9 ± 11.3, and 69.3 ± 10.5 years, respectively; P

OBJECTIVES Appendicitis is the most common surgical emergency encountered in the pediatric emergency department (ED). We analyzed the time course of children evaluated for suspected appendicitis in relation to implementation of a risk-stratified ultrasound scoring system and structured reporting template (Appy-Score). METHODS In July 2013, a 6-level ultrasound (US)-based appendicitis scoring system was developed and implemented. The records of children (age ≤18 years) who underwent limited abdominal US exams for suspected appendicitis at a large academic pediatric ED were reviewed retrospectively. Time periods evaluated were from January 1 to April 1, 2013 (before implementation of the US scoring system, "PRE") and July 1 to October 1, 2013 (after implementation of the US scoring system, "POST"). Times are presented as medians with interquartile range. RESULTS A total of 926 children were included (median age, 9.5 years [range, 0.1-18 years]; 49% female). Four hundred eighty-one patients were evaluated PRE and 445 POST. When comparing the 2 groups, there were no differences in the PRE and POST periods with regard to time from US ordered to first read (102 vs 112 minutes, P = 0.30), US ordered to disposition (215 vs 208 minutes, P = 0.40) and operating room posting (121 vs 122 minutes, P = 0.59), and overall ED stay (329 vs 333 minutes, P = 0.39). CONCLUSIONS The development of a radiographic appendicitis score, although allowing for a standardized reporting method, did not significantly alter the ED process flow for evaluation of appendicitis. This reflects the complexities in ED throughput and reveals the need for additional factors to change to improve patient flow.

Objectives African American girls in juvenile detention are disproportionately affected by sexually transmitted diseases (STDs) and other psychosocial health problems, yet few studies have examined associations between experiencing multiple psychosocial health problems and sexual risk behaviors and STD diagnosis. Method The study included 188 detained African American girls aged 13–17 years. We conducted three sets of logistic regressions. First, bivariate analyses assessed associations among seven psychosocial factors (substance use disorder; depression; post-traumatic stress disorder [PTSD]; emotional abuse; pregnancy coercion; physical abuse; and sexual abuse) and four outcomes (early sexual initiation; condomless sex; multiple sexual partners; self-reported STD) to examine their interrelationships. Second, we examined associations between experiencing multiple psychosocial factors and outcomes. Third, psychosocial factors were categorized into four domains: substance use disorder; mental health (depression, PTSD); psychological abuse (emotional abuse, pregnancy coercion); and violence (physical abuse, sexual abuse) and included as independent associations with each outcome to assess their relative importance. Results Multiple interrelationships among psychosocial factors and outcomes were identified. An increase of one psychosocial health problem was associated with an 18% to 27% increased odds of sexual risk behaviors or a previous STD diagnosis. Reporting violence was associated with increased odds of having multiple partners (odds ratio = 3.31; confidence interval = 1.57–6.97), and experiencing psychological abuse was associated with increased odds of reporting an STD diagnosis (odds ratio = 3.95; confidence interval = 1.62–9.63). Conclusion Multiple psychosocial health problems, particularly psychological abuse and violence, are associated with sexual risk and STDs in this vulnerable population.

The majority of patients undergoing endovascular stroke treatment (EST) in randomized controlled trials received additional systemic thrombolysis ("combination or bridging therapy (C/BT)"). Nevertheless, its usefulness in this subtype of acute ischemic stroke (AIS) is discussed controversially. Of all consecutive AIS patients, who received any kind of reperfusion therapy in a tertiary university stroke center between January 2015 and March 2016, those with large vessel occlusions (LVO) and EST with or without additional C/BT, were compared primarily regarding procedural aspects. Data were extracted from an investigator-initiated, single-center, prospective and blinded end-point study. 70 AIS patients with EST alone and 118 with C/BT were identified. Significant baseline differences existed in pre-existing cardiovascular disease (52.9% (EST alone) vs. 35.6% (C/BT), p = 0.023), use of anticoagulation (30.6% vs. 5.9%, p

Pemphigus is a life threatening autoimmune epidermal blistering disease involving skin and mucous membranes. Pemphigus usually affects middle age men and women involving oral mucosa first and then spreading on the skin. It is caused by the presence of autoantibodies (IgG and less frequently by IgA) directed against desmogleins, and/or other glycoproteins that plays a critical role in cell-cell attachment. Upon a predisposing genetic background, different agents have been shown to act as triggers for the pathogenesis of pemphigus. This guideline for the diagnosis and treatment of pemphigus has been developed by an Italian group of experts taking in account the Italian legislation and local pharmacological governance. Guidelines are adapted from the original article under the guidance of the European Dermatology Forum in collaboration with the European Academy of Dermatology and Venereology. It summarizes evidence-based and expert-based recommendations (S2 level).

Rates of teenage pregnancy remain high in sub-Saharan Africa. The KEMRI Health and Demographic Surveillance System provided the sampling frame for a survey. Analysis focused on 1,952 girls aged 13–19 years. Over a third (37.2%; n = 727) were sexually active and 23.3% (n = 454) had ever been pregnant. Adjusted odds of reporting a history of pregnancy were greater for older compared to younger teens, teens who were ever married or cohabiting compared to those who were single, teens with a primary education or less compared to those with a higher level of education, and teens who experienced partner violence in the last 12 months. Three-quarters of teens pregnant in the last 12 months did not want to get pregnant (n = 190); only 64.2% (n = 122) answered yes to using any family planning method. Teen pregnancy and its consequences are serious public health issues. Higher education levels are a crucial component to address the problem.

STUDY QUESTION: Does a reduced FSH dose in women with a predicted hyper response, apparent from a high antral follicle count (AFC), who are scheduled for IVF/ICSI lead to a different outcome with respect to cumulative live birth rate and safety?SUMMARY ANSWER: Although in women with a predicted hyper response (AFC > 15) undergoing IVF/ICSI a reduced FSH dose (100 IU per day) results in similar cumulative live birth rates and a lower occurrence of any grade of ovarian hyperstimulation syndrome (OHSS) as compared to a standard dose (150 IU/day), a higher first cycle cancellation rate and similar severe OHSS rate were observed.WHAT IS KNOWN ALREADY: Excessive ovarian response to controlled ovarian stimulation (COS) for IVF/ICSI may result in increased rates of cycle cancellation, the occurrence of OHSS and suboptimal live birth rates. In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can be used to predict response to COS. No consensus has been reached on whether ORT-based FSH dosing improves effectiveness and safety in women with a predicted hyper response.STUDY DESIGN SIZE, DURATION: Between May 2011 and May 2014, we performed an open-label, multicentre RCT in women with regular menstrual cycles and an AFC > 15. Women with polycystic ovary syndrome (Rotterdam criteria) were excluded. The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. Secondary outcomes included the occurrence of OHSS and cost-effectiveness. Since this RCT was embedded in a cohort study assessing over 1500 women, we expected to randomize 300 predicted hyper responders.PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with an AFC > 15 were randomized to an FSH dose of 100 IU or 150 IU/day. In both groups, dose adjustment was allowed in subsequent cycles (maximum 25 IU in the reduced and 50 IU in the standard group) based on pre-specified criteria. Both effectiveness and cost-effectiveness were evaluated from an intention-to-treat perspective.MAIN RESULTS AND THE ROLE OF CHANCE: We randomized 255 women to a daily FSH dose of 100 IU and 266 women to a daily FSH dose of 150 IU. The cumulative live birth rate was 66.3% (169/255) in the reduced versus 69.5% (185/266) in the standard group (relative risk (RR) 0.95 [95%CI, 0.85-1.07], P = 0.423). The occurrence of any grade of OHSS was lower after a lower FSH dose (5.2% versus 11.8%, RR 0.44 [95%CI, 0.28-0.71], P = 0.001), but the occurrence of severe OHSS did not differ (1.3% versus 1.1%, RR 1.25 [95%CI, 0.38-4.07], P = 0.728). As dose reduction was not less expensive (€4.622 versus €4.714, delta costs/woman €92 [95%CI, -479-325]), there was no dominant strategy in the economic analysis.LIMITATIONS, REASONS FOR CAUTION: Despite our training programme, the AFC might have suffered from inter-observer variation. Although strict cancellation criteria were provided, selective cancelling in the reduced dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as first cycle live birth rates did not differ from the cumulative results, the open design probably did not mask a potential benefit for the reduced dosing group. As this RCT was embedded in a larger cohort study, the power in this study was unavoidably lower than it should be. Participants had a relatively low BMI from an international perspective, which may limit generalization of the findings.WIDER IMPLICATIONS OF THE FINDINGS: In women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose did reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS. Future research into ORT-based dosing in women with a predicted hyper response should compare various safety management strategies and should be powered on a clinically relevant safety outcome while assessing non-inferiority towards live birth rates.STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by The Netherlands Organization for Health Research and Development (ZonMW, Project Number 171102020). SCO, TCvT and HLT received an unrestricted research grant from Merck Serono (the Netherlands). CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV and Merck Serono for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare.TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657.TRIAL REGISTRATION DATE: 20 December 2010.DATE OF FIRST PATIENT’S ENROLMENT: 12 May 2011.

STUDY QUESTION: Is there a difference in live birth rate and/or cost-effectiveness between antral follicle count (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment?SUMMARY ANSWER: In women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose.WHAT IS KNOWN ALREADY: In IVF or ICSI, ovarian reserve testing is often used to adjust the FSH dose in order to normalize ovarian response and optimize live birth rates. However, no robust evidence for the (cost-)effectiveness of this practice exists.STUDY DESIGN, SIZE, DURATION: Between May 2011 and May 2014 we performed a multicentre prospective cohort study with two embedded RCTs in women scheduled for IVF/ICSI. Based on the AFC, women entered into one of the two RCTs (RCT1: AFC < 11; RCT2: AFC > 15) or the cohort (AFC 11-15). The primary outcome was ongoing pregnancy achieved within 18 months after randomization resulting in a live birth (delivery of at least one live foetus after 24 weeks of gestation). Data from the cohort with weight 0.5 were combined with both RCTs in order to conduct a strategy analysis. Potential half-integer numbers were rounded up. Differences in costs and effects between the two treatment strategies were compared by bootstrapping.PARTICIPANTS/MATERIALS, SETTING, METHODS: In both RCTs women were randomized to an individualized (RCT1:450/225 IU, RCT2:100 IU) or standard FSH dose (150 IU). Women in the cohort all received the standard dose (150 IU). Anti-Müllerian hormone (AMH) was measured to assess AMH post-hoc as a biomarker to individualize treatment. For RCT1 dose adjustment was allowed in subsequent cycles based on pre-specified criteria in the standard group only. For RCT2 dose adjustment was allowed in subsequent cycles in both groups. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective.MAIN RESULTS AND THE ROLE OF CHANCE: We included 1515 women, of whom 483 (31.9%) entered the cohort, 511 (33.7%) RCT1 and 521 (34.4%) RCT2. Live births occurred in 420/747 (56.3%) women in the individualized strategy and 447/769 (58.2%) women in the standard strategy (risk difference -0.019 (95% CI, -0.06 to 0.02), P = 0.39; a total of 1516 women due to rounding up the half integer numbers). The individualized strategy was more expensive (delta costs/woman = €275 (95% CI, 40 to 499)). Individualized dosing reduced the occurrence of mild and moderate ovarian hyperstimulation syndrome (OHSS) and subsequently the costs for management of these OHSS categories (costs saved/woman were €35). The analysis based on AMH as a tool for dose individualization suggested comparable results.LIMITATIONS, REASONS FOR CAUTION: Despite a training programme, the AFC might have suffered from inter-observer variation. In addition, although strict cancel criteria were provided, selective cancelling in the individualized dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as both first cycle live birth rates and cumulative live birth rates show no difference between strategies, the open design probably did not mask a potential benefit for the individualized group. Despite increasing consensus on using GnRH antagonist co-treatment in women predicted for a hyper response in particular, GnRH agonists were used in almost 80% of the women in this study. Hence, in those women, the AFC and bloodsampling for the post-hoc AMH analysis were performed during pituitary suppression. As the correlation between AFC and ovarian response is not compromised during GnRH agonist use, this will probably not have influenced classification of response.WIDER IMPLICATIONS OF THE FINDINGS: Individualized FSH dosing for the IVF/ICSI population as a whole should not be pursued as it does not improve live birth rates and it increases costs. Women scheduled for IVF/ICSI with a regular menstrual cycle are therefore recommended a standard FSH starting dose of 150 IU per day. Still, safety management by individualized dosing in predicted hyper responders is open for further research.STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). AMH measurements were performed free of charge by Roche Diagnostics. TCT, HLT and SCO received an unrestricted personal grant from Merck BV. AH declares that the department of Obstetrics and Gynecology, University Medical Centre Groningen receives an unrestricted research grant from Ferring pharmaceutics BV, The Netherlands. CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other autors have nothing to declare.TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657.

OBJECTIVE To assess whether state criminal exposure laws are associated with HIV and stage 3 (AIDS) diagnosis rates in the United States. DESIGN We assessed the relationship between HIV and stage 3 (AIDS) diagnosis data from the National HIV Surveillance System and the presence of a state criminal exposure law as identified through WestlawNext by using generalized estimating equations. METHODS We limited analysis to persons aged at least 13 years with diagnosed HIV infection or AIDS reported to the National HIV Surveillance System of the Centers for Disease Control and Prevention. The primary outcome measures were rates of diagnosis of HIV (2001-2010 in 33 states) and AIDS (1994-2010 in 50 states) per 100 000 individuals per year. In addition to criminal exposure laws, state-level factors evaluated for inclusion in models included income, unemployment, poverty, education, urbanicity, and race/ethnicity. RESULTS At the end of the study period, 30 states had laws criminalizing HIV exposure. In bivariate models (P