Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases

Learning what I need to know: Experiences of rural cardiac surgery patients

Purpose: This hermeneutic study expands understandings of rural cardiac surgery patients’ experiences of their learning needs following cardiac surgery to inform the provision of patient education for this population. Sample: Eighteen rural residents provided accounts about their experiences. Findings: An interpretation as analysis approach revealed three themes: a) Learning: Family History Informing Preventive Care; b) Learning: The Notebook, Blue’s Clues, and Explanations; and c) Learning: Lifestyle Changes and Confronting Mortality. Conclusions: The first theme demonstrates needs to ensure patients from rural settings understand that preventing cardiovascular disease is not limited to family members’ experiences with secondary and tertiary prevention. The second theme underscores the importance of providing patient education materials that are readable and useable, and considers existential learning needs. The last theme highlights the importance of patients understanding how lifestyle changes involve embracing new ways of living that are enhanced through cardiac rehabilitation, and yet, can be experienced as life limiting

Structuring Formal Control Systems Specifications for Reuse: Surviving Hardware Changes

Formal capture and analysis of the required behavior of control systems have many advantages. For instance, it encourages rigorous requirements analysis, the required behavior is unambiguously defined, and we can assure that various safety properties are satisfied. Formal modeling is, however, a costly and time consuming process and if one could reuse the formal models over a family of products, significant cost savings would be realized. In an ongoing project we are investigating how to structure state-based models to achieve a high level of reusability within product families. In this paper we discuss a high-level structure of requirements models that achieves reusability of the desired control behavior across varying hardware platforms in a product family. The structuring approach is demonstrated through a case study in the mobile robotics domain where the desired robot behavior is reused on two diverse platforms-one commercial mobile platform and one build in-house. We use our language RSML (-e) to capture the control behavior for reuse and our tool NIMBUS to demonstrate how the formal specification can be validated and used as a prototype on the two platforms

Determinants of Neonatal Readmission in Healthy Term Infants: Results from a Nested Case-Control Study

Objective The aim of this study was to estimate the incidence and identify the factors associated with neonatal readmission among healthy term infants. Study Design A nested case-control study with matching was conducted at a large level III perinatal hospital with approximately 8,700 deliveries each year. Each case infant (n = 130) was matched to two control infants (n = 260) on the case infant\u27s date of birth (±7 days) and the mother\u27s maternal age (\u3c20 years, 20-29, 30-39, and \u3e39 years). All infants were selected from a cohort of eligible term, healthy, in-state infants admitted to the newborn unit postdelivery from January 1, 2016 to May 8, 2017. Data were analyzed using hierarchical conditional logistic regression. Results The incidence of neonatal readmission was 2.2%, and all readmissions occurred within 8.6 days of birth. Earlier gestational age (37 weeks; odds ratio [OR]: 4.11, 95% confidence interval [CI]: 1.79-9.45; 38 weeks OR: 1.29, CI 0.60-2.75; [ref] 39 weeks), jaundice on day two of life (OR: 2.45; CI: 1.40-4.30), maternal group B streptococcus chemoprophylaxis (OR: 2.55; CI: 1.23-5.28 [Ref N/A]) were associated with readmission. Delivery by cesarean section (OR: 0.31, CI: 0.12-0.79) and each milliliter of formula [first three days] (OR: 0.96; CI: 0.993-0.999) were protective. Conclusion Neonatal readmission in healthy term infants may potentially be reduced with identification of modifiable determinants of readmission prior to discharge. Policies to capture the true incidence of neonatal readmissions should include admissions to hospitals other than the birth hospital

Maternal Worry About Infant Weight and its Influence on Artificial Milk Supplementation and Breastfeeding Cessation

Background: Maternal worry about infant weight has inconsistently been reported as a breastfeeding barrier. Weight monitoring is a critical tool to assess adequacy of infant feeding. Yet, little is known about the intensity of maternal worry about infant weight or associated breastfeeding outcomes. Research aims: To examine (1) the frequency and intensity of maternal worry about infant weight; (2) the relationship between worry about weight and use of artificial milk; and 3) the relationship between worry about weight and breastfeeding cessation. Methods: A prospective cross-sectional design was used. A questionnaire was completed by women in the United States (N = 287) from 12 web-based maternal support groups. Results: Sixty-three percent of women (n = 182) had some worry about infant weight. Participants breastfeeding for the first time had more worry (p =.035). Participants still breastfeeding had less worry about weight compared to those who had stopped (67%, n = 147 vs. 41%, n = 28). Exclusive breastfeeding participants had less worry (p \u3c.001) compared to those who supplemented with artificial milk. Increased worry was associated with the use of artificial milk within 1 week of birth (p \u3c.001) and early breastfeeding cessation (p \u3c.001). Conclusions: Worry about weight is a significant breastfeeding barrier. It is associated with first time breastfeeding, less exclusive breastfeeding, use of artificial milk, and earlier breastfeeding cessation. Lactating mothers need anticipatory guidance about expected neonatal weight changes and interventions to help relieve worry about infant weight