Sickle cell pain: a critical reappraisal.

Sickle cell pain includes 3 types: acute recurrent painful crises, chronic pain syndromes, and neuropathic pain. The acute painful crisis is the hallmark of the disease and the most common cause of hospitalization and treatment in the emergency department. It evolves through 4 phases: prodromal, initial, established, and resolving. Each acute painful episode is associated with inflammation that worsens with recurrent episodes, often culminating in serious complications and organ damage, such as acute chest syndrome, multiorgan failure, and sudden death. Three pathophysiologic events operate in unison during the prodromal phase of the crisis: vaso-occlusion, inflammation, and nociception. Aborting the acute painful episode at the prodromal phase could potentially prevent or minimize tissue damage. Our hypothesis is that managing these events with hydration, anti-inflammatory drugs, aggressive analgesia, and possibly vasodilators could abort the crisis and prevent or minimize further damage. Chronic pain syndromes are associated with or accompany avascular necrosis and leg ulcers. Neuropathic pain is not well studied in patients with sickle cell disease but has been modeled in the transgenic sickle mouse. Management of sickle cell pain should be based on its own pathophysiologic mechanisms rather than borrowing guidelines from other nonsickle pain syndromes

Association between Hospital Admissions and Healthcare Provider Communication for Individuals with Sickle Cell Disease

Objective: To test the hypothesis that caregivers’ or adult participants’ low ratings of provider communication are associated with more hospital admissions among adults and children with sickle cell disease (SCD), respectively. Secondarily, we determined whether there was an association between the caregivers’ or participants’ health literacy and rating of providers’ communication. Methods: Primary data were collected from participants through surveys between 2014 and 2016, across six sickle cell centers throughout the U.S. In this cross-sectional cohort study, 211 adults with SCD and 331 caregivers of children with SCD completed surveys evaluating provider communication using the Consumer Assessment of Healthcare Providers and Systems (CAHPS), healthcare utilization, health literacy, and other sociodemographic and behavioral variables. Analyses included descriptive statistics, bivariate analyses, and logistic regression. Results: Participants with better ratings of provider communication were less likely to be hospitalized (odds ratio (OR) = 0.54, 95% confidence interval (CI) = [0.35, 0.83]). Positive ratings of provider communication were associated with fewer readmissions for children (OR = 0.23, 95% CI = [0.09, 0.57]). Participants with better ratings of provider communication were less likely to rate their health literacy as lower (regression coefficient (B) = −0.28, 95% CI = [−0.46, −0.10]). Conclusions: Low ratings of provider communication were associated with more hospitalizations and readmissions in SCD, suggesting the need for interventions targeted at improving patient-provider communication which could decrease hospitalizations for this population

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

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Recent treatment guidelines for managing adult patients with sickle cell disease: challenges in access to care, social issues, and adherence

Introduction: Advances in research, medical care, and public health practice have led to individuals with sickle cell disease (SCD) living into adulthood. However, premature mortality persists in youth and young adults with SCD, and adults with SCD are subjected to increased disease burden, organ damage, pain, and disruptions in family and work life. Areas covered: These issues have led to inappropriate utilization of hospital resources, significantly increasing costs related to prolonged inpatient stays, high readmission rates, and increased emergency room visits. Expert commentary: Steps are being taken to address these challenges to improve care, including development of evidence-based guidelines targeted to primary care providers, innovative care models, and programs to prepare adolescents for transition to adult care. Previous and current guidelines, as well as health-care policies and practices, for treatment of adults with SCD are reviewed

Multicenter COMPACT study of COMplications in Patients with sickle cell disease And utilization of iron Chelation Therapy

Background: Over the past few decades, lifespans of sickle cell disease (SCD) patients have increased; hence, they encounter multiple complications. Early detection, appropriate comprehensive care, and treatment may prevent or delay onset of complications. Objective: We collected longitudinal data on sickle cell disease (SCD) complication rates and associated resource utilization relative to blood transfusion patterns and iron chelation therapy (ICT) use in patients aged 16 years to address a gap in the literature. Research design and methods: Medical records of 254 SCD patients 16 years were retrospectively reviewed at three US tertiary care centers. Main outcome measures: We classified patients into cohorts based on cumulative units of blood transfused and ICT history: \u3c15 units, no ICT (Cohort 1 [C1]), 15 units, no ICT (Cohort 2 [C2]), and 15 units with ICT (Cohort 3 [C3]). We report SCD complication rates per patient per year; cohort comparisons use rate ratios (RRs). Results: Cohorts had 69 (C1), 91 (C2), and 94 (C3) patients. Pain led to most hospitalizations (76%) and emergency department (ED) (82%) visits. Among transfused patients (C2+C3), those receiving ICT were less likely to experience SCD complications than those who did not (RR [95% CI] C2 vs. C3: 1.33 [1.25-1.42]). Similar trends (RR [95% CI]) were observed in ED visits and hospitalizations associated with SCD complications (C2 vs. C3, ED: 1.94 [1.70-2.21]; hospitalizations: 1.61 [1.45-1.78]), but not in outpatient visits. Conclusions: Although the most commonly reported SCD complication among all patients was pain, patients who received ICT were less likely to experience pain and other complications than those who did not. These results highlight the need for increased patient and provider education on the importance of comprehensive disease management

A Transition Pilot Program for Adolescents With Sickle Cell Disease

Introduction: Transition from pediatric to adult care is challenging for adolescents with chronic illnesses, including those with sickle cell disease (SCD). We describe a pilot program created to facilitate transition from pediatric to adult care by helping adolescents with SCD identify an adult medical home. Methods: We investigated the feasibility of this program by evaluation of overall participation, satisfaction, and acceptance. A secondary objective was to compare the proportion of adolescents who fulfilled a first appointment with an adult hematologist among participants and nonparticipants. Results: During the first 18 months of the program, 83 adolescents were invited and 34 (41%) agreed to participate; 25 (74%) completed their first visit within 3 months after leaving the pediatric program, compared with 16 of 49 (33%) of nonparticipants (p = .0002). Overall, 41 of 83 adolescents (49%) completed an appointment with an adult SCD program, regardless of program participation, in contrast with 11 of 75 adolescents (15%) who did so during the 18 months before the program was created (p \u3c .0001). Discussion: This transition pilot program was feasible, and most adolescent participants with SCD established an adult medical home. © 2012 National Association of Pediatric Nurse Practitioners