bluuebunny/crossref_metadata_2025 huggingface dataset:
Osteoclast-Induced Immunosuppression Occurs through Dysregulation of Immune Checkpoint Axes in Multiple Myeloma
Authors: Mukaihara Kenta , D'Agostino Mattia , Panaroni Cristina , Fulzele Keertik , Mori Tomoaki , Siu Ka Tat , Chattopadhyay Shrikanta , Raje Noopur
Published: November 2019

Osteolytic bone disease has a significant impact on both quality of life and overall survival of patients with multiple myeloma (MM). Given that bone and immune cells share the same microenvironment and interact with each other via cytokines, signaling molecules and regulatory proteins in the bone marrow (Tsukasaki M et al., Nat Rev Immunol 2019), we sought to elucidate the effect of osteoclasts (OCs) on the immune microenvironment. Specifically, T cells significantly suppress differentiation of OCs through signaling crosstalk between RANKL and IFN-γ (Takayanagi H et al., Nature 2000). However, little is known regarding the effect of OCs on the immune system.

Here we investigated the effect of OCs on immune cells, especially on T cells. Dysregulation of several checkpoint molecules has been shown in MM (Kwon M et al., J Immunol 2017). We, therefore, assessed the expression of various immune checkpoint receptors, such as PD-1, TIGIT, OX40 and CD137 on T cells in co-culture with or without autologous OCs by multi-color flow cytometry. OC co-culture significantly increased co-inhibitory checkpoint (PD-1 and TIGIT) through direct contact, while decreasing co-stimulatory checkpoint (OX40 and CD137) in CD3+ T cells. Expression of the checkpoint ligand, PD-L1 was significantly increased on MM cells in the presence of both T cells and OCs compared to the presence of T cells alone. Conversely, OCs in the absence of T cells did not induce significant increase of PD-L1 on MM cells. According to previous literature, PD-L1 expression on MM cells is induced in part by IFN-γ (Liu J et al., Blood 2007). Interestingly, our data demonstrated that OCs activated IFN-γ producing T cells in co-culture conditions. Furthermore, we observed that T cell and OC-mediated upregulation of PD-L1 on MM cells was partially reversed by using IFN-γ neutralizing antibody. This implies that OCs indirectly induce PD-L1 upregulation on MM cells by enhancing IFN-γ secretion from T cells. In addition, we found that naïve CD4+ T cells have a higher propensity to differentiate into Th17 lineage in the presence of Th17 differentiation cytokines when co-cultured with OCs. Moreover, we observed an increased expansion of Th17 cells in co-culture with OCs. Those Th17 cells also showed a similar pattern of dysregulation of immune checkpoint axes.

Our study demonstrates that OCs positively regulate co-inhibitory checkpoint molecules and negatively regulate co-stimulatory molecules on T cells. These findings indicate that OCs play an important role in inhibiting T cell-mediated antitumor immunity. Targeting OCs may help restore impaired immune surveillance in MM in addition to their critical role in preventing lytic bone lesions in MM. These data may support the role of antiresorptives in immune surveillance with indirect anti-tumor effects.

Disclosures

No relevant conflicts of interest to declare.
Using Lean Six Sigma to Develop a Patient Centered Medical Home for Adults with Sickle Cell Disease
Authors: Johnson Shirley , Hartigan Sarah , Holt Emily , Sop Daniel , McHenry Chantal , Lipato Thokozeni , Elliott Taylor , Ferlis Mica , Mcmanus Caitlin , Smith Wally R
Published: November 2019

Background: Adults with sickle cell disease (SCD) suffer poor quality, disparities, higher utilization and mortality, and unmet medical need. Thus, in 2017 Virginia Commonwealth University Health (VCU) used pilot results and axioms of the Patient-Centered Medical Home (PCMH) and Lean Six Sigma quality improvement to build an Adult SCD Medical Home.

Methods and Results: VCU funded the program in October 2017. We implemented it over the next fifteen months. We first used a Six Sigma QI cycle called DMAIC (Define, Measure, Analyze, Improve and Control). Define: we defined three improvement targets in year one: inpatient, emergency department (ED), and ambulatory care. Behavioral health, program evaluation, ambulatory clinical policies, and pediatric to adult transition were added in year two. We identified ourselves or recruited hospital partners as champions/leaders for each care target area. Each formed a multidisciplinary implementation team. The inpatient care team actually preceded Medical Home funding. Where feasible, each team conducted PDSA cycles to test and improve best practices or metrics. Measure: we ranked 567 adult SCD patients based on their CY 2017 30-day readmissions, length of stay, 3-day ED returns, ED discharges, inpatient days and discharges, outpatient visits, ED use, and charges. Each team also developed metrics. Analyze: The top 50 highest utilizers by charges were targeted for intervention. Improve: We aimed for six 12-month intervention patient results: 1) reduce readmissions by 15%; 2) reduce average length of stay by 1.5 days; 3) reduce charges by 15%; 4) improve compliance with SCD inpatient guidelines; 5) improve quality, safety, and financial reporting; 6) improve patient experience. Leaders also used Six Sigma tools weekly to oversee teams, identify resources, plan, and hire staff: for example, we ranked the urgency of steps using "Now, Later, Latest" process charts, and documented progress using "Quick Wins" communication logs. Control: Processes were continuously amended. Stakeholders met and supported us monthly to quarterly. We distributed an annual report. Metric results are presented in a separate abstract.

Conclusion: Lean Six Sigma QI principles were effective for developing and implementing an adult SCD medical home. We believe the above processes could be replicated elsewhere.

Figure

Disclosures

Lipato: Novartis: Honoraria. Smith:Novartis: Consultancy, Honoraria.
Regulation of Erythroblast Protein Expression By an RNA Splicing Mechanism, Decoy Exon-Mediated Intron Retention
Authors: Parra Marilyn , Zhang Weiguo , Vu Jonathan , DeWitt Mark , Conboy John G
Published: November 2019

The erythroid transcriptome is extensively remodeled during terminal erythropoiesis by dynamic changes in RNA splicing of cassette exons and retained introns. Mechanistic studies of these RNA processing networks will provide new insight into pathways that impact structure and function of the erythroid proteome during erythroblast differentiation. We previously showed that up-regulation of EPB41 exon 16 splicing imparts new functionality to the encoded protein, enhancing protein-protein interactions that mechanically strengthen the red cell membrane. More recently, RNA-seq analysis revealed that numerous erythroid transcripts exhibit up-regulation of intron retention (IR) events, some of which are controlled by a decoy exon-mediated mechanism that can reduce the output of translated mRNA so as to limit protein expression. Here we demonstrate that modulation of decoy-mediated IR quantitatively affects protein expression in primary human erythroid cells. We first studied the OGT gene (O-GlcNAc transferase), a key regulator of O-GlcNAC homeostasis. OGT expression responds to pharmacological inhibitors by regulating intron 4 retention, by a mechanism requiring a intronic splicing silencer (1) that functions as a decoy exon (2) to nonproductively engage annotated splice sites at the ends of the intron, thereby blocking excision and enforcing its retention. In erythroid CD34+ progenitors at day 7 of culture, we found that treatment with an OGT inhibitor (OSMI-1) reduced OGT IR and increased spliced OGT RNA and OGT protein. Conversely, an inhibitor of the antagonistic OGA enzyme (thiamet-G) induced greater OGT IR and reduced OGT protein expression. These results are similar to what was reported previously in established cell lines (1), and suggest that modulation of IR can vary mRNA and protein expression in primary cells >5-fold. To further explore the model, we independently blocked OGT IR in erythroid cultures by electroporation of an antisense morpholino directed against the OGT decoy exon 5' splice site. RT-qPCR and western blot analysis confirmed substantial reduction in IR, coupled with an increase in spliced RNA and elevated OGT protein expression, compared to control cells or cells treated with an irrelevant morpholino. The OGT-specific MO also substantially blocked IR induced by thiamet-G. These results show that pharmacological- or antisense-mediated alteration in IR can significantly change protein expression in primary erythroblast cultures. We propose that the abundance of IR transcripts in late erythropoiesis represents a widespread modulation of protein output by post-transcriptional pathways operating at the level of intron retention. Park SK, et al. (2017) Cell Rep. 20: 1088-99.Parra M et al. (2018) RNA 24: 1255-65.

Disclosures

No relevant conflicts of interest to declare.
Prediction of Malingant Plasma Cell Biology Related Survival in AL-Amyloidosis
Authors: Beck Susanne , Emde Martina , Moreaux Jerome , Seckinger Anja , Hose Dirk
Published: November 2019

Background. Survival in AL-amyloidosis is thought to be primarily determined by signs and symptoms caused by deposition of amyloid light chains, most prominently in the heart. In contrast, molecular characteristics of the underlying malignant plasma cell disease have been described, but are mostly considered less important.

Aim of our study is to predict malignant plasma cell biology related survival in AL-amyloidosis by establishing the first gene expression based risk stratification (HDAL) and assessing its independence from clinical serum parameter assessing risk.

Methods. CD138+-purified plasma cell samples of 919 patients with malignant plasma cell diseases, i.e. 195 AL-amyloidosis and 724 symptomatic myeloma patients were investigated by gene expression profiling, 124 AL-amyloidosis patients by RNA-sequencing. Gene expression profiling data of AL-amyloidosis patients were spitted in a training (TG, n=99) and a validation group (VG, n=96). A two-step model according to Rème et al. was applied on the training group, including a running log rank test for gene selection and a multi-cut-off running log-rank algorithm for optimal cut-off-selection, leading to a selection of 15 genes associated with good and 44 genes with adverse prognosis. The resulting HDAL-score was validated on the independent VG and our myeloma patient cohort using survival estimates for censored data. Differences between curves were assessed using the Log-rank test. The continuous RNA-Seq HDAL-score (R-HDAL) was subsequently derived to validate the survival association of the selected genes. HDAL was tested for independence with serum parameter assessing clinical staging systems by multivariate Cox regression.

Results. Categorical split of the HDAL-score delineates three significantly predictive groups of 48%, 29% and 23% of AL-amyloidosis patients with a median survival of 105, 53 and 3 months in the training, and 72, 33 and 6 months in the validation group, respectively. In symptomatic myeloma patients, HDAL significantly stratifies two groups with a median survival of 128 and 78 months. Thus, HDAL is a malignant plasma biology related derived risk stratification. HDAL and R-HDAL are significantly predictive for survival as continuous parameters. Categorial and continuous HDAL are individually independent predictive from clinical staging systems, i.e. Mayo 2004, 2012 and Euro score, and the assessed serum parameters, i.e. NT-ProBNP, cTNT and dFLC.

In conclusion, malignant plasma cell biology related and amyloid deposition mediated survivals in AL-amyloidosis are independent. Prognosis driven by the first component can significantly be assessed by transcriptome profiling (HDAL or R-HDAL).

We thank U. Hegenbart and S. Schönland for clinical collaboration in this work.

Disclosures

Moreaux: Diag2Tec: Other: Co-founder of Diag2Tec company.
Efficacy of Fecal Microbiota Transplant in Hematological Cancers Patients with Recurrent Clostridioides Difficile Infection: A Systemic Review and Meta-Analysis
Authors: Tariq Raseen , Furqan Fateeha , Jamshed Saad , Khanna Sahil
Published: November 2019

Introduction:

Fecal microbiota transplant (FMT) has been shown to be an effective treatment for recurrent Clostridioides difficile infection (CDI). Immunosuppression is one of the risk factors for CDI. However, most of the trials evaluating efficacy of FMT have excluded immunocompromised patients. Patients with hematological cancers represent a major class of immunocompromised patients. Hence, we performed a meta-analysis to evaluate the efficacy of FMT in patients with hematological cancer for the treatment of recurrent CDI.

Methods:

A systematic search of Medline, Embase, and Web of Science was performed from January 2000 up to December 2018. Articles included for meta-analysis were case series and case reports that assessed efficacy of FMT in hematological cancer patients were included. Study quality was assessed using the Newcastle-Ottawa scale. The main outcomes were pooled proportions of patients achieving cure after first FMT. The cure rate was defined as resolution of diarrhea without any recurrence.

Results:

10 studies (5 case series and 5 case reports) were included in the analysis, making up 29 patients who underwent 38 total FMT procedures. The follow up period ranged from 1- 14 months. Of the included patients, 17 had leukemia, 10 had lymphoma and 2 patients had multiple myeloma and myelodysplastic syndrome each. 7 of these patients had undergone hematopoietic stem cell transplant.

The pooled cure rate was 82% [confidence interval (CI) 67-94%] after 1 FMT with no heterogeneity (I2=0%). Minor publication bias was seen on visual inspection of funnel plot.

FMT was generally well tolerated by these patients. No serious side effects were reported in any study. One of the studies reported death due to cardiac arrest 5 days after FMT which was thought to be unrelated to the procedure. Mild side effects including mild abdominal pain, transient diarrhea, fecal urgency, constipation and nausea were reported in 5 patients.

Conclusion:

Based on limited observational data, FMT seems to be an effective and safe modality for management of recurrent CDI in patients with hematological cancers. However, further prospective clinical trials are needed to establish its safety as a first line therapy for recurrent CDI in this population.

Figure

Disclosures

Jamshed: Takeda Pharmaceutical: Honoraria. Khanna:Rebiotix, Inc: Research Funding; Probio Tech, LLC: Consultancy; Facile Therapeutics: Consultancy; Shire, Plc: Consultancy.
In-Hospital Complications and Outcomes of Autologous Stem Cell Transplantation in Multiple Myeloma Patients Older Than 65-Years Old in the United States: National Inpatient Sample Analysis, 2011-2015
Authors: Bakalov Veli , Tang Amy , Shaikh Hira G. , Shah Shrunjal , Chahine Zena , Kaplan Robert B. , Lister John , Sadashiv Santhosh
Published: November 2019

Background. Use of Autologous Stem Cell Transplantation (ASCT) continues to increase in elderly patients with multiple myeloma. The main goal of our study was to describe in-hospital complications and outcomes after ASCT in patients younger and older than 65-years old utilizing the Nationwide Inpatient Sample (NIS) database.

Methods. Cohort selection. The NIS database for the years 2011 to 2015 was queried for the analysis. We used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) in order to identify patients with MM as a primary diagnosis for the hospitalization, and ASCT as a primary diagnosis of the hospitalization. In order to determine comorbidities in selected population we used Clinical Classifications Software (CCS) in conjunction with ICD-9-CM codes. Statistical Analysis.Complex weights were used throughout all calculations, enabling appropriate national projections. Chi-squared and independent t-tests were used for univariate analysis where appropriate. In our study p-value <0.05 was considered statistically significant. Data were analyzed using SAS v9.4 (SAS Institute, Cary, NC).

Results.A total of 3,664 patients with MM receiving ASCT were identified in our cohort. Males represented 57.1% of the population, majority of the patients were white, with private insurance, located at the urban teaching hospitals (Table 1). Main insurance in patients older than 65 years old was Medicare. Main comorbidities during hospitalization were anemia, hypertension, electrolyte abnormalities, acute kidney injury, cardiac dysrhythmias, sepsis and pneumonia (Table 2). Overall in-hospital mortality was low, 0.7%, and was significantly higher in patients older than 65 years old (1.3% vs 0.4%, p-value 0.002), however when adjusted for the baseline characteristics with multivariate logistic regression analysis in-hospital mortality was no longer statistically significant (Table 3).

Conclusions. We found that patients older than 65 years with MM receiving ASCT are more susceptible to in-hospital complications. However we found that in-hospital outcomes are not statistically significant when adjusted to baseline characteristics, suggesting that the procedure is safe even in the elderly population. Findings of our study can be used to design future randomized controlled trials.

Disclosures

No relevant conflicts of interest to declare.
Incidental Pulmonary Embolism. Analysis of Mayo Clinic Venous Thromboembolism Database
Authors: Wysokinska Ewa , Houghton Damon E. , Vlazny Danielle , Ashrani Aneel A. , Froehling David A , Hodge David O. , Peterson Lisa , McBane Robert D. , Wysokinski Waldemar E. , Casanegra Ana I
Published: November 2019

Background: Incidental pulmonary embolism (PE) is not infrequently found on CT scans with highest incidence reported in patients with cancer. It is unclear whether patients with symptomatic pulmonary embolism (iPE) have different clinical profile or outcomes compared to patients with symptomatic PE (sPE) and whether this is affected by the presence or type of malignancy.

Objective: Compare baseline characteristics of patients diagnosed with iPE to patients with sPE with attention to cancer-specific risk factors as well as evaluate clinical outcomes.

Methods: Consecutive patients enrolled in the Mayo Thrombophilia Clinic VTE Registry between March 1, 2013 and December 31st, 2018 with PE were followed prospectively. Outcomes of recurrent venous thromboembolism (VTE), major bleeding, clinically relevant non-major bleeding (CRNMB) and mortality data were collected every 3 months. Clinical outcomes were analyzed with specific focus on patients with cancer. Information was collected and managed using REDCap (Research Electronic Data Capture) and data analysis was performed using SAS software (SAS Institute Inc., Cary, North Carolina).

Results: Out of a total of 1033 patients with PE in VTE registry, there were 655 patients with PE (284 with incidental and 363 symptomatic) who completed at least 3 months of anticoagulation and were started on treatment within 14 days of diagnosis. Apixaban was used in 220 (34 %), Rivaroxaban 175 (27 %), Enoxaparin 179 (27%), and Warfarin in 81 (12 %) patients.

Overall cancer was present in 61% of patients and was more common in patients with iPE compared to sPE (80.2% vs 45.2%, p<0.001).

Patients with iPE were less likely to have previous VTE (8.2% vs 25.5%, p< 0.0001) and tended to have lower BMI (mean 28.8 vs 31.4, p<0.0001)

Characteristics of the subgroup of only cancer patients with PE are summarized in the Table.

Of note, pancreatic and GI cancers were more common in patients with iPE.

There were no differences in recurrent VTE, major bleeding and CRNMB in patients with iPE compared to sPE. This also held true for patients with underlying malignancies. Mortality rates were significantly higher in all patients with iPE even when adjusting for presence of malignancy (p=0.03). When adjusting for presence of metastatic malignancy though the difference was no longer present (p=0.33).

Conclusion: Patients with iPE were more likely to have an underlying malignancy, potentially due to higher likelihood of undergoing staging imaging studies. Additionally, patients with iPE more often had metastatic disease which was associated with higher mortality. Recurrent VTE and bleeding outcomes were similar in patients with iPE and sPE, this was independent of the presence of underlying malignancy.

Disclosures

McBane: BMS: Research Funding.
Ferroportin Downregulation Promotes Cell Proliferation By Modulating the Nrf2-Mir 17-5p Axis in Multiple Myeloma
Authors: Shi Jumei , Kong Yuanyuan , Hu Liangning , Chen Gege , Yu Dandan , Xie Yongsheng , Wang Yingcong , Wu Xiaosong
Published: November 2019

Recent findings demonstrate that aberrant downregulation of the iron-exporter protein, ferroportin (FPN1), is associated with poor prognosis and osteoclast differentiation in multiple myeloma (MM). Here, we show that FPN1 was downregulated in MM and that clustered regularly interspaced short palindromic repeat (CRISPR)-mediated FPN1 knockout promoted MM cell growth and survival. Using an microRNA target-scan algorithm, we identified miR 17-5p as an FPN1 regulator that promoted cell proliferation and cell cycle progression, and inhibited apoptosis - both in vitro and in vivo. miR 17-5p inhibited retarded tumor growth in a MM xenograft model. Moreover, restoring FPN1 expression at least partially abrogated the biological effects of miR 17-5p in MM cells. The cellular iron concentration regulated the expression of the iron-regulatory protein (IRP) via the 5-untranslated region of IRP messenger RNA and modulated the post-transcriptional stability of FPN1. Bioinformatics analysis with subsequent chromatin immunoprecipitation-polymerase chain reaction and luciferase activity experiments revealed that the transcription factor Nrf2 drove FPN1 transcription through promoter binding and suppressed miR 17-5p (which also increased FPN1 expression). Nrf2-mediated FPN1 downregulation promoted intracellular iron accumulation and reactive oxygen species. Our study links FPN1 transcriptional and post-transcriptional regulation with MM cell growth and survival, and validates the prognostic value of FPN1 and its utility as a novel therapeutic target in MM.

Figure 1

Disclosures

No relevant conflicts of interest to declare.
Impaired Bile Secretion Promotes Chronic Liver Injury in Sickle Cell Disease
Authors: Pradhan Tirthadipa , Sundd Prithu , Gladwin Mark T , Monga Satdarshan Pal , Kato Gregory J
Published: November 2019

Hepatic crisis is an emergent complication affecting sickle cell disease (SCD) patients, however, the molecular mechanism of sickle cell hepatobiliary crisis remains poorly understood. We examined the liver pathophysiology of SCD using a humanized mouse model (townes SCD mice; homozygous for Hbatm1(HBA)Tow, homozygous for Hbbtm2(HBG1,HBB*)Tow). These mice have the major features (irreversibly sickled red cells, splenomegaly, anemia, multiorgan pathology) found in humans with SCD and, as such, represent a useful in vivo system to study hepatobiliary changes in SCD disease.

SCD mice manifested progressive hepatomegaly, liver injury and hyperbilirubinemia. RNA-sequence analysis of total RNA from SCD mouse liver compared to control (AS) identified dysregulation of genes encoding proteins responsible for fibrosis, bile acid synthesis, bile transport and cholesterol metabolism. Immunohistochemical analysis confirmed inflammation, fibrosis and increased ductular reaction in SCD mice. To mechanistically address the cholestatic phenotype in SCD mice, we used our recently developed multi-photon-excitation (MPE) enabled in vivo real-time fluorescence microscopy of intact liver in live mice. We used Texas-Red (TXR) dextran to visualize the blood flow through liver sinusoids and carboxyfluorescein (used as a surrogate of bile flow) to visualize bile flow through biliary canaliculi. Real time imaging show that sinusoidal ischemia occurs in the liver of transgenic-humanized SCD mice under basal condition. Intravital imaging also revealed impaired bile secretion into the bile canaliculi, which was associated with loss of apical bile acid transporters and bile acid biosynthetic enzymes, hepatic bile accumulation, and activation of Farnesoid X receptor (FXR) and small heterodimer partner (Shp) in the liver of SCD mice. These findings are the first to identify that impaired bile acid synthesis and misexpression of bile transporters promote intrahepatic bile accumulation and impaired bile secretion, leading to hepatobiliary injury of SCD. Improved understanding of these processes could potentially benefit the development of new therapies to treat sickle cell hepatic crisis.

Disclosures

Gladwin: Globin Solutions, Inc: Patents & Royalties: Provisional patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning; Bayer Pharmaceuticals: Other: Co-investigator; United Therapeutics: Patents & Royalties: Co-inventor on an NIH government patent for the use of nitrite salts in cardiovascular diseases . Kato:Novartis, Global Blood Therapeutics: Consultancy, Research Funding; Bayer: Research Funding.
Impact of Asthma on Inpatient Outcome of Sickle Cell Crisis: A Population-Based Study
Authors: Gong Zimu , Ali Faisal Shaukat S , Zhao Yu , Garcia Jessica Lee
Published: November 2019

Introduction: Sickle cell disease (SCD) is one of the most common inherited hematological disorder in the United States. Sickle cell crisis is a common complication caused by excessive sickling of red blood cells, resulting in tissue ischemia. The frequency of such pain crisis, however, varies greatly among patients depending on disease control and other patient characteristics. Asthma is a common comorbidity in SCD patients which is associated with higher incidence of acute chest syndrome (ACS). However, the impact of asthma on short term outcome of acute sickle cell crisis remains unclear.

Methods: We analyzed data from the National Inpatient Sample database. Data entries from year 2005 through 2014 were included. The presence of SCD, sickle cell crisis, ACS, asthma are identified using corresponding ICD codes. Data regarding demographic information, performed procedures, inpatient mortality, and length of stay are extracted and analyzed accordingly.

Results: A total of 247,266 records were identified. The median age at admission was 26 years (interquartile range 18 - 37), with most patients being of African American origin (91.8%). A total of 16,828 (6.8%) patients presented with ACS, whereas 173,869 (70.3%) presented with non-ACS crisis. The remaining 56,569 (22.9%) patients were admitted for reasons other than sickle cell crisis, most commonly infection. Overall, 34,609 patients (14.0%) had asthma. Compared to patients without ACS, the incidence of asthma was significantly higher in patients with ACS (19.0% vs 13.6%, P<0.001), whereas patients with non-ACS crisis had a similar incidence of asthma compared to those without sickle cell crisis (13.7% vs 13.5%, P=0.42). Asthma patients who presented with ACS exhibited a lower inpatient mortality (0.4% vs 1.1%, P<0.001), as well as lower use of invasive mechanical ventilation (3.0% vs 4.1%, P=0.006). Similarly, in patients with non-ACS sickle cell crisis, asthma was associated with lower mortality (0.4% vs 0.2%, P<0.001), lower use of invasive mechanical ventilation (0.4% vs 0.7%, P<0.001), and lower frequency of transfusion (27.5% vs 31.9%, P<0.001).

Conclusion: Our study again demonstrated the association between asthma and ACS in SCD patients. Furthermore, asthma appears to be associated with superior outcome in both patients with ACS and non-ACS sickle cell crisis. Further studies are warranted to elucidate if asthma is associated with a milder form of sickle cell crisis which may correlate with the physiologic basis of these associations.

Disclosures

No relevant conflicts of interest to declare.
Does knowledge of evolutionary biology change high school students’ attitudes about healthy eating?
Authors: Sherry Diana S.
Published: November 2019

Background

Embedded in the emerging area of evolutionary medicine is the premise that evolutionary biology can serve a pedagogical function with widespread applications for education and outreach. Although great strides have been taken over the decades by the science education community to improve evolution education in general, the knowledge gulf or gap between advances in evolutionary medicine and public understanding through the educational system has widened at a rapid pace—and not without consequences for public health, especially for young people. Epidemiological data indicate that the high rates of obesity and type-2 diabetes have begun to extend to adolescents and teenagers, an alarming trend of great concern. Would knowledge of the evolutionary biology perspective on diet and health have value for young people? Little is known about the efficacy of evolutionary medicine education as a public health outreach strategy. A small study was conducted at a New England high school and consisted of two research components: (1) a cross-sectional survey of students’ views about what “healthy eating” means and (2) an intervention experiment designed to isolate exposure to knowledge of evolutionary biology. Data were collected through the use of questionnaires and analyzed according to qualitative methods.

Results

The survey results showed that students had an accurate view of general guidelines for healthy eating in alignment with public health messaging (e.g., avoiding junk food, eating lots of fruits and vegetables). The main result from the intervention experiment showed that students who received instruction in nutritional physiology alone did not change their view of what “healthy eating” means, whereas students who received instruction in nutritional physiology coupled with evolutionary biology changed their views of healthy food choices, leading to intended dietary changes.

Conclusions

A brief, one-time exposure to key concepts in evolutionary biology brought about a shift in students’ perceptions of healthy eating. An approach that can cause a shift in perception or attitude, considered an essential first step toward effecting behavioral change, merits further attention and development. Evolutionary medicine education holds strong potential as an untapped yet effective public health outreach strategy regarding the dietary choices of youth.
A compulsive act of excess water intake leading to hyponatraemia and rhabdomyolysis: a case report
Authors: Fernando Sudheera , Sivagnanam Francisca , Rathish Devarajan
Published: November 2019

Background

Primary polydipsia is commonly seen in patients with psychiatric illnesses. Excess water intake is also seen in patient with anorexia and anticholinergic medications. We report a patient who had hyponatraemia and rhabdomyolysis after consuming excess water for ureteric calculus.

Case presentation

A healthy middle-aged male presented with an episode of generalized tonic-clonic seizure and reduced level of consciousness preceded by consumption of excess water. He was recently diagnosed to have a ureteric calculus and was advised to consume plenty of water. On examination, he was disoriented in place, person and time. Except for the generalized diminished reflexes, other neurological and systemic examinations were normal. He had severe hyponatraemia, mild hypokalaemia and myoglobulinuria. His serum creatinine phosphokinase and aspartate aminotransferase were markedly elevated. The diagnosis of rhabdomyolysis in the setting of acute water intoxication was made. Optimum fluid and electrolyte management achieved a dramatic recovery of consciousness, hyponatraemia and rhabdomyolysis.

Discussion

The patient has had excess water intake due to a compulsive act in the background fear of ureteric calculus. Such act could lead to severe hyponatraemia and rhabdomyolysis. Therefore, future similar acts could be prevented by proper medical advice. Further, emergency physicians should be vigilant for rhabdomyolysis in patients with hyponatraemia or hypokalaemia.
Involvement of OsGF14b Adaptation in the Drought Resistance of Rice Plants
Authors: Liu Jianping , Sun Xinjiao , Liao Wencheng , Zhang Jianhua , Liang Jiansheng , Xu Weifeng
Published: November 2019

Background

Drought stress is one of the major abiotic stresses that restrict plant growth and development. 14–3-3 proteins have been validated to regulate many biological processes in plants. Previous research demonstrated that OsGF14b plays different roles in panicle and leaf blast resistance. In this study, we researched the function of OsGF14b in drought resistance in rice.

Findings

Here, we report that OsGF14b was strongly induced by soil drought stress. In comparison with wild type (WT), the osgf14b mutant exhibited improved resistance to drought and osmotic stress by changing the content of stress-relevant parameters, complementation of the osgf14b mutant restored the drought sensitivity to WT levels, whereas the OsGF14b-overexpression lines exhibited enhanced sensitivity to drought and osmotic stress. The osgf14b mutant plants were hypersensitive to abscisic acid (ABA), while the OsGF14b-overexpression plants showed reduced sensitivity to ABA. Furthermore, mutation and overexpression of OsGF14b affected the expression of stress-related genes under normal growth conditions and/or drought stress conditions.

Conclusions

We have demonstrated that OsGF14b is involved in the drought resistance of rice plants, partially in an ABA-dependent manner.
LOVE ON WINGS, a Dof family protein regulates floral vasculature in Vigna radiata
Authors: Guo Wuxiu , Zhang Xue , Peng Qincheng , Luo Da , Jiao Keyuan , Su Shihao
Published: November 2019

Background

The interaction among plants and their pollinators has been a major factor which enriched floral traits known as pollination syndromes and promoted the diversification of flowering plants. One of the bee-pollination syndromes in Faboideae with keel blossoms is the formation of a landing platform by wing and keel petals. However, the molecular mechanisms of elaborating a keel blossom remain unclear.

Results

By performing large scale mutagenesis, we isolated and characterized a mutant in Vigna radiata, love on wings (low), which shows developmental defects in petal asymmetry and vasculature, leading to a failure in landing platform formation. We cloned the locus through map-based cloning together with RNA-sequencing (RNA-seq) analysis. We found that LOW encoded a nucleus-localized Dof-like protein and was expressed in the flower provascular and vascular tissues. A single copy of LOW was detected in legumes, in contrast with other taxa where there seems to be at least 2 copies. Thirty one Dof proteins have been identified from the V. radiata’s genome, which can be further divided into four Major Cluster of Orthologous Groups (MCOGs). We also showed that ectopic expression of LOW in Arabidopsis driven by its native promoter caused changes in petal vasculature pattern.

Conclusions

To summarize, our study isolated a legume Dof-like factor LOW from V. radiata, which affects vasculature development in this species and this change can, in turn, impact petal development and overall morphology of keel blossom.
Interpreter proxy versus healthcare interpreter for administration of patient surveys following arthroplasty: a pilot study
Authors: Xue Daniel , Churches Timothy , Armstrong Elizabeth , Mittal Rajat , Naylor Justine Maree , Harris Ian Andrew
Published: November 2019

Background

Clinical quality registries and other systems that conduct routine post-discharge surveillance of patient outcomes following surgery may have difficulty surveying patients who have limited proficiency in the language of the healthcare provider. Interpreter proxies (family and carers) are often used due to limited access to certified healthcare interpreters (due to cost or availability). The aim of this study was to assess the reliability of engaging interpreter proxies compared with certified healthcare interpreters for the administration of patient-reported health-related surveys for people with limited English proficiency (LEP).

Methods

People with LEP and due for a routine 6-month telephone follow-up post knee or hip arthroplasty were invited to participate. Participants were randomly allocated to having their first interview with an interpreter proxy or a certified healthcare interpreter followed by the second (crossover) interview within 2 weeks (range: 4 to 12 days) after the first interview using the alternative method. Agreement between the two methods was assessed using quadratic weighted Cohen’s kappa, intraclass correlation and concordance correlation co-efficient where appropriate for EQ-5D health domains, total Oxford hip and knee scores, patient satisfaction, operation success, readmission, reoperation, and post-surgical complication responses. The mean of the differences between the same data items collected by each of the two methods was also calculated.

Results

Eighty five participants (96%) completed the study. There was substantial to excellent inter-rater agreement (kappa = 0.69–0.87 and ICCs above 0.74) for all but one measure. The mean differences between family proxy and healthcare interpreter scores for each participant were small, ranging from 0.01 (score range of 1–5) to 0.72 (score range of 0–100).

Conclusion

These results suggest that using interpreter proxies is a reliable alternative to certified healthcare interpreters in conducting patient-reported health surveys, potentially making this process easier and cost effective for researchers and registries.
Compound heterozygous LPIN2 pathogenic variants in a patient with Majeed syndrome with recurrent fever and severe neutropenia: case report
Authors: Liu Jun , Hu Xu-Yun , Zhao Zhi-Peng , Guo Ruo-Lan , Guo Jun , Li Wei , Hao Chan-Juan , Xu Bao-Ping
Published: November 2019

Background

Majeed syndrome is a rare, autosomal recessive autoinflammatory disorder first described in 1989. The syndrome starts during infancy with recurrent relapses of osteomyelitis typically associated with fever, congenital dyserythropoietic anemia (CDA), and often neutrophilic dermatosis. Mutations in the LPIN2 gene located on the short arm of chromosome 18 have been identified as being responsible for Majeed syndrome.

Case presentation

We report an 8-month-old boy, who presented with recurrent fever, mild to moderate anemia, and severe neutropenia. Erythrocyte sedimentation rate and C-reactive protein were elevated. Molecular testing identified a paternal splicing donor site variant c.2327 + 1G > C and a maternal frameshift variant c.1691_1694delGAGA (Arg564Lysfs*3) in LPIN2.

Conclusions

Only a few cases with LPIN2 mutation have been reported, mainly in the Middle East with homozygous variants. Our patient exhibited a mild clinical phenotype and severe neutropenia, different from previous reports.
PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma
Authors: Buckley Hannah L. , Collinson Fiona J. , Ainsworth Gemma , Poad Heather , Flanagan Louise , Katona Eszter , Howard Helen C. , Murden Geraldine , Banks Rosamonde E. , Brown Joanne , Velikova Galina , Waddell Tom , Fife Kate , Nathan Paul D. , Larkin James , Powles Thomas , Brown Sarah R. , Vasudev Naveen S.
Published: November 2019

Background

The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy.

Methods

The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored.

Discussion

The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established.

Trial registration

PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017).

Trial status

At the time of submission, PRISM is open to recruitment and data collection is ongoing.
Incidence of atrial fibrillation in different major cancer subtypes: a Nationwide population-based 12 year follow up study
Authors: Jakobsen Christina Boegh , Lamberts Morten , Carlson Nicholas , Lock-Hansen Morten , Torp-Pedersen Christian , Gislason Gunnar H. , Schou Morten
Published: November 2019

Background

The prevalence of both atrial fibrillation (AF) and malignancies are increasing in the elderly, but incidences of new onset AF in different cancer subtypes are not well described.The objectives of this study were therefore to determine the incidence of AF in different cancer subtypes and to examine the association of cancer and future AF.

Methods

Using national databases, the Danish general population was followed from 2000 until 2012. Every individual aged > 18 years and with no history of cancer or AF prior to study start was included. Incidence rates of new onset AF were identified and incidence rate ratios (IRRs) of AF in cancer patients were calculated in an adjusted Poisson regression model.

Results

A total of 4,324,545 individuals were included in the study. Cancer was diagnosed in 316,040 patients. The median age of the cancer population was 67.0 year and 51.5% were females. Incidences of AF were increased in all subtypes of cancer. For overall cancer, the incidence was 17.4 per 1000 person years (PY) vs 3.7 per 1000 PY in the general population and the difference increased with age. The covariate adjusted IRR for AF in overall cancer was 1.46 (95% confidence interval (CI) 1.44–1.48). The strength of the association declined with time from cancer diagnosis (IRR0-90days = 3.41 (3.29–3.54), (IRR-180 days-1 year = 1.57 (CI 1.50–1.64) and (IRR2–5 years = 1.12 (CI 1.09–1.15).

Conclusions

In this nationwide cohort study we observed that all major cancer subtypes were associated with an increased incidence of AF. Further, cancer and AF might be independently associated.
Mapping of sentinel lymph node drainage using SPECT/CT to tailor elective nodal irradiation in head and neck cancer patients (SUSPECT-2): a single-center prospective trial
Authors: de Veij Mestdagh Pieter D. , Schreuder Willem H. , Vogel Wouter V. , Donswijk Maarten L. , van Werkhoven Eric , van der Wal Jacqueline E. , Dirven Richard , Karakullukcu Baris , Sonke Jan-Jakob , van den Brekel Michiel W. M. , Marijnen Corrie A. M. , Al-Mamgani Abrahim
Published: November 2019

Background

The majority of patients with head and neck squamous cell carcinoma (HNSCC) receive bilateral elective nodal irradiation (ENI), in order to reduce the risk of regional failure. Bilateral ENI, as compared to unilateral ENI, is associated with higher incidence of acute and late radiation-induced toxicity with subsequent deterioration of quality of life. Increasing evidence that the incidence of contralateral regional failure (cRF) in lateralized HNSCC is very low (< 10%) suggests that it can be justified to treat selected patients unilaterally. This trial aims to minimize the proportion of patients that undergo bilateral ENI, by using lymph drainage mapping by SPECT/CT to select patients with a minimal risk of contralateral nodal failure for unilateral elective nodal irradiation.

Methods

In this one-armed, single-center prospective trial, patients with primary T1-4 N0-2b HNSCC of the oral cavity, oropharynx, larynx (except T1 glottic) or hypopharynx, not extending beyond the midline and planned for primary (chemo) radiotherapy, are eligible. After 99mTc-nanocolloid tracer injection in and around the tumor, lymphatic drainage is visualized using SPECT/CT. In case of contralateral lymph drainage, a contralateral sentinel node procedure is performed on the same day. Patients without contralateral lymph drainage, and patients with contralateral drainage but without pathologic involvement of any removed contralateral sentinel nodes, receive unilateral ENI. Only when tumor cells are found in a contralateral sentinel node the patient will be treated with bilateral ENI. The primary endpoint is cumulative incidence of cRF at 1 and 2 years after treatment. Secondary endpoints are radiation-related toxicity and quality of life. The removed lymph nodes will be studied to determine the prevalence of occult metastatic disease in contralateral sentinel nodes.

Discussion

This single-center prospective trial aims to reduce the incidence and duration of radiation-related toxicities and improve quality of life of HNSCC patients, by using lymph drainage mapping by SPECT/CT to select patients with a minimal risk of contralateral nodal failure for unilateral elective nodal irradiation.

Trial registration

ClinicalTrials.gov Identifier: NCT03968679, date of registration: May 30, 2019.