Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor.

Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell-driven malignancies. However, approved covalent BTK inhibitors (cBTKis) are associated with treatment limitations because of off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here, we describe the preclinical profile of pirtobrutinib, a potent, highly selective, noncovalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate binding region and shows no direct interaction with C481. Consequently, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKis, prevented Y551 phosphorylation in the activation loop. These data suggest that pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines, and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed that pirtobrutinib was highly selective for BTK in >98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained >100-fold selectivity over other tested kinases. Collectively, these findings suggest that pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical, and structural attributes with the potential to treat B-cell-driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies.

Exploring the invisible water insecurity of water utility shutoffs in Detroit, Michigan.

A lack of regular access to clean and safe water and sanitation is a persistent problem in many parts of the world. Most water insecurity studies focus on the world's less-industrialized and lower-income countries, where sanitation and water delivery infrastructure may never have existed. However, many individuals in higher-income countries experience invisible water insecurity, wherein specific households or individuals lack access to sanitation and clean water despite the relative wealth of their country. In the United States, invisible water insecurity tends to manifest as a result of homelessness, a lack of plumbing facilities, and water utility shut-offs. Using a water shut-off dataset from the Detroit Water and Sewerage Department, we investigate the relationship between a suite of demographic variables and the water shut-off rates in different neighborhoods throughout Detroit, Michigan. We find that shut-offs are more common in areas with more Black households that are more impoverished. Our findings indicate that this relationship links to structural disadvantage resulting from a legacy of racism and segregation in the city.

Neuropsychological, behavioral, and quality-of-life outcomes in children and adolescents with sickle cell disease treated with nonmyeloablative matched sibling donor hematopoietic cell transplantation: A case series.

BACKGROUND/OBJECTIVES: Despite advances in the treatment of sickle cell disease (SCD), cerebrovascular and cognitive insults can have lifelong consequences. Hematopoietic cell transplantation (HCT) is an established curative therapy, and recent studies have demonstrated efficacy with reduced toxicity nonmyeloablative (NMA) regimens, but little is known about neuropsychological outcomes. The objective of this study was to describe neuropsychological, behavioral, and quality-of-life outcomes with medical correlates in children with SCD who received an NMA matched sibling donor (MSD) HCT. DESIGN/METHODS: Retrospective cohort analysis of nine recipients with hemoglobin SS SCD who underwent MSD HCT using the National Institutes of Health (NIH) NMA protocol. RESULTS: Mean full-scale intellectual functioning (FSIQ) was average pre-HCT (FSIQ = 92.1, SD 9.0; n = 8) and 2 years post-HCT (mean FSIQ = 96.6; SD 11.1; N = 9). Neuropsychological functioning was largely average across all cognitive domains, and no pre/post-HCT differences were found to be statistically significant given the small sample size. However, effect sizes revealed moderate improvements in processing speed (Cohen's d = .72) and verbal memory (Cohen's d = .60) post-HCT, and declines in measures of attention (Cohen's d = -.54) and fine motor speed and dexterity (Cohen's d = -.94). Parents endorsed better quality of life (Cohen's d = .91), less impact of SCD on their family, and less worry about their child's future (Cohen's d = 1.44). CONCLUSION: Neuropsychological functioning in a sample of children and adolescents treated uniformly with NMA MSD HCT remained stable or improved in most cognitive domains, and improvements in quality of life and family functioning were observed.

ADaPTS "(AD)olescents (P)ath through (T)ransplant (S)ickle cell disease".

BACKGROUND: Sickle cell disease is an inherited chronic hematological disorder with an average lifespan of fifty years. The human cost of sickle cell disease includes missed school days, occupational opportunities, social isolation, stigmatization, and psychological sequelae. Hematopoietic cell transplantation (HCT) is the only curative therapy available but comes with potential morbidity and mortality. Our study explores how quality of life (QoL) is affected from the perspective of an adolescent who has undergone a nonmyeloablative matched sibling donor HCT. METHODS: We employed multiple case study methodology with purposeful sampling by selecting information-rich cases. DATA SOURCES: 1) QoL inventories 2) patient interviews 3) parent interview 4) vital support interview 5) medical record analysis. DATA ANALYSIS: Intra-case analysis by assembling evidence within a single case and then analyzing the differences within cases to create a rich case description. Next, a time series analysis was completed to track changes in patients' QoL. We used multiple sources of data to compose a timeline and changes across time. Then, we employed pattern matching as an analytical technique allowing for examination of patterns across cases. Finally, we used cross case synthesis to review results of each case. RESULTS: Quality of life was reported across the physical, social and psychological domains for 5 participants. All had sickle cell HgSS genotype, 80% were male and 80% were born outside of Canada. Physical domain: pre-transplant, 100% of patients experienced pain, and the majority suffered from fatigue, insomnia, and fevers resulting in hospitalizations. Afterwards, participants reported improved physical wellbeing. Social domain: pre-transplant, QoL was poor characterized by stigma, social isolation, and parental absenteeism. Post-HSCT adolescents gained social acceptance in areas that had stigmatized and excluded them. They were able to participate freely in activities with peers and their social life vastly improved. Psychological pre-transplant life experiences were overshadowed by psychological stress. The majority commented that their future was bleak and may lead to premature death. Afterwards adolescents described a crisis free life with positive psychological outcomes. CONCLUSIONS: Adolescents with sickle cell disease who undertook HCT demonstrated improved QoL one year post transplant with regard to physical, social and psychological well-being.

Glycinebetaine mitigates tomato chilling stress by maintaining high-cyclic electron flow rate of photosystem I and stability of photosystem II.

KEY MESSAGE: Glycinebetaine alleviates chilling stress by protecting photosystems I and II in BADH-transgenic and GB-treated tomato plants, which can be an effective strategy for improving crop chilling tolerance. Tomato (Solanum lycopersicum) is one of the most cultivated vegetables in the world, but is highly susceptible to chilling stress and does not naturally accumulate glycinebetaine (GB), one of the most effective stress protectants. The protective mechanisms of GB on photosystem I (PSI) and photosystem II (PSII) against chilling stress, however, remain poorly understood. Here, we address this problem through exogenous GB application and generation of transgenic tomatoes (Moneymaker) with a gene encoding betaine aldehyde dehydrogenase (BADH), which is the key enzyme in the synthesis of GB, from spinach. Our results demonstrated that GB can protect chloroplast ultramicrostructure, alleviate PSII photoinhibition and maintain PSII stability under chilling stress. More importantly, GB increased the electron transfer between QA and QB and the redox potential of QB and maintained a high rate of cyclic electron flow around PSI, contributing to reduced production of reactive oxygen species, thereby mitigating PSI photodamage under chilling stress. Our results highlight the novel roles of GB in enhancing chilling tolerance via the protection of PSI and PSII in BADH transgenic and GB-treated tomato plants under chilling stress. Thus, introducing GB-biosynthetic pathway into tomato and exogenous GB application are effective strategies for improving chilling tolerance.

A study of SARS-COV-2 outbreaks in US federal prisons: the linkage between staff, incarcerated populations, and community transmission.

BACKGROUND: Since the novel coronavirus SARS-COV-2 was first identified to be circulating in the US on January 20, 2020, some of the worst outbreaks have occurred within state and federal prisons. The vulnerability of incarcerated populations, and the additional threats posed to the health of prison staff and the people they contact in surrounding communities underline the need to better understand the dynamics of transmission in the inter-linked incarcerated population/staff/community sub-populations to better inform optimal control of SARS-COV-2. METHODS: We examined SARS-CoV-2 case data from 101 non-administrative federal prisons between 5/18/2020 to 01/31/2021 and examined the per capita size of outbreaks in staff and the incarcerated population compared to outbreaks in the communities in the counties surrounding the prisons during the summer and winter waves of the SARS-COV-2 pandemic. We also examined the impact of decarceration on per capita rates in the staff/incarcerated/community populations. RESULTS: For both the summer and winter waves we found significant inter-correlations between per capita rates in the outbreaks among the incarcerated population, staff, and the community. Over-all during the pandemic, per capita rates were significantly higher in the incarcerated population than in both the staff and community (paired Student's t-test p = 0.03 and p < 0.001, respectively). Average per capita rates of incarcerated population outbreaks were significantly associated with prison security level, ranked from lowest per capita rate to highest: High, Minimum, Medium, and Low security. Federal prisons decreased the incarcerated population by a relative factor of 96% comparing the winter to summer wave (one SD range [90%,102%]). We found no significant impact of decarceration on per capita rates of SARS-COV-2 infection in the staff community populations, but decarceration was significantly associated with a decrease in incarcerated per capita rates during the winter wave (Negative Binomial regression p = 0.015). CONCLUSIONS: We found significant evidence of community/staff/incarcerated population inter-linkage of SARS-COV-2 transmission. Further study is warranted to determine which control measures aimed at the incarcerated population and/or staff are most efficacious at preventing or controlling outbreaks.

Predictors of testing history and new HIV diagnosis among adult outpatients seeking care for symptoms of acute HIV infection in coastal Kenya: a cross-sectional analysis of intervention participants in a stepped-wedge HIV testing trial.

BACKGROUND: HIV testing is the first step to stop transmission. We aimed to evaluate HIV testing history and new diagnoses among adult outpatients in Kenya aged 18-39 years seeking care for symptoms of acute HIV infection (AHI). METHODS: The Tambua Mapema Plus study, a stepped-wedge trial, enrolled patients presenting to care at six primary care facilities with symptoms of AHI for a targeted HIV-1 nucleic acid (NA) testing intervention compared with standard provider-initiated testing using rapid antibody tests. Intervention participants underwent a questionnaire and NA testing, followed by rapid tests if NA-positive. Multinomial logistic regression was used to analyse factors associated with never testing or testing > 1 year ago ("late retesting") relative to testing ≤ 1 year ago ("on-time testers"). Logistic regression was used to analyse factors associated with new diagnosis. All analyses were stratified by sex. RESULTS: Of 1,500 intervention participants, 613 (40.9%) were men. Overall, 250 (40.8%) men vs. 364 (41.0%) women were late retesters, and 103 (16.8%) men vs. 50 (5.6%) women had never tested prior to enrolment. Younger age, single status, lower education level, no formal employment, childlessness, sexual activity in the past 6 weeks, and > 1 sexual partner were associated with testing history among both men and women. Intimate partner violence > 1 month ago, a regular sexual partner, and concurrency were associated with testing history among women only. New diagnoses were made in 37 (2.5%) participants (17 men and 20 women), of whom 8 (21.6%) had never tested and 16 (43.2%) were late retesters. Newly-diagnosed men were more likely to have symptoms for > 14 days, lower education level and no religious affiliation and less likely to be young, single, and childless than HIV-negative men; newly-diagnosed women were more likely to report fever than HIV-negative women. Among men, never testing was associated with fivefold increased odds (95% confidence interval 1.4-20.9) of new diagnosis relative to on-time testers in adjusted analyses. CONCLUSION: Most new HIV diagnoses were among participants who had never tested or tested > 1 year ago. Strengthening provider-initiated testing targeting never testers and late retesters could decrease time to diagnosis among symptomatic adults in coastal Kenya. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03508908 registered on 26/04/2018.

A population-based analysis of the presentation and outcomes of pediatric patients with osteosarcoma in Canada: a report from CYP-C.

BACKGROUND: Frequently occurring in adolescents, osteosarcoma is the most common primary malignant bone disease, with a reported 15% of patients who present with metastasis. With advances in imaging and improvements in surgical care, an updated analysis is warranted on the outcomes of pediatric patients with osteosarcoma. METHODS: We completed a retrospective review of pediatric patients who presented with osteosarcoma between 2001 and 2017, using The Cancer in Young People in Canada (CYP-C) national database. Data on 304 patients aged younger than 15 years were analyzed. RESULTS: The proportion of patients who presented with metastasis was 23.0%. The overall 5-year survival (OS) for patients who presented with metastasis was 37.4%. Overall survival and event-free survival (EFS) were lower in these patients than in patients with localized disease (hazard ratio [HR] 4.3, p < 0.0001 and HR 3.1, p < 0.0001). For patients who presented with metastatic disease, the OS for those undergoing an operative intervention was 44.1% compared with 17.6% for those who did not undergo resection (p < 0.0001). CONCLUSION: The proportion of patients who presented with metastatic osteosarcoma in our population is higher than previously reported. Overall outcomes of patients with metastatic disease have not changed. Our data reaffirm a role for surgical resection in patients with metastasis with a need to explore new treatment strategies to improve the overall prognosis of these patients.

Glycinebetaine mitigated the photoinhibition of photosystem II at high temperature in transgenic tomato plants.

Photosystem II (PSII), especially the D1 protein, is highly sensitive to the detrimental impact of heat stress. Photoinhibition always occurs when the rate of photodamage exceeds the rate of D1 protein repair. Here, genetically engineered codA-tomato with the capability to accumulate glycinebetaine (GB) was established. After photoinhibition treatment at high temperature, the transgenic lines displayed more thermotolerance to heat-induced photoinhibition than the control line. GB maintained high expression of LeFtsHs and LeDegs and degraded the damaged D1 protein in time. Meanwhile, the increased transcription of synthesis-related genes accelerated the de novo synthesis of D1 protein. Low ROS accumulation reduced the inhibition of D1 protein translation in the transgenic plants, thereby reducing protein damage. The increased D1 protein content and decreased phosphorylated D1 protein (pD1) in the transgenic plants compared with control plants imply that GB may minimize photodamage and maximize D1 protein stability. As D1 protein exhibits a high turnover, PSII maybe repaired rapidly and efficiently in transgenic plants under photoinhibition treatment at high temperature, with the resultant mitigation of photoinhibition of PSII.

Fludarabine, Campath, and Low-Dose Cyclophosphamide (FCClow) with or without TBI Conditioning Results in Excellent Transplant Outcomes in Children with Severe Aplastic Anemia.

Various reduced-intensity conditioning regimens are in use for allogeneic hematopoietic cell transplant (HSCT) in patients with idiopathic severe aplastic anemia (SAA). We describe the use of fludarabine, Campath, and low-dose cyclophosphamide (FCClow) conditioning in 15 children undergoing related or unrelated donor transplants. Total body irradiation (TBI) of 2 Gy was added for unrelated donor HSCT. At a median follow-up of 2.3 years, the failure-free survival was 100%, with low rates of infection and toxicity. There was no occurrence of grade III to IV acute graft-versus-host disease (GVHD). All patients had full donor myeloid chimerism post-HSCT, even with mixed chimerism in the T cell lineage. The absence of chronic GVHD and long-term stable mixed donor T cell chimerism confirms immune tolerance following FCClow (± TBI) conditioned transplantation in children with SAA.

T cells, natural killer cells, and γδT cells in a large patient cohort with rheumatoid arthritis: influence of age and anti-rheumatic therapy.

Objective: The aim of this cohort study was to evaluate the distribution of natural killer (NK) cells and T-cell subsets, including γδT cells, in the peripheral blood of patients with rheumatoid arthritis (RA) in a large real-life patient cohort, taking into account the patients' demographics, disease characteristics, and anti-rheumatic therapy.Method: The study recruited 508 RA patients between November 2013 and August 2015. Lymphocyte differentiation using eight-colour flow cytometry (fluorescence-activated cell sorting) of the peripheral blood was performed for all patients. Clinical data, including age, gender, disease duration, serostatus, disease activity, antibody status, immunosuppressive therapy including use of different biological disease-modifying anti-rheumatic drugs (bDMARDs) and conventional synthetic DMARDs, were retrospectively assessed using electronic patient files. Multivariate regression analysis was performed to assess the effect of these variables on T-cell, NK-cell, and γδT-cell counts.Results: The median patient age was 61.0 years and 74.1% were female. The median disease duration of RA was 12.0 years. Median Disease Activity Score based on 28-joint count was 2.8 and 56.3% were treated with bDMARDs. There were no differences in immunosuppressive therapy between different age groups. While rituximab, abatacept, and tocilizumab had no influence on lymphocyte subdifferentiation, tumour necrosis factor (TNF) inhibitors and age significantly influenced the numbers of T cells, T-helper cells, T-NK cells, NK cells, and γδT cells.Conclusion: Age and TNF-inhibition therapy influence lymphocyte subdifferentiation in patients with RA. It may be prudent to use age- and therapy-adjusted standard values for lymphocyte subsets during clinical trials and treatment of RA.

Regional differences in access to hematopoietic stem cell transplantation among pediatric patients with acute myeloid leukemia.

INTRODUCTION: Indications for hematopoietic stem cell transplantation (HSCT) in pediatric acute myeloid leukemia (AML) are primarily dependent on risk stratification at diagnosis and relapse status. We sought to determine whether access to HSCT is influenced by regional and socioeconomic factors. METHODS: Children with newly diagnosed AML aged < 15 years between 2001 and 2015 were identified using the Cancer in Young People in Canada national population-based registry. Factors potentially associated with the receipt of HSCT were studied using univariate and multivariable logistic regression models. RESULTS: Overall, 568 children with newly diagnosed AML were included and 262 (46%) received HSCT. A greater proportion of patients, 103/157 (65.6%), underwent HSCT after first or subsequent relapse compared to 159/411 (38.7%) patients who underwent transplant before relapse. Among patients for whom HSCT would be considered before relapse, factors associated with higher odds of HSCT in a multivariable analysis were: poor versus good-risk cytogenetics (Odds ratio [OR]: 30.0, 95% confidence interval [CI]: 7.7-117.0), diagnosis during 2012-2015 versus 2001-2006 (OR: 3.2, 95% CI: 1.6-6.3), diagnosis in eastern Canada versus central Canada (OR: 3.7, 95% CI: 1.9-7.3), and age 10-14 years versus age < 1 year (OR: 5.4, 95% CI: 2.3-12.8). Among patients for whom HSCT would be considered after first relapse, higher odds of HSCT was associated with diagnosis at a HSCT center (OR: 2.1, 95% CI: 1.1-4.1). CONCLUSION: Patients diagnosed at a HSCT performing center and patients from eastern Canada had higher odds of receiving HSCT. This may suggest preferential access to HSCT for certain patients.

Comparative effects of glycinebetaine on the thermotolerance in codA- and BADH-transgenic tomato plants under high temperature stress.

KEY MESSAGE: We propose that codA tomato plants exhibited higher degrees of enhanced thermotolerance than BADH tomato plants, and H2O2 as a signaling molecule also plays an important role in heat resistance. Betaine aldehyde dehydrogenase (BADH) and choline oxidase (COD) are key enzymes in glycinebetaine (GB) synthesis. In this study, two kinds of transgenic tomato plants, which were transformed with BADH gene and codA gene, respectively, were used to explore their thermotolerance. Our results showed that the levels of GB in leaves of the fourteen independent transgenic lines ranged from 1.9 µmol g-1 fresh weight to 3.4 µmol g-1 fresh weight, while GB was almost undetectable in leaves of WT plants. CO2 assimilation and photosystem II (PSII) photochemical activity in transgenic plants were more thermotolerant than WT plants, especially the codA-transgenic plants showed the most. Significant accumulation of hydrogen peroxide (H2O2), superoxide anion radical (O2·-), and malondialdehyde (MDA) were more in WT plants than transgenic plants, while this accumulation in codA-transgenic plant was the least. Furthermore, the expression of the heat response genes and the accumulation of heat shock protein 70 (HSP70) were found to be more in transgenic plants than that in WT plants during heat stress, as well as showing the most expression and accumulation of HSP70 in the codA-transgenic plants. Taken together, our results suggest that the enhanced thermotolerance in transgenic plants is due to the positive role of GB in response to heat stress. And interestingly, in addition to the major role of GB in codA-transgenic plants, H2O2 as a signaling molecule may also play an important role in heat resistance, leading to higher thermotolerance compared to BADH-transgenic plants.

Osteoporosis therapy in patients with inflammatory rheumatic diseases and osteonecrosis of the jaw.

BACKGROUND AND OBJECTIVES: The aim of the present study was to assess the prevalence of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients suffering from inflammatory rheumatic diseases, as well as to assess the prevalence of relevant dental, behavioral, and medical risk factors for MRONJ. MATERIALS AND METHODS: A total of 198 patients with inflammatory rheumatic diseases and osteoporosis therapy were recruited from a tertiary rheumatological/immunological referral center between June 2015 and September 2016. They were assessed using a structured interview. A maxillofacial surgeon later examined patients complaining of possible symptoms of osteonecrosis. In cases of osteonecrosis, dental records were obtained and evaluated. Preventive measures taken and dental as well as other clinical risk factors were evaluated. RESULTS: Of the 198 patients, three suffered from osteonecrosis of the jaw, none of whom had any history of malignant disease or radiation therapy, resulting in a prevalence of 1.5%. Of these three patients, only one was given bisphosphonates intravenously (i.v.), whereas all three had been treated orally. All three diagnoses of MRONJ had been previously known to the patients and their maxillofacial surgeons. Two of the patients had rheumatoid arthritis, and one patient suffered from large vessel vasculitis. Long anti-osteoporotic treatment duration, low functional status, and low bone density of the femur were significantly associated with MRONJ development. CONCLUSION: Inflammatory rheumatic diseases constitute a risk factor for MRONJ in patients treated with bisphosphonates for osteoporosis. Patients should be counseled accordingly and should be offered dental screening and regular dental check-ups.

Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease.

Sickle cell disease is a potentially debilitating hemoglobinopathy associated with early mortality. The only established curative therapy is hematopoietic cell transplantation (HCT) with a matched sibling donor. The National Institutes of Health nonmyeloablative regimen of alemtuzumab/300 cGy total body irradiation and prolonged sirolimus exposure for graft-versus-host disease (GVHD) prophylaxis was administered to 16 children and adolescents. Infused products were unmanipulated granulocyte colony stimulating factor mobilized peripheral blood stem cells. All patients achieved mixed donor-recipient engraftment with no cases of secondary graft failure to date. Two patients have donor myeloid chimerism in the range of 30% to 40%. No sickling crises post-HCT have been observed. Event-free and overall survival rates are 100% with median follow-up of 19.5 months. No cases of GVHD have been observed. Sirolimus weaning was possible in all but one eligible patient to date. Ongoing follow-up and a larger prospective clinical trial are required to determine the long-term safety and efficacy of this regimen in children.

Access to Hematopoietic Stem Cell Transplantation among Pediatric Patients with Acute Lymphoblastic Leukemia: A Population-Based Analysis.

Access to hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) primarily depends on disease-related factors but may be influenced by social and economic determinants. We included all children aged < 15 years with newly diagnosed ALL in Canada between 2001 and 2018 using the Cancer in Young People in Canada national registry. We examined factors potentially associated with the likelihood of receiving HSCT using univariate and multivariable logistic regression models. A total of 3992 patients with newly diagnosed ALL were included. Three hundred twenty-five (8.1%) received an HSCT and formed the transplant cohort. In multivariable analysis factors independently associated with an increased odds of receiving HSCT were male sex (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.05 to 1.93), initial WBC ≥ 50,000 × 109/L (OR, 1.58; 95% CI, 1.09 to 2.28), mixed phenotype acute leukemia relative to B-precursor ALL (OR, 34.32; 95% CI, 16.64 to 70.79), T cell relative to B-precursor ALL (OR, 1.77; 95% CI, 1.07 to 2.91), unfavorable relative to standard cytogenetics (OR, 3.96; 95% CI, 2.56 to 6.12), and relapse before HSCT (OR, 32.77; 95%, 23.89 to 44.96). No association was found between race, neighborhood income quintile or region at diagnosis, and receipt of HSCT. Diagnosis at an HSCT treating center (OR, 1.51; 95% CI, 1.09 to 2.09) and residential distance from the ALL treating center (OR, 1.84 for ≥300 km compared with <100 km; 95% CI, 1.17 to 2.91) were associated with higher odds of receiving HSCT. In a publically funded healthcare system, children with ALL had equitable access to HSCT, which was largely governed by biologic disease-related factors. Patients diagnosed at an HSCT performing center and patients who live farthest away from their treatment center had higher odds of receiving HSCT, although the effect was small, possibly suggesting preferential referral to HSCT for some patients.

Addition or removal of concomitant methotrexate alters adalimumab effectiveness in rheumatoid arthritis but not psoriatic arthritis.

Objective: Randomized trials have shown that concomitant methotrexate (MTX) augments the effectiveness of tumour necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA), but its benefit in psoriatic arthritis (PsA) has not been demonstrated. The goal of this study was to examine whether the impact of concomitant MTX on therapeutic outcomes in patients with PsA was similar to its effects in RA. Methods: We used data from highly comparable and concurrent observational studies of patients with PsA (N = 1424) or RA (N = 3148) who initiated adalimumab therapy during routine clinical care. The 28-joint Disease Activity Score (DAS28) and patient-reported pain scores were evaluated in patients who received 24 months of continuous treatment with adalimumab monotherapy or adalimumab + MTX and in patients who initiated or stopped concomitant MTX during ongoing adalimumab therapy. Results: Twenty-four months of continuous treatment with adalimumab + MTX was superior to adalimumab monotherapy in RA patients, while no significant difference was observed in patients with PsA. RA patients who added MTX during the study showed significant individual improvements in DAS28 and pain scores at 6 months after the change in therapy, while those who removed MTX had slight increases in disease activity. In contrast, in patients with PsA, neither initiation nor removal of MTX during continuous adalimumab therapy had a significant effect on therapeutic outcomes. Conclusion: Addition of MTX to adalimumab confers further therapeutic benefit in patients with RA, but not in those with PsA, suggesting differences in MTX effects in these two patient populations. Clinicaltrials.gov NCT01078090, NCT01077258, NCT01111240.

Targeted Polo-like Kinase Inhibition Combined With Aurora Kinase Inhibition in Pediatric Acute Leukemia Cells.

BACKGROUND: Recent studies have shown that cell cycle events are tightly controlled by complex and shared activities of a select group of kinases. Among these, polo-like kinases (Plks) are regulatory mitotic proteins that are overexpressed in several types of cancer and are associated with poor prognosis. MATERIALS AND METHODS: We have evaluated, in preclinical in vitro studies, the activity of a panel of Plk inhibitors against cell lines derived from refractory pediatric leukemia, as well as primary leukemia cells, in culture. Through in vitro growth inhibition studies, Western blot analysis for the expression and activation of key regulators of cell growth and survival and gene silencing studies, we specifically examined the ability of these agents to induce cytotoxicity through the activation of apoptosis and their capacity to interact and modulate the expression and phosphorylation of Aurora kinases. RESULTS: Our findings show that the various Plk-1 inhibitors in development show potential utility for the treatment of pediatric leukemia and exhibit a wide range of phosphorylation and target modulatory capabilities. Finally, we provide evidence for a complex interregulatory relationship between Plk-1 and Aurora kinases enabling the identification of synergy and biologic correlates of drug combinations targeting the 2 distinct enzyme systems. DISCUSSION: This information provide the rationale for the evaluation of Plk-1 as an effective target for therapeutics in refractory pediatric leukemia and indicate compensatory activities between Plk-1 and Aurora kinases, providing insight into some of the complex mechanisms involved in the process of cell division.

Predictive factors for successful peripheral blood stem cell mobilization and collection in children.

Factors affecting the success of peripheral blood stem cell collection (SCC) in children are not well characterized. We reviewed 218 stem cell collections among 199 pediatric donors, of which 35 were from healthy sibling donors and 164 were for autologous collections. Successful SCC, defined as a CD34+ cell count of ≥2 × 106 /kg of recipient weight per intended transplant, occurred in 188 of 199 donors (94%). Ideal SCC defined ≥5 × 106 CD34+ cells/kg of recipient per intended transplant, occurred in 147 (74%) patients. Failure of collection occurred in 11 (6%) patients and was significantly associated with an autologous collection for a brain tumor diagnosis (P = .003) and a pre-apheresis peripheral blood (PB) CD34+ count <20 × 106 cells/L (P = .002). Ideal SCC was significantly associated with age < 10 years (P = .01) and pre-apheresis PB-CD34+ count ≥20 × 106 cells/L (P < .0001). Factors associated with failure of SCC may be identified in advance of the collection procedure allowing appropriate counselling of patients as well as anticipatory guidance for multiple collections or justify the preemptive use of stem cell mobilizing agents.

Hurricane storm surge in Volusia County, Florida: evidence of a tipping point for infrastructure damage.

Storm surge often is the most destructive consequence of hurricanes and tropical storms, causing significant economic damage and loss of life. Many coastal communities that are located in high-risk areas vis-à-vis hurricanes and tropical storms are prepared for moderate (between six and eight feet) storm surges. Such preparation, though, is not commensurate with more severe, but less frequent, storm surges (greater than eight feet). These gaps in preparedness have serious implications for community resilience. This paper explores elements of the vulnerability and resilience of coastal communities during major storm surge events, drawing on Volusia County, Florida, United States, as a case study. It simulates the impacts of five hurricanes (Categories I-V) and their associated storm surges on local infrastructure systems, populations, and access to resources. The results suggest that Volusia County is subject to a 'tipping point' , where surge damage from Category IV storms is significantly greater than that from Category III and lower hurricanes.