Search

Purpose Expanded access programs (EAPs) allow patients with cancer who have unmet clinical needs to obtain access to pre-authorisation treatments. There is no standardised process or registry for implementing these programs nationally and real world data on their impact is lacking. We evaluated their prevalence and impact in a cancer centre.Methods Data relating to adult cancer patients treated via EAPs from 2011 to 2021 in three Cork university hospitals was collated. Descriptive statistics were employed to get an overview of the impact these programs currently have on cancer care provision.Results We identified 193 patients who accessed EAPs during the study period, availing of 33 separate drugs for a total of 50 different cancer indications. The prevalence of EAP usage was shown to have been trending upwards in recent years with a total of 189 programs being accessed throughout the period. Drugs provided were from a number of different anti-cancer drug classes, particularly targeted therapies (n = 18) and immune checkpoint inhibitors (n = 17). Cancers from a wide range of both solid and liquid tumour types were identified as having been treated with EAP drugs and patients treated were from across a broad spectrum of ages (26–82, SD:11.99).Conclusion EAPs have an increasing role in access to novel cancer therapies in our community and by extension nationally. Equity of EAP access would be facilitated by a national registry of available agents which we have now established. Assessment of their benefits and toxicities would be enhanced by the requirement for a real world data base as a condition of EAP approval.

This chapter examines how religion and politics play an important role in the increasing recognition of diverse family forms, such as same-sex marriage, and policies that acknowledge the rights of LGBT parents. Sean Cahill reviews the prevalence and current state of affairs regarding same-sex marriage and parenting in the United States, Canada, Western Europe, and East Asia. He notes that while studies have found that children of LGBT parents are not disadvantaged in their development compared to their peers, only 28 countries allow joint adoption by same-sex couples. Cahill reports that family policies that promote marriage equality for LGBT people are associated with better health and well-being for same-sex couples and their children.

Background Safe consumption sites (SCSs) serve diverse populations of people who use drugs (PWUD) and public health objectives. SCS implementation began in the 1980s, and today, there are at least 200 known SCSs operating in over twelve countries. While a growing literature supports their effectiveness as a harm reduction strategy, there is limited information on contextual factors that may support or hinder SCS implementation and sustainability. We aimed to fill this gap in knowledge by reviewing existing qualitative studies on SCSs. Methods We conducted a systematic review and thematic synthesis of qualitative studies. We identified all peer-reviewed, English-language qualitative studies on SCSs containing original data in PubMed, Web of Science, Google Scholar, and Science Direct as of September 23, 2019. Two authors independently screened, abstracted, and coded content relating to SCS implementation and sustainment aligned with the Exploration, Preparation, Implementation, Sustainment (EPIS) implementation science framework. Results After removing duplicates, we identified 765 unique records, of which ten qualitative studies met inclusion criteria for our synthesis. Across these ten studies, 236 total interviews were conducted. Overall, studies described how SCSs can (1) keep drug use out of public view while fostering a sense of inclusion for participants, (2) support sustainment by enhancing external communities’ acceptability of SCSs, and (3) encourage PWUD utilization. Most studies also described how involving PWUD and peer workers (i.e., those with lived experience) in SCS operation supported implementation and sustainability. Discussion Our thematic synthesis of qualitative literature identified engagement of PWUD and additional factors that appear to support SCS planning and operations and are critical to implementation success. However, the existing qualitative literature largely lacked perspectives of SCS staff and other community members who might be able to provide additional insight into factors influencing the implementation and sustainability of this promising public health intervention.

Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Application of differentiation therapy to other AML subtypes would be a major treatment advance. Recent studies have indicated that autophagy plays a key role in the differentiation of ATRA-responsive APL cells. In this study, we have investigated whether differentiation could be enhanced in ATRA resistant cells by promoting autophagy induction with valproic acid (VPA). ATRA sensitive (NB4) and resistant leukemia cells (NB4R and THP-1) were co-treated with ATRA and valproic acid, followed by assessment of autophagy and differentiation. The combination of VPA and ATRA induced autophagic flux and promoted differentiation in ATRA-sensitive and -resistant cell lines. shRNA knockdown of ATG7 and TFEB autophagy regulators impaired both autophagy and differentiation, demonstrating the importance of autophagy in the combination treatment. These data suggest that ATRA combined with valproic acid can promote differentiation in myeloid leukemia cells by mechanism involving autophagy.

There are limited prospective data on lenalidomide, subcutaneous bortezomib, and dexamethasone (RsqVd) in transplant-eligible/transplant-ineligible patients with newly diagnosed multiple myeloma. Reliable biomarkers for efficacy and toxicity are required to better tailor therapy. Two parallel studies were conducted by Cancer Trials Ireland (CTI; NCT02219178) and the Dana-Farber Cancer Institute (DFCI; NCT02441686). Patients received four 21-day cycles of RsqVd and could then receive either another 4 cycles of RsqVd or undergo autologous stem cell transplant. Postinduction/posttransplant, patients received lenalidomide maintenance, with bortezomib included for high-risk patients. The primary endpoint was overall response rate (ORR) after 4 cycles of RsqVd. Eighty-eight patients were enrolled and 84 treated across the two studies; median age was 64.7 (CTI study) and 60.0 years (DFCI study), and 59% and 57% had stage II-III disease. Pooled ORR after 4 cycles in evaluable patients was 93.5%, including 48.1% complete or very good partial responses (CTI study: 91.9%, 59.5%; DFCI study: 95.0%, 37.5%), and in the all-treated population was 85.7% (44.0%). Patients received a median of 4 (CTI study) and 8 (DFCI study) RsqVd cycles; 60% and 31% of patients (CTI study) and 33% and 51% of patients (DFCI study) underwent transplant or received further RsqVd induction, respectively. The most common toxicity was peripheral neuropathy (pooled: 68%, 7% grade 3-4; CTI study: 57%, 7%; DFCI study: 79%, 7%). Proteomics analyses indicated elevated kallikrein-6 in good versus poor responders, decreased midkine in good responders, and elevated macrophage inflammatory protein 1-alpha in patients who stopped treatment from neurotoxicity, suggesting predictive biomarkers warranting further investigation.

Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all

The actin cytoskeleton plays a central role in platelet formation and function. Alpha-actinins (actinins) are actin filament crosslinking proteins that are prominently expressed in platelets and have been studied in relation to their role in platelet activation since the 1970s. However, within the past decade, several groups have described mutations in ACTN1/actinin-1 that cause congenital macrothrombocytopenia (CMTP)—accounting for approximately 5% of all cases of this condition. These findings are suggestive of potentially novel functions for actinins in platelet formation from megakaryocytes in the bone marrow and/or platelet maturation in circulation. Here, we review some recent insights into the well-known functions of actinins in platelet activation before considering possible roles for actinins in platelet formation that could explain their association with CMTP. We describe what is known about the consequences of CMTP-linked mutations on actinin-1 function at a molecular and cellular level and speculate how these changes might lead to the alterations in platelet count and morphology observed in CMTP patients. Finally, we outline some unanswered questions in this area and how they might be addressed in future studies.

Essentials Uncontrolled clot breakdown with active bleeding can be seen in advanced cirrhosis. A literature review found little information on optimal management. We report a case of successful treatment with tranexamic acid for persistent subdural hematoma in this setting. A 50‐year‐old woman with advanced cirrhosis presented with spontaneous subdural hematoma. She had a worsening clinical course following craniotomy despite administration of multiple blood products. With elevation in D‐dimer, persistently low fibrinogen and poor response to factor/fibrinogen replacement therapies, we had a suspicion for uncontrolled fibrinolysis. A literature review was conducted on treatment of hyperfibrinolysis in cirrhosis, finding 4 reports in which antifibrinolytics were used to control bleeding with different outcomes. The dose of tranexamic acid used in our patient was employed from previous experience in trauma patients. We transitioned from intravenous to oral administration based on expected pharmacokinetics. Our patient had a successful outcome with resolution of bleeding.

CyBorD DARA as induction is well tolerated and induces deep responses when used in conjunction with ASCT for MM.Mechanism of action studies indicate that CyBorD DARA enhances macrophage activation, which may play a role in its clinical efficacy. Daratumumab (DARA) has shown impressive activity in combination with other agents for the treatment of multiple myeloma (MM). We conducted a phase 1b study to assess the safety and preliminary efficacy, as well as potential mechanisms of action, of DARA (16 mg/kg) in combination with a weekly schedule of subcutaneous bortezomib (1.3-1.5 mg/m2), cyclophosphamide (150-300 mg/m2), and dexamethasone (40 mg) (CyBorD DARA) as initial induction before autologous stem cell transplantation (ASCT). Eligible patients were ≤70 years of age with untreated MM requiring treatment and who lacked significant comorbidities. A total of 18 patients were enrolled. Their median age was 56 years (range, 32-66 years), and all patients had Eastern Cooperative Oncology Group performance status ≤1. The International Staging System stages were I, II, and III in 78%, 17%, and 6% of patients, respectively; 28% of patients had high-risk genetic features. There was no dose-limiting toxicity, and the incidence of grade 3 or 4 infection or neutropenia was

Background: Sickle cell anemia may be associated with cognitive dysfunction, and some complications of sickle cell anemia might affect those with sickle cell trait (SCT), so we hypothesized that SCT is a risk factor for cognitive impairment. Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled a national cohort of 30,239 white and black Americans from 2003 to 7, who are followed every 6 months. Baseline and annual global cognitive function testing used the Six-Item Screener (SIS), a validated instrument (scores range 0–6; ≤4 indicates cognitive impairment). Participants with baseline cognitive impairment and whites were excluded. Logistic regression was used to calculate the association of SCT with incident cognitive impairment, adjusted for risk factors. Linear mixed models assessed multivariable-adjusted change in test scores on a biennially administered 3-test battery measuring learning, memory, and semantic and phonemic fluency. Findings: Among 7743 participants followed for a median of 7·1 years, 85 of 583 participants with SCT (14·6%) developed incident cognitive impairment compared to 902 of 7160 (12·6%) without SCT. In univariate analysis, the odds ratio (OR) of incident cognitive impairment was 1·18 (95% CI: 0·93, 1·51) for those with SCT vs. those without. Adjustment did not impact the OR. There was no difference in change on 3-test battery scores by SCT status (all p > 0·11). Interpretation: In this prospective cohort study of black Americans, SCT was not associated with incident cognitive impairment or decline in test scores of learning, memory and executive function. Funding: National Institutes of Health, American Society of Hematology. Keywords: Sickle cell trait, Cognitive dysfunction, Cognition, Prospective studies, Risk factors, Epidemiology

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and risk of evolution to acute myeloid leukemia (AML) [1]. Presentation varies from mild cytopenia to profound symptom...

Aims The purpose of this study was to (1) characterise the procedure of phlebotomy, deconstruct it into its constituent parts and develop a performance metric for the purpose of training healthcare professionals in a large teaching hospital and to (2) evaluate the construct validity of the phlebotomy metric and establish a proficiency benchmark. Method By engaging with a multidisciplinary team with a wide range of experience of preanalytical errors in phlebotomy and observing video recordings of the procedure performed in the actual working environment, we defined a performance metric. This was brought to a modified Delphi meeting, where consensus was reached by an expert panel. To demonstrate construct validity, we used the metric to objectively assess the performance of novices and expert practitioners. Results A phlebotomy metric consisting of 11 phases and 77 steps was developed. The mean inter-rater reliability was 0.91 (min 0.83, max 0.95). The expert group completed more steps of the procedure (72 vs 69), made fewer errors (19 vs 13, p=0.014) and fewer critical errors (1 Vs 4, p=0.002) than the novice group. Conclusions The metrics demonstrated construct validity and the proficiency benchmark was established with a minimum observation of 69 steps, with no critical errors and no more than 13 errors in total.

Thrombotic events are common in patients with multiple myeloma (MM), smouldering myeloma (SM) and monoclonal gammopathy of undetermined significance (MGUS). Previous studies have indicated platelet hyperactivation as a feature of thrombotic risk in MM, but there is a dearth of data in MGUS. In the present study, multiparameter analysis of platelet activation and responsiveness was investigated by flow cytometry in patients with MGUS, SM/MM and healthy controls (HCs). The median platelet surface CD63 levels, annexin V and PAC-1 antibody (specific for activated integrin αIIbβ3) binding were significantly elevated in patients with MGUS versus the HCs. These markers were also elevated in SM/MM, but not significantly. In all, 74% of MGUS and 38% of SM/MM patients had one or more elevated marker of platelet activation, compared to 19% of the HCs. Marker-specific hyporesponsiveness of platelets to agonist [adenosine diphosphate (ADP), thrombin receptor-activating peptide 6] stimulation in vitro was observed, with significantly reduced surface levels of P-selectin in response to ADP in patients with MGUS. Platelet-leucocyte aggregates were not altered in patients, while platelet-associated immunoglobulins were elevated in a subset of patients. Overall, we found that platelet hyperactivation is prevalent in both MGUS and SM/MM patients and is potentially related to hyporesponsiveness. These observations suggest that further investigation of the predictive and prognostic value of platelet hyperactivation in such patients is warranted.

Acute myeloid leukaemia (AML) is a heterogeneous haematopoietic malignancy. Currently, treatment options offer a 5 year survival of60%. In elderly patients, where the incidence is highest, the survival is much lower. Current standard treatments have significant toxicity and are least well tolerated in older adults, where the need is greatest. Therefore, alternatives are required. Monoclonal antibodies (mAbs), due to the specific targeting to cell surface proteins (i.e. antigens), represent a promising strategy for drug delivery to malignant cells. This concept favours the therapeutic ratio simultaneously by reducing toxicity and increasing efficacy. Although delivery of chemotherapeutics, genes and imaging agents using multifunctional nanoparticles has been substantially explored in treating solid cancers, less information on this approach is available in the case of AML. This review describes the development of antibody-targeted nanoparticulate drug delivery systems, and discusses the barriers to clinical translation in the treatment of AML.

Background: Blood sampling errors including ‘wrong blood in tube’ (WBIT) may have adverse effects on clinical outcomes. WBIT errors occur when the blood sample in the tube is not that of the patient identified on the label. This study aims to determine the effect of proficiency-based progression (PBP) training in phlebotomy on the rate of blood sampling errors (including WBIT). Methods: A non-randomised controlled trial compared the blood sampling error rate of 43 historical controls who had not undergone PBP training in 2016 to 44 PBP trained interventional groups in 2017. In 2018, the PBP training programme was implemented and the blood sampling error rate of 46 interns was compared to the 43 historical controls in 2016. Data analysis was performed using logistic regression analysis adjusting for sample timing. Results: In 2016, 43 interns had a total blood sample error rate of 2.4%, compared to 44 interns in 2017, who had error rate of 1.2% (adjusted OR=0.50, 95% CI 0.36-0.70; Conclusions: The study demonstrates that PBP training in phlebotomy has the potential to reduce blood sampling errors. Trial registration number: NCT03577561

Background and aims: Acute myeloid leukaemia (AML) is a relatively rare haematological malignancy which is the most common acute leukaemia in adults. Patients with AML often have a substantial comorbidity burden. Consequently, different scores are used in clinical practice to predict outcomes in patients with multiple comorbidities. The Charlson Comorbidity Index (CCI), calculated based on 19 different medical conditions, weighs the comorbidities to measure a patient's burden of disease. Previous publications have suggested that the CCI may be useful in determining survival in AML patients. However, the CCI is not in routine use in Ireland for assessing patients with AML. In this study we examined the usefulness of the CCI to predict early mortality in AML patients, drawing on data from the Extended Blood Cancer Registration (EBCR) in Ireland. Methods: The EBCR was undertaken by National Cancer Registry Ireland registrars trained by consultant haematologists and deployed in national centres. Data collection began in 2017 and continued to 2019; 141 AML patients underwent extended data registration. Comorbidities were identified by ICD-9 codes and chart review. Kaplan Meier curves and Cox regression analyses were used to determine the usefulness of the CCI to predict early mortality in AML patients. Results: Of the 141 AML patients, 82% were between 50 and 70 years of age and 84 had died by 31/12/2019 (median survival time = 289.0 days). The median survival time for patients in the lowest tertile of the CCI was 498.5 days, compared to 246.0 and 116.5 days for subjects in tertiles 2 and 3, respectively (Figure 1. Log rank P-value Conclusions: Although results demonstrate a strong relationship between the CCI and early mortality in AML patients, our findings suggest that the CCI provides little or no additional prognostic information beyond that which is obtained from age at AML diagnosis alone. This study highlights the importance of validating risk assessment tools in order to determine their potential usefulness in a clinical setting and emphasise the importance of weighing in the treatment decision making paradigm. The Blood Cancer Network Ireland (BCNI) thank the Science Foundation of Ireland (SFI) and the Irish Cancer Society (ICS) for funding (2015-2021). We also thank our colleagues in the National Cancer Registry Ireland for assistance, advice and guidance. Figure 1 Figure 1. Disclosures Quinn: Takeda: Honoraria. O'Dwyer: Bristol Myers Squibb: Research Funding; Janssen: Consultancy; ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Szegezdi: ONK Therapeutics: Research Funding.

Background: Blood sampling errors including ‘wrong blood in tube’ (WBIT) may have adverse effects on clinical outcomes. WBIT errors occur when the blood sample in the tube is not that of the patient identified on the label. This study aims to determine the effect of proficiency-based progression (PBP) training in phlebotomy on the rate of blood sampling errors (including WBIT). Methods: A non-randomised controlled trial compared the blood sampling error rate of 43 historical controls who had not undergone PBP training in 2016 to 44 PBP trained interventional groups in 2017. In 2018, the PBP training programme was implemented and the blood sampling error rate of 46 interns was compared to the 43 historical controls in 2016. Data analysis was performed using logistic regression analysis adjusting for sample timing. Results: In 2016, 43 interns had a total blood sample error rate of 2.4%, compared to 44 interns in 2017, who had error rate of 1.2% (adjusted OR=0.50, 95% CI 0.36-0.70; Conclusions: The study demonstrates that PBP training in phlebotomy has the potential to reduce blood sampling errors. Trial registration number: NCT03577561

© 2017 American Chemical Society. Uranium (U) contamination occurs as a result of mining and ore processing; often in alluvial aquifers that contain organic-rich, reduced sediments that accumulate tetravalent U, U(IV). Uranium(IV) is sparingly soluble, but may be mobilized upon exposure to nitrate (NO3-) and oxygen (O2), which become elevated in groundwater due to seasonal fluctuations in the water table. The extent to which oxidative U mobilization can occur depends upon the transport properties of the sediments, the rate of U(IV) oxidation, and the availability of inorganic reductants and organic electron donors that consume oxidants. We investigated the processes governing U release upon exposure of reduced sediments to artificial groundwater containing O2or NO3-under diffusion-limited conditions. Little U was mobilized during the 85-day reaction, despite rapid diffusion of groundwater within the sediments and the presence of nonuraninite U(IV) species. The production of ferrous iron and sulfide in conjunction with rapid oxidant consumption suggested that the sediments harbored large concentrations of bioavailable organic carbon that fueled anaerobic microbial respiration and stabilized U(IV). Our results suggest that seasonal influxes of O2and NO3-may cause only localized mobilization of U without leading to export of U from the reducing sediments when ample organic carbon is present.

Minimal residual disease negative complete response (MRD-negative CR) provides an early marker for time to treatment failure (TTF) in CLL treated with fludarabine, cyclophosphamide, and rituximab (FCR). MRD was assessed after four FCR cycles (FCR4); MRD-negative CR patients discontinued treatment. Fifty-two patients (35M; 17F) were enrolled. Eighteen (18/52; 34.6%) patients reached MRD-negative CR after FCR4 and 29/52 (55.8%) were MRD-negative CR at end of treatment (EOT). Median TTF was 71.1 months (95% CI 61.3-84.1 months), with median overall survival not reached. Mutated immunoglobulin heavy chain gene rearrangements (IGHV) were associated with early MRD-negative remissions, translating into prolonged TTF. Unmutated-IGHV, mutated-SF3B1 and mutated-NOTCH1 were associated with shortened TTF. No TTF difference was observed between patients in MRD-negative CR after four versus six cycles (82.2 versus 85.3 months, p = .6306). Abbreviated FCR therapy is effective for patients achieving early MRD-negative remissions. Interim MRD assessment assists in personalizing therapy and reducing chemotherapy-associated toxicity.

Background Primary care test requests for serum immunoglobulins are rising rapidly, with concerns that many requests may be unnecessary. Evidence suggests some characteristics of general practitioners (GPs) and practices are associated with higher test ordering. Objective To identify the physician and practice characteristics associated with immunoglobulin test ordering. Methods Retrospective, cross-sectional study using routine laboratory data on primary care serum immunoglobulin requests. Data were linked with GP patient list size data. The primary outcome measure was the count of test requests per GP. Predictor variables were physician gender, years experience, practice region and type (number of GPs), GP patient list size and composition. Mixed-effects multilevel regression models were used to calculate incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for the associations between physician and practice characteristics and GP requesting. Sensitivity analysis was performed by limiting the model to the more than 70 years age category. Results In total, 5990 immunoglobulin tests were ordered by 481 GPs in the South of Ireland during 2013. The number of tests ordered by individual GPs varied from one to 377. In the final fully adjusted Poisson regression analysis, female gender (IRR: 1.81; 95% CI: 1.45-2.26) and less experience (IRR: 2.27; 95% CI: 1.47-3.51) were associated with higher requesting (P < 0.001). None of the practice factors were associated with test ordering. Sensitivity analysis on the 70 years or more age category found similar results. Conclusion Further research is required to explore the potential reasons for higher requesting among GPs with fewer years of experience and also among female GPs.

Atlanta Community Food Bank (ACFB) recently adopted the Choose Healthy Options Program (CHOP). CHOP uses a simple algorithm that designates a 1 (choose frequently), 2 (moderately), or 3 (infrequently) to foods based on nutrient profiles. Food orders of 402 partner agencies (PAs) in Atlanta and northwest Georgia were analyzed for the 6 weeks prior to and following CHOP implementation. Additionally, 9 PAs participated in in-depth interviews to explain purchasing motivations, impact of CHOP, client feedback mechanisms, and perceptions of clients’ needs. Agencies increased their pounds of CHOP 1 foods by nearly 43% during the study period. PAs indicated that CHOP was useful for deciding between food items of the same food category that had differing CHOP rankings.

Background Acute myeloid leukaemia (AML) is an aggressive blood cancer that, left untreated, proves fatal within a short period. Though numbers diagnosed annually are relatively small, treatment costs from induction therapy through to clinical remission potentially are in excess of €200,000. We present, for the first time, using cancer registration data, evidence on trends in the incidence of AML for Ireland, together with an assessment of the costs of manging the disease. Methods Cancer registration data on individuals aged 20 years and older diagnosed with AML (ICD-10 C92.0) 1994–2013 were extracted from a population register. EASR and crude incidence rates were calculated with 95% confidence intervals by five-year age bands. Cases were assigned to one of four treatment pathways on the basis of patient characteristics. These were an intensive chemotherapy pathway, a pathway with bone marrow transplantation, a low intensity chemotherapy pathway and a best supportive care pathway. Resource use for each pathway was determined using clinical guidelines, the published literature and expert opinion. Costs were adjusted to 2016 prices. Results There were 1,675 cases of adult AML between 1993 and 2013 with 733 (44%) in women and 942 in men (56%). There was a statistically significant annual percentage change of 2.45% in the incidence of AML in men while incidence in women also increased significantly by 1.21% per year…The costs associated with intensive chemotherapy management were €89,750 per case while the costs for transplantation, low-intensity chemotherapy and best supportive care were €145,220, €11,790 and €12,745 respectively. The annual cost of managing AML in Ireland between 2010 and 2015 was on average €12.8 million. Conclusion The rising incidence of AML, together with improving survival means that more patients will be treated, achieve clinical remission and also require management for relapse. As novel treatments for this complex condition transition into practice, the costs of managing the disease will also rise. While routinely-collected cancer registration data can help to quantify this cost, better information on treatment patterns and recurrence will be necessary to accurately project and model the burden of this disease into the future.

BackgroundImplementation science experts recommend that theory-based strategies, developed in collaboration with healthcare professionals, have greater chance of success.AimThis study evaluated the impact of a theory-based strategy for optimising the use of serum immunoglobulin testing in primary care.Design and settingAn interrupted time series with segmented regression analysis in the Cork–Kerry region, Ireland. An intervention was devised comprising a guideline and educational messages-based strategy targeting previously identified GP concerns relevant to testing for serum immunoglobulins.MethodInterrupted time series with segmented regression analysis was conducted to evaluate the intervention, using routine laboratory data from January 2012 to October 2016. Data were organised into fortnightly segments (96 time points pre-intervention and 26 post-intervention) and analysed using incidence rate ratios with their corresponding 95% confidence intervals.ResultsIn the most parsimonious model, the change in trend before and after the introduction of the intervention was statistically significant. In the 1-year period following the implementation of the strategy, test orders were falling at a rate of 0.42% per fortnight (PConclusionThe authors’ tailored guideline combined with educational messages reduced serum immunoglobulin test ordering in primary care over a 1-year period. Given the rarity of the conditions for which the test is utilised and the fact that the researchers had only population-level data, further investigation is required to examine the clinical implications of this change in test-ordering patterns.

Acute myeloid leukemia (AML) is characterized by the accumulation of immature white blood cell precursors in the bone marrow and peripheral circulation. In essence, leukemic cells fail to differentiate and are stalled at a particular step of hematopoietic maturation and are unable to complete their development into functional blood cells with a finite life cycle. They are thus said to possess a "differentiation block." Pharmacological override of this block is one attractive avenue of therapy, termed "differentiation therapy." The most successful example of this therapeutic strategy is the use of the physiologic retinoid all-trans-retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL). In this chapter, we will outline the methods used to characterize the mechanisms mobilized by retinoid signaling and will use the activation of a key regulator of autophagy, ATG7, as an example of the functional characterization of a retinoid regulated gene during differentiation. We will discuss how lentiviral delivery of shRNA constructs into cultured APL cells, such as NB4, can be used to functionally deplete key proteins. We will also describe how the effect of protein knockdown on ATRA-induced differentiation and autophagy can be assessed using quantitative PCR, Western blotting, and flow cytometry.

Multiple myeloma (MM) is a hematological malignancy characterized by infiltration of malignant plasma cells in the bone marrow (BM) and end-organ damage to the bone, BM, kidney and immune system. Although current treatments have improved the treatment of MM, it still remains an incurable disease. RNA interference (RNAi) effectors such as microRNAs and small interference RNAs have shown potential to selectively downregulate genes implicated in the pathology of a range of diseases. Signaling pathways that facilitate growth, survival and migration of MM cells, provide resistance to conventional therapies, and therefore, target these signaling pathways will prove promising for MM treatment.This review focuses on signaling pathways associated with the development of myeloma cells and how interaction of these cells with the tumor microenvironment impacts disease progression. Together these elements provide potential therapeutic targets for RNAi in the future.Recent advances in oncogenomic studies have revealed the molecular pathogenesis of MM, thus providing new therapeutic targets for RNAi therapy. Pre-clinical evidence suggests that non-viral delivery technology offers the potential to translate this concept into the next generation of RNAi-based therapeutics for MM.

Thanks to the Affordable Care Act, thousands of people living with HIV who have received Ryan White HIV/AIDS Program–funded care are now eligible for Medicaid or subsidized insurance. The protection against insurance discrimination on the basis of preexisting conditions is increasing health care access for many, but this does not mean that the Ryan White Program is no longer needed. Services essential to improving outcomes on the continuum of HIV care are not supported by any other source. Because of the growing number of people living with HIV, we must increase funding for the Ryan White Program and increase the number of HIV care providers.

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and is associated with high relapse rates. It is known that leukemia stem cells (LSCs), a very small subpopulation of the total number of leukemic cells, maintain the leukemia phenotype (∼80-90% of AML remain the same as at first diagnosis), display chemotherapy resistance, and contribute to disease regeneration. Therefore, targeting LSCs could control the relapse of AML. Small interfering RNA (siRNA), an effector of the RNA interference (RNAi) pathway, can selectively downregulate any gene implicated in the pathology of disease, presenting great potential for treatment of AML. In this study an antibody targeted cyclodextrin-based nanoparticle (NP) (CD.DSPE-PEG-Fab) was developed for siRNA delivery specifically to AML LSCs. The targeted CD.siRNA.DSPE-PEG-Fab formulation, where Fab specifically targets the IL-3 receptor α-chain (IL-3Rα, also known as CD123, a cell surface antigen for human AML LSCs), achieved antigen-mediated cellular uptake in KG1 cells (an AML leukemia stem and progenitor cell line). Efficient delivery of bromodomain-containing protein 4 (BRD4) siRNA using the targeted formulation resulted in downregulation of the corresponding mRNA and protein in KG1 cells and in ex vivo primary AML patient derived samples. The resulting silencing of BRD4 induced myeloid differentiation and triggered leukemia apoptosis. In addition, a synergistic therapeutic effect was detected when administered in combination with the chemotherapeutic, cytarabine (Ara-C). These results indicate the clinical potential of the antibody-tagged cyclodextrin NP for targeted delivery of therapeutic siRNA in the treatment of AML.

Retinoids are a family of signaling molecules derived from Vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies.

The loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein α (C/EBPα)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop for E2F1, C/EBPα, and Trib2 in AML cell proliferation and survival. Further analyses revealed that E2F1-mediated Trib2 expression was repressed by C/EBPα-p42, and in normal granulocyte/macrophage progenitor cells, we detect C/EBPα bound to the Trib2 promoter. Pharmacological inhibition of the cell cycle or Trib2 knockdown resulted in a block in AML cell proliferation. Our work proposes a novel paradigm whereby E2F1 plays a key role in the regulation of Trib2 expression important for AML cell proliferation control. Importantly, we identify the contribution of dysregulated C/EBPα and E2F1 to elevated Trib2 expression and leukemic cell survival, which likely contributes to the initiation and maintenance of AML and may have significant implications for normal and malignant hematopoiesis.

This retrospective analysis assessed the response, safety and duration of response to standard dose rituximab 375 mg/m(2) weekly for four weeks as therapy for patients with primary or secondary warm autoimmune haemolytic anaemia (WAIHA), who had failed initial treatment. Thirty-four patients received rituximab for WAIHA in seven centres in the Republic of Ireland. The overall response rate was 70 center dot 6% (24/34) with 26 center dot 5% (9/34) achieving a complete response (CR). The time to response was 1 month post-initiation of rituximab in 87 center dot 5% (21/24) and 3 months in 12 center dot 5% (3/24) of patients. The median duration of follow-up was 36 months (range 6-90 months). Of the patients who responded, 50% (12/24) relapsed during follow up with a median time to next treatment of 16 center dot 5 months (range 6-60 months). Three patients were re-treated with rituximab 375 mg/m2 weekly for four weeks at relapse and responded. There was a single episode of neutropenic sepsis. Rituximab is an effective and safe treatment for WAIHA but a significant number of patients will relapse in the first two years post treatment. Re-treatment was effective in a small number of patients, suggesting that intermittent pulse treatment or maintenance treatment may improve long-term response.

Lower back pain (LBP) is a widespread, expensive, and debilitating problem in Western industrialized countries. Though LBP can be caused by acute injuries, biomechanical discrepancies have also been indicated to cause chronic LBP. A possible link between podiatrical deviations and LBP has been established in the literature; yet, no comprehensive review investigating the effects of foot and ankle deviations on low back pain has been published. The aim of this study was to assess the relevant literature concerning the effects of foot and ankle deviations on LBP. After review, it was determined that there is limited research regarding ankle and foot deviations and their connection to LBP. Reviewed studies have linked flat feet, ankle instability, sagittal plane blockage and excessive pronation to LBP. Specifically, excessive pronation has been shown to cause leg length discrepancies leading to pelvic tilts and LBP. Based on these results, ankle and foot deviations can be considered a potential cause for LBP due to the disruption of the kinetic chain from the foot to the back. Clinicians should consider the foot and ankle when addressing LBP, especially if more conventional etiologies fail to describe the condition.

Chronic Myeloid Leukemia (CML) is a disease of hematopoietic stem cells which harbor the chimeric gene Bcr-Abl. Expression levels of this constitutively active tyrosine kinase are critical for response to tyrosine kinase inhibitor treatment and also disease progression, yet the regulation of protein stability is poorly understood. We have previously demonstrated that imatinib can induce autophagy in Bcr-Abl expressing cells. Autophagy has been associated with the clearance of large macromolecular signaling complexes and abnormal proteins, however, the contribution of autophagy to the turnover of Bcr-Abl protein in imatinib treated cells is unknown. In this study, we show that following imatinib treatment, Bcr-Abl is sequestered into vesicular structures that co-localize with the autophagy marker LC3 or GABARAP. This association is inhibited by siRNA mediated knockdown of autophagy regulators (Beclin 1/ATG7). Pharmacological inhibition of autophagy also reduced Bcr-Abl/LC3 co-localization in both K562 and CML patient cells. Bcr-Abl protein expression was reduced with imatinib treatment. Inhibition of both autophagy and proteasome activity in imatinib treated cells was required to restore Bcr-Abl protein levels to those of untreated cells. This ability to down-regulate Bcr-Abl protein levels through the induction of autophagy may be an additional and important feature of the activity of imatinib.

Haematologists are long standing proponents of evidence based practice-well exemplified among professionals who care for patients with haemophilia. The rapidly expanding range of therapeutic products and the numerous accompanying clinical trials are swiftly interpreted and translated into clinical practice. This translation is formalised by frequently updated quidelines issued by the United Kingdom Haemophilia Centre Directors' Organisation (UKHCDO) and relevant to all doctors involved in the care of patients with haemophilia. In the last five years eight sets of guidelines have been issued in the UK alone relating to the treatment of haemophilia and its complications [1-8]. Against this background we aim to review current practice in the treatment of haemophilia.

Introduction Myelodysplastic Syndrome (MDS) is classically a disease of older people, with median age at presentation of 70-75 years. The incidence of MDS is estimated at 5-13/100,000/year, but rises to >20/100,000/year in older populations. An increase in diagnosis over the last decades is in part due to improved recognition of MDS, but likely also to an increase in the ageing population. There is very little data on the clinical course, management and outcomes for very old patients (≥85 years of age) with MDS. Patients and Methods: This was a retrospective, multicentre analysis of 84 patients with MDS or Chronic Myelomonocytic Leukemia (CMML) aged ≥85 years at diagnosis from 6 centres in Ireland. Results: We identified 84 patients aged ≥85 years at time of diagnosis of MDS (n= 70) or CMML (n=14), including 47 men (56%) and 37 women (44%). Median age at diagnosis was 87 years (range 85-98). Most patients (93%) were anemic at presentation, including 45/47 men (96%) and 33/37 women (89%). Median hemoglobin (Hb) was 9.5 g/dl (range 5.9 -13.8). Median neutrophil count was 2.4 x109/L (range 0-72). Forty-four patients had thrombocytopenia (median platelet count 144 x 109/L (range 18-624)). Data regarding co-morbidities were available for 75 patients: 69% had hypertension, 36% ischemic heart disease, 39% atrial fibrillation, 31% heart failure, 19% diabetes and 39% renal dysfunction. Ferritin was elevated in 18 (32%) of 57 patients tested. 2006 WHO subgroups were reported for 81 patients: RCMD (32; 40%), CMML (14; 17%), RA (10; 12%), RAEB-1 (10; 12%), RAEB-2 (7; 9%), RARS (2; 3%), t-MDS (2; 3%), Hypoplastic MDS (1; 1%) and 5q- Syndrome (1; 1%). Cytogenetic analysis was performed in 49 patients (58%); results were available for 39 (46%). No patient had molecular studies for MDS-associated mutations or p53 deletions/mutations. Karyotype was normal in 23 patients (59% of those with results available), deletion Y in 5 (13%), Trisomy 8 in 5 (13%), complex in 3 (7.7%), 5q- in 2 (5.2%), and monosomy 7 in 1 (2.5%). Risk stratification by IPSS-R was available for only 37/84 patients, primarily due to lack of cytogenetic testing. Data were available regarding treatment strategies for 81 patients. Thirty-five (43%) received supportive care only. Forty-five patients (57%) were transfused; 29 (34%) became transfusion-dependent during the course of their disease. Of these, only 14 (48%) received erythropoietin (EPO). Of 50 patients with significant anemia likely to cause symptoms (Hb < 10g/dl), only 21 (42%) received EPO. Five patients (6%) received azacitidine (1-18 cycles; median 5), 7 (8%) received G-CSF; none received lenalidomide or iron chelation. Median survival for all patients was 17 months (range 0-147), 16 months for men (range 0-70), and 27 months for women (range 1-147). In 35 patients who had IPSS-R data available, median survival was 49 months for Very Good, 30 months for Good and 13 months for Intermediate category patients. For 4 patients in the Poor and Very Poor categories median survival was 1, 5, 7 and 28 months. Median survival for patients with RA was 28 months (n=10), RCMD 25 months (n=29), CMML 13 months (n= 14), RAEB-1 10 months (n=10) and RAEB-2 19 months (n=7). Six patients (including 3 with RAEB-1, 1 with CMML and 1 with t-MDS) developed Acute Myeloid Leukaemia (7%) at a median of 4.5 months from diagnosis. Median survival for these patients was 9.5 months. Of 84 patients, 60 have died. The main causes of death included marrow failure, sepsis, cardiac events, other malignancies and gastrointestinal bleeding. Conclusions Anemia is the commonest presenting feature of MDS in the very old, and may be the sole cytopenia. Unexplained anemia in the very old should trigger suspicion of underlying MDS, especially if associated with a high MCV. In many patients over 85 years cytogenetic analysis is not performed, precluding accurate prognostic evaluation. MDS in these very old patients is not often actively managed with pharmacological intervention or chemotherapy. Up to 50% of transfusion-dependent patients do not receive erythropoeitin. Azacitidine and lenalidomide are infrequently used. Co-morbidities (especially cardiac and renal disorders) are very common. Survival can be prolonged, especially in patients with low-risk disease. With an ageing population, management of very elderly patients with MDS is becoming more challenging and a more proactive approach should be considered. Figure. Figure. Disclosures Quinn: Janssen: Honoraria.

Acute coronary syndrome is associated with intracoronary thrombosis secondary to platelet activation. Previous groups have investigated platelet activation in both stable and unstable vascular disease. Most measures of platelet activation are not routinely available or easily adaptable to large scale clinical use. Recently, measurement of the mean platelet component (MPC) has become part of the routine data provided by an automated full blood count analyser, the Advia 120. MPC measures platelet density which changes on platelet activation. Our objectives were to determine if platelet activation, as measured by MPC, is increased in patients with stable coronary artery disease (CAD) and to determine if MPC could be useful in differentiating people with stable CAD from controls on an everyday clinical basis. Three hundred and forty-five consecutive patients attending for elective coronary angiography had full blood count analysis and MPC measurement performed using an ADVIA-120 analyser. Three hundred and twenty-four were analysed in our final dataset. Two hundred and fifty-three (78%) had CAD. Patients with CAD were significantly (p

C/EBPα (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBPα p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive. Using mouse genetics, our data reveal that in the complete absence of C/EBPα, TRIB2 was unable to induce AML. Only in the presence of C/EBPα p42 and p30, were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate that the molecular mechanism involved in the degradation of C/EBPα p42 requires site-specific direct interaction between TRIB2 and C/EBPα p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBPα p42. This interaction and ubiquitination is dependent on a critical C terminal lysine residue on C/EBPα. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2-positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML, and the direct interaction and degradation of C/EBPα p42 is required for TRIB2-mediated AML.

Most acute coronary syndromes result from a platelet-rich occlusion of the coronary arteries. Antiplatelet drugs are of proven efficacy in preventing myocardial infarction, unstable angina, and stroke. However, not all patients on aspirin (ASA) benefit. We studied the phenomenon of aspirin resistance with a simple and reliable platelet function analyzer--the PFA-100. Studying 31 patients with unstable angina and 105 controls, we found aspirin resistance in 42% of patients, most of whom were shown to be compliant utilizing concomitant salicylate levels.

Background Aspirin has a significant effect on hemostasis, so it is often recommended that patients taking aspirin discontinue treatment before elective surgery. While off aspirin, these patients may be at risk of thrombosis. The optimum period of time that aspirin should be withheld is controversial. The aim of this study was to establish the duration of the antihemostatic effect of prolonged aspirin therapy. Study design In a prospective study, 51 healthy volunteers were randomly assigned into 3 groups, each receiving an identical tablet for 14 days. One group received a placebo tablet; individuals in the other two groups received either 75 mg or 300 mg of aspirin once a day. Template bleeding times and specific platelet function testing (using the PFA-100; Dade Behring) were carried out on subjects before therapy and again after its completion until they returned to baseline. Results Thirty-eight volunteers complied sufficiently with the protocol to provide useful results. All bleeding times normalized within 96 hours and all platelet function tests within 144 hours after stopping aspirin. There was no demonstrable hemostatic defect in any volunteer persisting by or beyond the sixth day after treatment cessation. There was no apparent difference in duration of effect between those taking either 75 mg or 300 mg of aspirin. Conclusions This study uses sensitive measures of platelet function to demonstrate the duration of increased bleeding tendency after withdrawal of aspirin therapy. It supports discontinuation of aspirin therapy 5 days before elective surgery (with the operation being performed on the sixth day).

In 1998 new regulations [Misuse of Drugs (Supervision of Prescription and Supply of Methadone) Regulation, 1998; Government Publications, Dublin] obligated General Practitioners (GPs) in Ireland to have undergone a period of training before they could prescribe methadone and required collation of information about all patients treated on a Central Register. As a result of this new legislation patients who were previously being treated by private GPs, who were now no longer eligible to prescribe, were absorbed into the Health Authority's Addiction Services during the month of October 1998. Data were collected at entry and at three months follow-up on 464 of these patients. After three months the percentage on higher dose treatment (>90mg daily) dropped from 7% at entry to 2%; those positive for illicit opiates dropped from 64% to 28% (P < 0.001); and those positive for benzodiazepines dropped from 67% to 51% (P < 0.001). The introduction of new legislation regarding methadone treatment has underlined the need for a multi-disciplinary approach when treating opiate misuse. Since these regulations were introduced GPs can have access to training and support services.

Adjuvants that increase the pH of the spray mixture and solubilize nicosulfuron can enhance biological activity under specific conditions. These conditions include high nicosulfuron rates, difficult-to-control weeds, low spray volumes, and initially acidic spray conditions. The most effective pH adjusters are tribasic potassium phosphate, sodium carbonate, and triethanolamine. In low spray volumes, these adjusters make the spray mixture alkaline and often enhance the activity of nicosulfuron on common cocklebur and large crabgrass. Alkaline conditions rapidly dissolve the sulfonylurea particles and enhance activity with crop oil concentrate, modified seed oil, and hydrophilic nonionic surfactants. pH adjusters did not enhance activity with lipophilic surfactants. Ammonium sulfate slightly increases the pH of spray mixtures and increases nicosulfuron activity depending on species, adjuvant type, and pH adjuster. These results generally support the concept that herbicide solubilization is necessary to maxim...

Haemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal, haematological disorder, which can be clinically challenging to diagnose and manage. We report a case of HLH in a previously healthy 33-year-old primigravida. The patient presented at 22 weeks gestation with dyspnoea, abdominal pain, anaemia, thrombocytopenia and elevated liver enzymes suggestive of HELLP syndrome.HELLP, a syndrome characterised by haemolysis, elevated liver enzymes and low platelets is considered a severe form of pre-eclampsia. Despite delivery of the fetus, her condition deteriorated over 3–4 days with high-grade fever, worsening thrombocytopenia and anaemia requiring transfusion support. A bone marrow biopsy showed haemophagocytosis and a diagnosis of HLH was made. Partial remission was achieved with etoposide-based chemotherapy and complete remission following bone marrow transplantation. Eleven months post-transplant, the disease aggressively recurred, and the patient died within 3 weeks of relapse.

The two recognized types of osteochondritis, juvenile osteochondritis dissecans (JOCD), and adult osteochondritis dissecans (OCD), differ in several ways. A painful malady found most frequently in the femoral condyles of children, JOCD occurs before the closure of the distal femoral physis, whereas OCD is seen when the physis is closed. The prognosis for healing is much worse for OCD than for JOCD. The pathologic tissue of JOCD resides in the subchondral bone of the afflicted femoral condyles of children, especially active young athletes. If the condition is allowed to continue, the lesion usually will detach. Surgical attempts to repair these detachments seldom restore the articular surface to opticity. This results in early onset of gonarthrosis. On the other hand, when JOCD is diagnosed early, conservative treatment can often result in healing of the lesions. If healing occurs, the child can expect a normal adult knee. There is also a recognized subtype of JOCD, once called asymptomatic JOCD. After joint scintigraphy of a symptomatic JOCD knee, there is often an abnormal scintigram in the opposite, asymptomatic, knee. This JOCD subtype is discussed further in the section on OCD classification. Possibly the first recorded evidence of JOCD was in 1840, when Ambrose Pare reported his finding of a “stone” in the human knee. 11 The stone also might have been a product of degenerative joint disease, and not JOCD or OCD at all. It was not until 1887, in Konig's paper on OCD, that factual information was published that these were not all joint mice or stones. 8 This speculation forced Konig to give this newly described phenomenon a proper christening, thus, he may not have pondered this task for long. The eponym Konig selected was osteochondritis dissecans , literally “dry inflamed bone.” Konig believed that these lesions were the result of inflammation. Subsequent re-examination of these lesions by other surgeons and Konig himself revealed that, in reality, there was no visible sign of inflammation. Ironically, a definitive cause is still not agreed on. The current literature on JOCD is limited largely to the surgical aspects, especially internal fixation of these pernicious lesions. Although there is literature that discusses conservative treatment, there currently is none available focusing on the important role of compliance in successful outcomes, or the interdependent roles of the parents, patient, and the physician—a group we will refer to as the “compliance triad.” The incidence of JOCD has increased during the past 40 to 50 years. 6 This escalation is thought to be related to the increasing exercise dose to which young athletes are subjected. Given the increased incidence of JOCD-related presentations and the explosive growth of intensive, year-round sports for children of both sexes, we believe that it is critical for any physician working with children to be knowledgeable about this condition. Because of the minimal information available on conservative treatment, and the complete lack of articles on the complex roles of the individuals involved in the compliance triad, we believe a need exists to address these issues. This article describes the essence of conservative JOCD treatment, including how to develop compliance in the triad, the importance of early diagnosis, and the results of conservative treatment. This article refers to the knee as the affected joint, because most JOCD cases occur there, and presents only the authors' experience with JOCD.

Background:Sickle cell anemia (SCA) has been associated with cognitive dysfunction, perhaps in part due to vascular occlusive disease. Increasing evidence suggests that some complications of SCA might also affect those with sickle cell trait (SCT), including chronic and end-stage kidney disease and venous thromboembolism. Thus, SCT may not be a benign condition. Based on data that SCA may influence cognition, we hypothesized that SCT is a risk factor for cognitive impairment in African-Americans. Methods: Participants were African-American adults aged 45 and older from a national prospective cohort study of 30,239 white and black Americans; the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. The study collected extensive baseline risk factor data, and conducted baseline and annual cognitive function testing using the Six-Item Screener (SIS), a validated telephone-administered instrument for global cognitive function that yields a score from 0 to 6. Participants included in this analysis were African-Americans without SCA who had available data on baseline and at least one follow up SIS, SCT genotyping and principal components of ancestry. Participants with baseline SIS ≤4 were excluded as having prevalent impairment. Incident cognitive impairment was defined as having a score at the most recent assessment of ≤4. Logistic regression was used to model associations of SCT with incident cognitive impairment, adjusted for risk factors (listed in table footnote). Results:Among 5,507 participants (mean age 63.5), 731 developed incident cognitive impairment with average follow up of 8.1 years. Those with incident cognitive impairment were more likely to be male with prebaseline history of cardiovascular diseases, diabetes, hypertension and dyslipidemia, and had lower income and education. They were slightly more likely to have SCT (7.9% vs 7.3%). In sequentially adjusted models (table), there was no association of SCT with incident cognitive impairment, with a fully adjusted odds ratio of 1.16 (95% CI 0.79-1.71). There were no significant differences in this odds ratio by age, diabetes, hypertension, dyslipidemia, cardiovascular disease, kidney disease or smoking status (p for interaction with SCT all >0.4). Conclusion:In this prospectively followed general population cohort of middle-aged and older adults with longitudinal cognitive function testing, SCT was not associated with increased risk of incident cognitive impairment overall or in various high-risk subgroups. These findings suggest that unlike in SCA, SCT does not result in chronic cerebrovascular dysfunction. To confirm and extend these findings, further work is needed on associations of SCT with specific domains of cognitive function. Disclosures No relevant conflicts of interest to declare.

Fludarabine, cyclophosphamide and rituximab (FCR) therapy results in a complete remission (CR) rate of 72% and a median progression free survival (PFS) of 80 months in non-del (17P) CLL1. Achieving an MRD negative (MRD-ve) CR after completing therapy is an early surrogate marker for overall survival (OS) and PFS2. Specific genetic CLL subtypes determined by fluorescent in-situ hybridisation (FISH) analysis, immunoglobulin mutation IgVH, NOTCH1 and SF3B1 status determine response to chemotherapy3,4. We completed a multi-centre prospective study between 2008 and 2012, with a median follow up of 62.6 months using MRD status to determine length of therapy. Patients who achieved an MRD-veCR after 4 courses of FCR received no further therapy and the remaining patients completed 6 cycles of FCR. MRD status was tracked 6 monthly in patients who became MRD-veuntil MRD was detected. The genetic subtype was also analysed but did not influence treatment. Fifty-two patients {35M;17F, median age 61years (range 37-73)} were enrolled. Forty-six patients completed the MRD assessment after 4 cycles. Eleven patients discontinued assigned FCR therapy for the following reasons: prolonged cytopenia (4); non-compliance (1); autoimmune haemolytic anaemia (2); renal impairment (1); pleural effusion (1); not recorded (2). Eighteen (34.6%) patients achieved an MRD-veCR after 4 cycles and a further11 after 6cycles resulting in 29/52 (55.8%) MRD-veCRs in total. The median PFS was 72.3 months (95% Confidence Interval 61.3-84.1 months) and the median OS has not been reached. Patients who attained an MRD-veversusMRD+vestatus had a prolonged PFS (81.1 vs 46.2 months, p FISH results were available for 48 patients; del(13q) in 16/48 (33%), del(11q) in 15/48 (31%) no abnormality in 12/48 (25%), trisomy 12 in 4 (8%) and other abnormality in 1 patient. The IgVH status was unfavourable in 34/52 (65%), SF3B1 mutations were detected in 5/51 (9.8%) and NOTCH1 mutations in 10/52(19.2%) patients respectively, comparable to published studies of first-line treatment in CLL3,4. The median PFS for patients with good risk IgVH was not reached. Del(11q) did not impact on PFS (median PFS 66.5 vs 78.9 months, p=0.7301). SF3B1 and NOTCH1 mutated patients had a shortened PFS (median PFS 38.4 vs 71.1 months, p=0.038 and median PFS 62.4 vs 82.2 months p=0.0302, respectively). In conclusion abbreviated FCR therapy is effective for patients achieving MRD-veremission after 4 cycles. SF3B1 and NOTCH1 mutated patients had a short PFS and may benefit from alternative first-line treatment. This finding emphasizes the role mutational profiling will play in optimising and personalising therapy in CLL in the future. Reference: Tam C, O'Brien S, WierdaW, et al. “Long-term results of the fludarabine, cyclophosphamide and rituximab regimen as initial therapy of chronic lymphocytic leukemia” Blood 2008 Aug 15;112(4):975-80 Böttcher S, Ritgen M, Fischer K, et al. "Minimal Residual Disease Quantification is an Independent Predictor of Progression-Free and Overall Survival in Chronic Lymphocytic Leukemia: A Multivariate Analysis From the Randomized GCLLSG CLL8 Trial" J Clin Onc 2012 Mar 20; 30(9):980-8. StilgenbauerS,SchnaiterA,PaschkaP, et al. "Gene mutations and treatment outcome in chronic lymphocyticleukemia: results from the CLL8 trial" Blood 2014 May 22;123(21):3247-54 Chiaretti S, Marinelli M, Del Giudice I, et al."NOTCH1, SF3B1, BIRC3 and TP53 mutations in patients with chronic lymphocytic leukaemia undergoing first-line treatment: correlation with biological parameters and response to treatment"LeukLymphoma 2014 Dec; 55(12):2785-92 Figure 1 Patient outcomes by MRD status in ICORG 07-01 Trial Figure 1. Patient outcomes by MRD status in ICORG 07-01 Trial Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Crotty: BMS, Takeda, Novartis, Janssen, Roche: Honoraria. O'Dwyer:Glycomimetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.