Estimated glomerular filtration rate and risk of poor outcomes after stroke.

BACKGROUND AND PURPOSE: The relationship of the estimated glomerular filtration rate (eGFR) with complications after stroke has not been fully characterized for the entire clinical spectrum of eGFR and for the fluctuation in eGFR during hospital stay. METHODS: Data from the Norfolk and Norwich Stroke Registry recorded between January 2003 and April 2015 were analysed. eGFR was categorized into six clinically relevant categories as per the Kidney Disease Improving Global Outcomes guidelines. The change in eGFR during acute admission was categorized into the following: within 5% change (reference), 5%-20% decline, >20% decline, 5%-20% increase and >20% increase. All-cause mortality, recurrent stroke, incident myocardial infarction, prolonged hospital stay and stroke disability at discharge were outcomes of interest. RESULTS: In all, 10 329 stroke patients (mean age 77.8 years) were followed for a mean of 2.9 years (30 126 person-years). Multivariable adjusted hazard ratios (95% confidence interval) for all-cause mortality were 0.91 (0.80-1.04), 0.96 (0.83-1.11), 1.23 (1.06-1.43), 1.54 (1.31-1.82) and 2.38 (1.91-2.97) for eGFR levels 60-89, 45-59, 30-44, 15-29 and <15 respectively, compared to eGFR ≥ 90 ml/min/1.73 m2 . The hazard ratios (95% confidence interval) for eGFR change were 1.56 (1.36-1.79), 1.17 (1.05-1.30), 1.47 (1.32-1.62) and 1.71 (1.55-1.88) for >20% decline, 5%-20% decline, 5%-20% increase and >20% increase, respectively, compared to change within 5%. Results were similar for other outcomes except recurrent stroke. CONCLUSIONS: Stroke patients with eGFR < 45 ml/min/1.73 m2 at hospital admission and >5% decline or increase in eGFR during hospital stay were at substantially higher risk of poor outcomes, particularly all-cause mortality, myocardial infarction, prolonged hospital stay and disability at discharge.

Impact of stroke-associated pneumonia on mortality, length of hospitalization, and functional outcome.

OBJECTIVES: Stroke-associated pneumonia (SAP) is common and associated with adverse outcomes. Data on its impact beyond 1 year are scarce. MATERIALS AND METHODS: This observational study was conducted in a cohort of stroke patients admitted consecutively to a tertiary referral center in the east of England, UK (January 2003-April 2015). Logistic regression models examined inpatient mortality and length of stay (LOS). Cox regression models examined longer-term mortality at predefined time periods (0-90 days, 90 days-1 year, 1-3 years, and 3-10 years) for SAP. Effect of SAP on functional outcome at discharge was assessed using logistic regression. RESULTS: A total of 9238 patients (mean age [±SD] 77.61 ± 11.88 years) were included. SAP was diagnosed in 1083 (11.7%) patients. The majority of these cases (n = 658; 60.8%) were aspiration pneumonia. After controlling for age, sex, stroke type, Oxfordshire Community Stroke Project (OCSP) classification, prestroke modified Rankin scale, comorbidities, and acute illness markers, mortality estimates remained significant at 3 time periods: inpatient (OR 5.87, 95%CI [4.97-6.93]), 0-90 days (2.17 [1.97-2.40]), and 91-365 days (HR 1.31 [1.03-1.67]). SAP was also associated with higher odds of long LOS (OR 1.93 [1.67-2.22]) and worse functional outcome (OR 7.17 [5.44-9.45]). In this cohort, SAP did not increase mortality risk beyond 1 year post-stroke, but it was associated with reduced mortality beyond 3 years. CONCLUSIONS: Stroke-associated pneumonia is not associated with increased long-term mortality, but it is linked with increased mortality up to 1 year, prolonged LOS, and poor functional outcome on discharge. Targeted intervention strategies are required to improve outcomes of SAP patients who survive to hospital discharge.

PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment.

Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays. At concentration of the dual PI3Kδ/γ inhibitor duvelisib, which can be achieved in vivo we saw a decrease in AKT phosphorylation at s473 after tumour activation by bone marrow stromal cells (BMSC) and interleukin-6. Moreover, after drug treatment of BMSC/tumour co-culture activation assays only dual PI3kδ/γ inhibition was able to induce MM apoptosis. shRNA lentiviral-mediated targeting of either PI3Kδ or PI3Kγ alone, or both in combination, increased survival of NSG mice xeno-transplanted with MM cells. Moreover, treatment with duvelisib reduced MM tumour burden in vivo. We report that PI3Kδ and PI3Kγ isoforms have distinct functions in MM and that combined PI3kδ/γ isoform inhibition has anti-MM activity. Here we provide a scientific rationale for trials of dual PI3kδ/γ inhibition in patients with MM.

Addition of sodium criterion to SOAR stroke score.

OBJECTIVES: To examine the usefulness of including sodium (Na) levels as a criterion to the SOAR stroke score in predicting inpatient and 7-day mortality in stroke. MATERIALS AND METHODS: Data from the Norfolk and Norwich University Hospital Stroke & TIA register (2003-2015) were analysed. Univariate and then multivariate models controlling for SOAR variables were used to assess the association between admission sodium levels and inpatient and 7-day mortality. The prognostic ability of the SOAR and SOAR Na scores for mortality outcomes at both time points were then compared using the Area Under the Curve (AUC) values from the Receiver Operating Characteristic curves. RESULTS: A total of 8493 cases were included (male=47.4%, mean (SD) 77.7 (11.6) years). Compared with normonatremia (135-145 mmol/L), hypernatraemia (>145 mmol/L) was associated with inpatient mortality and moderate (125-129 mmol/L) and severe hypontraemia (<125 mmol/L) with 7-day mortality after adjustment for stroke type, Oxfordshire Community Stroke Project classification, age, prestroke modified Rankin score and sex. The SOAR and SOAR-Na scores both performed well in predicting inpatient mortality with AUC values of .794 (.78-.81) and .796 (.78-.81), respectively. 7-day mortality showed similar results. Both scores were less predictive in those with chronic kidney disease (CKD) and more so in those with hypoglycaemia. CONCLUSION: The SOAR-Na did not perform considerably better than the SOAR stroke score. However, the performance of SOAR-Na in those with CKD and dysglycaemias requires further investigation.

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival.

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5' untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics.

Bonding in women with postnatal anaemia: a pilot case control study looking at postnatal bonding in women who have been diagnosed with anaemia at a University Hospital in the East of England.

PURPOSE: Anaemia is common postpartum; however, the effect of anaemia on mother-infant bonding is presently unknown. This case controlled study was designed to evaluate the effects of anaemia on mother and baby bonding in the first month following delivery. METHODS: 945 consecutive postpartum women who gave birth at home or in the obstetric unit at a university hospital in the East of England were identified from the hospital computer records. Blood counts had been performed on 279 of these women within 48 h of delivery, entirely at the discretion of the clinical team. The women with available blood count data were sent a self-reporting questionnaire which included a validated postpartum bonding questionnaire (PBQ). Data were collected from the 115 (41%) responses and analysed for the evidence of an effect of anaemia on bonding. RESULTS: 57 (50%) of women responding to the questionnaire were anaemic (haemoglobin < 10 g/dL). There was no evidence of a difference between maternal, age, parity, mode of delivery, gestational age, baby weight or baby age at the time of completing questionnaire between the anaemic and non-anaemic groups. Moreover, there was no evidence of a difference in maternal perception of mother-infant bonding between the anaemic and non-anaemic groups. CONCLUSION: Our study suggested no evidence of an association between postnatal anaemia and the mother's ability to bond with the baby; however a small but significant effect may still exist which we were not able to detect due to a possible lack of power, hence we suggest, further larger studies to be conducted.

How much residual plasma may cause TRALI?

Although passive infusion of plasma-rich components containing white blood cell (WBC) antibodies are responsible for majority of the reported transfusion-related acute lung injury (TRALI) cases, the minimum volume of residual plasma, which might trigger TRALI, is not known. We report three cases of TRALI where the implicated donor component contained between 10 and 20 mL of residual plasma. Two cases were related to transfusion of red blood cells prepared in optimal additive solution, and the other was related to transfusion of pooled buffy coat platelets. In the latter case, WBC antibodies that matched the patient's human leucocyte antigen (HLA) antigens were only found in one buffy coat donor (female) who contributed a buffy coat for pooled platelets preparation. Plasma prepared from pooling platelets was collected from a male donor. Laboratory investigation confirmed that in all three cases, the donors' serum contained three to four different HLA class 1-specific and class 11-specific antibodies that matched with the patient's HLA type. Our cases suggest that the residual plasma volume as small as 10-20 mL containing donor derived WBC antibodies may cause TRALI. The risk of TRALI remains, despite providing pooled platelets suspended in male donor plasma. The significance of multiple HLA antigen/antibody matching between donor and recipient in immune TRALI warrants further study.

Predicting response to recombinant factor VIIa in non-haemophiliac patients with severe haemorrhage.

BACKGROUND: Despite increasing use of recombinant factor VIIa (rFVIIa) in non-haemophiliac patients, it is unclear when rFVIIa might be effective. METHODS: A single centre review of consecutive non-haemophiliac patients receiving rFVIIa for the management of severe haemorrhage. Treatments with rFVIIa were at a dose of 90 mug kg(-1) repeated at three hourly intervals at the clinicians' discretion. RESULTS: Eighteen patients received rFVIIa. Six patients survived to discharge and 12 patients died in hospital. The median (range) Sequential Organ Failure Assessment (SOFA) score at the time of administration of rFVIIa for the group that survived was 8.0 (5-12) compared with the group that died 12.0 (7.0-14.0) (P=0.03). One of the patients who survived (17%) had organ failure at the time of rFVIIa administration compared with 11 of those who died (92%) (P=0.004). Fifteen patients survived long enough to consider a second dose of rFVIIa, one patient who survived to discharge needed more than one dose (1/6, 17%), compared with seven of those who later died in hospital (7/9, 78%) (P=0.04). The survivors had a significant reduction in blood product requirements after rFVIIa, while patients who died did not. Neither the prothrombin time nor the activated partial thromboplastin time before or after rFVIIa predicted survival. CONCLUSIONS: High SOFA score and failure to respond to one adequate dose of rFVIIa appear to identify patients with poor prognosis. These observations may help in determining when rFVIIa treatment is likely to be futile.

Occupational injury in a fishmonger with a macular rash, hepatosplenomegaly and pancytopenia.

A 47-year-old fishmonger presented with a history of weight loss and lethargy. On investigation he was found to have myeloma. He presented again before follow up, with a 3-day history of fever and a maculopapular rash. He was admitted to the haematology ward and treated with broad-spectrum antibiotics. Blood cultures were found to be positive for Erysipelothrix rhusiopathiae. Penicillin treatment was given, and he made a good recovery. The importance of occupational illness in an already immunocompromised patient and of taking a proper social and occupational history from patients on admission is illustrated through this case.

Platelet size has diagnostic predictive value in patients with thrombocytopenia.

We studied 473 unselected patients with thrombocytopenia. The mean platelet volume (MPV) was 8.1 fl in patients with marrow disease and 9.8 fl in patients without marrow disease (P < 0.001). A total of 5% of patients with an MPV >or=10.5 fl have marrow disease (odds ratio 0.05, 95% CI 0.02-0.13). Conversely over three quarters of patients with an MPV of <8.0 fl have marrow disease (odds ratio 8.1, 95% CI 5.0-13.0). Therefore the MPV can strongly guide the clinician as to the likely presence or absence of bone marrow disease in thrombocytopenic patients.

Primary central nervous system lymphoma: a single-centre experience of 55 unselected cases.

AIMS: Current treatment for primary central nervous system lymphoma (PCNSL) involves high-dose methotrexate (HDMTX) with or without radiotherapy. Many published studies describing this approach include a highly selected group of patients. We report a single-centre experience of unselected cases of PCNSL. MATERIALS AND METHODS: We retrospectively reviewed the case notes of 55 consecutive patients diagnosed with biopsy-proven PCNSL between 1995 and 2003 at Addenbrooke's Hospital Cambridge, UK. We describe the treatment and outcome, including survival, treatment-related toxicity and long-term functional disability. RESULTS: At diagnosis, 45% of patients were considered unfit to receive treatment with HDMTX, owing to poor performance status or comorbidity. These patients had a median survival of 46 days and may not have been included in other published studies. The remaining patients were treated with a chemotherapy regimen, which included HDMTX. Patients who received at least one cycle of a chemotherapy containing HDMTX had a median survival of 31 months. Forty per cent did not complete planned chemotherapy owing to toxicity, disease progression or death. The median survival of patients treated with HDMTX aged 60 years compared with patients aged under 60 years was 26 months vs 41 months (P = 0.07), respectively. Younger patients treated with HDMTX, who achieved complete remission with chemotherapy, had a median survival of 56 months. We identified a high incidence of functional disability among survivors, resulting from a combination of the tumour itself, the neurosurgical procedure required for diagnosis and the late neurotoxicity of combined chemoradiotherapy. CONCLUSION: The treatment of PCNSL is associated with significant early and late toxicity. Further attempts to improve treatment should address mechanisms to reduce this toxicity. In particular, the benefit of radiotherapy in patients who achieve complete remission with HDMTX will remain uncertain until it is addressed in a multicentre, randomised trial.

Resolution of chronic severe refractory thrombocytopenia after treatment of hypothyroidism.

The case of a 52 year old woman with chronic severe refractory thrombocytopenia is presented. Over a three year period, her platelet count was persistently less than 20 x 10(9)/litre (normal range, 150-400). She required repeated hospital admission for management of bleeding and received multiple blood transfusions. She was given repeated courses of steroids, immunosuppression, immunoglobulin, and splenectomy, without success, in an attempt to stop the chronic blood loss. Eventually, she was found to be profoundly hypothyroid. On correction of her thyroid deficiency the platelet count returned to the normal range and all bleeding stopped. The platelet count remains in the normal range three years later.

Large-cell lymphoma. An unusual late relapse.

We report a case of a 40-year-old man with a stage 4, anaplastic, large-cell lymphoma. He had been diagnosed 13 years before as having a liposarcoma, at which point he was treated with combination chemotherapy, which included anthracycline. On review of the histopathology from 13 years before, the original diagnosis of liposarcoma was revised to that of an anaplastic large-cell lymphoma. A diagnosis of relapsed anaplastic large-cell lymphoma was made. A MUGA scan showed a reduced ejection fraction of 46%. Our patient responded initially to combination chemotherapy, which included anthracycline, without further reduction in his ejection fraction. This was followed by high-dose chemotherapy and peripheral blood stem-cell transplantation. Twenty months later he is well and remains in complete remission.