Use of the Obstetric Quality-of-Recovery score (ObsQoR-11) to measure the impact of an enhanced recovery programme for elective caesarean section.

BACKGROUND: Enhanced recovery after caesarean (ERAC) has been shown to postoperatively reduce opioid consumption, reduce pain scores, and shorten hospital stay. Arguably, none of these measures provide for a patient-centred approach. We believe that patient-reported outcome measures (PROMs) represent a more holistic approach to the reporting of outcomes. One such PROM is the Obstetric Quality-of-Recovery Score (ObsQoR-11). This has been shown to be a valid and reliable assessment of recovery after elective caesarean section. METHODS: This before-and-after quality improvement programme studied consecutive patients undergoing elective caesarean section. We implemented an ERAC pathway with the aim of improving quality of recovery and patient satisfaction. Our primary outcome was the change in the ObsQoR-11 score. RESULTS: A total of 318 medical records were reviewed (n = 93 before ERAC, n = 225 after ERAC). There was a significant improvement in ObsQoR-11 score in ERAC patients compared with pre-ERAC patients (85.0 vs 82.3, P < 0.001). Morphine consumption (MMEQ) was reduced by 10% overall in the ERAC group, with no increase in pain scores at day 1 postoperatively and a decrease in pain scores on day 2 in the ERAC group (P = 0.02). The length of hospital stay was significantly shorter in ERAC patients (63.1 h vs 79.9 h, P < 0.001). CONCLUSIONS: Our study demonstrated an improved ObsQoR-11 score after ERAC implementation. This is the first example in the literature of using ObsQoR-11 in ERAC. We believe this is a more comprehensive way to assess patient recovery and the impact of an ERAC programme.

Using taphonomy to infer differences in soft tissues between taxa: an example using basal and derived forms of Solnhofen pterosaurs.

In fossilised vertebrates, the presence of soft tissues is the most obvious way to determine aspects of anatomy and functional morphology; however, occurrences are rare and other lines of evidence must be sought to indicate its extent and strength. For example, pterosaurs possessed a large wing membrane that enabled powered flight but other tissues are not widely preserved. A semi-quantitative analysis comparing skeletal articulation and completeness of the pterodactyloid Pterodactylus and non-pterodactyloid pterosaur Rhamphorhynchus from Solnhofen-type deposits implies there were anatomical differences between soft-tissue structure and attachments articulating skeletal joints of each. Typically, skeletons of Pterodactylus disarticulate to a greater extent than those of Rhamphorhynchus, which in turn suggests decay progressed to more advanced states in the former. However, this generalisation masks a mosaic of differences between different body parts, for example Rhamphorhynchus tends to lose the wings as complete units but retains a complete and still articulated tail in a greater number of specimens than Pterodactylus.

Mental illness self-management: a randomised controlled trial of the Wellness Recovery Action Planning intervention for inpatients and outpatients with psychiatric illness.

OBJECTIVE: Wellness Recovery Action Planning (WRAP) is a cross-diagnostic, patient-centred, self-management intervention for psychiatric illness. WRAP utilises an individualised Wellness Toolbox, a six part structured monitoring and response system, and a crisis and post-crisis plan to promote recovery. The objective of this study was to evaluate the effect of WRAP on personal recovery, quality of life, and self-reported psychiatric symptoms. METHOD: A prospective randomised controlled trial, based on the CONSORT principles was conducted using a sample of 36 inpatients and outpatients with a diagnosis of a mental disorder. Participants were randomly allocated to Experimental Group or Waiting List Control Group conditions in a 1:1 ratio. Measures of personal recovery, personal recovery life areas, quality of life, anxiety, and depression were administered at three time points: (i) pre-intervention, (ii) post-Experimental Group intervention delivery, and (iii) 6-month follow-up. Data was analysed by available case analysis using univariate and bivariate methodologies. RESULTS: WRAP had a significant effect on two personal recovery life areas measured by the Mental Health Recovery Star: (i) addictive behaviour and (ii) identity and self-esteem. WRAP did not have a significant effect on personal recovery (measured by the Mental Health Recovery Measure), quality of life, or psychiatric symptoms. CONCLUSIONS: Findings indicate that WRAP improves personal recovery in the areas of (i) addictive behaviour and (ii) identity and self-esteem. Further research is required to confirm WRAP efficacy in other outcome domains. Efforts to integrate WRAP into recovery-orientated mental health services should be encouraged and evaluated.

Polycomb-dependent repression of the potassium channel-encoding gene KCNA5 promotes cancer cell survival under conditions of stress.

Relapse after clinical remission remains a leading cause of cancer-associated death. Although the mechanisms of tumor relapse are complex, the ability of cancer cells to survive physiological stress is a prerequisite for recurrence. Ewing sarcoma (ES) and neuroblastoma (NB) are aggressive cancers that frequently relapse after initial remission. In addition, both tumors overexpress the polycomb group (PcG) proteins BMI-1 and EZH2, which contribute to tumorigenicity. We have discovered that ES and NB resist hypoxic stress-induced death and that survival depends on PcG function. Epigenetic repression of developmental programs is the most well-established cancer-associated function of PcG proteins. However, we noted that voltage-gated potassium (Kv) channel genes are also targets of PcG regulation in stem cells. Given the role of potassium in regulating apoptosis, we reasoned that repression of Kv channel genes might have a role in cancer cell survival. Here we describe our novel finding that PcG-dependent repression of the Kv1.5 channel gene KCNA5 contributes to cancer cell survival under conditions of stress. We show that survival of cancer cells in stress is dependent upon suppression of Kv1.5 channel function. The KCNA5 promoter is marked in cancer cells with PcG-dependent chromatin repressive modifications that increase in hypoxia. Genetic and pharmacological inhibition of BMI-1 and EZH2, respectively, restore KCNA5 expression, which sensitizes cells to stress-induced death. In addition, ectopic expression of the Kv1.5 channel induces apoptotic cell death under conditions of hypoxia. These findings identify a novel role for PcG proteins in promoting cancer cell survival via repression of KCNA5.

Paediatric umbilical cord blood transplantation.

Umbilical cord blood is being used increasingly as a source of haematopoietic stem cells for transplantation because of rapid availability, and the unavailability of a HLA matched adult donor for some patients. This study reports the characteristics and outcomes of 15 patients who have undergone umbilical cord blood transplantation (UCBT) in Ireland between 1998 and 2009. The median total nucleated cell and CD34+ doses post-processing were 6.5 x 107cells/kg and 1.8 x 105 cells/kg, respectively. Median neutrophil recovery time was 30 days (range, 14-44). Median platelet recovery time was 46.5 days (range, 35-148). 33.3% of patients developed acute cutaneous graft-versus-host disease (GVHD) grade I-II. Three patients died of transplant-related toxicity and two died of leukaemic relapse. We conclude that, with a satisfactory stem cell dose, UCBT offers a high chance of engraftment with acceptable toxicity, and should be regarded as a favourable option in selected patients when satisfactory bone marrow or peripheral blood stem cell donors are not available.

BMI-1 suppresses contact inhibition and stabilizes YAP in Ewing sarcoma.

The polycomb group family protein BMI-1 is overexpressed by and functions as an oncogene in many different human cancers. We have previously shown that BMI-1 promotes the tumorigenicity of Ewing sarcoma family tumors (ESFTs) and that this is mediated independently of CDKN2A repression. In this study, we have discovered that high levels of BMI-1 confer resistance to contact inhibition in ESFT cells. Using stable retroviral transduction, we evaluated the consequences of BMI-1 knockdown on the growth of CDKN2A wild-type and mutant ESFT cells in subconfluent and confluent conditions. Although knockdown of BMI-1 had no effect on proliferation in low-density cultures, at high cell densities it resulted in cell cycle arrest and death. The normal cell contact inhibition response is mediated, in large part, by the recently described Hippo pathway which functions to inhibit cell proliferation and promote cell death by inactivating the Yes-Associated Protein (YAP). Significantly, we found that YAP levels, activity and expression did not diminish in confluent ESFT cells that expressed high levels of BMI-1. In contrast, YAP expression and nuclear localization were reduced in confluent BMI-1 knockdown cells suggesting that silencing of BMI-1 restored contact inhibition by restoring normal activation of the Hippo-YAP growth-suppressor pathway. Importantly, knockdown of YAP in ESFT cells resulted in profound inhibition of cell proliferation and anchorage-independent colony formation suggesting that stabilization and continued expression of YAP is critical for ESFT growth and tumorigenicity. Together, these studies reveal a previously unrecognized link between BMI-1, contact inhibition and the Hippo-YAP pathway and suggest that resistance to contact inhibition in BMI-1 overexpressing cancer cells may be in part a result of Hippo inhibition and aberrant stabilization of YAP.

HLA-A, B, Cw, DRB1, DQB1 and DPB1 alleles and haplotypes in the genetically homogenous Irish population.

The frequencies of human leucocyte antigen (HLA) class I and II alleles and haplotypes of 250 Irish unrelated bone marrow donors were determined by high resolution polymerase chain reaction (PCR), using a combination of reverse line blot hybridization and PCR with sequence-specific primers. Phylogenetic analyses indicate that this Irish population is closely related to British, North-western European, American and Australian Caucasian populations. These observations are consistent with recognized historical, geographical, cultural, ethnic and linguistic relationships between these populations and suggest that Irish haematopoietic stem cell transplant recipients have a greater likelihood of finding a phenotypically matched donor within registries based on these populations. HLA-A, B, Cw, DRB1, DQB1 and DPB1 analysis confirms that this young homogenous population is characterized by features of a North-western European anthropological type with limited influence of additional ethnic haplotypes.

Seven hundred and fifty-nine (759) chances to learn: a 3-year pilot project to analyse transfusion-related near-miss events in the Republic of Ireland.

BACKGROUND: The National Haemovigilance Office has collected and analysed reports on errors associated with transfusion since 2000. A 3-year pilot research project in near-miss event reporting commenced in November 2002. MATERIALS AND METHODS: Near-miss reports from 10 hospital sites were analysed between May 2003 and May 2005. The Medical Event Reporting System for Transfusion Medicine was used to collect and analyse the data. Root cause analysis was used to identify causes of error. RESULTS: A total of 759 near-miss events were reported. Near misses are occurring 18 times more frequently than adverse events causing harm. Sample collection was found to be the highest risk step in the work process and was the first site of error in 468 (62%) events. Of these, 13 (3%) involved samples taken from the wrong patient. Medical staff were frequently involved in error. The general wards and emergency department were identified as high-risk clinical areas, in addition, 78 (10%) events occurred within the transfusion laboratory. Three specific human and two system failures were shown to have been associated with the errors identified in this study. CONCLUSIONS: This study confirms that near-miss events occur far more frequently than adverse events causing harm. Collecting near-miss data is an effective means of highlighting human and system failures associated with transfusion that may otherwise go unnoticed. These data can be used to identify areas where resources need to be targeted in order to prevent future harm to patients, improving the overall safety of transfusion.

Human leucocyte antigen class II polymorphism in Irish patients with multiple sclerosis.

The contribution of human leucocyte antigen (HLA) to the genetic risk for multiple sclerosis (MS) in patients of Northern European Caucasoid ancestry has been known since the 1970s. The northern part of Ireland, including county Donegal, is known to be a high-risk area for the development of MS. Recorded prevalence rates for county Wexford in the south-east Ireland have been markedly lower and suggest the existence of a prevalence gradient within the island. To evaluate the association of HLA-DRB1 and -DQB1 haplotypes with MS in both Wexford and Donegal, we examined a total of 118 patients and 400 regionally matched controls. The aim of this exploratory study was to test the possibility of heterogeneity in HLA class II associations with MS and to identify potential predisposing or protective haplotypes, associated with MS risk in Ireland. We confirmed the association of DRB1*1501-DQB1*0602 haplotype carriage with MS in both Wexford [odds ratio (OR) = 2.95, P= 0.0020, P(cor)= 0.0220] and Donegal (OR = 2.29, P= 0.0030, P(cor)= 0.0420). A higher frequency and a significantly higher homozygosity rate of this haplotype in Donegal are likely contributing factors to the higher prevalence of MS in Donegal compared with Wexford. The distribution of HLA class II alleles among Irish MS patients and controls establishes that there is heterogeneity in HLA class II associations with MS within Ireland.

Oncogene-dependent tumor suppression: using the dark side of the force for cancer therapy.

Cancers arise by an evolutionary process that involves the protracted acquisition by somatic cells of suites of interlocking mutations that uncouple proliferation, survival, migration, and damage responses from the mechanisms (selective pressures) that normally restrain or restrict them in time and space. The relative rareness of cancer cells within the soma, in the face of huge numbers of available cell targets, substantial rates of mutation, and an abundance of proto-oncogenes and tumor suppressor gene targets, indicates that the evolutionary space available to incipient tumor cells is highly restricted. The principal way in which this is achieved is through intrinsic tumor suppression pathways-innate growth arrest and apoptotic programs that fulfill an essentially analogous functional role to checkpoints in the cell cycle machinery by antagonizing the tumorigenic potential of oncogenic mutations. Using switchable transgenic and knockin mouse models, it is possible to identify these various tumor suppressor programs and establish where, when, how, and why they act to forestall neoplasia in each tissue type and, consequently, how and why their failure leads to cancer.

Two sets of HLA Class II DRB and DQB1 alleles co-segregate among family members in a single maternal haplotype.

HLA class II typing by sequence specific oligonucleotide probes (SSOP) on the family of a Burkit's Lymphoma patient produced hybridization patterns indicating the presence of two DRB1, and two linked DQB1 genes on the same maternal chromosome. DRB and DQB1 exon 2 amplification products associated with the novel maternal haplotype were identified by DNA typing techniques: These products corresponded to DRB1*0101, DRB1*1501, DRB5*01, DQB1*0501 and DQB1*0602 alleles. These alleles were seen to co-segregate among siblings sharing the same maternal haplotype. The patient, his mother and two of his siblings each appeared to possess elements of three DRB1, DQA1 and DQB1 genes. HLA DNA typing results indicated that a DNA sequence of approximately 100 Kb, spanning the region between, and including, DRB1 and DQB1 genes was inserted into the maternal haplotype. Serological typing on EBV transformed B lymphocytes obtained from the patient's mother showed three expressed DRB1 antigens. Serology on EBV transformed patient's cells also indicated multiple DRB1 antigen expression. The expression of three DRB1 and DQB1 genes on the cells of this patient would make it virtually impossible to obtain a suitably matched unrelated stem cell donor.

Identification and nucleotide sequence of a new null allele, HLA B*3540N.

We report the definition of an HLA class I null allele that has been identified within the B35 group by a combination of serological and molecular typing. This allele, which has been named B*3540N, was detected in a French, potential unrelated hematopoietic stem cell donor of unknown ethnic origin, selected as a probable match for an Irish patient. The presence of the null allele was initially determined by the absence of B35 reactivity by serological typing, in contrast to positive reactions by PCR-SSP and PCR-SSO typing. Subsequent sequencing of clones containing the full genomic sequence of the B*35 allele identified a single nucleotide deletion within exon 4 which resulted in the introduction of a stop codon downstream within exon 4.

Case report: four donors with granulocyte-specific or HLA class I antibodies implicated in a case of transfusion-related acute lung injury (TRALI).

A 54-year-old female patient with a history of chronic liver disease and portal hypertension was admitted for an elective cholecystectomy. Preoperative evaluation revealed a prolonged prothrombin time of 17.4 seconds (control 12 to 15.5 seconds). Six units of fresh frozen plasma (FFP) were prescribed after failure of correction of the coagulopathy with intravenous vitamin K (10 mgs). During infusion of the fifth unit of FFP, the patient became acutely dyspneic. Arterial blood gas analysis revealed marked hypoxemia (PO(2) 6.58 kPa) and the chest X-ray showed new diffuse bilateral alveolar infiltrates. The patient remained hypoxemic with unstable oxygen saturations over the following 7 days, during which time she required 60 to 100 percent oxygen administered by face mask. Intravenous methylprednisolone (200 mgs) was given for 5 days. Mechanical ventilation was not required. The lung infiltrates gradually cleared over 3 to 4 days and the patient showed clinical improvement after 1 week. Four of the donors of the implicated units of plasma were female and all had a history of pregnancy. Two donors had HLA class I antibodies and two had granulocyte-specific antibodies detectable in their serum. In crossmatch studies, granulocyte-reactive antibodies from two donors bound to granulocytes from the patient, which suggested that these antibodies were clinically relevant. These clinical and serologic findings support a diagnosis of transfusion-related acute lung injury (TRALI).

The MHC is a major determinant of viral status, but not fibrotic stage, in individuals infected with hepatitis C.

BACKGROUND & AIMS: In hepatitis C infection, several studies have examined the role of the major histocompatibility complex (MHC) in determining outcome, with variable results. To clarify the importance of MHC, we examined class II DR and DQ antigens in a homogenous cohort of women exposed to hepatitis C genotype 1b from a single inoculum. METHODS: Of 243 participants, 95 had spontaneous viral clearance and 148 are chronically infected. The frequencies of HLA class II DR and DQ antigens were compared between the 2 groups and between liver biopsy findings of 145 chronically infected subjects. RESULTS: DRB1*0101 and DQB1*0501 alleles were more frequent in subjects who sustained viral clearance than in chronically infected subjects (32.3% and 36.8% vs. 8.8% and 14.2%, respectively; P = 0.002). DRB1*03011 and DQB1*0201 occurred more frequently in chronically infected subjects than in those who cleared the virus (41.5% and 42.6% vs. 16.7% and 15.8%, respectively; P = 0.001). Both DRB1*03011 and DQB1*0201 were significantly less frequent in those with higher inflammatory scores on liver biopsy. CONCLUSIONS: We show that in a homogenous cohort of women infected with the same hepatitis C virus, several HLA antigens are associated with either viral clearance or persistence. This suggests a strong role for host immunogenetic factors in determining outcome in hepatitis C infection.

A likelihood-based method of identifying contaminated lots of blood product.

BACKGROUND: In 1994 a small cluster of hepatitis-C cases in Rhesus-negative women in Ireland prompted a nationwide screening programme for hepatitis-C antibodies in all anti-D recipients. A total of 55 386 women presented for screening and a history of exposure to anti-D was sought from all those testing positive and a sample of those testing negative. The resulting data comprised 620 antibody-positive and 1708 antibody-negative women with known exposure history, and interest was focused on using these data to estimate the infectivity of anti-D in the period 1970-1993. METHODS: Any exposure to anti-D provides an opportunity for infection, but the infection status at each exposure time is not observed. Instead, the available data from antibody testing only indicate whether at least one of the exposures resulted in infection. Using a simple Bernoulli model to describe the risk of infection in each year, the absence of information regarding which exposure(s) led to infection fits neatly into the framework of 'incomplete data'. Hence the expectation-maximization (EM) algorithm provides estimates of the infectiousness of anti-D in each of the 24 years studied. RESULTS: The analysis highlighted the 1977 anti-D as a source of infection, a fact which was confirmed by laboratory investigation. Other suspect batches were also identified, helping to direct the efforts of laboratory investigators. CONCLUSIONS: We have presented a method to estimate the risk of infection at each exposure time from multiple exposure data. The method can also be used to estimate transmission rates and the risk associated with different sources of infection in a range of infectious disease applications.