Maternal morbidity and mortality: an iceberg phenomenon.

OBJECTIVE: To apply the iceberg model, quantifying absolute and relative incidence, to the four main causes of maternal morbidity and mortality in Ireland: haemorrhage, hypertension, sepsis and thrombosis. DESIGN: Secondary analysis of national data on maternal morbidity and mortality. SETTING: Republic of Ireland. POPULATION OR SAMPLE: Approximately 715 000 maternities, 1 200 000 maternal hospitalisations, 2138 cases of severe maternal morbidity (SMM) and 54 maternal deaths. METHODS: Incidence rates and case-fatality ratios were calculated. MAIN OUTCOME MEASURES: Maternal death, SMM and hospitalisation. RESULTS: At the 'tip of the iceberg', the incidence of maternal death per 10 000 maternities was 0.09 (95% CI 0.03-0.20) due to thrombosis and 0.03 (95% CI 0-0.11) due to haemorrhage, hypertension disorders or sepsis. For one death due to thrombosis there were 35 cases of pulmonary embolism and 257 thrombosis hospitalisations. For one death due to eclampsia, there were 58 eclampsia cases, 13 040 hospitalisations with pre-existing hypertension and 40 781 hospitalisations with gestational hypertension. For one death due to pregnancy-related sepsis, there were 92 cases of septicaemic shock and 9005 hospitalisations with obstetric sepsis. For one maternal death due to haemorrhage, there were 1029 cases of major obstetric haemorrhage and 53 715 maternal hospitalisations with haemorrhage. For every 100 maternities, there were approximately 16 hospitalisations associated with haemorrhage, 12 associated with hypertension disorders, three with sepsis and 0.2 with thrombosis. CONCLUSIONS: Haemorrhage and hypertension disorders are leading causes of maternal morbidity in Ireland but they have very low case fatality. This indicates that these morbidities are managed effectively but their prevention requires more focus. TWEETABLE ABSTRACT: Study shows that haemorrhage and hypertension are main causes of #maternalmorbidity in Ireland. Timely interventions for #maternalhealth and focus on prevention of severe and non-severe morbidities are needed. @NPEC #maternityservices #clinicalaudit #qualityimprovement.

Optimising Multi-stakeholder Practices in Patient Engagement: A Gap Analysis to Enable Focused Evolution of Patient Engagement in the Development and Lifecycle Management of Medicines.

BACKGROUND: The PARADIGM consortium aimed to make patient engagement in the development and lifecycle management of medicines easier and more effective for all, with the development of new tools that fulfil robustly defined gaps where engagement is suboptimal. AIMS: To generate an inventory of gaps in patient engagement practices and process from existing global examples. METHODS: A large set of criteria for effective patient engagement previously defined via a multi-stakeholder Delphi method, were mapped under fourteen overarching themes. A gap analysis was then performed by twenty-seven reviewers against the resulting forty-six mapped criteria, on a sample of seventy initiatives from global databases. RESULTS: An inventory of gaps was identified including contextual information as to why the gaps exist. Our work identified general patterns where patient engagement was suboptimal-defined as; fragmented reporting and dissemination of patient engagement activities, and the fundamental principles defined in frameworks or guidance being poorly adhered to in actual practice. Specific gaps were identified for sixteen criteria. Additionally, it was also common to observe primary aspects of a process were addressed for a given criteria (i.e. training for roles and responsibilities) but a secondary context element was lacking (i.e. making training material accessible/understandable/meaningful to all participants). CONCLUSION: The results show that the evolution towards meaningful and systematic patient engagement is occurring, yet more importantly they provide clear directional insights to help enhance collaborative practices and co-design solutions. This targeted impact to catalyse a needs-oriented health system that integrates patient engagement at its core is essential.

Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women.

BACKGROUND: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilpivirine (RPV), known as RPV LA for safety, pharmacokinetics and acceptability. METHODS: HPTN 076 (NTC 02165202) was a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg RPV LA (LA) to placebo (P). The study included a 28-day oral run-in phase of daily, self- administered oral RPV (25 mg), with directly observed oral dosing about six times. Of 136 enrolled sexually active, HIV-uninfected, low HIV-risk African (100) and US (36) adult women, injectable product was administered in two gluteal, intramuscular (IM) injections once every eight weeks to 122 participants following the oral run-in phase. A maximum of six injection time points occurred over a 48-week period. Acceptability, safety, tolerability and pharmacokinetic (PK) data were collected throughout the study. This paper includes primary endpoint data collected up to the week 52 post enrollment. FINDINGS: The median age of the enrolled population was 31 years (IQR: 25,38), median weight 75 kg (IQR: 64, 89), median body mass index (BMI) 30 (IQR: 27, 35), 46% married, 94% Black and 60% unemployed. A total of 122 (80 LA, 42 P) women received at least one injection and 98 (64 LA, 34 P) received all six injections. During the injection phase, three women withdrew from the study (2 LA, 1 P) and 16 women discontinued study product (10 LA, 6 P). Fourteen women (11 LA and 3 P) discontinued oral study product and did not enter the injection phase. Study product discontinuations were not significantly different between the two arms throughout. Of the product discontinuations in the injection phase, 8% in LA and 5% in P arm were due to adverse events (AEs), including one randomized to the P arm with prolonged QTc interval on EKG. The proportion of women who experienced Grade 2 or higher AEs during the injection phase as the primary outcome was not significantly different between the two arms [73.8%, 95% CI: (63.2%, 82.1%) for LA and 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]. Transient Grade ≥2 liver abnormalities occurred in 14% of women in the LA arm compared with 12% in P arm. Three LA women (4%) developed Grade 3 injection site reactions compared with none in P arm. In participants who received at least 1 injection, the geometric mean of overall RPV trough concentrations (Ctrough) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of CTrough through the injection phase and after the last injection were 72.8 ng/mL and 100.9 ng/mL, respectively. At week 52 (eight weeks after last injection), the geometric mean of RPV Ctrough was 75.0 ng/mL. At the last injection visit (Week 44), 80 % of women who answered acceptability questions strongly agreed that they would think about using- and 68% that they would definitely use a PrEP injectable in the future. INTERPRETATION: RPV LA IM injections every eight weeks in African and US women were safe and acceptable. Overall, despite more injection site reactions and pain in the participants receiving RPV LA the injections were well tolerated. Data from this study support the further development of injectable PrEP agents.

Knowledge gaps that hamper prevention and control of Mycobacterium avium subspecies paratuberculosis infection.

In the last decades, many regional and country-wide control programmes for Johne's disease (JD) were developed due to associated economic losses, or because of a possible association with Crohn's disease. These control programmes were often not successful, partly because management protocols were not followed, including the introduction of infected replacement cattle, because tests to identify infected animals were unreliable, and uptake by farmers was not high enough because of a perceived low return on investment. In the absence of a cure or effective commercial vaccines, control of JD is currently primarily based on herd management strategies to avoid infection of cattle and restrict within-farm and farm-to-farm transmission. Although JD control programmes have been implemented in most developed countries, lessons learned from JD prevention and control programmes are underreported. Also, JD control programmes are typically evaluated in a limited number of herds and the duration of the study is less than 5 year, making it difficult to adequately assess the efficacy of control programmes. In this manuscript, we identify the most important gaps in knowledge hampering JD prevention and control programmes, including vaccination and diagnostics. Secondly, we discuss directions that research should take to address those knowledge gaps.

Malnutrition in Hospitalised Older Adults: A Multicentre Observational Study of Prevalence, Associations and Outcomes.

BACKGROUND: Malnutrition is common in older adults and is associated with high costs and adverse outcomes. The prevalence, predictors and outcomes of malnutrition on admission to hospital are not clear for this population. DESIGN: Prospective Cohort Study. SETTING: Six hospital sites (five public, one private). PARTICIPANTS: In total, 606 older adults aged 70+ were included. All elective and acute admissions to any speciality were eligible. Day-case admissions and those moribund on admission were excluded. MEASUREMENTS: Socio-demographic and clinical data, including nutritional status (Mini-Nutritional Assessment - short form), was collected within 36 hours of admission. Outcome data was collected prospectively on length of stay, in-hospital mortality and new institutionalisation. RESULTS: The mean age was 79.7; 51% were female; 29% were elective admissions; 67% were admitted to a medical specialty. Nutrition scores were available for 602/606; 37% had a 'normal' status, 45% were 'at-risk', and 18% were 'malnourished'. Malnutrition was more common in females, acute admissions, older patients and those who were widowed/ separated. Dementia, functional dependency, comorbidity and frailty independently predicted a) malnutrition and b) being at-risk of malnutrition, compared to normal status (p < .001). Malnutrition was associated with outcomes including an increased length of stay (p < .001), new institutionalisation (p =<0.001) and in-hospital mortality (p < .001). CONCLUSIONS: These findings support the prioritisation of nutritional screening in clinical practice and public health policy, for all patients ≥70 on admission to hospital, and in particular for people with dementia, increased functional dependency and/or multi-morbidity, and those who are frail.

Successful control of Johne's disease in nine dairy herds: results of a six-year field trial.

The objective was to evaluate if a standardized Johne's disease control program significantly reduced the prevalence of cattle infected with Mycobacterium avium ssp. paratuberculosis in dairy herds with a moderate to high initial infection prevalence of >or=10% ELISA-positive adult cattle. Nine Wisconsin dairy herds of diverse sizes and management styles completed the 6-yr study. The control program involved changes to heifer rearing practices in combination with a routine testing program. For heifers, the program specifically required 1) segregated maternity pens for ELISA-positive and ELISA-negative cattle; 2) removal of calves from the maternity pen in <2h; 3) use of colostrum only from individual ELISA-negative cows (no colostrum pooling); 4) hygienic collection of colostrum; 5) feeding of pasteurized milk as milk replacer or on-farm pasteurized milk until weaning; and 6) minimizing contact with manure from the adult cattle until weaning. The testing program was designed to detect the most infectious cattle by using a commercial ELISA once on every adult during each lactation. Producers were required to cull cows with strong-positive ELISA results before the next calving and to label cows with low- to medium-level ELISA results and manage them to limit infection transmission. Outcomes were measured by comparing the apparent prevalence based on ELISA or fecal culture in the whole herd and in first-lactation cohorts at 2 time points: before implementation of the control program and at the end of the trial. The combined results from the 9 herds showed a significant reduction in ELISA-positive cows, from 11.6% at the start of the trial to 5.6% at conclusion of the trial. The apparent prevalence decline among first-lactation cows was greater and was evident by ELISA (10.4 vs. 3.0%) and by fecal culture (17.0 vs. 9.5%). Although variations among farms were observed, the collective results demonstrated that bovine paratuberculosis can be controlled in dairy herds through effective heifer husbandry practices in combination with diagnostic testing to identify, for culling or management, cows most likely infectious.

Ethnic variation in certain hematological and biochemical reference intervals in a south Indian healthy adult population.

BACKGROUND: We established the biochemical and hematological reference intervals among a south Indian healthy adult population attending an HIV referral centre in Chennai, southern India. METHODS: In a cross sectional study, 213 study subjects (129 male and 84 female) were studied between March and August 2005. All of the parameters were analyzed using standard hematological and biochemical techniques. RESULTS: Certain biochemical (viz. total bilirubin, alanine transaminase, albumin, creatinine, total protein, lipid profile, creatine phosphokinase, uric acid and lactate) and hematological (mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and lymphocyte levels) parameters presented higher upper limits. In addition, the upper limits of white blood cell count, platelet count, hematocrit, red blood cell count and hemoglobin level were low in comparison to the currently reported ranges. CONCLUSION: Ethnic variation in reference intervals was observed in certain biochemical and hematological analytes in a south Indian adult population.

Brief assessment of severe language impairments: initial validation of the Mississippi aphasia screening test.

PRIMARY OBJECTIVE: To validate the Mississippi Aphasia Screening Test (MAST) which includes nine sub-scales measuring expressive and receptive language abilities. RESEARCH DESIGN: Evaluation of inpatients admitted to neurology, neurosurgery or rehabilitation units at two local hospitals and who were within 60 days of onset of a unilateral ischemic or haemorrhagic stroke (left hemisphere (LH; n=38); right hemisphere (RH; n=20)). Additional participants were recruited from the community to comprise a non-patient control sample (NP; n=36). METHODS: Data collection included administration of the MAST and chart review. RESULTS: The LH group showed more impairment than the RH and NP groups on summary scores. The LH group performed worse than the NP group on all sub-scales. The object recognition and verbal fluency sub-scales did not discriminate the stroke groups. CONCLUSION: Analyses suggest good criterion validity for the MAST in differentiating communication impairments among clinical and control samples.

Survival among hospital in-patients with troponin T elevation below levels defining myocardial infarction.

BACKGROUND: Cardiac troponin T (cTnT) has an accepted place in the management of patients presenting with suspected acute coronary syndrome (ACS). Uncertainty remains about the significance and interpretation of elevated cTnT below the cut-off levels defining myocardial infarction (0.1 microg/l). AIM: To compare the mortality risks for elevation of cTnT in the ranges 0.01-0.029 microg/l, 0.03-0.099 microg/l and <0.01 microg/l. DESIGN: Retrospective record study in three hospitals. METHODS: All cTnT measurements with values in the range >0.01-0.099 microg/l analysed during January 2002 were extracted from clinical biochemistry laboratory databases. Following agreed exclusion criteria, 179 patients with cTnT in the range 0.01-0.099 microg/l and 60 patients <0.01 microg/l were selected at random from across the three sites. Six-month follow-up was completed by review of case notes and contact with the patients' GP. RESULTS: There was a graded increase in mortality with increasing cTnT, although only achieving statistical significance for patients in the 0.03-0.099 microg/l range. The graded increase in relative risk with cTnT was weaker after adjustment for potential confounding factors DISCUSSION: We found a trend for worse survival with increasing cTnT within the range 0.01-0.099 microg/l in unselected patient populations presenting with possible acute coronary syndrome. This suggests that the combined effects of assay imprecision and co-morbidity should be taken into account when interpreting borderline elevation of cTnT. The use of a cut-off based on current standards of assay precision should be used to define the sensitivity of cTnT as biochemical evidence of ischaemic cardiac damage and as an indicator of mortality risk. This level is likely to be between 0.03 and 0.1 microg/l.

Contribution of functional voltage-gated Na+ channel expression to cell behaviors involved in the metastatic cascade in rat prostate cancer: I. Lateral motility.

Previous work suggested that functional voltage-gated Na(+) channels (VGSCs) are expressed specifically in strongly metastatic cells of rat and human prostate cancer (PCa), thereby raising the possibility that VGSC activity could be involved in cellular behavior(s) related to the metastatic cascade. In the present study, the possible role of VGSCs in the lateral motility of rat PCa cells was investigated in vitro by testing the effect of modulators that either block or enhance VGSC activity. Two rat PCa cell lines of markedly different metastatic ability were used in a comparative approach: the strongly metastatic MAT-LyLu and the weakly metastatic AT-2 cell line, only the former being known to express functional VGSCs. Using both electrophysiological recording and a motility assay, the effects of two VGSC blockers (tetrodotoxin and phenytoin) and four potential openers (veratridine, aconitine, ATX II, and brevetoxin) were monitored on (a) Na(+) channel activity and (b) cell motility over 48 h. Tetrodotoxin (at 1 microM) and phenytoin (at 50 microM) both decreased the motility index of the MAT-LyLu cell line by 47 and 11%, respectively. Veratridine (at 20 microM) and brevetoxin (at 10 nM) had no effect on the motility of either cell line, whilst aconitine (at 100 microM) and ATX II (at 25 pM) significantly increased the motility of the MAT-LyLu cell line by 15 and 9%, respectively. Importantly, at the concentrations used, none of these drugs had effects on the proliferation or viability of either cell line. The results, taken together, would suggest strongly that functional VGSC expression enhances cellular motility of PCa cells. The relevance of these findings to the metastatic process in PCa is discussed.

Sensitivity of the Procleix HIV-1/HCV assay for detection of human immunodeficiency virus type 1 and hepatitis C virus RNA in a high-risk population.

The Procleix HIV-1/HCV Assay is a high-throughput nucleic acid test for the simultaneous detection of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) RNA during blood donor screening. This study evaluated the clinical sensitivity of the Procleix assay and assessed the assay's ability to identify HIV-1- and HCV-infected individuals undetected by standard serologic tests. Plasma samples were obtained prospectively from 539 individuals at high risk for HIV-1 and HCV infection at seven clinics affiliated with Johns Hopkins University. Samples were tested in the Procleix HIV-1/HCV Assay and, if reactive, were then tested in the Procleix HIV-1 and HCV discriminatory assays to differentiate the source of viral RNA positivity. Of these 539 subjects, 287 (53.2%) tested reactive in the Procleix HIV-1/HCV Assay. In discriminatory assay testing, 12 of 287 subjects (4.2%) were reactive for HIV-1 RNA only, 260 (90.6%) were reactive for HCV RNA only, and 11 (3.8%) were coinfected with HIV-1 and HCV. The clinical sensitivity for samples tested neat was 100% for HIV-1 and 99.3% for HCV. Three subjects with Procleix HCV reactive/seronegative results seroconverted upon follow-up and were confirmed as Procleix HCV yield cases. The Procleix HIV-1/HCV Assay is a highly sensitive test that detects ongoing and early HIV-1 and HCV infection in a significant number of subjects at high risk for these diseases. Confirmation of Procleix yield cases upon follow-up demonstrated the ability of the Procleix HIV-1/HCV Assay to detect the presence of HIV-1 and HCV in blood earlier than standard serologic tests.

Troponin T as a first-line test: the Royal Liverpool and Broadgreen University Hospital experience.

Many hospital laboratories are unable to offer a cardiac troponin service because of the cost of providing this assay in addition to existing cardiac enzyme profiles: we circumvented this problem by withdrawing the conventional cardiac enzyme service and substituting cardiac troponin T. By ensuring that only one specimen for cTnT is analysed per episode of chest pain. substantial financial savings have been achieved.

p300 forms a stable, template-committed complex with chromatin: role for the bromodomain.

The nature of the interaction of coactivator proteins with transcriptionally active promoters in chromatin is a fundamental question in transcriptional regulation by RNA polymerase II. In this study, we used a biochemical approach to examine the functional association of the coactivator p300 with chromatin templates. Using in vitro transcription template competition assays, we observed that p300 forms a stable, template-committed complex with chromatin during the transcription process. The template commitment is dependent on the time of incubation of p300 with the chromatin template and occurs independently of the presence of a transcriptional activator protein. In studies examining interactions between p300 and chromatin, we found that p300 binds directly to chromatin and that the binding requires the p300 bromodomain, a conserved 110-amino-acid sequence found in many chromatin-associated proteins. Furthermore, we observed that the isolated p300 bromodomain binds directly to histones, preferentially to histone H3. However, the isolated p300 bromodomain does not bind to nucleosomal histones under the same assay conditions, suggesting that free histones and nucleosomal histones are not equivalent as binding substrates. Collectively, our results suggest that the stable association of p300 with chromatin is mediated, at least in part, by the bromodomain and is critically important for p300 function. Furthermore, our results suggest a model for p300 function that involves distinct activator-dependent targeting and activator-independent chromatin binding activities.

Mycobacterium avium subsp. paratuberculosis: pathogen, pathogenesis and diagnosis.

Johne's disease, or paratuberculosis, is a chronic intestinal infection caused by Mycobacterium avium subsp. paratuberculosis. The usually fatal disease is characterised by cachexia, and in some species diarrhoea, after a long pre-clinical phase. Treatment is ineffective and economically impracticable. The infection primarily affects domestic and free-ranging ruminants, but has also been reported in primates, rabbits, stoats and foxes. Since paratuberculosis is often subclinical, under-reporting is suspected, even though the disease is notifiable in numerous countries. Herd prevalence of bovine paratuberculosis in Europe ranges from 7% to 55%. In the United States of America, herd prevalence is strongly associated with herd size; 40% of herds of more than 300 head were found to be infected. In Australia, reported dairy herd infection rates range between 9% and 22%. Paratuberculosis in domestic livestock entails significant economic losses due to several factors (e.g. reduced production, premature culling and increased veterinary costs). Free-ranging and captive wildlife are also at risk from paratuberculosis.

Mycobacterium avium subspecies paratuberculosis: a review of current knowledge.

Although Mycobacterium avium subsp. paratuberculosis infection has had its greatest effect on domestic agricultural animal species, it can also have a significant impact on wildlife species. More cases of infection are being reported, and because of its ability to elude immunologic control and to persist in the environment, M. paratuberculosis may spread within and among captive and free-ranging wildlife populations in the absence of organized control programs. Studies to improve our ability to detect the organism in biologic samples such as milk, blood, and manure through immunomagnetic separation, automated culture methods, and improved polymerase chain reaction procedures are underway in several countries. Studies of the organism's genetic components, virulence factors, and antigens support the development of new diagnostic tools and vaccines.

'The experience of community mental health case management provided from an acute in-patient psychiatric unit'.

In Australia, case management is the cornerstone of mental health service delivery for seriously ill clients living in the community. In this study, case management was provided from an acute, inpatient psychiatric unit; a model thought to be unique. Findings from this qualitative study explicated the experience of case management from client and case manager (CM) perspectives. They note the nature, purpose, processes and outcomes of case management within that context. Findings were positive, suggesting clients and CM's develop a therapeutic alliance through which interventions are implemented and which result in clients experiencing personal (re) integration and enhanced well-being. These findings are discussed and they suggest an alternative model of service delivery well regarded by both clients and CM's.

HIV-1 ICD p24 antigen detection in ugandan infants: use in early diagnosis of infection and as a marker of disease progression.

The objective of this study was to determine the use of immune-complex dissociated (ICD) p24 antigen detection for the diagnosis and prognosis of HIV-1 infection in Ugandan children. Plasma collected prospectively from children born to HIV-1 infected Ugandan women was stored and later analyzed for the presence of neutralizable HIV-1 p24 antigen using the Coulter ICD p24 antigen and neutralization kits. HIV-1 infection status, disease progression, and survival of the children were determined. Specimens from 311 children born to HIV-1 infected women, including 138 HIV-1 infected children, and 113 children born to negative women were tested. Sixty-nine (50%) infected children were p24 antigen positive at least once. For early HIV-1 diagnosis, the specificity and positive predictive value of the assay were consistently high (>95% and >83% respectively), but the sensitivity was low (6-53%), especially in the first months of life. The presence of p24 antigenemia in the first two years of life was associated with poor survival (20%) by 80 months of age compared with infected children without antigenemia (43%, P < 0.001). Early detection of p24 antigen (6 months, P < 0.001). The data suggest that ICD p24 antigen detection is not a sensitive method for the determination of infant HIV-1 status in our cohort of HIV-1 infected Ugandan children tested in the first two years of life. There was a strong correlation, however, between the presence and time of onset of p24 antigenemia and mortality among HIV-1 infected children.