Effects of dexmedetomidine on kidney and brain tissue microcirculation and histology in ovine cardiopulmonary bypass: a randomised controlled trial.

Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra-operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α2 -agonist, dexmedetomidine. We tested the effects of dexmedetomidine on renal and cerebral microcirculatory tissue perfusion, oxygenation and histology in a clinically relevant ovine model. Sixteen sheep were studied while conscious, after induction of anaesthesia and during 2 h of cardiopulmonary bypass. Eight sheep were allocated randomly to receive an intravenous infusion of dexmedetomidine (0.4-0.8 µg.kg-1 .h-1 ) from induction of anaesthesia to the end of cardiopulmonary bypass, and eight to receive an equivalent volume of matched placebo (0.9% sodium chloride). Commencement of cardiopulmonary bypass decreased renal medullary tissue oxygenation in the placebo group (mean (95%CI) 5.96 (4.24-7.23) to 1.56 (0.84-2.09) kPa, p = 0.001), with similar hypoxic levels observed in the dexmedetomidine group (6.33 (5.33-7.07) to 1.51 (0.33-2.39) kPa, p = 0.002). While no differences in kidney function (i.e. reduced creatinine clearance) were evident, a greater incidence of histological renal tubular injury was observed in sheep receiving dexmedetomidine (7/8 sheep) compared with placebo (2/8 sheep), p = 0.041. Graded on a semi-quantitative scale (0-3), median (IQR [range]) severity of histological renal tubular injury was higher in the dexmedetomidine group compared with placebo (1.5 (1-2 [0-3]) vs. 0 (0-0.3 [0-1]) respectively, p = 0.013). There was no difference in cerebral tissue microglial activation (neuroinflammation) between the groups. Dexmedetomidine did not reduce renal medullary hypoxia or cerebral neuroinflammation in sheep undergoing cardiopulmonary bypass.

Impact of the "39-week rule" on adverse pregnancy outcomes: a statewide analysis.

BACKGROUND: The "39-week rule," adopted by the American College of Obstetricians and Gynecologists circa 2009, discouraged routine elective induction of labor in early-term gestations (37 weeks 0 days-38 weeks 6 days) to decrease the risk of adverse neonatal outcomes. However, little research exists regarding any unintended adverse pregnancy outcomes associated with this policy shift. OBJECTIVE: This study aimed to quantify the difference in incidence of adverse pregnancy outcomes before and after the implementation of the 39-week rule. STUDY DESIGN: Deidentified data from all births in the state of South Carolina from 2000 to 2008 (before the 39-week rule) and from 2013 to 2017 (after statewide implementation and enforcement of the rule) were obtained from the South Carolina Revenue and Fiscal Affairs Office. Demographic data and International Classification of Diseases 9/10 codes were obtained for each birth. Our primary outcome was the incidence of any of the following adverse pregnancy outcomes: cesarean delivery, hypertensive disorders, chorioamnionitis, postpartum hemorrhage, high-degree lacerations, placental abruption, and intensive care unit admission. Propensity score analysis was used to control for age, body mass index, and race. After stratification by propensity score, the Cochran-Mantel-Haenszel test was used to compare the prerule and postrule groups. RESULTS: A total of 633,985 births were eligible for inclusion-412,632 from 2000 to 2008, and 221,353 from 2013 to 2017. There was a significant increase in the primary outcome in the postrule period (39.94% pre vs 42.76% post; P<.01). The incidence of all hypertensive disorders was significantly increased in the postrule period compared with the prerule period (7.75% pre vs 10.1% post; P<.01). The incidence of chorioamnionitis and cesarean delivery also increased in the postrule period (1.45% pre vs 1.92% post; P<.01; 29.6% pre vs 31.82% post; P<.01; respectively). CONCLUSION: There was a significant increase in the primary outcome following the implementation of the 39-week rule. Although the policy shift was driven by a desire to decrease adverse neonatal outcomes, aggregate benefit was not observed for pregnancy outcomes.

Impact of restricting early-term deliveries on adverse neonatal outcomes: a statewide analysis.

BACKGROUND: The "39-Week Rule" was adopted by the American College of Obstetricians and Gynecologists in 2009 to eliminate nonmedically indicated (elective) deliveries before 39 weeks in an effort to improve neonatal outcomes. OBJECTIVE: Our primary objective was to quantify the effect of this policy change on adverse neonatal outcomes among a cohort of term births in South Carolina. STUDY DESIGN: Deidentified data from all births in the state of South Carolina from 2000 to 2008 (before the 39-week rule) and from 2013 to 2017 (after statewide implementation and enforcement of the rule) were obtained from the South Carolina Revenue and Fiscal Affairs Office. Demographic data and International Statistical Classification of Diseases and Related Health Problems Ninth/Tenth Revision codes were obtained for each birth. Our primary outcome was admission to a neonatal intensive care unit. Our secondary outcomes were respiratory morbidities (including respiratory distress syndrome and transient tachypnea of the newborn), hypoxic-ischemic encephalopathy, seizure, sepsis, birth injuries, hyperbilirubinemia, hypoglycemia, and feeding difficulties. Propensity score analysis was used to control for maternal age, body mass index, race, gestational hypertension, infection, placental abruption, and gestational and pregestational diabetes mellitus. After stratification by propensity score, the Cochran-Mantel-Haenszel test was used to compare groups. RESULTS: A total of 620,121 infants were liveborn at term during the 2 study periods. After implementation of the 39-week rule, there was a significant reduction in early-term deliveries. In adjusted analyses, neonatal intensive care unit admission was significantly more common in the postimplementation period. Respiratory morbidities were also significantly more common postimplementation. In contrast, there were significant reductions in birth injuries and hyperbilirubinemia in the postimplementation period. CONCLUSION: Implementation of the 39-week rule was associated temporally with an increase in adverse neonatal outcomes. The outcomes intended to be reduced by the 39-week rule, including neonatal intensive care unit admission and respiratory morbidity, seem to have increased in incidence despite adherence to the proposed guidelines.

Examining the effectiveness of Gateway-an out-of-court community-based intervention to reduce recidivism and improve the health and well-being of young adults committing low-level offences: study protocol for a randomised controlled trial.

BACKGROUND: Young adult offenders represent a third of the UK prison population and are at risk of poor health outcomes including drug and alcohol misuse, self-harm and suicide. Court diversion interventions aim to reduce the negative consequences of formal criminal justice sanctions and focus resources on addressing the root causes of offending. Although diversions are widely used, evidence of their effectiveness has not yet been established. Hampshire Constabulary, working together with local charities, have developed the Gateway programme, an out-of-court intervention aimed at improving the life chances of young adults. Issued as a conditional caution, participants undertake a health and social care needs assessment, attend workshops encouraging analysis of own behaviour and its consequences and agree not to re-offend during the 16-week caution. METHODS: This is a pragmatic, multi-site, parallel-group, superiority randomised controlled trial with a target sample size of 334. Participants are aged 18-24, reside in Hampshire and Isle of Wight and are being questioned for an eligible low-level offence. Police investigators offer potential participants a chance to receive the Gateway caution, and those interested are also invited to take part in the study. Police officers obtain Stage 1 consent and carry out an eligibility check, after which participants are randomised on a 1:1 basis either to receive Gateway or follow the usual process, such as court appearance or a different conditional caution. Researchers subsequently obtain Stage 2 consent and collect data at weeks 4 and 16, and 1 year post-randomisation. The primary outcome is the Warwick-Edinburgh Mental Well-being Scale (WEMWBS). Secondary outcomes include health status, alcohol and drug use, recidivism and resource use. The primary analysis will compare the WEMWBS score between the two groups at 12 months. DISCUSSION: This pioneering trial aims to address the evidence gap surrounding diversion in 18-24-year-olds. The findings will inform law enforcement agencies, third sector organisations, policymakers and commissioners, as well as researchers working in related fields and with vulnerable target populations. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Register ( ISRCTN 11888938 ).

Maternal temperature in emergency caesarean section (MATES): an observational multicentre study.

BACKGROUND: Temperature regulation in women undergoing emergency caesarean section is a complex topic about which there is a paucity of evidence-based recommendations. The adverse effects of inadvertent peri-operative hypothermia are well described. Hyperthermia is also associated with adverse neonatal outcomes, an increased risk of obstetric intervention and increased treatment for suspected sepsis. We conducted a multi-centre observational cohort study to identify the prevalence of hypothermia and hyperthermia during emergency caesarean section. S: Participants undergoing emergency caesarean section were recruited across 14 sites in the UK. The primary end point was maternal temperature in the recovery room. Temperature was measured using a zero heat-flux temperature monitoring device. RESULTS: Two hundred and sixty-five participants were recruited over a 12-month period. The prevalence of hypothermia (<36.0°C) was 10.7% and the prevalence of hyperthermia (>37.5°C) was 14.7% on admission to recovery. The prevalence of hypothermia, normothermia, and hyperthermia differed among type of anaesthesia: 71.4% of the hypothermic group had received a spinal anaesthetic whereas 76.9% of the hyperthermic group had received epidural top-up anaesthesia. There was a significant decrease in maternal temperature between the time of delivery and admission to the recovery room of 0.20°C (95% CI 0.15 to 0.25, P<0.001). CONCLUSIONS: Both hypothermia and hyperthermia are prevalent findings in mothers who undergo emergency caesarean section. Therefore, accurate temperature measurement is essential to ensure that an appropriate intra-operative temperature management strategy is employed.

Assessing professional competence in optometry - a review of the development and validity of the written component of the competency in optometry examination (COE).

BACKGROUND: Credentialing assessment for overseas-educated optometrists seeking registration in Australia and New Zealand is administered by the Optometry Council of Australia and New Zealand. The aim was to review the validation and outcomes of the written components of this exam to demonstrate credentialing meets entry-level competency standards. METHODS: The Competency in Optometry Examination consists of two written and two clinical parts. Part 1 of the written exam comprises multiple choice questions (MCQ) covering basic and clinical science, while Part 2 has 18 short answer questions (SAQ) examining diagnosis and management. Candidates must pass both written components to progress to the clinical exam. Validity was evaluated using Kane's framework for scoring (marking criteria, item analysis), generalization (blueprint), extrapolation (standard setting), and implications (outcome, including pass rates). A competency-based blueprint, the Optometry Australia Entry-level Competency Standards for Optometry 2014, guided question selection with the number of items weighted towards key competencies. A standard setting exercise, last conducted in 2017, was used to determine the minimum standard for both written exams. Item response theory (Rasch) was used to analyse exams, produce reliability metrics, apply consistent standards to the results, calibrate difficulty across exams, and score candidates. RESULTS: Data is reported on 12 administrations of the written examination since 2014. Of the 193 candidates who sat the exam over the study period, 133 (68.9%) passed and moved on to the practical component. Ninety-one (47.2%) passed both the MCQ and SAQ exams on their first attempt. The MCQ exam has displayed consistently high reliability (reliability index range 0.71 to 0.93, average 0.88) across all 12 administrations. Prior to September 2017 the SAQ had a set cutscore of 50%, and the difficulty of the exam was variable. Since the introduction of Rasch analysis to calibrate difficulty across exams, the reliability and power of the SAQ exam has been consistently high (separation index range 0.82 to 0.93, average 0.86). CONCLUSIONS: The findings from collective evidence support the validity of the written components (MCQ and SAQ) of the credentialing of the competency of overseas-educated optometrists in Australia and New Zealand.

Temperature thresholds for germination in 20 short-range endemic plant species from a Greenstone Belt in southern Western Australia.

The study of climate-driven effects on seed traits such as germination has gained momentum over the past decade as the impact of global warming becomes more apparent on the health and survival of plant diversity. Seed response to warming was evaluated in a suite of short-range endemic species from the biodiverse Greenstone Belt of southern Western Australia. The temperature dimensions for germination in 20 woody perennials were identified using small unreplicated samples over 6 weeks on a temperature gradient plate (constant and fluctuating temperatures between 5 and 40 °C). These data were subsequently modelled against current and forecast (2070) mean monthly minimum and maximum temperatures to illustrate seasonal changes to germination timing and final percentage germination. All but one species attained full germination in at least one cell on the gradient plate. Modelling of the data suggested only minimal changes to percentage germination despite a forecast rise in diurnal temperatures over the next 50 years. Nine species were predicted to experience declines of between <1% and 7%, whilst 11 species were predicted to increase their germination by <1% to 3%. Overall, the speed of germination is predicted to increase but the timing of germination for most species shifts seasonally (both advances and delays) as a result of changing diurnal temperatures. The capacity of this suite of species to cope with warmer temperatures during a critical early life stage shows a degree of adaptation to heterogeneous environments. Predicting the effects of global change on terrestrial plant communities is crucial to managing and conserving plant diversity.

Renal haemodynamics and oxygenation during and after cardiac surgery and cardiopulmonary bypass.

Acute kidney injury (AKI) is a common complication following cardiac surgery performed on cardiopulmonary bypass (CPB) and has important implications for prognosis. The aetiology of cardiac surgery-associated AKI is complex, but renal hypoxia, particularly in the medulla, is thought to play at least some role. There is strong evidence from studies in experimental animals, clinical observations and computational models that medullary ischaemia and hypoxia occur during CPB. There are no validated methods to monitor or improve renal oxygenation during CPB, and thus possibly decrease the risk of AKI. Attempts to reduce the incidence of AKI by early transfusion to ameliorate intra-operative anaemia, refinement of protocols for cooling and rewarming on bypass, optimization of pump flow and arterial pressure, or the use of pulsatile flow, have not been successful to date. This may in part reflect the complexity of renal oxygenation, which may limit the effectiveness of individual interventions. We propose a multi-disciplinary pathway for translation comprising three components. Firstly, large-animal models of CPB to continuously monitor both whole kidney and regional kidney perfusion and oxygenation. Secondly, computational models to obtain information that can be used to interpret the data and develop rational interventions. Thirdly, clinically feasible non-invasive methods to continuously monitor renal oxygenation in the operating theatre and to identify patients at risk of AKI. In this review, we outline the recent progress on each of these fronts.

Parental experiences of their infant's hospitalization for cardiac surgery.

BACKGROUND: Parents are increasingly recognized as important partners in children's health care. Despite their involvement in care, parental experiences of their child's hospitalization have received little research attention. In this study we explored parents' perceptions of what they found difficult, what they would like to be different and what they found to be helpful during their infant's hospitalization and surgery for the treatment of congenital heart disease. METHODS: Structured interviews were conducted with 154 parents (91 mothers, 63 fathers) whose infant underwent cardiac surgery (at <3 months of age) 1 month post discharge from hospital. Thematic and frequency analyses were performed. RESULTS: Parents reported a range of difficulties from dealing with their baby's unfolding illness, surgery and recovery to the structural and systemic issues associated with the broader context of their experiences. In an effort to be near their baby, parents struggled to obtain the necessities for daily living at the hospital and negotiate transitions between their hospital and home lives throughout the admission. Domains parents identified for change included the availability of facilities and resources and the quantity and quality of information and emotional support. Parents reported relationships with hospital staff as the most common source of support during this challenging time. CONCLUSIONS: Opportunities to improve parents' experiences when their infant is in hospital exist at an organizational level as well as at the clinical level. The significance of parents' relationship with hospital staff indicates the potential for each professional to impact on families' experiences on a daily basis. The range of challenges indicates the scope and need for allied health services.

Components of the Risk Instrument for Screening in the Community (RISC) that Correlate with Public Health Nurses' Perception of Risk.

BACKGROUND: Functional decline and frailty are common in community-dwelling older adults, leading to an increased risk of adverse outcomes. OBJECTIVE: To examine the factors that public health nurses perceive to cause risk of three adverse outcomes: institutionalisation, hospitalisation, and death, in older adults, using the Risk Instrument for Screening in the Community (RISC). DESIGN: A quantitative, correlational, descriptive design was used. SETTING AND PARTICIPANTS: A sample of 803 community-dwellers, aged over 65 years receiving regular follow-up by public health nurses. Procedure and Measurements: Public health nurses (n=15) scored the RISC and the Clinical Frailty Scale (CFS) on patients in their caseload. We examined and compared correlations between the severity of concern and ability of the caregiver network to manage these concerns with public health nurses' perception of risk of the three defined adverse outcomes. RESULTS: In total, 782 RISC scores were available. Concern was higher for the medical state domain (686/782,88%) compared with the mental state (306/782,39%) and activities of daily living (595/782,76%) domains. Concern was rated as severe for only a small percentage of patients. Perceived risk of institutionalisation had the strongest correlation with concern over patients mental state,(r=0.53), while risk of hospitalisation,(r=0.53) and death,(r=0.40) correlated most strongly with concern over the medical state. Weaker correlations were found for the other domains and RISC scores. The CFS most strongly correlated with the ADL domain,(r=0.78). CONCLUSION: Although the prevalence of concern was high, it was mostly rated as mild. Perceived risk of institutionalisation correlated most with concern over the ability of caregiver networks to manage patients' mental state, while risk of hospitalisation and death correlated with patients' medical state. The findings suggest the importance of including an assessment of the caregiver network when examining community-dwelling older adults. Validation of the RISC and public health nurses' ratings are now required.

Practically convenient and industrially-aligned methods for iridium-catalysed hydrogen isotope exchange processes.

The use of alternative solvents in the iridium-catalysed hydrogen isotope exchange reaction with developing phosphine/NHC Ir(I) complexes has identified reaction media which are more widely applicable and industrially acceptable than the commonly employed chlorinated solvent, dichloromethane. Deuterium incorporation into a variety of substrates has proceeded to deliver high levels of labelling (and regioselectivity) in the presence of low catalyst loadings and over short reaction times. The preparative outputs have been complemented by DFT studies to explore ligand orientation, as well as solvent and substrate binding energies within the catalyst system.

Ex-vivo analysis of human natural killer T cells demonstrates heterogeneity between tissues and within established CD4(+) and CD4(-) subsets.

Our understanding of human type 1 natural killer T (NKT) cells has been heavily dependent on studies of cells from peripheral blood. These have identified two functionally distinct subsets defined by expression of CD4, although it is widely believed that this underestimates the true number of subsets. Two recent studies supporting this view have provided more detail about diversity of the human NKT cells, but relied on analysis of NKT cells from human blood that had been expanded in vitro prior to analysis. In this study we extend those findings by assessing the heterogeneity of CD4(+) and CD4(-) human NKT cell subsets from peripheral blood, cord blood, thymus and spleen without prior expansion ex vivo, and identifying for the first time cytokines expressed by human NKT cells from spleen and thymus. Our comparative analysis reveals highly heterogeneous expression of surface antigens by CD4(+) and CD4(-) NKT cell subsets and identifies several antigens whose differential expression correlates with the cytokine response. Collectively, our findings reveal that the common classification of NKT cells into CD4(+) and CD4(-) subsets fails to reflect the diversity of this lineage, and that more studies are needed to establish the functional significance of the antigen expression patterns and tissue residency of human NKT cells.

The changing face of hepatitis in boys with haemophilia associated with increased prevalence of obesity.

Hepatitis in children with haemophilia was historically most often associated with transfusion-transmitted infections. However, with the use of recombinant clotting factor concentrates, acquisition of such infections has now become rare. We studied the profile of hepatitis in North-American children with haemophilia in the modern era of safe blood products and excess childhood obesity. A total of 173 boys (<18 years) registered in the Pediatric Comprehensive Care Haemophilia Program were included in this retrospective study. Hospital records were reviewed for baseline data, serial height and weight measurements and serial alanine aminotransferase (ALT) levels. A body mass index (BMI) ranking was available for 170 boys, of whom 25 (14.7%, 95% CI 9.7-20.9%) were obese. The rate of obesity was higher in severe haemophilic boys. Compared with the general childhood population, the rate of obesity trended towards being higher in young haemophilic boys (2-5 years), but was similar in other age groups. A persistently high ALT (≥80 U L(-1) ) was documented in 5 boys and was associated with obesity. Three boys had clinical and imaging studies compatible with non-alcoholic fatty liver disease (NAFLD). Overweight and obesity are common among haemophilic boys, especially those who are younger and with severe disease. In this large group of haemophilic boys, chronic viral hepatitis was rare and NAFLD was a more common cause of liver disease. Overweight and obese haemophilic boys should be evaluated for NAFLD and interventional programmes should be designed to reduce the potential complications associated with obesity.

Acute humoral rejection in an ABO compatible combined liver-kidney transplant--the kidney is not always protected.

Combined liver-kidney transplantation has become a common practice for the treatment of patients with concurrent end-stage renal disease and end-stage liver disease. Liver transplantation in the setting of multiorgan transplantation is thought to have a protective effect against humoral rejection even when a positive crossmatch is obtained prior to surgery. In most centers, a pre liver-kidney transplant crossmatch is rarely performed because of the known immunoprotective effect of the liver allograft. In this report, a case of acute humoral rejection in the kidney allograft after a combined liver-kidney transplant is described. Although humoral rejection was treated using plasmapheresis, intravenous immunoglobulin and rituximab, the kidney required 3 months to recover function and finally progressed to chronic allograft nephropathy. A heightened index of suspicion for acute humoral rejection of the renal allograft is necessary when performing combined liver-kidney transplants to highly sensitized patients due to previous organ transplants.

Hepatitis A and B immunization for individuals with inherited bleeding disorders.

Hepatitis A and B vaccines are highly effective tools that can greatly reduce infection risk in the bleeding disorder population. Although hepatitis A and B immunization for individuals with bleeding disorders is universally recommended, various advisory bodies often differ with respect to many practical aspects of vaccination. To review the published literature and guidelines and form a practical, comprehensive and consistent approach to hepatitis A and B immunization for individuals with bleeding disorders. We reviewed published immunization guidelines from North American immunization advisory bodies and published statements from North American and international haemophilia advisory bodies. A search of the MEDLINE database was performed to find original published literature pertaining to hepatitis A or B immunization of patients with haemophilia or bleeding disorder patients that provided supporting or refuting evidence for advisory body guidelines. Various advisory bodies' immunization guidelines regarding individuals with bleeding disorders have contradictory statements and often did not clarify issues (e.g. post vaccination surveillance). Published literature addressing immunization in bleeding disorder patients is sparse and mostly examines route of vaccine administration, complications and corresponding antibody response. Although the risk of hepatitis A and B infection is low, the use of simple measures such as vaccination is reasonable and advocated by haemophilia advisory bodies. Following our review of the available literature and North American guidelines, we have developed comprehensive and practical recommendations addressing hepatitis A and B immunization for the bleeding disorder population that may be applicable in Bleeding Disorder clinics.

Viral fitness implications of variation within an immunodominant CD8+ T-cell epitope of HIV-1.

Cytotoxic T-lymphocyte (CTL) epitopes within the HIV genome are subject to negative and positive selective pressures, the balance of which influences CTL escape at a given epitope. We investigated whether viral fitness requirements dictate conservation of the HLA-A2 restricted immunodominant epitope SLYNTVATL (SL9). Viral clones incorporating changes throughout the SL9 epitope region were compared to consensus SL9 virus in terms of replication kinetics and relative viral fitness. Constructs recapitulating in vivo SL9-CTL escape variants showed markedly little effect on replication and fitness, as did non-natural conservative mutations targeting immunologically relevant positions of the epitope. Although certain residues of the epitope were constrained by viral requirements, our research reveals that there are multiple SL9 variants that are well tolerated virologically but fail to arise in vivo. In light of this data, assumptions regarding the balance of immune and viral selective pressures on this immunodominant epitope sequence need to be reassessed.

Immune characterization of an individual with an exceptionally high natural killer T cell frequency and her immediate family.

Natural killer T cells (NKT) are a regulatory subset of T lymphocytes whose frequency in peripheral blood is highly variable within the human population. Lower than normal NKT frequencies are associated with increased predisposition to a number of diseases, including type 1 diabetes and some forms of cancer, raising the possibility that an increased frequency may be protective. However, there is little or no understanding of how high NKT frequencies arise or, most importantly, whether the potential exists to boost and maintain NKT levels for therapeutic advantage. Here, we provide a detailed functional and phenotypic characterization of the NKT compartment of a human donor with NKT levels approximately 50 times greater than normal, including an analysis of NKT in her immediate family members. The study focuses upon the characteristics of this donor and her family, but demonstrates more broadly that the size and flexibility of the NKT niche is far greater than envisioned previously. This has important implications for understanding how the human NKT compartment is regulated, and supports the concept that the human NKT compartment might be expanded successfully for therapeutic benefit.

Initial results of primary device closure of large muscular ventricular septal defects in early infancy using perventricular access.

OBJECTIVES: To report our experience with the use of the Amplatzer muscular ventricular septal defect (VSD) occluder, using direct right ventricle free wall puncture for primary closure of muscular VSDs in infants. BACKGROUND: Young infants with heart failure due to large or multiple muscular VSDs often require intervention at a stage when percutaneous device closure is impractical due to delivery system limitations. There are considerable benefits to avoiding bypass in these infants. METHODS: Patients with suitable muscular VSDs, considered too small for transvenous closure, underwent periventricular muscular VSD closure under transesophageal echo (TEE) guidance. RESULTS: Eight infants underwent the procedure. The median age was 14 weeks (2-41) with median weight of 4 kg (3-6.6). Four patients had additional VSDs and one patient had previous repair of coarctation. One patient had dextrocardia and severe left ventricular impairment due to an associated cardiomyopathy. The median VSD size was 8 mm (range, 4-10 mm). A single device (6-12 mm) was deployed in each patient, the size chosen being 1-2 mm larger than the TEE measurement. Two patients had subsequent pulmonary artery banding, with absorbable bands, because of moderate residual shunting through additional VSDs. The latest echo study at a median of 7.2 weeks (0.5-66) post device implantation revealed no patients with a hemodynamically significant shunt. CONCLUSION: Perventricular muscular VSD closure can be safely and effectively undertaken in small infants with suitable muscular defects, and this strategy can avoid the need for bypass.

Nesiritide as bridge to multi-organ transplantation: a case report.

Nesiritide, an intravenous form of human B-type natriuretic peptide, has been approved as treatment for patients with acute decompensated heart failure. Due to its action on different receptors, nesiritide has many effects, including vasodilation and natriuresis. Cardiac preload and afterload decrease, leading to an increase in cardiac output through effects on smooth muscle and the kidneys. As a bridge to cardiac transplantation, nesiritide has been used to maintain vasodilation and diuresis without sacrificing kidney function. Our patient, prior to multi-organ transplantation, had a pulmonary capillary wedge pressure of 41 mm Hg on milrinone monotherapy, which decreased slightly with nitroprusside and further decreased to 4 mm Hg after the addition of nesiritide. The patient's measured creatinine clearance level was calculated to be 40 mL/min. When nesiritide therapy was begun, the renal function did not improve, but, as the hemodynamics improved, renal function did not decrease.

Use of modified U1 snRNAs to inhibit HIV-1 replication.

Control of RNA processing plays a central role in regulating the replication of HIV-1, in particular the 3' polyadenylation of viral RNA. Based on the demonstration that polyadenylation of mRNAs can be disrupted by the targeted binding of modified U1 snRNA, we examined whether binding of U1 snRNAs to conserved 10 nt regions within the terminal exon of HIV-1 was able to inhibit viral structural protein expression. In this report, we demonstrate that U1 snRNAs complementary to 5 of the 15 regions targeted result in significant suppression of HIV-1 protein expression and viral replication coincident with loss of viral RNA. Suppression of viral gene expression is dependent upon appropriate assembly of a U1 snRNP particle as mutations of U1 snRNA that affect binding of U1 70K or Sm proteins significantly reduced efficacy. However, constructs lacking U1A binding sites retained significant anti-viral activity. This finding suggests a role for these mutants in situations where the wild-type constructs cause toxic effects. The conserved nature of the sequences targeted and the high efficacy of the constructs suggests that this strategy has significant potential as an HIV therapeutic.