Alternative pathway activation in pregnancy, a measured amount "complements" a successful pregnancy, too much results in adverse events.

During pregnancy, the maternal host must adapt in order to enable growth of the fetus. These changes affect all organ systems and are designed both to protect the fetus and to minimize risk to the mother. One of the most prominent adaptations involves the immune system. The semi-allogenic fetoplacental unit has non-self components and must be protected against attack from the host. This requires both attenuation of adaptive immunity and protection from innate immune defense mechanisms. One of the key innate immune players is complement, and it is important that the fetoplacental unit is not identified as non-self and subjected to complement attack. Adaptation of the complement response must, however, be managed in such a way that maternal protection against infection is not compromised. As the complement system also plays a significant facilitating role in many of the stages of a normal pregnancy, it is also important that any necessary adaptation to accommodate the semi-allogenic aspects of the fetoplacental unit does not compromise this. In this review, both the physiological role of the alternative pathway of complement in facilitating a normal pregnancy, and its detrimental participation in pregnancy-specific disorders, are discussed.

Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study.

Historically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials of eculizumab with a short follow-up suggested efficacy. We prove, for the first time to our knowledge, in a genotype matched CaHUS cohort that the 5-year cumulative estimate of ESKD-free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab-treated cohort (hazard ratio, 4.95; 95% confidence interval [CI], 2.75-8.90; P = .000; number needed to treat, 2.17 [95% CI, 1.81-2.73]). The outcome of eculizumab treatment is associated with the underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure, and younger age at presentation as well as shorter time between presentation and the first dose of eculizumab were associated with estimated glomerular filtration rate >60 ml/min at 6 months in multivariate analysis. The rate of meningococcal infection in the treated cohort was 550 times greater than the background rate in the general population. The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for patients with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. No relapses were recorded in 67.3 person years off eculizumab in those with no rare genetic variants. Eculizumab was restarted in 6 individuals with functioning kidneys in whom it had been stopped, with no individual progressing to ESKD. We demonstrated that biallelic pathogenic mutations in RNA-processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab nonresponsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with thrombotic microangiopathy.

Plasminogen activator-coated nanobubbles targeting cellbound ß2-glycoprotein I as a novel thrombus-specific thrombolytic strategy.

ß2-glycoprotein I (ß2-GPI) is a serum protein widely recognized as the main target of antibodies present in patients with antiphospholipid syndrome (APS). ß2-GPI binds to activated endothelial cells, platelets and leukocytes, key players in thrombus formation. We developed a new targeted thrombolytic agent consisting of nanobubbles (NB) coated with recombinant tissue plasminogen activator (rtPA) and a recombinant antibody specific for cell-bound ß2-GPI. The therapeutic efficacy of targeted NB was evaluated in vitro, using platelet-rich blood clots, and in vivo in three different animal models: i) thrombosis developed in a rat model of APS; ii) ferric chloride-induced mesenteric thrombosis in rats, and iii) thrombotic microangiopathy in a mouse model of atypical hemolytic uremic syndrome (C3-gain-of-function mice). Targeted NB bound preferentially to platelets and leukocytes within thrombi and to endothelial cells through ß2-GPI expressed on activated cells. In vitro, rtPA-targeted NB (rtPA-tNB) induced greater lysis of platelet-rich blood clots than untargeted NB. In a rat model of APS, administration of rtPA-tNB caused rapid dissolution of thrombi and, unlike soluble rtPA that induced transient thrombolysis, prevented new thrombus formation. In a rat model of ferric chloride triggered thrombosis, rtPA-tNB, but not untargeted NB and free rtPA, induced rapid and persistent recanalization of occluded vessels. Finally, treatment of C3-gain-of-function mice with rtPA-tNB, that target ß2-GPI deposited in kidney glomeruli, decreased fibrin deposition, and improved urinalysis data with a greater efficiency than untargeted NB. Our findings suggest that targeting cell-bound ß2-GPI may represent an efficient and thrombus-specific thrombolytic strategy in both APS-related and APS-unrelated thrombotic conditions.

What are the evidence bases for developing models of rehabilitation for older people with mental illness in Australia?

OBJECTIVE: This paper updates clinicians and service leaders on evidence bases relevant to rehabilitation for older Australians with mental illness. METHODS: Narrative review of literature and relevant public domain data supported by reflections on NSW service development. RESULTS: There is a paucity of high-quality evidence regarding mental health rehabilitation in older people. Available evidence supports integrating lessons from physical healthcare with adaptations of 'adult' mental health rehabilitation. Adaptation is required to respond to the specific needs, strengths and service use of older people with mental illness. Challenges for older people include ageism, increased physical and cognitive comorbidities, lower access to mental health services and earlier residential aged care entry. Strengths of older people include an ongoing desire for recovery, ongoing developmental change and often closer connections with carers and GPs. Evidence is consistent with evaluation of relevant NSW service models and initiatives including the Pathways to Community Living Initiative. Integration of recovery-oriented practice and wellness models may provide a framework for future innovative inpatient and community-based models. CONCLUSIONS: There is sufficient evidence to guide development of models of rehabilitation with older people, but innovation and evaluation are essential if older people are to have equal opportunities in their recovery journeys.

Evaluation of a mental health service reform program, the Pathways to Community Living Initiative, for people with severe mental illness and complex needs.

OBJECTIVE: The Pathways to Community Living Initiative (PCLI) aims to reform mental health care for people with severe and persistent mental illness (SPMI) and complex needs. This study reports independent evaluation findings on transitions from hospital and practice change in mental health services. METHODS: Data for this mixed-methods evaluation were obtained from administrative collections and semi-structured interviews with PCLI program managers, teams and executive leads; aged care managers; and leaders in inpatient, community and older people's mental health services. RESULTS: Between July 2015 and December 2020, 674 participants (67% of those eligible for the PCLI) were transitioned from hospital to community. Of those transitioned, 21 required subsequent long-stay admissions. The PCLI introduced resources, clearly defined processes, and state-wide networks to guide changes in practice which are becoming embedded in the operations and governance of mental health services across New South Wales. CONCLUSIONS: Severe and persistent mental illness and complex needs can be managed in community settings with highly individualised planning and care, supported by specialised clinical teams in partnership with mental health, aged care and disability services. Evaluation findings highlight the importance of continued investment in rehabilitation psychiatry.

Teaching veterinary surgical skills: Comparison of massed versus spaced instruction.

OBJECTIVE: To determine the effect of massed instruction (MI) versus spaced instruction (SI) of veterinary surgical skills on students' cognitive load and skill retention. STUDY DESIGN: Prospective randomized cohort study STUDY POPULATION: First-year veterinary students from Louisiana State University (LSU; n = 47) and Lincoln Memorial University (LMU; n = 101). METHODS: Students were randomized to MI (two skills in a single session of twice the duration) or SI (one skill per session on two consecutive days). Instructors, instructional ratio, and total educational time was equivalent. Following instruction, students completed a cognitive load questionnaire and underwent a structured assessment immediately after (LMU only), 1 day after, and 3-4 weeks after learning the second skill. Students completed two supervised practice sessions one and 2 weeks after the initial laboratory session(s). RESULTS: Overall cognitive load did not differ between groups (p > .05), although LMUs MI group reported higher physical and time demands, effort, and frustration. At initial assessment, SI students scored higher than MI students for the first skill at both LSU (mean checklist score = 27.7 vs. mean = 24; p = .004) and LMU (mean global rating score = 4.76 vs. mean = 4.55; p = .029). Differences between groups were no longer evident by 3-4 weeks after instruction. CONCLUSION: SI may lead to improved immediate performance; however, supervised practice was sufficient to overcome the initial disparity. CLINICAL SIGNIFICANCE: SI may be beneficial for initial skill performance. However, SI and MI students had similar performance after 3 weeks, suggesting the more convenient curricular design of MI may be sufficient as long as practice sessions are incorporated.

Performance of a Predictive Model versus Prescription-Based Thresholds in Identifying Patients at Risk of Fatal Opioid Overdose.

Background: Prescription Drug Monitoring Programs (PDMPs) collect controlled substance prescriptions dispensed within a state. Many PDMP programs perform targeted outreach (i.e., "unsolicited reporting") for patients who exceed numerical thresholds, however, the degree to which patients at highest risk of fatal opioid overdose are identified has not been compared with one another or with a predictive model. Methods: A retrospective analysis was performed using statewide PDMP data for Maryland residents aged 18 to 80 years with an opioid fill between April to June 2015. The outcome was opioid-related overdose death in 2015 or 2016. A multivariable logistic regression model and three PDMP thresholds were evaluated: (1) multiple provider episodes; (2) high daily average morphine milligram equivalents (MME); and (3) overlapping opioid and benzodiazepine prescriptions. Results: The validation cohort consisted of 170,433 individuals and 244 deaths. The predictive model captured more individuals who died (46.3% of total deaths) and had a higher death rate (7.12 per 1000) when the risk score cutoff (0.0030) was selected for a comparable size of high-risk individuals (n = 15,881) than those meeting the overlapping opioid/benzodiazepine prescriptions (n = 17,440; 33.2% of total deaths; 4.64 deaths per 1000) and high MME (n = 14,675; 24.6% of total deaths; 4.09 deaths per 1000) thresholds. Conclusions: The predictive model identified more individuals at risk of fatal opioid overdose as compared with PDMP thresholds commonly used for unsolicited reporting. PDMP programs could improve their targeting of unsolicited reports to reach more individuals at risk of overdose by using predictive models instead of simple threshold-based approaches.

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

The Impact of Various Risk Assessment Time Frames on the Performance of Opioid Overdose Forecasting Models.

BACKGROUND: An individual's risk for future opioid overdoses is usually assessed using a 12-month "lookback" period. Given the potential urgency of acting rapidly, we compared the performance of alternative predictive models with risk information from the past 3, 6, 9, and 12 months. METHODS: We included 1,014,033 Maryland residents aged 18-80 with at least 1 opioid prescription and no recorded death in 2015. We used 2015 Maryland prescription drug monitoring data to identify risk factors for nonfatal opioid overdoses from hospital discharge records and investigated fatal opioid overdose from medical examiner data in 2016. Prescription drug monitoring program-derived predictors included demographics, payment sources for opioid prescriptions, count of unique opioid prescribers and pharmacies, and quantity and types of opioids and benzodiazepines filled. We estimated a series of logistic regression models that included 3, 6, 9, and 12 months of prescription drug monitoring program data and compared model performance, using bootstrapped C-statistics and associated 95% confidence intervals. RESULTS: For hospital-treated nonfatal overdose, the C-statistic increased from 0.73 for a model including only the fourth quarter to 0.77 for a model with 4 quarters of data. For fatal overdose, the area under the curve increased from 0.80 to 0.83 over the same models. The strongest predictors of overdose were prescription fills for buprenorphine and Medicaid and Medicare as sources of payment. CONCLUSIONS: Models predicting opioid overdose using 1 quarter of data were nearly as accurate as models using all 4 quarters. Models with a single quarter may be more timely and easier to identify persons at risk of an opioid overdose.

Predictors of Overdose Death Among High-Risk Emergency Department Patients With Substance-Related Encounters: A Data Linkage Cohort Study.

STUDY OBJECTIVE: Persons with substance use disorders frequently utilize emergency department (ED) services, creating an opportunity for intervention and referral to addiction treatment and harm-reduction services. However, EDs may not have the appropriate tools to distinguish which patients are at greatest risk for negative outcomes. We link hospital ED and medical examiner mortality databases in one state to identify individual-level risk factors associated with overdose death among ED patients with substance-related encounters. METHODS: This retrospective cohort study linked Maryland statewide ED hospital claims records for adults with nonfatal overdose or substance use disorder encounters in 2014 to 2015 with medical examiner mortality records in 2015 to 2016. Logistic regression was used to identify factors in hospital records associated with risk of opioid overdose death. Predicted probabilities for overdose death were calculated for hypothetical patients with different combinations of overdose and substance use diagnostic histories. RESULTS: A total of 139,252 patients had substance-related ED encounters in 2014 to 2015. Of these patients, 963 later experienced an opioid overdose death, indicating a case fatality rate of 69.2 per 10,000 patients, 6 times higher than that of patients who used the ED for any cause. Factors most strongly associated with death included having both an opioid and another substance use disorder (adjusted odds ratio 2.88; 95% confidence interval 2.04 to 4.07), having greater than or equal to 3 previous nonfatal overdoses (adjusted odds ratio 2.89; 95% confidence interval 1.54 to 5.43), and having a previous nonfatal overdose involving heroin (adjusted odds ratio 2.24; 95% confidence interval 1.64 to 3.05). CONCLUSION: These results highlight important differences in overdose risk among patients receiving care in EDs for substance-related conditions. The findings demonstrate the potential utility of incorporating routine data from patient records to assess risk of future negative outcomes and identify primary targets for initiation and linkage to lifesaving care.

Prevalence and intensity of persistent post-surgical pain following breast cancer surgery: a systematic review and meta-analysis of observational studies.

BACKGROUND: The prevalence and intensity of persistent post-surgical pain (PPSP) after breast cancer surgery are uncertain. We conducted a systematic review and meta-analysis to further elucidate this issue. METHODS: We searched MEDLINE, Embase, CINAHL, and PsycINFO, from inception to November 2018, for observational studies reporting persistent pain (≥3 months) after breast cancer surgery. We used random-effects meta-analysis and the Grading of Recommendations, Assessment, Development and Evaluations approach to rate quality of evidence. RESULTS: We included 187 observational studies with 297 612 breast cancer patients. The prevalence of PPSP ranged from 2% to 78%, median 37% (inter-quartile range: 22-48%); the pooled prevalence was 35% (95% confidence interval [CI]: 32-39%). The pooled pain intensity was 3.9 cm on a 10 cm visual analogue scale (95% CI: 3.6-4.2 cm). Moderate-quality evidence supported the subgroup effects of PPSP prevalence for localized pain vs any pain (29% vs 44%), moderate or greater vs any pain (26% vs 44%), clinician-assessed vs patient-reported pain (23% vs 36%), and whether patients underwent sentinel lymph node biopsy vs axillary lymph node dissection (26% vs 43%). The adjusted analysis found that the prevalence of patient-reported PPSP (any severity/location) was 46% (95% CI: 36-56%), and the prevalence of patient-reported moderate-to-severe PPSP at any location was 27% (95% CI: 10-43%). CONCLUSIONS: Moderate-quality evidence suggests that almost half of all women undergoing breast cancer surgery develop persistent post-surgical pain, and about one in four develop moderate-to-severe persistent post-surgical pain; the higher prevalence was associated with axillary lymph node dissection. Future studies should explore whether nerve sparing for axillary procedures reduces persistent post-surgical pain after breast cancer surgery.

Diversifying into the branches: Species boundaries in African green and bush snakes, Philothamnus (Serpentes: Colubridae).

The African green and bush snakes of the genus Philothamnus currently comprises 21 species and three subspecies and occurs throughout sub-Saharan Africa. The genus has been the subject of previous taxonomic revisions based on traditional morphological characters and limited genetic assessment, and may not reflect their evolutionary history. Indeed, previous findings based on phylogenetics show discordant results of interspecific relationships and question the monophyly of the genus, although taxon sampling has been limited to date. We investigated phylogenetic affinities within Philothamnus with more inclusive genetic and geographical sampling, with the aim of better understanding their evolutionary history, so that future taxonomic revision of Philothamnus can be better informed. Species relationships were examined within a phylogenetic context and sampling included 133 ingroup samples from 16 taxa. Phylogenies were constructed in Bayesian and likelihood frameworks using three mitochondrial (16S, cyt b and ND4) and two nuclear (c-mos and RAG1) markers. Competing hypotheses relating to the monophyly of the genus were tested with a Shimodaira-Hasegawa test. To examine species boundaries, Bayesian General Mixed Yule-Coalescent Model and multi-rate Poisson Tree Processes analyses were conducted. In addition, a barcoding approach was used to further clarify species-level relationships by comparing frequency distributions between intra- and interspecific sequence divergence. The genus was recovered as monophyletic; however, species-delimitation results suggest that the current taxonomy does not reflect the evolutionary history of this group. For example, Philothamnus s. semivariegatus is paraphyletic, with at least four distinct clades. Philothamnus carinatus consists of two cryptic (sister) lineages from Central and West Africa that are deeply divergent, suggesting a long history of isolation between those regions. Furthermore, the subspecies P. n. natalensis and P. n. occidentalis show strong support for species-level divergence, which reflects their morphological and ecological differences. Accordingly, we elevate P. occidentalisnov. comb. to a full species. A fully informed taxonomic revision of these taxa will require additional morphological and ecological data for corroboration, but it seems that the morphological characters (e.g. scalation, dentition) used to describe these species to date are labile within and between species. This most likely has clouded our understanding of the species boundaries within the genus. Our phylogeny and species-delimitation analyses should provide a sounder framework for taxonomy, but may also prove useful toward understanding the morphological adaptations of these species to their respective habitats.

An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy.

Background C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway of complement activation, and treatment options for C3G remain limited. Complement factor H (FH) is a potent regulator of the alternative pathway and might offer a solution, but the mass and complexity of FH makes generation of full-length FH far from trivial. We previously generated a mini-FH construct, with FH short consensus repeats 1-5 linked to repeats 18-20 (FH1-5^18-20), that was effective in experimental C3G. However, the serum t1/2 of FH1-5^18-20 was significantly shorter than that of serum-purified FH.Methods We introduced the oligomerization domain of human FH-related protein 1 (denoted by R1-2) at the carboxy or amino terminus of human FH1-5^18-20 to generate two homodimeric mini-FH constructs (FHR1-2^1-5^18-20 and FH1-5^18-20^R1-2, respectively) in Chinese hamster ovary cells and tested these constructs using binding, fluid-phase, and erythrocyte lysis assays, followed by experiments in FH-deficient Cfh-/- mice.Results FHR1-2^1-5^18-20 and FH1-5^18-20^R1-2 homodimerized in solution and displayed avid binding profiles on clustered C3b surfaces, particularly FHR1-2^1-5^18-20 Each construct was >10-fold more effective than FH at inhibiting cell surface complement activity in vitro and restricted glomerular basement membrane C3 deposition in vivo significantly better than FH or FH1-5^18-20 FH1-5^18-20^R1-2 had a C3 breakdown fragment binding profile similar to that of FH, a >5-fold increase in serum t1/2 compared with that of FH1-5^18-20, and significantly better retention in the kidney than FH or FH1-5^18-20Conclusions FH1-5^18-20^R1-2 may have utility as a treatment option for C3G or other complement-mediated diseases.

Increased Risk of Musculoskeletal Disorders and Mental Health Problems in Retired Professional Jockeys: A Cross-Sectional Study.

To examine the prevalence of chronic disease and mental health problems in retired professional, male jockeys compared to an age-matched reference population. A cross-sectional study comparing data from a cohort of retired professional jockeys with an age-matched general population sample. Male participants (age range: 50-89 years old) were used to compare health outcomes of self-reported physician-diagnosed conditions: heart disease, stroke, diabetes, hypertension, osteoporosis, osteoarthritis, depression and anxiety between study populations. Conditional logistic regression models were used to estimate associations between study groups and health outcome. In total, 810 participants (135 retired professional male jockeys and 675 participants from the reference population) were included, with an average age of 64.7±9.9 years old. Increased odds of having osteoporosis (OR=6.5, 95%CI 2.1-20.5), osteoarthritis (OR=7.5, 95%CI 4.6-12.2), anxiety (OR=2.8, 95%CI 1.3-5.9) and depression (OR=2.6, 95%CI 1.3-5.7) were seen in the retired professional jockeys. No differences were found for the remaining health outcomes. Retired professional jockeys had increased odds of musculoskeletal disease and mental health problems compared to the general population. Understanding the prevalence of chronic disease and mental health problems in retired professional jockeys will help inform screening and intervention strategies for jockeys.

Older people's mental health in rural areas: Converting policy into service development, service access and a sustainable workforce.

This paper describes the older people's mental health workforce development, policy development and implementation process and quantifies the rural service delivery and access impacts over a 15-year period in New South Wales. It highlights the factors that are considered to be critical to successful rural service development such as commitment to funding parity, investment in strong local service leadership, and development of innovative, locally adapted rural service models. Building on these foundations, the Older People's Mental Health Program in New South Wales was able to address key challenges relating to service access in rural health and develop new, sustainable specialist older people's mental health service networks. A sustained focus on policy and implementation which explicitly supports rural older people's mental health service enhancement, and development of evidence-based models of care, has significantly improved access to specialist mental health care for older people in rural areas. It has delivered 23 new rural older people's mental health community teams and a 440% increase in the number of people accessing these teams. It has also doubled the number of acute inpatient units and established new specialist mental health-residential aged care partnership services in rural New South Wales. It has resulted in increased access to services for the "older old," while not diminishing older people's rates of access to general adult mental health services. It has also supported innovative, sustainable rural service models such as "hub and spoke" models and step-up step-down inpatient services that build on existing health and hospital infrastructure and link geographically dispersed specialist clinicians and services together in rural service delivery.

Phylogeny and biogeography of the African burrowing snake subfamily Aparallactinae (Squamata: Lamprophiidae).

Members of the snake subfamily Aparallactinae occur in various habitats throughout sub-Saharan Africa. The monophyly of aparallactine snakes is well established, but relationships within the subfamily are poorly known. We sampled 158 individuals from six of eight aparallactine genera in sub-Saharan Africa. We employed concatenated gene-tree analyses, divergence dating approaches, and ancestral-area reconstructions to infer phylogenies and biogeographic patterns with a multi-locus data set consisting of three mitochondrial (16S, cyt b, and ND4) and two nuclear genes (c-mos and RAG1). As a result, we uncover several cryptic lineages and elevate a lineage of Polemon to full species status. Diversification occurred predominantly during the Miocene, with a few speciation events occurring subsequently in the Pliocene and Pleistocene. Biogeographic analyses suggested that the Zambezian biogeographic region, comprising grasslands and woodlands, facilitated radiations, vicariance, and dispersal for many aparallactines. Moreover, the geographic distributions of many forest species were fragmented during xeric and cooler conditions, which likely led to diversification events. Biogeographic patterns of aparallactine snakes are consistent with previous studies of other sub-Saharan herpetofauna.

Eculizumab in children with hemolytic uremic syndrome.

Greenbaum et al. report the first prospective trial of eculizumab in pediatric atypical hemolytic uremic syndrome. As in adult trials, eculizumab appears effective and no serious safety signals were reported. There is the first suggestion of a dichotomy in response to treatment with a trend toward poorer outcome in those without complement abnormalities. This group, however, had worse renal function at presentation, and it remains to be seen whether this represents true non-response or merely late presentation.

Multi time-step wavefront reconstruction for tomographic adaptive-optics systems.

In tomographic adaptive-optics (AO) systems, errors due to tomographic wavefront reconstruction limit the performance and angular size of the scientific field of view (FoV), where AO correction is effective. We propose a multi time-step tomographic wavefront reconstruction method to reduce the tomographic error by using measurements from both the current and previous time steps simultaneously. We further outline the method to feed the reconstructor with both wind speed and direction of each turbulence layer. An end-to-end numerical simulation, assuming a multi-object AO (MOAO) system on a 30 m aperture telescope, shows that the multi time-step reconstruction increases the Strehl ratio (SR) over a scientific FoV of 10 arc min in diameter by a factor of 1.5-1.8 when compared to the classical tomographic reconstructor, depending on the guide star asterism and with perfect knowledge of wind speeds and directions. We also evaluate the multi time-step reconstruction method and the wind estimation method on the RAVEN demonstrator under laboratory setting conditions. The wind speeds and directions at multiple atmospheric layers are measured successfully in the laboratory experiment by our wind estimation method with errors below 2 ms-1. With these wind estimates, the multi time-step reconstructor increases the SR value by a factor of 1.2-1.5, which is consistent with a prediction from the end-to-end numerical simulation.

Insights into hospitalisation of advanced cancer patients: a study of medical records.

The aim of this study was to explore reasons for the hospitalisation and place of death outcomes of terminal cancer patients. The methodology involved a qualitative content analysis of medical records pertaining to the last 3 months of life of 39 patients with one of four malignancies: prostate, breast, lung, or haematological. The results presentation is organised around three themes: decision hierarchy in health care, meanings of 'home', and late recognition of dying. Based on the detailed findings, this paper suggests that important insights into the broader goals of advanced cancer patients are offered by allied health staff, and that more effective use of the multidisciplinary team may support endeavours to achieve more home deaths for cancer patients who want this outcome. The analysis also provides new insights into the meaning of 'home' in interactions between advanced cancer patients and health professionals. The wish for 'home' appears bound up with other patient goals and the implications of this are discussed.

Establishment and preliminary outcomes of a palliative care research network.

OBJECTIVE: The difficulties in conducting palliative care research have been widely acknowledged. In order to generate the evidence needed to underpin palliative care provision, collaborative research is considered essential. Prior to formalizing the development of a research network for the state of Victoria, Australia, a preliminary study was undertaken to ascertain interest and recommendations for the design of such a collaboration. METHOD: Three data-collection strategies were used: a cross-sectional questionnaire, interviews, and workshops. The questionnaire was completed by multidisciplinary palliative care specialists from across the state (n = 61); interviews were conducted with senior clinicians and academics (n = 21) followed by two stakeholder workshops (n = 29). The questionnaire was constructed specifically for this study, measuring involvement of and perceptions of palliative care research. RESULTS: Both the interview and the questionnaire data demonstrated strong support for a palliative care research network and aided in establishing a research agenda. The stakeholder workshops assisted with strategies for the formation of the Palliative Care Research Network Victoria (PCRNV) and guided the development of the mission and strategic plan. SIGNIFICANCE OF RESULTS: The research and efforts to date to establish the PCRNV are encouraging and provide optimism for the evolution of palliative care research in Australia. The international implications are highlighted.