Outcomes in Patients With von Willebrand Disease Receiving Recombinant von Willebrand Factor on Demand and in Surgical Settings: Chart Review.

This European observational chart review assessed the efficacy/safety of recombinant von Willebrand factor (rVWF) for on-demand treatment of spontaneous/traumatic bleeds and prevention and/or treatment of surgery-related bleeding in adults with von Willebrand disease (VWD). Patients (n = 91) were enrolled at first rVWF administration (index). Data were collected for the 12 months before index and until death, loss to follow-up, or end of study (3-12 months after index). Fifteen patients reported an rVWF-treated spontaneous/traumatic bleed at index. Bleed resolution was obtained for 14 patients (unknown status, n = 1), and investigators assessed treatment satisfaction for 13 rVWF prescriptions (2 moderate, 5 good, and 6 excellent). rVWF was used to prevent/treat surgery-related bleeds at index in 76 patients. Bleed resolution was achieved in 25/58 rVWF-treated surgeries; bleed resolution was not applicable for 33 surgeries. In both groups, there were no reports of treatment-emergent adverse events after initiating rVWF, including hypersensitivity reactions, thrombotic events, and VWF inhibitor development. rVWF was shown to be effective for the on-demand treatment of spontaneous/traumatic bleeds, and for the prevention and treatment of surgical bleeds in this real-world VWD population.

Australian Paediatric Surveillance Unit (APSU) Annual Surveillance Report 2021.

Abstract: The Australian Paediatric Surveillance Unit (APSU) has been conducting surveillance of rare communicable and non-communicable conditions in children since its inception in 1993. In this report, the results are described of surveillance of ten communicable diseases (and complications) for 2021, including the numbers of cases and incidence estimates; demographics; clinical features; and management and short-term outcomes. The included diseases are: acute flaccid paralysis (AFP); congenital cytomegalovirus (CMV); neonatal herpes simplex virus (HSV) infection; paediatric human immunodeficiency virus (HIV) infection; perinatal exposure to HIV; severe complications from influenza; juvenile-onset respiratory papillomatosis (JoRRP); congenital rubella syndrome; congenital varicella syndrome; and neonatal varicella infection. In 2021, cases of JoRRP were reported to the APSU for the first time since 2017, indicating potential gaps in HPV vaccination. AFP surveillance by APSU again contributed to Australia achieving a minimum target incidence of one AFP case per 100,000 children aged < 15 years. There were no cases of children with severe complications of influenza. No cases of varicella or congenital rubella were reported; however, at-risk populations, especially young migrant and refugee women from countries without universal vaccination programs, need to be screened and prioritised for vaccination prior to pregnancy. Cases of perinatal exposure to HIV continue to increase; however, the rate of mother-to-child-transmission remains at low levels due to the use of effective intervention strategies. Case numbers of congenital CMV and neonatal HSV remain steady in the absence of vaccines, prompting the need for greater awareness and education, with recent calls for target screening of at-risk infants for congenital CMV.

Cost-effectiveness analysis of nivolumab plus ipilimumab plus two cycles of platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone for first-line treatment of stage IV or recurrent non-small cell lung cancer in the United States.

AIM: This economic analysis evaluated the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of platinum-doublet chemotherapy (PDC) compared with four cycles of PDC as first-line treatment for patients with advanced NSCLC in the United States (US). METHODS: A partitioned survival model was constructed with three mutually exclusive health states: progression free, progressed disease, and death. The analysis was conducted from a US healthcare payer perspective, using a time horizon of 25 years. Costs and outcomes were discounted at 3% annually. Survival outcomes from CheckMate 9LA were extrapolated with longer follow-up data from CheckMate 227 Part 1 (NIVO + IPI) and validated against data from other relevant clinical trials and real-world registries. Health-related quality of life utility values were derived from EQ-5D-3L data collected in CheckMate 9LA. US-specific costs (2020 dollars) were used for disease management; drug acquisition, administration, and monitoring; end-of-life care; adverse events; and subsequent treatments. Model outcomes included life years (LYs) gained, quality-adjusted LYs (QALYs) gained, and incremental cost-effectiveness ratio (ICER) for NIVO + IPI + PDC versus PDC. Sensitivity and scenario analyses were conducted. RESULTS: NIVO + IPI + PDC was associated with higher projected health benefits than PDC, including gains in LYs (3.71 vs 1.89) and QALYs (2.86 vs 1.37), and higher costs ($317,581 vs $119,909). The ICER was $132,960/QALY gained. NIVO + IPI + PDC had a 78-100% probability of being cost-effective at a willingness-to-pay threshold of $150,000-$250,000/QALY. Sensitivity and scenario analyses indicated that the results were robust to changes in key parameters. LIMITATIONS: The inherent limitation in extrapolating clinical trial data was mitigated using data from the more mature CheckMate 227 Part 1 trial and validating the outcomes against data from other relevant trials and real-world registries. CONCLUSION: NIVO + IPI + PDC (two cycles) provides a new first-line treatment option for patients with advanced NSCLC that is cost-effective within a range considered acceptable in the US.

Nurses' attitudes towards their jobs in outpatient human immunodeficiency virus facilities in Namibia: A qualitative descriptive study.

AIM: The aims were to (1) describe nurses' attitudes towards their jobs, (2) identify factors that contribute to nurses' job attitudes and (3) examine how nurses' job attitudes affect their ability to perform their jobs. BACKGROUND: Nurses' job attitudes affect their ability to do their jobs well. METHODS: This was a qualitative descriptive study of 18 semi-structured interviews with nurses who work in rural health facilities. Interviews were analysed using content analysis. RESULTS: Factors that influenced job attitudes included support from co-workers, workload, access to material resources, access to information, patient rapport and nurses' personal resilience. Nurses reported that positive attitudes helped them to do their jobs well and negative attitudes diminished their ability to do their jobs well. CONCLUSIONS: This study's findings support investment in factors to promote positive nurse attitudes and job performance such as a healthy work environment and self-efficacy. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers can improve nurses' attitudes by advocating for tangible supports for staff such as appropriate staffing ratios, sufficient equipment, necessary training and work environments that allow safe patient interactions.

"Mother's Health and Well-Being Matters: Is a Mediated Social Cohesion Public Health Intervention Feasible?"

PURPOSE: To test the feasibility of introducing 'Free Time for Wellness' (FT4W) an intervention to increase healthy behaviours and reduce the risk of cancer. DESIGN: Feasibility study; Setting: Washington Heights, New York, USA is a low socioeconomic status area. SUBJECTS: Mothers aged 18 and above with children under 12 years of age and living in Washington Heights were recruited. INTERVENTION: FT4W, a community-based intervention delivered through a neighbourhood-based app, offering weekly dance and yoga classes, food pantry visits and group playdates. Childcare professionals cared for participants' children during wellness activities. MEASURES: A bespoke before and after survey was designed and tested for its ability to collect relevant data to assess the impact of FT4W. Outcomes included recruitment rates, participation, attrition, acceptability, and success of the community champion. ANALYSIS: Comparisons of proportions and means. RESULTS: Twenty-one mothers participated in the study of which 90% attended ≥ 1 FT4W activity; 65% ≥ 2; 52% ≥ 3. The survey was completed by a 100% of participants indicating it was easy to understand and not too burdensome. All measures detected change in constructs from baseline to follow-up. Availability of childcare was the most commonly (66%) reported reason participants were able to engage in the offered wellness activities. CONCLUSION: Conducting a larger-scale trial to assess the impact of FT4W is feasible considering 4 major lessons. (1) Recruitment, retention, and acceptability rates were high; however, moms need additional support to increase participation in wellness activities and improve tech literacy. (2) Research measures were sensitive enough to detect change, but the timing of assessments needs to be considered. (3) Participants greatly valued access to professional childcare. (4) The Community Champion is a necessary, but difficult role to fill that requires careful consideration by the Institutional Review Board (IRB).

Free Time For Wellness: a co-designed intervention utilizing social networks to encourage physical activity for cancer prevention among low resourced mothers.

BACKGROUND: Physical activity is central to chronic disease prevention. Low resource mothers face structural barriers preventing them from increasing their physical activity to reduce their chronic disease risk. We co-designed an intervention, with the ultimate goal of building social cohesion through social media to increase physical activity for low resourced mothers in urban settings. METHODS: In 2019, we interviewed 10 mothers of children (< 12 years) living in Washington Heights, Manhattan. The interviews were transcribed and coded for themes that guided the creation of a co-design workshop. Washington Heights-based mothers (n = 16) attended a co-design workshop to generate the blueprint for the Free Time for Wellness intervention. RESULTS: Mothers in our sample had limited time, external support and resources, which hindered them from increasing their physical activity; we learned that in addition to physical health, mental health was a concern for participants. Participants had varying degrees of self-efficacy and trust in social media. Bringing mothers and researchers together in a co-design workshop, we identified types of physical activities they would enjoy participating in, the ideal time to do so, the kind of childcare they needed, and their preferences for communication with the community champion. The interviews and workshop highlighted the need for a community space that mothers and children could co-occupy. The intervention was designed to be 3 months' worth of sample programming with one activity per week, rotating between dance, yoga, food pantry visits and group playdates. Participants were invited to bring their children to a space with one room for the 'participants only' activity and a second room in which professional childcare providers supervised the children. CONCLUSIONS: Through this two-phased co-design process, we created an intervention with mothers in an urban community with the goal of using social media to bring them together for wellness, primarily through increased physical activity. Despite the co-design of this intervention with a specific community, there are some universal applications of our findings, and of the use of co-design workshops, to other settings.

Australian Paediatric Surveillance Unit (APSU) Annual Surveillance Report 2020.

ABSTRACT: For 27 years, national prospective data on selected rare childhood diseases have been collected monthly by the Australian Paediatric Surveillance Unit (APSU) from paediatricians and other clinical specialists who report cases in children aged up to 16 years. We report here the annual results of APSU surveillance in 2020 for ten rare communicable diseases and complications of communicable diseases, namely: acute flaccid paralysis (AFP); congenital cytomegalovirus (CMV) infection; neonatal herpes simplex virus (HSV) infection; perinatal exposure to human immunodeficiency virus (HIV); paediatric HIV infection; severe complications of seasonal influenza; juvenile onset recurrent respiratory papillomatosis (JoRRP); congenital rubella syndrome; congenital varicella syndrome; and neonatal varicella infection. We describe the results for each disease in the context of the total period of study, including demographics, clinical characteristics, treatment and short-term outcomes. Despite challenges presented by the coronavirus disease 2019 (COVID-19) pandemic in 2020, more than 1,400 paediatricians reported regularly to the APSU and an overall monthly reporting rate of > 90% was achieved. The minimum AFP target of 1 case per 100,000 children aged less than 15 years was achieved and there were few cases of vaccine-preventable diseases (JoRRP, rubella, varicella). However, high cases of congenital CMV, neonatal HSV and perinatal exposure to HIV persist. There were no severe complications of seasonal influenza reported for the first time in 13 years. This is consistent with other surveillance data reporting a decline of influenza and other communicable diseases in 2020, and likely reflects the wider effects of public health measures to reduce transmission of SARS-CoV-2 in the Australian community.

Use of Social Media for Cancer Prevention Through Neighborhood Social Cohesion: Protocol for a Feasibility Study.

BACKGROUND: Social cohesion is associated with healthier behaviors and better health outcomes, and therefore may offer a mechanism for promoting better health. Low socioeconomic status (SES) communities face higher rates of chronic disease due to both community- and individual-level factors. OBJECTIVE: The aim of this study is to leverage social cohesion to promote healthier behaviors and prevent chronic disease in a low SES community. This protocol outlines the methodology for a pilot study to assess the feasibility of an intervention (Free Time For Wellness [FT4W]) using a social networking platform (Nextdoor) with mothers living in an urban, low-income community to improve social cohesion and promote healthy behaviors. METHODS: The study will involve three phases: (I) co-designing the intervention with mothers in the neighborhoods of interest, (II) implementing the intervention with community leaders through the social networking platform, and (III) evaluating the intervention's feasibility. Phase I of the study will include qualitative data collection and analysis from in-depth, semistructured interviews and a co-design group session with mothers. Phases II and III of the study include a pre- and postintervention survey of participating mothers. Neighborhood-level data on social cohesion will also be collected to enable comparison of outcomes between neighborhoods with higher and lower baseline social cohesion. RESULTS: As of March 2021, recruitment and data collection for this study are complete. This protocol outlines our original study plan, although the final enrollment numbers and intervention implementation deviated from our initial planned methodology that is outlined in this protocol. These implementation learnings will be shared in subsequent publications of our study results. CONCLUSIONS: Ultimately, this study aims to: (1) determine the barriers and facilitators to finding free time for wellness among a population of low-income mothers to inform the co-design process, and (2) implement and study the feasibility of an intervention that leverages social cohesion to promote physical activity in a community of low-income mothers. The results of this study will provide preliminary feasibility evidence to inform a larger effectiveness trial, and will further our understanding of how social cohesion might influence well-being. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/28147.

A prospective observational study of patient-reported functioning and quality of life in advanced and metastatic breast cancer utilizing a novel mobile application.

PURPOSE: To assess and describe patient-reported outcomes (PROs) in women with locally advanced/unresectable or metastatic breast cancer (aBC/mBC) with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 -) status receiving palbociclib combination therapy in a US real-world setting. METHODS: A prospective, noninterventional, multicenter longitudinal study was conducted in US patients initiating treatment with palbociclib combination therapy for HR + /HER2 - aBC/mBC. PRO data (SF-12; CES-D-10; mood; pain; fatigue; interference of aBC/mBC or its treatment on family life, social life, physical activity, energy, and productivity; overall health rating; and quality of life [QOL]) were collected via a custom-developed mobile application at daily, weekly, and cycle-based intervals. Patient medical information (demographics, clinical characteristics, treatment information, and adverse events) was collected from medical records at baseline and at the end of the 6-month follow-up period. RESULTS: Patients' general health status (SF-12) remained consistent throughout treatment and was generally consistent with published norms for individuals diagnosed with cancer. The presence of depression (CES-D-10) was low and did not change substantially over time. Mean pain and fatigue scores using an 11-point numeric rating scale were low and remained stable. Patients, on average, reported neutral or positive moods. Patient-reported QOL and overall health was primarily "Good," "Very good," or "Excellent." Findings were consistent regardless of patient experience with neutropenia. CONCLUSIONS: Patients treated with palbociclib, on average, reported consistently low levels of pain and fatigue as well as good QOL and overall health that remained stable throughout the first 6 months of treatment regardless of episodes of neutropenia.

Aminoglycoside use in paediatric febrile neutropenia - Outcomes from a nationwide prospective cohort study.

Aminoglycosides are commonly prescribed to children with febrile neutropenia (FN) but their impact on clinical outcomes is uncertain and extent of guideline compliance is unknown. We aimed to review aminoglycoside prescription and additional antibiotic prescribing, guideline compliance and outcomes for children with FN. We analysed data from the Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) prospective multicentre cohort study, in children <18 years with FN between November 2016 and January 2018. Impact of aminoglycoside use in the first 12 hours of FN on composite unfavourable outcome of death, ICU admission, relapse of infection or late-onset sepsis was assessed using multivariable Cox regression. The study was conducted in Australia where antimicrobial resistance among gram negative organisms is relatively low. Data from 858 episodes of FN in 462 children from 8 centres were assessed, median age 5.8 years (IQR 3.5-10.8 years). Early empiric aminoglycosides were prescribed in 255 episodes (29.7%). Guideline non-compliance was common: in 46% (184/400) of eligible episodes, patients did not receive aminoglycosides, while aminoglycosides were prescribed in 9% (39/458) of guideline-ineligible episodes. Adjusted hazard of the composite unfavourable outcome was 3.81 times higher among patients prescribed empiric aminoglycosides than among those who weren't (95% confidence interval, 1.89-7.67), with no increased risk of unfavourable outcome in eligible patients who did not receive aminoglycosides. In a large paediatric FN cohort, aminoglycoside prescription was common and was often non-compliant with guidelines. There was no evidence for improved outcome with aminoglycosides, even in those who met guideline criteria, within a low-resistance setting. Empiric aminoglycoside prescription for children with FN requires urgent review in guidelines and in national practice.

Australian Paediatric Surveillance Unit (APSU) Annual Surveillance Report 2019.

The Australian Paediatric Surveillance Unit (APSU) has been prospectively collecting national data on rare childhood conditions since 1993, with monthly reporting of cases by paediatricians. In this report we describe annual results from studies for ten communicable diseases and complications of communicable diseases that were conducted using APSU surveillance in 2019 and place these in an historic context. Results are reported on acute flaccid paralysis, congenital cytomegalovirus infection, neonatal herpes simplex virus infection, perinatal exposure to HIV, paediatric HIV infection, severe complications of seasonal influenza, juvenile onset recurrent respiratory papillomatosis (JoRRP), congenital rubella syndrome, congenital varicella syndrome and neonatal varicella infection. APSU provides rich clinical data to complement data collected from other surveillance systems and to improve understanding and response to rare childhood infections.

Using qualitative methods for a conceptual analysis of measures of health status and presenteeism prior to a mapping study.

OBJECTIVES: The inclusion of productivity in economic evaluations is a contentious issue. Methods are currently being developed to assess how it may feasibly be included for specific interventions, such as workplace interventions (WPIs), where productivity is a key outcome. Mapping (also called cross-walking or prediction modelling) may offer a solution. Prior to producing a mapping algorithm, it is recommended that the conceptual validity between 'source' and 'target' measures be understood first. This study aimed to understand the conceptual validity of two existing measures of health status (EQ-5D; SF-6D) and presenteeism to inform the potential for a subsequent mapping algorithm. METHODS: A purposive sample of individuals who were currently working and had either rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriatic arthritis (PsA). Individuals were recruited through support groups. Semi-structured telephone interviews were conducted until data saturation (no new emerging themes) was reached. Deductive and inductive framework analysis methods were used to identify key aspects of the conditions (themes) that impact on presenteeism (working at reduced levels of health). RESULTS: Twenty-two (RA = 10; AS = 9; PsA = 3) employed individuals were interviewed. Deductive analysis identified evidence which confirmed the domains included in the EQ-5D and SF-6D capture those key aspects of RA, AS and PsA that increase presenteeism. Inductive analysis identified an additional theme; mental clarity, not captured by the EQ-5D or SF-6D, was also found to have a direct impact on presenteeism. CONCLUSIONS: The results of the study indicate conceptual validity of both health status measures to predict presenteeism. The next step is to develop a mapping algorithm for presenteeism.

Investigating the mechanism of ADP-forming acetyl-CoA synthetase from the protozoan parasite Entamoeba histolytica.

ADP-forming acetyl-CoA synthetase (ACD) catalyzes the interconversion of acetyl-CoA and acetate. The related succinyl-CoA synthetase follows a three-step mechanism involving a single phosphoenzyme, but a novel four-step mechanism with two phosphoenzyme intermediates was proposed for Pyrococcus ACD. Characterization of enzyme variants of Entamoeba ACD in which the two proposed phosphorylated His residues were individually altered revealed that only His252 is essential for enzymatic activity. Analysis of variants altered at two residues proposed to interact with the phosphohistidine loop that swings between distinct parts of the active site are consistent with a mechanism involving a single phosphoenzyme intermediate. Our results suggest ACDs with different subunit structures may employ slightly different mechanisms to bridge the span between active sites I and II.

Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis.

BACKGROUND: Despite the discovery of CSF and serum diagnostic autoantibodies in autoimmune encephalitis, there are still very limited CSF biomarkers for diagnostic and monitoring purposes in children with inflammatory or autoimmune brain disease. The cause of encephalitis is unknown in up to a third of encephalitis cohorts, and it is important to differentiate infective from autoimmune encephalitis given the therapeutic implications. AIM: To study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis. METHODS: We measured and compared 32 cytokine/chemokines using multiplex immunoassay and APRIL and BAFF using ELISA in CSF collected prior to commencing treatment from paediatric patients with confirmed acute disseminated encephalomyelitis (ADEM, n = 16), anti-NMDAR encephalitis (anti-NMDAR E, n = 11), and enteroviral encephalitis (EVE, n = 16). We generated normative data using CSF from 20 non-inflammatory neurological controls. The sensitivity of CSF cytokine/chemokines to diagnose encephalitis cases was calculated using 95th centile of control values as cut off. We correlated CSF cytokine/chemokines with disease severity and follow up outcome based on modified Rankin scale. One-way hierarchical correlational cluster analysis of molecules was performed in different encephalitis and outcome groups. RESULTS: In descending order, CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 had the best sensitivity (>79.1%) when all encephalitis patients were included. The combination of IL-6 and IFN-α was most predictive of inflammation on multiple logistic regression with area under the ROC curve 0.99 (CI 0.97-1.00). There were no differences in CSF cytokine concentrations between EVE and anti-NMDAR E, whereas ADEM showed more pronounced elevation of Th17 related (IL-17, IL-21) and Th2 (IL-4, CCL17) related cytokine/chemokines. Unlike EVE, heat map analysis showed similar clustering of cytokine/chemokine molecules in immune mediated encephalitis (ADEM and anti-NMDAR E). Th1 and B cell (CXCL13 and CXCL10) molecules clustered together in patients with severe encephalopathy at admission and worse disability at follow up in all encephalitis. There was no correlation between CSF neopterin and IFN-γ or IFN-α. CONCLUSION: A combination panel of cytokine/chemokines consisting of CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 measured using multiplex immunoassay may be used to diagnose and monitor intrathecal inflammation in the brain. Given their association with worse outcome, certain key chemokines (CXCL13, CXCL10) could represent potential therapeutic targets in encephalitis.

MicroRNA Regulation of Human Genes Essential for Influenza A (H7N9) Replication.

Influenza A viruses are important pathogens of humans and animals. While seasonal influenza viruses infect humans every year, occasionally animal-origin viruses emerge to cause pandemics with significantly higher morbidity and mortality rates. In March 2013, the public health authorities of China reported three cases of laboratory confirmed human infection with avian influenza A (H7N9) virus, and subsequently there have been many cases reported across South East Asia and recently in North America. Most patients experience severe respiratory illness, and morbidity with mortality rates near 40%. No vaccine is currently available and the use of antivirals is complicated due the frequent emergence of drug resistant strains. Thus, there is an imminent need to identify new drug targets for therapeutic intervention. In the current study, a high-throughput screening (HTS) assay was performed using microRNA (miRNA) inhibitors to identify new host miRNA targets that reduce influenza H7N9 replication in human respiratory (A549) cells. Validation studies lead to a top hit, hsa-miR-664a-3p, that had potent antiviral effects in reducing H7N9 replication (TCID50 titers) by two logs. In silico pathway analysis revealed that this microRNA targeted the LIF and NEK7 genes with effects on pro-inflammatory factors. In follow up studies using siRNAs, anti-viral properties were shown for LIF. Furthermore, inhibition of hsa-miR-664a-3p also reduced virus replication of pandemic influenza A strains H1N1 and H3N2.

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). METHODS: In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. FINDINGS: Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. INTERPRETATION: Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. FUNDING: Genentech.

Childhood hepatitis C virus infection: An Australian national surveillance study of incident cases over five years.

AIM: An estimated 1.1% of Australian adults are infected with hepatitis C virus (HCV). Many develop chronic liver disease, and some develop liver failure or hepatocellular carcinoma. HCV infection in Australian children is poorly defined. We aimed to determine the reported incidence, clinical and epidemiological features of newly diagnosed HCV infection in Australian children presenting to paediatricians. METHODS: We undertook prospective active national surveillance, using the Australian Paediatric Surveillance Unit, of incident HCV cases in children aged <15 years between 1(st) January 2003, and 31(st) December 2007. RESULTS: There were 45 confirmed cases of newly diagnosed HCV infection over five years (<1 per 100,000 children aged <15 years per year). Median age at diagnosis was 2.9 years. Positive maternal HCV serostatus was the most frequent reported risk factor for HCV infection in children (40/45). Three children (all aged > 14), were exposed through their own IV drug use. No children were co-infected with HIV and only one child was co-infected with HBV. All children were asymptomatic at diagnosis, although many had minor elevations in liver transaminases. Many clinicians reported difficulties with follow-up. CONCLUSIONS: Childhood HCV infection is uncommon in Australia, although our data likely underestimate the incidence. Only a small number of children aged <18 months was identified, despite known perinatal exposure. Opportunistic investigation of children at risk for HCV, improved education regarding vertical transmission for health care providers, and increased coordination of childhood HCV services are required to improve recognition and management of children with HCV.

Mild encephalopathy with reversible splenial lesion: an important differential of encephalitis.

Mild encephalopathy with a reversible splenial lesion (MERS) is a clinico-radiological syndrome characterized by a transient mild encephalopathy and a reversible lesion in the splenium of the corpus callosum on MRI. This syndrome has almost universally been described in children from Japan and East Asia. Here we describe seven cases of MERS occurring in Caucasian Australian children from one centre seen over a 3 year period. All patients had a fever-associated encephalopathy (n = 7), which presented with confusion (n = 4), irritability (n = 3), lethargy (n = 3), slurred speech (n = 3), drowsiness (n = 2) and hallucinations (n = 2). Other neurological symptoms included ataxia (n = 5) and seizures (n = 1). These symptoms resolved rapidly over 4-6 days followed by complete neurological recovery. In all patients, MRI performed within 1-3 days of onset of encephalopathy demonstrated a symmetrical diffusion-restricted lesion in the splenium of the corpus callosum. Three patients had additional lesions involving other parts of the corpus callosum and adjacent periventricular white matter. These same three patients had mild persisting white matter changes evident at followup MRI, while the other patients had complete resolution of radiological changes. A potential trigger was present in five of the seven cases: Kawasaki disease, Salmonella, cytomegalovirus, influenza B and adenovirus (all n = 1). Elevated white cell count (n = 4), elevated C reactive protein (n = 5) and hyponatremia (n = 6) were commonly observed. CSF was performed in four patients, which showed no pleocytosis. This case series of MERS demonstrates this condition occurs outside of East Asia and is an important differential to consider in children presenting with acute encephalopathy.

Biochemical and kinetic characterization of the recombinant ADP-forming acetyl coenzyme A synthetase from the amitochondriate protozoan Entamoeba histolytica.

Entamoeba histolytica, an amitochondriate protozoan parasite that relies on glycolysis as a key pathway for ATP generation, has developed a unique extended PPi-dependent glycolytic pathway in which ADP-forming acetyl-coenzyme A (CoA) synthetase (ACD; acetate:CoA ligase [ADP-forming]; EC 6.2.1.13) converts acetyl-CoA to acetate to produce additional ATP and recycle CoA. We characterized the recombinant E. histolytica ACD and found that the enzyme is bidirectional, allowing it to potentially play a role in ATP production or in utilization of acetate. In the acetate-forming direction, acetyl-CoA was the preferred substrate and propionyl-CoA was used with lower efficiency. In the acetyl-CoA-forming direction, acetate was the preferred substrate, with a lower efficiency observed with propionate. The enzyme can utilize both ADP/ATP and GDP/GTP in the respective directions of the reaction. ATP and PPi were found to inhibit the acetate-forming direction of the reaction, with 50% inhibitory concentrations of 0.81 ± 0.17 mM (mean ± standard deviation) and 0.75 ± 0.20 mM, respectively, which are both in the range of their physiological concentrations. ATP and PPi displayed mixed inhibition versus each of the three substrates, acetyl-CoA, ADP, and phosphate. This is the first example of regulation of ACD enzymatic activity, and possible roles for this regulation are discussed.