Immune biomarker evaluation of sequential tyrosine kinase inhibitor and nivolumab monotherapies in renal cell carcinoma: the phase I TRIBE trial.

Background: Predictive biomarkers for immune checkpoint blockade in the second-line treatment of metastatic renal cell carcinoma (mRCC) are lacking. Materials and methods: Patients with histologically confirmed RCC who started nivolumab after at least 4 months of tyrosine kinase inhibitors (TKIs) were recruited for this study. Serial tissue and blood samples were collected for immune biomarker evaluation. The primary endpoint was to determine the association of specific T-cell subsets with clinical outcomes tested using Wilcoxon rank sum for clinical benefit rate (CBR) and log-rank test for progression-free survival (PFS). Results: Twenty patients were included in this trial with a median age of 64 years and followed-up for a median of 12 months. The median PFS for patients who received TKI was 13.8 months, while for those subsequently treated with nivolumab following TKI therapy, the median PFS was 2.6 months. CBR of nivolumab was 20% with two partial responses. Functionally active programmed cell death protein 1+ CD4+ T cells were enriched in non-responders (q = 0.003) and associated with worse PFS on nivolumab (P = 0.04). Responders showed a significant reduction in the effector CD4+T-cell (TEF) fraction compared to non-responders at 3 months on nivolumab (0.40 versus 0.80, P = 0.0005). CD127+CD4+ T cells were enriched in patients who developed immune-related adverse effects (q = 0.003). Using in-house validated multiplex immunohistochemistry for six markers, we measured tumour-associated immune cell densities in tissue samples. Responders to nivolumab showed a significantly higher mean of immune cell densities in tissue samples compared to non-responders (346 versus 87 cells/mm2, P = 0.04). Conclusions: In this small study, analysis of tissue-based and peripheral blood immune cell subsets predicted clinical outcomes of nivolumab. Further studies are warranted with larger populations to validate these observations.

Multimodal decoding of human liver regeneration.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

Validation of the emergency surgery score (ESS) in a UK patient population and comparison with NELA scoring: a retrospective multicentre cohort study.

INTRODUCTION: Accurate risk scoring in emergency general surgery (EGS) is vital for consent and resource allocation. The emergency surgery score (ESS) has been validated as a reliable preoperative predictor of postoperative outcomes in EGS but has been studied only in the US population. Our primary aim was to perform an external validation study of the ESS in a UK population. Our secondary aim was to compare the accuracy of ESS and National Emergency Laparotomy Audit (NELA) scores. METHODS: We conducted an observational cohort study of adult patients undergoing emergency laparotomy over three years in two UK centres. ESS was calculated retrospectively. NELA scores and all other variables were obtained from the prospectively collected Emergency Laparotomy and Laparoscopic Scottish Audit (ELLSA) database. The primary and secondary outcomes were 30-day mortality and postoperative intensive care unit (ICU) admission, respectively. RESULTS: A total of 609 patients were included. Median age was 65 years, 52.7% were female, the overall mortality was 9.9% and 23.8% were admitted to ICU. Both ESS and NELA were equally accurate in predicting 30-day mortality (c-statistic=0.78 (95% confidence interval (CI), 0.71-0.85) for ESS and c-statistic=0.83 (95% CI, 0.77-0.88) for NELA, p=0.196) and predicting postoperative ICU admission (c-statistic=0.76 (95% CI, 0.71-0.81) for ESS and 0.80 (95% CI, 0.76-0.85) for NELA, p=0.092). CONCLUSIONS: In the UK population, ESS and NELA both predict 30-day mortality and ICU admission with no statistically significant difference but with higher c-statistics for NELA score. Both scores have certain advantages, with ESS being validated for a wider range of outcomes.

Relationship between surface dissolved iron inventories and net community production during a marine heatwave in the subarctic northeast Pacific.

From winter 2013-14 to the end of 2015-16, a high pressure atmospheric system induced elevated sea surface temperatures in the offshore subarctic northeast Pacific, resulting in a marine heatwave. Increased stratification due to the heatwave resulted in shoaling of the winter mixed layer and a decrease in nutrient re-supply to the euphotic zone. Here, we investigate relationships between dissolved iron (dFe) and macronutrients, net community production (NCP), (micro)nutrient uptake ratios, and phytoplankton community composition in the winter and summer from 2012 to 2015 to gain insight into coupled biogeochemical responses to the heatwave. Our investigation highlights the importance of external dFe supply during marine heatwave events, as a more shallow mixed layer reduces the transport of essential (micro)macronutrients to the surface layer. We conclude that recycled dFe did not contribute to NCP in 2014, but rather the vertical displacement of dFe rich water unrelated to mixed layer deepening played a major role. In 2015, such transport was not detected, resulting in abnormally low dFe and shift toward higher biomass of pico- and nano-phytoplankton size-classes.

Parry Romberg Syndrome in a Young Ghanaian: A Case Report and a Literature Review.

Parry Romberg syndrome (PRS), also known as progressive hemifacial atrophy, is a very rare self-limiting disease, which affects the skin and subcutaneous tissues, underlying musculature, cartilage, and bony structures of one half of the face with a resultant hemiatrophy and alopecia areata. It presents in children and young adults, with a slow progression of the atrophy for several years, and then becomes stable. Magnetic resonance imaging (MRI) or computed tomography (CT) scan of the cranium demonstrates the radiological feature of hemiatrophy very clearly. We report a case of PRS in a nine-year-old girl with characteristic features which was diagnosed based on medical history, clinical signs, and radiological findings on cranial CT scan and MRI.

Practice variation in the diagnosis of acute rejection among pediatric heart transplant centers: An analysis of the pediatric heart transplant society (PHTS) registry.

BACKGROUND: Freedom from rejection in pediatric heart transplant recipients is highly variable across centers. This study aimed to assess the center variation in methods used to diagnose rejection in the first-year post-transplant and determine the impact of this variation on patient outcomes. METHODS: The PHTS registry was queried for all rejection episodes in the first-year post-transplant (2010-2019). The primary method for rejection diagnosis was determined for each event as surveillance biopsy, echo diagnosis, or clinical. The percentage of first-year rejection events diagnosed by surveillance biopsy was used to approximate the surveillance strategy across centers. Methods of rejection diagnosis were described and patient outcomes were assessed based on surveillance biopsy utilization among centers. RESULTS: A total of 3985 patients from 56 centers were included. Of this group, 873 (22%) developed rejection within the first-year post-transplant. Surveillance biopsy was the most common method of rejection diagnosis (71.7%), but practices were highly variable across centers. The majority (73.6%) of first rejection events occurred within 3-months of transplantation. Diagnosis modality in the first-year was not independently associated with freedom from rejection, freedom from rejection with hemodynamic compromise, or overall graft survival. CONCLUSIONS: Rejection in the first-year after pediatric heart transplant occurs in 22% of patients and most commonly in the first 3 months post-transplant. Significant variation exists across centers in the methods used to diagnose rejection in pediatric heart transplant recipients, however, these variable strategies are not independently associated with freedom from rejection, rejection with hemodynamic compromise, or overall graft survival.

Investigating surface binding effects: antibacterial efficacy of bound 8-hydroxyquinoline against Staphylococcus aureus and Escherichia coli.

AIMS: To investigate the binding of the antimicrobial compound 8-hydroxyquinoline (8HQ) to a material interface and to determine whether immobilization affects the antibacterial efficacy. METHODS AND RESULTS: The 8HQ derivative 5-carboxy-8-hydroxyquinoline (5C8HQ) was attached to silica beads through amide bond coupling at the carboxyl moiety of 5C8HQ. Attachment of 5C8HQ was confirmed using a combination of mass spectrometry, thermogravimetric analysis, colorimetric testing and Soxhlet extraction. Computational modelling results indicated that this substitution did not compromise the active sites on the molecule, whereas other positions on the ring system could potentially inhibit antimicrobial activity. The antibacterial effect of 8HQ and the 5C8HQ-modified silica complex against Escherichia coli 15597 (ATCC® 25922) and Staphylococcus aureus (ATCC 25923) was evaluated. CONCLUSIONS: The test results show that the immobilized 8HQ continues to exhibit antibacterial activity, however, quantifying the efficacy compared to free 8HQ bears further investigation. The expected antibacterial mechanism requires that the metal chelation site of 8HQ be retained and available after attachment to a surface. The retention of antibacterial activity after surface bonding represents a novel mechanism of action not previously reported. SIGNIFICANCE AND IMPACT OF THE STUDY: Recent changes in regulations due to environmental concerns prompted many companies and organizations to explore antimicrobial treatments that are chemically bound to the product. Chemically bonding biocidal compounds to a surface limits environmental release; however, molecular mechanisms that drive antibacterial activity when compounds are immobilized are limited. The results reported here demonstrate that the 8HQ reactive site retains antibacterial efficacy even after covalent attachment to a surface. This approach supersedes other antimicrobial treatments where the active component is gradually released from the material surface in order to elicit antimicrobial effects. This specific antibacterial activity of bound 8HQ represents a novel mechanism of action not previously reported, and a potential conduit to a new class of bound antimicrobial materials.

Clinical characteristics and long-term outcome of E. coli-associated granulomatous ileocolitis in dogs: five cases (2010-2014).

OBJECTIVES: To describe the clinical characteristics and long-term outcome of Escherichia coli-associated granulomatous ileocolitis in dogs. METHODS: Retrospective review of medical records from dogs with periodic acid-Schiff positive (PAS+) granulomatous ileocolitis and mucosally invasive E. coli in the ileum and colon. Initial bacterial colonisation was evaluated using fluorescence in situ hybridization (FISH) in all dogs and corroborated with colonic and/or ileal culture, when performed. RESULTS: Four boxer dogs and 1 French Bulldog with PAS+ granulomatous ileocolitis (GIC) were evaluated. All dogs had chronic diarrhoea refractory to empirical therapy. Ileocolonoscopy revealed mucosal haemorrhage and ulceration in the ileum (3/4) and colon (5/5). E. coli were visualised as clusters within the ileal and colonic mucosa. Complete (CR, 4/5) or partial (PR, 1/5) clinical response to fluoroquinolones was noted in all dogs within 30 days. CR was sustained in three of four dogs (median disease-free interval 40 months, range 16 to 60). Two dogs relapsed while receiving fluoroquinolones. Repeat biopsy isolated multidrug-resistant, mucosally invasive E. coli in the ileum (1/2) and colon (2/2). Targeted antimicrobial therapy was associated with long-term PR (78 months) in both dogs. CLINICAL SIGNIFICANCE: Concurrent E. coli-associated granulomatous inflammation in the ileum and colon did not impart a poor clinical outcome or lack of response to the conventional standard of care for granulomatous colitis in dogs that were aggressively diagnosed and treated. Clinical outcome was influenced by antimicrobial resistance, with response dependent upon antimicrobial therapy informed by susceptibility testing.

Re-expression of miR-200s in claudin-low mammary tumor cells alters cell shape and reduces proliferation and invasion potentially through modulating other miRNAs and SUZ12 regulated genes.

BACKGROUND: MicroRNAs are a class of non-coding RNAs that regulate gene expression through binding to mRNAs and preventing their translation. One family of microRNAs known as the miR-200 family is an important regulator of epithelial identity. The miR-200 family consists of five members expressed in two distinct clusters; the miR-200c/141 cluster and the miR-200b/200a/429 cluster. We have found that murine and human mammary tumor cells with claudin-low characteristics are associated with very low levels of all five miR-200s. METHODS: To determine the impact of miR-200s on claudin-low mammary tumor cells, the miR-200c/141 cluster and the miR-200b/200a/429 cluster were stably re-expressed in murine (RJ423) and human (MDA-MB-231) claudin-low mammary tumor cells. Cell proliferation and migration were assessed using BrdU incorporation and transwell migration across Matrigel coated inserts, respectively. miRNA sequencing and RNA sequencing were performed to explore miRNAs and mRNAs regulated by miR-200 re-expression while Enrichr-based pathway analysis was utilized to identify cellular functions modified by miR-200s. RESULTS: Re-expression of the miR-200s in murine and human claudin-low mammary tumor cells partially restored an epithelial cell morphology and significantly inhibited proliferation and cell invasion in vitro. miRNA sequencing and mRNA sequencing revealed that re-expression of miR-200s altered the expression of other microRNAs and genes regulated by SUZ12 providing insight into the complexity of miR-200 function. SUZ12 is a member of the polycomb repressor complex 2 that suppresses gene expression through methylating histone H3 at lysine 27. Flow cytometry confirmed that re-expression of miR-200s increased histone H3 methylation at lysine 27. CONCLUSIONS: Re-expression of miR-200s in claudin-low mammary tumor cells alters cell morphology and reduces proliferation and invasion, an effect potentially mediated by SUZ12-regulated genes and other microRNAs.

Development of a cost-effective automated platform to produce human liver spheroids for basic and applied research.

Liver disease represents an increasing cause of global morbidity and mortality. Currently, liver transplant is the only treatment curative for end-stage liver disease. Donor organs cannot meet the demand and therefore scalable treatments and new disease models are required to improve clinical intervention. Pluripotent stem cells represent a renewable source of human tissue. Recent advances in three-dimensional cell culture have provided the field with more complex systems that better mimic liver physiology and function. Despite these improvements, current cell-based models are variable in performance and expensive to manufacture at scale. This is due, in part, to the use of poorly defined or cross-species materials within the process, severely affecting technology translation. To address this issue, we have developed an automated and economical platform to produce liver tissue at scale for modelling disease and small molecule screening. Stem cell derived liver spheres were formed by combining hepatic progenitors with endothelial cells and stellate cells, in the ratios found within the liver. The resulting tissue permitted the study of human liver biology 'in the dish' and could be scaled for screening. In summary, we have developed an automated differentiation system that permits reliable self-assembly of human liver tissue for biomedical application. Going forward we believe that this technology will not only serve as anin vitroresource, and may have an important role to play in supporting failing liver function in humans.

Quantifying Soft Tissue Artefacts and Imaging Variability in Motion Capture of the Fingers.

This study assessed the accuracy of marker-based kinematic analysis of the fingers, considering soft tissue artefacts (STA) and marker imaging uncertainty. We collected CT images of the hand from healthy volunteers with fingers in full extension, mid- and full-flexion, including motion capture markers. Bones and markers were segmented and meshed. The bone meshes for each volunteer's scans were aligned using the proximal phalanx to study the proximal interphalangeal joint (PIP), and using the middle phalanx to study the distal interphalangeal joint (DIP). The angle changes between positions were extracted. The HAWK protocol was used to calculate PIP and DIP joint flexion angles in each position based on the marker centroids. Finally the marker locations were 'corrected' relative to the underlying bones, and the flexion angles recalculated. Static and dynamic marker imaging uncertainty was evaluated using a wand. A strong positive correlation was observed between marker- and CT-based joint angle changes with 0.980 and 0.892 regression slopes for PIP and DIP, respectively, and Root Mean Squared Errors below 4°. Notably for the PIP joint, correlation was worsened by STA correction. The 95% imaging uncertainty interval was < ± 1° for joints, and < ± 0.25 mm for segment lengths. In summary, the HAWK marker set's accuracy was characterised for finger joint flexion angle changes in a small group of healthy individuals and static poses, and was found to benefit from skin movements during flexion.

Novel phase I trial design to evaluate the addition of cediranib or selumetinib to preoperative chemoradiotherapy for locally advanced rectal cancer: the DREAMtherapy trial.

BACKGROUND: The DREAMtherapy (Dual REctal Angiogenesis MEK inhibition radiotherapy) trial is a novel intertwined design whereby two tyrosine kinase inhibitors (cediranib and selumetinib) were independently evaluated with rectal chemoradiotherapy (CRT) in an efficient manner to limit the extended follow-up period often required for radiotherapy studies. PATIENTS AND METHODS: Cediranib or selumetinib was commenced 10 days before and then continued with RT (45 Gy/25#/5 wks) and capecitabine (825 mg/m2 twice a day (BID)). When three patients in the cediranib 15-mg once daily (OD) cohort were in the surveillance period, recruitment to the selumetinib cohort commenced. This alternating schedule was followed throughout. Three cediranib (15, 20 and 30 mg OD) and two selumetinib cohorts (50 and 75 mg BID) were planned. Circulating and imaging biomarkers of inflammation/angiogenesis were evaluated. RESULTS: In case of cediranib, dose-limiting diarrhoea, fatigue and skin reactions were seen in the 30-mg OD cohort, and therefore, 20 mg OD was defined as the maximum tolerated dose. Forty-one percent patients achieved a clinical or pathological complete response (7/17), and 53% (9/17) had an excellent clinical or pathological response (ECPR). Significantly lower level of pre-treatment plasma tumour necrosis factor alpha (TNFα) was found in patients who had an ECPR. In case of selumetinib, the 50-mg BID cohort was poorly tolerated (fatigue and diarrhoea); a reduced dose cohort of 75-mg OD was opened which was also poorly tolerated, and further recruitment was abandoned. Of the 12 patients treated, two attained an ECPR (17%). CONCLUSIONS: This novel intertwined trial design is an effective way to independently investigate multiple agents with radiotherapy. The combination of cediranib with CRT was well tolerated with encouraging efficacy. TNFα emerged as a potential predictive biomarker of response and warrants further evaluation.

A One Health investigation of Salmonella enterica serovar Wangata in north-eastern New South Wales, Australia, 2016-2017.

Salmonella enterica serovar Wangata (S. Wangata) is an important cause of endemic salmonellosis in Australia, with human infections occurring from undefined sources. This investigation sought to examine possible environmental and zoonotic sources for human infections with S. Wangata in north-eastern New South Wales (NSW), Australia. The investigation adopted a One Health approach and was comprised of three complimentary components: a case-control study examining human risk factors; environmental and animal sampling; and genomic analysis of human, animal and environmental isolates. Forty-eight human S. Wangata cases were interviewed during a 6-month period from November 2016 to April 2017, together with 55 Salmonella Typhimurium (S. Typhimurium) controls and 130 neighbourhood controls. Indirect contact with bats/flying foxes (S. Typhimurium controls (adjusted odds ratio (aOR) 2.63, 95% confidence interval (CI) 1.06-6.48)) (neighbourhood controls (aOR 8.33, 95% CI 2.58-26.83)), wild frogs (aOR 3.65, 95% CI 1.32-10.07) and wild birds (aOR 6.93, 95% CI 2.29-21.00) were statistically associated with illness in multivariable analyses. S. Wangata was detected in dog faeces, wildlife scats and a compost specimen collected from the outdoor environments of cases' residences. In addition, S. Wangata was detected in the faeces of wild birds and sea turtles in the investigation area. Genomic analysis revealed that S. Wangata isolates were relatively clonal. Our findings suggest that S. Wangata is present in the environment and may have a reservoir in wildlife populations in north-eastern NSW. Further investigation is required to better understand the occurrence of Salmonella in wildlife groups and to identify possible transmission pathways for human infections.

Eubacterial fluorescence in situ hybridisation and histologic features in 25 dogs with gallbladder mucocele.

OBJECTIVES: To detect and localise bacteria in gallbladder mucoceles using fluorescence in situ hybridisation (FISH). To report clinical signs, clinicopathologic abnormalities, sonographic findings and histopathological findings in FISH+ and FISH- dogs with gallbladder mucoceles. MATERIALS AND METHODS: Retrospective review of signalment, clinical signs, clinicopathologic and sonographic findings of 25 cases of histopathologically confirmed gallbladder mucocele. Histopathological sections of gallbladder mucocele were evaluated for cystic mucinous hyperplasia, cystic mucinous hyperplasia with cholecystitis and rupture. The number and spatial distribution of bacteria was determined by eubacterial FISH. Gallbladder contents were cultured in 21 dogs. RESULTS: Bacteria were detected within or adherent to the gallbladder wall in eight of 25 (32%) cases. Bacterial culture was positive in one dog. Cystic mucinous hyperplasia with concurrent cholecystitis was found in 17 of 25 (68%) of dogs with gallbladder mucocele. CLINICAL SIGNIFICANCE: FISH was more sensitive for detection of bacteria in gallbladder mucoceles when compared to bacterial culture of bile. Cholecystitis was common in dogs with gallbladder mucocele. Further study is required to elucidate the relationship of cystic mucinous hyperplasia, bacteria and cholecystitis in the aetiopathogenesis and progression of gallbladder mucocele.

Long-term outcome of primary immune-mediated thrombocytopenia in dogs.

OBJECTIVES: To determine the incidence of relapse after discharge from the hospital in dogs with a diagnosis of presumed primary immune-mediated thrombocytopenia, risk factors associated with relapse and whether or not indefinite use of immunosuppressive medication influences risk of relapse. MATERIALS AND METHODS: Medical records from August 2007 through July 2016 were reviewed to identify dogs with a diagnosis of presumed primary immune-mediated thrombocytopenia. Data collection included signalment, initial diagnostic tests, treatment, incidence of relapse, survival duration and follow-up testing. RESULTS: A total of 45 dogs were diagnosed, treated and monitored for at least one year for presumed primary immune-mediated thrombocytopenia. 89∙6% of patients survived to discharge and 31% of those experienced a relapse following discharge. The median time from diagnosis to relapse was 79 days. Of dogs that experienced a relapse, 50% had at least one further relapse. There was no difference in age, body weight, gender, breed, platelet count at presentation, nadir packed cell volume during hospitalisation, incidence of melaena or initial treatment between the relapsing and non-relapsing groups. In the relapsing group, time to platelet recovery was significantly longer and these patients were more likely to have received a blood transfusion. CLINICAL SIGNIFICANCE: This study does not provide evidence to support the use of long-term immunosuppressive medications to prevent relapse. However, the data suggest that patients with more severe disease at the time of diagnosis or that have already experienced a relapse should be monitored more closely.

Challenges in the diagnosis of leptospirosis outwith endemic settings: a Scottish single centre experience.

Background Leptospirosis is a zoonotic infection occurring worldwide but endemic in tropical countries. This study describes diagnostic testing for leptospirosis at our institution in Scotland over a 10-year period. Method We identified patients with blood samples referred to the Public Health England reference laboratory for leptospirosis testing between 2006 and 2016. Results A total of 480 samples were sent for IgM ELISA testing with 26 positive results from 14 patients. Two patients met criteria for 'confirmed' leptospirosis (microscopic agglutination test > 1:320 in one case and a positive PCR in the other) and the remaining 12 were 'probable' on the basis of IgM ELISA positivity, though 9 did not have microscopic agglutination testing performed. Nine infections were imported, mostly from Asia and with a history of fresh water exposure. Three co-infections (respiratory syncytial virus, influenza B and Campylobacter sp.) were identified. Conclusions Practical issues with microscopic agglutination testing (insufficient blood sent to reference laboratory) and PCR (travellers returning > 7 days after illness onset) represent challenges to the laboratory confirmation of a clinical diagnosis of leptospirosis. Co-infection and infectious/auto-immune causes of false positive serology should be evaluated.

Systematic review: non A-E, seronegative or indeterminate hepatitis; what is this deadly disease?

BACKGROUND: A significant proportion of cases of acute liver failure (ALF) do not have an identifiable cause; so called "non A-E," "non A, non B, non C," "seronegative" or "indeterminate" hepatitis. However, this entity is clinically not well described. AIM: To collate the known incidence and outcomes in indeterminate hepatitis. This systematic review sought to identify potential aetiologies that ought to be considered, and identify likely future objectives in classification and treatment strategies for indeterminate hepatitis. METHODS: Literature review to determine aetiological factors, prevalence and outcomes relating to indeterminate hepatitis. RESULTS: There is significant heterogeneity within the reported cases of indeterminate hepatitis in the literature. Some of the potential infective aetiologies which are reviewed here include: parvovirus B19 (PVB19), herpes simplex virus (HSV), Toga-Like Virus and the Annelloviridae (including SEN-V). Interestingly, this condition predominately affects middle aged women, with subacute progression of the liver failure. In addition, the prognosis of indeterminate hepatitis is poor, with reduced spontaneous survival compared with other causes of acute liver failure and increased need for emergency liver transplantation. CONCLUSIONS: Whilst various pathological processes have been implicated in the development of indeterminate hepatitis, the specific cause remains elusive. There is an urgent need for general consensus on a specific definition and exclusion of confounding aetiologies with coordinated multicentre investigation of this rare condition to identify aetiology and develop therapies to reduce the significant mortality and need for emergency liver transplantation associated with this condition.

Participation of children on the autism spectrum in home, school, and community.

BACKGROUND: Children on the autism spectrum participate less frequently, and in a narrower range of activities, than their nonautistic peers, but little is known about exact participation patterns across contexts or how this is perceived by caregivers. This study aimed to document patterns of participation and caregiver views with regard to frequency and intensity of activities. METHOD: Caregivers of children on the spectrum aged 5 (n = 90) and 9-10 years (n = 128) completed the Participation and Environment Measure for Children and Youth for home, school, and community. Caregivers reported on frequency of child's participation, level of involvement, and caregivers' desire for change in participation patterns. RESULTS: Item-level analyses revealed similar patterns of participation across home, school, and community for both cohorts with some small age-appropriate differences. Caregivers generally desired increased diversity, frequency, and involvement in activities but a decreased use of electronics (computers, games, TV, and DVDs). CONCLUSION: The possibility of autism-specific participation patterns could inform future interventions aimed at enhancing social inclusion. This warrants further investigation through multiinformant designs that seek the perspectives of the child and caregivers.