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We determine the algebra of holonomy symmetries of sigma models propagating on supersymmetric heterotic backgrounds with a non-compact holonomy group. We demonstrate that these close as a W-algebra, which in turn is specified by a Lie algebra structure on the space of covariantly constant forms that generate the holonomy symmetries. In addition, we identify the chiral anomalies associated with these symmetries. We argue that these anomalies are consistent and can be cancelled up to two loops in the sigma model perturbation theory.

Abstract We present the twisted covariant form hierarchies (TCFHs) of warped (massive) IIA AdS backgrounds. As a consequence we demonstrate that all Killing spinor form bilinears satisfy a generalisation of the conformal Killing-Yano equation with respect to the TCFH connections. We also explore some of the properties of TCFHs which include the reduced holonomy of the minimal TCFH connections for generic backgrounds. Furthermore, we investigate the interplay between TCFHs and hidden symmetries of probes propagating on IIA AdS backgrounds. We find that some of the Killing spinor form bilinears of near horizon geometries of a class of IIA intersecting brane configurations are Killing-Yano forms and so generate hidden symmetries for spinning particle probes.

Abstract We present the twisted covariant form hierarchies (TCFH) of type IIA and IIB 10-dimensional supergravities and show that all form bilinears of supersymmetric backgrounds satisfy the conformal Killing-Yano equation with respect to a TCFH connection. We also compute the Killing-Stäckel, Killing-Yano and closed conformal Killing-Yano tensors of all spherically symmetric type II brane backgrounds and demonstrate that the geodesic flow on these solutions is completely integrable by giving all independent charges in involution. We then identify all form bilinears of common sector and D-brane backgrounds which generate hidden symmetries for particle and string probe actions. We also explore the question on whether charges constructed from form bilinears are sufficient to prove the integrability of probes on supersymmetric backgrounds.

Abstract Background Additive manufacturing has allowed for the creation of a patient-specific custom solution that can resolve many of the limitations previously reported for canine cranioplasty. The purpose of this pilot study was to determine the schedule feasibility and workflow in manufacturing patient-specific titanium implants for canines undergoing cranioplasty immediately following craniectomy. Results Computed tomography scans from patients with tumors of the skull were considered and 3 cases were selected. Images were imported into a DICOM image processing software and tumor margins were determined based on agreement between a board-certified veterinary radiologist and veterinary surgical oncologist. Virtual surgical planning was performed and a bone safety margin was selected. A defect was created to simulate the planned intraoperative defect. Stereolithography format files of the skulls were then imported into a plate design software. In collaboration with a medical solution centre, a custom titanium plate was designed with the input of an applications engineer and veterinary surgery oncologist. Plates were printed in titanium and post-processed at the solution centre. Total planning time was approximately 2 h with a manufacturing time of 2 weeks. Conclusions Based on the findings of this study, with access to an advanced 3D metal printing medical solution centre that can provide advanced software and printing, patient-specific additive manufactured titanium implants can be planned, created, processed, shipped and sterilized for patient use within a 3-week turnaround.

People across the world are running on a daily basis to improvetheir health status. However, running can predispose an individual to injuryto the back and lower limb. Baseline data on prevalence, incidence rate ofinjury and aetiological factors associated with running injuries are neededby physiotherapists to develop and implement effective prevention programmesto allow optimal performance in runners. Thus, the purpose of this study wasto determine the prevalence and incidence of injuries in runners at a localathletic club.Methods: A prospective, non-experimental cohort study was conductedover a 16 week period. A sample of 50 runners completed a self-administeredquestionnaire and an injury report form recording injuries sustained during the 16 week study period. Injury prevalence andcumulative incidence was calculated as a proportion rate along with 95% confidence interval.Results: The prevalence rate of injuries was 32%. The incidence rate of injuries was 0.67 per 1000km run (95% CI: 0.41- 1.08).The most common anatomical sites for new injuries were the calf (20%) and the knee (18%).Conclusions: The study found a moderate prevalence and incidence rate of injury in runners, thus the need for physiotherapyledinjury surveillance and prevention programmes have been highlighted.

Under conditions of repeated exposure to ethanol, a sensitized locomotor stimulant response develops in some strains of mice. It has been hypothesized that the sensitized response is a consequence of tolerance development to the sedative/incoordinating effects of ethanol. Conversely, ethanol-induced sensitization and tolerance may be independent effects of repeated ethanol exposure. A published study in C57BL/6J by DBA/2J recombinant inbred strains concluded that the two phenomena are not genetically related and thus perhaps mechanistically distinct. To extend evaluation beyond the genetic variance found in C57BL/6J and DBA/2J mice and examine phenotypic associations, we simultaneously measured ethanol-induced sensitization and tolerance in a genetically diverse panel of 15 standard inbred mouse strains and a genetically heterogeneous stock that was produced by the intercrossing of eight inbred mouse strains. Changes in activity counts and ataxia ratio across repeated ethanol treatments indexed sensitization and tolerance, respectively. Photocell beam breaks provided the measure of activity, and foot slip errors corrected for activity in a grid test provided a measure of coordination. The results were strain and individual dependent. The genetic correlation between magnitude of sensitization and tolerance was not significant in the panel of inbred strains, but when individual data were correlated, without regard to strain, there was a significant correlation. This relationship was also significant in the genetically heterogeneous population of mice. However, magnitude of tolerance explained only 10% of the variance in sensitization among individuals of the inbred strain population, whereas it explained 44% of the variance among individuals of the eight-strain cross. When repeated exposures to ethanol were disassociated from the test apparatus, this relationship in the eight-strain cross disappeared. Furthermore, days to peak sensitization and tolerance across days did not perfectly mirror each other. Overall, our data do not support shared genetic mechanisms in sensitization and tolerance development but suggest a partial relationship among individuals that could be related to drug–environment associations.

Abstract In this global phase 2 study in patients with relapsed/refractory follicular lymphoma (FL), zandelisib was administered on intermittent dosing to mitigate immune‐related adverse events and infections that have been reported with oral PI3Kδ inhibitors administered daily continuously. Eligible patients with measurable disease and progression after at least two prior therapies were administered zandelisib until disease progression or intolerability. The primary efficacy endpoint was objective response rate (ORR) and the key secondary efficacy endpoint was duration of response (DOR). We report on 121 patients with FL administered zandelisib on intermittent dosing after 8 weeks of daily dosing for tumor debulking. The median number of prior therapies was 3 (range, 2–8) and 45% of patients had refractory disease. The ORR was 73% (95% confidence interval [CI], 63.9–80.4), the complete response (CR) rate was 38% (95% CI, 29.3–47.3), and the median DOR was 16.4 months (95% CI, 9.5–not reached). With a median follow‐up of 14.3 months (range, 1–30.5), the median progression‐free survival was 11.6 months (95% CI, 8.3–not reached). Twenty‐one patients (17%) discontinued therapy due to an adverse event. Grade 3–4 class‐related toxicities included 6% diarrhea, 5% lung infections, 3% colitis (confirmed by biopsy or imaging), 3% rash, 2% AST elevation, and 1% non‐infectious pneumonitis. Zandelisib achieved a high rate of durable responses in heavily pretreated patients with relapsed/refractory FL. The intermittent dosing resulted in a relatively low incidence of severe class‐related toxicities, which supports the evaluation of zandelisib as a single agent and in combination with indolent B‐cell malignancies.

Background: Severe cutaneous adverse reactions (SCAR) are a group of delayed presumed T-cell mediated hypersensitivities associated with significant morbidity and mortality. Despite their shared global healthcare burden and impact, the clinical phenotypes, genomic predisposition, drug causality, and treatment outcomes may vary. We describe the establishment and results from the first Australasian registry for SCAR (AUS-SCAR), that via a collaborative network advances strategies for the prevention, diagnosis and treatment of SCAR. Methods: Prospective multi-center registry of SCAR in Australian adult and adolescents, with planned regional expansion. The registry collects externally verified phenotypic data drug causality, therapeutics and long-term patient outcomes. In addition, biorepository specimens and DNA are collected at participating sites. Results: we report on the first 100 patients enrolled in the AUS-SCAR database. DRESS (50%) is the most predominant phenotype followed by SJS/TEN (39%) and AGEP (10%), with median age of 52 years old (IQR 37.5, 66) with 1:1 male-to-female ratio. The median latency for all implicated drugs is highly variable but similar for DRESS (median 15 days IQR 5,25) and SJS/TEN (median 21 days, IQR 7,27), while lowest for AGEP (median 2.5 days, IQR 1,8). Antibiotics (54.5%) are more commonly listed as primary implicated drug compare with non-antibiotics agent (45.5%). Mortality rate at 90 days was highest in SJS/TEN at 23.1%, followed by DRESS (4%) and AGEP (0%). Conclusion: In the first prospective national phenotypic and biorepository of SCAR in the southern hemisphere we demonstrate notable differences to other reported registries; including DRESS-predominant phenotype, varied antibiotic causality and low overall mortality rate. This study also highlights the lack of standardised preventative pharmacogenomic measures and in vitro/in vivo diagnostic strategies to ascertain drug causality. Trial registration: ANZCTR ACTRN12619000241134. Registered 19 February 2019.

Tapeworms of the genus Spirometra Faust, Campbell et Kellogg, 1929 have long been known as intestinal parasites of carnivores and their larvae (spargana) have been found in various vertebrates. Nevertheless, their species diversity, host associations and geographical distribution remain poorly understood. Molecular data clearly confirm the validity of the genus, which has been synonymised by several authors with Diphyllobothrium Cobbold, 1858. Despite morphological similarities between the species of the two genera, they are not closely related and also differ in their life cycle. The present review provides a list of the species recognised as valid and additional genotypes that may represent other species, with a basic characterisation of each taxon and comments on their validity, the probable range of definitive and intermediate hosts, and their distribution. The existing taxonomic problems and the insufficient knowledge of the host specificity and distribution of Spirometra tapeworms can only be solved by combining molecular and morphological data, i.e. by comparing genetically characterised specimens with corresponding morphological vouchers (hologenophores). Further targeted sampling and surveys are required to clarify the distribution and host associations.

Abstract The shared functions of the skull are thought to result in common evolutionary patterns in mammalian cranial shape. Craniofacial evolutionary allometry (CREA) is a particularly prominent pattern where larger species display proportionally elongate facial skeletons and smaller braincases. It was recently proposed that CREA arises from biomechanical effects of cranial scaling when diets are similar. Thus, deviations from CREA should occur with changes in cranial biomechanics, for example due to dietary change. Here, we test this using 3D geometric morphometric analysis in a dataset of Australian murine crania, which are highly allometric. We contrast allometric and non‐allometric variation in the cranium by comparing evolutionary mode, allometry, ordinations, as well as allometry, integration, and modularity in functional modules. We found evidence of stabilising selection in allometry‐containing and size‐free shape, and substantial non‐allometric variation aligned with dietary specialisation in parallel with CREA. Integration among cranial modules was higher, and modularity lower, with size included, but integration between rostrum and cranial vault, which are involved in the CREA pattern, dropped dramatically after size removal. Our results thus support the hypothesis that CREA is a composite arising from selection on cranial function, with substantial non‐allometric shape variation occurring alongside CREA where dietary specialisation impacts selection on gnawing function. This emphasises the need to research mammalian cranial evolution in the context of allometric and non‐allometric selection on biomechanical function.

A growing shift towards research and evidence based practice in academia is associated with requirements to disseminate research results in the form of publication in peer reviewed journals. Mentoring has been identified as an important component of developing young authors, as it increases confidence and competence, and facilitates professional development. This led to the formation of a support group to stimulate peer-review publication in the physiotherapy department at the University of the Western Cape. The Kirkpatrick Framework of Evaluation was used to evaluate the success of the mentoring process which made use of a participatory action research methodology. The writing group consisted of nine academic members of staff and took place over ten weeks. The programme included writing, giving feedback, discussion and peer review on a weekly basis. Focus group discussions were taped and transcribed in order to evaluate the mentoring process by identifying relationships within the data and categorising key concepts, which were shaped into a thematic framework. The findings indicated that participants experienced a variety of emotions throughout the programme, with an overall feeling of personal growth by the end. In addition, participants also reported improved writing, reviewing and communication skills. Six months following the programme, six participants had submitted at least one article to a peer reviewed journal. It is clear from this study that some academics still find the task of writing and reviewing articles daunting, and that guidance and support in the form of a writing programme can be useful.

Male rhesus monkeys (n = 24) had a biopsy of prefrontal cortical area 46 prior to chronic ethanol self-administration (n = 17) or caloric control (n = 7). Fourteen months of daily self-administration (water vs. 4% alcohol, 22 h access/day termed “open-access”) was followed by two cycles of prolonged abstinence (5 weeks) each followed by 3 months of open-access alcohol and a final abstinence followed by necropsy. At necropsy, a biopsy of Area 46, contralateral to the original biopsy, was obtained. Gene expression data (RNA-Seq) were collected comparing biopsy/necropsy samples. Monkeys were categorized by drinking status during the final post-abstinent drinking phase as light (LD), binge (BD), heavy (HD) and very heavy (VHD drinkers). Comparing pre-ethanol to post-abstinent biopsies, four animals that converted from HD to VHD status had significant ontology enrichments in downregulated genes (necropsy minus biopsy n = 286) that included immune response (FDR < 9 × 10−7) and plasma membrane changes (FDR < 1 × 10−7). Genes in the immune response category included IL16 and 18, CCR1, B2M, TLR3, 6 and 7, SP2 and CX3CR1. Upregulated genes (N = 388) were particularly enriched in genes associated with the negative regulation of MAP kinase activity (FDR < 3 × 10−5), including DUSP 1, 4, 5, 6 and 18, SPRY 2, 3, and 4, SPRED2, BMP4 and RGS2. Overall, these data illustrate the power of the NHP model and the within-subject design of genomic changes due to alcohol and suggest new targets for treating severe escalated drinking following repeated alcohol abstinence attempts.

Pitch-based carbon fibers are commonly used to produce polymeric carbon fiber structural composites. Several investigations have reported different methods for dispersing and subsequently aligning carbon nanotubes (CNTs) as a filler to reinforce polymer matrix. The significant difficulty in dispersing CNTs suggested the controlled-growth of CNTs on surfaces where they are needed. Here we compare between two techniques for depositing the catalyst iron used toward growing CNTs on pitch-based carbon fiber surfaces. Electrochemical deposition of iron using pulse voltametry is compared to DC magnetron iron sputtering. Carbon nanostructures growth was performed using a thermal CVD system. Characterization for comparison between both techniques was compared via SEM, TEM, and Raman spectroscopy analysis. It is shown that while both techniques were successful to grow CNTs on the carbon fiber surfaces, iron sputtering technique was capable of producing more uniform distribution of iron catalyst and thus multiwall carbon nanotubes (MWCNTs) compared to MWCNTs grown using the electrochemical deposition of iron.

Abstract Although the overall prognostic significance of maximal surgical resection of contrast-enhancing tumor in glioblastoma patients is well established, prior studies have not evaluated the combined importance of resection, molecular markers, patient characteristics, and chemoradiation. Incorporation of these factors may redefine the relative benefit of cytoreductive surgery and establish differing thresholds for extent of resection in varying clinical presentations. In the first study of its kind, we examine the interactive effects of volumetric extent of resection with molecular and clinical factors to develop a new roadmap for cytoreductive surgery. Based on a 20-year retrospective cohort of 850 glioblastoma patients who had initial surgery at UCSF, we employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS), both in the entire cohort as well as a subset diagnosed since 2005 (Stupp-era) with IDH1 mutation status available (n=470). For the entire cohort and the Stupp-era subset, the RPAs elucidate the combinatorial consequence of treatment, age, IDH1 status (in the subset), and resection of both enhancing and non-enhancing tumor. In the Stupp-era, temozolomide-treated patients that are IDH-wildtype and >65 clearly benefit from a reduction of the enhancing tumor (median OS: 10.1 vs 15.8 months). IDH-wildtype, temozolomide-treated patients under 65 benefit from reduction of both enhancing and non-enhancing tumor with a median survival similar to that of IDH-mutant, temozolomide-treated patients (combined median OS: 33.7 months). The patients faring worst are those that did not receive temozolomide that are >65 and/or have ≥0.3 cm3 residual enhancing tumor (median OS: 4 months). These risk models outperform all published prognostic models. This is the first study to combine resection of contrast-enhancing and non-enhancing tumor in conjunction with molecular and clinical information in a large single-institution study, and paves the way for rethinking surgical strategies for individual patients with newly diagnosed glioblastoma.

Abstract BACKGROUND Histone H3.3 or H3.1 mutant protein is commonly expressed in pediatric and adult diffuse midline gliomas, including diffuse intrinsic pontine gliomas (DIPGs), and portends a poor prognosis, regardless of histologic features. As such, “Diffuse midline glioma, H3-K27M-mutant” (DMG-H3K27M) was added to the 2016 WHO Classification as a grade IV entity. Knowledge of the clinical experience and natural history of this recently defined tumor in adults is limited. METHODS We retrospectively reviewed the pathology of adult (age ≥ 18) DMG-H3K27Ms diagnosed at our institution either via H3-K27M mutant-specific immunohistochemistry or via the UCSF500 targeted next-generation sequencing panel that includes the H3F3A, HIST1H3B, and HIST1H3C genes. Treatment, outcome, and imaging characteristics were reviewed. RESULTS We identified 26 adults with DMG-H3K27M and 2 with non-midline-H3K27M. Tumor locations included thalamus/basal ganglia (15), hypothalamus (2), pineal region (1), cerebellum (3), brainstem (2), spinal cord (2), mesial temporal (1), and non-midline sites (2). MRI imaging for 21/25 evaluable cases demonstrated enhancement. Of the 26 DMG-H3K27M cases, median age was 35 years (22–68 years). Of these, 17 patients had biopsy only. Median OS was 41 months (95%-CI 31-NA). In the 22 DMG-H3K27M patients with available clinical treatment data, 21 received radiation (19 with temozolomide) at initial diagnosis. At progression/recurrence, 11 patients received bevacizumab, 5 were re-treated with temozolomide, 8 received other chemotherapy, and 8 received > 1 course of re-irradiation. CONCLUSION While still poor overall, clinical outcome in adults with DMG-H3K27M is often better than that of pediatric DIPGs and other IDH-wildtype high-grade gliomas, such as glioblastoma. This may reflect a different cell of origin or other distinct biologic differences. Further investigation of both DMG-H3K27M and non-midline H3K27M mutant tumors in adults is warranted to study the genetic and epigenetic features of these rare tumors, as well as optimal treatment strategies.

Abstract BACKGROUND Analysis of tumors via next-generation sequencing is now routinely used in clinical practice. The UCSF500 NGS panel became available starting in June 2015. In Dec 2017, a glioblastoma precision medicine initiative started at our institution to sequence all newly-diagnosed WHO grade IV diffuse gliomas. We review our experience over a 3-year period. METHODS The UCSF500 Cancer Panel assesses approximately 500 cancer-associated genes for mutations, copy number alterations, and structural rearrangements, including fusions. The test can be run on tumor DNA alone or compared with normal DNA, allowing for discrimination of germline variants. Sequencing results are analyzed by a neuropathologist with genomics expertise (D.A.S.). Results from the 165 adult WHO grade IV diffuse glioma cases sequenced to date were analyzed, including 136 glioblastomas, IDH-wildtype; 19 glioblastomas, IDH-mutant; and 10 diffuse midline gliomas, H3 K27M-mutant. RESULTS Among the 136 IDH-wildtype glioblastomas, the most common alterations were in TERT, EGFR, CDKN2A, PTEN, NF1, TP53, PIK3R1, PDGFRA, CDK4, MDM2, LZTR1, and STAG2. Among the 19 IDH-mutant glioblastomas, the most common additional alterations were in TP53, ATRX, CDKN2A, and PDGFRA. Paired germline sequencing was performed on 71 patients, ten of which were found to harbor a germline mutation associated with increased cancer risk, including the CHEK2, MSH2, and NF1 genes. Somatic hypermutation was present in nine cases, four at initial resection and five at recurrence with a temozolomide-associated mutational signature. Among the four treatment-naïve glioblastomas with hypermutation, two were Lynch syndrome-associated in patients with damaging germline mutations in MSH2, and two were sporadic tumors that harbored somatic mutations in mismatch repair genes. CONCLUSIONS: Genomic profiling in adult glioblastoma patients results in identification of potentially actionable genetic alterations and also previously unknown germline mutations associated with increased cancer risk. A subset of glioblastomas (approximately 5%) harbor somatic hypermutation, indicating potential utility of immune checkpoint inhibition.

Abstract INTRODUCTION Diffuse low-grade gliomas (DLGG) treated with temozolomide (TMZ) can develop somatic hypermutation. We present data on the incidence and prognostic importance of somatic hypermutation in IDH-mutant DLGGs. METHODS We analyzed 120 patients treated on a phase II clinical trial of TMZ for sub-totally resected DLGGs to estimate the risk of recurrence and transformation after TMZ. To understand the prognostic significance of somatic hypermutation, we determined hypermutation status by exome or targeted sequencing on tumors from 81 patients with recurrent IDH-mutant DLGGs. 63/81 patients received TMZ before recurrence, including 28 patients treated on-trial. RESULTS With median follow-up of 8.7 years, 89 patients from the phase II trial progressed, 60 underwent 1 re-operation, and 36 had histologically confirmed transformation. The 8-year freedom from transformation was 48.2% and 59.9% for IDH-mutant astrocytomas and oligodendrogliomas, respectively; risk of transformation increased with pre-TMZ tumor volume (HR 2.5 per 100cc, p

Abstract Background Transoral laser microsurgery is widely used for treating T1/T2 glottic cancers. Hyaluronic acid (HA) is commonly used in vocal cord augmentation. We investigated the impact of intra-operative injection laryngoplasty on voice outcomes in early glottic cancer. Methods Twenty patients were randomized to the treatment group receiving HA injection to the vocal cord contralateral to the lesion; or the control group, receiving no injection. Patients had a Voice Handicap Index-10 (VHI-10) questionnaire and a Maximum Phonation Time (MPT) measurement preoperatively and at 3, 12 and 24 months post-operatively. Mean change in VHI-10 and MPT, compared to baseline and between time points, were compared. Survival estimates were calculated. Results Mean VHI-10 scores improved over time amongst all patients. There were no changes in mean VHI-10 from pre-operative values to 3, 12 or 24 months post-operatively. There were no significant differences when comparing various timepoints between groups. There were no significant changes in MPT amongst the groups, or the time-points compared. Two-year overall survival was 91.7%; disease free survival was 80.9%; no difference in recurrence free survival was seen between the groups. Conclusion Subjective voice scores improved over time in both groups; there were no improvements in VHI-10 or MPT scores in the injection group, over control, at any time points. We saw no significant impact for intra-operative HA injection laryngoplasty on subjective or objective voice outcomes following surgery for early glottic cancers. Graphical abstract