Agreement between the activPAL accelerometer and direct observation during a series of gait and sit-to-stand tasks in people living with cervical dystonia.

Background: Accelerometers are commonly used for the assessment of PA; however, these devices have not been validated in people with dystonia who experience movement limitations. To properly understand movement behaviors and deliver accurate exercise prescription in this population, the validity of these devices must be tested. Objective: This study aimed to validate step count and postural transitions detected by the activPAL accelerometer (AP) against direct observation (DO) during two functional assessments: the 30-s sit-to-stand (30STS) and 6-min usual-pace walk tests. Methods: A total of 11 participants with cervical dystonia (CD) (male/female n = 5/6; mean age = 61 years; BMI = 24 kg/m2) performed the 6-min usual pace walking and 30STS while wearing the activPAL. A trained observer counted steps and observed the number of sit-to-stands. Results: The average step count detected with AP and DO was 651.8 (218-758) and 654.5 (287-798) respectively. The average transitions detected were 11 (4-16) and 12 (4-17) respectively. Both methods showed good agreement and there was a statistically significant and strong correlation between the two methods, i.e., transitions (r = 0.983, p = 0.0001), and step counts (r = 0.9841, p = 0.0001). Conclusion: There is a good agreement between activPAL and direct observation for step counts and transitions between sitting and standing in people living with CD.

Reproducible preclinical models of androgen receptor driven human prostate cancer bone metastasis.

BACKGROUND: Preclinical models recapitulating the metastatic phenotypes are essential for developing the next-generation therapies for metastatic prostate cancer (mPC). We aimed to establish a cohort of clinically relevant mPC models, particularly androgen receptor positive (AR+) bone metastasis models, from LuCaP patient-derived xenografts (PDX) that reflect the heterogeneity and complexity of mPC. METHODS: PDX tumors were dissociated into single cells, modified to express luciferase, and were inoculated into NSG mice via intracardiac injection. The progression of metastases was monitored by bioluminescent imaging. Histological phenotypes of metastases were characterized by immunohistochemistry and immunofluorescence staining. Castration responses were further investigated in two AR-positive models. RESULTS: Our PDX-derived metastasis (PDM) model collection comprises three AR+ adenocarcinomas (ARPC) and one AR- neuroendocrine carcinoma (NEPC). All ARPC models developed bone metastases with either an osteoblastic, osteolytic, or mixed phenotype, while the NEPC model mainly developed brain metastasis. Different mechanisms of castration resistance were observed in two AR+ PDM models with distinct genotypes, such as combined loss of TP53 and RB1 in one model and expression of AR splice variant 7 (AR-V7) expression in another model. Intriguingly, the castration-resistant tumors displayed inter- and intra-tumor as well as organ-specific heterogeneity in lineage specification. CONCLUSION: Genetically diverse PDM models provide a clinically relevant system for biomarker identification and personalized medicine in metastatic castration-resistant prostate cancer.

Mitogenomic evidence of population differentiation of thorny skate, Amblyraja radiata, in the North Atlantic.

Management of thorny skate (Amblyraja radiata) in the Northwest Atlantic has posed a conservation dilemma for several decades due to the species' lack of response to strong conservation efforts in the US Gulf of Maine and the Canadian Scotian Shelf, confusion over the relationship between two reproductive size morphs of differing life histories that are sympatric in the Northwest Atlantic, and conflicting data on regional population connectivity throughout the species' broader range. To better assess potential A. radiata regional population differentiation and genetic links to life-history variation, we analysed complete mitochondrial genome sequences from 527 specimens collected across the species' North Atlantic geographic range, with particular emphasis on the Northwest Atlantic region. A high level of genetic diversity was evident across the North Atlantic, but significant genetic differentiation was identified between specimens inhabiting the Northwest (Gulf of Maine and Newfoundland) and Northeast (Greenland, Iceland, North Sea, and Arctic Circle) Atlantic. In the Northwest Atlantic, significant differentiation between the Gulf of Maine and Newfoundland regions was revealed; however, the overall level of differentiation was very low. No genetic difference was identified between the large and small reproductive morphs. The results of this study advance our understanding of A. radiata population structure in the North Atlantic but do not resolve all the questions confounding our understanding of the species' biology and evolutionary history.

Idiopathic membranous nephropathy and synchronous mononeuritis multiplex secondary to idiopathic small vessel vasculitis.

Membranous nephropathy has been associated with demyelinating polyneuropathies and antiglomerular membrane disease; however, an association with vasculitic neuropathy has not been described. This case describes a patient with biopsy-proven idiopathic membranous nephropathy and synchronous mononeuritis multiplex secondary to idiopathic small vessel vasculitis, who presented with lower limb microvascular ischaemia, peripheral neuropathy and active urinary sediment. Her extensive non-invasive screening for immunological disease and radiological investigations for occult malignancy were unremarkable. The patient received intravenous methylprednisolone and intravenous rituximab induction therapy resulting in complete remission of both the idiopathic membranous nephropathy and small vessel vasculitis at 7 months post treatment.

Fighting the Same Battles on a New Battleground: Embedding Technologies in a Virtual Care Environment.

The pandemic necessitated the rapid design, development and implementation of technologies to allow remote monitoring of COVID-19 patients at home. This study aimed to explore the environmental barriers and facilitators to the successful development and implementation of virtual care technologies in this fast-paced context. We interviewed eight staff at a virtual hospital in Australia. We found key facilitators to be a learning organizational culture and strong leadership support. Barriers included interoperability issues, legislative constraints and unrealistic clinician expectations. Also, we found that a combination of hot-desking and the lack of single sign on in the virtual care environment, was reported to create additional work for staff. Overall, despite this unique context, our findings are consistent with prior work examining design and implementation of healthcare technologies. The fast pace and high-pressure environment appeared to magnify previously reported barriers, but also cultivate and foster a learning culture.

How digital health translational research is prioritised: a qualitative stakeholder-driven approach to decision support evaluation.

OBJECTIVES: Digital health is now routinely being applied in clinical care, and with a variety of clinician-facing systems available, healthcare organisations are increasingly required to make decisions about technology implementation and evaluation. However, few studies have examined how digital health research is prioritised, particularly research focused on clinician-facing decision support systems. This study aimed to identify criteria for prioritising digital health research, examine how these differ from criteria for prioritising traditional health research and determine priority decision support use cases for a collaborative implementation research programme. METHODS: Drawing on an interpretive listening model for priority setting and a stakeholder-driven approach, our prioritisation process involved stakeholder identification, eliciting decision support use case priorities from stakeholders, generating initial use case priorities and finalising preferred use cases based on consultations. In this qualitative study, online focus group session(s) were held with stakeholders, audiorecorded, transcribed and analysed thematically. RESULTS: Fifteen participants attended the online priority setting sessions. Criteria for prioritising digital health research fell into three themes, namely: public health benefit, health system-level factors and research process and feasibility. We identified criteria unique to digital health research as the availability of suitable governance frameworks, candidate technology's alignment with other technologies in use,and the possibility of data-driven insights from health technology data. The final selected use cases were remote monitoring of patients with pulmonary conditions, sepsis detection and automated breast screening. CONCLUSION: The criteria for determining digital health research priority areas are more nuanced than that of traditional health condition focused research and can neither be viewed solely through a clinical lens nor technological lens. As digital health research relies heavily on health technology implementation, digital health prioritisation criteria comprised enablers of successful technology implementation. Our prioritisation process could be applied to other settings and collaborative projects where research institutions partner with healthcare delivery organisations.

Yersinia pestis genomes reveal plague in Britain 4000 years ago.

Extinct lineages of Yersinia pestis, the causative agent of the plague, have been identified in several individuals from Eurasia between 5000 and 2500 years before present (BP). One of these, termed the 'LNBA lineage' (Late Neolithic and Bronze Age), has been suggested to have spread into Europe with human groups expanding from the Eurasian steppe. Here, we show that the LNBA plague was spread to Europe's northwestern periphery by sequencing three Yersinia pestis genomes from Britain, all dating to ~4000 cal BP. Two individuals were from an unusual mass burial context in Charterhouse Warren, Somerset, and one individual was from a single burial under a ring cairn monument in Levens, Cumbria. To our knowledge, this represents the earliest evidence of LNBA plague in Britain documented to date. All three British Yersinia pestis genomes belong to a sublineage previously observed in Bronze Age individuals from Central Europe that had lost the putative virulence factor yapC. This sublineage is later found in Eastern Asia ~3200 cal BP. While the severity of the disease is currently unclear, the wide geographic distribution within a few centuries suggests substantial transmissibility.

Escape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars.

Although oncogene-induced senescence (OIS) is a potent tumor-suppressor mechanism, recent studies revealed that cells could escape from OIS with features of transformed cells. However, the mechanisms that promote OIS escape remain unclear, and evidence of post-senescent cells in human cancers is missing. Here, we unravel the regulatory mechanisms underlying OIS escape using dynamic multidimensional profiling. We demonstrate a critical role for AP1 and POU2F2 transcription factors in escape from OIS and identify senescence-associated chromatin scars (SACSs) as an epigenetic memory of OIS detectable during colorectal cancer progression. POU2F2 levels are already elevated in precancerous lesions and as cells escape from OIS, and its expression and binding activity to cis-regulatory elements are associated with decreased patient survival. Our results support a model in which POU2F2 exploits a precoded enhancer landscape necessary for senescence escape and reveal POU2F2 and SACS gene signatures as valuable biomarkers with diagnostic and prognostic potential.

Telomeres and replicative cellular aging of the human placenta and chorioamniotic membranes.

Recent hypotheses propose that the human placenta and chorioamniotic membranes (CAMs) experience telomere length (TL)-mediated senescence. These hypotheses are based on mean TL (mTL) measurements, but replicative senescence is triggered by short and dysfunctional telomeres, not mTL. We measured short telomeres by a vanguard method, the Telomere shortest length assay, and telomere-dysfunction-induced DNA damage foci (TIF) in placentas and CAMs between 18-week gestation and at full-term. Both the placenta and CAMs showed a buildup of short telomeres and TIFs, but not shortening of mTL from 18-weeks to full-term. In the placenta, TIFs correlated with short telomeres but not mTL. CAMs of preterm birth pregnancies with intra-amniotic infection showed shorter mTL and increased proportions of short telomeres. We conclude that the placenta and probably the CAMs undergo TL-mediated replicative aging. Further research is warranted whether TL-mediated replicative aging plays a role in all preterm births.

A long-term follow-up of safety and clinical efficacy of NTCELL® [Immunoprotected (Alginate-encapsulated) porcine choroid plexus cells for xenotransplantation] in patients with Parkinson's disease.

INTRODUCTION: In 2019, we published the results of a Phase IIb randomized controlled trial of putaminal encapsulated porcine choroid plexus cell (termed NTCELL®) administration in patients with Parkinson's disease. This study failed to meet its primary efficacy end-point of a change in UPDRS part III score in the 'off' state at 26-weeks post-implant. However, a number of secondary end-points reached statistical significance. We questioned whether with longer follow-up, clinically significant improvements would be observed. For this reason, we decided to follow-up all patients periodically to week 104. Herein, we report the results of this long-term follow-up. METHODS: All 18 patients included in the original study were periodically re-assessed at weeks 52, 78 and 104 post-implant. At each time-point, motor and non-motor function, quality of life and levodopa equivalent daily dose was assessed using a standardized testing battery. RESULTS: At week 104, no significant differences in UPDRS part III scores in the 'off' state were observed in any of the treatment groups compared to baseline. Only a single serious adverse event - hospitalisation due to Parkinson's disease rigidity not responding to changes in medications - was considered potentially related to the implant procedure. There was no evidence of xenogeneic viral transmission. CONCLUSION: Un-blinded, long-duration follow-up to week 104 post-implantation showed no evidence that putaminal NTCELL® administration produces significant clinical benefit in patients with moderately advanced Parkinson's disease.

Exploring the Effects of Geographic Scale on Spatial Learning.

BACKGROUND: Investigating the relationship between the human body and its spatial environment is a critical component in understanding the process of acquiring spatial knowledge. However, few empirical evaluations have looked at how the visual accessibility of an environment affects spatial learning. To address this gap, this paper focuses on geographic scale, defined as the spatial extent visually accessible from a single viewpoint. We present two experiments in which we manipulated geographic scale using two perspectives, a ground level and an elevated view, in order to better understand the scale effect on spatial learning. Learning outcomes were measured using estimates of direction and self-reports of mental workload. RESULTS: In contrast to our hypothesis, we found few differences in spatial learning when comparing different perspectives. However, our analysis of pointing errors shows a significant interaction effect between the scale and spatial ability: The elevated perspective reduced the differences in pointing errors between low and high spatial ability participants in contrast to when participants learned the environment at ground level alone. Bimodal pointing distributions indicate that participants made systematic errors, for example, forgetting turns or segments. Modeling these errors revealed a unified alternative representation of the environment and further suggests that low spatial ability participants benefited more from the elevated perspective in terms of spatial learning compared to high spatial ability participants. CONCLUSIONS: We conclude that an increased geographic scale, which was accessible through an elevated perspective in this study, can help bridge the performance gap in spatial learning between low and high spatial ability participants.

Author Correction: Intragenic antagonistic roles of protein and circRNA in tumorigenesis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

EWS-FLI1 modulated alternative splicing of ARID1A reveals novel oncogenic function through the BAF complex.

Connections between epigenetic reprogramming and transcription or splicing create novel mechanistic networks that can be targeted with tailored therapies. Multiple subunits of the chromatin remodeling BAF complex, including ARID1A, play a role in oncogenesis, either as tumor suppressors or oncogenes. Recent work demonstrated that EWS-FLI1, the oncogenic driver of Ewing sarcoma (ES), plays a role in chromatin regulation through interactions with the BAF complex. However, the specific BAF subunits that interact with EWS-FLI1 and the precise role of the BAF complex in ES oncogenesis remain unknown. In addition to regulating transcription, EWS-FLI1 also alters the splicing of many mRNA isoforms, but the role of splicing modulation in ES oncogenesis is not well understood. We have identified a direct connection between the EWS-FLI1 protein and ARID1A isoform protein variant ARID1A-L. We demonstrate here that ARID1A-L is critical for ES maintenance and supports oncogenic transformation. We further report a novel feed-forward cycle in which EWS-FLI1 leads to preferential splicing of ARID1A-L, promoting ES growth, and ARID1A-L reciprocally promotes EWS-FLI1 protein stability. Dissecting this interaction may lead to improved cancer-specific drug targeting.

Intragenic antagonistic roles of protein and circRNA in tumorigenesis.

circRNAs arise from back splicing events during mRNA processing, and when deregulated can play an active role in cancer. Here we characterize a new circRNA (circPOK) encoded by the Zbtb7a gene (also kown as POKEMON, LRF) in the context of mesenchymal tumor progression. circPOK functions as a non-coding proto-oncogenic RNA independently and antithetically to its linear transcript counterpart, which acts as a tumor suppressor by encoding the Pokemon transcription factor. We find that circPOK regulates pro-proliferative and pro-angiogenic factors by co-activation of the ILF2/3 complex. Importantly, the expression of Pokemon protein and circRNA is aberrantly uncoupled in cancer through differential post-transcriptional regulation. Thus, we identify a novel type of genetic unit, the iRegulon, that yields biochemically distinct RNA products, circular and linear, with diverse and antithetical functions. Our findings further expand the cellular repertoire towards the control of normal biological outputs, while aberrant expression of such components may underlie disease pathogenesis including cancer.

Steroid refractory giant cell arteritis with bilateral vertebral artery occlusion and middle cerebellar peduncle infarction.

Giant cell arteritis is the most common primary systemic vasculitis in adults aged ≥50 years and peaks in the eighth decade of life. Common symptoms include headache, scalp tenderness and jaw claudication. Elevated acute phase reactants (erythrocyte sedimentation rate and C-reactive protein) are present in >90% of patients. Visual loss is a well-recognised complication, but approximately 2-4% of giant cell arteritis patients experience stroke, most frequently in the vertebrobasilar territory. We describe a 72-year-old male who developed bilateral vertebral artery occlusion and middle cerebellar peduncle infarction secondary to giant cell arteritis in spite of high-dose steroids.

Dried blood spot and mini-tube blood sample collection kits for postal HIV testing services: a comparative review of successes in a real-world setting.

OBJECTIVES: This is a comparative review between using dried blood spot (DBS) and mini-tube (MT) HIV sampling kits as part of an online sexually transmitted infection (STI) postal testing service. England has recently seen increases in internet-based and postal (eHealth) STI services. Expanding accessibility and testing for patients, cost implications and narrowing the HIV undiagnosed margin are drivers for this. METHODS: In 2017, data were reviewed from an online postal STI kit requesting service at a time of transitioning from MT to DBS. We compared the STI postal kit and HIV blood sample return rates, and the successful processing/analysis rates of the DBS and MT kits. Descriptive statistics were applied to participant characteristics, with Pearson's χ2 or Fisher exact test used to demonstrate statistical differences. We also describe and calculate a 'request-to-result ratio' (RRR) for both kit types. The RRR is defined as the number of online kit requests required to produce one successfully analysed result. RESULTS: 550 STI postal kit requests from a North-West of England region were reviewed from 13 June 2017 to 22 September 2017 (275 MT, 275 DBS). Baseline characteristics between the two groups were comparable (63% woman, 90% white British and 86% heterosexual with a median age of 26 years). The successful processing rate for the DBS was 98.8% c.f. 55.7% for the MT (p<0.001). The RRR for MT was 2.96, c.f. 1.70 for DBS. There was a 5.4% false positive HIV rate in the MT c.f. none in the DBS. CONCLUSIONS: This comparative analysis suggests that in this community setting, the use of postal HIV DBS kits resulted in a significantly improved RRR compared with MT. The biggest factor was the large number of MT samples not analysed due to inadequate blood volumes. The unexpected level of false positive results in the MT samples needs confirming in larger studies.

A phase IIb, randomised, double-blind, placebo-controlled, dose-ranging investigation of the safety and efficacy of NTCELL® [immunoprotected (alginate-encapsulated) porcine choroid plexus cells for xenotransplantation] in patients with Parkinson's disease.

INTRODUCTION: Regenerative therapies in Parkinson's disease aim to slow neurodegeneration and re-establish damaged neuronal circuitry. Neurotrophins are potent endogenous regulators of neuronal survival, development and regeneration. They represent an attractive regenerative treatment option in Parkinson's disease. Porcine choroid plexus produces a number of neurotrophins, and can be safely delivered to the striatum in an encapsulated formulation (termed NTCELL®) to protect them from immune attack. NTCELL® has shown regenerative potential in animal models of stroke, Huntington's disease and Parkinson's disease. Following promising results from an initial open label safety study of intra-striatal delivery of NTCELL® in human subjects, we sought to specifically investigate the safety and efficacy of NTCELL® for the treatment of Parkinson's disease. METHODS: 18 patients aged 56-65 years with idiopathic Parkinson's disease of at least 5 years duration were randomised to receive either sham surgery (general anaesthesia and partial thickness burr holes) or intra-striatal delivery of NTCELL® (the 3 groups in the treatment arm receiving incremental NTCELL® doses). RESULTS: At 26 weeks, we found no significant difference in total UPDRS scores ('on' and 'off'), UPDRS motor scores ('on' and 'off'), PDQ-39, UDysRS, timed walk or modified Hoehn and Yahr stage between patients implanted with NTCELL® and patients undergoing sham procedure. There were no serious adverse events or xenogeneic viral transmission during the study. CONCLUSION: The study did not meet its primary efficacy end-point of a change in UPDRS at 26 weeks post-intervention compared with baseline. Stereotactic NTCELL® implantation was safe and well tolerated.

Patients' Perioperative Experience of Awake Deep-Brain Stimulation for Parkinson Disease.

BACKGROUND: Awake craniotomy for tumor resection and epilepsy surgery is a well-tolerated procedure. Qualitative data on patients' experience of awake deep-brain stimulation (DBS) are, however, lacking. We collected qualitative data on patients' experience of awake DBS with a view to identifying areas for improvement. METHODS: Forty-one patients undergoing DBS for Parkinson disease between 2009 and 2015 were surveyed with a structured questionnaire designed to receive patient feedback regarding perioperative management of the awake stage of the procedure. RESULTS: More than 90% of patients felt well-informed. Most remembered the procedure, and almost all were happy that they did. One half of the patients experienced pain, often significant, during the procedure. This mainly occurred during burr-hole drilling and stereotactic frame placement. CONCLUSIONS: Although awake DBS is well-tolerated, pain and off-period symptoms are an issue for a significant number of patients. Efforts should be made to minimize these unpleasant aspects of awake DBS.

Thoracic Myelopathy Due to Gnathostomiasis Acquired in New Zealand.

Gnathostomiasis is a zoonotic disease endemic in Asia. It most commonly manifests as gastrointestinal and cutaneous disease. Central nervous system involvement is a rare but feared complication, often leaving patients with permanent neurologic deficits. Clinicians outside of Asia and Latin America may have little experience with this illness, causing delays in diagnosis and treatment. We describe a 40-year-old woman who developed a progressive myelopathy over 18 months. She had never traveled outside of New Zealand. Cerebrospinal fluid (CSF) showed marked eosinophilia and Gnathostoma serology was positive in both serum and CSF. This is the first report of gnathostomiasis acquired in New Zealand, and the first case of neurognathostomiasis reported outside Asia. Clinicians should include neurognathostomiasis in the differential diagnosis of myelopathy and CSF eosinophilia, even if there is no history of travel to endemic areas.