The safety, feasibility, and efficacy of an 18-week exercise intervention for adults with primary brain cancer - the BRACE study.

PURPOSE: To determine the safety, feasibility, and potential effect of an 18-week exercise intervention for adults with primary brain cancer. MATERIALS AND METHODS: Eligible patients were 12-26-weeks post-radiotherapy for brain cancer. The individually-prescribed weekly exercise was ≥150-minutes of moderate-intensity exercise, including two resistance-training sessions. The intervention was deemed "safe" if exercise-related, serious adverse events (SAE) were experienced by <10% of participants, and feasible if recruitment, retention, and adherence rates were ≥75%, and ≥75% compliance rates were achieved in ≥75% of weeks. Patient-reported and objectively-measured outcomes were assessed at baseline, mid-intervention, end-intervention, and 6-month follow-up, using generalized estimating equations. RESULTS: Twelve participants enrolled (51 ± 19.5 years, 5 females). There were no exercise-related SAEs. The intervention was feasible (recruitment:80%, retention:92%, adherence:83%). Participants completed a median of 172.8 (min:77.5, max:560.8) minutes of physical activity per week. 17% met the compliance outcome threshold for ≥75% of the intervention. Improvements in quality of life (mean change (95% CI): 7.9 units (1.9, 13.8)), functional well-being (4.3 units (1.4, 7.2)), depression (-2.0 units (-3.8, -0.2)), activity (112.8 min (42.1, 183.4)), fitness (56.4 meters (20.4, 92.5)), balance (4.9 s (0.9, 9.0)), and lower-body strength (15.2 kg (9.3, 21.1)) were observed end-intervention. CONCLUSION: Preliminary evidence support that exercise is safe and beneficial to the quality of life and functional outcomes for people with brain cancer.Registration: ACTRN12617001577303.

The BRAin Cancer and Exercise (BRACE) study highlights the need for regular monitoring of disease- and treatment-related side effects which may present as barriers to exercise.Exercise prescription should be modified according to the presence and severity of disease- and treatment-related barriers.Adverse events observed, such as dizziness, highlight the importance of supervised exercise for people with brain cancer.If supervision is not possible, then exercise modes with low risk of harm from falls are recommended (e.g., walking, machine-based resistance training).

Approaches used to prevent and reduce the use of restrictive practices on adults with learning disabilities: Protocol for a realist review.

INTRODUCTION: The use of restrictive practices has significant adverse effects on the individual, care providers and organisations. This review will describe how, why, for whom, and in what circumstances approaches used by healthcare organisations work to prevent and reduce the use of restrictive practices on adults with learning disabilities. METHODS AND ANALYSIS: Evidence from the literature will be synthesised using a realist review approach - an interpretative, theory-driven approach to understand how complex healthcare approaches work in reducing the use of restrictive practices in these settings. In step 1, existing theories will be located to explore what approaches work by consulting with key topic experts, holding consultation workshops with healthcare professionals, academics, and experts by experience, and performing an informal search to help develop an initial programme theory. A systematic search will be performed in the second step in electronic databases. Further searches will be performed iteratively to test particular subcomponents of the initial programme theory, which will also include the use of the CLUSTER approach. Evidence judged as relevant and rigorous will be used to test the initial programme theory. In step three, data will be extracted and coded inductively and deductively. The final step will involve using a realist logic of analysis to refine the initial programme theory in light of evidence. This will then provide a basis to describe and explain what key approaches work, why, how and in what circumstances in preventing and reducing the use of restrictive practices in adults with learning disabilities in healthcare settings. RESULTS: Findings will be used to provide recommendations for practice and policymaking. REGISTRATION: In accordance with the guidelines, this realist review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 4th December 2019 (CRD42019158432).

Polysubstance abuse associated with more frequent opioid use among patients in rural primary care settings.

OBJECTIVE: Opioid use is a continuing problem for the United States. Individuals who use opioids have a high risk of misuse, especially with prescription opioids. Substances that are often used in combination with opioids include methamphetamines, sedatives, and benzodiazepines, as well as tobacco, alcohol, and marijuana, but not in a medical setting. We sought to determine (a) the relationship between various drugs (eg, methamphetamine, benzodiazepines) and opioid use, as well as (b) the relationship between polysubstance use and opioid use. DESIGN: We created a screening instrument that requested the patients seeking medical care at Federally Qualified Health Centers (FQHC) and Veterans Affairs (VA) hospitals in West Alabama self-report their substance usage. SETTING: This study took place in outpatient primary care settings (FQHCs and VA hospitals) in west Alabama. PARTICIPANTS: De-identified electronic health records for 346 adults were obtained from consenting medical facilities. Missing data were found in 33 of the records obtained. The final usable sample for this study was 311. MAIN OUTCOME MEASURE: The screening tool was comprised of five sections: demographics, tobacco use, alcohol abuse, drug use, and mental health. The primary outcome measure of this study was the number of days of opioid use in the past 30 days. RESULTS: Thirteen individuals (4.18 percent) reported opioid use in the last 30 days. While polysubstance or dual sub-stance use was not in the majority of the participant responses, the significant substances that were used in conjunction with opioids were methamphetamine, hallucinogens, and benzodiazepines. CONCLUSIONS: Individuals who are polysubstance users have a higher likelihood of opioid use. Interventions that target opioid use would serve the population stronger by including screenings and potential treatments for polysubstance use additionally.

Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme.

BACKGROUNDThe recent failure of checkpoint-blockade therapies for glioblastoma multiforme (GBM) in late-phase clinical trials has directed interest toward adoptive cellular therapies (ACTs). In this open-label, first-in-human trial, we have assessed the safety and therapeutic potential of cytomegalovirus-specific (CMV-specific) ACT in an adjuvant setting for patients with primary GBM, with an ultimate goal to prevent or delay recurrence and prolong overall survival.METHODSTwenty-eight patients with primary GBM were recruited to this prospective study, 25 of whom were treated with in vitro-expanded autologous CMV-specific T cells. Participants were monitored for safety, progression-free survival, overall survival (OS), and immune reconstitution.RESULTSNo participants showed evidence of ACT-related toxicities. Of 25 evaluable participants, 10 were alive at the completion of follow-up, while 5 were disease free. Reconstitution of CMV-specific T cell immunity was evident and CMV-specific ACT may trigger a bystander effect leading to additional T cell responses to nonviral tumor-associated antigens through epitope spreading. Long-term follow-up of participants treated before recurrence showed significantly improved OS when compared with those who progressed before ACT (median 23 months, range 7-65 vs. median 14 months, range 5-19; P = 0.018). Gene expression analysis of the ACT products indicated that a favorable T cell gene signature was associated with improved long-term survival.CONCLUSIONData presented in this study demonstrate that CMV-specific ACT can be safely used as an adjuvant therapy for primary GBM and, if offered before recurrence, this therapy may improve OS of GBM patients.TRIAL REGISTRATIONanzctr.org.au: ACTRN12615000656538.FUNDINGPhilanthropic funding and the National Health and Medical Research Council (Australia).

Distinct responses of antagonistic and mutualistic networks to agricultural intensification.

Species interaction networks, which govern the maintenance of biodiversity and ecosystem processes within ecological communities, are being rapidly altered by anthropogenic activities worldwide. Studies on the response of species interaction networks to anthropogenic disturbance have almost exclusively focused on one interaction type at a time, such as mutualistic or antagonistic interactions, making it challenging to decipher how networks of different interaction types respond to the same anthropogenic disturbance. Moreover, few studies have simultaneously focused on the two main components of network structure: network topology (i.e., architecture) and network ecology (i.e., species identities and interaction turnover), thereby limiting our understanding of the ecological drivers underlying changes in network topology in response to anthropogenic disturbance. Here, we used 16,400 plant-pollinator and plant-herbivore interaction observations from 16 sites along an agricultural intensification gradient to compare changes in network topology and ecology between mutualistic and antagonistic networks. We measured two aspects of network topology-nestedness and modularity-and found that although the mutualistic networks were consistently more nested than antagonistic networks and antagonistic networks were consistently more modular, the rate of change in nestedness and modularity along the gradient was comparable between the two network types. Change in network ecology, however, was distinct between mutualistic and antagonistic networks, with partner switching making a significantly larger contribution to interaction turnover in the mutualistic networks than in the antagonistic networks, and species turnover being a strong contributor to interaction turnover in the antagonistic networks. The ecological and topological changes we observed in the antagonistic and mutualistic networks have different implications for pollinator and herbivore communities in agricultural landscapes, and support the idea that pollinators are more labile in their interaction partner choice, whereas herbivores form more reciprocally specialized, and therefore more vulnerable, interactions. Our results also demonstrate that studying both topological and ecological network structure can help to elucidate the effects of anthropogenic disturbance on ecological communities, with applications for conservation and restoration of species interactions and the ecosystem processes they maintain.

Agricultural intensification drives changes in hybrid network robustness by modifying network structure.

Within ecological communities, species engage in myriad interaction types, yet empirical examples of hybrid species interaction networks composed of multiple types of interactions are still scarce. A key knowledge gap is understanding how the structure and stability of such hybrid networks are affected by anthropogenic disturbance. Using 15,169 interaction observations, we constructed 16 hybrid herbivore-plant-pollinator networks along an agricultural intensification gradient to explore changes in network structure and robustness to local extinctions. We found that agricultural intensification led to declines in modularity but increases in nestedness and connectance. Notably, network connectance, a structural feature typically thought to increase robustness, caused declines in hybrid network robustness, but the directionality of changes in robustness along the gradient depended on the order of local species extinctions. Our results not only demonstrate the impacts of anthropogenic disturbance on hybrid network structure, but they also provide unexpected insights into the structure-stability relationship of hybrid networks.

Phase 1 Safety, Pharmacokinetics, and Fluorescence Imaging Study of Tozuleristide (BLZ-100) in Adults With Newly Diagnosed or Recurrent Gliomas.

BACKGROUND: Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate molecule for FGS of glioma and other tumor types. OBJECTIVE: To perform a phase 1 dose-escalation study to characterize the safety, pharmacokinetics, and fluorescence imaging of tozuleristide in adults with suspected glioma. METHODS: Patients received a single intravenous dose of tozuleristide 3 to 29 h before surgery. Fluorescence images of tumor and cavity in Situ before and after resection and of excised tissue ex Vivo were acquired, along with safety and pharmacokinetic measures. RESULTS: A total of 17 subjects received doses between 3 and 30 mg. No dose-limiting toxicity was observed, and no reported adverse events were considered related to tozuleristide. At doses of 9 mg and above, the terminal serum half-life for tozuleristide was approximately 30 min. Fluorescence signal was detected in both high- and low-grade glial tumors, with high-grade tumors generally showing greater fluorescence intensity compared to lower grade tumors. In high-grade tumors, signal intensity increased with increased dose levels of tozuleristide, regardless of the time of dosing relative to surgery. CONCLUSION: These results support the safety of tozuleristide at doses up to 30 mg and suggest that tozuleristide imaging may be useful for FGS of gliomas.

Author Correction: A global test of ecoregions.

The original paper was published without unique DOIs for GBIF occurrence downloads. These have now been inserted as references 70-76, and the error has been corrected in the PDF and HTML versions of the article.

Impact of pre-therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV-specific T-cell therapy.

OBJECTIVES: Clinical response to antibody-based immunotherapies targeting checkpoint inhibitors is critically dependent on the tumor immune microenvironment (TIME). However, the precise impact of the TIME on adoptive cellular immunotherapy remains unexplored. Here we have conducted a long-term follow-up analysis of patients with recurrent glioblastoma multiforme (GBM) who were treated with autologous CMV-specific T-cell therapy to delineate the potential impact of the TIME on their clinical response. METHODS: Multiplexed immunohistochemical analysis of CD3, PD-L1 and Sox-2 in GBM tissue biopsies obtained before autologous T-cell therapy was carried out and correlated with long-term survival of GBM patients adoptively treated with T-cell therapy. RESULTS: Tumor microenvironment analyses revealed that the pre-treatment cellular composition of the tumor tissue may influence the subsequent response to adoptive T-cell therapy. GBM patients who showed prolonged overall survival following T-cell therapy had a significantly lower number of tumor-infiltrating CD3+ T cells in recurrent tumors than that in patients with short-term survival. Furthermore, long-term surviving patients showed low or undetectable PD-L1 expression in tumor cells in recurrent GBM biopsies. CONCLUSION: We hypothesise that lack of PD-L1-mediated immunosuppression in the TIME may allow efficient immune control following adoptive T-cell therapy. Future studies combining anti-PD-L1 or genetically modified T cells with PD-1 receptor knockdown could be considered to improve clinical responses in patients who have high PD-L1 expression in their tumors.

A global test of ecoregions.

A foundational paradigm in biological and Earth sciences is that our planet is divided into distinct ecoregions and biomes demarking unique assemblages of species. This notion has profoundly influenced scientific research and environmental policy. Given recent advances in technology and data availability, however, we are now poised to ask whether ecoregions meaningfully delimit biological communities. Using over 200 million observations of plants, animals and fungi we show compelling evidence that ecoregions delineate terrestrial biodiversity patterns. We achieve this by testing two competing hypotheses: the sharp-transition hypothesis, positing that ecoregion borders divide differentiated biotic communities; and the gradual-transition hypothesis, proposing instead that species turnover is continuous and largely independent of ecoregion borders. We find strong support for the sharp-transition hypothesis across all taxa, although adherence to ecoregion boundaries varies across taxa. Although plant and vertebrate species are tightly linked to sharp ecoregion boundaries, arthropods and fungi show weaker affiliations to this set of ecoregion borders. Our results highlight the essential value of ecological data for setting conservation priorities and reinforce the importance of protecting habitats across as many ecoregions as possible. Specifically, we conclude that ecoregion-based conservation planning can guide investments that simultaneously protect species-, community- and ecosystem-level biodiversity, key for securing Earth's life support systems into the future.

Human papillomavirus in benign prostatic hyperplasia and prostatic adenocarcinoma patients.

The aim of this study was to determine the prevalence of human papillomavirus (HPV) types in tissue and HPV antibodies in prostatic disease. Prostate tissue samples were collected from 51 patients diagnosed with adenocarcinoma and 11 with benign prostatic hyperplasia (BPH). All tissue samples were confirmed by histology. Plasma samples were available for 52 prostate patients. We investigated HPV DNA prevalence by PCR, and PCR positive samples were HPV type determined by sequencing. Prevalence of antibodies against twenty-seven HPV proteins from fourteen different HPV types was assessed in the plasma samples. The HPV DNA prevalence in the tissue samples was 14% (7/51) for prostate cancer samples and 27% (3/11) for BPHs. HPV-18 was the only type detected in tissue samples (10/62). No significant difference in HPV prevalence between the prostate cancer and BPH samples was found. HPV-positive cells were identified in eight of our thirteen prostate tissue slides (3/3 BPH and 5/10 adenocarcinoma) by in situ hybridisation, and the positive cells were found in epithelial cells and peripheral blood cells. Serology data showed no significant increase in levels of antibodies against any of the HPV-18 proteins tested for in prostatic disease patients. Antibodies against HPV-1, HPV-4, HPV-6 and HPV-11 were significantly higher in the group of males with prostatic disease. Our study did not show an association between prostatic disease and either presence of HPV DNA in samples or previous exposure of high-risk HPV.