Latin American Trans-ancestry INitiative for OCD genomics (LATINO): Study protocol

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but \u3e95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, https://www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5000 richly phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity

A Systematic Review of How Multiple Stressors from an Extreme Event Drove Ecosystem-Wide Loss of Resilience in an Iconic Seagrass Community

A central question in contemporary ecology is how climate change will alter ecosystem structure and function across scales of space and time. Climate change has been shown to alter ecological patterns from individuals to ecosystems, often with negative implications for ecosystem functions and services. Furthermore, as climate change fuels more frequent and severe extreme climate events (ECEs) like marine heatwaves (MHWs), such acute events become increasingly important drivers of rapid ecosystem change. However, our understanding of ECE impacts is hampered by limited collection of broad scale in situ data where such events occur. In 2011, a MHW known as the Ningaloo Niño bathed the west coast of Australia in waters up to 4°C warmer than normal summer temperatures for almost 2 months over 1000s of kilometres of coastline. We revisit published and unpublished data on the effects of the Ningaloo Niño in the seagrass ecosystem of Shark Bay, Western Australia (24.6 – 26.6o S), at the transition zone between temperate and tropical seagrasses. Therein we focus on resilience, including resistance to and recovery from disturbance across local, regional and ecosystem-wide spatial scales and over the past 8 yearsThermal effects on temperate seagrass health were severe and exacerbated by simultaneous reduced light conditions associated with sediment inputs from record floods in the south-eastern embayment and from increased detrital loads and sediment destabilisation. Initial extensive defoliation of Amphibolis antarctica, the dominant seagrass, was followed by rhizome death that occurred in 60-80% of the bay’s meadows, equating to decline of over 1000 km2 of meadows. This loss, driven by direct abiotic forcing, has persisted, while indirect biotic effects (e.g. dominant seagrass loss) have allowed colonisation of some areas by small fast-growing tropical species (e.g. Halodule uninervis). Those biotic effects also impacted multiple consumer populations including turtles and dugongs, with implications for species dynamics, food web structure, and ecosystem recovery. We show multiple stressors can combine to evoke extreme ecological responses by pushing ecosystems beyond their tolerance. Finally, both direct abiotic and indirect biotic effects need to be explicitly considered when attempting to understand and predict how ECEs will alter marine ecosystem dynamics

NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.

BACKGROUND: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older. METHODS: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm. RESULTS: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events. CONCLUSIONS: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population

Validating self-report and proxy reports of the Dexamethasone Symptom Questionnaire-Chronic for the evaluation of longer-term corticosteroid toxicity

PURPOSE: In brain tumours, brain metastases or advanced cancer; treatment with corticosteroids, side effects can add to symptoms. These are best assessed by patients, complementing clinical assessment. We assessed the feasibility and validity of the Dexamethasone Symptom Questionnaire-Chronic (DSQ-Chronic), patient and caregiver versions. METHODS: A longitudinal cohort study was conducted, collecting clinician-rated toxicity, performance status, dexamethasone dose and DSQ-Chronic (patient and caregiver versions) at baseline, then 2, 4 and 8 weeks later. Patients had a primary malignant brain tumour, brain metastases, or advanced cancer; Karnofsky Performance Status >/=40 and predicted survival >/=8 weeks. Analysis included questionnaire completion rates, frequency and severity of dexamethasone-attributable side effects, agreement between patient and caregiver ratings, comparison with clinician-rated toxicity and correlation with performance status. RESULTS: Sixty-six patients were recruited (mean age 60 years), with their caregivers. Completion of questionnaires was over 90 % for the dyad at baseline but dropped over time, with caregiver completion rates higher at all timepoints. Agreement between patients and proxies was fair to moderate, and while proxies systematically overestimated symptom severity on DSQ-chronic total scores, the bias was less than 10 points. Patient and clinician agreement was higher for more objective symptoms. CONCLUSION: The DSQ-Chronic is feasible when the patient is relatively well. As capacity to complete the DSQ-Chronic diminishes, caregivers can be proxy-raters. Clinicians capture corticosteroid toxicities, which may not be obvious to the patient. The DSQ-Chronic, patient and caregiver versions, are useful tools to be used with clinician assessment

The cycle of seagrass life: From flowers to new meadows

Abstract Understanding sexual reproduction and recruitment in seagrasses is crucial to their conservation and restoration. Flowering, seed production, seed recruitment, and seedling establishment data for the seagrass Posidonia australis was collected annually between 2013 and 2018 in meadows at six locations around Rottnest Island, Western Australia. Variable annual rates of flowering and seed production were observed among meadows between northern and southern sides of the island and among years. Meadows on the northern shore consistently flowered more intensely and produced more seeds across the years of the survey. Inter‐site variation in clonal diversity and size of clones, seed production, wind and surface currents during pollen and seed release, and the large, but variable, impact of seed predation are likely the principal drivers of successful recruitment into established meadows and in colonizing unvegetated sands. The prolific but variable annual reproductive investment increases the probability of low levels of continuous recruitment from seed in this seagrass, despite high rates of abiotic and biotic disturbance at seedling, shoot, and patch scales. This strategy also imparts a level of ecological resilience to this long‐lived and persistent species

Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma

Background. The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy. Methods. This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS). Results. One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64-1.33, P =. 66). ORR was 14% (combination) versus 6% (monotherapy) (P =. 18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82-1.69, P =. 38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately. Conclusions. Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies