An evaluation of the Johanson model for roller compaction process development for a high dose API

Roller compaction (RC) is a dry granulation technique applied to improve the flow and compressibility of drug formulations. RC implementation for high drug load formulations can be challenging due to flow issues and a high consumption of active pharmaceutical ingredient (API) for robust process development. This work addresses these challenges using process modelling for design and scale-up of an RC process on the same equipment and transfer to different equipment. A modified application of existing models incorporating a new description of mass transport in the feed screw is evaluated for guaifenesin formulations with a 90% drug loading. The model is calibrated using low-throughput data on a Vector Freund TF Mini RC and used to predict ribbon density and throughput for various process settings at high-throughput. It is found that the modelling framework can reasonably predict high-throughput behaviour on the same RC but the predictive performance decreases for transfer between equipment.</p

Disruption of cultural burning promotes shrub encroachment and unprecedented wildfires

Recent catastrophic fires in Australia and North America have raised broad-scale questions about how the cessation of Indigenous burning practices has impacted fuel accumulation and structure. For sustainable coexistence with fire, a better understanding of the ancient nexus between humans and flammable landscapes is needed. We used novel palaeoecological modeling and charcoal compilations to reassess evidence for changes in land cover and fire activity, focusing on southeast Australia before and after British colonization. Here, we provide what we believe is the first quantitative evidence that the region’s forests and woodlands contained fewer shrubs and more grass before colonization. Changes in vegetation, fuel structures, and connectivity followed different trajectories in different vegetation types. The pattern is best explained by the disruption of Indigenous vegetation management caused by European settlement. Combined with climate-change impacts on fire weather and drought, the widespread absence of Indigenous fire management practices likely preconditioned fire-prone regions for wildfires of unprecedented extent

The feasibility of implementing remote measurement technologies in psychological treatment for depression: a mixed-methods study on engagement

Background Remote Measurement Technologies (RMTs) such as smartphones and wearables, can help improve treatment for depression by providing more objective, continuous, and ecologically valid insight into mood and behavior. Engagement with RMTs is varied and highly context-dependent, yet few studies have investigated their feasibility in the context of treatment. Objective A mixed-methods design was used to evaluate engagement with active and passive data collection via RMT in people with depression undergoing psychotherapy. We evaluated the effects of treatment on two different types of engagement: study attrition (engagement with study protocol), and patterns of missing data (engagement with digital devices) which we termed data availability. Qualitative interviews were conducted to help interpret engagement differences. Methods Sixty-six people undergoing psychological therapy for depression were followed up for 7 months. Active data in the form of weekly questionnaires, speech, and cognitive tasks were generated, and passive data were gathered from smartphone sensors and a Fitbit wearable device Results Overall study retention was 60%. Higher-intensity treatment and higher baseline anxiety were associated with increased attrition, but depression severity was not. A trend towards significance was found for the association between longer treatments and increased attrition. Data availability was higher for active data than passive data but declined at a sharper rate (90% to 30% drop in 7 months). Within passive data, wearable data availability fell from a maximum of 80% to 45% at 7 months but showed higher overall data availability compared to smartphone-based data, which remained stable at the 20-40% range throughout. Missing data was more prevalent in GPS location data, followed by Bluetooth, than accelerometry. For active data, speech and cognitive tasks had lower completion rates than clinical questionnaires. Participants in treatment provided less Fitbit data but higher active data during treatment than those on the waiting list. Conclusions Different data streams showed varied patterns of missing data despite being gathered from the same device. Longer and more complex treatments as well as clinical characteristics like higher baseline anxiety may reduce long-term engagement with RMTs, and different devices may show opposite patterns of missingness during treatment. This has implications for the scalability and uptake of RMTs in healthcare settings, as well as for the generalisability and accuracy of the data collected by these methods, feature construction, and the appropriateness of their use in the long-term

Original plant diversity and ecosystems of a small, remote oceanic island (Corvo, Azores): Implications for biodiversity conservation

Remote islands harbour many endemic species and unique ecosystems. They are also some of the world's most human-impacted systems. It is essential to understand how island species and ecosystems behaved prior to major anthropogenic disruption as a basis for their conservation. This research aims to reconstruct the original, pre-colonial biodiversity of a remote oceanic island to understand the scale of past extinctions, vegetation changes and biodiversity knowledge gaps. We studied fossil remains from the North Atlantic island of Corvo (Azores), including pollen, charcoal, plant macrofossils, diatoms and geochemistry of wetland sediments from the central crater of the island, Caldeirão. A comprehensive list of current vascular plant species was compiled, along with a translation table comparing fossilized pollen to plant species and a framework for identifying extinctions and misclassifications. Pollen and macrofossils provide evidence for eight local extinctions from the island's flora and show that four species listed as ‘introduced’ are native. Up to 23% of the pollen taxa represent extinct/misclassified species. Corvo's past environment was dynamic, shifting from glacial-era open vegetation to various Holocene forest communities, then almost completely deforested by fires, erosion and grazing following Portuguese colonisation. Historical human impacts explain high ecological turnover, several unrecorded extinctions and the present-day abundance of vegetation types like Sphagnum blanket mire. We use Corvo as a case study on how fossil inventories can address the Wallacean and Hookerian biodiversity knowledge gaps on remote islands. Accurate baselines allow stakeholders to make informed conservation decisions using limited financial and human resources, particularly on islands where profound anthropogenic disruption occurred before comprehensive ecological research

Biogeographic patterns and environmental drivers of species richness in the globally distributed Millettioid/Phaseoloid clade (Fabaceae, subfamily Papilionoideae)

IntroductionThe Millettioid/Phaseoloid (MP) clade of Fabaceae is globally distributed, economically important, and highly diverse, making it an attractive system for studying biogeographic and macroecological patterns at a global scale. We conducted the first global macroecological study to map and explore the environmental drivers of the MP clade's species richness patterns.MethodsWe compiled 116,212 species occurrences (161 genera) for the MP clade and 20 environmental variables (19 bioclimatic variables and elevation). Geospatial analyses were performed to estimate species richness patterns and biogeographic heterogeneity. The effects of environmental variables on the species richness of the MP clade were measured through multiple regression models.ResultsOur study identified the megathermal regions as hotspots of species richness for the MP clade. While species distributions and richness largely fit the latitudinal diversity gradient pattern, there was a significant negative relationship between the species richness of the MP clade along the latitude and longitude. The Afrotropic biogeographic realm had the highest alpha diversity (~36%); in terms of biome types, tropical and subtropical moist broadleaf forests had the highest alpha diversity (25%), while the beta diversity revealed a high dispersal rate and habitat tracking. Furthermore, the species richness was positively influenced by multiple climatic factors, with the mean diurnal range of temperatures and precipitation in the warmest quarter having strongest influence.DiscussionOverall, the staggering species richness patterns could be explained by multiple diversity gradient hypotheses. Particularly, colder climates play a crucial role in shaping the species richness pattern by limiting the ecological opportunities for MP clade species in the higher latitudes of the Northern Hemisphere. This suggests that the species richness patterns of the MP clade can be described as "when dispersal meets adaptation." Our study provides a new basis for identifying priority regions for conservation of legumes

Author Correction: Federated learning enables big data for rare cancer boundary detection.

10.1038/s41467-023-36188-7NATURE COMMUNICATIONS14

Federated learning enables big data for rare cancer boundary detection.

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely