Reliability of dynamic causal modelling of resting-state magnetoencephalography.

This study assesses the reliability of resting-state dynamic causal modelling (DCM) of magnetoencephalography (MEG) under conductance-based canonical microcircuit models, in terms of both posterior parameter estimates and model evidence. We use resting-state MEG data from two sessions, acquired 2 weeks apart, from a cohort with high between-subject variance arising from Alzheimer's disease. Our focus is not on the effect of disease, but on the reliability of the methods (as within-subject between-session agreement), which is crucial for future studies of disease progression and drug intervention. To assess the reliability of first-level DCMs, we compare model evidence associated with the covariance among subject-specific free energies (i.e., the 'quality' of the models) with versus without interclass correlations. We then used parametric empirical Bayes (PEB) to investigate the differences between the inferred DCM parameter probability distributions at the between subject level. Specifically, we examined the evidence for or against parameter differences (i) within-subject, within-session, and between-epochs; (ii) within-subject between-session; and (iii) within-site between-subjects, accommodating the conditional dependency among parameter estimates. We show that for data acquired close in time, and under similar circumstances, more than 95% of inferred DCM parameters are unlikely to differ, speaking to mutual predictability over sessions. Using PEB, we show a reciprocal relationship between a conventional definition of 'reliability' and the conditional dependency among inferred model parameters. Our analyses confirm the reliability and reproducibility of the conductance-based DCMs for resting-state neurophysiological data. In this respect, the implicit generative modelling is suitable for interventional and longitudinal studies of neurological and psychiatric disorders.

A Narrative Review of the Effects of Mindfulness on Sleep and Hypertension.

PURPOSE OF REVIEW: The prevalence of both insomnia and hypertension in the general population is vast and the health implications to individuals and society are costly. The current pharmacological treatment options for insomnia and hypertension are limited and patients are becoming increasingly interested in non-pharmacological treatment options. Mindfulness, a disciplined mental training practice rooted in Eastern traditions, has become a widely popular treatment method for multiple chronic health problems. The aim of this paper was to review research on mindfulness-based intervention effects on sleep, insomnia, and hypertension from the past 3 years. Theoretical foundations of mindfulness are discussed. Empirical evidence and potential mechanisms of how mindfulness impacts sleep and hypertension are provided. RECENT FINDINGS: Our findings suggest that mindfulness-based interventions are safe and effective for people with insomnia and hypertension. We saw consistent, albeit small to moderate, effects of mindfulness-based interventions on reducing insomnia symptoms, improving sleep quality, and lowering systolic and diastolic blood pressure readings. While mindfulness interventions have shown to be effective for improving sleep and lowering hypertension, future research is needed to further evaluate their efficacy on larger samples of patient populations with long-term follow-up measures. These high-quality studies could help researchers and clinicians identify treatment response tendencies in patient populations which can lead to better tailoring of mindfulness-based interventions for specific health concerns.

Chemical Composition of Electronic Vaping Products from School Grounds in California.

INTRODUCTION: The use of electronic vaping products (EVPs) containing nicotine, marijuana, and/or other substances remains prominent among youth; with EVPs containing nicotine being the most commonly used tobacco product among youth since 2014. However, a detailed understanding of the chemical composition of these products is limited. METHODS: During February 25th-March 15th, 2019, a total of 576 EVPs, including 233 e-cigarette devices (with 43 disposable vape pens) and 343 e-liquid cartridges/pods/bottled e-liquids, were found or confiscated from a convenience sample of 16 public high schools in California. Liquids inside 251 vape pens and cartridges/pods/bottled e-liquids were analyzed using a gas chromatography/mass spectrometry (GC/MS). For comparison, new JUUL pods, the most commonly used e-cigarette among youth during 2018-2019, with different flavorings and nicotine content were purchased and analyzed. RESULTS: For e-cigarette cartridges/pods/bottled e-liquids, nicotine was detected in 204 of 208 (98.1%) samples. Propylene glycol (PG) and vegetable glycerin (VG) were dominant solvents in nicotine-containing EVPs. Among 43 disposable vape pen devices, cannabinoids such as tetrahydrocannabinol (THC) or cannabidiol (CBD) were identified in 39 of 43 (90.1%) samples, of which 3 contained both nicotine and THC. Differences in chemical compositions were observed between confiscated or collected JUULs and purchased JUULs. Measured nicotine was inconsistent with labels on some confiscated or collected bottled e-liquids. CONCLUSIONS: EVPs from 16 participating schools were found to widely contain substances with known adverse health effects among youth, including nicotine and cannabinoids. There was inconsistency between labeled and measured nicotine on the products from schools. IMPLICATIONS: This study measured the main chemical compositions of EVPs found at 16 California public high schools. Continued efforts are warranted, including at the school-level, to educate, prevent and reduce youth use of EVPs.

Database resources of the national center for biotechnology information.

The National Center for Biotechnology Information (NCBI) produces a variety of online information resources for biology, including the GenBank® nucleic acid sequence database and the PubMed® database of citations and abstracts published in life science journals. NCBI provides search and retrieval operations for most of these data from 35 distinct databases. The E-utilities serve as the programming interface for the most of these databases. Resources receiving significant updates in the past year include PubMed, PMC, Bookshelf, RefSeq, SRA, Virus, dbSNP, dbVar, ClinicalTrials.gov, MMDB, iCn3D and PubChem. These resources can be accessed through the NCBI home page at https://www.ncbi.nlm.nih.gov.

Direct machine learning reconstruction of respiratory variation waveforms from resting state fMRI data in a pediatric population.

In many functional magnetic resonance imaging (fMRI) studies, respiratory signals are unavailable or do not have acceptable quality due to issues with subject compliance, equipment failure or signal error. In large databases, such as the Human Connectome Projects, over half of the respiratory recordings may be unusable. As a result, the direct removal of low frequency respiratory variations from the blood oxygen level-dependent (BOLD) signal time series is not possible. This study proposes a deep learning-based method for reconstruction of respiratory variation (RV) waveforms directly from BOLD fMRI data in pediatric participants (aged 5 to 21 years old), and does not require any respiratory measurement device. To do this, the Lifespan Human Connectome Project in Development (HCP-D) dataset, which includes respiratory measurements, was used to both train a convolutional neural network (CNN) and evaluate its performance. Results show that a CNN can capture informative features from the BOLD signal time course and reconstruct accurate RV timeseries, especially when the subject has a prominent respiratory event. This work advances the use of direct estimation of physiological parameters from fMRI, which will eventually lead to reduced complexity and decrease the burden on participants because they may not be required to wear a respiratory bellows.

Principles to operationalize equity in cancer research and health outcomes: lessons learned from the cancer prevention and control research network.

Reflecting their commitment to advancing health equity, the Cancer Prevention and Control Research Network (CPCRN) established a Health Equity Workgroup to identify and distill guiding principles rooted in health equity, community-engaged participatory research (CBPR), social determinants of health, and racial equity frameworks to guide its collective work. The Health Equity Workgroup utilized a multi-phase, participatory consensus-building approach to: (1) identify recurrent themes in health and racial equity frameworks; (2) capture perspectives on and experiences with health equity research among CPCRN members through an online survey; (3) engage in activities to discuss and refine the guiding principles; and (4) collect case examples of operationalizing equity principles in cancer research. Representatives from all CPCRN centers endorsed nine core principles to guide the Network's strategic plan: (1) Engage in power-sharing and capacity building with partners; (2) Address community priorities through community engagement and co-creation of research; (3) Explore and address the systems and structural root causes of cancer disparities; (4) Build a system of accountability between research and community partners; (5) Establish transparent relationships with community partners; (6) Prioritize the sustainability of research benefits for community partners; (7) Center racial equity in cancer prevention and control research; (8) Engage in equitable data collection, analysis, interpretation, and dissemination practices; and (9) Integrate knowledge translation, implementation, and dissemination into research plans. Dissemination products, such as toolkits and technical assistance workshops, reflecting these principles will foster knowledge transfer to intentionally integrate health and racial equity principles in cancer prevention and control research.

The special sauce of the Cancer Prevention and Control Research Network: 20 years of lessons learned in developing the evidence base, building community capacity, and translating research into practice.

PURPOSE: The Cancer Prevention and Control Research Network (CPCRN) is a national network focused on accelerating the translation of cancer prevention and control research evidence into practice through collaborative, multicenter projects in partnership with diverse communities. From 2003 to 2022, the CPCRN included 613 members. METHODS: We: (1) characterize the extent and nature of collaborations through a bibliometric analysis of 20 years of Network publications; and (2) describe key features and functions of the CPCRN as related to organizational structure, productivity, impact, and focus on health equity, partnership development, and capacity building through analysis of 22 in-depth interviews and review of Network documentation. RESULTS: Searching Scopus for multicenter publications among the CPCRN members from their time of Network engagement yielded 1,074 collaborative publications involving two or more members. Both the overall number and content breadth of multicenter publications increased over time as the Network matured. Since 2004, members submitted 123 multicenter grant applications, of which 72 were funded (59%), totaling more than $77 million secured. Thematic analysis of interviews revealed that the CPCRN's success-in terms of publication and grant productivity, as well as the breadth and depth of partnerships, subject matter expertise, and content area foci-is attributable to: (1) its people-the inclusion of members representing diverse content-area interests, multidisciplinary perspectives, and geographic contexts; (2) dedicated centralized structures and processes to enable and evaluate collaboration; and (3) focused attention to strategically adapting to change. CONCLUSION: CPCRN's history highlights organizational, strategic, and practical lessons learned over two decades to optimize Network collaboration for enhanced collective impact in cancer prevention and control. These insights may be useful to others seeking to leverage collaborative networks to address public health problems.

Practical strategies for robust and inexpensive imaging of aqueous-cleared tissues.

Lightsheet microscopy offers an ideal method for imaging of large (mm-cm scale) biological tissues rendered transparent via optical clearing protocols. However the diversity of clearing technologies and tissue types, and how these are adapted to the microscope can make tissue mounting complicated and somewhat irreproducible. Tissue preparation for imaging can involve glues and or equilibration in a variety of expensive and/or proprietary formulations. Here we present practical advice for mounting and capping cleared tissues in optical cuvettes for macroscopic imaging, providing a standardised 3D cell that can be imaged routinely and relatively inexpensively. We show that acrylic cuvettes cause minimal spherical aberration with objective numerical apertures less than 0.65. Furthermore, we describe methods for aligning and assessing the light sheets, discriminating fluorescence from autofluorescence, identifying chromatic artefacts due to differential scattering and removing streak artefacts such that they do not confound downstream 3D object segmentation analyses, with mouse embryo, liver and heart imaging as demonstrated examples.

Intersectional Disparities in Youth Tobacco Use by Sexual and/or Gender Minority Status and Race and/or Ethnicity.

INTRODUCTION: The current study applied an intersectional lens to examine societal factors, individual psychological outcomes, and youth combustible tobacco and vape use at the intersection of sexual and/or gender minority (SGM) status and race and/or ethnicity. AIMS AND METHODS: Data were drawn from 133 969 youth respondents surveyed in the 2019-2020 California Student Tobacco Survey, a representative school-based survey of 8th and 10th-grade public school students throughout California. The impact of multiple marginalized group membership using four mutually exclusive intersectional positions (non-SGM white, SGM white, racial minority only, and both SGM and racial minority), in addition to specific differences across ten SGM by race and/or ethnicity groups (e.g. non-SGM black or African American, SGM black or African American, etc.) were assessed. RESULTS: Compared to heterosexual and cisgender white youth, SGM and racial minority adolescents were shown to experience poorer school tobacco education quality and cessation support, lower school and family connectedness, and higher anxiety and depression symptoms. SGM and racial minority youth had a higher prevalence of ever-combustible tobacco use but were less likely to be current vape users compared to non-SGM white respondents. In examining specific group differences, results revealed that SGM teens had the highest risk of ever combustible tobacco use. This disparity was amplified for those belonging to multiple marginalized groups, with black or AA SGM teens evidenced to be at the highest risk of current combustible tobacco. CONCLUSIONS: Information from this study has useful implications for SGM measurement in surveillance systems and highlights the usefulness of adopting an intersectional approach to inform equity-driven public health policy and intervention. IMPLICATIONS: This representative study of California youth supports that identifying as a sexual and/or gender minority (SGM) is an important risk factor for combustible tobacco use. Particularly, observed SGM disparities were magnified for the youth belonging to marginalized groups, as black or African American SGM teens were shown to be at the highest risk of current combustible tobacco use. Findings support that Intersectionality Theory represents a useful framework for examining tobacco-related disparities and underscores the importance of assessing how the intersection of multiple social categories impacts youth tobacco use.

HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: A good practices report of a joint ISPE/ISPOR task force.

PROBLEM: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias. WHAT WE DID: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The overarching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility. STRATEGIES TO DISSEMINATE AND FACILITATE USE: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years. CONCLUSION: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions.

Postpartum Hemorrhage in Patients with Type 1 von Willebrand Disease: A Systematic Review.

Type 1 von Willebrand disease (VWD) is the most common subtype of VWD, comprising 75% of VWD patients. We provide a systematic review of type 1 VWD in pregnancy. Our objective was to evaluate the rate of postpartum hemorrhage (PPH) in patients with known type 1 VWD. The primary outcome was rate of PPH. Primary PPH was defined as a cumulative blood loss ≥1,000 mL, or blood loss accompanied by signs and symptoms of hypovolemia within 24 hours postpartum or requiring blood products. Secondary PPH was defined as significant bleeding 24 hours to 12 weeks postpartum. Relevant articles published in English pertaining to VWD and pregnancy were identified without any time or study limitations. Seven articles (n = 144 pregnancies) met inclusion criteria. The rate of primary PPH was 4/144 (2.8%). The secondary PPH rate was reported in four studies, and occurred in 7/48 pregnancies (14.6%), ranging from 2 to 19 days postpartum. In conclusion, according to this systematic review, the frequency of primary PPH in pregnancies with known type 1 VWD is 2.8%. This is similar to the overall PPH rates of 3% reported in the literature. Although the sample size was small, secondary PPH occurred in almost 15% of pregnancies, while in the overall obstetrical population this occurs in approximately 1% of cases. Patients with known type 1 VWD may not be at increased risk of primary PPH, though they appear to bear increased risk of secondary PPH.

Identification of COVID-19 patients at risk of hospital admission and mortality: a European multicentre retrospective analysis of mid-regional pro-adrenomedullin.

BACKGROUND: Mid-Regional pro-Adrenomedullin (MR-proADM) is an inflammatory biomarker that improves the prognostic assessment of patients with sepsis, septic shock and organ failure. Previous studies of MR-proADM have primarily focussed on bacterial infections. A limited number of small and monocentric studies have examined MR-proADM as a prognostic factor in patients infected with SARS-CoV-2, however there is need for multicenter validation. An evaluation of its utility in predicting need for hospitalisation in viral infections was also performed. METHODS: An observational retrospective analysis of 1861 patients, with SARS-CoV-2 confirmed by RT-qPCR, from 10 hospitals across Europe was performed. Biomarkers, taken upon presentation to Emergency Departments (ED), clinical scores, patient demographics and outcomes were collected. Multiclass random forest classifier models were generated as well as calculation of area under the curve analysis. The primary endpoint was hospital admission with and without death. RESULTS: Patients suitable for safe discharge from Emergency Departments could be identified through an MR-proADM value of ≤ 1.02 nmol/L in combination with a CRP (C-Reactive Protein) of ≤ 20.2 mg/L and age ≤ 64, or in combination with a SOFA (Sequential Organ Failure Assessment) score < 2 if MR-proADM was ≤ 0.83 nmol/L regardless of age. Those at an increased risk of mortality could be identified upon presentation to secondary care with an MR-proADM value of > 0.85 nmol/L, in combination with a SOFA score ≥ 2 and LDH > 720 U/L, or in combination with a CRP > 29.26 mg/L and age ≤ 64, when MR-proADM was > 1.02 nmol/L. CONCLUSIONS: This international study suggests that for patients presenting to the ED with confirmed SARS-CoV-2 infection, MR-proADM in combination with age and CRP or with the patient's SOFA score could identify patients at low risk where outpatient treatment may be safe.

HARmonized Protocol Template to Enhance Reproducibility of Hypothesis Evaluating Real-World Evidence Studies on Treatment Effects: A Good Practices Report of a Joint ISPE/ISPOR Task Force.

OBJECTIVES: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias. METHODS: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The over-arching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility. STRATEGIES TO DISSEMINATE AND FACILITATE USE: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years. CONCLUSION: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions.

Gastrojejunal (GJ) tube feeding: developing a service and evaluating associated complications in a paediatric surgical centre.

INTRODUCTION: Gastrojejunal (GJ) tubes are becoming an established alternative method of delivering nutrition to children who do not tolerate gastric feeding. However, there is limited literature surrounding patient outcomes, the longevity of tubes or complications. We aim to highlight the development and evaluation of a service to provide children with GJ tube feeding. MATERIALS AND METHODS: A retrospective case-note review of children either undergoing an initial gastrostomy to gastrojejunal tube conversion or gastrojejunal tube replacement in our tertiary paediatric surgical centre between January 2015 and June 2018. RESULTS: 134 GJ feeding tubes were placed in 33 neurologically impaired children with a median age of 4.9 years (8 months-17 years) having a median 4 tube placements per child (1-11) within the study period. All tubes were 14 or 16 Fr 'AMT G-JET' tubes with a median replacement time of 174.9 days (13-504 days). The most common indication was foregut dysmotility in children with global developmental delay. The complication rate was 34.3% (46 tubes). In the study period, 2 patients (6.1%) reverted to oral feeding, 6 patients (18.2%) to gastric feeding and 25 children (75.7%) continued with jejunal feeding. No child required fundoplication. There were no procedure-related mortalities or mortality. CONCLUSIONS: GJ tube feeding is an effective and safe method of managing children with foregut dysmotility. Many patients do not require permanent jejunal feeding, and thus the reversibility of this method is an asset. A dedicated team is needed to co-ordinate tube replacements and provide efficient long-term jejunal feeding. LEVEL OF EVIDENCE: IV.

The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment.

INTRODUCTION: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI. METHODS: In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling. RESULTS: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed. DISCUSSION: This trial did not identify a significant treatment effect of single-administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens.

Rethinking Administrative Law for Algorithmic Decision Making.

The increasing prevalence of algorithmic decision making (ADM) by public authorities raises a number of challenges for administrative law in the form of technical decisions about the necessary metrics for evaluating such systems, their opacity, the scalability of errors, their use of correlation as opposed to causation and so on. If administrative law is to provide the necessary guidance to enable optimal use of such systems, there are a number of ways in which it will need to become more nuanced and advanced. However, if it is able to rise to this challenge, administrative law has the potential not only to do useful work itself in controlling ADM, but also to support the work of the Information Commissioner's Office and provide guidance on the interpretation of concepts such as 'meaningful information' and 'proportionality' within the General Data Protection Regulation.

Innate Immune Anti-Inflammatory Response in Human Spontaneous Intracerebral Hemorrhage.

Background and Purpose: Spontaneous intracerebral hemorrhage (sICH) is a common form of hemorrhagic stroke, with high mortality and morbidity. Pathophysiological mechanisms in sICH are poorly understood and treatments limited. Neuroinflammation driven by microglial-macrophage activation contributes to brain damage post-sICH. We aim to test the hypothesis that an anti-inflammatory (repair) process occurs in parallel with neuroinflammation in clinical sICH. Methods: We performed quantitative analysis of immunohistochemical markers for microglia and macrophages (Iba1, CD68, TMEM119, CD163, and CD206) in brain tissue biospecimens 1 to 12 days post-sICH and matched control cases. In a parallel, prospective group of patients, we assayed circulating inflammatory markers (CRP [C-reactive protein], total white cell, and monocyte count) over 1 to 12 days following sICH. Results: In 27 supratentorial sICH cases (n=27, median [interquartile range] age: 59 [52­80.5], 14F/13M) all microglia-macrophage markers increased post-sICH, relative to control brains. Anti-inflammatory markers (CD163 and CD206) were elevated alongside proinflammatory markers (CD68 and TMEM119). CD163 increased progressively post-sICH (15.0-fold increase at 7­12 days, P<0.001). CD206 increased at 3 to 5 days (5.2-fold, P<0.001) then returned to control levels at 7 to 12 days. The parenchymal immune response combined brain-derived microglia (TMEM119 positive) and invading monocyte-derived macrophages (CD206 positive). In a prospective sICH patient cohort (n=26, age 74 [66­79], National Institutes of Health Stroke Scale on admission: 8 [4­17]; 14F/12M) blood CRP concentration and monocyte density (but not white blood cell) increased post-sICH. CRP increased from 0 to 2 to 3 to 5 days (8.3-fold, P=0.020) then declined at 7 to 12 days. Monocytes increased from 0 to 2 to 3 to 5 days (1.8-fold, P<0.001) then declined at 7 to 12 days. Conclusions: An anti-inflammatory pathway, enlisting native microglia and blood monocytes, occurs alongside neuroinflammation post-sICH. This novel pathway offers therapeutic targets and a window of opportunity (3­5 days post-sICH) for delivery of therapeutics via invading monocytes.

Fluorescent Silica Nanoparticles to Label Metastatic Tumor Cells in Mineralized Bone Microenvironments.

During breast cancer bone metastasis, tumor cells interact with bone microenvironment components including inorganic minerals. Bone mineralization is a dynamic process and varies spatiotemporally as a function of cancer-promoting conditions such as age and diet. The functional relationship between skeletal dissemination of tumor cells and bone mineralization, however, is unclear. Standard histological analysis of bone metastasis frequently relies on prior demineralization of bone, while methods that maintain mineral are often harsh and damage fluorophores commonly used to label tumor cells. Here, fluorescent silica nanoparticles (SNPs) are introduced as a robust and versatile labeling strategy to analyze tumor cells within mineralized bone. SNP uptake and labeling efficiency of MDA-MB-231 breast cancer cells is characterized with cryo-scanning electron microscopy and different tissue processing methods. Using a 3D in vitro model of marrow-containing, mineralized bone as well as an in vivo model of bone metastasis, SNPs are demonstrated to allow visualization of labeled tumor cells in mineralized bone using various imaging modalities including widefield, confocal, and light sheet microscopy. This work suggests that SNPs are valuable tools to analyze tumor cells within mineralized bone using a broad range of bone processing and imaging techniques with the potential to increase the understanding of bone metastasis.

Guidelines for Reporting Trial Protocols and Completed Trials Modified Due to the COVID-19 Pandemic and Other Extenuating Circumstances: The CONSERVE 2021 Statement.

Importance: Extenuating circumstances can trigger unplanned changes to randomized trials and introduce methodological, ethical, feasibility, and analytical challenges that can potentially compromise the validity of findings. Numerous randomized trials have required changes in response to the COVID-19 pandemic, but guidance for reporting such modifications is incomplete. Objective: As a joint extension for the CONSORT and SPIRIT reporting guidelines, CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) aims to improve reporting of trial protocols and completed trials that undergo important modifications in response to extenuating circumstances. Evidence: A panel of 37 international trial investigators, patient representatives, methodologists and statisticians, ethicists, funders, regulators, and journal editors convened to develop the guideline. The panel developed CONSERVE following an accelerated, iterative process between June 2020 and February 2021 involving (1) a rapid literature review of multiple databases (OVID Medline, OVID EMBASE, and EBSCO CINAHL) and gray literature sources from 2003 to March 2021; (2) consensus-based panelist meetings using a modified Delphi process and surveys; and (3) a global survey of trial stakeholders. Findings: The rapid review yielded 41 673 citations, of which 38 titles were relevant, including emerging guidance from regulatory and funding agencies for managing the effects of the COVID-19 pandemic on trials. However, no generalizable guidance for all circumstances in which trials and trial protocols might face unanticipated modifications were identified. The CONSERVE panel used these findings to develop a consensus reporting guidelines following 4 rounds of meetings and surveys. Responses were received from 198 professionals from 34 countries, of whom 90% (n = 178) indicated that they understood the concept definitions and 85.4% (n = 169) indicated that they understood and could use the implementation tool. Feedback from survey respondents was used to finalize the guideline and confirm that the guideline's core concepts were applicable and had utility for the trial community. CONSERVE incorporates an implementation tool and checklists tailored to trial reports and trial protocols for which extenuating circumstances have resulted in important modifications to the intended study procedures. The checklists include 4 sections capturing extenuating circumstances, important modifications, responsible parties, and interim data analyses. Conclusions and Relevance: CONSERVE offers an extension to CONSORT and SPIRIT that could improve the transparency, quality, and completeness of reporting important modifications to trials in extenuating circumstances such as COVID-19.

Inverted channel variations identified on a distal portion of a bajada in the central Atacama Desert, Chile.

In deserts, the interplay between occasional fluvial events and persistent aeolian erosion can form composite modern and relict surfaces, especially on the distal portion of alluvial fans. There, relief inversion of alluvial deposits by differential erosion can form longitudinal ridges. We identified two distinct ridge types formed by relief inversion on converging alluvial fans in the hyperarid Chilean Atacama Desert. Although they are co-located and similar in scale, the ridge types have different ages and formation histories that apparently correspond to minor paleoclimate variations. Gravel-armored ridges are remnants of deflated alluvial deposits with a bimodal sediment distribution (gravel and sand) dated to a minor pluvial phase at the end of the Late Pleistocene (~12 kyr). In contrast, younger (~9 kyr) sulfate-capped ridges formed during a minor arid phase with evaporite deposition in a pre-existing channel that armored the underlying deposits. Collectively, inverted channels at Salar de Llamara resulted from multiple episodes of surface overland flow and standing water spanning several thousand years. Based on ridge relief and age, the minimum long-term deflation rate is 0.1-0.2 m/kyr, driven primarily by wind erosion. This case study is an example of the equifinality concept whereby different processes lead to similar landforms. The complex history of the two ridge types can only be generally constrained in remotely sensed data. In situ observations are required to discern the specifics of the aqueous history, including the flow type, magnitude, sequence, and paleoenvironment. These findings have relevance for interpreting similar landforms on Mars.