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Mature forests characterized by high cover of tall trees and complex understories are important habitat for native plant and wildlife species and support critical ecosystem functions globally. In California’s Sierra Nevada a combination of a century of fire exclusion and worsening climate change has led to increasingly severe wildfires and extreme drought that threaten habitats of sensitive species. Using spatially explicit datasets of forest structure and the Ecosystem Disturbance and Recovery Tracker, we quantified the loss of conifer forest cover in the southern Sierra Nevada between 2011 and 2020, a decade and region characterized by unprecedented mega-disturbances. Due to the combination of wildfires, drought, and drought-associated beetle kill, 30% of conifer forest extent was lost (fell below 25% canopy cover) during this period. Of the spatially limited mature forest habitats, 56% of moderate density (40-60% canopy cover) and 84% of high density (>60% canopy cover) forests were degraded. Drought and beetle-kill caused greater cumulative degradation than areas where wildfire mortality overlapped with the other disturbances. However, burned areas resulted in larger patches of forest loss and greater forest fragmentation on average. These results highlight that current conservation approaches are failing to protect mature forest habitats within disturbance-prone ecosystems like the conifer forests of California. We emphasize the need to switch from a static approach to conservation toward one focused on managing healthy disturbance dynamics, especially using frequent low-severity fire to increase forest resilience to future mega-disturbances. Without rapid management interventions, remaining mature forest habitat in the Sierra Nevada may be susceptible to complete loss in the coming decades.

In this paper, I argue that an adequate meta-semantic framework capable of accommodating the range of projects currently identified as projects in conceptual engineering must be sensitive to the fact that concepts (and hence projects relating to them) fall into distinct kinds. Concepts can vary, I will argue, with respect to their direction of determination, their modal range, and their temporal range. Acknowledging such variations yields a preliminary taxonomy of concepts and generates a meta-semantic framework that allows us both to accommodate the full range of cases and to identify a proper subset of concepts for special ameliorative consideration. Ignoring such variations, in contrast, leads to a restricted meta-semantic framework that accommodates only a subset of the particular projects while generating implausible accounts of others.

We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically-relevant genes is modest, and the highest yield comes from validation of novel disease-gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. We examined the utility of circulating tumor DNA (ctDNA) as a prognostic biomarker for EOC by assessing its relationship with patient outcome and CA-125, pre-surgically and during post-treatment surveillance.Plasma samples were collected from patients with stage I-IV EOC. Cohort A included patients with pre-surgical samples (N = 44, median follow-up: 2.7 years), cohort B and C included: patients with serially collected post-surgically (N = 12) and, during surveillance (N = 13), respectively (median follow-up: 2 years). Plasma samples were analyzed using a tumor-informed, personalized multiplex-PCR NGS assay; ctDNA status and CA-125 levels were correlated with clinical features and outcomes.Genomic profiling was performed on the entire cohort and was consistent with that seen in TCGA. In cohort A, ctDNA-positivity was observed in 73% (32/44) of presurgical samples and was higher in high nuclear grade disease. In cohort B and C, ctDNA was only detected in patients who relapsed (100% sensitivity and specificity) and preceded radiological findings by an average of 10 months. The presence of ctDNA at a single timepoint after completion of surgery +/- adjuvant chemotherapy and serially during surveillance was a strong predictor of relapse (HR:17.6, p = 0.001 and p0.0001, respectively), while CA-125 positivity was not (p = 0.113 and p = 0.056).The presence of ctDNA post-surgically is highly prognostic of reduced recurrence-free survival. CtDNA outperformed CA-125 in identifying patients at highest risk of recurrence. These results suggest that monitoring ctDNA could be beneficial in clinical decision-making for EOC patients.

IntroductionImmunotherapy (IO) has transformed the treatment paradigm for a wide variety of solid tumours. However, assessment of response can be challenging with conventional radiological imaging (eg, iRECIST), which do not precisely capture the unique response patterns of tumours treated with IO. Emerging data suggest that circulating tumour DNA (ctDNA) can aid in response assessment in patients with solid tumours receiving IO. The short half-life of ctDNA puts it in a unique position for early treatment response monitoring. The BESPOKE IO study is designed to investigate the clinical utility of serial ctDNA testing to assess treatment response using a tumour-informed, bespoke ctDNA assay (Signatera) and to determine its impact on clinical decision-making with respect to continuation/discontinuation, or escalation/de-escalation of immunotherapy in patients with advanced solid tumours.Methods and analysisThe BESPOKE IO is a multicentre, prospective, observational study with a goal to enroll over 1500 patients with solid tumours receiving IO in up to 100 US sites. Patients will be followed for up to 2 years with serial ctDNA analysis, timed with every other treatment cycle. The primary endpoint is to determine the percentage of patients who will have their treatment regimen changed as guided by post-treatment bespoke ctDNA results along with standard response assessment tools. The major secondary endpoints include progression-free survival, overall survival and overall response rate based on the ctDNA dynamics.Ethics and disseminationThe BESPOKE IO study was approved by the WCG Institutional Review Board (Natera-20–043-NCP BESPOKE Study of ctDNA Guided Immunotherapy (BESPOKE IO)) on 22 February 2021. Data protection and privacy regulations will be strictly observed in the capturing, forwarding, processing and storing patients’ data. Natera will approve the publication of any study results in accordance with the site-specific contract.Trial registration numberNCT04761783.

Genome-wide sequencing has emerged as a promising strategy for the timely diagnosis of rare diseases, but it is not yet available as a clinical test performed in Canadian diagnostic laboratories. We describe the protocol for evaluating a 2-year pilot project, Genome-wide Sequencing Ontario, to offer high-quality clinical genome-wide sequencing in Ontario, Canada.The Genome-wide Sequencing Ontario protocol was codesigned by the Ontario Ministry of Health, the Hospital for Sick Children in Toronto and the Children's Hospital of Eastern Ontario in Ottawa. Enrolment of a prospective cohort of patients began on Apr. 1, 2021. Eligible cases with blood samples available for the index case and both parents (i.e., trios) are randomized to receive exome sequencing or genome sequencing. We will collect patient-level data and ascertain costs associated with the laboratory workflow for exome sequencing and genome sequencing. We will compare point estimates for the diagnostic utility and timeliness of exome sequencing and genome sequencing, and we will determine an incremental cost-effectiveness ratio (expressed as the incremental cost of genome sequencing versus exome sequencing per additional patient with a causal variant detected).Findings from this work will provide robust evidence for the diagnostic utility, cost-effectiveness and timeliness of exome sequencing and genome sequencing, and will be disseminated via academic publications and policy briefs. Findings will inform provincial and cross-provincial policy related to the long-term organization, delivery and reimbursement of clinical-grade genome diagnostics for rare disease.

Many tree species might be threatened with extinction because they cannot disperse or adapt quickly enough to keep pace with climate change. One potential, and potentially risky, strategy to mitigate this threat is assisted migration, the intentional movement of species to facilitate population range shifts to more climatically suitable locations under climate change. The ability for assisted migration to minimize risk and maximize conservation and forestry outcomes depends on a multi-faceted decision process for determining, what, where, and how much to move. To quantify how the benefits and risks of assisted migration could affect the decision-making process, we used a dynamical vegetation model parameterized with 23 tree species in the western United States. We found that most of the modeled species are likely to experience a substantial decline in biomass, potentially facing regional extinction by 2100 under the high-emission SSP5-85 climate-change scenario. Though simulations show assisted migration had little effect on the forestry goal of total biomass across all species, its effects on the conservation goal of promoting individual species’ persistence were far more substantial. Among eight assisted migration strategies we tested that differ in terms of life cycle stage of movement and target destination selection criteria, the approach that conserved the highest biomass for individual species involved relocating target seedlings to areas with the highest canopy openness. Although this strategy significantly reduced extinction risk for six at-risk species compared to no action, it also slightly reduced biomass of four species, due to increasing competition. Species with relatively weak tolerance to drought, fire or high temperature were the most likely candidate groups for assisted migration. This model framework could be applied to other forest ecosystems to evaluate the efficacy of assisted migration globally.

In their book, Narrow Content, Juhani Yli-Vakkuri and John Hawthorne attempt to argue against the claim that there is a kind of thought content which is both narrow and theoretically significant. However, their failure to distinguish indexical from non-indexical thought renders their arguments ineffective; a large class of the arguments they present are in fact irrelevant to the question of whether thought content is narrow. The unified treatment of thought content they advocate fails to capture the distinctively mental aspects of indexical thought, and the kinds of indexical examples to which they appeal can tell us nothing very interesting about mental states.

Conceptual engineering is to be explained by appeal to the externalist distinction between concepts and conceptions. If concepts are determined by non-conceptual relations to objective properties rather than by associated conceptions (whether individual or communal), then topic preservation through semantic change will be possible. The requisite level of objectivity is guaranteed by the possibility of collective error and does not depend on a stronger level of objectivity, such as mind-independence or independence from linguistic or social practice more generally. This means that the requisite level of objectivity is exhibited not only by natural kinds, but also by a wide range of philosophical kinds, social kinds and artefactual kinds. The alternative externalist accounts of conceptual engineering offered by Herman Cappelen and Derek Ball fall back into a kind of descriptivism which is antithetical to externalism and fails to recognise this basic level of objectivity.

Content externalism implies first, that there is a distinction between concepts and conceptions, and second, that there is a distinction between thoughts and states of mind. The implications require us to rethink the nature of self-knowledge. In this paper, I argue for the partial-representation theory of self-knowledge, according to which the self-ascription of a thought is authoritative when it is based on a conscious, occurrent thought in virtue of which it partially represents an underlying state of mind. The model of self-knowledge I provide accommodates the distinction between concepts and conceptions and the distinction between thoughts and states of mind, and it also offers a middle path between absolute epistemic security on the one hand, and scepticism about first-personal self-knowledge on the other.

This is a contribution to the symposium on Herman Cappelen’s book Fixing Language. Cappelen proposes a metasemantic framework—the “Austerity Framework”—within which to understand the general phenomenon of conceptual engineering. The proposed framework is austere in the sense that it makes no reference to concepts. Conceptual engineering is then given a “worldly” construal according to which conceptual engineering is a process that operates on the world. I argue, contra Cappelen, that an adequate theory of conceptual engineering must make reference to concepts. This is because concepts are required to account for topic continuity, a phenomenon which lies at the heart of projects in conceptual engineering. I argue that Cappelen’s own account of topic continuity is inadequate as a result of the austerity of his metasemantic framework, and that his worldly construal of conceptual engineering is untenable.

This chapter provides an externalist account of talk and thought that clearly distinguishes the two. It is argued that linguistic meanings and concepts track different phenomena and have different explanatory roles. The distinction, understood along the lines proposed, brings theoretical gains in a cluster of related areas. It provides an account of meaning change which accommodates the phenomenon of contested meanings and the possibility of substantive disagreement across theoretical divides, and it explains the nature and value of conceptual engineering in a way that addresses recent prominent concerns.

This chapter discusses how players interact with, influence, experience, and embody their avatars through gameplay and how this type of exploration can influence development, identity, and social navigation. Particular focus is placed on identity development within video game play, how particular facets of identity (e.g. gender, personality) are malleable in this context, and the styles of exploration via types of games. Considerations of personalized characters, as well as their application to real-world behavior and approach to life, are discussed.

Words change meaning over time. Some meaning shift is accompanied by a corresponding change in subject matter; some meaning shift is not. In this paper I argue that an account of linguistic meaning can accommodate the first kind of case, but that a theory of concepts is required to accommodate the second. Where there is stability of subject matter through linguistic change, it is concepts that provide the stability. The stability provided by concepts allows for genuine disagreement and ameliorative change in the context of conceptual engineering.

Education and other strategies to promote optimal complementary feeding can significantly improve practices, but little is known about the specific techniques successful interventions use to achieve behaviour change. We reviewed the literature for complementary feeding interventions in low‐/middle‐income countries (LMIC) published since 2000. We systematically applied a validated taxonomy mapping process to code specific behaviour change techniques (BCTs) used in each intervention; effectiveness ratios for each BCT were estimated. Sixty‐four interventions met inclusion criteria, were abstracted, BCTs identified, and coded. Dietary diversity was the most commonly assessed component of complementary feeding, and interpersonal communication, either individually or in groups, was the most commonly used delivery platform. Of the 93 BCTs available for mapping, the 64 interventions included in this review applied a total of 28 BCTs. Interventions used a median of six techniques (max = 13; min = 2). All interventions used “instruction on how to perform the behaviour.” Other commonly applied BCTs included “use of a credible source” (n = 46), “demonstration of the behaviour” (n = 35), and “providing information about health consequences” (n = 30). Forty‐three interventions reported strategies to shift the physical or social environment. Among BCTs used in >20 interventions, five had effectiveness ratios >0.8: “provision of/enabling social support”; “providing information about health consequences”; “demonstration of the behaviour”; and “adding objects to the environment” namely, food, supplements, or agricultural inputs. The limited reporting of theory‐based BCTs in complementary feeding interventions may impede efforts to improve and scale effective programs and reduce the global burden of malnutrition.

OBJECTIVES: Suboptimal complementary feeding (CF) practices stunt child growth. Promotion of optimal CF can improve practices but little is known about how these interventions change behavior, limiting scalability. We conducted a systematic review of the literature for CF interventions in low/middle income countries and mapped behavior change techniques (BCT) using a previously validated method and taxonomy. METHODS: We searched peer-reviewed and grey literature for interventions published in English, since 2000. Interventions were eligible for inclusion if they aimed to shift CF behaviors among children 6–24 months using social and/or individual behavior change strategies. Reviewers abstracted 64 interventions meeting inclusion criteria. We applied a validated taxonomy mapping approach to identify and code BCTs. For interventions with plausibility or probability evaluation designs, we estimated effectiveness ratios for each BCT (n = 30). RESULTS: 22 interventions occurred in sub-Saharan Africa, 23 in South-East Asia, 8 in the Americas, 10 in the Western Pacific and two in the Eastern Mediterranean region. Interventions applied a total of 28 unique BCTs (out of a possible 96). The median number of BCTs used was 6; the maximum 13 and the minimum two. All interventions applied instruction on how to perform the CF behavior of interest. Other commonly applied BCTs were 1) use of a credible source (n = 46); 2) demonstration of the behavior (n = 35); and 3) information about health consequences (n = 30). Forty-three interventions used strategies to shift the physical or social environment. Four BCTs had effectiveness ratios >0.8: provision of/enabling social support; providing information about the consequences of the behavior; demonstration of the behavior; and adding objects to the environment (ie. food, supplements, agricultural inputs). CONCLUSIONS: Limited reporting of intervention details hindered our ability to identify and map BCTs. For those with sufficient detail, we noted limited application of theory based behavior change techniques; interventions relied predominantly on the provision of instruction. Research that develops, tests and scales theory-based behavior change techniques for CF interventions would hasten our ability to accelerate social and behavior change for child nutrition. FUNDING SOURCES: The Bill and Melinda Gates Foundation and Cornell University.

Juhani Yli-Vakkuri (2017) has recently argued that the Twin Earth thought experiments offered in favour of semantic externalism can be replaced by a straightforward deductive argument from premises widely accepted by both internalists and externalists alike. The deductive argument Yli-Vakkuri offers, however, depends on premises which are such that, on standard formulations of internalism, they cannot be satisfied by a single belief simultaneously; it does not therefore, constitute a proof of externalism. The aim of this paper is to explain why.

Type 2 diabetes is a chronic metabolic disorder that is becoming a leading cause of morbidity and mortality. The prolonged time-course of human type 2 diabetes makes modelling of the disease difficult and additional animal models and methodologies are needed. The goal of this study was to develop and characterise a new method that allows controlled, targeted and sustained induction of discrete stages of type 2 diabetes in rodents. Using adult, male rats, we employed a three-week high fat-diet regimen and confirmed development of obesity-associated glucose intolerance, a key feature of human type 2 diabetes. Next, we utilised osmotic mini-pumps to infuse streptozotocin (STZ; doses ranging 80–200 mg/kg) over the course of 14-days to decrease insulin-producing capacity thus promoting hyperglycemia. Using this new approach, we demonstrate a dose-dependent effect of STZ on circulating glucose and insulin levels as well as glucose tolerance, while retaining a state of obesity. Importantly, we found that insulin secretion in response to a glucose load was present, but reduced in a dose-dependent manner by increasing STZ. In conclusion, we demonstrate a novel method that enables induction of discrete stages of type 2 diabetes in rodents that closely mirrors the different stages of type 2 diabetes in humans.

The use of conventional modalities for chronic neck pain remains debatable, primarily because most treatments have had limited success. We conducted a review of the literature published up to December 2013 on the diagnostic and treatment modalities of disorders related to chronic neck pain and concluded that, despite providing temporary relief of symptoms, these treatments do not address the specific problems of healing and are not likely to offer long-term cures. The objectives of this narrative review are to provide an overview of chronic neck pain as it relates to cervical instability, to describe the anatomical features of the cervical spine and the impact of capsular ligament laxity, to discuss the disorders causing chronic neck pain and their current treatments, and lastly, to present prolotherapy as a viable treatment option that heals injured ligaments, restores stability to the spine, and resolves chronic neck pain.The capsular ligaments are the main stabilizing structures of the facet joints in the cervical spine and have been implicated as a major source of chronic neck pain. Chronic neck pain often reflects a state of instability in the cervical spine and is a symptom common to a number of conditions described herein, including disc herniation, cervical spondylosis, whiplash injury and whiplash associated disorder, postconcussion syndrome, vertebrobasilar insufficiency, and Barré-Liéou syndrome.When the capsular ligaments are injured, they become elongated and exhibit laxity, which causes excessive movement of the cervical vertebrae. In the upper cervical spine (C0-C2), this can cause a number of other symptoms including, but not limited to, nerve irritation and vertebrobasilar insufficiency with associated vertigo, tinnitus, dizziness, facial pain, arm pain, and migraine headaches. In the lower cervical spine (C3-C7), this can cause muscle spasms, crepitation, and/or paresthesia in addition to chronic neck pain. In either case, the presence of excessive motion between two adjacent cervical vertebrae and these associated symptoms is described as cervical instability.Therefore, we propose that in many cases of chronic neck pain, the cause may be underlying joint instability due to capsular ligament laxity. Currently, curative treatment options for this type of cervical instability are inconclusive and inadequate. Based on clinical studies and experience with patients who have visited our chronic pain clinic with complaints of chronic neck pain, we contend that prolotherapy offers a potentially curative treatment option for chronic neck pain related to capsular ligament laxity and underlying cervical instability.

In this paper, I argue that an externalist theory of thought content provides the means to resolve two debates in moral philosophy. The first�that between judgement internalism and judgement externalism�concerns the question of whether there is a conceptual connection between moral judgement and motivation. The second�that between reasons internalism and reasons externalism�concerns the relationship between moral reasons and an agent's subjective motivational set. The resolutions essentially stem from the externalist claim that concepts can be grasped partially, and a new moral theory, which I call �moral externalism�, emerges.

In this paper, I draw on a recent account of perceptual knowledge according to which knowledge is contrastive. I extend the contrastive account of perceptual knowledge to yield a contrastive account of self-knowledge. Along the way, I develop a contrastive account of the propositional attitudes (beliefs, desires, regrets and so on) and suggest that a contrastive account of the propositional attitudes implies an anti-individualist account of propositional attitude concepts (the concepts of belief, desire, regret, and so on).

In a series of recent articles, Robin Jeshion has developed a theory of singular thought which she calls ‘cognitivism’. According to Jeshion, cognitivism offers a middle path between acquaintance theories—which she takes to impose too strong a requirement on singular thought, and semantic instrumentalism—which she takes to impose too weak a requirement. In this article, I raise a series of concerns about Jeshion's theory, and suggest that the relevant data can be accommodated by a version of acquaintance theory that distinguishes unsuccessful thoughts of singular form from successful singular thoughts, and in addition allows for ‘trace-based’ acquaintance.

In 1987 Fitzsimmons and Guilbert described identical male twins with progressive spastic paraplegia, brachydactyly with cone shaped epiphyses, short stature, dysarthria, and "low-normal" intelligence. In subsequent years, four other patients, including one set of female identical twins, a single female child, and a single male individual were described with the same features, and the eponym Fitzsimmons syndrome was adopted (OMIM #270710). We performed exome analysis of the patient described in 2009, and one of the original twins from 1987, the only patients available from the literature. No single genetic etiology exists that explains Fitzsimmons syndrome; however, multiple different genetic causes were identified. Specifically, the twins described by Fitzsimmons had heterozygous mutations in the SACS gene, the gene responsible for autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), as well as a heterozygous mutation in the TRPS1, the gene responsible in Trichorhinophalangeal syndrome type 1 (TRPS1 type 1) which includes brachydactyly as a feature. A TBL1XR1 mutation was identified in the patient described in 2009 as contributing to his cognitive impairment and autistic features with no genetic cause identified for his spasticity or brachydactyly. The findings show that these individuals have multiple different etiologies giving rise to a similar phenotype, and that "Fitzsimmons syndrome" is in fact not one single syndrome. Over time, we anticipate that continued careful phenotyping with concomitant genome-wide analysis will continue to identify the causes of many rare syndromes, but it will also highlight that previously delineated clinical entities are, in fact, not syndromes at all. © 2016 Wiley Periodicals, Inc.

In this paper I argue first, that a contrastive account of self-knowledge and the propositional attitudes entails an anti-individualist account of propositional attitude concepts (the concepts of belief, desire, regret, and so on), second, that the final account provides a solution to the McKinsey paradox, and third, that the account has the resources to explain why certain anti-skeptical arguments fail.

Asa Maria Wikforss has proposed a response to Burge's thought experiments in favour of social externalism, one which allows the individualist to maintain that narrow content is truth?conditional without being idiosyncratic. The narrow aim of this paper is to show that Wikforss's argument against social externalism fails, and hence that the individualist position she endorses is inadequate. The more general aim is to attain clarity on the social externalist thesis. Social externalism need not rest, as is typically thought, on the possibility of incomplete linguistic understanding or conceptual error. I identify the unifying principle that underlies the various externalist thought-experiments.

Burge's thesis is the thesis that certain second-order self-ascriptions are self-verifying in virtue of their self-referential form. The thesis has recently come under attack on the grounds that it does not yield a theory of self-knowledge consistent with semantic externalism, and also on the groundsthat it is false. In this paper I defend Burge's thesis against both charges,in particular against the arguments of Bernecker, Gallois and Goldberg. The alleged counterexamples they provide are merely apparent counterexamples, and the thesis is adequate to its proper task. To think otherwise is simply to misunderstand the thesis.

A partir de la dividision metaphysique entre l'esprit et le corps chez Descartes, l'A. examine le phenomene d'insecurite epistemique qui en resulte a l'egard du monde exterieur, dont la connaissance indirecte requiert la justification et l'observation, d'une part, et montre que l'asymetrie entre l'esprit et les faits engendre une division epistemique entre la connaissance mentale et la connaissance du monde, d'autre part.