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Abstract Background There are limited tools to measure the burden of disease and effectiveness of medical/surgical interventions in patients with cryptoglandular fistulas. The aim of this study was to explore concepts that are relevant and important to patients with complex cryptoglandular fistulas (CCF) and to develop a patient-centred, disease-specific, patient-reported outcome measure (PROM) to assess symptom burden and impacts of CCF. Methods A targeted literature review was conducted, followed by one-to-one telephone interviews with five colorectal surgeons (USA, n = 3; UK, n = 1; Spain, n = 1) and 20 US adult patients with CCF to inform the development of a conceptual model and a CCF-specific PROM. The targeted literature review informed the development of the preliminary conceptual model and identified a PROM in the literature that was used as a reference to generate the draft CCF-specific PROM. The colorectal surgeon interviews provided insights on the experience of patients with CCF to refine the conceptual model, formulate probing questions for use in patient interviews, and to develop the draft CCF-specific PROM. Patients’ descriptions of their experiences with symptoms and the impacts on their lives and evaluation of the draft CCF-specific PROM in concept elicitation and cognitive interviews were used to develop the final conceptual model and final CCF-specific PROM. Results Ten symptoms (odour, pain during bowel movement, abscess, post-operative pain, discharge/drainage/leakage, anal/perianal pain, inflammation/swelling, skin irritation, bleeding and itchiness) and 11 impacts (discomfort, inability to exercise, embarrassment, difficulty sitting, worry about disease, adapted life to maintain hygiene, negatively impacted social life/isolation, inability to perform daily activities, reduced interest in sex, negatively impacted intimate relationships and negatively impacted mood) were reported as most salient by patients. The patient experience, clinician perspective, and literature review provided input to item generation. Evaluation of relevance and patient understanding through cognitive interviews with patients provided evidence for the content validity of the new patient-reported outcome measure: the 20-item Complex Cryptoglandular Fistula Questionnaire™ (CCFQ-20™). Conclusion The CCFQ-20™ is a new clinician-guided, patient-validated, disease-specific patient-reported outcome measure that measures disease impact and quality of life in patients with CCF.

Abstract Generalization is difficult to quantify, and many classifications exist. A beta diversity framework can be used to establish a numeric measure of generalist tendencies that jointly describes many important features of species interactions, namely spatiotemporal heterogeneity. This framework is promising for studying generalized symbiotic relationships of any form. We formulated a novel index, turnover importance (T). T describes spatiotemporal heterogeneity in interactor assemblages, an inherent feature of generalist relationships that is not captured by available metrics. We simulated the behaviour of T relative to other available metrics, calculated T for native North American orchid‐insect relationships, and tested correlations between T and eco‐geographic variables. We performed case studies to demonstrate applications of T for conservation and eco‐evolutionary studies. T behaves predictably across simulations, and dynamically interacts with site number, gamma diversity, and species range sizes. T is moderately sensitive to sampling depth. Orchids with higher T scores occupy larger ranges and broader climatic niches. Alternative interactor‐specific measures of generalism are best employed for local‐level community networks over short timespans. While these interactor metrics can assess use versus availability in local communities, T can be used to measure spatiotemporal patterns of variation in interactor assemblages across a focal species' range. This study provides a roadmap for future work focused on better understanding the patterns and consequences of generalized relationships.

Lung transplantation is an established management strategy for advanced end-stage lung disease with the goal of restoring normal pulmonary physiology. This principle guided our management approach to the clinical challenge of a lung transplant recipient with a small chest cavity from fibrotic lung disease. Size matching should occur based on the recipient’s predicted total lung capacity, which best reflects the recipient’s normal chest cavity size. We present an instructive case that suggests that the small chest cavity size adjusts relatively quickly toward normal once the fibrotic lungs are removed, and normal allograft is implanted.

We herein describe a new species, Panax siamensis J. Wen, from the tropical monsoon forests in northern Thailand. Panax siamensis is characterized by a combination of characters including horizontally elongated rhizomes with thick internodes, 3–5 whorled leaves each with 7–9 sessile and lanceolate leaflets, lanceolate bracteoles not persisting at the fruiting stage, 2-locular ovaries, and red fruits with a black top. The new species is most closely related to Panax zingiberensis C.Y. Wu & Feng from southeastern Yunnan province of China, sharing the character of sessile leaflets, but differing in that P. siamensis has well developed, elongated rhizomes (vs. compact, ginger-like rhizomes and rootstock in P. zingiberensis), and 7–9 leaflets (vs. (3–) 5–7 leaflets in P. zingiberensis). We also compare Panax siamensis to other related Asian Panax species, including P. assamicus Banerjee, P. bipinnatifidus Seem., P. pseudoginseng Wallich, and P. vietnamensis Ha & Grushv. The new taxon is preliminarily assessed as Vulnerable (VU D2), according to the IUCN Red List criteria. A taxonomic key is provided to facilitate the identification of P. siamensis and its close allies.

Abstract Background Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening hereditary disorder that causes patients to experience significant morbidity and decreased health-related quality of life (HRQoL). A cTTP disease-specific patient-reported outcome (PRO) instrument that is reflective of patients’ experiences with the disorder does not currently exist. The objective of this study was to evaluate and validate the psychometric properties of the Congenital Thrombotic Thrombocytopenic Purpura–Patient Experience Questionnaire (cTTP-PEQ), developed using a literature review, interviews with expert clinicians, and qualitative concept elicitation and cognitive debriefing interviews. Methods This prospective, observational study (NCT03519672) was conducted with patients diagnosed with cTTP currently receiving treatment. Patients were enrolled through investigator sites and direct-to-patient recruitment. Individuals completed electronic self-administered PRO measures, including the cTTP-PEQ, at baseline and Day 14 (+ up to 10 days). The cTTP-PEQ consisted of five multi-item domains (Pain/Bruising, Cognitive Impairment, Visual Impairment, Mood, Treatment Burden) and three single-item domains (Fatigue, Headache, Activity Limitation), and assessed symptoms and impact of cTTP in the previous 24 h, 7 days, and 2 weeks. Convergent and discriminant validity were evaluated using Spearman’s rank correlation coefficients. Known-groups validity was assessed between patient groups separated by Patient Global Impression of Severity (PGI-S; normal vs. mild/moderate/severe). Internal reliability was assessed using Cronbach’s alpha. Test–retest reliability was assessed using intraclass correlation coefficients (ICCs). Results Thirty-six patients participated in this study. Convergent validity was confirmed with high-to-moderate correlations (r ≥ 0.4) for 12/15 hypothesized relationships between pairs of domains and/or total scores. Discriminant validity was confirmed with low correlations (r

Lung transplantation is the major surgical procedure, which restores normal lung functioning and provides years of life for patients suffering from major lung diseases. Lung transplant recipients are at high risk of primary graft dysfunction, and chronic lung allograft dysfunction (CLAD) in the form of bronchiolitis obliterative syndrome (BOS). Regulatory T cell (Treg) suppresses effector cells and clinical studies have demonstrated that Treg levels are altered in transplanted lung during BOS progression as compared to normal lung. Here, we discuss levels of Tregs/FOXP3 gene expression as a crucial prognostic biomarker of lung functions during CLAD progression in clinical lung transplant recipients. The review will also discuss Treg mediated immune tolerance, tissue repair, and therapeutic strategies for achieving in-vivo Treg expansion, which will be a potential therapeutic option to reduce inflammation-mediated graft injuries, taper the toxic side effects of ongoing immunosuppressants, and improve lung transplant survival rates.

Societal Impact Statement The impact of humans on Earth's biodiversity varies across the Tree of Life. The extirpation and extinction of species is often determined by compatibility with human activities. Here we classify, where data are available, a significant portion (~30%) of vascular plant species as winners or losers with respect to this compatibility and show that currently losers greatly outnumber winners and that these losers will continue to exceed winners in the future even if species now deemed tentative winners succeed. In a rapidly changing world, species may tolerate shifting conditions, adapt, or migrate to new habitats. Species that benefit humankind may have an additional advantage of survival. Those that cannot tolerate, adapt, migrate, or prove useful will be the ultimate losers in the Anthropocene and may become extinct. Summary The impact of humans on the Earth continues to accelerate, affecting climate, land use, resource exploitation, species migrations, and habitat pollution. All of these changes have the potential to result in a massive extinction of populations and species of plants, fungi, and animals. However, the impact will vary across the diversity of life: some species, the “losers,” will decline and become extinct while others, the “winners,” will thrive as a result of human activities. We surveyed a variety of sources of information on economic uses, environmental tolerances, and conservation status and were able to classify 86,592 species of vascular plant into seven categories of winners and losers as follows: winners useful to humans and winners not useful to humans, losers useful to humans and losers not useful to humans, and currently neutral species. We also recognized tentative winners and potential losers, which we could not confidently categorize into the above five classes. We then mapped, both taxonomically and phylogenetically, the clear winners and losers across the major groups of vascular plants. The results suggest that currently many more species are losers than winners and that if the tentative winners and potential losers realize their projected trajectories, losers in the future will continue to greatly outnumber future winners. Furthermore, although winners and losers are today distributed across nearly all orders of vascular plants, all but two of the nine major phylogenetic lineages favor losers over winners. A significant phylogenetic signal was detected for percentages of both winners and losers and some of the smaller ancestral orders with a high percentage of losers may be at risk of extinction. In a rapidly changing world, plant species that tolerate human pressures, adapt, or shift distributions will continue to be the winners and survive the extinction bottleneck while the many more species that cannot do so will become the ultimate losers in the Anthropocene.

Background: There are limited tools to measure the burden of disease and effectiveness of medical/surgical interventions in patients with cryptoglandular fistulas. The aim of this study was to explore concepts that are relevant and important to patients with complex cryptoglandular fistulas (CCF) and to develop a patient-centred, disease-specific, patient-reported outcome measure (PROM) to assess symptom burden and impacts of CCF. Methods: A targeted literature review was conducted, followed by one-to-one telephone interviews with five colorectal surgeons (USA, n = 3; UK, n = 1; Spain, n = 1) and 20 US adult patients with CCF to inform the development of a conceptual model and a CCF-specific PROM. The targeted literature review informed the development of the preliminary conceptual model and identified a PROM in the literature that was used as a reference to generate the draft CCF-specific PROM. The colorectal surgeon interviews provided insights on the experience of patients with CCF to refine the conceptual model, formulate probing questions for use in patient interviews, and to develop the draft CCF-specific PROM. Patients' descriptions of their experiences with symptoms and the impacts on their lives and evaluation of the draft CCF-specific PROM in concept elicitation and cognitive interviews were used to develop the final conceptual model and final CCF-specific PROM. Results: Ten symptoms (odour, pain during bowel movement, abscess, post-operative pain, discharge/drainage/leakage, anal/perianal pain, inflammation/swelling, skin irritation, bleeding and itchiness) and 11 impacts (discomfort, inability to exercise, embarrassment, difficulty sitting, worry about disease, adapted life to maintain hygiene, negatively impacted social life/isolation, inability to perform daily activities, reduced interest in sex, negatively impacted intimate relationships and negatively impacted mood) were reported as most salient by patients. The patient experience, clinician perspective, and literature review provided input to item generation. Evaluation of relevance and patient understanding through cognitive interviews with patients provided evidence for the content validity of the new patient-reported outcome measure: the 20-item Complex Cryptoglandular Fistula Questionnaire™ (CCFQ-20™). Conclusion: The CCFQ-20™ is a new clinician-guided, patient-validated, disease-specific patient-reported outcome measure that measures disease impact and quality of life in patients with CCF. [ABSTRACT FROM AUTHOR]

Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor–dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration–approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology. Editor's summary: Respiratory failure frequently occurs after lung resection and may not be fully explained by underlying respiratory disease or the size of the resection. Here, Mei and colleagues used patient samples and mouse models of pneumonectomy to show that lung resection specifically leads to increased percentages of eosinophils through a mechanism involving production of IL-7 by γδ T cells, leading to granulocyte-macrophage colony-stimulating factor production by type 2 innate lymphoid cells, ultimately resulting in increased eosinophil maturation, activation, and production of reactive oxygen species that injure the remaining lung. Targeting different points in this pathway reduced lung damage and improved survival of mice after lung resection, suggesting that perioperative administration of agents that target eosinophils or neutralize nitric oxide synthase could potentially reduce the risk of respiratory failure after lung resection. —Melissa L. Norton [ABSTRACT FROM AUTHOR]

The US Environmental Protection Agency (EPA) bases its estimate of the value of statistical life (VSL) on 17 hedonic wage studies and five contingent valuation studies conducted between 1974 and 1991. We summarize advances in the mortality risk valuation literature since these papers were published, focusing on studies conducted in the United States that value risks to adults. We review hedonic wage, other revealed preference, and stated preference studies, identifying papers that satisfy appropriate validity criteria. We conclude that the recent literature is sufficiently rich to permit a revision of EPA's baseline estimate. Importantly, VSL estimates from both the averting behavior and stated preference studies we review reflect the preferences of a wider range of demographic groups than the current VSL, and newer studies better target causes of death relevant to EPA regulations. [ABSTRACT FROM AUTHOR]

Abstract Background Late-onset Pompe Disease (LOPD) is a rare, heterogeneous disease manifested by a range of symptoms varying in severity. Research establishing the frequency of these symptoms and their impact on patients’ daily lives is limited. The objective of this study was to develop a conceptual model that captures the most relevant symptoms and functional limitations experienced by patients with LOPD, to inform the development of new patient-reported outcome (PRO) tools. Methods A preliminary conceptual model was constructed following a literature review and revised through interviews with expert clinicians to identify important and relevant concepts regarding symptoms and impacts of LOPD. This preliminary model informed the development of a qualitative patient interview guide, which was used to gather the patient perspective on symptoms and impacts relating to LOPD or its treatment (including symptom/impact frequency and levels of disturbance). Patient interviews aided further refinement of the conceptual model. The findings from the patient interviews were triangulated with the literature review and clinician interviews to identify the most relevant and significant effects of LOPD from the patient perspective. Results Muscle weakness, fatigue, pain, and breathing difficulties (especially while lying down) were the most common and highly disturbing symptoms experienced by patients. Limitations associated with mobility (e.g., difficulty rising from a sitting position, getting up after bending) and activities of daily living, (e.g., reduced ability to participate in social/family activities or work/study) were the most frequently reported impacts with the highest levels of disturbance on the patient’s daily life. These identified symptoms and impacts were included in the new conceptual model of disease. Conclusions This qualitative patient interview study, also informed by a literature review and clinician interviews, identified the most frequent and relevant symptoms and the functional impact of LOPD on patients. The study interviews also captured the patient-preferred language to describe symptoms and impacts of LOPD. The results from this study can be used to develop future PRO instruments that are tailored to the specific symptoms and impacts experienced by patients with LOPD.

Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2+ monocyte-driven BOS development. Moreover, we found TGF-β receptor 2–dependent differentiation of CCR2+ monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8+ T cells that inflicted airway injury through Blimp-1–mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β–dependent network that couples CCR2+ monocyte recruitment and differentiation to alloimmunity and BOS.

Acute lung injury (ALI) is a heterogeneous inflammatory condition associated with high morbidity and mortality. Neutrophils play a key role in the development of different forms of ALI, and the release of neutrophil extracellular traps (NETs) is emerging as a common pathogenic mechanism. NETs are essential in controlling pathogens, and their defective release or increased degradation leads to a higher risk of infection. However, NETs also contain several pro-inflammatory and cytotoxic molecules than can exacerbate thromboinflammation and lung tissue injury. To reduce NET-mediated lung damage and inflammation, DNase is frequently used in preclinical models of ALI due to its capability of digesting NET DNA scaffold. Moreover, recent advances in neutrophil biology led to the development of selective NET inhibitors, which also appear to reduce ALI in experimental models. Here we provide an overview of the role of NETs in different forms of ALI discussing existing gaps in our knowledge and novel therapeutic approaches to modulate their impact on lung injury.

Lymph node (LN) fibroblastic reticular cells (FRCs) define LN niches and regulate lymphocyte homeostasis through producing diverse extracellular matrix (ECM) components. We examined the role of ECM laminin α4 (Lama4) using FRC-Lama4 conditional KO Pdgfrb-Cre–/– × Lama4fl/fl mice. Single-cell RNA-sequencing (scRNA-Seq) data showed the promoter gene Pdgfrb was exclusively expressed in FRCs. Depleting FRC-Lama4 reduced Tregs and dendritic cells, decreased high endothelial venules, impaired the conduit system, and downregulated T cell survival factors in LNs. FRC-Lama4 depletion impaired the homing of lymphocytes to LNs in homeostasis and after allografting. Alloantigen-specific T cells proliferated, were activated to greater degrees in LNs lacking FRC-Lama4, and were more prone to differentiate into effector phenotypes relative to the Treg phenotype. In murine cardiac transplantation, tolerogenic immunosuppression was not effective in FRC-Lama4 recipients, which produced more alloantibodies than WT. After lung transplantation, FRC-Lama4–KO mice had more severe graft rejection with fewer Tregs in their LNs. Overall, FRC-Lama4 critically contributes to a tolerogenic LN niche by supporting T cell migration, constraining T cell activation and proliferation, and promoting Treg differentiation. Hence, it serves as a therapeutic target for immunoengineering.

Cytokine therapy is limited by undesirable off-target side effects as well as terminal differentiation and exhaustion of chronically stimulated T cells. Here, we describe the signaling properties of a potentially unique cytokine by design, where T cell surface binding and signaling are separated between 2 different families of receptors. This fusion protein cytokine, called OMCPmutIL-2, bound with high affinity to the cytotoxic lymphocyte-defining immunoreceptor NKG2D but signaled through the common γ chain cytokine receptor. In addition to precise activation of cytotoxic T cells due to redirected binding, OMCPmutIL-2 resulted in superior activation of both human and murine CD8+ T cells by improving their survival and memory cell generation and decreasing exhaustion. This functional improvement was the direct result of altered signal transduction based on the reorganization of surface membrane lipid rafts that led to Janus kinase-3–mediated phosphorylation of the T cell receptor rather than STAT/AKT signaling intermediates. This potentially novel signaling pathway increased CD8+ T cell response to low-affinity antigens, activated nuclear factor of activated T cells transcription factors, and promoted mitochondrial biogenesis. OMCPmutIL-2 thus outperformed other common γ chain cytokines as a catalyst for in vitro CD8+ T cell expansion and in vivo CD8+ T cell–based immunotherapy.

Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-[beta] bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-[beta] and reduce TGF-[beta] bioavailability through secretion of the TGF-[beta] antagonist decorin. In untreated recipients, high airway TGF-[beta] activity stimulated AMs to express CCL2, leading to [CCR2.sup.+] monocyte-driven BOS development. Moreover, we found TGF-[beta] receptor 2-dependent differentiation of [CCR2.sup.+] monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8* T cells that inflicted airway injury through Blimp-1-mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-[beta]-dependent network that couples [CCR2.sup.+] monocyte recruitment and differentiation to alloimmunity and BOS., Introduction Bronchiolitis obliterans syndrome (BOS) is the most common form of chronic lung allograft dysfunction (CLAD) and the leading cause of rejection after the first year of transplantation (1). The [...]

Non-cognitive skills are essential for success in a variety of settings but are not commonly taught and assessed in undergraduate curricula. The challenge for curricular integration of non-cognitive skills stems from varying interpretations of what it means to apply a specific skill effectively. In addition, teaching these skills requires going beyond the foregrounded academic content in traditional coursework. At Minerva University, we articulate core non-cognitive skills precisely and transparently as learning outcomes to guide the design of courses and assessments. We integrate these skills into the academic curriculum and student life alongside traditional learning outcomes. Students are introduced to these outcomes in their first year and continue to apply them throughout their 4 years, receiving feedback and scores across academic, disciplinary, and real-world, experiential learning contexts. We provide examples of the Learning Outcomes, detailing their introduction and application in various contexts across the 4-year arc Students’ college experience. We identify aspects of our approach that can be generalized and implemented in different settings, from individual courses to programs, departments, or entire institutions.