Cell competition drives bronchiolization and pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease arising from the maladaptive differentiation of lung stem cells into bronchial epithelial cells rather than into alveolar type 1 (AT1) cells, which are responsible for gas exchange. Here, we report that healthy lungs maintain their stem cells through tonic Hippo and ß-catenin signaling, which promote Yap/Taz degradation and allow for low level expression of the Wnt target gene Myc. Inactivation of upstream activators of the Hippo pathway in lung stem cells inhibits this tonic ß-catenin signaling and Myc expression and promotes their Taz mediated differentiation into AT1 cells. Vice versa, increased Myc in collaboration with Yap promotes the differentiation of lung stem cells along the basal and myoepithelial like lineages allowing them to invade and bronchiolize the lung parenchyma in a process reminiscent of submucosal gland development. Our findings indicate that stem cells exhibiting the highest Myc levels become supercompetitors that drive remodeling, whereas loser cells with lower Myc levels terminally differentiate into AT1 cells.

Interventions on gender equity in the workplace: a scoping review.

BACKGROUND: Various studies have demonstrated gender disparities in workplace settings and the need for further intervention. This study identifies and examines evidence from randomized controlled trials (RCTs) on interventions examining gender equity in workplace or volunteer settings. An additional aim was to determine whether interventions considered intersection of gender and other variables, including PROGRESS-Plus equity variables (e.g., race/ethnicity). METHODS: Scoping review conducted using the JBI guide. Literature was searched in MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, ERIC, Index to Legal Periodicals and Books, PAIS Index, Policy Index File, and the Canadian Business & Current Affairs Database from inception to May 9, 2022, with an updated search on October 17, 2022. Results were reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension to scoping reviews (PRISMA-ScR), Sex and Gender Equity in Research (SAGER) guidance, Strengthening the Integration of Intersectionality Theory in Health Inequality Analysis (SIITHIA) checklist, and Guidance for Reporting Involvement of Patients and the Public (GRIPP) version 2 checklist. All employment or volunteer sectors settings were included. Included interventions were designed to promote workplace gender equity that targeted: (a) individuals, (b) organizations, or (c) systems. Any comparator was eligible. Outcomes measures included any gender equity related outcome, whether it was measuring intervention effectiveness (as defined by included studies) or implementation. Data analyses were descriptive in nature. As recommended in the JBI guide to scoping reviews, only high-level content analysis was conducted to categorize the interventions, which were reported using a previously published framework. RESULTS: We screened 8855 citations, 803 grey literature sources, and 663 full-text articles, resulting in 24 unique RCTs and one companion report that met inclusion criteria. Most studies (91.7%) failed to report how they established sex or gender. Twenty-three of 24 (95.8%) studies reported at least one PROGRESS-Plus variable: typically sex or gender or occupation. Two RCTs (8.3%) identified a non-binary gender identity. None of the RCTs reported on relationships between gender and other characteristics (e.g., disability, age, etc.). We identified 24 gender equity promoting interventions in the workplace that were evaluated and categorized into one or more of the following themes: (i) quantifying gender impacts; (ii) behavioural or systemic changes; (iii) career flexibility; (iv) increased visibility, recognition, and representation; (v) creating opportunities for development, mentorship, and sponsorship; and (vi) financial support. Of these interventions, 20/24 (83.3%) had positive conclusion statements for their primary outcomes (e.g., improved academic productivity, increased self-esteem) across heterogeneous outcomes. CONCLUSIONS: There is a paucity of literature on interventions to promote workplace gender equity. While some interventions elicited positive conclusions across a variety of outcomes, standardized outcome measures considering specific contexts and cultures are required. Few PROGRESS-Plus items were reported. Non-binary gender identities and issues related to intersectionality were not adequately considered. Future research should provide consistent and contemporary definitions of gender and sex. TRIAL REGISTRATION: Open Science Framework https://osf.io/x8yae .

Haptoglobin Phenotype and Intensive Glycemic Control for Coronary Artery Disease Risk Reduction in People With Type 2 Diabetes: The ADVANCE Study.

OBJECTIVE: Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study participants with the haptoglobin (Hp)2-2 phenotype but not in participants without the Hp2-2 phenotype. It is unknown whether and how these results translate across different demographic/clinical characteristics and treatment strategies. RESEARCH DESIGN AND METHODS: Haptoglobin phenotype was measured in available samples from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) biomarker case-cohort study. Weighted multivariable-adjusted Cox regression models were used to evaluate the association between intensive glycemic control (HbA1c target of ≤6.5%) versus standard therapy (based on local guidelines) and major CAD events among participants with (n = 1,327) and without (n = 2,077) the Hp2-2 phenotype separately and within prespecified stratifications by sex, race, previous cardiovascular disease (CVD), diabetes duration, and HDL-cholesterol. RESULTS: While the hazard ratios (HRs) were in the hypothesized differing directions, compared with standard therapy, intensive glycemic control was not significantly associated with risk of CAD events among participants without (1.04, 95% CI 0.82-1.32) or with (0.84, 0.63-1.14, Pinteraction = 0.27) the Hp2-2 phenotype overall. Intensive therapy was associated with lower CAD risk among participants with the Hp2-2 phenotype who had no previous CVD (0.47, 0.29-0.76, Pinteraction = 0.01). CONCLUSIONS: Our findings suggest that intensive glycemic control contributes to the prevention of major CAD events among ADVANCE participants with the Hp2-2 phenotype and no previous CVD and are in alignment with our hypothesis that intensive glycemic control may be beneficial in a subset of people with the Hp2-2 phenotype.

Intensive lifestyle intervention in type 2 diabetes and risk of incident coronary artery disease for the common haptoglobin phenotypes: the Look AHEAD study.

BACKGROUND: Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD) participants with the haptoglobin (Hp) 2-2 phenotype only. It remains unknown whether Hp phenotype modifies the effect of an intensive lifestyle intervention (ILI) on CAD in type 2 diabetes. METHODS: Haptoglobin phenotype was measured in 4542 samples from the Action for Health in Diabetes (Look AHEAD) study. Cox regression models assessed the effect of ILI (focused on weight loss from caloric restriction and physical activity) versus diabetes support and education (DSE) on CAD events in each phenotype group, and within pre-specified subgroups including race/ethnicity, sex, history of cardiovascular disease, diabetes medication use, and diabetes duration. RESULTS: 1590 (35%) participants had the Hp2-2 phenotype. The ILI did not lower glycated hemoglobin (%HbA1c) to < 6.5% in either phenotype, with a peak significant difference between treatment arms of 0.5% [non-Hp2-2] and 0.6% [Hp2-2]. The cumulative CAD incidence was 13.4% and 13.8% in the DSE arm and 12.2% and 13.6% in the ILI arm for non-Hp2-2 and Hp2-2 groups, respectively. Compared to DSE, the ILI was not associated with CAD among participants without (HR = 0.95, 95% CI 0.78-1.17) or with (0.89, 0.68-1.19) the Hp2-2 phenotype (p-interaction between Hp phenotype and ILI = 0.58). After Bonferroni correction, there were no significant results among any subgroups. CONCLUSIONS: Hp phenotype did not modify the effect of the weight loss ILI on risk of CAD in Look AHEAD, potentially because it did not substantially impact glycemic control among participants with or without the Hp2-2 phenotype. Further research is needed to determine if these results are conclusive.

Relationship Between Time-Varying Achieved High-Density Lipoprotein Cholesterol and Risk of Coronary Events Depends on Haptoglobin Phenotype Within the ACCORD Lipid Study.

Background The Hp (haptoglobin)2-2 phenotype (~40% of people) is associated with dysfunctional high-density lipoprotein (HDL) that is heavily oxidized in hyperglycemia, which may explain why raising HDL-cholesterol (HDL-C) does not reliably prevent coronary artery disease (CAD) in diabetes. Methods and Results In this observational study using longitudinal data from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) lipid trial, time-varying (achieved) HDL-C updated at 4, 8, and 12 months, and annually thereafter over a mean of 4.7 years, was analyzed in relation to risk of CAD and secondary outcomes using Cox proportional hazards regression with time-varying covariables among participants with (n=1781) and without (n=3191) the Hp2-2 phenotype. HDL-C did not differ between the phenotypes throughout the study. Having low HDL-C (<40 mg/dL for male participants and <50 mg/dL for female participants) was associated with a greater risk of CAD compared with non-low HDL-C among participants with the non-Hp2-2 phenotype (hazard ratio [HR], 1.48 [95% CI, 1.18-1.87]) but not among the Hp2-2 phenotype (HR, 0.97 [95% CI, 0.70-1.35]; P interaction=0.03). Similarly, an inverse relationship was observed between HDL-C quintiles and CAD risk among participants without the Hp2-2 phenotype, whereas no significant inverse relationship was observed among participants with the Hp2-2 phenotype (P interaction=0.38). Among the Hp2-2 phenotype group, having low HDL-C was associated with higher risk of CVD mortality (HR, 2.09 [95% CI, 1.05-4.13]), and compared with the lowest HDL-C quintile, higher quintiles were associated with lower risk of CVD mortality and congestive heart failure. Conclusions Hp phenotype modified the association between HDL-C and risk of CAD in the ACCORD lipid study, suggesting that HDL dysfunction in the Hp2-2 phenotype may hinder CAD-protective properties of HDL-C.

The Relationship Between Time-Varying Achieved HbA1c and Risk of Coronary Events Depends on Haptoglobin Phenotype Among White and Black ACCORD Participants.

OBJECTIVE: Intensive glycemic therapy reduced coronary artery disease (CAD) events among White participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with the haptoglobin (Hp)2-2 phenotype, while participants without the Hp2-2 phenotype had no CAD benefit. The association between achieved glycated hemoglobin (HbA1c) and CAD for each Hp phenotype remains unknown. RESEARCH DESIGN AND METHODS: Achieved HbA1c was similar in each phenotype throughout the study. Prospectively collected HbA1c data (categorized as <6.0%, 6.0-6.5%, 6.6-6.9%, or ≥8.0% compared with 7.0-7.9%) from the ACCORD study, updated every 4 months over a median of 4.7 years, were analyzed in relation to CAD in the Hp2-2 (n = 3,322) and non-Hp2-2 (n = 5,949) phenotypes separately overall, and within White (63%, 37% Hp2-2) and Black (19%, 26% Hp2-2) participants using Cox proportional hazards regression with time-varying covariables. RESULTS: Compared with HbA1c of 7.0-7.9%, having HbA1c ≥8.0% was associated with CAD risk among White (adjusted HR [aHR] 1.43, 95% CI 1.03-1.98) and Black (2.86, 1.09-7.51) participants with the Hp2-2 phenotype, but not when all Hp2-2 participants were combined overall (1.30, 0.99-1.70), and not among participants without the Hp2-2 phenotype. HbA1c <7.0% was not associated with a lower risk of CAD for any Hp phenotype. CONCLUSIONS: Achieving HbA1c >8.0% compared with 7.0-7.9% was consistently associated with incident CAD risk among White and Black ACCORD participants with the Hp2-2 phenotype, while no association was observed among participants without the Hp2-2 phenotype. We found no evidence that HbA1c concentration <7.0% prevents CAD in either Hp phenotype group.

Protocol for the use of signal amplification by exchange reaction-fluorescence in situ hybridization on adult formalin-fixed paraffin-embedded mouse lung tissue.

Fluorescence in situ hybridization (FISH) is a useful tool for analyzing RNA expression, but difficulties arise with low-abundance RNA and in tissues that are formalin-fixed paraffin-embedded (FFPE) because reagents can be expensive. In this protocol, we adapt a previously designed FISH amplification protocol (SABER [signal amplification by exchange reaction]) for adult mouse FFPE lung sections by using probes that are extended and branched to amplify the signal. We combine FISH and immunostaining to identify cell-specific RNA. For complete details on the use and execution of this protocol, please refer to Kishi et al.1 and Lyu et al.2.

Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicates that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis. Recent reports indicate increased YAP activity in respiratory epithelial cells in IPF lungs. Individual IPF epithelial cells with aberrant YAP activation in bronchiolized regions frequently co-express AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating 'indeterminate' states of differentiation and suggesting that aberrant YAP signaling might promote pulmonary fibrosis. Yet, Yap and Taz have recently also been shown to be important for AT1 cell maintenance and alveolar epithelial regeneration after Streptococcus pneumoniae-induced injury. To investigate how epithelial Yap/Taz might promote pulmonary fibrosis or drive alveolar epithelial regeneration, we inactivated the Hippo pathway in AT2 stem cells resulting in increased nuclear Yap/Taz, and found that this promotes their alveolar regenerative capacity and reduces pulmonary fibrosis following bleomycin injury by pushing them along the AT1 cell lineage. Vice versa, inactivation of both Yap1 and Wwtr1 (encoding Taz) or Wwtr1 alone in AT2 cell stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, the inactivation of only Yap1 in AT2 stem cells promoted alveolar epithelial regeneration and reduced pulmonary fibrosis. Together, these data suggest that epithelial Yap promotes, and epithelial Taz reduces pulmonary fibrosis suggesting that targeting Yap but not Taz-mediated transcription might help promote AT1 cell regeneration and treat pulmonary fibrosis.

Global evidence of gender equity in academic health research: a scoping review.

OBJECTIVES: To chart the global literature on gender equity in academic health research. DESIGN: Scoping review. PARTICIPANTS: Quantitative studies were eligible if they examined gender equity within academic institutions including health researchers. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcomes related to equity across gender and other social identities in academia: (1) faculty workforce: representation of all genders in university/faculty departments, academic rank or position and salary; (2) service: teaching obligations and administrative/non-teaching activities; (3) recruitment and hiring data: number of applicants by gender, interviews and new hires for various rank; (4) promotion: opportunities for promotion and time to progress through academic ranks; (5) academic leadership: type of leadership positions, opportunities for leadership promotion or training, opportunities to supervise/mentor and support for leadership bids; (6) scholarly output or productivity: number/type of publications and presentations, position of authorship, number/value of grants or awards and intellectual property ownership; (7) contextual factors of universities; (8) infrastructure; (9) knowledge and technology translation activities; (10) availability of maternity/paternity/parental/family leave; (11) collaboration activities/opportunities for collaboration; (12) qualitative considerations: perceptions around promotion, finances and support. RESULTS: Literature search yielded 94 798 citations; 4753 full-text articles were screened, and 562 studies were included. Most studies originated from North America (462/562, 82.2%). Few studies (27/562, 4.8%) reported race and fewer reported sex/gender (which were used interchangeably in most studies) other than male/female (11/562, 2.0%). Only one study provided data on religion. No other PROGRESS-PLUS variables were reported. A total of 2996 outcomes were reported, with most studies examining academic output (371/562, 66.0%). CONCLUSIONS: Reviewed literature suggest a lack in analytic approaches that consider genders beyond the binary categories of man and woman, additional social identities (race, religion, social capital and disability) and an intersectionality lens examining the interconnection of multiple social identities in understanding discrimination and disadvantage. All of these are necessary to tailor strategies that promote gender equity. TRIAL REGISTRATION NUMBER: Open Science Framework: https://osf.io/8wk7e/.

Trends in FDA Adverse Events Reporting for Inferior Vena Cava Filters and Estimated Insertions in the US, 2016 to 2020.

This quality improvement study identifies adverse events for inferior vena cava filters and reports changes in adverse event reporting and estimated insertions between 2016 and 2020 in the US.

Incidence and Progression of Fibrotic Lung Disease in an At-Risk Cohort.

Rationale: Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis and develop preclinical pulmonary fibrosis (PrePF). Objectives: We defined the incidence and progression of new-onset PrePF and its relationship to survival among first-degree relatives of families with FIP. Methods: This is a cohort study of family members with FIP who were initially screened with a health questionnaire and chest high-resolution computed tomography (HRCT) scan, and approximately 4 years later, the evaluation was repeated. A total of 493 asymptomatic first-degree relatives of patients with FIP were evaluated at baseline, and 296 (60%) of the original subjects participated in the subsequent evaluation. Measurements and Main Results: The median interval between HRCTs was 3.9 years (interquartile range, 3.5-4.4 yr). A total of 252 subjects who agreed to repeat evaluation were originally determined not to have PrePF at baseline; 16 developed PrePF. A conservative estimate of the annual incidence of PrePF is 1,023 per 100,000 person-years (95% confidence interval, 511-1,831 per 100,000 person-years). Of 44 subjects with PrePF at baseline, 38.4% subjects had worsening dyspnea compared with 15.4% of those without PrePF (P = 0.002). Usual interstitial pneumonia by HRCT (P < 0.0002) and baseline quantitative fibrosis score (P < 0.001) are also associated with worsening dyspnea. PrePF at the initial screen is associated with decreased survival (P < 0.001). Conclusions: The incidence of PrePF in this at-risk population is at least 100-fold higher than that reported for sporadic idiopathic pulmonary fibrosis (IPF). Although PrePF and IPF represent distinct entities, our study demonstrates that PrePF, like IPF, is progressive and associated with decreased survival.

Niche-mediated repair of airways is directed in an occupant-dependent manner.

In injured airways of the adult lung, epithelial progenitors are called upon to repair by nearby mesenchymal cells via signals transmitted through the niche. Currently, it is unclear whether repair is coordinated by the mesenchymal cells that maintain the niche or by the airway epithelial cells that occupy it. Here, we show that the spatiotemporal expression of Fgf10 by the niche is primarily orchestrated by the niche's epithelial occupants-both those that reside prior to, and following, injury. During homeostasis, differentiated airway epithelial cells secrete Sonic hedgehog (Shh) to inhibit Fgf10 expression by Gli1+ peribronchial mesenchymal cells in the niche. After injury, remaining epithelial cells produce Wnt7b to induce Fgf10 expression in airway smooth muscle cells in the niche. We find that this reliance on a common activator of airway epithelial stem cells also allows for the recruitment of remote stem cell populations when local populations have been exhausted.

Comparative-effectiveness research of COVID-19 treatment: a rapid scoping review.

OBJECTIVES: The COVID-19 pandemic has stimulated growing research on treatment options. We aim to provide an overview of the characteristics of studies evaluating COVID-19 treatment. DESIGN: Rapid scoping review DATA SOURCES: Medline, Embase and biorxiv/medrxiv from inception to 15 May 2021. SETTING: Hospital and community care. PARTICIPANTS: COVID-19 patients of all ages. INTERVENTIONS: COVID-19 treatment. RESULTS: The literature search identified 616 relevant primary studies of which 188 were randomised controlled trials and 299 relevant evidence syntheses. The studies and evidence syntheses were conducted in 51 and 39 countries, respectively.Most studies enrolled patients admitted to acute care hospitals (84%), included on average 169 participants, with an average age of 60 years, study duration of 28 days, number of effect outcomes of four and number of harm outcomes of one. The most common primary outcome was death (32%).The included studies evaluated 214 treatment options. The most common treatments were tocilizumab (11%), hydroxychloroquine (9%) and convalescent plasma (7%). The most common therapeutic categories were non-steroidal immunosuppressants (18%), steroids (15%) and antivirals (14%). The most common therapeutic categories involving multiple drugs were antimalarials/antibiotics (16%), steroids/non-steroidal immunosuppressants (9%) and antimalarials/antivirals/antivirals (7%). The most common treatments evaluated in systematic reviews were hydroxychloroquine (11%), remdesivir (8%), tocilizumab (7%) and steroids (7%).The evaluated treatment was in favour 50% and 36% of the evaluations, according to the conclusion of the authors of primary studies and evidence syntheses, respectively. CONCLUSIONS: This rapid scoping review characterised a growing body of comparative-effectiveness primary studies and evidence syntheses. The results suggest future studies should focus on children, elderly ≥65 years of age, patients with mild symptoms, outpatient treatment, multimechanism therapies, harms and active comparators. The results also suggest that future living evidence synthesis and network meta-analysis would provide additional information for decision-makers on managing COVID-19.

Ataxia telangiectasia mutated is required for efficient proximal airway epithelial cell regeneration following influenza A virus infection.

Children and young adults with mutant forms of ataxia telangiectasia mutated (ATM), a kinase involved in DNA damage signaling and mitochondrial homeostasis, suffer from recurrent respiratory infections, immune deficiencies, and obstructive airways disease associated with disorganized airway epithelium. We previously showed in mice how Atm was required to mount a protective immune memory response to influenza A virus [IAV; Hong Kong/X31 (HKx31), H3N2]. Here, Atm wildtype (WT) and knockout (Atm-null) mice were used to investigate how Atm is required to regenerate the injured airway epithelium following IAV infection. When compared with WT mice, naive Atm-null mice had increased airway resistance and reduced lung compliance that worsened during infection before returning to naïve levels by 56 days postinfection (dpi). Although Atm-null lungs appeared pathologically normal before infection by histology, they developed an abnormal proximal airway epithelium after infection that contained E-cadherin+, Sox2+, and Cyp2f2+ cells lacking secretoglobin family 1 A member 1 (Scgb1a1) protein expression. Patchy and low expression of Scgb1a1 were eventually observed by 56 dpi. Genetic lineage tracing in HKx31-infected mice revealed club cells require Atm to rapidly and efficiently restore Scgb1a1 expression in proximal airways. Since Scgb1a1 is an immunomodulatory protein that protects the lung against a multitude of respiratory challenges, failure to efficiently restore its expression may contribute to the respiratory diseases seen in individuals with ataxia telangiectasia.

Haptoglobin Phenotype Modifies the Effect of Fenofibrate on Risk of Coronary Event: ACCORD Lipid Trial.

OBJECTIVE: The haptoglobin (Hp)2-2 phenotype (∼35-40% of people) is associated with increased oxidation and dysfunctional HDL in hyperglycemia and may explain why drugs designed to pharmacologically raise HDL cholesterol and lower triglycerides have not reliably prevented cardiovascular disease in diabetes. We aimed to determine whether the effect of adding fenofibrate versus placebo to simvastatin on the risk of coronary artery disease (CAD) events depends on Hp phenotype in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial. RESEARCH DESIGN AND METHODS: Cox proportional hazards regression models quantified the relationship between fenofibrate therapy and CAD events in the ACCORD lipid trial in participants with the Hp2-2 phenotype (n = 1,795) separately from those without (n = 3,201). RESULTS: Fenofibrate therapy successfully lowered the risk of CAD events in participants without the Hp2-2 phenotype (multivariable adjusted hazard ratio 0.74 [95% CI 0.60-0.90] compared with no fenofibrate therapy) but not in participants with the Hp2-2 phenotype (1.16 [0.87-1.56]; P interaction = 0.009). Subgroup analyses revealed that this protective effect of fenofibrate against CAD events among the non-Hp2-2 phenotype group was pronounced in participants with severe dyslipidemia (P interaction = 0.01) and in males (P interaction = 0.02) with an increased CAD risk from fenofibrate treatment observed in females with the Hp2-2 phenotype (P interaction = 0.002). CONCLUSIONS: The effect of fenofibrate added to simvastatin on risk of CAD events depends on Hp phenotype in the ACCORD lipid trial.

Anti-vascular endothelial growth factor therapy for age-related macular degeneration: a systematic review and network meta-analysis.

BACKGROUND: The comparative safety and efficacy between anti-vascular endothelial growth factor agents (anti-VEGFs) and between combined therapies for patients with neovascular age-related macular degeneration (nAMD) is unclear. We conducted a systematic review to examine the comparative safety and efficacy anti-VEGFs for adults with nAMD. METHODS: Studies were identified through MEDLINE, EMBASE, and Cochrane CENTRAL (inception to June 3, 2019), grey literature, and scanning reference lists. Two reviewers independently screened citations and full-text articles to identify randomized controlled trials (RCTs), extracted data, and appraised risk of bias. Pairwise random-effects meta-analysis and Bayesian network meta-analysis (NMA) were conducted. The primary outcomes were the proportion of patients experiencing moderate vision gain (≥ 15 letters on the Early Treatment Diabetic Retinopathy Study chart) and the proportion of patients experiencing moderate vision loss (≤ 15 letters). RESULTS: After screening 3647 citations and 485 potentially relevant full-text articles, 92 RCTs with 24,717 patients were included. NMA (34 RCTs, 8809 patients, 12 treatments) showed small differences among anti-VEGFs in improving the proportion of patients with moderate vision gain, with the largest for conbercept versus broluczumab (OR 0.15, 95% CrI: 0.05-0.56), conbercept versus ranibizumab (OR 0.17, 95% CrI: 0.05-0.59), conbercept versus aflibercept (OR 0.19, 95% CrI: 0.06-0.65), and conbercept versus bevacizumab (OR 0.2, 95% CrI: 0.06-0.69). In NMA (36 RCTs, 9081 patients, 13 treatments) for the proportion of patients with moderate vision loss, small differences were observed among anti-VEGFs, with the largest being for conbercept versus aflibercept (OR 0.24, 95% CrI: 0-4.29), conbercept versus brolucizumab (OR 0.24, 95% CrI: 0-4.71), conbercept versus bevacizumab (OR 0.26, 95% CrI: 0-4.65), and conbercept versus ranibizumab (OR 0.27, 95% CrI: 0-4.67). CONCLUSION: The only observed differences were that ranibizumab, bevacizumab, aflibercept, and brolucizumab were statistically superior to conbercept in terms of the proportion of patients with nAMD who experienced moderate vision gain. However, this finding is based on indirect evidence through one small trial comparing conbercept with placebo. This does not account for drug-specific differences when assessing anatomic and functional treatment efficacy in variable dosing regimens. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42015022041.

Low-dose hyperoxia primes airways for fibrosis in mice after influenza A infection.

It is well known that supplemental oxygen used to treat preterm infants in respiratory distress is associated with permanently disrupting lung development and the host response to influenza A virus (IAV). However, many infants who go home with normally functioning lungs are also at risk for hyperreactivity after a respiratory viral infection. We recently reported a new, low-dose hyperoxia mouse model (40% for 8 days; 40×8) that causes a transient change in lung function that resolves, rendering 40×8 adult animals functionally indistinguishable from room air controls. Here we report that when infected with IAV, 40×8 mice display an early transient activation of TGFß signaling and later airway hyperreactivity associated with peribronchial inflammation (profibrotic macrophages) and fibrosis compared with infected room air controls, suggesting neonatal oxygen induced hidden molecular changes that prime the lung for hyperreactive airways disease. Although searching for potential activators of TGFß signaling, we discovered that thrombospondin-1 (TSP-1) is elevated in naïve 40×8 mice compared with controls and localized to lung megakaryocytes and platelets before and during IAV infection. Elevated TSP-1 was also identified in human autopsy samples of former preterm infants with bronchopulmonary dysplasia. These findings reveal how low doses of oxygen that do not durably change lung function may prime it for hyperreactive airways disease by changing expression of genes, such as TSP-1, thus helping to explain why former preterm infants who have normal lung function are susceptible to airway obstruction and increased morbidity after viral infection.

Addressing risks to biodiversity arising from a changing climate: The need for ecosystem restoration in the Tana River Basin, Kenya.

Climate change is projected to have significant effects on the distribution of species globally, but research into the implications in parts of Africa has been limited. Using species distribution modelling, this study models climate change-related risks to the terrestrial biodiversity (birds, mammals, reptiles, amphibians and plants) of Kenya's economically-important and ecologically diverse Tana River Basin. Large reductions in species richness are projected with just 2°C warming (relative to preindustrial levels) with birds and plants seeing the greatest impact. Potential climate refugia for biodiversity are identified within the basin, but often overlap with areas already converted to agriculture or set aside for agricultural expansion, and the majority are outside protected areas. Similarly, some protected areas contain no projected refugia at higher levels of global warming, showing they may be insufficient to protect the basin's biodiversity as climate changes. However, risks to biodiversity are much smaller if the Paris Agreement's goal of limiting global warming to 'well below 2°C' warming, rather than 2°C only, is met. The potential for refugia for plants and animals decreases strongly with warming. For example, 82% of the basin remaining climatically suitable for at least 75% of the plants currently present at 1.5°C warming, as compared with 23% at 2°C and 3% at 4.5°C. This research provides the first assessment of the combined effects of development plans and climate change on biodiversity of the Tana River Basin, including identifying potential areas for restoration, and contributes to a greater understanding of biodiversity protection and adaptation options in Kenya.

Investigating the potential impact of 1.5, 2 and 3 °C global warming levels on crop suitability and planting season over West Africa.

West African rainfed agriculture is highly vulnerable to climate variability and change. Global warming is projected to result in higher regional warming and have a strong impact on agriculture. This study specifically examines the impact of global warming levels (GWLs) of 1.5°, 2° and 3 °C relative to 1971-2000 on crop suitability over West Africa. We used 10 Coupled Model Intercomparison Project Phase5 Global Climate Models (CMIP5 GCMs) downscaled by Coordinated Regional Downscaling Experiment (CORDEX) Rossby Centre's regional Atmospheric model version 4, RCA4, to drive Ecocrop, a crop suitability model, for pearl millet, cassava, groundnut, cowpea, maize and plantain. The results show Ecocrop simulated crop suitability spatial representation with higher suitability, observed to the south of latitude 14°N and lower suitability to its north for 1971-2000 for all crops except for plantain (12°N). The model also simulates the best three planting months within the growing season from September-August over the past climate. Projected changes in crop suitability under the three GWLs 1.5-3.0 °C suggest a spatial suitability expansion for legume and cereal crops, notably in the central southern Sahel zone; root and tuber and plantain in the central Guinea-Savanna zone. In contrast, projected decreases in the crop suitability index value are predicted to the south of 14°N for cereals, root and tuber crops; nevertheless, the areas remain suitable for the crops. A delay of between 1-3 months is projected over the region during the planting month under the three GWLs for legumes, pearl millet and plantain. A two month delay in planting is projected in the south, notably over the Guinea and central Savanna zone with earlier planting of about three months in the Savanna-Sahel zones. The effect of GWL2.0 and GWL3.0 warming in comparison to GWL1.5 °C are more dramatic on cereals and root and tuber crops, especially cassava. All the projected changes in simulated crop suitability in response to climatic variables are statistically significant at 99% confidence level. There is also an increasing trend in the projected crop suitability change across the three warming except for cowpea. This study has implications for improving the resilience of crop production to climate changes, and more broadly, to food security in West Africa.

Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival.

Master regulators of the unfolded protein response (UPR), IRE1α and PERK, promote adaptation or apoptosis depending on the level of endoplasmic reticulum (ER) stress. Although the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNET) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. Genetic and pharmacologic modulation of IRE1α and PERK in cultured cells, xenograft, and spontaneous genetic (RIP-Tag2) mouse models of PanNETs revealed that UPR signaling was optimized for adaptation and that inhibiting either IRE1α or PERK led to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. These results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers with elevated ER stress. SIGNIFICANCE: The UPR is upregulated in pancreatic neuroendocrine tumors and its inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in these cancers.