Use of Sensitivity Analyses to Assess Uncontrolled Confounding from Unmeasured Variables in Observational, Active Comparator Pharmacoepidemiologic Studies: A Systematic Review.

Understanding the potential for, direction, and magnitude of uncontrolled confounding is critical for generating informative real-world evidence. Many sensitivity analyses are available to assess robustness of study results to residual confounding, but it is unclear how researchers are using these methods. We conducted a systematic review of published active comparator cohort studies of drugs or biologics to summarize use of sensitivity analyses aimed at assessing uncontrolled confounding from an unmeasured variable. We reviewed articles in five medical and seven epidemiologic journals published between January 1, 2017, and June 30, 2022. We identified 158 active comparator cohort studies, 76 from medical and 82 from epidemiologic journals. Residual, unmeasured, or uncontrolled confounding was noted as a potential concern in 93% of studies, but only 84 (53%) implemented one or more sensitivity analysis to assess uncontrolled confounding from an unmeasured variable. The most common analyses were E-values among medical journal articles (21%) and restriction on measured variables among epidemiologic journal articles (22%). Researchers must rigorously consider the role of residual confounding in their analyses and the best sensitivity analyses for assessing this potential bias.

Applications of cell therapy in the treatment of virus-associated cancers.

A diverse range of viruses have well-established roles as the primary driver of oncogenesis in various haematological malignancies and solid tumours. Indeed, estimates suggest that approximately 1.5 million patients annually are diagnosed with virus-related cancers. The predominant human oncoviruses include Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis B and C viruses (HBV and HCV), human papillomavirus (HPV), human T-lymphotropic virus type 1 (HTLV1), and Merkel cell polyomavirus (MCPyV). In addition, although not inherently oncogenic, human immunodeficiency virus (HIV) is associated with immunosuppression that contributes to the development of AIDS-defining cancers (specifically, Kaposi sarcoma, aggressive B cell non-Hodgkin lymphoma and cervical cancer). Given that an adaptive T cell-mediated immune response is crucial for the control of viral infections, increasing research is being focused on evaluating virus-specific T cell therapies for the treatment of virus-associated cancers. In this Review, we briefly outline the roles of viruses in the pathogenesis of these malignancies before describing progress to date in the field of virus-specific T cell therapy and evaluating the potential utility of these therapies to treat or possibly even prevent virus-related malignancies.

Image-guided patient-specific optimization of catheter placement for convection-enhanced nanoparticle delivery in recurrent glioblastoma.

BACKGROUND: Proper catheter placement for convection-enhanced delivery (CED) is required to maximize tumor coverage and minimize exposure to healthy tissue. We developed an image-based model to patient-specifically optimize the catheter placement for rhenium-186 (186Re)-nanoliposomes (RNL) delivery to treat recurrent glioblastoma (rGBM). METHODS: The model consists of the 1) fluid fields generated via catheter infusion, 2) dynamic transport of RNL, and 3) transforming RNL concentration to the SPECT signal. Patient-specific tissue geometries were assigned from pre-delivery MRIs. Model parameters were personalized with either 1) individual-based calibration with longitudinal SPECT images, or 2) population-based assignment via leave-one-out cross-validation. The concordance correlation coefficient (CCC) was used to quantify the agreement between the predicted and measured SPECT signals. The model was then used to simulate RNL distributions from a range of catheter placements, resulting in a ratio of the cumulative RNL dose outside versus inside the tumor, the "off-target ratio" (OTR). Optimal catheter placement) was identified by minimizing OTR. RESULTS: Fifteen patients with rGBM from a Phase I/II clinical trial (NCT01906385) were recruited to the study. Our model, with either individual-calibrated or population-assigned parameters, achieved high accuracy (CCC > 0.80) for predicting RNL distributions up to 24 h after delivery. The optimal catheter placements identified using this model achieved a median (range) of 34.56 % (14.70 %-61.12 %) reduction on OTR at the 24 h post-delivery in comparison to the original placements. CONCLUSIONS: Our image-guided model achieved high accuracy for predicting patient-specific RNL distributions and indicates value for optimizing catheter placement for CED of radiolabeled liposomes.

Environmental monitoring of current good manufacturing practices cleanroom facilities for manufacturing of cellular therapy products in an academic hospital setting.

As the field of cell and gene therapy (CGT) continues to grow, so too must the infrastructure and regulatory guidance supporting the manufacture of these potentially life-saving products-especially early-phase products manufactured at an increasing number of academic or hospital-based facilities providing decentralized (or point of care) manufacturing. An important component of current good manufacturing practices, including those regulating cell and gene therapies, is the establishment of an effective environmental monitoring (EM) program. While several guidelines for establishing an EM program are available, these guidelines do not specifically address the unique aspects of manufacturing CGT products and they do not provide real-world evidence demonstrating the effectiveness of the program. Here, we describe the establishment and evolution of an EM program in a cell therapy manufacturing facility at an academic hospital. With 10 years of EM data, we analyze the effectiveness for identifying trends in environmental conditions and highlight important findings, with the aim of providing practical evidence and guidance for the development of future early-phase EM programs.

Synergistic innovations enabled the radiation of anglerfishes in the deep open ocean.

Major ecological transitions are thought to fuel diversification, but whether they are contingent on the evolution of certain traits called key innovations1 is unclear. Key innovations are routinely invoked to explain how lineages rapidly exploit new ecological opportunities.1,2,3 However, investigations of key innovations often focus on single traits rather than considering trait combinations that collectively produce effects of interest.4 Here, we investigate the evolution of synergistic trait interactions in anglerfishes, which include one of the most species-rich vertebrate clades in the bathypelagic, or "midnight," zone of the deep sea: Ceratioidea.5 Ceratioids are the only vertebrates that possess sexual parasitism, wherein males temporarily attach or permanently fuse to females to mate.6,7 We show that the rapid transition of ancestrally benthic anglerfishes into pelagic habitats occurred during a period of major global warming 50-35 million years ago.8,9 This transition coincided with the origins of sexual parasitism, which is thought to increase the probability of successful reproduction once a mate is found in the midnight zone, Earth's largest habitat.5,6,7 Our reconstruction of the evolutionary history of anglerfishes and the loss of immune genes support that permanently fusing clades have convergently degenerated their adaptive immunity. We find that degenerate adaptive immune genes and sexual body size dimorphism, both variably present in anglerfishes outside the ceratioid radiation, likely promoted their transition into the bathypelagic zone. These results show how traits from separate physiological, morphological, and reproductive systems can interact synergistically to drive major transitions and subsequent diversification in novel environments.

Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3.

Statins are known to be anti-inflammatory, but the mechanism remains poorly understood. Here, we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the adenosine triphosphate (ATP) synthase in the inner mitochondrial membrane and changes the proton gradient in the mitochondria. This activates nuclear factor kappa-B (NF-κB) and Jmjd3 expression, which removes the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus lipopolysaccharide (M1), macrophages, either treated with statins in vitro or isolated from statin-fed mice, express lower levels proinflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL-4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment.

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.

Characteristics of Rodeo Injuries and Suggestions for Injury Prevention: A Systematic Review.

Background: Rodeo is a globally popular sport, with its athletes prone to various types of injuries. There is no systematic review discussing rodeo injuries across all age groups. Purpose: To (1) review the published literature on incidence, types of injuries, and factors leading to injuries in rodeo athletes; (2) provide prevention recommendations for health care providers; and (3) identify gaps in the research. Study Design: Systematic review; Level of evidence, 4. Methods: A comprehensive search of available literature was electronically performed through MEDLINE, Embase, and SPORTDiscus databases using the key terms "rodeo" and "injury" or "trauma" between 1995 and 2021. A systematic review was performed using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, which identified 116 eligible studies. Outcome data included frequency of injuries, risk factors for injury, and types of injury. Results: A total of 23 studies met the inclusion criteria (N = 2105 athletes), of which 13 were retrospective studies. In the included studies, the injury rate per competition exposure (CE) ranged from 4.2 to 19.1 injuries per 1000 CE. Sprains and strains accounted for the highest percentage of injury types, ranging from 15% to 34%. The knee was the most common location of injury, making up 11.1% to 17% of injuries. Concussions occurred in up to 15.3% of injuries for all events and up to 77% of injuries in roughstock events. Of all rodeo events reported, bull riding caused the highest percentage of injuries, making up 19.4% to 58.4% of injuries, and bareback had the second highest at 15.3% to 28.8% of injuries. Conclusion: There was a high prevalence of various injury types and mechanisms in rodeo. Improved injury surveillance and the introduction of a comprehensive standardized injury reporting system would be helpful in the future prevention, diagnosis, and treatment of rodeo injuries.

The genomic signatures of evolutionary stasis.

Evolutionary stasis characterizes lineages that seldom speciate and show little phenotypic change over long stretches of geological time. Although lineages that appear to exhibit evolutionary stasis are often called living fossils, no single mechanism is thought to be responsible for their slow rates of morphological evolution and low species diversity. Some analyses of molecular evolutionary rates in a handful of living fossil lineages have indicated that these clades exhibit slow rates of genomic change. Here, we investigate mechanisms of evolutionary stasis using a dataset of 1,105 exons for 481 vertebrate species. We demonstrate that two ancient clades of ray-finned fishes classically called living fossils, gars and sturgeons, exhibit the lowest rates of molecular substitution in protein-coding genes among all jawed vertebrates. Comparably low rates of evolution are observed at fourfold degenerate sites in gars and sturgeons, implying a mechanism of stasis decoupled from selection that we speculate is linked to a highly effective DNA repair apparatus. We show that two gar species last sharing common ancestry over 100 million years ago produce morphologically intermediate and fertile hybrids in the wild. This makes gars the oldest naturally hybridizing divergence among eukaryotes and supports a theoretical prediction that slow rates of nucleotide substitution across the genome slow the accumulation of genetic incompatibilities, enabling hybridization across deeply divergent lineages and slowing the rate of speciation over geological timescales. Our results help establish molecular stasis as a barrier to speciation and phenotypic innovation and provide a mechanism to explain the low species diversity in living fossil lineages.

Land-use change interacts with island biogeography to alter bird community assembly.

Anthropogenic activities have reshaped biodiversity on islands worldwide. However, it remains unclear how island attributes and land-use change interactively shape multiple facets of island biodiversity through community assembly processes. To answer this, we conducted bird surveys in various land-use types (mainly forest and farmland) using transects on 34 oceanic land-bridge islands in the largest archipelago of China. We found that bird species richness increased with island area and decreased with isolation, regardless of the intensity of land-use change. However, forest-dominated habitats exhibited lower richness than farmland-dominated habitats. Island bird assemblages generally comprised species that share more similar traits or evolutionary histories (i.e. functional and/or phylogenetic clustering) than expected if assemblages were randomly assembled. Contrary to our expectations, we observed that bird assemblages in forest-dominated habitats were more clustered on large and close islands, whereas assemblages in farmland-dominated habitats were more clustered on small islands. These contrasting results indicate that land-use change interacts with island biogeography to alter the community assembly of birds on inhabited islands. Our findings emphasize the importance of incorporating human-modified habitats when examining the community assembly of island biota, and further suggest that agricultural landscapes on large islands may play essential roles in protecting countryside island biodiversity.

The Effects of Human Immunodeficiency Virus Type 1 (HIV-1) Antigen-Expanded Specific T-Cell Therapy and Vorinostat on Persistent HIV-1 Infection in People With HIV on Antiretroviral Therapy.

BACKGROUND: The histone deacetylase inhibitor vorinostat (VOR) can reverse human immunodeficiency virus type 1 (HIV-1) latency in vivo and allow T cells to clear infected cells in vitro. HIV-specific T cells (HXTCs) can be expanded ex vivo and have been safely administered to people with HIV (PWH) on antiretroviral therapy. METHODS: Six PWH received infusions of 2 × 107 HXTCs/m² with VOR 400 mg, and 3 PWH received infusions of 10 × 107 HXTCs/m² with VOR. The frequency of persistent HIV by multiple assays including quantitative viral outgrowth assay (QVOA) of resting CD4+ T cells was measured before and after study therapy. RESULTS: VOR and HXTCs were safe, and biomarkers of serial VOR effect were detected, but enhanced antiviral activity in circulating cells was not evident. After 2 × 107 HXTCs/m² with VOR, 1 of 6 PWH exhibited a decrease in QVOA, and all 3 PWH exhibited such declines after 10 × 107 HXTCs/m² and VOR. However, most declines did not exceed the 6-fold threshold needed to definitively attribute decline to the study intervention. CONCLUSIONS: These modest effects provide support for the strategy of HIV latency reversal and reservoir clearance, but more effective interventions are needed to yield the profound depletion of persistent HIV likely to yield clinical benefit. Clinical Trials Registration. NCT03212989.

Cardiovascular Outcomes of α-Blockers vs 5-α Reductase Inhibitors for Benign Prostatic Hyperplasia.

Importance: The most prescribed class of medications for benign prostatic hyperplasia (BPH) is α-blockers (ABs). However, the cardiovascular safety profile of these medications among patients with BPH is not well understood. Objective: To compare the safety of ABs vs 5-α reductase inhibitors (5-ARIs) for risk of adverse cardiovascular outcomes. Design, Setting, and Participants: This active comparator, new-user cohort study was conducted using insurance claims data from a 20% random sample of Medicare beneficiaries from 2007 to 2019 to evaluate the 1-year risk of adverse cardiovascular outcomes. Males aged 66 to 90 years were indexed into the cohort at new use of an AB or 5-ARI. Twelve months of continuous enrollment and at least 1 diagnosis code for BPH within 12 months prior to initiation were required. Data were analyzed from January 2007 through December 2019. Exposures: Exposure was defined by a qualifying prescription fill for an AB or 5-ARI after at least 12 months without a prescription for these drug classes. Main Outcomes and Measures: Follow-up began at a qualified refill for the study drug. Primary study outcomes were hospitalization for heart failure (HF), composite major adverse cardiovascular events (MACE; hospitalization for stroke, myocardial infarction, or death), composite MACE or hospitalization for HF, and death. Inverse probability of treatment and censoring-weighted 1-year risks, risk ratios (RRs), and risk differences (RDs) were estimated for each outcome. Results: Among 189 868 older adult males, there were 163 829 patients initiating ABs (mean [SD] age, 74.6 [6.2] years; 579 American Indian or Alaska Native [0.4%], 5890 Asian or Pacific Islander [3.6%], 9179 Black [5.6%], 10 610 Hispanic [6.5%], and 133 510 non-Hispanic White [81.5%]) and 26 039 patients initiating 5-ARIs (mean [SD] age, 75.3 [6.4] years; 76 American Indian or Alaska Native [0.3%], 827 Asian or Pacific Islander [3.2%], 1339 Black [5.1%], 1656 Hispanic [6.4%], and 21 605 non-Hispanic White [83.0%]). ABs compared with 5-ARIs were associated with an increased 1-year risk of MACE (8.95% [95% CI, 8.81%-9.09%] vs 8.32% [95% CI, 7.92%-8.72%]; RR = 1.08 [95% CI, 1.02-1.13]; RD per 1000 individuals = 6.26 [95% CI, 2.15-10.37]), composite MACE and HF (RR = 1.07; [95% CI, 1.03-1.12]; RD per 1000 individuals = 7.40 [95% CI, 2.88-11.93 ]), and death (RR = 1.07; [95% CI, 1.01-1.14]; RD per 1000 individuals = 3.85 [95% CI, 0.40-7.29]). There was no difference in risk for HF hospitalization alone. Conclusions and Relevance: These results suggest that ABs may be associated with an increased risk of adverse cardiovascular outcomes compared with 5-ARIs. If replicated with more detailed confounder data, these results may have important public health implications given these medications' widespread use.

A Morrison stem gekkotan reveals gecko evolution and Jurassic biogeography.

Geckos are a speciose and globally distributed clade of Squamata (lizards, including snakes and amphisbaenians) that are characterized by a host of modifications for nocturnal, scansorial and insectivorous ecologies. They are among the oldest divergences in the lizard crown, so understanding the origin of geckoes (Gekkota) is essential to understanding the origin of Squamata, the most species-rich extant tetrapod clade. However, the poor fossil record of gekkotans has obscured the sequence and timing of the assembly of their distinctive morphology. Here, we describe the first North American stem gekkotan based on a three-dimensionally preserved skull from the Morrison Formation of western North America. Despite its Late Jurassic age, the new species already possesses several key characteristics of the gekkotan skull along with retained ancestral features. We show that this new stem gekkotan, and several previously named species of uncertain phylogenetic relationships, comprise a widespread clade of early crown lizards, substantiating faunal homogeneity in Laurasia during the Late Jurassic that extended across disparate ecological, body-size and physiological classes.

Incidence of new outpatient long-acting reversible contraceptive insertions among a commercially insured, US population from 2010 to 2020.

Objectives: Characterize new use of long-acting reversible contraceptives (LARCs), highly effective contraceptive methods, in a broad population over time. Study Design: We constructed a retrospective cohort of commercially insured individuals aged 15 to 54 years from 2010 to 2020 and estimated monthly incidence of new LARC insertions. Results: The monthly standardized incidence increased from 6.0 insertions per 10,000 individuals in January 2010 to 14.1 in December 2020, with a dip in insertions after March 2020. Hormonal intrauterine devices were consistently the most inserted LARC; implants were increasingly favored over time. Conclusions: LARCs are increasingly popular forms of contraception among commercially insured individuals. Implications: Given the increasing popularity, ensuring access to LARCs is critical.

The affinities of the Late Triassic Cryptovaranoides and the age of crown squamates.

Most living reptile diversity is concentrated in Squamata (lizards, including snakes), which have poorly known origins in space and time. Recently, †Cryptovaranoides microlanius from the Late Triassic of the United Kingdom was described as the oldest crown squamate. If true, this result would push back the origin of all major lizard clades by 30-65 Myr and suggest that divergence times for reptile clades estimated using genomic and morphological data are grossly inaccurate. Here, we use computed tomography scans and expanded phylogenetic datasets to re-evaluate the phylogenetic affinities of †Cryptovaranoides and other putative early squamates. We robustly reject the crown squamate affinities of †Cryptovaranoides, and instead resolve †Cryptovaranoides as a potential member of the bird and crocodylian total clade, Archosauromorpha. Bayesian total evidence dating supports a Jurassic origin of crown squamates, not Triassic as recently suggested. We highlight how features traditionally linked to lepidosaurs are in fact widespread across Triassic reptiles. Our study reaffirms the importance of critically choosing and constructing morphological datasets and appropriate taxon sampling to test the phylogenetic affinities of problematic fossils and calibrate the Tree of Life.

Controlling for Differential Regression-To-The-Mean via Propensity Scores: A Simulation Study.

Purpose: Regression-to-the-mean (RTM) is a statistical phenomenon that may occur in epidemiologic studies where inclusion in the study cohort is contingent upon experiencing a laboratory/clinical measurement beyond a defined threshold. When differential across treatment groups, RTM could bias the final study estimate. This poses substantial challenges in observational studies that index patients upon experiencing extreme laboratory or clinical values. Our objective was to investigate propensity score-based methods as a tool for mitigating this source of bias via simulation. Methods: We simulated a noninterventional comparative effectiveness study, comparing treatment with romiplostim to standard-of-care therapies for immune thrombocytopenia (ITP), a disease characterized by low platelet counts. Platelet counts were generated from normal distributions according to the underlying ITP severity, a strong confounder of treatment and outcome. Patients were assigned treatment probabilities based upon ITP severity, which created varied levels of differential and non-differential RTM. Treatments were compared via the difference in median platelet counts during 23 weeks of follow-up. We calculated four summary metrics of the platelet counts measured prior to cohort entry and built six propensity score models to adjust for those variables. We adjusted for these summary metrics using inverse probability of treatment weights. Results: Across all simulated scenarios, propensity score adjustment reduced bias and increased precision of the treatment effect estimator. Adjusting for combinations of the summary metrics was most effective at reducing bias. Adjusting for the mean of prior platelet counts or the difference between the cohort-qualifying platelet count and the largest prior count eliminated the most bias when assessed individually. Conclusion: These results suggest that differential RTM could be reasonably addressed by propensity score models with summaries of historical laboratory values. This approach can be easily applied to any comparative effectiveness or safety study, though investigators should carefully consider the best summary metric for their data.

Rates and Correlates of Uptake of Continuous Glucose Monitors Among Adults with Type 2 Diabetes in Primary Care and Endocrinology Settings.

BACKGROUND: Clinical trials indicate continuous glucose monitor (CGM) use may benefit adults with type 2 diabetes, but CGM rates and correlates in real-world care settings are unknown. OBJECTIVE: We sought to ascertain prevalence and correlates of CGM use and to examine rates of new CGM prescriptions across clinic types and medication regimens. DESIGN: Retrospective cohort using electronic health records in a large academic medical center in the Southeastern US. PARTICIPANTS: Adults with type 2 diabetes and a primary care or endocrinology visit during 2021. MAIN MEASURES: Age, gender, race, ethnicity, insurance, clinic type, insulin regimen, hemoglobin A1c values, CGM prescriptions, and prescribing clinic type. KEY RESULTS: Among 30,585 adults with type 2 diabetes, 13% had used a CGM. CGM users were younger and more had private health insurance (p < .05) as compared to non-users; 72% of CGM users had an intensive insulin regimen, but 12% were not taking insulin. CGM users had higher hemoglobin A1c values (both most recent and most proximal to the first CGM prescription) than non-users. CGM users were more likely to receive endocrinology care than non-users, but 23% had only primary care visits in 2021. For each month in 2021, a mean of 90.5 (SD 12.5) people started using CGM. From 2020 to 2021, monthly rates of CGM prescriptions to new users grew 36% overall, but 125% in primary care. Most starting CGM in endocrinology had an intensive insulin regimen (82% vs. 49% starting in primary care), whereas 28% starting CGM in primary care were not using insulin (vs. 5% in endocrinology). CONCLUSION: CGM uptake for type 2 diabetes is increasing rapidly, with most growth in primary care. These trends present opportunities for healthcare system adaptations to support CGM use and related workflows in primary care to support growth in uptake.

A global analysis of avian island diversity-area relationships in the Anthropocene.

Research on island species-area relationships (ISAR) has expanded to incorporate functional (IFDAR) and phylogenetic (IPDAR) diversity. However, relative to the ISAR, we know little about IFDARs and IPDARs, and lack synthetic global analyses of variation in form of these three categories of island diversity-area relationship (IDAR). Here, we undertake the first comparative evaluation of IDARs at the global scale using 51 avian archipelagic data sets representing true and habitat islands. Using null models, we explore how richness-corrected functional and phylogenetic diversity scale with island area. We also provide the largest global assessment of the impacts of species introductions and extinctions on the IDAR. Results show that increasing richness with area is the primary driver of the (non-richness corrected) IPDAR and IFDAR for many data sets. However, for several archipelagos, richness-corrected functional and phylogenetic diversity changes linearly with island area, suggesting that the dominant community assembly processes shift along the island area gradient. We also find that archipelagos with the steepest ISARs exhibit the biggest differences in slope between IDARs, indicating increased functional and phylogenetic redundancy on larger islands in these archipelagos. In several cases introduced species seem to have 're-calibrated' the IDARs such that they resemble the historic period prior to recent extinctions.

Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production.

Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of MM0299, a tetracyclic dicarboximide with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a "shunt" pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant, and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.