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Background Hypertension affects nearly half of US adults yet remains inadequately controlled in over three‐quarters of these cases. This study aimed to assess the association between adherence to antihypertensive medications and total medical costs, health care use, and productivity‐related outcomes. Methods and Results We conducted cross‐sectional analyses using MarketScan databases, which included individuals aged 18 to 64 years with noncapitated health insurance plans in 2019. Adherence was defined as ≥80% medication possession ratio for prescribed antihypertensive medications. We used a generalized linear model to estimate total medical costs, a negative binomial model to estimate health care use (emergency department visits and inpatient admissions), an exponential hurdle model to estimate productivity‐related outcomes (number of sick absences, short‐term disability, long‐term disability), and a 2‐part model to estimate productivity‐related costs in 2019 US dollars. All models were adjusted for age, sex, urbanicity, census region, and comorbidities. We reported average marginal effects for outcomes related to antihypertensive medication adherence. Among 379 503 individuals with hypertension in 2019, 54.4% adhered to antihypertensives. Per person, antihypertensive medication adherence was associated with $1441 lower total medical costs, $11 lower sick absence costs, $291 lower short‐term disability costs, and $69 lower long‐term disability costs. Per 1000 individuals, medication adherence was associated with lower health care use, including 200 fewer emergency department visits and 90 fewer inpatient admissions, and productivity‐related outcomes, including 20 fewer sick absence days and 442 fewer short‐term disability days. Conclusions Adherence to antihypertensives was consistently associated with lower total medical costs, reduced health care use, and improved productivity‐related outcomes.

ABSTRACT Introduction Improved access to rehabilitation is highlighted as a key pathway to achieving the World Health Organisation's (WHO) goal of ensuring healthy lives and promoting well‐being for all (Sustainable Development Goal 3). This article is the second in a two‐part series outlining the findings from the Rehabilitation Choices study, which aimed to identify how health professionals and consumers in Australia are informed to make decisions about rehabilitation, and their experience with barriers and enablers to accessing that rehabilitation. In this study, we present the perspectives of consumers with different health conditions and a range of experiences with rehabilitation services. Methods This was a qualitative study using focus groups and semi‐structured interviews. People with self‐reported lived experience of rehabilitation and carers were recruited using maximum variation sampling. Thematic analysis of data was conducted using an inductive approach. Results Fifty‐six consumers with diverse lived experiences of rehabilitation (19–80 years, 49 patients, 7 carers) participated in focus groups and interviews to discuss how they sourced information about rehabilitation and their experiences of what made it hard or easy to access rehabilitative care to meet their needs. Four themes were produced from the data: (1) service‐centricity of options limits access, (2) access is the patient's responsibility, (3) enabling decision‐making about rehabilitation with appropriate information and (4) provision of a psychologically safe environment. Conclusions Any planned (re)design of services to improve consumer access to rehabilitation should consider the themes identified in this study. This will ensure that consumers are provided with rehabilitation options that suit their holistic and unique needs beyond consideration of their medical diagnoses, and are actively supported to navigate this access, provided with information to help them make informed choices and provided a psychologically safe environment to engage effectively with rehabilitation. Patient or Public Contribution Three consumer research partners with lived experience of rehabilitation as patients or carers were core team members. They were involved in the design and implementation of the recruitment and communications strategies, design of the interview approach and discussion guide, contributed to the interpretation and contextualisation of findings and writing of this manuscript and are included as co‐authors (A. O., T. W. and S. W.).

Abstract Low‐grade epilepsy‐associated tumors (LEATs) are a common cause of drug‐resistant epilepsy in children. Herein, we demonstrate the feasibility of using tumor tissue derived from stereoelectroencephalography (sEEG) electrodes upon removal to molecularly characterize tumors and aid in diagnosis. An 18‐year‐old male with focal epilepsy and MRI suggestive of a dysembryoplastic neuroepithelial tumor (DNET) in the left posterior temporal lobe underwent implantation of seven peri‐tumoral sEEG electrodes for peri‐operative language mapping and demarcation of the peri‐tumoral ictal zone prior to DNET resection. Using electrodes that passed through tumor tissue, we show successful isolation of tumor DNA and subsequent analysis using standard methods for tumor classification by DNA, including Glioseq targeted sequencing and DNA methylation array analysis. This study provides preliminary evidence for the feasibility of molecular diagnosis of LEATs or other lesions using a minimally invasive method with microscopic tissue volumes. The implications of sEEG electrodes in tumor characterization are broad but would aid in diagnosis and subsequent targeted therapeutic strategies.

In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high‐grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain‐penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) was employed to compare the molecular signatures enriched in resistant compared with drug‐naïve cells. The levels of adenosine 5′‐triphosphate (ATP), nicotinamide adenine dinucleotide (NAD)+ content, hexokinase activity, and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD+ content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, which required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat‐ and marizomib‐resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.

Abstract Background Racial and socioeconomic disparities in receipt of care for non‐small‐cell lung cancer (NSCLC) are well described. However, no previous studies have evaluated the association between mortgage denial rates and receipt of timely and guideline‐concordant care for NSCLC and patient outcomes. Methods We identified individuals ≥18 years diagnosed with NSCLC between 2014 and 2019 from the National Cancer Database. Using the Home Mortgage Disclosure Act database, we calculated the proportion of denied home loans to total loans at the zip‐code level and categorized them into quintiles. Our outcomes included receipt of guideline‐concordant care based on clinical and pathologic stage at diagnosis and the National Comprehensive Cancer Network guidelines, time from surgery to chemotherapy initiation, and overall survival. Results Of the 629,288 individuals diagnosed with NSCLC (median age 69; IQR 61–76 years, 49.1% female), 47.8% did not receive guideline‐concordant care. Residing in areas with higher mortgage denial rates and lower income was associated with worse guideline‐concordant care overall (aRR = 1.28; 95% CI = 1.25–1.32) and for each cancer treatment modality, worse receipt of timely chemotherapy (aHR = 1.14; 95% CI = 1.11–1.17) and worse overall survival (aHR = 1.21; 95% CI = 1.19–1.22), compared with residing in areas with the lowest mortgage denial rate and highest income. Conclusions Area‐level mortgage denial rate was associated with worse receipt of timely and guideline‐concordant NSCLC care and survival. This highlights the critical need to understand and address systemic practices, such as mortgage denial, that limit access to resources and are associated with worse access to quality cancer care and outcomes.

Abstract Background Retinoblastoma is a rare malignancy involving the retina, although, more common among children, with genetic inheritance explaining the incidence as well as acquired forms. The incidence varies among race and sex as well as mortality and survival. The current study aimed to assess retinoblastoma cumulative incidence (CMI), mortality, and survival by sex. Methods A retrospective cohort design was used to assess the CMI, mortality, and survival in this pediatric malignancy based on the Surveillance Epidemiology and End Results (SEER) data 2000–2017. The binomial regression model was used to examine sex differentials in mortality, as well as other study variables, while Cox proportional hazard model was used for the survival variability by sex. Results The CMI during this period was higher among males relative to females (males n = 249, 56.7%; females n = 190, 43.3%, χ2 = 2.90, df = 1, p = 0.089). There were sex differences in mortality, with excess mortality observed among males compared to females, risk ratio = 3.40, 95% CI [1.0–15.72]. The survival differences by sex indicated decreased survival among males relative to females, hazard ratio (HR) = 3.39, 95% CI [1.0–15.72]. After controlling for the potential confoundings, namely tumor grade, urbanity, and median income the survival disadvantage of males persisted. Compared to females’, males were more than three times as likely to die, adjusted HR = 3.42, 99% CI [0.37–31.60]. Conclusion In a representative sample of pediatric retinoblastoma, there was a sex differential in survival with excess risk of dying identified among males relative to females, which may be explained in part by male X‐linkage.

Abstract Large‐scale estimations of flood losses are often based on spatially aggregated inputs. This makes risk assessments vulnerable to aggregation bias, a well‐studied, sometimes substantial outcome in analyses that model fine‐grained spatial phenomena at coarse spatial units. To evaluate this potential in the context of large‐scale flood risk assessments, we use data from a high‐resolution flood hazard model and structure inventory for over 1.3 million properties in Massachusetts and examine how prominent data aggregation approaches affect the magnitude and spatial distribution of flood loss estimates. All considered aggregation approaches rely on aggregate structure inventories but differ in whether flood hazard is also aggregated. We find that aggregating only structure inventories slightly underestimates overall losses (−10% bias), and when flood hazard data is spatially aggregated to even relatively small spatial units (census block), statewide aggregation bias can reach +366%. All aggregation‐based procedures fail to capture the spatial covariation of inputs distributions in the upper tails that disproportionately generate total expected losses. Our findings are robust to several key assumptions, add important context to published risk assessments and highlight opportunities to improve flood loss estimation uncertainty quantification.

Abstract Sex is evolutionarily more costly than parthenogenesis, evolutionary ecologists therefore wonder why sex is much more frequent than parthenogenesis in the majority of animal lineages. Intriguingly, parthenogenetic individuals and species are as common as or even more common than sexuals in some major and putative ancient animal lineages such as oribatid mites and rotifers. Here, we analyzed oribatid mites (Acari: Oribatida) as a model group because these mites are ancient (early Paleozoic), widely distributed around the globe, and include a high number of parthenogenetic species, which often co‐exist with sexual oribatid mite species. There is evidence that the reproductive mode is phylogenetically conserved in oribatid mites, which makes them an ideal model to test hypotheses on the relationship between reproductive mode and species' ecological strategies. We used oribatid mites to test the frozen niche variation hypothesis; we hypothesized that parthenogenetic oribatid mites occupy narrow specialized ecological niches. We used the geographic range of species as a proxy for specialization as specialized species typically do have narrower geographic ranges than generalistic species. After correcting for phylogenetic signal in reproductive mode and demonstrating that geographic range size has no phylogenetic signal, we found that parthenogenetic lineages have a higher probability to have broader geographic ranges than sexual species arguing against the frozen niche variation hypothesis. Rather, the results suggest that parthenogenetic oribatid mite species are more generalistic than sexual species supporting the general‐purpose genotype hypothesis. The reason why parthenogenetic oribatid mite species are generalists with wide geographic range sizes might be that they are of ancient origin reflecting that they adapted to varying environmental conditions during evolutionary history. Overall, our findings indicate that parthenogenetic oribatid mite species possess a widely adapted general‐purpose genotype and therefore might be viewed as “Jack‐of‐all‐trades.”

Abstract Background Olaratumab, a fully human monoclonal antibody, selectively binds to human platelet‐derived growth factor receptor alpha and blocks ligand binding. This study assessed the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin and the safety of olaratumab alone and in combination with doxorubicin. Methods This open‐label randomized phase 1 trial enrolled 49 patients ages 27 to 83 with metastatic or locally advanced soft tissue sarcoma (STS). Patients participated in 21‐day treatment cycles (up to 8) until they met discontinuation criteria. In cycles 1 and 2, patients received olaratumab (15 mg/kg in Part A, 20 mg/kg in Part B) and doxorubicin (75 mg/m2). In cycles 3 through 8, patients continued combination treatment (15 mg/kg olaratumab + doxorubicin). Effect of olaratumab on PK of doxorubicin was determined in patients who received all doses in cycles 1 and 2. Results PK properties of doxorubicin administered alone or in combination with olaratumab (15 or 20 mg/kg) were similar for AUC(0‐tlast), AUC(0‐∞), and Cmax. PK properties of olaratumab (15 or 20 mg/kg) were also similar when administered alone or in combination with doxorubicin. Three patients died (2 of disease progression and 1 of neutropenic enterocolitis). Fatigue and nausea (>75% of patients) were the most common treatment‐emergent adverse events (TEAEs). Other common TEAEs included musculoskeletal pain, mucositis, constipation, and diarrhea. Conclusions Olaratumab at 15 or 20 mg/kg before doxorubicin infusion had no clinically relevant effect on systemic exposure to doxorubicin compared with doxorubicin alone in patients with metastatic or locally advanced STS.

Abstract Protecting biodiversity requires an understanding of how anthropogenic changes impact the genetic processes associated with extinction risk. Studies of the genetic changes due to anthropogenic fragmentation have revealed conflicting results. This is likely due to the difficulty in isolating habitat loss and fragmentation, which can have opposing impacts on genetic parameters. The well‐studied orchid, Platanthera leucophaea, provides a rich dataset to address this issue, allowing us to examine range‐wide genetic changes. Midwestern and Northeastern United States. We sampled 35 populations of P. leucophaea that spanned the species’ range and varied in patch composition, degree of patch isolation, and population size. From these populations we measured genetic parameters associated with increased extinction risk. Using this combined dataset, we modeled landscape variables and population metrics against genetic parameters to determine the best predictors of increased extinction risk. All genetic parameters were strongly associated with population size, while development and patch isolation showed an association with genetic diversity and genetic structure. Genetic diversity was lowest in populations with small census sizes, greater urbanization pressures (habitat loss), and small patch area. All populations showed moderate levels of inbreeding, regardless of size. Contrary to expectation, we found that critically small populations had negative inbreeding values, indicating non‐random mating not typically observed in wild populations, which we attribute to selection for less inbred individuals. The once widespread orchid, Platanthera leucophaea, has suffered drastic declines and extant populations show changes in the genetic parameters associated with increased extinction risk, especially smaller populations. Due to the important correlation with risk and habitat loss, we advocate continued monitoring of population sizes by resource managers, while the critically small populations may need additional management to reverse genetic declines.