Citations

Abstract Objectives Two pilot studies of AR‐42, a pan‐histone deacetylase inhibitor, in human neurofibromatosis type 2 (NF2), vestibular schwannomas (VS), and meningiomas are presented. Primary endpoints included safety, and intra‐tumoral pharmacokinetics (PK) and pharmacodynamics (PD). Methods Pilot 1 is a subset analysis of a phase 1 study of AR‐42 in solid tumors, which included NF2 or sporadic meningiomas. Tumor volumes and treatment‐related adverse events (TRAEs) are reported (NCT01129193). Pilot 2 is a phase 0 surgical study of AR‐42 assessing intra‐tumoral PK and PD. AR‐42 was administered for 3 weeks pre‐operatively. Plasma and tumor drug concentrations and p‐AKT expression were measured (NCT02282917). Results Pilot 1: Five patients with NF2 and two with sporadic meningiomas experienced a similar incidence of TRAEs to the overall phase I trial. The six evaluable patients had 15 tumors (8 VS, 7 meningiomas). On AR‐42, tumor volume increased in six, remained stable in eight, and decreased in one tumor. The annual percent growth rate decreased in eight, remained stable in three, and increased in four tumors. Pilot 2: Four patients with sporadic VS and one patient with meningioma experienced no grade 3/4 toxicities. Expression of p‐AKT decreased in three of four VS. All tumors had higher AR‐42 concentrations than plasma. Conclusions AR‐42 is safe. Tumor volumes showed a mixed response, but most slowed growth. On a 40‐mg regimen, drug concentrated in tumors and growth pathways were suppressed in most tumors, suggesting this may be a well‐tolerated and effective dose. A phase 2 study of AR‐42 for NF2‐associated tumors appears warranted. Level of Evidence 1b, 4.

Abstract Aims The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems‐level analysis. Methods Imaging‐based cortical structural maps from a large‐scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell‐type deconvolution, differential expression analysis and cell‐type enrichment analyses were used to identify differences in cell‐type distribution. These differences were followed up in post‐mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell‐type‐specific depletion was used in a murine model of acquired epilepsy. Results We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post‐mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non‐spatial memory test seen in epileptic mice not depleted of microglia. Conclusions These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.

Background: While NKX2-5 plays pivotal roles in human cardiac development and disease, no ChIP-Seq studies of NKX2-5 in human cardiac tissues currently exist, resulting in an incomplete understanding of its direct gene targets. Modern computational methods which identify binding sites using transcription factor motif and tissue-specific experimental data can help to fill this knowledge gap. Objective: To use computational methods to identify likely NKX2-5 binding sites and downstream gene targets using human heart-specific experimental data. Methods: Human cardiomyocyte DNAse hypersensitivity data (2 replicates) were downloaded from the Encyclopedia of DNA Elements (ENCODE) database. The position weight matrix (PWM) representing the transcription factor motif of NKX2-5 was obtained from JASPAR. We applied the Protein Interaction Quantification (PIQ) algorithm to detect NKX2-5 binding sites using the PWM and DNAse hypersensitivity data as inputs. RNA-Seq data from 108 human heart-specific samples (atrial appendages and left ventricles) were downloaded from the Genotype-Tissue Expression (GTEx) database. Protein-coding genes significantly expressed in the heart (RPKM <= 1 based on the GTEx RNA-Seq data) that were within 100kb of the predicted binding sites were then identified. Pathway analysis of these genes was performed using Ingenuity Pathway Analysis (IPA). Results: 1283 binding sites for NKX2-5 were discovered by PIQ. Of 12698 protein-coding, heart-expressed genes, 625 were within 100kb of these binding sites. The identified genes were highly enriched in physiologic categories like “Vasculogenesis” and “Development of Cardiovascular Tissue” (p = 2.36x10-9 and 2.31x10-8 respectively). Notable genes included: cardiac transcription factors (MEF2A, TBX20); growth factors (TGFB2, BMP2); muscle and ion channel function (ACTA2, BIN1), and; calcium signaling (CALM2, CAMK2D). Conclusion: By using computational analyses of transcription factor motif and human heart-specific experimental data, we have identified candidate downstream targets of NKX2-5. Future work will include validation studies in an external cohort and analysis of associations between these candidate genes and cardiac disease.

Abstract Most patients with coronavirus disease 2019 (COVID-19) have mild to moderate illness not requiring hospitalization. However, no study has detailed the evolution of symptoms in the first month of illness. At our institution, we conducted remote (telephone and video) visits for all adult outpatients diagnosed with COVID-19 within 24 h of a positive nasopharyngeal polymerase chain test for SARS-CoV-2. We repeated regular video visits at 7, 14, and 28 days after the positive test, retrospectively reviewed the prospective data collected in the remote visits, and constructed a week by week profile of clinical illness, through week 4 of illness. We reviewed the courses of 458 symptomatic patients diagnosed between March 12, 2020, and June 22, 2020, and characterized their weekly courses. Common initial symptoms included fever, headache, cough, and chest pain, which frequently persisted through week 3 or longer. Upper respiratory or gastrointestinal symptoms were much shorter lived, present primarily in week 1. Anosmia/ageusia peaked in weeks 2 to 3. Emergency department visits were frequent, with 128 visits in the 423 patients who were not hospitalized and 48 visits among the 35 outpatients (7.6%) who were eventually hospitalized (2 subsequently died). By the fourth week, 28.9% said their illness had completely resolved. After the 4-week follow up, 20 (4.7%) of the 423 nonhospitalized patients had further medical evaluation and management for subacute or chronic COVID-19 symptoms. Mild to moderate outpatient COVID-19 is a prolonged illness, with evolving symptoms commonly lasting into the fourth week of illness.

Abstract Purpose To report historical patterns of pharmaceutical expenditures, to identify factors that may influence future spending, and to predict growth in drug spending in 2021 in the United States, with a focus on the nonfederal hospital and clinic sectors. Methods Historical patterns were assessed by examining data on drug purchases from manufacturers using the IQVIA National Sales Perspectives database. Factors that may influence drug spending in hospitals and clinics in 2021 were reviewed—including new drug approvals, patent expirations, and potential new policies or legislation. Focused analyses were conducted for biosimilars, cancer drugs, generics, coronavirus disease 2019 (COVID-19) pandemic influence, and specialty drugs. For nonfederal hospitals, clinics, and overall (all sectors), estimates of growth of pharmaceutical expenditures in 2021 were based on a combination of quantitative analyses and expert opinion. Results In 2020, overall pharmaceutical expenditures in the United States grew 4.9% compared to 2019, for a total of $535.3 billion. Utilization (a 2.9% increase) and new drugs (a 1.8% increase) drove this increase, with price changes having minimal influence (a 0.3% increase). Adalimumab was the top drug in 2020, followed by apixaban and insulin glargine. Drug expenditures were $35.3 billion (a 4.6% decrease) and $98.4 billion (an 8.1% increase) in nonfederal hospitals and clinics, respectively. In clinics, growth was driven by new products and increased utilization, whereas in hospitals the decrease in expenditures was driven by reduced utilization. Several new drugs that will influence spending are expected to be approved in 2021. Specialty and cancer drugs will continue to drive expenditures along with the evolution of the COVID-19 pandemic. Conclusion For 2021, we expect overall prescription drug spending to rise by 4% to 6%, whereas in clinics and hospitals we anticipate increases of 7% to 9% and 3% to 5%, respectively, compared to 2020. These national estimates of future pharmaceutical expenditure growth may not be representative of any particular health system because of the myriad of local factors that influence actual spending.

PURPOSE This study determined whether an electronic version of the geriatric assessment is feasible in a multi-institutional, diverse setting. METHODs Ten sites within the Alliance for Clinical Trials in Oncology participated. Patients who had active cancer or a history of cancer and were 65 years of age or older were eligible. The geriatric assessment was completed with an electronic data capture system that had been loaded onto iPads. Feasibility was defined a priori as completion in at least 70% of patients either with or without help. To enhance racial diversity, the original sample size was later changed and augmented by 50% with the intention of increasing enrollment of older minority patients. RESULTS A total of one hundred fifty-four patients were registered with a median age of 72 years (range, 65-91 years). Forty-three (28%) identified themselves as African American or Black. One hundred forty-one patients (92%) completed the electronic geriatric assessment. Feasibility was observed across all subgroups, regardless of race, education, performance status, comorbidities, and cognition; 124 patients (81%) completed the geriatric assessment without help. Reasons for not completing the geriatric assessment are as follows: clinic visit did not occur (n = 6), no iPad connection to the Internet (n = 3), patient declined (n = 2), prolonged hospitalization (n = 1), and patient died (n = 1). Reasons for needing help, as reported by study personnel, were as follows: the patient preferred that research personnel ask the questions (n = 9), vision problem (n = 3), lack of comfort with the iPad (n = 2), questions were not clear (n = 1), less proficient in English (n = 1), and challenge in pressing the green button to go to the next question (n = 1). CONCLUSION The electronic geriatric assessment is feasible in a multi-institutional setting that includes a notable proportion of African American or Black patients.

Abstract Context Peripheral artery disease (PAD) is highly prevalent in the general population, affecting up to 25% of patients 55 years of age or older. There is a known association with acute ischemic stroke, but limited large cohort studies exist pertaining to the relationship between PAD severity and incident ischemic stroke. Objectives To evaluate the risk of incident ischemic stroke and mortality along the spectrum of low and elevated ankle brachial index (ABI) measurement. Methods We performed a retrospective extraction of ABI data of all adult patients who underwent lower extremity physiology study for any indication from January 1, 1996 to June 30, 2018 in the Mayo Clinic health system. PAD was categorized into severe, moderate, mild, and borderline based on ABI measurements and poorly compressible arteries (PCA). These were compared with normal ABI measurements. Associations of PAD/PCA with new ischemic stroke events and all cause mortality were analyzed. Hazard ratios (HR) were calculated using multivariable Cox proportional regression with 95% confidence intervals. Results A total of 39,834 unique patients were included with a median follow up duration of 4.59 years. All abnormal ABI groups, except borderline PAD, were associated with increased risk of incident ischemic stroke after multivariate regression compared to normal ABI. A severity-dependent association was observed between PAD and ischemic stroke with moderate (HR, 1.22 [95% CI, 1.10–1.35]) and severe (HR, 1.19 [95% CI, 1.02–1.40]) categories conferring similar risk in comparison to normal ABI. Patients with PCA carried the greatest ischemic stroke risk (HR, 1.30 [95% CI, 1.15–1.46]). Similarly, abnormal ABI groups were associated with a significant risk for all cause mortality in a severity-dependent manner, with severe PAD conferring the greatest risk (HR, 3.07 [95% CI, 2.88–3.27]). Conclusions This study adds to the growing body of evidence that both PAD and PCA are independent risk factors for incident ischemic stroke and all cause mortality. The association of PAD severity and PCA with risk of ischemic stroke may help clinicians with risk stratification and determining treatment intensity.

Background Patients and clinicians expect the information in patient decision aids to be based on the best available research evidence. The objectives of this International Patient Decision Aid Standards (IPDAS) review were to 1) check the currency of, and where needed, update evidence for the domain of “basing the information in decision aids on comprehensive, critically appraised, and up-to-date syntheses of the evidence”; 2) analyze the evidence characteristics of decision aids; and 3) propose updates to relevant IPDAS criteria. Methods We searched MEDLINE and PubMed to inform updates of this domain’s definitions, justifications, and components. We also searched 5 sources to identify all publicly available decision aids ( N = 471). Two assessors independently extracted each aid’s evidence characteristics. Results Minor updates to the definitions and theoretical justifications of this IPDAS domain are provided and changes to relevant IPDAS criteria proposed. Nearly all aids (97%) provided a year of creation/update, but most (81%) did not report an explicit update or expiration policy. No scientific references were cited in 33% of aids. Of the 314 that cited at least 1 reference, 39% cited at least 1 guideline, 44% cited at least 1 systematic review, and 23% cited at least 1 randomized trial. In 35%, it was unclear what statement in the aid the citations referred to. Only 14% reported any of the processes used to find and decide on evidence inclusion. Only 14% reported the evidence quality. Many emerging issues and future research areas were identified. Conclusions Although many emerging issues need to be addressed, this IPDAS domain is validated and criteria refined. High-quality patient decision aids should be based on comprehensive and up-to-date syntheses of critically appraised evidence.