Prior authorization for diabetes medications: Clinical outcomes and health disparities.

BACKGROUND: Prior authorization (PA) is a utilization management strategy used by health plans to ensure affordable, cost-effective care; however, PA may lead to therapy delay/abandonment and exacerbate health disparities. The purpose of this observational study was to assess the clinical outcomes and any health disparities associated with PA for diabetes mellitus (DM) medications. MATERIALS AND METHODS: This was a cohort study of US adult patients from health plans with integrated and non-integrated system providers who were prescribed a DM medication that required a PA. Patients were categorized into three groups: received the requested DM medication (PA Med) or a new, alternative DM medication (DM Med), or did not receive the requested or new DM medication (No Med). The primary outcome was change in hemoglobin A1c (HbA1c). Adjusted and unadjusted analyses were performed. Patient characteristics associated with the No Med group were identified, also, with multivariable logistic regression modeling. RESULTS: 6305 patients were included: 2434, 1323, and 2548 in the PA Med, DM Med, and No Med groups, respectively. Patients in the PA Med (-0.9 %) and DM Med (-1.0 %) groups had statistically significantly greater reductions in HbA1c compared to the No Med group (-0.4 %) in both unadjusted and adjusted analyses (all p < 0.05). Patients who were Hispanic/Latino, had a non-integrated system prescriber, and had a higher burden of chronic disease were statistically significantly associated with the No Med group. CONCLUSIONS: Receiving a new DM medication following PA was associated with better clinical outcomes but health disparities were present in the PA process.

Studying Conversational Adjustments in Interaction: Beyond Acoustic Phonetic Changes.

PURPOSE: We examined which measures of complexity are most informative when studying language produced in interaction. Specifically, using these measures, we explored whether native and nonnative speakers modified the higher level properties of their production beyond the acoustic-phonetic level based on the language background of their conversation partner. METHOD: Using a subset of production data from the Wildcat Corpus that used Diapix, an interactive picture matching task, to elicit production, we compared English language production at the dyad and individual level across three different pair types: eight native pairs (English-English), eight mixed pairs (four English-Chinese and four English-Korean), and eight nonnative pairs (four Chinese-Chinese and four Korean-Korean). RESULTS: At both the dyad and individual levels, native speakers produced longer and more clausally dense speech. They also produced fewer silent pauses and fewer linguistic mazes relative to nonnative speakers. Speakers did not modify their production based on the language background of their interlocutor. CONCLUSIONS: The current study examines higher level properties of language production in true interaction. Our results suggest that speakers' productions were determined by their own language background and were independent of that of their interlocutor. Furthermore, these demonstrated promise for capturing syntactic characteristics of language produced in true dialogue. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24712956.

The tubulin database: Linking mutations, modifications, ligands and local interactions.

Microtubules are polymeric filaments, constructed of α-ß tubulin heterodimers that underlie critical subcellular structures in eukaryotic organisms. Four homologous proteins (γ-, δ-, ε- and ζ-tubulin) additionally contribute to specialized microtubule functions. Although there is an immense volume of publicly available data pertaining to tubulins, it is difficult to assimilate all potentially relevant information across diverse organisms, isotypes, and categories of data. We previously assembled an extensive web-based catalogue of published missense mutations to tubulins with >1,500 entries that each document a specific substitution to a discrete tubulin, the species where the mutation was described and the associated phenotype with hyperlinks to the amino acid sequence and citation(s) for research. This report describes a significant update and expansion of our online resource (TubulinDB.bio.uci.edu) to nearly 18,000 entries. It now encompasses a cross-referenced catalog of post-translational modifications (PTMs) to tubulin drawn from public datasets, primary literature, and predictive algorithms. In addition, tubulin protein structures were used to define local interactions with bound ligands (GTP, GDP and diverse microtubule-targeting agents) and amino acids at the intradimer interface, within the microtubule lattice and with associated proteins. To effectively cross-reference these datasets, we established a universal tubulin numbering system to map entries into a common framework that accommodates specific insertions and deletions to tubulins. Indexing and cross-referencing permitted us to discern previously unappreciated patterns. We describe previously unlinked observations of loss of PTM sites in the context of cancer cells and tubulinopathies. Similarly, we expanded the set of clinical substitutions that may compromise MAP or microtubule-motor interactions by collecting tubulin missense mutations that alter amino acids at the interface with dynein and doublecortin. By expanding the database as a curated resource, we hope to relate model organism data to clinical findings of pathogenic tubulin variants. Ultimately, we aim to aid researchers in hypothesis generation and design of studies to dissect tubulin function.

Real-World Clinical Outcomes of Bevacizumab-awwb Biosimilar versus Bevacizumab Reference Product in Patients with Metastatic Colorectal Cancer.

BACKGROUND: Bevacizumab-awwb was the first biosimilar approved for cancer treatment in the USA. Limited information is available on the real-world comparative safety and effectiveness of bevacizumab biosimilars, especially for indications granted approval through extrapolation. OBJECTIVE: To evaluate the real-world outcomes of patients with metastatic colorectal cancer (mCRC) initiated on bevacizumab-awwb versus bevacizumab reference product. PATIENTS AND METHODS: This was an observational, longitudinal cohort study of US adult patients with mCRC from four integrated care delivery systems who were newly initiated on bevacizumab-awwb between 1 July 2019 and 30 March 2020 or bevacizumab reference product between 1 July 2015 and 30 June 2018. Patients were followed until 1 year after treatment initiation, end of plan membership, or death, whichever occurred first. The primary outcome of overall survival (OS) was analyzed using a binary non-inferiority test with lower margin of 10% and adjusted Cox proportional hazards regression analysis to assess all-cause mortality if non-inferiority was met. Secondary outcomes included counts of doses received, treatment duration, all-cause hospitalizations, and incidence of serious adverse events. RESULTS: A total of 1445 patients initiated on either bevacizumab-awwb (n = 239) or bevacizumab reference product (n = 1206) were included in the analysis. The mean overall age was 60 ± 13 years, 46% of patients were female, and 51% were white. The OS rate was 72.8% and 73.1% for patients receiving bevacizumab-awwb and bevacizumab reference product, respectively (p < 0.01 for non-inferiority). The adjusted hazard ratio for mortality was 1.01 (0.77-1.33, p = 0.93). There were no statistically significant differences in secondary outcomes between the study groups. CONCLUSIONS: These findings suggest that bevacizumab-awwb is as effective and safe as bevacizumab reference product for the real-world treatment of mCRC.

Assessment of FDA-Approved Drugs Not Recommended for Use or Reimbursement in Other Countries, 2017-2020.

Importance: Drug expenditures in the US are higher than in any other country and are projected to continue increasing, so US health systems may benefit from evaluating international regulatory and reimbursement decision-making of new drugs. Objective: To evaluate regulatory decisions and health technology assessments (HTAs) in Australia, Canada, and the UK regarding new drugs approved by the US Food and Drug Administration (FDA) in 2017 through 2020, as well as to estimate the US cost per patient per year for drugs receiving negative recommendations. Design and Setting: In this cross-sectional study, recommendations issued by agencies in Australia, Canada, and the UK were collected for new drugs approved by the FDA in 2017 through 2020. All data were current as of May 31, 2022. Exposures: Authorizations and HTAs in selected countries. Main Outcomes and Measures: All FDA-approved drugs were matched by active ingredient to decision summary reports published by drug regulators and HTA agencies in Australia, Canada, and the UK. Regulatory approval concordance and reasons for negative recommendations were assessed using descriptive statistics. For drugs not recommended by an international agency, the annual US drug cost per patient was estimated from FDA labeling and wholesale acquisition costs. Results: The FDA approved 206 new drugs in 2017 through 2020, of which 162 (78.6%) were granted marketing authorization by at least 1 other regulatory agency at a median (IQR) delay of 12.1 (17.7) months following US approval. Conversely, 5 FDA-approved drugs were refused marketing authorization by an international regulatory agency due to unfavorable benefit-to-risk assessments. An additional 42 FDA-approved drugs received negative reimbursement recommendations from HTA agencies in Australia, Canada, or the UK due to uncertainty of clinical benefits or unacceptably high prices. The median (IQR) US cost of the 47 drugs refused authorization or not recommended for reimbursement by an international agency was $115 281 ($166 690) per patient per year. Twenty drugs were for oncology indications, and 36 were approved by the FDA through expedited regulatory pathways or the Orphan Drug Act. Conclusions and Relevance: This cross-sectional study assessed reasons for which drugs recently approved by the FDA were refused marketing authorization or not recommended for public reimbursement in other countries. Drugs with limited international market presence may require close examination by US health care professionals and health systems.

Noise-induced differences in the complexity of spoken language.

Although speaking in noisy environments is a common occurrence, few studies have investigated how noise affects language production beyond the acoustic level. In seeking to differentiate between speaker- and listener-oriented modifications, this study examines the effect of noise on the complexity of language production and examines whether cognitive control predicts noise-induced modifications. Participants completed a picture description task via videoconferencing software while both the speaker (the participant) and listener (the experimenter) were exposed to multi-talker babble. Speakers produced fewer T-units, clauses, and words as well as fewer, but longer, unfilled pauses in noise. The degree of reduction in number of clauses, words, and unfilled pauses was significantly associated with weaker cognitive control. Thus, we consider these modifications to be speaker-oriented, driven by the distracting nature of noise. However, participants also produced fewer filled pauses and mazes in noise. These modifications were not significantly correlated with cognitive control, and they diverge from prior work demonstrating that speakers tend to produce more disfluencies when they alone shoulder the burden of a noisy environment. This pattern of results suggests that speakers may alter their speech to alleviate cognitive burden on themselves as well as to facilitate comprehension for their listener.

Fulfillment of Postmarket Commitments and Requirements for New Drugs Approved by the FDA, 2013-2016.

This cohort study used the Drugs@FDA database to identify new drugs approved by the US Food and Drug Administration (FDA) and assess fulfillment of postmarket commitments and requirements.

Trends in the Quality of Evidence Supporting FDA Drug Approvals: Results from a Literature Review.

CONTEXT: New drug approvals in the United States must be supported by substantial evidence from "adequate and well-controlled" trials. The Food and Drug Administration (FDA) has flexibility in how it applies this standard. METHODS: The authors conducted a systematic literature review of studies evaluating the design and outcomes of the key trials supporting new drug approvals in the United States. They extracted data on the trial characteristics, endpoint types, and expedited regulatory pathways. FINDINGS: Among 48 publications eligible for inclusion, 30 covered trial characteristics, 23 covered surrogate measures, and 30 covered regulatory pathways. Trends point toward less frequent randomization, double-blinding, and active controls, with variation by drug type and indication. Surrogate measures are becoming more common but are not consistently well correlated with clinical outcomes. Drugs approved through expedited regulatory pathways often have less rigorous trial design characteristics. CONCLUSIONS: The characteristics of trials used to approve new drugs have evolved over the past two decades along with greater use of expedited regulatory pathways and changes in the nature of drugs being evaluated. While flexibility in regulatory standards is important, policy changes can emphasize high-quality data collection before or after FDA approval.

Analysis of Supportive Evidence for US Food and Drug Administration Approvals of Novel Drugs in 2020.

Importance: In recent years, drug approvals have been based on fewer, smaller, and less rigorous pivotal trials. Less robust preapproval testing raises questions about the efficacy and clinical value of these drugs. Objective: To assess the regulatory context, pivotal design characteristics, and postmarket requirements (PMRs) and postmarket commitments (PMCs) of novel 2020 drug approvals to characterize the state of evidence at the time of approval. Design, Setting, and Participants: This cohort study identified novel drugs approved by the US Food and Drug Administration's (FDA) Center for Drug Evaluation and Research in 2020. The Drugs@FDA database was used to extract key characteristics of each drug's pivotal trials. Drug approval packages provided regulatory information. The prevalence of key trial design features was compared between oncology and nononcology drugs. Exposures: Drug names, date of approval, indication on labeling, and clinical and regulatory details. Main Outcomes and Measures: Number of pivotal trials, pivotal trial design (randomization, masking, groups), trial comparator, trial hypothesis, trial end points, results, number and type of expedited pathway designations, and number and type of PMRs and PMCs. Results: The 49 novel therapeutics approved in 2020 were supported by 75 pivotal trials. More than half of drugs (28 [57.1%]) were supported by a single pivotal trial. Trial sizes ranged from 19 to 2230 participants. More than three-fourths of trials (57 [76.0%]) had a randomization component, and nearly two-thirds (46 [61.3%]) were double-masked. Most used a superiority approach. Roughly half (39 [52.0%]) compared the novel therapeutic with a placebo or vehicle control; 13 (17.3%), an active control; 2 (2.7%), both a placebo and active control; and 21 (28.0%), a historical, external, or other control. Nearly half of pivotal trials (34 [45.3%]) used a surrogate measure as a primary end point. Pivotal trials supporting oncology approvals were much more likely to have historical controls than nononcology approvals (13 of 18 [72.2%] vs 8 of 57 [14.0%]; P < .001) and to use at least 1 surrogate measure as a primary end point (17 [94.4%] vs 17 [29.8%]; P < .001). Forty drugs had at least 1 PMR or PMC, accounting for 178 PMRs and PMCs across the cohort. Conclusions and Relevance: These findings suggest that the increased flexibility in the characteristics of acceptable preapproval evidence can be partially explained by the increase in trials of drugs for rare and other serious conditions that require flexible testing strategies as well as the associated regulatory changes that have accumulated over time. The FDA and consumers may benefit from a revised approach that better balances time to market with ensuring that approved drugs show evidence of efficacy.

New Drug Postmarketing Requirements and Commitments in the US: A Systematic Review of the Evidence.

INTRODUCTION: After the approval of a new drug, the Food and Drug Administration (FDA) may issue postmarketing requirements (PMRs), studies that the law requires manufacturers to conduct for drugs approved under certain conditions, and postmarketing commitments (PMCs), studies that the FDA and manufacturers agree should be conducted as a condition of approval. OBJECTIVE: With regulators' increasing reliance on gathering important evidence after initial product approval, we sought to assess the track record of PMRs and PMCs by synthesizing information about postmarketing study completion rates, timeliness, study types, and results reporting. METHODS: A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. Studies published in academic journals or government reports that reported original data about the characteristics of PMRs or PMCs were included. Studies of post-approval trial mandates issued by regulators outside the USA were excluded, as were those that addressed post-approval research without mentioning either PMCs or PMRs or a specific approval pathway associated with statutorily required PMRs. Two investigators independently screened and extracted data from studies and reports. Data sources included the Federal Register from 2003 to 2020, FDA backlog reviews from 2008 to 2020, PubMed from January 2006 to April 2021, and the US Government Accountability Office (GAO) database for reports from January 2006 to April 2021. PMR/PMC characteristics (e.g., completion rates, timeliness, results reporting, outcomes) were not meta-analyzed due to the heterogeneity in study designs. RESULTS: Twenty-seven peer-reviewed articles from PubMed, five GAO reports, 17 annual Federal Register notices, and 12 annual backlog reviews were included. Among the 27 studies, 13 reviewed PMRs and PMCs, one reviewed only PMCs, and 13 reviewed only PMRs. A majority of new drugs were approved with at least one PMR or PMC. PMCs were completed at higher rates than PMRs, although delays were common and neither was found to be completed more than two-thirds of the time. Over two-thirds of PMRs and PMCs reported their findings in publications and trial registries. Over half of PMCs and PMRs produced novel information for clinical practice or leading to regulatory action, such as confirmation of benefit or a labeling change. CONCLUSION: PMRs and PMCs are common for new drugs and can lead to worthwhile outcomes, but are often delayed or incomplete. Greater attention is needed to timely completion, improving transparency of findings, and ensuring that PMRs and PMCs produce optimally useful information for prescribers and patients.

Dynamic changes in chromatin accessibility, altered adipogenic gene expression, and total versus de novo fatty acid synthesis in subcutaneous adipose stem cells of normal-weight polycystic ovary syndrome (PCOS) women during adipogenesis: evidence of cellular programming.

BACKGROUND: Normal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis. RESULTS: SC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two-sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12. CONCLUSIONS: In normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.

The tubulin mutation database: A resource for the cytoskeleton community.

Over the last 40 years, the phenotypic consequences of point mutations to tubulin genes have been described in a wide variety of eukaryotes. A publicly available web-based catalog of all published point mutations to tubulin was assembled. Each entry records a specific substitution to a discrete tubulin, the species where the mutation was described, the associated phenotype, and provides hyperlinks to the parental amino acid sequence and citation(s) for the original research. The data is represented in individual tables for the universal tubulin families (α-, ß-, and γ-tubulins) with the smaller datasets for point mutations to δ-, ε-, and ζ-tubulins individually appended to the γ-tubulin mutation table. Because tubulins are highly conserved proteins, the benefit of organizing the database tables in order of amino acid position is that comparison between equivalent residues in different isotypes or species is straightforward. For example, it was shown that seven substitutions which are associated with human brain malformations known as tubulinopathies were previously identified in other contexts that suggest that they influence microtubule stability. It was anticipated that this resource will simplify evaluation of the role of specific amino acids or domains in microtubule function.

Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression.

Misexpression of developmental transcription factors occurs often in human cancers, where embryonic programs may be reinstated in a context that promotes or sustains malignant development. In this study, we report the involvement of the kidney development transcription factor Six2 in the metastatic progression of human breast cancer. We found that Six2 promoted breast cancer metastasis by a novel mechanism involving both transcriptional and epigenetic regulation of E-cadherin. Downregulation of E-cadherin by Six2 was necessary for its ability to increase soft agar growth and in vivo metastasis in an immunocompetent mouse model of breast cancer. Mechanistic investigations showed that Six2 represses E-cadherin expression by upregulating Zeb2, in part, through a microRNA-mediated mechanism and by stimulating promoter methylation of the E-cadherin gene (Cdh1). Clinically, SIX2 expression correlated inversely with CDH1 expression in human breast cancer specimens, corroborating the disease relevance of their interaction. Our findings establish Six2 as a regulator of metastasis in human breast cancers and demonstrate an epigenetic function for SIX family transcription factors in metastatic progression through the regulation of E-cadherin.

Preparative two-dimensional liquid chromatography/mass spectrometry for the purification of complex pharmaceutical samples.

A new preparative two-dimensional liquid chromatography/mass spectrometry system (2D LC-LC/MS) has been designed and implemented to enhance capability and resolving power for the separation and purification of pharmaceutical samples. The system was constructed by modifications of a conventional preparative LC/MS instrument with the addition of a set of switching valves and a sample loop, as well as interfacing a custom software program with MassLynx. The system integrates two chromatographic separations from the first and second dimensions into a single automated run to perform the purification of a target compound from a complex mixture without intermediate steps of sample preparation. The chromatography in the first dimension, operated in the heart-cutting mode, separates the target compound from the impurities by mass-triggered fractionation based on its molecular weight. This purified fraction from the first dimension is stored in the sample loop, and then gets transferred to the second column by using at-column dilution. A control software program, coined Prep 2D LCMS, was designed to integrate with MassLynx to retrieve data acquisition status. All of the chromatographic hardware components used in this preparative 2D LC-LC/MS system are from the original open access preparative LC/MS system, which has high level of robustness and affords easy and user-friendly operation. The new system is very versatile and capable of collecting multiple fractions with different masses under various purification modes as configured in the methods, such as conventional one-dimensional (1D) purification and/or 2D purification. This new preparative 2D LC-LC/MS system is therefore the ideal tool for medicinal chemistry lab in drug discovery environment.

Case of metastatic basal cell carcinoma to bone marrow, resulting in myelophthisic anemia.

BACKGROUND: While basal cell carcinoma (BCC) remains the most common skin cancer, the incidence of metastasis is rare. Most cases of metastatic BCC have been to regional lymph nodes. Metastasis to bone marrow with myelophthisic anemia is especially rare. To our knowledge, there have been only 5 reported cases in literature. We report a sixth case. OBSERVATIONS: A 46-year-old male patient presented with an 8 × 7-cm ulcerated plaque on his chest, found to be morpheaform basal cell on pathology. Laboratory findings were notable for normocytic anemia, thrombocytopenia, and elevated LDH. Further work up with bone marrow biopsy revealed tumor cells staining positive for CK AE1/AE3, BerEP4, CK7, CD56, and PIN-4. This confirmed the diagnosis of metastatic BCC (MBCC) to bone marrow. CONCLUSIONS: Although the rate of metastasis for BCC is rare, once it occurs, prognosis is poor. MBCC remains a challenge to treat. Therefore, it is critical to resolve the primary BCC and obtain vigilant follow-up, especially in patients with multiple risk factors for MBCC.

Superficial epidermolytic ichthyosis: a report of two families.

Superficial epidermolytic ichthyosis (SEI), previously known as ichthyosis bullosa of Siemens, is a rare genetic skin condition, characterized by blisters and hyperkeratosis. It can be easily confused with epidermolytic hyperkeratosis, known now as epidermolytic ichthyosis, and genetic testing can be helpful in differentiating between the two conditions. We describe two children with SEI confirmed by genetic testing, including one with a novel mutation. We also describe other affected family members with SEI.

Anion exchange of the cationic layered material [Pb2F2]2+.

We demonstrate the complete exchange of the interlamellar anions of a 2-D cationic inorganic material. The α,ω-alkanedisulfonates were exchanged for α,ω-alkanedicarboxylates, leading to two new cationic materials with the same [Pb(2)F(2)](2+) layered architecture. Both were solved by single crystal X-ray diffraction and the transformation also followed by in situ optical microscopy and ex situ powder X-ray diffraction. This report represents a rare example of metal-organic framework displaying highly efficient and complete replacement of its anionic organic linker while retaining the original extended inorganic layer. It also opens up further possibilities for introducing other anions or abatement of problematic anions such as pharmaceuticals and their metabolites.