Antidepressant Prescriptions Increased For Privately Insured People With Perinatal Mood And Anxiety Disorder, 2008-20.

We aimed to determine whether antidepressant prescriptions for perinatal mood and anxiety disorder (PMAD) increased after several professional organizations issued clinical recommendations in 2015 and 2016. This serial, cross-sectional, logistic regression analysis evaluated changes in antenatal and postpartum antidepressant prescriptions among commercially insured people who had a live-birth delivery as well as a PMAD diagnosis during the period 2008-20. For people with antenatal PMAD, the odds of an antenatal antidepressant prescription decreased 3 percent annually from 2008 to 2016 and increased by 32 percent in 2017, and the annual rate of change increased 5 percent for 2017-20 compared with 2008-16. For people with postpartum PMAD, the odds of a postpartum antidepressant prescription decreased 2 percent annually from 2008 to 2016 and experienced no significant change in 2017, but the annual rate of change increased 3 percent for 2017-20 compared with 2008-16. The clinical recommendations issued in 2015 and 2016 were associated with increased antidepressant prescriptions for PMAD, particularly for antenatal PMAD. These findings indicate that clinical recommendations represent an effective tool for changing prescribing patterns.

Perinatal Mood And Anxiety Disorders Rose Among Privately Insured People, 2008-20.

Nationwide, perinatal mood and anxiety disorder (PMAD) diagnoses among privately insured people increased by 93.3 percent from 2008 to 2020, growing faster in 2015-20 than in 2008-14. Most states and demographic subgroups experienced increases, suggesting worsening morbidity in maternal mental health nationwide. PMAD-associated suicidality and psychotherapy rates also increased nationwide from 2008 to 2020. Relative to 2008-14, psychotherapy rates continued to rise in 2015-20, whereas suicidality rates declined.

Diagnosed behavioral health conditions during the perinatal period among a commercially insured population by race/ethnicity, 2008-2020.

Objective: We sought to examine trends in diagnosed behavioral health (BH) conditions [mental health (MH) disorders or substance use disorders (SUD)] among pregnant and postpartum individuals between 2008-2020. We then explored the relationship between BH conditions and race/ethnicity, acknowledging race/ethnicity as a social construct that influences health disparities. Methods: This study included delivering individuals, aged 15-44 years, and continuously enrolled in a single commercial health insurance plan for 1 year before and 1 year following delivery between 2008-2020. We used BH conditions as our outcome based on relevant ICD 9/10 codes documented during pregnancy or the postpartum year. Results: In adjusted analyses, white individuals experienced the highest rates of BH conditions, followed by Black, Hispanic, and Asian individuals, respectively. Asian individuals had the largest increase in BH rates, increasing 292%. White individuals had the smallest increase of 192%. The trend remained unchanged even after adjusting for age and Bateman comorbidity score, the trend remained unchanged. Conclusions: The prevalence of diagnosed BH conditions among individuals in the perinatal and postpartum periods increased over time. As national efforts continue to work toward improving perinatal BH, solutions must incorporate the needs of diverse populations to avert preventable morbidity and mortality.

Clinical and Economic Outcomes in Patients With Metastatic Urothelial Carcinoma Receiving First-Line Systemic Treatment (the IMPACT UC I Study).

BACKGROUND: The IMPACT UC I study assessed real-world treatment patterns, outcomes, healthcare resource utilization (HCRU), and costs in patients with metastatic urothelial carcinoma (mUC) receiving first-line (1L) systemic treatment after the FDA approval of 1L immune checkpoint inhibitor (ICI) monotherapy. PATIENTS AND METHODS: This retrospective study used 100% Medicare fee-for-service claims from 1/1/2015 to 6/30/2019 to identify patients aged ≥18 years diagnosed with UC with evidence of metastatic disease, continuously enrolled for 6 months before and after initial diagnosis. Patients were grouped by 1L treatment: cisplatin-containing chemotherapy, carboplatin-containing chemotherapy, ICI monotherapy, or nonplatinum-containing therapy. Unadjusted time on 1L treatment (TOT), overall survival (OS), HCRU, and total healthcare costs were analyzed. RESULTS: Of 18 888 patients with mUC, 8630 (45.7%) had received identified 1L systemic treatment; platinum-containing chemotherapy was the most common (cisplatin-containing chemotherapy, 37.6%; carboplatin-containing chemotherapy, 30.2%). Cisplatin- and carboplatin-containing chemotherapy had the shortest time-to-treatment initiation (median, 1.7-3.0 months) and longest TOT (median, 4.0-4.3 months). Median OS was longest with cisplatin-containing chemotherapy (20.0 months) and shortest with ICI monotherapy (7.6 months). Cisplatin- and carboplatin-containing chemotherapy were associated with highest HCRU; total healthcare costs were approximately 2-fold higher with ICI monotherapy vs other 1L treatments ($10 359 vs $5042-$5709 per patient per month). CONCLUSION: 1L platinum-containing chemotherapy resulted in the longest median OS and highest HCRU, whereas 1L ICI treatment had the shortest median OS and the highest costs. Over 50% of patients diagnosed with advanced UC (aUC) received no systemic therapy, highlighting the importance of optimal 1L treatment decisions in aUC.

Trends in chronic pain conditions among delivering women with and without mood and anxiety disorders.

OBJECTIVE: The co-existence of chronic pain conditions with anxiety and/or depression is common in the general population but poorly described during pregnancy. In this study, we sought to describe trends in chronic pain among a sample of delivering people and describe the co-existence of chronic pain with anxiety and/or depression among delivering people. METHODS: This cross-sectional study used data from Optum's de-identified Clinformatics® Data Mart Database between 2008 and 2021, for delivering persons with coverage by single employer-based health plan. We computed predicted margins from generalized estimating equations to determine the marginal predicted probability of chronic pain among all delivering and non-delivering persons who identify as women with and without diagnosed anxiety and/or depression. RESULTS: Musculoskeletal and pelvic pain occurred most often regardless of delivering status. Delivering persons with anxiety and/or depression had higher marginal predicted probabilities of chronic pain compared to all delivering persons. Between 2008 and 2021, the predicted probabilities ranged from 0.400 to 0.527 and 0.221-0.261, respectively. CONCLUSION: Chronic pain conditions are common in pregnancy and nearly two times higher among individuals with anxiety and/or depression. The frequency of comorbid depression and/or anxiety with pain disorders among delivering persons highlights the importance of proper detection, coordination of care, and safe treatment options for this population.

Medicare characteristics, treatment, cost and survival in triple class exposed relapsed or refractory multiple myeloma.

Background: This study describes real-world treatment patterns of Medicare beneficiaries with relapsed or refractory multiple myeloma (RRMM) who are triple class exposed (TCE). Materials & methods: Retrospective analysis of Medicare fee for service claims to identify a cohort age >65 with RRMM + TCE, 1 January 2016 to 30 June 2019. Outcomes: Initiation of a new treatment regimen (TCE1), healthcare resource utilization, cost and mortality. Results: Of 5395 patients with RRMM + TCE, 1672 (31.0%) initiated a new therapy (TCE1). During TCE1, 97 TCE1 drug combinations were observed and RRMM treatments were the largest cost driver. Median time to TCE1 discontinuation was 3.3 months. Few patients received subsequent treatment and 41.3% of study patients died. Conclusion: There is no clear standard-of-care for Medicare patients with RRMM + TCE and prognosis remains poor.

This research study describes outcomes in older Medicare patients with relapse or refractory multiple myeloma (RRMM) who failed three different classes of treatment (triple class exposed [TCE]) between 2016 and 2019. The authors utilized data from Medicare to follow patients who started a new treatment after TCE (this group was labeled 'TCE1'), and this article describes their cancer treatment, hospitalizations, emergency department visits, physician visits, costs of care, and length of survival. The authors identified 5395 Medicare patients with RRMM + TCE during the study period, of which 1672 (31.0%) started a new therapy and were considered TCE1. Patients were 75.6 years old, on average, when they started TCE1 treatment. The authors observed 97 different TCE1 drug combinations, and 50% of patients discontinued TCE1 treatment within 3 months. Few patients received additional treatment, and 41.3% of study patients died during the study period. More than 90% of healthcare costs were related to cancer care (rather than management of other conditions). There is no clear standard-of-care for older Medicare patients with RRMM + TCE, and prognosis remains poor.

The Association between NICU Admission and Mental Health Diagnoses among Commercially Insured Postpartum Women in the US, 2010-2018.

Maternal mental health (MH) conditions represent a leading cause of preventable maternal death in the US. Neonatal Intensive Care Unit (NICU) hospitalization influences MH symptoms among postpartum women, but a paucity of research uses national samples to explore this relationship. Using national administrative data, we examined the rates of MH diagnoses of anxiety and/or depression among those with and without an infant admitted to a NICU between 2010 and 2018. Using generalized estimating equation models, we explored the relationship between NICU admission and MH diagnoses of anxiety and/or depression, secondarily examining the association of NICU length of stay and race/ethnicity with MH diagnoses of anxiety and/or depression post NICU admission. Women whose infants became hospitalized in the NICU for <2 weeks had 19% higher odds of maternal MH diagnoses (aOR: 1.19, 95% CI: 1.14%−1.24%) and those whose infants became hospitalized for >2 weeks had 37% higher odds of maternal MH diagnoses (aOR: 1.37 95% CI: 1.128%−1.47%) compared to those whose infants did not have a NICU hospitalization. In adjusted analyses, compared to white women, all other race/ethnicities had significantly lower odds of receiving a maternal MH condition diagnosis [Black (aOR = 0.76, 0.73−0.08), Hispanic (aOR = 0.69, 0.67−0.72), and Asian (aOR: 0.32, 0.30−0.34)], despite higher rates of NICU hospitalization. These findings suggest a need to target the NICU to improve maternal MH screening, services, and support while acknowledging the influence of social determinants, including race and ethnicity, on health outcomes.

Burden of illness and outcomes in second-line large B-cell lymphoma treatment: real-world analysis of Medicare beneficiaries.

Aims: To characterize elderly large B-cell lymphoma patients who progress to second-line treatment to identify potential unmet treatment needs. Patients & methods: Retrospective USA cohort study, patients receiving second-line autologous stem cell transplant (SCT) preparative regimen ('ASCT-intended') versus those who did not; stratified further into those who received a stem cell transplant and those who did not. Primary outcomes were: healthcare resource utilization, costs and adverse events. Results: 1045 patients (22.0%) were included in the ASCT-intended group, 23.3% of whom received SCT (5.1% of entire second-line population). Non-SCT patients were older and had more comorbidities and generally higher rates of healthcare resource utilization and costs. Conclusion: Elderly second-line large B-cell lymphoma patients incurred substantial costs and a minority received potentially curative SCT, suggesting significant unmet need.

Lay abstract Large B-cell lymphoma (LBCL) is an aggressive form of cancer. Although chemotherapy is often initially successful, LBCL recurs in about 50% of patients. For many years, the standard of care for recurrent LBCL has been a course of strong chemotherapy followed by stem cell transplant (SCT). However, many older patients cannot tolerate or do not respond well to chemotherapy and therefore cannot proceed to SCT. In this real-world study of Medicare patients, we found that only 5.1% of patients with recurrent LBCL ever received potentially curative SCT. They also had higher healthcare costs than similar patients who did receive SCT. This shows a significant unmet need in elderly LBCL patients that may potentially be addressed with recent treatment innovations.

Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21.

FGF21 is a stress-induced hormone with potent anti-obesity, insulin-sensitizing, and hepatoprotective properties. Although proteolytic cleavage of recombinant human FGF21 in preclinical species has been observed previously, the regulation of endogenously produced FGF21 is not well understood. Here we identify fibroblast activation protein (FAP) as the enzyme that cleaves and inactivates human FGF21. A selective chemical inhibitor, immunodepletion, or genetic deletion of Fap stabilized recombinant human FGF21 in serum. In addition, administration of a selective FAP inhibitor acutely increased circulating intact FGF21 levels in cynomolgus monkeys. On the basis of our findings, we propose selective FAP inhibition as a potential therapeutic approach to increase endogenous FGF21 activity for the treatment of obesity, type 2 diabetes, non-alcoholic steatohepatitis, and related metabolic disorders.

Regulation of corepressor alternative mRNA splicing by hormonal and metabolic signaling.

Alternative mRNA splicing diversifies the products encoded by the NCoR and SMRT corepressor loci. There is a programmed alteration in NCoR mRNA splicing during adipocyte differentiation from an NCoRω isoform, which contains three nuclear receptor interaction domains, to an NCoRδ isoform that contains two nuclear receptor interaction domains. This alternative mRNA splicing of NCoR has profound effects on adiposity and on diabetes in mouse models. We report here that dexamethasone, a powerful regulator of metabolism and of adipocyte differentiation, confers this change in NCoR mRNA splicing in cultured adipocytes. We also demonstrate that changes in dietary components can consistently, if moderately, modulate the total transcript levels and the mRNA splicing of NCoR and SMRT in both cultured cells and intact mice. This ability of alternative corepressor mRNA splicing to respond to nutritional changes confirms its importance in regulating glucose and lipid metabolism, and its promise as a therapeutic candidate for metabolic disorders such as type 2 diabetes.

Alteration of NCoR corepressor splicing in mice causes increased body weight and hepatosteatosis without glucose intolerance.

Alternative mRNA splicing is an important means of diversifying function in higher eukaryotes. Notably, both NCoR and SMRT corepressors are subject to alternative mRNA splicing, yielding a series of distinct corepressor variants with highly divergent functions. Normal adipogenesis is associated with a switch in corepressor splicing from NCoRω to NCoRδ, which appears to help regulate this differentiation process. We report here that mimicking this development switch in mice by a splice-specific whole-animal ablation of NCoRω is very different from a whole-animal or tissue-specific total NCoR knockout and produces significantly enhanced weight gain on a high-fat diet. Surprisingly, NCoRω(-/-) mice are protected against diet-induced glucose intolerance despite enhanced adiposity and the presence of multiple additional, prodiabetic phenotypic changes. Our results indicate that the change in NCoR splicing during normal development both helps drive normal adipocyte differentiation and plays a key role in determining a metabolically appropriate storage of excess calories. We also conclude that whole-gene "knockouts" fail to reveal how important gene products are customized, tailored, and adapted through alternative mRNA splicing and thus do not reveal all the functions of the protein products of that gene.

Thyroid hormones, t3 and t4, in the brain.

Thyroid hormones (THs) are essential for fetal and post-natal nervous system development and also play an important role in the maintenance of adult brain function. Of the two major THs, T4 (3,5,3',5'-tetraiodo-l-thyronine) is classically viewed as an pro-hormone that must be converted to T3 (3,5,3'-tri-iodo-l-thyronine) via tissue-level deiodinases for biological activity. THs primarily mediate their effects by binding to thyroid hormone receptor (TR) isoforms, predominantly TRα1 and TRß1, which are expressed in different tissues and exhibit distinctive roles in endocrinology. Notably, the ability to respond to T4 and to T3 differs for the two TR isoforms, with TRα1 generally more responsive to T4 than TRß1. TRα1 is also the most abundantly expressed TR isoform in the brain, encompassing 70-80% of all TR expression in this tissue. Conversion of T4 into T3 via deiodinase 2 in astrocytes has been classically viewed as critical for generating local T3 for neurons. However, deiodinase-deficient mice do not exhibit obvious defectives in brain development or function. Considering that TRα1 is well-established as the predominant isoform in brain, and that TRα1 responds to both T3 and T4, we suggest T4 may play a more active role in brain physiology than has been previously accepted.

The ability of thyroid hormone receptors to sense t4 as an agonist depends on receptor isoform and on cellular cofactors.

T4 (3,5,3',5'-tetraiodo-l-thyronine) is classically viewed as a prohormone that must be converted to the T3 (3,5,3'-triiodo-l-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T4 and to T3 differed for the different thyroid hormone receptor (TR) isoforms, with TRα1 generally more responsive to T4 than was TRß1. The response to T4 vs T3 also differed dramatically in different cell types in a manner that could not be attributed to differences in deiodinase activity or in hormone affinity, leading us to examine the role of TR coregulators in this phenomenon. Unexpectedly, several coactivators, such as steroid receptor coactivator-1 (SRC1) and thyroid hormone receptor-associated protein 220 (TRAP220), were recruited to TRα1 nearly equally by T4 as by T3 in vitro, indicating that TRα1 possesses an innate potential to respond efficiently to T4 as an agonist. In contrast, release of corepressors, such as the nuclear receptor coreceptor NCoRω, from TRα1 by T4 was relatively inefficient, requiring considerably higher concentrations of this ligand than did coactivator recruitment. Our results suggest that cells, by altering the repertoire and abundance of corepressors and coactivators expressed, may regulate their ability to respond to T4, raising the possibility that T4 may function directly as a hormone in specific cellular or physiological contexts.

The two major isoforms of thyroid hormone receptor, TRα1 and TRß1, preferentially partner with distinct panels of auxiliary proteins.

Thyroid hormone receptors (TRs) are expressed primarily as two major isoforms, TRα1 and TRß1, which are expressed at different times in development and at different tissue abundances in the adult. The transcription properties and biological properties of TRα1 and TRß1 can differ. We report here that although overlapping, TRα1 and TRß1 recruit distinct panels of partner proteins that may account for their divergent biological functions, and which appear to explain their distinct target gene regulatory properties.

Transgenic soybean plants overexpressing O-acetylserine sulfhydrylase accumulate enhanced levels of cysteine and Bowman-Birk protease inhibitor in seeds.

Soybeans provide an excellent source of protein in animal feed. Soybean protein quality can be enhanced by increasing the concentration of sulfur-containing amino acids. Previous attempts to increase the concentration of sulfur-containing amino acids through the expression of heterologous proteins have met with limited success. Here, we report a successful strategy to increase the cysteine content of soybean seed through the overexpression of a key sulfur assimilatory enzyme. We have generated several transgenic soybean plants that overexpress a cytosolic isoform of O-acetylserine sulfhydrylase (OASS). These transgenic soybean plants exhibit a four- to tenfold increase in OASS activity when compared with non-transformed wild-type. The OASS activity in the transgenic soybeans was significantly higher at all the stages of seed development. Unlike the non-transformed soybean plants, there was no marked decrease in the OASS activity even at later stages of seed development. Overexpression of cytosolic OASS resulted in a 58-74% increase in protein-bound cysteine levels compared with non-transformed wild-type soybean seeds. A 22-32% increase in the free cysteine levels was also observed in transgenic soybeans overexpressing OASS. Furthermore, these transgenic soybean plants showed a marked increase in the accumulation of Bowman-Birk protease inhibitor, a cysteine-rich protein. The overall increase in soybean total cysteine content (both free and protein-bound) satisfies the recommended levels required for the optimal growth of monogastric animals.

Threonine-insensitive homoserine dehydrogenase from soybean: genomic organization, kinetic mechanism, and in vivo activity.

Aspartate kinase (AK) and homoserine dehydrogenase (HSD) function as key regulatory enzymes at branch points in the aspartate amino acid pathway and are feedback-inhibited by threonine. In plants the biochemical features of AK and bifunctional AK-HSD enzymes have been characterized, but the molecular properties of the monofunctional HSD remain unexamined. To investigate the role of HSD, we have cloned the cDNA and gene encoding the monofunctional HSD (GmHSD) from soybean. Using heterologously expressed and purified GmHSD, initial velocity and product inhibition studies support an ordered bi bi kinetic mechanism in which nicotinamide cofactor binds first and leaves last in the reaction sequence. Threonine inhibition of GmHSD occurs at concentrations (K(i) = 160-240 mM) more than 1000-fold above physiological levels. This is in contrast to the two AK-HSD isoforms in soybean that are sensitive to threonine inhibition (K(i) approximately 150 microM). In addition, GmHSD is not inhibited by other aspartate-derived amino acids. The ratio of threonine-resistant to threonine-sensitive HSD activity in soybean tissues varies and likely reflects different demands for amino acid biosynthesis. This is the first cloning and detailed biochemical characterization of a monofunctional feedback-insensitive HSD from any plant. Threonine-resistant HSD offers a useful biotechnology tool for manipulating the aspartate amino acid pathway to increase threonine and methionine production in plants for improved nutritional content.

A redox-active isopropylmalate dehydrogenase functions in the biosynthesis of glucosinolates and leucine in Arabidopsis.

We report a detailed functional characterization of an Arabidopsis isopropylmalate dehydrogenase (AtIPMDH1) that is involved in both glucosinolate biosynthesis and leucine biosynthesis. AtIPMDH1 shares high homology with enzymes from bacteria and yeast that are known to function in leucine biosynthesis. In plants, AtIPMDH1 is co-expressed with nearly all the genes known to be involved in aliphatic glucosinolate biosynthesis. Mutation of AtIPMDH1 leads to a significant reduction in the levels of free leucine and of glucosinolates with side chains of four or more carbons. Complementation of the mutant phenotype by ectopic expression of AtIPMDH1, together with the enzyme's substrate specificity, implicates AtIPMDH1 in both glucosinolate and leucine biosynthesis. This functional assignment is substantiated by subcellular localization of the protein in the chloroplast stroma, and the gene expression patterns in various tissues. Interestingly, AtIPMDH1 activity is regulated by a thiol-based redox modification. This work characterized an enzyme in plants that catalyzes the oxidative decarboxylation step in both leucine biosynthesis (primary metabolism) and methionine chain elongation of glucosinolates (specialized metabolism). It provides evidence for the hypothesis that the two pathways share a common origin, and suggests a role for redox regulation of glucosinolate and leucine synthesis in plants.

Contributions of conserved serine and tyrosine residues to catalysis, ligand binding, and cofactor processing in the active site of tyrosine ammonia lyase.

Tyrosine ammonia lyase (TAL) catalyzes the conversion of L-tyrosine to p-coumaric acid using a 3,5-dihydro-5-methylidene-4H-imidazole-4-one (MIO) prosthetic group. In bacteria, TAL is used for production of the photoactive yellow protein chromophore and for caffeic acid biosynthesis in certain actinomycetes. Here we biochemically examine wild-type and mutant forms of TAL from Rhodobacter sphaeroides (RsTAL). Kinetic analysis of RsTAL shows that the enzyme displays a 90-fold preference for L-tyrosine versus L-phenylalanine as a substrate. The pH-dependence of TAL activity with L-tyrosine and L-phenylalanine demonstrates a common protonation state for catalysis, but indicates a difference in charge-state for binding of either amino acid. Site-directed mutagenesis demonstrates that Ser150, Tyr60, and Tyr300 are essential for catalysis. Mutation of Ser150 to an alanine abrogates formation of the MIO prosthetic group, as shown by mass spectrometry, and prevents catalysis. The Y60F and Y300F mutants were inactive with both amino acid substrates, but bound p-coumaric and cinnamic acids with less than 12-fold changes in affinity compared the wild-type enzyme. Analysis of MIO-dithiothreitol adduct formation shows that the reactivity of the prosthetic group is not significantly altered by mutation of either Tyr60 or Tyr300. The mechanistic roles of Ser150, Tyr60, and Tyr300 are discussed in relation to the three-dimensional structure of RsTAL and related MIO-containing enzymes.