Single-cell transcriptomic analysis of pea shoot development and cell-type-specific responses to boron deficiency.

Understanding how nutrient stress impacts plant growth is fundamentally important to the development of approaches to improve crop production under nutrient limitation. Here we applied single-cell RNA sequencing to shoot apices of Pisum sativum grown under boron (B) deficiency. We identified up to 15 cell clusters based on the clustering of gene expression profiles and verified cell identity with cell-type-specific marker gene expression. Different cell types responded differently to B deficiency. Specifically, the expression of photosynthetic genes in mesophyll cells (MCs) was down-regulated by B deficiency, consistent with impaired photosynthetic rate. Furthermore, the down-regulation of stomatal development genes in guard cells, including homologs of MUTE and TOO MANY MOUTHS, correlated with a decrease in stomatal density under B deficiency. We also constructed the developmental trajectory of the shoot apical meristem (SAM) cells and a transcription factor interaction network. The developmental progression of SAM to MC was characterized by up-regulation of genes encoding histones and chromatin assembly and remodeling proteins including homologs of FASCIATA1 (FAS1) and SWITCH DEFECTIVE/SUCROSE NON-FERMENTABLE (SWI/SNF) complex. However, B deficiency suppressed their expression, which helps to explain impaired SAM development under B deficiency. These results represent a major advance over bulk-tissue RNA-seq analysis in which cell-type-specific responses are lost and hence important physiological responses to B deficiency are missed. The reported findings reveal strategies by which plants adapt to B deficiency thus offering breeders a set of specific targets for genetic improvement. The reported approach and resources have potential applications well beyond P. sativum species and could be applied to various legumes to improve their adaptability to multiple nutrient or abiotic stresses.

Home-Based Pediatric Hospice and Palliative Care Provider Visits: Effects on Healthcare Utilization.

OBJECTIVE: This hypothesis-generating study sought to assess the impact of home-based hospice and palliative care (HBHPC) provider home visits (HV) on healthcare use. STUDY DESIGN: Retrospective review of individuals ages 1 month to 21 years receiving an in-person HBHPC provider (MD/DO or APN) HV through 2 HBHPC programs in the Midwest from January 1, 2013, through December 31, 2018. Descriptive statistics were calculated for healthcare use variables. Paired t test or Wilcoxon signed-rank test compared the changes in healthcare use the year before and year after initial provider HVs. RESULTS: The cohort included 195 individuals (49% female), with diagnoses composed of 49% neurologic, 30% congenital chromosomal, 11% oncologic, 7% cardiac, and 3% other. After implementation of HBHPC services, these patients showed decreases in the median (IQR) number of intensive care unit days (before HV, 12 [IQR, 4-37]; after HV, 0 [IQR, 0-8]; P < .001); inpatient admissions (before HV, 1 [IQR, 1-3]; after HV, 1 [IQR, 0-2]; P = .005); and number of inpatient days (before HV, 5 [IQR, 1-19]; after HV, 2 [IQR, 0-8]; P = .009). There was an increase in clinically relevant phone calls to the HBHPC team (before HV, 1 [IQR, 0-4] vs after HV, 4 [IQR, 1-7]; P < .001) and calls to the HBHPC team before emergency department visits (before HV, 0 [IQR, 0-0] vs after HV, 1 [IQR, 1-2]; P < .001). CONCLUSION: HBHPC provider HVs were associated with fewer inpatient admissions, hospital days, and intensive care unit days, and increased clinically relevant phone calls and phone calls before emergency department visit. These findings indicate that HBHPC HV may contribute to decreased inpatient use and increased use of the HBHPC team.

Individualistic culture increases economic mobility in the United States.

Where an individual grows up has large implications for their long-term economic outcomes, including earnings and intergenerational mobility. Even within the United States, the "causal effect of place" varies greatly and cannot be fully explained by socioeconomic conditions. Across different nations, variation in growth and mobility have been linked to more individualistic cultures. We assess how variation of historically driven individualism within the United States affects mobility. Areas in the United States that were isolated on the frontier for longer periods of time during the 19th century have a stronger culture of "rugged individualism" [S. Bazzi, M. Fiszbein, M. Gebresilasse, Econometrica 88, 2329-2368 (2020)]. We combine county-level measures of frontier experience with modern measures of the causal effect of place on mobility-the predicted percentage change in an individual's earnings at age 26 y associated with "growing up" in a particular county [R. Chetty, N. Hendren, Q. J. Econ. 133, 1163-1228 (2018)]. Using commuting zone fixed effects and a suite of county-level controls to absorb regional variation in frontier experience and modern economic conditions, we find an additional decade of frontier experience results in 25% greater modern-day income mobility for children of parents in the 25th percentile of income and 14% for those born to parents in the 75th percentile. We use mediation analysis to present suggestive evidence that informal manifestations of "rugged individualism"-those embodied by the individuals themselves-are more strongly associated with upward mobility than formal policy or selective migration.

Risk-Taking, Social Support, and Belongingness Contribute to the Risk for Cannabis Use Frequency in University Students.

Background: Cannabis use and misuse is known to be associated with a variety of negative health, academic, and work-related outcomes; therefore, it is important to study the factors that contribute to or moderate its use. Objectives: The aim of this study was to determine whether risky behavior, belongingness and social support as clustering variables play a role in cannabis use frequency. Method: In a university student sample, participant data on risky behavior, belongingness and social support were used to generate vulnerability profiles through cluster analysis (low vulnerability with low risk, low vulnerability with high belonging, moderate vulnerability, and high vulnerability). Using an analysis of variance, the vulnerability profiles were compared with respect to cannabis use frequency and quantity. Through chi-square tests we assessed whether these profiles are overrepresented in certain demographics. Results: The cluster analysis yielded four groups, which differed in their vulnerability for cannabis use. The most vulnerable cluster group had higher cannabis use frequency relative to the two least vulnerable groups. Low income vs. high income was also associated with high vulnerability group membership. International students were overrepresented in the low vulnerability with high belonging group relative to the low vulnerability with low-risk group. The opposite was observed for domestic students. Conclusions: This research adds to the expanding body of literature on cannabis use and misuse in Canada, which may contribute to public health policy and the prevention and treatment of cannabis addiction by providing new insight on who may be at risk.

Phytohormones in plant responses to boron deficiency and toxicity.

Boron (B) is an essential element for plant growth. Many agricultural soils around the globe have either insufficient or excessive amounts of available B, with major implications for crop production. Understanding major limitations imposed by B nutritional disorders may allow breeding crops for improved B use efficiency as well as make them more resilient to excessive B, thus reducing yield penalties. It has become apparent that B-related physiological disorders are mediated in large part by their impact on plant hormone production and signaling. The aim of this review is to summarize current knowledge of the roles of hormones in plant responses to B and their impact on plant growth and development. The most significant effect of B deficiency is the inhibition of root elongation. Boron deficiency promotes the redistribution of auxin in the root elongation zone. Together with cytokinin signals and ethylene, this redistribution and modulation of auxin content triggers inhibition of the root cell elongation. Under B deficiency, root development is also regulated by brassinosteroids and jasmonic acid. Excess B can induce the production of reactive oxygen species (ROS). Abscisic acid and salicylic acid are both produced in response to B toxicity, and both can induce the antioxidant defense system to detoxify ROS. Another adaptation to B toxicity involves changes in the expression levels and activity of aquaporins in roots, thus reducing the uptake of water and delivery of B into the transpiration stream. In addition, abscisic acid mediates stomatal closure to further limit transpiration and the consequent accumulation of B in leaves.

Strigolactone and Karrikin Signaling Pathways Elicit Ubiquitination and Proteolysis of SMXL2 to Regulate Hypocotyl Elongation in Arabidopsis.

Strigolactones (SLs) and karrikins (KARs) are related butenolide signaling molecules that control plant development. In Arabidopsis (Arabidopsis thaliana), they are recognized separately by two closely related receptors but use the same F-box protein MORE AXILLARY GROWTH2 (MAX2) for signal transduction, targeting different members of the SMAX1-LIKE (SMXL) family of transcriptional repressors for degradation. Both signals inhibit hypocotyl elongation in seedlings, raising the question of whether signaling is convergent or parallel. Here, we show that synthetic SL analog GR244DO enhanced the interaction between the SL receptor DWARF14 (D14) and SMXL2, while the KAR surrogate GR24 ent-5DS induced association of the KAR receptor KARRIKIN INSENSITIVE2 (KAI2) with SMAX1 and SMXL2. Both signals trigger polyubiquitination and degradation of SMXL2, with GR244DO dependent on D14 and GR24 ent-5DS dependent mainly on KAI2. SMXL2 is critical for hypocotyl responses to GR244DO and functions redundantly with SMAX1 in hypocotyl response to GR24 ent-5DS Furthermore, GR244DO induced response of D14-LIKE2 and KAR-UP F-BOX1 through SMXL2, whereas GR24 ent-5DS induced expression of these genes via both SMAX1 and SMXL2. These findings demonstrate that both SLs and KARs could trigger polyubiquitination and degradation of SMXL2, thus uncovering an unexpected but important convergent pathway in SL- and KAR-regulated gene expression and hypocotyl elongation.

Risk of Fractures With Concomitant Use of Calcium Channel Blockers and Selective Serotonin Reuptake Inhibitors.

BACKGROUND: Despite their frequent concurrent use, little is known about the concomitant use of calcium channel blockers (CCBs) and selective serotonin reuptake inhibitors (SSRIs) on fracture risk. We compared risk of fractures in patients concomitantly treated with CCBs and SSRIs versus CCB-only users. We compared risk of fractures among concomitant CCB-SSRI users initiating cytochrome P450 3A4 (CYP3A4)-inhibiting SSRIs versus non-CYP3A4 inhibiting SSRIs. METHODS: This retrospective cohort study used IBM MarketScan commercial claims and Medicare Supplemental database (2007-2019). We included adults diagnosed with hypertension and depression, newly initiating SSRIs while being treated with CCBs (ie, concomitant CCB-SSRI users) and those who did not (ie, CCB-only users). Primary outcome was the first occurrence of any fracture. We used stabilized inverse probability of treatment weighting (sIPTW) based on propensity scores to balance baseline risk between groups. Cox proportional hazard regression modeling was used to compare fracture risk. RESULTS: We identified 191 352 concomitant CCB-SSRI and 956 760 CCB-only users (mean age = 56 years, 50.1% males). After sIPTW, compared with CCB-only users, CCBs-SSRIs users had a higher risk of fractures (hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.22-1.66). No difference in the risk of fractures between concomitant users of CCB-CYP3A4-inhibiting SSRIs and those of CCB-non-CYP3A4 inhibiting SSRIs (HR: 1.10, 95% CI: 0.87-1.40) was observed. CONCLUSION AND RELEVANCE: Short-term concomitant CCB-SSRI use was associated with increased fracture risk. Concomitant CCBs and CYP3A4-inhibiting SSRIs compared with CCBs and non-CYP3A4 inhibiting SSRIs use was not associated with increased risk.

Impact of Piperacillin-Tazobactam Dosing in Septic Shock Patients Using Real-World Evidence: An Observational, Retrospective Cohort Study.

BACKGROUND: Sepsis and septic shock are associated with significant morbidity and mortality. Rapid initiation of appropriate antibiotic therapy is essential, as inadequate therapy early during septic shock has been shown to increase the risk of mortality. However, despite the importance of appropriate antibiotic initiation, in clinical practice, concerns for renal dysfunction frequently lead to antibiotic dose reduction, with scant evidence on the impact of this practice in septic shock patients. OBJECTIVE: The purpose if this article is to investigate the rate and impact of piperacillin-tazobactam dose adjustment in early phase septic shock patients using real-world electronic health record (EHR) data. METHODS: A multicenter, observational, retrospective cohort study was conducted of septic shock patients who received at least 48 hours of piperacillin-tazobactam therapy and concomitant receipt of norepinephrine. Subjects were stratified into 2 groups according to their cumulative 48-hour piperacillin-tazobactam dose: low piperacillin-tazobactam dosing (LOW; <27 g) group and normal piperacillin-tazobactam dosing (NORM; ≥27 g) group. To account for potential confounding variables, propensity score matching was used. The primary study outcome was 28-day norepinephrine-free days (NFD). RESULTS: In all, 1279 patients met study criteria. After propensity score matching (n = 608), the NORM group had more median NFD (23.9 days [interquartile range, IQR: 0-27] vs 13.6 days [IQR: 0-27], P = 0.021). The NORM group also had lower rates of in-hospital mortality/hospice disposition (25.9% [n = 79] vs 35.5% [n = 108]), P = 0.014). Other secondary outcomes were similar between the treatment groups. CONCLUSIONS AND RELEVANCE: In the propensity score-matched cohort, the NORM group had significantly more 28-day NFD. Piperacillin-tazobactam dose reduction in early phase septic shock is associated with worsened clinical outcomes. Clinicians should be vigilant to avoid piperacillin-tazobactam dose reduction in early phase septic shock.

High-throughput screening for prescribing cascades among real world statin initiators.

PURPOSE: Statins are among the most prevalent medications prescribed and associated with adverse events that may prompt additional treatment (i.e., a prescribing cascade). No comprehensive assessment of statin-related prescribing cascades has been performed to our knowledge. METHODS: We utilized sequence symmetry analysis to iteratively screen prescribing sequences of all therapeutic classes ("marker" classes) based on Level 4 Anatomical Therapeutic Chemical codes among adult statin initiators, using IBM Marketscan commercial and Medicare supplemental claims databases (2005-2019). Order of initiation and secular trend-adjusted sequence ratios were calculated for each statin-marker class dyad, among marker class initiators ±90 days of statin initiation. Among signals classified as prescribing cascades, we calculated naturalistic number needed to harm (NNTH) within 1 year as the inverse of the excess risk among exposed. RESULTS: We identified 2 265 519 statin initiators (mean ± SD age, 56.4 ± 12.0 years; 48.7% women; 7.5% with cardiovascular disease). Simvastatin (34.4% of statin initiators) and atorvastatin (33.9%) were the most commonly initiated statins. We identified 160 significant statin-marker class dyad signals, of which 35.6% (n = 57) were classified as potential prescribing cascades. Of the top 25 strongest signals (lowest NNTH), 12 were classified as potential prescribing cascades, including osmotically acting laxatives (NNTH, 44, 95% CI 43-46), opioids + non-opioid combination analgesics (81, 95% CI 74-91), and first-generation cephalosporins (204, 95% CI 175-246). CONCLUSIONS: Using high-throughput sequence symmetry analysis screening, we identified previously known prescribing cascades as well as potentially new prescribing cascades based on known and unknown statin-related adverse events.

Molecular basis for high ligand sensitivity and selectivity of strigolactone receptors in Striga.

Seeds of the root parasitic plant Striga hermonthica can sense very low concentrations of strigolactones (SLs) exuded from host roots. The S. hermonthica hyposensitive to light (ShHTL) proteins are putative SL receptors, among which ShHTL7 reportedly confers sensitivity to picomolar levels of SL when expressed in Arabidopsis thaliana. However, the molecular mechanism underlying ShHTL7 sensitivity is unknown. Here we determined the ShHTL7 crystal structure and quantified its interactions with various SLs and key interacting proteins. We established that ShHTL7 has an active-site pocket with broad-spectrum response to different SLs and moderate affinity. However, in contrast to other ShHTLs, we observed particularly high affinity of ShHTL7 for F-box protein AtMAX2. Furthermore, ShHTL7 interacted with AtMAX2 and with transcriptional regulator AtSMAX1 in response to nanomolar SL concentration. ShHTL7 mutagenesis analyses identified surface residues that contribute to its high-affinity binding to AtMAX2 and residues in the ligand binding pocket that confer broad-spectrum response to SLs with various structures. Crucially, yeast-three hybrid experiments showed that AtMAX2 confers responsiveness of the ShHTL7-AtSMAX1 interaction to picomolar levels of SL in line with the previously reported physiological sensitivity. These findings highlight the key role of SL-induced MAX2-ShHTL7-SMAX1 complex formation in determining the sensitivity to SL. Moreover, these data suggest a strategy to screen for compounds that could promote suicidal seed germination at physiologically relevant levels.

Racial and ethnic differences in blood pressure before and after the 2016 United States general election.

OBJECTIVES: The 2016 U.S. presidential election was a major source of stress among many adults. Psychosocial stress can manifest physiologically in elevated blood pressure (BP). Little is known regarding the association of macro-level sociopolitical events with BP changes at the population-level. This study sought to characterize population-level changes in BP following the 2016 U.S. presidential election. METHODS: Using 2015-2018 National Health and Nutrition Examination Survey, we included participants aged ≥18 years during the same periods prior to (May to October 2015/2016) and after (May to October 2017/2018) the election. Survey-weighted data were analyzed to compare population-level systolic BP (SBP) and diastolic BP (DBP) pre- and post-election, stratified by race/ethnicity. Sex differences were also investigated. RESULTS: We observed significant increases in SBP among non-Hispanic (NH) Asian participants (+3.4 mmHg; p = .046), but not among other racial/ethnic participants. DBP increased among NH Black participants (+2.3 mmHg; p = .049) and Mexican American participants (+2.9 mmHg; p = .007), but not among other racial/ethnic participants. These changes appeared attributable to differential BP changes by sex. CONCLUSIONS: At the population-level, variable changes in BP were observed by race/ethnicity following the 2016 U.S. presidential election, possibly driven by SBP elevations among women.

A Core Regulatory Pathway Controlling Rice Tiller Angle Mediated by the LAZY1-Dependent Asymmetric Distribution of Auxin.

Tiller angle in cereals is a key shoot architecture trait that strongly influences grain yield. Studies in rice (Oryza sativa) have implicated shoot gravitropism in the regulation of tiller angle. However, the functional link between shoot gravitropism and tiller angle is unknown. Here, we conducted a large-scale transcriptome analysis of rice shoots in response to gravistimulation and identified two new nodes of a shoot gravitropism regulatory gene network that also controls rice tiller angle. We demonstrate that HEAT STRESS TRANSCRIPTION FACTOR 2D (HSFA2D) is an upstream positive regulator of the LAZY1-mediated asymmetric auxin distribution pathway. We also show that two functionally redundant transcription factor genes, WUSCHEL RELATED HOMEOBOX6 (WOX6) and WOX11, are expressed asymmetrically in response to auxin to connect gravitropism responses with the control of rice tiller angle. These findings define upstream and downstream genetic components that link shoot gravitropism, asymmetric auxin distribution, and rice tiller angle. The results highlight the power of the high-temporal-resolution RNA-seq data set and its use to explore further genetic components controlling tiller angle. Collectively, these approaches will identify genes to improve grain yields by facilitating the optimization of plant architecture.

Experiences of Discrimination Are Associated With Worse Metabolic Syndrome Severity Among African Americans in the Jackson Heart Study.

BACKGROUND: Metabolic syndrome (MetS) is a risk factor for the development of cardiovascular disease and type 2 diabetes. Although the development of MetS is attributed to known lifestyle factors, perceived discrimination may also contribute to MetS development and severity. PURPOSE: We examined the associations of perceived discrimination with MetS severity among African American adults at baseline and 8-year follow-up. METHODS: Three thousand eight hundred and seventy participants (mean age 53.8 ± 13.0; 63.1% female) without diabetes and no missing MetS severity scores at baseline were included. Each self-reported measure of discrimination at baseline (everyday, lifetime, and burden of lifetime) was classified into tertiles (low, medium, high). After adjustment for demographics and MetS risk factors, associations of discrimination were examined with a sex- and race/ethnicity-specific MetS severity Z-score. We employed a mixed model approach that allowed for the assessment of an overall association between reported discrimination at baseline and MetS severity, and for the possible change over time. RESULTS: Sex and age differences were observed in experiences with discrimination, such that men reported higher levels of all aspects of discrimination relative to women. Everyday discrimination decreased with age, whereas lifetime discrimination increased with age (p < .05). Independent of lifestyle and demographic factors, everyday and lifetime discrimination were significantly associated with MetS severity (p = .003 and p = .017, respectively) and the associations remained constant over the 8 years (i.e., no interaction with time). CONCLUSIONS: Our results suggest that, in a large community-based sample of African Americans, discrimination is a salient psychosocial risk factor for severity of MetS.

Creativity on demand - Hacking into creative problem solving.

How can creative problem solving be enhanced? The paper identifies and examines modulatory approaches from the cognitive and neuroscientific literature that have been made to make creative problem solving better. We review neuromodulatory approaches of both global and local effects. Through a 2-process model of creative problem solving that involves both automatic and controlled processes, we demonstrate how these approaches could be used and what potential they may have for enhancing creative problem solving. We conclude that direct neuromodulation will be best used in unison with behavioral manipulations of cognition, and that better understanding of these manipulations should inform and guide research on direct neuromodulatory procedures.

Twelve-year trends in pharmacologic treatment of type 2 diabetes among patients with heart failure in the United States.

We conducted a cross-sectional analysis using a database from commercial health plans in the United States to describe trends in the use of antidiabetic medications among patients with type 2 diabetes and heart failure (HF) from 2006 through 2017. We used loop diuretic dose as a surrogate for HF severity (mild HF 0-40 mg/day, moderate-severe HF >40 mg/day). We assessed antidiabetic medication dispensing in the 90 days following HF diagnosis. Over the 12-year period, we identified an increase in the use of metformin (39.2% vs. 62.6%), dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.5% vs. 17.1%) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) (0.0% vs. 9.0%), but a decrease in the use of sulphonylureas (47.8% vs. 27.8%) and thiazolidinediones (TZDs) (31.7% vs. 5.3%). In 2017, patients with moderate-severe HF more commonly used insulin (43.1%); a majority of mild HF patients used metformin (62.8%). A proportion of patients with moderate-severe HF used TZDs (4.4%). Among patients with diabetes and HF, the use of metformin and DPP-4i rapidly increased, but a proportion of patients with moderate-severe HF continued to use TZDs. Despite their promising cardiovascular safety profile, SGLT-2i use remains limited.

Entrenchment: effects of multiple red herrings on memory blocks in word fragment completion.

Two experiments examined blocking and entrenchment using a word fragment completion task. After incidental priming tasks in which varying numbers of red herring stimuli (i.e., wrong answers to subsequent problems) were seen, word fragment completion was tested for items orthographically similar to primed words. Both experiments showed a memory blocking effect, poorer fragment completion when any red herrings had been seen, relative to a control (zero red herrings) condition. An entrenchment effect, poorer performance when more red herrings were primed, was also observed. Both experiments show that entrenchment effects occur with indirect measures of memory, and these results have implications for fixation effects in problem solving.

An allelic series at the KARRIKIN INSENSITIVE 2 locus of Arabidopsis thaliana decouples ligand hydrolysis and receptor degradation from downstream signalling.

Karrikins are butenolide compounds present in post-fire environments that can stimulate seed germination in many species, including Arabidopsis thaliana. Plants also produce endogenous butenolide compounds that serve as hormones, namely strigolactones (SLs). The receptor for karrikins (KARRIKIN INSENSITIVE 2; KAI2) and the receptor for SLs (DWARF14; D14) are homologous proteins that share many similarities. The mode of action of D14 as a dual enzyme receptor protein is well established, but the nature of KAI2-dependent signalling and its function as a receptor are not fully understood. To expand our knowledge of how KAI2 operates, we screened ethyl methanesulphonate (EMS)-mutagenized populations of A. thaliana for mutants with kai2-like phenotypes and isolated 13 new kai2 alleles. Among these alleles, kai2-10 encoded a D184N protein variant that was stable in planta. Differential scanning fluorimetry assays indicated that the KAI2 D184N protein could interact normally with bioactive ligands. We developed a KAI2-active version of the fluorescent strigolactone analogue Yoshimulactone Green to show that KAI2 D184N exhibits normal rates of ligand hydrolysis. KAI2 D184N degraded in response to treatment with exogenous ligands, suggesting that receptor degradation is a consequence of ligand binding and hydrolysis, but is insufficient for signalling activity. Remarkably, KAI2 D184N degradation was hypersensitive to karrikins, but showed a normal response to strigolactone analogues, implying that these butenolides may interact differently with KAI2. These results demonstrate that the enzymatic and signalling functions of KAI2 can be decoupled, and provide important insights into the mechanistic events that underpin butenolide signalling in plants.

Cardiovascular outcomes of sodium glucose cotransporter-2 inhibitors in patients with type 2 diabetes.

AIMS: To determine the association between cardiovascular diseases (CVD) and SGLT2 inhibitors compared to sulfonylureas and dipeptidyl peptidase-4 (DPP4) inhibitors and to examine within-class effects of SGLT2 inhibitors. METHODS: A retrospective cohort analysis was conducted using Truven Health MarketScan. New users of SGLT2 inhibitors, sulfonylureas or DPP-4 inhibitors were included. Primary outcome was incident CVD, defined as non-fatal myocardial infarction or non-fatal stroke; secondary outcomes were hospitalization because of heart failure and lower extremity amputation. Proportional hazards models, after propensity score matching, were used to obtain hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: In fully adjusted models, use of SGLT2 inhibitors was associated with a decreased risk of developing CVD compared with use of sulfonylureas (HR, 0.50; 95% CI, 0.45, 0.55) and DPP-4 inhibitors (HR, 0.57; 95% CI, 0.52, 0.62), respectively. Analyses revealed no evidence of within-class effects: dapagliflozin vs sulfonylureas (HR, 0.55; 95% CI, 0.43, 0.70) or DPP-4 inhibitors (HR, 0.57; 95% CI, 0.46, 0.70); and canagliflozin vs sulfonylureas (HR, 0.61; 95% CI, 0.54, 0.69) or DPP-4 inhibitors (HR, 0.66; 95% CI, 0.54, 0.71). Additionally, SGLT2 inhibitors were associated with lower risk of hospitalization because of heart failure compared to both sulfonylureas and DPP-4 inhibitors, as well as lower risk of lower extremity amputation compared to sulfonylureas. CONCLUSION: Using population-based data, incident use of SGLT-2 inhibitors was associated with a decreased incidence of CVD compared to use of sulfonylureas and DPP-4 inhibitors. These findings were consistent between dapagliflozin and canagliflozin, suggesting that CVD reduction is a class effect for SGLT2 inhibitors. In addition, SGLT2 inhibitors portended lower risk of hospitalization because of heart failure (vs sulfonylureas and DPP-4 inhibitors) and lower risk of lower extremity amputation (vs sulfonylureas).

Erenumab: A First-in-Class Monoclonal Antibody for Migraine Prevention.

Objective: To review the pharmacology, efficacy, and safety of the calcitonin gene-related peptide (CGRP) inhibitor erenumab for migraine preventive therapy. Data Sources: A MEDLINE/PubMed search (January 2000 to January 2019) was conducted using the keywords erenumab-aooe, erenumab, migraine, migraine prophylaxis, migraine prevention, and chronic migraine. Additional articles were identified by hand from references. Study Selection and Data Extraction: We included English-language articles (excluding poster presentations) evaluating erenumab pharmacology, efficacy, or safety in humans for migraine prevention. Data Synthesis: Erenumab is a CGRP inhibitor that inhibits vasodilation in response to acute migraines, which decreases pain perception during the migraine. Erenumab efficacy and safety has only been compared with placebo, but its reduction in monthly migraine days (MMDs) and medication response (≥50% reduction in MMDs) are comparable to current recommended off-label therapies for migraine prevention in short-term treatment studies. Additionally, erenumab is associated with low adverse event burden with no difference found compared with placebo per published clinical trials. Relevance to Patient Care and Clinical Practice: Erenumab is the first medication approved in the United States for the prevention of migraines in adults. No head-to-head data are available, but existing data suggest that erenumab is at least as effective as current off-label products and with reduced adverse effects. Conclusion: Erenumab is an effective once-monthly injectable agent for migraine prevention in patients with chronic or episodic migraine. It is also effective for patients who have previously failed migraine preventive therapy. Erenumab has a favorable adverse effect profile, which may improve patient adherence.

Critical roles of soluble starch synthase SSIIIa and granule-bound starch synthase Waxy in synthesizing resistant starch in rice.

Changes in human lifestyle and food consumption have resulted in a large increase in the incidence of type-2 diabetes, obesity, and colon disease, especially in Asia. These conditions are a growing threat to human health, but consumption of foods high in resistant starch (RS) can potentially reduce their incidence. Strategies to increase RS in rice are limited by a lack of knowledge of its molecular basis. Through map-based cloning of a RS locus in indica rice, we have identified a defective soluble starch synthase gene (SSIIIa) responsible for RS production and further showed that RS production is dependent on the high expression of the Waxya (Wxa ) allele, which is prevalent in indica varieties. The resulting RS has modified granule structure; high amylose, lipid, and amylose-lipid complex; and altered physicochemical properties. This discovery provides an opportunity to increase RS content of cooked rice, especially in the indica varieties, which predominates in southern Asia.