Biological Control of Root Rot of Strawberry by Bacillus amyloliquefaciens Strains CMS5 and CMR12.

Strawberry root rot caused by Fusarium solani is one of the main diseases of strawberries and significantly impacts the yield and quality of strawberry fruit. Biological control is becoming an alternative method for the control of plant diseases to replace or decrease the application of traditional chemical fungicides. To obtain antagonistic bacteria with a high biocontrol effect on strawberry root rot, over 72 rhizosphere bacteria were isolated from the strawberry rhizosphere soil and screened for their antifungal activity against F. solani by dual culture assay. Among them, strains CMS5 and CMR12 showed the strongest inhibitory activity against F. solani (inhibition rate 57.78% and 65.93%, respectively) and exhibited broad-spectrum antifungal activity. According to the phylogenetic tree based on 16S rDNA and gyrB genes, CMS5 and CMR12 were identified as Bacillus amyloliquefaciens. Lipopeptide genes involved in surfactin, iturin, and fengycin biosynthesis were detected in the DNA genomes of CMS5 and CMR12 by PCR amplification. The genes related to the three major lipopeptide metabolites existed in the DNA genome of strains CMS5 and CMR12, and the lipopeptides could inhibit the mycelial growth of F. solani and resulted in distorted hyphae. The inhibitory rates of lipopeptides of CMS5 and CMR12 on the spore germination of F. solani were 61.00% and 42.67%, respectively. The plant-growth-promoting (PGP) traits in vitro screening showed that CMS5 and CMR12 have the ability to fix nitrogen and secreted indoleacetic acid (IAA). In the potting test, the control efficiency of CMS5, CMR12 and CMS5+CMR12 against strawberry root rot were 65.3%, 67.94% and 88.00%, respectively. Furthermore, CMS5 and CMR12 enhanced the resistance of strawberry to F. solani by increasing the activities of defense enzymes MDA, CAT and SOD. Moreover, CMS5 and CMR12 significantly promoted the growth of strawberry seedlings such as root length, seedling length and seedling fresh weight. This study revealed that B. amyloliquefaciens CMS5 and CMR12 have high potential to be used as biocontrol agents to control strawberry root rot.

Potential Impact of Slowing Disease Progression in Early Symptomatic Alzheimer's Disease on Patient Quality of Life, Caregiver Time, and Total Societal Costs: Estimates Based on Findings from GERAS-US Study.

Background: Impact of Alzheimer's disease (AD) progression on patient health-related quality of life (HRQoL), caregiver time, and societal costs is not well characterized in early AD. Objective: To assess the association of change in cognition with HRQoL, caregiver time, and societal costs over 36 months, and estimate the impact of slowing disease progression on these outcomes. Methods: This post-hoc analysis included patients with amyloid-positive mild cognitive impairment (MCI) and mild AD dementia (MILD AD) from the 36-month GERAS-US study. Disease progression was assessed using the Mini-Mental State Examination score. Change in outcomes associated with slowing AD progression was estimated using coefficients from generalized linear models. Results: At baseline, 300 patients had MCI and 317 had MILD AD. Observed natural progression over 36 months was associated with: 5.1 point decline in the Bath Assessment of Subjective Quality of Life in Dementia (BASQID) score (for HRQoL), increase in 1,050 hours of total caregiver time, and $8,504 total societal costs for MCI; 6.6 point decline in the BASQID score, increase in 1,929 hours of total caregiver time, and $12,795 total societal costs for MILD AD per person. Slowing AD progression by 30% could result in per person savings in HRQoL decline, total caregiver time, and total societal costs: for MCI: 1.5 points, 315 hours, and $2,638; for MILD AD: 2.0 points, 579 hours, and $3,974. Conclusions: Slowing AD progression over 36 months could slow decline in HRQoL and save caregiver time and societal cost in patients with MCI and MILD AD.

Clinical and biochemical characteristics, and outcome in 33 patients with ceftriaxone-induced liver injury.

PURPOSE: To summarize the clinical and biochemical characteristics of patients with ceftriaxone-induced liver injury and guide the selection of safe medication. METHODS: Retrieved domestic and foreign databases from inception to October 2023, collected case data conforming to ceftriaxone-induced liver injury, and statistically analyzed the data. RESULTS: A total of 617 articles were retrieved, and 16 articles with 33 cases (10 children, 23 adults) were included. Males represented 60% (18/30), with a male-to-female ratio of 1.5:1. The age of onset ranged from 2 days to 96 years, with 15 of 23 adults (65%) over 55 years old. The time from ceftriaxone use to liver injury fluctuated between 0.5 and 47 days. Only 9 patients (27.3%, 9/33) had clinical symptoms, and the clinical classification was dominated by cholestatic injury (46.2%, 12/26). There was a significant difference in the clinical classification of ceftriaxone-induced liver injury between children and adults (P = 0.0126), with hepatocellular injury predominating in children and cholestatic injury predominating in adults. The severity of liver injury was mainly mild (66.7%, 12/18). Peak values of alanine aminotransferase ranging from 228.5 to 8098 U/L, aspartate aminotransferase ranging from 86.7 to 21575 U/L, alkaline phosphatase ranging from 143 to 2434 U/L, and total bilirubin ranging from 3.35 to 66.1 mg/dL. There was a significant difference in peak values of alkaline phosphatase between children and adults (P = 0.027), with a higher peak value of alkaline phosphatase in adults (1039 ± 716.4 U/L vs. 257 ± 134.9 U/L). Patients with normal imaging examinations accounted for the majority (61.5%, 7/13). The prognosis of 32 patients (97%, 32/33) was good, and one child with sickle cell anemia who developed immune hemolysis, progressive renal failure, and acute liver injury after using ceftriaxone died in the end. CONCLUSION: Ceftriaxone-induced liver injury can occur at any age, with a higher risk in the elderly, and age may be related to the clinical classification. Although the clinical manifestations are not specific, close monitoring of liver biochemical indicators during the use can detect liver injury early. Most cases have a good prognosis, but for people with concomitant sickle cell anemia, it is necessary to be vigilant about the occurrence of severe hemolytic anemia.

Magnaporthe oryzae Effector AvrPik-D Targets Rice Rubisco Small Subunit OsRBCS4 to Suppress Immunity.

Rice blast, caused by the fungal pathogen Magnaporthe oryzae (M. oryzae), is a highly destructive disease that significantly impacts rice yield and quality. During the infection, M. oryzae secretes effector proteins to subvert the host immune response. However, the interaction between the effector protein AvrPik-D and its target proteins in rice, and the mechanism by which AvrPik-D exacerbates disease severity to facilitate infection, remains poorly understood. In this study, we found that the M. oryzae effector AvrPik-D interacts with the Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase) small subunit OsRBCS4. The overexpression of the OsRBCS4 gene in transgenic rice not only enhances resistance to M. oryzae but also induces more reactive oxygen species following chitin treatment. OsRBCS4 localizes to chloroplasts and co-localizes with AvrPik-D within these organelles. AvrPik-D suppresses the transcriptional expression of OsRBCS4 and inhibits Rubisco activity in rice. In conclusion, our results demonstrate that the M. oryzae effector AvrPik-D targets the Rubisco small subunit OsRBCS4 and inhibits its carboxylase and oxygenase activity, thereby suppressing rice innate immunity to facilitate infection. This provides a novel mechanism for the M. oryzae effector to subvert the host immunity to promote infection.

Identification and Biological Characteristics of Mortierella alpina Associated with Chinese Flowering Cherry (Cerasus serrulata) Leaf Blight in China.

The Chinese flowering cherry (Cerasus serrulata), an ornamental tree with established medicinal values, is observed to suffer from leaf blight within Xi'an's greenbelts. This disease threatens both the plant's growth and its ornamental appeal. In this study, 26 isolates were obtained from plants with typical leaf blight, and only 3 isolates (XA-10, XA-15, and XA-18) were found to be pathogenic, causing similar symptoms on the leaves of the host plant. Based on sequence alignment, the ITS and LSU sequences of the three selected isolates were consistent, respectively. Following morphological and molecular analyses, the three selected isolates were further identified as Mortierella alpina. The three selected isolates exhibited similar morphological characteristics, including wavy colonies with dense, milky-white aerial mycelia on PDA medium. Therefore, isolate XA-10 was used as a representative strain for subsequent experiments. The representative strain XA-10 was found to exhibit optimal growth at a temperature of 30 °C and a pH of 7.0. Host range infection tests further revealed that the representative strain XA-10 could also inflict comparable disease symptoms on both the leaves and fruits of three different Rosaceae species (Prunus persica, Pyrus bretschneideri, and Prunus salicina). This study reveals, for the first time, the causative agent of leaf blight disease affecting the Chinese flowering cherry. This provides a deeper understanding of the biology and etiology of M. alpina. This study lays a solid foundation for the sustainable control and management of leaf blight disease in the Chinese flowering cherry.

Supramolecular Assemblies of Glycopeptides Enhance Gap Junction Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes via Inducing Spheroids Formation to Optimize Cardiac Repair.

Stem cell-based therapies have demonstrated significant potential for use in heart regeneration. An effective paradigm for heart repair in rodent and large animal models is the transplantation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Despite this, the functional and phenotypical immaturity of 2D-cultured hiPSC-CMs, particularly their low electrical integration, poses a caveat for clinical translation. In this study, a supramolecular assembly of a glycopeptide containing a cell adhesion motif-RGD, and saccharide-glucose (Bio-Gluc-RGD) is designed to enable the 3D spheroid formation of hiPSC-CMs, promoting cell-cell and cell-matrix interactions that occur during spontaneous morphogenesis. HiPSC-CMs in spheroids are prone to be phenotypically mature and developed robust gap junctions via activation of the integrin/ILK/p-AKT/Gata4 pathway. Monodispersed hiPSC-CMs encapsulated in the Bio-Gluc-RGD hydrogel are more likely to form aggregates and, therefore, survive in the infarcted myocardium of mice, accompanied by more robust gap junction formation in the transplanted cells, and hiPSC-CMs delivered with the hydrogels also displayed angiogenic effect and anti-apoptosis capacity in the peri-infarct area, enhancing their overall therapeutic efficacy in myocardial infarction. Collectively, the findings illustrate a novel concept for modulating hiPSC-CM maturation by spheroid induction, which has the potential for post-MI heart regeneration.

Validation and meaningful within-patient change in work productivity and activity impairment questionnaire (WPAI) for episodic or chronic migraine.

BACKGROUND: No available studies demonstrate validity and meaningful change thresholds of Work Productivity and Activity Impairment (WPAI) questionnaire in patients with migraine. In this post-hoc analysis, we assessed reliability, validity, responsiveness, and meaningful within-patient change from baseline to Month 3 for Work Productivity and Activity Impairment (WPAI) domain scores in patients with episodic migraine (EM) or chronic migraine (CM). METHOD: The Phase 3, multicenter, randomized, double-blind, placebo-controlled CONQUER study (NCT03559257, N = 462) enrolled patients with EM or CM who failed two to four categories of prior preventive medication in past ten years. The analyses were performed for WPAI domain scores (absenteeism, presenteeism, overall work productivity, and non-work-related activity impairment). Migraine Specific Quality of Life Questionnaire version 2.1 (MSQv2.1) domain scores (Role Function-Restrictive [RFR] and Role Function-Preventive [RFP]), and monthly migraine headache days were used as anchors. Responder criteria were changes from baseline to Month 3 for each of these anchors and were defined as: increase in MSQ-RFR by ≥ 25.71 points and MSQ-RFP by ≥ 20.00 points and a 50% reduction in monthly migraine headache days. Assessments were performed for overall population, and patients with EM or CM. The meaningful change threshold was determined based on Youden index, Phi coefficient and sensitivity. RESULTS: Of 462 randomized patients, 444 who completed WPAI questionnaire were included in post-hoc analysis. Test-retest reliability over 3 months in a stable subgroup revealed moderate correlations for non-work-related Activity Impairment (ICC = 0.446) presenteeism (ICC = 0.438) and a fair correlation for overall work productivity loss (ICC = 0.360). At baseline, all correlations between WPAI domain scores and continuous anchor variables exceeded recommended threshold of ≥ 0.30, except for WPAI domain scores with number of monthly migraine headache days. Patients achieving pre-specified responsiveness thresholds for monthly migraine headache days, and MSQ-RFP, MSQ-RFR from baseline to Month 3 (responders) showed significant improvements in WPAI domain scores compared with non-responders (P < 0.001). The meaningful change thresholds of -20 (% unit) were identified for WPAI domain scores. CONCLUSION: In conclusion, WPAI has sufficient validity, reliability, responsiveness, and appropriate interpretation standards to assess the impact of EM or CM on presenteeism and overall work productivity loss and non-work-related activity impairment. TRIAL REGISTRATION: NCT number of CONQUER study, NCT03559257.

Real-World Treatment Patterns and Outcomes Among Patients with Episodic Migraine in China: Results from the Adelphi Migraine Disease Specific Programme™.

Objective: This study assessed treatment patterns, disease burden, outcomes, and unmet needs among patients with episodic migraine (EM) in China using Adelphi Migraine Disease Specific Programme™ (DSP) real-world data. Background: Migraine is a prevalent and debilitating neurological disorder which presents a major public health burden globally. Research on characteristics, disease burden, and treatment patterns in EM patients in China is limited. Methods: Data were drawn from an existing data set Adelphi Migraine DSP, a point-in-time survey conducted in China (January-June 2014). Internists/neurologists completed patient record forms for the next 9 patients who consulted them in clinical practice; these same patients completed the 'patient self-completion questionnaires'. Descriptive analyses were used to assess key variables: patient demographics, treatment patterns (current acute and preventive medication [AM/PM]), effectiveness, issues with existing treatment, Migraine Disability Assessment (MIDAS) scores, and Work Productivity and Activity Impairment scores. Results: Total of 125 internists/neurologists provided data on 1113 patients with EM (headache days/month <15). Mean (standard deviation [SD]) age was 43.8 (13.1) years; mean (SD) number of migraine days/month was 3.2 (1.7). AM was prescribed in 86.1% of patients (non-steroid anti-inflammatory drugs [NSAIDs]: 62.7%; triptans: 7.7%), PM in 38.5%, and both in 24.9% of patients. Approximately 55% of patients experienced ≥1 issue with their current AM or PM. Migraine-related symptoms (including nausea, photophobia, and phonophobia) were fully controlled in <50% of patients receiving NSAIDs (21.7-38.4%) or triptans (32.4-43.5%). Insufficient response to current AM (migraine headache fully resolved within 2 hours in ≤3/5 attacks) was reported by 42.5% of patients. Mild-to-severe disability was reported by 36.8% of patients with a mean (SD) MIDAS score of 5.8 (7.3). Overall, 58.0% of work time was impaired (including time missed and impairment while working). Conclusion: This analysis suggests, despite existing treatment options, disease burden and unmet medical needs remain substantial in Chinese patients with EM.

Annual indirect costs savings in patients with episodic or chronic migraine: a post-hoc analysis of phase 3 galcanezumab clinical trials in the United States.

BACKGROUND: Galcanezumab (GMB) improved quality-of-life and reduced disability of patients with episodic (EM) and chronic migraine (CM) in Phase 3 trials. AIM: To estimate indirect cost savings associated with GMB treatment in patients with migraine in the United States (US). METHODS: We analyzed data of patients from the US from three randomized, Phase 3, double-blind, placebo (PBO)-controlled GMB studies: EVOLVE-1 and EVOLVE-2 (EM patients), REGAIN (CM patients). Annual indirect costs were calculated using items of the Migraine Disability Assessment (MIDAS) questionnaire: lost time/productivity at work/school, household work, and leisure time. All costs were annualized and expressed in 2019 US dollars. While the main analysis considered lost time/productivity at work/school and household work as a full day, a sensitivity analysis was performed by discounting them by half. For EM, annual indirect costs savings were estimated using mixed model repeated measures analysis. For CM, ANCOVA models were used to estimate annual indirect costs savings as change from baseline. RESULTS: The analysis included 805 patients with EM (mean age = 41.4 years; PBO = 534; GMB = 271) and 423 patients with CM (mean age = 38.9 years; PBO = 279; GMB = 144). Compared to PBO, GMB significantly reduced annual indirect costs among patients with EM at 3 months (least square mean [95% confidence interval] work/school = $1,883.6 [603.64-3,163.65], p = .0040, household work = $628.9 [352.95-904.88], p <.0001, and leisure activity = $499.17 [42.36-955.98], p = .0323) and 6 months (work/school = $2,382.29 [1,065.48-3,699.10], p = .0004, household work = $559.45 [268.99-849.90], p = .0002, and leisure activity = $753.81 [334.35-1,173.27], p = .0004), whereas a significant difference was not observed among patients with CM. Sensitivity analysis results were similar to primary analysis results. CONCLUSIONS: GMB treatment versus PBO resulted in significantly greater indirect cost savings in patients with EM through improved productivity at work/school, household work, and leisure days. Patients with CM receiving GMB versus PBO attained greater cost savings, although not statistically significant, through reduced lost productivity at work/school.

Migraine causes missed time or reduced productivity at home and work, which further imposes an economic burden on patients, referred to as indirect costs. In this study, we evaluated the indirect cost savings in patients with episodic or chronic migraine taking either galcanezumab or placebo for treatment. We collected data using a questionnaire called the Migraine Disability Assessment (MIDAS) that was completed by patients enrolled in three clinical studies in the United States (US), namely EVOLVE-1, EVOVLE-2 (episodic migraine patients), and REGAIN (chronic migraine patients). The MIDAS questionnaire evaluated time lost/reduced productivity at work/school, household work, and leisure activity in patients with episodic or chronic migraine. Using scores of the MIDAS questionnaire and standard annual wages for the US population, we calculated indirect costs in patients. A total of 805 patients with episodic migraine and 423 patients with chronic migraine were included in this study. In galcanezumab-treated patients with episodic migraine, a significant indirect cost saving was observed through decrease in time lost/reduced productivity at work/school, household work, and leisure activity compared with patients who received placebo. In galcanezumab-treated patients with chronic migraine, indirect cost saving observed through decrease in time lost/reduced productivity at work/school were not statistically different from placebo-treated patients. The relatively lower cost savings observed in patients with chronic migraine may be due to greater disease burden compared to patients with episodic migraine. Results of this study suggest that patients with migraine receiving galcanezumab may obtain indirect cost savings.

The Effect of Mother Phubbing on Young Children's Emotional and Behavioral Problems: A Moderated Mediation Model of Mother-Child Attachment and Parenting Stress.

Phubbing-the act of ignoring someone physically present in favor of a mobile phone-is increasingly prevalent in families, and mothers' phubbing behaviors may have a particularly important effect on young children's development. Accordingly, this study explores the mediating role of mother-child attachment in the relationship between mother phubbing and children's emotional and behavioral problems, as well as the role of maternal parenting stress in moderating the mediation effect. A total of 988 mothers of young children (mean age = 4.93, SD = 0.94) were surveyed using four scales, and the resulting data was statistically analyzed. The study found that (1) mother phubbing was significantly and positively correlated with children's emotional and behavioral problems (r = 0.19, p < 0.01), (2) mother-child attachment mediated the relationship between mother phubbing and children's emotional and behavioral problems, and (3) the relationship between mother-child attachment and children's emotional and behavioral problems was moderated by maternal parenting stress. The present study offers fresh evidence of how mother phubbing affects young children's emotional and behavioral difficulties. The need to reduce maternal parental stress and buffer mothers from its effects are highlighted as vital factors in promoting secure mother-child attachment and alleviating young children's problems.

Micro-physical parameter dynamic evolution behaviour of a natural ester molecular chain under a changing electric field and its correlation mechanism with lightning impulse discharge: theoretical analysis.

The lightning impulse breakdown properties of natural esters are very important for their further applications. This paper focuses on the discharge mechanism investigation of a natural ester insulating liquid under a lightning impulse electric field. Based on density functional theory (DFT), the configuration, electron structure, ionization and electron affinity process, excitation process and molecular orbital of natural ester molecules were calculated under different electric field strengths. A correlation mechanism between the micro-physical parameters of ester insulating liquid molecules and discharge was proposed. The molecular electrostatic potential was used to predict the active point of discharge. The results show that the molecular structure of triglycerides shows yield behaviour under electric field action. The electrons are redistributed in the direction of the source of the electric field. Among the four triglycerides, the ionization and electron affinity process, excitation process and molecular orbital of glycerol tripalmitate were least affected by the electric field. The microscopic properties of other triglycerides were significantly affected by the electric field. According to the electrostatic potential (ESP) result of natural ester molecules, it can be predicted in the experiment that the surface of H atoms of the triglyceride ester group easily forms electron traps to bind electrons, while the surface of an O atom at the ester of a triglyceride undergoes electron collisions resulting in an electrical discharge. The proportion of palmitic acid in natural esters could be increased or pure glycerol tripalmitate could be used as an insulating oil to solve the problem of the low lightning impulse breakdown voltage of natural esters.

Health care resource utilization and costs associated with treatment among patients initiating calcitonin gene-related peptide inhibitors vs other preventive migraine treatments in the United States.

BACKGROUND: Limited data are available on health care resource utilization (HCRU) and health care costs of calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) for preventive treatment of migraine. OBJECTIVE: To compare all-cause and migraine-related HCRU and direct health care costs in patients with migraine initiating CGRP mAbs, galcanezumab (GMB), vs standard-of-care (SOC) preventive treatments in the United States. METHODS: This retrospective observational study used insurance claims data collected from IBM MarketScan Research Databases. Adults (aged ≥ 18 years) with 1 or more claims for CGRP mAb (GMB, erenumab, or fremanezumab) or SOC preventive treatment between May 1, 2018, and June 30, 2019, were included. The date of earliest migraine treatment claim during this period was the index date. Annual all-cause and migraine-related HCRU included inpatient visits, emergency department visits, and acute and preventive migraine medication fills. After matching, HCRU and costs at 6- and 12-month follow-up in CGRP mAb, specifically GMB, vs SOC cohorts were analyzed using paired t-test and chi-square test. RESULTS: In the 12-month follow-up study, 4,528 patients using CGRP mAb (GMB, n = 426) and 10,897 patients using SOC were included. After matching, 3,082 pairs were identified in the CGRP mAb and SOC cohorts and 421 pairs in the GMB and SOC cohorts. After matching, all variables were well balanced across cohorts. At 12-month follow-up, the percentage decrease in acute and preventive migraine medication fills was significantly greater in the CGRP mAb (acute: -1.5% vs -0.2%, P < 0.001; preventive: -1.1% vs 3.8, P < 0.001) and GMB cohorts (acute: -1.5% vs -0.2%, P = 0.002; preventive: -1.8 vs 3.0, P < 0.001) compared with the SOC cohort. At follow-up, compared with the SOC cohort, the mean change of annual all-cause total costs was significantly higher in both the CGRP mAb ($6,043 vs $1,323, P < 0.001) and GMB cohorts ($8,398 vs $68, P < 0.001), and the mean change of annual migraine-related total costs was significantly higher in both the CGRP mAb ($3,416 vs $976, P < 0.001) and GMB cohorts ($4,334 vs $1,245, P < 0.001). Significant cost savings in mean acute and preventive migraine prescription costs occurred in both the CGRP mAb (acute: -$358 vs -$80, P < 0.001; preventive: -$298 vs $1,376, P < 0.001) and GMB cohorts (acute: -$280 vs -$36, P = 0.034; preventive: -$374 vs $1,537, P < 0.001) compared with the SOC cohort. CONCLUSIONS: Although treatment with CGRP mAbs and GMB increase total costs, they may lead to significantly greater cost savings in outpatient acute and preventive migraine medication costs vs SOC. Further studies assessing indirect health care costs are important to understand additional cost savings with CGRP mAbs. DISCLOSURES: Drs Varnado, Ye, and Schuh are employees and stockholders of Eli Lilly and Company. Dr Wenzel is a former employee of Eli Lilly and Company. Dr Manjelievskaia is an employee of IBM Watson Health. Ms Perry is a former employee of IBM Watson Health. This study was sponsored by Eli Lilly and Company. IBM Watson Health received funding for this study from Eli Lilly and Company. Independent analyses were conducted by IBM Watson Health. Eli Lilly and Company and IBM Watson Health collaborated on designing the study and interpreting results.

Patient characteristics and treatment utilization among patients with migraine initiating self-injectable calcitonin gene-related peptide monoclonal antibody and novel acute medication.

OBJECTIVE: This study describes patient characteristics and utilization of recently approved novel acute medication and calcitonin gene-related peptide (CGRP) monoclonal antibodies. METHODS: This retrospective observational study utilized the IBM MarketScan Research Database and Optum's Clinformatics Data Mart from May 2017 through December 2020 (index period). Adult patients initiating self-injectable CGRP monoclonal antibodies (mAbs) (erenumab, fremanezumab, galcanezumab) and novel acute migraine medications (lasmiditan, rimegepant, ubrogepant) with: (a) ≥3 months overlap between the index medication and second medication initiated along with it; (b) ≥1 claim for migraine diagnosis; and (c) continuous medical and pharmacy benefits 12 months pre- and 3 months post-index were included. Data are presented descriptively. RESULTS: A total of 2840 patients from the MarketScan database and 657 patients from the Optum database were included. Identified patients' (MarketScan/Optum) mean age was 44.7/51.2 years; they were mostly women (88.8%/87.7%); a majority had a chronic migraine diagnosis (64.4%/71.4%) and were prescribed both preventive and acute treatments for migraine in the pre-index period. Most patients received a combination of both preventive and acute medications binding CGRP receptors (43.6%/59.0%) or preventive medication binding CGRP ligands and acute medication binding CGRP receptors (51.9%/34.9%). Mean (SD) number of days of concomitant use of CGRP and novel acute medications were: MarketScan, 29.1 (18.7); Optum, 31.8 (20.4). Prescribing patterns were similar across healthcare provider types within each database. CONCLUSIONS: Understanding patient characteristics and treatment utilization patterns among patients prescribed both a CGRP mAb and novel acute medication may provide valuable insight regarding migraine treatment selection for healthcare decision makers.

Annual indirect cost savings in patients with episodic or chronic migraine: post-hoc analyses from multiple galcanezumab clinical trials.

AIM: This post-hoc analysis estimated annual indirect cost savings with galcanezumab (GMB) treatment in patients with episodic migraine (EM) or chronic migraine (CM). METHODS: Data from 4 randomized, Phase 3, double-blind (DB), placebo (PBO)-controlled studies of GMB were analyzed: EVOLVE-1 and EVOLVE-2 (EM, 6-months DB), REGAIN (CM, 3-months DB), and CONQUER (previous failure of 2-4 migraine preventive medication categories, 3-months DB). Indirect costs were calculated at baseline and Month 3 using the first 2 items in Migraine Disability Assessment (MIDAS): (A + B)/60*country specific annual wage (A = days of missed work/school; B = days of reduced productivity at work/school; assuming 60 working days in 3 months). All costs were annualized and expressed in international dollars (Int$) in 2018. ANCOVA models estimated the indirect cost savings as a change from baseline. Secondary analyses determined cost savings by employment and responder status. RESULTS: Patients (>80% females) from EVOLVE-1 and -2 (n = 1,201; mean age 41.9 years), REGAIN (n = 759; mean age 41.3 years), and CONQUER (n = 453; mean age ∼46.0 years) were analyzed. GMB showed significant indirect cost savings for EM (Int$6256, p < .0001) and CM (Int$7129, p = .0002), with substantial savings for patients with previous failure of 2-4 migraine preventive medication categories (EM: Int$5664, p = .0030; CM: Int$5181, p = .1300). Compared with PBO, GMB showed significantly greater indirect cost savings for EM (p = .0156) and patients with previous failure of 2-4 migraine preventive medication categories (p = .0340). Employed patients with CM (p = .0018) and with previous failure of 2-4 migraine preventive medication categories (p < .0001) had significant cost savings after GMB treatment. GMB showed significant indirect cost savings in patients with a reduction in migraine headache days. CONCLUSION: GMB treatment resulted in annual indirect cost savings in patients with EM, CM, and with previous failure of 2-4 migraine preventive medication categories, with similar observations in the sensitivity analyses.

Treatment Patterns for Calcitonin Gene-Related Peptide Monoclonal Antibodies Including Galcanezumab versus Conventional Preventive Treatments for Migraine: A Retrospective US Claims Study.

Background: Most conventional, oral, preventive treatments for migraine are non-specific and ~50% of patients discontinue them within six months. In 2018, the Food and Drug Administration approved three preventive migraine treatments: monoclonal antibodies (mAb) targeting the calcitonin gene-related peptide (CGRP) pathway implicated in migraine; galcanezumab and fremanezumab which target CGRP ligand; and erenumab which targets CGRP receptor. Real-world treatment patterns for CGRP mAb are limited. Purpose: To compare real-world treatment patterns for CGRP mAb, specifically galcanezumab versus standard-of-care (SOC) migraine preventive treatments. Patients and methods: This retrospective, observational study included 12-month baseline and 6- and 12-month follow-up analyses using IBM® MarketScan® databases. Patients identified were aged ≥18 years with ≥1 claim (first claim=index) for CGRP mAb (erenumab, fremanezumab, or galcanezumab) or SOC preventives (eg, antiepileptics, beta-blockers, antidepressants, or onabotulinumtoxinA) as index drugs between May/01/2018 and June/30/2019. Propensity score matching was used to address confounding by observed covariates. Outcomes analyzed included proportion of days covered (PDC), persistence (≤60-day gap), and first non-index drug switch. Descriptive, chi-square (categorical), and t-test (continuous) analyses were conducted. Results: The study included 3082 (CGRP mAb versus SOC) and 421 (galcanezumab versus SOC) matched patient pairs with 12-month follow-up. Mean age across cohorts ranged 43.2-44.4 years (females: 85.7-88.6%). Compared with SOC, the CGRP mAb cohort had higher mean persistence (212.5 vs 131.9 days), adherence (PDC: 55.1% vs 35.2%), and more patients were adherent with PDC ≥80% (32.7% vs 18.7%) (all p <0.001). During 12-month follow-up, fewer patients discontinued CGRP mAb versus SOC (58.8% vs 77.6%, p <0.001). Galcanezumab versus SOC comparisons yielded similar results. In the CGRP mAb cohort, most switchers (28.3%) used galcanezumab as subsequent treatment. Largely similar results were observed for 6-month follow-up cohorts. Conclusion: Patients on CGRP mAb and specifically galcanezumab showed higher adherence and persistence than patients on SOC migraine preventive treatments.

Practical recommendations on double score matching for estimating causal effects.

Unlike in randomized clinical trials (RCTs), confounding control is critical for estimating the causal effects from observational studies due to the lack of treatment randomization. Under the unconfoundedness assumption, matching methods are popular because they can be used to emulate an RCT that is hidden in the observational study. To ensure the key assumption hold, the effort is often made to collect a large number of possible confounders, rendering dimension reduction imperative in matching. Three matching schemes based on the propensity score (PSM), prognostic score (PGM), and double score (DSM, ie, the collection of the first two scores) have been proposed in the literature. However, a comprehensive comparison is lacking among the three matching schemes and has not made inroads into the best practices including variable selection, choice of caliper, and replacement. In this article, we explore the statistical and numerical properties of PSM, PGM, and DSM via extensive simulations. Our study supports that DSM performs favorably with, if not better than, the two single score matching in terms of bias and variance. In particular, DSM is doubly robust in the sense that the matching estimator is consistent requiring either the propensity score model or the prognostic score model is correctly specified. Variable selection on the propensity score model and matching with replacement is suggested for DSM, and we illustrate the recommendations with comprehensive simulation studies. An R package is available at https://github.com/Yunshu7/dsmatch.

Direct cost and healthcare resource utilization of patients with migraine before treatment initiation with calcitonin gene-related peptide monoclonal antibodies by the number of prior preventive migraine medication classes.

OBJECTIVE: This study compared all-cause direct cost and healthcare resource utilization (HCRU) among preventive migraine medication (PMM)-naïve patients and patients with up to 3 PMM category switches before initiating calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs). METHODS: This was a retrospective analysis of the IBM Marketscan database. Patients who initiated injectable CGRP mAbs between May 2018 and December 2019 (index period) were included in 4 groups based on the number of prior non-CGRP PMM classes used during the 24-month pre-index period: P0 = none; P1 = one; P2 = two; P3 ≥ three. All-cause direct cost and HCRU for groups were compared without adjustment and after generalized propensity score (GPS) matching. RESULTS: Of the 23,288 patients included (mean age ± standard deviation [SD] 45.4 ± 12.0 years), 85.6% were females, and the mean Charlson Comorbidity Index was 0.69 ± 1.2. P3 group had the highest average annual unadjusted total healthcare costs per patient ($50,274±$76,629); the highest costs attributed to procedure/imaging-related expenses ($20,105±$36,401) and pharmacy ($11,633±$29,763). P0 group had the lowest cost ($25,288±$41,427). Pairwise comparison of GPS matched costs showed significantly greater average annual direct costs per patient in the P3 group vs. P0 (p = .003), P1 (p = .014), and P2 (p = .021) groups. GPS matched HCRU also increased with the number of prior PMM classes used. Anti-epileptics (48.9%) were the most commonly used PMM class, with triptans (75.2%) being the most common acute medication class. CONCLUSIONS: Total direct healthcare cost and HCRU increased significantly with increasing use of PMM classes with the greatest cost difference existing between the P0 and the P3 groups.

Medications used for the prevention of migraine (PMM) are underused as they might cause adverse effects, intolerance, or may lack efficacy. This leads to the discontinuation of the current treatment and switching to other treatments. Calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) are a new class of drugs for the prevention of migraine. Since 2018, four CGRP mAbs have been approved for use in the prevention of migraine. It is known that patients who use more preventive migraine treatments incur greater total direct (caused by a number of medical visits or increased healthcare resource utilization, surgery, drugs, equipment, etc.) annual healthcare costs and healthcare resource utilization (HCRU) in patients with migraine. In the current study, the annual average direct cost and HCRU were compared between patients who had not used preventive medicine and patients who had used 1, 2, or ≥3 preventive medicines for migraine before starting CGRP mAbs. We observed that the healthcare costs and HCRU increased with the use of a higher number of preventive medicines for migraine. Patients who started using injectable CGRP mAbs after at least 3 preventive medicines had the highest healthcare costs and HCRU compared with other groups.

Patient-Reported Outcomes for Migraine in the US and Europe: Burden Associated with Multiple Preventive Treatment Failures.

PURPOSE: To evaluate patient-reported outcomes (PROs) among patients with migraine, including those who were preventive-naïve and preventive-treated. METHODS: This was a point-in-time, real-world study of patients with migraine in the US and EU5 (France, Germany, Spain, Italy, and UK) and their physicians using data from the Adelphi Migraine Disease Specific Programme (DSP™). Physicians completed patient record forms (PRFs) for the next nine consulting patients with migraine plus a tenth patient, who did not need to be consecutive, for whom prior preventive migraine treatments had failed at least once, in order to achieve oversampling of such patients. Patients were given self-completion (PSC) forms that included the Migraine-Specific Quality of Life Questionnaire v2.1 (MSQ), Migraine Disability Assessment Scale (MIDAS), and Work Productivity and Activity Impairment (WPAI) questionnaire. Populations of interest included preventive-naïve and preventive-treated patients defined by the number of treatment lines (1-2 or 3+ preventive regimens). Continuous variables were compared using t-test or ANOVA if normally distributed and Mann-Whitney if not. Chi-squared was used for categorical variables. RESULTS: During August-December 2017, 615 physicians (359 PCPs, 256 neurologists) completed PRFs for 5785 patients (71% female; mean age 40 (±14) years; 65% in full- or part-time employment). Of these, 2798 completed a PSC (preventive-naïve/1-2/3+ preventive lines, n=1707/1034/57). Preventive-treated patients had a greater patient-reported burden across multiple measures versus preventive-naïve patients. Preventive-treated patients had lower MSQ scores indicating greater functional impairment, higher MIDAS scores indicating greater migraine-associated disability, and higher WPAI scores indicating greater overall work and activity impairment than preventive-naïve patients. The magnitude of difference was greatest for the 3+ preventive-treatments cohort. Patterns were similar in the US and EU5. CONCLUSION: Among patients with migraine who are preventive-treated, including those with multiple lines of therapy, there remain considerable unmet needs in terms of restoring patient function.

Antibiotic Use Among Hospitalized Children and Neonates in China: Results From Quarterly Point Prevalence Surveys in 2019.

Background: Antimicrobial resistance is a significant clinical problem in pediatric practice in China. Surveillance of antibiotic use is one of the cornerstones to assess the quality of antibiotic use and plan and assess the impact of antibiotic stewardship interventions. Methods: We carried out quarterly point prevalence surveys referring to WHO Methodology of Point Prevalence Survey in 16 Chinese general and children's hospitals in 2019 to assess antibiotic use in pediatric inpatients based on the WHO AWaRe metrics and to detect potential problem areas. Data were retrieved via the hospital information systems on the second Monday of March, June, September and December. Antibiotic prescribing patterns were analyzed across and within diagnostic conditions and ward types according to WHO AWaRe metrics and Anatomical Therapeutic Chemical (ATC) Classification. Results: A total of 22,327 hospitalized children were sampled, of which 14,757 (66.1%) were prescribed ≥1 antibiotic. Among the 3,936 sampled neonates (≤1 month), 59.2% (n = 2,331) were prescribed ≥1 antibiotic. A high percentage of combination antibiotic therapy was observed in PICUs (78.5%), pediatric medical wards (68.1%) and surgical wards (65.2%). For hospitalized children prescribed ≥1 antibiotic, the most common diagnosis on admission were lower respiratory tract infections (43.2%, n = 6,379). WHO Watch group antibiotics accounted for 70.4% of prescriptions (n = 12,915). The most prescribed antibiotic ATC classes were third-generation cephalosporins (41.9%, n = 7,679), followed by penicillins/ß-lactamase inhibitors (16.1%, n = 2,962), macrolides (12.1%, n = 2,214) and carbapenems (7.7%, n = 1,331). Conclusion: Based on these data, overuse of broad-spectrum Watch group antibiotics is common in Chinese pediatric inpatients. Specific interventions in the context of the national antimicrobial stewardship framework should aim to reduce the use of Watch antibiotics and routine surveillance of antibiotic use using WHO AWaRe metrics should be implemented.

Microbial community associated with ectomycorrhizal Russula symbiosis and dominated nature areas in southern China.

Russula griseocarnosa is one of the uncultivable important mycorrhizal edible fungi. Currently, there is a limited insight into the dynamic composition of the microbial communities associated with Russula. Here, the microbiota in the root and mycorrhizosphere from Russula-Fagaceae nature areas of Fujian province were identified by Illumina MiSeq high-throughput sequencing. First, we compared three types of fungal communities associated with Russula-Fagaceae root mycelia-running stage (stage-1), Russula sporocarping stage-2 (stage-2) and Russula-free Fagaceae root (stage-3). Fungal diversity negatively correlated with Russula. Russula, Tomentella and Lactarius were core EcM in Fagaceae roots. A total of eight genera, including Boletus, are likely a positive indicator of Russula sporocarp production in Russula-Fagaceae roots, while Tomentella and Elaphomyces for Russula symbiosis. Secondly, analysis of fungal and bacterial communities within rhizosphere soils from the three stages revealed six genera, including Dacryobolus and Acidocella, as possible indicator species associated with sporocarping in Russula. Elaphomyces, Tomentella, Sorangium, Acidicaldus, Acidobacterium and Haliangium occurred more frequently in the Russula rhizosphere. Furthermore, operational taxonomic unit (OTU) network analysis showed a positive correlation between Russula,Tomentella, Elaphomyces and Sorangium. Overall, our results revealed a relationship between micro-community and Russula, which may provide a new strategy for improving Russula symbiosis and sporocarp production.