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.

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.

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.

Pediatric Antibiotic Prescribing in China According to the 2019 World Health Organization Access, Watch, and Reserve (AWaRe) Antibiotic Categories.

OBJECTIVES: To assess clinical indication-specific antibiotic prescribing in pediatric practice in China based on the World Health Organization (WHO) Access, Watch, and Reserve (AWaRe) metrics and to detect potential problem areas. STUDY DESIGN: Pediatric prescription records on the 16th of each month during 2018 were sampled for all encounters at outpatient and emergency departments of 16 tertiary care hospitals via hospital information systems. Antibiotic prescribing patterns were analyzed across and within diagnostic conditions according to WHO AWaRe metrics and Anatomical Therapeutic Chemical (ATC) classification. RESULTS: A total of 260 001 pediatric encounters were assessed, and antibiotics were prescribed in 94 453 (36.3%). In 35 167 encounters (37.2%), at least 1 intravenous antibiotic was administered. WHO Watch group antibiotics accounted for 82.2% (n = 84 176) of all antibiotic therapies. Azithromycin (n = 15 791; 15.4%) was the most commonly prescribed antibiotic, and third-generation cephalosporins (n = 44 387; 43.3%) were the most commonly prescribed antibiotic class. In at least 66 098 encounters (70.0%), antibiotics were prescribed for respiratory tract conditions, mainly for bronchitis/bronchiolitis (n = 25 815; 27.3%), upper respiratory tract infection (n = 25 184; 26.7%), and pneumonia (n = 13 392; 14.2%). CONCLUSIONS: Overuse and misuse of WHO Watch group antibiotics for respiratory tract conditions and viral infectious diseases is common in pediatric outpatients in China. Pediatric antimicrobial stewardship should be strengthened using WHO AWaRe metrics.

Factors associated with insufficient response to acute treatment of migraine in Japan: analysis of real-world data from the Adelphi Migraine Disease Specific Programme.

BACKGROUND: Real-world data on sufficient/insufficient response, and predictors of insufficient response, to acute treatments for migraine are limited in Japan. This study aimed to identify factors associated with insufficient response to acute treatment of migraine by exploring significant differences between people with migraine who sufficiently/insufficiently respond to prescribed acute treatment in Japan. METHODS: This was a retrospective analysis of 2014 Adelphi Migraine Disease Specific Programme cross-sectional survey data collected from physicians and their consulting adult patients with migraine in Japan. Insufficient responders to prescribed acute treatment were patients who achieved headache pain freedom within 2 h of acute treatment in no more than three of their last five migraine attacks. Factors associated with insufficient response to prescribed acute migraine treatment were identified using backward logistic regression. RESULTS: Overall, 227/538 (42.2%) patients were classified as insufficient responders to prescribed acute migraine treatment. Significantly more insufficient responders than sufficient responders had consulted a neurologist or a migraine/headache specialist, and had chronic migraine or medication-overuse or tension-type headaches (p < 0.05). More insufficient responders than sufficient responders reported taking acute treatment when/after the pain started (77.0 vs. 68.9%) than at first sign of migraine (p < 0.05). Compared with sufficient responders, insufficient responders reported a significantly higher mean ± standard deviation (SD) Migraine Disability Assessment total score (12.7 ± 23.3 vs. 5.8 ± 10.4, p < 0.001) and lower quality of life (EuroQol-5 Dimensions utility score 0.847 ± 0.19 vs. 0.883 ± 0.16, p = 0.024). Factors significantly associated with insufficient response to acute treatment included seeing a neurologist versus an internist (odds ratio [OR] 1.93; 95% confidence interval [CI] 1.29-2.88; p = 0.002), taking acute medication when/after pain started versus at first sign of migraine (OR 1.65; 95% CI 1.05-2.60; p = 0.030), a higher MIDAS total score (OR 1.04; 95% CI 1.02-1.06; p < 0.001), and presence of comorbid cardiovascular disease (OR 0.53; 95% CI 0.28-0.98; p = 0.044). CONCLUSIONS: Many people with migraine in Japan struggle to adequately treat migraine attacks with prescribed acute medication and exhibit high levels of unmet need for acute treatment. Optimized management strategies utilizing existing therapeutic options as well as additional effective therapeutic options for migraine are required to improve symptoms and quality of life.

A Real-World Analysis of Patient Characteristics, Treatment Patterns, and Level of Impairment in Patients With Migraine Who are Insufficient Responders vs Responders to Acute Treatment.

OBJECTIVE: The objective of this study was to examine if patients with migraine who responded sufficiently to acute treatment were significantly different from those who did not in terms of patient characteristics, treatment patterns, and patient level of impairment, and to identify characteristics associated with insufficient response. BACKGROUND: Migraine is highly prevalent and impacts functional ability substantially. Current treatment approaches are not sufficiently meeting the needs of patients, and inadequate response to acute treatment is reported by at least 56% of patients with migraine in the United States. METHODS: Data were obtained from the 2014 Adelphi Migraine Disease-Specific Program, a cross-sectional survey. Using logistic regression, we assessed the association between patient factors and insufficient response. Responders were defined as patients with migraine who achieved pain freedom within 2 hours of acute treatment in ≥4 of 5 attacks, while insufficient responders achieved it in ≤3 of 5 attacks. RESULTS: Of 583 patients included, insufficient responders to acute treatment constituted 34.3% (200/583) of the study population. A statistically significantly larger proportion of insufficient responders vs responders had ≥4 migraine headache days/month (46.3% [88/190] vs 31% [114/368]), had ever been prescribed ≥3 unique preventive treatment regimens (11.7% [21/179] vs 6.3% [22/347]), and had chronic migraine, medication-overuse headaches, and comorbid depression (all P values ≤.05). Patient level of impairment was statistically significantly greater among insufficient responders vs responders. Factors associated with insufficient response after adjusting for covariates included Migraine Disability Assessment total score (odds ratio [OR] = 1.04, 95% CI [1.02, 1.05]), time of administration of acute treatment (OR = 1.83, 95% CI [1.15, 2.92]), depression (OR = 1.98, 95% CI [1.21, 3.23]), sensitivity to light not listed as current most troublesome symptom (OR = 2.30, 95% CI [1.21, 4.37]), and change in the average headache days per month before being prescribed an acute treatment vs now (OR = 1.75, 95% CI [1.05, 2.90]). CONCLUSIONS: Clinical characteristics, treatment patterns, and health-related quality of life measures are statistically significantly different between insufficient responders and responders to acute treatment in patients with migraine.

A global real-world assessment of the impact on health-related quality of life and work productivity of migraine in patients with insufficient versus good response to triptan medication.

BACKGROUND: Migraine is a chronic, disabling neurological disease characterized by moderate-to-severe headache pain with other symptoms, including nausea, vomiting, and photophobia. Triptans, while generally effective, are insufficiently efficacious in 30-40% of patients and poorly tolerated by or contraindicated in others. We assessed the impact of insufficient response to triptans on health-related quality of life (HRQoL) and work productivity in patients currently receiving any prescribed triptan formulation as their only acute migraine medication. METHODS: Data were from the 2017 Adelphi Migraine Disease Specific Programme, a cross-sectional survey of primary care physicians, neurologists, and headache specialists and their consulting patients with migraine in the USA, France, Germany, Italy, Spain, and UK. Triptan insufficient responders (TIRs) achieved freedom from headache pain within 2 h of acute treatment in ≤3/5 migraine attacks; triptan responders (TRs) achieved pain freedom within 2 h in ≥4/5 attacks. Multivariable general linear model examined differences between TIRs and TRs in HRQoL and work productivity. Logistic regression identified factors associated with insufficient response to triptans. RESULTS: The study included 1413 triptan-treated patients (TIRs: n = 483, 34.2%; TRs: n = 930, 65.8%). TIRs were more likely to be female (76% vs. 70% for TIRs vs TRs, respectively; p = 0.011), older (mean age 42.6 vs. 40.5 years; p = 0.003), and had more headache days/month (7.0 vs. 4.4; p < 0.001). TIRs had significantly more disability, with higher Migraine Disability Scores (MIDAS; 13.2 vs. 7.7; p < 0.001), lower Migraine-specific Quality of Life scores, indicating greater impact (Role Function Restrictive: 62.4 vs. 74.5; Role Function Preventive: 70.0 vs. 82.2; Emotional Function: 67.7 vs. 82.1; all p < 0.001), and lower EQ5D utility scores (0.84 vs. 0.91; p = 0.001). Work productivity and activity were impaired (absenteeism, 8.6% vs. 5.1% for TIRs vs. TRs; presenteeism, 34.3% vs. 21.0%; work impairment, 37.1% vs. 23.3%; overall activity impairment, 39.8% vs. 25.3%; all p < 0.05). CONCLUSION: HRQoL and work productivity were significantly impacted in TIRs versus TRs in this real-world analysis of patients with migraine acutely treated with triptans, highlighting the need for more effective treatments for patients with an insufficient triptan response. Further research is needed to establish causal relationships between insufficient response and these outcomes.

[Research of Methods to Reduce Alarm Fatigue of Monitoring System].

OBJECTIVE: In order to solve alarm fatigue, the algorithm optimization strategies were researched to reduce false and worthless alarms. METHODS: A four-lead arrhythmia analysis algorithm, a multiparameter fusion analysis algorithm, an intelligent threshold reminder, a refractory period delay technique were proposed and tested with collected 28 679 alarms in multi-center study. RESULTS: The sampling survey indicate that the 80.8% of arrhythmia false alarms were reduced by the four-lead analysis, the 55.9% of arrhythmia and pulse false alarms were reduced by the multi-parameter fusion analysis, the 28.0% and 29.8% of clinical worthless alarms were reduced by the intelligent threshold and refractory period delay techniques respectively. Finally, the total quantity of alarms decreased to 12 724. CONCLUSIONS: To increase the dimensionality of parametric analysis and control the alarm limits and delay time are conducive to reduce alarm fatigue in intensive care units.

Difference Analysis of Gas Molecules Diffusion Behavior in Natural Ester and Mineral Oil Based on Molecular Dynamic Simulation.

Natural ester, as a new environmentally green insulating oil, has been widely used in transformer. In an oil-immersed transformer, the normal aging, thermal failure, and discharge failure could easily lead to the decomposition of the oil-paper insulation system and produce different kinds of gases. Studying gas dissolution in natural ester and mineral oil could provide assistance in applying criteria to make a diagnosis of different kinds of faults in the transformer. In this paper, the molecular dynamics method was used to investigate the diffusion behavior of seven fault characteristic gases (including H2, CO, CH4, C2H2, CO2, C2H4, C2H6) in natural ester and mineral oil. The simulation parameters of free volume, interaction energy, mean square displacement, and diffusion coefficient were compared between the natural ester and mineral oil. Meanwhile, the influence of temperature on the diffusion of gas molecules in two kinds of oils was also analyzed. Results showed that the free volume, the interaction energy, and the relative molecular mass of gas molecules were the factors influenced by the diffusion of gas molecules in natural ester and mineral oil. The order of the diffusion coefficients of gas molecules in natural ester was as follows: H2 > CH4 > CO > C2H2 > C2H4 > CO2 > C2H6 and that in mineral oil was as follows: H2 > CH4 > CO> C2H2 > C2 H4 > C2H6 > CO2. By comparing the diffusion behavior of gas molecules in natural ester and mineral oil, it was found that the smaller free volume and higher interaction energy of gas molecules in natural ester were the major reasons for the gas molecules to be more difficult to diffuse in natural ester. The rising temperature could enhance the free volume and reduce the interaction energy between gas molecules and oil. The diffusion coefficient of gas molecules increased exponentially with the follow of temperature. However, the temperature didn't affect the ordering of diffusion coefficient, free volume, and interaction energy of gas molecules in natural ester and mineral oil.

Real-world treatment patterns and patient-reported outcomes in episodic and chronic migraine in Japan: analysis of data from the Adelphi migraine disease specific programme.

BACKGROUND: In Japan, detailed information on the characteristics, disease burden, and treatment patterns of people living with migraine is limited. The aim of this study was to compare clinical characteristics, disease burden, and treatment patterns in people with episodic migraine (EM) or chronic migraine (CM) using real-world data from clinical practice in Japan. METHODS: This was an analysis of data collected in 2014 by the Adelphi Migraine Disease Specific Programme, a cross-sectional survey of physicians and their consulting adult patients in Japan, using physician and patient questionnaires. We report patient demographics, prescribed treatment, work productivity, and quality-of-life data for people with CM (≥15 headache days/month) or EM (not fulfilling CM criteria). In descriptive analyses, continuous and categorical measures were assessed using t-tests and Chi-squared tests, respectively. RESULTS: Physicians provided data for 977 patients (mean age 44.5 years; 77.2% female; 94.5% with EM, 5.5% with CM). A total of 634/977 (64.9%) invited patients (600 with EM; 34 with CM) also provided data. Acute therapy was currently being prescribed in 93.7% and 100% of patients with EM and CM, respectively (p = 0.069); corresponding percentages for current preventive therapy prescriptions were 40.5% and 68.5% (p < 0.001). According to physicians who provided data, preventive therapy was used at least once by significantly fewer patients with EM than with CM (42.3% vs. 68.5%, respectively; p < 0.001). Among patients who provided physicians with information on issues with their current therapy (acute therapy: n = 668 with EM, n = 38 with CM; preventive therapy: n = 295 with EM, n = 21 with CM), lack of efficacy was the most frequently identified problem (acute therapy: EM 35.3%, CM 39.5% [p = 0.833]; preventive therapy: EM 35.3%, CM 52.4% [p = 0.131]). Moderate-to-severe headache-related disability (Migraine Disability Assessment total score ≥ 11) was reported by significantly fewer patients with EM than with CM (21.0% vs. 60.0%, respectively; p < 0.001) among patients who provided data. CONCLUSIONS: Preventive treatment patterns in people with EM versus CM differ in Japan, with both types of migraine posing notable disease burdens. Our findings demonstrate that more effective migraine therapies are required to reduce the burden of the disease.

Assessing the economic burden of Alzheimer's disease patients first diagnosed by specialists.

BACKGROUND: It is not known if there is a differential impact on Alzheimer's disease (AD) diagnosis and outcomes if/when patients are diagnosed with cognitive decline by specialists versus non-specialists. This study examined the cost trajectories of Medicare beneficiaries initially diagnosed by specialists compared to similar patients who received their diagnosis in primary care settings. METHODS: Patients with ≥2 claims for AD were selected from de-identified administrative claims data for US Medicare beneficiaries (5 % random sample). The earliest observed diagnosis of cognitive decline served as the index date. Patients were required to have continuous Medicare coverage for ≥12 months pre-index (baseline) and ≥12 months following the first AD diagnosis, allowing for up to 3 years from index to AD diagnosis. Time from index date to AD diagnosis was compared between those diagnosed by specialists (i.e., neurologist, psychiatrist, or geriatrician) versus non-specialists using Kaplan-Meier analyses with log-rank tests. Patient demographics, Charlson Comorbidity Index (CCI) during baseline, and annual all-cause medical costs (reimbursed by Medicare) in baseline and follow-up periods were compared across propensity-score matched cohorts. RESULTS: Patients first diagnosed with cognitive decline by specialists (n = 2593) were younger (78.8 versus 80.8 years old), more likely to be male (40 % versus 34 %), and had higher CCI scores and higher medical costs at baseline than those diagnosed by non-specialists (n = 13,961). However, patients diagnosed by specialists had a significantly shorter time to AD diagnosis, both before and after matching (mean [after matching]: 3.5 versus 4.6 months, p < 0.0001). In addition, patients diagnosed by specialists had significantly lower average total all-cause medical costs in the first 12 months after their index date, a finding that persisted after matching ($19,824 versus $25,863, p < 0.0001). Total per-patient annual medical costs were similar for the two groups starting in the second year post-index. CONCLUSIONS: Before and after matching, patients diagnosed by a specialist had a shorter time to AD diagnosis and incurred lower costs in the year following the initial cognitive decline diagnosis. Differences in costs converged during subsequent years. This suggests that seeking care from specialists may yield more timely diagnosis, appropriate care and reduced costs among those with cognitive decline.

Fracture risk and healthcare resource utilization and costs among osteoporosis patients with type 2 diabetes mellitus and without diabetes mellitus in Japan: retrospective analysis of a hospital claims database.

BACKGROUND: Osteoporosis, osteoporosis-related fractures, and diabetes are considerable health burdens in Japan. Diabetes in patients with osteoporosis has been reported to be associated with increased fracture risk. This retrospective analysis of a Japanese hospital claims database investigated the real-world effect of type 2 diabetes mellitus (T2DM) on the incidence of clinical fractures, costs, and healthcare resource utilization in patients with osteoporosis and a subgroup of patients prescribed raloxifene. METHODS: Women aged ≥50 years diagnosed with osteoporosis who had a first prescription claim for osteoporosis treatment with a pre-index period ≥12 months and a post-index period of 30 months were selected from a database extract (April 2008-July 2013). Patients prescribed raloxifene were classed as a subgroup. Patients diagnosed with T2DM constituted the T2DM group; all other patients (excluding patients with type 1 diabetes mellitus) constituted the non-diabetes mellitus (non-DM) group. Groups were matched by exact matching, using selected baseline characteristics. Patient demographic and clinical characteristics were compared using chi-squared tests, t-tests, or Wilcoxon rank sum tests. Time to first fracture was examined using Kaplan-Meier survival analysis. RESULTS: Overall, the T2DM and non-DM groups had 7580 and 7979 patients, respectively; following matching, there were 3273 patients per group. In the raloxifene subgroup, the T2DM and non-DM groups had 668 and 699 patients, respectively; following matching, there were 239 patients per group. At baseline, the T2DM group (overall and raloxifene subgroup) had significantly higher healthcare resource utilization and comorbidities. During the post-index period, a similar pattern was observed in the overall group, even after matching; the T2DM group also had a higher incidence of fracture. In the raloxifene subgroup, after matching, there were no significant differences in fracture incidence or costs and fewer differences in healthcare resource utilization between the T2DM and non-DM groups. CONCLUSIONS: These findings suggest that comorbid T2DM increases fracture incidence in patients with osteoporosis, compared with patients without DM. Increases in fracture incidence were accompanied by greater costs and healthcare resource utilization, which are important considerations for clinical practice in Japan. Further research investigating the use of raloxifene for treatment of osteoporosis with comorbid T2DM may also be warranted.

Health care resource utilization and direct medical costs for patients with schizophrenia initiating treatment with atypical versus typical antipsychotics in Tianjin, China.

BACKGROUND: It is uncertain whether the extra acquisition costs of atypical antipsychotics over typical antipsychotics are offset by their other reduced resource use especially in hospital services in China. This study compared the psychiatric-related health care resource utilization and direct medical costs for patients with schizophrenia initiating atypical or typical antipsychotics in Tianjin, China. METHODS: Data were obtained from the Tianjin Urban Employee Basic Medical Insurance database (2008-2010). Adult patients with schizophrenia with ≥1 prescription for antipsychotics after ≥90-day washout and 12-month continuous enrollment after first prescription was included. Psychiatric-related resource utilization and direct medical costs of the atypical and typical cohorts were estimated during the 12-month follow-up period. Logistic regressions, ordinary least square (OLS), and generalized linear models (GLM) were employed to estimate differences of resource utilization and costs between the two cohorts. One-to-one propensity score matching was conducted as a sensitivity analysis. RESULTS: 1131 patients initiating either atypical (N = 648) or typical antipsychotics (N = 483) were identified. Compared with the typical cohort, the atypical cohort had a lower likelihood of hospitalization (45.8% vs. 56.7%, P < 0.001; adjusted OR: 0.58, P < 0.001) over the follow-up period. Medication costs for the atypical cohort were higher than the typical cohort ($438 vs. $187, P < 0.001); however, their non-medication medical costs were significantly lower ($1223 vs. $1704, P < 0.001). The total direct medical costs were similar between the atypical and typical cohorts before ($1661 vs. $1892, P = 0.100) and after matching ($1711 vs. 1868, P = 0.341), consistent with the results from OLS and GLM models for matched cohorts. CONCLUSIONS: The atypical cohort had similar total direct medical costs compared to the typical cohort. Higher medication costs associated with atypical antipsychotics were offset by a reduction in non-medication medical costs, driven by fewer hospitalizations.

Putative RhoGAP proteins orchestrate vegetative growth, conidiogenesis and pathogenicity of the rice blast fungus Magnaporthe oryzae.

Rho GTPases, acting as molecular switches, are involved in the regulation of diverse cellular functions. Rho GTPase activating proteins (Rho GAPs) function as negative regulators of Rho GTPases and are required for a variety of signaling processes in cell development. But the mechanisms underlying Rho GAPs in Rho-mediated signaling pathways in fungi are still elusive. There are eight RhoGAP domain-containing genes annotated in the Magnaporthe oryzae genome. To understand the function of these RhoGAP genes, we generated knockout mutants of each of the RhoGAP genes through a homologous recombination-based method. Phenotypic analysis showed that growth rate of aerial hyphae of the Molrg1 deletion mutant decreased dramatically. The ΔMolrg1 mutant showed significantly reduced conidiation and appressorium formation by germ tubes. Moreover, it lost pathogenicity completely. Deletion of another Rho GAP (MoRga1) resulted in high percentage of larger or gherkin-shaped conidia and slight decrease in conidiation. Appressorial formation of the ΔMoRga1 mutant was delayed significantly on hydrophobic surface, while the development of mycelial growth and pathogenicity in plants was not affected. Confocal fluorescence microscopy imaging showed that MoRga1-GFP localizes to septal pore of the conidium, and this localization pattern requires both LIM and RhoGAP domains. Furthermore, either deleting the LIM or RhoGAP domain or introducing an inactivating R1032A mutation in the RhoGAP domain of MoRga1 caused similar defects as the Morga1 deletion mutant in terms of conidial morphology and appressorial formation, suggesting that MoRga1 is a stage-specific regulator of conidial differentiation by regulating some specific Rho GTPases. In this regard, MoRga1 and MoLrg1 physically interacted with both MoRac1-CA and MoCdc42-CA in the yeast two-hybrid and pull-down assays, suggesting that the actions of these two GAPs are involved in MoRac1 and MoCdc42 pathways. On the other hand, six other putative Rho GAPs (MoRga2 to MoRga7) were dispensable for conidiation, vegetative growth, appressorial formation and pathogenicity, suggesting that these Rho GAPs function redundantly during fungal development. Taking together, Rho GAP genes play important roles in M. oryzae development and infectious processes through coordination and modulation of Rho GTPases.

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.

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.

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.

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.

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.

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.