[Mechanism of Qiwei Guibao Granules in treatment of premature ovarian failure based on metabolomics].

In this study, a mouse model of premature ovarian failure(POF) was constructed by injecting D-galactose(200 mg·kg~(-1)) into the back of the neck for 6 weeks. The mice were randomly divided into a normal group(group N), a model group(group M), and a Qiwei Guibao Granules group(group A, 12.87 g·kg~(-1)). Starting from the 11th day of modeling, group A was treated with Qiwei Guibao Granules by gavage for 32 days, while group M and group N were given equal volume of saline. Metabolomics analysis was used to explore the mechanism of action of Qiwei Guibao Granules in the treatment of POF. The results showed that compared with group N, the group M exhibited decreased wet weight of bilateral ovaries, increased levels of LH and FSH in serum, and significantly decreased levels of E_2 and PROG. After treatment with Qiwei Guibao Granules, compared with the group M, the group A showed a significant increase in the wet weight of bilateral ovaries, a significant decrease in the levels of FSH and LH in serum, and a significant increase in the level of E_2. Metabolomics analysis revealed 55 differential metabolites identified between group N and group M(14 upregulated and 41 downregulated compared with group N) and 82 differential metabolites identified between group M and group A(56 upregulated and 26 downregulated compared with group M), with 5 metabolites showing consistent changes between the group N vs group M. After excluding these 5 metabolites, 77 metabolites that changed after intervention with Qiwei Guibao Granules were focused on. These mainly involved histidine metabolism, glycine, serine, and threonine metabolism, and glycerophospholipid metabolism. Among them, carnosine, 1-methyl-L-histidine, imidazoleacetic acid, choline, L-threonine, beta-hydroxypyruvic acid, phosphatidylcholine, and glycerol-3-phosphate were the major differential metabolites in these three metabolic pathways. Therefore, Qiwei Guibao Granules may exert therapeutic effects on POF mice by regulating amino acid metabolism and lipid metabolism in the mouse body.

The combined effect of triglyceride-glucose index and high-sensitivity C-reactive protein on cardiovascular outcomes in patients with chronic coronary syndrome: A multicenter cohort study.

BACKGROUND: The triglyceride-glucose (TyG) index and high-sensitivity C-reactive protein (hsCRP) are the commonly used biomarkers for insulin resistance and systemic inflammation, respectively. We aimed to investigate the combined association of TyG and hsCRP with the major adverse cardiovascular events (MACE) in patients with chronic coronary syndrome (CCS). METHODS: A total of 9421 patients with CCS were included in this study. The primary endpoint was defined as a composite of MACE covering all-cause death, nonfatal myocardial infarction, and revascularization. RESULTS: During the 2-year follow-up period, 660 (7.0%) cases of MACE were recorded. Participants were divided equally into three groups according to TyG levels. Compared with the TyG T1 group, the risk of MACE was significantly higher in the TyG T3 group. It is noteworthy that among patients in the highest tertile of TyG, hsCRP >3 mg/L was significantly associated with an increased risk of MACE, whereas the results were not significant in the medium to low TyG groups. When patients were divided into six groups according to hsCRP and TyG, the Cox regression analysis showed that patients in the TyG T3 and hsCRP >3 mg/L group had a significantly higher risk of MACE than those in the TyG T1 and hsCRP ≤3 mg/L group. However, no significant interaction was found between TyG and hsCRP on the risk of MACE. CONCLUSION: Our study suggests that the concurrent assessment of TyG and hsCRP may be valuable in identifying high-risk populations and guiding management strategies among CCS patients.

Sequential severe immune-related adverse events induced by PD-1 inhibitor: a case report and literature review.

In a variety of cancers, immune checkpoint inhibitors (ICIs) have demonstrated substantial survival advantages. Nevertheless, the widespread use of ICIs in the clinic has resulted in a growing interest in immune-related adverse events (irAEs) and their treatment methods. This paper reports a case in which a patient with three sequential severe irAEs was successfully treated. After undergoing two regimens of sintilimab in conjunction with chemotherapy for advanced lung cancer, the patient developed myocarditis combined with hepatitis. Subsequently, the patient developed pneumonia following remission from treatment. We also discuss the mechanism of irAEs, principles of treatment, and progress in the study of biomarkers for early prediction of irAEs by reviewing the literature.

Association between reproductive lifespan and multimorbidity among Chinese postmenopausal women.

OBJECTIVE: Although menopause is considered a risk factor for multimorbidity, few studies have explored the association between reproductive lifespan and multimorbidity. This study aimed to explore the association between reproductive lifespan and multimorbidity in postmenopausal Chinese women. METHODS: This cross-sectional study selected postmenopausal women as study participants. The reproductive lifespan refers to the interval between menarche and menopause. Multimorbidity refers to having two or more self-reported chronic diseases. We used a logistic regression model to explore potential associations based on the adjustment of a set of covariates. RESULTS: In total, 1,310 postmenopausal women with an average reproductive lifespan of 34 years were included in this study. The prevalence of multimorbidity was 22.2% (291/1,310) in postmenopausal women. Our findings showed that compared with postmenopausal women with the Q1 of reproductive lifespan (≤32 reproductive years), those with Q3 (35-37 reproductive years) and Q4 (≥38 reproductive years) were less likely to have multimorbidity (ORQ3 = 0.529, 95% CIQ3 = 0.347-0.805, ORQ4 = 0.510, 95% CIQ4 = 0.308-0.842), whereas those with Q2 (33-34 reproductive years) were not (OR = 0.700, 95% CI = 0.446-1.098). This study also revealed a linear trend in the association between the reproductive lifespan and multimorbidity; that is, the longer the reproductive lifespan, the lower the risk of multimorbidity. CONCLUSIONS: In postmenopausal Chinese women, a longer reproductive lifespan was associated with a lower prevalence of multimorbidity. This study suggests that for the prevention and intervention of multimorbidity in postmenopausal women, healthcare professionals should screen and assess reproductive factors to identify high-risk individuals.

Deep ultraviolet laser at 223.8†nm with adjustable repetition rate and narrow pulse width.

We presented the first, to our knowledge, demonstration of an ultraviolet (UV) laser at 223.8 nm by six-harmonic generation of an electro-optic Q-switched cavity dumping 1342 nm Nd:YVO4 laser. It offers high power, constant short pulse duration, and adjustable pulse repetition rate. The pulse duration is independent of the pump power and repetition rate compared to classical Q-switched oscillators. The output efficiency of the UV laser is optimized by adjusting the focusing lens. With the incident pump power of 30 W, an maximum average output power of 249 mW was obtained at 13 kHz. The pulse width maintained 3.4-3.5 ns from 5 to 20 kHz. The maximum pulse energy of 28.1 µJ was obtained at 5 kHz, and the corresponding peak power was up to 8.1 kW.

Detection of atrial fibrillation using a nonlinear Lorenz Scattergram and deep learning in primary care.

BACKGROUND: Atrial fibrillation (AF) is highly correlated with heart failure, stroke and death. Screening increases AF detection and facilitates the early adoption of comprehensive intervention. Long-term wearable devices have become increasingly popular for AF screening in primary care. However, interpreting data obtained by long-term wearable ECG devices is a problem in primary care. To diagnose the disease quickly and accurately, we aimed to build AF episode detection model based on a nonlinear Lorenz scattergram (LS) and deep learning. METHODS: The MIT-BIH Normal Sinus Rhythm Database, MIT-BIH Arrhythmia Database and the Long-Term AF Database were extracted to construct the MIT-BIH Ambulatory Electrocardiograph (MIT-BIH AE) dataset. We converted the long-term ECG into a two-dimensional LSs. The LSs from MIT-BIH AE dataset was randomly divided into training and internal validation sets in a 9:1 ratio, which was used to develop and internally validated model. We built a MOBILE-SCREEN-AF (MS-AF) dataset from a single-lead wearable ECG device in primary care for external validation. Performance was quantified using a confusion matrix and standard classification metrics. RESULTS: During the evaluation of model performance based on the LS, the sensitivity, specificity and accuracy of the model in diagnosing AF were 0.992, 0.973, and 0.983 in the internal validation set respectively. In the external validation set, these metrics were 0.989, 0.956, and 0.967, respectively. Furthermore, when evaluating the model's performance based on ECG records in the MS-AF dataset, the sensitivity, specificity and accuracy of model diagnosis paroxysmal AF were 1.000, 0.870 and 0.876 respectively, and 0.927, 1.000 and 0.973 for the persistent AF. CONCLUSIONS: The model based on the nonlinear LS and deep learning has high accuracy, making it promising for AF screening in primary care. It has potential for generalization and practical application.

Intervention strategies for management of comorbid depression among individuals with hypertension: a scoping review protocol.

INTRODUCTION: Hypertension and depression often coexisted, leading to poor health outcome and significant challenges in healthcare management. Since no guidelines or consensus are available for health professionals to manage this comorbidity, identifying interventions in current literature is crucial for gaining a clear picture of evidence and informing future research directions and clinical practice. This scoping review is designed to address this gap by systematically mapping the range of potential interventions for managing comorbid hypertension and depression. METHODS AND ANALYSIS: Following the Joanna Briggs Institute guidelines for scoping review, this review will comprehensively search databases including PUBMED, Embase, PsycINFO, CINAHL, Cochrane Library Databases, Chinese Biomedical Literature Database and Chinese National Knowledge Infrastructure. Grey literature will be sourced from Google Scholar. A year limit of January 2004-December 2023 will be applied to retrieve the most current peer-reviewed articles in English and Chinese language only. Two reviewers will individually screen and the process will be documented in Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews. This review will explore a range of non-pharmacological and multicomponent interventions including psychosocial support, educational programmes, telemedicine and integrated healthcare models. Data extraction will follow the Template for Intervention Description and Replication checklist to ensure detailed and standardised reporting of intervention components. The synthesis of findings will employ both quantitative and qualitative methods to provide a comprehensive overview of the intervention landscape. ETHICS AND DISSEMINATION: This scoping review, which involves secondary data analysis of publicly available sources, does not require ethical approval. Findings will be disseminated through peer-reviewed publications and presentations at relevant conferences. STUDY REGISTRATION: Open Science Framework registry (osf.io/j7gt8) in Centre for Open Science on 29 January 2024.

Mushroom poisoning of Panaeolus subbalteatus from Ningxia, northwest China, with species identification and tryptamine detection.

Mushroom poisoning is a significant contributor to foodborne disease outbreaks in China. This study focuses on two Panaeolus subbalteatus poisoning incidents accompanied by epidemiological investigations, species identification, and toxin detection in Ningxia, northwest China. In these two poisoning incidents, some patients exhibited gastrointestinal or neurological symptoms approximately 0.5 h after ingestion of a large amount of wild mushroom. Specifically, in Case 1, one of the three patients experienced nausea, vomiting, and numbness in the throat and limbs; in Case 2, one patient reported dizziness and an abnormal sense of direction. Through morphological and phylogenetic analyses, mushroom specimens were identified as P. subbalteatus. Psilocybin and psilocin were detected in mushroom samples, and only psilocin was detected in biological samples by liquid chromatography-triple quadrupole-linear ion trap mass spectrometry screening. The average psilocybin and psilocin contents in mushroom samples were 1532.2-1760.7 and 114.5-136.0 mg/kg (n = 3), respectively. Moreover, only psilocin was detected in blood and urine samples, with average concentrations 0.5-1.2 ng/mL (n = 3) and 2.5-3.1 ng/mL (n = 3), respectively. These findings provide technical support for managing similar incidents in the future.

Efficient exact exchange using Wannier functions and other related developments in planewave-pseudopotential implementation of RT-TDDFT.

The plane-wave pseudopotential (PW-PP) formalism is widely used for the first-principles electronic structure calculation of extended periodic systems. The PW-PP approach has also been adapted for real-time time-dependent density functional theory (RT-TDDFT) to investigate time-dependent electronic dynamical phenomena. In this work, we detail recent advances in the PW-PP formalism for RT-TDDFT, particularly how maximally localized Wannier functions (MLWFs) are used to accelerate simulations using the exact exchange. We also discuss several related developments, including an anti-Hermitian correction for the time-dependent MLWFs (TD-MLWFs) when a time-dependent electric field is applied, the refinement procedure for TD-MLWFs, comparison of the velocity and length gauge approaches for applying an electric field, and elimination of long-range electrostatic interaction, as well as usage of a complex absorbing potential for modeling isolated systems when using the PW-PP formalism.

Efficient all-electron hybrid density functionals for atomistic simulations beyond 10 000 atoms.

Hybrid density functional approximations (DFAs) offer compelling accuracy for ab initio electronic-structure simulations of molecules, nanosystems, and bulk materials, addressing some deficiencies of computationally cheaper, frequently used semilocal DFAs. However, the computational bottleneck of hybrid DFAs is the evaluation of the non-local exact exchange contribution, which is the limiting factor for the application of the method for large-scale simulations. In this work, we present a drastically optimized resolution-of-identity-based real-space implementation of the exact exchange evaluation for both non-periodic and periodic boundary conditions in the all-electron code FHI-aims, targeting high-performance central processing unit (CPU) compute clusters. The introduction of several new refined message passing interface (MPI) parallelization layers and shared memory arrays according to the MPI-3 standard were the key components of the optimization. We demonstrate significant improvements of memory and performance efficiency, scalability, and workload distribution, extending the reach of hybrid DFAs to simulation sizes beyond ten thousand atoms. In addition, we also compare the runtime performance of the PBE, HSE06, and PBE0 functionals. As a necessary byproduct of this work, other code parts in FHI-aims have been optimized as well, e.g., the computation of the Hartree potential and the evaluation of the force and stress components. We benchmark the performance and scaling of the hybrid DFA-based simulations for a broad range of chemical systems, including hybrid organic-inorganic perovskites, organic crystals, and ice crystals with up to 30 576 atoms (101 920 electrons described by 244 608 basis functions).

Influence of the examination position and distension medium on the rectal sensory test in patients with functional constipation.

PURPOSE: To evaluate the impact of two different parameters (body position and distension medium) on the rectal sensory test in patients with functional constipation and provide data support for the development of standardized operating procedures in clinical practice. METHODS: Based on a single-center process of the rectal sensory test, 39 patients with functional constipation were recruited for rectal sensory test under different body positions and distension mediums. RESULTS: Among the items of the Constipation Scoring System, the score of frequency of bowel movements showed a negative correlation with the first constant sensation volume (r = -0.323, P = 0.045). Conversely, the score of painful evacuation effort showed a positive correlation with the desire to defecate volume (r = 0.343, P = 0.033). There was a statistically significant difference in the first constant sensation volume (when the distension medium was gas) measured in different body positions (left lateral position, sitting position, squatting position), and the data measured in the squatting position were significantly higher than those in left lateral position (P < 0.05). In terms of research on distension medium, it was found that the first constant sensation volume measured in the squatting position (when the distension medium was water) was significantly lower than that of gas (P < 0.05). CONCLUSION: For patients with functional constipation, there are differences in the results of rectal sensory tests between body positions and distension mediums. When conducting multicenter studies, it is necessary to unify the standard operating procedure (SOP) for operational details to ensure consistency and reliability of the test results.

Legionella maceachernii pneumonia: a case report and literature review.

BACKGROUND: Legionella maceachernii pneumonia is a severe respiratory infection with low incidence but high mortality. However, the optimal treatment for this disease remains unclear. We report a case of successful treatment of Legionella maceachernii pneumonia, which is the first report of such a case in China. CASE PRESENTATION: An 87-year-old man with concomitant chronic obstructive pulmonary disease, liver cirrhosis, and history of left nephrectomy was diagnosed with Legionella maceachernii pneumonia using Dano-seq pathogen metagenomic testing. After two weeks of treatment with cefoperazone/sulbactam combined with quinolone antibiotics, the patient showed improvement and was discharged. The patient continued to take oral quinolone antibiotics for one week after discharge and recovered during outpatient follow-up. CONCLUSIONS: Dano-seq pathogen metagenomic testing can rapidly diagnose Legionella maceachernii pneumonia, and taking quinolone antibiotics is an effective treatment.

Integrating network pharmacology and experimental verification to explore the pharmacological mechanisms of phlorizin against osteoarthritis.

To study the pharmacological effects and mechanisms of phlorizin in the treatment of osteoarthritis (OA) through network pharmacological analysis, molecular docking, and experimental validation. First, we screened out the relevant targets related to phlorizin and OA from the public database. The key targets, biological processes, and signaling pathways of phlorizin against OA were identified by protein-protein interaction (PPI) network, Gene Ontology (GO), and Encyclopedia of Kyoto Genes and Genomes (KEGG) pathway enrichment analysis. Subsequently, molecular docking was performed to predict the binding activity between phlorizin and key targets. Finally, we evaluated the effects of phlorizin on hydrogen peroxide-induced OA in rats and validated its possible mechanism of action based on the findings of the network pharmacology analysis. Network pharmacology revealed a total of 235 cross-targets involved in the treatment of OA. Phlorizin's anti-OA effect was found to be primarily mediated through oxidoreductase activity, with JAK-STAT and NF-κB signaling pathways playing a regulating role, according to pathway enrichment analysis. Phlorizin demonstrated a strong affinity for NF-κB1 targets through molecular docking. Moreover, in vitro experiments demonstrated that phlorizin could enhance intracellular antioxidant enzyme activities with good ROS scavenging ability and significantly reduce the expression of NF-κB1 and inflammatory cytokines. Phlorizin can inhibit the progression of OA. The potential underlying mechanism involves inhibiting the NF-κB pathway to reduce inflammation and promote intracellular antioxidant action.

Sirt3-Mediated Opa1 Deacetylation Protects Against Sepsis-Induced Acute Lung Injury by Inhibiting Alveolar Macrophage Pro-Inflammatory Polarization.

Aims: Mitochondrial dynamics in alveolar macrophages (AMs) are associated with sepsis-induced acute lung injury (ALI). In this study, we aimed to investigate whether changes in mitochondrial dynamics could alter the polarization of AMs in sepsis-induced ALI and to explore the regulatory mechanism of mitochondrial dynamics by focusing on sirtuin (SIRT)3-induced optic atrophy protein 1 (OPA1) deacetylation. Results: The AMs of sepsis-induced ALI showed imbalanced mitochondrial dynamics and polarization to the M1 macrophage phenotype. In sepsis, SIRT3 overexpression promotes mitochondrial dynamic equilibrium in AMs. However, 3-(1H-1, 2, 3-triazol-4-yl) pyridine (3TYP)-specific inhibition of SIRT3 increased the mitochondrial dynamic imbalance and pro-inflammatory polarization of AMs and further aggravated sepsis-induced ALI. OPA1 is directly bound to and deacetylated by SIRT3 in AMs. In AMs of sepsis-induced ALI, SIRT3 protein expression was decreased and OPA1 acetylation was increased. OPA1 acetylation at the lysine 792 amino acid residue (OPA1-K792) promotes self-cleavage and is associated with an imbalance in mitochondrial dynamics. However, decreased acetylation of OPA1-K792 reversed the pro-inflammatory polarization of AMs and protected the barrier function of alveolar epithelial cells in sepsis-induced ALI. Innovation: Our study revealed, for the first time, the regulation of mitochondrial dynamics and AM polarization by SIRT3-mediated deacetylation of OPA1 in sepsis-induced ALI, which may serve as an intervention target for precision therapy of the disease. Conclusions: Our data suggest that imbalanced mitochondrial dynamics promote pro-inflammatory polarization of AMs in sepsis-induced ALI and that deacetylation of OPA1 mediated by SIRT3 improves mitochondrial dynamic equilibrium, thereby ameliorating lung injury.

The ATP-bound inward-open conformation of ABCC4 reveals asymmetric ATP binding for substrate transport.

The multidrug resistance-associated protein (MRP) ABCC4 facilitates substrate transport across the cytoplasmic membrane, crucial for normal physiology and mediating multidrug resistance in tumor cells. Despite intensive studies on MRPs, ABCC4's transport mechanism remains incompletely understood. In this study, we unveiled an inward-open conformation with an ATP bound to degenerate NBD1. Additionally, we captured the structure with both ATP and substrate co-bound in the inward-open state. Our findings uncover the asymmetric ATP binding in ABCC4 and provide insights into substrate binding and transport mechanisms. ATP binding to NBD1 is parallel to substrate binding to ABCC4, and is a prerequisite for ATP-bound NBD2-induced global conformational changes. Our findings shed new light on targeting ABCC4 in combination with anticancer therapy.

Exploring the interplay of depression, sleep quality, and hearing in tinnitus-related handicap: insights from polysomnography and pure-tone audiometry.

BACKGROUND: Tinnitus affects approximately 740 million adults globally, involving hearing, emotion, and sleep systems. However, studies using polysomnography and pure-tone audiometry (PTA) are limited. We aimed to assess the correlation between tinnitus and hearing, sleep quality, characteristics, and depression using polysomnography and PTA. METHODS: In this cross-sectional study, we divided participants into tinnitus and non-tinnitus groups. We included 100 outpatients (65 with tinnitus, 35 without) from a medical center in Taiwan, who underwent polysomnography and completed rating scales including the Patient Health Questionnaire-9 (PHQ-9), Chinese version of the Pittsburgh Sleep Quality Index (PSQI), and Chinese-Mandarin version of the Tinnitus Handicap Inventory (THI-CM). We analyzed correlations, conducted group comparisons, assessed factors related to THI-CM scores, constructed ROC curves to predict depression in the tinnitus group, and performed multinomial and logistic regression to explore associations. RESULTS: Descriptive statistics identified a cohort with mean age 53.9 ± 12.80 years, 63% exhibited PHQ-9 scores ≥ 10, and 66% had Apnea-Hypopnea Index (AHI) > 5. The ratio of rapid eye movement and deep sleep to stage 1 + 2 sleep was relatively low and non-significant. Likewise, leg movements was higher in the tinnitus group but not statistically significant. In the tinnitus group, 63.08% had depression, and 81.54% had AHI > 5. Univariate logistic regression linked tinnitus to AHI > 5 (Odds ratio (OR) 2.67, p = 0.026) and male sex (OR 2.49, p = 0.034). A moderate positive correlation was found between the THI-CM score and PHQ-9 score (rs = 0.50, p < 0.001). Further adjustment for obstructive sleep apnea showed associations between PHQ-9 (total score) or depression and THI-CM Grade 3-5 (OR = 1.28; OR = 8.68). Single- and multifactor regression analyses highlighted significant associations of PSQI scores > 13 (OR 7.06, p = 0.018) and THI-CM scores > 47 (OR 7.43, p = 0.002) with depression. CONCLUSIONS: Our study recruited tinnitus participants with slight or mild hearing loss and mild tinnitus handicap. Depression was identified as a predominant factor in tinnitus-related handicap. The mild tinnitus handicap in tinnitus participants may explain the lack of significant differences in depression, sleep quality, and polysomnographic sleep characteristics between tinnitus and non-tinnitus groups. Further extensive and prospective studies are needed to elucidate the complex links among depression, sleep, and tinnitus.

Disagreements in risk of bias assessment for randomized controlled trials in hypertension-related Cochrane reviews.

BACKGROUND: The inter-reviewer reliability of the risk of bias (RoB) assessment lacked agreement in previous studies. It is important to analyse these disagreements to improve the repeatability of RoB assessment. The objective of the study was to evaluate the frequency and reasons for disagreements in RoB assessments for randomised controlled trials (RCTs) that were included in multiple Cochrane reviews in the field of hypertension. METHODS: A cross-sectional study was employed. We retrieved any RCTs that had been included in multiple Cochrane reviews in the field of hypertension from ARCHIE. The results of the RoB assessments were extracted, and the distributions of agreements and possible reasons for disagreement were analyzed. RESULTS: Twenty-six Cochrane reviews were included in this study. A total of 78 RCTs appeared in more than one Cochrane review. The level of agreement ranged from domain to domain. "Blinding of outcome assessment" showed a reasonably high level of agreement (94.9%), while "incomplete outcome data", "selective outcome reporting" and "other sources of bias" showed moderate levels of agreement (74.6%, 79.2% and 75.6%, respectively). However, the domains of "allocation concealment", "random sequence generation" and "blinding of participants and personnel" showed low levels of agreement (24.4%, 23.5%, and 47.4%, respectively). In the domains of "allocation concealment" and "blinding of participants and personnel", the agreement group had higher proportion of publication year ≤ 1996 than the disagreement group (P = 0.008 and P < 0.001, respectively). In the "blinding of participants and personnel", the impact factor was higher in the agreement group (P < 0.001). By analyzing the support text, we found that the most likely reason for disagreement was extracting different information from the same RCT. CONCLUSION: For Cochrane reviews in the field of hypertension using the 2011 version of the RoB tool, there was a large disagreement in the RoB assessment. It is suggested that the results of RoB assessments in systematic reviews that used the 2011 version of the RoB tool need to be interpreted with caution. More accurate information from RCTs needs to be collected when we synthesize clinical evidence.