Genome-Wide Identification and Characterization of Auxin Response Factor (ARF) Gene Family Involved in Wood Formation and Response to Exogenous Hormone Treatment in Populus trichocarpa.

Auxin is a key regulator that virtually controls almost every aspect of plant growth and development throughout its life cycle. As the major components of auxin signaling, auxin response factors (ARFs) play crucial roles in various processes of plant growth and development. In this study, a total of 35 PtrARF genes were identified, and their phylogenetic relationships, chromosomal locations, synteny relationships, exon/intron structures, cis-elements, conserved motifs, and protein characteristics were systemically investigated. We also analyzed the expression patterns of these PtrARF genes and revealed that 16 of them, including PtrARF1, 3, 7, 11, 13-17, 21, 23, 26, 27, 29, 31, and 33, were preferentially expressed in primary stems, while 15 of them, including PtrARF2, 4, 6, 9, 10, 12, 18-20, 22, 24, 25, 28, 32, and 35, participated in different phases of wood formation. In addition, some PtrARF genes, with at least one cis-element related to indole-3-acetic acid (IAA) or abscisic acid (ABA) response, responded differently to exogenous IAA and ABA treatment, respectively. Three PtrARF proteins, namely PtrARF18, PtrARF23, and PtrARF29, selected from three classes, were characterized, and only PtrARF18 was a transcriptional self-activator localized in the nucleus. Moreover, Y2H and bimolecular fluorescence complementation (BiFC) assay demonstrated that PtrARF23 interacted with PtrIAA10 and PtrIAA28 in the nucleus, while PtrARF29 interacted with PtrIAA28 in the nucleus. Our results provided comprehensive information regarding the PtrARF gene family, which will lay some foundation for future research about PtrARF genes in tree development and growth, especially the wood formation, in response to cellular signaling and environmental cues.

Core Outcome Set for Clinical Trials on Coronavirus Disease 2019 (COS-COVID).

Since its outbreak in December 2019, a series of clinical trials on coronavirus disease 2019 (COVID-19) have been registered or carried out. However, the significant heterogeneity and less critical outcomes of such trials may be leading to a waste of research resources. This study aimed to develop a core outcome set (COS) for clinical trials on COVID-19 in order to tackle the outcome issues. The study was conducted according to the Core Outcome Measures in Effectiveness Trials (COMET) Handbook: Version 1.0, a guideline for COS development. A research group was set up that included experts in respiratory and critical medicine, traditional Chinese medicine (TCM), evidence-based medicine, clinical pharmacology, and statistics, in addition to medical journal editors. Clinical trial registry websites (www.chictr.org.cn and clinicaltrials.gov) were searched to retrieve clinical trial protocols and outcomes in order to form an outcome pool. A total of 78 clinical trial protocols on COVID-19 were included and 259 outcomes were collected. After standardization, 132 outcomes were identified within seven different categories, of which 58 were selected to develop a preliminary outcome list for further consensus. After two rounds of Delphi survey and one consensus meeting, the most important outcomes for the different clinical classifications of COVID-19 were identified and determined to constitute the COS for clinical trials on COVID-19 (COS-COVID). The COS-COVID includes one outcome for the mild type (time to 2019 novel coronavirus (2019-nCoV) reverse transcription-polymerase chain reaction (RT-PCR) negativity), four outcomes for the ordinary type (length of hospital stay, composite events, score of clinical symptoms, and time to 2019-nCoV RT-PCR negativity), five outcomes for the severe type (composite events, length of hospital stay, arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2), duration of mechanical ventilation, and time to 2019-nCoV RT-PCR negativity), one outcome for critical type (all-cause mortality), and one outcome for rehabilitation period (pulmonary function). The COS-COVID is currently the most valuable and practical clinical outcome set for the evaluation of intervention effect, and is useful for evidence assessment and decision-making. With a deepening understanding of COVID-19 and application feedback, the COS-COVID should be continuously updated.

Motherwort Injection for Preventing Postpartum Hemorrhage in Women with Vaginal Delivery: A Systematic Review and Meta-Analysis of Randomized Evidence.

BACKGROUND: Motherwort injection, a common traditional Chinese medicine, is widely used for the prevention of postpartum hemorrhage (PPH), which has been found to be potential benefit in clinical practice. OBJECTIVES: This study aimed to conduct a rigorous systematic review of randomized evidence to offer a comprehensive overview regarding the efficacy and safety of motherwort injection in maternal women with virginal delivery. METHODS: We included all randomized controlled trials involving pregnant women in vaginal delivery comparing motherwort injection or combination of motherwort injection and oxytocin with oxytocin alone for preventing postpartum hemorrhage. Paired reviewers independently screened citations, assessed risk of bias, and extracted data. Random-effects model by Mantel-Haenszal method was applied to pool the data. Predefined subgroup analyses and sensitivity analyses were conducted to explore the heterogeneity and robustness of results. The GRADE approach was used to rate the quality of evidence. MAIN RESULTS: 37 randomized controlled trials involving 7887 participants were included, all of which were at moderate to high risk of bias. Meta-analyses of eight trials showed no significant difference in blood loss and PPH events between oxytocin versus motherwort injection (very low quality). However, pooling of 29 trials suggested a reduced risk of blood loss (within 2 hours: MD -55.06mL, 95% CI -84.06 to -26.06; within 24 hours: MD -85.57 mL, 95% CI -94.26 to -76.88, very low quality), PPH events (RR 0.29, 95% CI 0.21 to 0.39, low quality), and adverse events (Peto OR 0.53, 95% CI 0.40 to 0.70, very low quality) in participants treated with motherwort injection and oxytocin versus oxytocin alone. CONCLUSIONS: The current evidence supports the suggestion that the additional use of motherwort injection on oxytocin had a preferable outcome. However, given that the evidence is not definitive with low quality, further careful designed and conducted randomized controlled trials in larger population are warranted to conform the effects.

Detoxification therapy of traditional Chinese medicine for genital tract high-risk human papillomavirus infection: A systematic review and meta-analysis.

BACKGROUND: Persistence of high-risk human papillomavirus (hr-HPV) infections is the most critical risk factor for cervical intraepithelial neoplasia (CIN) and cervical cancer (CC). Treatment of persistent oncogenic HPV-positive women after 12-24 months follow-up is still controversy. Detoxification therapy of Chinese medicine (DTCM) has been conducted recently. However, the conclusions are still unclear. We planned to conduct a systematic review and meta-analysis to explore DTCM in the treatment of persistent hr-HPV infections. METHODS: Nine electronic databases were systematically searched from their inception to 30 September 2018. Randomized controlled trials comparing DTCM with follow-up or placebo were included. Risk of bias was assessed by the Cochrane 'Risk of Bias' tool. Review Manager 5.3 was used for statistical analyses. Relative ratios (RR) and 95% confidence intervals were used for dichotomous data, and the mean difference (MD) was used for continuous data. We assessed the quality of trials by the GRADE. RESULTS: Seventeen RCTs from 2011 to 2018 with 1906 participants were included. The evidence showed that DTCM had a pooled efficacy difference in favor of increasing the HPV clearance rate compared to placebo groups (RR = 2.62, 95% CI 1.28 to 5.33, very low quality) and follow-up groups (RR = 1.88, 95% CI 1.60 to 2.22, low quality). The median HPV persistence tended to decline from 50% within six months to 41.5% at 12 months, and 31.5% at 24 months. A significantly increased regression rate of CIN was found in the DTCM compared with placebo groups (RR = 3.61, 95% CI 1.21 to 10.83, very low quality) and follow-up groups (RR = 1.79, 95% CI 1.31 to 2.45, very low quality). Additionally, we found DTCM have an impact on TNF-α (MD = 2.99, 95% CI 1.90 to 4.07; very low quality), IFN-α (MD = 3.47, 95% CI 2.42 to 4.52; very low quality), CD4+/CD8+ cells (MD = 0.21, 95% CI 0.05 to 0.37; very low quality) compared with follow up groups in some trials with small sample sizes. The major adverse events were genital mucosal irritation symptoms (10%, 5/50). CONCLUSIONS: DTCM have favorable outcomes on improving the HPV clearance rate, increasing the regression rate of CIN, and impacting the proportion of some immune cells and cytokine levels. However, most of the evidence was of low quality. Any future high-quality trials and a more extended follow-up period of 24 months or more should be performed.

Motherwort injection for preventing postpartum hemorrhage in pregnant women with cesarean section: A systematic review and meta-analysis.

OBJECTIVE: To assess the impact of motherwort injection alone or combined with oxytocin for preventing postpartum hemorrhage in pregnant women with caesarean section. METHODS: A systematic review and meta-analysis of randomized trials were performed. PubMed, EMbase, The Cochrane Central Register of Controlled Trials (CENTRAL), Chinese database Sino-Med, Chinese National Knowledge Infrastructure Database (CNKI), VIP Chinese Science and Technique Journals Database, WanFang, and ClinicalTrials.gov were searched. Randomized controlled trials (RCTs) that compared motherwort injection alone or motherwort injection combined with oxytocin in pregnant women receiving cesarean section were included. Paired reviewers independently screened abstracts and full texts for eligibility, assessed risk of bias, and extracted data. We performed random-effects meta-analyses of RCTs along with a limited number of prespecified subgroup hypotheses, and sensitivity analyses were carried out with other statistical approaches. RESULTS: Forty-six RCTs (n = 7359) proved eligible. Compared with oxytocin, both motherwort injection and motherwort injection combined with oxytocin had a significantly lower blood loss within 2 hours (MD = -21.81, 95% CI -37.05 to -6.58 and MD = -53.04, 95% CI -61.68 to -44.39); lower blood loss within 24 hours (MD = -25.44, 95% CI -39.38 to -11.51 and MD = -67.81, 95% CI -78.02 to -57.60); and lower the risk of adverse events (ORPeto 0.40, 95% CI 0.16 to 0.96 and ORPeto 0.50, 95% CI 0.35 to 0.71). Motherwort injection combined with oxytocin also decreased the risk of postpartum hemorrhage (OR 0.22, 95% CI 0.14 to 0.35.) CONCLUSIONS: In pregnant women with cesarean section, motherwort injection suggests an obvious benefit and less adverse event.

The quality of reporting in randomized controlled trials of acupuncture for knee osteoarthritis: A cross-sectional survey.

OBJECTIVE: To assess the reporting quality of acupuncture trials for knee osteoarthritis (KOA), and explore the factors associated with the reporting. METHOD: Three English and four Chinese databases were searched from inception to December 2016 for randomized control trials testing effects of acupuncture for knee osteoarthritis. We used the standard CONSORT (2010 version), CONSORT Extension for Non-Pharmacological Treatments, and STRICTA for measuring the quality of reporting. Using pre-specified study characteristics, we undertook regression analyses to examine factors associated with the reporting quality. RESULTS: A total of 318 RCT reports were included. For the standard CONSORT, ten items were substantially under-reported (reported in less than 5% of RCTs), including specification of important changes to methods after trial commencement (0.6%), description of any changes to trial outcomes (0.0%), implementation of interim analyses and stopping guidelines (0.6%), statement about why the trial ended or was stopped (1.6%), statement about the registration status (4.4%), accessibility of full trial protocol (4.7%), implementation of randomization (4.7%), description of the similarity of interventions (3.5%), conduct of ancillary analyses (3.8%) and presentation of methods for additional analyses (4.4%). Four of the STRICTA items were under-reported (reported in less than 10% of RCTs), including description of acupuncture style (8.5%), presentation of extent to which treatment varied (1.3%), statement of practitioner background (7.2%) and rationale for the control (9.1%). For CONSORT Extension, the reporting was poor across all items (reported in less than 10% of trials). Trials including authors with expertise in epidemiology or statistics, published in English, or enrolling patients from multiple centers were more likely to have better reporting. CONCLUSIONS: The reporting in RCTs of acupuncture for KOA was generally poor. To improve the reporting quality, journals should encourage strict adherence to the reporting guidelines.

Interconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies.

Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion. Here, we report an approach to co-culture multiple different MPSs linked together physiologically on re-useable, open-system microfluidic platforms that are compatible with the quantitative study of a range of compounds, including lipophilic drugs. We describe three different platform designs - "4-way", "7-way", and "10-way" - each accommodating a mixing chamber and up to 4, 7, or 10 MPSs. Platforms accommodate multiple different MPS flow configurations, each with internal re-circulation to enhance molecular exchange, and feature on-board pneumatically-driven pumps with independently programmable flow rates to provide precise control over both intra- and inter-MPS flow partitioning and drug distribution. We first developed a 4-MPS system, showing accurate prediction of secreted liver protein distribution and 2-week maintenance of phenotypic markers. We then developed 7-MPS and 10-MPS platforms, demonstrating reliable, robust operation and maintenance of MPS phenotypic function for 3 weeks (7-way) and 4 weeks (10-way) of continuous interaction, as well as PK analysis of diclofenac metabolism. This study illustrates several generalizable design and operational principles for implementing multi-MPS "physiome-on-a-chip" approaches in drug discovery.

Risk of bias and methodological issues in randomised controlled trials of acupuncture for knee osteoarthritis: a cross-sectional study.

OBJECTIVE: To assess risk of bias and to investigate methodological issues concerning the design, conduct and analysis of randomised controlled trials (RCTs) testing acupuncture for knee osteoarthritis (KOA). METHODS: PubMed, EMBASE, Cochrane Central Register of Controlled Trials and four major Chinese databases were searched for RCTs that investigated the effect of acupuncture for KOA. The Cochrane tool was used to examine the risk of bias of eligible RCTs. Their methodological details were examined using a standardised and pilot-tested questionnaire of 48 items, together with the association between four predefined factors and important methodological quality indicators. RESULTS: A total of 248 RCTs were eligible, of which 39 (15.7%) used computer-generated randomisation sequence. Of the 31 (12.5%) trials that stated the allocation concealment, only one used central randomisation. Twenty-five (10.1%) trials mentioned that their acupuncture procedures were standardised, but only 18 (7.3%) specified how the standardisation was achieved. The great majority of trials (n=233, 94%) stated that blinding was in place, but 204 (87.6%) did not clarify who was blinded. Only 27 (10.9%) trials specified the primary outcome, for which 7 used intention-to-treat analysis. Only 17 (6.9%) trials included details on sample size calculation; none preplanned an interim analysis and associated stopping rule. In total, 46 (18.5%) trials explicitly stated that loss to follow-up occurred, but only 6 (2.4%) provided some information to deal with the issue. No trials prespecified, conducted or reported any subgroup or adjusted analysis for the primary outcome. CONCLUSION: The overall risk of bias was high among published RCTs testing acupuncture for KOA. Methodological limitations were present in many important aspects of design, conduct and analyses. These findings inform the development of evidence-based methodological guidance for future trials assessing the effect of acupuncture for KOA.

Internal fixation treatments for intertrochanteric fracture: a systematic review and meta-analysis of randomized evidence.

The relative effects of internal fixation strategies for intertrochanteric fracture after operation remain uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to address this important issue. We searched PubMed, EMBASE and CENTRAL for RCTs that compared different internal fixation implants in patients with intertrochanteric fracture at 6-month follow-up or longer. We ultimately included 43 trials enrolling 6911 patients; most trials were small in sample sizes and events. Their risk of bias was generally unclear due to insufficient reporting. Because of these, no statistically significant differences were present from most of the comparisons across all the outcomes, and no definitive conclusions can be made. However, a number of trials compared two commonly used internal fixation strategies, gamma nail (GN) and sliding hip screw (SHS). There is good evidence suggesting that, compared to SHS, GN may increase the risk of cut out (OR = 1.87, 95% CI, 1.08 to 3.21), re-operation (OR = 1.61, 95% CI, 1.02 to 2.53), intra-operative (OR = 3.14, 95% CI, 1.34 to 7.35) and later fractures (OR = 3.67, 95% CI, 1.37 to 9.83). Future randomized trials or observational studies that are carefully designed and conducted are warranted to establish the effects of alternative internal fixation strategies for intertrochanteric fracture.

Three dimensional human small intestine models for ADME-Tox studies.

In vitro human small intestine models play a crucial part in preclinical drug development. Although conventional 2D systems possess many advantages, such as facile accessibility and high-throughput capability, they can also provide misleading results due to their relatively poor recapitulation of in vivo physiology. Significant progress has recently been made in developing 3D human small intestine models, suggesting that more-reliable preclinical results could be obtained by recreating the 3D intestinal microenvironment in vitro. Although there are still many challenges, 3D human small intestine models have the potential to facilitate drug screening and drug development.