bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incorporating estimands into clinical trial statistical analysis plans
Authors: Kang Minhee , Kendall Michelle A , Ribaudo Heather , Tierney Camlin , Zheng Lu , Smeaton Laura , Lindsey Jane C 
Published: March 2022

Background: International Council for Harmonisation (ICH) E9 Statistical Principles for Clinical Trials was developed as a consensus guidance document to encourage worldwide harmonization of the principles of statistical methodology in clinical trials. Addendum E9 (R1) clarified and extended ICH E9 with a focus on estimands and sensitivity analyses. Since the release of E9 (R1), clinical trial protocols have included estimands, but there is variation in how they are presented. Statistical analysis plans (SAPs) are increasingly becoming publicly available (e.g. posting on ClinicalTrials.gov) and present an opportunity to link estimands with planned analyses to present the alignment of trial objectives, design, conduct, and analysis. Methods: A table format was used to create a template for inclusion in SAPs that satisfies ICH E9 (R1) guidance to align statistical analysis to the estimand. The template provides a consistent structure for presentation of estimands and the associated analysis, and is applicable to a wide range of trial designs. We illustrate use of the template with a hypothetical clinical trial in HIV-1. Results: The estimand-to-analysis table template starts with the study objective describing the clinical question of interest as written in the trial protocol. The remainder of the table describes each attribute of the estimand (treatment, target population, variable, intercurrent events, and population-level summary) in the left column (ESTIMAND), while the right column describes how each attribute will be handled using the data collected in the clinical trial (ANALYSIS). The template was applied to a hypothetical, early-phase single-arm trial, modeled after a pediatric trial in HIV, where the objective was to determine the safety of a new antiretroviral drug as part of a combination antiretroviral treatment regimen in the pediatric population. Three intercurrent events were illustrated in the table: death, premature treatment discontinuation before 24 weeks, and pregnancy. An estimand-to-analysis table from a grant application that addresses the primary objective of a placebo-controlled randomized trial is also presented to demonstrate an alternative usage. Conclusion: We found the template to be useful in study design, providing a snapshot of the objective, target population, potential intercurrent events, analysis plan, and considerations for missing data in one place and facilitating discussion among stakeholders. The proposed standardized presentation of estimand attributes and analysis considerations in SAPs will provide guidance to SAP authors and consistency across studies to facilitate reviews.
The effect of metabolic syndrome and/or hyperglycemia on outcomes of acute ischemic stroke patients treated with intravenous thrombolysis
Authors: Duan Zuowei , Wei Xiu’e , Liu Haiyan , Zhai Yujia , Hu Ting , Xu Jiang , Liu Tengfei , Yang Ming , Rong Liangqun 
Published: March 2022

Backgrounds and Objectives: The impact of metabolic syndrome (MetS)/hyperglycemia on the clinical outcomes of ischemic stroke treated with intravenous thrombolysis (IVT) remains controversial. This study aimed to determine the risks conferred by MetS and hyperglycemia to clinical outcomes in acute ischemic stroke patients treated with IVT. Method: Three hundred forty-three ischemic stroke patients treated with IVT were prospective recruited and stratified into four groups: neither, MetS only, hyperglycemia only, or both. The primary outcome was the 3-month poor functional outcome (PFO) which was defined as a 3-month modified Rankin Score (mRS) score ≧3. The secondary outcome included the hemorrhagic transformation (HT) and symptomatic intracranial hemorrhage (sICH) after IVT. Results: MetS was recognized in 197 (57.43%) patients. During the first 24 h after IVT, 44 (12.83%) patients had HT, of which 17 had sICH. Three-month PFO was found in 98 (28.57%) patients. After adjustment for potential confounders, MetS (odds ratio (OR) = 3.140, 95% confidence interval (CI) = 1.724–5.718) was independently associated with PFO. However, neither MetS nor its components were associated with 24-h HT or sICH. In the further subgroup analysis, we used the “neither” group as reference and found that the presence of both MetS and hyperglycemia (OR = 3.192, 95% CI = 1.338–7.615) and the presence of hyperglycemia only (OR = 2.097, 95% CI = 1.052–4.179) were significantly related to the 3-month PFO. Conclusion: MetS is an independent risk factor on 3-month PFO in acute ischemic stroke patients treated with IVT. Compared with “neither,” hyperglycemia only or concurrent with MetS was associated with an elevated risk of PFO after receiving IVT.
Vedolizumab has longer persistence than infliximab as a first-line biological agent but not as a second-line biological agent in moderate-to-severe ulcerative colitis: real-world registry data from the Persistence Australian National IBD Cohort (PANIC) study
Authors: Pudipeddi Aviv , Ko Yanna , Paramsothy Sudarshan , Leong Rupert W. 
Published: March 2022

Background: The choice between infliximab (IFX) and vedolizumab (VED) as a first-line biological agent in moderate-to-severe ulcerative colitis (UC) can be difficult. Second-line vedolizumab (VED) efficacy may decline following prior infliximab (IFX) treatment failure in UC patients. However, it is not known whether second-line IFX efficacy declines after failure of first-line VED. Aims: We aimed to compare first-line and second-line persistence of IFX and VED, in particular whether second-line IFX persistence declines after failure of first-line VED. Methods: Persistence of IFX and VED was analysed from the Australian Pharmaceutical Benefits Scheme registry data as either first- or second-line treatment in UC. Propensity score matching (1:1) was conducted in the comparison of first-line treatments. Cox proportional hazard regression analysis was used to identify significant predictors and expressed as a hazard ratio (HR and 95% CI). Results: There were 420 subjects with moderate-to-severe UC who received either first-line IFX ( n = 251) or VED ( n = 169), with 774 patient-years of follow-up. First-line VED had significantly longer persistence than first-line IFX (>50.2 versus 22.2 months, p = 0.001). Fifty-three subjects failed first-line IFX and swapped to second-line VED (IFX→VED group). Twenty-two subjects failed first-line VED group and swapped to second-line IFX (VED→IFX group). First-line VED persistence was significantly longer than second-line VED (>50.2 versus 32.0 months, p = 0.03), but first-line IFX persistence was not statistically significantly different to second-line IFX (27.6 months versus  > 38.6 months, p = 0.30). Immunomodulator co-therapy was significantly associated with a lower risk of nonpersistence of first-line VED (HR: 0.55, 95% CI: 0.33–0.89, p = 0.02) and IFX (HR: 0.63,95%CI: 0.33–0.92, p = 0.02). Conclusion: VED had a significantly longer persistence than IFX as first-line biological agent but does not disadvantage second-line IFX use in moderate-to-severe UC. VED after IFX is associated with significantly poorer persistence. VED, therefore, should be considered as the first-line biological agent of choice in UC.
Determinants of practice of birth preparedness and complication readiness among pregnant women in Sodo Zuria District, Southern Ethiopia: Content analysis using Poisson’s regression
Authors: Haile Dereje , Wolde Jegnaw , Yohannes Dereje 
Published: March 2022

Objectives: Every pregnancy can face risk. One of the World Health Organization recommendations for health promotion interventions for maternal and newborn health was to increase birth preparedness and complication readiness. The main objective of this recommendation was to increase the use of skilled care at birth and to increase the timely use of facility care for obstetric and newborn complications. However, to the best of our knowledge, there is a dearth of documented evidence on the magnitude of birth preparedness and complication readiness and factors associated with it in our study area. Thus, the aim of this study was to identify factors affecting the practice of birth preparedness and complication readiness. Methods: A community-based cross-sectional study was carried out from 15 February to 15 March 2020. A total of 698 pregnant women were randomly selected and interviewed using a pretested semi-structured questionnaire. A multivariate generalized linear regression with Poisson link was carried out to see the effect of each independent variable on the dependent variable. Result: Of the sampled 710 participants, 698 participated, which made a response rate of 98.3%. The mean score of practice of birth preparedness and complication readiness was 3.3 (standard deviation = 1.8). Mothers who used pre-pregnancy contraception methods (adjusted odds ratio = 1.22 (95% confidence interval = 1.09, 1.37)), used bare feet as a mode of transportation (adjusted odds ratio = 1.11 (95% confidence interval = 1.01, 1.21)), used more antenatal care content (adjusted odds ratio = 1.09 (95% confidence interval = 1.06, 1.13)), and whose husbands were educated at the primary level of education (adjusted odds ratio = 1.19 (95% confidence interval = 1.03, 1.37)) were predictors in multivariable general. Conclusion: The mean score and overall practice of birth preparedness and complication readiness were low. This study revealed a low level of birth preparedness and complication readiness. In order to improve access to lifesaving care for women and neonates, there is a pressing need for implementation of existing strategies to increase practice of birth preparedness and complication readiness.
First report of phaeohyphomycosis caused by Phialophora americana in a domestic cat from Argentina
Authors: Borrás Pablo , Messina Fernando , Abrantes Rubén , Iachini Ricardo , Minatel Leonardo , Santiso Gabriela 
Published: March 2022

Case summary A 10-year-old male neutered domestic shorthair cat from Quilmes (Province of Buenos Aires, Argentina) presented at the Infectious Diseases and Parasitology Unit with a hyperpigmented nodule of 5 cm diameter on the nasal plane with a small ulceration of more than 1 year’s evolution. A scaly and hyperpigmented alopecic lesion of 3 cm in diameter was found on the lower edge of the tail. The patient was under immunosuppressive therapy with corticosteroids for lymphoplasmacytic duodenitis. Samples of the lesion present on the nasal plane were taken under a surgical procedure. In the wet mount preparations, pigmented irregular hyphae were observed. They developed dark colonies when cultured on Sabouraud medium. On micromorphology, structures compatible with Phialophora species were identified. PCR and sequencing of ITS (ITS1-5.8S-ITS2) confirmed Phialophora americana as the etiologic agent. A therapeutic scheme that included a combination of itraconazole oral solution (1.5 mg/kg PO q12h) with terbinafine (30 mg/kg PO q24h) was indicated for a period of 10 months. The patient died of complications resulting from its underlying disease. Relevance and novel information As far as the authors are aware, this is the first study to report P americana as an etiologic agent of phaeohyphomycosis in cats. In this case study, the species was identified using molecular tests.
Full-Thickness Massive Rotator Cuff Repair With a Dermal Allograft Using CuffMend Augmentation Technique
Authors: Dasari Suhas P. , Fortier Luc M. , Bodendorfer Blake M. , DeFroda Steven F. , Cole Brian J. , Verma Nikhil N. 
Published: March 2022

Background: Rotator cuff repair using graft augmentation for large-to-massive, full-thickness rotator cuff tears has been reported to have improved clinical outcomes relative to other therapeutic interventions. Although an effective and promising technique, graft augmentation can be technically challenging, particularly with deployment and positioning of the graft. CuffMend is a user-friendly rotator cuff augmentation technique that combines a decellularized dermal allograft with a novel graft deployment device, tendon anchor, and set of lateral knotless, tension-able anchors to allow for a reliable and stable implantation of the graft. Indications: Graft augmentation using CuffMend is indicated for tears with a high risk of retear or incomplete healing. This includes revision tears, poor-quality degenerative tissue, and massive full-thickness rotator cuff tears. Severe glenohumeral osteoarthritic change is the primary contraindication to this technique. Technique Description: The rotator cuff is reduced medially and secured using 3 anchors with sutures passed in a mattress configuration. Graft augmentation is then performed using the CuffMend graft spreader that facilitates placement and attachment of the graft onto the repaired tendon. Results: The patient is recovering as expected and started physical therapy 1 month postoperatively. He is able to perform light activities of daily living and reach the top of his head for daily self-care without pain. He will begin strengthening at 12 weeks postoperatively. Discussion/Conclusion: CuffMend is a new graft augmentation technique that uses a novel graft deployment device for consistent and precise deployment of a decellularized dermal allograft. This facilitates an expedited repair using the graft augmentation technique for optimal clinical and biomechanical outcomes in patients with rotator cuff tears with high risk of retear.
Abbreviated Ultrasonography Examination Protocols for COVID-19 Patients: A Streamlined Process to Reduce Staff Exposure
Authors: Luna Cibele , Estanga Indira , Patricia Castillo Rosa 
Published: March 2022

Objective: The primary goal of this article is to show that an abbreviated ultrasonography (US) examination protocols can decrease imaging time and staff exposure. Materials and Methods: This is a single-center institutional review board (IRB)-approved retrospective cohort study in which 39 patients, positive for 2019 coronavirus disease (COVID-19), underwent an abbreviated US examination protocol from April to May 2020. Radiologists, specializing in body imaging, created these protocols. Descriptive statistics were performed, including the mean duration of the abbreviated US protocols and the mean duration of the standard US protocols, as a control group. Results: The abbreviated US protocols resulted in a significant time reduction ( P < .05) compared with the regular protocol duration. Conclusion: As radiology services face this unprecedented pandemic, implementing reduced US protocols can result in safer practices decreasing staff exposure.
New developments in tuberculosis diagnosis and treatment
Authors: Gill Cara M. , Dolan Lorraine , Piggott Laura M. , McLaughlin Anne Marie 
Published: March 2022

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. It is estimated that 25% of the world's population are infected withMycobacterium tuberculosis, with a 5–10% lifetime risk of progression into TB disease. Early recognition of TB disease and prompt detection of drug resistance are essential to halting its global burden. Culture, direct microscopy, biomolecular tests and whole genome sequencing are approved methods of diagnosis; however, their widespread use is often curtailed owing to costs, local resources, time constraints and operator efficiency. Methods of optimising these diagnostics, in addition to developing novel techniques, are under review. The selection of an appropriate drug regimen is dependent on the susceptibility pattern of the isolate detected. At present, there are 16 new drugs under evaluation for TB treatment in phase I or II clinical trials, with an additional 22 drugs in preclinical stages. Alongside the development of these new drugs, most of which are oral medications, new shorter regimes are under evaluation. The aim of these shorter regimens is to encourage patient adherence, and prevent relapse or the evolution of further drug resistance. Screening for TB infection, especially in vulnerable populations, provides an opportunity for intervention prior to progression towards infectious TB disease. New regimens are currently under evaluation to assess the efficacy of shorter durations of treatment in this population. In addition, there is extensive research into the use of post-exposure vaccinations in this cohort. Worldwide collaboration and sharing of expertise are essential to our ultimate aim of global eradication of TB disease.Educational aimsDifferentiate between TB infection and TB disease.Understand the different methods of diagnosing TB disease and resistance.Recognise the different drugs and regimens currently in use for TB disease.Be able to discuss risk of TB disease in TB infection, and assist patients in making an informed decision on treatment for TB infection.
How COVID-19 interacts with interstitial lung disease
Authors: Myall Katherine J. , Martinovic Jennifer L. , West Alex 
Published: March 2022

The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had far-reaching impacts on patients with interstitial lung disease (ILD), from diagnosis to management. In addition, after infection, persistent parenchymal change is associated with ongoing symptoms and functional impairment even in patients without pre-existing lung disease. The challenge of investigating and treating these patients has often fallen to ILD physicians. This review therefore seeks to explore the relationship between COVID-19 and the interstitium, as well as the model of care for patients with pre-existing ILD and those patients with persistent disease following recovery from their initial infection.Educational aimsTo understand the impact of the COVID-19 pandemic on patients with existing interstitial lung disease.To explore the development of interstitial lung disease after COVID-19 infection.
Calcitonin gene-related peptide receptor antagonist BIBN4096BS regulates synaptic transmission in the vestibular nucleus and improves vestibular function via PKC/ERK/CREB pathway in an experimental chronic migraine rat model
Authors: Tian Ruimin , Zhang Yun , Pan Qi , Wang Yunfeng , Wen Qianwen , Fan Xiaoping , Qin Guangcheng , Zhang Dunke , Chen Lixue , Zhang Yixin , Zhou Jiying 
Published: March 2022

Abstract
Background
Vestibular symptoms are frequently reported in patients with chronic migraine (CM). However, whether vestibular symptoms arise through overlapping neurobiology of migraine remains to be elucidated. The neuropeptide calcitonin gene-related peptide (CGRP) and CGRP1 receptor play important pathological roles in facilitating central sensitization in CM. Therefore, we aimed to investigate whether CGRP1 receptor contributes to vestibular dysfunction after CM by improving synaptic transmission in the vestibular nucleus (VN).

Methods
A CM rat model was established by recurrent intermittent administration of nitroglycerin (NTG). Migraine- and vestibular-related behaviors were assessed. CGRP1 receptor specific antagonist, BIBN4096BS, and protein kinase C (PKC) inhibitor chelerythrine chloride (CHE) were administered intracerebroventricularly. The expressions of CGRP and CGRP1 receptor components, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were evaluated by western blot, immunofluorescent staining and quantitative real-time polymerase chain reaction in the vestibular nucleus (VN). Synaptic associated proteins and synaptic morphological characteristics were explored by western blot, transmission electron microscope, and Golgi-cox staining. The expressions of PKC, phosphorylated extracellular signal regulated kinase (p-ERK), phosphorylated cAMP response element-binding protein at serine 133 site (p-CREB-S133) and c-Fos were detected using western blot or immunofluorescent staining.

Results
The expressions of CGRP, CLR and RAMP1 were significantly upregulated in CM rats. CLR and RAMP1 were expressed mainly in neurons. BIBN4096BS treatment and PKC inhibition alleviated mechanical allodynia, thermal hyperalgesia and vestibular dysfunction in CM rats. Additionally, BIBN4096BS treatment and PKC inhibition markedly inhibited the overexpression of synaptic associated proteins and restored the abnormal synaptic structure in VN after CM. Furthermore, BIBN4096BS treatment dysregulated the expression levels of PKC, p-ERK and p-CREB-S133, and attenuated neuronal activation in VN after CM.

Conclusions
The present study demonstrated that CGRP1 receptor inhibition improved vestibular function after CM by reversing the aberrant synaptic transmission via downregulating PKC/ERK/CREB signaling pathway. Therapeutic interventions by inhibiting CGRP/CGRP1 signaling may be a new target for the treatment of vestibular symptoms in CM.
Global analysis of switchgrass (Panicum virgatum L.) transcriptomes in response to interactive effects of drought and heat stresses
Authors: Hayford Rita K. , Serba Desalegn D. , Xie Shaojun , Ayyappan Vasudevan , Thimmapuram Jyothi , Saha Malay C. , Wu Cathy H. , Kalavacharla Venu Kal 
Published: March 2022

Abstract
Background
Sustainable production of high-quality feedstock has been of great interest in bioenergy research. Despite the economic importance, high temperatures and water deficit are limiting factors for the successful cultivation of switchgrass in semi-arid areas. There are limited reports on the molecular basis of combined abiotic stress tolerance in switchgrass, particularly the combination of drought and heat stress. We used transcriptomic approaches to elucidate the changes in the response of switchgrass to drought and high temperature simultaneously.

Results
We conducted solely drought treatment in switchgrass plant Alamo AP13 by withholding water after 45 days of growing. For the combination of drought and heat effect, heat treatment (35 °C/25 °C day/night) was imposed after 72 h of the initiation of drought. Samples were collected at 0 h, 72 h, 96 h, 120 h, 144 h, and 168 h after treatment imposition, total RNA was extracted, and RNA-Seq conducted. Out of a total of 32,190 genes, we identified 3912, as drought (DT) responsive genes, 2339 and 4635 as, heat (HT) and drought and heat (DTHT) responsive genes, respectively. There were 209, 106, and 220 transcription factors (TFs) differentially expressed under DT, HT and DTHT respectively. Gene ontology annotation identified the metabolic process as the significant term enriched in DTHT genes. Other biological processes identified in DTHT responsive genes included: response to water, photosynthesis, oxidation-reduction processes, and response to stress. KEGG pathway enrichment analysis on DT and DTHT responsive genes revealed that TFs and genes controlling phenylpropanoid pathways were important for individual as well as combined stress response. For example, hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferase (HCT) from the phenylpropanoid pathway was induced by single DT and combinations of DTHT stress.

Conclusion
Through RNA-Seq analysis, we have identified unique and overlapping genes in response to DT and combined DTHT stress in switchgrass. The combination of DT and HT stress may affect the photosynthetic machinery and phenylpropanoid pathway of switchgrass which negatively impacts lignin synthesis and biomass production of switchgrass. The biological function of genes identified particularly in response to DTHT stress could further be confirmed by techniques such as single point mutation or RNAi.