One- and Two-Stage Arrhenius Models for Pharmaceutical Shelf Life Prediction

One of the most challenging aspects of the pharmaceutical development is the demonstration and estimation of chemical stability. It is imperative that pharmaceutical products be stable for two or more years. Long-term stability studies are required to support such shelf life claim at registration. However, during drug development to facilitate formulation and dosage form selection, an accelerated stability study with stressed storage condition is preferred to quickly obtain a good prediction of shelf life under ambient storage conditions. Such a prediction typically uses Arrhenius equation that describes relationship between degradation rate and temperature (and humidity). Existing methods usually rely on the assumption of normality of the errors. In addition, shelf life projection is usually based on confidence band of a regression line. However, the coverage probability of a method is often overlooked or under-reported. In this paper, we introduce two nonparametric bootstrap procedures for shelf life estimation based on accelerated stability testing, and compare them with a one-stage nonlinear Arrhenius prediction model. Our simulation results demonstrate that one-stage nonlinear Arrhenius method has significant lower coverage than nominal levels. Our bootstrap method gave better coverage and led to a shelf life prediction closer to that based on long-term stability data.     

Y-configuration double-stent-retriever thrombectomy for refractory thrombus in middle cerebral artery bifurcation: A case report

Rationale:Stent retriever mechanical thrombectomy is a recommended treatment for acute ischemic stroke. However, refractory thrombus in artery bifurcation can reduce the rate of successful revascularization.Patient concerns:A 72-year-old male, owing to the acute onset of almost complete right-sided hemiplegia and global aphasia, received bridging therapy. National Institutes of Health Stroke Scale score was 16 at the time of admission.Diagnoses:Cerebral digital subtraction angiography revealed occlusion of the M1 segment of the left MCA.Interventions:Thrombectomy with 3 passes of the Solitaire FR device (Medtronic, Minneapolis, MN) was unsuccessful. Two stent retrievers were inserted in parallel by one microcatheter access point to each M2 branch, and then both stents were gradually retrieved out of the catheter while continuous suction was maintained.Outcomes:After thrombectomy, subsequent follow-up angiograms showed mTICI 3 reperfusion of MCA. The patient has mRS 2 at discharge and the 3-month mRS score after stroke is 1 score.Lessons:The presented Y-configuration double-stent-retriever thrombectomy technique constitutes a safe and effective rescue treatment method for refractory thrombus in MCA bifurcation.     

Altered oral microbiota composition associated with recurrent aphthous stomatitis in young females

Oral microbiota has been implicated in pathogenesis of recurrent aphthous stomatitis (RAS), which is a common mucosal disorder with unclear etiology. This study has explored the association between oral microbiota disorder and RAS in high-risk young female population.Forty-five young females were enrolled, including 24 RAS patients and 21 healthy individuals. Oral microbiome was analyzed by Illumina Miseq sequencing.Oral microbiota associated with RAS was characterized by the lower alpha-diversity indices (Chao1 and ACE). Several infectious pathogens increased in RAS, such as genera Actinobacillus, Haemophilus, Prevotella and Vibrio. The PICRUSt analysis indicated that the oral microbiota might be related with the up-regulation of genes involving infectious and neurodegenerative diseases, environmental adaptation, the down-regulation of genes involving basal metabolism, such as carbohydrate, energy, and amino acid metabolism.This study indicated that oral microbiota may play a significant role in RAS development.     

Self-administered acupressure for chronic severe functional constipation: A study protocol for a randomized controlled trial

Background:Functional constipation is a disease with a high incidence, which has a bad effect on general health, mental health, and social functioning. However, current treatment is sometimes unsatisfactory. Acupuncture has been proven effective in some randomized controlled trials. Acupressure is a subtype of acupuncture and can be manipulated by the patients at home. But the evidence is limited now. This study aims to provide some strict evidence for the use of self-administered acupressure in the treatment of functional constipation.Methods:This 2-armed, parallel, nonspecific controlled, randomized trial will be conducted at The Third Affiliated Hospital of Zhejiang Chinese Medical University in Hangzhou. A total of 154 FC patients will be enrolled into the acupoint group and the sham acupoint group with a ratio of 1:1 into this trial and it will consist of a 2-week run-in period, an 8-week intervention period, and an 8-week follow-up period. The treatment will be done by the patients themselves at home twice a day and they should sign in on the WeChat APP every day to make sure they have done the acupressure. The outcome will also be collected in WeChat APP through the diary and questionnaires. For the one who is unable to use the WeChat, the print edition of the diary and questionnaires are provided and the supervision will be done by the short message. The primary outcome will be the proportion of participants whose CSBM≥3 during week 3 to 10. The secondary outcome will be the proportion of participants whose CSBM ≥3 between 2 groups in week 11 to 18, Spontaneous bowel movements, Bristol Stool Form Scale, Straining severity scores, Patient assessment of constipation quality of life, and Medicine use.Discussion:Acupressure is not an invasive method and can be done by the patient itself at home. We hope this trial will provide credible evidence to the application of self-acupressure for the management of severe chronic functional constipation.Trial registration:This trial has been registered at the Chinese Clinical Trial Registry (ChiCTR2000038594).     

Abnormal Anterior Cingulate N-Acetylaspartate and Executive Functioning in Treatment-Resistant Depression After rTMS Therapy

Background:

Cognitive impairment is a key feature of treatment-resistant depression (TRD) and can be related to the anterior cingulate cortex (ACC) function. Repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the last two decades. However, no studies to date have investigated the association between neurobiochemical changes within the anterior cingulate and executive dysfunction measured in TRD being treated with rTMS.

Methods:

Thirty-two young depressed patients with treatment-resistant unipolar depression were enrolled in a double-blind, randomized study [active (n=18) vs. sham (n=14)]. ACC metabolism was investigated before and after high-frequency (15Hz) rTMS using 3-tesla proton magnetic resonance spectroscopy (1H-MRS). The results were compared with 28 age- and gender-matched healthy controls. Executive functioning was measured with the Wisconsin Card Sorting Test (WCST) among 34 subjects with TRD and 28 healthy subjects.

Results:

Significant reductions in N-acetylaspartate (NAA) and choline-containingCompound levels in the left ACC were found in subjects with TRD pre-rTMS when compared with healthy controls. After successful treatment, NAA levels increased significantly in the left ACC of subjects and were not different from those of age-matched controls. In the WCST, more perseverative errors and fewer correct numbers were observed in TRD subjects at baseline. Improvements in both perseverative errors and correct numbers occurred after active rTMS. In addition, improvement of perseverative errors was positively correlated with enhancement of NAA levels in the left ACC in the active rTMS group.

Conclusions:

Our results suggest that the NAA concentration in the left ACC is associated with an improvement in cognitive functioning among subjects with TRD response to active rTMS.     

The global state of research in pain management of osteoarthritis (2000–2019): A 20-year visualized analysis

There has been a highly active area in the pain management of osteoarthritis (OA) over the past 2 decades. The study aims to unmask the global status and trends in this field.Publications on pain management of OA from 2000 to 2019 were retrieved from the Web of Science (WOS) database. The data were analyzed using bibliometric statistical methodology. The software VOS viewer was used for bibliographic coupling, co-authorship, co-citation, co-occurrence analysis and to investigate the publication trends in pain management of OA.A total of 8207 researches in amount were included. The relative research interests and number of publications indicated a rising trend. The USA made the greatest contribution to this field, with the most publications, total citations and the highest H-index, while Sweden had the highest average citation per publication. The most contributive organization was Boston University. The journal OA and Cartilage published the most relative articles. Researches could be grouped into 5 clusters based on co-occurrence network map: Health and Epidemiology; Sport Medicine; Clinical Study; Mechanism Research and Medical Technology and Science. Medical Technology and Science was predicted as the next research topic in this field.The number of publications about pain management of OA would be increasing based on current global trends. The USA made the largest contribution to this field. The development of Medical Technology and Science may be the next popular topics in the pain management of OA research.     

A meta-analysis on the relationship of exosomes and the prognosis of lung cancer

Background:A lot of research evidence shows that exosomes play an indelible role in the prognosis of lung cancer, but there are many disputes. Therefore, we conduct a meta-analysis to further demonstrate.Methods:A literature retrieval was performed through a search of PubMed, Embase, Web of Science, Cochrane, CKNI, Wanfang, and other databases to locate documents from the literature that satisfied the inclusion criteria. There were four outcome indicators: overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS). Subgroup analysis was conducted according to sample size, country, detection method, analysis method, and pathological type. Stata 14.0 software was used to evaluate the prognostic value of exosomes in lung cancer.Results:A total of 2456 patients with lung cancer from 29 studies in 16 articles were included. The expression level of exosomes was closely associated with the OS and DFS of patients, although no statistical difference was observed between exosomes and DSS or PFS. Eighteen studies with 2,110 patients were evaluated to examine the prognostic value of exosomes in lung cancer by exploring the association between exosomes and OS. The results showed that exosomes were strongly associated with worse OS, and the combined hazard ratio (HR) was 2.01 (95% confidence interval [CI]: 1.70–2.39, P = .000). Six studies investigated the association between exosomes and DFS, and showed a pooled HR of 2.48 (95% CI: 1.75–3.53, P = .000).Conclusion:Our analysis indicated that the expression level of exosomes was closely associated with the OS and DFS of patients with lung cancer, suggesting that exosomes are associated with poor prognosis of lung cancer. Exosomes may be a new biomarker for the prognosis of lung cancer, although a large number of prospective studies are still needed to support this.     

Risk factors of enteral feeding intolerance in severe acute pancreatitis patients: A protocol for systematic review and meta-analysis

Background:Patients with severe acute pancreatitis (SAP) have gastrointestinal dysfunction, and enteral nutrition intolerance is easy to occur during the implementation of enteral nutrition, which leads to the suspension or termination of enteral nutrition. Enteral nutrition cannot tolerate the influence of many factors. At present, there is a lack of analysis on the influencing factors of enteral nutrition intolerance in patients with SAP. Therefore, this study analyzed the factors of enteral nutrition intolerance in patients with SAP by meta-analysis, to provide a basis for the protection of enteral nutrition in patients with SAP.Methods:Databases (PubMed, Embase, Cochrane Library, Web of Science, China Biology Medicine Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, and Wanfang) were searched using index words to find relevant studies published before March 2021. Meta-analyses of relative risk were performed for the identification of risk factors.Results:We will disseminate the findings of this systematic review and meta-analysis via publications in peer-reviewed journals.Conclusion:This study systematically reviewed the existing evidence and determined the incidence and predictors of enteral nutrition intolerance in patients with SAP.     

Perioperative dexmedetomidine reduces emergence agitation without increasing the oculocardiac reflex in children: A systematic review and meta-analysis

Background:Intravenous dexmedetomidine (DEX) has been used to prevent emergence agitation (EA) in children. The aim of this meta-analysis was to evaluate whether DEX decreases EA incidence without augmenting oculocardiac reflex (OCR) in pediatric patients undergoing strabismus surgery.Methods:We searched PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), Wan Fang, and the Cochrane Library to collect the randomized controlled trials (RCTs) investigating the effects of intraoperative DEX in children undergoing strabismus surgery from inception to October 2019. Postoperative Pediatric Agitation and Emergence Delirium (PAED) score, postoperative EA, extubation or laryngeal mask airway (LMA) removal time, postanesthetic care unit (PACU) stay time, OCR, and postoperative vomiting (POV) were evaluated.Results:11 RCTs including 801 patients were included in this study. Compared with control group, intravenous DEX significantly reduced postoperative PAED score (WMD, 3.05; 95% CI: -3.82 to -2.27, P = .017) and incidences of postoperative EA 69% (RR, 0.31; 95% CI: 0.17 to 0.55, P < .00) and POV (RR, 0.28; 95% CI: 0.13 to 0.61, P = .001). Furthermore, the use of DEX significantly delayed extubation or LMA removal time (WMD, 2.11; 95% CI: 0.25 to 3.97, P < .001). No significant difference was found in the incidence of ORC and PACU stay time.Conclusion:Intravenous DEX reduced the incidences of EA without increasing OCR in pediatric patients undergoing strabismus surgery. Meanwhile, DEX infusion decreased the incidence of POV in children.     

The comparison of accuracy and practicability between ultrasound and spiral CT in the diagnosis of intestinal obstruction: A protocol for systematic review and meta-analysis

Background:Acute abdominal pain is often caused by intestinal obstruction, with high morbidity, and mortality, so that the early diagnosis is particularly important. Currently, both spiral CT and ultrasound are common imaging diagnostic methods. However, the accuracy and practicality of the diagnosis are controversial. Therefore, the purpose of this study is to systematically evaluate the accuracy and practicality of spiral CT and ultrasound in the diagnosis of intestinal obstruction.Methods:Retrieval of English database (PubMed, Embase, Web of Science, the Cochrane Library) and Chinese database (CNKI, WAN FANG, VIP, CBMDISC) by computers. From the establishment of the database to October 2020, a diagnostic experimental study on the diagnosis of intestinal obstruction by ultrasound and spiral CT was conducted. Two researchers independently conducted data extraction and quality evaluation of literature on the included studies, and Meta Disc1.4 and RevMan5.3 were used for meta-analysis on the included literature.Results:Sensitivity, specificity, po-sitive Likelihood ratio, NE-Gative likelihood ratio, diagnostic odds ratio and other indicators were used to determine the diagnostic efficacy of ultrasound and helical CT.Conclusion:This study is aimed at providing an evidence-based basis for clinicians to choose an appropriate or optimal diagnostic method by comparison of the accuracy and practicality between spiral CT and ultrasound in the diagnosis of intestinal obstruction.Ethics and dissemination:The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.OSF Registration number:DOI 10.17605/ OSF.IO / Q5RNS.