bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of siponimod for multiple sclerosis
Authors: Song Yumeng , Lao Yongfeng , Liang Fuxiang , Li Jing , Jia Bibo , Wang Zixuan , Hui Xu , Lu Zhenxing , Zhou Biao , Luo Wei , Song Bing
Published: August 2019

Background:

Multiple sclerosis is the most common demyelinating disease of the central nervous system with serious social and economic burden. Siponimod is a sphingosine-1-phosphate receptor agonist, and clinical trials in the past decade have shown good prospects for the treatment of multiple sclerosis. But there is a lack of comprehensive understanding of the dose–effect relationship and safety in different subtypes of multiple sclerosis at present.

Methods:

We will perform a systematic review and meta-analysis of clinical randomized controlled trials to evaluate the efficacy and safety of siponimod in multiple sclerosis. We will search PubMed, EMBASE, Cochrane Library, Clinical Trials, Cochrane Central Register of Controlled Trials (CENTRAL) using a comprehensive strategy. The reference lists of the articles we select for inclusion will be checked to identify additional studies for potential inclusion. Two reviewers will review all literature independently. Upon inclusion of articles, another 2 reviewers will extract available data using a standardized form and assess the potential bias. Review Manager will be used to conduct data synthesis. There is no requirement of ethical approval and informed consent.

Result:

This is the first systematic assessment of siponimod for the treatment of multiple sclerosis. We predict it will provide high-quality synthesis of existing evidence for the efficacy and safety of siponimod for multiple sclerosis and a relatively comprehensive reference for clinical practice and clinical trials about siponimod to be conducted.

Conclusion:

The results of the systematic review and meta-analysis will provide updated evidence for the use of siponimod for multiple sclerosis.

Registration:

The systematic review and meta-analysis is registered in the PROSPERO international prospective register of systematic review (PROSPERO#CRD42018112721).
Perioperative combined administration of tranexamic acid and dexamethasone in total knee arthroplasty—benefit versus harm?
Authors: Yu You , Lin Hai , Wu Zhitao , Xu Peng , Lei Zhengliang
Published: August 2019

Background:

The purpose of this study was to investigate the benefits and harm of combined administration of tranexamic acid (TXA) and dexamethasone (Dexa) in total knee arthroplasty (TKA).

Methods:

A total of 88 consecutive patients undergoing TKA for knee osteoarthritis were stratified in 2 groups. All surgeries were performed under general anesthesia. Brief, patients in the TXA + Dexa group (n = 45) received 10 mg Dexa just after the anesthesia, and repeated at 24 hours after the surgery; and patients in the TXA group (n = 43) received 2 ml of normal saline solution at the same time. The measured outcomes were the C-reactive protein (CRP) and interleukin-6 (IL-6) from preoperatively to postoperatively, and postoperative nausea and vomiting (PONV), fatigue, range of motion (ROM), length of stay (LOS), and the analgesic and antiemetic rescue consumption

Results:

The level of CRP and IL-6 in the TXA + Dexa group were lower than that in the TXA group at 24 hours (P < .001, P < .001), 48 hours (P < .001, P < .001), and 72 hours (P < .001, P < .001) after the surgery. The pain scores in the TXA + Dexa group were lower during walking at 24 hours (P < .001), 48 hours (P < .001), and 72 hours (P < .001) and at rest at 24 hours (P = .022) after the surgery. Patients in the TXA + Dexa group had a lower nausea score, the incidence of PONV, fatigue, and the analgesic and antiemetic rescue consumption, and had a greater ROM than that in the TXA group. No significant differences were found in LOS and complications.

Conclusion:

The combined administration of TXA + Dexa significantly reduced the level of postoperative CRP and IL-6, relieve postoperative pain, ameliorate the incidence of POVN, provide additional analgesic and antiemetic effects, reduce postoperative fatigue, and improve ROM, without increasing the risk of complications in primary TKA.
Low serum vitamin D levels increase the mortality of cardiovascular disease in older adults
Authors: Yang Jun , Ou-Yang Juan , Huang Ji
Published: August 2019

Lower circulating vitamin D is common in older adults and may be a potential reversible risk factor for cardiovascular disease (CVD) in older adults, however, presented controversial results.

Database was searched update to February 2018. Key data were extracted from eligible studies. Dose–response meta-analysis were conducted for synthesizing data from eligible studies.

A total of 13 eligible studies involving 21,079 participants were included in this meta-analysis. Person with lower 25-hydroxyvitamin D status (25 (OH)D level <50 nmol/L) appeared to have higher mortality of CVD in older adults (RR = 1.54, 95% CI 1.24–1.91). Furthermore, a significantly higher mortality of CVD in older adults was observed for the deficient (<25 nmol/L; RR = 1.47, 95% CI 1.15–1.81) and insufficient (25–50 nmol/L; RR = 1.16, 95% CI 1.04–1.27) categories of 25 (OH)D, compared to the reference category of >75 nmol/L. Additionally, decrease of 10 nmol/L 25-hydroxyvitamin D was associated with a 7% incremental in the risk of CVD mortality in older adults.

Considering these promising results, circulating vitamin D is associated with CVD mortality increment in older adults.
Extranodal natural killer/T-cell lymphoma nasal type with central nervous system involvement mimicked tuberculous meningitis
Authors: Yang Yina , Li Zhouling , Zhiyang Chen , Liang Hui
Published: August 2019

Rationale:

Neurologic deficits are rare in patients with extranodal natural killer/T-cell lymphoma (NKTL), nasal type. We present a case that was initially suspected as tuberculous meningitis, but later diagnosed as central nervous system metastasis of NKTL, nasal type, which has never been published previously.

Patient concerns:

A 55-year-old Chinese man presented with persistent headache and fever. The initial head computed tomography and magnetic resonance imaging (MRI) scan was normal. Low glucose, elevated protein, and pleocytosis of cerebral spinal fluid led to a diagnosis of tuberculous meningitis. The patient did not respond to anti-tuberculosis treatment, and his symptoms aggravated. MRI showed abnormal lesions in the right hemisphere and a lesion in the maxillary sinus region.

Diagnosis:

Endoscopic biopsy of the maxillary lesion showed features consistent with NKTL. Positron emission tomography revealed a hypermetabolic mass involving the right maxillary sinus and brain.

Interventions:

The patient received chemotherapy.

Outcomes:

The patient died 30 days after chemotherapy.

Lessons:

Lymphoma of the nasal cavity and paranasal sinuses is extremely rare and may be easily misdiagnosed. Nasal NKTL metastasis should be considered when a patient presents with symptoms of leptomeningeal involvement.
Vertebral collapse and polymethylmethacrylate breakage after vertebroplasty
Authors: Huang Anquan , Fang Shenyun , Wang Liyu , Xu Renjie , Shen Jun , Zhu Guoqing , Miao Ye , Zou Tianming
Published: August 2019

Rationale:

Vertebral augmentation has become the main treatment for osteoporotic vertebral fractures (VFs). In this article, we report a very rare case of vertebral collapse and polymethylmethacrylate (PMMA) breakage after vertebroplasty. We describe the clinical characteristics and revision surgery performed to remove the broken PMMA cement, maintain stability, and corrects the kyphotic deformity, and we analyze the possible causes.

Patient concerns:

A 72-year-old man who suffered back pain underwent first lumbar vertebra (L1) percutaneous vertebroplasty (PVP) due to osteoporosis and a vertebral fracture in May 2013. Postoperatively, the patient's back pain was markedly alleviated. Unfortunately, his lumbar back pain recurred in November 2015.

Diagnoses:

Plain radiographs showed collapse of the L1 vertebral body, breakage of the PMMA cement, and severe kyphosis at the thoracolumbar junction.

Interventions:

The posterior pedicle was internally fixed and an anterior artificial vertebral body implant was placed to maintain stability and correct the kyphotic deformity in a 2-step surgical procedure.

Outcomes:

The back pain was alleviated and the patient returned to daily life for more than two years.

Lessons:

This case demonstrates that PVP is not a simple minimally invasive surgery, and significant postsurgical care is necessary. The true cause of this rare phenomenon remains unclear, but the long-term use of steroids, new injuries, and poorly corrected kyphosis after PVP may play a role. Surgeons must be aware of the kinds of complications that may occur, including rare complications such as vertebral lysis.
Comparison of 2 approaches in management of pregnant women with inherited trombophilias
Authors: Dugalic Stefan , Petronijevic Milos , Stefanovic Aleksandar , Stefanovic Katarina , Petronijevic Svetlana Vrzic , Stanisavljevic Dejana , Kepeci Sonja Perkovic , Milincic Nemanja , Pantic Igor , Perovic Milan
Published: August 2019

Previous adverse pregnancy outcomes (APO) in women with hereditary thrombophilia have emerged as new indications for prophylactic use of low-molecular-weight heparin (LMWH) during pregnancy. Recent meta-analysis conducted to establish if LMWH may prevent recurrent placenta-mediated pregnancy complications point to important therapeutic effect but these findings are absolutely not universal. Furthermore, previous studies regarding LMWH prophylaxis for APO in women with inherited thrombophilia were performed in high risk patients with previous adverse health outcomes in medical, family and/or obstetric history. Therefore, the aim of this study was to investigate the effects of LMWH prophylaxis on pregnancy outcomes in women with inherited thrombophilias regardless of the presence of previous adverse health outcomes in medical, family, and obstetric history.

Prospective analytical cohort study included all referred women with inherited thrombophilia between 11 and 15 weeks of gestation and followed-up to delivery. Patients were allocated in group with LWMH prophylaxis (study group) and control group without LWMH prophylaxis. The groups were compared for laboratory parameters and Doppler flows of umbilical artery at 28th to 30th, 32nd to 34th and 36th to 38th gestational weeks (gw), and for obstetric and perinatal outcomes.

The study group included 221 women and control group included 137 women. Mean resistance index of the umbilical artery Ri in 28 to 30, 32 to 34, and 36 to 38 gw were significantly higher in the control group compared to study group (0.71 ± 0.02 vs 0.69 ± 0.02; 0.67 ± 0.03 vs 0.64 ± 0.02; and 0.67 ± 0.05 vs 0.54 ± 0.08, respectively). Intrauterine fetal death (IUFD) and miscarriages were statistically significantly more frequent in control group compared to the patients in study (P < .001). The frequencies of fetal growth restriction (FGR) and APO were significantly higher in the control group compared to the study group (P = .008 and P < .001, respectively). In a multivariate regression model with APO as a dependent variable, only Ri was detected as a significant protective factor for APO, after adjusting for age and LMWH prophylaxis (P < .001).

We have demonstrated better perinatal outcomes in women with LMWH prophylaxis for APO compared to untreated women.
Rare concurrence of ectopic intrathyroidal parathyroid gland and papillary thyroid carcinoma within a thyroid lobe
Authors: Chen Jianguo , Wan Yingying , Chen Shuguang
Published: August 2019

Rationale:

The inferior parathyroid glands derive from the third branchial pouch and seldom ectopically migrate to thyroid grand, mediastinum, thymus. Ectopic intrathyroidal parathyroid grand (ETPG) is rare and it cannot be consistently detected by any imaging examinations. The unusual ETPG is easily resected during thyroidectomy, which might cause postoperative hypoparathyroidism. Auto-transplantation of even a parathyroid gland can restore parathyroid function to some extent. Until now, there are not any guidelines on the management of ETPG.

Patient concerns:

Without any symptoms, a 27-year-old female patient was admitted to our hospital for a thyroid nodule. Thyroid ultrasonography demonstrated a hypoechoic nodule, measuring 0.6 cm × 0.6 cm × 0.7 cm, with multiple punctate micro-calcifications within the right thyroid lobe. Thyroid function tests were normal. The invasive fine needle aspiration cytology for the thyroid nodule was rejected by patient.

Diagnoses:

The patient was firstly diagnosed as right thyroid hypoechoic nodule, which was pathologically proved to be papillary thyroid carcinoma (PTC) finally.

Interventions:

The patient underwent right thyroidectomy, central compartment neck dissection, parathyroid exploration, and auto-transplantation of the normal ETPG.

Outcomes:

The right thyroid hypoechoic nodule was diagnosed as PTC by pathological examination. The inferior parathyroid gland could not found in normal locations. On the cut surface of excised thyroid lobe, a yellow and soft nodule was discovered and it was pathologically diagnosed as a normal parathyroid grand. In the end, auto-transplantation of the normal ETPG was conducted. Postoperative follow-ups found both serum calcium and parathyroid hormone tests were normal.

Lessons:

ETPG in a patient with PTC is easily overlooked and unexpectedly excised for its rarity. ETPG brings about a failed parathyroid exploration. However, within the thyroid parenchyma, it might be occasionally discovered by cutting a thyroid lobe into slices. Auto-transplantation of normal ETPG is necessary.
Finite element analysis of spiral plate and Herbert screw fixation for treatment of midshaft clavicle fractures
Authors: Zhang Xiaojuan , Cheng Xiaodong , Yin Bing , Wang Jianzhao , Li Sheng , Liu Guobin , Hu Zusheng , Wu Weiwei , Zhang Yingze
Published: August 2019

Both spiral plate and Herbert screw fixations have been clinically adopted for treating midshaft displaced clavicle fractures. However, the biomechanical properties of the 2 implant fixations have not yet been thoroughly evaluated. Here we report the results of a finite element analysis of the biomechanical properties of midshaft clavicle fractures treated with Herbert screw and spiral plate fixation. Hebert screw fixation showed stress distribution similar to intact clavicle under all loading conditions, but provided less stability than did spiral plate fixation. Postoperatively, excessive shoulder activities and weight-bearing should be avoided. Spiral plate fixation provides greater stability, but is associated with stress shielding. These results demonstrate that Herbert screw fixation is suitable for the treatment of simple displaced clavicluar fractures, but excessive shoulder activity and weight-bearing should be avoided after the operation. Therefore, spiral plate fixation may be preferred for patients requiring an early return to activity.
A study on the paraspinal muscle surface electromyography in acute nonspecific lower back pain
Authors: Qiao Jie , Zhang Shu-Li , Zhang Jun , Feng Dan
Published: August 2019

Aim of this study was to determine if surface electromyography (sEMG) could provide objective data in monitoring the alteration of signal amplitude of myoelectric activity of the paraspinal muscles in the patients with acute nonspecific lower back pain (ANLBP), and to explore the correlation between sEMG data and symptom relief in the ANLBP patients before and after massage therapy.

Forty-five ANLBP patients and 20 healthy subjects were enrolled into this study. Patients were given massage therapy for 1 week. The average electromyography (AEMG), visual analogue scale (VAS), and distance of finger to floor (DFTF) were measured before and after treatment.

AEMG at flexion and maintained flexion positions were significantly higher in the ANLBP group compared to that in the control group. At extension position, in contrast, AEMG was significantly lower in the ANLBP patients than that of control group, and there was no significant difference between the 2 groups at upright position. After massage therapy for the ANLBP patients, AEMG was significantly reduced at flexion and maintained flexion positions, but significantly increased at extension position than that before treatment. VAS and DFTF were also significantly reduced after treatment. In addition, AEMG alteration at maintained flexion position was significantly correlated with improvement of VAS or DFTF.

Myoelectric activity of the paraspinal muscles in the ANLBP patients was different from that of healthy subjects. Massage therapy not only relived patients’ symptoms, but also normalized myoelectric activity of the paraspinal muscles in the ANLBP patients.
Clinical characteristics and chest computed tomography findings of smear-positive and smear-negative pulmonary tuberculosis in hospitalized adult patients
Authors: Kim Jong Hun , Kim Min Ja , Ham Soo-Youn
Published: August 2019

Pulmonary tuberculosis (PTB) continues to be one of the significant public health threats with significant morbidity and mortality. The present study was aimed to assess the clinical characteristics and chest computed tomography (CT) findings of smear-positive and smear-negative PTB in hospitalized adult patients.

Hospitalized adult patients diagnosed with PTB by positive Mycobacterium tuberculosis growth on acid-fast bacilli culture from bronchial aspiration or sputum from 2015 to 2017 were reviewed. Only the patients who had chest CT within 14 days of the diagnosis of PTB were included. Medical records and CT images were analyzed.

A total of 189 patients was enrolled. The median age was 62 years, and there were 118 males (62.4%). More than half of the patients had underlying chronic medical conditions (55.5%). The most common CT finding was nodular lesions (96.8%). The patients were categorized in 2 groups of smear-positive (n = 94, 49.7%) and smear-negative (n = 95, 50.3%). Between 2 groups, there was no difference in underlying medical conditions. However, there were more lesions of cavity, consolidation, bronchiectasis, upper lobe involvement, multiple lobe involvement, and lymphadenopathy in the smear-positive group. A predictive model for smear-positive tuberculosis was created based on the comparison analysis that had an area of 0.724 under the receiver operating characteristic curve. In a multivariate logistic regression analysis, CT findings of consolidation (odds ratio [OR] 2.521, 95% confidence interval [CI] 1.175–5.408, P = .02), lymphadenopathy (OR 1.947, 95% CI 1.025–3.696, P = .04), and multi-lobe involvement (OR 2.795, 95% CI 1.084–7.205, P = .03) were associated with smear-positive PTB.

PTB patients who have chest CT findings of cavity, consolidation, bronchiectasis, upper lobe involvement, multiple lobe involvement, and lymphadenopathy may be at higher risk for smear-positive TB. A predictive model may be helpful for further assessment.
Integrated analysis of circular RNA-associated ceRNA network in cervical cancer
Authors: Gong Jun , Jiang Hui , Shu Chang , Hu Mei-qin , Huang Yan , Liu Qin , Li Rong-feng , Wei Yin-zhi
Published: August 2019

Background:

Circular RNAs (circRNAs) have displayed dysregulated expression in several types of cancer. Nevertheless, their function and underlying mechanisms in cervical cancer remains largely unknown. This study aimed to describe the regulatory mechanisms in cervical cancer.

Methods:

We downloaded the circRNAs expression profiles from Gene Expression Omnibus database, and RNAs expression profiles from The Cancer Genome Atlas database. We established a circRNA-miRNA-mRNA and circRNA-miRNA-hubgene network. The interactions between proteins were analyzed using the STRING database and hubgenes were identified using MCODE plugin. Then, we conducted a circRNA-miRNA-hubgenes regulatory module. Functional and pathway enrichment analyses were conducted using R packages “Clusterprofile”.

Results:

Six circRNAs, 15 miRNAs, and 158 mRNAs were identified to construct the ceRNA network of cervical cancer. PPI (protein-protein interaction) network and module analysis identified 7 hubgenes. Then, a circRNA-miRNA-hubgene subnetwork was constructed based on the 1 DEcircRNAs, 3 DEmiRNAs, and 3 DEmRNAs. The KEGG pathway analysis indicated DEmRNAs are involved in progesterone-mediated oocyte maturation, cell cycle, and oocyte meiosis.

Conclusion:

These ceRNAs are critical in the pathogenesis of cervical and may serve as future therapeutic biomarkers.
Epidemiologic features of shigellosis and associated climatic factors in Taiwan
Authors: Chen Chian-Ching , Lin Chuan-Yao , Chen Kow-Tong
Published: August 2019

The consistent, sporadic transmission of shigellosis in Taiwan necessitates an exploration of risk factors for the occurrence of shigellosis. The purpose of this study was to study the epidemiologic characteristics and the relationship between climatic factors and the incidence of shigellosis in Taiwan. We collected data from cases of shigellosis reported to the Taiwan Centers for Disease Control (Taiwan CDC) from 2001 to 2016. Climatic data were obtained from the Taiwan Central Weather Bureau. The relationships between weather variability and the incidence of shigellosis in Taiwan were determined via Poisson regression analyses. During the 16-year study period, a total of 4171 clinical cases of shigellosis were reported to the Taiwan CDC. Among them, 1926 (46.2%) were classified as confirmed cases. The incidence of shigellosis showed significant seasonality, with the majority of cases occurring in summertime (for oscillation, P < .001). The number of shigellosis cases started to increase when temperatures reached 21°C (r2 = 0.88, P < .001). Similarly, the number of shigellosis cases began to increase at a relative humidity of 70–74% (r2 = 0.75, P < .005). The number of shigellosis cases was positively associated with the mean temperature and relative humidity in the period preceding the infection. In conclusion, the occurrence of shigellosis is significantly associated with increasing temperature and relative humidity in Taiwan. Therefore, these factors could be regarded as warning signals indicating the need to implement preventive measures.
Predictive performance of plasma neutrophil gelatinase-associated lipocalin for neurologic outcomes in out-of-hospital cardiac arrest patients treated with targeted temperature management
Authors: Lee Ji Hwan , Park Incheol , You Je Sung , Kim Min Joung , Lee Hye Sun , Park Yoo Seok , Park Hyeong Cheon , Chung Sung Phil
Published: August 2019

Few studies have demonstrated the prognostic potential of neutrophil gelatinase-associated lipocalin (NGAL) in post-cardiac arrest patients. This study evaluated the usefulness of plasma NGAL in predicting neurologic outcome and mortality in out-of-hospital cardiac arrest (OHCA) patients treated with targeted temperature management (TTM). A prospective observational study was conducted between October 2013 and April 2016 at a single tertiary hospital. We enrolled 75 patients treated with TTM and collected their demographic data, cardiopulmonary resuscitation-related information, data on plasma NGAL concentration, and prognostic test results. Plasma NGAL was measured at 4 hours after return of spontaneous circulation (ROSC). The primary endpoint was the neurologic outcome at discharge and the secondary outcome was 28-day mortality. Neurologic outcomes were analyzed using a stepwise multivariate logistic regression while 28-day mortality was analyzed using a stepwise Cox regression. The predictive performance of plasma NGAL for neurologic outcome was measured by the area under the receiver operating characteristic curve and the predictability of 28-day mortality was measured using Harrell C-index. We also compared the predictive performance of plasma NGAL to that of other traditional prognostic modalities for outcome variables. Thirty patients (40%) had good neurologic outcomes and 53 (70.7%) survived for more than 28 days. Plasma NGAL in patients with good neurologic outcomes was 122.7 ± 146.7 ng/ml, which was significantly lower than that in the poor neurologic outcome group (307.5 ± 269.6 ng/ml; P < .001). The probability of a poor neurologic outcome was more than 3.3-fold in the NGAL >124.3 ng/ml group (odds ratio, 3.321; 95% confidence interval [CI], 1.265–8.721]). Plasma NGAL in the survived group was significantly lower than that in the non-survived group (172.7 ± 191.6 vs 379.9 ± 297.8 ng/ml; P = .005). Plasma NGAL was significantly correlated with 28-day mortality (hazard ratio 1.003, 95% CI 1.001–1.004; P < .001). The predictive performance of plasma NGAL was not inferior to that of other prognostic modalities except electroencephalography. Plasma NGAL is valuable for predicting the neurologic outcome and 28-day mortality of patients with OHCA at an early stage after ROSC.

This study was registered at ClinicalTrials.gov on November 19, 2013 (Identifier: NCT01987466).
Characterisation of blood microbiota in patients with liver cirrhosis
Authors: Kajihara Mikio , Koido Shigeo , Kanai Tomoya , Ito Zensho , Matsumoto Yoshihiro , Takakura Kazuki , Saruta Masayuki , Kato Kumiko , Odamaki Toshitaka , Xiao Jin-zhong , Sato Nobuhiro , Ohkusa Toshifumi
Published: August 2019

Background and aims

Bacterial infections arising in patients with liver cirrhosis are associated with life-threatening complications such as hepatic encephalopathy and spontaneous bacterial peritonitis in relation to bacterial translocation. To investigate the state of bacterial translocation, we surveyed the peripheral blood microbiota by 16S rRNA gene sequencing and analysed the blood microbial profiles.

Methods

Sixty-six patients with liver cirrhosis were enrolled in this study, whereas 14 healthy individuals were also analysed as controls. Total RNA was purified from the peripheral blood, and an approximately 430 base pair genomic locus which included the V3-V4 region of the 16s rRNA gene was amplified and assessed using bacterial pyrosequencing.

Results

At the genus level, a total of 183 operational taxonomic units were identified in cirrhotic patients, whereas 123 units in controls. Intergroup differences in gut microbiota were analysed by the linear discriminant analysis effect size, which showed that the abundance of Enterobacteriaceae was significantly higher in cirrhotics. On the contrary, the abundance of Akkermansia, Rikenellaceae and Erysipelotrichales were significantly lower in cirrhotics (relative abundance of Akkermansia in cirrhotics and controls: 0% and 0.2%, respectively; Rikenellaceae: 0.1% and 0.92%; Erysipelotrichales: 0.58% and 1.21%).

Conclusion

The present study has demonstrated that various circulating bacteria are present in cirrhotic patients, and the diversity of such bacteria is consistent with the presence of dysbiosis in cirrhotics. Although the clinical significance of the findings remains to be clarified, the findings may potentially facilitate diagnostic and therapeutic attempts to comprehend and furthermore to manipulate bacterial infections in cirrhotic patients.
The correlations between hepatitis B virus infection and hepatocellular carcinoma with portal vein tumor thrombus or extrahepatic metastasis
Authors: Chen Jie , Shi Xianmao , Luo Tao , Zhao Yuan , Ye Jiazhou , Bai Tao , Li Lequn
Published: August 2019

Background:

Portal vein tumor thrombus (PVTT) and extrahepatic metastasis are associated with the prognosis of hepatocellular carcinoma (HCC). We aimed to investigate the effect of hepatitis B virus (HBV) infection on HCC patients with PVTT or extrahepatic metastasis.

Patients and methods:

The clinical data of 639 patients with HCC from our hospital were retrospectively analyzed to analyze the correlation between HBV and HCC with PVTT or extrahepatic metastasis.

Results:

Univariate analysis revealed that positive hepatitis B virus surface antigen (HBsAg), a detectable serum hepatitis B virus DNA load (>500 IU/ml), cirrhosis and ascites were associated with the presence of PVTT. Positive hepatitis B virus e antigen (HBeAg), cirrhosis and ascites were associated with the presence of extrahepatic metastasis. In a multivariate regression analysis carried out a detectable serum hepatitis B virus DNA load, cirrhosis and ascites were independent risk factors of PVTT. Ascites was an independent risk factor of extrahepatic metastasis. The patients in the PVTT of type III/IV group and the PVTT of type I/II group had a significantly higher rate of positive serum HBsAg, a detectable serum hepatitis B virus DNA load (>500 IU/ml) and HBsAg + HBeAb + HBcAb test positive compared with those in the PVTT-negative group. HBsAg + HBeAb + HBcAb test positive was significantly associated with the presence of extrahepatic metastasis (P=0.028).

Conclusions:

HBV infection and replication status are associated with the formation of PVTT or extrahepatic metastasis in patients with HCC.
The legacy of larval infection on immunological dynamics over metamorphosis
Authors: Critchlow Justin T. , Norris Adriana , Tate Ann T.
Published: August 2019

Insect metamorphosis promotes the exploration of different ecological niches, as well as exposure to different parasites, across life stages. Adaptation should favour immune responses that are tailored to specific microbial threats, with the potential for metamorphosis to decouple the underlying genetic or physiological basis of immune responses in each stage. However, we do not have a good understanding of how early-life exposure to parasites influences immune responses in subsequent life stages. Is there a developmental legacy of larval infection in holometabolous insect hosts? To address this question, we exposed flour beetle (Tribolium castaneum) larvae to a protozoan parasite that inhabits the midgut of larvae and adults despite clearance during metamorphosis. We quantified the expression of relevant immune genes in the gut and whole body of exposed and unexposed individuals during the larval, pupal and adult stages. Our results suggest that parasite exposure induces the differential expression of several immune genes in the larval stage that persist into subsequent stages. We also demonstrate that immune gene expression covariance is partially decoupled among tissues and life stages. These results suggest that larval infection can leave a lasting imprint on immune phenotypes, with implications for the evolution of metamorphosis and immune systems.

This article is part of the theme issue ‘The evolution of complete metamorphosis'.
Antipredator strategies of pupae: how to avoid predation in an immobile life stage?
Authors: Lindstedt Carita , Murphy Liam , Mappes Johanna
Published: August 2019

Antipredator strategies of the pupal stage in insects have received little attention in comparison to larval or adult stages. This is despite the fact that predation risk can be high during the pupal stage, making it a critical stage for subsequent fitness. The immobile pupae are not, however, defenceless; a wide range of antipredator strategies have evolved against invertebrate and vertebrate predators. The most common strategy seems to be ‘avoiding encounters with predators' by actively hiding in vegetation and soil or via cryptic coloration and masquerade. Pupae have also evolved behavioural and secondary defences such as defensive toxins, physical defences or deimatic movements and sounds. Interestingly, warning coloration used to advertise unprofitability has evolved very rarely, even though the pupal stage often contains defensive toxins in chemically defended species. In some species, pupae gain protection from conspecifics or mimic chemical and auditory signals and thereby manipulate other species to protect them. Our literature survey highlights the importance of studying selection pressures across an individual's life stages to predict how ontogenetic variation in selective environments shapes individual fitness and population dynamics in insects. Finally, we also suggest interesting avenues for future research to pursue.

This article is part of the theme issue ‘The evolution of complete metamorphosis’.
Cooking up the perfect insect: Aristotle's transformational idea about the complete metamorphosis of insects
Authors: Reynolds Stuart
Published: August 2019

Aristotle made important contributions to the study of developmental biology, including the complete metamorphosis of insects. One concept in particular, that of the perfect or complete state, underlies Aristotle's ideas about metamorphosis, the necessity of fertilization for embryonic development, and whether morphogenesis involves an autonomous process of self-assembly. Importantly, the philosopher erroneously views metamorphosis as a necessary developmental response to lack of previous fertilization of the female parent, a view that is intimately connected with his readiness to accept the idea of the spontaneous generation of life. Aristotle's work underpins that of the major seventeenth century students of metamorphosis, Harvey, Redi, Malpighi and Swammerdam, all of whom make frequent reference to Aristotle in their writings. Although both Aristotle and Harvey are often credited with inspiring the later prolonged debate between proponents of epigenesis and preformation, neither actually held firm views on the subject. Aristotle's idea of the perfect stage also underlies his proposal that the eggs of holometabolous insects hatch ‘before their time’, an idea that is the direct precursor of the much later proposals by Lubbock and Berlese that the larval stages of holometabolous insects are due to the ‘premature hatching’ from the egg of an imperfect embryonic stage.

This article is part of the theme issue ‘The evolution of complete metamorphosis’.
89Zr-oxine labelling and PET imaging shows lung delivery of a cell/gene cancer therapy
Authors: Patrick P. Stephen , Kolluri Krishna K. , Thin May Z. , Edwards Adam , Sage Elizabeth K. , Sanderson Tom , Weil Benjamin D. , Dickson John C. , Lythgoe Mark F. , Lowdell Mark , Janes Sam M. , Kalber Tammy L.
Published: August 2019

Purpose

MSCTRAIL is a new stem cell-based therapy for lung cancer, currently in phase I evaluation (ClinicalTrials.gov ref: NCT03298763). Biodistribution of cell therapies is rarely assessed in clinical trials, despite cell delivery to the target site often being critical to presumed mechanism of action. This preclinical study demonstrates that MSCTRAIL biodistribution dynamics can be detected non-invasively using 89Zr-oxine labelling and PET imaging, thus supporting use of this cell tracking technology in phase II evaluation.

Methods

MSCTRAIL were radiolabelled with a range of 89Zr-oxine doses, and assayed for cell viability, phenotype and therapeutic efficacy post-labelling. Cell biodistribution was imaged in a mouse model of lung cancer using PET imaging and bioluminescence imaging (BLI) to confirm cell viability and location in vivo up to 1 week post-injection.

Results

MSCTRAIL retained therapeutic efficacy and MSC phenotype at doses up to and above those required for clinical imaging. The effect of 89Zr-oxine labelling on cell proliferation rate was dose and time-dependent. PET imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer, with PET signal correlating with the presence of viable cells as assessed by bioluminescence imaging, ex vivo autoradiography and matched fluorescence imaging on lung tissue sections. Human dosimetry estimates were produced using simulations and preclinical biodistribution data.

Conclusion

89Zr-oxine labelling and PET imaging present an attractive method of evaluating the biodistribution of new cell-therapies, such as MSCTRAIL. This offers to improve understanding of mechanism of action, migration dynamics and interpatient variability of MSCTRAIL and other cell-based therapies.
HESC-derived sensory neurons reveal an unexpected role for PIEZO2 in nociceptor mechanotransduction
Authors: Schrenk-Siemens Katrin , Pohle Jörg , Rostock Charlotte , El Hay Muad Abd , Lam Ruby M. , Szczot Marcin , Lu Shiying , Chesler Alexander T. , Siemens Jan
Published: August 2019

Somatosensation, the detection and transduction of external and internal stimuli, has fascinated scientists for centuries. But still, some of the mechanisms how distinct stimuli are detected and transduced are not entirely understood. Over the past decade major progress has increased our understanding in areas such as mechanotransduction or sensory neuron classification. Additionally, the accessibility to human pluripotent stem cells and the possibility to generate and study human sensory neurons has enriched the somatosensory research field.

Based on our previous work, the generation of functional human mechanoreceptors, we describe here the generation of hESC-derived nociceptor-like cells. We show that by varying the differentiation strategy, we can produce different nociceptive subpopulations. One protocol in particular allowed the generation of a sensory neuron population, homogeneously expressing TRPV1, a prototypical marker for nociceptors. Accordingly, we find the cells to homogenously respond to capsaicin, to become sensitized upon inflammatory stimuli, and to respond to temperature stimulation.

Surprisingly, all of the generated subtypes show mechano-nociceptive characteristics and, quite unexpectedly, loss of mechanotransduction in the absence of PIEZO2.
Population genetics of Bull Trout (Salvelinus confluentus) in the Upper Athabasca river basin
Authors: Carroll Emma K. T. , Vamosi Steven M.
Published: August 2019

Across its native range, Bull Trout (Salvelinus confluentus) extent and abundance are in decline due to historic overharvest and habitat degradation. Because Bull Trout are dependent on extensively connected, cold, clean headwater habitats, fragmentation from land use changes causes difficulty when determining the true extent and health of their populations, with Bull Trout of Alberta’s Eastern Slope region being no exception. Across this region, 431 Bull Trout from 20 sites were sampled from the Athabasca and Saskatchewan River basins and compared using 10 microsatellite loci to characterize within- and among-population genetic variation. The Saskatchewan and Athabasca River basins contained similar levels of heterozygosity but were differentiated from one another. Within the Athabasca River basin, five genetically differentiated clusters were found. Additionally, no isolation-by-distance pattern was observed between these sites. These results suggest these populations have ample genetic diversity, but genetic differentiation should be considered when deciding whether and how to alter connectivity between populations.
Loss of the Krüppel-like factor 4 tumor suppressor is associated with epithelial-mesenchymal transition in colorectal cancer
Authors: Agbo Kimberley C. , Huang Jessie Z. , Ghaleb Amr M. , Williams Jennie L. , Shroyer Kenneth R. , Bialkowska Agnieszka B. , Yang Vincent W.
Published: August 2019

Colorectal cancer (CRC) is the third leading cancer-related cause of death due to its propensity to metastasize. Epithelial-mesenchymal transition (EMT) is a multistep process important for invasion and metastasis of CRC. Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor highly expressed in differentiated cells of the intestinal epithelium. KLF4 has been shown to play a tumor suppressor role during CRC tumorigenesis - its loss accelerates development and progression of cancer. The present study examines the relationship between KLF4 and markers of EMT in CRC.

Methods

Immunofluorescence staining for KLF4 and EMT markers was performed on archived patient samples after colorectal cancer resection and on colonic tissues of mice with colitis-associated cancer.

Results

We found that KLF4 expression is lost in tumor sections obtained from CRC patients and in those of mouse colon following azoxymethane and dextran sodium sulfate (AOM/DSS) treatment when compared to their respective normal appearing mucosa. Importantly, in CRC patient tumor sections we observed a negative correlation between KLF4 levels and mesenchymal markers including TWIST, β-catenin, claudin-1, N-cadherin, and vimentin. Similarly, in tumor tissues from AOM/DSS-treated mice KLF4 levels were negatively correlated with mesenchymal markers including SNAI2, β-catenin, and vimentin and positively correlated with the epithelial marker E-cadherin.

Conclusion

These findings suggest that the loss of KLF4 expression is a potentially significant indicator of EMT in CRC.
Impact of crowding on the diversity of expanding populations
Authors: Schreck Carl F. , Fusco Diana , Karita Yuya , Martis Stephen , Kayser Jona , Duvernoy Marie-Cécilia , Hallatschek Oskar
Published: August 2019

Crowding effects are key to the self-organization of densely packed cellular assemblies, such as biofilms, solid tumors, and developing tissues. When cells grow and divide they push each other apart, remodeling the structure and extent of the population’s range. It has recently been shown that crowding has a strong impact on the strength of natural selection. However, the impact of crowding on neutral processes remains unclear, which controls the fate of new variants as long as they are rare. Here, we quantify the genetic diversity of expanding microbial colonies and uncover signatures of crowding in the site frequency spectrum. By combining Luria-Delbrück fluctuation tests, lineage tracing in a novel microfluidic incubator, cell-based simulations, and theoretical modeling, we find that the majority of mutations arise behind the expanding frontier, giving rise to clones that are mechanically “pushed out” of the growing region by the proliferating cells in front. These excluded-volume interactions result in a clone size distribution that solely depends on where the mutation first arose relative to the front and is characterized by a simple power-law for low-frequency clones. Our model predicts that the distribution only depends on a single parameter, the characteristic growth layer thickness, and hence allows estimation of the mutation rate in a variety of crowded cellular populations. Combined with previous studies on high-frequency mutations, our finding provides a unified picture of the genetic diversity in expanding populations over the whole frequency range and suggests a practical method to assess growth dynamics by sequencing populations across spatial scales.

Significance Statement

Growing cell populations become densely packed as cells proliferate and fill space. Crowding prevents spatial mixing of individuals, significantly altering the evolutionary outcome from established results for well-mixed populations. Despite the fundamental differences between spatial and well-mixed populations, little is known about the impact of crowding on genetic diversity. Looking at microbial colonies growing on plates, we show that the allele frequency spectrum is characterized by a simple power law for low frequencies. Using cell-based simulations and microfluidic experiments, we identify the origin of this distribution in the volume-exclusion interactions within the crowded cellular environment, enabling us to extend this findings to a broad range of densely packed populations. This study highlights the importance of cellular crowding for the emergence of rare genetic variants.
An Active Inference Approach to Dissecting Reasons for Non-Adherence to Antidepressants
Authors: Smith Ryan , Khalsa Sahib , Paulus Martin
Published: August 2019

Background

Antidepressant medication adherence is among the most important problems in health care worldwide. Interventions designed to increase adherence have largely failed, pointing towards a critical need to better understand the underlying decision-making processes that contribute to adherence. A computational decision-making model that integrates empirical data with a fundamental action selection principle could be pragmatically useful in 1) making individual level predictions about adherence, and 2) providing an explanatory framework that improves our understanding of non-adherence.

Methods

Here we formulate a partially observable Markov decision process model based on the active inference framework that can simulate several processes that plausibly influence adherence decisions.

Results

Using model simulations of the day-to-day decisions to take a prescribed selective serotonin reuptake inhibitor (SSRI), we show that several distinct parameters in the model can influence adherence decisions in predictable ways. These parameters include differences in policy depth (i.e., how far into the future one considers when deciding), decision uncertainty, beliefs about the predictability (stochasticity) of symptoms, beliefs about the magnitude and time course of symptom reductions and side effects, and the strength of medication-taking habits that one has acquired.

Conclusions

Clarifying these influential factors will be an important first step toward empirically determining which are contributing to non-adherence to antidepressants in individual patients. The model can also be seamlessly extended to simulate adherence to other medications (by incorporating the known symptom reduction and side effect trajectories of those medications), with the potential promise of identifying which medications may be best suited for different patients.
DNA Replication Stress Generates Distinctive Landscapes of DNA Copy Number Alterations and Chromosome Scale Losses
Authors: Mazzagatti Alice , Shaikh Nadeem , Bakker Bjorn , Spierings Diana Carolina Johanna , Wardenaar René , Maniati Eleni , Wang Jun , Boemo Michael A. , Foijer Floris , McClelland Sarah Elizabeth
Published: August 2019

Background

We previously showed that a major driver of cancer chromosomal instability (CIN) is replication stress, the slowing or stalling of DNA replication. However, the precise drivers of replication stress in cancer and the mechanisms by which these cause CIN and influence tumour evolution remain unclear. Common fragile sites are well-known genomic locations of breakage after aphidicolin-induced replication stress, but their precise causes of fragility are debated, and additional genomic consequences of replication stress are not fully explored.

Results

Using single cell sequencing we detected DNA copy number alterations (CNAs) caused by one cell cycle under replication stress in diploid non-transformed cells. Aphidicolin-induced replication stress caused multiple types of CNAs associated with different genomic regions and features. Coupling cell type-specific analysis of CNAs to gene expression and single cell replication timing analyses allowed us to pinpoint the causative large genes of the most recurrent chromosome-scale CNAs. In RPE1 cells these were largely confined to three sites on chromosomes 1, 2 and 7 and generated acentric lagging chromatin and micronuclei containing these chromosomes. Different replicative stresses generated distinct profiles of CNAs providing the potential to interpret specific replication stress mechanisms from cancer cells.

Conclusions

Chromosomal instability driven by replication stress occurs via focal CNAs and chromosome arm-scale changes, with the latter confined to a very small subset of chromosome regions, potentially heavily skewing cancer genome evolution trajectories. Single cell CNA analysis thus reveals new insights into the impact of replication stress on the genome and provides a platform to further dissect molecular mechanisms involved in the replication stress response and to gain insights into how replication stress fuels chromosomal instability in cancer.