bluuebunny/crossref_metadata_2025 huggingface dataset:
Reporting and Assessing the Quality of Diagnostic Accuracy Studies for Cervical Cancer Screening and Management
Authors: Clarke Megan A. , Darragh Teresa M. , Nelson Erin , Unger Elizabeth R. , Zuna Rosemary , Cremer Miriam , Stockdale Colleen K. , Einstein Mark H. , Wentzensen Nicolas
Published: April 2020

Objective

We adapted the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool for studies of cervical cancer screening and management and used the adapted tool to evaluate the quality of studies included in a systematic review supporting the 2019 Risk-Based Management Consensus Guidelines.

Methods

We evaluated the quality of all studies included in our systematic review for postcolposcopy (n = 5) and posttreatment (n = 23) surveillance using QUADAS-2 criteria. Subsequently, we adapted signaling questions to indications of cervical cancer screening and management. An iterative process was carried out to evaluate interrater agreement between 2 study authors (M.A.C. and N.W.). Discrepant ratings were discussed, and criteria were adapted accordingly. We also evaluated the influence of study quality on risk estimates and between study variation using stratified subgroup meta-analyses.

Results

Twelve signaling questions for bias assessment that were adapted to or newly developed for cervical cancer screening and management are described here. Interrater agreement on bias assessment increased from 70% to 83% during the adaptation process. Detailed assessment of bias and applicability showed that all studies on postcolposcopy management and 90% of studies on posttreatment management had high risk of bias in at least 1 domain. Most commonly, high risk of bias was observed for the patient selection domain, indicating the heterogeneity of study designs and clinical practice in reported studies.

Conclusions

The adapted QUADAS-2 will have broad application for researchers, evidence evaluators, and journals who are interested in designing, conducting, evaluating, and publishing studies for cervical cancer screening and management.
2019 ASCCP Risk-Based Management Consensus Guidelines: Methods for Risk Estimation, Recommended Management, and Validation
Authors: Cheung Li C. , Egemen Didem , Chen Xiaojian , Katki Hormuzd A. , Demarco Maria , Wiser Amy L. , Perkins Rebecca B. , Guido Richard S. , Wentzensen Nicolas , Schiffman Mark
Published: April 2020

Objective

To manage cervical screening abnormalities, the 2019 ASCCP management consensus guidelines will recommend clinical action on the basis of risk of cervical precancer and cancer. This article details the methods used to estimate risk, to determine the risk-based management, and to validate that the risk-based recommendations are of general use in different settings.

Methods

Based on 1.5 million patients undergoing triennial cervical screening by cotesting at the Kaiser Permanente Northern California from 2003 to 2017, we estimated risk profiles for different clinical scenarios and combinations of past and current human papillomavirus and cytology test results. We validated the recommended management by comparing with the estimated risks in several external data sources.

Results

Risk and management tables are presented separately by Egemen et al.
1
and Demarco et al.
2
Risk-based management derived from the Kaiser Permanente Northern California largely agreed with the management implied from the estimated risks of the other data sources.

Conclusions

The new risk-based guidelines present management of abnormal cervical screening results. By describing the steps used to develop these guidelines, the methods presented in this article can provide a basis for future extensions of the risk-based guidelines.
Factors influencing treatment outcome in hepatitis C virus minority patients at an inner-city hospital
Authors: Sherif Zaki A. , Nouraie Mehdi , Begum Rehana , Afsari Ali , Shokrani Babak , Lee Edward , Laiyemo Adeyinka O. , Brim Hassan , Ashktorab Hassan
Published: April 2020

Chronic hepatitis C virus (HCV) infection disproportionately affects African-Americans (AAs) and is a major contributor to liver failure and mortality. Genetic factors may not be the only cause in outcome disparity. We retrospectively investigated whether genetic host factors, viral genotypes, and treatment compliance in AA patients impacted the efficacy and the sustained virological response (SVR) rate of the interferon (IFN)-based treatment regimen. The medical chart review included 76 African-American patients (age ranging from 26 to 76) with varying levels of hepatitis condition. Fifty-seven (75%) of them had a clinically verifiable HCV infection and were followed by a hepatologist for 2 years at Howard University Hospital in Washington, DC. Both comprehensive metabolic profile and complete blood count analyses were performed. Among the 57 patients whose viral and IL28B genotypes were determined, sixty-eight percent (68%) were infected with viral genotype 1 and 71% harbored the CT allele of the IL28B gene. Among the 12 patients who completed treatment with IFN-based dual or triple therapy, 58% had achieved SVR 12 weeks following completion of treatment; 33% had a partial response with under 6000 viral count after 16 weeks of treatment; and there was one patient with viral genotype 1a and CT allele who did not respond to the medications. The results of this study prove that the PEG IFN-based regimen was effective in treating HCV-infected AA patients despite the current availability of new direct-acting antivirals. The major obstacles contributing to a low reduction in HCV infection and outcome in the AA community were avoidance or lack of treatment or compliance; contraindications, medication side effects, non-adherence, and payer eligibility restrictions.
Comparison of short-term outcome between diverting colostomy and colonic stent as a bridge to surgery for left colonic malignant obstruction
Authors: Jung Won Beom , Shin Jin Yong , Park Jong Kwon
Published: April 2020

The self-expanding metallic stent (SEMS) has been comprehensively investigated as a bridge to surgery. SEMS enables the control of acute colonic obstruction. However, comparison between SEMS and diverting colostomy as another bridge procedure was still challenging issue. Thus, the aim of this study was to compare these 2 procedures.

In this retrospective cohort study, patients who received diverting colostomy and SEMS for acute left colonic obstruction between February 2016 and August 2018 were included. They were classified into the colostomy group (n = 27), including 5 patients who had SEMS failure previously, and the SEMS group (n = 23). The clinicopathologic parameters, pathologic results, and short-term outcomes were compared.

No significant differences were found in clinicopathologic characteristics and complication rates between the 2 groups. After the bridge procedures, the SEMS group showed a higher rate of laparoscopic colonic resection than the colostomy group (100% vs 76%, P = .023). The colostomy group showed a higher rate of rectal cancer (24.0% vs 9.1%, P = .019) and later recovery of flatus (3 vs 2 days, P = .011) than the SEMS group. Additionally, the length of resected colon was longer in the colostomy group than in the SEMS group (33.9 vs 23.4 cm, P = .007).

Although SEMS might permit higher laparoscopic resection rates and faster recovery of bowel habits than diverting colostomy, SEMS showed meaningful failure rate including migration and perforation. In addition, diverting colostomy showed acceptable complication rates and feasible performance. An individualized approach is necessary considering the advantages and disadvantages of both procedures.
A randomized controlled trial for acupuncture combined with conventional therapy in the treatment of pain caused by prostate cancer
Authors: Lei Yi , Duan Yunyun , Wang Jisheng , Yu Xudong , Deng Sheng , Liu Ruijia , Si Hongmei , Li Jiameng , Zhang Bao
Published: April 2020

Introduction:

Prostate cancer refers to an epithelial malignant tumor that occurs in the prostate area. In recent years, with the improvement of people's living standards, the incidence of prostate cancer has gradually increased, which has greatly affected people's life and health and quality of life. Acupuncture has its unique advantages in treating cancer pain. We will evaluate the efficacy and safety of acupuncture and moxibustion in the treatment of pain caused by prostate cancer using a clinical randomized parallel control method.

Methods/design:

This pragmatic randomized controlled trial will recruit 120 patients who are diagnosed with prostate cancer. Simple randomization to conventional drug treatment with a 1:1 allocation ratio will be used. Based on the patient's pain location and the primary lesion, the acupuncture needle insertion position was determined according to the principle of local selection of acupoints. All participants will continue to receive conventional drug treatment.

Discussion:

This trial may provide evidence regarding the clinical effectiveness, safety, and cost-effectiveness of acupuncture for pain caused by prostate cancer.

Trial registration:

ClinicalTrials.gov, ChiCTR2000029801, Registered on 14 February 2020.
Clinical analgesic efficacy of pectoral nerve block in patients undergoing breast cancer surgery
Authors: Sun Qianchuang , Liu Shuyan , Wu Huiying , Kang Wenyue , Dong Shanshan , Cui Yunfeng , Pan Zhenxiang , Liu Kexiang
Published: April 2020

Background:

Breast cancer is the most commonly diagnosed cancer in women, and more than half of breast surgery patients experience severe acute postoperative pain. This meta-analysis is designed to examine the clinical analgesic efficacy of Pecs block in patients undergoing breast cancer surgery.

Methods:

An electronic literature search of the Library of PubMed, EMBASE, Cochrane Library, and Web of Science databases was conducted to collect randomized controlled trials (RCTs) from inception to November 2018. These RCTs compared the effect of Pecs block in combination with general anesthesia (GA) to GA alone in mastectomy surgery. Pain scores, intraoperative and postoperative opioid consumption, time to first request for analgesia, and incidence of postoperative nausea and vomiting were analyzed.

Results:

Thirteen RCTs with 940 patients were included in our analysis. The use of Pecs block significantly reduced pain scores in the postanesthesia care unit (weighted mean difference [WMD] = −1.90; 95% confidence interval [CI], −2.90 to −0.91; P < .001) and at 24 hours after surgery (WMD = −1.01; 95% CI, −1.64 to −0.38; P < .001). Moreover, Pecs block decreased postoperative opioid consumption in the postanesthesia care unit (WMD = −1.93; 95% CI, −3.51 to −0.34; P = .017) and at 24 hours (WMD = −11.88; 95% CI, −15.50 to −8.26; P < .001). Pecs block also reduced intraoperative opioid consumption (WMD = −85.52; 95% CI, −121.47 to −49.56; P < .001) and prolonged the time to first analgesic request (WMD = 296.69; 95% CI, 139.91–453.48; P < .001). There were no statistically significant differences in postoperative nausea and vomiting and block-related complications.

Conclusions:

Adding Pecs block to GA procedure results in lower pain scores, less opioid consumption and longer time to first analgesic request in patients undergoing breast cancer surgery compared to GA procedure alone.
Optimization of serum thyroglobulin measured at different time points for prognostic evaluation in differentiated thyroid carcinoma patients
Authors: Mutsuddy Pupree , Jeon Subin , Yoo Su Woong , Zhang Yingjie , Chowdhury Md. Sunny Anam , Kim Jahae , Song Ho-Chun , Bom Hee-Seung , Min Jung-Joon , Kwon Seong Young
Published: April 2020

Although serum thyroglobulin (Tg) is a reliable differentiated thyroid carcinoma (DTC) prognostic marker, its cutoff values can be affected by TSH stimulation status. Serum Tg prognostic values measured at different time points before and after radioactive iodine (RAI) therapy prepared with recombinant human TSH (rhTSH) in DTC patients, were investigated.

This study included 160 DTC patients who underwent surgery followed by rhTSH-aided RAI therapy. Their serum Tg levels were measured 7 days before (D-7Tg), on the day of (D0Tg), and 2 days after (D2Tg) the RAI therapy. For response evaluation, the patients were classified into 2 groups: acceptable response and non-acceptable response (non-AR). Optimal Tg level cutoff values measured at different time points were evaluated for persistent or recurrent disease (PRD) prediction, as well as therapeutic response.

Multivariate analysis showed that D-7Tg, D0Tg, and D2Tg significantly predicted non-AR (P < .05, for all). Optimal Tg level cutoff values for non-AR prediction were 0.6, 2.6, and 3.7 ng/mL for D-7Tg, D0Tg, and D2Tg, respectively. Cox regression analysis showed that Tg levels were significantly associated with PRD free survival with D-7Tg, D0Tg, and D2Tg cutoff values of 0.8, 4.0, and 6.0 ng/mL, respectively (D-7Tg, P = .010; D0Tg, P = .005; D2Tg, P = .011).

Serum Tg levels measured at the different time points could predict PRD free survival as well as therapeutic response with different cutoff values in DTC patients who underwent rhTSH-aided RAI therapy.
Treatment for acute flares of gout
Authors: Tang Hongzhi , Xu Guixing , Zheng Qianhua , Cheng Ying , Zheng Hui , Li Juan , Yin Zihan , Liang Fanrong , Chen Jiao
Published: April 2020

Introduction:

The current evidence confirms the effectiveness and safety of several drug interventions in the treatment of acute flares of gout, however, the most preferred drugs are still unclear. We, therefore, seek to conduct a network meta-analysis that can systematically compare non-steroidal anti-inflammatory drugs (NSAIDs), COXIBs, colchicine, hormones, or IL-1 receptor antagonists, etc. for acute gout based on the latest evidence.

Methods and analysis:

Nine online databases are searched with inception to September 1, 2019; there will be no language restrictions on the included trials. Randomized controlled trials that include patients with acute flares of gout receiving drug therapy versus a control group will be included. The selection of studies, risk of bias assessment and data extraction will be conducted by 2 independent researchers. Bayesian network meta-analysis is applied using the Markov chain Monte Carlo method with Stata or R. The dichotomous data will be presented as risk ratios with 95% CIs and the continuous data will be presented as weighted mean differences or standardized mean differences with 95% CIs. Evidence quality will be evaluated using the GRADE system.

Ethics and dissemination:

This network meta-analysis will not involve private information from personal or imperil their rights, so, ethical approval is not required. The results of this network meta-analysis may be published in a journal or publicized in concerned conferences.
Tumor-associated antigens and their antibodies in the screening, diagnosis, and monitoring of esophageal cancers
Authors: Perisetti Abhilash , Bellamkonda Mahita , Konda Manojna , Edwards Samantha , Ali Khan Salman , Bansal Pardeep , Hu Zhi-De , Goyal Hemant
Published: April 2020

Despite the advances in the treatment and management, esophageal cancers continue to carry a dismal prognosis with an overall 5-year survival rate ranging from 15 to 25%. Delayed onset of symptoms and lack of effective screening methods and guidelines for diagnosis of the early disease contribute to the high mortality rate of esophageal cancers. Detection of esophageal cancer at their early stage is really a challenge for physicians including primary care physicians, gastroenterologists and oncologists. Although imaging, endoscopy and biopsy have been proved to be useful diagnostic tools for esophageal cancers, their diagnostic accuracy is unsatisfactory. In addition, expensive costs, invasiveness and special training operator have limited the clinical application of these tools. Recently, tumor-associated antigens (TAAs) and their antibodies have been reported to be potential markers in esophageal cancer screening, diagnosis, monitoring and prognostication. Because TAAs and their antibodies have the advantages of inexpensive cost, noninvasiveness and easy access, they have attracted much attention as an affordable option for early esophageal cancer diagnosis. In this review, we summarized the advances in TAAs and their antibodies in esophageal cancer screening, diagnosis, monitoring and prognostication.
European Society For Emergency Medicine position paper on emergency medical systems’ response to COVID-19
Authors: Garcia-Castrillo Luis , Petrino Roberta , Leach Robert , Dodt Christoph , Behringer Wilhelm , Khoury Abdo , Sabbe Marc
Published: April 2020

The 2019 novel coronavirus acute respiratory epidemic is creating a stressed situation in all the health systems of the affected countries. Emergency medical systems and specifically the emergency departments as the front line of the health systems are suffering from overload and severe working conditions, the risk of contagion and transmission of the health professionals adds a substantial burden to their daily work. Under the perspective of European Society For Emergency Medicine, the recommendations provided by the health authorities are reviewed focus on the emergency department’s activity.
Effects of Cryopreservation and Replantation on Muscles
Authors: He Bo , Su Shouwen , Lu Yunxiang , Wen Xiaoyue , Duan Jiekui , Liu Xiangxia , Zhu Zhaowei , Liu Xiaolin
Published: April 2020

Background

Wang successfully replanted the severed fingers of 2 patients after cryopreservation in 2002 and 2003, which has enabled us to share our own experience for the knowledge interests of our colleagues and to further develop this technology.

Methods

Fifteen healthy adult male Sprague-Dawley rats were selected and divided into 5 groups (group 1: normal control, group 2: cryopreservation with protectant, group 3: cryopreservation without protectant, group 4: 6-hour postoperative, and group 5: 72-hour postoperative). After harvesting the hind limbs, cryoprotectant was applied to 20 limbs, and the rest were cryopreserved without cryoprotectant for 15 days. After being thawed, the amputated limb was replanted in situ. Nerves, skins and gastrocnemius muscles were collected for hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and transmission electron microscopy observation.

Results

Muscle and skin tissues treated with cryoprotectant restored a better outline after being frozen than those not treated, whereas nerves were not significantly different between the 2 groups. After replantation, some of the myofibrils of the muscle were in disarray, but the sarcomere structure remained intact at approximately 6 hours postoperatively. At 72 hours, a transmission electron microscopy scan showed that the myofibrillar arrangement was disorderly, with segmental myofilament breakage, and the sarcomere structure was destroyed in some cases. In addition, the scan revealed increased apoptotic cells and collapse of basic structures in the skin and nerves.

Conclusions

Relative to that of skin and neuronal tissue, the replantation of muscle tissues through the cryopreservation method is more difficult.
A Prospective Comparative Study of Color Doppler Ultrasound and Infrared Thermography in the Detection of Perforators for Anterolateral Thigh Flaps
Authors: Xiao Wentian , Li Ke , Kiu-Huen NG Sally , Feng Shaoqing , Zhou Huihong , Nicoli Fabio , Blondeel Phillip , Zhang Yixin
Published: April 2020

Background

Preoperative localization of the perforators allows precise planning of the flap design and improves surgical efficiency. Recently, infrared thermography is introduced as a reliable alternative, where the perforator corresponds to the “hot spot” on the thermogram. This study aims to compare the application of color Doppler ultrasound (CDU) and infrared thermography in preoperative perforator mapping of the anterolateral thigh (ALT) perforator flap.

Patients and Methods

From September 2017 to January 2019, CDU and infrared thermography were both applied on 20 patients to locate the perforators originated from lateral circumflex femoral artery preoperatively. The perforators identified using each modality were marked on the anterolateral thigh region. The accuracy of both mapping methods was analyzed according to the intraoperative findings. The relation between location bias and the thickness of subcutaneous tissue was analyzed.

Results

A total of 20 ALT flaps were included. Fifty-three perforators were detected by CDU, and 51 “hot spots” were identified by infrared thermography, in which 50 “hot spots” corresponded to CDU, and the consistency test showed that the κ index was 0.712 (P < 0.05), representing high consistency. The infrared thermography has a sensitivity of 94.3% and a specificity of 85.7% compared with CDU. The deviation between thermal imaging and CDU was positively correlated with the thickness of the subcutaneous tissue. The Pearson correlation coefficient was 0.84 (R = 0.84). Forty-four perforators marked by CDU were selected for designing the flap. Anatomical findings showed that the accuracy rate of CDU and infrared thermal was 93.2% (41 of 44) and 86.3% (38 of 44), respectively. There was no statistical difference (P > 0.05).

Conclusions

Compared with CDU, infrared thermography can be used to locate perforators, in this case, the ALT perforators, with a high degree of consistency. It is portable, economical, noninvasive, and easy to operate. It has higher accuracy in patients with thinner subcutaneous tissue. We believe that infrared thermography can be a useful technique for perforator mapping, especially in patients where the subcutaneous tissue is thinner.
Free Medial Plantar Flap Versus Free Dorsal Myocutaneous Flap for the Reconstruction of Traumatic Foot Sole Defects
Authors: Han Yan , Han Yudi , Song Baoqiang , Guo Lingli , Tao Ran , Chai Mi
Published: April 2020

Background

Trauma can cause large defects in the weight-bearing foot sole. The reconstruction of such defects poses a major challenge in providing a flap that is durable, sensate, and stable. The pedicled medial plantar flap has been commonly used for reconstructing heel and plantar forefoot defects; however, the ipsilateral instep region is usually compromised by trauma. The purpose of this article was to report the use of contralateral free medial plantar flaps for the coverage of weight-bearing plantar defects and to compare these with distant free flaps.

Methods

Between 2005 and 2019, 15 patients (10 men and 5 women) with weight-bearing foot plantar defects were treated with a contralateral medial plantar flap, 11 (7 men and 4 women) with either a latissimus dorsi flap or a scapular flap. The average age was 18.07 ± 10.14 years (range, 4–34 years) and 26.55 ± 13.05 years (range, 13–56 years), respectively. Surgery was performed as a primary or secondary reconstruction after a trauma by the same surgical team.

Results

The mean size of defects was 9.73 ± 3.55 × 6.43 ± 2.8 cm in the contralateral free medial plantar flap group and 17.14 ± 6.84 × 11.41 ± 4.29 cm in the free dorsal flap group. All flaps survived in both groups. In the instep flap group, the appearance was satisfactory, the flap was durable, and tactile sensation was preserved in all patients, and none required a revision procedure. Two patients experienced delayed union of the donor-site grafted skin. In the dorsal flap group, 5 patients complained of a partial necrosis or delayed union at the recipient site, and 9 developed recurrent ulcerations over the weight-\bearing area. Five patients achieved only partial sensation in the flap.

Conclusions

The contralateral medial plantar flap provides superior appearance, duration, and sensation over distant muscle flaps, without recurrent ulcerations. However, dorsal myocutaneous flaps may be used as a substitute when the defects are beyond the maximum boundaries of the instep area or are combined with bone loss.
Global Health Microsurgery Training With Cell Phones
Authors: Inchauste Suzanne M. , Deptula Peter L. , Zelones Justin T. , Nazerali Rahim S. , Nguyen Dung H. , Lee Gordon K.
Published: April 2020

Background

Lack of surgical care for trauma, burns, congenital anomalies, and other surgical diseases is a growing portion of global disability and death accounting for 30% of the global disease burden. Global surgical and anesthesia care aim to achieve excellence and equality of clinical care through leadership, innovation, teaching, research, and advocacy. Stanford University Division of Plastic Surgery faculty partnered with ReSurge International to teach reconstructive microsurgery in low- and middle-income countries.

Challenge

Global surgery teaching and training are challenged by limited resources. Surgical loupes and operating microscopes used to perform complex microsurgery magnify the surgical field are very expensive. Our goal was to identify low-cost alternatives to teach and practice microsurgery suturing.

Innovation

Use cell phone camera with zoom capacity to teach and practice microsurgery suturing.

Results

Cell phones with zoom feature are widely available even in low- and middle-income countries. A cell phone was placed on a stand over a microsurgery practice station. The camera was used to zoom and focus on the suturing station to mimic a surgical field with loupes or microscope magnification. Nine attending surgeons and 7 residents practiced microsurgery with microsurgical instruments and 9-0 nylon suture under the magnification of a cell phone camera. The Stanford Microsurgery and Resident Training Scale was used to track their progress. A feedback survey was given to the participants to identify the usefulness of the cell phone setup for microsurgery suture practice.

Conclusions

Global surgery teaching and training face many challenges especially limited resources. Identifying low-cost alternative is crucial. Cell phone camera with zoom is a low-cost alternative to loupes or operating microscope for microsurgical teaching and training.
Neuroprotective effects of peroxisome proliferator-activated receptor γ agonist through activation of Akt and signal transducers and activators of transcription 3 in transient forebrain ischemia
Authors: Sui Xin , Yoshioka Hideyuki , Wakai Takuma , Fukumoto Yuichiro , Kinouchi Hiroyuki
Published: April 2020

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear hormone receptor family and is a ligand-modulated transcriptional factor. Pioglitazone, a PPARγ ligand of the thiazolidinedione class, exerts several pleiotropic effects including neuroprotection in addition to reducing blood glucose and insulin resistance; however, its mechanism remains obscure. In this study, we examined the PPARγ expression and the protective effects of pioglitazone after transient forebrain ischemia. We focused on Akt and signal transducers and activators of transcription 3 (STAT3), key pathways of prosurvival signaling in ischemic neuronal injury as the mechanisms of pioglitazone’s effects. Male Sprague–Dawley rats were given daily oral administration of pioglitazone (0.2, 2 and 20 mg/kg/d) or the vehicle, and transient forebrain ischemia was induced by 5-minute occlusion of bilateral common carotid arteries with hypotension. Western blot and immunohistochemistry revealed that PPARγ expression in the hippocampal CA1 subregion was upregulated 1–8 h after forebrain ischemia, which was observed mainly in pyramidal neurons. Most CA1 neurons were positive for TUNEL staining 5 days after ischemia, and pioglitazone administration reduced TUNEL-positive cells in a dose-dependent manner, with a significant difference in the 20 mg/kg/d group compared with the vehicle. Phosphorylation of Akt (Ser473) and its target, glycogen synthase kinase-3β (Ser9), was increased after ischemia, and 20 mg/kg/d dose of pioglitazone significantly increased phosphorylation of these proteins. Furthermore, pioglitazone treatment enhanced phosphorylation of STAT3 (Tyr705) after ischemia. These results indicate that pioglitazone attenuates neuronal ischemic injury through the activation of Akt and STAT3 pathways.
Glycine as a signaling molecule and chemoattractant in Trichoplax (Placozoa): insights into the early evolution of neurotransmitters
Authors: Romanova Daria Y. , Heyland Andreas , Sohn Dosung , Kohn Andrea B. , Fasshauer Dirk , Varoqueaux Frederique , Moroz Leonid L.
Published: April 2020

The origin and early evolution of neurotransmitter signaling in animals are unclear due to limited comparative information, primarily about prebilaterian animals. Here, we performed the comparative survey of signal molecules in placozoans – the simplest known free-living animals without canonical synapses, but with complex behaviors. First, using capillary electrophoresis with laser-induced fluorescence detection, we performed microchemical analyses of transmitter candidates in Trichoplax adhaerens – the classical reference species in comparative biology. We showed that the endogenous level of glycine (about 3 mM) was significantly higher than for other candidates such as L-glutamate, L-aspartate, or gamma-aminobutyric acid. Neither serotonin nor dopamine were detected. The absolute glycine concentrations in Trichoplax were even higher than we measured in ctenophores (Beroe) and cnidarians (Aequorea). We found that at millimolar concentrations of glycine (similar to the endogenous level), induced muscle-like contractions in free behaving animals. But after long incubation (24 h), 10−3 M of glycine could induce cytotoxicity and cell dissociation. In contrast, micromolar concentrations (10−5–10−4 M) increased Trichoplax ciliated locomotion, suggesting that glycine might act as an endogenous signal molecule. However, we showed than glycine (10−6 M) can also be a chemoattractant (a guiding factor for food sources), and therefore, act as the exogenous signal. These findings provide an evolutionary base for the origin of transmitters as a result of the interplay between exogenous and endogenous signaling systems early in animal evolution.
miR-149 rs2292832 C allele enhances the cytotoxic effect of temozolomide against glioma cells
Authors: Xu Binchu , Luo Xinlin , Ning Xinjie , Luo Juncheng , Guo Jian , Liu Qingchang , Ling Gengqiang
Published: April 2020

Glioma is a common cancer that affects people worldwide with high morbidity and mortality. Human miR-149 rs2292832 C/T polymorphism and miR-149-5p expressions have been documented to play important roles in various type of cancers. This study aims to assess the impact of miR-149 rs2292832 C/T polymorphism and miR-149-5p expressions in cytotoxic effect of temozolomide against glioma cells. A total of 137 cases of glioma patients and 21 healthy cases were enrolled in this study for clinical research. We found that miR-149-5p was significantly downregulated in glioma cell lines and in blood leukocyte of glioma patients. Furthermore, miR-149 rs2292832 C/T polymorphism was significantly associated with glioma prognosis and temozolomide resistance. Subsequently, the glioma cell lines stable transfected with common miR-149 expression construct (miR-149-T) and the variant miR-149 expression construct (miR-149-C) were used to determine the regulatory effect of miR-149 rs2292832 C on glioma cells progression. Data revealed that miR-149 rs2292832 C allele could enhance the miR-149-5p expressions, and therefore, prevent the proliferation of glioma cells and increase the cytotoxicity of temozolomide against glioma cells. These functions of miR-149-C were demonstrated to be triggered by CDK6/SOX2 pathway inhibition. The above results demonstrated that miR-149 rs2292832 C/T polymorphism was a potential prognostic biomarker for glioma development by regulating miR-149/CDK6 axis.
Metagenomic sequencing of clinical samples reveals a single widespread clone of Lawsonia intracellularis responsible for porcine proliferative enteropathy
Authors: Bengtsson Rebecca J. , Wee Bryan A. , Yebra Gonzalo , Bacigalupe Rodrigo , Watson Eleanor , Guedes Roberto M. C. , Jacobson Magdalena , Stadejek Tomasz , Archibald Alan L. , Fitzgerald J. Ross , Ait-Ali Tahar
Published: April 2020

Lawsonia intracellularis

is a Gram-negative obligate intracellular bacterium that is the aetiological agent of proliferative enteropathy (PE), a common intestinal disease of major economic importance in pigs and other animal species. To date, progress in understanding the biology of

L. intracellularis

for improved disease control has been hampered by the inability to culture the organism in vitro. In particular, our understanding of the genomic diversity and population structure of clinical L. intercellularis is very limited. Here, we utilized a metagenomic shotgun approach to directly sequence and assemble 21

L

.

intracellularis

genomes from faecal and ileum samples of infected pigs and horses across three continents. Phylogenetic analysis revealed a genetically monomorphic clonal lineage responsible for infections in pigs, with distinct subtypes associated with infections in horses. The genome was highly conserved, with 94 % of genes shared by all isolates and a very small accessory genome made up of only 84 genes across all sequenced strains. In part, the accessory genome was represented by regions with a high density of SNPs, indicative of recombination events importing novel gene alleles. In summary, our analysis provides the first view of the population structure for

L. intracellularis

, revealing a single major lineage associated with disease of pigs. The limited diversity and broad geographical distribution suggest the recent emergence and clonal expansion of an important livestock pathogen.
Investigating the potential for machine learning prediction of patient outcomes: a retrospective study of hospital acquired pressure injuries
Authors: Levy Joshua J. , Lima Jorge F. , Miller Megan W. , Freed Gary L. , O’Malley A. James , Emeny Rebecca T.
Published: April 2020

Background

While recent research efforts to reduce pressure ulcers in the clinical context have focused on key retrospective characteristics, little work has focused on creating real-time predictive models to prevent this avoidable hospital-acquired injury. Furthermore, existing machine learning heuristics often fail to surpass traditional statistical models or provide individual-level risk assessments with explanations for each patient. Thus, we sought to compare the predictive performance of five machine learning and traditional statistical modeling techniques to predict the occurrence of Hospital Acquired Pressure Injuries (HAPI).

Methods

Electronic Medical Record (EMR) information was collected from 57,227 hospitalizations, containing 241 positive HAPI cases, acquired from Dartmouth Hitchcock Medical Center from April 2011 to December 2016. The five classifiers were trained to predict HAPI incidence and performance was assessed using the C-statistic or Area Under the Receiver Operating Curve (AUC).

Results

Logistic Regression was the best modeling approach (AUC=0.91±0.034). We report discordance between predictors deemed important by the machine learning models compared to traditional statistical model. We provide means to visually assess factors important to every patient’s prediction, regardless of the modeling approach, through Shapley Additive Explanations.

Conclusions

Machine learning models will continue to inform decision making processes but should be compared to traditional modeling approaches to ensure proper utilization. Disagreements between important predictors found by traditional and machine learning modeling approaches can potentially confuse clinicians and as such need to be reconciled. Future efforts to analyze time-stamped, prospective medical record data will be enhanced by patient-specific details. These developments represent important steps forward in developing real-time predictive models that can be integrated and readily deployed in electronic medical record systems to reduce unnecessary harm.
ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy
Authors: Asselta Rosanna , Paraboschi Elvezia Maria , Mantovani Alberto , Duga Stefano
Published: April 2020

Background

As the outbreak of coronavirus disease 2019 (COVID-19) progresses, prognostic markers for early identification of high-risk individuals are an urgent medical need. Italy has the highest rate of SARS-CoV-2 infection, the highest number of deaths, and the highest mortality rate among large countries. Worldwide, a more severe course of COVID-19 is associated with older age, comorbidities, and male sex. Hence, we searched for possible genetic components of the peculiar severity of COVID-19 among Italians, by looking at expression levels and variants in ACE2 and TMPRSS2 genes, which are crucial for viral infection.

Methods

Exome and SNP array data from a large Italian cohort representative of the country’s population were used to compare the burden of rare variants and the frequency of polymorphisms with European and East Asian populations. Moreover, we looked into gene expression databases to check for sex-unbalanced expression.

Results

While we found no significant evidence that ACE2 is associated with disease severity/sex bias in the Italian population, TMPRSS2 levels and genetic variants proved to be possible candidate disease modulators, contributing to the observed epidemiological data among Italian patients.

Conclusions

Our analysis suggests a role for TMPRSS2 variants and expression levels in modulating COVID-19 severity, a hypothesis that fosters a rapid experimental validation on large cohorts of patients with different clinical manifestations.
Wave Reflection: More Than A Round Trip
Authors: Afkhami Rashid , Johnson Sarah
Published: April 2020

Reflected pressure waves are key to the understanding of vascular ageing, a prominent factor in major cardiovascular events. Several different metrics have been proposed to index the effect of wave reflection on the pressure waveform and thereby serve as an indicator of vascular ageing. The extent to which these indices are influenced by factors other than vascular health remains a matter of concern. In this paper, we use transmission-line theory to derive a mathematical model for the reflection time (Trefl), and the augmentation index (AI), assuming a general extended model of the arterial system. Then, we test the proposed model against values reported in the literature. Finally, we discuss insights from the model to common observations in the literature such as age-related “shift” in the reflection site, the variation of AI with heart rate, and the flattening of Trefl in older participants.
SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium
Authors: Fodoulian Leon , Tuberosa Joel , Rossier Daniel , Boillat Madlaina , Kan Chenda , Pauli Véronique , Egervari Kristof , Lobrinus Johannes A. , Landis Basile N. , Carleton Alan , Rodriguez Ivan
Published: April 2020

Various reports indicate an association between COVID-19 and anosmia, suggesting an infection of the olfactory sensory epithelium, and thus a possible direct virus access to the brain. To test this hypothesis, we generated RNA-seq libraries from human olfactory neuroepithelia, in which we found substantial expression of the genes coding for the virus receptor angiotensin-converting enzyme-2 (ACE2), and for the virus internalization enhancer TMPRSS2. We analyzed a human olfactory single-cell RNA-seq dataset and determined that sustentacular cells, which maintain the integrity of olfactory sensory neurons, expressACE2andTMPRSS2. We then observed that the ACE2 protein was highly expressed in a subset of sustentacular cells in human and mouse olfactory tissues. Finally, we foundACE2transcripts in specific brain cell types, both in mice and humans. Sustentacular cells thus represent a potential entry door for SARS-CoV-2 in a neuronal sensory system that is in direct connection with the brain.
SPONTANEOUS ECHO CONTRAST IN MITRAL STENOSIS: WHY AND HOW?
Authors: Bilgel Ziya Gokalp , Gullu Ibrahim Hakan , Hamad Saif , Kasar Mutlu , Erol Tansel , Demircan Senol , MUderrisoglu Haldun
Published: April 2020

Background

Spontaneous echo contrast(SEC) is an echocardiographic finding particularly found in left atrium of patients with mitral stenosis and known as a risk factor for stroke. However, its pathophysiology is not fully understood.

Material and Method

Forty-eight patients with mitral stenosis scheluded for percutaneous mitral valvuloplasty were included in the study. SEC was graded from 0 to 4 according to its density. Blood samples were taken from the aorta and left atrium during the procedure. Whole blood viscosity, plasma viscosity(PV) and peripheral blood smears were obtained and analysed separately from these sites. Prior to the procedure, all participants also underwent transthoracic and transesophageal echocardiography.

Results

Severe SEC(grade 3-4) was found in 23 patients(48%), remaining 25 patients(52%) had mild to moderate SEC(grade 0-1-2). The patients with atrial fibrillation(AF) and hypertension(HT) had more significantly severe SEC compared to other patients. Compared to patients with mild to moderate SEC, patients with severe SEC had increased age, body mass index, left atrial diameter, left atrial area and left atrial PV. However, ejection fraction, left atrial appendage(LAA) filling and emptying velocities, LAA lateral wall late systolic velocity, LAA fractional area change and pulmonary vein(PVe) systolic velocity were found to be significantly reduced in patients with severe SEC compared to mild to moderate SEC. On multiple linear regression analysis, AF, left atrium PV and left atrial diameter were the strongly correlated with SEC grade.

Conclusion

We have shown that AF, HT, systolic dysfunction of LAA, increased left atrial dimensions, reduced ejection fraction, decreased PVe flow velocity and increased left atrial PV were related with the development of SEC in patients with mitral stenosis.
STABILITY ANALYSIS OF DISEASE FREE EQUILIBRIUM STATE (E0) FOR AN ENDEMIC DETERMINISTIC MODEL FOR HIV/AIDS
Authors: Victor A. O. , Oduwole H. K.
Published: April 2020

This paper focused on determining the asymptotical stability of the new model which establishes that a disease-free equilibrium state exists and is locally asymptotically stable when the basic reproduction number 0 ≤ R0 < 1 and the following threshold conditions (0 ≤ R1 < 1, 0 ≤ R2 < 1, 0 ≤ R3 < 1, 0 ≤ R4 < 1 and 0 ≤ R5 < 1, 0 ≤ R6 < 1, 0 ≤ R7 < 1, 0 ≤ R8 < 1) are satisfied. Results from the model analysis shows that the proportion of infected juvenile and adult sub-population in the presence of High Active Anteritroviral Therapy (HAART) drastically reduce to a zero (R0 = 0) as compared to the infected age-structured population when treatment rate is low and the net transmission rate is near zero.
Episignatures stratifying ADNP syndrome show modest correlation with phenotype
Authors: Breen Michael S. , Garg Paras , Tang Lara , Mendonca Danielle , Levy Tess , Barbosa Mafalda , Arnett Anne B , Kurtz-Nelson Evangeline , Agolini Emanuele , Battaglia Agatino , Chiocchetti Andreas G , Freitag Christine M , Garcia-Alcon Alicia , Grammatico Paola , Hertz-Picciotto Irva , Ludena-Rodriguez Yunin , Moreno Carmen , Novelli Antonio , Parellada Mara , Pascolini Giulia , Tassone Flora , Grice Dorothy E , Bernier Raphael A , Kolevzon Alexander , Sharp Andrew , Buxbaum Joseph D , Siper Paige M , De Rubeis Silvia
Published: April 2020

ADNP syndrome, also known as Helsmoortel-van Der Aa syndrome, is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. ADNP syndrome is caused by mutations in the activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with ADNP syndrome, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with ADNP syndrome into two groups, based on the location of the mutations. Here, we conducted an independent study on 24 individuals with ADNP syndrome and replicated the existence of the two, mutation-dependent ADNP episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of ADNP syndrome. We found limited phenotypic differences between the two ADNP groups, and no evidence that individuals with more widespread methylation changes are more severely affected. Also, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with ADNP syndrome. Our data warrant caution in harnessing methylation signatures in ADNP syndrome as a tool for clinical stratification, at least with regards to behavioral phenotypes.
Constructing and Optimizing 3D Atlases From 2D Data With Application to the Developing Mouse Brain
Authors: Young David M , Darbandi Siavash Fazel , Schwartz Grace , Bonzell Zachary , Yuruk Deniz , Nojima Mai , Gole Laurent , Rubenstein John , Yu Weimiao , Sanders Stephan J
Published: April 2020

3D imaging data necessitate 3D reference atlases for accurate quantitative interpretation. Existing computational methods to generate 3D atlases from 2D-derived atlases result in extensive artifacts, while manual curation approaches are labor-intensive. We present a computational approach for 3D atlas construction that substantially reduces artifacts by identifying anatomical boundaries in the underlying imaging data and using these to guide 3D transformation. Anatomical boundaries also allow extension of atlases to complete edge regions. Applying these methods to the eight developmental stages in the Allen Developing Mouse Brain Atlas (ADMBA) led to more comprehensive and accurate atlases. We generated imaging data from fifteen whole mouse brains to validate atlas performance and observed qualitative and quantitative improvement (37% greater alignment between atlas and anatomical boundaries). We provide the methods as the MagellanMapper software and the eight 3D reconstructed ADMBA atlases. These resources facilitate whole-organ quantitative analysis between samples and across development.
Distinct Vegfa isoforms control endothelial cell proliferation through PI3 kinase signalling mediated regulation of cdkn1a/p21
Authors: Lange Martin , Leonard Elvin , Ohnesorge Nils , Hoffmann Dennis , Rocha Susana F. , Benedito Rui , Siekmann Arndt F.
Published: April 2020

The formation of appropriately patterned blood vessel networks requires endothelial cell migration and proliferation. Signaling through the Vascular Endothelial Growth Factor A (VEGFA) pathway is instrumental in coordinating these processes. mRNA splicing generates short (diffusible) and long (extracellular matrix bound) Vegfa isoforms. The differences between these isoforms in controlling cellular functions are not understood. In zebrafish,vegfaagenerates short and long isoforms, whilevegfabonly generates long isoforms. We found that mutations invegfaaaffected endothelial cell migration and proliferation. Surprisingly, mutations invegfabspecifically reduced endothelial cell proliferation. Analysis of downstream signaling revealed no change in MAPK (ERK) activation, while inhibiting PI3 kinase signaling phenocopiedvegfabmutants. The cell cycle inhibitorcdkn1a/p21was upregulated invegfabdeficient embryos. Accordingly, reducingcdkn1a/p21restored endothelial cell proliferation. Together, these results suggest that extracellular matrix bound Vegfa acts through PI3K signaling to specifically control endothelial cell proliferation during angiogenesis independently of MAPK (ERK) regulation.