bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of hand-sewn versus mechanical esophagogastric anastomosis in esophageal cancer
Authors: Wang Yang , Zhang Xiangwei , Jiang Yuanzhu , Ma Guoyuan , Wang Zhaoyang , Xue Xianbiao , Sang Shaowei , Zhang Lin
Published: June 2019

Background:

Many studies have been conducted to compare the hand-sewn and mechanical staples in esophageal cancer (EC) patients who received esophagogastric anastomosis. However, the results remain controversial. Hence, the purpose of the meta-analysis is to evaluate the impact of different anastomosis methods on the early and long-term outcomes.

Methods:

We will perform a systematic electronic search of the PubMed, Embase, Cochrane Library, Web of Science for relevant articles published in English language. Pooled odds ratios will be calculated for the effect on discrete variables including anastomotic leakage, anastomotic strictures, 30-day mortality, quality of life, cardiac and pulmonary complications. The weighted mean difference was calculated for the effect size on continuous variables such as operative time and bleeding amount. We will use the software Review Manager 5.3 and STATA 14.0 to perform the meta-analysis to calculate the data synthesis.

Results:

The review will provide a high-quality synthesis of current evidence of the impact of different anastomosis methods on postoperative course in ECs after esophagectomy. The results will be published in a peer-reviewed journal.

Conclusion:

This systematic review and meta-analysis will compare the different anastomosis methods in EC patients. The results will better offer some specific suggestions for esophagogastric anastomosis.

PROSPERO registration number:

This systematic review protocol has been registered in the PROSPERO network (No. CRD 42019109523).
Radiofrequency ablation for lung squamous cell carcinoma in a single-lung patient
Authors: Song Guo-qiang , Li Guan-gnan , Chen Fei , Chen Dun-shun , Qian Hui-juan , Deng Xiao-e , Lu Huo-quan , Lin Bin
Published: June 2019

Rationale:

High morbidity and high mortality are the main features of non-small cell lung cancer (NSCLC). Radiofrequency ablation, which produces a large amount of heat to kill tumor cells, is one effective way to treat this disease.

Patient concerns:

We report the case of a 74-year-old man who presented with a 1-month history of right chest pain. His left lung was removed 12 years prior. Chest computed tomography (CT) revealed a mass in the right lower lobe.

Diagnoses:

An excision biopsy of the mass showed lung squamous cell carcinoma.

Interventions:

We performed radiofrequency ablation.

Outcomes:

The patient underwent 3.5 and 10 months of follow-up, with a partial response and complete remission, respectively.

Lessons:

CT-guided radiofrequency ablation is a safe and an effective minimally invasive treatment option. Radiofrequency appears to be a valuable alternative to surgery for inoperable patients presenting with a single-lung NSCLC.
Revision surgery with dermal regeneration template and vacuum sealing drainage for reconstruction of complex wounds following necrosis of reattached avulsed skins in a degloving injury
Authors: Lv Zhenmu , Yu Lili , Fu Lei , Wang Qiusheng , Jia Rui , Ding Wenyuan , Shen Yong
Published: June 2019

Rationale:

Degloving injury of the upper limb often extends to underlying tendons and bone, which is at high risk of treatment failure if only simple reattachment of defatted avulsed skins was performed. Pelnac dermal regeneration template could be used as a treatment choice for necrosis of the reattached avulsed skins in a degloving injury.

Patient concerns:

A 48-year-old woman with a degloving injury of the right forearm, wrist, and hand received initial treatment by reattachment of the defatted avulsed skins over the wound bed. However, 17 days postoperatively, the reattached skins developed complete necrosis, leaving large size of tissue defects and tendon/bone exposure.

Diagnosis:

Failure to reconstruct the skin and soft-tissue envelop by reattachment of the defatted avulsed skins in a severe degloving injury of the upper limb.

Interventions:

We decided to use a 2-stage procedure of Pelnac dermal regeneration template and secondary skin graft to solve this issue, in consideration of these conditions and the patient’ demanding of limb function and aesthetic appearance.

Outcomes:

At the final follow-up, this patient obtained an excellent result, in term of scar quality, aesthetic appearance, and the ability to perform the daily activities.

Lessons:

We believe this could become an interesting option in patients who needed revision procedure for management of complex wounds with tendon/bone exposure following the necrosis of reattached skins in degloving injuries.
Risk factors for lymph node metastasis in duodenal neuroendocrine tumors
Authors: Park Sang Gyu , Lee Bong Eun , Kim Gwang Ha , Park Joon Woo , Lee Moon Won , Kim Su Jin , Choi Cheol Woong , Lee Sojeong , Park Do Youn
Published: June 2019

Duodenal neuroendocrine tumors (NETs) are rare, and risk factors associated with lymph node (LN) metastasis are still not well defined. The aim of this study was to investigate risk factors of LN metastasis in duodenal NETs based on the final histopathologic results and clinical follow-up data.

This study included a total of 44 duodenal NETs in 38 patients who underwent endoscopic or surgical resection between January 2008 and December 2015. Diagnosis of duodenal NETs was confirmed based on immunohistochemical staining of chromogranin A, synaptophysin, and CD56; the clinicopathologic records were collected at the time of the initial diagnosis of duodenal NETs.

Most duodenal NETs were small (≤1 cm in 33 tumors), World Health Organization (WHO) grade G1 (in 32 tumors), limited to the mucosa and/or submucosa (in 40 tumors), and located at the duodenal bulb (in 32 tumors). Of 44 tumors, lymphovascular invasion was present in 4 (9.1%), and among 38 patients, LN metastasis was detected in 4 (10.5%). LN metastases were significantly associated with the non-bulb location, tumor size >10 mm, tumor invasion into the muscularis propria or deeper, WHO grade G2, and lymphovascular invasion. During the mean follow-up period of 54.5 months (range, 24–123 months), recurrence occurred in 1 patient.

Non-bulb location, tumor size >10 mm, invasion beyond the submucosa, WHO grade G2, and lymphovascular invasion are risk factors of LN metastasis in duodenal NETs. These findings can help clinicians choose the appropriate therapeutic modality for duodenal NETs.
Effect of pregabalin for the treatment of chronic refractory cough
Authors: Li Jun , Ye Ling
Published: June 2019

Rationale:

Chronic refractory cough (CRC) is a common clinical problem which is more likely associated with some physical problems. Although many patients have received satisfactory treatment, there were still many patients suffered from long-term cough symptoms after standardized treatment.

Patient concerns:

A patient suffered from postherpetic neuralgia (PHN) and also he complained CRC for more than 20 years.

Diagnosis:

The patient was diagnosed with PHN and CRC.

Interventions:

Pregabalin was originally administered to treat PHN.

Outcomes:

pregabalin not only alleviated her pain of PHN but also relieved chronic cough.

Lessons:

This report demonstrated the surprising effect of pregabalin on the treatment of CRC.
Advantages of laparoscopic left hemihepatectomy
Authors: Yin Xiangbao , Luo Dilai , Huang Yong , Huang Mingwen
Published: June 2019

Background:

Laparoscopic left hemihepatectomy (LLH) has been widely accepted as a minimally invasive alternative to open liver surgery. We assessed the benefits and drawbacks of LLH compared with open left hemihepatectomy (OLH) using meta-analysis.

Methods:

Relevant literature was retrieved using PubMed, Embase, Cochrane, and Ovid Medline databases. Multiple parameters of efficacy and safety were compared between the treatment groups. Results are expressed as odds ratio (OD) or mean difference (MD) with 95% confidence interval (95% CI) for fixed- and random-effects models.

Results:

The meta-analysis included 13 trials involving 1163 patients. Compared with OLH, LLH significantly reduced intraoperative blood loss (MD, −91.01; 95% CI, −139.12 to −42.89; P = .0002), transfusion requirement (OR, 0.24; 95% CI, 0.11–0.54; P = .0004), time to oral intake (MD, −0.80; 95% CI, −1.27 to −0.33; P = .0008), and hospital stay (MD, −3.94; 95% CI, −4.85 to −3.03; P < .0001). However, operative time; complications rate; and postoperative alanine transferase, albumin, and total bilirubin levels did not differ significantly between the 2 surgical groups (P > .05). For hepatolithiasis treatment, there were no significant differences in operative time, residual stones, stone recurrence, and complications rate between the groups (P > .05), but LLH resulted in lower incisional infection rate (OR, 0.44; 95% CI, 0.22–0.89; P = .02) than OLH. The LLH group demonstrated higher bile leakage rate (OR, 1.79; 95% CI, 1.14–2.81; P = .01) and incurred greater hospital costs (MD, 618.56; 95% CI, 154.47–1082.64; P = .009).

Conclusions:

LLH has multiple advantages over OLH and should thus be considered as the first choice for left hemihepatectomy.
A meta-analytic investigation of the impact of mindfulness-based interventions on ADHD symptoms
Authors: Xue Jiaming , Zhang Yun , Huang Ying
Published: June 2019

Background:

Mindfulness-based interventions (MBIs) have been reported to be efficacious in treating attention deficit hyperactivity disorder (ADHD). However, the value of the control effect of MBIs on ADHD core symptoms remains controversial. To clarify the literature on the control effect of MBIs on the symptoms of ADHD and guide future researches, an effect-size analysis was conducted.

Methods:

A systematic search in PubMed, Embase, Web of Science, Medline, Cochrane Library, China National Knowledge Infrastructure, and Wangfang Data databases was performed up to January 11, 2019. The overall effect size of MBIs on ADHD core symptoms (ie, inattention and hyperactivity/impulsivity) was recorded by the metric of Hedges’ g with 95% confidence interval, Z-value, and P-value.

Results:

Eleven eligible studies featuring 682 participants were included in the meta-analysis. The overall results indicated that MBIs had large effects on inattention (Hedges’ g = −0.825) and hyperactivity/impulsivity (Hedges’ g = −0.676) relative to the control group. Results from subgroup analyses between self- and observer rating on ADHD symptoms revealed that the effect of MBIs both remained in a large range and self-rated ADHD core symptom had a greater impact on heterogeneity across the studies. Meta-regression found that the overall effect might be moderated by participant age group and control condition.

Conclusion:

The present meta-analysis suggested that MBIs had large effects in reducing ADHD core symptoms in comparison with the control group. Future researches are needed to assess follow-up effects of MBIs on ADHD core symptoms and explore the correlation between the individual level of mindfulness and reduction of ADHD symptoms.
TCM nonpharmacological interventions for chronic obstructive pulmonary disease (COPD)
Authors: Zhang Furong , Chen Xixi , Wu Xiaoyan , Liu Xicen , Sun Mingsheng , Shen Xiaoyu , Li Juan , Zheng Hui , Jin Rongjiang
Published: June 2019

Background:

Traditional Chinese medicine (TCM) nonpharmacological interventions are gaining an increasing popularity for chronic pulmonary obstructive disease (COPD) treatment and rehabilitation, yet their comparative effectiveness and safety remains unclear. Therefore, this study will aim to compare their effectiveness and safety for COPD by implementing a network-meta analysis.

Methods:

Electronic databases including MEDLINE via Ovid, and EMBASE via Ovid, the Cochrane Central Register of Controlled Trials (CENTRAL), China National Knowledge Infrastructure (CNKI) and Chinese BioMedical Literature Database (CBM) will be searched for related randomized controlled trials (RCTs) from inceptions to the search date without language restrictions. RCTs that compare TCM nonpharmacological interventions with placebo or conventional treatments will be included. The primary outcome will be lung function measures, dyspnea level and COPD-specified life quality and secondary ones will include functional exercise capacity, and general health-related life quality. Both classical meta-analysis and network meta-analysis will be implemented to investigate direct and indirect evidences on this topic. Continuous data will be expressed as standard mean differences (SMDs) and categorical data as risk ratios (RRs) with 95% confidence intervals. The evidence transitivity and consistency within network will be evaluated with Cochrane Q statistic and net-heat plot.

Results:

The study results will be disseminated through a peer-reviewed journal publication or conference presentation.

Conclusions:

The review findings will provide a ranking evidence of current TCM nonpharmacological interventions and help to inform clinical practitioners, COPD patients, and policy-makers in the decision-making.

Trial registration number:

PROSPERO CRD42019126554
Development and validation of a nomogram for osteosarcoma-specific survival
Authors: Zhang Jun , Yang Jin , Wang Hai-Qiang , Pan Zhenyu , Yan Xiaoni , Hu Chuanyu , Li Yuanjie , Lyu Jun
Published: June 2019

This study aimed to establish a comprehensive prognostic system for osteosarcoma based on a large population database with high quality.

The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify patients with osteosarcoma from 1973 to 2015. Multivariate analysis was performed to screen statistically significant variables. A nomogram was constructed by R software to predict the 3-, 5- and 10-year survival rates. Predictive abilities were compared by C-indexes, calibration plots, integrated discrimination improvement (IDI), net reclassification improvement (NRI), as well as decision curve analysis (DCA).

In total, 4505 osteosarcoma patients were identified. They were divided into training (70%, n = 3153) and validating (30%, n = 1352) groups. Multivariate analyses identified independent predictors. Subsequently, the nomogram system of a new model was established, which comprised 7 variables as age, sex, site, decade of diagnosis (DOD), extent of disease (EOD), tumor size and patients undergoing tri-modality therapy (surgery, radiotherapy and chemotherapy). It provided better C-indexes than the model without therapies (0.727, 0.712 vs 0.705, 0.668) in the 2 cohort, respectively. As well, the new model had good performances in the calibration plots. Moreover, both IDI and NRI improved for 3-, 5- and 10-year follow-up of C-indexes. Finally, DCA demonstrated that the nomogram of new model was clinically meaningful.

We developed a reliable nomogram for prognostic determinants and treatment outcome analysis of osteosarcoma, thus helping better choose medical examinations and optimize therapeutic regimen under the cooperation among oncologists and surgeons.
Efficacy and safety of sertraline for the treatment of premature ejaculation
Authors: Yi Zhan-Miao , Chen Shi-Di , Tang Qi-Yu , Tang Hui-Lin , Zhai Suo-Di
Published: June 2019

Backgroud:

Evidence on the efficacy and safety of sertraline in patients with premature ejaculation (PE) was inconsistent. The objective of this article is to evaluate the efficacy and safety of sertraline for the treatment of PE.

Methods:

We searched Medline (OVID), Embase, the Cochrane Library, and 2 Chinese databases for randomized controlled trials (RCTs) and randomized crossover trials (RTs) that evaluated the efficacy and safety of sertraline in patients with PE. A meta-analysis was performed to calculate their pooled estimates with 95% confidence interval.

Results:

Of the 645 records obtained, we included 12 RCTs and 2 RTs (n = 977). Meta-analysis showed that sertraline prolonged intravaginal ejaculation latency time (IELT) in PE patients ((standard mean difference (SMD) = 2.14, 95% CI 1.20 to 3.08). Subgroup analyses indicated a prolonged IELT for different treatment courses: 4 weeks (SMD = 2.66, 1.06 to 4.26), 6 weeks (SMD = 0.95, 0.31 to 1.58), and 8 weeks (SMD = 1.81, 0.78 to 2.85). The sexual satisfaction rates of patients (SMD = 2.20, 1.57 to 2.84) and spouses (SMD = 2.27, 1.44 to 3.09) were also improved. We observed a significant increased risk of gastrointestinal upset (risk ratio = 2.71, 1.39 to 5.28) in the sertraline group.

Conclusion:

Sertraline can prolong IELT of PE patients, improve sexual satisfaction rates of patients and spouses, but increase risk of gastrointestinal upset.
Clinical outcomes of a cohort of migrants and citizens living with human immunodeficiency virus in Botswana: implications for Joint United Nation Program on HIV and AIDS 90-90-90 targets
Authors: Marukutira Tafireyi , Yin Dwight , Cressman Laura , Kariuki Ruth , Malone Brighid , Spelman Tim , Mawandia Shreshth , Ledikwe Jenny H. , Semo Bazghina-Werq , Crowe Suzanne , Stoove Mark , Hellard Margaret , Dickinson Diana
Published: June 2019

The aim of the study was to evaluate the human immunodeficiency virus (HIV) treatment cascade and mortality in migrants and citizens living with HIV in Botswana.

Retrospective 2002 to 2016 cohort study using electronic medical records from a single center managing a high migrant case load.

Records for 768 migrants and 3274 citizens living with HIV were included. Maipelo Trust, a nongovernmental organization, funded care for most migrants (70%); most citizens (85%) had personal health insurance. Seventy percent of migrants and 93% of citizens had received antiretroviral therapy (ART). At study end, 44% and 27% of migrants and citizens, respectively were retained in care at the clinic (P < .001). Among the 35% and 60% of migrants and citizens on ART respectively with viral load (VL) results in 2016, viral suppression was lower among migrants (82%) than citizens (95%) (P < .001). Citizens on ART had a median 157-unit [95% confidence interval (CI) 122–192] greater increase in CD4+ T-cell count (last minus first recorded count) than migrants after adjusting for baseline count (P < .001). Five-year survival was 92% (95% CI = 87.6–94.8) for migrants and 96% (95% CI = 95.4–97.2) for citizens. Migrants had higher mortality than citizens after entry into care (hazard ratio = 2.3, 95% CI = 1.34–3.89, P = .002) and ART initiation (hazard ratio = 2.2, 95% CI = 1.24–3.78, P = .01).

Fewer migrants than citizens living with HIV in Botswana were on ART, accessed VL monitoring, achieved viral suppression, and survived. The HIV treatment cascade appears suboptimal for migrants, undermining local 90-90-90 targets. These results highlight the need to include migrants in mainstream-funded HIV treatment programs, as microepidemics can slow HIV epidemic control.
Fecal microbiota transplantation in children: current concepts
Authors: Gurram Bhaskar , Sue Paul K.
Published: June 2019

Purpose of review

Administration of fecal material into the gastrointestinal tract, termed fecal microbiota transplantation (FMT), is increasingly recognized as an effective treatment option for recurrent Clostridium difficile infection (RCDI). The impact of FMT on host microbial communities and subsequent disease states has also been explored in recent years for conditions as varied as inflammatory bowel disease especially ulcerative colitis, metabolic diseases, such as diabetes, graft-versus-host disease in hematopoietic stem cell transplant recipients, and autism and autism spectrum disorders. The purpose of this article is to review the evidence for FMT as a treatment option in various pediatric illnesses.

Recent findings

The rate of C. difficile infection is rising among children, and is associated with significant morbidity and disease, with recurrence in up to 20% of pediatric patients. Several randomized controlled trials evaluating the utility of FMT in RCDI in comparison to vancomycin have been published and demonstrate high rates of efficacy between 70 and 100%. In addition, the safety of FMT in the treatment of RCDI has been well described in the adult population, with several pediatric case series demonstrating similar rates of tolerability and adverse events. FMT in ulcerative colitis appears promising, especially with multiple infusions administered via the lower gastrointestinal tract. However, there are several limitations, including the lack of uniformity of protocols used, source of FMT, route of administration and the lack of standardization of concomitant therapies. The data on usage of FMT for other indications are preliminary and limited.

FMT is recognized as an effective treatment option for RCDI and is increasing sought by parents. Although limited, pediatric studies to date on the use of FMT for RCDI demonstrate similar efficacy rates as in the adult population. FMT has been proposed as a treatment option for an increasing number of pediatric conditions, and additional studies are needed to delineate the efficacy of FMT outside of RCDI, as well as its short and long-term impacts on human health.
Current state of organ transplant tolerance
Authors: Rickert Charles G. , Markmann James F.
Published: June 2019

Purpose of review

Immunological tolerance has long been considered the ‘holy grail’ of organ transplantation. Although tolerance has been an active area of research for 70 years, its clinical application has only been possible in the last two decades and widespread use remains an, as yet, unattained goal. Recent advances in the understanding of immune regulation have identified many new approaches to tolerance induction and several clinical trials are currently aimed at bringing this treatment to more patients.

Recent findings

Mixed chimerism remains the most successful approach to tolerance induction. However, many treatments, including adoptive transfer of regulatory T cells, regulatory B cells, and immune suppressive dendritic cells and myeloid derived suppressor cells have shown great promise in preclinical models. Recent clinical studies have found that both kidney and liver operational tolerance are achievable in the appropriate settings. Furthermore, combining multiple tolerance approaches has shown potential to produce durable and safer tolerance.

Tolerance to protect kidney and liver allografts has become a valuable therapy in the correct circumstances. Through further clinical trials and an improved understanding of immune regulatory components, tolerance is poised to have a significant impact on transplantation in the years to come.
Nurse Residency Programs
Authors: Chant Kimberly J. , Westendorf Denise S.
Published: June 2019

The purpose of this integrative literature review was to identify commonalities among nurse residency programs deployed for greater than 3 years, showing improved job retention and satisfaction. The Johns Hopkins Nursing Evidence-Based Practice Model guided this review. Successful, sustainable nurse residency programs have a strong foundation with committed leadership to support transition; a structured program with defined outcomes to promote clinical competence, safe patient care, and professional development; and an evaluation process to guide continual improvement and meet organizational needs.
Placebo and nocebo effects and operant pain-related avoidance learning
Authors: Janssens Thomas , Meulders Ann , Cuyvers Bien , Colloca Luana , Vlaeyen Johan W.S.
Published: June 2019

Introduction:

Research on learning in placebo and nocebo has relied predominantly on Pavlovian conditioning procedures. Operant learning procedures may more accurately model learning in real-life situations in which placebo and nocebo effects occur.

Objectives:

To investigate the development and persistence of placebo and nocebo effects using an operant avoidance learning task.

Methods:

Pain-free participants (n = 58) could learn to avoid pain by performing movements that differed in difficulty and intensity of painful stimulation. Participants performed movements in 2 contexts. In the high cost of avoidance context, pain stimulus intensity reduced with increasing movement difficulty. In the low cost of avoidance context, contingencies were reversed. Participants rated pain expectations and pain intensity. During test, movement difficulties were unchanged, but participants always received a medium-intensity pain stimulus. Placebo and nocebo effects were defined as lower/higher pain intensity ratings for trajectories that previously resulted in low/high-intensity compared with medium-intensity stimulation.

Results:

As expected, participants acquired differential movement-pain expectations and differential movement choices. Testing with a medium-intensity pain stimulus quickly erased differences in movement choice across contexts, but differences in pain expectations were maintained. Pain modulation across context was in line with movement-pain expectations. However, we only observed placebo effects within the low cost of avoidance context and found no evidence of nocebo effects.

Conclusion:

Operant learning can change pain expectations, pain modulation, and pain-related avoidance behavior. Persisting pain expectations suggest that acquired pain beliefs may be resistant to disconfirmation, despite self-initiated experience with novel pain-movement contingencies.
National Patterns of Filled Prescriptions and Third-Line Treatment Utilization for Privately Insured Women With Overactive Bladder
Authors: Linder Brian J. , Gebhart John B. , Elliott Daniel S. , Van Houten Holly K. , Sangaralingham Lindsey R. , Habermann Elizabeth B.
Published: June 2019

Objective

The aim of this study was to evaluate national patterns of care for women with overactive bladder (OAB) in an administrative data set and identify potential areas for improvement.

Methods

We performed an analysis using the OptumLabs Data Warehouse, which contains deidentified administrative claims data from a large national US health insurance plan. The study included women, older than 18 years, with a new OAB diagnosis from January 1, 2007, to June 30, 2017. We excluded those with an underlying neurologic etiology, with interstitial cystitis/painful bladder syndrome, were pregnant, or did not have continuous enrollment for 12 months before and after OAB diagnosis. Trends in management were assessed via the Cochran-Armitage test. Time to discontinuation among medications was compared using t test.

Results

Of 1.4 million women in the database during the study time frame, 60,246 (4%) were included in the study. Median age was 61 years [interquartile range (IQR), 50–73], and median follow-up was 2.6 years (IQR, 1.6–4.2). Overall, 37% were treated with anticholinergics, 5% with beta-3 agonists, 7% with topical estrogen, and 2% with pelvic floor physical therapy; 26% saw a specialist; and 2% underwent third-line therapy. Median time to cessation of prescription filling was longer for beta-3 agonists versus anticholinergics [median, 4.1 months (IQR, 1–15) vs 3.6 months (IQR, 1–10); P < 0.0001]. Use of third-line therapies significantly increased over the study time frame, from 1.1% to 2.2% (P < 0.0001).

Conclusions

Most of the patients do not continue filling prescriptions for OAB medications, and a minority of patients were referred for specialty evaluation. Although third-line therapy use is increasing, it is used in a small proportion of women with OAB. Given these patterns, there may be underutilization of specialist referral and other OAB therapies.
Rift Valley fever virus minigenome system for investigating the role of L protein residues in viral transcription and replication
Authors: Jérôme Hanna , Rudolf Martin , Lelke Michaela , Pahlmann Meike , Busch Carola , Bockholt Sabrina , Wurr Stephanie , Günther Stephan , Rosenthal Maria , Kerber Romy
Published: June 2019

Replicon systems are important tools for investigating viral RNA synthesis. We have developed an ambisense minigenome system for Rift Valley fever virus (RVFV) with the aim to analyse the effects of L gene mutations on viral transcription versus replication. The overall activity of the replication complex was assessed by expression of a luciferase reporter gene. Northern blot analysis enabled differentiation between synthesis of viral mRNA and replication intermediates. The functionality of the system was demonstrated by probing residues predictably involved in the cap-snatching endonuclease active site in the L protein. Corresponding mutations led to a selective defect in the viral mRNA synthesis as described for other bunyaviruses. The analysis of further L gene mutants revealed an essential role of a C-terminal region in the RVFV L protein in viral transcription. In summary, the established minigenome system is suitable for functional testing of the relevance of residues for viral transcription and replication.
Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity
Authors: Baars Matthijs , Douma Thera , Simeonov Dimitre R. , Myers Darienne R. , Banerjee Saikat , Kulhanek Kayla , Zwakenberg Susan , Baltissen Marijke P. , de Roock Sytze , van Wijk Femke , Vermeulen Michiel , Marson Alexander , Roose Jeroen P. , Vercoulen Yvonne
Published: June 2019

RasGRP1 is a Ras guanine nucleotide exchange factor, and an essential regulator of lymphocyte receptor signaling. In mice, Rasgrp1 deletion results in defective T lymphocyte development. RASGRP1-deficient patients suffer from immune deficiency, and the RASGRP1 gene has been linked to autoimmunity. However, how RasGRP1 levels are regulated, and if RasGRP1 dosage alterations contribute to autoimmunity remains unknown. We demonstrate that diminished Rasgrp1 expression caused defective T lymphocyte selection in C57BL/6 mice, and that the severity of inflammatory disease inversely correlates with Rasgrp1 expression levels. In patients with autoimmunity, active inflammation correlated with decreased RASGRP1 levels in CD4+ T cells. By analyzing H3K27 acetylation profiles in human T cells, we identified a RASGRP1 enhancer that harbors autoimmunity-associated SNPs. CRISPR-Cas9 disruption of this enhancer caused lower RasGRP1 expression, and decreased binding of RUNX1 and CBFB transcription factors. Analyzing patients with autoimmunity, we detected reduced RUNX1 expression in CD4+ T cells. Lastly, we mechanistically link RUNX1 to transcriptional regulation of RASGRP1 to reveal a key circuit regulating RasGRP1 expression, which is vital to prevent inflammatory disease.
Dissociating decisional and temporal information in interval categorisation
Authors: Morita Vanessa C. , Sato João R. , Caetano Marcelo S. , Cravo André M.
Published: June 2019

Interval timing is fundamental for humans and non-human animals to interact with their environment. Several studies that investigate temporal processing combine behavioural tasks with neurophysiological methods, such as electrophysiological recordings (EEG). However, in the majority of these studies, it is hard to dissociate whether EEG activity reflects temporal or decisional information. In the present study, we investigated how time and decision is encoded in the EEG signal while human participants performed a temporal categorisation task with two different temporal references. Using a combination of evoked potentials and multivariate pattern analysis, we show that: (1) During the interval to-be-timed, both temporal and decisional information are encoded; (2) Activity evoked by the end of the interval encodes almost exclusively decisional information. These results suggest that decisional aspects of the task better explain EEG activity commonly related to temporal processing. The interplay between the encoding of time and decision is consistent with recent proposals that approximate temporal processing with decisional models.
Behavioral and neural signatures of working memory in childhood
Authors: Rosenberg Monica D. , Martinez Steven A. , Rapuano Kristina M. , Conley May I. , Cohen Alexandra O. , Cornejo M. Daniela , Hagler Donald J. , Anderson Kevin M. , Wager Tor D. , Feczko Eric , Earl Eric , Fair Damien A. , Barch Deanna M. , Watts Richard , Casey BJ
Published: June 2019

Working memory function changes across development and varies across individuals. The patterns of behavior and brain function that track individual differences in working memory during development, however, are not well understood. Here we establish associations between working memory, cognitive abilities, and functional MRI activation in data from over 4,000 9–10-year-olds enrolled in the Adolescent Brain Cognitive Development study, an ongoing longitudinal study in the United States. Behavioral analyses reveal robust relationships between working memory, short-term memory, language skills, and fluid intelligence. Analyses relating out-of-scanner working memory performance to memory-related fMRI activation in an emotional n-back task demonstrate that frontoparietal activity in response to an explicit memory challenge indexes working memory ability. Furthermore, this relationship is domain-specific, such that fMRI activation related to emotion processing during the emotional n-back task, inhibitory control during a stop-signal task, and reward processing during a monetary incentive delay task does not track memory abilities. Together these results inform our understanding of the emergence of individual differences in working memory and lay the groundwork for characterizing the ways in which they change across adolescence.
Multi-task learning of a deep k-nearest neighbour network for histopathological image classification and retrieval
Authors: Peng Tingying , Boxberg Melanie , Weichert Wilko , Navab Nassir , Marr Carsten
Published: June 2019

Deep neural networks have achieved tremendous success in image recognition, classification and object detection. However, deep learning is often criticised for its lack of transparency and general inability to rationalize its predictions. The issue of poor model interpretability becomes critical in medical applications, as a model that is not understood and trusted by physicians is unlikely to be used in daily clinical practice. In this work, we develop a novel multi-task deep learning framework for simultaneous histopathology image classification and retrieval, leveraging on the classic concept of k-nearest neighbors to improve model interpretability. For a test image, we retrieve the most similar images from our training databases. These retrieved nearest neighbours can be used to classify the test image with a confidence score, and provide a human-interpretable explanation of our classification. Our original framework can be built on top of any existing classification network (and therefore benefit from pretrained models), by (i) adding a triplet loss function with a novel triplet sampling strategy to compare distances between samples and (ii) a Cauchy hashing loss function to accelerate neighbour searching. We evaluate our method on colorectal cancer histology slides, and show that the confidence estimates are strongly correlated with model performance. The explanations provided by nearest neighbors are intuitive and useful for expert evaluation by giving insights into understanding possible model failures, and can support clinical decision making by comparing archived images and patient records with the actual case.
Household socio-economic status and likelihood of HIV infection among under five-year children in Muheza district, north-eastern Tanzania
Authors: Bwana Veneranda M. , Simulundu Edgar , Mboera Leonard E.G. , Mfinanga Sayoki G. , Michelo Charles
Published: June 2019

Background

There are evidences of the association between socio-economic factors and HIV prevalence in Sub-Saharan Africa. However, there is dearth of information on such relationship in Tanzania. Here, we present data on the relationship between household’s socio-economic factors and HIV prevalence among under five-year children in Muheza district, Tanzania.

Methods

We conducted a facility-based study from June 2015 to June 2016 in which we enrolled under five-year children born to HIV positive mothers. Information on HIV status of the child and socio-demographic characteristic of the head of the household was collected using a structured questionnaire. Data analysis was done using STATA version 13.0.

Results

A total of 576 mothers/guardians were interviewed each with respective HIV exposed under five-year child. Children who belonged to a head of household with at least a high education level (AOR= 0.4, 95% CI 0.2-0.8) and living in a relatively wealthy household (AOR = 0.5, 95% CI 0.2-0.9) was associated with reduced odds of HIV infection among children. Univariate analysis revealed that the odds of HIV infection was three-fold (COR = 2.9, 95% CI 1.2-7.0) higher among children living in rural than in urban areas. The heads of household living in rural areas (AOR=0.3 95% CI 0.1-0.9) had low education level compared to those living in urban areas.

Conclusion

Children who belong to the head of households with high educational level, high household wealth were associated with reduced likelihood of HIV infection in Tanzania. Children living in rural areas had increased likelihood of acquiring HIV infection. These findings stress the need to focus on improving education status of the population and economically disadvantaged populations as a strategy for HIV prevention and control measures.
Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52
Authors: Min Jaewon , Wright Woodring E. , Shay Jerry W.
Published: June 2019

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. One of the hallmarks of ALT cancer is the excessively clustered telomeres in promyelocytic leukemia (PML) bodies, represented as large bright telomere foci. Here, we present a model system that generates telomere clustering in nuclear polySUMO (small ubiquitin-like modification)/polySIM (SUMO-interacting motif) condensates, analogous to PML bodies, and thus artificially engineered ALT-associated PML body (APB)-like condensates in vivo. We observed that the ALT-like phenotypes (i.e., a small fraction of heterogeneous telomere lengths and formation of C circles) are rapidly induced by introducing the APB-like condensates together with BLM through its helicase domain, accompanied by ssDNA generation and RPA accumulation at telomeres. Moreover, these events lead to mitotic DNA synthesis (MiDAS) at telomeres mediated by RAD52 through its highly conserved N-terminal domain. We propose that the clustering of large amounts of telomeres in human cancers promotes ALT that is mediated by MiDAS, analogous to Saccharomyces cerevisiae type II ALT survivors.
GADD45 promotes locus-specific DNA demethylation and 2C cycling in embryonic stem cells
Authors: Schüle Katrin M. , Leichsenring Manuel , Andreani Tommaso , Vastolo Viviana , Mallick Medhavi , Musheev Michael U. , Karaulanov Emil , Niehrs Christof
Published: June 2019

Mouse embryonic stem cell (ESC) cultures contain a rare cell population of “2C-like” cells resembling two-cell embryos, the key stage of zygotic genome activation (ZGA). Little is known about positive regulators of the 2C-like state and two-cell stage embryos. Here we show that GADD45 (growth arrest and DNA damage 45) proteins, regulators of TET (TET methylcytosine dioxygenase)-mediated DNA demethylation, promote both states. Methylome analysis of Gadd45a,b,g triple-knockout (TKO) ESCs reveal locus-specific DNA hypermethylation of ∼7000 sites, which are enriched for enhancers and loci undergoing TET–TDG (thymine DNA glycosylase)-mediated demethylation. Gene expression is misregulated in TKOs, notably upon differentiation, and displays signatures of DNMT (DNA methyltransferase) and TET targets. TKOs manifest impaired transition into the 2C-like state and exhibit DNA hypermethylation and down-regulation of 2C-like state-specific genes. Gadd45a,b double-mutant mouse embryos display embryonic sublethality, deregulated ZGA gene expression, and developmental arrest. Our study reveals an unexpected role of GADD45 proteins in embryonic two-cell stage regulation.
A machine-learning approach for accurate detection of copy number variants from exome sequencing
Authors: Pounraja Vijay Kumar , Jayakar Gopal , Jensen Matthew , Kelkar Neil , Girirajan Santhosh
Published: June 2019

Copy number variants (CNVs) are a major cause of several genetic disorders, making their detection an essential component of genetic analysis pipelines. Current methods for detecting CNVs from exome-sequencing data are limited by high false-positive rates and low concordance because of inherent biases of individual algorithms. To overcome these issues, calls generated by two or more algorithms are often intersected using Venn diagram approaches to identify “high-confidence” CNVs. However, this approach is inadequate, because it misses potentially true calls that do not have consensus from multiple callers. Here, we present CN-Learn, a machine-learning framework that integrates calls from multiple CNV detection algorithms and learns to accurately identify true CNVs using caller-specific and genomic features from a small subset of validated CNVs. Using CNVs predicted by four exome-based CNV callers (CANOES, CODEX, XHMM, and CLAMMS) from 503 samples, we demonstrate that CN-Learn identifies true CNVs at higher precision (∼90%) and recall (∼85%) rates while maintaining robust performance even when trained with minimal data (∼30 samples). CN-Learn recovers twice as many CNVs compared to individual callers or Venn diagram–based approaches, with features such as exome capture probe count, caller concordance, and GC content providing the most discriminatory power. In fact, ∼58% of all true CNVs recovered by CN-Learn were either singletons or calls that lacked support from at least one caller. Our study underscores the limitations of current approaches for CNV identification and provides an effective method that yields high-quality CNVs for application in clinical diagnostics.
Clinical and genetic characterization of individuals with predicted deleterious PHIP variants
Authors: Craddock Kirsten E. , Okur Volkan , Wilson Ashley , Gerkes Erica H. , Ramsey Keri , Heeley Jennifer M. , Juusola Jane , Vitobello Antonio , Dupeyron Marie-Noelle Bonnet , Faivre Laurence , Chung Wendy K.
Published: June 2019

Heterozygous deleterious variants in PHIP have been associated with behavioral problems, intellectual disability/developmental delay, obesity/overweight, and dysmorphic features (BIDOD syndrome). We report an additional 10 individuals with pleckstrin homology domain-interacting protein (PHIP)-predicted deleterious variants (four frameshift, three missense, two nonsense, and one splice site; six of which are confirmed de novo). The mutation spectrum is diverse, and there is no clustering of mutations across the protein. The clinical phenotype of these individuals is consistent with previous reports and includes behavioral problems, intellectual disability, developmental delay, hypotonia, and dysmorphic features. The additional individuals we report have a lower frequency of obesity than previous reports and a higher frequency of gastrointestinal problems, social deficits, and behavioral challenges. Characterizing additional individuals with diverse mutations longitudinally will provide better natural history data to assist with medical management and educational and behavioral support.
Minimizing experimental artefacts in synchrotron-based X-ray analyses of Fe speciation in tissues of rice plants
Authors: Wang Peng , McKenna Brigid A. , Menzies Neal W. , Li Cui , Glover Chris J. , Zhao Fang-Jie , Kopittke Peter M.
Published: June 2019

Iron (Fe) plays an important role within environmental systems. Synchrotron-based X-ray approaches, including X-ray absorption spectroscopy (XAS), provide powerful tools for in situ analyses of Fe speciation, but beam damage during analysis may alter Fe speciation during its measurement. XAS was used to examine whether experimental conditions affect the analysis of Fe speciation in plant tissues. Even when analyzed in a cryostat at 12 K, it was found that FeIII can rapidly (within 0.5–1 min) photoreduce to FeII, although the magnitude of photoreduction varied depending upon the hydration of the sample, the coordination chemistry of the Fe, as well as other properties. For example, photoreduction of FeIII was considerably higher for aqueous standard compounds than for hydrated plant-root tissues. The use of freeze-dried samples in the cryostat (12 K) markedly reduced the magnitude of this FeIII photoreduction, and there was no evidence that the freeze-drying process itself resulted in experimental artefacts under the current experimental conditions, such as through the oxidation of FeII, although some comparatively small differences were observed when comparing spectra of hydrated and freeze-dried FeII compounds. The results of this study have demonstrated that FeIII photoreduction can occur during X-ray analysis, and provides suitable conditions to preserve Fe speciation to minimize the extent of beam damage when analyzing environmental samples. All studies utilizing XAS are encouraged to include a preliminary experiment to determine if beam damage is occurring, and, where appropriate, to take the necessary steps (such as freeze drying) to overcome these issues.
Crystal structure of the flavin-dependent thymidylate synthase Thy1 from Thermus thermophilus with an extra C-terminal domain
Authors: Ogawa Aoba , Sampei Gen-ichi , Kawai Gota
Published: June 2019

The thymidylate synthases ThyA and Thy1 are enzymes that catalyse the formation of thymidine monophosphate from 2′-deoxyuridine monophosphate. Thy1 (or ThyX) requires flavin for catalytic reactions, while ThyA does not. In the present study, the crystal structure of the flavin-dependent thymidylate synthase Thy1 from Thermus thermophilus HB8 (TtThy1, TTHA1096) was determined in complex with FAD and phosphate at 2.5 Å resolution. TtThy1 is a tetrameric molecule like other Thy1 proteins, to which four FAD molecules are bound. In the crystal of TtThy1, two phosphate ions were bound to each dUMP-binding site. The characteristic feature of TtThy1 is the existence of an extra C-terminal domain (CTD) consisting of three α-helices and a β-strand. The function of the CTD is unknown and database analysis showed that this CTD is only shared by part of the Deinococcus–Thermus phylum.
Crystal structure of bis(benzoato-κO)[5,15-diphenyl-10,20-bis(pyridin-4-yl)porphyrinato-κ4
N,N′,N′′,N′′′]tin(IV)
Authors: Shee Nirmal K. , Lee Chang-Ju , Kim Hee-Joon
Published: June 2019

In the crystal structure of the title compound, [Sn(C42H26N6)(C7H5O2)2], the SnIV ion is located on a crystallographic inversion centre and is octahedrally coordinated with an N4O2 set. Four N atoms of the porphyrin ring form the equatorial plane while the axial positions are occupied by two O atoms from benzoate anions. The molecular packing of the title complex involves non-classical hydrogen bonds of the types C—H...O and C—H...N, leading to a three-dimensional network structure.