bluuebunny/crossref_metadata_2025 huggingface dataset:
Multivariate transcriptome analysis identifies networks and key drivers of chronic lymphocytic leukemia relapse risk and patient survival
Authors: Griffen Ti’ara L. , Dammer Eric B. , Dill Courtney D. , Carey Kaylin M. , Young Corey D. , Nunez Sha’Kayla K. , Ohandjo Adaugo Q. , Kornblau Steven M. , Lillard James W.
Published: June 2021

Background

Chronic lymphocytic leukemia (CLL) is an indolent heme malignancy characterized by the accumulation of CD5+CD19+B cells and episodes of relapse. The biological signaling that influence episodes of relapse in CLL are not fully described. Here, we identify gene networks associated with CLL relapse and survival risk.

Methods

Networks were investigated by using a novel weighted gene network co-expression analysis method and examining overrepresentation of upstream regulators and signaling pathways within co-expressed transcriptome modules across clinically annotated transcriptomes from CLL patients (N = 203). Gene Ontology analysis was used to identify biological functions overrepresented in each module. Differential Expression of modules and individual genes was assessed using an ANOVA (Binet Stage A and B relapsed patients) or T-test (SF3B1 mutations). The clinical relevance of biomarker candidates was evaluated using log-rank Kaplan Meier (survival and relapse interval) and ROC tests.

Results

Eight distinct modules (M2, M3, M4, M7, M9, M10, M11, M13) were significantly correlated with relapse and differentially expressed between relapsed and non-relapsed Binet Stage A CLL patients. The biological functions of modules positively correlated with relapse were carbohydrate and mRNA metabolism, whereas negatively correlated modules to relapse were protein translation associated. Additionally, M1, M3, M7, and M13 modules negatively correlated with overall survival. CLL biomarkers BTK, BCL2, and TP53 were co-expressed, while unmutated IGHV biomarker ZAP70 and cell survival-associated NOTCH1 were co-expressed in modules positively correlated with relapse and negatively correlated with survival days.

Conclusions

This study provides novel insights into CLL relapse biology and pathways associated with known and novel biomarkers for relapse and overall survival. The modules associated with relapse and overall survival represented both known and novel pathways associated with CLL pathogenesis and can be a resource for the CLL research community. The hub genes of these modules, e.g., ARHGAP27P2, C1S, CASC2, CLEC3B, CRY1, CXCR5, FUT5, MID1IP1, and URAHP, can be studied further as new therapeutic targets or clinical markers to predict CLL patient outcomes.
Efficacy of budesonide/glycopyrronium/formoterol metered dose inhaler in patients with COPD: post-hoc analysis from the KRONOS study excluding patients with airway reversibility and high eosinophil counts
Authors: Muro Shigeo , Sugiura Hisatoshi , Darken Patrick , Dorinsky Paul
Published: June 2021

Background

In the Phase III KRONOS study, triple therapy with budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied.

Methods

KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 μg, GFF 14.4/10 μg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 μg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV1 over weeks 12–24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported.

Results

Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS < 300 cells/mm3. In this group, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM (least squares mean treatment difference, 95% confidence interval [CI] 69 mL [39, 99], unadjusted p < 0.0001 and 51 mL [20, 81], unadjusted p = 0.0011, respectively) and was comparable to GFF. BGF also significantly reduced annual moderate-to-severe exacerbation rates versus GFF (rate ratio [95% CI] 0.53 [0.37, 0.76], unadjusted p = 0.0005), with numerical reductions observed versus BFF and BUD/FORM. These results were similar for the overall study population. Safety findings were generally similar between non-reversible patients with EOS < 300 cells/mm3 and the overall population.

Conclusions

In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm3, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM and significantly reduced the rate of moderate-to-severe exacerbations versus GFF. These findings demonstrate that BGF can provide benefits for a broad range of patients with COPD, and that the overall findings of the KRONOS primary analysis were not driven by patients with reversible airflow obstruction or high eosinophil counts.

Trial registration ClinicalTrials.gov, NCT02497001. Registered 14 July 2015, https://clinicaltrials.gov/ct2/show/NCT02497001
Effects of air pollution exposure on social behavior: a synthesis and call for research
Authors: Weitekamp Chelsea A. , Hofmann Hans A.
Published: June 2021

Background

There is a growing literature from both epidemiologic and experimental animal studies suggesting that exposure to air pollution can lead to neurodevelopmental and neuropsychiatric disorders. Here, we suggest that effects of air pollutant exposure on the brain may be even broader, with the potential to affect social decision-making in general.

Methods

We discuss how the neurobiological substrates of social behavior are vulnerable to air pollution, then briefly present studies that examine the effects of air pollutant exposure on social behavior-related outcomes.

Results

Few experimental studies have investigated the effects of air pollution on social behavior and those that have focus on standard laboratory tests in rodent model systems. Nonetheless, there is sufficient evidence to support a critical need for more research.

Conclusion

For future research, we suggest a comparative approach that utilizes diverse model systems to probe the effects of air pollution on a wider range of social behaviors, brain regions, and neurochemical pathways.
Risk and space: modelling the accessibility of stroke centers using day- & nighttime population distribution and different transportation scenarios
Authors: Rauch S. , Taubenböck H. , Knopp C. , Rauh J.
Published: June 2021

Purpose

Rapid accessibility of (intensive) medical care can make the difference between life and death. Initial care in case of strokes is highly dependent on the location of the patient and the traffic situation for supply vehicles. In this methodologically oriented paper we want to determine the inequivalence of the risks in this respect.

Methods

Using GIS we calculate the driving time between Stroke Units in the district of Münster, Germany for the population distribution at day- & nighttime. Eight different speed scenarios are considered. In order to gain the highest possible spatial resolution, we disaggregate reported population counts from administrative units with respect to a variety of factors onto building level.

Results

The overall accessibility of urban areas is better than in less urban districts using the base scenario. In that scenario 6.5% of the population at daytime and 6.8% at nighttime cannot be reached within a 30-min limit for the first care. Assuming a worse traffic situation, which is realistic at daytime, 18.1% of the population fail the proposed limit.

Conclusions

In general, we reveal inequivalence of the risks in case of a stroke depending on locations and times of the day. The ability to drive at high average speeds is a crucial factor in emergency care. Further important factors are the different population distribution at day and night and the locations of health care facilities. With the increasing centralization of hospital locations, rural residents in particular will face a worse accessibility situation.
Oncologic and long-term outcomes of enhanced recovery after surgery in cancer surgeries — a systematic review
Authors: Pang Qianyun , Duan Liping , Jiang Yan , Liu Hongliang
Published: June 2021

Background

Clinical evidence has proved that enhanced recovery after surgery (ERAS) can improve short-term clinical outcomes after various types of surgeries, but the long-term benefits have not yet been examined, especially with respect to cancer surgeries. Therefore, a systematic review of the current evidence was conducted.

Methods

The Pubmed, Cochrane Library, Embase, and Web of Science databases were searched using the following key words as search terms: “ERAS” or “enhanced recovery” or “fast track”, “oncologic outcome”, “recurrence”, “metastasis”, “long-term outcomes”, “survival”, and “cancer surgery”. The articles were screened using the inclusion and exclusion criteria, and the data from the included studies were extracted and analyzed.

Results

A total of twenty-six articles were included in this review. Eighteen articles compared ERAS and conventional care, of which, 12 studies reported long-term overall survival (OS), and only 4 found the improvement by ERAS. Four studies reported disease-free survival (DFS), and only 1 found the improvement by ERAS. Five studies reported the outcomes of return to intended oncologic treatment after surgery (RIOT), and 4 found improvements in the ERAS group. Seven studies compared high adherence to ERAS with low adherence, of which, 6 reported the long-term OS, and 3 showed improvements by high adherence. One study reported high adherence could reduce the interval from surgery to RIOT. Four studies reported the effect of altering one single item within the ERAS protocol, but the results of 2 studies were controversial regarding the long-term OS between laparoscopic and open surgery, and 1 study showed improvements in OS with restrictive fluid therapy.

Conclusions

The use of ERAS in cancer surgeries can improve the on-time initiation and completion of adjuvant chemotherapy after surgery, and the high adherence to ERAS can lead to better outcomes than low adherence. Based on the current evidence, it is difficult to determine whether the ERAS protocol is associated with long-term overall survival or cancer-specific survival.
Comparison of anticoagulated versus non-anticoagulated patients with intra-aortic balloon pumps
Authors: Kelly Julie , Malloy Rhynn , Knowles Danielle
Published: June 2021

Background

There is limited guidance regarding the use of anticoagulation in patients on intra-aortic balloon pumps (IABP). The purpose of this study is to compare the safety outcomes in anticoagulated versus non-anticoagulated patients with an IABP.

Methods

This was a single center, retrospective chart review of patients admitted to the coronary care unit or cardiac surgery unit who received an IABP from May 2015 to July 2018. Patients who were anticoagulated with heparin while on an IABP were compared to those who were not anticoagulated. Major endpoints included a composite of thrombotic events and a composite of bleeding events. The major composite endpoint of thrombotic events included the incidence of ischemic stroke, any venous thromboembolism, device thrombosis, and limb ischemia. The major composite endpoint of bleeding events included major access site bleeding, minor access site bleeding, major non-access site bleeding, and minor non-access site bleeding. Minor endpoints included any major endpoint events occurring within 24 and 48 h of IABP insertion, hospital length of stay, intensive care unit length of stay, and in-hospital mortality.

Results

A total of 185 patients were evaluated for inclusion and 147 were included in the final analysis. There were 82 and 65 patients in the heparin and non-heparin groups, respectively. The composite endpoint of thrombotic events occurred in 7.3 and 7.7% in the heparin and non-heparin groups, respectively (p = 1). The composite bleeding endpoint occurred in 20.7 and 20.0% in the heparin and non-heparin groups, respectively (p = 0.91). There were no differences found in minor endpoints between groups.

Conclusion

There were no significant differences found in major endpoints of bleeding and thrombotic events in patients who received anticoagulation while on an IABP versus those who did not receive anticoagulation.
A review of thromboembolic events in hospitalized COVID-19 patients
Authors: Fontelo Paul , Bastola Mrigendra M. , Zheng Zhaonian , Baik Seo Hyon
Published: June 2021

Context

A higher incidence of thromboembolic disorders in COVID-19 has been reported by many clinicians worldwide.

Objective, design and data sources

Selected studies found in PubMed that reported thromboembolic events were included for meta-analysis using weighted fixed and random effects. Data from 19 articles on cohort studies in patients diagnosed with COVID-19 and thromboembolic events, including thrombosis and embolism were included in this review.

Results

The likelihood for developing thromboembolic disorders in hospitalized COVID-19 patients was 0.28 (95% CI 0.21–0.36).

Conclusion

This study further validates the increased risk of VTE in COVID-19 patients when compared to healthy, non-hospitalized people, and hospitalized patients. These findings will be useful to researchers and medical practitioners caring for COVID-19 patients.
Global prevalence of physical activity for children and adolescents; inconsistencies, research gaps, and recommendations: a narrative review
Authors: Aubert Salomé , Brazo-Sayavera Javier , González Silvia A. , Janssen Ian , Manyanga Taru , Oyeyemi Adewale L. , Picard Patrick , Sherar Lauren B. , Turner Evan , Tremblay Mark S.
Published: June 2021

Background

One of the strategic actions identified in the Global Action Plan on Physical Activity (PA) 2018–2030 is the enhancement of data systems and capabilities at national levels to support regular population surveillance of PA. Although national and international standardized surveillance of PA among children and adolescents has increased in recent years, challenges for the global surveillance of PA persist. The aims of this paper were to: (i) review, compare, and discuss the methodological inconsistencies in children and adolescents’ physical activity prevalence estimates from intercontinental physical activity surveillance initiatives; (ii) identify methodological limitations, surveillance and research gaps.

Methods

Intercontinental physical activity surveillance initiatives for children and adolescents were identified by experts and through non-systematic literature searches. Prevalence of meeting PA guidelines by country, gender, and age were extracted when available. A tool was created to assess the quality of the included initiatives. Methods and PA prevalence were compared across data/studies and against the methodological/validity/translation differences.

Results

Eight intercontinental initiatives were identified as meeting the selection criteria. Methods and PA definition inconsistencies across and within included initiatives were observed, resulting in different estimated national prevalence of PA, and initiatives contradicting each other’s cross-country comparisons. Three findings were consistent across all eight initiatives: insufficient level of PA of children and adolescents across the world; lower levels of PA among girls; and attenuation of PA levels with age. Resource-limited countries, younger children, children and adolescents not attending school, with disability or chronic conditions, and from rural areas were generally under/not represented.

Conclusions

There are substantial inconsistencies across/within included initiatives, resulting in varying estimates of the PA situation of children and adolescents at the global, regional and national levels. The development of a new PA measurement instrument that would be globally accepted and harmonized is a global health priority to help improve the accuracy and reliability of global surveillance.
Clinical and psychosocial stress factors are associated with decline in physical activity over time in children with juvenile idiopathic arthritis
Authors: Heale Liane D. , Houghton Kristin M. , Rezaei Elham , Baxter-Jones Adam D. G. , Tupper Susan M. , Muhajarine Nazeem , Benseler Susanne M. , Boire Gilles , Cabral David A. , Campillo Sarah , Chédeville Gaëlle , Chetaille Anne-Laure , Dancey Paul , Duffy Ciaran , Duffy Karen Watanabe , Ellsworth Janet , Guzman Jaime , Huber Adam M. , Jurencak Roman , Lang Bianca , Laxer Ronald M. , Morishita Kimberly , Oen Kiem G. , Petty Ross E. , Ramsey Suzanne E. , Roth Johannes , Schneider Rayfel , Scuccimarri Rosie , Spiegel Lynn , Stringer Elizabeth , Tse Shirley M. L. , Tucker Lori B. , Turvey Stuart E. , Yeung Rae S. M. , Rosenberg Alan M. ,   for the BBOP Study Group
Published: June 2021

Background

Physical activity (PA) patterns in children with juvenile idiopathic arthritis (JIA) over time are not well described. The aim of this study was to describe associations of physical activity (PA) with disease activity, function, pain, and psychosocial stress in the 2 years following diagnosis in an inception cohort of children with juvenile idiopathic arthritis (JIA).

Methods

In 82 children with newly diagnosed JIA, PA levels, prospectively determined at enrollment, 12 and 24 months using the Physical Activity Questionnaire for Children (PAQ-C) and Adolescents (PAQ-A) raw scores, were evaluated in relation to disease activity as reflected by arthritis activity (Juvenile Arthritis Disease Activity Score (JADAS-71)), function, pain, and psychosocial stresses using a linear mixed model approach. Results in the JIA cohort were compared to normative Pediatric Bone Mineral Accrual Study data derived from healthy children using z-scores.

Results

At enrollment, PA z-score levels of study participants were lower than those in the normative population (median z-score − 0.356; p = 0.005). At enrollment, PA raw scores were negatively associated with the psychosocial domain of the Juvenile Arthritis Quality of Life Questionnaire (r = − 0.251; p = 0.023). There was a significant decline in PAQ-C/A raw scores from baseline (median and IQR: 2.6, 1.4–3.1) to 24 months (median and IQR: 2.1, 1.4–2.7; p = 0.003). The linear mixed-effect model showed that PAQ-C/A raw scores in children with JIA decreased as age, disease duration, and ESR increased. The PAQ-C/A raw scores of the participants was also negatively influenced by an increase in disease activity as measured by the JADAS-71 (p <  0.001).

Conclusion

Canadian children with newly diagnosed JIA have lower PA levels than healthy children. The decline in PA levels over time was associated with disease activity and higher disease-specific psychosocial stress.
Properties of the surface electromyogram following traumatic spinal cord injury: a scoping review
Authors: Balbinot Gustavo , Li Guijin , Wiest Matheus Joner , Pakosh Maureen , Furlan Julio Cesar , Kalsi-Ryan Sukhvinder , Zariffa Jose
Published: June 2021

Traumatic spinal cord injury (SCI) disrupts spinal and supraspinal pathways, and this process is reflected in changes in surface electromyography (sEMG). sEMG is an informative complement to current clinical testing and can capture the residual motor command in great detail—including in muscles below the level of injury with seemingly absent motor activities. In this comprehensive review, we sought to describe how the sEMG properties are changed after SCI. We conducted a systematic literature search followed by a narrative review focusing on sEMG analysis techniques and signal properties post-SCI. We found that early reports were mostly focused on the qualitative analysis of sEMG patterns and evolved to semi-quantitative scores and a more detailed amplitude-based quantification. Nonetheless, recent studies are still constrained to an amplitude-based analysis of the sEMG, and there are opportunities to more broadly characterize the time- and frequency-domain properties of the signal as well as to take fuller advantage of high-density EMG techniques. We recommend the incorporation of a broader range of signal properties into the neurophysiological assessment post-SCI and the development of a greater understanding of the relation between these sEMG properties and underlying physiology. Enhanced sEMG analysis could contribute to a more complete description of the effects of SCI on upper and lower motor neuron function and their interactions, and also assist in understanding the mechanisms of change following neuromodulation or exercise therapy.
Heart rate variability as a strain indicator for psychological stress for emergency physicians during work and alert intervention: a systematic review
Authors: Thielmann Beatrice , Pohl Robert , Böckelmann Irina
Published: June 2021

Background

The workloads of emergency physicians are severe. The prevalence of burnout among emergency physicians is higher than with other physicians or compared to the general population. The analysis of heart rate variability (HRV) is a valid method for objective monitoring of workload. The aim of this paper is to systematically evaluate the literature on heart rate variability as an objective indicator for mental stress of emergency physicians.

Methods

A systematic literature review examining heart rate variability of emergency physicians in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement for reporting systematic reviews was performed. PubMed, Ovid, Cochrane Libary, Scopus, and Web of Science electronic databases were used. The methodological quality was evaluated by using a modified STARD for HRV.

Results

Two studies matched the inclusion criteria by using HRV between alert intervention and two other studies were considered that used HRV in other question areas. It showed an adaptation of HRV under stress. The studies were not comparable.

Conclusions

There is a need for occupational health studies that examine strains and stress of emergency physicians. The well-established parasympathetic mediated HRV parameters seem to be suitable parameters to objectify the stress.
Class II correction by maxillary en masse distalization using a completely customized lingual appliance and a novel mini-screw anchorage concept – preliminary results
Authors: Beyling Frauke , Klang Elisabeth , Niehoff Eva , Schwestka-Polly Rainer , Helms Hans-Joachim , Wiechmann Dirk
Published: June 2021

Background

The aim of the study was to evaluate the efficacy of a novel en masse distalization method in the maxillary arch in combination with a completely customized lingual appliance (CCLA; WIN, DW Lingual Systems, Germany). Therefore, we tested the null-hypothesis of a significant deviation from an Angle-Class I canine relationship and a normal overjet defined by an individual target set-up after dentoalveolar compensation in Angle Class II subjects.

Methods

This retrospective study included 23 patients, (m/f 3/20, mean age 29.6 years (min/max, 13.6/50.9 years)), with inclusion criteria of an Angle Class II occlusion of more than half a cusp prior to en masse distalization and treatment completed consecutively with a CCLA in combination with a mini-screw (MS) anchorage for uni- or bilateral maxillary distalization (12 bilateral situations, totalling 35). Plaster casts taken prior to (T0) and following CCLA treatment (T3) were compared with the treatment plan / set-up (TxP, with a Class I canine relationship and a normal overjet as the treatment objective). MSs were placed following levelling and aligning (T1) and removed at the end of en masse distalization at T2. Statistical analysis was carried out using Schuirmann’s TOST [two one-sided tests] equivalence test, based on a one-sample t-test with α = 0.025 on each side (total α = 0.05).

Results

Ninety-seven percent of planned correction of the canine relationship was achieved (mean 3.6 of 3.7 mm) and also 97 % of the planned overjet correction (mean 3.1 of 3.2 mm), with a statistically significant equivalence (p < 0.0001) for canine relationship and overjet between the individual treatment plan (set-up) and the final outcome. Adverse effects were limited to the loss of n = 2 of 35 mini-screws. However, in each instance, the treatment was completed, as scheduled, without replacing them. Accordingly, the null-hypothesis was rejected.

Conclusions

The technique presented allows for a predictable correction of an Angle-Class II malocclusion via dentoalveolar compensation with maxillary en masse distalization.
Which triggers could support timely identification of primary antibody deficiency? A qualitative study using the patient perspective
Authors: Janssen Lisanne M. A. , van den Akker Kim , Boussihmad Mohamed A. , de Vries Esther
Published: June 2021

Background

Patients with predominantly (primary) antibody deficiencies (PADs) commonly develop recurrent respiratory infections which can lead to bronchiectasis, long-term morbidity and increased mortality. Recognizing symptoms and making a diagnosis is vital to enable timely treatment. Studies on disease presentation have mainly been conducted using medical files rather than direct contact with PAD patients. Our study aims to analyze how patients appraised their symptoms and which factors were involved in a decision to seek medical care.

Methods

14 PAD-patients (11 women; median 44, range 16-68 years) were analyzed using semi-structured interviews until saturation of key emergent themes was achieved.

Results

Being always ill featured in all participant stories. Often from childhood onwards periods of illness were felt to be too numerous, too bad, too long-lasting, or antibiotics were always needed to get better. Recurrent or persistent respiratory infections were the main triggers for patients to seek care. All participants developed an extreme fatigue, described as a feeling of physical and mental exhaustion and thus an extreme burden on daily life that was not solved by taking rest. Despite this, participants tended to normalize their symptoms and carry on with usual activities. Non-immunologists, as well as patients, misattributed the presenting signs and symptoms to common, self-limiting illnesses or other ‘innocent’ explanations. Participants in a way understood the long diagnostic delay. They know that the disease is rare and that doctors have to cover a broad medical area. But they were more critical about the way the doctors communicate with them. They feel that doctors often don’t listen very well to their patients. The participants’ symptoms as well as the interpretation of these symptoms by their social environment and doctors had a major emotional impact on the participants and a negative influence on their future perspectives.

Conclusions

To timely identify PAD, ‘pattern recognition’ should not only focus on the medical ‘red flags’, but also on less differentiating symptoms, such as ‘being always ill’ and ‘worn out’ and the way patients cope with these problems. And, most important, making time to really listen to the patient remains the key.
Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation
Authors: Cole Shannon L. , Chandra Ramesh , Harris Maya , Patel Ishan , Wang Torrance , Kim Hyunjae , Jensen Leah , Russo Scott J. , Turecki Gustavo , Gancarz-Kausch Amy M. , Dietz David M. , Lobo Mary Kay
Published: June 2021

Mitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrate that cocaine affects mitochondrial dynamics and morphological characteristics within the nucleus accumbens (NAc). Further, mitochondria are differentially regulated by cocaine in dopamine receptor-1 containing medium spiny neurons (D1-MSNs) vs dopamine receptor-2 (D2)-MSNs. However, there is little understanding into cocaine-induced transcriptional mechanisms and their role in regulating mitochondrial processes. Here, we demonstrate that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Moreover, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial nuclear genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. Further, blunting Egr3 expression in D1-MSNs blocks cocaine-enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reduction of D1-MSN Egr3 expression attenuates cocaine-induced enhancement of small-sized mitochondria, causally demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts mitochondrial dynamics and morphology by Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts; indicating roles for these molecular mechanisms in neuronal function and plasticity occurring with cocaine exposure.
A case of synchronous serous ovarian cancer and uterine serous endometrial intraepithelial carcinoma
Authors: Shimizu Maho , Yamanaka Keitaro , Azumi Maho , Tomimoto Masako , Washio Keiichi , Takahashi Ryosuke , Nagamata Satoshi , Murata Yuka , Yamasaki Yui , Terai Yoshito
Published: June 2021

Background

Serous endometrial intraepithelial carcinoma (SEIC) is now considered to represent an early stage of uterine serous carcinoma (USC). It is an intraepithelial lesion but has been reported to cause extrauterine metastases. We report a case of SEIC with serous ovarian carcinoma and lymph node metastasis.

Case presentation

A 57-year-old post-menopausal woman (gravida 3, para 2, SA1) was referred to our hospital with lower abdominal pain. An ultrasound and MRI showed that the ovary had swollen to 8 cm in size and had a solid lesion. The uterus was normal. The patient underwent exploratory laparoscopy on the suspicion of torsion of the ovarian tumor. Intraoperative findings showed a right ovarian tumor, but no ovarian tumor torsion was observed. A small amount of bloody ascites was found in the Douglas fossa, and bleeding was observed from the tumor itself. A right salpingo-oophorectomy was then performed. Histopathological results revealed a high-grade serous carcinoma. Forty days after the first surgery, we performed a staging laparotomy: a total abdominal hysterectomy, left salpingo-oophorectomy, systematic pelvic and paraaortic lymphadenectomy, and a partial omentectomy. A complete cytoreduction was achieved. In the pathological examination, the invasion of the serous carcinoma was observed in the left ovarian ligament, and lymph node metastasis was found in the paraaortic lymph nodes. Atypical columnar cells formed irregular papillary lesions which had proliferated in the endometrium, and this was diagnosed as SEIC. The final diagnosis was serous ovarian cancer, FIGO stage IIIA1(ii), pT2bN1M0, with SEIC.

Conclusion

We report a case of SEIC with synchronous serous carcinoma of the adnexa uteri. Both were serous carcinomas and, thus, it was difficult to identify the primary lesion. The distinction between metastatic cancer and two independent primary tumors is important for an accurate diagnosis and tumor staging. Histological diagnostic criteria remain controversial, and further development of a method for differentiating between both diseases is required.
Evolution of mouse circadian enhancers from transposable elements
Authors: Judd Julius , Sanderson Hayley , Feschotte Cédric
Published: June 2021

Background

Transposable elements are increasingly recognized as a source of cis-regulatory variation. Previous studies have revealed that transposons are often bound by transcription factors and some have been co-opted into functional enhancers regulating host gene expression. However, the process by which transposons mature into complex regulatory elements, like enhancers, remains poorly understood. To investigate this process, we examined the contribution of transposons to the cis-regulatory network controlling circadian gene expression in the mouse liver, a well-characterized network serving an important physiological function.

Results

ChIP-seq analyses reveal that transposons and other repeats contribute ~ 14% of the binding sites for core circadian regulators (CRs) including BMAL1, CLOCK, PER1/2, and CRY1/2, in the mouse liver. RSINE1, an abundant murine-specific SINE, is the only transposon family enriched for CR binding sites across all datasets. Sequence analyses and reporter assays reveal that the circadian regulatory activity of RSINE1 stems from the presence of imperfect CR binding motifs in the ancestral RSINE1 sequence. These motifs matured into canonical motifs through point mutations after transposition. Furthermore, maturation occurred preferentially within elements inserted in the proximity of ancestral CR binding sites. RSINE1 also acquired motifs that recruit nuclear receptors known to cooperate with CRs to regulate circadian gene expression specifically in the liver.

Conclusions

Our results suggest that the birth of enhancers from transposons is predicated both by the sequence of the transposon and by the cis-regulatory landscape surrounding their genomic integration site.
Viral metagenomics reveals the presence of novel Zika virus variants in Aedes mosquitoes from Barbados
Authors: Thannesberger J. , Rascovan N. , Eisenmann A. , Klymiuk I. , Zittra C. , Fuehrer H. P. , Scantlebury-Manning T. , Gittens-St.Hilaire M. , Austin S. , Landis R. C. , Steininger C.
Published: June 2021

Background

The Zika virus (ZIKV) epidemic of 2015/2016 spread throughout numerous countries. It emerged in mainland Latin America and spread to neighboring islands, including the Caribbean island of Barbados. Recent studies have indicated that the virus must have already been circulating in local mosquito populations in Brazil for almost 2 years before it was identified by the World Health Organization in 2015. Metagenomic detection assays have the potential to detect emerging pathogens without prior knowledge of their genomic nucleic acid sequence. Yet their applicability as vector surveillance tools has been widely limited by the complexity of DNA populations from field-collected mosquito preparations. The aim of this study was to investigate local vector biology and characterize metagenomic arbovirus diversity in Aedes mosquitoes during the ongoing 2015/2016 ZIKV epidemic.

Methods

We performed a short-term vector screening study on the island of Barbados during the ongoing 2015/2016 ZIKV epidemic, where we sampled local Aedes mosquitoes. We reanalyzed mosquito viral microbiome data derived from standard Illumina MiSeq sequencing to detect arbovirus sequences. Additionally, we employed deep sequencing techniques (Illumina HiSeq) and designed a novel bait capture enrichment assay to increase sequencing efficiency for arbovirus sequences from complex DNA samples.

Results

We found that Aedes aegypti seemed to be the most likely vector of ZIKV, although it prevailed at a low density during the observed time period. The number of detected viruses increased with sequencing depth. Arbovirus sequence enrichment of metagenomic DNA preparations allowed the detection of arbovirus sequences of two different ZIKV genotypes, including a novel one. To our knowledge, this is the first report of the S3116W mutation in the NS5 gene region of ZIKV polyprotein.

Conclusions

The metagenomic arbovirus detection approach presented here may serve as a useful tool for the identification of epidemic-causing arboviruses with the additional benefit of enabling the collection of phylogenetic information on the source. Apart from detecting more than 88 viruses using this approach, we also found evidence of novel ZIKV variants circulating in the local mosquito population during the observed time period.

Graphical abstract
iSeq 100 for metagenomic pathogen screening in ticks
Authors: Kim Ju Yeong , Yi Myung-hee , Mahdi Alghurabi Areej Sabri , Yong Tai-Soon
Published: June 2021

Background

Ticks are blood-sucking ectoparasites that play a pivotal role in the transmission of various pathogens to humans and animals. In Korea, Haemaphysalis longicornis is the predominant tick species and is recognized as the vector of pathogens causing various diseases such as babesiosis, borreliosis, rickettsiosis, and severe fever with thrombocytopenia syndrome.

Methods

In this study, the targeted high-throughput sequencing of the 16S rRNA V4 region was performed using the state-of-the-art sequencing instrument, iSeq 100, to screen bacterial pathogens in H. longicornis, and the findings were compared with those using conventional PCR with specific primers. Microbiome analyses were performed with EzBioCloud, a commercially available ChunLab bioinformatics cloud platform. ANOVA-Like Differential Expression tool (ALDEx2) was used for differential abundance analysis.

Results

Rickettsia spp. were detected in 16 out of 37 samples using iSeq 100, and this was confirmed using a PCR assay. In the phylogenetic analysis using gltA and ompA sequences of the detected Rickettsia, the highest sequence similarity was found with ‘Candidatus Rickettsia jingxinensis’ isolate Xian-Hl-79, ‘Ca. R. jingxinensis’ isolate F18, and ‘Ca. R. longicornii‘ isolate ROK-HL727. In the microbiome study, Coxiella AB001519, a known tick symbiont, was detected in all 37 tick samples. Actinomycetospora chiangmaiensis was more abundant in Rickettsia-positive samples than in Rickettsia-negative samples.

Conclusions

In this study, iSeq 100 was used to investigate the microbiome of H. longicornis, and the potentially pathogenic Rickettsia strain was detected in 16 out of 37 ticks. We believe that this approach will aid in large-scale pathogen screening of arthropods to be used in vector-borne disease control programs.

Graphical Abstract
Muscle elasticity is different in individuals with diastasis recti abdominis than healthy volunteers
Authors: He Kai , Zhou Xiuling , Zhu Yulan , Wang Bo , Fu Xiaojian , Yao Qiyuan , Chen Hao , Wang Xiaohong
Published: June 2021

Objective

To determine the value of shear wave elastography (SWE) in assessing abdominal wall muscles, including rectus abdominis (RA), external oblique muscle (EO), internal oblique muscle, and transversus abdominis (TrA) in patients with diastasis recti abdominis (DRA) and healthy controls.

Methods

From October 2018 to December 2019, 36 postpartum DRA patients and 24 nulliparous healthy women were identified. Inter-rectus distance (IRD) measurements were taken by B-mode ultrasound. Shear wave speed (SWS) values were acquired by one operator at ten specific locations. Clinical and ultrasound variables, including demographics, IRD, muscle thickness, and muscle SWS, were compared between the two groups using Student’s t test or Fisher's exact test. Pearson correlation analyses were conducted for the variables of IRD, muscle thickness, and SWS in the 36 DRA patients.

Results

The maximum diameter of recti abdominus separation was located at the umbilicus in DRA patients (4.59 ± 1.14 cm). The SWS value was significantly lower in the RA (p = 0.003) and higher in the TrA muscle (p < 0.001) in DRA patients compared with the age-matched controls. However, SWS in both muscles (RA and TrA) showed a statistically positive correlation with IRD (p < 0.05). In addition, the SWS value in EO statistically decreased in DRA patients compared with the healthy controls (1.65 ± 0.15 vs. 1.79 ± 0.14, p = 0.001).

Conclusions

The application of SWE to abdominal wall muscles in DRA patients is feasible. The correlation between SWS value and IRD in RA should be interpreted with caution.
Deletion of Jdp2 enhances Slc7a11 expression in Atoh-1 positive cerebellum granule cell progenitors in vivo
Authors: Ku Chia-Chen , Wuputra Kenly , Kato Kohsuke , Pan Jia-Bin , Li Chia-Pei , Tsai Ming-Ho , Noguchi Michiya , Nakamura Yukio , Liu Chung-Jung , Chan Te-Fu , Hou Ming-Feng , Wakana Shigeharu , Wu Yang-Chang , Lin Chang-Shen , Wu Deng-Chyang , Yokoyama Kazunari K.
Published: June 2021

Background

The cerebellum is the sensitive region of the brain to developmental abnormalities related to the effects of oxidative stresses. Abnormal cerebellar lobe formation, found in Jun dimerization protein 2 (Jdp2)-knockout (KO) mice, is related to increased antioxidant formation and a reduction in apoptotic cell death in granule cell progenitors (GCPs). Here, we aim that Jdp2 plays a critical role of cerebellar development which is affected by the ROS regulation and redox control.

Objective

Jdp2-promoter-Cre transgenic mouse displayed a positive signal in the cerebellum, especially within granule cells. Jdp2-KO mice exhibited impaired development of the cerebellum compared with wild-type (WT) mice. The antioxidation controlled gene, such as cystine-glutamate transporter Slc7a11, might be critical to regulate the redox homeostasis and the development of the cerebellum.

Methods

We generated the Jdp2-promoter-Cre mice and Jdp2-KO mice to examine the levels of Slc7a11, ROS levels and the expressions of antioxidation related genes were examined in the mouse cerebellum using the immunohistochemistry.

Results

The cerebellum of Jdp2-KO mice displayed expression of the cystine-glutamate transporter Slc7a11, within the internal granule layer at postnatal day 6; in contrast, the WT cerebellum mainly displayed Sla7a11 expression in the external granule layer. Moreover, development of the cerebellar lobes in Jdp2-KO mice was altered compared with WT mice. Expression of Slc7a11, Nrf2, and p21Cip1 was higher in the cerebellum of Jdp2-KO mice than in WT mice.

Conclusion

Jdp2 is a critical regulator of Slc7a11 transporter during the antioxidation response, which might control the growth, apoptosis, and differentiation of GCPs in the cerebellar lobes. These observations are consistent with our previous study in vitro.
Spinal vertebrae localization and analysis on disproportionality in curvature using radiography—a comprehensive review
Authors: Fatima Joddat , Akram Muhammad Usman , Jameel Amina , Syed Adeel Muzaffar
Published: June 2021

In human anatomy, the central nervous system (CNS) acts as a significant processing hub. CNS is clinically divided into two major parts: the brain and the spinal cord. The spinal cord assists the overall communication network of the human anatomy through the brain. The mobility of body and the structure of the whole skeleton is also balanced with the help of the spinal bone, along with reflex control. According to the Global Burden of Disease 2010, worldwide, back pain issues are the leading cause of disability. The clinical specialists in the field estimate almost 80% of the population with experience of back issues. The segmentation of the vertebrae is considered a difficult procedure through imaging. The problem has been catered by different researchers using diverse hand-crafted features like Harris corner, template matching, active shape models, and Hough transform. Existing methods do not handle the illumination changes and shape-based variations. The low-contrast and unclear view of the vertebrae also makes it difficult to get good results. In recent times, convolutional nnural Network (CNN) has taken the research to the next level, producing high-accuracy results. Different architectures of CNN such as UNet, FCN, and ResNet have been used for segmentation and deformity analysis. The aim of this review article is to give a comprehensive overview of how different authors in different times have addressed these issues and proposed different mythologies for the localization and analysis of curvature deformity of the vertebrae in the spinal cord.
Impact of abortion law reforms on women’s health services and outcomes: a systematic review protocol
Authors: Ishola Foluso , Ukah U. Vivian , Nandi Arijit
Published: June 2021

Background

A country’s abortion law is a key component in determining the enabling environment for safe abortion. While restrictive abortion laws still prevail in most low- and middle-income countries (LMICs), many countries have reformed their abortion laws, with the majority of them moving away from an absolute ban. However, the implications of these reforms on women’s access to and use of health services, as well as their health outcomes, is uncertain. First, there are methodological challenges to the evaluation of abortion laws, since these changes are not exogenous. Second, extant evaluations may be limited in terms of their generalizability, given variation in reforms across the abortion legality spectrum and differences in levels of implementation and enforcement cross-nationally. This systematic review aims to address this gap. Our aim is to systematically collect, evaluate, and synthesize empirical research evidence concerning the impact of abortion law reforms on women’s health services and outcomes in LMICs.

Methods

We will conduct a systematic review of the peer-reviewed literature on changes in abortion laws and women’s health services and outcomes in LMICs. We will search Medline, Embase, CINAHL, and Web of Science databases, as well as grey literature and reference lists of included studies for further relevant literature. As our goal is to draw inference on the impact of abortion law reforms, we will include quasi-experimental studies examining the impact of change in abortion laws on at least one of our outcomes of interest. We will assess the methodological quality of studies using the quasi-experimental study designs series checklist. Due to anticipated heterogeneity in policy changes, outcomes, and study designs, we will synthesize results through a narrative description.

Discussion

This review will systematically appraise and synthesize the research evidence on the impact of abortion law reforms on women’s health services and outcomes in LMICs. We will examine the effect of legislative reforms and investigate the conditions that might contribute to heterogeneous effects, including whether specific groups of women are differentially affected by abortion law reforms. We will discuss gaps and future directions for research. Findings from this review could provide evidence on emerging strategies to influence policy reforms, implement abortion services and scale up accessibility.

Systematic review registration

PROSPEROCRD42019126927