bluuebunny/crossref_metadata_2025 huggingface dataset:
The double agents in liquid biopsy: promoter and informant biomarkers of early metastases in breast cancer
Authors: Richard Vinitha , Davey Matthew G. , Annuk Heidi , Miller Nicola , Kerin Michael J.
Published: April 2022

Breast cancer continues to be a major global problem with significant mortality associated with advanced stage and metastases at clinical presentation. However, several findings suggest that metastasis is indeed an early occurrence. The standard diagnostic techniques such as invasive core needle biopsy, serological protein marker assays, and non-invasive radiological imaging do not provide information about the presence and molecular profile of small fractions of early metastatic tumor cells which are prematurely dispersed in the circulatory system. These circulating tumor cells (CTCs) diverge from the primary tumors as clusters with a defined secretome comprised of circulating cell-free nucleic acids and small microRNAs (miRNAs). These circulatory biomarkers provide a blueprint of the mutational profile of the tumor burden and tumor associated alterations in the molecular signaling pathways involved in oncogenesis. Amidst the multitude of circulatory biomarkers, miRNAs serve as relatively stable and precise biomarkers in the blood for the early detection of CTCs, and promote step-wise disease progression by executing paracrine signaling that transforms the microenvironment to guide the metastatic CTCs to anchor at a conducive new organ. Random sampling of easily accessible patient blood or its serum/plasma derivatives and other bodily fluids collectively known as liquid biopsy (LB), forms an efficient alternative to tissue biopsies. In this review, we discuss in detail the divergence of early metastases as CTCs and the involvement of miRNAs as detectable blood-based diagnostic biomarkers that warrant a timely screening of cancer, serial monitoring of therapeutic response, and the dynamic molecular adaptations induced by miRNAs on CTCs in guiding primary and second-line systemic therapy.
miR-218-5p in endometrial microenvironment prevents the migration of ectopic endometrial stromal cells by inhibiting LASP1
Authors: Zhang Ziyu , Wang Yaoqing , Zeng Liqin , Yu Kaihui , Wang Yuanqin , Luo Yong , Liu Faying , Yang Bicheng , Zou Yang , Wang Liqun , Huang Ouping
Published: April 2022

Background

Our previous two-dimensional electrophoresis experiment showed that the expression of LASP1 in patients with endometriosis was significantly higher than that of control endometrium. However, the molecular mechanism by which LASP1 is regulated in endometriosis/adenomyosis is unknown.

Methods

Herein, qPCR was performed to analyze the expression levels of LASP1 and miR-218-5p between endometriosis (Ems) cells and control cells. Fluorescence in situ hybridization was carried out to measure the expression level of miR-218-5p in ectopic endometrium versus normal endometrium. After miR-218-5p mimic or inhibitor were transfected, the transwell experiment was carried out to see the effect of miR-218-5p on the migration of endometrial stromal cells (ESCs). EdU was used to measure cell proliferation rate. Dual-luciferase reporter assay was used to verify the binding of hsa-miR-218-5p to the 3’UTR of LASP1. Western blot and immunofluorescence analysis were carried out to identify the protein expression pattern of LASP1 and EMT markers in endometrial tissue.

Results

The miR-218-5p is mainly secreted from blood vessels and expressed in the muscle layer around the endometrium, which inhibits the expression level of LASP1 by binding the 3’UTR region of LASP1 in normal ESCs. Overexpression of miR-218-5p impedes the epithelial-to-mesenchymal transition (EMT) and prevents the migration of ESCs and the expression of Vimentin in Ems.

Conclusions

Our findings revealed that miR-218-5p in endometrial microenvironment prevents the migration of ectopic endometrial stromal cells by inhibiting LASP1.
Effects of an intravenous ketamine infusion on inflammatory cytokine levels in male and female Sprague–Dawley rats
Authors: Spencer Haley F. , Berman Rina Y. , Boese Martin , Zhang Michael , Kim Sharon Y. , Radford Kennett D. , Choi Kwang H.
Published: April 2022

Background

Ketamine, a multimodal dissociative anesthetic drug, is widely used as an analgesic following traumatic injury. Although ketamine may produce anti-inflammatory effects when administered after injury, the immunomodulatory properties of intravenous (IV) ketamine in a non-inflammatory condition are unclear. In addition, most preclinical studies use an intraperitoneal (IP) injection of ketamine, which limits its clinical translation as patients usually receive an IV ketamine infusion after injury.

Methods

Here, we administered sub-anesthetic doses of a single IV ketamine infusion (0, 10, or 40 mg/kg) to male and female Sprague–Dawley rats over a 2-h period. We collected blood samples at 2- and 4-h post-ketamine infusion to determine plasma inflammatory cytokine levels using multiplex immunoassays.

Results

The 10 mg/kg ketamine infusion reduced spontaneous locomotor activity in male and female rats, while the 40 mg/kg infusion stimulated activity in female, but not male, rats. The IV ketamine infusion produced dose-dependent and sex-specific effects on plasma inflammatory cytokine levels. A ketamine infusion reduced KC/GRO and tumor necrosis factor alpha (TNF-α) levels in both male and female rats, interleukin-6 (IL-6) levels in female rats, and interleukin-10 (IL-10) levels in male rats. However, most cytokine levels returned to control levels at 4-h post-infusion, except for IL-6 levels in male rats and TNF-α levels in female rats, indicating a different trajectory of certain cytokine changes over time following ketamine administration.

Conclusions

The current findings suggest that sub-anesthetic doses of an IV ketamine infusion may produce sex-related differences in the effects on peripheral inflammatory markers in rodents, and further research is warranted to determine potential therapeutic effects of an IV ketamine infusion in an inflammatory condition.
Comparative analysis of the effects of OLIF and TLIF on adjacent segments after treatment of L4 degenerative lumbar spondylolisthesis
Authors: Li Guang-qing , Tong Tong , Wang Lin-feng
Published: April 2022

Background

The fusion of the lumbar spine may lead to the degeneration of the adjacent segments. In this study, the effects of OLIF and TLIF on adjacent segments after treatment of L4 degenerative lumbar spondylolisthesis (DLS) were compared and analysed.

Methods

This was a retrospective analysis of the medical records of consecutive patients treated with OLIF or TLIF for L4DLS. They were divided into the OLIF group and TLIF group based on different treatment methods. Cage height, segmental lordosis (SL), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS) were compared between the two groups, and the postoperative biomechanical changes were analysed by establishing the disc angle (DA). The clinical outcomes were analysed by comparing the visual analogue scale (VAS), Oswestry Disability Index (ODI) and incidence of adjacent segment disease (ASDis) between the two groups. The intervertebral disc height (IDH), intervertebral foramen height (IDH), intervertebral foramen area (IFA), sliding distance (SD), and angular displacement (AD) in L3-4 and L5-S1 were compared between the two groups. The incidence of aggravated disc degeneration (ADD), the incidence of aggravated zygapophyseal joint degeneration (AJD) and the incidence of adjacent segment degeneration (ASDeg) were compared between the two groups for radiological degeneration.

Results

At the last follow-up, there was one case of ASDis in the OLIF group (2.78%) and two cases in the TLIF group (5.56%). At the last follow-up, compared with the preoperative values, IDH, IFH, and IFA of the adjacent segments above and below L4-5 decreased in both groups (P < 0.05); the SD and AD increased in both groups (P < 0.05). The cage height and L4-5 IDH in the OLIF group were significantly higher than those in the TLIF group (P < 0.05). SL, LL, PT, SS, and L5- S1DA were significantly improved in the OLIF group compared with the TLIF group (P < 0.05). The incidence of L3-4ASDeg in the two groups was higher than that of L5-S1. The incidence of ASDeg and the incidence of L5-S1ADD in the OLIF group were lower than those in the TLIF group, but the incidence of L5-S1AJD was higher than that in the TLIF group.

Conclusion

L4DLS after OLIF and TLIF treatment will cause adjacent segment degeneration, and L3-4 degeneration is more obvious than L5-S1 degeneration. OLIF has more advantages in restoring lumbar sagittal balance. Compared with TLIF, OLIF can weaken the degeneration of the L5-S1 disc and increase the degeneration of the L5-S1 zygapophyseal joints.
Functional outcome of unstable pelvic fractures treated in a level III hospital in a developing country: a 10-year prospective observational study
Authors: Nana Chunteng Theophile , Ngo-Yamben M. A. , Fokam Pius , Mahamat Ali , Bombah F. M. , Boukar M. Ekani , Kenedy Muluem , Chichom-Mefire A.
Published: April 2022

Background

Unstable pelvic fractures are severe and life-threatening injuries with high morbi-mortality rates. Management of these fractures is a major challenge in orthopaedic practice in limited resource communities. The aim of this study is to evaluate the functional outcome of unstable pelvic fractures managed in a hospital with limited diagnostic and therapeutic facilities.

Methodology

This was a hospital-based prospective observational study carried out from 1st of January 2009 to 31st of December 2018 at the Limbe Regional Hospital, a level III health institution in the South-West region of Cameroon.

Results

A total of 68 patients were included in the study. The ages ranged from 18 to 80 years with a mean age of 39 ± 5 years. The average follow-up duration at the latest visit was 36 months (range 3–84 months). There were 59 cases that were evaluated. The overall average Majeed score was fair. Poor outcomes were noted in patients aged 60 years and above, those with co-morbidities, and those managed conservatively.

Conclusion

Although the functional outcomes following unstable pelvic fractures have improved with modernised diagnostic and therapeutic modalities, it is not the case in poor resource settings where the lack of these modalities makes the management challenging, consequently affecting the functional outcome.
Computer simulation of optimal lipped polyethylene liner orientation against prosthetic impingement
Authors: Hu Yi , Zhou Xianhao , Qiao Hua , Zhu Zhenan , Li Huiwu , Zhang Jingwei
Published: April 2022

Background

Lipped or elevated acetabular liners are to improve posterior stability and are widely used in hip arthroplasty. However, concerns of increasing impingement exist when using such liners and optimal orientation of the elevated rim remains unknown. We aimed to identify the impact of lipped liner on the range of motion (ROM) before impingement and propose its optimal orientation.

Methods

An isochoric three-dimensional model of a general hip-replacement prosthesis was generated, and flex-extension, add-abduction and axial rotation were simulated on a computer. The maximum ROM of the hip was measured before the neck impinged on the liner. Different combinations of acetabular anteversion angles ranging from 5 to 30 degrees, and lipped liner orientations from posterior to anterior were tested.

Results

When acetabular anteversion was 10 or 15 degrees, placing the lip of the liner in the posterosuperior of the acetabulum allowed satisfactory ROM in all directions. When acetabular anteversion was 20 degrees, extension and external rotation were restricted. Adjusting the lip to the superior restored satisfactory ROM. When acetabular anteversion was 25 degrees, only placing the lip into the anterosuperior could increase extension and external rotation to maintain satisfactory ROM.

Conclusions

This study showed that optimal lipped liner orientation should depend on acetabular anteversion. When acetabular anteversion was smaller than 20 degrees, placing lip in the posterior allowed an optimally ROM. When acetabular anteversion was greater than 20 degrees, adjusting lip to the anterior allowed a comprehensive larger ROM to avoid early impingement.
Clinical features and treatment outcomes of pediatric Langerhans cell histiocytosis with macrophage activation syndrome-hemophagocytic lymphohistiocytosis
Authors: Wang Dong , Chen Xi-Hua , Wei Ang , Zhou Chun-Ju , Zhang Xue , Ma Hong-Hao , Lian Hong-Yun , Zhang Li , Zhang Qing , Huang Xiao-Tong , Wang Chan-Juan , Yang Ying , Liu Wei , Wang Tian-You , Li Zhi-Gang , Cui Lei , Zhang Rui
Published: April 2022

Background

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm. A few LCH patients had Macrophage activation syndrome-hemophagocytic lymphohistiocytosis (MAS-HLH), a life-threatening, hyper-inflammatory syndrome. We retrospectively described the clinical-biological characteristics of a series of 28 pediatric LCH patients with MAS-HLH in a single center. We further analyzed the difference in treatment outcomes between second-line chemotherapy (cytarabine and cladribine) and targeted therapy (dabrafenib) for BRAF-V600E-positive patients.

Results

LCH patients with MAS-HLH were aged < 2 years, harbored high frequencies of risk organ, skin, or lymph nodes involvement, and most of them carried BRAF-V600E mutation in lesions (88.0%) or plasma (90.5%). Patients were firstly treated with the initial induction first-line therapy (vindesine-steroid combination), and most of them (26/28) failed to control the active MAS-HLH after one six-week course of induction treatment. Then they were shifted to second-line chemotherapy or targeted therapy dabrafenib. BRAF-V600E-mutant patients treated with dabrafenib had prompt resolution of MAS-HLH signs and symptoms with less toxicity than second-line chemotherapy. Moreover, the progression-free survival (PFS) rate for patients given dabrafenib was much higher than those treated with chemotherapy (4 year-PFS: 75% vs. 14.6%, P = 0.034).

Conclusions

LCH patients with MAS-HLH harbored specific clinical-biology characteristics compared to the multisystem LCH without MAS-HLH. The BRAF inhibitor dabrafenib provides a promising treatment option for LCH with MAS-HLH.
A new risk-assessment tool for venous thromboembolism in advanced lung cancer: a prospective, observational study
Authors: Tsubata Yukari , Hotta Takamasa , Hamai Kosuke , Furuya Naoki , Yokoyama Toshihide , Saito Ryota , Nakamura Atsushi , Masuda Takeshi , Hamaguchi Megumi , Kuyama Shoichi , Honda Ryoichi , Senoo Tadashi , Nakanishi Masamoto , Yamasaki Masahiro , Ishikawa Nobuhisa , Fujitaka Kazunori , Kubota Tetsuya , Kobayashi Kunihiko , Isobe Takeshi
Published: April 2022

Management of cancer-associated venous thromboembolism (VTE) is essential in treatment selection and cancer prognosis. However, to date, there is no method to assess the risk of VTE specifically associated with advanced lung cancer. Our aim was to create a new risk assessment scoring system that can predict the concomitant or incidence of VTE in advanced lung cancer. We used the dataset of 1008 patients with lung cancer in the Rising-VTE/NEJ037 study, of which 100 (9.9%) developed VTE. The items extracted in the multivariate analysis included female sex, adenocarcinoma, performance status, N factor, lymphocyte count, platelet count, prothrombin fragment 1 + 2, and diastolic blood pressure. This model had a maximum score of 8 points, with ≥ 5 points indicating a high risk of VTE. This simple risk-assessment model for VTE complications with advanced lung cancer could help identify cases that required monitoring for VTE.
Gender and leg‐dominance differences in shoe properties and foot injuries in badminton: a cross‐sectional survey
Authors: Shen Siqin , Lam Wing‐Kai , Teng Jin , Jia Sheng‐Wei , Baker Julien S. , Ugbolue Ukadike C. , Fekete Gusztáv , Gu Yaodong
Published: April 2022

Background

While the roles of injury prevention and performance enhancement have increasingly been investigated for badminton footwear, there is a lack of research on gender‐specific badminton footwear. The purpose of this study was to examine the gender differences in footwear demands and foot injuries in badminton.

Methods

The study was a cross‐sectional survey, in which 326 recreational badminton players were recruited. The questionnaire was divided into four sections enquiring about the characteristics of (1) participant profiles, (2) importance of shoe properties (3) shoe complaints (4) and pain or discomfort in different foot regions. The Mann‐Whitney U test and Wilcoxon Signed Ranks test were performed to determine the differences between genders and the differences between leg dominance, respectively. The significance level was set at 0.05.

Results

Both males and females rated shoe fit as the most important features, followed by the overall comfort and injury protection. Females considered the shoe forefoot cushioning, comfort, breathability and colour as more important compared with the other properties, which showed distinct pattern differences from males. The shoe problem results indicated that plantar pain of the non‐dominant foot was considered the most commonly reported footwear problem by both males and females. The problem of excessive arch‐support on the dominant and non‐dominant sides of male participants was significantly higher than females (p < 0.05). Occasional pain or frequent pain were mainly distributed in the forefoot, followed by the rearfoot and midfoot regions.

Conclusion

There were small differences in footwear demand between the dominant and non‐dominant sides, but several differences existed between females and males. The results from gender differences suggested that female shoes prefer a specific shoe last for better fit, rather than a modified version of male shoes. In the future, the design of badminton shoes should consider footwear demands and foot discomfort profiles in respective male and female badminton players.
Continuous renal replacement therapy versus intermittent hemodialysis as first modality for renal replacement therapy in severe acute kidney injury: a secondary analysis of AKIKI and IDEAL-ICU studies
Authors: Gaudry Stéphane , Grolleau François , Barbar Saber , Martin-Lefevre Laurent , Pons Bertrand , Boulet Éric , Boyer Alexandre , Chevrel Guillaume , Montini Florent , Bohe Julien , Badie Julio , Rigaud Jean-Philippe , Vinsonneau Christophe , Porcher Raphaël , Quenot Jean-Pierre , Dreyfuss Didier
Published: April 2022

Background

Intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) are the two main RRT modalities in patients with severe acute kidney injury (AKI). Meta-analyses conducted more than 10 years ago did not show survival difference between these two modalities. As the quality of RRT delivery has improved since then, we aimed to reassess whether the choice of IHD or CRRT as first modality affects survival of patients with severe AKI.

Methods

This is a secondary analysis of two multicenter randomized controlled trials (AKIKI and IDEAL-ICU) that compared an early RRT initiation strategy with a delayed one. We included patients allocated to the early strategy in order to emulate a trial where patients would have been randomized to receive either IHD or CRRT within twelve hours after the documentation of severe AKI. We determined each patient’s modality group as the first RRT modality they received. The primary outcome was 60-day overall survival. We used two propensity score methods to balance the differences in baseline characteristics between groups and the primary analysis relied on inverse probability of treatment weighting.

Results

A total of 543 patients were included. Continuous RRT was the first modality in 269 patients and IHD in 274. Patients receiving CRRT had higher cardiovascular and total-SOFA scores. Inverse probability weighting allowed to adequately balance groups on all predefined confounders. The weighted Kaplan–Meier death rate at day 60 was 54·4% in the CRRT group and 46·5% in the IHD group (weighted HR 1·26, 95% CI 1·01–1·60). In a complementary analysis of less severely ill patients (SOFA score: 3–10), receiving IHD was associated with better day 60 survival compared to CRRT (weighted HR 1.82, 95% CI 1·01–3·28; p < 0.01). We found no evidence of a survival difference between the two RRT modalities in more severe patients.

Conclusion

Compared to IHD, CRRT as first modality seemed to convey no benefit in terms of survival or of kidney recovery and might even have been associated with less favorable outcome in patients with lesser severity of disease. A prospective randomized non-inferiority trial should be implemented to solve the persistent conundrum of the optimal RRT technique.
Predictors of response to intra-arterial vasodilatory therapy of non-occlusive mesenteric ischemia in patients with severe shock: results from a prospective observational study
Authors: Rittgerodt Nina , Pape Thorben , Busch Markus , Becker Lena S. , Schneider Andrea , Wedemeyer Heiner , Seeliger Benjamin , Schmidt Julius , Hunkemöller Anna Maria , Fuge Jan , Knitsch Wolfgang , Fegbeutel Christine , Gillmann Hans-Jörg , Meyer Bernhard C. , Hoeper Marius M. , Hinrichs Jan B. , David Sascha , Stahl Klaus
Published: April 2022

Background

Non-occlusive mesenteric ischemia (NOMI) is a life-threatening condition occurring in patients with shock and is characterized by vasoconstriction of the mesenteric arteries leading to intestinal ischemia and multi-organ failure. Although minimal invasive local intra-arterial infusion of vasodilators into the mesenteric circulation has been suggested as a therapeutic option in NOMI, current knowledge is based on retrospective case series and it remains unclear which patients might benefit. Here, we prospectively analyzed predictors of response to intra-arterial therapy in patients with NOMI.

Methods

This is a prospective single-center observational study to analyze improvement of ischemia (indicated by reduction of blood lactate > 2 mmol/l from baseline after 24 h, primary endpoint) and 28-day mortality (key secondary endpoint) in patients with NOMI undergoing intra-arterial vasodilatory therapy. Predictors of response to therapy concerning primary and key secondary endpoint were identified using a) clinical parameters as well as b) data from 2D-perfusion angiography and c) experimental biomarkers of intestinal injury.

Results

A total of 42 patients were included into this study. At inclusion patients had severe shock, indicated by high doses of norepinephrine (NE) (median (interquartile range (IQR)) 0.37 (0.21–0.60) μg/kg/min), elevated lactate concentrations (9.2 (5.2–13) mmol/l) and multi-organ failure. Patients showed a continuous reduction of lactate following intra-arterial prostaglandin infusion (baseline: (9.2 (5.2–13) mmol/l vs. 24 h: 4.4 (2.5–9.1) mmol/l, p < 0.001) with 22 patients (52.4%) reaching a lactate reduction > 2 mmol/l at 24 h following intervention. Initial higher lactate concentrations and lower NE doses at baseline were independent predictors of an improvement of ischemia. 28-day mortality was 59% in patients with a reduction of lactate > 2 mmol/l 24 h after inclusion, while it was 85% in all other patients (hazard ratio 0.409; 95% CI, 0.14–0.631, p = 0.005).

Conclusions

A reduction of lactate concentrations was observed following implementation of intra-arterial therapy, and lactate reduction was associated with better survival. Our findings concerning outcome predictors in NOMI patients undergoing intra-arterial prostaglandin therapy might help designing a randomized controlled trial to further investigate this therapeutic approach.

Trial registration Retrospectively registered on January 22, 2020, at clinicaltrials.gov (REPERFUSE, NCT04235634), https://clinicaltrials.gov/ct2/show/NCT04235634?cond=NOMI&draw=2&rank=1.
The contribution of evolutionarily volatile promoters to molecular phenotypes and human trait variation
Authors: Young Robert S. , Talmane Lana , Marion de Procé Sophie , Taylor Martin S.
Published: April 2022

Background

Promoters are sites of transcription initiation that harbour a high concentration of phenotype-associated genetic variation. The evolutionary gain and loss of promoters between species (collectively, termed turnover) is pervasive across mammalian genomes and may play a prominent role in driving human phenotypic diversity.

Results

We classified human promoters by their evolutionary history during the divergence of mouse and human lineages from a common ancestor. This defined conserved, human-inserted and mouse-deleted promoters, and a class of functional-turnover promoters that align between species but are only active in humans. We show that promoters of all evolutionary categories are hotspots for substitution and often, insertion mutations. Loci with a history of insertion and deletion continue that mode of evolution within contemporary humans. The presence of an evolutionary volatile promoter within a gene is associated with increased expression variance between individuals, but only in the case of human-inserted and mouse-deleted promoters does that correspond to an enrichment of promoter-proximal genetic effects. Despite the enrichment of these molecular quantitative trait loci (QTL) at evolutionarily volatile promoters, this does not translate into a corresponding enrichment of phenotypic traits mapping to these loci.

Conclusions

Promoter turnover is pervasive in the human genome, and these promoters are rich in molecularly quantifiable but phenotypically inconsequential variation in gene expression. However, since evolutionarily volatile promoters show evidence of selection, coupled with high mutation rates and enrichment of QTLs, this implicates them as a source of evolutionary innovation and phenotypic variation, albeit with a high background of selectively neutral expression variation.
Development of a new adapted QuinteT Recruitment Intervention (QRI-Two) for rapid application to RCTs underway with enrolment shortfalls—to identify previously hidden barriers and improve recruitment
Authors: Donovan Jenny L. , Jepson Marcus , Rooshenas Leila , Paramasivan Sangeetha , Mills Nicola , Elliott Daisy , Wade Julia , Reda Domenic , Blazeby Jane M. , Moghanaki Drew , Hwang E. Shelley , Davies Louise
Published: April 2022

Background

Many randomised controlled trials (RCTs) struggle to recruit, despite valiant efforts. The QRI (QuinteT Recruitment Intervention) uses innovative research methods to optimise recruitment by revealing previously hidden barriers related to the perceptions and experiences of recruiters and patients, and targeting remedial actions. It was designed to be integrated with RCTs anticipating difficulties at the outset. A new version of the intervention (QRI-Two) was developed for RCTs already underway with enrolment shortfalls.

Methods

QRIs in 12 RCTs with enrolment shortfalls during 2007–2017 were reviewed to document which of the research methods used could be rapidly applied to successfully identify recruitment barriers. These methods were then included in the new streamlined QRI-Two intervention which was applied in 20 RCTs in the USA and Europe during 2018–2019. The feasibility of the QRI-Two was investigated, recruitment barriers and proposed remedial actions were documented, and the QRI-Two protocol was finalised.

Results

The review of QRIs from 2007 to 2017 showed that previously unrecognised recruitment barriers could be identified but data collection for the full QRI required time and resources usually unavailable to ongoing RCTs. The streamlined QRI-Two focussed on analysis of screening/accrual data and RCT documents (protocol, patient-information), with discussion of newly diagnosed barriers and potential remedial actions in a workshop with the RCT team. Four RCTs confirmed the feasibility of the rapid application of the QRI-Two. When the QRI-Two was applied to 14 RCTs underway with enrolment shortfalls, an array of previously unknown/underestimated recruitment barriers related to issues such as equipoise, intervention preferences, or study presentation was identified, with new insights into losses of eligible patients along the recruitment pathway. The QRI-Two workshop enabled discussion of the newly diagnosed barriers and potential remedial actions to improve recruitment in collaboration with the RCT team. As expected, the QRI-Two performed less well in six RCTs at the start-up stage before commencing enrolment.

Conclusions

The QRI-Two can be applied rapidly, diagnose previously unrecognised recruitment barriers, and suggest remedial actions in RCTs underway with enrolment shortfalls, providing opportunities for RCT teams to develop targeted actions to improve recruitment. The effectiveness of the QRI-Two in improving recruitment requires further evaluation.
A randomised controlled trial investigating the clinical and cost-effectiveness of Alpha-Stim AID cranial electrotherapy stimulation (CES) in patients seeking treatment for moderate severity depression in primary care (Alpha-Stim-D Trial)
Authors: Patel Shireen , Boutry Clement , Patel Priya , Craven Michael P. , Guo Boliang , Zafar Azhar , Kai Joe , Smart David , Butler Debbie , Higton Fred , McNaughton Rebecca , Briley Paul M. , Griffiths Chris , Nixon Neil , Sayal Kapil , Morriss Richard
Published: April 2022

Background

Major depression is the second leading cause of years lost to disability worldwide and is a leading contributor to suicide. However, first-line antidepressants are only fully effective for 33%, and only 40% of those offered psychological treatment attend for two sessions or more. Views gained from patients and primary care professionals are that greater treatment uptake might be achieved if people with depression could be offered alternative and more accessible treatment options. Although there is evidence that the Alpha-Stim Anxiety Insomnia and Depression (AID) device is safe and effective for anxiety and depression symptoms in people with anxiety disorders, there is much less evidence of efficacy in major depression without anxiety. This study investigates the effectiveness of the Alpha-Stim AID device, a cranial electrotherapy stimulation (CES) treatment that people can safely use independently at home. The device provides CES which has been shown to increase alpha oscillatory brain activity, associated with relaxation.

Methods

The aim of this study is to investigate the clinical and cost-effectiveness of Alpha-Stim AID in treatment-seeking patients (aged 16 years upwards) with moderate to moderately severe depressive symptoms in primary care. The study is a multi-centre parallel-group, double-blind, non-commercial, randomised controlled superiority trial. The primary objective of the study is to examine the clinical efficacy of active daily use of 8 weeks of Alpha-Stim AID versus sham Alpha-Stim AID on depression symptoms at 16 weeks (8 weeks after the end of treatment) in people with moderate severity depression. The primary outcome is the 17-item Hamilton Depression Rating Scale at 16 weeks. All trial and treatment procedures are carried out remotely using videoconferencing, telephone and postal delivery considering the COVID-19 pandemic restrictions.

Discussion

This study is investigating whether participants using the Alpha-Stim AID device display a reduction in depressive symptoms that can be maintained over 8 weeks post-treatment. The findings will help to determine whether Alpha-Stim AID should be recommended, including being made available in the NHS for patients with depressive symptoms.

Trial registration

ISRTCN ISRCTN11853110. Registered on 14 August 2020
Comparing Sugarbaker versus keyhole mesh technique for open retromuscular parastomal hernia repair: study protocol for a registry-based randomized controlled trial
Authors: Miller Benjamin T. , Thomas Jonah D. , Tu Chao , Costanzo Adele , Beffa Lucas R. A. , Krpata David M. , Prabhu Ajita S. , Rosen Michael J. , Petro Clayton C.
Published: April 2022

Background

Parastomal hernia, common after stoma creation, negatively impacts patient quality of life. For patients with a permanent stoma, durable parastomal hernia repair remains a challenge, with few high-quality studies for guidance. An alternative to open retromuscular parastomal hernia repair with retromuscular “keyhole” mesh is the recent Sugarbaker modification. We aim to compare these two techniques in a head-to-head prospective study.

Methods

This is a registry-based randomized controlled trial designed to investigate whether the retromuscular Sugarbaker technique is superior to the retromuscular keyhole technique for parastomal hernia repair. The primary study endpoint is parastomal hernia recurrence at 2 years. Secondary endpoints include hospital length-of-stay, readmission, wound morbidity, mesh-related complications, re-operation, all 30-day morbidity, and patient-reported outcomes, including hernia-related quality of life, stoma-specific quality of life, pain, and decision regret.

Discussion

Based on the post hoc analysis of a recent randomized controlled trial, we hypothesize that the retromuscular Sugarbaker technique will reduce parastomal hernia recurrence by 20% at 2 years compared to the retromuscular keyhole mesh technique. The results of this study may provide evidence-based guidance for surgeons repairing parastomal hernias.

Trial registration

ClinicalTrials.gov NCT03972553. Registered on 3 June 2019
The structural diversity of CACTA transposons in genomes of Chenopodium (Amaranthaceae, Caryophyllales) species: specific traits and comparison with the similar elements of angiosperms
Authors: Belyayev Alexander , Josefiová Jiřina , Jandová Michaela , Kalendar Ruslan , Mahelka Václav , Mandák Bohumil , Krak Karol
Published: April 2022

Background

CACTA transposable elements (TEs) comprise one of the most abundant superfamilies of Class 2 (cut-and-paste) transposons. Over recent decades, CACTA elements were widely identified in species from the plant, fungi, and animal kingdoms, but sufficiently studied in the genomes of only a few model species although non-model genomes can bring additional and valuable information. It primarily concerned the genomes of species belonging to clades in the base of large taxonomic groups whose genomes, to a certain extent, can preserve relict and/or possesses specific traits. Thus, we sought to investigate the genomes ofChenopodium(Amaranthaceae,Caryophyllales) species to unravel the structural variability of CACTA elements.Caryophyllalesis a separate branch of Angiosperms and until recently the diversity of CACTA elements in this clade was unknown.

Results

Application of the short-read genome assembly algorithm followed by analysis of detected complete CACTA elements allowed for the determination of their structural diversity in the genomes of 22Chenopodium albumaggregate species. This approach yielded knowledge regarding: (i) the coexistence of two CACTA transposons subtypes in single genome; (ii) gaining of additional protein conserved domains within the coding sequence; (iii) the presence of captured gene fragments, including key genes for flower development; and (iv)) identification of captured satDNA arrays. Wide comparative database analysis revealed that identified events are scattered through Angiosperms in different proportions.

Conclusions

Our study demonstrated that while preserving the basic element structure a wide range of coding and non-coding additions to CACTA transposons occur in the genomes ofC. albumaggregate species. Ability to relocate additions inside genome in combination with the proposed novel functional features of structural-different CACTA elements can impact evolutionary trajectory of the host genome.
Late metachronous cerebral metastasis of pancreatic adenocarcinoma of the tail of the pancreas: a case report
Authors: Papadimitriou Kyriakos , Kiss-Bodolay Daniel , Hedjoudje Abderrahmane , Millan Diego San , Simonin Alexandre , Fournier Jean-Yves , Huscher Karen
Published: April 2022

Background

Pancreatic cancer is one of the leading causes of cancer mortality and one of the most lethal malignant neoplasms worldwide. It is known for its local tumor extension to the liver; other common sites include the lung, distant lymph nodes, and bone. Brain metastases are extremely rare and represent less than 0.6% of all brain metastases.

Case report

We report the case of a 66-year-old Caucasian female known to have adenocarcinoma of the tail of the pancreas treated with chemotherapy. During follow-up, thoracoabdominal computed tomography scans did not reveal any residual tumor or any metastasis. Moreover, tumor markers were within normal limits. She presented to the emergency department of our institution following an episode of a generalized tonic–clonic seizure 5 years following the initial diagnosis. Brain magnetic resonance imaging revealed an expansive left frontal intraaxial lesion compatible with high-grade glioma. The patient underwent surgical treatment. Histological examination revealed pancreatic metastasis.

Conclusions

Thought to be rare, metachronous cerebral pancreatic metastasis should be kept in mind in patients with pancreatic cancer. Early diagnosis and complete surgical resection play a key role in the survival of these patients.
Episodic apnea: gastroesophageal reflux associated with gastric organo-axial malrotation: a case report
Authors: Turk Sena , Gokce Sule , Koc Feyza Umay
Published: April 2022

Background

Gastroesophageal reflux is a normal physiologic process occurring several times a day in healthy infants. On the other hand, symptoms such as failure to thrive, feeding or sleeping problems, chronic respiratory distress, persistent forceful vomiting, and choking may indicate reflux associated with underlying anatomic, neurological, or infectious abnormalities. Gastric malrotation is an extremely rare disorder in the pediatric population and one of the anatomic causes associated with severe reflux, which could lead to serious complications. In such cases, life-threatening symptoms overlapping with other diseases cause delayed diagnosis and treatment.

Case presentation

We report a 2.5-month-old white girl diagnosed with gastric malrotation-related reflux, which caused inadequate weight gain, feeding difficulties, episodes of apnea with cyanosis, and choking after successive coughing, hence previously misdiagnosed as epilepsy and pertussis.

Conclusion

Life-threatening symptoms in an infant with reflux suggest anatomic, neurological, or infectious conditions. Gastric malrotation is more common than generally thought and specifically looked for in young children with severe reflux symptoms, and should be diagnosed and treated as soon as possible.
Emerging role of exosomes in the pathology of chronic obstructive pulmonary diseases; destructive and therapeutic properties
Authors: Rajabi Hadi , Konyalilar Nur , Erkan Sinem , Mortazavi Deniz , Korkunc Seval Kubra , Kayalar Ozgecan , Bayram Hasan , Rahbarghazi Reza
Published: April 2022

Chronic obstructive pulmonary disease (COPD) is known as the third leading cause of human death globally. Enhanced chronic inflammation and pathological remodeling are the main consequences of COPD, leading to decreased life span. Histological and molecular investigations revealed that prominent immune cell infiltration and release of several cytokines contribute to progressive chronic remodeling. Recent investigations have revealed that exosomes belonging to extracellular vesicles are involved in the pathogenesis of COPD. It has been elucidated that exosomes secreted from immune cells are eligible to carry numerous pro-inflammatory factors exacerbating the pathological conditions. Here, in this review article, we have summarized various and reliable information about the negative role of immune cell-derived exosomes in the remodeling of pulmonary tissue and airways destruction in COPD patients.
PA1 participates in the maintenance of blood–testis barrier integrity via cooperation with JUN in the Sertoli cells of mice
Authors: Liu Bo , Liu Chao , Ma Binfang , Zhang Ruidan , Zhao Zhiwei , Xiao Sai , Cao Wanjun , Ma Yanjie , Zhu Guozhang , Li Wei , Li Zhen
Published: April 2022

Background

The blood–testis barrier (BTB) is essential to the microenvironment of spermatogenesis, and Sertoli cells provide the cellular basis for BTB construction. Numerous nuclear transcription factors have been identified to be vital for the proper functioning of Sertoli cells. PA1 has been reported to play important roles during diverse biological processes, yet its potential function in male reproduction is still unknown.

Results

Here, we show that PA1 was highly expressed in human and mouse testis and predominantly localized in the nuclei of Sertoli cells. Sertoli cell-specific Pa1 knockout resulted in an azoospermia-like phenotype in mice. The knockout of this gene led to multiple defects in spermatogenesis, such as the disorganization of the cytoskeleton during basal and apical ectoplasmic specialization and the disruption of the BTB. Further transcriptomic analysis, together with Cut-Tag results of PA1 in Sertoli cells, revealed that PA1 could affect the expression of a subset of genes that are essential for the normal function of Sertoli cells, including those genes associated with actin organization and cellular junctions such as Connexin43 (Cx43). We further demonstrated that the expression of Cx43 depended on the interaction between JUN, one of the AP-1 complex transcription factors, and PA1.

Conclusion

Overall, our findings reveal that PA1 is essential for the maintenance of BTB integrity in Sertoli cells and regulates BTB construction-related gene expression via transcription factors. Thus, this newly discovered mechanism in Sertoli cells provides a potential diagnostic or even therapeutic target for some individuals with azoospermia.
Rebuilding hippocampus neural circuit with hADSC-derived neuron cells for treating ischemic stroke
Authors: Wang Jian , Hao Rui , Jiang Tianfang , Guo Xuanxuan , Zhou Fei , Cao Limei , Gao Fengjuan , Wang Guangming , Wang Juan , Ning Ke , Zhong Chunlong , Chen Xu , Huang Ying , Xu Jun , Gao Shane
Published: April 2022

Background

Human adipose-derived stem cells (hADSCs) have been demonstrated to be a promising autologous stem cell source for treating various neuronal diseases. Our study indicated that hADSCs could be induced into neuron-like cells in a stepwise manner that are characterized by the positive expression of MAP2, SYNAPSIN 1/2, NF-200, and vGLUT and electrophysiological activity. We first primed hADSCs into neuron-like cells (hADSC-NCs) and then intracerebrally transplanted them into MCAO reperfusion mice to further explore their in vivo survival, migration, integration, fate commitment and involvement in neural circuit rebuilding.

Results

The hADSC-NCs survived well and transformed into MAP2-positive, Iba1- or GFAP-negative cells in vivo while maintaining some proliferative ability, indicated by positive Ki67 staining after 4 weeks. hADSC-NCs could migrate to multiple brain regions, including the cortex, hippocampus, striatum, and hypothalamus, and further differentiate into mature neurons, as confirmed by action potential elicitation and postsynaptic currents. With the aid of a cell suicide system, hADSC-NCs were proven to have functionally integrated into the hippocampal memory circuit, where they contributed to spatial learning and memory rescue, as indicated by LTP improvement and subsequent GCV-induced relapse. In addition to infarction size shrinkage and movement improvement, MCAO-reperfused mice showed bidirectional immune modulation, including inhibition of the local proinflammatory factors IL-1α, IL-1β, IL-2, MIP-1β and promotion proinflammatory IP-10, MCP-1, and enhancement of the anti-inflammatory factors IL-15.

Conclusion

Overall, hADSC-NCs used as an intermediate autologous cell source for treating stroke can rebuild hippocampus neuronal circuits through cell replacement.
UBIAD1 alleviates ferroptotic neuronal death by enhancing antioxidative capacity by cooperatively restoring impaired mitochondria and Golgi apparatus upon cerebral ischemic/reperfusion insult
Authors: Huang Yan , Liu Jianyang , He Jialin , Hu Zhiping , Tan Fengbo , Zhu Xuelin , Yuan Fulai , Jiang Zheng
Published: April 2022

Background

Neuronal death due to over-oxidative stress responses defines the pathology of cerebral ischemic/reperfusion (I/R) insult. Ferroptosis is a form of oxidative cell death that is induced by disruption of the balance between antioxidants and pro-oxidants in cells. However, the potential mechanisms responsible for cerebral I/R-induced ferroptotic neuronal death have not been conclusively determined. UBIAD1, is a newly identified antioxidant enzyme that catalyzes coenzyme Q10 (CoQ10) and vitamin K2 biosynthesis in the Golgi apparatus membrane and mitochondria, respectively. Even though UBIAD1 is a significant mediator of apoptosis in cerebral I/R challenge, its roles in ferroptotic neuronal death remain undefined. Therefore, we investigated whether ferroptotic neuronal death is involved in cerebral I/R injury. Further, we evaluated the functions and possible mechanisms of UBIAD1 in cerebral I/R-induced ferroptotic neuronal death, with a major focus on mitochondrial and Golgi apparatus dysfunctions.

Results

Ferroptosis occurred in cerebral I/R. Ferroptotic neuronal death promoted cerebral I/R-induced brain tissue injury and neuronal impairment. UBIAD1 was expressed in cerebral tissues and was localized in neurons, astrocytes, and microglia. Under cerebral I/R conditions overexpressed UBIAD1 significantly suppressed lipid peroxidation and ferroptosis. Moreover, upregulated UBIAD1 protected against brain tissue damage and neuronal death by alleviating I/R-mediated lipid peroxidation and ferroptosis. However, UBIAD1 knockdown reversed these changes. Enhanced UBIAD1-mediated ferroptosis elevated the antioxidative capacity by rescuing mitochondrial and Golgi apparatus dysfunction in cerebral I/R-mediated neuronal injury. They improved the morphology and biofunctions of the mitochondria and Golgi apparatus, thereby elevating the levels of SOD, T-AOC and production of CoQ10, endothelial nitric oxide synthase (eNOS)-regulated nitric oxide (NO) generation as well as suppressed MDA generation.

Conclusions

The neuroprotective agent, UBIAD1, modulates I/R-mediated ferroptosis by restoring mitochondrial and Golgi apparatus dysfunction in damaged brain tissues and neurons, thereby enhancing antioxidative capacities. Moreover, the rescue of impaired mitochondrial and Golgi apparatus as a possible mechanism of regulating ferroptotic neuronal death is a potential treatment strategy for ischemic stroke.

Graphical Abstract