bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of 14 patients with cornual heterotopic pregnancy following embryo transfer: experience from the past decade
Authors: Li Sichen , Cao Mingzhu , Liu Hanyan , He Yuxia , Liu Jianqiao
Published: October 2021

Objective

There are two major management approach for cornual heterotopic pregnancy, transvaginal cornual embryo reduction with ultrasound guidance, or laparoscopic cornual resection. This no consensus on the optimal management for cornual heterotopic pregnancy. Here, we are trying to determine the optimal management approach for patients with viable cornual heterotopic pregnancy following embryo transfer.

Methods

This is a retrospective cohort study conducted at the locally largest reproductive center of a tertiary hospital.A total of 14 women diagnosed as viable cornual heterotopic pregnancy following embryo transfer. Six patients were treated with cornual pregnancy reduction under transvaginal ultrasound guidance without the use of feticide drug (treatment 1), and eight patients were treated with laparoscopic cornual pregnancy resection (treatment 2).

Results

All 14 patients of cornual heterotopic pregnancy following embryo transfer due to fallopian tubal factor, among which, 12 patients had cornual pregnancy occurred in the ipsilateral uterine horn of tubal pathological conditions. Nine (64.29%) showed a history of ectopic pregnancy. Thirteen (92.86%) patients were transferred with two embryos and only one patient had single embryo transferred. Six patients received treatment 1, and 2 (33.33%) had uterine horn rupture and massive bleeding which required emergency laparoscopic surgery for homostasis. No cornual rupture occurred among patients received treatment 2. Each treatment group had one case of spontaneous miscarriage. The remaining 5 cases in treatment 1 group and the remaining 7 cases in treatment 2 group delivered healthy live offspring.

Conclusion

Patients with tubal factors attempting for embryo transfer, especially those aiming for multiple embryos transfer, should be informed with risk of cornual heterotopic pregnancy and the subsequent cornual rupture. Compared with cornual pregnancy reduction under transvaginal ultrasound guidance, laparoscopic cornual resection might be a favorable approach for patients with viable cornual heterotopic pregnancy.
Extracellular vesicles from maternal uterine cells exposed to risk factors cause fetal inflammatory response
Authors: Shepherd Megan C. , Radnaa Enkhtuya , Tantengco Ourlad Alzeus , Kechichian Talar , Urrabaz-Garza Rheanna , Kammala Ananth Kumar , Sheller-Miller Samantha , Menon Ramkumar
Published: October 2021

Background

Fetal cell-derived exosomes (extracellular vesicles, 40–160 nm) are communication channels that can signal parturition by inducing inflammatory changes in maternal decidua and myometrium. Little is known about maternal cell-derived exosomes and their functional roles on the fetal side. This study isolated and characterized exosomes from decidual and myometrial cells grown under normal and inflammatory/oxidative stress conditions and determined their impact on fetal membrane cells.

Methods

Decidual and myometrial cells were grown under standard culture conditions (control) or exposed for 48 h to cigarette smoke extract or tumor necrosis factor-α, as proxies for oxidative stress and inflammation, respectively. Exosomes were isolated from media (differential ultra-centrifugation followed by size exclusion chromatography), quantified (nano particle tracking analysis), and characterized in terms of their size and morphology (cryo-electron microscopy), markers (dot blot), and cargo contents (proteomics followed by bioinformatics analysis). Maternal exosomes (109/mL) were used to treat amnion epithelial cells and chorion trophoblast cells for 24 h. The exosome uptake by fetal cells (confocal microscopy) and the cytokine response (enzyme-linked immunosorbent assays for IL-6, IL-10, and TNF-α) was determined.

Results

Exosomes from both decidual and myometrial cells were round and expressed tetraspanins and endosomal sorting complexes required for transport (ESCRT) protein markers. The size and quantity was not different between control and treated cell exosomes. Proteomic analysis identified several common proteins in exosomes, as well as unique proteins based on cell type and treatment. Compared to control exosomes, pro-inflammatory cytokine release was higher in both amnion epithelial cell and chorion trophoblast cell media when the cells had been exposed to exosomes from decidual or myometrial cells treated with either cigarette smoke extract or tumor necrosis factor-α. In chorion trophoblast cells, anti-inflammatory IL-10 was increased by exosomes from both decidual and myometrial cells.

Conclusion

Various pathophysiological conditions cause maternal exosomes to carry inflammatory mediators that can result in cell type dependent fetal inflammatory response.
IgA vasculitis nephritis clinical course and kidney biopsy – national study in children
Authors: Mizerska-Wasiak Małgorzata , Turczyn Agnieszka , Cichoń-Kawa Karolina , Małdyk Jadwiga , Miklaszewska Monika , Drożdż Dorota , Bieniaś Beata , Sikora Przemysław , Drożyńska-Duklas Magdalena , Żurowska Aleksandra , Szczepańska Maria , Pańczyk-Tomaszewska Małgorzata
Published: October 2021

The aim of the study was to investigate the relationship between the severity of typical clinical symptoms, severity of histopathological lesions in kidney biopsies in IgA vasculitis nephritis (IgAVN) and to propose indications for kidney biopsy in children.

Material and methods

This retrospective study enrolled 106 patients, included in the IgAVN registry of Polish children, diagnosed by kidney biopsy. Renal and extrarenal symptoms at onset of the disease were analyzed. Biopsy results were assessed using Oxford classifications (MEST-C). The patients were divided into 3 groups depending on the severity of proteinuria: A-nephrotic proteinuria with hematuria; B-non-nephrotic proteinuria with hematuria; C-isolated hematuria.

Results

The first symptoms of nephropathy were observed at the 0.7 (1–128.4) months from the onset of extrarenal symptoms. Kidney biopsy was performed on 39 (6–782) days after the onset of nephropathy symptoms. MEST-C score 4 or 5 was significantly more frequent in children from group A than in groups B and C. Significantly higher mean MEST-C score was found in patients with abdominal symptoms than without.

In group A: S0 and T0 we found in significantly shorter time to kidney biopsy than in S1, T1–2 p < 0.05) and in group B the significantly shorter time in T0 compare to T1–2 p < 0.05). The ROC analysis shows that S1 changes appear in kidney biopsies in group A with cut off 21 days (AUC 0,702, p = 0.004, sensitivity 0.895 specificity 0.444) T1–2 changes after 35 days (AUC 0.685, p = 0.022, sensitivity 0.750, specificity 0.615), and in goupn B T1–2 cut off is 74 days (AUC 0,738, p = 0.002, sensitivity 0.667, specificity 0.833).

Conclusions

In childhood IgAVN, the severity of changes in the urine is clearly reflected in the result of a kidney biopsy. The biopsy should be performed in patients with nephrotic proteinuria no later than 3 weeks after the onset of this symptom in order to promptly apply appropriate treatment and prevent disease progression. Accompanying abdominal symptoms predispose to higher MESTC score.
Development of a women’s empowerment index for Tanzania from the demographic and health surveys of 2004–05, 2010, and 2015–16
Authors: Mganga Andrew Evarist , Renju Jenny , Todd Jim , Mahande Michael Johnson , Vyas Seema
Published: October 2021

Background

Women’s empowerment is a multidimensional construct which varies by context. These variations make it challenging to have a concrete definition that can be measured quantitatively. Having a standard composite measure of empowerment at the individual and country level would help to assess how countries are progressing in efforts to achieve gender equality (SDG 5), enable standardization across and within settings and guide the formulation of policies and interventions. The aim of this study was to develop a women’s empowerment index for Tanzania and to assess its evolution across three demographic and health surveys from 2004 to 2016.

Results

Women’s empowerment in Tanzania was categorized into six distinct domains namely; attitudes towards violence, decision making, social independence, age at critical life events, access to healthcare, and property ownership. The internal reliability of this six-domain model was shown to be acceptable by a Cronbach’s α value of 0.658. The fit statistics of the root mean squared error of approximation (0.05), the comparative fit index (0.93), and the standardized root mean squared residual (0.04) indicated good internal validity. The structure of women’s empowerment was observed to have remained relatively constant across three Tanzanian demographic and health surveys.

Conclusions

The use of factor analysis in this research has shown that women’s empowerment in Tanzania is a six-domain construct that has remained relatively constant over the past ten years. This could be a stepping stone to reducing ambiguity in conceptualizing and operationalizing empowerment and expanding its applications in empirical research to study different women related outcomes in Tanzania.
Treatment of hepatitis C virus infection with direct-acting antiviral agent-based regimens in Iranian patients with hereditary bleeding disorders
Authors: Sharafi Heidar , Behnava Bita , Azizi-saraji Alireza , Namvar Ali , Anvar Ali , Salimi Shima , Alavian Seyed Moayed
Published: October 2021

Background

Chronic hepatitis C (CHC) is one of the most important comorbidities in patients with hereditary bleeding disorders (HBD). The present study aimed at evaluating the effectiveness of direct-acting antiviral agent (DAA)-based interferon-free HCV antiviral regimens in patients with HBD.

Patients and methods

The present study was performed on the patients with HBD and CHC between 2015 and 2019. Sofosbuvir-based interferon-free regimens with or without ribavirin were prescribed to treat HCV infection. The main endpoint of the study was to determine the sustained virologic response (SVR), assessed 12 weeks after the completion of treatment.

Results

A total of 147 patients with a mean age of 41.1 years were enrolled in the study; 4.1% of them were co-infected with HIV, 25.2% had cirrhosis, and 76.9% of them were diagnosed with hemophilia A. HCV genotype-1 includes the largest number (68.1%) of patients. 46.3% of patients were treatment-naïve and others had a treatment history with interferon-based regimens. Out of 147 patients, 15 patients were lost to follow-up during treatment or for SVR evaluation or discontinued treatment. 132 subjects completed treatment and were evaluated for SVR, 12 weeks after the completion of treatment. All of the patients achieved SVR 12 (SVR rate: 100%, 95% CI 97.2–100%).

Conclusion

Hepatitis C DAA-based regimens are the effective treatments for CHC in patients with HBD, regardless of the treatment modifiers such as previous treatment experience, cirrhosis, HIV co-infection, and HCV genotype.
Axial variation in flexural stiffness of plant stem segments: measurement methods and the influence of measurement uncertainty
Authors: Martin-Nelson Nathanael , Sutherland Brandon , Yancey Michael , Liao Chung Shan , Stubbs Christopher J. , Cook Douglas D.
Published: October 2021

Background

Flexural three-point bending tests are useful for characterizing the mechanical properties of plant stems. These tests can be performed with minimal sample preparation, thus allowing tests to be performed relatively quickly. The best-practice for such tests involves long spans with supports and load placed at nodes. This approach typically provides only one flexural stiffness measurement per specimen. However, by combining flexural tests with analytic equations, it is possible to solve for the mechanical characteristics of individual stem segments.

Results

A method is presented for using flexural tests to obtain estimates of flexural stiffness of individual segments. This method pairs physical test data with analytic models to obtain a system of equations. The solution of this system of equations provides values of flexural stiffness for individual stalk segments. Uncertainty in the solved values for flexural stiffness were found to be strongly dependent upon measurement errors. Row-wise scaling of the system of equations reduced the influence of measurement error. Of many possible test combinations, the most advantageous set of tests for performing these measurements were identified. Relationships between measurement uncertainty and solution uncertainty were provided for two different testing methods.

Conclusions

The methods presented in this paper can be used to measure the axial variation in flexural stiffness of plant stem segments. However, care must be taken to account for the influence of measurement error as the individual segment method amplifies measurement error. An alternative method involving aggregate flexural stiffness values does not amplify measurement error, but provides lower spatial resolution.
New bakuchiol dimers from Psoraleae Fructus and their inhibitory activities on nitric oxide production
Authors: Xu Qingxia , lv Qian , Liu Lu , Zhang Yingtao , Yang Xiuwei
Published: October 2021

Background

Dried fruits of Psoralea corylifolia L. (Psoraleae Fructus) is one of the most popular traditional Chinese medicine with treatment for nephritis, spermatorrhea, pollakiuria, asthma, and various inflammatory diseases. Bakuchiol is main meroterpenoid with bioactive diversity from Psoraleae Fructus. This study was designed to seek structural diverse bakuchiol derivants with anti-inflammatory activities from this plant.

Methods

Various column chromatography methods were used for isolation experiment. Structures and configurations of these compounds were determined by spectroscopic methods and single-crystal X-ray diffraction. Their inhibition on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were evaluated by the Griess reaction.

Results

Twelve unpresented bakuchiol dimmers, bisbakuchiols M–U (1–9) and bisbakuchiol ethers A–C (10–12), along with five known compounds (13–17), were isolated from the fruits of Psoralea corylifolia L. Compounds 1–3, 10–12, 16 and 17 exhibited inhibitory activities against LPS-induced NO production in RAW264.7 macrophages, and the inhibition of compound 1 (half maximal inhibitory concentration (IC50) value = 11.47 ± 1.57 μM) was equal to that of L-N(6)-(1-iminoethyl)-lysine (IC50 = 10.29 ± 1.10 μM) as a positive control.

Conclusions

Some compounds exhibited inhibitory activities against NO production, and the study of structure–activity relationship suggested that uncyclized compounds with oxygen substitution at C-12/12′ showed strong inhibitory activities, and carbonyl units contributed to enhanced activities.
Comparative metabolic profiling of posterior parietal cortex, amygdala, and hippocampus in conditioned fear memory
Authors: Jeon Yoonjeong , Lim Yun , Yeom Jiwoo , Kim Eun-Kyoung
Published: October 2021

Fear conditioning and retrieval are suitable models to investigate the biological basis of various mental disorders. Hippocampus and amygdala neurons consolidate conditioned stimulus (CS)-dependent fear memory. Posterior parietal cortex is considered important for the CS-dependent conditioning and retrieval of fear memory. Metabolomic screening among functionally related brain areas provides molecular signatures and biomarkers to improve the treatment of psychopathologies. Herein, we analyzed and compared changes of metabolites in the hippocampus, amygdala, and posterior parietal cortex under the fear retrieval condition. Metabolite profiles of posterior parietal cortex and amygdala were similarly changed after fear memory retrieval. While the retrieval of fear memory perturbed various metabolic pathways, most metabolic pathways that overlapped among the three brain regions had high ranks in the enrichment analysis of posterior parietal cortex. In posterior parietal cortex, the most perturbed pathways were pantothenate and CoA biosynthesis, purine metabolism, glutathione metabolism, and NAD+ dependent signaling. Metabolites of posterior parietal cortex including 4′-phosphopantetheine, xanthine, glutathione, ADP-ribose, ADP-ribose 2′-phosphate, and cyclic ADP-ribose were significantly regulated in these metabolic pathways. These results point to the importance of metabolites of posterior parietal cortex in conditioned fear memory retrieval and may provide potential biomarker candidates for traumatic memory-related mental disorders.
Intratumor heterogeneity: the hidden barrier to immunotherapy against MSI tumors from the perspective of IFN-γ signaling and tumor-infiltrating lymphocytes
Authors: Wu Wantao , Liu Yihan , Zeng Shan , Han Ying , Shen Hong
Published: October 2021

In this era of precision medicine, with the help of biomarkers, immunotherapy has significantly improved prognosis of many patients with malignant tumor. Deficient mismatch repair (dMMR)/microsatellite instability (MSI) status is used as a biomarker in clinical practice to predict favorable response to immunotherapy and prognosis. MSI is an important characteristic which facilitates mutation and improves the likelihood of a favorable response to immunotherapy. However, many patients with dMMR/MSI still respond poorly to immunotherapies, which partly results from intratumor heterogeneity propelled by dMMR/MSI. In this review, we discuss how dMMR/MSI facilitates mutations in tumor cells and generates intratumor heterogeneity, especially through type II interferon (IFN-γ) signaling and tumor-infiltrating lymphocytes (TILs). We discuss the mechanism of immunotherapy from the perspective of dMMR/MSI, molecular pathways and TILs, and we discuss how intratumor heterogeneity hinders the therapeutic effect of immunotherapy. Finally, we summarize present techniques and strategies to look at the tumor as a whole to design personalized regimes and achieve favorable prognosis.
An exploration of changes in plantar pressure distributions during walking with standalone and supported lateral wedge insole designs
Authors: Tse Calvin T. F. , Ryan Michael B. , Dien Jason , Scott Alex , Hunt Michael A.
Published: October 2021

Background

Lateral wedge insoles (LWI), standalone or with medial arch support (supported‐LWI), have been thoroughly investigated for their effects on modifying gait biomechanics for people with knee osteoarthritis. However, plantar pressure distribution between these insole types has not been investigated and could provide insight towards insole prescription with concomitant foot symptoms taken into consideration.

Methods

In a sample of healthy individuals (n = 40), in‐shoe plantar pressure was measured during walking with LWI, with or without medial arch support (variable‐ and uniform‐stiffness designs), and a flat control insole condition. Pressure data from the plantar surface of the foot were divided into seven regions: medial/lateral rearfoot, midfoot, medial/central/lateral forefoot, hallux. Plantar pressure outcomes assessed were the medial‐lateral pressure index (MLPI) for the whole foot, and the peak pressure, pressure‐time integral (PTI), and contact area in each plantar region. Comfort in each insole condition was rated as a change relative to the flat control insole condition. Repeated‐measures analyses of variance were calculated to compare the plantar pressure outcomes between insole conditions.

Results

Regionally, medial rearfoot and forefoot pressure were reduced by all wedged insoles, with the variable‐stiffness supported‐wedge showing greater reductions than the standalone wedge. Lateral rearfoot and forefoot pressure were reduced by both supported‐LWI, but unchanged by the standalone wedge. In the midfoot, the standalone wedge maintained pressure but reduced regional contact area, while both supported‐LWI increased midfoot pressure and contact area. All LWI increased the MLPI, indicating a lateral shift in plantar pressure distribution throughout the weightbearing phase of gait. Comfort ratings were not significantly different between insole conditions.

Conclusions

Regional differences in plantar pressure may help determine an appropriate lateral wedge insole variation to avoid exacerbation of concomitant foot symptoms by minimizing pressure in symptomatic regions. Lateral shifts in plantar pressure distribution were observed in all laterally wedged conditions, including one supported‐LWI that was previously shown to be biomechanically ineffective for modifying knee joint load distribution. Thus, shifts in foot centre of pressure may not be a primary mechanism by which LWI can modify knee joint load distribution for people with knee osteoarthritis.
Identification and clinical significance of somatic oncogenic mutations in epithelial ovarian cancer
Authors: Watanabe Takafumi , Nanamiya Hideaki , Endo Yuta , Kojima Manabu , Nomura Shinji , Furukawa Shigenori , Soeda Shu , Tamura Hirosumi , Ryufuku Masae , Tanaka Daisuke , Isogai Takao , Imai Jun-ichi , Watanabe Shinya , Fujimori Keiya
Published: October 2021

Objective

Epithelial ovarian cancer (EOC) is a heterogeneous disease with diverse clinicopathological features and behaviors, and its heterogeneity may be concerned with the accumulation of multiple somatic oncogenic mutations. The major goals of this study are to systematically perform the comprehensive mutational profiling in EOC patients, and investigate the associations between somatic mutations and clinicopathological characteristics.

Methods

A total of 80 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery, and genomic DNAs were extracted from fresh-frozen tissues. We investigated mutational status in hot spot regions of 50 cancer-related genes by targeted next-generation sequencing using an Ion AmpliSeq Cancer Hotspot Panel v2 Kit.

Results

Validated mutations were detected in 66 of the 80 tumors (82.5%). The five most frequently mutated genes were TP53 (43.8%), PIK3CA (27.5%), KRAS (23.8%), PTEN (10%) and CTNNB1 (10%). PTEN and CTNNB1 mutations were associated with younger age. PIK3CA1, KRAS and CTNNB1 mutations were observed in early-stage, whereas TP53 mutations were more common in advanced stage. Significant associations were observed between TP53 mutation and serous carcinoma, and between KRAS mutation and mucinous carcinoma. Both PIK3CA mutation and CTNNB1 mutation were also significantly associated with endometrioid and clear cell carcinoma. The patients with PIK3CA and KRAS mutations were significantly associated with favorable progression free survival (PFS). In particular, PIK3CA mutations had more significant associations with favorable PFS than PIK3CA wild-type in the endometrioid subtype (P = 0.012). Patients with mutations only in TP53 were significantly associated with worse PFS.

Conclusion

EOCs were heterogeneous at the genomic level and harbored somatic oncogenic mutations. Our molecular profiling may have the potential for becoming a novel stratification within histological subtypes of EOC. Further studies are needed to define molecular classification for improved clinical outcomes and treatment of EOC patients in future.
Hemoglobin life-threatening value (1.9 g/dl) in good general condition: a pediatric case-report
Authors: Parodi Emilia , Riboldi Lorenzo , Ramenghi Ugo
Published: October 2021

Background

We report a pediatric patient presenting in good general condition despite a hemoglobin value of 1,9 g/dL, which is normally regarded as life-threatening.

Case presentation

An African 5 years-old girl presented to our Emergency Department (ED) for worsening asthenia, within a clinical picture of good general condition. The hemoglobin value at admission was 1,9 g/dL. The subsequent diagnostic-therapeutic pathway highlighted the presence of two different causes, both well known to be responsible for chronic anemia (with slow reduction of hemoglobin values): iron deficiency anemia (IDA) due to a very low dietary intake of iron-rich foods, and homozygous sickle cell disease (HbSS). She received transfusions of packed red blood cells (overall 15 ml/kg) and subsequently intravenous iron preparations (total amount 200 mg) followed by oral iron supplements. The Hb value at discharge, 10 days after the admission, was 9.8 g/dL.

Conclusions

When approaching a picture of severe anemia, we suggest pediatricians take into consideration clinical conditions rather than laboratory values and to take advantage of detailed anamnestic data in order to make the diagnosis.
Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by coding sequence composition and mRNA localization
Authors: Gillen Sarah L. , Giacomelli Chiara , Hodge Kelly , Zanivan Sara , Bushell Martin , Wilczynska Ania
Published: October 2021

Background

Regulation of protein output at the level of translation allows for a rapid adaptation to dynamic changes to the cell’s requirements. This precise control of gene expression is achieved by complex and interlinked biochemical processes that modulate both the protein synthesis rate and stability of each individual mRNA. A major factor coordinating this regulation is the Ccr4-Not complex. Despite playing a role in most stages of the mRNA life cycle, no attempt has been made to take a global integrated view of how the Ccr4-Not complex affects gene expression.

Results

This study has taken a comprehensive approach to investigate post-transcriptional regulation mediated by the Ccr4-Not complex assessing steady-state mRNA levels, ribosome position, mRNA stability, and protein production transcriptome-wide. Depletion of the scaffold protein CNOT1 results in a global upregulation of mRNA stability and the preferential stabilization of mRNAs enriched for G/C-ending codons. We also uncover that mRNAs targeted to the ER for their translation have reduced translational efficiency when CNOT1 is depleted, specifically downstream of the signal sequence cleavage site. In contrast, translationally upregulated mRNAs are normally localized in p-bodies, contain disorder-promoting amino acids, and encode nuclear localized proteins. Finally, we identify ribosome pause sites that are resolved or induced by the depletion of CNOT1.

Conclusions

We define the key mRNA features that determine how the human Ccr4-Not complex differentially regulates mRNA fate and protein synthesis through a mechanism linked to codon composition, amino acid usage, and mRNA localization.
Mapping and modeling the genomic basis of differential RNA isoform expression at single-cell resolution with LR-Split-seq
Authors: Rebboah Elisabeth , Reese Fairlie , Williams Katherine , Balderrama-Gutierrez Gabriela , McGill Cassandra , Trout Diane , Rodriguez Isaryhia , Liang Heidi , Wold Barbara J. , Mortazavi Ali
Published: October 2021

The rise in throughput and quality of long-read sequencing should allow unambiguous identification of full-length transcript isoforms. However, its application to single-cell RNA-seq has been limited by throughput and expense. Here we develop and characterize long-read Split-seq (LR-Split-seq), which uses combinatorial barcoding to sequence single cells with long reads. Applied to the C2C12 myogenic system, LR-split-seq associates isoforms to cell types with relative economy and design flexibility. We find widespread evidence of changing isoform expression during differentiation including alternative transcription start sites (TSS) and/or alternative internal exon usage. LR-Split-seq provides an affordable method for identifying cluster-specific isoforms in single cells.
The challenge of equipoise in trials with a surgical and non-surgical comparison: a qualitative synthesis using meta-ethnography
Authors: Davies Loretta , Beard David , Cook Jonathan A. , Price Andrew , Osbeck Ida , Toye Francine
Published: October 2021

Background

Randomised controlled trials in surgery can be a challenge to design and conduct, especially when including a non-surgical comparison. As few as half of initiated surgical trials reach their recruitment target, and failure to recruit is cited as the most frequent reason for premature closure of surgical RCTs. The aim of this qualitative evidence synthesis was to identify and synthesise findings from qualitative studies exploring the challenges in the design and conduct of trials directly comparing surgical and non-surgical interventions.

Methods

A qualitative evidence synthesis using meta-ethnography was conducted. Six electronic bibliographic databases (Medline, Central, Cinahl, Embase and PsycInfo) were searched up to the end of February 2018. Studies that explored patients’ and health care professionals’ experiences regarding participating in RCTs with a surgical and non-surgical comparison were included. The GRADE-CERQual framework was used to assess confidence in review findings.

Results

In total, 3697 abstracts and 49 full texts were screened and 26 published studies reporting experiences of patients and healthcare professionals were included. The focus of the studies (24/26) was primarily related to the challenge of recruitment. Two studies explored reasons for non-compliance to treatment allocation following randomisation. Five themes related to the challenges to these types of trials were identified: (1) radical choice between treatments; (2) patients’ discomfort with randomisation: I want the best treatment for me as an individual; (3) challenge of equipoise: patients’ a priori preferences for treatment; (4) challenge of equipoise: clinicians’ a priori preferences for treatment and (5) imbalanced presentation of interventions.

Conclusion

The marked dichotomy between the surgical and non-surgical interventions was highlighted in this review as making recruitment to these types of trials particularly challenging. This review identified factors that increase our understanding of why patients and clinicians may find equipoise more challenging in these types of trials compared to other trial comparisons. Trialists may wish to consider exploring the balance of potential factors influencing patient and clinician preferences towards treatments before they start recruitment, to enable issues specific to a particular trial to be identified and addressed. This may enable trial teams to make more efficient considered design choices and benefit the delivery of such trials.
Wild populations of malaria vectors can mate both inside and outside human dwellings
Authors: Nambunga Ismail H. , Msugupakulya Betwel J. , Hape Emmanuel E. , Mshani Issa H. , Kahamba Najat F. , Mkandawile Gustav , Mabula Daniel M. , Njalambaha Rukiyah M. , Kaindoa Emmanuel W. , Muyaga Letus L. , Hermy Marie R. G. , Tripet Frederic , Ferguson Heather M. , Ngowo Halfan S. , Okumu Fredros O.
Published: October 2021

Background

Wild populations ofAnophelesmosquitoes are generally thought to mate outdoors in swarms, although once colonized, they also mate readily inside laboratory cages. This study investigated whether the malaria vectorsAnopheles funestusandAnopheles arabiensiscan also naturally mate inside human dwellings.

Method

Mosquitoes were sampled from three volunteer-occupied experimental huts in a rural Tanzanian village at 6:00 p.m. each evening, after which the huts were completely sealed and sampling was repeated at 11:00 p.m and 6 a.m. the next morning to compare the proportions of inseminated females. Similarly timed collections were done inside local unsealed village houses. Lastly, wild-caught larvae and pupae were introduced inside or outside experimental huts constructed inside two semi-field screened chambers. The huts were then sealed and fitted with exit traps, allowing mosquito egress but not entry. Mating was assessed in subsequent days by sampling and dissecting emergent adults caught indoors, outdoors and in exit traps.

Results

Proportions of inseminated females inside the experimental huts in the village increased from approximately  60% at 6 p.m. to approximately 90% the following morning despite no new mosquitoes entering the huts after 6 p.m. Insemination in the local homes increased from approximately 78% to approximately 93% over the same time points. In the semi-field observations of wild-caught captive mosquitoes, the proportions of inseminatedAn. funestuswere 20.9% (95% confidence interval [CI]: ± 2.8) outdoors, 25.2% (95% CI: ± 3.4) indoors and 16.8% (± 8.3) in exit traps, while the proportions of inseminatedAn. arabiensiswere 42.3% (95% CI: ± 5.5) outdoors, 47.4% (95% CI: ± 4.7) indoors and 37.1% (CI: ± 6.8) in exit traps.

Conclusion

Wild populations ofAn. funestusandAn. arabiensisin these study villages can mate both inside and outside human dwellings. Most of the mating clearly happens before the mosquitoes enter houses, but additional mating happens indoors. The ecological significance of such indoor mating remains to be determined. The observed insemination inside the experimental huts fitted with exit traps and in the unsealed village houses suggests that the indoor mating happens voluntarily even under unrestricted egress. These findings may inspire improved vector control, such as by targeting males indoors, and potentially inform alternative methods for colonizing strongly eurygamicAnophelesspecies (e.g.An. funestus) inside laboratories or semi-field chambers.

Graphical Abstract
Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder
Authors: Mahjani Behrang , De Rubeis Silvia , Gustavsson Mahjani Christina , Mulhern Maureen , Xu Xinyi , Klei Lambertus , Satterstrom F. Kyle , Fu Jack , Talkowski Michael E. , Reichenberg Abraham , Sandin Sven , Hultman Christina M. , Grice Dorothy E. , Roeder Kathryn , Devlin Bernie , Buxbaum Joseph D.
Published: October 2021

Background

The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV).

Methods

SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes.

Results

Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy.

Limitations

The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification.

Conclusions

In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD.
Prediction learning in adults with autism and its molecular correlates
Authors: Sapey-Triomphe Laurie-Anne , Temmerman Joke , Puts Nicolaas A. J. , Wagemans Johan
Published: October 2021

Background

According to Bayesian hypotheses, individuals with Autism Spectrum Disorder (ASD) have difficulties making accurate predictions about their environment. In particular, the mechanisms by which they assign precision to predictions or sensory inputs would be suboptimal in ASD. These mechanisms are thought to be mostly mediated by glutamate and GABA. Here, we aimed to shed light on prediction learning in ASD and on its neurobiological correlates.

Methods

Twenty-six neurotypical and 26 autistic adults participated in an associative learning task where they had to learn a probabilistic association between a tone and the rotation direction of two dots, in a volatile context. They also took part in magnetic resonance spectroscopy (MRS) measurements to quantify Glx (glutamate and glutamine), GABA + and glutathione in a low-level perceptual region (occipital cortex) and in a higher-level region involved in prediction learning (inferior frontal gyrus).

Results

Neurotypical and autistic adults had their percepts biased by their expectations, and this bias was smaller for individuals with a more atypical sensory sensitivity. Both groups were able to learn the association and to update their beliefs after a change in contingency. Interestingly, the percentage of correct predictions was correlated with the Glx/GABA + ratio in the occipital cortex (positive correlation) and in the right inferior frontal gyrus (negative correlation). In this region, MRS results also showed an increased concentration of Glx in the ASD group compared to the neurotypical group.

Limitations

We used a quite restrictive approach to select the MR spectra showing a good fit, which led to the exclusion of some MRS datasets and therefore to the reduction of the sample size for certain metabolites/regions.

Conclusions

Autistic adults appeared to have intact abilities to make predictions in this task, in contrast with the Bayesian hypotheses of ASD. Yet, higher ratios of Glx/GABA + in a frontal region were associated with decreased predictive abilities, and ASD individuals tended to have more Glx in this region. This neurobiological difference might contribute to suboptimal predictive mechanisms in ASD in certain contexts.
Long-term survival of cultivated oral mucosal epithelial cells in human cornea: generating cell sheets using an animal product-free culture protocol
Authors: Ma David Hui-Kang , Hsueh Yi-Jen , Ma Kevin Sheng-Kai , Tsai Yueh-Ju , Huang Shiang-Fu , Chen Hung-Chi , Sun Chi-Chin , Kuo Ming-Tse , Chao An-Shine , Lai Jui-Yang
Published: October 2021

Previously, we reported a collagenase-based, animal product-free protocol for cultivated oral mucosal epithelial cell sheets for transplantation (COMET). Here, we reported the long-term outcomes of first 2 clinical cases. A 27-year-old man suffered from thermal burn, which resulted in symblepharon of lower fornix OD. COMET was performed, and the cornea remained clear with few peripheral NV and no more symblepharon 34 months postoperatively. Another 42-year-old man suffered from severe alkaline burn OD. He underwent COMET, followed by corneal transplantation half a year later. A biopsy taken two years after COMET showed stratified epithelium positive for keratin 4, 13, and 3 in the suprabasal layer. Staining for p63 and p75NTR was both positive in the basal layer. The graft remained clear up to post-OP 4 years. Our study confirmed the long-term survival of the transplanted OMECs, suggesting that collagenase-based spheroidal suspension culture is a promising technique for COMET.

Trial registration ClinicalTrials.gov, ClinicalTrials.gov ID: NCT03943797 Registered 9 May 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03943797.
Additional benefit of induced pluripotent stem cell-derived mesenchymal stem cell therapy on sepsis syndrome-associated acute kidney injury in rat treated with antibiotic
Authors: Yang Chih-Chao , Sung Pei‐Hsun , Chen Chih-Hung , Chiang John Y. , Shao Pei-Lin , Wu Shun-Cheng , Yip Hon‐Kan
Published: October 2021

Background

This study tested whether human induced-pluripotent stem-cell-derived mesenchymal-stem-cells (iPS-MSCs) would offer an additional benefit to the rodent with acute kidney injury (AKI) (ischemia for 1 h followed by reperfusion for 120 h) associated sepsis syndrome (SS) (by cecal-ligation-puncture immediately after AKI-induction) undergoing ciprofloxacin therapy.

Results

Male-adult SD rats (n = 80) were categorized into group 1 (sham-operated-control, n = 10), group 2 (AKI + SS, n = 24), group 3 (AKI + SS + ciprofloxacin/3 mg/kg, orally for 120 h, n = 12), group 4 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 3 h after AKI, n = 12), group 5 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 18 h after AKI, n = 12), group 6 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 3 h after AKI induction + ciprofloxacin, n = 10] and euthanized by 120 h. The result showed that the mortality was significantly higher in group 2 than in other groups (all p < 0.01). The creatinine level was highest in group 2, lowest in group 1, significantly lower in group 6 than in groups 3, 4 and 5, (all p < 0.0001), but it showed no difference among the latter 3 groups. Flow cytometric analysis showed that the circulatory inflammatory cells (Ly6G/CD11b/c), early (AN-V+/PI−)/late (AN-V+/PI+) apoptosis, and circulatory/splenic immune cells (CD3+/CD4+, CD3+/CD8a+) were highest in group 2, lowest in group 1, significantly lower in group 6 than in groups 3/4/5 and significantly lower in group 4 than in groups 3/5 (all p < 0.0001), but they showed no difference between groups 3/5. Protein expressions of oxidative-stress (NOX-1/NOX2/oxidized protein), apoptotic (cleaved-caspase3/cleaved-PARP/mitochondrial-Bax), fibrotic (TGF-ß/Smad3), inflammatory (MMP-9/IL-6/TNF-α) and autophagic (Atg5/Beclin) biomarkers in kidney exhibited an identical pattern of circulatory inflammatory cells (all p < 0.0001).

Conclusion

Combined iPS-MSCs-ciprofloxacin therapy was superior to either one alone for protecting AKI complicated by SS.
Therapeutic effects of mesenchymal stem cells-derived extracellular vesicles’ miRNAs on retinal regeneration: a review
Authors: Rajool Dezfuly Ali , Safaee Azadeh , Salehi Hossein
Published: October 2021

Extracellular vesicles (EVs), which consist of microvesicles and exosomes, are secreted from all cells to transform vital information in the form of lipids, proteins, mRNAs and small RNAs such as microRNAs (miRNAs). Many studies demonstrated that EVs’ miRNAs have effects on target cells. Numerous people suffer from the blindness caused by retinal degenerations. The death of retinal neurons is irreversible and creates permanent damage to the retina. In the absence of acceptable cures for retinal degenerative diseases, stem cells and their paracrine agents including EVs have become a promising therapeutic approach. Several studies showed that the therapeutic effects of stem cells are due to the miRNAs of their EVs. Considering the effects of microRNAs in retinal cells development and function and studies which provide the possible roles of mesenchymal stem cells-derived EVs miRNA content on retinal diseases, we focused on the similarities between these two groups of miRNAs that could be helpful for promoting new therapeutic techniques for retinal degenerative diseases.
A redescription of the Late Jurassic (Tithonian) turtle Uluops uluops and a new phylogenetic hypothesis of Paracryptodira
Authors: Rollot Yann , Evers Serjoscha W. , Joyce Walter G.
Published: October 2021

We study the Late Jurassic (Tithonian) turtle Uluops uluops using micro-computed tomography scans to investigate the cranial anatomy of paracryptodires, and provide new insights into the evolution of the internal carotid artery and facial nerve systems, as well as the phylogenetic relationships of this group. We demonstrate the presence of a canalis caroticus lateralis in Uluops uluops, the only pleurosternid for which a palatine artery canal can be confidently identified. Our phylogenetic analysis retrieves Uluops uluops as the earliest branching pleurosternid, Helochelydridae within Pleurosternidae, and Compsemydidae including Kallokibotion bajazidi within Baenidae, which suggests at least two independent losses of the palatine artery within paracryptodires. We expect future studies will provide additional insights into the evolution of the circulation system of paracryptodires, as well as clarifying relationships along the turtle stem.
Review on PRNP genetics and susceptibility to chronic wasting disease of Cervidae
Authors: Moazami-Goudarzi Katayoun , Andréoletti Olivier , Vilotte Jean-Luc , Béringue Vincent
Published: October 2021

To date, chronic wasting disease (CWD) is the most infectious form of prion disease affecting several captive, free ranging and wild cervid species. Responsible for marked population declines in North America, its geographical spread is now becoming a major concern in Europe. Polymorphisms in the prion protein gene (PRNP) are an important factor influencing the susceptibility to prions and their rate of propagation. All reported cervid PRNP genotypes are affected by CWD. However, in each species, some polymorphisms are associated with lower attack rates and slower progression of the disease. This has potential consequences in terms of genetic selection, CWD diffusion and strain evolution. CWD also presents a zoonotic risk due to prions capacity to cross species barriers. This review summarizes our current understanding of CWD control, focusing on PRNP genetic, strain diversity and capacity to infect other animal species, including humans.
Case report of the first cured patient with Mycobacterium Chimaera infection following cardiac valve replacement in the mainland of China
Authors: Lu Di , Zhang Chun-Hong , Chen Li-Jiang , Jin Pei-Feng , Feng Xia-Fei , Zhou Xi , Huang Wei-Cong , Wang Jue , Dai Ying , Fu Yun
Published: October 2021

Background

Mycobacterium chimaera infections subsequent to cardiac surgery are related to contaminated heater-cooler devices, with high mortality. Nevertheless, few studies have been reported in Asia.

Case presentation

We described the case of a 55-year-old man with Mycobacterium chimaera infection following cardiac surgery in the mainland of China. He was diagnosed with endocarditis caused by Mycobacterium chimaera subsequent to open heart surgery. Metagenomic next-generation sequencing (mNGS) and 16S rRNA gene PCR analysis were used to identify potential pathogens. The patient underwent redo valve replacement surgery and received combination therapy with azithromycin, ethambutol, linezolid, and amikacin. No signs of relapse were observed during the 11-month follow-up visit.

Conclusions

This is the first documented case of Mycobacterium chimaera infection following cardiac surgery in the mainland of China and the first documented transnational imported case worldwide. Moreover, mNGS is a novel diagnostic technology that can guide antimicrobial therapy prior to obtaining fluid/tissue culture results for Mycobacterium chimaera, providing a new approach for the detection of potential Mycobacterium chimaera infection.