bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: a study protocol for an open-label phase I/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma
Authors: Mizutani Yasuyuki , Iida Tadashi , Ohno Eizaburo , Ishikawa Takuya , Kinoshita Fumie , Kuwatsuka Yachiyo , Imai Miwa , Shimizu Shinobu , Tsuruta Toshihisa , Enomoto Atsushi , Kawashima Hiroki , Fujishiro Mitsuhiro
Published: February 2022

Background

Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer.

Methods

The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety.

The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II.

Discussion

Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma.

Trial registration

Clinicaltrial.gov: NCT05064618, registered on 1 October 2021.

jRCT: jRCT2041210056, registered on 27 August 2021.
Melatonin for pre-medication in children: a systematic review
Authors: Mellor Katie , Papaioannou Diana , Thomason Anna , Bolt Robert , Evans Chris , Wilson Matthew , Deery Chris
Published: February 2022

Background

Melatonin’s effectiveness as an anxiolytic medication has been confirmed in adults; however, its efficacy in a paediatric population is unclear. A number of small studies have assessed its use in children as a pre-operative anxiolytic, with conflicting results.

Methods

We undertook a systematic review of pre-operative melatonin use in children. Four databases (MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Web of Science), and ‘ClinicalTrials.gov’ were searched for ongoing and completed clinical trials of relevance. Citation tracking reference lists and relevant articles were also accessed. The review was unrestricted by comparator or outcomes. Eleven studies were judged eligible for inclusion. There were high levels of heterogeneity in melatonin administration (in terms of dose and timing). Variable outcomes were reported and included: anxiety; anaesthetic success; analgesia; sedation; post-operative recovery; and safety. Outcomes were not always assessed with the same measures.

Results

Evidence to support melatonin’s anxiolytic properties in this setting is conflicting. Melatonin was associated with reduced sedative effects, post-operative excitement and improved emergence behaviour, compared to comparator drugs. One study reported the benefit of melatonin use on sleep disturbance at two weeks post-surgery. No adverse safety events were identified to be significantly associated with melatonin, affirming its excellent safety profile.

Conclusion

Despite potential advantages, including improved emergence behaviour, based on current evidence we cannot confirm whether melatonin is non-inferior to current “usual care” pre-medications. Further consideration of melatonin as an anxiolytic pre-medication in paediatric surgery is needed.
Stress eating: an online survey of eating behaviours, comfort foods, and healthy food substitutes in German adults
Authors: Gemesi Kathrin , Holzmann Sophie Laura , Kaiser Birgit , Wintergerst Monika , Lurz Martin , Groh Georg , Böhm Markus , Krcmar Helmut , Gedrich Kurt , Hauner Hans , Holzapfel Christina
Published: February 2022

Background

In many people, stress is associated with changes in eating behaviour. Food products consumed during stress (comfort foods) are often unhealthy. It is rather unknown what comfort foods are consumed in Germany and what healthier food products are considered as alternatives to support stress-eaters in making healthier food choices.

Methods

This online survey was conducted in spring 2021 throughout Germany. Participants were digitally recruited by newsletters, homepages, social media, and mailing lists. The survey included a standardized questionnaire with items concerning e.g. sociodemography, stress, and nutrition. Comfort foods were pre-selected through literature search and food substitutes were defined and discussed by experts. Analyses examined comfort food consumption and substitute preferences dependent on sex, age, body mass index (BMI), and being a self-identified stress-eater. The statistical analysis was performed using R.

Results

Survey participants were mostly female (80.6%, 994/1234), had a mean age of 31.4 ± 12.8 years and a mean BMI of 23.4 ± 4.3 kg/m2. Participants stated, that the two favourite comfort foods were chocolate (consumed often/very often by 48.3%, 596/1234) and coffee (consumed often/very often by 45.9%, 566/1234). Regarding food substitutes, the most frequently named alternative food for chocolate and cookies was fresh fruits (for chocolate: 74.4%, 815/1096, for cookies: 62.6%, 565/902). Tea without added sugar (64.4%, 541/840) was the preferred substitute for coffee. Almost 50% of participants (48.1%, 594/1234) identified themselves as stress-eaters, of which 68.9% (408/592) stated to eat (very) often more than usual in subjective stress situations.

Conclusions

The results from this work suggest that specific comfort foods and substitutes are preferred by the participants in stressful situations. This knowledge about food choices and substitutes should be investigated in further studies to improve eating behaviour in stressful situations.

Trial registration

The survey was registered in the German Register of Clinical Studies (Registration number: DRKS00023984).
Evaluation of ‘Shisha No Thanks’ – a co-design social marketing campaign on the harms of waterpipe smoking
Authors: Chan Lilian , El-Haddad Nouhad , Freeman Becky , MacKenzie Ross , Woodland Lisa , O’Hara Blythe J. , Harris-Roxas Ben F.
Published: February 2022

Background

Waterpipe (shisha) is becoming increasingly popular worldwide, particularly among young people; and in some countries, it is one of the few forms of tobacco use that is increasing. While there is a growing body of evidence of the harms of waterpipe smoke, there is a scarcity of research of interventions to address this form of tobacco consumption.

Methods

TheShisha No Thanksproject was a co-design social marketing campaign that aimed to raise awareness of the harms of waterpipe smoking among young people from an Arabic speaking background in Sydney, Australia. The campaign distributed material through social media and community events. We evaluated the project through an SMS community panel using a longitudinal study design. The cohort were sent questions before and after the project asking about their awareness of messages of harms, attitudes, intention to reduce waterpipe smoking, and awareness of support services. Data was analysed as matched pre- post- data.

Results

The evaluation recruited 133 people to the panel. There was a significantly greater proportion of people who reported seeing, hearing or reading something about the harms of waterpipe smoking after the campaign (67.5%) compared with before (45.0%) (p=0.003). Post-campaign, there were higher proportions of people who strongly agreed that waterpipe smoking causes damage, and that it contains cancer-causing substances, but these increases were not statistically significant. There was low awareness of waterpipe cessation services at baseline and post campaign (22.5%).

Conclusions

TheShisha No Thanksproject increased awareness of messages about the harms of waterpipe smoking. Although this is a small study, the longitudinal evaluation findings have international relevance and make a useful contribution to the understanding of the impact such interventions can have in addressing one of the few forms of tobacco use that is growing in both developed and developing countries.
Health system responsiveness and associated factors among outpatients in primary health care facilities in Ethiopia
Authors: Negash Wubshet Debebe , Tsehay Chalie Tadie , Yazachew Lake , Asmamaw Desale Bihonegn , Desta Dawit Zenamarkos , Atnafu Asmamaw
Published: February 2022

Background

Health system responsiveness is defined as the outcome of designing health facility relationships so that they are familiar and responsive to patients’ universally legitimate expectations. Even though different strategies have been implemented to measure responsiveness, only limited evidence exists in Sub-Saharan Africa. In Ethiopia, information about health system responsiveness among outpatients is limited. Assessing responsiveness could help facilities in improving service delivery based on patient expectations.

Objective

The study aimed to assess health system responsiveness and associated factors among outpatients in primary health care facilities, Asagirt District, Ethiopia, 2021.

Methods

Facility-based cross-sectional quantitative study was implemented between March 30 and April 30/2021. A systematic random sampling technique was employed to select 423 participants, and interviewer-administered data were collected using structured and pretested questionnaires. Both bivariable and multivariable logistic regressions were employed to identify factors associated with health system responsiveness. Adjusted Odds Ratio with their corresponding 95% CI was used to declare factors associated with health system responsiveness. Ap-value less than 0.05 was used to declare significant statistical variables.

Results

The overall health system responsiveness performance was 66.2% (95% CI: 61.4—70.7). Confidentiality and dignity were the highest responsive domains. Health system responsiveness was higher among satisfied patients (AOR: 9.9, 95% CI: 5.11–19.46), utilized private clinics (AOR: 8.8, 95% CI: 4.32–18.25), and no transport payment (AOR: 1.7, 95% CI: 1.03–2.92) in the study setting.

Conclusion

Overall, health system responsiveness performance was higher than a case-specific study in Ethiopia. To improve the health systems responsiveness and potentially fulfil patients’ legitimate expectations, we need to facilitate informed treatment choice, provide reasonable care within a reasonable time frame, and give patients the option of consulting a specialist. Aside from that, enhancing patient satisfaction, using input from service users, Collaboration, and exchanging experiences between public and private facilities will be important interventions to improve HSR performance.
Prevalence and WGS-based characteristics of Staphylococcus aureus in the nasal mucosa and pastern of horses with equine pastern dermatitis
Authors: Kaiser-Thom Sarah , Gerber Vinzenz , Collaud Alexandra , Hurni Joel , Perreten Vincent
Published: February 2022

Background

Many contributing factors are involved in the development of equine pastern dermatitis (EPD). Among the most frequently suspected isStaphylococcus aureus, known for its pathogenic potential in skin and soft tissue infections. We therefore investigated the association betweenS. aureuscarriage and EPD.

Results

One hundred five EPD-affected horses and 95 unaffected controls were examined for the presence of methicillin-resistant and -susceptibleStaphylococcus aureus(MRSA and MSSA) on the pastern skin and in the nostrils.S. aureusisolates were cultivated from swab samples on selective MSSA and MRSA chromogenic agar and identified using MALDI-TOF MS. Isolates were analysed by Illumina whole genome sequencing for genetic relatedness (cgMLST,spatyping), and for the presence of antimicrobial resistance and virulence determinants. A markedly higher proportion of samples from EPD-affected horses proved positive forS. aureus, both from the pastern (59.0 % vs. 6.3 % in unaffected horses;P<0.001), and from the nose (59.0 % vs. 8.4 %;P<0.001). Isolates belonged to 20 sequence types (ST) with lineages ST15-t084 (spa) (18 %), ST1-t127 (13 %), and ST1-t1508 (12 %) being predominant. EightS. aureuswere MRSA ST398-t011 and ST6239-t1456, and contained the staphylococcal cassette chromosome SCCmecIVa. Antimicrobial resistance genes were almost equally frequent in pastern and in nasal samples, whereas some virulence factors such as the beta-hemolysin, ESAT-6 secretion system, and some enterotoxins were more abundant in isolates from pastern samples, possibly enhancing their pathogenic potential.

Conclusions

The markedly higher prevalence ofS. aureuscontaining specific virulence factors in affected skin suggests their contribution in the development and course of EPD.
A novel prognostic model for hepatocellular carcinoma based on 5 microRNAs related to vascular invasion
Authors: Chen Wei , Wang Hao , Li Tong , Liu Te , Yang Wenjing , Jin Anli , Ding Lin , Zhang Chunyan , Pan Baishen , Guo Wei , Wang Beili
Published: February 2022

Background

Hepatocellular carcinoma (HCC) is prevalent worldwide with a high mortality rate. Prognosis prediction is crucial for improving HCC patient outcomes, but effective tools are still lacking. Characteristics related to vascular invasion (VI), an important process involved in HCC recurrence and metastasis, may provide ideas on prognosis prediction.

Methods

Tools, including R 4.0.3, Funrich version 3, Cytoscape 3.8.2, STRING 11.5, Venny 2.1.0, and GEPIA 2, were used to perform bioinformatic analyses. The VI-related microRNAs (miRNAs) were identified using Gene Expression Omnibus HCC miRNA dataset GSE67140, containing 81 samples of HCC with VI and 91 samples of HCC without VI. After further evaluated the identified miRNAs based on The Cancer Genome Atlas database, a prognostic model was constructed via Cox regression analysis. The miRNAs in this model were also verified in HCC patients. Moreover, a nomogram was developed by integrating risk score from the prognostic model with clinicopathological parameters. Finally, a potential miRNA-mRNA network related to VI was established through weighted gene co-expression network analysis of HCC mRNA dataset GSE20017, containing 40 samples of HCC with VI and 95 samples of HCC without VI.

Results

A prognostic model of 5 VI-related miRNAs (hsa-miR-126-3p, hsa-miR-148a-3p, hsa-miR-15a-5p, hsa-miR-30a-5p, hsa-miR-199a-5p) was constructed. The area under receiver operating characteristic curve was 0.709 in predicting 5-year survival rate, with a sensitivity of 0.74 and a specificity of 0.63. The nomogram containing risk score could also predict prognosis. Moreover, a VI-related miRNA-mRNA network covering 4 miRNAs and 15 mRNAs was established.

Conclusion

The prognostic model and nomogram might be potential tools in HCC management, and the VI-related miRNA-mRNA network gave insights into how VI was developed.
Novel feature selection method via kernel tensor decomposition for improved multi-omics data analysis
Authors: Taguchi Y-h. , Turki Turki
Published: February 2022

Background

Feature selection of multi-omics data analysis remains challenging owing to the size of omics datasets, comprising approximately$$10^2$$102–$$10^5$$105features. In particular, appropriate methods to weight individual omics datasets are unclear, and the approach adopted has substantial consequences for feature selection. In this study, we extended a recently proposed kernel tensor decomposition (KTD)-based unsupervised feature extraction (FE) method to integrate multi-omics datasets obtained from common samples in a weight-free manner.

Method

KTD-based unsupervised FE was reformatted as the collection of kernelized tensors sharing common samples, which was applied to synthetic and real datasets.

Results

The proposed advanced KTD-based unsupervised FE method showed comparative performance to that of the previously proposed KTD method, as well as tensor decomposition-based unsupervised FE, but required reduced memory and central processing unit time. Moreover, this advanced KTD method, specifically designed for multi-omics analysis, attributesPvalues to features, which is rare for existing multi-omics–oriented methods.

Conclusions

The sample R code is available athttps://github.com/tagtag/MultiR/.
The sustained PGE2 release matrix improves neovascularization and skeletal muscle regeneration in a hindlimb ischemia model
Authors: Huang Haoyan , Chen Shang , Cheng Hui , Cao Jiasong , Du Wei , Zhang Jun , Chang Yuqiao , Shen Xiaohong , Guo Zhikun , Han Zhibo , Hua Guoqiang , Han Zhong-Chao , Benkirane-Jessel Nadia , Chang Ying , Li Zongjin
Published: February 2022

Background

The promising therapeutic strategy for the treatment of peripheral artery disease (PAD) is to restore blood supply and promote regeneration of skeletal muscle regeneration. Increasing evidence revealed that prostaglandin E2 (PGE2), a lipid signaling molecule, has significant therapeutic potential for tissue repair and regeneration. Though PGE2 has been well reported in tissue regeneration, the application of PGE2 is hampered by its short half-life in vivo and the lack of a viable system for sustained release of PGE2.

Results

In this study, we designed and synthesized a new PGE2 release matrix by chemically bonding PGE2 to collagen. Our results revealed that the PGE2 matrix effectively extends the half-life of PGE2 in vitro and in vivo. Moreover, the PGE2 matrix markedly improved neovascularization by increasing angiogenesis, as confirmed by bioluminescence imaging (BLI). Furthermore, the PGE2 matrix exhibits superior therapeutic efficacy in the hindlimb ischemia model through the activation of MyoD1-mediated muscle stem cells, which is consistent with accelerated structural recovery of skeletal muscle, as evidenced by histological analysis.

Conclusions

Our findings highlight the chemical bonding strategy of chemical bonding PGE2 to collagen for sustained release and may facilitate the development of PGE2-based therapies to significantly improve tissue regeneration.

Graphical Abstract
Signaling mechanisms and their regulation during in vivo or in vitro maturation of mammalian oocytes
Authors: Strączyńska Patrycja , Papis Krzysztof , Morawiec Emilia , Czerwiński Michał , Gajewski Zdzisław , Olejek Anita , Bednarska-Czerwińska Anna
Published: February 2022

In vitro fertilization (IVF) is currently one of the most effective methods of infertility treatment. An alternative to commonly used ovarian hyperstimulation can become extracorporeal maturation of oocytes (in vitro maturation; IVM). Fertilization and normal development of the embryo depends on the cytoplasmic, nuclear and genomic maturity of the oocyte. The microenvironment of the ovarian follicle and maternal signals, which mediate bidirectional communication between granulosa, cumulus and oocyte cells, influence the growth, maturation and acquisition of oocyte development capability. During oogenesis in mammals, the meiosis is inhibited in the oocyte at the prophase I of the meiotic division due to the high cAMP level. This level is maintained by the activity of C-type natriuretic peptide (CNP, NPPC) produced by granulosa cells. The CNP binds to the NPR2 receptor in cumulus cells and is responsible for the production of cyclic guanosine monophosphate (cGMP). The cGMP penetrating into the oocyte through gap junctions inhibits phosphodiesterase 3A (PDE3A), preventing cAMP hydrolysis responsible for low MPF activity. The LH surge during the reproductive cycle reduces the activity of the CNP/NPR2 complex, which results in a decrease in cGMP levels in cumulus cells and consequently in the oocyte. Reduced cGMP concentration unblocks the hydrolytic activity of PDE3A, which decreases cAMP level inside the oocyte. This leads to the activation of MPF and resumption of meiosis. The latest IVM methods called SPOM, NFSOM or CAPA IVM consist of two steps: prematuration and maturation itself. Taking into account the role of cAMP in inhibiting and then unblocking the maturation of oocytes, they have led to a significant progress in terms of the percentage of mature oocytes in vitro and the proportion of properly developed embryos in both animals and humans.
Prenatal breastfeeding knowledge, attitude and intention, and their associations with feeding practices during the first six months of life: a cohort study in Lebanon and Qatar
Authors: Naja Farah , Chatila Aya , Ayoub Jennifer J. , Abbas Nada , Mahmoud Amira ,   MINA collaborators, Abdulmalik Mariam Ali , Nasreddine Lara
Published: February 2022

Background

Prenatal knowledge, attitude, and intention related to breastfeeding are postulated as important modulators of feeding practices. Using data from the Mother and Infant Nutritional Assessment (MINA) study, a three year cohort conducted in Lebanon and Qatar, this study aimed to characterize breastfeeding practices during the first six months postnatally and examine their associations with prenatal breastfeeding knowledge, attitude, exposure, and intention.

Methods

Pregnant women during their first trimester were recruited from primary healthcare centers in Beirut and Doha. Data collection was conducted in 2015 − 2018. Participants were followed-up until the child was twoyears old. Exposure, knowledge, attitude, and intentions regarding breastfeeding were assessed during the third trimester of pregnancy (n = 230), using validated questionnaires and scales. Breastfeeding practices were evaluated at four months (n = 185) and six months (n = 151) postpartum. Early initiation of breastfeeding was defined as putting the infant to the breast within one hour of birth, and exclusive breastfeeding (EBF) as feeding exclusively with breast milk.

Results

Breastfeeding practices were as follows: ever breastfeeding: 95.8%; early initiation of breastfeeding: 72.8%; breastfeeding at four and six months: 70.3% and 62.3%; EBF at four and six months: 35.7% and 18.5%. Over 95% of participants had high breastfeeding exposure, and 68.8% had strong / very strong intentions to breastfeed. Only 25% had very good knowledge, and 9.2% reported positive/strong positive attitude towards breastfeeding. After adjustment, high exposure was associated with greater odds of breastfeeding initiation (OR 10.1: 95% CI 1.25, 80.65). Both positive attitude towards breastfeeding and strong intention to breastfeed were associated with EBF at four months (OR 2.51; 95% CI 1.02, 6.16 and OR 4.0; 95% CI 1.67, 9.6), breastfeeding at four months (OR 2.92: 95% CI 1.29, 6.62 and OR 5.00: 95% CI 2.25, 11.1), and breastfeeding at six months (OR 3.74: 95% CI 1.24, 11.32 and OR 8.29: 95% CI 2.9, 23.68).

Conclusions

Findings of this study documented suboptimal knowledge and attitude towards breastfeeding and showed that prior exposure, a positive attitude, and a strong intention to breastfeed prenatally were significant predictors of breastfeeding practices postnatally. This highlights the need to develop specific interventions and policies aimed at improving breastfeeding attitudes and creating an enabling environment that supports women throughout their breastfeeding journey.
MR-guided radiotherapy in node-positive non-small cell lung cancer and severely limited pulmonary reserve: a report proposing a new clinical pathway for the management of high-risk patients
Authors: Eze Chukwuka , Lombardo Elia , Nierer Lukas , Xiong Yuqing , Niyazi Maximilian , Belka Claus , Manapov Farkhad , Corradini Stefanie
Published: February 2022

Introduction

Online MR-guided radiotherapy (MRgRT) is a relatively novel advancement in the field of radiation oncology, ensuring superior soft-tissue visualisation, allowing for online plan adaptation to anatomical and functional interfractional changes and improved motion management. Platinum-based chemoradiation followed by durvalumab is the recommended treatment for stage IIB(N1)/III NSCLC. However, this is only the case for patients with favourable risk factors and sufficient pulmonary function and reserve.

Methods

Herein, we present a technical report on tumour motion and breathing curve analyses of the first patient with node-positive stage IIB NSCLC and severely compromised pulmonary function and reserve [total lung capacity (TLC) 8.78L/132% predicted, residual volume (RV) 6.35L/271% predicted, vital capacity (VC) max 2.43L/58% predicted, FEV1 1.19L/38% predicted, DLCO-SB corrected for hemoglobin 2.76 mmol/min/kPa/30% predicted] treated in a prospective observational study with moderately hypofractionated MRgRT to a total dose of 48.0 Gy/16 daily fractions on the MRIdian system (Viewray Inc, Oakwood, USA).

Results

Radiotherapy was well tolerated with no relevant toxicity. First follow-up imaging at 3 months post-radiotherapy showed a partial remission. The distinctive features of this case are the patient’s severely compromised pulmonary function and the first online MR-guided accelerated hypofractionated radiotherapy treatment for primary node-positive NSCLC.

Conclusions

This technical report describes the first patient treated in a prospective observational study evaluating the feasibility of this relatively novel technology in stage IIB(N1)/III disease, proposing a clinical pathway for the management of high-risk patients.
Optimal time period for blood glucose level evaluation after total knee arthroplasty in patients without diabetes: a prospective, observational study
Authors: Nagashima Masaki , Takeshima Kenichiro , Sasaki Ryo , Aibara Noriyuki , Aomatsu Shuji , Otani Toshiro , Ishii Ken
Published: February 2022

Background

Postoperative hyperglycemia has been reported to be a risk factor for postoperative infection even in patients without diabetes mellitus (DM). However, there is no standard for how long blood glucose level (BGL) monitoring should be performed after total knee arthroplasty (TKA). The purpose of this study was to determine the optimal time period for BGL evaluation after TKA in patients without DM.

Methods

This prospective study included 132 knees of 110 patients who underwent TKA between March 2018 and July 2021 in our hospital. Fasting BGLs were measured preoperatively, at 9:00 PM on the day of surgery (DOS), and at 7:00 AM on postoperative days (PODs) 1, 2, and 3. Patients were divided into two groups with a preoperative hemoglobin A1c (HbA1c) cut-off value of 5.9%, and the BGLs on POD 1 were compared between the two groups.

Results

The BGLs were significantly higher on the DOS, POD 1, and POD 2 than preoperative levels. The BGL was significantly higher on POD 1 than at any other time point. Patients with an HbA1c ≥ 5.9% had significantly higher BGLs than those with an HbA1c < 5.9% on POD 1.

Conclusions

The optimal time period for BGL evaluation after TKA in patients without DM was considered to be from postoperative to POD 2. Patients with an HbA1c ≥ 5.9% may require careful perioperative glycemic control.
The effect of special educational assistance in early childhood education and care on psycho-social difficulties in elementary school children
Authors: Biele Guido , Lekhal Ratib , Overgaard Kristin R. , Vaage Wang Mari , Eek Brandlistuen Ragnhild , Friis Svein , Zeiner Pål
Published: February 2022

Background

Three to seven percent of pre-schoolers have developmental problems or child psychiatric disorders. Randomized controlled trials (RCTs) indicate that interventions in early childhood education and care (ECEC) improve long-term outcomes of children from disadvantaged backgrounds. It is unknown if such effects generalize beyond the well-structured context of RCTs and to children who may not have a disadvantaged background but have developmental problems or psychiatric disorders.

Methods

We used data from the population-based Norwegian Mother, Father and Child Cohort Study, recruiting pregnant women from 1999 to 2009, with child follow-up from ages 6, 18, and 36 months to ages 5, 7, and 8 years. This sub-study included 2499 children with developmental problems or psychiatric disorders at age five. We investigated the effects of special educational assistance at age five on mother-reported internalizing, externalizing, and communication problems at age eight. We analysed bias due to treatment by indication with directed acyclic graphs, adjusted for treatment predictors to reduce bias, and estimated effects in different patient groups and outcome domains with a hierarchical Bayesian model.

Results

In the adjusted analysis, pre-schoolers who received special educational assistance had on average by 0.1 (0.04–0.16) standardised mean deviation fewer psycho-social difficulties in elementary school.

Conclusion

In a sample of children from mostly higher socioeconomic backgrounds we estimate a positive effects of special educational assistance during the transition from preschool to the school years. It may therefore be considered as an intervention for pre-schoolers with developmental or behaviour problems. More research with improved measurements of treatment and outcomes is needed to solidify the findings and identify success factors for the implementation of special educational assistance in ECEC.
Effect of fecal microbiota transplantation on primary hypertension and the underlying mechanism of gut microbiome restoration: protocol of a randomized, blinded, placebo-controlled study
Authors: Fan Luyun , Ren Jie , Chen Youren , Wang Yang , Guo Zihong , Bu Peili , Yang Jinfeng , Ma Wenjun , Zhu Bingpo , Zhao Yanyan , Cai Jun
Published: February 2022

Background

Hypertension is currently the leading modifiable cause of global morbidity and mortality, leading to substantial health and financial burdens. Although multiple studies of management models and innovative therapeutic strategies for hypertension have been conducted, there are still gaps in the field, with a poor control rate reflecting a lack of novel, effective, clinically translated medication or intervention options. Recent animal and human studies repeatedly confirmed a link between the microbiota and hypertension. Of note is our previous study establishing a cause-and-effect relationship between the gut microbiota and blood pressure elevation. A hypothesis of gut microbiota intervention for treating hypertension is thus postulated, and fecal microbiota transplantation (FMT) from healthy donors was performed.

Methods

A multicenter, randomized, placebo-controlled, blinded clinical trial will be performed in 120 grade 1 hypertensive patients for 3 months. All recruited patients will be randomly assigned in a 1:1 ratio to take oral FMT capsules or placebo capsules on day 1, day 7, and day 14 and will be followed up on day 30, day 60, and day 90. The primary outcome is the change in office systolic blood pressure from baseline to day 30. The main secondary outcomes are BP indicators, including changes in systolic and diastolic blood pressure from office and 24-h ambulatory blood pressure monitoring; assessments of ankle-branchial index and pulse wave velocity; profiling of fecal microbial composition and function; profiling of fecal and serum metabolome; changes in levels of blood glucose, blood lipids, and body mass index; and assessment of adverse events as a measure of safety.

Discussion

Expanding upon our previous research on the role of the gut microbiota in the pathogenesis of hypertension, this study serves as a clinical translation advancement and explores the potential of fecal microbiota transplantation for treating hypertension. The underlying mechanisms, particularly the roles of specific microorganisms or their postbiotics in blood pressure amelioration, will also be investigated via multiple approaches, such as metagenomic sequencing and metabolomic profiling.

Trial registration

ClinicalTrials.govNCT04406129. Registered on May 28, 2020
Mononeuritis multiplex as a rare and severe neurological complication of immune checkpoint inhibitors: a case report
Authors: Abdelhakim Safa , Klapholz Jonah D. , Roy Bhaskar , Weiss Sarah A. , McGuone Declan , Corbin Zachary A.
Published: February 2022

Background

Mononeuritis multiplex is a rare autoimmune peripheral neuropathy that typically presents in the context of vasculitis, diabetes, infection, or as a paraneoplastic syndrome. Adverse immune-related neurological conditions have been increasingly reported with the use of immune checkpoint inhibitors against cytotoxic T-lymphocyte antigen-4 and/or the programmed cell death protein 1/programmed death ligand-1 axis. Mononeuritis multiplex has only been reported twice from treatment of cancers with immunotherapy.

Case presentation

Here we report a case of mononeuritis multiplex as a complication of immune checkpoint inhibitor therapy for melanoma. An 80-year-old non-Hispanic white female with recurrent melanoma was treated with combination ipilimumab and nivolumab and subsequently presented with progressive leg weakness, back pain, and difficulty ambulating. The diagnosis of mononeuritis multiplex was made, which was resistant to steroid pulses, chronic steroids, intravenous immunoglobulin, and rituximab. She developed progressive neurologic dysfunction and elected for hospice care. We found only two other cases reported in the literature.

Conclusions

Increased awareness, prompt recognition, and aggressive treatments are likely the best opportunity for improved outcomes in this severe side effect.
MicroRNA regulates the toxicological mechanism of four mycotoxins in vivo and in vitro
Authors: Chen Jia , Yang Shuhua , Li Peng , Wu Aibo , Nepovimova Eugenie , Long Miao , Wu Wenda , Kuca Kamil
Published: February 2022

Mycotoxins can cause body poisoning and induce carcinogenesis, often with a high mortality rate. Therefore, it is of great significance to seek new targets that indicate mycotoxin activity and to diagnose and intervene in mycotoxin-induced diseases in their early stages. MicroRNAs (miRNAs) are physiological regulators whose dysregulation is closely related to the development of diseases. They are thus important markers for the occurrence and development of diseases. In this review, consideration is given to the toxicological mechanisms associated with four major mycotoxins (ochratoxin A, aflatoxin B1, deoxynivalenol, and zearalenone). The roles that miRNAs play in these mechanisms and the interactions between them and their target genes are explained, and summarize the important role of histone modifications in their toxicity. As a result, the ways that miRNAs are regulated in the pathogenicity signaling pathways are revealed which highlights the roles played by miRNAs in preventing and controlling the harmful effects of the mycotoxins. It is hoped that this review will provide a theoretical basis for the prevention and control of the damage caused by these mycotoxins.
Digital technologies to support adolescents with depression and anxiety: review
Authors: Bevan Jones Rhys , Hussain Faris , Agha Sharifah Shameem , Weavers Bryony , Lucassen Mathijs , Merry Sally , Stallard Paul , Simpson Sharon Anne , Rice Frances
Published: February 2022

Depression and anxiety are common in adolescents, but most affected will not get any formal help. Digital mental health technologies (i.e. resources and interventions to support and improve mental health) are a potential way to extend the reach and increase adolescents’ access to therapies, at a relatively low cost. Many young people can access the internet and mobile technologies, including in low- and middle-income countries. There has been increased interest in integrating technologies in a range of settings, especially because of the effect of the COVID-19 pandemic on adolescent mental health, at a time when services are under pressure. This clinical review gives an overview of digital technologies to support the prevention and management of depression and anxiety in adolescence. The technologies are presented in relation to their technological approaches, underlying psychological or other theories, setting, development, evaluations to date and how they might be accessed. There is also a discussion of the potential benefits, challenges and future developments in this field.
PTEN Loss and BRCA1 Promoter Hypermethylation Negatively Predict for Immunogenicity in BRCA-Deficient Ovarian Cancer
Authors: Kraya Adam A. , Maxwell Kara N. , Eiva Monika A. , Wubbenhorst Bradley , Pluta John , Feldman Michael , Nayak Anupma , Powell Daniel J. , Domchek Susan M. , Vonderheide Robert H. , Nathanson Katherine L.
Published: February 2022

PURPOSE

Ovarian cancers can exhibit a prominent immune infiltrate, but clinical trials have not demonstrated substantive response rates to immune checkpoint blockade monotherapy. We aimed to understand genomic features associated with immunogenicity in BRCA1/2 mutation–associated cancers.

MATERIALS AND METHODS

Using the Cancer Genome Atlas whole-exome sequencing, methylation, and expression data, we analyzed 66 ovarian cancers with either germline or somatic loss of BRCA1/2 and whole-exome sequencing, immunohistochemistry, and CyTOF in 20 ovarian cancers with germline BRCA1/2 pathogenic variants from Penn.

RESULTS

We found two groups of BRCA1/2 ovarian cancers differing in their immunogenicity: (1) 37 tumors significantly enriched for PTEN loss (11, 30%) and BRCA1 promoter–hypermethylated (10, 27%; P = .0016) and (2) PTEN wild-type (28 of 29 tumors) cancers, with the latter group having longer overall survival (OS; P = .0186, median OS not reached v median OS = 66.1 months). BRCA1/2-mutant PTEN loss and BRCA1 promoter–hypermethylated cancers were characterized by the decreased composition of lymphocytes estimated by gene expression ( P = .0030), cytolytic index ( P = .034), and cytokine expression but higher homologous recombination deficiency scores ( P = .00013). Large-scale state transitions were the primary discriminating feature ( P = .001); neither mutational burden nor neoantigen burden could explain differences in immunogenicity. In Penn tumors, PTEN loss and high homologous recombination deficiency cancers exhibited fewer CD3+ ( P = .05), CD8+ ( P = .012), and FOXP3+ ( P = .0087) T cells; decreased PRF1 expression ( P = .041); and lower immune costimulatory and inhibitory molecule expression.

CONCLUSION

Our study suggests that within ovarian cancers with genetic loss of BRCA1/2 are two subsets exhibiting differential immunogenicity, with lower levels associated with PTEN loss and BRCA hypermethylation. These genomic features of BRCA1/2-associated ovarian cancers may inform considerations around how to optimally deploy immune checkpoint inhibitors in the clinic.
Clinically relevant orthotopic xenograft models of patient-derived glioblastoma in zebrafish
Authors: Ai Xiaolin , Ye Zengpanpan , Xiao Chaoxin , Zhong Jian , Lancman Joseph J. , Chen Xuelan , Pan Xiangyu , Yang Yu , Zhou Lin , Wang Xiang , Shi Huashan , Zhang Dongmei , Yao Yuqin , Cao Dan , Zhao Chengjian
Published: February 2022

An accurate prediction of the intracranial infiltration tendency and drug response of individual glioblastoma (GBM) cells is essential for personalized prognosis and treatment for this disease. However, the clinical utility of mouse patient-derived orthotopic xenograft (PDOX) models remains limited given current technical constraints, including difficulty in generating sufficient sample numbers from small tissue samples and a long latency period for results. To overcome these issues, we established zebrafish GBM xenografts of diverse origin, which can tolerate intracranial engraftment and maintain their unique histological features. Subsequent single-cell RNA-sequencing (scRNA-seq) analysis confirmed significant transcriptional identity to that of invading GBM microtumors observed in the proportionally larger brains of model animals and humans. Endothelial scRNA-seq confirmed that the zebrafish blood–brain barrier is homologous to the mammalian blood–brain barrier. Finally, we established a rapid and efficient zebrafish PDOX (zPDOX) model, which can predict long-term outcomes of GBM patients within 20 days. The zPDOX model provides a novel avenue for precision medicine of GBM, especially for the evaluation of intracranial infiltration tendency and prediction of individual drug sensitivity.
Discriminating predation attempt outcomes during natural foraging using the post-buzz pause in the Japanese large-footed bat, Myotis macrodactylus
Authors: Mizuguchi Yuuka , Fujioka Emyo , Heim Olga , Fukui Dai , Hiryu Shizuko
Published: February 2022

Bats emit a series of echolocation calls with an increasing repetition rate (the terminal buzz) when attempting to capture prey. This is often used as an acoustic indicator of prey-capture attempts. However, because it is directly linked to foraging efficiency, predation success is a more useful measure than predation attempts in ecological research. The characteristics of echolocation calls that consistently signify predation success across different situations have not been identified. Owing to additional influencing factors, identification of these characteristics is particularly challenging for wild bats foraging in their natural environment compared with those in flight chambers. This study documented the natural foraging behavior of wild Japanese large-footed bats (Myotis macrodactylus) using synchronized acoustic and video recordings. From the video recordings, we could assign 137 attacks to three outcome categories: prey captured (51.8%), prey dropped (29.2%) and failed attempt (19%). Based on previous indications from laboratory studies that the length of the silent interval following the terminal buzz (post-buzz pause) might reflect the prey-capture outcome, we compared post-buzz pause durations among categories of attack outcomes. The post-buzz pause was longest in the case of successful capture, suggesting that the length of the post-buzz pause is a useful acoustic indicator of predation success during natural foraging in M. macrodactylus. Our finding will advance the study of bat foraging behavior using acoustic data, including estimations of foraging efficiency and analyses of feeding habitat quality.
Synthesis of Novel Heteronanographenes via Fold-in Approach
Authors: Tanaka Takayuki
Published: February 2022

The design of the precursor for intramolecular oxidative coupling is a key to construct novel polycyclic compounds. Fold-in type oxidative fusion reactions of heteroaromatic necklace-like molecules have been proved to be a powerful method to afford heteroatom-embedded circulenes and helicenes. The scope and limitation of this unique transformation as well as the intriguing properties of the particular products have been summarized.
Wireless localisation of breast lesions with MagSeed. A radiological perspective of 300 cases
Authors: Constantinidis Fotios , Sakellariou Sophia , Chang Sau Lee , Linder Svetlana , MacPherson Barbara , Seth Subodh , Gill Nicola , Seth Archana
Published: February 2022

Objectives:

The purpose of this article is to review the technical and radiological aspects of MagSeed® localisation, to assess its accuracy based on post-localisation mammograms and excision specimen X-rays and to discuss the radiological experience of our institutions.

Methods:

Two-year data were collected retrospectively from three NHS boards from the West of Scotland. A total of 309 MagSeeds® were inserted under mammographic or ultrasonographic guidance in 300 women with unifocal, multifocal and/or bilateral breast lesions at the day of surgery or up to 30 days prior to it. Radiological review of post-localisation mammograms and intraoperative specimen X-rays as well as a review of the surgical outcomes were performed to assess the accuracy and efficacy of the method. Our experience relating to the technique’s strengths and downsides were also noted.

Results:

The MagSeeds® were inserted on average 7.2 days before surgery. The localisation technique was straight forward for the radiologists. In 99% of the cases, the MagSeed® was successfully deployed and 100% of the successfully localised lesions were excised at surgery. There was no difference in the accuracy of the localisation whether this was mammographically or ultrasonographically guided. On post-localisation mammograms, the MagSeed® was radiologically accurately positioned in 97.3% of the cases. No delayed MagSeed® migration was observed. On the specimen X-rays, the lesion was centrally positioned in 45.1%, eccentric within more than 1 mm from the margin in 35.7% and in 14.8% it was at the specimen’s margin. The re-excision rate was 18.3%.

Conclusion:

The MagSeed® is an accurate and reliable localisation method in breast conserving surgery with good surgical outcomes.

Advances in knowledge:

To our knowledge, the radiological aspects of MagSeed® localisation have not been widely described in peer-reviewed journals thus far.
La médiation linguistique dans le système de certifications de France Education International en Grèce
Authors: Ασφή Μάρθα
Published: February 2022

Η παρούσα εργασία έχει σαν στόχο τη διερεύνηση του ρόλου της γραπτής γλωσσικής διαμεσολάβησης και τις δυνατότητες αξιολόγησης της γλωσσικής επικοινωνιακής δραστηριότητας μέσα στο πλαίσιο ανάπτυξης της πολυγλωσσικής/πολυπολιτισμικής δραστηριότητας και της αλληλοκατανόησης. Η διατριβή αντανακλά τη διαδρομή που διανύσαμε ξεκινώντας από τη θεωρητική μελέτη των εννοιών που σχετίζονται με τη γλωσσική διαμεσολάβηση (αξιολόγηση, πιστοποιήσεις, διαμεσολάβηση, σύνθεση γραπτών κειμένων, αναδιατύπωση, διαγλωσσικές επιδράσεις, υπονοούμενο λόγου, απόκτηση γνώσεων) και συνεχίζοντας με μια μεικτή ανάλυση (ποσοτική και ποιοτική) των γραπτών της εξέτασης παραγωγής γραπτού λόγου (‘Ασκηση 1 : Σύνθεση γραπτών κειμένων) των υποψηφίων στις εξετάσεις για την απόκτηση της πιστοποίησης DALF C1 του France Education International στην Ελλάδα το Μάιο του 2016. Στα πλαίσια αυτής της διαδρομής, μελετήθηκαν οι τάσεις, οι παράγοντες και οι μεταβλητές που καθορίζουν που καθορίζουν τις επιδόσεις των υποψηφίων στην εξέταση της γραπτής διαμεσολάβησης. Στο τέλος αυτής της εργασίας, προτείνεται σχάρα αξιολόγησης της γραπτής διαμεσολάβησης συνοδευόμενη από συμπεράσματα και σκέψεις σχετικά με την οδηγία της σύνθεσης αλλά και με τον ρόλο του διαμεσολαβητή και του γλωσσικού περιβάλλοντος.