bluuebunny/crossref_metadata_2025 huggingface dataset:
Review article: randomised controlled trials in inflammatory bowel disease—common challenges and potential solutions
Authors: Schreiber Stefan , Irving Peter M. , Sharara Ala I. , Martín‐Arranz María Dolores , Hébuterne Xavier , Penchev Plamen , Danese Silvio , Anthopoulos Prodromos , Akhundova‐Unadkat Gamar , Baert Filip
Published: February 2022

Background

Recruitment rates for Crohn’s disease and ulcerative colitis clinical trials continue to decrease annually. The inability to reach recruitment targets and complete trials has serious implications for stakeholders in the inflammatory bowel disease (IBD) community. Action is required to ensure patients with an unmet medical need have access to new therapies to improve the management of their IBD.

Aims

Identify challenges contributing to recruitment decline in IBD clinical trials and propose potential solutions.

Methods

PubMed and Google were used to identify literature, regulatory guidelines and conference proceedings related to IBD clinical trials and related concepts. Data on IBD clinical trials conducted between 1989 and 2020 were extracted from the Trialtrove database.

Results

Key aspects that may improve recruitment rates were identified. An increasingly patient‐centric approach should be taken to study design including improvements to the readability of key trial documentation and inclusion of patient representatives in trial planning. Placebo is unappealing to patients; approaches including platform trials should be explored to minimise placebo exposure. Non‐invasive imaging, biomarkers and novel digital endpoints should continue to be examined to reduce the burden on patients. Reducing the administrative burden associated with trials via the use of electronic signatures, for example, may benefit study sites and investigators. Changes implemented to IBD trials during the COVID‐19 pandemic provided examples of how trial conduct can be rapidly and constructively adapted.

Conclusions

To improve recruitment in Crohn’s disease and ulcerative colitis trials, the IBD community should address a broad range of issues related to clinical trial conduct.
The association of four genetic variants with myelosuppression in gemcitabine‐treated Japanese is not evident in gemcitabine/carboplatin‐treated Swedes
Authors: Björn Niclas , Jakobsen Ingrid , Udagawa Chihiro , Brandén Eva , Koyi Hirsh , Lewensohn Rolf , De Petris Luigi , Zembutsu Hitoshi , Gréen Henrik
Published: February 2022

Gemcitabine/carboplatin‐induced myelosuppressive adverse drug reactions (ADRs) are clinical problems leading to patient suffering and dose alterations. There is a need for personalised medicine to improve treatment effects and patients' well‐being. We tested four genetic variants, rs11141915, rs1901440, rs12046844 and rs11719165, previously suggested as potential biomarkers for gemcitabine‐induced leukopenia/neutropenia in Japanese patients, in 213 Swedish gemcitabine/carboplatin‐treated non‐small cell lung cancer (NSCLC) patients. DNA was genotyped using TaqMan probes and real‐time PCR. The relationships between the risk alleles and low toxicity (non‐ADR: Common Terminology Criteria for Adverse Events [CTCAE] grades 0) or high toxicity (ADR: CTCAE grades 3–4) of platelets, leukocytes and neutrophils were evaluated using Fisher's exact test. The risk alleles did not correlate with myelosuppression, and the strongest borderline significance (not withstanding adjustment for multiple testing) was for rs1901440 (neutropenia, p = 0.043) and rs11719165 (leukopenia, p = 0.049) where the risk alleles trended towards lower toxicity, contrasting with previous study findings. Risk alleles and higher risk scores were more common among our patients. We conclude that the genetic variants do not apply to Swedish patients treated with gemcitabine/carboplatin. However, they can still be important in other populations and cohorts, especially in a gemcitabine monotherapy setting, where the causal genetic variation might influence myelosuppressive ADRs.
Effects of Zuojin Pill (Rhizoma CoptidisandFructus Evodiaepreparation) on the pharmacokinetics and side effects of venlafaxine in humans
Authors: Yan Dongmin , Wu Ming , Hu Wenjuan , Li Yue , Jin Jingyi , Yan Shaoqing , Zhu Wei , Ye Chaoyang , Liu Jia , Liu Guobin , Tan Bo
Published: February 2022

Venlafaxine (VEN), a first‐line antidepressant, and Zuojin Pill (ZJP), a common herbal medicine consisting ofRhizoma CoptidisandFructus Evodiae, are high likely co‐administered in China. ZJP could significantly inhibit VEN pharmacokinetics in vitro and in rats through suppression of CYP2D6 activity. To date, however, no clinical study has demonstrated the clinical relevance. Here, the VEN pharmacokinetics at a single dose of VEN with or without co‐administration of ZJP was compared. ZJP had a weak herb–drug interactions (HDI) on the pharmacokinetics of VEN. The geometric means ofCmaxand AUC0‐∞of VEN increased by 36.7% and 34.6%, respectively, and the corresponding 90% confidence intervals (CIs) of geometric mean ratios (GMRs) exceed outside bioequivalent range of 0.80–1.25. However, the corresponding 90% CIs of GMRs of these parameters for ODV were within the range. Since ODV exposure (AUC), approximately 3.4‐fold higher than that of VEN, hardly changed, the systemic exposure of VEN active moiety (VEN + ODV) with ZJP increased slightly (≤8.5%) compared with that of VEN alone. In addition, the incidence of VEN‐related side effects, especially gastrointestinal relevance, was significantly reduced with ZJP. Therefore, rational concomitant use of VEN and ZJP might have low risk of HDI and be promising in clinical practice.
Primary‐secondary school transition under Covid‐19: Exploring the perceptions and experiences of children, parents/guardians, and teachers
Authors: Bagnall Charlotte Louise , Skipper Yvonne , Fox Claire Louise
Published: February 2022

The transition from primary to secondary school is a major life event for eleven‐year‐old children in the United Kingdom, where they face simultaneous changes. Following the outbreak of Covid‐19, transfer children face additional uncertainty on top of this. Negotiation of the multiple challenges, combined with the reduced support associated with Covid‐19, could have a negative impact on children’s school adjustment and mental health. Given the rapidity of changes associated with Covid‐19, there are key empirical and practical gaps on how best to support children as they negotiate these two key events. To date, there is no published research which has explored the experiences of transfer children, and that of their parents and teachers during this time. The present research aimed to narrow this research gap by answering the research question: What are parents’, children’s, and teachers’ experiences of primary‐secondary school transition during Covid‐19? This research used a series of UK wide surveys to gather data from 101 Year 7 children, 88 Year 7 parents, 26 primary school teachers, and 40 secondary school teachers using a mixture of open and closed questions. The data were analysed using Thematic Framework Analysis, taking an inductive‐open coding approach. All three stakeholders reported negative impacts of Covid‐19 on the transition, for example, in terms of missed opportunities. There were also many comments about the emotional impact of Covid‐19 on children, parents, and teachers. Numerous strategies were reported that were used to meet children’s needs pre and post‐transition, highlighting areas of good practice, along with practical suggestions for how to approach transition in the future. The study has identified ways that transition can be managed more effectively, thus, having short term implications in providing an evidence base to support transfer children this year, and long‐term implications for future transition years.
Karl and Tilla König and the creation of the Camphill Movement
Authors: Jackson Robin
Published: February 2022

The Camphill Movement is one of the largest independent providers of social care for people with a learning disability: there are 119 communities located throughout the world. From the start, the principal aim of the Movement—co‐founded by Dr. Karl König and his wife Tilla (née Maasberg) in Aberdeen—was to build communities in which children and adults with a learning disability could live, learn, and work with others in healthy social relationships. Karl König was born in Leopoldstadt, Vienna on the 25 September 1902 and died on the 27 March 1966 in a Camphill community in Brachenreuthe, Germany. Mathilde Maasberg was born in Gnadenfrei, Silesia, on the 9 March 1902 and died on the 17 September 1983 in the Camphill community of Fairways in South Africa. The paper focuses primarily on the lives of Karl and Tilla König and highlights the key points in their respective biographies. Whilst it is usually the name of Dr. Karl König that is associated with the Camphill Movement, a case is presented here that his wife significantly shaped the essential character of the Camphill way of life. She had been born into a Moravian Brethren settlement and latterly wove a strong, discernible and enduring element of Moravian practice into the fabric of Camphill life and work. Since the deaths of Karl and Tilla König Camphill communities have continued to seek the creation of environments where the economic, social and spiritual aspects of the community life complement one another. The paper identifies six key constituents that it is argued are central to the essence of Camphillness: mutuality, rhythmicity, spirituality, tranquillity, ecological sensitivity and economic sustainability. The paper ends with reflections on the 21st Century relevance of Camphill communities.
Voices from parents on the sexuality of their child with intellectual disabilities: A socioemotional perspective in a Chinese context
Authors: Lam Angus , Yau Matthew K. , Franklin Richard C. , Leggat Peter A.
Published: February 2022

Background

This qualitative study explored the attitudes and experiences of Hong Kong Chinese parents/carers relating to the sexual needs of their child with intellectual disabilities.

Methods

Semi‐structured interviews were conducted in Hong Kong with seven parents/carers applying Interpretative Phenomenological Analysis to explore their experiences of and attitudes towards the sexual needs of their adult child with intellectual disabilities.

Findings

Data revealed three salient variations in participants' attitudes towards the child's sexual needs: concern, reluctance and prohibition. Participants' anxiety about discussing sexuality was evident. Most participants further displayed a layer of feeling that combined ‘love’ and ‘grief’. Based on Goffman's dramaturgical perspective, participants exhibited front stage and back stage behaviours that are believed to be strongly influenced by stigmatisation and collectivist culture.

Conclusion

Various levels of intervention to reduce stigma are identified and discussed. This study also highlighted the role of caring professionals in generating awareness of the cultural impact on the family and the need to carefully address the subtle feelings experienced by family members with intellectual disabilities.
‘In the circumstances I think we've all managed really well’ an exploration of the impact of the COVID‐19 restrictions on a Child Development Advisor (Portage) Service
Authors: Higgs Pippa , McElwee Jennifer
Published: February 2022

Background

The Child Development Advisor (CDA)  (Portage) service provides developmental support to children with significant developmental delays and emotional support for their families through fortnightly home visits. However, the onset of the COVID‐19 pandemic and subsequent restrictions imposed to control its spread prevented services from providing face‐to‐face sessions with families and caregivers, thus removing the CDA (Portage) service's primary means of supporting children and their families. This article aims to explore the impact of those changes on a team of CDAs.

Methods

Semi‐structured interviews were conducted with six CDAs representing the CDA (Portage) service within one NHS Health Board.

Findings

The CDAs expressed feeling an initial negative impact of the COVID‐19 restrictions on the service, but in the longer term they noticed a number of positive impacts, including caregiver empowerment and improved working with other professionals.

Conclusion

Despite having their primary means of providing support removed as part of the COVID‐19 restrictions, the service has been able to adapt to continuously support families and promote child development throughout the pandemic and inadvertently developed a service offer that may be more beneficial for both families and professionals in the future.
Trauma‐specific treatment among individuals with intellectual/developmental disabilities: A case series with progressive counting
Authors: Keesler John M. , McCoy Pamela , Wiltz James
Published: February 2022

Background

Individuals with intellectual/developmental disabilities are vulnerable to potentially traumatic events and trauma sequelae. Despite ongoing advances surrounding trauma and intellectual/developmental disabilities, trauma‐specific treatments are needed for people with intellectual/developmental disabilities. This study explores the first implementation of Progressive Counting (PC), a novel trauma treatment, with people with intellectual/developmental disabilities.

Methods

A case series with descriptive analyses was used to explore the implementation and effectiveness of PC among four adults with intellectual/developmental disabilities and trauma histories.

Findings

PC was associated with reductions in symptoms and increased quality of life. Although individual experiences required modest adaptations to the intervention, PC was generally well‐tolerated and required a limited number of treatment sessions.

Conclusions

PC demonstrates promise as a trauma‐specific treatment. Additional research with increased methodological rigor is warranted to further establish its efficacy. Recommendations for future research and practice are provided.
Remarkable properties for diagnostics and inference of ranking data modelling
Authors: Mollica Cristina , Tardella Luca
Published: February 2022

The Plackett‐Luce model (PL) for ranked data assumes the forward order of the ranking process. This hypothesis postulates that the ranking process of the items is carried out by sequentially assigning the positions from the top (most liked) to the bottom (least liked) alternative. This assumption has been recently relaxed with the Extended Plackett‐Luce model (EPL) through the introduction of the discrete reference order parameter, describing the rank attribution path. By starting from two formal properties of the EPL, the former related to the inverse ordering of the item probabilities at the first and last stage of the ranking process and the latter well‐known as independence of irrelevant alternatives (or Luce's choice axiom), we derive novel diagnostic tools for testing the appropriateness of the EPL assumption as the actual sampling distribution of the observed rankings. These diagnostic tools can help uncovering possible idiosyncratic paths in the sequential choice process. Besides contributing to fill the gap of goodness‐of‐fit methods for the family of multistage models, we also show how one of the two statistics can be conveniently exploited to construct a heuristic method, that surrogates the maximum likelihood approach for inferring the underlying reference order parameter. The relative performance of the proposals, compared with more conventional approaches, is illustrated by means of extensive simulation studies.
Molecular dynamic and pharmacological studies on protein‐engineered hirudin variants of Hirudinaria manillensis and Hirudo medicinalis
Authors: Sun Yan , Wang Baochun , Pei Jinli , Luo Ying , Yuan Nan , Xiao Zhengpan , Wu Hao , Luo Chenghui , Wang Jiaxuan , Wei Shuangshuang , Pei Yechun , Fu Shengmiao , Wang Dayong
Published: February 2022

Background and Purpose

Hirudin variants are the most powerful thrombin inhibitors discovered to date, with a lower risk of bleeding than heparin. For anticoagulation, the C‐termini of hirudin variants bind to the exocite I of thrombin. Anticoagulant effects of gene‐recombinant hirudin are weaker than natural hirudin for the reason of lacking tyrosine O‐sulfation at C‐terminus.

Experimental Approach

An integrative pharmacological study was carried out using molecular dynamic, molecular biological and in vivo and in vitro experiments to elucidate the anticoagulant effects of protein‐engineered hirudins.

Key Results

Molecular dynamic analysis showed that modifications of the C‐termini of hirudin variant 1 of Hirudo medicinalis (HV1) and hirudin variant 2 of Hirudinaria manillensis (HM2) changed the binding energy of the C‐termini to human thrombin. The study indicated that Asp61 of HM2 that corresponds to sulfated Tyr63 of HV1 is critical for inhibiting thrombin activities. Further, the anticoagulant effects of HV1 and HM2 were improved when the amino acid residues adjacent to Asp61 were mutated to Asp. These improvements were prolongation of the activated partial thromboplastin time, prothrombin time and thrombin time of human blood, and decreased Ki and IC50 values. In the in vivo experiments, mutations at C‐termini of HV1 and HM2 significantly changed partial thromboplastin time, prothrombin and thrombin time

Conclusion and Implications

The study indicated that the anticoagulant effects of gene‐engineered HM2 are stronger than gene‐engineered HV1 and HM2‐E60D‐I62D has the strongest effects and could be an antithrombotic with better therapeutic effects.
CHIP‐associated mutant ASXL1 in blood cells promotes solid tumor progression
Authors: Liu Xiaoxiao , Sato Naru , Shimosato Yuko , Wang Teh‐Wei , Denda Tamami , Chang Yu‐Hsuan , Yabushita Tomohiro , Fujino Takeshi , Asada Shuhei , Tanaka Yosuke , Fukuyama Tomofusa , Enomoto Yutaka , Ota Yasunori , Sakamoto Takeharu , Kitamura Toshio , Goyama Susumu
Published: February 2022

Clonal hematopoiesis of indeterminate potential (CHIP) is an age‐associated phenomenon characterized by clonal expansion of blood cells harboring somatic mutations in hematopoietic genes, including DNMT3A, TET2, and ASXL1. Clinical evidence suggests that CHIP is highly prevalent and associated with poor prognosis in solid‐tumor patients. However, whether blood cells with CHIP mutations play a causal role in promoting the development of solid tumors remained unclear. Using conditional knock‐in mice that express CHIP‐associated mutant Asxl1 (Asxl1‐MT), we showed that expression of Asxl1‐MT in T cells, but not in myeloid cells, promoted solid‐tumor progression in syngeneic transplantation models. We also demonstrated that Asxl1‐MT–expressing blood cells accelerated the development of spontaneous mammary tumors induced by MMTV‐PyMT. Intratumor analysis of the mammary tumors revealed the reduced T‐cell infiltration at tumor sites and programmed death receptor‐1 (PD‐1) upregulation in CD8+ T cells in MMTV‐PyMT/Asxl1‐MT mice. In addition, we found that Asxl1‐MT induced T‐cell dysregulation, including aberrant intrathymic T‐cell development, decreased CD4/CD8 ratio, and naïve‐memory imbalance in peripheral T cells. These results indicate that Asxl1‐MT perturbs T‐cell development and function, which contributes to creating a protumor microenvironment for solid tumors. Thus, our findings raise the possibility that ASXL1‐mutated blood cells exacerbate solid‐tumor progression in ASXL1‐CHIP carriers.
Tumor‐penetrating peptide internalizing RGD enhances radiotherapy efficacy through reducing tumor hypoxia
Authors: Meng Fanyan , Liu Jun , Wei Jia , Yang Ju , Zhou Chong , Yan Jing , Liu Baorui
Published: February 2022

Resistance to irradiation (IR) remains a major therapeutic challenge in tumor radiotherapy. The development of novel tumor‐specific radiosensitizers is crucial for effective radiotherapy against solid tumors. Here, we revealed that remodeling tumor tissue penetration via tumor‐penetrating peptide internalizing arginine–glycine–aspartic acid RGD (iRGD) enhanced irradiation efficacy. The growth of 4T1 and CT26 multicellular tumor spheroids (MCTS) and tumors was delayed significantly by the treatment with IR and iRGD. Mechanistically, iRGD reduced hypoxia in MCTS and tumors, resulting in enhanced apoptosis after MCTS and tumors were treated with IR and iRGD. This is the first report that shows enhanced radiation efficacy by remodeling tumor‐specific tissue penetration with iRGD, implying the potential clinical application of peptides in future tumor therapy.
Twelve‐month evaluation of a novel mineral–organic adhesive material used to stabilize dental implants placed in oversized osteotomies in vivo in an animal model
Authors: Cochran David L. , Jones Archie A. , Sugita Ryushiro , Brown Michael C. , Prasad Hari , Kay George W.
Published: February 2022

Objectives

The aim of this study is to evaluate long‐term in vivo stability of dental implants stabilized at time of placement in oversized osteotomies with a novel, self‐setting, mineral–organic bone adhesive.

Materials/Methods

Canine (26) mandibular teeth were removed, and three oversized osteotomies prepared bilaterally. Implants were placed with either adhesive, particulate xenograft, or with blood clot filling the implant/osteotomy gaps. Removal torque and histology were assessed.

Results

The adhesive provided significant and clinically relevant immediate implant stability of 22.2 N‐cm (95% CI 5.3; 39.0), which continued throughout the early postoperative course and persisted through the nine‐ (155 N‐cm 95% CI 113; 197) and 12‐month (171 N‐cm 95% CI 134.2; 209.4) time points. This is in comparison with the blood clot of 1.4 N‐cm (95% CI 0.7; 2.1), 128.6 N‐cm (95% CI 66.8; 190.4), and 140.7 N‐cm (95% CI 78.8; 202.5) and particulate xenograft, 1.3 N‐cm (95% CI 0.6; 2.0), 132.1 N‐cm (95% CI 94.5; 169.7), and 101.5 (95% CI 59.5; 143.5), respectively. Histological examination shows the adhesive establishes intimate contact with the implant and bony walls and is replaced with new bone without compromising stability. Soft tissue does not penetrate the adhesive, and marginal bone/biomaterial level is maintained. Control sites filled with xenograft or blood clot heal with reduced bone levels, and in some cases, xenograft particles were encapsulated in connective tissue.

Conclusions

Implants placed in oversized osteotomies and lacking primary stability can be stabilized at placement with a novel, highly osteoconductive, and resorbable adhesive. Gradual replacement of the biomaterial allows osseointegration without loss of stability through 12 months of follow‐up. This novel adhesive has the potential to stabilize implants placed in sites with inadequate bony support.
Is sacral nerve modulation reprogramming effective after permanent implantation for faecal incontinence?
Authors: Desprez Charlotte , Grange Audrey , Gourcerol Guillaume , Deperrois Alexis , Garçonnet Oriane , Leroux Clémence , Mosni Grégory , Poux Laurence , Breemeersch Justine , Goblot Cécile , Kepka Sébastien , Ruillon Julie , Vannier Margot , Bridoux Valérie , Leroi Anne‐Marie
Published: February 2022

Aim

Sacral nerve modulation (SNM) is recommended as a first‐line surgical therapy for patients with faecal incontinence (FI). During patient follow‐up, it is recommended that stimulation settings be reprogrammed to optimize patient outcomes. The aim of the present study was to evaluate the efficacy of stimulator reprogramming in patients with an implanted SNM device to treat FI.

Method

The data from patients who received a permanent SNM implant in a single centre from January 2008 to December 2019 were retrospectively analysed. Symptoms that occurred after implantation, the stimulator settings of the SNM device and changes made at each follow‐up visit were noted. The efficacy of reprogramming was determined by assessing patient satisfaction.

Results

Of the 117 patients (male/female 4/113; mean age 59.5 ± 11.8 years) with a SNM implant for FI, 84 (72%) had at least one symptom requiring reprogramming of the stimulator, most often during the first year after implantation (p = 0.05). The most frequently reported symptoms were loss of efficacy (68.5%; p = 1 × 10−3) and pain (20.5%; p = 1 × 10−3). Reprogramming was effective 53% of the time when treating loss of efficacy and 76% of the time when treating pain. When the stimulation parameters were reprogrammed at least four consecutive times to correct a symptom, the reprogramming was less effective in treating the symptom (p = 0.02).

Conclusion

Regular follow‐up of patients with SNM device implants associated with reprogramming of stimulation parameters to improve the treatment of reported symptoms would optimize the efficacy of SNM.
Laparoscopic ovarian transposition in teenage and young women with locally advanced rectal cancer: Respite amidst cancer chaos
Authors: Shylasree Thumkur S. , Singh Pooja , Kazi Mufaddal , Gupta Stuti , Engineer Reena , Patil Prachi S. , DeSouza Ashwin , Saklani Avanish
Published: February 2022

Aim

Ovarian transposition is an established surgical technique to salvage ovaries in premenopausal women requiring pelvic radiation. The success rate of ovarian transposition varies widely depending on the route, technique of surgery, type of cancer and treatment. Here, we aimed to analyse the effectiveness of laparoscopic ovarian transposition (LOT) in teenage and young women prior to pelvic radiation in locally advanced rectal cancers (LARC).

Methods

Patients who underwent LOT for rectal cancers were retrieved from a prospectively maintained database from June 2013–September 2019. Disease characteristics, return of menstrual function and oncological outcomes were analysed.

Results

A total of 46 women with a mean age of 25.2 years who underwent LOT at the cancer centre were included in the study. Seventy percent were nulliparous. All patients were fit for discharge by 24 h. Mean time to start radiation was 19.6 days (range 3–47 days). Median follow‐up of patients was 42 months. A total of 41 patients were assessable for ovarian function, 65.5% had resumption of menses. Median ovarian survival was 79 months and 5‐year ovarian survival was 54%. Median overall survival from rectal cancer was 51 months.

Conclusion

Laparoscopic ovarian transposition is a safe and effective technique of ovarian protection from the gonadotoxic effects of pelvic radiation in LARC. It does not delay primary treatment and does not compromise oncological outcomes. Long‐term follow‐up is required to evaluate fertility and quality of life.
Robotic abdominal resection of tailgut cysts – A technical note with step‐by‐step description
Authors: Solís‐Peña Alejandro , Ngu Lena W. S. , Kraft Carré Miquel , Gomez Jurado María José , Vallribera Valls Francesc , Pellino Gianluca , Espin‐Basany Eloy
Published: February 2022

Aim

Here, we describe a step‐by‐step standardized technique for tailgut cyst resection using a single‐docking robotic approach.

Method

Each step of the technique is illustrated using a composite collection of four operative patient videos to demonstrate the advantages and feasibility of this technique. The robot platform utilised is Da Vinci Xi.

Results

Five female patients have undergone this operation in our unit. The size of tumours ranged from 12 to 45 mm. Median operating time was 100 min (range 90–150). Mean blood loss in all the patients was less than 50 ml. There were no major intraoperative complications. One patient had a postoperative presacral collection which required radiological drainage. Length of stay in all patients was one day.

Conclusions

This technique using a single‐docking robotic approach appears safe and feasible. The robotic approach results in improved dexterity and more accurate dissection, better retraction and excellent vision which improves the ease of operating in the pelvis. Therefore, this approach can be replicated for use in a wide variety of patients with tailgut cysts.
Safety, tolerability, and pharmacokinetics of single and multiple topical ophthalmic administration of imatinib mesylate in healthy subjects
Authors: Na Joo Young , Huh Ki Young , Yu Kyung‐Sang , Hyon Joon Young , Koo Hye Cheong , Lee Jong Ho , You Ji Chang , Chung Jae‐Yong
Published: February 2022

For the long‐term efficacy of dry eye disease treatment, relieving underlying inflammation is necessary. Imatinib mesylate is a novel ophthalmic formulation of imatinib mesylate, which is expected to alleviate inflammation by inhibiting the discoidin domain receptor 1 activity. This study aims to evaluate the safety and pharmacokinetics of imatinib mesylate in healthy subjects. A randomized, double‐blind, placebo‐controlled study was conducted. In a single ascending dose, 16 subjects received a single eye drop of imatinib mesylate 0.1%, 0.3%, or matching placebo. In the multiple ascending dose (MAD), subjects received multiple eye drops of imatinib mesylate 0.1%, 0.3%, or matching placebo once daily for 7 days. Safety and tolerability were assessed by ophthalmic examination, including the visual analog scale (VAS) to monitor the burning sensation in the eyes. A total of four treatment‐emergent adverse events (TEAEs) occurred during the study. All TEAEs were mildly severe with no serious cases. VAS results in the 0.1% MAD group exhibited highest score of two points, whereas it was less than one point in others. Insignificant difference between the imatinib mesylate and placebo groups in the VAS results was seen. After a single dose administration of imatinib mesylate 0.1%, all plasma concentrations were below the lower limit of quantification. The peak plasma concentrations of imatinib were less than 0.54 µg/L in all groups. In conclusion, a single and multiple topical ophthalmic administration of imatinib mesylate was well‐tolerated in healthy subjects. Because there was minimal systemic exposure to imatinib, the adverse effect in the body seems to be insignificant.
Anomalous right ventricular muscle bands obstructing a large apical muscular ventricular septal defect: From fetal to post‐natal three‐dimensional assessment
Authors: Farruggio Silvia , Caruso Elio
Published: February 2022

Anomalous right ventricle muscle bands and apical ventricular septal defect are two anomalies sometimes associated. We report a fetal diagnosis of a large apical ventricular septal defect, right intraventricular obstruction caused by anomalous muscle bands; consequently, the high right intraventricular pressure resulted in a right‐to‐left bulging of ventricular septum and moderate tricuspid regurgitation. Postnatal echocardiogram confirmed the fetal diagnosis and defined accurately the right ventricular anatomy through the three‐dimensional echocardiographic assessment.
Assessment model blending formative and summative assessments using the SOLO taxonomy
Authors: Svensäter Gunnel , Rohlin Madeleine
Published: February 2022

Introduction

Formative assessment with emphasis on feedback has been linked to developmental purposes of assessment, whilst summative assessment is assumed to focus on judgemental and quality assurance purposes. This dichotomy is questioned but designs to blend formative and summative assessments in constructive ways are rare in health care education.

Materials and Methods

We have designed an assessment model blending formative and summative assessments. In the formative assessment at the end of a course, students’ responses to real‐life scenarios with questions demanding responses at the relational level of understanding were assessed at three levels of understanding (incorrect, descriptive and relational) modified after the SOLO taxonomy. Students were presented with individual feedback for each response. At the summative assessment of a subsequent course, the students’ new responses were assessed underpinning a final judgement of students’ performance. The assessment model was justified across three student cohorts.

Results

Both formative and summative assessment events of the model provided information about the levels of understanding, unique to each student. A comparison of results from the assessments demonstrated that most responses developed to a higher level of understanding. With the summative assessment, it was possible to make judgements about whether or not individual students passed the pre‐set standards.

Conclusions

We argue that the current assessment model presents real interdependence between formative and summative assessments and can provide information that meets the needs of students as learners, education institutes and health care organisations. The SOLO taxonomy can be used to emphasise the importance of developing and assessing cognitive complexity.
Interacting global change drivers suppress a foundation tree species
Authors: Flory S. Luke , Dillon Whalen , Hiatt Drew
Published: February 2022

Ecological stress caused by climate change, invasive species and anthropogenic disturbance is driving global environmental change, but how these stressors interact to impact native species are poorly understood. We used a field experiment to test how two stressors (drought and plant invasion byImperata cylindrica) interacted to determine the effects of a third stressor (fire) on a foundation tree species (Pinus palustris). The invasion combined with prolonged drought resulted in shorter trees than invasion alone. The invasion also resulted in 65% greater fuel loads, four times taller flames, greater maximum temperatures and longer heating duration. Consequently, nearly all tree mortality occurred due to a synergistic interaction between the drought + invasion treatment and fire, where invasion caused taller flames that impacted trees that were shorter due to drought. These findings demonstrate that synergy amongst ecological stressors can dramatically impact native species, with significant implications for forecasting the effects of multiple stressors under global change.
Sulfasalazine decreases astrogliosis‐mediated seizure burden
Authors: Alcoreza Oscar , Jagarlamudi Sai , Savoia Andrew , Campbell Susan L. , Sontheimer Harald
Published: February 2022

Objective

Previously, we reported that inhibition of the astrocytic cystine/glutamate antiporter system xc‐ (SXC), using sulfasalazine (SAS), decreased evoked excitatory signaling in three distinct hyperexcitability models ex vivo. The current study expands on this work by evaluating the in vivo efficacy of SAS in decreasing astrogliosis‐mediated seizure burden seen in the beta‐1 integrin knockout (B1KO) model.

Methods

Video‐EEG (electroencephalography) monitoring (24/7) was obtained using Biopac EEG acquisition hardware and software. EEG spectral analysis was performed using MATLAB. SAS was used at an equivalence of doses taken by Crohn’s disease patients. Whole‐cell patch‐clamp recordings were made from cortical layer 2/3 pyramidal neurons.

Results

We report that 100% of B1KO mice that underwent 24/7 video‐EEG monitoring developed spontaneous recurrent seizures and that intraperitoneal administration of SAS significantly reduced seizure frequency in B1KOs compared to B1KOs receiving sham saline. Spectral analysis found an acute reduction in EEG power following SAS treatment in B1KOs; however, this effect was not observed in nonepileptic control mice receiving SAS. Finally, whole‐cell recordings from SXC knockout mice had hyperpolarized neurons and SXC‐B1 double knockouts fired significantly less action potentials in response to current injection compared to B1KOs with SXC.

Significance

To devise effective strategies in finding relief for one‐in‐three patients with epilepsy who experience drug‐resistant epilepsy we must continue to explore the mechanisms regulating glutamate homeostasis. This study explored the efficacy of targeting an astrocytic glutamate antiporter, SXC, as a novel antiepileptic drug (AED) target and further characterized a unique mouse model in which chronic astrogliosis is sufficient to induce spontaneous seizures and epilepsy. These findings may serve as a foundation to further assess the potential for SAS or inform the development of more potent and specific compounds that target SXC as a novel treatment for epilepsy.
The Ecumenical Factor in African Theology and Ecclesiology
Authors: Maluleke Tinyiko
Published: February 2022

In addition to the continental and national councils of churches and ecumenical theological institutions, Black and African theologies are some of the most ecumenical initiatives in Africa. This article explores the ecumenical factor in the emergence and the continued flourishing of Black and African theologies. Notably, these theologies have, from their earliest days, endeavoured to include indigenous religions and cultures as well as environmental issues. This essay also outlines a sample of the most prominent types of ecumenical theologies in contemporary Africa, arguing that these theologies are simultaneously the result of an ecumenical outlook and the greatest advocates for ecumenism in Africa.
Propositions on Ecumenicity
Authors: Pedroso Mateus Odair
Published: February 2022

The 14 propositions in this article were prepared for the opening session of the international online consultation “Teaching Ecumenism in the Context of World Christianity,” organized in June 2021 by the Ecumenical Institute at Bossey and related programme units in the World Council of Churches. They were drafted as a discussion starter, based on two observations: the first is that the notion of “World Christianity,” in the sense that it is understood in the title of the conference, presupposes a critical reference to the interrelated Eurocentric projects of global modernization and Christianization; the second is the truism that the understanding of ecumenicity and the teaching of ecumenism are interwoven.
A miniaturized thin‐plate low cycle fatigue test method at elevated temperature
Authors: Li Ming , Maskill Shane , Wen Zhixun , Yue Zhufeng , Sun Wei
Published: February 2022

This study aims to develop a high‐temperature low cycle fatigue test method using a nonstandard miniature thin‐plate specimen in order to characterize the cyclic viscoplasticity behavior of a component material. For demonstration, fully reversed strain‐range controlled low cycle fatigue and creep‐fatigue tests at 600°C have been performed for a martensitic steel using standard‐sized full‐scale specimens and miniaturized thin‐plate specimens, respectively. Because the displacement is not directly measured from the uniform gauge section of the miniaturized specimen, a geometry‐dependent scaling factor is obtained and used to convert the uniaxial strain. The results obtained are shown that the miniaturized test method developed in this work has exhibited a clear possibility to produce comparable low cycle fatigue data with those that are normally obtained by conventional standard specimen tests.
Haemophilia management and treatment: An Italian survey on patients’, caregivers’ and clinicians’ point of view
Authors: Cortesi Paolo Angelo , Rocino Angiola , Preti Daniele , Fragomeno Anna , Cucuzza Francesco , Ceresi Nicola , Santoro Cristina , Ferretti Antonietta , Fornari Arianna , Antonazzo Ippazio Cosimo , Facchetti Rita , Cozzolino Paolo , Biasoli Chiara , Cassone Cristina , Coppola Antonio , Mantovani Lorenzo G.
Published: February 2022

Introduction: Haemophilia management and patients’ quality of life significantly improved. However, data on current patients’, caregivers’ and clinicians’ satisfaction and limitations of treatments and haemophilia management are limited.

Aim: Assessing the management satisfaction and unmet needs from the perspective of Italian patients with haemophilia (PWH) without inhibitors (or caregivers if children) and of specialist physicians.

Methods: Surveys (for patients≥18 years, caregivers of children and haemophilia specialists) were developed by a multidisciplinary working group and conducted from November 2019 to June 2020.

Results: Among 275 participants, 120 (43.6%) were PWH without inhibitors, 79 (28.7%) caregivers and 37 (13.4%) clinicians. Patients and caregivers perceived a higher control of the disease compared to clinicians. However, more than 40% of patients and caregivers reported to feel significantly conditioned by the risk of bleeding during their daily life. PWH reported a 6‐month mean/median (range) of bleeds 2.3/.0 (0‐24) and caregivers 1.3/.0 (0‐16) in children. The treatment burden (frequency of administration) was not satisfactory for more than half adults and caregivers of children treated with prophylaxis. A good access to treatment, haemophilia centres and medical service was reported, with issues associated to the multidisciplinary approach and treatment at emergency department.

Conclusions: This large national study provides an updated overview of haemophilia care in Italy from different points of views, highlighting positive aspects and unmet needs. This information can guide future interventions to improve haemophilia management and the assessment of impact of new treatment options.
Considerations for cutaneous physiologic changes of pregnancy that fail to resolve postpartum
Authors: Anzelc Madison J. , Bechtel Mark A.
Published: February 2022

Pregnancy prompts many adaptive and unique physiologic modifications, with cutaneous changes being possibly the most noticeable. These cutaneous changes are of interest to physicians, since they must be diagnosed as anticipated normal physiologic changes or potentially harmful and managed accordingly. Research has been conducted on physiologically normal and abnormal cutaneous manifestations of pregnancy but is lacking in regard to the persistence of these changes after delivery. This prompts the question as to whether these are normal physiologic changes taking longer to resolve, abnormal changes that may have been previously misdiagnosed, or a separate underlying change that is incorrectly attributed to a common dermatosis caused by pregnancy. Some of the conditions that may persist longer than expected during or after pregnancy, and thus require further workup for an underlying condition, include telogen effluvium, severe hirsutism, palmar erythema, and striae. The objective of this review is to focus on these four common cutaneous physiologic changes of pregnancy, and what to consider when they do not resolve as expected.
Impact of oleuropein on rheology and breadmaking performance of wheat doughs, and functional features of bread
Authors: Renoldi Niccolò , Lucci Paolo , Peressini Donatella
Published: February 2022

Oleuropein (OP) is a polyphenol present in drupes and leaves of olive tree with health benefits and, as antioxidant, potentiality to alter gluten functionality. Effects of OP inclusion to wheat flour (0.01% and 0.02% on flour weight basis) on dough rheology and breadmaking performance, and bread features were investigated. Farinograph, uniaxial extension and shear rheometry (oscillatory and creep‐recovery) were applied. Doughs containing OP were stronger, more elastic, and less sticky indicating the ability of OP to act as flour improver. The strengthening effect of OP on gluten led to the increase in bread volume and softer crumb compared to control. A lower crumb density of bread with the addition of OP was related to a higher in vitro glycaemic response. An increase in the antioxidant capacity of bread made with the phenolic compound was also found.
Effect of oil oxidation on aggregation of wheat gluten–peanut oil complexes during extrusion
Authors: Chen Yu , Liang Ying , Tian Xiaoling , Wang Xiaohua , Liu Hao , Jia Feng , Zhang Xia , Wang Jinshui
Published: February 2022

To better understand the aggregation mechanism of wheat gluten–peanut oil complex (WPE), the oxidation properties of peanut oil and wheat gluten at different extrusion temperatures were investigated. With the increase in extrusion temperature from 100 to 180 °C, the total oxidation value of peanut oil in WPE increased from 5.04 ± 0.26 to 10.01 ± 0.87, and the carbonyls content of gluten increased from 21.73 ± 0.62 to 31.43 ± 0.58 nmol mg−1. The results of surface hydrophobicity and carbonyls content indicated that peanut oil could induce gluten oxidation in WPE. The morphology of the extrudates showed that the addition of peanut oil promoted the aggregation of gluten protein. These results enhance our understanding of the interactions between peanut oil and gluten in extrudates and provide a theoretical basis for gluten‐based extrudates with favourable textural properties.
Determining programmed cell death ligand 1 expression in circulating tumor cells of patients with clear cell renal cell carcinoma and its correlation with response to programmed cell death protein 1 inhibitors
Authors: Chen Bo‐Han , Kao Chien‐Chang , Xu Ting , Yang Yung‐Ning , Cha Tai‐Lung , Tsai Yi‐Ta , Liu Shu‐Yu , Wu Sheng‐Tang , Meng En , Tsao Chih‐Wei , Chen Chin‐Li , Sun Guang‐Huan , Yu Dah‐Shyong , Chang Sun‐Yran , Yang Ming‐Hsin
Published: February 2022

Objective

There is a great interest in determining whether the expression of the programmed cell death ligand 1 is correlated with the efficacy of immune checkpoint inhibitors in patients with clear cell renal cell carcinoma; however, primary tumor biopsies can only provide limited information. Therefore, we explored the expression of programmed cell death ligand 1 on circulating tumor cells, which is a potential predictor of therapeutic response.

Methods

Circulating tumor cells were isolated from 20 clear cell renal cell carcinoma patients based on cell surface markers targeting clear cell renal cell carcinoma using IsoFlux device, followed by identification according to cell morphology and immunofluorescence studies. Programmed cell death ligand 1 expression status and clinical correlations were also analyzed.

Results

Before treatment with programmed cell death protein 1 inhibitors, circulating tumor cells were detected in all patients, ranging from 1 to 22 (median 7), with 75% (15/20) of the patients having programmed cell death ligand 1 + circulating tumor cells. Circulating tumor cell programmed cell death ligand 1 expression did not correlate with the immunohistochemical staining of programmed cell death ligand 1 in primary tumors. During treatment with programmed cell death protein 1 inhibitors, the disease control rate was much higher in the patients harboring programmed cell death ligand 1 + circulating tumor cells (73%, 11/15) than others (20%, 1/5). We also found that changes in total circulating tumor cell numbers and programmed cell death ligand 1 + circulating tumor cell counts correlated well with the disease outcome.

Conclusion

We showed that the presence of programmed cell death ligand 1 + circulating tumor cells before programmed cell death protein 1 inhibition treatment could be a prognosis predictive factor and that the dynamic changes in circulating tumor cell numbers may be used to monitor the therapeutic response. Our study confirms the possibility of programmed cell death ligand 1 + circulating tumor cell detection in clear cell renal cell carcinoma patients’ blood samples, which can potentially be used as an individualized immunotherapy molecular biomarker for real‐time exploration.