bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of a standardised protocol to measure the disease burden of respiratory syncytial virus infection in young children in primary care
Authors: van Summeren J. J. G. T. , Rizzo C. , Hooiveld M. , Korevaar J. C. , Hendriksen J. M. T. , Dückers M. L. A. , Loconsole D. , Chironna M. , Bangert M. , Demont C. , Meijer A. , Caini S. , Pandolfi E. , Paget J.
Published: July 2021

Background

A better understanding of the burden of respiratory syncytial virus (RSV) infections in primary care is needed for policymakers to make informed decisions regarding new preventive measures and treatments. The aim of this study was to develop and evaluate a protocol for the standardised measurement of the disease burden of RSV infection in primary care in children aged < 5 years.

Methods

The standardised protocol was evaluated in Italy and the Netherlands during the 2019/20 winter. Children aged < 5 years who consulted their primary care physician, met the WHO acute respiratory infections (ARI) case definition, and had a laboratory confirmed positive test for RSV (RT-PCR) were included. RSV symptoms were collected at the time of swabbing. Health care use, duration of symptoms and socio-economic impact was measured 14 days after swabbing. Health related Quality of life (HRQoL) was measured using the parent-proxy report of the PedsQL™4.0 generic core scales (2–4 years) and PedsQL™4.0 infant scales (0–2 years) 30 days after swabbing. The standardised protocol was evaluated in terms of the feasibility of patient recruitment, data collection procedures and whether parents understood the questions.

Results

Children were recruited via a network of paediatricians in Italy and a sentinel influenza surveillance network of general practitioners in the Netherlands. In Italy and the Netherlands, 293 and 152 children were swabbed respectively, 119 and 32 tested RSV positive; for 119 and 12 children the Day-14 questionnaire was completed and for 116 and 11 the Day-30 questionnaire. In Italy, 33% of the children had persistent symptoms after 14 days and in the Netherlands this figure was 67%. Parents had no problems completing questions concerning health care use, duration of symptoms and socio-economic impact, however, they had some difficulties scoring the HRQoL of their young children.

Conclusion

RSV symptoms are common after 14 days, and therefore, measuring disease burden outcomes like health care use, duration of symptoms, and socio-economic impact is also recommended at Day-30. The standardised protocol is suitable to measure the clinical and socio-economic disease burden of RSV in young children in primary care.
A case report of secondary neurolymphomatosis showing selective nerve infiltration and massive lumbar plexus enlargement
Authors: Hamaguchi Mai , Kokubun Norito , Matsuda Hadzki , Onuma Hiroki , Aoki Reika , Takahashi Wataru , Mitani Kinuko , Suzuki Keisuke
Published: July 2021

Background

Neurolymphomatosis (NL) is a rare manifestation of malignant lymphoma that shows selective infiltration to the peripheral nervous system primarily or secondarily. We report a patient with secondary NL caused by germinal center B-cell (GCB)-type diffuse large B-cell lymphoma (DLBCL) who showed selective infiltration of the lumbar plexus to the spinal cord and massive nerve enlargement resulting in severe pain.

Case presentation

A 72-year-old female exhibited asymmetric motor and sensory impairments and pain in the lower limbs that progressed for five months. Magnetic resonance imaging (MRI) showed an enlarged lumbar plexus, which continued to the cauda equina via the L3 and L4 spinal nerves. Her symptoms gradually worsened. Ten months after the onset of symptoms, the enlarged cauda equina filled the spinal canal space, and the spinal cord was swollen. A cauda equina biopsy was performed, and she was diagnosed with GCB-type DLBCL with CD10 positivity. The primary tumor was found in a mammary cyst. The autopsy study did not show apparent infiltration, except in the nervous system.

Conclusions

Although there are many neurologic phenotypes of malignant lymphoma, the association between the cytological characteristics of lymphoma and the neurological phenotypes is still unclear. Several reports of CD10-positive secondary NL are available, whereas peripheral or central nervous tissue origin lymphoma cases are mostly negative for CD10. CD10 staining may be useful for distinguishing primary NL from secondary NL. NL often has a strong organotropism for peripheral nervous tissue, which makes early diagnosis challenging.
Neoadjuvant everolimus plus letrozole versus fluorouracil, epirubicin and cyclophosphamide for ER-positive, HER2-negative breast cancer: a randomized pilot trial
Authors: Wu Wei , Chen Jiewen , Deng Heran , Jin Liang , He Zhanghai , Rao Nanyan , Nie Yan , Yao Yandan , Yang Yaping , Su Fengxi , Liu Jieqiong
Published: July 2021

Background

Here we evaluated the feasibility, efficacy, tolerability, and treatment-mediated immune modulation of neoadjuvant everolimus plus letrozole versus chemotherapy in treating postmenopausal patients with ER-positive, HER2-negative breast cancer.

Methods

Postmenopausal women with ER-positive, HER2-negative breast cancer who had a primary tumor > 2 cm or positive axillary lymph node(s) proofed by biopsy were randomly (1,1) enrolled to receive neoadjuvant everolimus plus letrozole for 18 weeks or fluorouracil, epirubicin plus cyclophosphamide (FEC) for 6 cycles before surgery. Primary outcome was feasibility of the trial. Secondary outcome included ultrasound response rate, pathological complete response rate, breast-conserving surgery rate, toxicities, treatment-mediated immune modulation and biomarkers.

Results

Forty patients were randomized. Completion rate was 90.0% in the neoadjuvant endocrine therapy (NET) arm but 70.0% in the neoadjuvant chemotherapy (NAC) arm. The ultrasound response rate was 65.0% in NET arm and 40.0% in FEC arm, respectively. In terms of the adverse events, clearly favored NET arm. Everolimus plus letrozole increased the ratio of peripheral Tregs to CD4+T cells and tumor PD-L1 expression, and decreased Ki67 index and tumor-infiltrating Tregs, and patients with a greater increase of tumor-specific CTLs showed more sensitive to NET.

Conclusion

This pilot trial showed that neoadjuvant everolimus plus letrozole might achieve a favorable ultrasound response rate with low toxicities in treating postmenopausal ER-positive, HER2-negative breast cancer patients. Everolimus plus letrozole might have positive antitumoral immunity effects. Further large randomized controlled trials are needed to confirm our findings.

Trail registration

A Trial of Neoadjuvant Everolimus Plus Letrozole Versus FEC in Women With ER-positive, HER2-negative Breast Cancer, registered on 07/04/2016 and first posted on 18/04/2016,NCT02742051.
Indirect health effects of the COVID-19 pandemic in Kenya: a mixed methods assessment
Authors: Barasa Edwine , Kazungu Jacob , Orangi Stacey , Kabia Evelyn , Ogero Morris , Kasera Kadondi
Published: July 2021

Background

The COVID-19 pandemic and country measures to control it can lead to negative indirect health effects. Understanding these indirect health effects is important in informing strategies to mitigate against them. This paper presents an analysis of the indirect health effects of the pandemic in Kenya.

Methods

We employed a mixed-methods approach, combining the analysis of secondary quantitative data obtained from the Kenya Health Information System database (from January 2019 to November 2020) and a qualitative inquiry involving key informant interviews (n = 12) and document reviews. Quantitative data were analysed using an interrupted time series analysis (using March 2020 as the intervention period). Thematic analysis approach was employed to analyse qualitative data.

Results

Quantitative findings show mixed findings, with statistically significant reduction in inpatient utilization, and increase in the number of sexual violence cases per OPD visit that could be attributed to COVID-19 and its mitigation measures. Key informants reported that while financing of essential health services and domestic supply chains were not affected, international supply chains, health workforce, health infrastructure, service provision, and patient access were disrupted. However, the negative effects were thought to be transient, with mitigation measures leading to a bounce back.

Conclusion

Finding from this study provide some insights into the effects of the pandemic and its mitigation measures in Kenya. The analysis emphasizes the value of strategies to minimize these undesired effects, and the critical role that routine health system data can play in monitoring continuity of service delivery.
Impacts of English language proficiency on healthcare access, use, and outcomes among immigrants: a qualitative study
Authors: Pandey Mamata , Maina R. Geoffrey , Amoyaw Jonathan , Li Yiyan , Kamrul Rejina , Michaels C. Rocha , Maroof Razawa
Published: July 2021

Background

Immigrants from culturally, ethnically, and linguistically diverse countries face many challenges during the resettlement phase, which influence their access to healthcare services and health outcomes. The “Healthy Immigrant Effect” or the health advantage that immigrants arrive with is observed to deteriorate with increased length of stay in the host country.

Methods

An exploratory qualitative design, following a community-based research approach, was employed. The research team consisted of health researchers, clinicians, and community members. The objective was to explore the barriers to healthcare access among immigrants with limited English language proficiency. Three focus groups were carried out with 29 women and nine men attending English language classes at a settlement agency in a mid-sized city. Additionally, 17 individual interviews were carried out with healthcare providers and administrative staff caring for immigrants and refugees.

Results

A thematic analysis was carried out with transcribed focus groups and healthcare provider interview data. Both the healthcare providers and immigrants indicated that limited language proficiency often delayed access to available healthcare services and interfered with the development of a therapeutic relationship between the client and the healthcare provider. Language barriers also impeded effective communication between healthcare providers and clients, leading to suboptimal care and dissatisfaction with the care received. Language barriers interfered with treatment adherence and the use of preventative and screening services, further delaying access to timely care, causing poor chronic disease management, and ultimately resulting in poor health outcomes. Involving untrained interpreters, family members, or others from the ethnic community was problematic due to misinterpretation and confidentiality issues.

Conclusions

The study emphasises the need to provide language assistance during medical consultations to address language barriers among immigrants. The development of guidelines for recruitment, training, and effective engagement of language interpreters during medical consultation is recommended to ensure high quality, equitable and client-centered care.
Genome of the pincer wasp Gonatopus flavifemur reveals unique venom evolution and a dual adaptation to parasitism and predation
Authors: Yang Yi , Ye Xinhai , Dang Cong , Cao Yunshen , Hong Rui , Sun Yu H. , Xiao Shan , Mei Yang , Xu Le , Fang Qi , Xiao Huamei , Li Fei , Ye Gongyin
Published: July 2021

Background

Hymenoptera comprise extremely diverse insect species with extensive variation in their life histories. The Dryinidae, a family of solitary wasps of Hymenoptera, have evolved innovations that allow them to hunt using venom and a pair of chelae developed from the fore legs that can grasp prey. Dryinidae larvae are also parasitoids of Auchenorrhyncha, a group including common pests such as planthoppers and leafhoppers. Both of these traits make them effective and valuable for pest control, but little is yet known about the genetic basis of its dual adaptation to parasitism and predation.

Results

We sequenced and assembled a high-quality genome of the dryinid waspGonatopus flavifemur, which at 636.5 Mb is larger than most hymenopterans. The expansion of transposable elements, especially DNA transposons, is a major contributor to the genome size enlargement. Our genome-wide screens reveal a number of positively selected genes and rapidly evolving proteins involved in energy production and motor activity, which may contribute to the predatory adaptation of dryinid wasp. We further show that three female-biased, reproductive-associatedyellowgenes, in response to the prey feeding behavior, are significantly elevated in adult females, which may facilitate the egg production. Venom is a powerful weapon for dryinid wasp during parasitism and predation. We therefore analyze the transcriptomes of venom glands and describe specific expansions in venomIdgf-like genes and neprilysin-like genes. Furthermore, we find theLWS2-opsingene is exclusively expressed in maleG. flavifemur, which may contribute to partner searching and mating.

Conclusions

Our results provide new insights into the genome evolution, predatory adaptation, venom evolution, and sex-biased genes inG. flavifemur, and present genomic resources for future in-depth comparative analyses of hymenopterans that may benefit pest control.
Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1
Authors: Ozaki Nozomu , Okuda Hiroko , Kobayashi Hatasu , Harada Kouji H. , Inoue Sumiko , Youssefian Shohab , Koizumi Akio
Published: July 2021

Background

Brachydactyly type A1 (BDA1) is an autosomal dominant disorder characterized by uniform shortening of the middle phalanges in all digits. It is associated with variants in the Indian Hedgehog (IHH) gene, which plays a key role in endochondral ossification. To date, heterozygous pathogenic IHH variants involving several codons, which are restricted to a specific region of the N-terminal active fragment of IHH, have been reported. The purpose of this study was to identify the pathogenic variant in a Japanese family with BDA1 and to evaluate its pathogenesis with regard to previous reports.

Methods

The proband, a 9-year-old boy, his siblings, and his father had shortened digits and a short stature of variable severity. Based on physical examinations, radiographic findings and family history, they were diagnosed with BDA1. This family is the first case of an isolated malformation in Japan. Sanger sequencing of IHH was performed on these individuals and on the proband’s unaffected mother. The significance of the variants was assessed using three-dimensional analysis methods.

Results

Sanger sequencing showed a novel IHH heterozygous variant, NM_002181.4:c.544_549delTCAAAG(p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del].. These two residues are located outside the cluster region considered a hotspot of pathogenic variants. Three-dimensional modelling showed that S182 and K183 are located on the same surface as other residues associated with BDA1. Analysis of residue interactions across the interface between IHH and its interacting receptor protein revealed the presence of hydrogen bonds between them.

Conclusions

We report a novel variant, NM_002181.4:c.544_549delTCAAAG (p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del] in a Japanese family with BDA1. Indeed, neither variations in codons 182 or 183 nor with such two-amino-acid deletions in IHH have been reported previously. Although these two residues are located outside the cluster region considered a hotspot of pathogenic variants, we speculate that this variant causes BDA1 through impaired interactions between IHH and target receptor proteins in the same manner as other pathogenic variants located in the cluster region. This report expands the genetic spectrum of BDA1.
IGHG1 upregulation promoted gastric cancer malignancy via AKT/GSK-3β/β-Catenin pathway
Authors: Li Xinyu , Chen Wen , Yang Chunkang , Huang Yisen , Jia Jing , Xu Rongyu , Guan Shen , Ma Ruijun , Yang Haitao , Xie Lifeng
Published: July 2021

Background

Despite current advances in gastric cancer treatment, disease metastasis and chemo-resistance remain as major hurdles against better overall prognosis. Previous studies indicated that IGHG1 as well as -Catenin serve as important regulators of tumor cellular malignancy. Therefore, understanding detailed molecular mechanism and identifying druggable target will be of great potentials in future therapeutic development.

Methods

Surgical tissues and gastric cancer cell lines were retrieved to evaluate IGHG1 expression for patients with or without lymph node/distal organ metastasis. Functional assays including CCK8 assay, Edu assay, sphere formation assay and transwell assay, wound healing assay, etc. were subsequently performed to evaluate the impact of IGHG1/-catenin axis on tumor cell proliferation, migration and chemo-resistance.

Results

Gastric cancer tissues and tumor cell lines demonstrated significantly higher level of IGHG1. Functional study further demonstrated that IGHG1 promoted proliferative and migration as well as chemo-resistance of gastric cancer tumor cells. Further experiments indicated that IGHG1 activated AKT/GSK-3/-Catenin axis, which played crucial role in regulation of proliferative and chemo-resistance of gastric cancer cells.

Conclusion

This study provided novel evidences that IGHG1 acted as oncogene by promotion of gastric cancer cellular proliferation, migration and chemo-resistance. Our research further suggested that IGHG1/AKT/GSK-3β/β-Catenin axis acted as novel pathway which regulated gastric cancer cellular malignant behavior. Our research might inspire future therapy development to promote overall prognosis of gastric cancer patients.
Characterization of resistance profile (intensity and mechanisms) of Anopheles gambiae in three communes of northern Benin, West Africa
Authors: Kpanou Casimir Dossou , Sagbohan Hermann W. , Dagnon Fortuné , Padonou Germain G. , Ossè Razaki , Salako Albert Sourou , Sidick Aboubakar , Sewadé Wilfried , Sominahouin André , Condo Patrick , Ahmed Saadani Hassani , Impoinvil Daniel , Akogbéto Martin
Published: July 2021

Background

The selection and the spread of insecticide resistance in malaria vectors to the main classes of insecticides used in vector control tools are a major and ongoing challenge to malaria vector control programmes. This study aimed to determine the intensity of vector resistance to insecticides in three regions of Benin with different agro-ecological characteristics.

Methods

Larvae of Anopheles gambiae sensu lato (s.l.) were collected from September to November 2017 in different larval sites in three northern Benin communes: Parakou, Kandi and Malanville. Two to five-day-old, non-blood-fed, female mosquitoes were exposed to papers impregnated with deltamethrin, permethrin and bendiocarb at dosages of 1 × the diagnostic dose, 5 × and 10 × to determine the intensity of resistance in these vectors. Molecular frequencies of the kdr L1014F and ace-1R G119S insecticide resistance mutations and levels of detoxification enzymes were determined for mosquitoes sampled at each study site.

Results

Resistance to pyrethroids (permethrin and deltamethrin) was recorded in all three communes with mortality rates below 60% using the diagnostic dose (1x). The results obtained after exposure of An. gambiae to permethrin 10 × were 99% in Kandi, 98% in Malanville and 99% in Parakou. With deltamethrin 10x, mortality rates were 100% in Kandi, 96% in Malanville and 73% in Parakou. For the diagnostic dose of bendiocarb, suspected resistance was recorded in the communes of Malanville (97%) and Kandi (94%) while sensitivity was observed in Parakou (98%).Using the 10 × dose, mortality was 98% in Kandi, 100% in Malanville and 99% in Parakou. The frequencies of the kdr L1014F allele varied between 59 and 83% depending on the sites and species of the An. gambiae complex, while the frequency of the ace-1R G119S gene varied between 0 and 5%. Biochemical tests showed high levels of oxidase and esterase activity compared to the susceptible colony strain of An. gambiae sensu stricto (Kisumu strain).

Conclusion

Anopheles gambiae showed a generalized loss of susceptibility to permethrin and deltamethrin but also showed moderate to high intensity of resistance in different regions of Benin. This high intensity of resistance is a potential threat to the effectiveness of vector control.
Amplification of oxidative stress with lycorine and gold-based nanocomposites for synergistic cascade cancer therapy
Authors: Hu Hongzhi , Yang Wenbo , Liang Zihui , Zhou Zezhu , Song Qingcheng , Liu Weijian , Deng Xiangtian , Zhu Jian , Xing Xin , Zhong Binglong , Wang Baichuan , Wang Shangyu , Shao Zengwu , Zhang Yingze
Published: July 2021

Background

Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the therapeutic efficacy of current therapeutic protocol for osteosarcoma (OS) is still seriously compromised by multi-drug resistance and severe side effects. Amplification of intracellular oxidative stress is considered as an effective strategy to induce cancer cell death. The purpose of this study was to develop a novel strategy that can amplify the intracellular oxidative stress for synergistic cascade cancer therapy.

Methods and results

A novel nanocomposite, composed of folic acid (FA) modified mesoporous silica–coated gold nanostar (GNS@MSNs-FA) and traditional Chinese medicine lycorine (Ly), was rationally designed and developed. Under near-infrared (NIR) irradiation, the obtained GNS@MSNs-FA/Ly could promote a high level of ROS production via inducing mitochondrial dysfunction and potent endoplasmic reticulum (ER) stress. Moreover, glutathione (GSH) depletion during ER stress could reduce ROS scavenging and further enable efficient amplification of intracellular oxidative stress. Both in vitro and in vivo studies demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation exhibited excellent antitumor efficacy without noticeable toxicity in MNNG/HOS tumor-bearing mice.

Conclusion

All these results demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation could dramatically amplify the intra-tumoral oxidative stress, exhibiting excellent antitumor ability without obvious systemic toxicity. Taken together, this promising strategy provides a new avenue for the effective cancer synergetic therapy and future clinical translation.
Proprioceptive elbow training reduces pain and improves function in painful lateral epicondylitis—a prospective trial
Authors: Schiffke-Juhász B. , Knobloch K. , Vogt P. M. , Hoy L.
Published: July 2021

Background

In painful epicondylitis, previous studies reported deficiencies in elbow proprioception. In line, proprioceptive training of the lower limb has been reported substantial beneficial in a number of indications. Therefore, we have asked if a specified proprioceptive training using training devices that are capable of activating the deep musculature in the upper limb is able to reduce the symptoms of epicondylitis.

Materials and methods

We included 71 patients with painful lateral epicondylitis > 3 months. Interventions: Group A: Proprioceptive training intervention with a Flexibar® (9 min daily for 12 weeks). Group B: at least 40 min running or walking/week with the XCO® in addition to the proprioceptive training with the Flexibar® (9 min daily for 12 weeks), follow-up for 12 weeks. Primary end point: Pain on visual analogue scale (VAS, 0-10); secondary end points: DASH-Score (0 = very good, 100 = very poor), grip strength according to Jamar dynamometer (kg), vibration sensation measured with a 128 Hz tuning fork.

Results

The pain on VAS in group A was reduced significantly. 3.6 ± 2.0 to 2.4 ± 2.1 (−33%, p = 0.013), and from 3.7 ± 2.4 to 2.2 ± 1.9 (−41%, p = 0.004) in group B after 12 weeks. There was no significant difference between A and B (p = 0.899). In both groups, there was a significant improvement of the DASH-Score (A: 32 ± 15 to 14 ± 12, −56%, p < 0.001; B: 27 ± 12 to 12 ± 11, −55%, p = 0.001) without any difference between groups A and B (p = 0.339). Grip strength improvement in group A from 24 ± 12 to 33 ± 11 kg (+38%, p < 0.001), and from 29 ± 14 to 34 ± 11 kg (+15%, p < 0.001) in group B. In line, vibration sensation improved in both groups (A: 6.3 ± 0.6 to 6.5 ± 0.5, p = 0.0001; B: 6.3 ± 0.7 to 6.6 ± 0.5, p = 0.003).

Conclusion

A 12-week proprioceptive training with the Flexibar® improves pain, quality of life, grip strength and vibration sensation in patients with painful lateral epicondylitis.

Level of evidence

Ib, randomised clinical trial

Trial registration

German Clinical Trials Register, DRKS00024857, registered on 25 March 2021—retrospectively registered, http://apps.who.int/trialsearch/
N6-methyladenosine methyltransferases: functions, regulation, and clinical potential
Authors: Huang Wei , Chen Tian-Qi , Fang Ke , Zeng Zhan-Cheng , Ye Hua , Chen Yue-Qin
Published: July 2021

N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies.
Whole genome resequencing data sets of different species from Pistacia genus
Authors: Tajabadipour Ali , Esmailizadeh Ali
Published: July 2021

Objectives

Pistacia genus belongs to the flowering plants in the cashew family and contains at least 11 species. The whole-genome resequencing data of different species from Pistacia genus are described herein. The data reported here will be useful for better understand the adaptive evolution, demographic history, genetic diversity, population structure, and domestication of pistachio.

Data description

Genomic DNA was isolated from fresh leaves and used to construct libraries with insert size of 350 bp. Sequence libraries were made and sequenced on the Illumina Hiseq 4000 platform to produce 150 bp paired-end reads. A total number of 4,851,118,730 billion reads (ranging from 33,305,900 to 34,990,618 reads per sample) were created across all samples. We produced a total of 727.67 Gbp data which have been deposited in the Genome Sequence Archive (GSA) database with the Accession of CRA000978. All of the data are also available as the sequence read archive (SRA) format in the National Center for Biotechnology Information (NCBI) with identifier of SRP189222, mirroring our deposited data in GSA.
Characterization of genomic DNA sequence of the candidate gene for FB_Mfu10 associated with fire blight resistance in Malus species
Authors: Emeriewen Ofere Francis , Flachowsky Henryk , Peil Andreas
Published: July 2021

Objective

The proposed candidate gene underlying the Malus fusca fire blight resistance locus on chromosome 10 was previously predicted to possess 880 amino acids and 8 exons. Eight base pair (8 bp) insertion/deletion in the first exon potentially distinguished resistant genotypes from susceptible ones. This study aimed at analyzing the candidate gene sequence in another set of original resistant and susceptible progeny, characterizing the sequence in a transgenic line transformed with the candidate gene under its own native promoter, as well as deciphering the potential genomic differences between this candidate gene and its homolog in the ‘Golden Delicious’ doubled haploid genome (GDDH13).

Results

Sequences of amplicons of part of the candidate gene amplified in two progenies that showed resistant and susceptible fire blight phenotypes, confirmed the 8 bp insertion that distinguishes susceptible and resistant progenies. The transgenic line was positive for the candidate gene sequence, confirming a successful transfer into the background of apple cultivar ‘Pinova’, and possessed the same genomic sequence as the progeny with a resistant phenotype. Sequence analysis showed that the homolog gene on GDDH13 possesses a significant 18 bp deletion in exon 1 leading to a difference of 15 amino acid from the protein sequence of the candidate gene.
Spatial epi-proteomics enabled by histone post-translational modification analysis from low-abundance clinical samples
Authors: Noberini Roberta , Savoia Evelyn Oliva , Brandini Stefania , Greco Francesco , Marra Francesca , Bertalot Giovanni , Pruneri Giancarlo , McDonnell Liam A. , Bonaldi Tiziana
Published: July 2021

Background

Increasing evidence linking epigenetic mechanisms and different diseases, including cancer, has prompted in the last 15 years the investigation of histone post-translational modifications (PTMs) in clinical samples. Methods allowing the isolation of histones from patient samples followed by the accurate and comprehensive quantification of their PTMs by mass spectrometry (MS) have been developed. However, the applicability of these methods is limited by the requirement for substantial amounts of material.

Results

To address this issue, in this study we streamlined the protein extraction procedure from low-amount clinical samples and tested and implemented different in-gel digestion strategies, obtaining a protocol that allows the MS-based analysis of the most common histone PTMs from laser microdissected tissue areas containing as low as 1000 cells, an amount approximately 500 times lower than what is required by available methods. We then applied this protocol to breast cancer patient laser microdissected tissues in two proof-of-concept experiments, identifying differences in histone marks in heterogeneous regions selected by either morphological evaluation or MALDI MS imaging.

Conclusions

These results demonstrate that analyzing histone PTMs from very small tissue areas and detecting differences from adjacent tumor regions is technically feasible. Our method opens the way for spatial epi-proteomics, namely the investigation of epigenetic features in the context of tissue and tumor heterogeneity, which will be instrumental for the identification of novel epigenetic biomarkers and aberrant epigenetic mechanisms.
Serum exosomes from young rats improve the reduced osteogenic differentiation of BMSCs in aged rats with osteoporosis after fatigue loading in vivo
Authors: Xun Jingqiong , Li Chan , Liu Meilu , Mei Yueming , Zhou Qiongfei , Wu Bo , Xie Fen , Liu Yuling , Dai Ruchun
Published: July 2021

Background

Osteoporosis is a major public health concern for the elderly population and is characterized by fatigue load resulting in bone microdamage. The ability of bone mesenchymal stem cells (BMSCs) to repair bone microdamage diminishes with age, and the accumulation of bone microdamage increases the risk of osteoporotic fracture. There is a lack of effective means to promote the repair of bone microdamage in aged patients with osteoporosis. Exosomes have been shown to be related to the osteogenic differentiation of BMSCs. Here, we aimed to evaluate the changes in the osteogenic differentiation capacity of BMSCs in aged osteoporotic rats after fatigue loading and the treatment potential of serum exosomes from young rats.

Methods

The tibias of six aged osteoporotic rats were subjected to fatigue loading in vivo for 2 weeks, and the bone microdamage, microstructures, and mechanical properties were assessed. Subsequently, BMSCs were extracted to evaluate their proliferation and osteogenic differentiation abilities. In addition, the BMSCs of aged osteoporotic rats after fatigue loading were treated with serum exosomes from young rats under osteogenic induction conditions, and the expression of osteogenic-related miRNAs was quantified. The osteogenetic effects of miRNA-19b-3p in exosomes and the possible target protein PTEN was detected.

Results

Obvious bone microdamage at the fatigue load stress point, the bone microstructure and biomechanical properties were not obviously changed. A decreased osteogenic differentiation ability of BMSCs was observed after fatigue loading, while serum exosomes from young rats highly expressing miRNA-19b-3p improved the decreased osteogenic differentiation ability of BMSCs. Transfection with miRNA-19b-3p mimic could promote osteoblastic differentiation of BMSCs and decreased the expression of PTEN. After transfection of miRNA-19b-3p inhibitor, the promotional effect of exosomes on bone differentiation was weakened. Treatment with transfected exosomes increased the expression of PTEN.

Conclusion

Serum exosomes derived from young rats can improve the decreased osteogenic differentiation ability of BMSCs in aged rats with osteoporosis after fatigue loading and can provide a new treatment strategy for the repair of bone microdamage and prevention of fractures.
Some bounds of the generalized μ-scrambling indices of primitive digraphs with d loops
Authors: Zhang Ling , Mou Gu-Fang , Liu Feng , Li Zhong-Shan
Published: July 2021

In 2010, Huang and Liu introduced a useful parameter called the generalized μ-scrambling indices of a primitive digraph. In this paper, we give some bounds for μ-scrambling indices of some primitive digraphs with d loops and the digraphs attained the sharp upper bounds are provided.
Utilisation and predictors of use of exposure therapy in the treatment of anxiety, OCD and PTSD in an Australian sample: a preliminary investigation
Authors: Moses Karen , Gonsalvez Craig , Meade Tanya
Published: July 2021

Background

Cognitive-behavior therapy (CBT) is known to be an effective treatment for the anxiety and related disorders, with exposure therapy being a key component of this treatment package. However, research on the use of exposure therapy in clinical practice has presented mixed results, potentially due to differences in samples and training programs across countries. The present study aimed to extend upon existing research by examining the use and predictors of use of exposure therapy in a sample of psychologists working in clinical practice in Australia who treat clients with an anxiety disorder, obsessive compulsive disorder (OCD) or post-traumatic stress disorder (PTSD).

Methods

One hundred registered psychologists (Mage = 40.60; SD = 10.78; range 23 to 71 years; 84% female) participated in an online study investigating their clinical practices.

Results

Results suggested that while the general use of exposure therapy is high, the use of disorder specific techniques was considerably lower, particularly for anxiety disorders and PTSD but not OCD. Psychology registration status and level of training were positively associated with use of exposure therapy as was the experience in treating anxiety disorders.

Conclusions

These findings suggest that further or ongoing professional training may be required to optimize the use of disorder specific techniques.
Integrable solution for light shaping based on a Fourier-pair mapping
Authors: Yang Liangxin , Badar Irfan , Hellmann Christian , Wyrowski Frank
Published: July 2021

In far-field light shaping, one of the design methods is based on a one-to-one map between the irradiance of the source and target. However, an integrability issue may occur in this kind of algorithms, either in the ray mapping method for designing a freeform surface or in those geometric-optics-based methods for achieving a required output phase. We introduce another mapping-type algorithm to tackle the integrability problem, which instead of establishing a mapping between both the source and target irradiance in the space domain, the mapping is assumed on electric fields of a Fourier pair between the space domain and the spatial-frequency domain. By solving the mapping from the Fourier pair, the gradient of the output phase is achieved, that the gradient is equivalent to the obtained mapping function. Moreover, the existence and the characterization of the mapping guarantees the integrability of the gradient so that a smooth output phase can be directly integrated. Based on the obtained smooth output phase, a freeform surface can then be designed for the light-shaping task. Numerical examples are demonstrated for the comparison of the approaches with different mapping assumptions.
Content validation of a self-report daily diary in patients with sickle cell disease
Authors: White Michelle K. , Saucier Cory , Bailey Miranda , D’Alessio Denise , Foster April , St. Pierre Danielle , Raymond Kimberly
Published: July 2021

Background

Sickle Cell Disease (SCD) is a genetic progressive vascular disease that impacts patients overall health and quality of life. Sickle-cell pain crises (SCPCs) are a hallmark clinical presentation of SCD and have been associated with increased morbidity and mortality. The Sickle Cell Pain Diary- Self Report (SCPD-S) was developed as a daily patient-reported outcome (PRO) measure primarily intended to capture the frequency and severity of SCD-related pain during and outside of a SCPC. The SCPD-S also examines the impact of the pain associated with an SCPC on other health-related quality of life concepts. The objective of this study was to investigate the content validity of the SCPD-S.

Methods

The content validation testing included 18 in-depth hybrid concept elicitation and cognitive debriefing interviews conducted with SCD patients in the US aged 12 years and older. Interviewers used a semi-structured interview guide and a think-aloud approach for the cognitive debriefing portion. All interviews were recorded, transcribed, coded and analyzed.

Results

Eighteen interviews across two rounds were conducted. Round 1 hybrid interviews (n = 12) resulted in the expansion of the SCPD-S from 13 to 19 items. Items on the impact of an SCPC on social and recreational activities, sleep, and emotional well-being were added. Five items were significantly revised, as were three response choice sets. Round 2 hybrid interviews (n = 6) confirmed the comprehensiveness of the revised diary, understandability of the wording, and appropriateness of the recall period and response sets. Saturation analyses specific to concept elicitation revealed that no additional interviews were needed.

Conclusions

This study provided evidence to support the content validity of the SCPD-S, a self-report daily diary. Data gathered during patient interviews indicated that the SCPD-S is a fit for purpose measure of SCD and SCPC-related pain frequency and severity and the impact of this pain on other health-related quality of life concepts including fatigue and emotional health. The numerous changes to the SCPD-S as a result of the study findings highlight the importance of the content validation process when developing a PRO measure.
Development and assessment of a telesonography system for musculoskeletal imaging
Authors: Obaid Mohammed , Zhang Qianwei , Adams Scott J. , Fotouhi Reza , Obaid Haron
Published: July 2021

Background

Telesonography systems have been developed to overcome barriers to accessing diagnostic ultrasound for patients in rural and remote communities. However, most previous telesonography systems have been designed for performing only abdominal and obstetrical exams. In this paper, we describe the development and assessment of a musculoskeletal (MSK) telesonography system.

Methods

We developed a 4-degrees-of-freedom (DOF) robot to manipulate an ultrasound probe. The robot was remotely controlled by a radiologist operating a joystick at the master site. The telesonography system was used to scan participants’ forearms, and all participants were conventionally scanned for comparison. Participants and radiologists were surveyed regarding their experience. Images from both scanning methods were independently assessed by an MSK radiologist.

Results

All ten ultrasound exams were successfully performed using our developed MSK telesonography system, with no significant delay in movement. The duration (mean ± standard deviation) of telerobotic and conventional exams was 4.6 ± 0.9 and 1.4 ± 0.5 min, respectively (p = 0.039). An MSK radiologist rated quality of real-time ultrasound images transmitted over an internet connection as “very good” for all telesonography exams, and participants rated communication with the radiologist as “very good” or “good” for all exams. Visualisation of anatomic structures was similar between telerobotic and conventional methods, with no statistically significant differences.

Conclusions

The MSK telesonography system developed in this study is feasible for performing soft tissue ultrasound exams. The advancement of this system may allow MSK ultrasound exams to be performed over long distances, increasing access to ultrasound for patients in rural and remote communities.
Induction of colorectal carcinogenesis in the C57BL/6J and A/J mouse strains with a reduced DSS dose in the AOM/DSS model
Authors: Arnesen Henriette , Müller Mette Helen Bjørge , Aleksandersen Mona , Østby Gunn Charlotte , Carlsen Harald , Paulsen Jan Erik , Boysen Preben
Published: July 2021

Background

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide and thus mouse models of CRC are of significant value to study the pathogenesis. The Azoxymethane/Dextran sulfate sodium (AOM/DSS) model is a widely used, robust initiation-promotion model for chemical induction of colitis-associated CRC in rodents. However, the dosage of chemicals, treatment regimens and outcome measures vary greatly among studies employing this model. Thus, the aim of this study was to examine an AOM/DSS model involving a reduced (1%) dose of DSS for induction of carcinogenesis in A/J and C57BL/6J (B6) mice.

Results

We show that colonic preneoplastic lesions can be reliably detected in A/J and B6 mice by use of a AOM/DSS model involving a single injection of 10 mg/kg AOM followed by three 7-day cycles of a low-dose (1%) DSS administration. Supporting existing evidence of A/J mice exhibiting higher susceptibility to AOM than B6 mice, our AOM/DSS-treated A/J mice developed the highest number of large colonic lesions. Clinical symptoms in both strains subjected to the AOM/DSS treatment did not persist in-between treatment cycles, demonstrating that the animals tolerated the treatment well.

Conclusions

Our findings suggest that a reduced dose of DSS in the AOM/DSS model can be considered in future studies of early phase colorectal carcinogenesis in the A/J and B6 mouse strains using preneoplastic lesions as an outcome measure, and that such regimen may reduce the risk of early trial terminations to accommodate human endpoints. Overall, our data emphasize the importance of devoting attention towards choice of protocol, outcome measures and mouse strain in studies of CRC in mice according to the study purpose.
Accuracy of emergency physicians’ self-estimates of CT scan utilization and its potential effect on an audit and feedback intervention: a randomized trial
Authors: Larkin Celine , Sanseverino Alexandra M. , Joseph James , Eisenhauer Lauren , Reznek Martin A.
Published: July 2021

Background

Audit and feedback (A&F) has been used as a strategy to modify clinician behavior with moderate success. Although A&F is theorized to work by improving the accuracy of clinicians’ estimates of their own behavior, few interventions have included assessment of clinicians’ estimates at baseline to examine whether they account for intervention success or failure. We tested an A&F intervention to reduce computed tomography (CT) ordering by emergency physicians, while also examining the physicians’ baseline estimates of their own behavior compared to peers.

Methods

Our study was a prospective, multi-site, 20-month, randomized trial to examine the effect of an A&F intervention on CT ordering rates, overall and by test subtype. From the electronic health record, we obtained 12 months of baseline CT ordering per 100 patients treated for every physician from four emergency departments. Those who were randomized to receive A&F were shown a de-identified graph of the group’s baseline CT utilization, asked to estimate wherein the distribution of their own CT order practices fell, and then shown their actual performance. All participants also received a brief educational intervention. CT ordering rates were collected for all physicians for 6 months after the intervention. Pre-post ordering rates were compared using independent and repeated measures t tests.

Results

Fifty-one of 52 eligible physicians participated. The mean CT ordering rate increased significantly in both experimental conditions after the intervention (intervention pre = 35.7, post = 40.3, t = 4.13, p < 0.001; control pre = 33.9, post = 38.9, t = 3.94, p = 0.001), with no significant between-group difference observed at follow-up (t = 0.43, p = 0.67). Within the intervention group, physicians had poor accuracy in estimating their own ordering behavior at baseline: most overestimated and all guessed that they were in the upper half of the distribution of their peers. CT ordering increased regardless of self-estimate accuracy.

Conclusions

Our A&F intervention failed to reduce physician CT ordering: our feedback to the physicians showed most of them that they had overestimated their CT ordering behavior, and they were therefore unlikely to reduce it as a result. After “audit,” it may be prudent to assess baseline clinician awareness of behavior before moving toward a feedback intervention.
Are Faculty Changing? How Reform Frameworks, Sampling Intensities, and Instrument Measures Impact Inferences about Student-Centered Teaching Practices
Authors: Sbeglia Gena C. , Goodridge Justin A. , Gordon Lucy H. , Nehm Ross H.
Published: July 2021

This study highlights the risks of broad, decontextualized sampling protocol recommendations and illustrates how reform frameworks, sampling intensities, and COPUS measures interact to impact inferences about faculty change.
PhDepression: Examining How Graduate Research and Teaching Affect Depression in Life Sciences PhD Students
Authors: Gin Logan E. , Wiesenthal Nicholas J. , Ferreira Isabella , Cooper Katelyn M.
Published: July 2021

This interview study of 50 biology PhD students with depression examines how aspects of graduate teaching and research affect depression and how depression affects students’ experiences teaching and researching. This work identifies aspects of graduate school that PhD programs can target to improve mental health among graduate students.
Prescribing antipsychotic medication for adults with intellectual disability: shared responsibilities between mental health services and primary care
Authors: Paton Carol , Roy Ashok , Purandare Kiran , Rendora Olivia , Barnes Thomas R. E.
Published: July 2021

Aims and method

We conducted a secondary analysis of data from a Prescribing Observatory for Mental Health audit to assess the quality of requests from intellectual disability services to primary care for repeat prescriptions of antipsychotic medication.

Results

Forty-six National Health Service Trusts submitted treatment data on 977 adults with intellectual disability, receiving antipsychotic medication for more than a year, for whom prescribing responsibility had been transferred to primary care. Therapeutic effects had been monitored in the past 6 months in 80% of cases with a documented communication indicating which service was responsible for this and 72% of those with no such communication. The respective proportions were 69% and 42% for side-effect monitoring, and 79% and 30% for considering reducing/stopping antipsychotic medication.

Clinical implications

Where continuing antipsychotic medication is prescribed in primary care for people with intellectual disability, lack of guidance from secondary care regarding responsibilities for monitoring its effectiveness may be associated with inadequate review.