bluuebunny/crossref_metadata_2025 huggingface dataset:
Salt-inducible kinase 2 (SIK2) inhibitor ARN-3236 attenuates bleomycin-induced pulmonary fibrosis in mice
Authors: Zou Liangneng , Hong Dequn , Li Kecong , Jiang Bingyuan
Published: April 2022

Background

Pulmonary fibrosis is a fatal lung disease with complex pathogenesis and limited effective therapies. Salt-inducible kinase 2 (SIK2) is a kinase that phosphorylates CRTCs and regulates many physiological processes. However, the role of SIK2 on pulmonary fibrosis remains unclear, and whether SIK2 inhibitor can attenuate pulmonary fibrosis is unknown.

Method

We subjected human fetal lung fibroblasts (HFLs) to transforming growth factor-β1 (5 ng/mL) for 12 h, and examined the expression of SIK2, CRTCs and pCRTCs in fibroblasts by western-blot. To address the roles of SIK2 and CRTCs involved in the progression of pulmonary fibrosis, HFLs were treated with a small-molecule inhibitor ARN-3236 or by siRNA-mediated knockdown of SIK2 expression. Pulmonary fibrosis model was established with mice by exposing to bleomycin, and assessed by H&E and Masson’s trichrome staining. COL1A and α-SMA distributions were detected in lung tissues by immunohistochemical staining.

Results

We discovered that SIK2 and phosphorylated-CRTC2 were expressed at a low basal level in normal lung tissues and quiescent fibroblasts, but increased in fibrotic lung tissues and activated fibroblasts. Inhibition of SIK2 by ARN-3236 prevented the fibroblasts differentiation and extracellular matrix expression in HFLs and attenuated bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inactivation of SIK2 resulted in the dephosphorylation and nuclear translocation of CRTC2. Within the nucleus, CRTC2 binds to CREB, promoting CREB-dependent anti-fibrotic actions.

Conclusion

In conclusion, our results elucidated a previously unexplored role of SIK2 in pulmonary fibrosis, and identified SIK2 as a new target for anti-fibrosis medicines.
Vaspin promotes chondrogenic differentiation of BMSCs via Akt activation in osteoarthritis
Authors: Wang Junfeng , Zhang Keshi , Zhang Shaolong , Guan Zhenpeng
Published: April 2022

Background

The aim of this study was to investigate the role of Vaspin on the chondrogenic differentiation of bone mesenchymal stem cells (BMSCs), and its effect on chondrocyte survival and ECM secretion. We also assessed whether the Akt activation participates in these processes.

Methods

In vivo, ﻿immunohistochemistry was used to examine the positive rate of the protein expressions of Akt in Wistar rat articular cartilage and subchondral bone after Vaspin intraperitoneal injection for 14 days. In vitro, we isolated and expanded BMSCs from Wistar rats, and further cultured BMSCs as pellets in a chondrogenic-differentiation medium supplemented with different concentrations of Vaspin. After 21 days, the pellets were processed for cell counting kit assay. The mRNA level of Akt, SOX9 and COL2A1 in the pellets were investigated using quantitative Real-Time polymerase chain reaction, and the protein level of COMP was detected using western blot.

Results

During the chondrogenic differentiation of BMSCs, Vaspin promoted the chondrogenic differentiation of BMSCs and chondrocyte survival by activating the Akt pathway. These effects were significantly reduced by treatment with an Akt inhibitor. Moreover, Vaspin promoted chondrogenic differentiation of BMSCs by increasing the expression of markers in cartilage formation and extracellular matrix secretion. Furthermore, our study also found that Vaspin could increase Akt expression in cartilage cavities and subchondral bone in vivo.

Conclusion

These findings demonstrate that Vaspin can promote the chondrogenic differentiation of BMSCs and chondrocyte survival via Akt activation. Our study provides new insights into the potential ability of Vaspin to ameliorate the chondrogenic differentiation of BMSCs and chondrocyte survival in OA.
Orai1 downregulation causes proliferation reduction and cell cycle arrest via inactivation of the Ras-NF-κB signaling pathway in osteoblasts
Authors: Guo Yunshan , Fan Jinzhu , Liu Shuguang , Hao Dingjun
Published: April 2022

Background

The purpose of this study was to determine the role of Orai1 in the regulation of the proliferation and cell cycle of osteoblasts.

Methods

The expression of Orai1 was inhibited by Orai1 small interfering RNA (siRNA) in MC3T3-E1 cells. Following Orai1 downregulation, cell proliferation and cell cycle were examined. Furthermore, the expression of cyclin D1, cyclin E, CDK4, and CDK6 was analyzed. The activity of the Ras-NF-κB signaling pathway was investigated to identify the role of Orai1 in the regulation of osteoblast proliferation.

Results

Orai1 was successfully downregulated in MC3T3-E1 cells by the Orai1 siRNA transfection (p < 0.05). We found that MC3T3-E1 cell proliferation was decreased, and the cell cycle was arrested by Orai1 downregulation (p < 0.05). Additionally, the expression of cyclin D1 was decreased by Orai1 downregulation (p < 0.05), as was the activity of the Ras-NF-κB signaling pathway (p < 0.05). Orai1 siRNA did not further reduce cell proliferation, the proportion of cells in the S phase, and cyclin D1 expression after chemical blockage of the Ras signaling pathway in MC3T3-E1 cells (p > 0.05).

Conclusions

The results reveal that Orai1 downregulation may reduce cyclin D1 expression by inactivating the Ras-NF-κB signaling pathway thus blocking osteoblast proliferation and cell cycle.
The Kocher-Langenbeck approach combined with robot-aided percutaneous anterior column screw fixation for transverse-oriented acetabular fractures: a retrospective study
Authors: Liu Zhao-jie , Gu Ya , Jia Jian
Published: April 2022

Objective

Transverse-oriented acetabular fractures (TOAFs), including transverse, transverse with posterior wall and T-shaped fractures, are always challenging for double-column reduction and fixation with minimally invasive method. The purpose of this study is to compare the therapeutic effects of robot-aided percutaneous anterior column screw fixation versus minimally invasive anterior plate fixation for TOAFs based on the Kocher-Langenbeck (K-L) approach.

Methods

Patients suffering TOAFs that were fixed by robot-aided percutaneous anterior column screw fixation or minimally invasive anterior plate fixation associated with posterior fixation via the K-L approach were divided into two groups: group A (screw fixation) and group B (plate fixation). Surgical time, blood loss, incision length for anterior fixation and complications were recorded. Fracture reduction quality was evaluated using criteria described by Matta. Fracture healing was assessed on the series of pelvic radiographs at each follow-up. Functional outcomes were investigated using the modified Postel Merle D’Aubigne score at the final follow-up.

Results

Twenty-nine patients with TOAFs, including 12 patients in group A and 17 patients in group B, were evaluated for study eligibility. The mean surgical time of anterior fracture fixation was 18.7 ± 4.6 min in group A and 33.4 ± 5.0 min in group B (P < 0.001). The amount of intraoperative blood loss was 615.6 ± 178.7 ml in group A and 719.3 ± 199.0 ml in group B (P < 0.001). Incision length for anterior fixation was 9.0 ± 1.8 mm in group A and 81.2 ± 7.3 mm in group B (P < 0.001). The complications related to the surgery of anterior column only occurred in group B (lateral femoral cutaneous nerve palsy in 1 patient and groin discomfort in 1 patient). No significant differences in reduction quality, hospital stay, fracture healing time and functional results were noted between the two groups.

Conclusion

The K-L approach combined with robot-aided anterior column screw fixation is a safe and effective option for TOAFs. Compared with minimally invasive anterior plate fixation, robot-aided screw fixation has obvious advantages on surgical time, blood loss, and invasiveness. The K-L approach combined with minimally invasive anterior plate fixation can also be a reliable alternative for TOAFs, with the similar reduction quality and functional results.
Intraoperative navigation system with a multi-modality fusion of 3D virtual model and laparoscopic real-time images in laparoscopic pancreatic surgery: a preclinical study
Authors: Du Chengxu , Li Jiaxuan , Zhang Bin , Feng Wenfeng , Zhang Tengfei , Li Dongrui
Published: April 2022

Background

Laparoscopy is widely used in pancreatic surgeries nowadays. The efficient and correct judgment of the location of the anatomical structures is crucial for a safe laparoscopic pancreatic surgery. The technologies of 3-dimensional(3D) virtual model and image fusion are widely used for preoperative planning and intraoperative navigation in the medical field, but not in laparoscopic pancreatic surgery up to now. We aimed to develop an intraoperative navigation system with an accurate multi-modality fusion of 3D virtual model and laparoscopic real-time images for laparoscopic pancreatic surgery.

Methods

The software for the navigation system was developed ad hoc. The preclinical study included tests with the laparoscopic simulator and pilot cases. The 3D virtual models were built using preoperative Computed Tomography (CT) Digital Imaging and Communications in Medicine (DICOM) data. Manual and automatic real-time image fusions were tested. The practicality of the navigation system was evaluated by the operators using the National Aeronautics and Space Administration-Task Load Index (NASA-TLX) method.

Results

The 3D virtual models were successfully built using the navigation system. The 3D model was correctly fused with the real-time laparoscopic images both manually and automatically optical orientation in the preclinical tests. The statistical comparative tests showed no statistically significant differences between the scores of the rigid model and those of the phantom model(P > 0.05). There was statistically significant difference between the total scores of automatic fusion function and those of manual fusion function (P = 0.026). In pilot cases, the 3D model was correctly fused with the real-time laparoscopic images manually. The Intraoperative navigation system was easy to use. The automatic fusion function brought more convenience to the user.

Conclusions

The intraoperative navigation system applied in laparoscopic pancreatic surgery clearly and correctly showed the covered anatomical structures. It has the potentiality of helping achieve a more safe and efficient laparoscopic pancreatic surgery.
BMC Endocrine Disorders’ collection of articles on “Reducing inequalities in the Management of Endocrine Disorders”
Authors: Mentis Alexios-Fotios A. , Chrousos George P.
Published: April 2022

Endocrine disorders represent a large component of the so-called “chronic non-communicable diseases”, which are responsible for the lion share of morbidity and mortality in contemporary societies. As discussed in this retrospective collection of articles, solid evidence from diabetes mellitus, the exemplar of common chronic endocrine disorders, highlights profound inequity in all aspects of endocrine disorders’ management and outcomes that should be considered and addressed at large.
The side effects of dopamine receptor agonist drugs in Chinese prolactinoma patients: a cross sectional study
Authors: Ke Xiaoan , Wang Linjie , Chen Meiping , Liu Shanshan , Yu Na , Duan Lian , Gong Fengying , Zhu Huijuan
Published: April 2022

Background

Recently, side effects from Dopamine Receptor Agonist Drugs (DAs) in treating pituitary prolactinoma have raised widespread concern. This study explores the incidence and influencing factors of DAs-related side effects in Chinese prolactinoma patients.

Methods

A cross-sectional study was conducted. 51 prolactinoma patients treated with DAs, 12 prolactinoma or pituitary microadenoma patients without DAs treatment, and 33 healthy controls were included. The Barratt impulsivity scale-11, Patient Health Questionnaire 9, and the ICD screening questionnaire were all used to evaluate the psychological and physical side effects of DAs. Clinical data of all subjects were collected from their electronic medical records.

Results

The incidence of ICDs in the treated group, the untreated group, and control group was 9.8% (5/51), 16.7% (2/12), and 9.1% (3/33), respectively. In the treated group in particular, there were 1 patient (2%, 1/51), 2 patients (3.9%, 2/51), and 2 patients (3.9%, 2/51) with positive screening for punding, compulsive shopping, and hypersexuality, respectively. In terms of depression, the incidence of "minimal", "mild" and "moderate" depression in the treated group was 62.8% (32/51), 25.5% (13/51), and 5.9% (3/51), respectively. The incidence of physical symptoms was 51.0% (26/51) in the treated group and gastrointestinal symptoms were the most common symptoms (33.3%, 17/51). In addition, we found that the various parameters of DAs treatment had no association with the occurrence of physical symptoms or ICDs (all P > 0.05).

Conclusions

Chinese prolactinoma patients treated with DAs had a lower incidence of ICDs (9.8%), while gastrointestinal symptoms were common. In this way, more attention should be paid to side effects, especially physical symptoms, in Chinese prolactinoma patients with DAs therapy during follow-up regardless of dose.
Clinical and genetic analysis of pseudohypoparathyroidism complicated by hypokalemia: a case report and review of the literature
Authors: Huang Shaohan , He Yingzi , Lin Xihua , Sun Shuiya , Zheng Fenping
Published: April 2022

Background

Pseudohypoparathyroidism (PHP) encompasses a highly heterogenous group of disorders, characterized by parathyroid hormone (PTH) resistance caused by mutations in the GNAS gene or other upstream targets. Here, we investigate the characteristics of a female patient diagnosed with PHP complicated with hypokalemia, and her family members.

Case presentation and gene analysis

A 27-year-old female patient occasionally exhibited asymptomatic hypocalcemia and hypokalemia during her pregnancy 1 year ago. Seven months after delivery, she experienced tetany and dysphonia with diarrhea. Tetany symptoms were relieved after intravenous calcium gluconate supplementation and she was then transferred to our Hospital. Laboratory assessments of the patient revealed hypokalemia, hypocalcemia and hyperphosphatemia despite elevated PTH levels. CT scanning of the brain revealed globus pallidus calcification. Possible mutations in GNAS and hypokalemia related genes were identified using WES, exon copies of STX16 were analized by MLPA and the methylation status of GNAS in three differential methylated regions (DMRs) was analyzed by methylation-specific polymerase chain reaction, followed by confirmation with gene sequencing. The patient was clinically diagnosed with PHP-1b. Loss of methylation in the A/B region and hypermethylation in the NESP55 region were detected. No other mutations in GNAS or hypokalemia related genes and no deletions of STX16 exons were detected. A negative family history and abnormal DMRs in GNAS led to a diagnosis of sporadic PHP-1b of the patient.

Conclusions

Hypokalemia is a rare disorder associated with PHP-1b. Analysis of genetic and epigenetic mutations can aid in the diagnosis and accurate subtyping of PHP.
Factors associated with a reduced food intake after third molar extraction among adults: a cross-sectional study
Authors: Taniguchi Shinichi , Abe Atsushi , Ito Yu , Ishihama Takanori , Hayashi Hiroki , Momokita Moeko , Naito Ryuta , Shibata Kanae
Published: April 2022

Background

Functional impairment after third molar extraction may decrease the food intake. Elucidation of associated factors will contribute to a more appropriate postoperative nutritional management, and was the aim of the present study.

Methods

Adults aged < 60 years who were admitted for an extraction of one or more mandibular third molars were included. Those with diabetes mellitus, anemia, metabolic diseases, mental retardation, altered dietary intake, and postoperative paralysis of the lower lip and tongue were excluded. Patient-specific risk factors were compared in relation to a decrease in the food intake on postoperative day 1. Multivariate analysis took into account the patients’ background factors.

Results

A total of 254 patients were included (median age: 26.8 ± 9.3 years, 142 women); 508 third molars were extracted. Postoperative dietary intake reduction was more common (p < 0.05) after an exclusively mandibular extraction (16.0%) than after an extraction including the maxilla (29.4%). The reduction was also more common (p < 0.05) for an extraction difficulty of Pell–Gregory class III (39.5%) than for extraction difficulties of Pell–Gregory classes I (22.6%) and II (21.3%). The reduction was also more common (p < 0.05) in patients who experienced postoperative pain (66.7%) than in those who did not (23.3%). Significant differences were observed in sex (women: 34.5%, men: 11.6%) and age (young patients [< 26 years]: 31.1%, adult patients [≥ 26 years]: 17.2%); however, no significant difference was found in terms of experiencing trismus (p < 0.11). Simple regression analysis showed significant differences between patients who did and did not have a reduced postoperative food intake depending on the sex, age, extraction site, degree of extraction difficulty, trismus, and postoperative pain. Reduced dietary intake was significantly associated with sex (odds ratio [OR]: 0.30; 95% confidence interval [CI]: 0.14–0.38), age (OR: 1.6; 95% CI: 1.0–2.5), extraction site (OR: 0.51; 95% CI: 0.31–0.83), difficulty of extraction (OR: 0.66; 95% CI: 0.50–0.88), and postoperative pain (OR: 0.12; 95% CI: 0.04–0.37).

Conclusions

A younger age, female sex, extraction including the maxilla with deep implantation, and complaints of pain on postoperative day 1 were factors associated with a decreased food intake after third molar extraction.
Crossword puzzle as a learning tool to enhance learning about anticoagulant therapeutics
Authors: Bawazeer Ghada , Sales Ibrahim , Albogami Huda , Aldemerdash Ahmed , Mahmoud Mansour , Aljohani Majidah A. , Alhammad Abdullah
Published: April 2022

Background

Educational games make the learning process more enjoyable, fun, and create a competitive classroom environment that can positively affect learning. The purpose of this study was to evaluate pharmacy students’ perceptions of crossword puzzles (CWPs) as a learning tool in the pharmacotherapy cardiovascular module focusing on anticoagulants’ therapeutics and assessing if students’ preference of learning style influenced their perception.

Methods

Clues for the puzzle were developed, validated, and piloted by course faculty. A free internet puzzle generator was used to create puzzles with 10 to 20 clues. Students were given 30 min to solve the puzzle following six hours of didactic lectures about the topic. An 8-item survey instrument and Pharmacists’ Inventory of Learning Styles (PILS) questionnaire were administered to examine students’ perceptions of the game and their learning style preference, respectively.

Results

Two hundred sixty-seven students participated in the activity from both undergraduate programs (BPharm and PharmD) over three consecutive course offerings. Most students expressed favorable perceptions of the puzzle. Female and BPharm students had significantly more favorable perceptions than male and PharmD students on several perception items. The dominant preferred learning style (PLS) was converger (35.6%), followed by assimilator (25.3%), while 15.1% had mixed learning styles. The study did not find a significant association between PLS and students’ perceptions toward the CWP.

Conclusions

The CWP game presented an innovative, creative, and easy active learning tool to enhance information recall, retention, and class engagement while accommodating all learning style preferences.
What ethical approaches are used by scientists when sharing health data? An interview study
Authors: Viberg Johansson Jennifer , Bentzen Heidi Beate , Mascalzoni Deborah
Published: April 2022

Background

Health data-driven activities have become central in diverse fields (research, AI development, wearables, etc.), and new ethical challenges have arisen with regards to privacy, integrity, and appropriateness of use. To ensure the protection of individuals’ fundamental rights and freedoms in a changing environment, including their right to the protection of personal data, we aim to identify the ethical approaches adopted by scientists during intensive data exploitation when collecting, using, or sharing peoples’ health data.

Methods

Twelve scientists who were collecting, using, or sharing health data in different contexts in Sweden, were interviewed. We used systematic expert interviews to access these scientists’ specialist knowledge, and analysed the interviews with thematic analysis. Phrases, sentences, or paragraphs through which ethical values and norms were expressed, were identified and coded. Codes that reflected similar concepts were grouped, subcategories were formulated, and categories were connected to traditional ethical approaches.

Results

Through several examples, the respondents expressed four different ethical approaches, which formed the main conceptual categories: consideration of consequences, respect for rights, procedural compliance, and being professional.

Conclusions

To a large extent, the scientists’ ethical approaches were consistent with ethical and legal principles. Data sharing was considered important and worth pursuing, even though it is difficult. An awareness of the complex issues involved in data sharing was reflected from different perspectives, and the respondents commonly perceived a general lack of practical procedures that would by default ensure ethical and legally compliant data collection and sharing. We suggest that it is an opportune time to move on from policy discussions to practical technological ethics-by-design solutions that integrate these principles into practice.
Evaluation of a cross-sectoral care intervention for families with psychosocial burden: a study protocol of a controlled trial
Authors: Metzner Gloria , Horstmann Sabine , Barth Michael , Giesler Jürgen M. , Jünemann Susanne , Kaier Klaus , Schlett Christian , Schroeder Nora , Siebolds Marcus , Sinss Frank , van Staa Juliane , Glattacker Manuela , Renner Ilona
Published: April 2022

Background

Family risk factors, e.g. low socioeconomic status or parental mental health disorders, can affect children’s health and development. Thus, targeted preventive services for families with psychosocial burden are crucial. The German Early Childhood Intervention (ECI) program is a preventive approach that aims to strengthen parent’s resources by supportive services. However, research has revealed that only a proportion of the families considered to have substantial risk factors access the ECI program. To increase pediatricians’ skills in identifying risk factors, and to improve the cross-sectoral collaboration between relevant professionals and the referral of families to supportive services, the PATH-intervention (Pediatric Attention To Help) was developed. The PATH-intervention includes interprofessional quality circles and a one-day training program for the pediatricians. This study aims to evaluate this complex cross-sectoral care intervention for families with psychosocial burden.

Methods

Using a prospective quasi-experimental, controlled (matched-pair), longitudinal mixed-method design, we will compare families under treatment of pediatricians trained in the PATH-intervention with families under treatment of a control group of pediatricians. Participating families are asked to complete online-surveys. As a primary outcome, we will examine the use of supportive services of the ECI by burdened families. Secondary outcomes are the proportion of correctly identified families with psychosocial burden by the pediatricians, as well as information provision and motivation of the families to use the supportive services. Additionally, the cost-effectiveness ratio will be investigated. In the process evaluation, we will qualitatively explore the acceptance of the PATH-intervention of all involved stakeholders and the treatment fidelity of the trained pediatricians.

Discussion

This study will determine whether the PATH-intervention enables the pediatricians to identify and recommend supportive services to burdened families, as well as the families’ use of the supportive services of the ECI. Qualitative data will give insight into the acceptance of the intervention from the perspective of all stakeholders and the treatment fidelity. Results of this study could be the starting point for the broader implementation of the PATH-intervention as standard care.

Trial registration

German Clinical Trials Register (DRKS): DRKS00023461 (3rd December 2020); WHO UTN: U1111- 260-6575.
High activity and high functional connectivity are mutually exclusive in resting state zebrafish and human brains
Authors: Zarei Mahdi , Xie Dan , Jiang Fei , Bagirov Adil , Huang Bo , Raj Ashish , Nagarajan Srikantan , Guo Su
Published: April 2022

Background

The structural connectivity of neurons in the brain allows active neurons to impact the physiology of target neuron types with which they are functionally connected. While the structural connectome is at the basis of functional connectome, it is the functional connectivity measured through correlations between time series of individual neurophysiological events that underlies behavioral and mental states. However, in light of the diverse neuronal cell types populating the brain and their unique connectivity properties, both neuronal activity and functional connectivity are heterogeneous across the brain, and the nature of their relationship is not clear. Here, we employ brain-wide calcium imaging at cellular resolution in larval zebrafish to understand the principles of resting state functional connectivity.

Results

We recorded the spontaneous activity of >12,000 neurons in the awake resting state forebrain. By classifying their activity (i.e., variances of ΔF/F across time) and functional connectivity into three levels (high, medium, low), we find that highly active neurons have low functional connections and highly connected neurons are of low activity. This finding holds true when neuronal activity and functional connectivity data are classified into five instead of three levels, and in whole brain spontaneous activity datasets. Moreover, such activity-connectivity relationship is not observed in randomly shuffled, noise-added, or simulated datasets, suggesting that it reflects an intrinsic brain network property. Intriguingly, deploying the same analytical tools on functional magnetic resonance imaging (fMRI) data from the resting state human brain, we uncover a similar relationship between activity (signal variance over time) and functional connectivity, that is, regions of high activity are non-overlapping with those of high connectivity.

Conclusions

We found a mutually exclusive relationship between high activity (signal variance over time) and high functional connectivity of neurons in zebrafish and human brains. These findings reveal a previously unknown and evolutionarily conserved brain organizational principle, which has implications for understanding disease states and designing artificial neuronal networks.
Combined obstructive airflow limitation associated with interstitial lung diseases (O-ILD): the bad phenotype ?
Authors: Guiot Julien , Henket Monique , Frix Anne-Noëlle , Gester Fanny , Thys Marie , Giltay Laurie , Desir Colin , Moermans Catherine , Njock Makon-Sébastien , Meunier Paul , Corhay Jean-Louis , Louis Renaud
Published: April 2022

Background

Patients suffering from combined obstructive and interstitial lung disease (O-ILD) represent a pathological entity which still has to be well clinically described. The aim of this descriptive and explorative study was to describe the phenotype and functional characteristics of a cohort of patients suffering from functional obstruction in a population of ILD patients in order to raise the need of dedicated prospective observational studies and the evaluation of the impact of anti-fibrotic therapies.

Methods

The current authors conducted a retrospective study including 557 ILD patients, with either obstructive (O-ILD, n = 82) or non-obstructive (non O-ILD, n = 475) pattern. Patients included were mainly males (54%) with a mean age of 62 years.

Results

Patients with O-ILD exhibited a characteristic functional profile with reduced percent predicted forced expired volume in 1 s (FEV1) [65% (53–77) vs 83% (71–96), p < 0.00001], small airway involvement assessed by maximum expiratory flow (MEF) 25/75 [29% (20–41) vs 81% (64–108), p < 0.00001], reduced sGaw [60% (42–75) vs 87% (59–119), p < 0.01] and sub-normal functional residual capacity (FRC) [113% (93–134) vs 92% (75–109), p < 0.00001] with no impaired of carbon monoxide diffusing capacity of the lung (DLCO) compared to those without obstruction. Total lung capacity (TLC) was increased in O-ILD patients [93% (82–107) vs 79% (69–91), p < 0.00001]. Of interest, DLCO sharply dropped in O-ILD patients over a 5-year follow-up. We did not identify a significant increase in mortality in patients with O-ILD. Interestingly, the global mortality was increased in the specific sub-group of patients with O-ILD and no progressive fibrosing ILD phenotype and in those with connective tissue disease associated ILD especially in case of rheumatoid arthritis.

Conclusions

The authors individualized a specific functional-based pattern of ILD patients with obstructive lung disease, who are at risk of increased mortality and rapid DLCO decline over time. As classically those patients are excluded from clinical trials, a dedicated prospective study would be of interest in order to define more precisely treatment response of those patients.
MicroRNA-146a promotes proliferation, migration, and invasion of HepG2 via regulating FLAP
Authors: Wang Huihui , Zhang Shubing , Li Tao , Wang Lianzi , Lv Wei , Wang Shanshan , Ma Dongyue , Zang Yan , Zhu Xinyue , Xu Yuanhong , Zheng Lan , Shen Jilong , Wei Wei
Published: April 2022

Abnormal expression of 5-Lipoxygenase Activating Protein (FLAP) has been detected in many tumor cells. MicroRNAs (miRNAs) negatively regulate gene expression post-transcriptionally by binding to the 3'–untranslated region (3'–UTR) of the target mRNA sequences and have been shown to be involved in various types of cancers. Herein, we aimed to demonstrate the expression of miR-146a and FLAP in human HCC tissues and liver cancer cell lines. We demonstrated that miR-146a expression is overexpressed, while FLAP protein and mRNA are suppressed in hepatocellular carcinoma tissues and HepG2 cells compared to para-carcinoma tissues and HL–7702 cells. Dual luciferase reporter gene assay showed that miR-146a-5p can directly target FLAP mRNA. Knockdown of miR-146a also resulted in increased FLAP expression of cancer cells. Additionally, miR-146a silencing or restoration of FLAP led to a reduction of HepG2 cell proliferation, cell cycle progression, migration, and invasion. This study showed that miR-146a has a stimulatory role in HepG2 cells and promotes HepG2 cell migration and invasion by targeting FLAP mRNA. Thus, miR-146a may be a tumor promoter and a potential therapeutic target for the treatment of HCC patients.
Proteolysis-targeting chimeras (PROTACs) in cancer therapy
Authors: Li Xinyi , Pu Wenchen , Zheng Qingquan , Ai Min , Chen Song , Peng Yong
Published: April 2022

Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted protein degradation. A bifunctional PROTAC molecule with two covalently-linked ligands recruits target protein and E3 ubiquitin ligase together to trigger proteasomal degradation of target protein by the ubiquitin-proteasome system. PROTAC has emerged as a promising approach for targeted therapy in various diseases, particularly in cancers. In this review, we introduce the principle and development of PROTAC technology, as well as the advantages of PROTACs over traditional anti-cancer therapies. Moreover, we summarize the application of PROTACs in targeting critical oncoproteins, provide the guidelines for the molecular design of PROTACs and discuss the challenges in the targeted degradation by PROTACs.
Mitigating psychological distress in healthcare workers as COVID-19 waves ensue: a repeated cross-sectional study from Jordan
Authors: Obeidat Nour A. , Dodin Yasmeen I. , Hawari Feras I. , Albtoosh Asma S. , Manasrah Rasha M. , Mansour Asem H.
Published: April 2022

Background

Jordan has experienced several COVID-19 waves in the past 2 years. Cross-sectional studies have been conducted to evaluate distress in healthcare practitioners (HCPs), but there is limited evidence with regards to the impact of continuing pandemic waves on levels of distress in HCPs. We previously studied psychological distress in HCPs during the start of the pandemic (period 1, when cases were infrequent and the country was in lockdown), and demonstrated that HCPs were experiencing considerable stress, despite the country reporting low caseloads at the time. In this study, we sought to utilize the same methodology to reexamine levels of distress as COVID-19 peaked in the country and HCPs began managing large numbers of COVID-19 cases (period 2).

Methods

A cross-sectional online survey utilizing a tool previously used during period 1 was completed by HCPs working in various settings. Demographic, professional and psychological factors such as distress, anxiety, depression, burnout, sleep issues, exhaustion, and fear were assessed; and coping strategies also were measured. Items in the tool were assessed for reliability and validity. A multivariable regression was used to identify factors that continued to impact distress during period 2.

Results

Samples in both periods (n = 937,n = 876, respectively) were relatively comparable in demographic characteristics, but in period 2, a greater proportion of nurses and healthcare practitioners reported working in general hospitals. During the pandemic peak (period 2), 49.0% of HCPs reported high levels of distress (compared to 32% in period 1); anxiety and depression scores were approximately 21% higher in period 2; and 50.6% reported fatigue (compared to 34.3% in period 1). Variables significantly associated with greater distress in period 2 included experiencing burnout, experiencing sleep disturbances, being fatigued, having fatalistic fears, and having fears related to workload. Conversely, being male, reporting satisfaction at work, and using positive coping practices were associated with a significantly lower odds of being in distress.

Conclusions

Between the two periods (early pandemic and first wave), COVID-19-related mental health continued to deteriorate among HCPs, highlighting the need to do more to support HCP front-liners facing COVID-19 surges.
Irritable bowel syndrome and microbiome; Switching from conventional diagnosis and therapies to personalized interventions
Authors: Ghaffari Pouyan , Shoaie Saeed , Nielsen Lars K.
Published: April 2022

The human microbiome has been linked to several diseases. Gastrointestinal diseases are still one of the most prominent area of study in host-microbiome interactions however the underlying microbial mechanisms in these disorders are not fully established. Irritable bowel syndrome (IBS) remains as one of the prominent disorders with significant changes in the gut microbiome composition and without definitive treatment. IBS has a severe impact on socio-economic and patient’s lifestyle. The association studies between the IBS and microbiome have shed a light on relevance of microbial composition, and hence microbiome-based trials were designed. However, there are no clear evidence of potential treatment for IBS. This review summarizes the epidemiology and socioeconomic impact of IBS and then focus on microbiome observational and clinical trials. At the end, we propose a new perspective on using data-driven approach and applying computational modelling and machine learning to design microbiome-aware personalized treatment for IBS.
A novel rat model for cerebral venous sinus thrombosis: verification of similarity to human disease via clinical analysis and experimental validation
Authors: Mu Shuwen , Lin Yinghong , Xu Yongjun , Wei Xianqing , Zeng Zihuan , Lin Kunzhe , Zhu Linghua , Liu Qinghong , Qi Xingfeng , Wei Liangfeng , Liang Shengxiang , Wang Shousen
Published: April 2022

Background

Cerebral venous sinus thrombosis (CVST) is a rare neurovascular disorder with highly variable manifestations and clinical courses. Animal models properly matched to the clinical form of CVST are necessary for elucidating the pathophysiology of the disease. In this study, we aimed to establish a rat model that accurately recapitulates the clinical features of CVST in human patients.

Methods

This study consisted of a clinical analysis and animal experiments. Clinical data for two centres obtained between January 2016 and May 2021 were collected and analysed retrospectively. In addition, a Sprague–Dawley rat model of CVST was established by inserting a water-swellable rubber device into the superior sagittal sinus, following which imaging, histological, haematological, and behavioural tests were used to investigate pathophysiological changes. Principal component analysis and hierarchical clustering heatmaps were used to evaluate the similarity between the animal models and human patients.

Results

The imaging results revealed the possibility of vasogenic oedema in animal models. Haematological analysis indicated an inflammatory and hypercoagulable state. These findings were mostly matched with the retrospective clinical data. Pathological and serological tests further revealed brain parenchymal damage related to CVST in animal models.

Conclusions

We successfully established a stable and reproducible rat model of CVST. The high similarity between clinical patients and animal models was verified via cluster analysis. This model may be useful for the study of CVST pathophysiology and potential therapies.
Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report
Authors: Broser Philip , von Mengershausen Ursula , Heldt Katrin , Bartholdi Deborah , Braun Dominique , Wolf Christine , Lee-Kirsch Min Ae
Published: April 2022

Background

Singleton-Merten syndrome 1 (SGMRT1) is a rare type I interferonopathy caused by heterozygous mutations in the IFIH1 gene. IFIH1 encodes the pattern recognition receptor MDA5 which senses viral dsRNA and activates antiviral type I interferon (IFN) signaling. In SGMRT1, IFIH1 mutations confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation.

Case presentation

We report the case of a nine year old child who initially presented with a slowly progressive decline of gross motor skill development and muscular weakness. At the age of five years, he developed osteoporosis, acro-osteolysis, alveolar bone loss and severe psoriasis. Whole exome sequencing revealed a pathogenic de novo IFIH1 mutation, confirming the diagnosis of SGMRT1. Consistent with constitutive type I interferon activation, patient blood cells exhibited a strong IFN signature as shown by marked up-regulation of IFN-stimulated genes. The patient was started on the Janus kinase (JAK) inhibitor, ruxolitinib, which inhibits signaling at the IFN-α/β receptor. Within days of treatment, psoriatic skin lesions resolved completely and the IFN signature normalized. Therapeutic efficacy was sustained and over the course muscular weakness, osteopenia and growth also improved.

Conclusions

JAK inhibition represents a valuable therapeutic option for patients with SGMRT1. Our findings also highlight the potential of a patient-tailored therapeutic approach based on pathogenetic insight.
Identification of a conserved neutralizing epitope in Seneca Valley virus VP2 protein: new insight for epitope vaccine designment
Authors: Wen Wei , Chen Xinghua , Lv Qiang , Chen Huanchun , Qian Ping , Li Xiangmin
Published: April 2022

Background

Seneca Valley virus (SVV) is a picornavirus that causes vesicular disease in swine. Clinical characteristics of the disease are similar to common viral diseases such as foot-and-mouth disease virus, porcine vesicular disease virus, and vesicular stomatitis virus, which can cause vesicles in the nose or hoof of pigs. Therefore, developing tools for detecting SVV infection is critical and urgent.

Methods

The neutralizing antibodies were produced to detect the neutralizing epitope.

Results

Five SVV neutralizing monoclonal antibodies (mAb), named 2C8, 3E4, 4C3, 6D7, and 7C11, were generated by immunizing mouses with ultra-purified SVV-LNSY01-2017. All five monoclonal antibodies exhibited high neutralizing titers to SVV. The epitopes targeted by these mAbs were further identified by peptide scanning using GST fusion peptides. The peptide 153QELNEE158 is defined as the smallest linear neutralizing epitope. The antibodies showed no reactivity to VP2 single mutants E157A. Furthermore, the antibodies showed no neutralizing activity with the recombinant virus (SVV-E157A).

Conclusions

The five monoclonal antibodies and identified epitopes may contribute to further research on the structure and function of VP2 and the development of diagnostic methods for detecting different SVV strains. Additionally, the epitope recognized by monoclonal antibodies against VP2 protein may provide insights for novel SVV vaccines and oncolytic viruses development.
Establishment and evaluation of a quadruple quantitative real-time PCR assay for simultaneous detection of human coronavirus subtypes
Authors: Zhao Mengchuan , Xu Yi , Zhang Dijun , Li Guixia , Gao Huixia , Zeng Xianping , Tie Yanqing , Wu Yong , Dai Erhei , Feng Zhishan
Published: April 2022

Background

The newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and four seasonal human coronaviruses (HCoVs) (HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1) still circulate worldwide. The early clinical symptoms of SARS-CoV-2 and seasonal HCoV infections are similar, so rapid and accurate identification of the subtypes of HCoVs is crucial for early diagnosis, early treatment, prevention and control of these infections. However, current multiplex molecular diagnostic techniques for HCoV subtypes including SARS-CoV-2 are limited.

Methods

We designed primers and probes specific for the S and N genes of SARS-CoV-2, the N gene of severe acute respiratory syndrome coronavirus (SARS-CoV), and the ORF1ab gene of four seasonal HCoVs, as well as the human B2M gene product. We developed and optimized a quadruple quantitative real-time PCR assay (qq-PCR) for simultaneous detection of SARS-CoV-2, SARS-CoV and four seasonal HCoVs. This assay was further tested for specificity and sensitivity, and validated using 184 clinical samples.

Results

The limit of detection of the qq-PCR assay was in the range 2.5 × 101 to 6.5 × 101 copies/μL for each gene and no cross-reactivity with other common respiratory viruses was observed. The intra-assay and inter-assay coefficients of variation were 0.5–2%. The qq-PCR assay had a 91.9% sensitivity and 100.0% specificity for SARS-CoV-2 and a 95.7% sensitivity and 100% specificity for seasonal HCoVs, using the approved commercial kits as the reference. Compared to the commercial kits, total detection consistency was 98.4% (181/184) for SARS-CoV-2 and 98.6% (142/144) for seasonal HCoVs.

Conclusion

With the advantages of sensitivity, specificity, rapid detection, cost-effectiveness, and convenience, this qq-PCR assay has potential for clinical use for rapid discrimination between SARS-CoV-2, SARS-CoV and seasonal HCoVs.
Characteristics and productivity of the chiropractic workforce of the Veterans Health Administration
Authors: Corcoran Kelsey L. , Peterson Douglas R. , Zhao Xiwen , Moran Eileen A. , Lisi Anthony J.
Published: April 2022

Background

Increasingly, integrated healthcare systems such as the United States Veterans Health Administration (VHA) are employing chiropractors. However, little is known about chiropractor employee clinical productivity which may be important for resource planning and monitoring care delivery. With its history of delivering chiropractic care and its enterprise-level assessment metrics, the VHA is an ideal setting to study a chiropractic workforce. We aim to assess characteristics of chiropractors employed by the VHA and explore associations between these characteristics and clinical productivity.

Methods

This was a cross-sectional and serial analyses of VHA administrative data. Characteristics of the chiropractor workforce were evaluated from fiscal year (FY) 2016 to FY2019. Productivity was calculated using the VHA productivity measure, the quotient of an individual’s total work relative value units (wRVUs) per FY divided by the direct clinical full-time equivalent (FTE) worked. A multivariable regression model was used to analyze the association between productivity and characteristics of the chiropractor and VHA facility.

Results

From FY2016 to FY2019, the number of chiropractor employees increased from 102 to 167. In FY2019, the typical chiropractor employee was male, white, and 45.9 years old with 5.2 years of VHA experience. In FY2019, the VHA chiropractor workforce was 25.1% female, 79% white, and 20.4% Veteran. The productivity measure of a chiropractor was 3040 in FY2019. A higher facility complexity measure, presence of 3 chiropractor employees at a facility, and older age of the providers were the only characteristics studied that had a significant impact on productivity after adjusting for other covariates.

Conclusion

Provider characteristics and productivity metrics of the VHA chiropractor employee workforce are presented. The productivity measure provides an initial benchmarking that may be relevant to future modeling of chiropractor personnel in VHA and other healthcare systems.