bluuebunny/crossref_metadata_2025 huggingface dataset:
Modifiable and non-modifiable risk factors for obstetric anal sphincter injury in a Norwegian Region: a case–control study
Authors: Klokk Ragnhild , Bakken Kjersti S. , Markestad Trond , Holten-Andersen Mads N.
Published: April 2022

Background

Obstetric anal sphincter injury (OASI) is a common and severe complication of vaginal delivery and may have short- and long-term consequences, including anal incontinence, sexual dysfunction and reduced quality of life. The rate of OASI varies substantially between studies and national birth statistics, and a recent meta-analysis concluded that there is a need to identify unrecognized risk factors. Our aim was therefore to explore both potential modifiable and non-modifiable risk factors for OASI.

Methods

We performed a case–control study in a single center maternity clinic in South-Eastern Norway. Data were extracted retrospectively from an institutional birth registry. The main outcome measure was the occurrence of the woman’s first-time 3rd or 4th degree perineal lesion (OASI) following singleton vaginal birth after 30 weeks’ gestation. For each woman with OASI the first subsequent vaginal singleton delivery matched for parity was elected as control. The study population included 421 women with OASI and 421 matched controls who gave birth during 1990–2002. Potential risk factors for OASI were assessed by conditional logistic regression analyses.

Results

The mean incidence of OASI was 3.4% of vaginal deliveries, but it increased from 1.9% to 5.8% during the study period. In the final multivariate regression model, higher maternal age and birthweight for primiparous women, and higher birthweight for the multiparous women, were the only non-modifiable variables associated with OASI. Amniotomy was the strongest modifiable risk factor for OASI in both primi- (odds ratio [OR] 4.84; 95% confidence interval [CI] 2.60–9.02) and multiparous (OR 3.76; 95% CI 1.45–9.76) women, followed by augmentation with oxytocin (primiparous: OR 1.63; 95% CI 1.08–2.46, multiparous: OR 3.70; 95% CI 1.79–7.67). Vacuum extraction and forceps delivery were only significant risk factors in primiparous women (vacuum: OR 1.91; 95% CI 1.03–3.57, forceps: OR 2.37; 95% CI 1.14–4.92), and episiotomy in multiparous women (OR 2.64; 95% CI 1.36–5.14).

Conclusions

Amniotomy may be an unrecognized independent modifiable risk factor for OASI and should be further investigated for its potential role in preventive strategies.
Clustering of countries according to the COVID-19 incidence and mortality rates
Authors: Gohari Kimiya , Kazemnejad Anoshirvan , Sheidaei Ali , Hajari Sarah
Published: April 2022

Background

Two years after the beginning of the COVID-19 pandemic on December 29, 2021, there have been 281,808,270 confirmed cases of COVID-19, including 5,411,759 deaths. This information belongs to almost 216 Countries, areas, or territories facing COVID-19. The disease trend was not homogeneous across these locations, and studying this variation is a crucial source of information for policymakers and researchers. Therefore, we address different patterns in mortality and incidence of COVID-19 across countries using a clustering approach.

Methods

The daily records of new cases and deaths of 216 countries were available on the WHO online COVID-19 dashboard. We used a three-step approach for identifying longitudinal patterns of change in quantitative COVID-19 incidence and mortality rates. At the first, we calculated 27 summary measurements for each trajectory. Then we used factor analysis as a dimension reduction method to capture the correlation between measurements. Finally, we applied a K-means algorithm on the factor scores and clustered the trajectories.

Results

We determined three different patterns for the trajectories of COVID-19 incidence and the three different ones for mortality rates. According to incidence rates, among 206 countries the 133 (64.56) countries belong to the second cluster, and 15 (7.28%) and 58 (28.16%) belong to the first and 3rd clusters, respectively. All clusters seem to show an increased rate in the study period, but there are several different patterns. The first one exhibited a mild increasing trend; however, the 3rd and the second clusters followed the severe and moderate increasing trend. According to mortality clusters, the frequency of sets is 37 (18.22%) for the first cluster with moderate increases, 157 (77.34%) for the second one with a mild rise, and 9 (4.34%) for the 3rd one with severe increase.

Conclusions

We determined that besides all variations within the countries, the pattern of a contagious disease follows three different trajectories. This variation looks to be a function of the government’s health policies more than geographical distribution. Comparing this trajectory to others declares that death is highly related to the nature of epidemy.
Application of network teaching in nursing undergraduate education during the coronavirus disease 2019 epidemic
Authors: Chen Xiuwen , Liu Shiqing , Tao Zirong , Ou Yangyang , Xiao Yao
Published: April 2022

Background and objectives

Coronavirus disease 2019 (COVID-19) is currently raging all over the world. COVID-19 can be transmitted among humans. To control the spread of the epidemic and meet the learning needs of students, Chinese universities have used a variety of multimedia forms to conduct online teaching. However, the influence of different teaching methods on the learning effects of nursing students has not been conclusive, and few studies have directly compared the differences in the effects of different teaching methods. Therefore, it is necessary to evaluate the impact of different teaching methods on students’ learning effects.

Methods

A total of 119 participants from the graduating class of 2022 performed 4 validated classes (fundamental nursing, medical nursing, surgical nursing, and paediatric nursing) through network teaching. A total of 126 participants from the graduating class of 2021 used the traditional teaching method and were enrolled as a control group. All participants completed a questionnaire, which was designed by the school for teaching evaluation, and took a test after the courses.

Results

A total of 245 nursing undergraduates were ultimately enrolled. The analysis of the academic performance and the student evaluations from the four courses showed no significant difference between the network teaching group and the traditional teaching group for nursing undergraduates (all P > 0.05).

Conclusion

Through the convenience of network teaching, teachers and students can choose the time and place of both their teaching and learning independently. Moreover, such use effectively prevents the spread of the epidemic. After the epidemic concludes, the continued use of the network teaching method can help improve teaching efficiency by being combined with the traditional teaching method.
Balancing standardisation and individualisation in transitional care pathways: a meta-ethnography of the perspectives of older patients, informal caregivers and healthcare professionals
Authors: Kvæl Linda Aimée Hartford , Hellesø Ragnhild , Bergland Astrid , Debesay Jonas
Published: April 2022

Background

Transitional care implies the transfer of patients within or across care settings in a seamless and safe way. For frail, older patients with complex health issues, high-quality transitions are especially important as these patients typically move more frequently within healthcare settings, requiring treatment from different providers. As transitions of care for frail people are considered risky, securing the quality and safety of these transitions is of great international interest. Nevertheless, despite efforts to improve quality in transitional care, research indicates that there is a lack of clear guidance to deal with practical challenges that may arise. The aim of this article is to synthesise older patients, informal caregivers and healthcare professionals’ experiences of challenges to achieving high-quality transitional care.

Methods

We used the seven-step method for meta-ethnography originally developed by Noblit and Hare. In four different but connected qualitative projects, the authors investigated the challenges to transitional care for older people in the Norwegian healthcare system from the perspectives of older patients, informal caregivers and healthcare professionals. In this paper, we highlight and discuss the cruciality of these challenging issues by synthesising the results from twelve articles.

Results

The analysis resulted in four themes: i) balancing person-centred versus efficient care, ii) balancing everyday patient life versus the treatment of illness, iii) balancing user choice versus “What Matters to You”, and iv) balancing relational versus practical care. These expressed challenges represent tensions at the system, organisation and individual levels based on partial competing assumptions on person-centred-care-inspired individualisation endeavours and standardisation requirements in transitional care.

Conclusions

There is an urgent need for a clearer understanding of the tension between standardisation and individualisation in transitional care pathways for older patients to ensure better healthcare quality for patients and more realistic working environments for healthcare professionals. Incorporating a certain professional flexibility within the wider boundary of standardisation may give healthcare professionals room for negotiation to meet patients’ individual needs, while at the same time ensuring patient flow, equity and evidence-based practice.
Failure mode effect and criticality analysis of ultrasound device by classification tracking
Authors: Wang Longchen , Li Bin , Hu Bing , Shen Guofeng , Zheng Yunxin , Zheng Yuanyi
Published: April 2022

Background

Medical ultrasound device has been more and more widely used in the hospital and Its safety risk is significantly increased when failures occur. However, there is a lack of quantitative risk assessments of different types of failure modes for medical ultrasound device. This study utilizes a failure mode, effect and criticality analysis (FMECA) approach for quantitative risk evaluation of different failure modes for ultrasound devices.

Methods

The 4216 medical ultrasound device failure records at various hospitals were investigated. A failure mode and effect analysis method was developed for the quantitative evaluation of the risks of different failure modes. Visual correlation analysis was conducted for all categories to identify the causes of various failure modes. Based on the severity, occurrence and detectability of the failure causes determined, the risk priority number (RPN) for each failure mode was back-calculated through the obtained tracking diagram.

Results

The failure modes of unclear images, unable to power on and dark shadows on an image had the highest RPNs. One failure mode could be caused by various factors, and the failure location was not necessarily related to the cause of the failure.

Conclusions

This quantitative approach more accurately evaluated the risks of different failure modes, and the results of the corresponding analysis of failure modes and causes could support the rapid determination of the causes of failures in clinical practice.
A versatile transposon-based technology to generate loss- and gain-of-function phenotypes in the mouse liver
Authors: Kopasz Anna Georgina , Pusztai Dávid Zsolt , Karkas Réka , Hudoba Liza , Abdullah Khaldoon Sadiq Ahmed , Imre Gergely , Pankotai-Bodó Gabriella , Migh Ede , Nagy Andrea , Kriston András , Germán Péter , Drubi Andrea Bakné , Molnár Anna , Fekete Ildikó , Dani Virág Éva , Ocsovszki Imre , Puskás László Géza , Horváth Péter , Sükösd Farkas , Mátés Lajos
Published: April 2022

Background

Understanding the contribution of gene function in distinct organ systems to the pathogenesis of human diseases in biomedical research requires modifying gene expression through the generation of gain- and loss-of-function phenotypes in model organisms, for instance, the mouse. However, methods to modify both germline and somatic genomes have important limitations that prevent easy, strong, and stable expression of transgenes. For instance, while the liver is remarkably easy to target, nucleic acids introduced to modify the genome of hepatocytes are rapidly lost, or the transgene expression they mediate becomes inhibited due to the action of effector pathways for the elimination of exogenous DNA. Novel methods are required to overcome these challenges, and here we develop a somatic gene delivery technology enabling long-lasting high-level transgene expression in the entire hepatocyte population of mice.

Results

We exploit the fumarylacetoacetate hydrolase (Fah) gene correction-induced regeneration in Fah-deficient livers, to demonstrate that such approach stabilizes luciferase expression more than 5000-fold above the level detected in WT animals, following plasmid DNA introduction complemented by transposon-mediated chromosomal gene transfer. Building on this advancement, we created a versatile technology platform for performing gene function analysis in vivo in the mouse liver. Our technology allows the tag-free expression of proteins of interest and silencing of any arbitrary gene in the mouse genome. This was achieved by applying the HADHA/B endogenous bidirectional promoter capable of driving well-balanced bidirectional expression and by optimizing in vivo intronic artificial microRNA-based gene silencing. We demonstrated the particular usefulness of the technology in cancer research by creating a p53-silenced and hRas G12V-overexpressing tumor model.

Conclusions

We developed a versatile technology platform for in vivo somatic genome editing in the mouse liver, which meets multiple requirements for long-lasting high-level transgene expression. We believe that this technology will contribute to the development of a more accurate new generation of tools for gene function analysis in mice.
Thyroid and endostyle development in cyclostomes provides new insights into the evolutionary history of vertebrates
Authors: Takagi Wataru , Sugahara Fumiaki , Higuchi Shinnosuke , Kusakabe Rie , Pascual-Anaya Juan , Sato Iori , Oisi Yasuhiro , Ogawa Nobuhiro , Miyanishi Hiroshi , Adachi Noritaka , Hyodo Susumu , Kuratani Shigeru
Published: April 2022

Background

The endostyle is an epithelial exocrine gland found in non-vertebrate chordates (amphioxi and tunicates) and the larvae of modern lampreys. It is generally considered to be an evolutionary precursor of the thyroid gland of vertebrates. Transformation of the endostyle into the thyroid gland during the metamorphosis of lampreys is thus deemed to be a recapitulation of a past event in vertebrate evolution. In 1906, Stockard reported that the thyroid gland in hagfish, the sister cyclostome group of lampreys, develops through an endostyle-like primordium, strongly supporting the plesiomorphy of the lamprey endostyle. However, the findings in hagfish thyroid development were solely based on this single study, and these have not been confirmed by modern molecular, genetic, and morphological data pertaining to hagfish thyroid development over the last century.

Results

Here, we showed that the thyroid gland of hagfish undergoes direct development from the ventrorostral pharyngeal endoderm, where the previously described endostyle-like primordium was not found. The developmental pattern of the hagfish thyroid, including histological features and regulatory gene expression profiles, closely resembles that found in modern jawed vertebrates (gnathostomes). Meanwhile, as opposed to gnathostomes but similar to non-vertebrate chordates, lamprey and hagfish share a broad expression domain of Nkx2-1/2-4, a key regulatory gene, in the pharyngeal epithelium during early developmental stages.

Conclusions

Based on the direct development of the thyroid gland both in hagfish and gnathostomes, and the shared expression profile of thyroid-related transcription factors in the cyclostomes, we challenge the plesiomorphic status of the lamprey endostyle and propose an alternative hypothesis where the lamprey endostyle could be obtained secondarily in crown lampreys.
GINS4 might be a novel prognostic immune-related biomarker of not only esophageal squamous cell carcinoma and other cancers
Authors: Jin Donghui , Yuan Ligong , Li Feng , Wang Shuaibo , Mao Yousheng
Published: April 2022

Background

Immunotherapy using immune checkpoint inhibitors (ICIs), such as antibody of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) has showed as a promising treatment for esophageal squamous cell carcinoma (ESCC), but resistance is unavoidable. This study aimed to find more immune-related genes to promote the efficiency of immunotherapy.

Materials and methods

Three datasets were downloaded from Gene Expression Omnibus (GEO) database. Gene differential analysis was performed to identify differentially expressed genes (DEGs), then ceRNA network was constructed based on differentially expressed lncRNAs and mRNAs. Next, Functional enrichment analysis and protein–protein interaction (PPI) network were built to reveal the potential function of mRNAs in ceRNA network. Survival analysis and immune cell infiltration level analysis were utilized to identify prognostic immune-related genes. Finally, pan-cancer analysis was performed to show the role of immune-related genes in other cancers.

Results

The data of 215 samples in total were obtained from GEO database (98 normal tissues and 117 tumor tissues), and 1685 differentially expressed mRNAs (176 downregulated and 1509 upregulated) and 3 upregulated lncRNAs (MCM3AP-AS1, HCP5 and GUSBP11, all upregulated) were found. ceRNA network was constructed to reveal some special correlation. Function enrichment showed some potential functions of mRNAs in ceRNA network such as mitotic cell cycle process, negative regulation of DNA-binding transcription factor activity, ossification, VEGFA-VEGFR2 signaling pathway, epithelial to mesenchymal transition, embryonic morphogenesis and so on. PPI network showed the physical interactions between each mRNA in ceRNA network. Through survival analysis and immune cell infiltration level analysis, GINS4 was confirmed as an immune-related prognostic gene in ESCC. GSEA showed some potential functions such as negative regulation of monocyte chemotaxis, antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, positive regulation of antigen processing and presentation, dendritic cell antigen processing and presentation and so on. Finally, pan-cancer analysis revealed that GINS4 might be a novel immune-related prognostic gene in ESCC and other cancers.

Conclusion

Our study suggested that GINS4 was correlated with prognosis and immune cell infiltration level of ESCC and other cancers. It may deserve further investigation as a potential immune-related prognostic biomarker of ESCC and other cancers.
Gonadotropins treatment prior to microdissection testicular sperm extraction in non-obstructive azoospermia: a single-center cohort study
Authors: Peng Tianwen , Liao Chen , Ye Xin , Chen Zhicong , Lan Yu , Fu Xin , An Geng
Published: April 2022

Background

Microdissection testicular sperm extraction (micro-TESE) in combination with ICSI can make paternity possible for non-obstructive azoospermia (NOA) patients. Testicular sperm can be successfully retrieved in nearly half of NOA patients. Nevertheless, not many convincing protocols are established to improve sperm retrieval rate (SRR). The goal of this study was to evaluate whether gonadotropins therapy before micro-TESE could improve sperm retrieval rate and affect the ICSI outcomes in non-obstructive azoospermia patients with hypergonadotropic hypogonadism.

Methods

This retrospective cohort study included a total of 569 non-obstructive azoospermia men who underwent micro-TESE with or without 3-month of preoperative hCG / hCG plus highly purified urinary FSH (uFSH) between January 2016 and December 2019. The primary outcome was the sperm retrieval rate of micro-TESE.

Results

Sperm was found in 27 patients among 395 NOA men who accepted preoperative gonadotropins treatment (6.8%, 27/395) in post-treatment semen analysis for ICSI. One hundred forty nine out of 542 patients could successfully obtain enough sperm for ICSI through the micro-TESE (overall SRR = 27.5%). There was a statistically significant difference in the SRR between the preoperative gonadotropins treatment and non-gonadotropins treatment groups (31.2%, 115/368 vs. 19.5%, 34/174,P = 0.006). In the multivariable analysis with IPTW according to the propensity score, there was a significant association between preoperative gonadotropins treatment and the SRR (OR, 1.59; 95% CI: 1.02–2.52;P = 0.042). No differences in the clinical pregnancy rate, live birth delivery rate, or miscarriage rate were observed between the two groups.

Conclusion

Preoperative gonadotropins therapy seems to have a role in improving SRR in NOA patients with hypergonadotropic hypogonadism. We found that gonadotropins therapy had no effect on ICSI clinical outcomes and live birth.
A simple approach to assess the cancer risk of occupational exposure to genotoxic drugs in healthcare settings
Authors: Gerding Johannes , Anhäuser Lea , Eickmann Udo , Nienhaus Albert
Published: April 2022

Background

Several drugs for human use possess genotoxic properties as a necessary consequence of their intended therapeutic effect (e.g. antineoplastics). Health workers may be exposed to these chemicals in various occupational settings such as dose preparation and administration. To date, there are no quantitative risk assessment models to estimate the cancer risk of health workers due to the handling of genotoxic drugs. We therefore developed a quantitative risk assessment model to assess the cancer risk of occupational exposure to genotoxic drugs in healthcare settings based on the threshold of toxicological concern (TTC) concept. This model was used to evaluate the cancer risk of health workers due to the handling of genotoxic drugs in modern health care facilities.

Methods

We modified the threshold of toxicological concern (TTC) concept to fit the purpose of occupational cancer risk assessment. The risk model underlying ICH guideline M7 (R1): “assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk” was used as a starting point for our model. We conducted a short review of studies on the occupational exposure of health workers to genotoxic drugs. These occupational exposure data were compared to the acceptable exposure levels resulting from our TTC based risk model.

Results

Based on the threshold of toxicological concern (TTC) concept, we defined an acceptable daily intake (ADI) of 4 μg/day as threshold of no concern for the exposure of health workers to genotoxic drugs. Regarding the dermal exposure of health workers to genotoxic drugs, we derived a corresponding acceptable surface contamination level (ASCL) of 20 ng/cm2. Both ADI and ASCL are usually not exceeded in modern healthcare settings. Current safety precautions provide sufficient protection to health workers.

Conclusions

The application of our model indicates that workers in modern healthcare facilities are not at risk of developing work related cancer above widely accepted cancer risk levels due to the occupational exposure to genotoxic drugs. Hence, the present study may assist employers and public authorities to make informed decisions concerning the need for (further) protective measures and during risk communication to health workers.
The roles of CC chemokines in response to radiation
Authors: Wang Lei , Jiang Jizong , Chen Yuan , Jia Qingzhu , Chu Qian
Published: April 2022

Radiotherapy is an effective regimen for cancer treatment alone or combined with chemotherapy or immunotherapy. The direct effect of radiotherapy involves radiation-induced DNA damage, and most studies have focused on this area to improve the efficacy of radiotherapy. Recently, the immunomodulatory effect of radiation on the tumour microenvironment has attracted much interest. Dying tumour cells can release multiple immune-related molecules, including tumour-associated antigens, chemokines, and inflammatory mediators. Then, immune cells are attracted to the irradiated site, exerting immunostimulatory or immunosuppressive effects. CC chemokines play pivotal roles in the trafficking process. The CC chemokine family includes 28 members that attract different immune subsets. Upon irradiation, tumour cells or immune cells can release different CC chemokines. Here, we mainly discuss the importance of CCL2, CCL3, CCL5, CCL8, CCL11, CCL20 and CCL22 in radiotherapy. In irradiated normal tissues, released chemokines induce epithelial to mesenchymal transition, thus promoting tissue injury. In the tumour microenvironment, released chemokines recruit cancer-associated cells, such as tumour-infiltrating lymphocytes, myeloid-derived suppressor cells and tumour-associated macrophages, to the tumour niche. Thus, CC chemokines have protumour and antitumour properties. Based on the complex roles of CC chemokines in the response to radiation, it would be promising to target specific chemokines to alleviate radiation-induced injury or promote tumour control.
The protective effect of kirenol in osteoarthritis: an in vitro and in vivo study
Authors: Hu Wei , Mao Chao , Sheng Weibin
Published: April 2022

Background

Osteoarthritis (OA) is a chronic degenerative disease, its main characteristic involves articular cartilage destruction and inflammation response, absent of effective medical treatment. Our current research aimed to explore anti-inflammatory effect of kirenol, a diterpenoid natural product compound, in the development of OA and its potential molecular mechanism through in vitro and in vivo study.

Methods

In vitro, chondrocytes were pretreated with kirenol for 2 h before IL-1β stimulation. Production of NO, PGE2, TNF-α, IL-6, aggrecan, collagen-II, MMP13and ADAMTS5 were evaluated by the Griess reaction and ELISAs. The mRNA (aggrecan and collagen-II) and protein expression (COX-2, iNOS, P65, IκB, PI3K, AKT) were measured by qRT-PCR and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and P65. The in vivo effect of kirenol was evaluated in mice OA models induced by destabilization of the medial meniscus (DMM).

Results

We found that kirenol inhibited IL-1β-induced expression of NO, PGE2, TNF-α, IL-6, COX-2, iNOS, ADAMTS-5. Besides, kirenol remarkably decreased IL-1β-induced degradation of aggrecan and collagen-II. Furthermore, kirenol significantly inhibited IL-1β-induced phosphorylation of PI3K/Akt and NF-κB signaling. In vivo, the cartilage in kirenol-treated mice exhibited less cartilage degradation and lower OARSI scores.

Conclusions

Taken together, the results of this study provide potent evidence that kirenol could be utilized as a potentially therapeutic agent in prevention and treatment of OA.
IgG4-related lung disease with recurrent pulmonary lesions during steroid therapy and difficulty in differentiating from malignancy: a case report
Authors: Okubo Tomohito , Nakashima Nariyasu , Tokunaga Yoshimasa , Kita Nobuyuki , Nakamura Hiroyuki , Ishikawa Ryou , Okada Setsuo , Go Tetsuhiko , Yokomise Hiroyasu
Published: April 2022

Background

Immunoglobulin G4-related disease (IgG4-RD) is characterized by the formation of inflammatory lesions with fibrosis and infiltration of IgG4-positive plasma cells and lymphocytes in various organs of the body. Since the first report of IgG4-related autoimmune pancreatitis, IgG4-RD affecting various organs has been reported; however, only a few reports of IgG4-related lung disease (IgG4-RLD) exist. In this report, we describe a case of IgG4-RLD that was difficult to differentiate from malignancy, and the usefulness of the surgical approach in determining the appropriate diagnosis and treatment plan.

Case presentation

A 61-year-old man was referred to our hospital after a chest radiograph revealed an abnormal chest shadow. At the time of his first visit, he had a slight fever and dyspnea on exertion. Chest computed tomography (CT) revealed a middle lobe hilar mass with irregular margins and swelling of the right hilar and mediastinal lymph nodes. These findings were not present on CT 1.5 years ago. 18F-fluorodeoxyglucose-positron emission tomography revealed a mass lesion with a maximum diameter of 5.5 cm, maximum standardized uptake value (SUVmax) of 11.0, and areas with high SUV in the hilar and mediastinal lymph nodes. We suspected lung cancer or malignant lymphoma and performed a thoracoscopic lung biopsy to confirm the diagnosis. Histopathological examination revealed no malignant findings, and IgG4-RLD was diagnosed. One month after treatment with prednisolone (PSL), the tumor had shrunk, but a CT scan during the third month of PSL treatment revealed multiple nodular shadows in both lungs. Considering the possibility of malignant complications and multiple lung metastases, we performed thoracoscopic partial lung resection of the new left lung nodules to determine the treatment strategy. Histopathological examination revealed no malignant findings in any of the lesions, and the patient was diagnosed with IgG4-RLD refractory to PSL monotherapy.

Conclusions

IgG4-RLD refractory to PSL monotherapy showed changes from a solitary large mass (pseudotumor) to multiple nodules on chest CT. It was difficult to distinguish malignancy from IgG4-RLD based on imaging tests and blood samples alone, and the surgical approach was useful in determining the appropriate diagnosis and treatment plan.
From non-targeted to targeted GC–MS metabolomics strategy for identification of TCM preparations containing natural and artificial musk
Authors: Ding Meng , Fan Jun-Li , Huang Dong-Fang , Jiang Yue , Li Meng-Ning , Zheng Yu-Qing , Yang Xiao-Ping , Li Ping , Yang Hua
Published: April 2022

Background

Moschus is a rare and precious natural medicine. Due to the properties of resources scarcity and expensive price of natural musk, artificial musk has been developed as substitute materials in some prescriptions. Rapid and accurate identification of natural or artificial musk in complex traditional Chinese medicine (TCM) preparations is also a challenge.

Method

A strategy from non-targeted to targeted gas chromatography-mass spectrometry (GC–MS) metabolomics was developed for discrimination of natural and artificial musk. Firstly, GC–MS-based non-targeted analysis combined with chemometrics was used to find the potential chemical markers to distinguish natural musk and artificial musk. Subsequently, targeted metabolomics was used to analyze musk in preparations with multiple reaction monitoring (MRM) mode by use gas chromatography coupled with triple quadrupole mass spectrometry (GC-QQQ MS).

Results

Two chemical markers named prasterone and androsterone have been selected and could be detected in all Compound Pien Tze Huang preparations (CPZHs) containing artificial musk, while the CPZHs containing natural musk did not detect two markers with S/N (signal to noise ratio) less than 3.

Conclusion

Our work provides an applicable approach to select the practical chemical markers for the assessment of musk in preparations to realize the traceability of musk in TCM and improve the quality control of musk-containing preparations.
Expanding the phenotype of TTLL5-associated retinal dystrophy: a case series
Authors: Oh Jin Kyun , Vargas Del Valle José G. , Lima de Carvalho Jose Ronaldo , Sun Young Joo , Levi Sarah R. , Ryu Joseph , Yang Jing , Nagasaki Takayuki , Emanuelli Andres , Rasool Nailyn , Allikmets Rando , Sparrow Janet R. , Izquierdo Natalio J. , Duncan Jacque L. , Mahajan Vinit B. , Tsang Stephen H.
Published: April 2022

Background

Inherited retinal dystrophies describe a heterogeneous group of retinal diseases that lead to the irreversible degeneration of rod and cone photoreceptors and eventual blindness. Recessive loss-of-function mutations in Tubulin Tyrosine Ligase Like 5 (TTLL5) represent a recently described cause of inherited cone–rod and cone dystrophy. This study describes the unusual phenotypes of three patients with autosomal recessive mutations in TTLL5. Examination of these patients included funduscopic evaluation, spectral-domain optical coherence tomography, short-wavelength autofluorescence, and full-field electroretinography (ffERG). Genetic diagnoses were confirmed using whole exome capture. Protein modeling of the identified variants was performed to explore potential genotype–phenotype correlations.

Results

Genetic testing revealed five novel variants in TTLL5 in three unrelated patients with retinal dystrophy. Clinical imaging demonstrated features of sectoral cone–rod dystrophy and cone dystrophy, with phenotypic variability seen across all three patients. One patient also developed high-frequency hearing loss during a similar time period as the onset of retinal disease, potentially suggestive of a syndromic disorder. Retinal structure findings were corroborated with functional measures including ffERG findings that supported these diagnoses. Modeling of the five variants suggest that they cause different effects on protein function, providing a potential reason for genotype–phenotype correlation in these patients.

Conclusions

The authors report retinal phenotypic findings in three unrelated patients with novel mutations causing autosomal recessive TTLL5-mediated retinal dystrophy. These findings broaden the understanding of the phenotypes associated with TTLL5-mediated retinal disease and suggest that mutations in TTLL5 should be considered as a potential cause of sectoral retinal dystrophy in addition to cone–rod and cone dystrophies.
Trend of hoverboard related injuries at a pediatric emergency department
Authors: Ferro Valentina , Nacca Raffaella , Boccuzzi Elena , Federici Tatiana , Ossella Chiara , Merenda Alessandra , Toniolo Renato Maria , Musolino Anna Maria , Reale Antonino , Raucci Umberto
Published: April 2022

Introduction

Understanding how the use of hoverboards (HBs) can affect a child’s safety is crucial. We describe the characteristics of HB related injuries and provide key messages about child prevention when using these leisure devices.

Methods

This was a retrospective study at an emergency department (ED) of a level-III-trauma center from 2016 to 2019. We tested the differences in children presenting for injury associated with HBs between 2016-2017 and 2018-2019 to better describe the temporal trend of the phenomenon.

Results

The rate ofInjury associated with HBs / Total injury per 1,000increased from 0.84 in 2016 to 7.7 in 2017, and then there was a gradual decline. The likelihood of injury was more common in younger children, increasing by 17% with decreasing age in 2018-2019 compared with 2016-2017 (OR: 0.83; 95%CI: 0.71-0.97;p= 0.021). The occurrence of injury in the April-June period was over twice as common in 2018-2019 (OR: 2.05; 95%CI: 1.0-2.05;p= 0.05). Patients were over 4 times more likely to have injured the lower extremity during the 2018-2019 period rather than other body regions (OR: 4.58; 95%CI: 1.23-4.58;p= 0.02). The odds of the indoor injury were more than twice as high in 2018-2019 (OR: 2.04; 95%CI: 1.077-2.04;p= 0.03).

Conclusion

Despite a decrease in the frequency of HB related injuries after 2017, during the 2018-2019 period, the younger the children, the more they were exposed to injury risk, in addition to a greater occurrence of indoor injuries from HBs compared with 2016-2017. The enhancement of preventive measures is necessary to ensure child safety when using HBs.
Digital therapeutics and the need for regulation: how to develop products that are innovative, patient-centric and safe
Authors: Rassi-Cruz Marcela , Valente Fernando , Caniza Maria Vanina
Published: April 2022

Background

Digital therapeutics are defined as therapeutic interventions that are driven by high quality software programs to prevent, manage or treat a medical disorder. These products provide great potential to improve patient outcomes, particularly for chronic disease sufferers, including people with Diabetes.

Main text

As yet, regulatory pathways for these products are rather unclear across all jurisdictions, although somewhat more progress has been made in the US and UK. Since digital therapeutics use cutting-edge technology and a logic of continuous innovation, regulation used for medical devices may not be completely appropriate. However, these products could present risks to patients if not developed and used appropriately. In the article, we consider the importance of a regulation framework and the role of self-regulation by developers as a way of ensuring patient safety while promoting innovation. We particularly emphasize the inclusion of doctors and other medical professionals in the design of the products, not only as a way of ensuring safe and effective applications, but also to encourage their take-up by patients, who tend to have high levels of trust for their HCPs.

Conclusion

Developers of digital therapeutics have the duty to create products that are safe, ethical and effective, without waiting for government regulation. Further, by self-regulating, following principles such as those provided by the Digital Therapeutics Alliance, they can develop products that serve patients better, while continuing to innovate.
A synthetic ‘essentialome’ for axenic culturing of ‘Candidatus Liberibacter asiaticus’
Authors: Cai Lulu , Jain Mukesh , Munoz-Bodnar Alejandra , Huguet-Tapia Jose C. , Gabriel Dean W.
Published: April 2022

Objective

‘Candidatus Liberibacter asiaticus’ (CLas) is associated with the devastating citrus ‘greening’ disease. All attempts to achieve axenic growth and complete Koch’s postulates with CLas have failed to date, at best yielding complex cocultures with very low CLas titers detectable only by PCR. Reductive genome evolution has rendered all pathogenic ‘Ca. Liberibacter’ spp. deficient in multiple key biosynthetic, metabolic and structural pathways that are highly unlikely to be rescued in vitro by media supplementation alone. By contrast, Liberibacter crescens (Lcr) is axenically cultured and its genome is both syntenic and highly similar to CLas. Our objective is to achieve replicative axenic growth of CLas via addition of missing culturability-related Lcr genes.

Results

Bioinformatic analyses identified 405 unique ORFs in Lcr but missing (or truncated) in all 24 sequenced CLas strains. Site-directed mutagenesis confirmed and extended published EZ-Tn5 mutagenesis data, allowing elimination of 310 of these 405 genes as nonessential, leaving 95 experimentally validated Lcr genes as essential for CLas growth in axenic culture. Experimental conditions for conjugation of large GFP-expressing plasmids from Escherichia coli to Lcr were successfully established for the first time, providing a practical method for transfer of large groups of ‘essential’ Lcr genes to CLas.
Long-term prophylaxis with lanadelumab for HAE: authorization for temporary use in France
Authors: Fain Olivier , Du-Thanh Aurelie , Gobert Delphine , Launay David , Inhaber Neil , Boudjemia Karima , Aubineau Magali , Sobel Alain , Boccon-Gibod Isabelle , Weiss Laurence , Bouillet Laurence
Published: April 2022

Background

Hereditary angioedema (HAE) is associated with a heavy burden of illness.

Objective

To evaluate use of lanadelumab in a French Authorization for Temporary Use (ATU) program.

Methods

ATU requests were made between October 12, 2018, and March 13, 2019; patients were followed through September 23, 2019. At entry, patients received lanadelumab 300 mg every 2 weeks. HAE attack characteristics were evaluated at day (D) 0 and months (M) 3 and 6. Patients completed the Angioedema Quality of Life (AE-QoL) questionnaire at initiation and monthly and the Angioedema Activity Score questionnaire daily in 28 day cycles (AAS28).

Results

In total, 77 patients received ≥ 1 lanadelumab dose; 69 had ≥ 1 quarterly follow-up visit (analyzed population). Mean (standard deviation [SD]) lanadelumab exposure was 240.4 (53.7) days. Lanadelumab dose was modified in 12 patients (mostly to every 4 weeks). For the analyzed population, compared with attacks/month (mean [SD]) within 6 months before ATU (2.68 [2.54]), fewer attacks occurred between initiation and first visit (0.16 [0.42]; P < 0.001) or last visit (0.16 [0.42]; P < 0.001); D15 and last visit (0.15 [0.41]); and D70 and last visit (0.17 [0.70]). AE-QoL total and domain scores were significantly higher at initiation versus M3 and M6; 55% and 65% of patients, respectively, achieved a minimal clinically important difference from D0 to M3 and D0 to M6. Proportion of patients with AAS28 of 0 was higher during M3 (90%) and M6 (83%) than initiation (59%). The most frequently reported adverse events included headache (7.3%) and injection site pain (6.3%).

Conclusions

Lanadelumab reduced attack rates, improved quality of life, and was generally well tolerated.
Recurrent hepatocellular carcinoma with osteoclast-like giant cells: a case report
Authors: Tsukimoto Mone , Sugimoto Kazushi , Shigefuku Ryuta , Sugimoto Ryosuke , Yuasa Hiroto , Uchida Katsunori , Yamamoto Norihiko
Published: April 2022

Background

Hepatocellular carcinoma with osteoclast-like giant cells is very rare and has an extremely poor prognosis. Here, we report a case of hepatocellular carcinoma with osteoclast-like giant cells that had a relatively better prognosis.

Case presentation

A 70-year-old Japanese man with hepatitis B virus-related liver cirrhosis was admitted to our hospital for the treatment of recurrent hepatocellular carcinoma. At the age of 60 years, he was first diagnosed as having hepatocellular carcinoma in the right lobe (9 cm in diameter), and liver resection of segment 7/8 was performed. Histological findings showed well-differentiated hepatocellular carcinoma. Since then, imaging studies have been performed every 3 or 4 months. One year later, hepatocellular carcinoma recurred in the lateral segment, and radiofrequency ablation was performed. Nine years after the first presentation, hepatocellular carcinoma recurrences were detected in the caudate lobe and segment 5 by imaging studies. Surgical resection of the caudate lobe was performed, and ultrasonography-guided radiofrequency ablation was subsequently performed for the segment 5 tumor. The resected tumor was simple nodular, well-differentiated HCC; it measured 21 × 21 mm and contained many osteoclast-like giant cells. As neither vascular nor bile duct invasion was found, we believe that radical resection was achieved. Since then, the hepatocellular carcinoma has not recurred for over a year and a half.

Conclusion

Hepatocellular carcinoma with osteoclast-like giant cells is very rare and the prognosis is extremely poor, but early detection can lead to a better clinical course.
A “cluster” of ten uterine anomalies observed in a single center over a short period of 4 weeks: a case series
Authors: Kabadi Yogindrakumar M. , Ayyanar Abirami
Published: April 2022

Background

Uterine anomalies occur because of Müllerian duct maldevelopment. Few of them are associated with adverse obstetric outcome (Reyes-Muñoz et al. in Diagnostics. 2019;9:4. https://doi.org/10.3390/diagnostics9040149). Genital outflow tract obstructive uterine anomalies invariably present in the adolescent age group.

Case details

We report a case series of uterine anomalies. Ten such cases presented like a “cluster” within a short span of just one month. Eight of these ten cases were diagnosed intraoperatively during cesarean section. One case was diagnosed during laparoscopic sterilization, and the other case was diagnosed before doing manual vacuum aspiration. There were four cases of bicornuate uterus, two cases each of unicornuate uterus and uterine didelphys, and one case each of septate uterus and arcuate uterus. All eight babies were healthy and without any obvious congenital anomalies. To the best of the authors’ knowledge, literature regarding these anomalies has been mentioned mostly as case reports (Bruand et al. in Cureus. 2020;12:3. https://doi.org/10.7759/cureus.7191) and a few case series (Ross et al. in BMJ Case Rep. 2018. https://doi.org/10.1136/bcr-2017-221815). All women were of Kannadiga ethnicity and in the age range of 19–35 years. They were from places nearby to our institute within a range of approximately 250 km.

Conclusion

We describe herein almost all types of uterine anomalies. These rare uterine anomalies presented in a short span of just four weeks like a “cluster”. This incidental finding is unusual. We need to design studies to understand the reasons for clustering of such cases in our clinical practice.
Cell-free fat extract attenuates osteoarthritis via chondrocytes regeneration and macrophages immunomodulation
Authors: Jia Zhuoxuan , Kang Bijun , Cai Yizuo , Chen Chingyu , Yu Zheyuan , Li Wei , Zhang Wenjie
Published: April 2022

Background

The prevalence of osteoarthritis (OA) is increasing, yet clinically effective and economical treatments are unavailable. We have previously proposed a cell-free fat extract (CEFFE) containing multiple cytokines, which possessed antiapoptotic, anti-oxidative, and proliferation promotion functions, as a “cell-free” strategy. In this study, we aimed to evaluate the therapeutic effect of CEFFE in vivo and in vitro.

Methods

In vivo study, sodium iodoacetate-induced OA rats were treated with CEFFE by intra-articular injections for 8 weeks. Behavioral experiments were performed every two weeks. Histological analyses, anti-type II collagen, and toluidine staining provided structural evaluation. Macrophage infiltration was assessed by anti-CD68 and anti-CD206 staining. In vitro study, the effect of CEFFE on macrophage polarization and secretory factors was evaluated by flow cytometry, immunofluorescence, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of CEFFE on cartilage regeneration was accessed by cell counting kit-8 assay and qRT-PCR. The generation of reactive oxygen species (ROS) and levels of ROS-related enzymes were investigated by qRT-PCR and western blotting.

Results

In rat models with sodium iodoacetate (MIA)-induced OA, CEFFE increased claw retraction pressure while decreasing bipedal pressure in a dose-dependent manner. Moreover, CEFFE promoted cartilage structure restoration and increased the proportion of CD206+macrophages in the synovium. In vitro, CEFFE decreased the proportion of CD86+cells and reduced the expression of pro-inflammatory factors in LPS + IFN-γ induced Raw 264.7. In addition, CEFFE decreased the expression of interleukin-6 and ADAMTs-5 and promoted the expression of SOX-9 in mouse primary chondrocytes. Besides, CEFFE reduced the intracellular levels of reactive oxygen species in both in vitro models through regulating ROS-related enzymes.

Conclusions

CEFFE inhibits the progression of OA by promoting cartilage regeneration and limiting low-grade joint inflammation.

Graphical abstract
Explaining and avoiding failure modes in goal-directed generation of small molecules
Authors: Langevin Maxime , Vuilleumier Rodolphe , Bianciotto Marc
Published: April 2022

Despite growing interest and success in automated in-silico molecular design, questions remain regarding the ability of goal-directed generation algorithms to perform unbiased exploration of novel chemical spaces. A specific phenomenon has recently been highlighted: goal-directed generation guided with machine learning models produce molecules with high scores according to the optimization model, but low scores according to control models, even when trained on the same data distribution and the same target. In this work, we show that this worrisome behavior is actually due to issues with the predictive models and not the goal-directed generation algorithms. We show that with appropriate predictive models, this issue can be resolved, and molecules generated have high scores according to both the optimization and the control models.