bluuebunny/crossref_metadata_2025 huggingface dataset:
A scoping review of the perceptions of death in the context of organ donation and transplantation
Authors: Skowronski George , Ramnani Anil , Walton-Sonda Dianne , Forlini Cynthia , O’Leary Michael J. , O’Reilly Lisa , Sheahan Linda , Stewart Cameron , Kerridge Ian
Published: December 2021

Background

Socio-cultural perceptions surrounding death have profoundly changed since the 1950s with development of modern intensive care and progress in solid organ transplantation. Despite broad support for organ transplantation, many fundamental concepts and practices including brain death, organ donation after circulatory death, and some antemortem interventions to prepare for transplantation continue to be challenged. Attitudes toward the ethical issues surrounding death and organ donation may influence support for and participation in organ donation but differences between and among diverse populations have not been studied.

Objectives

In order to clarify attitudes toward brain death, organ donation after circulatory death and antemortem interventions in the context of organ donation, we conducted a scoping review of international English-language quantitative surveys in various populations.

Study appraisal

A search of literature up to October 2020 was performed, using multiple databases. After screening, 45 studies were found to meet pre-specified inclusion criteria.

Results

32 studies examined attitudes to brain death, predominantly in healthcare professionals. In most, around 75% of respondents accepted brain death as equivalent to death of the person. Less common perspectives included equating death with irreversible coma and willingness to undertake organ donation even if itcauseddeath. 14 studies examined attitudes to organ donation following circulatory death. Around half of respondents in most studies accepted that death could be confidently diagnosed after only 5 min of cardiorespiratory arrest. The predominant reason was lack of confidence in doctors or diagnostic procedures. Only 6 studies examined attitudes towards antemortem interventions in prospective organ donors. Most respondents supported minimally invasive procedures and only where specific consent was obtained.

Conclusions

Our review suggests a considerable proportion of people, including healthcare professionals, have doubts about the medical and ethical validity of modern determinations of death. The prognosis of brain injury was a more common concern in the context of organ donation decision-making than certainty of death.
The prediction of hospital length of stay using unstructured data
Authors: Chrusciel Jan , Girardon François , Roquette Lucien , Laplanche David , Duclos Antoine , Sanchez Stéphane
Published: December 2021

Objective

This study aimed to assess the performance improvement for machine learning-based hospital length of stay (LOS) predictions when clinical signs written in text are accounted for and compared to the traditional approach of solely considering structured information such as age, gender and major ICD diagnosis.

Methods

This study was an observational retrospective cohort study and analyzed patient stays admitted between 1 January to 24 September 2019. For each stay, a patient was admitted through the Emergency Department (ED) and stayed for more than two days in the subsequent service. LOS was predicted using two random forest models. The first included unstructured text extracted from electronic health records (EHRs). A word-embedding algorithm based on UMLS terminology with exact matching restricted to patient-centric affirmation sentences was used to assess the EHR data. The second model was primarily based on structured data in the form of diagnoses coded from the International Classification of Disease 10th Edition (ICD-10) and triage codes (CCMU/GEMSA classifications). Variables common to both models were: age, gender, zip/postal code, LOS in the ED, recent visit flag, assigned patient ward after the ED stay and short-term ED activity. Models were trained on 80% of data and performance was evaluated by accuracy on the remaining 20% test data.

Results

The model using unstructured data had a 75.0% accuracy compared to 74.1% for the model containing structured data. The two models produced a similar prediction in 86.6% of cases. In a secondary analysis restricted to intensive care patients, the accuracy of both models was also similar (76.3% vs 75.0%).

Conclusions

LOS prediction using unstructured data had similar accuracy to using structured data and can be considered of use to accurately model LOS.
Transition of care in stroke patients discharged home: a single-center prospective cohort study
Authors: de Mooij M. J. , Ahayoun I. , Leferink J. , Kooij M. J. , Karapinar-Çarkit F. , Van den Berg-Vos R. M.
Published: December 2021

Introduction

Approximately two-thirds of the patients admitted to the hospital with an ischemic stroke are discharged directly home. Discontinuity of care may result in avoidable patient harm, re-admissions and even death. We hypothesized that the transfer of information is most essential in this patient group since any future care for these patients relies solely on the information that is available to the care provider responsible at that time.

Aim

The objective of this study was to evaluate the continuity of transmural care in ischemic stroke patients by assessing 1) the transfer of clinical information through discharge letters to general practitioners (GPs), 2) subsequent documentation of this information and early follow-up by GPs and 3) the documentation of medication-related information in discharge letters, at GPs and community pharmacies (CPs).

Methods

This prospective cohort study was conducted from September 2019 through March 2020 in OLVG, Amsterdam, the Netherlands, in patients with a first stroke discharged directly home. Outcome measures were derived from national guidelines and regional agreements. Results were analyzed using descriptive analysis.

Results

A total of 33 patients were included. Discharge letters (n = 33) and outpatient clinic letters (n = 24) to GPs contained most of the essential items, but 16% (n = 9) of the letters were sent in time. GPs (n = 31) infrequently adhered to guidelines since 10% (n = 3) of the diagnoses were registered using the correct code and 55% (n = 17) of the patients received follow-up shortly after discharge. Medication overviews were inaccurately communicated to GPs since 62% (n = 150) of all prescriptions (n = 243) were correctly noted in the discharge letter. Further loss of information was seen as only 39% (n = 95) of all prescriptions were documented correctly in GP overviews. We found that 59% (n = 144) of the prescriptions were documented correctly in CP overviews.

Conclusion

In this study, we found that discontinuity of care occurred to a varying extent throughout transmural care in patients with a first stroke who were discharged home.
Characterization and differentiation potential of mesenchymal stem cells isolated from multiple canine adipose tissue sources
Authors: Rashid Usman , Yousaf Arfan , Yaqoob Muhammad , Saba Evelyn , Moaeen-ud-Din Muhammad , Waseem Shahid , Becker Sandra K. , Sponder Gerhard , Aschenbach Jörg R. , Sandhu Mansur Abdullah
Published: December 2021

Background

Mesenchymal stem cells (MSCs) are undifferentiated cells that can give rise to a mesoderm lineage. Adipose-derived MSCs are an easy and accessible source for MSCs isolation, although each source of MSC has its own advantages and disadvantages. Our study identifies a promising source for the isolation and differentiation of canines MSCs. For this purpose, adipose tissue from inguinal subcutaneous (SC), perirenal (PR), omental (OM), and infrapatellar fat pad (IPFP) was isolated and processed for MSCs isolation. In the third passage, MSCs proliferation/metabolism, surface markers expression, in vitro differentiation potential and quantitative reverse transcription PCR (CD73, CD90, CD105, PPARγ, FabP4, FAS, SP7, Osteopontin, and Osteocalcin) were evaluated.

Results

Our results showed that MSCs derived from IPFP have a higher proliferation rate, while OM-derived MSCs have higher cell metabolism. In addition, MSCs from all adipose tissue sources showed positive expression of CD73 (NT5E), CD90 (THY1), CD105 (ENDOGLIN), and very low expression of CD45. The isolated canine MSCs were successfully differentiated into adipogenic and osteogenic lineages. The oil-red-O quantification and adipogenic gene expression (FAS, FabP4, and PPARγ) were higher in OM-derived cells, followed by IPFP-MSCs. Similarly, in osteogenic differentiation, alkaline phosphatase activity and osteogenic gene (SP7 and Osteocalcin) expression were higher in OM-derived MSCs, while osteopontin expression was higher in PR-derived MSCs.

Conclusion

In summary, among all four adipose tissue sources, OM-derived MSCs have better differentiation potential toward adipo- and osteogenic lineages, followed by IPFP-MSCs. Interestingly, among all adipose tissue sources, MSCs derived from IPFP have the maximum proliferation potential. The characterization and differentiation potential of canine MSCs isolated from four different adipose tissue sources are useful to assess their potential for application in regenerative medicine.
Integrative multi-omics identifies high risk multiple myeloma subgroup associated with significant DNA loss and dysregulated DNA repair and cell cycle pathways
Authors: Ortiz-Estévez María , Towfic Fadi , Flynt Erin , Stong Nicholas , Jang In Sock , Wang Kai , Trotter Matthew W. B. , Thakurta Anjan
Published: December 2021

Background

Despite significant therapeutic advances in improving lives of multiple myeloma (MM) patients, it remains mostly incurable, with patients ultimately becoming refractory to therapies. MM is a genetically heterogeneous disease and therapeutic resistance is driven by a complex interplay of disease pathobiology and mechanisms of drug resistance. We applied a multi-omics strategy using tumor-derived gene expression, single nucleotide variant, copy number variant, and structural variant profiles to investigate molecular subgroups in 514 newly diagnosed MM (NDMM) samples and identified 12 molecularly defined MM subgroups (MDMS1-12) with distinct genomic and transcriptomic features.

Results

Our integrative approach let us identify NDMM subgroups with transversal profiles to previously described ones, based on single data types, which shows the impact of this approach for disease stratification. One key novel subgroup is our MDMS8, associated with poor clinical outcome [median overall survival, 38 months (global log-rankp-value < 1 × 10−6)], which uniquely presents a broad genomic loss (> 9% of entire genome,t-testpvalue < 1e−5) driving dysregulation of various transcriptional programs affecting DNA repair and cell cycle/mitotic processes. This subgroup was validated on multiple independent datasets, and a master regulator analyses identified transcription factors controlling MDMS8 transcriptomic profile, including CKS1B and PRKDC among others, which are regulators of the DNA repair and cell cycle pathways.

Conclusion

Using multi-omics unsupervised clustering we were able to discover a new high-risk multiple myeloma patient segment. This high-risk group presents diverse previously known genetic markers, but also a new characteristic defined by accumulation of genomic loss which seems to drive transcriptional dysregulation of cell cycle, DNA repair and DNA damage. Finally, our work identified various master regulators, including E2F2 and CKS1B as the genes controlling these key biological pathways.
M2 macrophages secrete CXCL13 to promote renal cell carcinoma migration, invasion, and EMT
Authors: Xie Yingwei , Chen Zhiliang , Zhong Qiyu , Zheng Zaosong , Chen Yuqing , Shangguan Wentai , Zhang Yishan , Yang Jingying , Zhu Dingjun , Xie Wenlian
Published: December 2021

Objective

M2 macrophages are associated with a poor prognosis in a variety of malignancies. There are, however, few relevant investigations in clear cell renal cell carcinoma (ccRCC).

Methods

The expression of M2 macrophages in ccRCC tissues was first discovered using immunohistochemistry in this study. Then, M2 macrophages were created in vitro to see how they affected the proliferation, migration, invasion, and EMT of ccRCC cells. Using qPCR and prognostic analysis identifies important chemokine. Antibody neutralization tests confirmed the chemokine’s involvement and function. Pathway inhibitors confirmed the main pathway of M2 macrophages in ccRCC. Finally, qPCR and IHC were used to confirm the expression of chemokine receptors in ccRCC tissues.

Results

The presence of M2 macrophages was linked to a poor outcome in ccRCC. M2 macrophages enhanced the proliferation, migration, invasion, and EMT of ccRCC lines in vitro. CXCL13 was identified as the main chemokine by prognostic analysis and qPCR tests. CXCL13 neutralizing antibodies can inhibit the stimulation of M2 macrophages in ccRCC lines’ proliferation, migration, invasion, and EMT. M2 macrophages and CXCL13 may activate the Akt pathway in ccRCC lines, and Akt inhibitors decrease ccRCC lines proliferation, migration, invasion, and EMT. CXCR5 expression is a poor prognostic factor for renal cell carcinoma, according to qPCR and immunohistochemistry. In vivo experiments further proved that CXCL13 secreted by M2 macrophages can promote tumor proliferation.

Conclusions

M2 macrophages in the immunological milieu secrete CXCL13, which promotes ccRCC proliferation, migration, invasion, and EMT. Our findings contribute to a better understanding of the function of the tumor microenvironment in the incidence and progression of ccRCC, and they may point to novel therapeutic targets for ccRCC.
TKTL1 participated in malignant progression of cervical cancer cells via regulating AKT signal mediated PFKFB3 and thus regulating glycolysis
Authors: Zhu Yingping , Qiu Yu , Zhang Xueqin
Published: December 2021

Background

Cervical cancer (CC) is the second most common cancer among women with high morbidity and mortality. TKTL1 is a key protein in glucose metabolism in cancer cells and controls the pentose phosphate pathway (PPP). In this paper, we aim to explore whether TKTL1 can participate in the malignant process of CC cells through glucose metabolism.

Methods

The expression and activity of TKTL1 in CC cell lines were detected by RT-qPCR and Western blot. Cell transfection was conducted to interfere the expression of TKTL1 in SiHa cells, with efficiency detected by RT-qPCR and Western blot. Cell proliferation was then measured by CCK-8 kits. Wound Healing and Transwell experiments were performed to respectively detect the levels of cell migration and invasion, and western blot was used to detect the expressions of migration-related proteins. Tunel and Western blot were used to detect the apoptosis and apoptosis-related proteins. Glucose uptake, lactate production, and ATP production were measured by corresponding commercial kits. Next, the expression of p-Akt, AKT, p-MTOR, mTOR, HK2 and PFKFB3 was detected by Western blot. The mechanism was further investigated by interfering the expression of HK2 and PFKFB3 and adding AKT agonist SC79. At the animal level, the tumor bearing mouse model of CC was constructed, and the weight, volume and pathological morphology of the tumor tissue were detected to verify the cell experiment.

Results

TKTL1 expression was increased in CC cells. Interference of TKTL1 expression can inhibit TKTL1 enzyme activity, proliferation, invasion and migration of CC cells, and simultaneously suppress the generation of glycolysis. In addition, the results showed that TKTL1 activated PFKFB3 through AKT rather than HK2 signaling and is involved in glycolysis, cell invasion, migration, and apoptosis of CC cells. In animal level, inhibition of TKTL1 also contributed to decreased tumor volume of CC tumor bearing mice and improved histopathological status.

Conclusion

TKTL1 participated in malignant progression of CC cells via regulating AKT signal-mediated HK2 and PFKFB3 and thus regulating glucose metabolism.
Microarray analysis and functional prediction of differentially expressed circular RNAs in acquired middle ear cholesteatoma
Authors: Xie Shumin , Jin Li , Yin Tuanfang , Ren Jihao , Liu Wei
Published: December 2021

Background

Middle ear cholesteatoma is characterized by hyper-proliferation of keratinocytes. Circular RNA (circRNA) plays an essential role in the pathogenesis of many proliferative diseases. However, the role of circRNA in the etiopathogenesis of middle ear cholesteatoma is rarely investigated so far. We aimed to investigate the differential expression profiling of circRNAs between acquired middle ear cholesteatoma and normal skin, and to identify potential circRNAs contributing to the etiopathogenesis of middle ear cholesteatoma. Microarray analysis and functional prediction were performed to investigate the circRNA expression profiling between middle ear cholesteatoma and normal skin. Validation of differentially expressed circRNAs was conducted by qRT-PCR. Prediction of m6A modification was also carried out.

Results

Microarray analysis displayed that totally 93 up-regulated and 85 down-regulated circRNAs were identified in middle ear cholesteatoma. Through validation, expressions of hsa_circRNA_104327 and hsa_circRNA_404655 were significantly higher, while hsa_circRNA_000319 was significantly down-regulated in cholesteatoma. GO classification, KEGG pathway, and ceRNA network analyses suggested that these differentially expressed circRNAs might play important roles in the etiopathogenesis of middle ear cholesteatoma. Prediction of m6A modification exhibited that hsa_circRNA_000319 possessed 4 m6A sites with very high confidence, and hsa_circRNA_404655 had 3 m6A sites with high confidence.

Conclusions

Our study revealed that these differentially expressed circRNAs might contribute to the etiopathogenesis of middle ear cholesteatoma. Further researches should be conducted to investigate the exact mechanism of these differentially expressed circRNAs in the etiopathogenesis of middle ear cholesteatoma. Targeting on these circRNAs may provide a new strategy for middle ear cholesteatoma therapy in the future.
Implementation of paediatric vision screening in urban and rural areas in Cluj County, Romania
Authors: Kik Jan , Nordmann Mandy , Cainap Simona , Mara Mihai , Rajka Daniela , Ghițiu Monica , Vladescu Alin , Sloot Frea , Horwood Anna , Fronius Maria , Vladutiu Cristina , Simonsz Huibert Jan
Published: December 2021

Background

In 2018 and 2019, paediatric vision screening was implemented in Cluj County, Romania, where universal paediatric vision screening does not yet exist. We report on the preparation and the first year of implementation.

Methods

Objectives, target population and screening protocol were defined. In cities, children were screened by kindergarten nurses. In rural areas, kindergartens have no nurses and children were screened by family doctors’ nurses, initially at the doctors’ offices, later also in rural kindergartens.

CME-accredited training courses and treatment pathways were organised.

Implementation was assessed through on-site observations, interviews, questionnaires and analysis of screening results of referred children.

Results

Out of 12,795 eligible four- and five-year-old children, 7,876 were screened in 2018. In the cities, kindergarten nurses screened most children without difficulties. In Cluj-Napoca 1.62x the average annual birth rate was screened and in the small cities 1.64x. In the rural areas, however, nurses of family doctors screened only 0.49x the birth rate. In 51 out of 75 rural communes, no screening took place in the first year. Of 118 rural family doctors’ nurses, 51 had followed the course and 26 screened children. They screened only 41 children per nurse, on average, as compared to 80 in the small cities and 100 in Cluj-Napoca. Screening at rural kindergartens met with limited success. These are attended by few children because of low population density, parents working abroad or children being kept at home in case of bad weather and road conditions.

Conclusions

Three times fewer children were screened in rural areas as compared to urban areas. Kindergartens in rural areas are too small to employ nurses and family doctors’ nurses do not have easy access to many children and have competing healthcare priorities: there are 1.5x as many family doctors in urban areas as compared to rural areas. For nationwide scaling-up of vision screening, nurses should be enabled to screen a sufficient number of children in rural areas.
Are we really all in this together? The social patterning of mortality during the first wave of the COVID-19 pandemic in Belgium
Authors: Gadeyne Sylvie , Rodriguez-Loureiro Lucia , Surkyn Johan , Van Hemelrijck Wanda , Nusselder Wilma , Lusyne Patrick , Vanthomme Katrien
Published: December 2021

Background

Belgium was one of the countries that was struck hard by COVID-19. Initially, the belief was that we were ‘all in it together’. Emerging evidence showed however that deprived socioeconomic groups suffered disproportionally. Yet, few studies are available for Belgium. The main question addressed in this paper is whether excess mortality during the first COVID-19 wave followed a social gradient and whether the classic mortality gradient was reproduced.

Methods

We used nationwide individually linked data from the Belgian National Register and the Census 2011. Age-standardized all-cause mortality rates were calculated during the first COVID-19 wave in weeks 11-20 in 2020 and compared with the rates during weeks 11-20 in 2015-2019 to calculate absolute and relative excess mortality by socioeconomic and -demographic characteristics. For both periods, relative inequalities in total mortality between socioeconomic and -demographic groups were calculated using Poisson regression. Analyses were stratified by age, gender and care home residence.

Results

Excess mortality during the first COVID-19 wave was high in collective households, with care homes hit extremely hard by the pandemic. The social patterning of excess mortality was rather inconsistent and deviated from the usual gradient, mainly through higher mortality excesses among higher socioeconomic groups classes in specific age-sex groups. Overall, the first COVID-19 wave did not change the social patterning of mortality, however. Differences in relative inequalities between both periods were generally small and insignificant, except by household living arrangement.

Conclusion

The social patterning during the first COVID-19 wave was exceptional as excess mortality did not follow the classic lines of higher mortality in lower classes and patterns were not always consistent. Relative mortality inequalities did not change substantially during the first COVID-19 wave compared to the reference period.
Introduction of gasless laparoscopic surgery as a minimally invasive procedure for endometrial cancer and its usefulness from the viewpoint of the learning curve
Authors: Ito Hiroe , Moritake Tetsuya , Terauchi Fumitoshi , Isaka Keiichi
Published: December 2021

Background

We investigated the usefulness of gasless laparoscopic surgery (GLS) using a subcutaneous abdominal wall lifting method for endometrial cancer.

Methods

We studied 105 patients with early endometrial cancer who underwent GLS (55) or open surgery (50). A uterine manipulator was used in all GLS cases. We compared operative time, blood loss, number of lymph nodes removed, hospital stay, perioperative complications, cases converted to laparotomy, and recurrence and survival rates. We also studied the learning curve and proficiency of GLS.

Results

The GLS group had significantly longer operative time (265 vs. 191 min), reduced blood loss (184 vs. 425 mL), shorter hospital stay (9.9 vs. 17.6 days), and fewer postoperative complications (1.8 vs. 12.0%) than the open group. No case was converted to laparotomy. Disease-free and overall survival rates at 4 years postoperatively (GLS vs. open groups) were 98.0 versus 97.8 and 100 versus 95.7%, respectively, and there was no significant difference between the groups. Regarding the learning curve for GLS, two different phases were observed in approximately 10 cases. Operator 2, who was not accustomed to laparoscopic surgery, showed a significant reduction in operative time in the later phase 2.

Conclusions

GLS for endometrial cancer results in less bleeding, shorter hospital stay, and fewer complications than open surgery. Recurrence and survival rates were not significantly different from those of open surgery. This technique may be introduced in a short time for operators who are skilled at open surgery but not used to laparoscopic surgery.
Regulated cell death: discovery, features and implications for neurodegenerative diseases
Authors: Cui Juntao , Zhao Suhan , Li Yinghui , Zhang Danyang , Wang Bingjing , Xie Junxia , Wang Jun
Published: December 2021

Regulated cell death (RCD) is a ubiquitous process in living organisms that is essential for tissue homeostasis or to restore biological balance under stress. Over the decades, various forms of RCD have been reported and are increasingly being found to involve in human pathologies and clinical outcomes. We focus on five high-profile forms of RCD, including apoptosis, pyroptosis, autophagy-dependent cell death, necroptosis and ferroptosis. Cumulative evidence supports that not only they have different features and various pathways, but also there are extensive cross-talks between modes of cell death. As the understanding of RCD pathway in evolution, development, physiology and disease continues to improve. Here we review an updated classification of RCD on the discovery and features of processes. The prominent focus will be placed on key mechanisms of RCD and its critical role in neurodegenerative disease.

Graphical Abstract
Nine weeks of high-intensity indoor cycling training induced changes in the microbiota composition in non-athlete healthy male college students
Authors: Donati Zeppa Sabrina , Amatori Stefano , Sisti Davide , Gervasi Marco , Agostini Deborah , Piccoli Giovanni , Pazienza Valerio , Gobbi Pietro , Rocchi Marco B. L. , Sestili Piero , Stocchi Vilberto
Published: December 2021

Background

The gut microbiota constitutes a dynamic microbial system constantly challenged by environmental conditions, including physical exercise. Limited human studies suggest that exercise could play a beneficial role for gut health, increasing microbial diversity, even if the effects of exercise on gut microbial microorganisms depends on its intensity and duration. This study aimed to investigate the effects of nine weeks of high-intensity interval exercise on gut microbiota composition in healthy young adults.

Methods

The gut microbiota composition of seventeen healthy male college students was analysed before and after nine weeks of high-intensity interval cycling training by 16S rRNA amplicon sequencing. PERMANOVA for repeated measures was used to test pre-post differences in the relative abundance of all taxonomic levels, and correlations between variations in microbial composition and physical and dietary features were also assessed.

Results

Physical exercise induced changes in microbiota composition, at all taxonomic levels analysed (phyla: F [1, 32]=3.97, p=0.029; classes: F [1, 32]=3.39, p=0.033, orders: F [1, 32]=3.17, p=0.044, families: F [1, 32]=1.54, p=0.037, genera: F [1, 32]=1.46, p=0.015, species: F [1, 32]=1.38, p=0.007). Conversely, no differences were found between pre and post-training conditions for microbial community richness (Chao1: V=105, p=0.06) or diversity (Shannon index: V=62, p=0.52; Simpson index: V=59, p=0.43). Changes in the relative abundance of eighteen genera were correlated to changes of twenty environmental factors grouped in physical features, sport-related features, and dietary features.

Conclusions

Nine weeks of high-intensity exercise induced modifications in gut microbiota composition in healthy male college students, shifting the gut microbial population towards a healthier microbiome with benefit to human health in general.
Editing out HIV: application of gene editing technology to achieve functional cure
Authors: Xun Jingna , Zhang Xinyu , Guo Shuyan , Lu Hongzhou , Chen Jun
Published: December 2021

Highly active antiretroviral therapy (HAART) successfully suppresses human immunodeficiency virus (HIV) replication and improves the quality of life of patients living with HIV. However, current HAART does not eradicate HIV infection because an HIV reservoir is established in latently infected cells and is not recognized by the immune system. The successful curative treatment of the Berlin and London patients following bone marrow transplantation inspired researchers to identify an approach for the functional cure of HIV. As a promising technology, gene editing-based strategies have attracted considerable attention and sparked much debate. Herein, we discuss the development of different gene editing strategies in the functional cure of HIV and highlight the potential for clinical applications prospects.

Graphical Abstract
Prediction of robotic neurorehabilitation functional ambulatory outcome in patients with neurological disorders
Authors: Kuo Chao-Yang , Liu Chia-Wei , Lai Chien-Hung , Kang Jiunn-Horng , Tseng Sung-Hui , Su Emily Chia-Yu
Published: December 2021

Introduction

Conflicting results persist regarding the effectiveness of robotic-assisted gait training (RAGT) for functional gait recovery in post-stroke survivors. We used several machine learning algorithms to construct prediction models for the functional outcomes of robotic neurorehabilitation in adult patients.

Methods and materials

Data of 139 patients who underwent Lokomat training at Taipei Medical University Hospital were retrospectively collected. After screening for data completeness, records of 91 adult patients with acute or chronic neurological disorders were included in this study. Patient characteristics and quantitative data from Lokomat were incorporated as features to construct prediction models to explore early responses and factors associated with patient recovery.

Results

Experimental results using the random forest algorithm achieved the best area under the receiver operating characteristic curve of 0.9813 with data extracted from all sessions. Body weight (BW) support played a key role in influencing the progress of functional ambulation categories. The analysis identified negative correlations of BW support, guidance force, and days required to complete 12 Lokomat sessions with the occurrence of progress, while a positive correlation was observed with regard to speed.

Conclusions

We developed a predictive model for ambulatory outcomes based on patient characteristics and quantitative data on impairment reduction with early-stage robotic neurorehabilitation. RAGT is a customized approach for patients with different conditions to regain walking ability. To obtain a more-precise and clearer predictive model, collecting more RAGT training parameters and analyzing them for each individual disorder is a possible approach to help clinicians achieve a better understanding of the most efficient RAGT parameters for different patients.

Trial registration: Retrospectively registered.
Frequencies of emergency department use and hospitalization comparing patients with different types of substance or polysubstance-related disorders
Authors: Armoon Bahram , Grenier Guy , Cao Zhirong , Huỳnh Christophe , Fleury Marie-Josée
Published: December 2021

Background

This study measured emergency department (ED) use and hospitalization for medical reasons among patients with substance-related disorders (SRD), comparing four subgroups: cannabis-related disorders, drug-related disorders other than cannabis, alcohol-related disorders and polysubstance-related disorders, controlling for various clinical, sociodemographic and service use variables.

Methods

Clinical administrative data for a cohort of 22,484 patients registered in Quebec (Canada) addiction treatment centers in 2012-13 were extracted for the years 2009-10 to 2015-16. Using negative binomial models, risks of frequent ED use and hospitalization were calculated for a 12-month period (2015-16).

Results

Patients with polysubstance-related disorders used ED more frequently than other groups with SRD. They were hospitalized more frequently than patients with cannabis or other drug-related disorders, but less frequently than those with alcohol-related disorders. Patients with alcohol-related disorders used ED more frequently than those with cannabis-related disorders and underwent more hospitalizations than both patients with cannabis-related and other drug-related disorders. Co-occurring SRD-mental disorders or SRD-chronic physical illnesses, more years with SRD, being women, living in rural territories, more frequent consultations with usual general practitioner or outpatient psychiatrist, and receiving more interventions in community healthcare centers increased frequency of ED use and hospitalization, whereas both adverse outcomes decreased with high continuity of physician care. Behavioral addiction, age less than 45 years, living in more materially deprived areas, and receiving 1-3 interventions in addiction treatment centers increased risk of frequent ED use, whereas living in semi-urban areas decreased ED use. Patients 25-44 years old receiving 4+ interventions in addiction treatment centers experienced less frequent hospitalization.

Conclusion

Findings showed higher risk of ED use among patients with polysubstance-related disorders, and higher hospitalization risk among patients with alcohol-related disorders, compared with patients affected by cannabis and other drug-related disorders. However, other variables contributed substantially more to the frequency of ED use and hospitalization, particularly clinical variables regarding complexity and severity of health conditions, followed by service use variables. Another important finding was that high continuity of physician care helped decrease the use of acute care services. Strategies like integrated care and outreach interventions may enhance SRD services.
Acupressure in patients with seasonal allergic rhinitis: a randomized controlled exploratory trial
Authors: Israel Lukas , Rotter Gabriele , Förster-Ruhrmann Ulrike , Hummelsberger Josef , Nögel Rainer , Michalsen Andreas , Tissen-Diabaté Tatjana , Binting Sylvia , Reinhold Thomas , Ortiz Miriam , Brinkhaus Benno
Published: December 2021

Background

Acupuncture has shown beneficial effects for seasonal allergic rhinitis (SAR); however, it is time and cost intensive. We investigated feasibility and effects of self-administered body acupressure as a self-care technique that stimulates acupuncture points with manual pressure in SAR patients.

Methods

We conducted a two-armed randomized controlled exploratory trial to compare effects of self-administered acupressure over 4 weeks at five acupuncture points plus rescue medication (RM) with cetirizine compared to RM alone in SAR patients. Among other outcome parameters, we assessed disease-related quality of life (Rhinitis Quality of Life Questionnaire [RQLQ]), overall SAR symptoms by a visual analogue scale (VAS) and a rescue medication score (RMS) after 4 and 8 weeks.

Results

Forty-one SAR patients (mean age 38.5 ± 10.0 years, n = 21, 51.2% women) were randomized. Compared to RM alone (n = 21), acupressure plus RM (n = 20) was associated with relevant improvements after 4 weeks, shown by the difference between groups in adjusted means of RQLQ: − 0.9 points (95% CI − 1.6 to − 0.2; p = 0.011) and VAS overall SAR symptoms: − 21.6 mm (95% CI − 36.3 to − 6.8; p = 0.005). The RMS was lower in the acupressure group than in the control group: 1.9 points (95% CI − 3.8 to − 0.1; p = 0.120). Group differences decreased slightly until week 8. The acupressure was feasible and safe.

Conclusion

Results of this exploratory study indicate that self-applied acupressure is feasible, may improve disease-specific quality of life and reduce disease-related symptoms as well as anti-allergic medication intake in SAR patients. High-quality confirmatory studies including a sham-control group are needed in the future.

Trial registrationDRKS-ID: DRKS00014310. Date of registration in DRKS: 2018/04/24. Investigator sponsored/initiated trial (IST/IIT): yes. Ethics approval/approval of the ethics committee: Approved (leading) Ethics Committee No. EA1/033/18, Ethik-Kommission der Charité -Universitätsmedizin Berlin. URL:https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00014310
Neuropathology and molecular diagnosis of Synucleinopathies
Authors: Koga Shunsuke , Sekiya Hiroaki , Kondru Naveen , Ross Owen A. , Dickson Dennis W.
Published: December 2021

Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions. Synucleinopathies can be divided into two major disease entities: Lewy body disease and multiple system atrophy (MSA). Common clinical presentations of Lewy body disease are Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia and MSA with predominant parkinsonism. There are currently no disease-modifying therapies for the synucleinopathies, but information obtained from molecular genetics and models that explore mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and glial cytoplasmic inclusions) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence fromin vitroandin vivoexperiments suggests that α-synuclein species derived from Lewy body disease and MSA are distinct “strains” having different seeding properties. Recent advancements inin vitroseeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a discussion of the evolution of classification and staging of Lewy body disease. We also provide a brief discussion on proposed mechanisms of Lewy body formation, as well as evidence supporting the existence of distinct α-synuclein strains in Lewy body disease and MSA.
Prevalence of multimodal treatment in children and adolescents with ADHD in Germany: a nationwide study based on health insurance data
Authors: Riedel Oliver , Klau Simon , Langner Ingo , Bachmann Christian , Scholle Oliver
Published: December 2021

Background

Attention-deficit hyperactivity disorder (ADHD) ranks top among neurodevelopmental disorders in children and adolescents. Due to a large number of unfavorable outcomes including psychiatric comorbidities, school problems, and lower socioeconomic status, early and effective treatment of ADHD is essential. Multimodal treatment has become the gold standard in ADHD management, comprising pharmacotherapy and psychosocial interventions, e.g., psychotherapy. Yet, little is known about the prevalence of multimodal treatment in routine care.

Methods

Based on German health claims data for the years 2009–2017, we identified children and adolescents aged 3–17 years diagnosed with ADHD and characterized them cross-sectionally (per calendar year) in terms of treatment status and psychiatric comorbidities. The detection of pharmacotherapy was based on dispensations of drugs to treat ADHD (e.g., methylphenidate); psychotherapeutic treatment was based on corresponding billing codes. Multimodal treatment was assumed if ADHD medication and psychotherapeutic treatment were coded within the same calendar year. Psychiatric comorbidities were based on outpatient and inpatient diagnoses. Prevalences of ADHD and proportions of different treatment options were calculated and standardized by age and sex.

Results

In 2017, 91,118 children met the study criteria for ADHD (prevalence: 42.8/1000). Of these, 25.2% had no psychiatric comorbidity, 28.8% had one, 21.6% had two, and 24.5% had three or more. Regarding overall treatment status, 36.2% were treated only pharmacologically, 6.5% received multimodal treatment, and 6.8% were treated with psychotherapy only (neither treatment: 50.2%). With increasing numbers of psychiatric comorbidities, the proportions of patients with multimodal treatment increased from 2.2% (no psychiatric comorbidities) to 11.1% (three or more psychiatric comorbidities) while the proportions of untreated (from 56.8% to 42.7%) or only pharmacologically treated patients (38.4% to 35.0%) decreased. From 2009 to 2017, prevalences were stable and the proportion of patients with only pharmacotherapy decreased from 48% to 36.5%. Concurrently, the proportion of patients with neither pharmacotherapy nor psychotherapy increased from 40.5% to 50.2%. The fraction of patients with multimodal treatment ranged between 6.5% (2017) and 7.4% (2013).

Conclusions

Multimodal treatment, although recommended as the standard of treatment, is rather the exception than the rule. It is, however, increasingly common in ADHD patients with psychiatric comorbidities.
The upside: coping and psychological resilience in Australian adolescents during the COVID-19 pandemic
Authors: Beames Joanne R. , Li Sophie H. , Newby Jill M. , Maston Kate , Christensen Helen , Werner-Seidler Aliza
Published: December 2021

Background

Since the COVID-19 outbreak, few studies have investigated the positive psychological consequences on young people. This study examined resilience, positive experiences, and coping strategies reported by Australian adolescents during COVID-19.

Methods

Self-report surveys were administered online to a sample of 760 Australian adolescents aged 12–18 years. Quantitative and qualitative methods were used to assess resilience, positive experiences, and coping strategies. Exploratory regression analyses were conducted to explore the relationship between resilience and demographics and mental illness history, as well as between resilience and positive experiences.

Results

Overall, adolescents were somewhat resilient (M = 20.93, SD = 8.29). They reported positive experiences during COVID-19, including increased empathy, compassion, gratitude, and connection with others, and reported using a range of active coping strategies. Having a mental illness history and identification as female or non-binary gender were associated with lower resilience (Bs > 2.82, ps < 0.001). Further, resilience was associated with decreased psychological distress (OR = 0.89, p < 0.001) and with increased positive experiences (ORs > 1.03, ps < 0.001).

Conclusions

Our results indicate that Australian adolescents commonly reported positive experiences and used active coping strategies during COVID-19. Some young people demonstrated higher levels of resilience and were able to make the most out of an unpredictable situation that severely disrupted their daily routine. However, further prospective research using longitudinal methods is necessary to examine causal relationships between variables. An implication of our findings is that resilience-building programs for adolescents may be effective in increasing adaptability after adversity (e.g., climate change, bushfires, pandemics).
Molecular and phenotypic characteristics of 15q24 microdeletion in pediatric patients with developmental disorders
Authors: Zhang Yuanyuan , Liu Xiaoliang , Gao Haiming , Cui Wanting , Zhang Bijun , Zhao Yanyan
Published: December 2021

Chromosome 15q24 microdeletion is a rare genetic disorder characterized by development delay, facial dysmorphism, congenital malformations, and occasional autism spectrum disorder (ASD). In this study, we identified five cases of 15q24 microdeletion using multiplex ligation-dependent probe amplification (MLPA) technology in a cohort of patients with developmental delay and/or intellectual disability. Two of these five cases had deletions that overlapped with the previously defined 1.1 Mb region observed in most reported cases. Two cases had smaller deletions (< 0.57 Mb) in the 15q24.1 low copy repeat (LCR) B-C region. They presented significant neurobehavioral features, suggesting that this smaller interval is critical for core phenotypes of 15q24 microdeletion syndrome. One case had minimal homozygous deletion of less than 0.11 Mb in the 15q24.1 LCR B-C region, which contained CYP1A1 (cytochrome P450 family 1 subfamily A member 1) and EDC3 (enhancer of mRNA decapping 3) genes, resulting in poor immunity, severe laryngeal stridor, and lower limbs swelling. This study provides additional evidence of 15q24 microdeletion syndrome with genetic and clinical findings. The results will be of significance to pediatricians in their daily practice.
Triptonide effectively inhibits triple-negative breast cancer metastasis through concurrent degradation of Twist1 and Notch1 oncoproteins
Authors: Zhang Mengli , Meng Mei , Liu Yuxi , Qi Jindan , Zhao Zhe , Qiao Yingnan , Hu Yanxing , Lu Wei , Zhou Zhou , Xu Peng , Zhou Quansheng
Published: December 2021

Background

Triple-negative breast cancer (TNBC) is highly metastatic and lethal. Due to a lack of druggable targets for this disease, there are no effective therapies in the clinic.

Methods

We used TNBC cells and xenografted mice as models to explore triptonide-mediated inhibition of TNBC metastasis and tumor growth. Colony formation assay was used to quantify the tumorigenesis of TNBC cells. Wound-healing and cell trans-well assays were utilized to measure cell migration and invasion. Tube formation assay was applied to access tumor cell-mediated vasculogenic mimicry. Western blot, quantitative-PCR, immunofluorescence imaging, and immunohistochemical staining were used to measure the expression levels of various tumorigenic genes in TNBC cells.

Results

Here, we showed that triptonide, a small molecule from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, potently inhibited TNBC cell migration, invasion, and vasculogenic mimicry, and effectively suppressed TNBC tumor growth and lung metastasis in xenografted mice with no observable toxicity. Molecular mechanistic studies revealed that triptonide strongly triggered the degradation of master epithelial-mesenchymal transition (EMT)-inducing protein Twist1 through the lysosomal system and reduced Notch1 expression and NF-κB phosphorylation, which consequently diminished the expression of pro-metastatic and angiogenic genes N-cadherin, VE-cadherin, and vascular endothelial cell growth factor receptor 2 (VEGFR2).

Conclusions

Triptonide effectively suppressed TNBC cell tumorigenesis, vasculogenic mimicry, and strongly inhibited the metastasis of TNBC via degradation of Twist1 and Notch1 oncoproteins, downregulation of metastatic and angiogenic gene expression, and reduction of NF-κB signaling pathway. Our findings provide a new strategy for treating highly lethal TNBC and offer a potential new drug candidate for combatting this aggressive disease.