bluuebunny/crossref_metadata_2025 huggingface dataset:
Accelerating GPCR Drug Discovery With Conformation-Stabilizing VHHs
Authors: Laeremans Toon , Sands Zara A. , Claes Pieter , De Blieck Ann , De Cesco Stephane , Triest Sarah , Busch Andreas , Felix David , Kumar Abhinav , Jaakola Veli-Pekka , Menet Christel
Published: May 2022

The human genome encodes 850 G protein-coupled receptors (GPCRs), half of which are considered potential drug targets. GPCRs transduce extracellular stimuli into a plethora of vital physiological processes. Consequently, GPCRs are an attractive drug target class. This is underlined by the fact that approximately 40% of marketed drugs modulate GPCRs. Intriguingly 60% of non-olfactory GPCRs have no drugs or candidates in clinical development, highlighting the continued potential of GPCRs as drug targets. The discovery of small molecules targeting these GPCRs by conventional high throughput screening (HTS) campaigns is challenging. Although the definition of success varies per company, the success rate of HTS for GPCRs is low compared to other target families (Fujioka and Omori, 2012; Dragovich et al., 2022). Beyond this, GPCR structure determination can be difficult, which often precludes the application of structure-based drug design approaches to arising HTS hits. GPCR structural studies entail the resource-demanding purification of native receptors, which can be challenging as they are inherently unstable when extracted from the lipid matrix. Moreover, GPCRs are flexible molecules that adopt distinct conformations, some of which need to be stabilized if they are to be structurally resolved. The complexity of targeting distinct therapeutically relevant GPCR conformations during the early discovery stages contributes to the high attrition rates for GPCR drug discovery programs. Multiple strategies have been explored in an attempt to stabilize GPCRs in distinct conformations to better understand their pharmacology. This review will focus on the use of camelid-derived immunoglobulin single variable domains (VHHs) that stabilize disease-relevant pharmacological states (termed ConfoBodies by the authors) of GPCRs, as well as GPCR:signal transducer complexes, to accelerate drug discovery. These VHHs are powerful tools for supporting in vitro screening, deconvolution of complex GPCR pharmacology, and structural biology purposes. In order to demonstrate the potential impact of ConfoBodies on translational research, examples are presented of their role in active state screening campaigns and structure-informed rational design to identify de novo chemical space and, subsequently, how such matter can be elaborated into more potent and selective drug candidates with intended pharmacology.
Impact of APOE ε4 Carrier Status on Associations Between Subthreshold, Positive Amyloid-β Deposition, Brain Function, and Cognitive Performance in Cognitively Normal Older Adults: A Prospective Study
Authors: Kang Dong Woo , Wang Sheng-Min , Um Yoo Hyun , Kim Nak-Young , Lee Chang Uk , Lim Hyun Kook
Published: May 2022

Background

A growing body of evidence suggests a deteriorating effect of subthreshold amyloid-beta (Aβ) accumulation on cognition before the onset of clinical symptoms of Alzheimer's disease (AD). Despite the association between the Aβ-dependent pathway and the APOE ε4 allele, the impact of this allele on the progression from the subthreshold Aβ deposits to cognitive function impairment is unclear. Furthermore, the comparative analysis of positive Aβ accumulation in the preclinical phase is lacking.

Objective

This study aimed to explore the differential effect of the APOE ε4 carrier status on the association between Aβ deposition, resting-state brain function, and cognitive performance in cognitively normal (CN) older adults, depending on the Aβ burden status.

Methods

One hundred and eighty-two older CN adults underwent resting-state functional magnetic resonance imaging, [18F] flutemetamol (FMM) positron emission tomography, a neuropsychological battery, and APOE genotyping. We evaluated the resting-state brain function by measuring the local and remote functional connectivity (FC) and measured the remote FC in the default-mode network (DMN), central-executive network (CEN), and salience network (SN). In addition, the subjects were dichotomized into those with subthreshold and positive Aβ deposits using a neocortical standardized uptake value ratio with the cut-off value of 0.62, which was calculated with respect to the pons.

Results

The present result showed that APOE ε4 carrier status moderated the relationship between Aβ deposition, local and remote resting-state brain function, and cognitive performance in each CN subthreshold and positive Aβ group. We observed the following: (i) the APOE ε4 carrier status-Aβ deposition and APOE ε4 carrier status-local FC interaction for the executive and memory function; (ii) the APOE ε4 carrier status-regional Aβ accumulation interaction for the local FC; and (iv) the APOE ε4 carrier status-local FC interaction for the remote inter-network FC between the DMN and CEN, contributing higher cognitive performance in the APOE ε4 carrier with higher inter-network FC. Finally, these results were modulated according to Aβ positivity.

Conclusion

This study is the first attempt to thoroughly examine the influence of the APOE ε4 carrier status from the subthreshold to positive Aβ accumulation during the preclinical phase.
Motor Training After Stroke: A Novel Approach for Driving Rehabilitation
Authors: Lodha Neha , Patel Prakruti , Casamento-Moran Agostina , Christou Evangelos A.
Published: May 2022

Background

A key component of safe driving is a well-timed braking performance. Stroke-related decline in motor and cognitive processes slows braking response and puts individuals with stroke at a higher risk for car crashes. Although the impact of cognitive training on driving has been extensively investigated, the influence of motor interventions and their effectiveness in enhancing specific driving-related skills after stroke remains less understood. We compare the effectiveness of two motor interventions (force-control vs. strength training) to facilitate braking, an essential skill for safe driving.

Methods

Twenty-two stroke survivors were randomized to force-control training or strength training. Before and after training, participants performed a braking task during car-following in a driving simulator. We quantified the cognitive and motor components of the braking task with cognitive processing time and movement execution time.

Results

The cognitive processing time did not change for either training group. In contrast, the movement execution became significantly faster (14%) following force-control training but not strength training. In addition, task-specific effects of training were found in each group. The force-control group showed improved accuracy and steadiness of ankle movements, whereas the strength training group showed increased dorsiflexion strength following training.

Conclusion

Motor intervention that trains ankle force control in stroke survivors improves the speed of movement execution during braking. Driving rehabilitation after stroke might benefit from incorporating force-control training to enhance the movement speed for a well-timed braking response.
A Preliminary Study on Change of Serum Immunoglobulin G Glycosylation in Patients With Migraine
Authors: Xu Jingwei , Wang Yuan , Han Yating , Liu Ningfeng , Liu Zhenming , Guo Huailian , Zou Xiajuan , Zhang Jun
Published: May 2022

Background and Objective

Migraine is a common neurological disease, but its pathogenesis is still unclear. Previous studies suggested that migraine was related to immunoglobulin G (IgG). We intended to analyze the immune characteristics of migraine from the perspective of IgG glycosylation and provide theoretical assistance for exploring its pathogenesis.

Methods

The differences in the serum level of IgG glycosylation and glycopeptides between patients with episodic migraine and healthy controls were analyzed by applying the poly(glycerol methacrylate)@chitosan (PGMA@CS) nanomaterial in combination with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). We constructed a binary classification model with a feedforward neural network using PyTorch 1.6.0 in Python 3.8.3 to classify the episodic migraine and healthy control groups.

Results

Twenty patients with migraine and 20 healthy controls were enrolled and the blood samples and clinical information were collected. Forty-nine IgG N-glycopeptides were detected in the serum of the subjects. The serum level of N-glycopeptide IgG1 G0-NF (p = 0.012) was increased in patients with migraine. The serum level of N-glycopeptide IgG3/4 G2FS (p = 0.041) was decreased in patients with migraine with family history of headache. It was found that the serum level of the IgG1 G1 (p = 0.004) and IgG2 G0 (p = 0.045) was increased in patients with migraine with aura, while the serum level of IgG2 G0N (p = 0.043) in patients with migraine with aura was significantly lower than that in patients with migraine without aura. In addition, a linear feedforward neural network (FFNN) was used to construct a binary classification model by detected IgG N-glycopeptides. The area under the curve (AUC) value of the binary classification model, which was constructed with 7 IgG N-glycopeptides, was 0.857, suggesting a good prediction performance. Among these IgG N-glycopeptides that were constructed the model, IgG1 G0-NF was overlapped with the differential IgG N-glycopeptide between patients with migraine and healthy controls detected with MALDI-TOF-MS.

Conclusion

Our results indicated that the serum level of N-glycopeptides IgG1 G0-NF might be one of the important biomarkers for the diagnosis of migraine. To the best of our knowledge, this is the first study about the changes of IgG N-glycosylation in patients with migraine by the method of MALDI-TOF-MS. The results indicated a relationship between the migraine and immune response.
Impact of Early Rehabilitation on Outcomes in Patients With Acute Ischemic Stroke After Endovascular Treatment
Authors: He Yi , Nie Ximing , He Tao , Qi Xiao , Chen Zhenzhen , Duan Wei , Wei Yufei , Liu Xiran , Liu Yong
Published: May 2022

Background

This study aims to examine the effects of early rehabilitation on functional outcomes in patients with acute ischemic stroke treated with endovascular treatment (EVT).

Methods

Eligible patients with large vessel occlusion stroke treated with EVT, who received early rehabilitation or standard care treatment during hospitalization, were enrolled in a multicenter registration, prospective observational study, a registration study for Critical Care of Acute Ischemic Stroke After Recanalization. Early rehabilitation was defined as rehabilitation interventions initiated within 1 week after acute stroke. The primary outcome was the favorable functional outcome (defined as modified Rankin Scale scores of 0 to 2) at 90 days. Independent association between early rehabilitation and the primary outcome was investigated using multivariable logistic regression in the entire sample and in subgroups.

Results

A total of 1,126 patients (enrolled from July 2018 to May 2019) were included in the analyses, 273 (24.2%) in the early rehabilitation group and 853 (75.8%) in the standard care group. There was no significant difference in favorable functional outcomes at 90 days between the two groups (45.4 vs. 42.6%, p = 0.41). Patients in the early rehabilitation group had a lower death rate within 90 days compared with the standard care group (6.2 vs. 20.5%, p < 0.01). The multivariable logistic regression analyses showed that the early rehabilitation was not significantly associated with the favorable functional outcome at 90 days (adjusted odds ratio, 1.01 [95% CI, 0.70–1.47]; p = 0.95). There was no significant difference between subgroups in the favorable functional outcome at 90 days. No significant interaction was found between subgroups.

Conclusions

Patients with stroke receiving early rehabilitation had a lower death rate. However, these clinically meaningful effects of early rehabilitation did not show on functional outcome at 90 days in patients with large vessel occlusion stroke treated with EVT.

Registration

URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900022154.
The Association of Nocturnal Blood Pressure Patterns and Other Influencing Factors With Lacunes and Enlarged Perivascular Spaces in Hypertensive Patients
Authors: Gao Yang , Deng Weiping , Sun Jialan , Yue Dongqi , Zhang Bei , Feng Yulan , Han Jun , Shen Fanxia , Hu Jin , Fu Yi
Published: May 2022

Purpose

Nocturnal blood pressure dipping patterns have been associated with an increased risk of Cerebral Small Vessel Disease (CSVD), which has not been well-studied. This study is aimed to explore the association of dipping patterns and other factors with lacunes and enlarged perivascular spaces (EPVS) in patients with hypertension.

Methods

We enrolled a total of 1,322 patients with essential hypertension in this study. Magnetic resonance imaging (MRI) scans and 24-h ambulatory blood pressure (BP) monitoring were completed. Nocturnal BP decline was calculated, and then dipping patterns were classified. Patients were classified into four groups according to the performance of lacunes and EPVS in the MRI scan for statistical analysis.

Results

(1) Nocturnal BP decline showed independent negative correlation with both lacunes and EPVS while mean systolic BP (mSBP) level showed an independent positive correlation with them (P < 0.05). (2) The frequency of reverse-dippers in the control group was significantly lower than that in other groups; the frequency of non-dippers in the lacunes group and EPVS group was significantly lower than that in the control group; the frequency of extreme-dippers in the EPVS group was significantly higher than that in the mixed (lacunes with EPVS) group (P < 0.05).

Conclusions

Both mSBP and dipping patterns might play an important role in developing lacunes and EPVS in patients with hypertension.
Minimal Manifestation Status Indicates a Stable State in Myasthenia Gravis: A Quantitative Study
Authors: Jiang Ping , Li Jie , Li Hong-Yan , Zhang Bin , Yue Yao-Xian , Wang Su-Yun , Zi Xi-Cun , Liu Shuang-Shuang , Li Yi-Fan , Jiao Li-Dong , Li Hai-Feng
Published: May 2022

Introduction

Minimal manifestation (MM) or better was recommended as the treatment goal for myasthenia gravis (MG). The sustainability of this status has not been described quantitatively in patients who had attained or are close to it.

Methods

Patients who were with no or slight impact on daily living were recruited and followed at baseline and 3, 6, and 12 months. The included patients were classified into 3 post-intervention status (PIS) categories: remission (R), MM, and slight impact (SI). The proportion of patients belonging to real-time (not considering the intervals between assessments) and sustained (considering the intervals between assessments) PIS categories was compared at each follow-up. A sensitivity analysis (SA) cohort was established by including patients with PIS categories in all four follow-ups. The QMGS, MG-ADL, and MG-QOL15 scores in patients belonging to each PIS category at each follow-up were compared. The sustainability of the R/MM status was examined and correlated with real-time R/MM status at follow-ups.

Results

At baseline, 376 patients could be classified, including 55 as R (14.2%), 209 as MM (54.0%), and 112 as SI (28.9%). In the whole cohort, 68.8–89.7%, 71–76.7% and 19.8–77.1% of the patients classified into real-time R, MM, and SI categories remained unchanged in each follow-up compared with the previous follow-up. The proportion of patients belonging to each real-time or sustained R/MM status at the three follow-ups was 89.7–92.1 or 60.8–67. In the SA cohort, at least 86.4% of the baseline R/MM patients remained in R/MM status till 12 months. There were no differences in keeping real-time R/MM status at 6 or 12 months between patients with and without sustained R/MM status at 3 and 6 months. There were differences in the QMGS, MG-ADL, and MG-QOL15 scores among patients belonging to each real-time category at baseline and follow-ups, ranking as R < MM < SI. The same trend was observed in patients belonging to each sustained PIS category with smaller scores than the same items of real-time categories.

Conclusion

The sustainability of the R/MM status was confirmed. The R/MM status indicated a stable state of MG. The QMGS, MG-ADL, and MG-QOL15 scores may provide a quantitative reference for these PIS.
Case Report: Baló's Concentric Sclerosis-Like Lesion in a Patient With Relapsing-Remitting Multiple Sclerosis Treated With Dimethyl Fumarate
Authors: Kania Karolina , Ambrosius Wojciech , Kozubski Wojciech , Kalinowska Alicja
Published: May 2022

Baló's concentric sclerosis (BCS) is a rare demyelinating disorder characterized by acute or subacute neurological symptoms associated with characteristic lesions of concentric onion skin appearance on MRI images and in pathology. The connection between BCS and classic MS is still a subject of debates. Our report presents a case of a patient who developed a symptomatic Baló-like lesion following several years of classical relapsing-remitting multiple sclerosis treated with dimethyl fumarate.
Development of Two Diagnostic Prediction Models for Leptomeningeal Metastasis in Patients With Solid Tumors
Authors: Gao Tianqi , Chen Fengxi , Li Man
Published: May 2022

Objectives

For accurate diagnosis of leptomeningeal metastasis (LM) and to avoid unnecessary examinations or lumber puncture (LP), we develop two diagnostic prediction models for patients with solid tumors.

Study Design, Setting, and Participants

This is a retrospective cohort study launched at the Second Affiliated Hospital of Dalian Medical University. In total, 206 patients who had been admitted between January 2005 and December 2021 with a solid tumor and clinical suspicion of LM were enrolled to develop model A. In total, 152 patients of them who underwent LPs for cytology and biochemistry were enrolled to develop model B.

Model Development

Diagnostic factors included skull metastasis, active brain metastasis, progressed extracranial disease, number of extracranial organs involved, number of symptoms, cerebrospinal fluid (CSF) protein, and CSF glucose. The outcome predictor was defined as the clinical diagnosis of LM. Logistic least absolute shrinkage and selection operator (LASSO) regression was used to identify relevant variables and fit the prediction model. A calibration curve and the concordance index (c-index) were used to evaluate calibration and discrimination ability. Then-fold cross-validation method was used to internally validate the models. The decision curve analysis (DCA) and the interventions avoided analysis (IAA) were used to evaluate the clinical application.

Results

The area under the curve (AUC) values of models A and B were 0.812 (95% CI: 0.751–0.874) and 0.901 (95% CI: 0.852–0.949). Respectively, compared to the first magnetic resonance imaging (MRI) and first LP, models A and B showed a higher AUC (model A vs. first MRI: 0.812 vs. 0.743,p= 0.087; model B vs. first LP: 0.901 vs. 0.800,p= 0.010). The validated c-indexes were 0.810 (95% CI: 0.670–0.952) and 0.899 (95% CI: 0.823–0.977). The calibration curves show a good calibrated ability. The evaluation of clinical application revealed a net clinical benefit and a reduction of unnecessary interventions using the models.

Conclusions

The models can help improve diagnostic accuracy when used alone or in combination with conventional work-up. They also exhibit a net clinical benefit in medical decisions and in avoiding unnecessary interventions for patients with LM. Studies focused on external validation of our models are necessary in the future.
Effect of Celastrol on LncRNAs and mRNAs Profiles of Cerebral Ischemia-Reperfusion Injury in Transient Middle Cerebral Artery Occlusion Mice Model
Authors: Liu Jiandong , Guo Xiangna , Yang Lu , Tao Tao , Cao Jun , Hong Zexuan , Zeng Fanning , Lu Yitian , Lin Chunshui , Qin Zaisheng
Published: May 2022

Celastrol plays a significant role in cerebral ischemia-reperfusion injury. Although previous studies have confirmed that celastrol post-treatment has a protective effect on ischemic stroke, the therapeutic effect of celastrol on ischemic stroke and the underlying molecular mechanism remain unclear. In the present study, focal transient cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) in mice and celastrol was administered immediately after reperfusion. We performed lncRNA and mRNA analysis in the ischemic hemisphere of adult mice with celastrol post-treatment through RNA-Sequencing (RNA-Seq). A total of 50 differentially expressed lncRNAs (DE lncRNAs) and 696 differentially expressed mRNAs (DE mRNAs) were identified between the sham and tMCAO group, and a total of 544 DE lncRNAs and 324 DE mRNAs were identified between the tMCAO and tMCAO + celastrol group. Bioinformatic analysis was done on the identified deregulated genes through gene ontology (GO) analysis, KEGG pathway analysis and network analysis. Pathway analysis indicated that inflammation-related signaling pathways played vital roles in the treatment of ischemic stroke by celastrol. Four DE lncRNAs and 5 DE mRNAs were selected for further validation by qRT-PCR in brain tissue, primary neurons, primary astrocytes, and BV2 cells. The results of qRT-PCR suggested that most of selected differentially expressed genes showed the same fold change patterns as those in RNA-Seq results. Our study suggests celastrol treatment can effectively reduce cerebral ischemia-reperfusion injury. The bioinformatics analysis of lnRNAs and mRNAs profiles in the ischemic hemisphere of adult mice provides a new perspective in the neuroprotective effects of celastrol, particularly with regards to ischemic stroke.
Effect of Probiotics on Liver Enzymes in Patients With Non-alcoholic Fatty Liver Disease: An Umbrella of Systematic Review and Meta-Analysis
Authors: Musazadeh Vali , Roshanravan Neda , Dehghan Parvin , Ahrabi Sana Sedgh
Published: May 2022

Non-alcoholic fatty liver disease (NAFLD) has become prevalent in recent decades, especially in developed countries; yet the approaches for preventing and treating NAFLD are not clear. This study aimed to summarize meta-analyses of randomized controlled trials that examined the effects of probiotics on NAFLD. We systematically searched PubMed, Scopus, Embase, Web of Science, and Cochrane Central Library databases up to August 2021. All Meta-analysis studies assessing the effect of probiotics on liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and Gamma-glutamyl transferase (GGT)] were included. Meta-analysis was conducted using a random-effects model. Sensitivity and subgroup analyses were also performed. The umbrella study covered ten eligible studies involving 5,162 individuals. Beneficial effects of probiotics supplementation were revealed on ALT (ES = −10.54 IU/L; 95% CI: −12.70, −8.39; p < 0.001; I2 = 60.9%, p = 0.006), AST (ES = −10.19 IU/L, 95%CI: −13.08, −7.29, p < 0.001; I2 = 79.8%, p < 0.001), and GGT (ES = −5.88 IU/L, 95% CI: −7.09, −4.67, p = 0.009; I2 = 0.0%, p = 0.591) levels. Probiotics have ameliorating effects on ALT, AST, and GGT levels in patients with NAFLD. Overall, Probiotics could be recommended as an adjuvant therapeutic method for the management of NAFLD.
Six Types of Tea Reduce Acute Alcoholism in Mice by Enhancing Ethanol Metabolism, Suppressing Oxidative Stress and Inflammation
Authors: Lai Xingfei , Wang Xinrong , Wen Shuai , Sun Lingli , Chen Ruohong , Zhang Zhenbiao , Li Qiuhua , Cao Junxi , Lai Zhaoxiang , Li Zhigang , Sun Shili , Liu Xiaohui
Published: May 2022

Acute alcoholic intoxication (AAI) is a pathological process of multiple system damage caused by a large amount of alcohol, especially in the liver. Although tea extracts alleviate AAI and alcohol-induced liver damage, the mechanisms underlying the protective actions of different types of Chinese tea are unclear. In this study, the AAI mice model was used to explore the functions and mechanisms of six types of tea extract (WEATs) in alleviating AAI. The losing righting reflexes of mice were evaluated to assess the effects of the WEATs on AAI. The levels of the ethanol metabolism enzymes (ADH, ALDH2, CYP2E1), the oxidative stress-related indicators (NRF-2, HO-1, SOD, GSH, CAT, and TG) and the inflammatory factors (TNF-α, iNOS, IL-6, and IL-10) were determined. Black tea and dark tea significantly shortened the sleep time (duration of the loss of righting reflex) and had a good sobering effect. Green tea and oolong tea had the dual effect of prolonging tolerance time (time of losing righting reflex) and shortening sleep time. While white tea had the most significant effect on prolonging tolerance time but with no obvious sobering effect. Black tea, dark tea, and oolong tea significantly up-regulated ADH and ALDH2, and down-regulated CYP2E1. Green tea and white tea significantly increased the levels of Nrf2, GSH, and CAT. Black tea, dark tea and oolong tea markedly increased the levels of HO-1, IL-10, and inhibited TG. Therefore, it is possible that black tea, dark tea and oolong tea reduced AAI by increasing ethanol metabolism, suppressing oxidative stress and inflammation. While green tea was mainly by regulating oxidative stress. White tea may prolong the tolerance time by increasing ethanol metabolism and reducing oxidative stress. Different types of tea have specific chemical compositions and can alleviate AAI. In conclusion, despite variations in the composition and mechanism of action, tea is a potent natural product to alleviate a hangover and protect the liver.
Bioactive Compounds and Functional Properties of Herbal Preparations of Cystus creticus L. Collected From Rhodes Island
Authors: Mocan Andrei , Fernandes Ângela , Calhelha Ricardo C. , Gavrilaş Laura , Ferreira Isabel C. F. R. , Ivanov Marija , Sokovic Marina , Barros Lillian , Babotă Mihai
Published: May 2022

The members of Cystus genus are perenial shrubs with a well-established use in traditional medicine. Among these, C. creticus is the most popular, herbal preparations obtained from its aerial parts being recognized as antimicrobial, antitumor and anti-inflammatory agents. The present study aimed to evaluate phytochemical profile and bioactive potential of aqueous and hydroethanolic extracts of C. creticus aerial parts harvested from two different areas of Rhodes island. LC-DAD-ESI/MSn analysis revealed the presence of myricetin and quercetin glycosides as main compounds, especially in aqueous extracts, being probably responsible for their enhanced antioxidant and antimicrobial potential. On the other side, hydroethanolic preparations exerted a strong anti-inflammatory and anti-biofilm activity. Our findings suggest that the use of solvents with intermediate polarity can assure the best recovery of bioactive compounds from C. creticus, increasing the extraction yield for other non-phenolic compounds which can enhance therapeutic potential of the extract through a synergistic action.
The Feasibility and User-Experience of a Digital Health Intervention Designed to Prevent Weight Gain in New Kidney Transplant Recipients—The ExeRTiOn2 Trial
Authors: Castle Ellen M. , Dijk Giulia , Asgari Elham , Shah Sapna , Phillips Rachel , Greenwood James , Bramham Kate , Chilcot Joseph , Greenwood Sharlene A.
Published: May 2022

Half of kidney transplant recipients (KTRs) gain more than 5% of their body weight in the first year following transplantation. KTRs have requested support with physical activity (PA) and weight gain prevention, but there is no routine care offered. There are few high-quality studies investigating the clinical value of diet, PA or combined interventions to prevent weight gain. The development and evaluation of theoretically informed complex-interventions to mitigate weight gain are warranted. The aims of this mixed-methods randomized controlled trial (RCT) were to explore the feasibility, acceptability and user-experience of a digital healthcare intervention (DHI) designed to prevent post-transplant weight gain, in preparation for a large multi-center trial. New KTRs (<3 months) with access to an internet compatible device were recruited from a London transplant center. The usual care (UC) group received standard dietary and PA advice. The intervention group (IG) received access to a 12-week DHI designed to prevent post-transplant weight gain. Primary feasibility outcomes included screening, recruitment, retention, adherence, safety and hospitalizations and engagement and experience with the DHI. Secondary outcomes (anthropometrics, bioimpedance, arterial stiffness, 6-minute walk distance and questionnaires) were measured at baseline, 3- and 12-months. 38 KTRs were screened, of which 32 (84.2%) were eligible, and of those 20 (62.5%) consented, with 17 participants (85%) completing baseline assessment (Median 49 years, 58.8% male, Median 62 days post-transplant). Participants were randomized using a computer-generated list (n = 9 IG, n = 8 UC). Retention at 12-months was 13 (76.4%) (n = 6 IG, n = 7 UC). All a priori progression criteria were achieved. There were no associated adverse events. Reflexive thematic analysis revealed four themes regarding trial participation and experience whilst using the DHI. Halting recruitment due to COVID-19 resulted in the recruitment of 40% of the target sample size. Mixed-methods data provided important insights for future trial design. A definitive RCT is warranted and welcomed by KTRs.

Clinical Trial Registration

www.clinicalTrials.gov, identifier: NCT03996551.
Real-World Treatment Patterns and Clinical Outcomes in Patients With Stage III Non-Small-Cell Lung Cancer: Results of KINDLE-Vietnam Cohort
Authors: Van Dao Tu , Diep Tuan Bao , Le Phuong Tri , Huggenberger Reto , Kumar Amit
Published: May 2022

Objective

KINDLE-Vietnam was a part of a real-world KINDLE study with an aim to characterise treatment patterns and clinical outcomes of patients with stage III non-small cell lung cancer (NSCLC).

Materials and Methods

Retrospective data from patients diagnosed with stage III NSCLC (American Joint Committee on Cancer, 7th edition) between January 2013 and December 2017 with at least 9 months of follow-up were collected from 2 centres in Vietnam. Descriptive statistics were used to summarise demographics, disease characteristics and treatment modalities. Kaplan-Meier methodology evaluated survival estimates; 2-sided 95% confidence intervals (CIs) were computed. Inferential statistics were used to correlate clinical and treatment variables with median progression-free survival (mPFS) and median overall survival (mOS).

Results

A total of 150 patients (median age: 60 years [range 26-82]) were enrolled; 75.3% were male, 62.0% had smoking history, 56.4% had stage IIIB disease and 62.5% had adenocarcinoma. The majority of the cases (97.3%) were not discussed at a multidisciplinary team meeting. Overall, chemotherapy alone (43.3%), radiotherapy alone (17.0%), sequential chemoradiation (13.5%) and concurrent chemoradiation (12.8%) were preferred as initial therapy. Surgery-based treatment was administered in limited patients (stage IIIA, 10%; stage IIIB, 1.3%). Palliative therapy was the most commonly administered treatment upon relapse in the second-and third-line setting. The mPFS and mOS for the Vietnam cohort were 8.7 months (95% CI, 7.59-9.72) and 25.7 months (95% CI, 19.98-42.61), respectively. The mPFS and mOS for stage IIIA were 11.9 months (95% CI, 8.64-14.95) and 28.2 months (95% CI, 24.15-not-calculable) and for stage IIIB were 7.8 months (95% CI, 6.64-8.71) and 20.0 months (95% CI, 13.01-42.61).

Conclusions

KINDLE-Vietnam offers insights into the clinical findings of stage III NSCLC. There is a high unmet need for identifying patients in the early stages of NSCLC. Strategies for improving clinical outcomes in this patient population include physician education, multidisciplinary management and catering to increased access to novel agents like immunotherapy and targeted therapy.
Neurotropic Cutaneous Malignancies: Case Report on Keratinocyte Derived Malignancies of the Head and Neck With Perineural Invasion
Authors: Ahn Grace Sora , Hinds Brian , Kolb Frederic , Reisenauer Amy K. , Soon Seaver L. , Sepahdari Ali R. , Bollin Kathryn B. , Park Soo J.
Published: May 2022

Background

The recent addition of immunotherapy as a treatment modality to surgery and radiation has vastly improved disease control for patients with keratinocyte-derived carcinomas (KCs) that are incurable with local therapies alone. With the advent of immune checkpoint inhibitors (ICPis) in non-melanoma skin cancers comes diagnostic and therapeutic challenges when considering treatment strategies for patients presenting with clinical perineural invasion (cPNI) of locally advanced KC of the head and neck.

Objectives

We report four cases that convey the diagnostic and therapeutic complexity of managing patients with neuropathic symptoms from cutaneous neurotropic carcinomas of the head and neck. We also discuss an updated review regarding immunotherapies and perineural invasion within KC management.

Conclusion

Patients presenting with symptoms suspicious for cPNI warrant an expanded diagnostic evaluation to correlate neurological findings with neurotropic spread of disease. While nerve biopsies can be precarious in sensitive areas, a history of skin cancer and clinical presentation suggestive of neurotropism may be enough to pursue timely management in the form of surgery, radiation, and/or systemic therapy given each patient’s individual priorities, comorbidities, and prognosis. When adding ICPi as a treatment modality for patients with disease not amenable to local therapies, the potential for immune-related adverse events must be considered. A multi-disciplinary review and approach to the management of patients with KC and cPNI is essential for obtaining optimal patient outcomes.
Image-Based Differentiation of Benign and Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1
Authors: Liu Jun , Huang Jing-Ning , Wang Ming-Han , Ni Zhen-Yang , Jiang Wei-Hao , Chung Manhon , Wei Cheng-Jiang , Wang Zhi-Chao
Published: May 2022

Neurofibromatosis type 1 (NF1) is a dominant hereditary disease characterized by the mutation of the NF1 gene, affecting 1/3000 individuals worldwide. Most NF1 patients are predisposed to benign peripheral nerve sheath tumors (PNSTs), including cutaneous neurofibromas (CNFs) and plexiform neurofibromas (PNFs). However, 5%-10% of PNFs will ultimately develop into malignant peripheral nerve sheath tumors (MPNSTs), which have a poor prognosis. Early and reliable differentiation of benign and malignant tumors in NF1 patients is of great necessity. Pathological evaluation is the “gold standard” for a definite diagnosis, but the invasive nature of the biopsy procedure restricts it from applying as a screening tool during the decades-long follow-up of these patients. Non-invasive image-based diagnostic methods such as CT and MRI are often considered essential screening tools for multiple types of tumors. For NF1 patients’ lifelong regular follow-ups, these radiological methods are currently used for tumor evaluation. However, no consensus was established on screening the malignant transformation of benign PNSTs. Moreover, novel technologies like radiogenomics and PET-MRI have not been well evaluated and fully adopted for NF1 patients. This review summarizes current studies of different imaging methods for differentiating benign and malignant tumors in NF1. Meanwhile, we discussed the prospects of the usage of new tools such as radiogenomics and PET-MRI to distinguish MPNST from benign PNSTs more precisely. Summarizing these findings will help clarify the directions of future studies in this area and ultimately contribute to the radiology images-based clinical screening of MPNST in NF1 patients and finally improve the overall survival rates of these patients.
The Short Term Influence of Chest Physiotherapy on Lung Function Parameters in Children With Cystic Fibrosis and Primary Ciliary Dyskinesia
Authors: Vandervoort Bjarne , De Beuckeleer Django , Huenaerts Elke , Schulte Marianne , Vermeulen François , Proesmans Marijke , Troosters Thierry , Vreys Myriam , Boon Mieke
Published: May 2022

Airway clearance therapy (ACT) is one of the cornerstone treatment modalities to improve mucociliary clearance for patients with bronchiectasis. The progression of lung disease in patients with bronchiectasis can be evaluated by spirometry and multiple breath washout (MBW) and it is advised to monitor these on a regular basis. However, the short term effect of ACT on spirometry and MBW parameters is insufficiently clear and this variability may impact standardization. For cystic fibrosis (CF), available literature refutes a short time effect on spirometry and MBW parameters in children, however, for primary ciliary dyskinesia (PCD) no data are available. We performed a single-center, prospective cross-over study to evaluate the short term effect of a single ACT session using positive expiratory pressure mask on forced expiratory volume in 1 s (FEV1) and lung clearance index (LCI), derived from MBW, compared to no ACT (control) in pediatric patients with CF and PCD. A total of 31 children were included: 14 with PCD and 17 with CF. For the whole group, there was no difference in median change of FEV1 pp between the treatment and the control group (p 0.969), nor in median change of LCI (p 0.294). For the CF subgroup, the mean change in FEV1 pp with ACT was −1.4% (range −9 to + 5) versus −0.2% (range −6 to + 5) for no ACT (p 0.271), the mean change in LCI with ACT was + 0.10 (range −0.7 to + 1.2) versus + 0.17 (range −0.5 to + 2.8) for no ACT (p 0.814). In the PCD subgroup, the mean change in FEV1 pp with ACT was + 1.0 (range −7 to + 8) versus −0.3 (range −6 to + 5) for no ACT (p 0.293) and the mean change in LCI with ACT was −0.46 (range −3.7 to + 0.9) versus −0.11 (range −1.4 to + 1.3) for no ACT (p 0.178). There was no difference between PCD and CF for change in FEV1 pp after ACT (p = 0.208), nor for LCI (p = 0.095). In this small group of pediatric patients, no significant short-term effect of chest physiotherapy on FEV1 pp nor LCI in PCD and CF values nor variability was documented.
Machine Learning-Based CT Radiomics Method for Identifying the Stage of Wilms Tumor in Children
Authors: Ma Xiao-Hui , Shu Liqi , Jia Xuan , Zhou Hai-Chun , Liu Ting-Ting , Liang Jia-Wei , Ding Yu-shuang , He Min , Shu Qiang
Published: May 2022

Purpose

To develop and validate a machine learning-based CT radiomics method for preoperatively predicting the stages (stage I and non-stage I) of Wilms tumor (WT) in pediatric patients.

Methods

A total of 118 patients with WT, who underwent contrast-enhanced computed tomography (CT) scans in our center between 2014 and 2021, were studied retrospectively and divided into two groups: stage I and non-stage I disease. Patients were randomly divided into training cohorts (n = 94) and test cohorts (n = 24). A total of 1,781 radiomic features from seven feature classes were extracted from preoperative portal venous–phase images of abdominal CT. Synthetic Minority Over-Sampling Technique (SMOTE) was used to handle imbalanced datasets, followed by a t-test and Least Absolute Shrinkage and Selection Operator (LASSO) regularization for feature selection. Support Vector Machine (SVM) was deployed using the selected informative features to develop the predicting model. The performance of the model was evaluated according to its accuracy, sensitivity, and specificity. The receiver operating characteristic curve (ROC) and the area under the ROC curve (AUC) was also arranged to assess the model performance.

Results

The SVM model was fitted with 15 radiomic features obtained by t-test and LASSO concerning WT staging in the training dataset and demonstrated favorable performance in the testing dataset. Cross-validated AUC on the training dataset was 0.79 with a 95 percent confidence interval (CI) of 0.773–0.815 and a coefficient of variation of 3.76%, while AUC on the test dataset was 0.81, and accuracy, sensitivity, and specificity were 0.79, 0.87, and 0.69, respectively.

Conclusions

The machine learning model of SVM based on radiomic features extracted from CT images accurately predicted WT stage I and non-stage I disease in pediatric patients preoperatively, which provided a rapid and non-invasive way for investigation of WT stages.
Neonatal Mortality Rate and Its Determinants: A Community–Based Panel Study in Ethiopia
Authors: Shiferaw Kasiye , Mengistie Bezatu , Gobena Tesfaye , Dheresa Merga , Seme Assefa
Published: May 2022

Background

The Sustainable Development Goals specifically target a reduction in neonatal mortality rates. However, the highest neonatal mortality rates occur in sub-Saharan Africa, including Ethiopia. Although several factors contributing to these high rates have been explored, there continues to be a general dearth of studies and inconsistencies of factors to understand the problem. Therefore, this study aimed to identify the prevalence and factors associated with neonatal mortality in Ethiopia.

Methods

A panel study was conducted among 2,855 pregnant or recently postpartum women selected using the multistage cluster sampling technique from October 2019 to September 2020. Data were collected by experienced and trained female resident enumerators and coded, cleaned, and analyzed using STATA version 16.1 software. We used the Kaplan–Meier survival curve to show the pattern of neonatal deaths during the first 28 days of life. Frequencies and rates were reported along with the percentages and using a 95% confidence interval, respectively. The Cox proportional hazard regression model was used to explore the association of explanatory and outcome variables. Finally, an adjusted hazard ratio with a 95% confidence interval was used to report the results, with a p < 0.05 to declare statistical significance.

Results

The neonatal mortality rate was 26.84 (95% CI: 19.43, 36.96) per 1,000 live births. Neonates born to rural resident mothers (AHR = 2.18, 95% CI: 1.05, 4.54), mothers of advanced age (AHR = 2.49, 95% CI: 1.19, 5.21), and primipara mothers (AHR = 3.16, 95% CI: 1.52, 6.60) had a higher hazard of neonatal mortality. However, neonates born to women who attended technical and vocational level education (AHR = 0.08, 95% CI: 0.01, 0.62) had a lower hazard of neonatal mortality.

Conclusions

The neonatal mortality rate in Ethiopia is high, with increased risk among specific subsets of the population. The findings highlight that neonatal survival can be improved through tailored interventions for rural residents, emerging regions, and primipara women by improving female education and avoiding pregnancy at an advanced maternal age to achieve Sustainable Development Goal target 3.2.
Long-Term Non-invasive Ventilation in Children With Down Syndrome: A Systematic Review
Authors: Hudson Summer , Abusido Tamer , Sebastianski Meghan , Castro-Codesal Maria L. , Lewis Melanie , MacLean Joanna E.
Published: May 2022

Context

Children with Down syndrome are at risk for obstructive sleep apnea, which may not be resolved by adenotonsillecotmy, as well as other respiratory disorders that may impact breathing during sleep. Long-term non-invasive ventilation, including continuous and bilevel positive airway pressure delivery, is an alternate treatment strategy.

Objective

To assess the use and outcomes of long-term non-invasive ventilation in children with Down syndrome including comparison to other children using long-term non-invasive ventilation.

Data Sources

The search strategy for the scoping review used Medical Subject Headings (MeSH) and free-text terms for “child” and “non-invasive ventilation.” MEDLINE (Ovid), Embase (Ovid), CINAHL (Ebsco), Cochrane Library (Wiley), and PubMed databases were searched (1990-2021).

Study Selection

The scoping review results were searched to identify studies including data on at least three children with Down Syndrome using long-term non-invasive ventilation.

Data Extraction

Study characteristics, subject characteristics, technology type, and outcome measurements were extracted.

Results

A total of 28 articles included 543 children with Down syndrome using long-term non-invasive ventilation. Children with Down syndrome accounted for 18% of children using long-term non-invasive ventilation. Data on efficacy, feasibility, and adherence in children with Down syndrome are comparable to other children. Children with Down syndrome may have greater difficulty initiating long-term non-invasive ventilation, longer time to establish use, and a higher rate of inability to establish use. Outcome data is limited but suggest favorable impact on cardiac function and attention.

Limitations

Articles related to long-term non-invasive ventilation use in adolescents and young adults may have been excluded.

Conclusions

Children with Down syndrome make up a significant portion of the population of children using long-term non-invasive ventilation. While there is more limited data available with respect to the use and outcomes for children with Down syndrome compared to the other children, long-term non-invasive ventilation is an effective and well-tolerated therapy with no clear differences in the use or outcomes for children with Down syndrome. Additional work is needed to understand potential challenges around establishing long-term non-invasive ventilation use in children with Down syndrome.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=206533, identifier: CRD206533.
Prophylactic Low-Dose Paracetamol Administration for Ductal Closure and Amplitude-Integrated Electroencephalography in Preterm Infants
Authors: Schreiner Christina , Sappler Maria , Höck Michaela , Hammerl Marlene , Neubauer Vera , Kiechl-Kohlendorfer Ursula , Griesmaier Elke
Published: May 2022

Introduction

Prophylactic low-dose paracetamol administration is used to induce closure of the ductus arteriosus in preterm infants. In our recent study we found no impairment on microstructural maturation processes in the brain of preterm infants at term-equivalent age following prophylactic low-dose paracetamol administration. We now assessed amplitude-integrated electroencephalography (aEEG) signals in preterm infants with and without exposure to prophylactic low-dose paracetamol administration.

Methods

Infants <32 gestational weeks born between 10/2014 and 12/2018 received prophylactic paracetamol (10 mg/kg intravenously every 8 h until echocardiography after at least 72 h) and form the paracetamol group; infants born between 02/2011 and 09/2014 formed the control group. Four single parameters (continuity, cyclicity, amplitude of lower border, bandwidth span) together with their sum (Burdjalov total score) and presence of sleep-wake cycles were compared between the groups.

Results

Included in the study were 338 infants. Two-hundred and seventeen infants received prophylactic paracetamol and 121 formed the control group. The paracetamol group showed a significantly higher number of sleep-wake cycles per hour and a significantly higher total scores compared to the control group (p < 0.05).

Conclusion

Paracetamol exposure has been regarded critically with respect to safety in preterm infants in recent years. We found no impairment on amplitude-integrated electroencephalography signals in preterm infants receiving low-dose prophylactic paracetamol compared to controls. Growing awareness and greater availability of data may encourage the clinicians to administer prophylactic paracetamol for ductal closure in preterm infants. The clinical relevance of our findings has to be evaluated in long-term follow up studies on neurodevelopmental outcome.