bluuebunny/crossref_metadata_2025 huggingface dataset:
A rare co-occurrence of duchenne muscular dystrophy, congenital adrenal hypoplasia and glycerol kinase deficiency due to Xp21 contiguous gene deletion syndrome: case report
Authors: Rathnasiri Asanka , Senarathne Udara , Arunath Visvalingam , Hoole Thabitha , Kumarasiri Ishara , Muthukumarana Oshanie , Jasinge Eresha , Mettananda Sachith
Published: October 2021

Background

Contiguous gene deletion syndromes are rare genomic disorders caused by deletion of large segments of DNA resulting in co-occurrence of apparently unrelated multiple clinical phenotypes. We report a boy with contiguous gene deletion involving Xp21 genomic location.

Case presentation

A Sri Lankan boy with developmental delay and failure to thrive first presented at three years of age with hypovolaemia, hyperpigmentation and drowsiness. Investigations done at that time revealed hypoglycaemia, hyponatraemia, hyperkalaemia, low cortisol, low aldosterone, high ACTH and low 17-hydroxyprogesterone. He was diagnosed to have primary adrenal insufficiency.

During follow-up at five years, he was noted to have progressive difficulty in walking, waddling gait, hypotonia, calf hypertrophy and positive Gower’s sign. His creatine kinase was very high, and the electromyogram showed myopathy. Genetic analysis revealed hemizygous deletion involving the final 35 exons of the dystrophin gene confirming the diagnosis of Duchenne muscular dystrophy.

Further investigations revealed pseudohypertriglyceridemia, large glycerol peak on urine organic acid analysis and hemizygous deletion of the glycerol kinase gene confirming glycerol kinase deficiency. Based on the presence of Duchenne muscular dystrophy, glycerol kinase deficiency and probable congenital adrenal hypoplasia along with genetic confirmation of deletions involving dystrophin and glycerol kinase genes, the diagnosis of Xp21 contiguous gene deletion syndrome was made.

Conclusions

We report a child with contiguous gene deletion syndrome who was initially diagnosed as having isolated primary adrenal insufficiency probably due to congenital adrenal hypoplasia. Later he was confirmed to have Duchenne muscular dystrophy and glycerol kinase deficiency, as well. This case report highlights the importance of pre-emptive evaluation and identification of genetic defects when patients present with seemingly unrelated diseases that could aid in accurate diagnoses of contiguous gene deletion syndromes.
Are racial/ethnic minorities recently diagnosed with diabetes less likely than white individuals to receive guideline-directed diabetes preventive care?
Authors: Marcondes Felippe O. , Cheng David , Alegria Margarita , Haas Jennifer S.
Published: October 2021

Background

Diabetes mellitus has reached epidemic proportions in the United States. As the prevalence of diabetes continues to rise, the burden of disease is divided unevenly among different populations. Racial/ethnic disparities in diabetes care are pervasive, including the provision of care for prevention of complications. Prevention efforts should be focused on the time that immediately follows a diagnosis of diabetes. The aim of this study was to assess racial/ethnic differences in the receipt of guideline-directed diabetes care for complication prevention by individuals recently diagnosed with diabetes.

Methods

We used repeated cross-sections of individuals recently diagnosed with diabetes (within the past 5 years) from the National Health Interview Survey from 2011 to 2017. Multivariate regression was used to estimate the associations between race/ethnicity (non-Hispanic White, non-Hispanic Black and Hispanic) and guideline-directed process measures for prevention of diabetes complications (visits to an eye and foot specialist, and blood pressure and cholesterol checks by a health professional - each in the prior year). We assessed effect modification of these associations by socioeconomic status (SES).

Results

In a sample of 7,341 participants, Hispanics had lower rates of having any insurance coverage (75.9 %) than Non-Hispanic Whites (93.2 %) and Blacks (88.1 %; p<0.001). After adjustment for demographics, total comorbidities, SES, and health insurance status, Hispanics were less likely to have an eye exam in the prior year (OR 0.80; (95 % CI 0.65-0.99); p=0.04) and a blood pressure check (OR 0.42; (95 % CI 0.28-0.65); p<0.001) compared to Non-Hispanic Whites. There was no significant effect modification of race/ethnicity by SES.

Conclusions

Hispanics recently diagnosed with diabetes were less likely to receive some indicators of guideline-directed care for the prevention of complications. Lack of insurance and SES may partially explain those differences. Future work should consider policy change and providers’ behaviors linked to racial/ethnic disparities in diabetes care.
Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis
Authors: Sivakumar Pitchumani , Ammar Ron , Thompson John Ryan , Luo Yi , Streltsov Denis , Porteous Mary , McCoubrey Carly , Cantu Edward , Beers Michael F. , Jarai Gabor , Christie Jason D.
Published: October 2021

Background

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need. Development of transformational therapies for IPF is challenging in part to due to lack of robust predictive biomarkers of prognosis and treatment response. Importantly, circulating biomarkers of IPF are limited and none are in clinical use.

Methods

We previously reported dysregulated pathways and new disease biomarkers in advanced IPF through RNA sequencing of lung tissues from a cohort of transplant-stage IPF patients (n = 36) in comparison to normal healthy donors (n = 19) and patients with acute lung injury (n = 11). Here we performed proteomic profiling of matching plasma samples from these cohorts through the Somascan-1300 SomaLogics platform.

Results

Comparative analyses of lung transcriptomic and plasma proteomic signatures identified a set of 34 differentially expressed analytes (fold change (FC) ≥  ± 1.5, false discovery ratio (FDR) ≤ 0.1) in IPF samples compared to healthy controls. IPF samples showed strong enrichment of chemotaxis, tumor infiltration and mast cell migration pathways and downregulated extracellular matrix (ECM) degradation. Mucosal (CCL25 and CCL28) and Th2 (CCL17 and CCL22) chemokines were markedly upregulated in IPF and highly correlated within the subjects. The mast cell maturation chemokine, CXCL12, was also upregulated in IPF plasma (fold change 1.92, FDR 0.006) and significantly correlated (Pearson r = − 0.38, p = 0.022) to lung function (%predicted FVC), with a concomitant increase in the mast cell Tryptase, TPSB2. Markers of collagen III and VI degradation (C3M and C6M) were significantly downregulated (C3M p < 0.001 and C6M p < 0.0001 IPF vs control) and correlated, Pearson r = 0.77) in advanced IPF consistent with altered ECM homeostasis.

Conclusions

Our study identifies a panel of tissue and circulating biomarkers with clinical utility in IPF that can be validated in future studies across larger cohorts.
MYCN and MAX alterations in Wilms tumor and identification of novel N-MYC interaction partners as biomarker candidates
Authors: Jiménez Martín Ovidio , Schlosser Andreas , Furtwängler Rhoikos , Wegert Jenny , Gessler Manfred
Published: October 2021

Background

Wilms tumor (WT) is the most common renal tumor in childhood. Among others, MYCN copy number gain and MYCN P44L and MAX R60Q mutations have been identified in WT. MYCN encodes a transcription factor that requires dimerization with MAX to activate transcription of numerous target genes. MYCN gain has been associated with adverse prognosis in different childhood tumors including WT. The MYCN P44L and MAX R60Q mutations, located in either the transactivating or basic helix-loop-helix domain, respectively, are predicted to be damaging by different pathogenicity prediction tools, but the functional consequences remain to be characterized.

Methods

We screened a large cohort of unselected WTs for MYCN and MAX alterations. Wild-type and mutant protein function were characterized biochemically, and we analyzed the N-MYC protein interactome by mass spectrometric analysis of N-MYC containing protein complexes.

Results

Mutation screening revealed mutation frequencies of 3% for MYCN P44L and 0.9% for MAX R60Q that are associated with a higher risk of relapse. Biochemical characterization identified a reduced transcriptional activation potential for MAX R60Q, while the MYCN P44L mutation did not change activation potential or protein stability. The protein interactome of N-MYC-P44L was likewise not altered as shown by mass spectrometric analyses of purified N-MYC complexes. Nevertheless, we could identify a number of novel N-MYC partner proteins, e.g. PEG10, YEATS2, FOXK1, CBLL1 and MCRS1, whose expression is correlated with MYCN in WT samples and several of these are known for their own oncogenic potential.

Conclusions

The strongly elevated risk of relapse associated with mutant MYCN and MAX or elevated MYCN expression corroborates their role in WT oncogenesis. Together with the newly identified co-expressed interactors they expand the range of potential biomarkers for WT stratification and targeting, especially for high-risk WT.
The structure of blood–tumor barrier and distribution of chemotherapeutic drugs in non-small cell lung cancer brain metastases
Authors: Ye Ling-yun , Sun Li-xiang , Zhong Xiu-hua , Chen Xue-song , Hu Song , Xu Rong-rong , Zeng Xiao-ning , Xie Wei-ping , Kong Hui
Published: October 2021

Background

Brain metastasis is an important cause of increased mortality in patients with non-small cell lung cancer (NSCLC). In brain metastasis, the blood–brain barrier (BBB) is frequently impaired, forming blood–tumor barrier (BTB). The efficacy of chemotherapy is usually very poor. However, the characteristics of BTB and the impacts of BTB on chemotherapeutic drug delivery remain unclear. The present study investigated the structure of BTB, as well as the distribution of routine clinical chemotherapeutic drugs in both brain and peripheral tumors.

Methods

Bioluminescent image was used to monitor the tumor load after intracranial injection of lung cancer Lewis cells in mice. The permeability of BBB and BTB was measured by fluorescent tracers of evans blue and fluorescein sodium. Transmission electron microscopy (TEM), immunohistochemistry and immunofluorescence were performed to analyze structural differences between BBB and BTB. The concentrations of chemotherapeutic drugs (gemcitabine, paclitaxel and pemetrexed) in tissues were assayed by liquid chromatography with tandem mass spectrometry (LC-MS/MS).

Results

Brain metastases exhibited increased BTB permeability compared with normal BBB detected by fluorescence tracers. TEM showed abnormal blood vessels, damaged endothelial cells, thick basement membranes, impaired intercellular endothelial tight junctions, as well as increased fenestrae and pinocytotic vesicles in metastatic lesions. Immunohistochemistry and immunofluorescence revealed that astrocytes were distributed surrounded the blood vessels both in normal brain and the tumor border, but no astrocytes were found in the inner metastatic lesions. By LC-MS/MS analysis, gemcitabine showed higher permeability in brain metastases.

Conclusions

Brain metastases of lung cancer disrupted the structure of BBB, and this disruption was heterogeneous. Chemotherapeutic drugs can cross the BTB of brain metastases of lung cancer but have difficulty crossing the normal BBB. Among the three commonly used chemotherapy drugs, gemcitabine has the highest distribution in brain metastases. The permeability of chemotherapeutic agents is related to their molecular weight and liposolubility.
Elevated expression of MKRN3 in squamous cell carcinoma of the head and neck and its clinical significance
Authors: Zhang Shuiting , Liu Chao , Li Guo , Liu Yong , Wang Xingwei , Qiu Yuanzheng
Published: October 2021

Background

Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common types of cancer that cause a substantial number of cancer-related deaths. Our previous study has revealed that makorin ring finger protein 3 (MKRN3) may act as a key regulator of the SCCHN tumorigenesis; however, its specific role in SCCHN progression has not been reported.

Methods

The Cancer Genome Atlas (TCGA) data analysis and quantitative polymerase chain reaction (qPCR) were used to quantify the MKRN3 mRNA expression levels in SCCHN; immunohistochemical staining or immunoblotting analyses were performed to detect MKRN3 protein expression. Kaplan–Meier plotter was used to assess the prognostic values of MKRN3 in terms of overall survival and disease-free survival. The expression differences based on various clinicopathological features were evaluated using subgroup analysis and forest map analysis. The regulatory mechanism of MKRN3 was further investigated using gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Subsequently, STRING was used to perform a co-expression and enrichment analysis for MKRN3. Homologous modeling, molecular docking, and western blot analyses were performed to investigate the relationship between MKRN3 and its potential target gene P53.

Results

MKRN3 was ectopically expressed between cancerous and noncancerous SCCHN tissues, and its expression level was tightly associated with high T classifications as well as advanced clinical stages. qPCR analysis revealed that MKRN3 was upregulated in the SCCHN cell line. Moreover, Kaplan–Meier and Cox regression analyses indicated that SCCHN patients with high MKRN3 expression had poorer prognosis and that MKRN3 was a potential prognostic marker for SCCHN. Using gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses, we determined that MKRN3 may be involved in the regulation of synthesis and metabolism and cell growth, death and motility, as well as cancer pathways associated with SCCHN progression. Mechanism investigation further revealed that P53, a potential target of MKRN3, may be involved in the SCCHN tumorigenesis mediated by MKRN3.

Conclusions

We performed a comprehensive evaluation of the clinical significance of MKRN3 and explored its underlying mechanisms. We concluded that MKRN3 represents a valuable predictive biomarker and potential therapeutic target in SCCHN.
An urban-to-rural continuum of malaria risk: new analytic approaches characterize patterns in Malawi
Authors: Larson Peter S. , Eisenberg Joseph N. S. , Berrocal Veronica J. , Mathanga Don P. , Wilson Mark L.
Published: October 2021

Background

The urban–rural designation has been an important risk factor in infectious disease epidemiology. Many studies rely on a politically determined dichotomization of rural versus urban spaces, which fails to capture the complex mosaic of infrastructural, social and environmental factors driving risk. Such evaluation is especially important for Plasmodium transmission and malaria disease. To improve targeting of anti-malarial interventions, a continuous composite measure of urbanicity using spatially-referenced data was developed to evaluate household-level malaria risk from a house-to-house survey of children in Malawi.

Methods

Children from 7564 households from eight districts throughout Malawi were tested for presence of Plasmodium parasites through finger-prick blood sampling and slide microscopy. A survey questionnaire was administered and latitude and longitude coordinates were recorded for each household. Distances from households to features associated with high and low levels of development (health facilities, roads, rivers, lakes) and population density were used to produce a principal component analysis (PCA)-based composite measure for all centroid locations of a fine geo-spatial grid covering Malawi. Regression methods were used to test associations of the urbanicity measure against Plasmodium infection status and to predict parasitaemia risk for all locations in Malawi.

Results

Infection probability declined with increasing urbanicity. The new urbanicity metric was more predictive than either a governmentally defined rural/urban dichotomous variable or a population density variable. One reason for this was that 23% of cells within politically defined rural areas exhibited lower risk, more like those normally associated with “urban” locations.

Conclusions

In addition to increasing predictive power, the new continuous urbanicity metric provided a clearer mechanistic understanding than the dichotomous urban/rural designations. Such designations often ignore urban-like, low-risk pockets within traditionally rural areas, as were found in Malawi, along with rural-like, potentially high-risk environments within urban areas. This method of characterizing urbanicity can be applied to other infectious disease processes in rapidly urbanizing contexts.
Prevalence of malaria in an area receiving seasonal malaria chemoprevention in Niger
Authors: Coldiron Matthew E. , Assao Bachir , Guindo Ousmane , Sayinzoga-Makombe Nathan , Koscalova Alena , Sterk Esther , Quere Michel , Ciglenecki Iza , Mumina Ann , Atti Salifou , Langendorf Céline , Grais Rebecca F.
Published: October 2021

Background

Malaria transmission is highly seasonal in Niger. Despite the introduction of seasonal malaria chemoprevention (SMC) in the Magaria District, malaria incidence remains high, and the epidemiology of malaria in the community is not well-understood.

Methods

Four cross-sectional, household-based malaria prevalence surveys were performed in the Magaria District of Niger between October 2016 and February 2018. Two occurred during the peak malaria season and two during the low malaria season. Individuals in each of three age strata (3–59 months, 5–9 years, and 10 years and above) were sampled in randomly-selected households. Capillary blood was collected by fingerprick, thick and thin blood films were examined. Microscopy was performed at Epicentre, Maradi, Niger, with external quality control. The target sample size was 396 households during the high-season surveys and 266 households during the low-season surveys.

Results

Prevalence of parasitaemia was highest in children aged 5–9 years during all four surveys, ranging between 53.6% (95%CI 48.8–63.6) in February 2018 and 73.2% (66.2–79.2) in September 2017. Prevalence of parasitaemia among children aged 3–59 months ranged between 39.6% (33.2–46.4) in February 2018 and 51.9% (45.1–58.6) in October 2016. Parasite density was highest in children aged 3–59 months during all four surveys, and was higher in high season surveys than in low season surveys among all participants. The prevalence of gametocytaemia in children aged 3–59 months ranged between 9.9% (6.5–14.8) in February 2018 and 19.3% (14.6–25.2) in October 2016. The prevalence of gametocytaemia in children aged 5–9 years ranged between 6.3% (3.5–11.1) in February 2018 and 18.5% (12.7–26.1) in October 2016.

Conclusions

Asymptomatic malaria infection is highly prevalent in this area, even during the season with low incidence of clinical malaria. The high prevalence of parasitaemia in children aged 5–9 years warrants considering their inclusion in SMC programmes in this context.
Instantaneous radiated power of brain activity: application to prepulse inhibition and facilitation for body dysmorphic disorder
Authors: Giannopoulos Anastasios E. , Spantideas Sotirios T. , Capsalis Christos , Papageorgiou Panos , Kapsalis Nikolaos , Kontoangelos Konstantinos , Papageorgiou Charalabos
Published: October 2021

Background

Global measures of neuronal activity embrace the advantage of a univariate, holistic and unique description of brain activity, reducing the spatial dimensions of electroencephalography (EEG) analysis at the cost of lower precision in localizing effects. In this work, the instantaneous radiated power (IRP) is proposed as a new whole-brain descriptor, reflecting the cortical activity from an exclusively electromagnetic perspective. Considering that the brain consists of multiple elementary dipoles, the whole-brain IRP takes into account the radiational contribution of all cortical sources. Unlike conventional EEG analyses that evaluate a large number of scalp or source locations, IRP reflects a whole-brain, event-related measure and forces the analysis to focus on a single time-series, thus efficiently reducing the EEG spatial dimensions and multiple comparisons.

Results

To apply the developed methodology in real EEG data, two groups (25 controls vs 30 body dysmorphic disorder, BDD, patients) were matched for age and sex and tested in a prepulse inhibition (PPI) and facilitation (PPF) paradigm. Two global brain descriptors were extracted for between-groups and between-conditions comparison purposes, namely the global field power (GFP) and the whole-brain IRP. Results showed that IRP can replicate the expected condition differences (with PPF being greater than PPI responses), exhibiting also reduced levels in BDD compared to control group overall. There were also similar outcomes using GFP and IRP, suggesting consistency between the two measures. Finally, regression analysis showed that the PPI-related IRP (during N100 time-window) is negatively correlated with BDD psychometric scores.

Conclusions

Investigating the brain activity with IRP significantly reduces the data dimensionality, giving insights about global brain synchronization and strength. We conclude that IRP can replicate the existing evidence regarding sensorimotor gating effects, revealing also group electrophysiological alterations. Finally, electrophysiological IRP responses exhibited correlations with BDD psychometrics, potentially useful as supplementary tool in BDD symptomatology.
Project20: interpreter services for pregnant women with social risk factors in England: what works, for whom, in what circumstances, and how?
Authors: Rayment-Jones Hannah , Harris James , Harden Angela , Silverio Sergio A. , Turienzo Cristina Fernandez , Sandall Jane
Published: October 2021

Background

Black and minority ethnic women and those with social risk factors such as deprivation, refugee and asylum seeker status, homelessness, mental health issues and domestic violence are at a disproportionate risk of poor birth outcomes. Language barriers further exacerbate this risk, with women struggling to access, engage with maternity services and communicate concerns to healthcare professionals. To address the language barrier, many UK maternity services offer telephone interpreter services. This study explores whether or not women with social risk factors find these interpreter services acceptable, accessible and safe, and to suggest solutions to address challenges.

Methods

Realist methodology was used to refine previously constructed programme theories about how women with language barriers access and experience interpreter services during their maternity care. Twenty-one longitudinal interviews were undertaken during pregnancy and the postnatal period with eight non-English speaking women and their family members. Interviews were analysed using thematic framework analysis to confirm, refute or refine the programme theories and identify specific contexts, mechanisms and outcomes relating to interpreter services.

Results

Women with language barriers described difficulties accessing maternity services, a lack of choice of interpreter, suspicion around the level of confidentiality interpreter services provide, and questioned how well professional interpreters were able to interpret what they were trying to relay to the healthcare professional during appointments. This resulted in many women preferring to use a known and trusted family member or friend to interpret for them where possible. Their insights provide detailed insight into how poor-quality interpreter services impact on their ability to disclose risk factors and communicate concerns effectively with their healthcare providers. A refined programme theory puts forward mechanisms to improve their experiences and safety such as regulated, high-quality interpreter services throughout their maternity care, in which women have choice, trust and confidence.

Conclusions

The findings of this study contribute to concerns highlighted in previous literature around interpreter services in the wider healthcare arena, particularly around the lack of regulation and access to high-quality interpretation. This is thought to have a significant effect on pregnant women who are living socially complex lives as they are not able to communicate their concerns and access support. This not only impacts on their safety and pregnancy outcomes, but also their wider holistic needs. The refined program theory developed in this study offers insights into the mechanisms of equitable access to appropriate interpreter services for pregnant women with language barriers.
Elevated gamma-glutamyl transferase has a non-linear association with incident non-alcoholic fatty liver disease in the non-obese Chinese population: a secondary retrospective study
Authors: Wu Liling , Zhang Man , Hu Haofei , Wan Qijun
Published: October 2021

Background

Effective and applicable predictors of non-alcoholic fatty liver disease (NAFLD) are needed for the non-obese Chinese population. This study was undertaken to investigate: whether serum gamma-glutamyl transferase (GGT) was associated with incident NAFLD in the non-obese Chinese population.

Methods

This was a retrospective cohort study that enrolled 33,153 initially NAFLD-free individuals who underwent a health examination in Wenzhou Medical Center of Wenzhou People’s Hospital from January 2010 to December 2014.

Serum GGT levels at the time of enrollment were evaluated in 11,906 persons who follow-up. The relationship between GGT levels and incident NAFLD was analyzed using Cox regression and generalized additive models after adjusting for demographic and clinical variables. In addition, Subgroup analysis was conducted, which was explored by Cox proportional hazard models. It was stated that the data had been downloaded from the DATADRYAD website.

Results

Multivariable Cox regression models were used to estimate the hazard ratio (HR) for GGT with incident NAFLD after adjusted demographic and clinical variables (HR, 1.010; 95% CI, 1.007–1.012; P < 0.001). The incident NAFLD in the highest quartile of GGT levels was 3.653 times as high (95% confidence interval, 2.915 to 4.579) as that the lowest quartile. A non-linear relationship was firstly detected between GGT and incidence of NAFLD, which had an inflection point of GGT was 26 U/L. The effect sizes and the confidence intervals on the left and right sides of the inflection point were 1.104 (1.089–1.120) and 1.001 (0.999–1.004), respectively. In subgroup analyses, the hazard ratio for incident NAFLD remained consistent across subgroups.

Conclusions

In conclusion, the GGT level in the non-obese Chinese population was statistically significantly associated with incident NAFLD. The relationship between GGT level and incident NAFLD is non-linear. When GGT level is less than 26 U/L, GGT was strong positively with incident NAFLD.
An intelligent responsive macrophage cell membrane-camouflaged mesoporous silicon nanorod drug delivery system for precise targeted therapy of tumors
Authors: Li Minghua , Gao Xiaolong , Lin Chao , Shen Aijun , Luo Jing , Ji Qiongqiong , Wu Jiaqi , Wang Peijun
Published: October 2021

Macrophage cell membrane-camouflaged nanocarriers can effectively reduce immune cell clearance and actively target tumors. In this study, a macrophage cell membrane-camouflaged mesoporous silica nanorod (MSNR)-based antitumor drug carrier equipped with a cationic polymer layer was developed. As drug carriers, these MSNRs were loaded with the thermosensitive phase change material L-menthol (LM), the chemotherapy drug doxorubicin (DOX) and the fluorescent molecule indocyanine green (ICG). The rod-like shape of the MSNRs was shown to enhance the penetration of the drug carriers to tumors. In the weakly acidic tumor microenvironment, the cationic polymer exhibited a proton sponge effect to trigger macrophage cell membrane coating detachment, promoting tumor cell uptake. Following nanocarrier uptake, ICG is heated by near-infrared (NIR) irradiation to make LM undergo a phase transition to release DOX and generate a synergistic effect of thermochemotherapy which kills tumor cells and inhibits tumor growth together with reactive oxygen species (ROS) produced by ICG. Overall, this nanohybrid drug delivery system demonstrates an intelligent cascade response, leads to tissue-cell specific targeting and improves drug release accuracy, thus proving to be an effective cancer therapy.

Graphical Abstract
Targeted theranostic photoactivation on atherosclerosis
Authors: Song Joon Woo , Ahn Jae Won , Lee Min Woo , Kim Hyun Jung , Kang Dong Oh , Kim Ryeong Hyun , Kang Un Gyo , Kim Yeon Hoon , Han Jeongmoo , Park Ye Hee , Nam Hyeong Soo , Yoo Hongki , Park Kyeongsoon , Kim Jin Won
Published: October 2021

Background

Photoactivation targeting macrophages has emerged as a therapeutic strategy for atherosclerosis, but limited targetable ability of photosensitizers to the lesions hinders its applications. Moreover, the molecular mechanistic insight to its phototherapeutic effects on atheroma is still lacking. Herein, we developed a macrophage targetable near-infrared fluorescence (NIRF) emitting phototheranostic agent by conjugating dextran sulfate (DS) to chlorin e6 (Ce6) and estimated its phototherapeutic feasibility in murine atheroma. Also, the phototherapeutic mechanisms of DS-Ce6 on atherosclerosis were investigated.

Results

The phototheranostic agent DS-Ce6 efficiently internalized into the activated macrophages and foam cells via scavenger receptor-A (SR-A) mediated endocytosis. Customized serial optical imaging-guided photoactivation of DS-Ce6 by light illumination reduced both atheroma burden and inflammation in murine models. Immuno-fluorescence and -histochemical analyses revealed that the photoactivation of DS-Ce6 produced a prominent increase in macrophage-associated apoptotic bodies 1 week after laser irradiation and induced autophagy with Mer tyrosine-protein kinase expression as early as day 1, indicative of an enhanced efferocytosis in atheroma.

Conclusion

Imaging-guided DS-Ce6 photoactivation was able to in vivo detect inflammatory activity in atheroma as well as to simultaneously reduce both plaque burden and inflammation by harmonic contribution of apoptosis, autophagy, and lesional efferocytosis. These results suggest that macrophage targetable phototheranostic nanoagents will be a promising theranostic strategy for high-risk atheroma.

Graphical abstract
Tumor microenvironment-activated cancer cell membrane-liposome hybrid nanoparticle-mediated synergistic metabolic therapy and chemotherapy for non-small cell lung cancer
Authors: Zhang Wei , Gong Chunai , Chen Ziqiang , Li Ming , Li Yuping , Gao Jing
Published: October 2021

Background

Biomimetic nanotechnology-based RNA interference (RNAi) has been successful in improving theranostic efficacy in malignant tumors. Its integration with hybrid biomimetic membranes made of natural cell membranes fused with liposomal membranes is mutually beneficial and extends their biofunctions. However, limited research has focused on engineering such biomimetics to endow them with unique properties and functions, in particular, those essential for a “smart” drug delivery system, such as a tumor microenvironment (TME)-activated multifunctional biomimetic nanoplatform.

Results

Herein, we utilized an integrated hybrid nanovesicle composed of cancer cell membranes (Cm) and matrix metallopeptidase 9 (MMP-9)-switchable peptide-based charge-reversal liposome membranes (Lipm) to coat lipoic acid-modified polypeptides (LC) co-loaded with phosphoglycerate mutase 1 (PGAM1) siRNA (siPGAM1) and DTX. The nanovesicle presented a negatively charged coating (citraconic anhydride-grafted poly-l-lysine, PC) in the middle layer for pH-triggered charge conversion functionalization. The established chemotherapeutic drug (DTX) co-delivery system CLip-PC@CO-LC nanoparticles (NPs) have a particle size of ~ 193 nm and present the same surface proteins as the Cm. Confocal microscopy and flow cytometry results indicated a greater uptake of MMP-9-treated CLip-PC@CO-LC NPs compared with that of the CLip-PC@CO-LC NPs without MMP-9 pretreatment. The exposure to MMP-9 activated positively charged cell-penetrating peptides on the surface of the hybrid nanovesicles. Moreover, pH triggered membrane disruption, and redox triggered DTX and siRNA release, leading to highly potent target-gene silencing in glycolysis and chemotherapy with enhanced antiproliferation ability. The biodistribution results demonstrated that the CLip-PC@LC-DiR NPs accumulated in the tumor owing to a combination of long blood retention time, homologous targeting ability, and TME-activated characteristics. The CLip-PC@CO-LC NPs led to more effective tumor growth inhibition than the DTX and free siPGAM1 formulations.

Conclusions

TME-activated cancer cell membrane-liposome integrated hybrid NPs provide an encouraging nanoplatform that combines RNAi with chemotherapy for precise treatment of non-small cell lung cancer.

Graphical abstract
Radiomics-based machine learning analysis and characterization of breast lesions with multiparametric diffusion-weighted MR
Authors: Sun Kun , Jiao Zhicheng , Zhu Hong , Chai Weimin , Yan Xu , Fu Caixia , Cheng Jie-Zhi , Yan Fuhua , Shen Dinggang
Published: October 2021

Background

This study aimed to evaluate the utility of radiomics-based machine learning analysis with multiparametric DWI and to compare the diagnostic performance of radiomics features and mean diffusion metrics in the characterization of breast lesions.

Methods

This retrospective study included 542 lesions from February 2018 to November 2018. One hundred radiomics features were computed from mono-exponential (ME), biexponential (BE), stretched exponential (SE), and diffusion-kurtosis imaging (DKI). Radiomics-based analysis was performed by comparing four classifiers, including random forest (RF), principal component analysis (PCA), L1 regularization (L1R), and support vector machine (SVM). These four classifiers were trained on a training set with 271 patients via ten-fold cross-validation and tested on an independent testing set with 271 patients. The diagnostic performance of the mean diffusion metrics of ME (mADCall b, mADC0–1000), BE (mD, mD*, mf), SE (mDDC, mα), and DKI (mK, mD) were also calculated for comparison. The area under the receiver operating characteristic curve (AUC) was used to compare the diagnostic performance.

Results

RF attained higher AUCs than L1R, PCA and SVM. The AUCs of radiomics features for the differential diagnosis of breast lesions ranged from 0.80 (BE_D*) to 0.85 (BE_D). The AUCs of the mean diffusion metrics ranged from 0.54 (BE_mf) to 0.79 (ME_mADC0–1000). There were significant differences in the AUCs between the mean values of all diffusion metrics and radiomics features of AUCs (all P < 0.001) for the differentiation of benign and malignant breast lesions. Of the radiomics features computed, the most important sequence was BE_D (AUC: 0.85), and the most important feature was FO-10 percentile (Feature Importance: 0.04).

Conclusions

The radiomics-based analysis of multiparametric DWI by RF enables better differentiation of benign and malignant breast lesions than the mean diffusion metrics.
Hydroxyapatite/collagen composite graft for posterior lumbar interbody fusion: a comparison with local bone graft
Authors: Yoshii Toshitaka , Hashimoto Motonori , Egawa Satoru , Hirai Takashi , Inose Hiroyuki , Okawa Atsushi
Published: October 2021

Background

Autologous bone has been used for posterior lumbar intervertebral fusion (PLIF). However, harvesting autologous bone graft is associated with donor site complications. We previously developed a hydroxyapatite/collagen (HAp/Col) composite as an osteoconductive artificial bone, characterized by having a highly porous structure with sponge‐like elasticity. This study aims to investigate the effectiveness of HAp/Col composite with bone marrow aspirate (BMA) as a graft substitute in PLIF for the treatment of lumbar spinal diseases.

Methods

This study prospectively investigated patients who received one-level PLIF. For the interbody fusion, two titanium cages were inserted. On the one side of interbody space, HAp/Col composite incorporated with BMA filling the titanium cage was grafted. On the other side, local bone graft (LBG) harvested during decompressive laminotomy was grafted and then one-level instrumentation using pedicle screws was performed. The target levels were at L2/3 in 2 cases, L3/4 in 3 cases, L4/5 in 36 cases, and L5/S in 5 cases. We evaluated clinical symptoms and radiological outcomes of 46 patients and compared the fusion status of HAp/Col composite with that of LBG.

Results

The 1-year postoperative CT evaluation demonstrated that, in the HAp/Col, a complete fusion was observed in 38 patients (82.6%), whereas in the LBG, a complete fusion was observed in 35 patients (76.1%). There were no statistical differences between the HAp/Col and LBG. In the HAp/Col, incomplete fusion was observed in five patients (10.9%) and non-fusion in two patients (4.3%), and in the LBG, incomplete fusion was observed in nine patients (19.6%) and non-fusion in two patients (4.3%). At 2 years after the surgery, complete fusion increased to 44 patients (95.7%) in the HAp/Col and 41 patients (89.1%) in the LBG. There were no significant differences in the clinical scores for lumbar spine between patients with fusion and non-fusion.

Conclusions

The HAp/Col composite with BMA in the titanium cage can be effectively used as an alternative to conventional autologous LBG for intervertebral spinal fusion.

Trial registrationUniversity hospital Medical Information Network, UMIN000045010, July 30th, 2021, Retrospectively registered,https://www.umin.ac.jp/english/.
Multivariate data analysis identifies natural clusters of Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND)
Authors: de Vries Petrus J. , Leclezio Loren , Gardner-Lubbe Sugnet , Krueger Darcy , Sahin Mustafa , Sparagana Steven , De Waele Liesbeth , Jansen Anna
Published: October 2021

Background

Tuberous Sclerosis Complex (TSC), a multi-system genetic disorder, is associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND). Individuals have apparently unique TAND profiles, challenging diagnosis, psycho-education, and intervention planning. We proposed that identification of natural TAND clusters could lead to personalized identification and treatment of TAND. Two small-scale studies showed cluster and factor analysis could identify clinically meaningful natural TAND clusters. Here we set out to identify definitive natural TAND clusters in a large, international dataset.

Method

Cross-sectional, anonymized TAND Checklist data of 453 individuals with TSC were collected from six international sites. Data-driven methods were used to identify natural TAND clusters. Mean squared contingency coefficients were calculated to produce a correlation matrix, and various cluster analyses and exploratory factor analysis were examined. Statistical robustness of clusters was evaluated with 1000-fold bootstrapping, and internal consistency calculated with Cronbach’s alpha.

Results

Ward’s method rendered seven natural TAND clusters with good robustness on bootstrapping. Cluster analysis showed significant convergence with an exploratory factor analysis solution, and, with the exception of one cluster, internal consistency of the emerging clusters was good to excellent. Clusters showed good clinical face validity.

Conclusions

Our findings identified a data-driven set of natural TAND clusters from within highly variable TAND Checklist data. The seven natural TAND clusters could be used to train families and professionals and to develop tailored approaches to identification and treatment of TAND. Natural TAND clusters may also have differential aetiological underpinnings and responses to molecular and other treatments.
Clinical spectrum and risk factors for mortality among seawater and freshwater critically ill drowning patients: a French multicenter study
Authors: Reizine Florian , Delbove Agathe , Dos Santos Alexandre , Bodenes Laetitia , Bouju Pierre , Fillâtre Pierre , Frérou Aurélien , Halley Guillaume , Lesieur Olivier , Jonas Maud , Berteau Florian , Morin Jean , Luque-Paz David , Marnai Rémy , Le Meur Anthony , Aubron Cécile , Reignier Jean , Tadié Jean-Marc , Gacouin Arnaud
Published: October 2021

Background

Drowning is a global threat and one of the leading causes of injury around the world. The impact of drowning conditions including water salinity on patients’ prognosis remains poorly explored in Intensive Care Units (ICUs) patients.

Methods

We conducted a retrospective multicenter study on patients admitted to 14 ICUs in the west of France from January 2013 to January 2020. We first compared demographic and clinical characteristics at admission as well as clinical courses of these patients according to the salinity of drowning water. Then, we aimed to identify variables associated with 28-day survival using a Cox proportional hazard model.

Results

Of the 270 consecutive included patients, drowning occurred in seawater in 199 patients (73.7%) and in freshwater in 71 patients (26.3%). Day-28 mortality was observed in 55 patients (20.4%). Freshwater was independently associated with 28-day mortality (Adjusted Hazard Ratio (aHR) 1.84 [95% Confidence Interval (CI) 1.03–3.29], p = 0.04). A higher proportion of freshwater patients presented psychiatric comorbidities (47.9 vs. 19.1%; p < 0.0001) and the etiology of drowning appeared more frequently to be a suicide attempt in this population (25.7 vs. 4.2%; p < 0.0001). The other factors independently associated with 28-day mortality were the occurrence of a drowning-related cardiac arrest (aHR 11.5 [95% CI 2.51–52.43], p = 0.0017), duration of cardiopulmonary resuscitation (aHR 1.05 [95% CI 1.03–1.07], p < 0.0001) and SOFA score at day 1 (aHR 1.2 [95% CI 1.11–1.3], p < 0.0001).

Conclusions

In this large multicenter cohort, freshwater drowning patients had a poorer prognosis than saltwater drowning patients. Reasons for such discrepancies include differences in underlying psychiatric comorbidity, drowning circumstances and severities. Patients with initial cardiac arrest secondary to drowning remain with a very poor prognosis.
Advancing motor rehabilitation for adults with chronic neurological conditions through increased involvement of kinesiologists: a perspective review
Authors: Mang Cameron S. , Peters Sue
Published: October 2021

Many people with neurological conditions experience challenges with movement. Although rehabilitation is often provided acutely and sub-acutely following the onset of a condition, motor deficits commonly persist in the long-term and are exacerbated by disuse and inactivity. Notably, motor rehabilitation approaches that incorporate exercise and physical activity can support gains in motor function even in the chronic stages of many neurological conditions. However, delivering motor rehabilitation on a long-term basis to people with chronic neurological conditions is a challenge within health care systems, and the onus is often placed on patients to find and pay for services. While neurological motor rehabilitation is largely the domain of physical and occupational therapists, kinesiologists may be able to complement existing care and support delivery of long-term neurological motor rehabilitation, specifically through provision of supported exercise and physical activity programs. In this perspective style review article, we discuss potential contributions of kinesiologists to advancing the field through exercise programming, focusing on community-based interventions that increase physical activity levels. We conclude with recommendations on how kinesiologists’ role might be further optimized towards improving long-term outcomes for people with chronic neurological conditions, considering issues related to professional regulation and models of care.
Repeatability of methylation measures using a QIAseq targeted methyl panel and comparison with the Illumina HumanMethylation450 assay
Authors: Yu Chenglong , Dugué Pierre-Antoine , Dowty James G. , Hammet Fleur , Joo JiHoon E. , Wong Ee Ming , Hosseinpour Mahnaz , Giles Graham G. , Hopper John L. , Nguyen-Dumont Tu , MacInnis Robert J. , Southey Melissa C.
Published: October 2021

Objective

In previous studies using Illumina Infinium methylation arrays, we have identified DNA methylation marks associated with cancer predisposition and progression. In the present study, we have sought to find appropriate technology to both technically validate our data and expand our understanding of DNA methylation in these genomic regions. Here, we aimed to assess the repeatability of methylation measures made using QIAseq targeted methyl panel and to compare them with those obtained from the Illumina HumanMethylation450 (HM450K) assay. We included in the analysis high molecular weight DNA extracted from whole blood (WB) and DNA extracted from formalin-fixed paraffin-embedded tissues (FFPE).

Results

The repeatability of QIAseq-methylation measures was assessed at 40 CpGs, using the Intraclass Correlation Coefficient (ICC). The mean ICCs and 95% confidence intervals (CI) were 0.72 (0.62–0.81), 0.59 (0.47–0.71) and 0.80 (0.73–0.88) for WB, FFPE and both sample types combined, respectively. For technical replicates measured using QIAseq and HM450K, the mean ICCs (95% CI) were 0.53 (0.39–0.68), 0.43 (0.31–0.56) and 0.70 (0.59–0.80), respectively. Bland–Altman plots indicated good agreement between QIAseq and HM450K measurements. These results demonstrate that the QIAseq targeted methyl panel produces reliable and reproducible methylation measurements across the 40 CpGs that were examined.
The impact of near visual impairment on instrumental activities of daily living among community-dwelling older adults in Selangor
Authors: Kee Qiu Ting , Abd Rahman Mohd Harimi , Mohamad Fadzil Norliza , Mohammed Zainora , Shahar Suzana
Published: October 2021

Objective

Near visual impairment (VI) is a common disability in an aging population. Near vision is crucial in activity of daily living including reading, smartphone and computer use and meal preparation. This study was conducted to determine the association between near visual acuity (VA) and contrast sensitivity (CS) with activity of daily living (ADL) among visually impaired older adults.

Results

A total of 208 participants aged  ≥  60 were recruited from the population-based longitudinal study on neuroprotective model for healthy longevity. Habitual near VA and CS were measured using Lighthouse near VA chart and Pelli-Robson CS chart, respectively. Lawton instrumental activities of daily living (IADL) was used to assess ADL. There are 41.8% participants with near visual impairment and 28.7% among them had IADL disability. Independent t test showed significant lower mean IADL score among visually impaired participants [t(206)  =  2.03, p  =  0.04]. IADL score significantly correlated with near VA (r  =   − 0.21, p  =  0.05) but not with CS (r  =   − 0.14, p = 0.21). Near VA (B  =   − 0.44, p  =  0.03) and age (B  =   − 0.07, p  =  0.01) significantly predicted IADL. The findings show poorer VA renders higher IADL disability, which may necessitate interventions to improve ADL among visually impaired older adults.