bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of a novel online depression symptom severity rating scale: the R8 Depression
Authors: Takao Yuki , Figueroa Eduardo , Berna Kevin Fernand Jean , Jo Youjin , Kissane Lee Andrew , Yoshimura Kimio , Tranter Richard , Porter Richard J
Published: June 2021

Background

An automated web-based assessment and monitoring system (www.psynary.com) has been developed to assist non-specialist clinicians in managing common mood and anxiety disorders. Psynary promotes the use of standardised outcome measures to assess symptom severity and optimise treatments with the aim of improving outcomes and enabling faster recovery. This paper analyses the results from two parallel studies in New Zealand and Japan (OptiMA-1 NZ and Japan) to assess the validity of the R8 Depression scale, one of the system’s core outcome measures.

Methods

Clinical samples were recruited from a public secondary care and a private psychiatry clinic. Participants completed the outcome measures for the study via the online Psynary system. The R8 Depression scale is a 30-item questionnaire which includes all symptom domains covered in the ICD-10 classification of depression. The Patient Health Questionnaire (PHQ-9) was completed at the same time points as the R8 Depression, with a smaller sample also completing a paper-based Quick Inventory of Depressive Symptomatology (QIDS-SR16). Internal validity was quantified via Cronbach’s alpha and Guttman lower bounds method. External validation against the PHQ-9 and QIDS used the Pearson’s and Kendall’s correlation coefficients. Severity categories were set using a multivariate regression model.

Results

270 patients participated in the study and completed a maximum of 1 baseline and 5 reviews within a 90-day period, giving a total of 1124 assessments with the PHQ-9 also being completed in 1053 of these assessments. R8 Depression normative data was also collected from 204 non-clinical volunteers with 187 of these also completing the PHQ9. Internal reliability scores were all higher than 0.9 (n = 1328). There was overall good external validity when comparing the R8 Depression to the PHQ-9, with a correlation of 0.91 for the combined normative and clinical samples (n = 1240).

Conclusions

The R8 Depression has been developed as a patient-rated outcome measure for depression for administration on an online system called “Psynary”. It has high internal and external validity against current widely used scales. Further work is underway to determine the sensitivity to change of the R8 Depression.
Letter to the Editor concerning the article “Clinical outcomes of chondroblastoma treated using synthetic bone substitute: risk factors for developing radiographic joint degeneration”
Authors: Zheng Bo-Wen , Zheng Bo-Yv , Niu Hua-Qing , Wang Xiao-Bin , Li Jing
Published: June 2021

The purpose of this letter to the Editor is to report some shortcomings in the statistical analysis and variable grouping in the recent publication of the article “Clinical outcomes of chondroblastoma treated using synthetic bone substitute: risk factors for developing radiographic joint degeneration,” and to further explore some of the factors that may affect the clinical prognosis of chondroblastoma patients. We also suggest future prospective controlled studies with large samples to improve the limitations encountered by Outani et al. (World J Surg Oncol. 18(1):47, 2020) due to insufficient statistical power of variables and lack of controls.
Significance of a preoperative systemic immune-inflammation index as a predictor of postoperative survival outcomes in gastric cancer
Authors: Inoue Hiroyuki , Kosuga Toshiyuki , Kubota Takeshi , Konishi Hirotaka , Shiozaki Atsushi , Okamoto Kazuma , Fujiwara Hitoshi , Otsuji Eigo
Published: June 2021

Background

Since inflammation and the immune system contribute to the development and progression of malignancies, parameters that reflect a host’s immune-inflammatory status may be useful prognostic indicators of gastric cancer (GC). The present study examined the clinical significance of a preoperative systemic immune-inflammation index (SII) for predicting postoperative survival outcomes in GC.

Methods

A total of 447 patients who underwent curative gastrectomy for GC were included in the present study. SII was calculated as platelet count × neutrophil count/lymphocyte count. The prognostic impact of preoperative SII was examined using univariate and multivariate analyses.

Results

Preoperative SII ranged between 105 and 4455 (median 474), and the optimal cutoff value for predicting overall survival (OS) was 395 based on a receiver operating characteristic curve. The 5-year OS rate of the SII ≥ 395 group was 80.0%, which was significantly worse than that (92.7%) of the SII < 395 group (p< 0.001). The multivariate analysis identified SII ≥ 395 (hazard ratio [HR] 2.95; 95% confidence interval [CI] 1.49–6.39;p= 0.001), heart disease (HR 2.14, 95% CI 1.07–4.07), C-reactive protein ≥ 0.5 (HR 2.45, 95% CI 1.15–4.94), pT4 (HR 4.46, 95% CI 2.44–8.14), and pN+ (HR 4.02, 95% CI 2.10–7.93) as independent predictors of worse OS. Peritoneal recurrence was more frequent in the high SII group than in the low SII group (p= 0.028).

Conclusion

Preoperative SII may be a useful predictor of postoperative survival outcomes in GC. The meticulous surveillance of GC relapse, particularly peritoneal dissemination, is necessary for patients with SII ≥ 395 even after curative gastrectomy.
HDAC4 induces the development of asthma by increasing Slug-upregulated CXCL12 expression through KLF5 deacetylation
Authors: Wei Wendi , Chen Weida , He Naifeng
Published: June 2021

Background

Asthma is a frequently occurring respiratory disease with an increasing incidence around the world. Airway inflammation and remodeling are important contributors to the occurrence of asthma. We conducted this study aiming at exploring the effect of Histone deacetylase 4 (HDAC4)-mediated Kruppel-like factor 5 (KLF5)/Slug/CXC chemokine ligand-12 (CXCL12) axis on the development of asthma in regulation of airway inflammation and remodeling.

Methods

An asthmatic rat model was induced by ovalbumin (OVA) irrigation, and determined HDAC4, KLF5, Slug, and CXCL12 expression in the lung tissues by RT-qPCR and Western blot assay. OVA was also used to induce a cell model of asthma in human BEAS-2B and HBE135-E6E7bronchial epithelial cells. The airway hyperresponsiveness (AHR), and expression of inflammatory cytokines in model mice were examined using methacholine challenge test and ELISA. The biological behaviors were measured in asthma model bronchial smooth muscle cells (BSMCs) following loss- and gain- function approaches. The interactions between HDAC4, KLF5, Slug, and CXCL12 were also detected by IP assay, dual luciferase gene reporter assay, and ChIP.

Results

HDAC4 was upregulated in lung tissues of OVA-induced asthmatic mice, and inhibition of HDAC4 alleviated the airway inflammation and remodeling. HDAC4 increased KLF5 transcriptional activity through deacetylation; deacetylated KLF5 bound to the promoter of Slug and transcriptionally upregulated Slug expression, which in turn increased the expression of CXCL12 to promote the inflammation in bronchial epithelial cells and thus induce the proliferation and migration of BSMCs.

Conclusion

Collectively, HDAC4 deacetylates KLF5 to upregulate Slug and CXCL12, thereby causing airway remodeling and facilitating progression of asthma.
miR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling
Authors: Feng Yan , Li Yan , Zhang Ying , Zhang Bo-Hao , Zhao Hui , Zhao Xin , Shi Fu-Dong , Jin Wei-Na , Zhang Xiao-An
Published: June 2021

Background

Brain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate NK cell activation and cytotoxicity after ischemic stroke.

Methods

Using a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia.

Results

We observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice.

Conclusions

These findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain.
Targeting S100A4 with niclosamide attenuates inflammatory and profibrotic pathways in models of amyotrophic lateral sclerosis
Authors: Milani Martina , Mammarella Eleonora , Rossi Simona , Miele Chiara , Lattante Serena , Sabatelli Mario , Cozzolino Mauro , D’Ambrosi Nadia , Apolloni Savina
Published: June 2021

Background

An increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the upregulation in ALS models of a gene called fibroblast-specific protein-1 or S100A4, recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functions, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology.

Methods

Here, we employed fibroblasts derived from ALS patients harboring the C9orf72 hexanucleotide repeat expansion and ALS patients with no mutations in known ALS-associated genes and we downregulated S100A4 using siRNA or the S100A4 transcriptional inhibitor niclosamide. Mice overexpressing human FUS were adopted to assess the effects of niclosamide in vivo on ALS pathology.

Results

We demonstrated that S100A4 underlies impaired autophagy and a profibrotic phenotype, which characterize ALS fibroblasts. Indeed, its inhibition reduces inflammatory, autophagic, and profibrotic pathways in ALS fibroblasts, and interferes with different markers known as pathogenic in the disease, such as mTOR, SQSTM1/p62, STAT3, α-SMA, and NF-κB. Importantly, niclosamide in vivo treatment of ALS-FUS mice reduces the expression of S100A4, α-SMA, and PDGFRβ in the spinal cord, as well as gliosis in central and peripheral nervous tissues, together with axonal impairment and displays beneficial effects on muscle atrophy, by promoting muscle regeneration and reducing fibrosis.

Conclusion

Our findings show that S100A4 has a role in ALS-related mechanisms, and that drugs such as niclosamide which are able to target inflammatory and fibrotic pathways could represent promising pharmacological tools for ALS.
Functional electrical stimulation cycling exercise after spinal cord injury: a systematic review of health and fitness-related outcomes
Authors: van der Scheer Jan W. , Goosey-Tolfrey Victoria L. , Valentino Sydney E. , Davis Glen M. , Ho Chester H.
Published: June 2021

Objectives

The objective of this review was to summarize and appraise evidence on functional electrical stimulation (FES) cycling exercise after spinal cord injury (SCI), in order to inform the development of evidence-based clinical practice guidelines.

Methods

PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, SPORTDiscus, and CINAHL were searched up to April 2021 to identify FES cycling exercise intervention studies including adults with SCI. In order to capture the widest array of evidence available, any outcome measure employed in such studies was considered eligible. Two independent reviewers conducted study eligibility screening, data extraction, and quality appraisal using Cochranes’ Risk of Bias or Downs and Black tools. Each study was designated as a Level 1, 2, 3 or 4 study, dependent on study design and quality appraisal scores. The certainty of the evidence for each outcome was assessed using GRADE ratings (‘High’, ‘Moderate’, ‘Low’, or ‘Very low’).

Results

Ninety-two studies met the eligibility criteria, comprising 999 adults with SCI representing all age, sex, time since injury, lesion level and lesion completeness strata. For muscle health (e.g., muscle mass, fiber type composition), significant improvements were found in 3 out of 4 Level 1–2 studies, and 27 out of 32 Level 3–4 studies (GRADE rating: ‘High’). Although lacking Level 1–2 studies, significant improvements were also found in nearly all of 35 Level 3–4 studies on power output and aerobic fitness (e.g., peak power and oxygen uptake during an FES cycling test) (GRADE ratings: ‘Low’).

Conclusion

Current evidence indicates that FES cycling exercise improves lower-body muscle health of adults with SCI, and may increase power output and aerobic fitness. The evidence summarized and appraised in this review can inform the development of the first international, evidence-based clinical practice guidelines for the use of FES cycling exercise in clinical and community settings of adults with SCI.

Registration review protocol: CRD42018108940 (PROSPERO)
Molecular and cellular pathways contributing to brain aging
Authors: Zia Aliabbas , Pourbagher-Shahri Ali Mohammad , Farkhondeh Tahereh , Samarghandian Saeed
Published: June 2021

Aging is the leading risk factor for several age-associated diseases such as neurodegenerative diseases. Understanding the biology of aging mechanisms is essential to the pursuit of brain health. In this regard, brain aging is defined by a gradual decrease in neurophysiological functions, impaired adaptive neuroplasticity, dysregulation of neuronal Ca2+ homeostasis, neuroinflammation, and oxidatively modified molecules and organelles. Numerous pathways lead to brain aging, including increased oxidative stress, inflammation, disturbances in energy metabolism such as deregulated autophagy, mitochondrial dysfunction, and IGF-1, mTOR, ROS, AMPK, SIRTs, and p53 as central modulators of the metabolic control, connecting aging to the
pathways, which lead to neurodegenerative disorders. Also, calorie restriction (CR), physical exercise, and mental activities can extend lifespan and increase nervous system resistance to age-associated neurodegenerative diseases. The neuroprotective effect of CR involves increased protection against ROS generation, maintenance of cellular Ca2+ homeostasis, and inhibition of apoptosis. The recent evidence about the modem molecular and cellular methods in neurobiology to brain aging is exhibiting a significant potential in brain cells for adaptation to aging and resistance to neurodegenerative disorders.
SWI/SNF-deficient undifferentiated/rhabdoid carcinoma of the gallbladder carrying a POLE mutation in a 30-year-old woman: a case report
Authors: Gerber Tiemo S. , Agaimy Abbas , Hartmann Arndt , Habekost Michael , Roth Wilfried , Stenzinger Albrecht , Schirmacher Peter , Straub Beate K.
Published: June 2021

Background

Undifferentiated carcinoma of the biliary tract are highly aggressive malignancies. In other organs, a subgroup of undifferentiated carcinoma related to SWI/SNF complex–deficiency have been described.

Case presentation

A 30-year-old woman presented with rising inflammatory markers (C-reactive protein (CRP)). Ultrasound examination revealed a large tumor of the liver. A computed tomography scan was performed and was primarily interpreted as a tumor-forming liver abscess, possibly caused by gallbladder perforation. Subsequent liver segment resection was performed. Microscopic examination showed an undifferentiated carcinoma with rhabdoid morphology and prominent inflammatory infiltrate in the gallbladder base. With SWI/SNF immunohistochemistry, intact expression of SMARCB1, SMARCA4, ARID1A, but loss of SMARCA2 and PBRM1 was detected. Next-generation-sequencing detected KRAS, PBRM1 and ARID1B mutations, a deleterious splice-site mutation in the POLE-gene and a mutation in the TP53-gene.

Conclusions

We were able to demonstrate loss of SMARCA2 expression and mutations characteristic of an SWI/SNF-deficient carcinoma in a tumor derived from the gallbladder. This is the first reported case of an undifferentiated carcinoma with rhabdoid features in the gallbladder carrying a POLE mutation and SWI/SNF-deficiency of PBRM1 and SMARCA2.
Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells
Authors: Russell Emily , Dunne Victoria , Russell Ben , Mohamud Hibaaq , Ghita Mihaela , McMahon Stephen J. , Butterworth Karl T. , Schettino Giuseppe , McGarry Conor K. , Prise Kevin M.
Published: June 2021

Purpose

The recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. Through preclinical 225 kVp exposures, this study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model.

Methods

SPIONs were also characterised to determine their hydrodynamic radius using dynamic light scattering and uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Sensitisation Enhancement Ratios (SERs) were compared with the predicted Dose Enhancement Ratios (DEFs) based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs.

Results

The hydrodynamic radius was found to be between 110 and 130 nm, with evidence of being monodisperse in nature. SPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 h post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P < 0.05) in the linear quadratic curve fit for 1 h exposure to 23.5 μg/ml SPIONs. There was also a 30.1% increase in the number of DNA damage foci found for HEPG2 cells at 2 Gy. No strong correlation was found between SPION uptake and DNA damage at any dose, yet the biological consequences of SPIONs on radiosensitisation were found to be much greater, with SERs up to 1.28 ± 0.03, compared with predicted physical dose enhancement levels of 1.0001. In vivo, intra-tumoural injection of SPIONs combined with radiation showed significant tumour growth delay compared to animals treated with radiation or SPIONs alone (P < 0.05).

Conclusions

SPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.
The value of primary and adjuvant radiotherapy for cutaneous squamous cell carcinomas of the head-and-neck region in the elderly
Authors: Haehl Erik , Rühle Alexander , Klink Rabea , Kalckreuth Tobias , Sprave Tanja , Gkika Eleni , Zamboglou Constantinos , Meiß Frank , Grosu Anca-Ligia , Nicolay Nils H.
Published: June 2021

Purpose

To examine treatment patterns, oncological outcomes and toxicity rates in elderly patients receiving radiotherapy for cutaneous squamous cell carcinoma (cSCC) of the head-and-neck region.

Material and methods

In this retrospective single-center analysis, locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) of elderly patients > 65 years with cSCC of the head-and-neck region undergoing radiotherapy between 2010 and 2019 were calculated. The prognostic value of clinicopathological parameters on radiotherapy outcomes was analyzed using the Cox proportional hazards model. In addition, both acute and chronic toxicities were retrospectively quantified according to CTCAE version 5.0.

Results

A total of 69 elderly patients with cSCC of the head-and-neck region with a median age of 85 years were included in this analysis, of whom 21.7% (15 patients) presented with nodal disease. The majority of patients exhibited a good performance status, indicated by a median Karnofsky performance status (KPS) and Charlson Comorbidity Index (CCI) of 80% and 6 points, respectively. Radiotherapy was administered as primary (48%), adjuvant (32%) or palliative therapy (20%). 55 patients (79.7%) completed treatment and received the scheduled radiotherapy dose. Median EQD2 radiation doses were 58.4 Gy, 60 Gy and 51.3 Gy in the definitive, adjuvant and palliative situation, respectively. 2-year LRC, PFS and OS ranged at 54.2%, 33.5 and 40.7%, respectively. Survival differed significantly between age groups with a median OS of 20 vs. 12 months (p < 0.05) for patients aged 65–80 or above 80 years. In the multivariate analysis, positive lymph node status remained the only significant prognostic factor deteriorating OS (HR 3.73, CI 1.54–9.03, p < 0.01). Interestingly, neither KPS nor CCI impaired survival in this elderly patient cohort. Only 3 patients (4.3%) experienced acute CTCAE grade 3 toxicities, and no chronic CTCAE grade 2–5 toxicities were observed in our cohort.

Conclusion

Radiotherapy was feasible and well-tolerated in this distinct population, showing the general feasibility of radiotherapy for cSCC of the head-and-neck region also in the older and oldest olds. The very mild toxicities may allow for moderate dose escalation to improve LRC.
Phase II study of stereotactic body radiotherapy with hydrogel spacer for prostate cancer: acute toxicity and propensity score-matched comparison
Authors: Ogita Mami , Yamashita Hideomi , Nozawa Yuki , Ozaki Sho , Sawayanagi Subaru , Ohta Takeshi , Nakagawa Keiichi
Published: June 2021

Background

The efficacy of a hydrogel spacer in stereotactic body radiotherapy (SBRT) has not been clarified. We evaluated the safety and efficacy of SBRT in combination with a hydrogel spacer for prostate cancer.

Methods

This is a prospective single-center, single-arm phase II study. Prostate cancer patients without lymph node or distant metastasis were eligible. All patients received a hydrogel spacer insertion, followed by SBRT of 36.25 Gy in 5 fractions with volumetric modulated arc therapy. The primary endpoint was physician-assessed acute gastrointestinal (GI) toxicity within 3 months. The secondary endpoints were physician-assessed acute genitourinary (GU) toxicity, patient-reported outcomes evaluated by the EPIC and FACT-P questionnaires, and dosimetric comparison. We used propensity score-matched analyses to compare patients with the hydrogel spacer with those without the spacer. The historical data of the control without a hydrogel spacer was obtained from our hospital’s electronic records.

Results

Forty patients were enrolled between February 2017 and July 2018. A hydrogel spacer significantly reduced the dose to the rectum. Grade 2 acute GI and GU toxicity occurred in seven (18%) and 17 (44%) patients. The EPIC bowel and urinary summary score declined from the baseline to the first month (P < 0.01, < 0.01), yet it was still significantly lower in the third month (P < 0.01, P = 0.04). For propensity score-matched analyses, no significant differences in acute GI and GU toxicity were observed between the two groups. The EPIC bowel summary score was significantly better in the spacer group at 1 month (82.2 in the spacer group and 68.5 in the control group).

Conclusions

SBRT with a hydrogel spacer had the dosimetric benefits of reducing the rectal doses. The use of the hydrogel spacer did not reduce physician-assessed acute toxicity, but it improved patient-reported acute bowel toxicity.

Trial registration: Trial registration: UMIN-CTR, UMIN000026213. Registered 19 February 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000029385.
Lockdowns, lives and livelihoods: the impact of COVID-19 and public health responses to conflict affected populations - a remote qualitative study in Baidoa and Mogadishu, Somalia
Authors: Braam Dorien H. , Srinivasan Sharath , Church Luke , Sheikh Zakaria , Jephcott Freya L. , Bukachi Salome
Published: June 2021

Background

Authorities in Somalia responded with drastic measures after the first confirmed COVID-19 case in mid-March 2020, closing borders, schools, limiting travel and prohibiting most group functions. However, the impact of the pandemic in Somalia thereafter remained unclear. This study employs a novel remote qualitative research method in a conflict-affected setting to look at how some of the most at-risk internally displaced and host populations were impacted by COVID-19, what determined their responses, and how this affected their health and socio-economic vulnerability.

Methods

We conducted a remote qualitative study, using Katikati, a 1-to-1 conversation management and analysis platform using short message service (SMS) developed by Lark Systems with Africa’s Voices Foundation (AVF), for semi-structured interviews over three months with participants in Mogadishu and Baidoa. We recruited a gender balanced cohort across age groups, and used an analytical framework on the social determinants of health for a narrative analysis on major themes discussed, triangulating data with existing peer-reviewed and grey literature.

Results

The remote research approach demonstrated efficacy in sustaining trusted and meaningful conversations for gathering qualitative data from hard-to-reach conflict-affected communities. The major themes discussed by the 35 participants included health, livelihoods and education. Two participants contracted the disease, while others reported family or community members affected by COVID-19. Almost all participants faced a loss of income and/or education, primarily as a result of the strict public health measures. Some of those who were heavily affected economically but did not directly experienced disease, denied the pandemic. Religion played an important role in participants’ beliefs in protection against and salvation from the disease. As lockdowns were lifted in August 2020, many believed the pandemic to be over.

Conclusions

While the official COVID-19 burden has remained relatively low in Somalia, the impact to people’s daily lives, income and livelihoods due to public health responses, has been significant. Participants describe those ‘secondary’ outcomes as the main impact of the pandemic, serving as a stark reminder of the need to broaden the public health response beyond disease prevention to include social and economic interventions to decrease people’s vulnerability to future shocks.
The biogenesis and biological function of PIWI-interacting RNA in cancer
Authors: Chen Silu , Ben Shuai , Xin Junyi , Li Shuwei , Zheng Rui , Wang Hao , Fan Lulu , Du Mulong , Zhang Zhengdong , Wang Meilin
Published: June 2021

Small non-coding RNAs (ncRNAs) are vital regulators of biological activities, and aberrant levels of small ncRNAs are commonly found in precancerous lesions and cancer. PIWI-interacting RNAs (piRNAs) are a novel type of small ncRNA initially discovered in germ cells that have a specific length (24–31 nucleotides), bind to PIWI proteins, and show 2′-O-methyl modification at the 3′-end. Numerous studies have revealed that piRNAs can play important roles in tumorigenesis via multiple biological regulatory mechanisms, including silencing transcriptional and posttranscriptional gene processes and accelerating multiprotein interactions. piRNAs are emerging players in the malignant transformation of normal cells and participate in the regulation of cancer hallmarks. Most of the specific cancer hallmarks regulated by piRNAs are involved in sustaining proliferative signaling, resistance to cell death or apoptosis, and activation of invasion and metastasis. Additionally, piRNAs have been used as biomarkers for cancer diagnosis and prognosis and have great potential for clinical utility. However, research on the underlying mechanisms of piRNAs in cancer is limited. Here, we systematically reviewed recent advances in the biogenesis and biological functions of piRNAs and relevant bioinformatics databases with the aim of providing insights into cancer diagnosis and clinical applications. We also focused on some cancer hallmarks rarely reported to be related to piRNAs, which can promote in-depth research of piRNAs in molecular biology and facilitate their clinical translation into cancer treatment.
Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation
Authors: Dou Zhihui , Zhao Dapeng , Chen Xiaohua , Xu Caipeng , Jin Xiaodong , Zhang Xuetian , Wang Yupei , Xie Xiaodong , Li Qiang , Di Cuixia , Zhang Hong
Published: June 2021

Bcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.
Influence of the medial longitudinal arch of the foot in adult women in ankle isokinetic performance: a cross‐sectional study
Authors: Guenka Leandro C. , Carrasco Aline C. , Pelegrinelli Alexandre R. M. , Silva Mariana F. , Dela Bela Laís F. , Moura Felipe A. , Cardoso Jefferson Rosa
Published: June 2021

Background

Maintenance of the medial longitudinal arch (MLA) of the foot is fundamental during functional tasks and disorders can lead to clinical alterations. Studies have demonstrated that deficits in ankle isokinetic performance can predispose an individual to lower limb injuries.

Objectives

To evaluate the muscular performance of cavus, planus, and normal feet by means of torque/body mass and the isokinetic phases, to generate 3D surface map analysis, and to verify whether there is a relationship between MLA height and arch height flexibility with isokinetic performance.

Methods

The sample consisted of 105 healthy adult women, divided into three groups: normal, cavus, and planus. Assessment in concentric mode at 30, 60, and 90 °/s in the dorsiflexion and plantarflexion of the ankle joint were analyzed during the three isokinetic phases (acceleration, sustained velocity, and deceleration). The variables total range of motion, peak of torque (PT), and angle of PT were extracted within the sustained velocity.

Results

In dorsiflexion at 60 °/s, the phase where the velocicty is sustained (load range phase) was higher in the planus group (MeanDifference=10.9 %; ω2p = 0.06) when compared with the cavus group. Deficits in the peak torque/body mass in dorsiflexion at 60 °/s (cavus feet: MD=‐3 N.m/kg; ω2p = 0.06; and planus feet: MD=‐1.1 N.m/kg; ω2p = 0.06) were also observed as well as in the 3D surface maps, when compared with the normal group. The flexibility of MLA had a negative correlation of PT at 30 °/s in cavus group. The heigth of MLA had a postive correlation with the PT for the cavus and planus group ate 60 °/s. All other results did not show differences between the groups.

Conclusions

The planus groups showed a better capacity of attain and sustained the velocity in dorsiflexion in relation the cavus group. The cavus and planus group had deficts in torque in relation the normal. The correlations were weak between the measures of MLA and PT. Thereby, in general the differences between foot types showed small effect in isokinetic muscle performance measures of the plantar and dorsi flexores.

Trial registration

Study design was approved by the IRB (#90238618.8.0000.5231).
Effects of levosimendan on renal blood flow and glomerular filtration in patients with acute kidney injury after cardiac surgery: a double blind, randomized placebo-controlled study
Authors: Tholén Maria , Ricksten Sven-Erik , Lannemyr Lukas
Published: June 2021

Background

Acute kidney injury (AKI) is a common and serious complication after cardiac surgery, and current strategies aimed at treating AKI have proven ineffective. Levosimendan, an inodilatating agent, has been shown to increase renal blood flow and glomerular filtration rate in uncomplicated postoperative patients and in patients with the cardiorenal syndrome. We hypothesized that levosimendan through its specific effects on renal vasculature, a preferential vasodilating effect on preglomerular resistance vessels, could improve renal function in AKI-patients with who did not have clinical indication for inotropic support.

Methods

In this single-center, double-blind, randomized controlled study, adult patients with postoperative AKI within 2 days after cardiac surgery, who were hemodynamically stable with a central venous oxygen saturation (ScvO2) ≥ 60% without inotropic support were eligible for inclusion. After randomization, study drug infusions, levosimendan (n = 16) or placebo (n = 13) were given for 5 h. A bolus infusion of levosimendan (12 µg/kg), were given for 30 min followed by 0.1 µg/kg/min for 5 h. Renal blood flow and glomerular filtration rate were measured using infusion clearance of para-aminohippuric acid and a filtration marker, respectively. As a safety issue, norepinephrine was administered to maintain mean arterial pressure between 70–80 mmHg. Intra-group differences were tested by Mann–Whitney U-tests, and a linear mixed model was used to test time and group interaction.

Results

Twenty-nine patients completed the study. At inclusion, the mean serum creatinine was higher in the patients randomized to levosimendan (148 ± 29 vs 127 ± 22 µmol/L, p = 0.030), and the estimated GFR was lower (46 ± 12 vs 57 ± 11 ml/min/1.73 m2, p = 0.025). Levosimendan induced a significantly (p = 0.011) more pronounced increase in renal blood flow (15%) compared placebo (3%) and a more pronounced decrease in renal vascular resistance (− 18% vs. − 4%, respectively, p = 0.043). There was a trend for a minor increase in glomerular filtration rate with levosimendan (4.5%, p = 0.079), which did differ significantly from the placebo group (p = 0.440). The mean norepinephrine dose was increased by 82% in the levosimedan group and decreased by 29% in the placebo group (p = 0.012).

Conclusions

In hemodynamically stable patients with AKI after cardiac surgery, levosimendan increases renal blood flow through renal vasodilatation.

Trial registration

NCT02531724, prospectly registered on 08/20/2015. https://clinicaltrials.gov/ct2/show/NCT02531724?cond=AKI&cntry=SE&age=1&draw=2&rank=1
The small G-protein RalA promotes progression and metastasis of triple-negative breast cancer
Authors: Thies Katie A. , Cole Matthew W. , Schafer Rachel E. , Spehar Jonathan M. , Richardson Dillon S. , Steck Sarah A. , Das Manjusri , Lian Arthur W. , Ray Alo , Shakya Reena , Knoblaugh Sue E. , Timmers Cynthia D. , Ostrowski Michael C. , Chakravarti Arnab , Sizemore Gina M. , Sizemore Steven T.
Published: June 2021

Background

Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-associated mortality in women. In particular, triple-negative BC (TNBC) has the highest rate of mortality due in large part to the lack of targeted treatment options for this subtype. Thus, there is an urgent need to identify new molecular targets for TNBC treatment. RALA and RALB are small GTPases implicated in growth and metastasis of a variety of cancers, although little is known of their roles in BC.

Methods

The necessity of RALA and RALB for TNBC tumor growth and metastasis were evaluated in vivo using orthotopic and tail-vein models. In vitro, 2D and 3D cell culture methods were used to evaluate the contributions of RALA and RALB during TNBC cell migration, invasion, and viability. The association between TNBC patient outcome and RALA and RALB expression was examined using publicly available gene expression data and patient tissue microarrays. Finally, small molecule inhibition of RALA and RALB was evaluated as a potential treatment strategy for TNBC in cell line and patient-derived xenograft (PDX) models.

Results

Knockout or depletion of RALA inhibited orthotopic primary tumor growth, spontaneous metastasis, and experimental metastasis of TNBC cells in vivo. Conversely, knockout of RALB increased TNBC growth and metastasis. In vitro, RALA and RALB had antagonistic effects on TNBC migration, invasion, and viability with RALA generally supporting and RALB opposing these processes. In BC patient populations, elevated RALA but not RALB expression is significantly associated with poor outcome across all BC subtypes and specifically within TNBC patient cohorts. Immunohistochemical staining for RALA in patient cohorts confirmed the prognostic significance of RALA within the general BC population and the TNBC population specifically. BQU57, a small molecule inhibitor of RALA and RALB, decreased TNBC cell line viability, sensitized cells to paclitaxel in vitro and decreased tumor growth and metastasis in TNBC cell line and PDX models in vivo.

Conclusions

Together, these data demonstrate important but paradoxical roles for RALA and RALB in the pathogenesis of TNBC and advocate further investigation of RALA as a target for the precise treatment of metastatic TNBC.
Selective delignification of poplar wood with a newly isolated white-rot basidiomycete Peniophora incarnata T-7 by submerged fermentation to enhance saccharification
Authors: Ma Jiangshan , Yue Huimin , Li Hongqian , Zhang Jing , Zhang Yanghong , Wang Xiaoling , Gong Si , Liu Gao-Qiang
Published: June 2021

Background

Pretreatment is a critical step required for efficient conversion of woody biomass into biofuels and platform chemicals. Fungal pretreatment is regarded as one of the most promising technology for woody biomass conversion but remains challenging for industrial application. The exploration of potential fungus strain with high efficient delignification and less processing time for woody biomass pretreatment will be valuable for development of biorefinery industry. Here, a newly isolated white-rot basidiomycete Peniophora incarnate T-7 was employed for poplar wood pretreatment.

Results

The chemical component analysis showed that cellulose, hemicellulose and lignin from poplar wood declined by 16%, 48% and 70%, respectively, after 7 days submerged fermentation by P. incarnate T-7. Enzymatic saccharification analysis revealed that the maximum yields of glucose and xylose from 7 days of P. incarnate T-7 treated poplar wood reached 33.4% and 27.6%, respectively, both of which were enhanced by sevenfold relative to the untreated group. Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), X-ray diffraction (XRD) and pyrolysis gas chromatography–mass spectrometry (Py-GC/MS) characterization confirmed that lignocellulosic structure of poplar wood was largely broken by P. incarnate T-7, including delignification and de-crystalline of cellulose. Meanwhile, lignin component of poplar wood was selectively degraded by P. incarnate T-7, and G-type unit of lignin was preferentially attacked by the strain. Furthermore, quantitative proteomic analysis revealed that a considerable amount of lignocellulolytic enzymes were detected in the secretory proteins of P. incarnate T-7, especially with high abundance of lignin-degrading enzymes and hemicellulases. Combination of quantitative proteomic with transcriptomic analysis results showed that most of those lignocellulolytic enzymes were highly upregulated on poplar wood substrate compared to glucose substrate.

Conclusions

This study showed that P. incarnate T-7 could selectively delignify poplar wood by submerged fermentation with short time of 7 days, which greatly improved its enzymatic saccharification efficiency. Our results suggested that P. incarnate T-7 might be a promising candidate for industrial woody biomass pretreatment.
Role of liraglutide in Alzheimer’s disease pathology
Authors: Vargas-Soria Maria , Carranza-Naval Maria Jose , del Marco Angel , Garcia-Alloza Monica
Published: June 2021

Background

The described relationship between Alzheimer’s disease (AD) and type 2 diabetes (T2D) and the fact that AD has no succesful treatment has led to the study of antidiabetic drugs that may limit or slow down AD pathology.

Main body

Although T2D treatment has evident limitations, options are increasing including glucagon-like peptide 1 analogs. Among these, liraglutide (LRGT) is commonly used by T2D patients to improve β cell function and suppress glucagon to restore normoglycaemia. Interestingly, LRGT also counterbalances altered brain metabolism and has anti-inflammatory properties. Previous studies have reported its capacity to reduce AD pathology, including amyloid production and deposition, tau hyperphosphorylation, or neuronal and synaptic loss in animal models of AD, accompanied by cognitive improvement. Given the beneficial effects of LRGT at central level, studies in patients have been carried out, showing modest beneficial effects. At present, the ELAD trial (Evaluating Liraglutide in Alzheimer’s Disease NCT01843075) is an ongoing phase IIb study in patients with mild AD. In this minireview, we resume the outcomes of LRGT treatment in preclinical models of AD as well as the available results in patients up to date.

Conclusion

The effects of LRGT on animal models show significant benefits in AD pathology and cognitive impairment. While studies in patients are limited, ongoing clinical trials will probably provide more definitive conclusions on the role of LRGT in AD patients.
Optimal control of buoyancy-driven liquid steel stirring modeled with single-phase Navier–Stokes equations
Authors: Wilbrandt Ulrich , Alia Najib , John Volker
Published: June 2021

Gas stirring is an important process used in secondary metallurgy. It allows to homogenize the temperature and the chemical composition of the liquid steel and to remove inclusions which can be detrimental for the end-product quality. In this process, argon gas is injected from two nozzles at the bottom of the vessel and rises by buoyancy through the liquid steel thereby causing stirring, i.e., a mixing of the bath. The gas flow rates and the positions of the nozzles are two important control parameters in practice. A continuous optimization approach is pursued to find optimal values for these control variables. The effect of the gas appears as a volume force in the single-phase incompressible Navier–Stokes equations. Turbulence is modeled with the Smagorinsky Large Eddy Simulation (LES) model. An objective functional based on the vorticity is used to describe the mixing in the liquid bath. Optimized configurations are compared with a default one whose design is based on a setup from industrial practice.
The Ockham’s razor for estimating the needs of ICU beds during a pandemic
Authors: Squara Pierre
Published: June 2021

Background

It is possible to monitor an epidemic evolution by plotting the number of patients, or its log-transform, as a function of time. However, these representations do not allow quick identifications of significant changes in the outbreak; a key information for estimating the needs for hospital and ICU beds, for decision-making, and resource allocation. Moreover, an epidemic is characterised by a heterogeneous evolution that depends on many unpredictable factors, coming from the virus itself or from its ecosystem. Simulations are very complex and based on hypotheses that are impossible to certify a priori, since each outbreak is different and has specific characteristics. A validation phase is necessary that may delay the usefulness of these tools. We tested a simpler method for monitoring the epidemic and rapidly predicting the peak.

Results

We present here a simple and easy-to-draw figure by plotting the daily rate of change in the number of patients as a function of time. This allows: (1) to rapidly identify the changes in the infection growth, (2) to extrapolate the regression lines for predicting the peaks, and (3) to use simple statistical models for identifying the significant inflexions and deriving the uncertainties. This figure predicted confidently the peak epidemic of the three waves in France.

Conclusion

Plotting the daily rate of change in the number of patients as a function of time is a simple tool for monitoring an epidemic growth, allowing to quickly identify significant changes and to help in predicting the peak of the infection, with its confidence interval.
Generalizations of some integral inequalities related to Hardy type integral inequalities via $(p,q)$-calculus
Authors: Thongjob Suriyakamol , Nonlaopon Kamsing , Tariboon Jessada , Ntouyas Sortiris K.
Published: June 2021

In this paper, we study generalizations of some integral inequalities related to Hardy type integral inequalities via$(p, q)$(p,q)-calculus. Many results obtained in this paper provide extensions of existing results in the literature. Furthermore, some examples are given to illustrate the investigated results.
Dynamics and bifurcation analysis of a state-dependent impulsive SIS model
Authors: Wang Jinyan
Published: June 2021

Recently, considering the susceptible population size-guided implementations of control measures, several modelling studies investigated the global dynamics and bifurcation phenomena of the state-dependent impulsive SIR models. In this study, we propose a state-dependent impulsive model based on the SIS model. We firstly recall the complicated dynamics of the ODE system with saturated treatment. Based on the dynamics of the ODE system, we firstly discuss the existence and the stability of the semi-trivial periodic solution. Then, based on the definition of the Poincaré map and its properties, we systematically investigate the bifurcations near the semi-trivial periodic solution with all the key control parameters; consequently, we prove the existence and stability of the positive periodic solutions.
Studies on the basic reproduction number in stochastic epidemic models with random perturbations
Authors: Ríos-Gutiérrez Andrés , Torres Soledad , Arunachalam Viswanathan
Published: June 2021

In this paper, we discuss the basic reproduction number of stochastic epidemic models with random perturbations. We define the basic reproduction number in epidemic models by using the integral of a function or survival function. We study the systems of stochastic differential equations for SIR, SIS, and SEIR models and their stability analysis. Some results on deterministic epidemic models are also obtained. We give the numerical conditions for which the disease-free equilibrium point is asymptotically stable.