bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of drivers of mycobacterial resistance to peptidoglycan synthesis inhibitors
Authors: Olivença Francisco , Ferreira Cláudia , Nunes Alexandra , Silveiro Cátia , Pimentel Madalena , Gomes João Paulo , Catalão Maria João
Published: September 2022

Beta-lactams have been excluded from tuberculosis therapy due to the intrinsic resistance of Mycobacterium tuberculosis (Mtb) to this antibiotic class, usually attributed to a potent beta-lactamase, BlaC, and to an unusually complex cell wall. In this pathogen, the peptidoglycan is cross-linked by penicillin-binding proteins (PBPs) and L,D-transpeptidases, the latter resistant to inhibition by most beta-lactams. However, recent studies have shown encouraging results of beta-lactam/beta-lactamase inhibitor combinations in clinical strains. Additional research on the mechanisms of action and resistance to these antibiotics and other inhibitors of peptidoglycan synthesis, such as the glycopeptides, is crucial to ascertain their place in alternative regimens against drug-resistant strains. Within this scope, we applied selective pressure to generate mutants resistant to amoxicillin, meropenem or vancomycin in Mtb H37Rv or Mycolicibacterium smegmatis (Msm) mc2-155. These were phenotypically characterized, and whole-genome sequencing was performed. Mutations in promising targets or orthologue genes were inspected in Mtb clinical strains to establish potential associations between altered susceptibility to beta-lactams and the presence of key genomic signatures. The obtained isolates had substantial increases in the minimum inhibitory concentration of the selection antibiotic, and beta-lactam cross-resistance was detected in Mtb. Mutations in L,D-transpeptidases and major PBPs, canonical targets, or BlaC were not found. The transcriptional regulator PhoP (Rv0757) emerged as a common denominator for Mtb resistance to both amoxicillin and meropenem, while Rv2864c, a lipoprotein with PBP activity, appears to be specifically involved in decreased susceptibility to the carbapenem. Nonetheless, the mutational pattern detected in meropenem-resistant mutants was different from the yielded by amoxicillin-or vancomycin-selected isolates, suggesting that distinct pathways may participate in increased resistance to peptidoglycan inhibitors, including at the level of beta-lactam subclasses. Cross-resistance between beta-lactams and antimycobacterials was mostly unnoticed, and Msm meropenem-resistant mutants from parental strains with previous resistance to isoniazid or ethambutol were isolated at a lower frequency. Although cell-associated nitrocefin hydrolysis was increased in some of the isolates, our findings suggest that traditional assumptions of Mtb resistance relying largely in beta-lactamase activity and impaired access of hydrophilic molecules through lipid-rich outer layers should be challenged. Moreover, the therapeutical potential of the identified Mtb targets should be explored.
Gut community alterations associated with Clostridioides difficile colonization in hospitalized gastroenterological patients with or without inflammatory bowel disease
Authors: Mahnic Aleksander , Pintar Spela , Skok Pavel , Rupnik Maja
Published: September 2022

Clostridioides difficile colonization and development of infection commonly occur in inflammatory bowel disease (IBD) patients and can trigger flare-ups. Both conditions are inherently linked to disrupted gut microbiota. This study included 149 hospitalized gastrointestinal patients, which were divided into IBD (n = 48) and non-IBD patients (n = 101). Patients were tested for C. difficile colonization (qPCR and selective plating), and gut bacterial communities were analyzed with 16S amplicon sequencing. Blood test results were retrospectively collected from the medical records. IBD and non-IBD patients had comparable C. difficile colonization rates (31.7 and 33.3%, respectively). Compared to non-IBD C. difficile-non-colonized patients, IBD and C. difficile-colonized patients shared multiple common bacterial community characteristics including decreased diversity and reduced abundance of strict anaerobic bacteria. Furthermore, certain microbiota alterations were enhanced when IBD was accompanied by C. difficile colonization, indicating a synergistic effect between both medical complications. Conversely, certain microbial patterns were specific to C. difficile colonization, e.g., co-occurrence with Enterococcus, which was most common in IBD patients (81.3%).
ProDFace: A web-tool for the dissection of protein-DNA interfaces
Authors: Pal Arumay , Chakrabarti Pinak , Dey Sucharita
Published: September 2022

Protein-DNA interactions play a crucial role in gene expression and regulation. Identifying the DNA binding surface of proteins has long been a challenge–in comparison to protein-protein interactions, limited progress has been made in the development of efficient DNA binding site prediction and protein-DNA docking methods. Here we present ProDFace, a web tool that characterizes the binding region of a protein-DNA complex based on amino acid propensity, hydrogen bond (HB) donor capacity (number of solvent accessible HB donor groups), sequence conservation at the interface core and rim region, and geometry. The program takes as input the structure of a protein-DNA complex in PDB (Protein Data Bank) format, and outputs various physicochemical and geometric parameters of the interface, as well as conservation of the interface residues in the protein component. Values are provided for the whole interface, and after dissecting it into core and rim regions. Details of water mediated HBs between protein and DNA, potential HB donor groups present at the binding surface of protein, and conserved interface residues are also provided as downloadable text files. These parameters can be useful in evaluating and validating protein-DNA docking solutions, structures derived from simulation as well as solutions from the available prediction tools, and facilitate the development of more efficient prediction methods. The web-tool is freely available at structbioinfo.iitj.ac.in/resources/bioinfo/pd_interface.
Mild cognitive impairment in patients with Parkinson’s disease: An updated mini-review and future outlook
Authors: Yu Rwei-Ling , Wu Ruey-Meei
Published: September 2022

Mild cognitive impairment (MCI) is one of the common non-motor symptoms in patients with Parkinson’s disease (PD). MCI is the transition stage between normal aging and full-blown dementia and is also a powerful predictor of dementia. Although the concept of MCI has been used to describe some of the PD symptoms for many years, there is a lack of consistent diagnostic criteria. Moreover, because of the diverse patterns of the cognitive functions, each cognitive impairment will have a different progression. In this review, we overviewed the diagnostic criteria for PD-MCI, primarily focused on the heterogeneity of PD-MCI patients’ cognitive function, including various types of cognitive functions and their progression rates. A review of this topic is expected to be beneficial for clinical diagnosis, early intervention, and treatment. In addition, we also discussed the unmet needs and future vision in this field.
The therapeutic efficacy of transcranial magnetic stimulation in managing Alzheimer’s disease: A systemic review and meta-analysis
Authors: Wei Zhenyu , Fu Jiaqi , Liang Huazheng , Liu Mingli , Ye Xiaofei , Zhong Ping
Published: September 2022

Background

Repetitive Transcranial Magnetic Stimulation (rTMS) is widely used to treat Alzheimer’s Disease. However, the effect of rTMS is still controversial. The purpose of the present study is to evaluate the effectiveness of rTMS on cognitive performance of AD patients.

Methods

We systematically searched relevant literatures in four major databases - PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials [Central] before 28th April 2022. Both randomized controlled trials and cross-section studies that compared the therapeutic effect of rTMS with blank control or sham stimuli were included.

Results

A total of 14 studies involving 513 AD patients were finally included for meta-analysis. It was found that rTMS significantly improved global cognitive function (SMD = 0.24, 95%CI, 0.12 to 0.36, P = 0.0001) and daily living ability (IADL: SMD = 0.64, 95%CI, 0.21to 1.08, P = 0.004) in patients with AD, but did not show improvement in language, memory, executive ability, and mood. In further analyses, rTMS at 10 Hz, on a single target with 20 sessions of treatment was shown to produce a positive effect. In addition, improvement in cognitive functions lasted for at least 6 weeks (SMD = 0.67, 95%CI, 0.05 to 1.30,P = 0.04).

Conclusion

rTMS can improve the global cognition and daily living ability of AD patients. In addition, attention should be paid to the safety of rTMS in AD patients with seizures. Given the relatively small sample size, our results should be interpreted with caution.
Efficacy evaluation of contrast-enhanced magnetic resonance imaging in differentiating glioma from metastatic tumor of the brain and exploration of its association with patients’ neurological function
Authors: Shi Zhuo , Jiang Jiuming , Xie Lizhi , Zhao Xinming
Published: September 2022

Objective

To determine the efficacy of contrast-enhanced MRI in differentiating glioma (GL) from the metastatic tumor of the brain (MTB) and its association with patients’ neurological function.

Methods

A retrospective analysis was conducted on 49 cases of pathologically confirmed GL and 42 cases of MTB admitted between April 2019 and January 2022. All patients were examined by a set of MRI sequences that included T1WI, T2WI, FLAIR, and DWI. The values of fractional anisotropy (FA), apparent diffusion coefficient (ADC), and operation coefficient (Ktrans) were calculated by taking the tumor parenchyma area, cystic area, and peritumor edema area as the regions of interest (ROIs). And according to the Mini-mental state examination (MMSE) results, the contrast-enhanced MRI with patients’ neurological dysfunction was observed.

Results

The clinical symptoms and MRI findings of MTB and GL were basically the same, mainly showing neurological symptoms. The tumor parenchyma area and cystic area were mainly located in the tumor periphery and tumor central area, respectively, while the peritumor edema area was widely distributed, showing an irregular patchy edema zone. Contrast-enhanced scans suggested an obvious enhancement in the tumor parenchymal area, presenting with nodular and annular enhancement, but no enhancement in the tumor cystic and peritumor edema areas. There was no difference between GL and MTB in FA values of tumor cystic area and peritumor edema area (P > 0.05), but the FA value of the parenchyma area of GL was higher (P < 0.05). Besides, GL and MTB showed no difference in ADC and Ktrans values (P > 0.05), while the former presented lower ADC values and higher Ktrans values of the peritumor edema area than the latter (P < 0.05). In patients with GL and MTB, the FA and Ktrans values of all ROIs in those with neurological dysfunction were higher compared with those without neurological dysfunction, while the ADC values were lower (P < 0.05).

Conclusion

Contrast-enhanced MRI of peritumor edema area can effectively distinguish GL from MTB, and improve the accuracy of early clinical screening, thus providing more reliable life security for patients.
Proteostasis unbalance in prion diseases: Mechanisms of neurodegeneration and therapeutic targets
Authors: Thellung Stefano , Corsaro Alessandro , Dellacasagrande Irene , Nizzari Mario , Zambito Martina , Florio Tullio
Published: September 2022

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are progressive neurodegenerative disorders of the central nervous system that affect humans and animals as sporadic, inherited, and infectious forms. Similarly to Alzheimer's disease and other neurodegenerative disorders, any attempt to reduce TSEs' lethality or increase the life expectancy of affected individuals has been unsuccessful. Typically, the onset of symptoms anticipates the fatal outcome of less than 1 year, although it is believed to be the consequence of a decades-long process of neuronal death. The duration of the symptoms-free period represents by itself a major obstacle to carry out effective neuroprotective therapies. Prions, the infectious entities of TSEs, are composed of a protease-resistant protein named prion protein scrapie (PrPSc) from the prototypical TSE form that afflicts ovines. PrPSc misfolding from its physiological counterpart, cellular prion protein (PrPC), is the unifying pathogenic trait of all TSEs. PrPSc is resistant to intracellular turnover and undergoes amyloid-like fibrillation passing through the formation of soluble dimers and oligomers, which are likely the effective neurotoxic entities. The failure of PrPSc removal is a key pathogenic event that defines TSEs as proteopathies, likewise other neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, characterized by alteration of proteostasis. Under physiological conditions, protein quality control, led by the ubiquitin-proteasome system, and macroautophagy clears cytoplasm from improperly folded, redundant, or aggregation-prone proteins. There is evidence that both of these crucial homeostatic pathways are impaired during the development of TSEs, although it is still unclear whether proteostasis alteration facilitates prion protein misfolding or, rather, PrPSc protease resistance hampers cytoplasmic protein quality control. This review is aimed to critically analyze the most recent advancements in the cause-effect correlation between PrPC misfolding and proteostasis alterations and to discuss the possibility that pharmacological restoring of ubiquitin-proteasomal competence and stimulation of autophagy could reduce the intracellular burden of PrPSc and ameliorate the severity of prion-associated neurodegeneration.
The hypolipidemic mechanism of chrysanthemum flavonoids and its main components, luteolin and luteoloside, based on the gene expression profile
Authors: Sun Jihan , Wang Zhaodan , Lin Chen , Xia Hui , Yang Ligang , Wang Shaokang , Sun Guiju
Published: September 2022

In this study, the following four groups of mice with hyperlipidemia were involved: the model control group (MC), the Chrysanthemum flavonoids group (CF), the luteolin group, and the luteoloside group. The whole gene expression profile was detected in the liver tissues of each group. Differential genes significantly enriched in the biological process of gene ontology (GO) items and Kyoto Encyclopedia of Genes and Genomes (KEGG) were selected, and 4 differential genes related to lipid metabolism were selected for further real-time quantitative PCR verification. Compared with the MC, 41 differential genes such as Sqle, Gck, and Idi1 were screened in the CF intervention group; 68 differential genes such as Acsl3, Cyp7a1, and Lpin1 were screened in the luteolin intervention group (CF); and 51 differential genes such as Acaca, Cyp7a1, and Lpin1 were screened in the luteoloside group. The mechanism of CF to improve hyperlipidemia is very complex, mainly involving biological processes such as cholesterol and fatty acid metabolism and glycolysis, luteolin mainly involves the synthesis and transport of cholesterol, and luteoloside mainly involves fatty acid metabolism. The functional pathways of CF may not be completely the same as luteolin and luteoloside, and further study is needed on the mechanism of action of other components.
A cohort study of vitamins contents in human milk from maternal-infant factors
Authors: Qiao Weicang , Chen Jingyao , Zhang Minghui , Wang Yaling , Yang Baoyu , Zhao Junying , Jiang Tiemin , Chen Lijun
Published: September 2022

Human milk vitamin content is an important indicator to evaluate the nutritional composition of human milk. This paper investigates the influence of maternal and infant factors on the dynamics of human milk vitamin content. A total of 147 mother-infant pairs from 3 different cities (north-south distribution) in China were selected and 9 major vitamins were measured in 332 human milk samples. The three vitamins (vitamin A, β-carotene, and pantothenic acid) showed significant downward trends with lactation period (| r | > 0.3, p < 0.05). The lactation period factor could explain the negative variation of vitamin A (21.2%) and pantothenic acid (9.5%). The factors of lactation period and oils intake could jointly explain variations of β-carotene (11.8%). (Registration number: NCT02658500).
Identification of pulmonary adenocarcinoma and benign lesions in isolated solid lung nodules based on a nomogram of intranodal and perinodal CT radiomic features
Authors: Yi Li , Peng Zhiwei , Chen Zhiyong , Tao Yahong , Lin Ze , He Anjing , Jin Mengni , Peng Yun , Zhong Yufeng , Yan Huifeng , Zuo Minjing
Published: September 2022

To develop and validate a predictive model based on clinical radiology and radiomics to enhance the ability to distinguish between benign and malignant solitary solid pulmonary nodules. In this study, we retrospectively collected computed tomography (CT) images and clinical data of 286 patients with isolated solid pulmonary nodules diagnosed by surgical pathology, including 155 peripheral adenocarcinomas and 131 benign nodules. They were randomly divided into a training set and verification set at a 7:3 ratio, and 851 radiomic features were extracted from thin-layer enhanced venous phase CT images by outlining intranodal and perinodal regions of interest. We conducted preprocessing measures of image resampling and eigenvalue normalization. The minimum redundancy maximum relevance (mRMR) and least absolute shrinkage and selection operator (lasso) methods were used to downscale and select features. At the same time, univariate and multifactorial analyses were performed to screen clinical radiology features. Finally, we constructed a nomogram based on clinical radiology, intranodular, and perinodular radiomics features. Model performance was assessed by calculating the area under the receiver operating characteristic curve (AUC), and the clinical decision curve (DCA) was used to evaluate the clinical practicability of the models. Univariate and multivariate analyses showed that the two clinical factors of sex and age were statistically significant. Lasso screened four intranodal and four perinodal radiomic features. The nomogram based on clinical radiology, intranodular, and perinodular radiomics features showed the best predictive performance (AUC=0.95, accuracy=0.89, sensitivity=0.83, specificity=0.96), which was superior to other independent models. A nomogram based on clinical radiology, intranodular, and perinodular radiomics features is helpful to improve the ability to predict benign and malignant solitary pulmonary nodules.
Sub-arc collimator angle optimization based on the conformity index heatmap for VMAT planning of multiple brain metastases SRS treatments
Authors: Shen Jiuling , Dai Zhitao , Yu Jing , Yuan Qingqing , Kang Kailian , Chen Cheng , Liu Hui , Xie Conghua , Wang Xiaoyong
Published: September 2022

Objective

The aim of this study was to investigate the impact of collimator angle optimization in single-isocenter coplanar volume modulated arc therapy (VMAT) stereotactic radiosurgery (SRS) for multiple metastases with respect to dosimetric quality and treatment delivery efficiency. In particular, this is achieved by a novel algorithm of sub-arc collimator angle optimization (SACAO).

Methods

Twenty patients with multiple brain metastases were retrospectively included in this study. A multi-leaf collimator (MLC) conformity index (MCI) that is defined as the ratio of the area of target projection in the beam’s eye view (BEV) to the related area fitted by MLC was applied. Accordingly, for each control point, 180 MCI values were calculated with a collimator angle interval of 1°. A two-dimensional heatmap of MCI as a function of control point and collimator angle for each full arc was generated. The optimal segmentation of sub-arcs was achieved by avoiding the worst MCI at each control point. Then, the optimal collimator angle for each sub-arc would be determined by maximizing the summation of MCI. Each patient was scheduled to undergo single-center coplanar VMAT SRS based on either the novel SACAO algorithm or the conventional VMAT with static collimator angle (ST-VMAT). The dosimetric parameters, field sizes, and the monitoring units (Mus) were evaluated.

Results

The mean dose-volumetric parameters for the target volume of SACAO were comparable to ST-VMAT, while the conformity index (CI), homogeneity index (HI), and gradient index (GI) were reduced by SACAO. Improved sparing of organs at risk (OARs) was also obtained by SACAO. In particular, the SACAO method significantly (p < 0.01) reduced the field size (76.59 ± 32.55 vs. 131.95 ± 56.71 cm2) and MUs (655.35 ± 71.99 vs. 729.85 ± 73.52) by 41.11%.

Conclusions

The SACAO method could be superior in improving the CI, HI, and GI of the targets as well as normal tissue sparing for multiple brain metastases SRS. In particular, SACAO has the potential of increasing treatment efficiency in terms of field size and MU.
CD20 expression is closely associated with Epstein–Barr virus infection and an inferior survival in nodular sclerosis classical Hodgkin lymphoma
Authors: Zhao Xia , Ma Yushuo , Bian Haiyan , Liu Zhihe
Published: September 2022

Background

Nodular sclerosis classical Hodgkin lymphoma (NSCHL) is a rare disease in which Epstein–Barr virus (EBV) and CD20 can be detected. The clinical significance of EBV infection, CD20 expression and their relationship are still unclear in NSCHL presently. The aim of this research was to systematically explore the clinical significance of EBV infection, expression of CD20 and their relationship in NSCHL.

Methods

109 NSCHL patients diagnosed in Qingdao University’s Affiliated Hospital were chosen from January 2010 to July 2019, and the clinical and survival data of all patients were collected retrospectively.

Results

Among 109 patients, 33 patients were assigned to the group of EBV-positives, following the results of the EBV-encoded RNA (EBER1). Compared with EBV-negative group patients, those in the group of EBV-positive were older (P=0.004) and their β2-microglobulin (β2-MG) levels were higher (P=0.006). The CD20 positivity rate in the group of EBV-positive was substantially higher than that in the EBV-negative group (54.5% vs 27.6%, P=0.007). Among 109 patients, EBV+ and CD20+ double positive patients acquired the least overall survival (OS), and patients with EBV- and CD20- double negative had the best OS (P < 0.001). Although old age, gender, EBV infection and CD20 positive were the risk factors for OS in NSCHL, multivariate analysis showed that CD20 positivity was the only characteristic that showed to be an independent risk factor for OS in NSCHL patients.

Conclusion

CD20 was found to be strongly expressed in NSCHL patients who had been infected with EBV, and it was found to be an independent risk factor for NSCHL patients’ survival.
Radiofrequency ablation in combination with CD73 inhibitor AB680 reduces tumor growth and enhances anti-tumor immunity in a syngeneic model of pancreatic ductal adenocarcinoma
Authors: Faraoni Erika Y. , Strickland Lincoln N. , O’Brien Baylee J. , Barraza Joseph F. , Thosani Nirav C. , Wray Curtis J. , Mills Tingting W. , Bailey-Lundberg Jennifer M.
Published: September 2022

Pancreatic ductal adenocarcinoma presents a 5-year overall survival rate of 11%, placing an imperative need for the discovery and application of innovative treatments. Radiofrequency ablation represents a promising therapy for PDA, as studies show it induces coagulative necrosis and a host adaptive immune response. In this work we evaluated the effects of RFA treatment in vivo by establishing a syngeneic mouse model of PDA and performing tumor ablation in one flank. Our studies revealed RFA acutely impaired PDA tumor growth; however, such effects were not sustained one week after treatment. Adenosine (ADO) pathway represents a strong immunosuppressive mechanism that was shown to play a role in PDA progression and preliminary data from ongoing clinical studies suggest ADO pathway inhibition may improve therapeutic outcomes. Thus, to investigate whether ADO generation may be involved in tumor growth relapse after RFA, we evaluated adenosine-monophosphate (AMP), ADO and inosine (INO) levels by HPLC and found they were acutely increased after treatment. Thus, we evaluated an in vivo CD73 inhibition in combination with RFA to study ADO pathway implication in RFA response. Results showed combination therapy of RFA and a CD73 small molecule inhibitor (AB680) in vivo promoted sustained tumor growth impairment up to 10 days after treatment as evidenced by increased necrosis and anti-tumor immunity, suggesting RFA in combination with CD73 inhibitors may improve PDA patient response.
Pomegranate juice anthocyanidins induce cell death in human cancer cells by mobilizing intracellular copper ions and producing reactive oxygen species
Authors: Farhan Mohd , Rizvi Asim , Ali Ferasat , Ahmad Aamir , Aatif Mohammad , Malik Arshi , Alam Mir Waqas , Muteeb Ghazala , Ahmad Saheem , Noor Awal , Siddiqui Farhan Asif
Published: September 2022

Anthocyanidins are the most abundant polyphenols in pomegranate juice. This class of molecules includes Delphinidin (Del), Cyanidin (Cya), and Pelargonidin (Pel). Using prostate, breast and pancreatic cancer cell lines PC3, MDA-MB-231, BxPC-3 and MiaPaCa-2, we show that anthocyanidins inhibit cell proliferation (measured by MTT assay) and induce apoptosis like cell death (measured by DNA/Histone ELISA). Copper chelator neocuproine and reactive oxygen species scavengers (thiourea for hydroxyl radical and superoxide dismutase for superoxide anion) significantly inhibit this reaction thus demonstrating that intracellular copper reacts with anthocyanidins in cancer cells to cause DNA damage via ROS generation. We further show that copper-supplemented media sensitizes normal breast epithelial cells (MCF-10A) to Del-mediated growth inhibition as determined by decreased cell proliferation. Copper supplementation results in increased expression of copper transporters Ctr1 and ATP7A in MCF-10A cells, which is attenuated by the addition of Del in the medium. We propose that the copper mediated, ROS-induced mechanism of selective cell death of cancer cells may in part explain the anticancer effects of anthocyanidins.
Screening trials of spinal cord stimulation for neuropathic pain in England—A budget impact analysis
Authors: Duarte Rui V. , Houten Rachel , Nevitt Sarah , Brookes Morag , Bell Jill , Earle Jenny , Gulve Ashish , Thomson Simon , Baranidharan Ganesan , North Richard B. , Taylor Rod S. , Eldabe Sam
Published: September 2022

Screening trials of spinal cord stimulation (SCS) prior to full implantation of a device are recommended by expert guidelines and international regulators. The current study sought to estimate the budget impact of a screening trial of SCS and the costs or savings of discontinuing the use of a screening trial. A budget impact analysis was performed considering a study population that reflects the size and characteristics of a patient population with neuropathic pain in England eligible for SCS. The perspective adopted was that of the NHS with a 5-year time horizon. The base case analysis indicate that a no screening trial strategy would result in cost-savings to the NHS England of £400,000–£500,000 per year. Sensitivity analyses were conducted to evaluate different scenarios. If ≥5% of the eligible neuropathic pain population received a SCS device, cost-savings would be >£2.5 million/year. In contrast, at the lowest assumed cost of a screening trial (£1,950/patient), a screening trial prior to SCS implantation would be cost-saving. The proportion of patients having an unsuccessful screening trial would have to be ≥14.4% for current practice of a screening trial to be cost-saving. The findings from this budget impact analysis support the results of a recent UK multicenter randomized controlled trial (TRIAL-STIM) of a policy for the discontinuation of compulsory SCS screening trials, namely that such a policy would result in considerable cost-savings to healthcare systems.
A systematic review of hot weather impacts on infant feeding practices in low-and middle-income countries
Authors: Edney Jessica M. , Kovats Sari , Filippi Veronique , Nakstad Britt
Published: September 2022

Background

Increased rates of exclusive breastfeeding could significantly improve infant survival in low- and middle-income countries. There is a concern that increased hot weather due to climate change may increase rates of supplemental feeding due to infants requiring fluids, or the perception that infants are dehydrated.

Objective

To understand how hot weather conditions may impact infant feeding practices by identifying and appraising evidence that exclusively breastfed infants can maintain hydration levels under hot weather conditions, and by examining available literature on infant feeding practices in hot weather.

Methods

Systematic review of published studies that met inclusion criteria in MEDLINE, EMBASE, Global Health and Web of Science databases. The quality of included studies was appraised against predetermined criteria and relevant data extracted to produce a narrative synthesis of results.

Results

Eighteen studies were identified. There is no evidence among studies of infant hydration that infants under the age of 6months require supplementary food or fluids in hot weather conditions. In some settings, healthcare providers and relatives continue to advise water supplementation in hot weather or during the warm seasons. Cultural practices, socio-economic status, and other locally specific factors also affect infant feeding practices and may be affected by weather and seasonal changes themselves.

Conclusion

Interventions to discourage water/other fluid supplementation in breastfeeding infants below 6 months are needed, especially in low-middle income countries. Families and healthcare providers should be advised that exclusive breastfeeding (EBF) is recommended even in hot conditions.
Microbiological screening tests for SARS-CoV-2 in the first hour since the hospital admission: A reliable tool for enhancing the safety of pediatric care
Authors: Vetrugno Giuseppe , Grassi Simone , Clemente Francesco , Cazzato Francesca , Rossi Vittoria , Grassi Vincenzo M. , Buonsenso Danilo , Filograna Laura , Sanguinetti Maurizio , Focardi Martina , Valentini Piero , Ozonoff Al , Pinchi Vilma , Oliva Antonio
Published: September 2022

Introduction/purpose

Since a significant proportion of SARS-CoV-2 infections occur within healthcare facilities, a multidisciplinary approach is required for careful and timely assessment of the risk of infection in asymptomatic patients or those whose COVID-19 diagnosis has not yet been made. The aim of this study was to investigate whether an adaptative model based on microbiological testing can represent a valid risk management strategy.

Material and methods

We collected data from the risk management unit database of a 1,550-bed tertiary hospital (Fondazione Policlinico Gemelli IRCCS, Rome, Italy) concerning pediatric admissions to the Emergency Department (ED) from 1 March 2020 to 31 December 2021. The study period was subdivided in period A and period B according to the technique used for the microbiological screening, respectively reverse-transcription polymerase chain reaction (RT-PCR) and antigen-detection test.

Results

In Period A, 426 children (mean age: 6 years) underwent microbiological screening at the ED. The total number of molecular tests performed was 463. 459/463 tested negative at the molecular test. In Period B, 887 children (mean age: 6 years) underwent microbiological screening in the ED. The total number of molecular tests performed was 1,154. 1,117/1,154 tested negative at the molecular test. Neither in Period A nor in Period B hospital-acquired SARS-CoV-2 infections were reported.

Discussion and conclusion

Despite high volumes, no cases of hospital-acquired SARS-CoV-2 infection have been reported. SARS-CoV-2 antigen-based tests can be used as a first-line option as they provide rapid results compared to RT-PCR, reducing the risk of infection in ED waiting rooms.
Epigenetic modifications and targeted therapy in pediatric acute myeloid leukemia
Authors: Xu Huan , Wen Yuxi , Jin Runming , Chen Hongbo
Published: September 2022

Acute myeloid leukemia (AML) is a hematological malignancy resulting from the genetic alterations and epigenetic dysregulations of the hematopoietic progenitor cells. One-third of children with AML remain at risk of relapse even though outcomes have improved in recent decades. Epigenetic dysregulations have been identified to play a significant role during myeloid leukemogenesis. In contrast to genetic changes, epigenetic modifications are typically reversible, opening the door to the development of epigenetic targeted therapy. In this review, we provide an overview of the landscape of epigenetic alterations and describe the current progress that has been made in epigenetic targeted therapy, and pay close attention to the potential value of epigenetic abnormalities in the precision and combinational therapy of pediatric AML.
Compassion fatigue in pediatric nephrology—The cost of caring
Authors: Goldberg Aviva M.
Published: September 2022

Compassion fatigue is the result of repeated vicarious trauma from caring for those who have suffered. Although not well-researched in pediatric nephrology to date, there is reason to believe that it is a real and sustained threat to the pediatric nephrology workforce. Interventions aimed at individuals, the profession, and the organizations in which pediatric nephrologists work can create spaces to discuss and ameliorate compassion fatigue. This will result in better care for patients, more stable pediatric nephrology divisions and a stronger, more resilient pediatric nephrology workforce.
Integrated transcriptomics and metabolomics analysis of the hippocampus reveals altered neuroinflammation, downregulated metabolism and synapse in sepsis-associated encephalopathy
Authors: Xu Kejia , Li Hui , Zhang Bing , Le Meini , Huang Qiong , Fu Rao , Croppi Giorgia , Qian Gang , Zhang Junjie , Zhang Guangming , Lu Yinzhong
Published: September 2022

Sepsis-associated encephalopathy (SAE) is an intricated complication of sepsis that brings abnormal emotional and memory dysfunction and increases patients’ mortality. Patients’ alterations and abnormal function seen in SAE occur in the hippocampus, the primary brain region responsible for memory and emotional control, but the underlying pathophysiological mechanisms remain unclear. In the current study, we employed an integrative analysis combining the RNA-seq-based transcriptomics and liquid chromatography/mass spectrometry (LC-MS)-based metabolomics to comprehensively obtain the enriched genes and metabolites and their core network pathways in the endotoxin (LPS)-injected SAE mice model. As a result, SAE mice exhibited behavioral changes, and their hippocampus showed upregulated inflammatory cytokines and morphological alterations. The omics analysis identified 81 differentially expressed metabolites (variable importance in projection [VIP] > 1 and p < 0.05) and 1747 differentially expressed genes (Foldchange >2 and p < 0.05) were detected in SAE-grouped hippocampus. Moreover, 31 compounds and 100 potential target genes were employed for the Kyoto Encyclopedia of Genes and Genomes (KEGG) Markup Language (KGML) network analysis to explore the core signaling pathways for the progression of SAE. The integrative pathway analysis showed that various dysregulated metabolism pathways, including lipids metabolism, amino acids, glucose and nucleotides, inflammation-related pathways, and deregulated synapses, were tightly associated with hippocampus dysfunction at early SAE. These findings provide a landscape for understanding the pathophysiological mechanisms of the hippocampus in the progression of SAE and pave the way to identify therapeutic targets in future studies.
Co-prescribing of opioids and benzodiazepines/Z-drugs associated with all-cause mortality—A population-based longitudinal study in primary care with weak opioids most commonly prescribed
Authors: Linnet Kristjan , Thorsteinsdottir Heidrun Sjofn , Sigurdsson Johann Agust , Sigurdsson Emil Larus , Gudmundsson Larus Steinthor
Published: September 2022

Introduction: The risk of mortality associated with the co-prescribing of benzodiazepines and opioids has been explored in a number of papers mainly focusing on strong opioids. The mortality risk associated with the use of weak opioids has not been dealt with to a similar extent.

Objective: To assess the mortality risk in primary care patients with consistent 3-year co-prescribing of benzodiazepine/Z-drugs (benzodiazepine receptor modulators) and mainly weak opioids (codeine, tramadol).

Methods: Of 221,804 patients contacting the primary healthcare centres, 124,436 were selected for further analysis, 88,832 participants fulfilled the inclusion criteria, aged 10–69 years and were divided into four groups with neither any use of benzodiazepines/Z-drugs nor opioids as Group 1, 3 years’ use of opioids and no/minimal benzodiazepines/Z-drugs as Group 2, with benzodiazepines/Z-drugs and no/minimal opioids as Group 3, and finally both benzodiazepines/Z-drugs and opioids as Group 4. Hazard ratios were calculated with the no-drug group as a reference, using Cox proportional hazards regression model adjusted for age, sex, number of chronic conditions and cancer patients excluded (n = 87,314).

Results: Hazard ratios for mortality increased both in Group 3 where it was 2.66 (95% CI 2.25–3.09) and in Group 4 where it was 5.12 (95% CI 4.25–6.17), with increased dose and higher number of chronic conditions. In Group 4 an opioid dose-dependent increase in mortality among persons using >1000 DDDs benzodiazepines/Z-drugs was observed when those on less than ≤300 DDDs of opioids with HR 4.94 (95% CI 3.54–6.88) were compared to those on >300 DDDs with HR 7.61/95% CI 6.08–9.55). This increase in mortality was not observed among patients on <1000 DDDs of benzodiazepines/Z-drugs.

Conclusion: The study supports evidence suggesting that mortality increases in a dose-dependent manner in patients co-prescribed benzodiazepines/Z-drugs and weak opioids (codeine, tramadol). An association between the number of chronic conditions and a rise in mortality was found. Long-term use of these drugs should preferably be avoided. Non-pharmacological therapy should be seriously considered instead of long-term use of benzodiazepines/Z-drugs, and deprescribing implemented for chronic users of these drugs when possible.
Muscarinic receptor M3 activation promotes fibrocytes contraction
Authors: Henrot Pauline , Eyraud Edmée , Maurat Elise , Point Sophie , Cardouat Guillaume , Quignard Jean-François , Esteves Pauline , Trian Thomas , Girodet Pierre-Olivier , Marthan Roger , Zysman Maéva , Berger Patrick , Dupin Isabelle
Published: September 2022

Fibrocytes are monocyte-derived cells able to differentiate into myofibroblasts-like cells. We have previously shown that they are increased in the bronchi of Chronic Obstructive Pulmonary Disease (COPD) patients and associated to worse lung function. COPD is characterized by irreversible airflow obstruction, partly due to an increased cholinergic environment. Our goal was to investigate muscarinic signalling in COPD fibrocytes. Fibrocytes were isolated from 16 patients with COPD’s blood and presence of muscarinic M3 receptor was assessed at the transcriptional and protein levels. Calcium signalling and collagen gels contraction experiments were performed in presence of carbachol (cholinergic agonist) ± tiotropium bromide (antimuscarinic). Expression of M3 receptor was confirmed by Western blot and flow cytometry in differentiated fibrocytes. Immunocytochemistry showed the presence of cytoplasmic and membrane-associated pools of M3. Stimulation with carbachol elicited an intracellular calcium response in 35.7% of fibrocytes. This response was significantly blunted by the presence of tiotropium bromide: 14.6% of responding cells (p< 0.0001). Carbachol induced a significant contraction of fibrocytes embedded in collagen gels (13.6 ± 0.3% versus 2.5 ± 4.1%;p< 0.0001), which was prevented by prior tiotropium bromide addition (4.1 ± 2.7% of gel contraction;p< 0.0001). Finally, M3-expressing fibrocytes were also identifiedin situin the peri-bronchial area of COPD patients’ lungs, and there was a tendency to an increased density compared to healthy patient’s lungs. In conclusion, around 1/3 of COPD patients’ fibrocytes express a functional muscarinic M3 receptor. Cholinergic-induced fibrocyte contraction might participate in airway diameter reduction and subsequent increase of airflow resistance in patients with COPD. The inhibition of these processes could participate to the beneficial effects of muscarinic antagonists for COPD treatment.
The effects of oral and vaporized cannabis alone, and in combination with alcohol, on driving performance using the STISIM driving simulator: A two-part, double-blind, double-dummy, placebo-controlled, randomized crossover clinical laboratory protocol
Authors: Zamarripa C. Austin , Novak Matthew D. , Weerts Elise M. , Vandrey Ryan , Spindle Tory R.
Published: September 2022

The legalization of cannabis for medicinal and non-medicinal purposes, and the corresponding increase in diversity of cannabis products, has resulted an urgent need for cannabis regulatory science. Among the most pressing needs is research related to impairment due to cannabis exposure, especially on driving performance. The present project was designed to evaluate the impact of oral and vaporized cannabis, when administered alone or in combination with alcohol, on simulated driving performance (STISIM driving simulator), cognitive/psychomotor ability, and field sobriety performance. Healthy adults will complete two, double-blind, double-dummy, placebo-controlled, randomized crossover clinical laboratory studies, one with oral cannabis (16 men/16 women) and the second with vaporized cannabis (16 men/16 women). In each study, participants will complete seven experimental sessions during which acute doses of placebo or high Δ9-THC cannabis containing 0, 10, or 25 mg Δ9-THC will be administered both alone and in combination with placebo or alcohol-containing beverages (target breath alcohol concentrations, BAC, of 0.0% or 0.05%). A positive control session (i.e., alcohol at target BAC of 0.08% with placebo cannabis) will also be completed. Simulated driving performance tests (available for download; see Methods), field sobriety assessments, subjective drug effect questionnaires, a mobile device impairment test (DRUID app), and collection of whole blood specimens will be completed repeatedly during each session. Linear mixed models will be used to test for differences across experimental conditions and a priori planned comparisons will be used to determine differences between conditions of interest (e.g., cannabis alone vs cannabis with alcohol). This research is designed to extend prior studies of cannabis and alcohol on driving performance by using oral and vaporized routes of cannabis administration. By increasing understanding of impairment associated with co-use of alcohol and these novel forms of cannabis, this research could inform impairment detection standards for cannabis and alcohol and have important implications for law enforcement, public policy decisions regarding accessibility of these substances, and education of the general population who may use cannabis and/or alcohol. Lastly, this manuscript provides interested researchers with access to the simulated driving scenarios and data extraction tools developed for this study as a means of facilitating future cross-study comparisons, which is important given the heterogeneity in methods used across laboratories in prior research.
Online survey of medicinal cannabis users: Qualitative analysis of patient-level data
Authors: Garcia-Romeu Albert , Elmore Joshua , Mayhugh Rhiannon E. , Schlienz Nicolas J. , Martin Erin L. , Strickland Justin C. , Bonn-Miller Marcel , Jackson Heather , Vandrey Ryan
Published: September 2022

Aim: To characterize perceived benefits and challenges experienced by medicinal cannabis users.

Methods: An anonymous online survey collected demographics, health information, and open-ended responses from medicinal cannabis users regarding perceptions, motivations, and experience of treatment. Qualitative open-ended responses were thematically analyzed.

Results: Respondents (N = 808) were predominantly White (79%), female (63%), with a mean (SD) age of 38 (20). Two hundred eighty-four (35%) respondents provided data on a dependent family member (e.g., child; 22% of total sample). Most used cannabidiol (CBD)-dominant products (58%), primarily for neurological disorders (38%) or pain (25%). Primary motivations for medicinal cannabis use were based on beliefs that traditional treatments were ineffective and/or had intolerable side effects (51%), positive scientific or media portrayals of the safety/efficacy of cannabis as a therapeutic (29%), or preference for “natural” treatments over pharmaceuticals (21%). A majority of respondents (77%) attributed positive effects to the medicinal use of cannabis/cannabinoids. These included physical symptom improvements such as reduced pain (28%), improved sleep (18%), and seizure reduction (18%), and mental health improvements including reduced anxiety (22%) and improved mood (11%). Additionally, respondents reported reduced use of other medications (e.g., opioids) (12%), and improved quality of life (14%). Problems associated with use were cited by 41% of respondents, and included unwanted side effects (16%), lack of information or medical support (16%), prohibitive costs (12%), and legal concerns (10%).

Conclusion: Most participants reported benefits from cannabis use for a variety of conditions where traditional treatments were ineffective or unacceptable. Concerns regarding cannabis side effects, legality, lack of information, and cost were raised. Data indicate greater research and education on the safety and efficacy of medicinal cannabis/cannabinoid use is warranted.