bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of RT234 vardenafil inhalation powder on exercise parameters in pulmonary arterial hypertension: phase II, dose-escalation study design
Authors: Benza Raymond L. , Franco Veronica , Aras Mandar A. , Spikes Leslie , Grinnan Daniel , Satler Carol
Published: December 2022

Background

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by high mean pulmonary arterial pressure (≥ 20 mmHg) and remodeling of the vascular arteries. Approved therapies improve symptoms and delay clinical worsening in the long term, but they do not relieve acute exertional symptoms. RT234, a drug/device combination (Respira Therapeutics, Palo Alto, CA, USA) that delivers the phosphodiesterase 5 inhibitor vardenafil to the lungs via inhalation, has been shown to reduce pulmonary vascular resistance in patients with PAH. This study aims to evaluate whether RT234 can increase oxygen capacity during cardiopulmonary exercise testing (CPET) in patients with PAH.

Methods

This prospective, multi-center, open-label, two-cohort, dose-escalation, phase IIb trial in patients with PAH will evaluate the safety and efficacy of RT234 in improving exercise parameters. The trial began in September 2020 and is expected to be completed by early 2024. Patients eligible for enrollment will have a right heart catheterization–confirmed diagnosis of PAH, a 6-minute walking distance of ≥ 150 m, a minute ventilation/carbon dioxide production slope of ≥ 36, and will be on up to three stable oral and/or inhaled (not parenteral) PAH-specific background therapies. The estimated sample size is 86 patients, who will be divided into two dose cohorts. Cohort 1 will receive 0.5 mg RT234, and cohort 2 will receive 1.0 mg RT234. Each cohort will contain two subgroups based on the number of PAH background medications (up to two vs three). The trial will assess patients’ changes from baseline in peak oxygen consumption (VO2) during CPET 30 minutes after a single dose of 0.5 mg or 1.0 mg RT234, the change in the 6-minute walking distance, and the pharmacokinetics and safety profile of single doses of RT234.

Conclusion

This is the first trial involving an as-needed medication for PAH. The trial will provide insights into the safety and efficacy of as-needed RT234 in treating the acute symptoms of PAH during exercise and will inform the design of further trials.

Trial registration number: ClinicalTrials.gov identifier NCT04266197.
Sputum from patients with primary ciliary dyskinesia contains high numbers of dysfunctional neutrophils and inhibits efferocytosis
Authors: Blanter Marfa , Cockx Maaike , Wittebols Liesel , Abouelasrar Salama Sara , De Bondt Mirre , Berghmans Nele , Pörtner Noëmie , Vanbrabant Lotte , Lorent Natalie , Gouwy Mieke , Boon Mieke , Struyf Sofie
Published: December 2022

Background

Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by recurrent airway infection and inflammation. There is no cure for PCD and to date there are no specific treatments available. Neutrophils are a crucial part of the immune system and are known to be dysfunctional in many inflammatory diseases. So far, the role of the neutrophils in PCD airways is largely unknown. The purpose of this study was to investigate the phenotype and function of airway neutrophils in PCD, and compare them to blood neutrophils.

Methods

Paired peripheral blood and spontaneously expectorated sputum samples from patients with PCD (n = 32) and a control group of patients with non-PCD, non-cystic fibrosis bronchiectasis (n = 5) were collected. The expression of neutrophil-specific surface receptors was determined by flow cytometry. Neutrophil function was assessed by measuring the extent of actin polymerization, production of reactive oxygen species (ROS) and release of neutrophil extracellular traps (NETs) in response to activating stimuli.

Results

Sputum neutrophils displayed a highly activated phenotype and were unresponsive to stimuli that would normally induce ROS production, actin polymerization and the expulsion of NETs. In addition, PCD sputum displayed high activity of neutrophil elastase, and impaired the efferocytosis by healthy donor macrophages.

Conclusions

Sputum neutrophils in PCD are dysfunctional and likely contribute to ongoing inflammation in PCD airways. Further research should focus on anti-inflammatory therapies and stimulation of efferocytosis as a strategy to treat PCD.
Considerations on dosimetry for in vitro assessment of e-cigarette toxicity
Authors: Forest Valérie , Mercier Clément , Pourchez Jérémie
Published: December 2022

Electronic cigarettes (or e-cigarettes) can be used as smoking cessation aid. Some studies tend to show that they are less hazardous than tobacco cigarettes, even if it does not mean they are completely safe. The huge variation in study designs assessing in vitro toxicity of e-cigarettes aerosol makes it difficult to make comparisons and draw robust and irrefutable conclusions. In this paper, we review this heterogeneity (in terms of e-cigarette products, biological models, and exposure conditions) with a special focus on the wide disparity in the doses used as well as in the way they are expressed. Finally, we discuss the major issue of dosimetry and show how dosimetry tools enable to align data between different exposure systems or data from different laboratories and therefore allow comparisons to help further exploring the risk potential of e-cigarettes.
A purified and lyophilized Pseudomonas aeruginosa derived pyocyanin induces promising apoptotic and necrotic activities against MCF-7 human breast adenocarcinoma
Authors: Abdelaziz Ahmed A. , Kamer Amal M. Abo , Al-Monofy Khaled B. , Al-Madboly Lamiaa A.
Published: December 2022

Background

Pyocyanin, a specific extracellular secondary metabolite pigment produced by Pseudomonas aeruginosa, exhibits redox activity and has toxic effects on mammalian cells, making it a new and potent alternative for treating cancer. Breast cancer (BC) treatment is now defied by acquired and de novo resistance to chemotherapy, radiation, or targeted therapies. Therefore, the anticancer activity of purified and characterized pyocyanin was examined against BC in our study.

Results

The maximum production of pyocyanin (53 µg/ml) was achieved by incubation of the highest pyocyanin-producing P. aeruginosa strain (P32) in pH-adjusted peptone water supplemented with 3% cetrimide under shaking conditions at 37 °C for 3 days. The high purity of the extracted pyocyanin was proven by HPLC against standard pyocyanin. The stability of pyocyanin was affected by the solvent in which it was stored. Therefore, the purified pyocyanin extract was lyophilized to increase its shelf-life up to one year. Using the MTT assay, we reported, for the first time, the cytotoxic effect of pyocyanin against human breast adenocarcinoma (MCF-7) with IC50 = 15 μg/ml while it recorded a safe concentration against human peripheral blood mononuclear cells (PBMCs). The anticancer potential of pyocyanin against MCF-7 was associated with its apoptotic and necrotic activities which were confirmed qualitatively and quantitively using confocal laser scanning microscopy, inverted microscopy, and flow cytometry. Caspase-3 measurements, using real-time PCR and western blot, revealed that pyocyanin exerted its apoptotic activity against MCF-7 through caspase-3 activation.

Conclusion

Our work demonstrated that pyocyanin may be an ideal anticancer candidate, specific to cancer cells, for treating MCF-7 by its necrotic and caspase-3-dependent apoptotic activities.
Emerging roles and mechanisms of miR-206 in human disorders: a comprehensive review
Authors: Khalilian Sheyda , Hosseini Imani Seyedeh Zahra , Ghafouri-Fard Soudeh
Published: December 2022

As a member of the miR-1 family, miR-206 is located between IL-17 and PKHD1 genes in human. This miRNA has been shown to be involved in the pathogenic processes in a variety of human disorders including cancers, amyotrophic lateral sclerosis, Alzheimer’s disease, atherosclerosis, bronchopulmonary dysplasia, coronary artery disease, chronic obstructive pulmonary disease, epilepsy, nonalcoholic fatty liver disease, Hirschsprung disease, muscular dystrophies, pulmonary arterial hypertension, sepsis and ulcerative colitis. In the current review, we summarize the role of miR-206 in both malignant and non-malignant situations and explain its possible therapeutic implications.
Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action
Authors: Lai Jing Wei , Maah Mohd Jamil , Tan Kong Wai , Sarip Rozie , Lim Yvonne Ai Lian , Ganguly Rakesh , Khaw Loke Tim , Ng Chew Hee
Published: December 2022

Background

Malaria remains one of the most virulent and deadliest parasitic disease in the world, particularly in Africa and Southeast Asia. Widespread occurrence of artemisinin-resistant Plasmodium falciparum strains from the Greater Mekong Subregion is alarming. This hinders the national economies, as well as being a major drawback in the effective control and elimination of malaria worldwide. Clearly, an effective anti-malarial drug is urgently needed.

Methods

The dinuclear and mononuclear copper(II) and zinc(II) complexes were synthesized in ethanolic solution and characterized by various physical measurements (FTIR, CHN elemental analysis, solubility, ESI-MS, UV-Visible, conductivity and magnetic moment, and NMR). X-ray crystal structure of the dicopper(II) complex was determined. The in vitro haemolytic activities of these metal complexes were evaluated spectroscopically on B+ blood while the anti-malarial potency was performed in vitro on blood stage drug-sensitive Plasmodium falciparum 3D7 (Pf3D7) and artemisinin-resistant Plasmodium falciparum IPC5202 (Pf5202) with fluorescence dye. Mode of action of metal complexes were conducted to determine the formation of reactive oxygen species using PNDA and DCFH-DA dyes, JC-1 depolarization of mitochondrial membrane potential, malarial 20S proteasome inhibition with parasite lysate, and morphological studies using Giemsa and Hoechst stains.

Results

Copper(II) complexes showed anti-malarial potency against both Pf3D7 and Pf5202 in sub-micromolar to micromolar range. The zinc(II) complexes were effective against Pf3D7 with excellent therapeutic index but encountered total resistance against Pf5202. Among the four, the dinuclear copper(II) complex was the most potent against both strains. The zinc(II) complexes caused no haemolysis of RBC while copper(II) complexes induced increased haemolysis with increasing concentration. Further mechanistic studies of both copper(II) complexes on both Pf3D7 and Pf5202 strains showed induction of ROS, 20S malarial proteasome inhibition, loss of mitochondrial membrane potential and morphological features indicative of apoptosis.

Conclusion

The dinuclear [Cu(phen)-4,4′-bipy-Cu(phen)](NO3)4 is highly potent and can overcome the total drug-resistance of Pf5202 towards chloroquine and artemisinin. The other three copper(II) and zinc(II) complexes were only effective towards the drug-sensitive Pf3D7, with the latter causing no haemolysis of RBC. Their mode of action involves multiple targets.

Graphical Abstract
Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors
Authors: Wong Kwong-Kwok , Bateman Nicholas W. , Ng Chun Wai , Tsang Yvonne T. M. , Sun Charlotte S. , Celestino Joseph , Nguyen Tri V. , Malpica Anais , Hillman R. Tyler , Zhang Jianhua , Futreal P. Andrew , Rojas Christine , Conrads Kelly A. , Hood Brian L. , Dalgard Clifton L. , Wilkerson Matthew D. , Phippen Neil T. , Conrads Thomas P. , Maxwell George L. , Sood Anil K. , Gershenson David M.
Published: December 2022

Background

Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared the proteogenomic analyses of LGSOCs from short- and long-term survivors (defined as < 40 and > 60 months, respectively). Our goal was to identify novel mutations, proteins, and mRNA transcripts that are dysregulated in LGSOC, particularly in short-term survivors.

Methods

Initially, targeted sequencing of 409 cancer-related genes was performed on 22 LGSOC and 6 serous borderline ovarian tumor samples. Subsequently, whole-genome sequencing analysis was performed on 14 LGSOC samples (7 long-term survivors and 7 short-term survivors) with matched normal tissue samples. RNA sequencing (RNA-seq), quantitative proteomics, and phosphoproteomic analyses were also performed.

Results

We identified single-nucleotide variants (SNVs) (range: 5688–14,833 per sample), insertion and deletion variants (indels) (range: 880–1065), and regions with copy number variants (CNVs) (range: 62–335) among the 14 LGSOC samples. Among all SNVs and indels, 2637 mutation sites were found in the exonic regions. The allele frequencies of the detected variants were low (median12%). The identified recurrent nonsynonymous missense mutations included KRAS, NRAS, EIF1AX, UBR5, and DNM3 mutations. Mutations in DNM3 and UBR5 have not previously been reported in LGSOC. For the two samples, somatic DNM3 nonsynonymous missense mutations in the exonic region were validated using Sanger sequencing. The third sample contained two missense mutations in the intronic region of DNM3, leading to a frameshift mutation detected in RNA transcripts in the RNA-seq data. Among the 14 LGSOC samples, 7754 proteins and 9733 phosphosites were detected by global proteomic analysis. Some of these proteins and signaling pathways, such as BST1, TBXAS1, MPEG1, HBA1, and phosphorylated ASAP1, are potential therapeutic targets.

Conclusions

This is the first study to use whole-genome sequencing to detect somatic mutations in LGSOCs with matched normal tissues. We detected and validated novel mutations in DNM3, which were present in 3 of the 14 samples analyzed. Additionally, we identified novel indels, regions with CNVs, dysregulated mRNA, dysregulated proteins, and phosphosites that are more prevalent in short-term survivors. This integrated proteogenomic analysis can guide research into the pathogenesis and treatment of LGSOC.
A novel frameshift variant in the ADA2 gene of a patient with a neurological phenotype: a case report
Authors: Lucane Z. , Davidsone Z. , Micule I. , Auzenbaha M. , Kurjane N.
Published: December 2022

Background

Adenosine deaminase 2 (ADA2) deficiency is an inherited autoinflammatory syndrome caused by a defect in the ADA2 gene. Most common manifestations include peripheral vasculopathy, early-onset stroke, immunodeficiency, and haematological manifestations. Patients with pathogenic variants that are more detrimental to ADA2’s enzymatic function (e.g. frameshift) have been reported to be prone to developing hematological phenotype. We report here the case of a 13-year-old Caucasian girl with a novel frameshift variant in the ADA2 gene and a clinical phenotype of early-onset stroke.

Case presentation

The patient was admitted to hospital with complaints of weakness in her right arm, unilateral facial weakness and speech problems. Her initial laboratory workup was normal; however, magnetic resonance imaging of her brain confirmed acute/subacute ischaemic changes in the posterior limb of the left-sided internal capsule and in the apical part of the thalamus. She also had manifestations of immunodeficiency – recurrent skin infections and otitis, chronic Molluscum contagiosum infection in anamnesis and B cell deficiency with a low level of serum IgA. The patient’s DNA was analysed and two pathogenic variants were identified in the ADA2 gene, confirming a diagnosis of adenosine deaminase 2 (ADA2) deficiency. While one of the variants (c.506G > A (p.Arg169Gln)) has been reported previously, the other one is a novel frameshift variant, namely, c.464del (p.Pro155Hisfs*29). The patient received stroke rehabilitation, which significantly improved her functional state. Tumour necrosis factor inhibitor and methotrexate treatment was commenced, and the patient has remained stable with no further ischaemic events.

Conclusions

Although rare, ADA2 deficiency should be considered in patients with early-onset stroke, especially with concomitant manifestations of inflammatory features or immunodeficiency. This case report extends the genotypic spectrum of ADA2 deficiency.
Poorer surgical outcomes at 2 years postoperatively in patients with lumbar spinal stenosis with long-term preoperative leg numbness: a single-center retrospective study
Authors: Li Kuan , Han Xiao , Chen Xin , Zhang Haozhi , Huang Changfa , Li Zheng
Published: December 2022

Background

The purpose of this study was to assess whether differences in duration of preoperative leg numbness lead to different surgical outcomes.

Methods

This study included patients with lumbar spinal stenosis (LSS) who underwent lumbar fusion surgery in our hospital from January 2018 to September 2020. Patients were divided into three groups based on duration of preoperative leg numbness: no numbness (NN) group, short-term numbness (STN) group (leg numbness ≤ 3 months) and long-term numbness (LTN) group (leg numbness > 3 months). The Numerical Rating Scale of leg pain (NRS-LP) and leg numbness (NRS-LN), Oswestry Disability Index (ODI) and Short-Form Health Survey (SF-36) were collected before surgery and at 3, 6, 12 and 24 months postoperatively.

Results

178 patients were included in this study. At 24 months postoperatively, NRS-LP was significantly higher in LTN than in NN [NN vs. STN vs. LTN: 0 (0,1) vs. 0 (0,1) vs. 1 (0,1)] (p = 0.033). NRS-LN in STN [2 (1,3)] was significantly lower than in LTN [3 (2,3)] (p < 0.001). SF-36 was significantly lower in LTN than in other two groups (NN vs. STN vs. LTN: 86.10 ± 6.02 vs. 84.09 ± 5.59 vs. 78.93 ± 6.57) (p < 0.001). ODI was significantly higher in LTN than in other two groups [NN vs. STN vs. LTN: 18 (15,22) vs. 18 (16,20) vs. 21 (19,24)] (p = 0.001).

Conclusions

Patients with LSS with long-term preoperative leg numbness have poorer outcomes at 2 years postoperatively. Surgical intervention should be performed before persistent leg numbness for more than 3 months to obtain a better prognosis.
A multidisciplinary care pathway improves quality of life and reduces pain in patients with fibrous dysplasia/McCune-Albright syndrome: a multicenter prospective observational study
Authors: Meier Maartje E. , Hagelstein-Rotman Marlous , van de Ven Annenienke C. , Van der Geest Ingrid C. M. , Donker Olav , Pichardo Sarina E. C. , Hissink Muller Petra C. E. , van der Meeren Stijn W. , Dorleijn Desirée M. J. , Winter Elizabeth M. , van de Sande Michiel A. J. , Appelman-Dijkstra Natasha M.
Published: December 2022

Background

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) may cause pain, impaired ambulation and decreased quality of life (QoL). International guidelines advocate management of FD/MAS in a tertiary multidisciplinary care pathway, but no longitudinal data are available to support this recommendation. This multicenter prospective observational study aimed to evaluate effects of 1 year of treatment in the FD/MAS care pathway in 2 tertiary clinics on QoL and pain, assessed by change in Short Form 36 and Brief Pain Inventory between baseline and follow-up. Patients completing baseline questionnaires < 1 year after intake were classified as new referrals, others as under chronic care.

Results

92 patients were included, 61 females (66%). 22 patients (24%) had monostotic disease, 16 (17%) isolated craniofacial FD, 27 (40%) polyostotic FD and 17 (19%) MAS. 26 were new referrals (28%) and 66 chronic patients (72%). Median age at baseline was 47 years (Q1–Q3 36–56). Skeletal burden correlated with baseline Physical Function (rs = − 0.281, p = 0.007). QoL was in all domains lower compared to the general population. New referrals reported clinically important differences (CID) over time in domains Physical Function (mean 67 ± SD24 to 74 ± 21, effect size (ES) 0.31, p = 0.020), Role Physical (39 ± 41 to 53 ± 43, ES 0.35, p = 0.066), Social Functioning (64 ± 24 to 76 ± 23, ES 0.49, p = 0.054), and Health Change (39 ± 19 to 53 ± 24, ES 0.76, p = 0.016), chronic patients in Physical Function (52 ± 46 to 66 ± 43, ES 0.31, p = 0.023) and Emotional Wellbeing (54 ± 27 to 70 ± 15, ES 0.59, p < 0.001). New referrals reported a CID of 1 point in maximum pain, average pain and pain interference, chronic patients reported stable scores. Change in pain interference and Role Physical were correlated (rs = − 0.472, p < 0.001). Patients with limited disease extent improved more than patients with severe disease. Patients receiving FD-related therapy had lower baseline scores than patients not receiving therapy and reported improvements in QoL after 1 year. Yet also patients without FD-related therapy improved in Physical Function.

Conclusions

All FD-subtypes may induce pain and reduced QoL. A multidisciplinary care pathway for FD/MAS may improve pain and QoL, mainly in new referrals without MAS comorbidities with low baseline scores. Therefore, we recommend referral of patients with all subtypes of FD/MAS to specialized academic centers.
Foot self‐care competence reported by patients with rheumatoid arthritis: a cross‐sectional study
Authors: Laitinen Anne‐Marie , Pasanen Miko , Wasenius Elina , Stolt Minna
Published: December 2022

Background

Foot self‐care is important for preventing foot problems and maintaining one's foot health. Foot self‐care requires competence to identify foot problems, knowledge and skills to care for those problems, and a willing attitude to care for one's foot health. However, there is major gap in the research evidence of foot self‐care competence among patients with rheumatoid arthritis. This study aimed to analyse self‐reported levels of competence in foot self‐care among patients with rheumatoid arthritis.

Methods

A cross‐sectional study design was used. Data were collected using a survey consisting of a self‐reported competence in foot self‐care competence scale (response options on 5‐point Likert scale, higher values indicate higher competence) and background questions. The data were analysed with descriptive and inferential statistics and the psychometric properties of the scale using Rasch analysis.

Results

The participants' (n = 251) self‐reported level of competence in foot self‐care was moderate (mean 3.50, standard deviation [SD], 0.66). On the sum variable level, the highest mean score was for attitude towards foot self‐care (3.98; SD, 0.69), followed by foot self‐care knowledge (3.45; SD, 0.67) and experience providing foot self‐care (3.38; SD, 0.69). Higher self‐reported foot self‐care knowledge and female sex were associated with higher self‐reported competence in every sum variable.

Conclusions

Patients with rheumatoid arthritis evaluated their level of competence in foot self‐care as moderate and some deficiencies were identified. These results indicate the importance of educating patients with rheumatoid arthritis about how to advance their foot self‐care skills and knowledge. In the future, patients with rheumatoid arthritis could benefit from interventions that increase their knowledge of foot self‐care together with practical examples, such as online videos, that demonstrate the practical conduct of foot self‐care skills in daily life.
Ten rules for optimizing ventilatory settings and targets in post-cardiac arrest patients
Authors: Battaglini Denise , Pelosi Paolo , Robba Chiara
Published: December 2022

Cardiac arrest (CA) is a major cause of morbidity and mortality frequently associated with neurological and systemic involvement. Supportive therapeutic strategies such as mechanical ventilation, hemodynamic settings, and temperature management have been implemented in the last decade in post-CA patients, aiming at protecting both the brain and the lungs and preventing systemic complications. A lung-protective ventilator strategy is currently the standard of care among critically ill patients since it demonstrated beneficial effects on mortality, ventilator-free days, and other clinical outcomes. The role of protective and personalized mechanical ventilation setting in patients without acute respiratory distress syndrome and after CA is becoming more evident. The individual effect of different parameters of lung-protective ventilation, including mechanical power as well as the optimal oxygen and carbon dioxide targets, on clinical outcomes is a matter of debate in post-CA patients. The management of hemodynamics and temperature in post-CA patients represents critical steps for obtaining clinical improvement. The aim of this review is to summarize and discuss current evidence on how to optimize mechanical ventilation in post-CA patients. We will provide ten tips and key insights to apply a lung-protective ventilator strategy in post-CA patients, considering the interplay between the lungs and other systems and organs, including the brain.
ARDS: hidden perils of an overburdened diagnosis
Authors: Tobin Martin J.
Published: December 2022

A diagnosis of ARDS serves as a pretext for several perilous clinical practices. Clinical trials demonstrated that tidal volume 12 ml/kg increases patient mortality, but 6 ml/kg has not proven superior to 11 ml/kg or anything in between. Present guidelines recommend 4 ml/kg, which foments severe air hunger, leading to prescription of hazardous (yet ineffective) sedatives, narcotics and paralytic agents. Inappropriate lowering of tidal volume also fosters double triggering, which promotes alveolar overdistention and lung injury. Successive panels have devoted considerable energy to developing a more precise definition of ARDS to homogenize the recruitment of patients into clinical trials. Each of three pillars of the prevailing Berlin definition is extremely flimsy and the source of confusion and unscientific practices. For doctors at the bedside, none of the revisions have enhanced patient care over that using the original 1967 description of Ashbaugh and colleagues. Bedside doctors are better advised to diagnose ARDS on the basis of pattern recognition and instead concentrate their vigilance on resolving the numerous hidden dangers that follow inevitably once a diagnosis has been made.
Parasite-host relationships of water mites (Acari: Hydrachnidia) and black flies (Diptera: Simuliidae) in southeastern Spain
Authors: López-Peña David , Gerecke Reinhard , García-Roger Eduardo Moisés , Martin Peter , Jiménez-Peydró Ricardo
Published: December 2022

Background

Documentation on water mites in Spain is scarce, as is information on the parasite-host relationship between certain water mite species and representatives of the dipteran family Simuliidae. The discomfort caused to humans and animals by black flies seems to be increasing in recent years. In this context, an investigation of parasitic water mites is of great importance, not only from the point of view of biodiversity, but also in terms of their potential to control black fly populations.

Methods

Rivers across a wide region of eastern Spain were sampled to determine the specific richness of simuliid dipterans and to investigate their possible parasites, such as water mites, mermithid nematodes and microsporidia (fungal microbes). Data on environmental variables, abundance, prevalence and intensity of parasitism on the collected specimens were analyzed.

Results

In 10 streams, 15,396 simuliid pupae were collected and checked for the presence of water mite larvae; 426 pupae in seven streams were found to be associated with water mite larvae. Of the 21 simuliid species identified based on morphological characters, eight were found to be associated with water mite larvae. Water mite infection was not equally distributed among black fly species. Also, the prevalence of parasitism was low and differed among simuliid species, ranging from one to 13 water mites per black fly pupa. Variation at the intra- and interspecific levels was detected in terms of the number of water mites inside the black fly cocoons. Free-living deutonymphal and adult water mites representing 15 different species of six genera and five families were morphologically identified. The taxonomic identity of the parasitic mite larvae is unclear at present. Morphologically, they fit descriptions of larval Sperchon (Hispidosperchon) algeriensis Lundblad, 1942, but the possibility cannot be excluded that they represent Sperchon algeriensis, the most abundant species at the adult stage in this study and unknown at the larval stage, or even another species of the genus. A molecular analysis produced for the first time cytochrome oxidase I gene sequences for S. algeriensis.

Conclusions

Our results contribute to current knowledge on Spanish Hydrachnidia and their relationships with simuliids as hosts. However, further research is needed to evaluate the diversity, distribution, bioecology and prevalence of this parasitism.

Graphical Abstract
The effect of the smartphone app DiaCert on health related quality of life in patients with type 2 diabetes: results from a randomized controlled trial
Authors: Hummel Madeleine , Bonn Stephanie Erika , Trolle Lagerros Ylva
Published: December 2022

Background

Type 2 diabetes mellitus is associated with an increased risk of impaired quality of life. Improving health related quality of life (HRQoL) is therefore an important goal in the multimodal management of diabetes. The aim of this study was to evaluate whether the use of the smartphone app DiaCert, that encourage physical activity by promoting daily steps, also impacts HRQoL in patients with type 2 diabetes.

Methods

In this randomized controlled trial, a total of 181 participants with type 2 diabetes were recruited from six health care centers in Stockholm, Sweden. At baseline, participants were randomized 1:1 to the use of the smartphone app DiaCert for a 3 month physical activity intervention in addition to routine care, or to a control group with routine care only. HRQoL was measured using the RAND-36 questionnaire at baseline and at follow-up after 3 months and 6 months. We analysed the HRQoL scores within the intervention and the control groups, respectively, using the Wilcoxon signed-rank test. Between group differences including intervention effect after the 3 month long intervention and after 6 months of follow-up, were assessed using generalized estimating equation models.

Results

In total, 166 participants, 108 men and 58 women, with complete baseline data on RAND-36 were included in analysis. The mean age was 60.2 (SD 11.4) years and the mean Body Mass Index 30.3 (SD 5.4) kg/m2. The intervention effect, expressed in terms of the difference in change in HRQoL from baseline to follow-up after 3 months of intervention, showed improvement in the health concept role limitations due to physical health problems (− 16.9; 95% CI − 28.5 to − 5.4), role limitations due to emotional problems (− 13.9; 95% CI − 25.8 to − 2.1), and emotional well-being (− 5.7; 95% CI − 10.4 to − 1.0), in the intervention group compared to the control group. No intervention effect was seen at follow-up after 6 months.

Conclusions

Being randomized to use the smartphone app DiaCert promoting physical activity for 3 months, improved aspects of both physical and emotional HRQoL in patients with type 2 diabetes compared to routine care, but the effect did not last 3 months after the intervention ended.

Trial Registration ClinicalTrials.gov Identifier: NCT03053336.
Comparing the accuracy of point-of-care with laboratory (capillary, venous, and arterial) blood glucose levels in critically ill patients with and without shock
Authors: Alshaer Abdulaziz , Badgheish Basma A. , Alsadah Zahra Hashim , Sewify Khalid , Alghazal Sarah , Alzahrani Sarah , Qadi Abeer , Alqahtani Reham , Farsani Ghadeer Abdullah , Shilash Amal
Published: December 2022

Objectives

To compare the accuracy of point-of-care capillary and venous/arterial samples to laboratory testing of venous/arterial samples in critically sick shocked and non-shocked patients. This is a prospective case–control study including capillary, venous, and arterial blood samples from 268 critically ill patients. The King Fahd Military Medical Complex in Dhahran, Saudi Arabia, was the site of this investigation.

Results

We were able to obtain data on 268 patients for this investigation. POCT and lab findings of venous and central blood did not differ significantly (P = 0.389 and 0.208), while POCT indicated somewhat higher results with venous glucose concentrations of 10.18 and 10.05 (POCT and lab tests respectively) and 9.18 and 9.54 (POCT and lab tests respectively). In addition, the mean differences between POC and laboratory analyses of venous, arterial, and central glucose were 0.13, − 1.75, and − 0.36 mmol/L for venous, arterial, and central glucose, respectively. Except for arterial blood glucose, we did not observe a significant difference between POCT and routine laboratory analysis of glucose concentrations in critically ill patients. Compared to laboratory blood analysis, the use of POCT is marginally accurate, with no difference between shocked and non-shocked patients.
The spectrum of tuberculosis described as differential DNA methylation patterns in alveolar macrophages and alveolar T cells
Authors: Pehrson Isabelle , Sayyab Shumaila , Das Jyotirmoy , Idh Nina , Paues Jakob , Méndez-Aranda Melissa , Ugarte-Gil César , Lerm Maria
Published: December 2022

Background

Host innate immune cells have been identified as key players in the early eradication of Mycobacterium tuberculosis and in the maintenance of an anti-mycobacterial immune memory, which we and others have shown are induced through epigenetic reprogramming. Studies on human tuberculosis immunity are dominated by those using peripheral blood as surrogate markers for immunity. We aimed to investigate DNA methylation patterns in immune cells of the lung compartment by obtaining induced sputum from M. tuberculosis- exposed subjects including symptom-free subjects testing positively and negatively for latent tuberculosis as well as patients diagnosed with active tuberculosis. Alveolar macrophages and alveolar T cells were isolated from the collected sputum and DNA methylome analyses performed (Illumina Infinium Human Methylation 450 k).

Results

Multidimensional scaling analysis revealed that DNA methylomes of cells from the tuberculosis-exposed subjects and controls appeared as separate clusters. The numerous genes that were differentially methylated between the groups were functionally connected and overlapped with previous findings of trained immunity and tuberculosis. In addition, analysis of the interferon-gamma release assay (IGRA) status of the subjects demonstrated that the IGRA status was reflected in the DNA methylome by a unique signature.

Conclusions

This pilot study suggests that M. tuberculosis induces epigenetic reprogramming in immune cells of the lung compartment, reflected as a specific DNA methylation pattern. The DNA methylation signature emerging from the comparison of IGRA-negative and IGRA-positive subjects revealed a spectrum of signature strength with the TB patients grouping together at one end of the spectrum, both in alveolar macrophages and T cells. DNA methylation-based biosignatures could be considered for further development towards a clinically useful tool for determining tuberculosis infection status and the level of tuberculosis exposure.
Overview of the meningeal lymphatic vessels in aging and central nervous system disorders
Authors: Jiang Huimin , Wei Huimin , Zhou Yifan , Xiao Xuechun , Zhou Chen , Ji Xunming
Published: December 2022

In the aging process and central nervous system (CNS) diseases, the functions of the meningeal lymphatic vessels (MLVs) are impaired. Alterations in MLVs have been observed in aging-related neurodegenerative diseases, brain tumors, and even cerebrovascular disease. These findings reveal a new perspective on aging and CNS disorders and provide a promising therapeutic target. Additionally, recent neuropathological studies have shown that MLVs exchange soluble components between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) and drain metabolites, cellular debris, misfolded proteins, and immune cells from the CSF into the deep cervical lymph nodes (dCLNs), directly connecting the brain with the peripheral circulation. Impairment and dysfunction of meningeal lymphatics can lead to the accumulation of toxic proteins in the brain, exacerbating the progression of neurological disorders. However, for many CNS diseases, the causal relationship between MLVs and neuropathological changes is not fully clear. Here, after a brief historical retrospection, we review recent discoveries about the hallmarks of MLVs and their roles in the aging and CNS diseases, as well as potential therapeutic targets for the treatment of neurologic diseases.
A systematic review on effective energy utilization management strategies in cloud data centers
Authors: Panwar Suraj Singh , Rauthan M. M. S. , Barthwal Varun
Published: December 2022

Data centers are becoming considerably more significant and energy-intensive due to the exponential growth of cloud computing. Cloud computing allows people to access computer resources on demand. It provides amenities on the pay-as-you-go basis across the data center locations spread over the world. Consequently, cloud data centers consume a lot of electricity and leave a proportional carbon impact on the environment. There is a need to investigate efficient energy-saving approaches to reduce the massive energy usage in cloud servers. This review paper focuses on identifying the research done in the field of energy consumption (EC) using different techniques of machine learning, heuristics, metaheuristics, and statistical methods. Host CPU utilization prediction, underload/overload detection, virtual machine selection, migration, and placement have been performed to manage the resources and achieve efficient energy utilization. In this review, energy savings achieved by different techniques are compared. Many researchers have tried various methods to reduce energy usage and service level agreement violations (SLAV) in cloud data centers. By using the heuristic approach, researchers have saved 5.4% to 90% of energy with their proposed methods compared with the existing methods. Similarly, the metaheuristic approaches reduce energy consumption from 7.68% to 97%, the machine learning methods from 1.6% to 88.5%, and the statistical methods from 5.4% to 84% when compared to the benchmark approaches for a variety of settings and parameters. So, making energy use more efficient could cut down the air pollution, greenhouse gas (GHG) emissions, and even the amount of water needed to make power. The overall outcome of this review work is to understand different methods used by researchers to save energy in cloud data centers.
Changes in quality-adjusted life expectancy in Belgium, 2013 and 2018
Authors: Scohy Aline , Charafeddine Rana , Van Wilder Lisa , Van Oyen Herman , De Smedt Delphine , Devleesschauwer Brecht
Published: December 2022

Introduction

No information is available in Belgium on life expectancy adjusted for health-related quality of life (HRQoL). Quality-adjusted life expectancy (QALE) captures the multidimensionality of health by accounting for losses in mortality and HRQoL linked to physical, mental, and social impairments. The objective of this study is to estimate for Belgium QALE, the changes in QALE between 2013 and 2018 and the contribution of mortality, HRQoL and its dimensions to this trend.

Methods

The Belgian Health Interview Survey (BHIS), a representative sample of the general population, included the EQ-5D-5L instrument in 2013 and 2018. The tool assesses HRQoL comprising five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) using a 5-level severity scoring to define a large variety of health states. The Sullivan method was used to compute at different ages QALE by gender using mortality data from the Belgian statistical office and average EQ-5D scores from the BHIS. QALE was calculated for 2013 and 2018, and changes in QALE over time were decomposed into mortality and ill-health effect.

Results

In 2018, QALE at age 15 years (QALE15) was 56.3 years for women and 55.8 years for men, a decrease from 2013 by 0.7 year for women and a stagnation for men. In men, the decrease in mortality counterbalanced the decline in HRQoL. The decline in QALE in women is driven by a decrease in mortality rates that is too small to compensate for the substantial decline in HRQoL before the age of 50 years. In women at older ages, improvements in HRQoL are observed. In women, QALE15 is decreasing due to an increase in pain/discomfort, anxiety/depression and problems in usual activities. In men at age 15, the pain/discomfort and anxiety/depression domains contributed to the stagnation. QALE65 increased somewhat, due to an improvement in self-care and mobility for both genders, and usual activities and anxiety/depression in men only.

Conclusion

The strength of QALE as member of the family of composite indicators, the health expectancies, is the multidimensional structure of the underlying health component, including both ill-health with different health domains as levels of severity. The ability to decompose differences in the health expectancy not only into a mortality and health component but also into the different health dimensions allows to better inform on general population health trends. Next, compared to other health expectancy indicators, QALE is more sensitive to changes at younger ages.
Degradation of low density polyethylene by Bacillus species
Authors: Yao Zhuang , Seong Hyeon Jeong , Jang Yu-Sin
Published: December 2022

Since its invention, polyethylene (PE) has brought many conveniences to human production and life. In recent years, however, environmental pollution and threats to human health caused by insufficient PE recycling have attracted widespread attention. Biodegradation is a potential solution for preventing PE pollution. In this study, Bacillus subtilis and Bacillus licheniformis, which are widespread in the environment, were examined for their PE degradation abilities. Biodegradation of low-density polyethylene (LDPE) was assessed by weight loss, Fourier transform infrared spectroscopy (FTIR), and high performance liquid chromatography (HPLC) analyses. Weight losses of 3.49% and 2.83% were observed for samples exposed to strains B. subtilis ATCC6051 and B. licheniformis ATCC14580 for 30 days. Optical microscopy revealed obvious structural changes, such as cracks, pits, and roughness, on the surfaces of the microorganism-exposed LDPE sheets. Oxidation of the LDPE sheet surfaces was also demonstrated by the FTIR-based observation of carbon-unsaturated, –OH, –NO, –C=C, and –C–O bonds. These results support the notion that B. subtilis ATCC6051 and B. licheniformis ATCC14580 can degrade PE and could potentially be used as PE-biodegrading microorganisms. Further research is needed to examine potential relevant degradation mechanisms, such as those involving key enzymes.
Association of tumor immune microenvironment profiling and 21-gene recurrence assay in early breast cancer patients
Authors: Tong Yiwei , Huang Jiahui , Ren Weili , Yu Jing , Zhang Xu , Wang Zheng , Hong Jin , Gao Weiqi , Wu Jiayi , Ji Min , Shen Kunwei , Chen Xiaosong
Published: December 2022

Introduction

Tumor immune microenvironment (TIME) plays a vital role in breast cancer development, treatment resistance, and prognosis. This study evaluates the association of TIME profiling and 21-gene recurrence score (RS) in early Luminal breast cancer patients.

Methods

ER+ /HER2-, pN0 breast cancer patients with available RS results who received surgery between January 2009 and December 2013 were enrolled. TIME markers, including stromal tumor infiltrating lymphocytes (TILs), CD3, CD4, CD8, and tumor PD-L1 expression, were comprehensively analyzed. Association of TIME markers with RS, as well as their correlation with breast cancer-specific survival (BCSS) were tested.

Results

Overall, 385 patients were included, of whom 341 (88.6%) had TILs ≤10%. TIME markers were positively but moderately correlated with each other (Spearman r 0.28–0.53, all P < 0.05). Continuous RS showed a weak correlation with continuous TILs, CD3, CD8, and PD-L1. Regarding single gene mRNA level in the 21-gene RS panel, higher expression of TIME markers was related to lower ER group genes expression, but higher proliferation and invasion group genes level. After a median follow-up of 91.67 (range 5.03–134.03) months, TILs (P = 0.049) and PD-L1 (P = 0.034) were inversely associated with BCSS.

Conclusions

Breast cancer TIME markers, including TILs, CD3, CD4, CD8, and PD-L1, were correlated with 21-gene RS score. Lower expression of ER group genes, as well as higher expression of proliferation and invasion group genes were associated with a higher level of these TIME markers, warranting further exploration.
Early predicting 30-day mortality in sepsis in MIMIC-III by an artificial neural networks model
Authors: Su Yingjie , Guo Cuirong , Zhou Shifang , Li Changluo , Ding Ning
Published: December 2022

Objective

Early identifying sepsis patients who had higher risk of poor prognosis was extremely important. The aim of this study was to develop an artificial neural networks (ANN) model for early predicting clinical outcomes in sepsis.

Methods

This study was a retrospective design. Sepsis patients from the Medical Information Mart for Intensive Care-III (MIMIC-III) database were enrolled. A predictive model for predicting 30-day morality in sepsis was performed based on the ANN approach.

Results

A total of 2874 patients with sepsis were included and 30-day mortality was 29.8%. The study population was categorized into the training set (n = 1698) and validation set (n = 1176) based on the ratio of 6:4. 11 variables which showed significant differences between survivor group and nonsurvivor group in training set were selected for constructing the ANN model. In training set, the predictive performance based on the area under the receiver-operating characteristic curve (AUC) were 0.873 for ANN model, 0.720 for logistic regression, 0.629 for APACHEII score and 0.619 for SOFA score. In validation set, the AUCs of ANN, logistic regression, APAHCEII score, and SOFA score were 0.811, 0.752, 0.607, and 0.628, respectively.

Conclusion

An ANN model for predicting 30-day mortality in sepsis was performed. Our predictive model can be beneficial for early detection of patients with higher risk of poor prognosis.