bluuebunny/crossref_metadata_2025 huggingface dataset:
Left anti-politics or left populism? Political distinctions at the end of the end of history
Authors: Kiersey Nicholas
Published: October 2022

This review essay argues that once a fuller genealogy of populism is presented, Hochuli et al.’s rationale for attempting to corral the left into an embrace of nationalism begins to look suspicious. Despite the authors’ claims, the genealogy of American left populism reveals a political project that is not at all aligned with the virtue-hoarding desires of the left flank of the Professional Managerial Class (PMC). To the contrary, it is a political project synonymous with the material struggles of the global working class. Thus, while we should concede that the contemporary Left has been captured to no small degree by PMC sensibilities, a full understanding of today’s ongoing revival in socialism requires further explanation. To this end, this essay argues that we need a proper discussion about the history of left populism in the United States, its meaningful achievements, and its potential as a strategic partner. Admittedly, the term “populism” has very different valences, depending on whether it is used in an American or European context. But it cannot be gainsaid that the term originated in America, and that American populism has hewed more toward working class struggle over the sort of “woke” ideologies, worried about in The End of the End of History.
General anesthesia versus conscious sedation during endovascular treatment in posterior circulation large vessel occlusion: A systematic review and meta-analysis
Authors: Terceño Mikel , Bashir Saima , Cienfuegos Juan , Murillo Alan , Vera-Monge Víctor Augusto , Pardo Laura , Reina Montserrat , Gubern-Mérida Carme , Puigoriol-Illamola Dolors , Carballo Laia , Costa Anna , Buxó Maria , Serena Joaquín , Silva Yolanda
Published: October 2022

Purpose:

The optimal anesthetic approach in the endovascular treatment (EVT) of patients with posterior circulation large vessel occlusion (PC-LVO) strokes is not clear. Little data has been published and no randomized clinical trials have been conducted so far. We aimed to perform an updated meta-analysis to compare clinical and procedural outcomes between conscious sedation (CS) and general anesthesia (GA).

Methods:

We reviewed the literature of the studies reporting CS and GA in patients with endovascularly-treated PC-LVO. The primary outcome was the functional outcome at 3 months measured using the modified Rankin Scale (mRS). A good functional outcome was defined as having a mRS 0–2. Secondary outcomes were mortality at 3 months, final successful recanalization (modified Thrombolysis in Cerebral Infarction (mTICI) scale from 2b to 3) and complete recanalization (mTICI of 3) and times from stroke onset to EVT completion. Random-effects models were completed to pool the outcomes and the I2 value was calculated to assess heterogeneity.

Findings:

Eight studies with a total of 1351 patients were included. The pooled results reveal that CS use was associated with higher rates of good outcome (OR 2.41, 95% CI 1.58–3.64, I2 = 49.67%) and with lower mortality at 3 months (OR 0.48, 95% CI 0.28–0.82, I2 =57.11%). No significant differences were observed in the final reperfusion rates, procedural duration, and time from stroke onset to EVT completion.

Conclusion:

In this meta-analysis, GA was associated with significantly lower rates of functional independence at 3 months in patients with PC-LVO strokes.
Different dosing regimens of Tenecteplase in acute ischemic stroke: A network meta-analysis of the clinical evidence
Authors: The Ei Zune , Lin Ne Naing , Matar Mazen , Teoh Hock Luen , Yeo Leonard Leong Litt
Published: October 2022

Introduction:

Acute ischemic stroke remains the major cause of death and disability and conclusive evidence of Tenecteplase in treating stroke is lacking.

Objective:

To conduct a meta-analysis to determine whether Tenecteplase produces better outcomes than Alteplase and a network meta-analysis comparing the different dosing regimens of Tenecteplase.

Methods:

Searches were made in MEDLINE, CENTRAL, and ClinicalTrials.gov. The outcome measures are recanalization, early neurological improvement, functional outcomes at 90 days (modified Rankin Scale 0–1 and 0–2), intracranial hemorrhage, symptomatic intracranial hemorrhage, and mortality within 90 days from treatment.

Results:

Fourteen studies are included in the meta-analyses and 18 studies in the network meta-analyses. In the meta-analysis, Tenecteplase 0.25 mg/kg has significant results in early neurological improvement (OR = 2.35, and 95% CI = 1.16–4.72) and excellent functional outcome (OR = 1.20, and 95% CI = 1.02–1.42). In the network meta-analysis, Tenecteplase 0.25 mg/kg produces significant results in early neurological improvement (OR = 1.52 [95% CI = 1.13–2.05], p-value = 0.01), functional outcomes (mRS 0–1 and 0–2) (OR = 1.19 [95% CI = 1.03–1.37], p-value = 0.02; OR = 1.21 [95% CI = 1.05–1.39], p-value = 0.01; respectively) and mortality (OR = 0.78 [95% CI = 0.64–0.96], p-value = 0.02) whereas Tenecteplase 0.40 mg/kg increases the chances of symptomatic intracranial hemorrhage (OR = 2.35 [95% CI = 1.19–4.64], p-value = 0.01).

Conclusion:

While not conclusive, our study lends evidence to 0.25 mg/kg Tenecteplase dose for ischemic stroke treatment. Further randomized trials need to be done to validate this finding.

Registration:

International prospective register of systematic reviews (PROSPERO) – CRD42022339774 URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=339774
Aberrant function of pathogenic STAT3 mutant proteins is linked to altered stability of monomers and homodimers
Authors: Kasembeli Moses M. , Kaparos Efiyenia , Bharadwaj Uddalak , Allaw Ahmad , Khouri Alain , Acot Bianca , Tweardy David J.
Published: October 2022

STAT3 mutations, predominantly in the DNA-binding domain (DBD) and Src-homology 2 domain (SH2D), cause rare cases of immunodeficiency, malignancy, and autoimmunity. The exact mechanisms by which these mutations abrogate or enhance STAT3 function are not completely understood. Here, we examined how loss-of-function (LOF) and gain-of-function (GOF) STAT3 mutations within the DBD and SH2D affect monomer and homodimer protein stability as well as their effect on key STAT3 activation events, including recruitment to phosphotyrosine (pY) sites within peptide hormone receptors, tyrosine phosphorylation at Y705, dimerization, nuclear translocation, and DNA binding. The DBD LOF mutants showed reduced DNA binding when homodimerized, whereas the DBD GOF mutants showed increased DNA binding. DBD LOF and GOF mutants showed minimal changes in other STAT3 functions or in monomer or homodimer protein stability. However, SH2D LOF mutants demonstrated reduced conformational stability as either monomers or homodimers, leading to decreased pY-peptide recruitment, tyrosine phosphorylation, dimerization, nuclear localization, and DNA binding. In contrast, cancer-causing SH2D GOF mutants showed increased STAT3 homodimer stability, which increased their DNA binding. Of note, a small-molecule inhibitor of STAT3 that targets the tyrosine phosphopeptide–binding pocket within the STAT3 SH2D potently inhibited cell proliferation driven by STAT3 SH2D GOF mutants. These findings indicate that the stability of STAT3 protein monomer and homodimer is critical for the pathogenesis of diseases caused by SH2D LOF and GOF mutations and suggest that agents that modulate STAT3 monomer and/or homodimer protein stability may have therapeutic value in diseases caused by these mutations.
Integrated flow cytometry and sequencing to reconstruct evolutionary patterns from dysplasia to acute myeloid leukemia
Authors: Simoes Catia , Chillon Maria-Carmen , Martínez-Cuadrón David , Calasanz Maria-José , Vridiales María-Belén , Vazquez Iria , Hernández-Ruano Montserrat , Ariceta Beñat , Aguirre-Ruiz Paula , Burgos Leire , Alignani Diego , Sarvide Sarai , Villar Sara , Pierola Ana Alfonso , Prosper Felipe , Ayala Rosa , Martínez-López Joaquin , Bergua Burgues Juan Miguel , Vives Susana , Perez-Simon Jose A. , Garcia-Fortes Maria , Bernal del Castillo Teresa , Colorado Mercedes , Olave Mayte , Rodríguez-Gutiérrez Juan I. , Labrador Jorge , González Marcos , San-Miguel Jesús F. , Sanz Miguel Ángel , Montesinos Pau , Paiva Bruno
Published: October 2022

Clonal evolution in acute myeloid leukemia (AML) originates long before diagnosis and is a dynamic process that may affect survival. However, it remains uninvestigated during routine diagnostic workups. We hypothesized that the mutational status of bone marrow dysplastic cells and leukemic blasts, analyzed at the onset of AML using integrated multidimensional flow cytometry (MFC) immunophenotyping and fluorescence-activated cell sorting (FACS) with next-generation sequencing (NGS), could reconstruct leukemogenesis. Dysplastic cells were detected by MFC in 285 of 348 (82%) newly diagnosed patients with AML. Presence of dysplasia according to MFC and World Health Organization criteria had no prognostic value in older adults. NGS of dysplastic cells and blasts isolated at diagnosis identified 3 evolutionary patterns: stable (n = 12 of 21), branching (n = 4 of 21), and clonal evolution (n = 5 of 21). In patients achieving complete response (CR), integrated MFC and FACS with NGS showed persistent measurable residual disease (MRD) in phenotypically normal cell types, as well as the acquisition of genetic traits associated with treatment resistance. Furthermore, whole-exome sequencing of dysplastic and leukemic cells at diagnosis and of MRD uncovered different clonal involvement in dysplastic myelo-erythropoiesis, leukemic transformation, and chemoresistance. Altogether, we showed that it is possible to reconstruct leukemogenesis in ∼80% of patients with newly diagnosed AML, using techniques other than single-cell multiomics.
A novel candidate disease gene prioritization method using deep graph convolutional networks and semi-supervised learning
Authors: Azadifar Saeid , Ahmadi Ali
Published: October 2022

Background

Selecting and prioritizing candidate disease genes is necessary before conducting laboratory studies as identifying disease genes from a large number of candidate genes using laboratory methods, is a very costly and time-consuming task. There are many machine learning-based gene prioritization methods. These methods differ in various aspects including the feature vectors of genes, the used datasets with different structures, and the learning model. Creating a suitable feature vector for genes and an appropriate learning model on a variety of data with different and non-Euclidean structures, including graphs, as well as the lack of negative data are very important challenges of these methods. The use of graph neural networks has recently emerged in machine learning and other related fields, and they have demonstrated superior performance for a broad range of problems.

Methods

In this study, a new semi-supervised learning method based on graph convolutional networks is presented using the novel constructing feature vector for each gene. In the proposed method, first, we construct three feature vectors for each gene using terms from the Gene Ontology (GO) database. Then, we train a graph convolution network on these vectors using protein–protein interaction (PPI) network data to identify disease candidate genes. Our model discovers hidden layer representations encoding in both local graph structure as well as features of nodes. This method is characterized by the simultaneous consideration of topological information of the biological network (e.g., PPI) and other sources of evidence. Finally, a validation has been done to demonstrate the efficiency of our method.

Results

Several experiments are performed on 16 diseases to evaluate the proposed method's performance. The experiments demonstrate that our proposed method achieves the best results, in terms of precision, the area under the ROC curve (AUCs), and F1-score values, when compared with eight state-of-the-art network and machine learning-based disease gene prioritization methods.

Conclusion

This study shows that the proposed semi-supervised learning method appropriately classifies and ranks candidate disease genes using a graph convolutional network and an innovative method to create three feature vectors for genes based on the molecular function, cellular component, and biological process terms from GO data.
Insights on the performance of phenotypic tests versus genotypic tests for the detection of carbapenemase-producing Gram-negative bacilli in resource-limited settings
Authors: Kamel Noha A. , Tohamy Sally T. , Yahia Ibrahim S. , Aboshanab Khaled M.
Published: October 2022

Background:

Carbapenemase-producing Gram-negative (CPGN) bacteria impose life-threatening infections with limited treatment options. Rigor and rapid detection of CPGN-associated infections is usually associated with proper treatment and better disease prognosis. Accordingly, this study aimed at evaluating the phenotypic methods versus genotypic methods used for the detection of such pathogens and determining their sensitivity/specificity values.

Methods:

A total of 71 CPGN bacilli (30 Enterobacterales and 41 non-glucose-fermenting bacilli) were tested for the carbapenemase production by the major phenotypic approaches including, the modified Hodge test (MHT), modified carbapenem inactivation method (mCIM), combined disk test by EDTA (CDT) and blue-carba test (BCT). The obtained results were statistically analyzed and correlated to the obtained resistant genotypes that were determined by using polymerase chain reactions (PCR) for the detection of the major carbapenemase-encoding genes covering the three classes (Class A, B, and D) of carbapenemases.

Results:

In comparison to PCR, the overall sensitivity/specificity values for detection of carbapenemase-producing organism were 65.62%/100% for MHT, 68.65%/100% for mCIM, 55.22%/100% for CDT and 89.55%/75% for BCT. The sensitivity/specificity values for carbapenemase-producing Enterobacterales were, 74%100% for MHT, 51.72%/ 100% for mCIM, 62.07%/100% for CDT and 82.75%/100% for BCT. The sensitivity/specificity values for carbapenemase-producing non-glucose fermenting bacilli were, 62.16%/100% for MHT, 81.57%/100% for mCIM, 50/100% for CDT and 94.74%/66.66% for BCT. Considering these findings, BCT possess a relatively high performance for the efficient and rapid detection of carbapenemase producing isolates. Statistical analysis showed significant association (p < 0.05) between blaNDM and/or blaVIM genotypes with MHT/CDT; blaKPC/blaGIM genotypes with CDT and blaGIM genotype with BCT.

Conclusion:

The current study provides an update on the performance of the phenotypic tests which are varied depending on the tested bacterial genera and the type of the carbapenemase. The overall sensitivity/specificity values for detection of CPO were 65.62%/100% for MHT, 68.65%/100% for mCIM, 55.22%/100% for CDT and 89.55%/75% for BCT. Based on its respective diagnostic efficiency and rapid turnaround time, BCT is more likely to be recommended in a resource-limited settings particularly, when molecular tests are not available.
Cellular messengers involved in the inhibition of the Arabidopsis primary root growth by bacterial quorum-sensing signal N-decanoyl-L-homoserine lactone
Authors: Cao Xiang-yu , Zhao Qian , Sun Ya-na , Yu Ming-Xiang , Liu Fang , Zhang Zhe , Jia Zhen-hua , Song Shui-shan
Published: October 2022

Background

N-acyl-homoserine lactones (AHLs) are used as quorum-sensing signals by Gram-negative bacteria, but they can also affect plant growth and disease resistance. N-decanoyl-L-homoserine lactone (C10-HSL) is an AHL that has been shown to inhibit primary root growth in Arabidopsis, but the mechanisms underlying its effects on root architecture are unclear. Here, we investigated the signaling components involved in C10-HSL-mediated inhibition of primary root growth in Arabidopsis, and their interplay, using pharmacological, physiological, and genetic approaches.

Results

Treatment with C10-HSL triggered a transient and immediate increase in the concentrations of cytosolic free Ca2+ and reactive oxygen species (ROS), increased the activity of mitogen-activated protein kinase 6 (MPK6), and induced nitric oxide (NO) production in Arabidopsis roots. Inhibitors of Ca2+ channels significantly alleviated the inhibitory effect of C10-HSL on primary root growth and reduced the amounts of ROS and NO generated in response to C10-HSL. Inhibition or scavenging of ROS and NO neutralized the inhibitory effect of C10-HSL on primary root growth. In terms of primary root growth, the respiratory burst oxidase homolog mutants and a NO synthase mutant were less sensitive to C10-HSL than wild type. Activation of MPKs, especially MPK6, was required for C10-HSL to inhibit primary root growth. The mpk6 mutant showed reduced sensitivity of primary root growth to C10-HSL, suggesting that MPK6 plays a key role in the inhibition of primary root growth by C10-HSL.

Conclusion

Our results indicate that MPK6 acts downstream of ROS and upstream of NO in the response to C10-HSL. Our data also suggest that Ca2+, ROS, MPK6, and NO are all involved in the response to C10-HSL, and may participate in the cascade leading to C10-HSL-inhibited primary root growth in Arabidopsis.
Evaluation of penehyclidine for prevention of post operative nausea and vomitting in patients undergoing total thyroidectomy under total intravenous anaesthesia with propofol-remifentanil
Authors: Lu Ting , Li Rongrong , Sun Jiacheng , Chen Jing
Published: October 2022

Backgroud

Postoperative nausea and vomiting (PONV) is one of the most common complications after total thyroidectomy under general anesthesia. Total intravenous anesthesia (TIVA) has been documented to prevent PONV in patients undergoing total thyroidectomy. Penehyclidine, an anticholinergic agent with an elimination half-life of over 10 h, is widely used as premedication to reduce glandular secretion. This study aimed to explore the preventative effects of penehyclidine with propofol-remifentanil-TIVA to single-TIVA on PONV in patients undergoing total thyroidectomy.

Methods

A total of 100 patients scheduled for total thyroidectomy were randomly assigned to either the penehyclidine group (n = 50) or TIVA group (n = 50). Propofol and remifentanil were was used for TIVA in all patients. No patients who received premedication. Patients were administrated with either 5 ml of normal saline or 0.5 mg of penehyclidine soon after anesthesia induction. The incidence of nausea and vomiting, the severity of nausea, the requirement of rescue antiemetics, and adverse effects were investigated during the first 24 h in two time periods (0–2 h and 2–24 h).

Results

The overall PONV incidence during the 24 h after surgery was significantly lower in the penehyclidine group compared with the TIVA group (12% vs 36%, P < 0.005). Besides, the incidence of nausea and the incidence of vomiting were significantly lower in the penehyclidine group compared with the TIVA group at 2–24 h after surgery. However, there was no significant difference between the two groups at 0–2 h after surgery.

Conclusions

Administration of penehyclidine under TIVA with propofol-remifentanil is more effective for prevention of PONV than TIVA alone, especially 2–24 h after total thyroidectomy.

Trial registration

https://www.chictr.org.cn/edit.aspx?pid=132463&htm=4 (Ref: ChiCTR2100050278, the full date of first registration: 25/08/2021).
Potential living kidney donors’ positive experiences of an information letter from healthcare: a descriptive qualitative study
Authors: Lagging Eva , Larsson Kjerstin , Wadström Jonas , Krekula Linda Gyllström , Tibell Annika
Published: October 2022

Background

Patients who need a live donor kidney transplant (LDKT) must often ask potential donors (PLDs) themselves. This is a difficult task and healthcare could unburden them by making this first contact, ensuring also that PLDs receive correct information. We investigated how PLDs experience receiving a letter from healthcare about LDKT, live kidney donation, and inviting them to meet with professionals to get more information.

Methods

The letter (LD-letter) was sent to a cohort of 46 individuals, from which a purposeful sample of 15 were interviewed using a semi-structured guide covering their experience of the letter, views on being approached by healthcare, and opinions on style and content. Interviews were analyzed using conventional inductive analysis.

Results

We identified three categories of experiences: Category (1) Reflections on receiving the letter, contains three subcategories relating to how the letter did not induce pressure to donate, did not affect the PLD’s relationship with the patient with kidney disease, and made the letter-receiver feel important in the transplant process; Category (2) The letter creates clarification and trust, also contains three subcategories, relating to how it clarified the voluntariness of donation and neutrality of healthcare providers with respect to the PLD’s decision, elucidated the patient with kidney disease’s current stage of disease (where transplantation was approaching), and unburdened patients from the responsibility of contacting PLDs on their own; Category (3) Opinions and suggestions about the letter and further communication, with four subcategories, relating to preference of a letter as the first step for communication about LDKT, suggestions on style and content, views on following up the letter, and how open meetings about LDKT were an important information source. Furthermore, 80% of the interviewees found the letter’s information comprehensive, 67% found it easy to read and respectful, and 86% rated it as good or very good.

Conclusion

Potential donors prefer and recommend a letter as the first step for communication regarding LD. The LD-letter unburdens patients from the task of asking PLDs and stresses the voluntariness of donation, does not leave PLDs feeling coerced or lead to negative effects in their relationship with the patient.
Culturally adapted flowcharts in obstetric emergencies: a participatory action research study
Authors: Bautista-Valarezo Estefanía , Espinosa María Elena , Michels Nele R. M. , Hendrickx Kristin , Verhoeven Veronique
Published: October 2022

Introduction

Maternal mortality is a health problem in developing countries and is the result of several factors such as sociodemographic and economic inequalities and difficulties in accessing the health services. In addition, training strategies in obstetric emergencies targeting the non-medical personnel such as traditional midwives are scarce. The focus of this study is to develop learning and communication bridges on the management of obstetric emergencies and on policies of patients’ referral to the biomedical health system in rural areas.

Methodology

A Participant Action Research (PAR) study with a mixed methods approach was set up to elaborate culturally adapted flowcharts. The project lasted approximately 3,5 years, from September 2016 to January 2021.

Results

The study was conducted with 94 traditional midwives from southern Ecuador and is divided into 4 phases, namely: 1) Exploration: focus groups and interviews were conducted to document the management of obstetric emergencies through the presentation of “clinical case” scenarios in three important topics, namely: pre-eclampsia, shoulder dystocia and postpartum hemorrhage, 2) Planning: a number of reflective sessions were conducted between the researchers and the healers/midwives to elaborate flowcharts. 3) Action: the training was conducted in rooms dedicated to proficiency in the aforementioned topics and using the flowcharts, 4) Evaluation: 90% of the participants reported having used the flowcharts during the first year after the training. The most frequently used flowchart was that of pre-eclampsia for the recognition of warning signs during pregnancy control.

Conclusion

This study documents common practices of pregnancy and delivery management by traditional midwives. Furthermore, cultural flowcharts were developed for and together with midwives to improve the clinical response to obstetric emergencies. The preliminary evaluation was favorable; the most frequently used flowchart concerned preeclampsia. In this process, establishing a partnership was crucial for successful intercultural collaboration.
Stigma in the health clinic and implications for PrEP access and use by adolescent girls and young women: conflicting perspectives in South Africa
Authors: Nyblade Laura , Ndirangu Jacqueline W. , Speizer Ilene S. , Browne Felicia A. , Bonner Courtney Peasant , Minnis Alexandra , Kline Tracy L. , Ahmed Khatija , Howard Brittni N. , Cox Erin N. , Rinderle Abigail , Wechsberg Wendee M.
Published: October 2022

Background

Globally, an urgent need exists to expand access to HIV prevention among adolescent girls and young women (AGYW), but the need is particularly acute in sub-Saharan Africa. Oral pre-exposure prophylaxis (PrEP) offers an effective HIV prevention method. In many countries, however, accessing PrEP necessitates that AGYW visit their local health clinic, where they may face access challenges. Some countries have implemented youth-friendly services to reduce certain challenges in local health clinics, but barriers to access persist, including clinic stigma. However, evidence of clinic stigma toward AGYW, particularly with respect to PrEP service delivery, is still limited. This mixed methods study explores stigma toward AGYW seeking clinic services, in particular PrEP, from the perspective of both clinic staff (clinical and nonclinical) and AGYW who seek services at clinic sites in Tshwane province, South Africa.

Methods

Six focus group discussions were conducted with AGYW (43 total participants) and four with clinic staff (42 total participants) and triangulated with survey data with AGYW (n = 449) and clinic staff (n = 130). Thematic analysis was applied to the qualitative data and descriptive statistics were conducted with the survey data.

Results

Four common themes emerged across the qualitative and quantitative data and with both AGYW and clinic staff, although with varying degrees of resonance between these two groups. These themes included (1) clinic manifestations of stigma toward AGYW, (2) concerns about providing PrEP services for AGYW, (3) healthcare providers’ identity as mothers, and (4) privacy and breaches of confidentiality. An additional theme identified mainly in the AGYW data pertained to stigma and access to healthcare.

Conclusion

Evidence is needed to inform strategies for addressing clinic stigma toward AGYW, with the goal of removing barriers to PrEP services for this group. While awareness has increased and progress has been achieved around the provision of comprehensive, youth-friendly sexual and reproductive health services, these programs need to be adapted for the specific concerns of young people seeking PrEP services. Our findings point to the four key areas noted above where programs seeking to address stigma toward AGYW in clinics can tailor their programming.
Multimorbidity and its socio-economic associations in community-dwelling older adults in rural Tanzania; a cross-sectional study
Authors: Lewis Emma Grace , Gray William K. , Walker Richard , Urasa Sarah , Witham Miles , Dotchin Catherine
Published: October 2022

Objectives

This paper aims to describe the prevalence and socio-economic associations with multimorbidity, by both self-report and clinical assessment/screening methods in community-dwelling older people living in rural Tanzania.

Methods

A randomised frailty-weighted sample of non-institutionalised adults aged ≥ 60 years underwent comprehensive geriatric assessment and in-depth assessment. The comprehensive geriatric assessment consisted of a history and focused clinical examination. The in-depth assessment included standardised questionnaires, screening tools and blood pressure measurement. The prevalence of multimorbidity was calculated for self-report and non-self-reported methods (clinician diagnosis, screening tools and direct measurement). Multimorbidity was defined as having two or more conditions. The socio-demographic associations with multimorbidity were investigated by multiple logistic regression.

Results

A sample of 235 adults participated in the study, selected from a screened sample of 1207. The median age was 74 years (range 60 to 110 inter-quartile range (IQR) 19) and 136 (57.8%) were women. Adjusting for frailty-weighting, the prevalence of self-reported multimorbidity was 26.1% (95% CI 16.7–35.4), and by clinical assessment/screening was 67.3% (95% CI 57.0–77.5). Adjusting for age, sex, education and frailty status, multimorbidity by self-report increased the odds of being financially dependent on others threefold (OR 3.3 [95% CI 1.4–7.8]), and of a household member reducing their paid employment nearly fourfold (OR 3.8. [95% CI 1.5–9.2]).

Conclusions

Multimorbidity is prevalent in this rural lower-income African setting and is associated with evidence of household financial strain. Multimorbidity prevalence is higher when not reliant on self-reported methods, revealing that many conditions are underdiagnosed and undertreated.
Bi-directional and multivariate mendelian randomization analysis of the relationship between circulating 25-hydroxyvitamin D concentration and obstructive sleep apnea
Authors: Luo Xi , Chang Ruijing , Zhang Jianli , Jiang Peng , Xu Sicheng
Published: October 2022

Background

25-hydroxyvitamin D [25(OH)D] deficiency in patients with Obstructive Sleep Apnea (OSA) has long been noted, but identifying the exact causal relationship remains hard. Investigation of the causality between 25(OH)D deficiency and OSA would help facilitate disease prevention.

Methods

We conducted a two-sample bi-directional Mendelian randomization (MR) study. For forward analysis, 237 newly identified genetic variants are used as proxies for 25(OH)D to estimate the unconfounded effect on OSA among 16,761 OSA cases and 201,194 controls of European ancestry. Reverse analysis was performed to detect the causal impact of OSA on 25(OH)D levels. The inverse variance weighted (IVW) method was used as the primary analysis. Sensitivity analysis was performed to evaluate the robustness of our results. Multivariate MR analysis was conducted to evaluate the direct link between 25(OH)D and OSA after accounting for body mass index (BMI).

Results

IVW indicated that OSA causally associated with a lower level of 25(OH)D ((β = -0.03, 95% CI = -0.06 ~ -0.007,P = 0.01). No evidence of the causal link from 25(OH)D to OSA was detected (OR = 0.99, 95% CI = 0.88 ~ 1.12,P = 0.85). Sensitivity analysis suggested the MR estimates were not biased. Multivariate MR analysis indicated the effect of OSA on 25(OH)D vanished upon accounting for BMI (β = -0.011, 95% CI = -0.028 ~ 0.007,P = 0.23).

Conclusion

This MR study provided evidence that OSA was causally associated with a lower level of 25(OH)D, which might be driven by BMI. Obesity management should be enhanced in patients with OSA to prevent 25(OH)D deficiency.
Antimicrobial therapy of community-acquired pneumonia during stewardship efforts and a coronavirus pandemic: an observational study
Authors: Waagsbø Bjørn , Tranung Morten , Damås Jan Kristian , Heggelund Lars
Published: October 2022

Background

Community-acquired pneumonia (CAP) is the most frequent infection diagnosis in hospitals. Antimicrobial therapy for CAP is depicted in clinical practice guidelines, but adherence data and effect of antibiotic stewardship measures are lacking.

Methods

A dedicated antibiotic team pointed out CAP as a potential target for antimicrobial stewardship (AMS) measures at a 1.000-bed, tertiary care, teaching university hospital in Norway from March until May for the years 2016 throughout 2021. The aim of the AMS program was to increase diagnostic and antimicrobial therapy adherence to national clinical practice guideline recommendations through multiple and continuous AMS efforts. Descriptive statistics were retrospectively used to delineate antimicrobial therapy for CAP. The primary outcomes were proportions that received narrow-spectrum beta-lactams, and broad-spectrum antimicrobial therapy.

Results

1.112 CAP episodes were identified. The annual proportion that received narrow-spectrum beta-lactams increased from 56.1 to 74.4% (p = 0.045). Correspondingly, the annual proportion that received broad-spectrum antimicrobial therapy decreased from 34.1 to 17.1% (p = 0.002). Trends were affected by the coronavirus pandemic. Mortality and 30-day readmission rates remained unchanged. De-escalation strategies were frequently unutilized, and overall therapy duration exceeded clinical practice guideline recommendations substantially. Microbiologically confirmed CAP episodes increased from 33.7 to 56.2% during the study period.

Conclusion

CAP is a suitable model condition that is sensitive to AMS measures. A continuous focus on improved microbiological diagnostics and antimicrobial therapy initiation is efficient in increasing adherence to guideline recommendations. There is an unmet need for better antimicrobial de-escalation strategies.
Trajectories of Health-related quality of life in patients with Advanced Cancer during the Last Year of Life: findings from the COMPASS study
Authors: Lee Jonathan , Shafiq Mahham , Malhotra Rahul , Ozdemir Semra , Teo Irene , Malhotra Chetna
Published: October 2022

Background

Patients with advanced cancer prioritise health-related quality of life (HrQoL) in end-of-life care, however an understanding of pre-death HrQoL trajectories is lacking. We aimed to delineate and describe the trajectories of physical, social, emotional and functional HrQoL during last year of life among advanced cancer patients. We assessed associations between these trajectories and patient socio-demographic characteristics, healthcare use and place of death.

Methods

We used data from 345 decedents from a prospective cohort study of 600 patients with a solid advanced cancer receiving secondary care at public hospitals in Singapore. Patients were surveyed every three months until death and HrQoL was assessed using the Functional Assessment of Cancer Therapy – General (FACT-G) questionnaire. Interviews were conducted between July 2016 and December 2019. Group-based multi-trajectory modelling was used to assess potential heterogeneity in the four HrQoL dimensions during patients’ last year of life.

Results

We identified four distinct trajectories of HrQoL − (1) overall high HrQoL (47% of sample), (2) progressively decreasing HrQoL (32%), (3) asymmetric decline in HrQoL (13%), (4) overall low HrQoL (8%). Compared to patients with secondary or above education, those with primary education or less (β = 1.39, SE = 0.55, p-value = 0.012) were more likely to have “progressively decreasing HrQoL” or “overall low HrQoL” in contrast to “overall high HrQoL”. Compared to patients with ‘overall high HrQoL’, those with ‘overall low HrQoL’ had longer length of hospital stay during the last year of life (β = 0.47, SE = 0.21, p-value = 0.026) and were more likely to die in a hospice/care home (β = 1.86, SE = 0.66, p-value = 0.005).

Conclusion

Our results showed heterogeneity in deterioration of HrQoL among patients with advanced cancer in the last year of life. Systematic monitoring of HrQoL, early identification and referral of high-risk patients to palliative care may provide timely relief and mitigate the steep decline in their HrQoL.

Trial Registration

: NCT02850640.
Fallopia Japonica and Prunella vulgaris inhibit myopia progression by suppressing AKT and NFκB mediated inflammatory reactions
Authors: Chen Chih-Sheng , Hsu Yu-An , Lin Chia-Hung , Wang Yao-Chien , Lin En-Shyh , Chang Ching-Yao , Chen Jamie Jiin-Yi , Wu Ming-Yen , Lin Hui-Ju , Wan Lei
Published: October 2022

Background

The increased global incidence of myopia requires the establishment of therapeutic approaches. This study aimed to investigate the effect of Fallopia Japonica (FJ) and Prunella vulgaris (PV) extract on myopia caused by monocular form deprivation (MFD).

Methods

We used human retinal pigment epithelial cell to study the molecular mechanisms on how FJ extract (FJE) and PV extract (PVE) lowering the inflammation of the eye. The effect of FJE and PVE in MFD induced hamster model and explore the role of inflammation cytokines in myopia.

Results

FJE + PVE reduced IL-6, IL-8, and TNF-α expression in RPE cells. Furthermore, FJE and PVE inhibited inflammation by attenuating the phosphorylation of protein kinase B (AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) pathway. In addition, we report two resveratrol + ursolic acid compounds from FJ and PV and their inhibitory activities against IL-6, IL-8, and TNF-α expression levels in RPE cells treated with IL-6 and TNF-α. FJE, PVE, and FJE + PVE were applied to MFD hamsters and their axial length was measured after 21 days. The axial length showed statistically significant differences between phosphate-buffered saline- and FJE-, PVE-, and FJE + PVE-treated MFD eyes. FJE + PVE suppressed expressions of IL-6, IL-8, and TNF-α. They also inhibited myopia-related transforming growth factor-beta (TGF)-β1, matrix metalloproteinase (MMP)-2, and NF-κB expression while increasing type I collagen expression.

Conclusions

Overall, these results suggest that FJE + PVE may have a therapeutic effect on myopia and be used as a potential treatment option.
Perceptions and experiences of medical student first responders: a mixed methods study
Authors: Orsi Andrew , Watson Adam , Wijegoonewardene Nimali , Botan Vanessa , Lloyd Dylan , Dunbar Nic , Asghar Zahid , Siriwardena A Niroshan
Published: October 2022

Context

Medical Student First Responders (MSFRs) are volunteers who respond to emergency calls, managing patients before ambulance staff attend. The MSFR role provides opportunities to manage acutely unwell patients in the prehospital environment, not usually offered as part of formal undergraduate medical education. There are few previous studies describing activities or experiences of MSFRs or exploring the potential educational benefits. We aimed to investigate the activity of MSFRs and explore their experiences, particularly from an educational perspective.

Methods

We used a mixed methods design, combining quantitative analysis of ambulance dispatch data with qualitative semi-structured interviews of MSFRs. Dispatch data were from South Central and East Midlands Ambulance Service NHS Trusts from 1st January to 31st December 2019. Using propensity score matching, we compared incidents attended by MSFRs with those attended by other Community First Responders (CFRs) and ambulance staff. We interviewed MSFRs from five English (UK) medical schools in those regions about their experiences and perceptions and undertook thematic analysis supported by NVivo 12.

Results

We included 1,939 patients (median age 58.0 years, 51% female) attended by MSFRs. Incidents attended were more urgent category calls (category 1 n = 299, 14.9% and category 2 n = 1,504, 77.6%), most commonly for chest pain (n = 275, 14.2%) and shortness of breath (n = 273, 14.1%). MSFRs were less likely to attend patients of white ethnicity compared to CFRs and ambulance staff, and more likely to attend incidents in areas of higher socioeconomic deprivation (IMD – index of multiple deprivation) (p < 0.05). Interviewees (n = 16) consistently described positive experiences which improved their clinical and communication skills.

Conclusion

MSFRs’ attendance at serious medical emergencies provide a range of reported educational experiences and benefits. Further studies are needed to explore whether MSFR work confers demonstrable improvements in educational or clinical performance.
AGuIX nanoparticles enhance ionizing radiation-induced ferroptosis on tumor cells by targeting the NRF2-GPX4 signaling pathway
Authors: Sun Hao , Cai Hui , Xu Chang , Zhai Hezheng , Lux François , Xie Yi , Feng Li , Du Liqing , Liu Yang , Sun Xiaohui , Wang Qin , Song Huijuan , He Ningning , Zhang Manman , Ji Kaihua , Wang Jinhan , Gu Yeqing , Leduc Géraldine , Doussineau Tristan , Wang Yan , Liu Qiang , Tillement Olivier
Published: October 2022

In the frame of radiotherapy treatment of cancer, radioresistance remains a major issue that still needs solutions to be overcome. To effectively improve the radiosensitivity of tumors and reduce the damage of radiation to neighboring normal tissues, radiosensitizers have been given increasing attention in recent years. As nanoparticles based on the metal element gadolinium, AGuIX nanoparticles have been shown to increase the radiosensitivity of cancers. Although it is a rare nanomaterial that has entered preclinical trials, the unclear biological mechanism hinders its further clinical application. In this study, we demonstrated the effectiveness of AGuIX nanoparticles in the radiosensitization of triple-negative breast cancer. We found that AGuIX nanoparticles increased the level of DNA damage by compromising the homologous recombination repair pathway instead of the non-homologous end joining pathway. Moreover, the results showed that AGuIX nanoparticles induced apoptosis, but the degree of apoptosis ability was very low, which cannot fully explain their strong radiosensitizing effect. Ferroptosis, the other mode of cell death, was also discovered to play a significant role in radiation sensitization, and AGuIX nanoparticles may regulate the anti-ferroptosis system by inhibiting the NRF2-GSH-GPX4 signaling pathway.

Graphical Abstract
The expression of stromal biomarkers in small papillary thyroid carcinomas
Authors: Bayadsi Haytham , Barghout George , Gustafsson Moa , Sund Malin , Hennings Joakim
Published: October 2022

Background

The importance of stroma for tumor progression is recognized for many cancer types. In this study, we aim to evaluate the expression of types I (Col1) and IV (Col4) collagens, alpha-smooth muscle actin (a-SMA), and matrix metallopeptidase 9 (MMP-9) in the tumor stroma of small papillary thyroid carcinoma (PTC).

Material and methods

Twenty-five non-metastatic small PTCs (pT1N0) and nineteen metastatic small PTCs (pT1N1b) including corresponding metastatic lateral lymph nodes were selected and paraffinized tissue blocks retrieved. The samples were stained for Col1, COL4, a-SMA, and MMP-9 antibodies using immunohistochemistry. The expression of the stromal proteins was scored and analyzed based on the location, intensity, and distribution.

Results

Col1 and Col4 expression were significantly higher in normal thyroid tissue compared to PTC tissue. On the contrary, expression of a-SMA and MMP-9 was higher in PTC tissue compared to normal thyroid tissue. Both Col1 and Col4 were significantly more highly expressed in the non-metastatic tumors compared with metastatic tumors. The expression of a-SMA and MMP9 was slightly, but not significantly, higher in the metastasized tumors and their respective lymph nodes. There was a significant correlation between the metastasized tumors and their respective lymph nodes in Col1 and MMP-9 expression.

Conclusions

Col1, Col4, a-SMA, and MMP-9 expression in PTCs differs significantly from that of normal thyroid tissue. The higher expression of Col1 and Col4 in normal thyroid tissue and in the non-metastasized tumors indicates that Col1 and 4 might have a potential protective role in tumor progression. The higher expression of a-SMA and MMP9 in PTCs indicates that these proteins might have a role in promoting PTC progression and aggressiveness.
Effect of high-fat diet and empagliflozin on cardiac proteins in mice
Authors: Pan Xiaoyu , Chen Shuchun , Chen Xing , Ren Qingjuan , Yue Lin , Niu Shu , Li Zelin , Zhu Ruiyi , Chen Xiaoyi , Jia Zhuoya , Zhen Ruoxi , Ban Jiangli
Published: October 2022

Using proteomic techniques the impact of the sodium-glucose transport protein 2 inhibitor empagliflozin on cardiac protein expression in a mouse model was assessed under normal and high-fat diet (HFD) conditions. We examined the effect of obesity on serological markers and heart function in obese mice treated with or without empagliflozin and used proteomic techniques to investigate alterations in cardiac protein expression. Using bioinformatic techniques, data were screened for differentially expressed proteins (DEPs) implicated in the putative mechanism of empagliflozin's cardioprotective effects. In C57BL/6 mice, HFD increased body weight, blood lipid, and glucose levels and was associated with structural damage to the heart. Empagliflozin reduces body weight, improves glucose and lipid metabolism, alleviates obesity-induced cardiac ventricular wall thickening, and lowers cardiac tissue collagen. The expression of several proteins was altered in the heart, mainly related to lipid metabolism. Following empagliflozin treatment, the expression of several lipid metabolism-related proteins was considerably reduced. Further examination of DEPs revealed that following empagliflozin treatment, the expressions of Apoe, Apoc1, Saa2, Apoa2, and Pon1 altered dramatically, suggesting that these proteins may be the main proteins that empagliflozin uses to treat obesity-induced aberrant lipid metabolism. Empagliflozin may protect the heart by altering the expression of genes including Apoe, Apoc1, Saa2, Apoa2, and Pon1, which are all involved in lipid metabolism disturbance in obesity.
Toxicokinetic study following intratracheal instillation or oral gavage of two [7Be]-tagged carbon black samples
Authors: Creutzenberg Otto , Hammann Volker , Wolf Stefanie , Daul Jürgen , Ngiewih Yufanyi , Chaudhuri Ishrat , Levy Len
Published: October 2022

Background

The toxicokinetic behaviour of nanostructured particles following pulmonary or oral deposition is of great scientific interest. In this toxicokinetic study, following the general principles of OECD TG 417, the systemic availability of carbon black, a nanostructured material consisting of agglomerated aggregates was characterised.

Methods

Each of two grades of beryllium-7 labelled carbon black (Monarch® 1000, oxidized and Printex® 90; untreated) was administered either intratracheally or orally to adult rats. Independent of route, rats received a single dose of approximately 0.3 mg radiolabelled carbon black. A total of 12 rats were treated per grade and per exposure route: 4 females each for feces/urine/organs and serial blood kinetics; 4 males for organs. At necropsy, the complete suite of organs was analysed for females, but only the lungs, liver, kidney, reproductive organs for males.

Results

In the pulmonarily exposed animals, 7Be-Monarch® 1000 and 7Be-Printex® 90 was detected in feces in the first 3 days after treatment at significant levels, i.e. 17.6% and 8.2%, respectively. In urine, small percentages of 6.7% and 0.4% were observed, respectively. In blood, radioactivity, representative of carbon black was within the background noise of the measurement method. At necropsy, 20 days post-instillation, both test items were practically exclusively found in lungs (75.1% and 91.0%, respectively) and in very small amounts (approximately 0.5%) in the lung-associated lymph nodes (LALN). In the other organs/tissues the test item was not detectable. BAL analyses indicated that carbon black particles were completely engulfed by alveolar macrophages.

In orally exposed animals, 98% (7Be-Monarch® 1000) and 99% (7Be-Printex® 90) of the measured radioactivity was detected in feces. Excretion was complete within the first 3 days following treatment. 1.3% and 0.5% of measured activity was attributable to urine in animals that received 7Be-Monarch® 1000 and 7Be-Printex® 90, respectively. Radioactivity was absent in blood and other organs and tissues.

Conclusion

Radioactivity, representative of carbon black, was not detected beyond the experimentally defined limit of quantitation systemically after deposition in lungs or stomach in rats. Under these experimental conditions, the two CB samples were not shown to translocate beyond the lung or the GI tract into the blood compartment.