bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient’s safety and satisfaction on same day discharge after robotic and laparoscopic radical prostatectomy versus discharge after 24 or 48 h: a longitudinal randomized prospective study
Authors: Faria Eliney Ferreira , Machado Roberto Dias , Gualberto Rodrigo José Costa , Milani Marina Assunção Valadares , Bidinotto Lucas Tadeu , Machado Marcos Tobias , dos Reis Ricardo , Bidinotto Daniele Natália Pacharone Bertolini
Published: September 2023

Background

There is a tendency of prompted global health systems to reduce the length of hospital stay without compromising patient safety or satisfaction. We evaluated the safety and viability of early discharge in patients undergoing minimally invasive radical prostatectomy (MIRP), as well as patient satisfaction with this strategy.

Methods

This longitudinal prospective study included 72 patients who underwent MIRP for prostate cancer. Three groups were performed according to the day of hospital discharge following surgery: same day (G1), first day after (G2), and second day after (G3). Satisfaction, adverse events, and readmission were analyzed for each group. Associations between clinicopathologic variables and same-day discharge were analyzed by comparing data between G1 patients who did and did not achieve same-day discharge.

Results

16.7% of patients were not discharged according to randomization (10 randomized to G1). 80% of G1 patients who did not achieve same-day discharge had Gleason scores of 3 + 4 or 4 + 3, which were observed in 35.7% of patients discharged on the same day (P < 0.05). Average prostate weight was significantly lower in patients who achieved same-day discharge than in those who did not (P < 0.01). Univariable logistic regression points to Gleason scores of 3 + 4 or 4 + 3 as the main factors associated with unsuccessful same-day discharge (P < 0.05). There were no significant differences in satisfaction scores.

Conclusions

Same-day discharge was both safe and feasible and does not appear to affect satisfaction in a subset of patients with prostate cancer. Surgeons should consider the Gleason score when determining whether same-day discharge is appropriate.
The long non-coding RNA BBOX1 antisense RNA 1 is upregulated in polycystic ovary syndrome (PCOS) and suppresses the role of microRNA-19b in the proliferation of ovarian granulose cells
Authors: Zhou Zhi , Zhang Yong , Tan Can , Zhang Juan , Yi Guohui , Wang Bangbei , Li Yejuan , Lu Hui , Lu Weiying , Zhang Xiaopo
Published: September 2023

Background

MicroRNA-19b (miR-19b) has been reported to be downregulated in polycystic ovary syndrome (PCOS), while its upstream regulators are unclear. We speculated that miR-19b could potentially form a binding relationship with BBOX1 antisense RNA 1 (BBOX1-AS1), a long non-coding RNA recognized for its critical role in ovarian cancer. Subsequently, we investigated into their interaction in PCOS.

Methods

The expression of miR-19b and BBOX1-AS1 in follicular fluid from both control women (n = 80) and women with PCOS (n = 80) was detected by RT-qPCR. Correlations were analyzed with Pearson’ correlation coefficient. The binding of miR-19b to the wild-type (-wt) ad mutant (-mut) BBOX1-AS1 was determined by RNA-RNA pulldown assay. Their interactions were detected by overexpression assay. Bromodeoxyuridine (BrdU) assay was applied for proliferation analysis.

Results

BBOX1-AS1 was highly upregulated, while miR-19b was downregulated in PCOS. There was no close correlation across PCOS and the control samples. Consistently, they did not regulate the expression of each other in granulosa cells. However, BBOX1-AS1-wt, but not BBOX1-AS1-mut, could directly interact with miR-19b. BBOX1-AS1 suppressed the role of miR-19b in inhibiting granulosa cell proliferation.

Conclusion

BBOX1-AS1 is highly upregulated in PCOS, and it may serve as an endogenous competing RNA for miR-19b to suppress its role in inhibiting granulosa cell proliferation. Our study suggested the role of BBOX1-AS1 as a potential target to treat PCOS.
Determinants of puerperal sepsis among post-partum mothers in Mekelle city public hospitals, Tigray, Ethiopia, 2021: a case control study
Authors: Sahle Solomon Gebretsion , Weldemariam Solomon , Mehari Mihret-ab , Abraha Tomas Amare
Published: September 2023

Background

Puerperal sepsis is among the leading causes of preventable maternal death not only in developing countries but also in developed countries which is usually reported as the third or fourth common direct cause of maternal death. Although the prevalence of puerperal sepsis is low, it is the significant cause of maternal mortality, morbidities and other long-term complications like secondary infertility. The aim of this study was to assess the determinants of puerperal sepsis among post-partum mothers at Mekelle city public hospitals.

Method

Institution based unmatched case control study was conducted among 444 total sample size (111 cases and 333 controls) in Mekelle city public hospitals from March 21, 2021 to April 20, 2021. Consecutive sampling for the cases and systematic sampling for the controls was used. Pretested structured questionnaire was used to collect data and the data was entered into Epi data version 4.1 then cleaned, coded and edited and exported to SPSS version 23 statistical software for analysis. Logistic regression was done and variables with aP-value of < 0.25 on Binary logistic regression were taken to multiple logistic regression analysis. At 95% confidence interval, aP-value of < 0.05 was used as cut-off point to declare the association with the dependent variable.

Results

Multiple logistic regression analysis revealed that rural residence (AOR: 3, 95% CI: 1.50–5.90), no ANC follow up (AOR: 2.7, 95% CI: 1.08–6.71), duration of rupture of membrane > 24 h (AOR: 4.1, 95% CI: 1.60–10.58), duration of labor > 24 h (AOR: 4.3, 95% CI: 1.86–9.92), number of vaginal examination >  = 5 (AOR: 2.8, 95% CI: 1.26–6.26), cesarean section mode of delivery (AOR: 2.8, 95% CI: 1.48–5.20) and no PNC follow up (AOR: 3.9, 95% CI: 1.60–9.36) were the determinant factors of puerperal sepsis in this study.

Conclusion

The determinants of puerperal sepsis in this study were rural residence, not having antenatal care, prolonged duration of rupture of membrane, prolonged duration of labor, frequent number of vaginal examination, cesarean section and not having postnatal care. It is recommended that strengthening provision of health education on danger signs of pregnancy, parthograph utilization and avoiding of frequent vaginal examinations.
Embedding interpersonal stigma resistance into the medical curriculum: a focus group study of medical students
Authors: McAllister Ashley , Dickson Kara , Rangi Mediya , Griffiths Leonie , Dimov Stefanie , Reavley Nicola , Knaak Stephanie
Published: September 2023

Background

Mental-health-related stigma among physicians towards people with mental illnesses remains a barrier to quality care, yet few curricula provide training with a proactive focus to reduce the potential negative impacts of stigma. The aim of our study was to explore medical students’ perspectives on what areas of learning should be targeted (where stigma presents) and how they could be supported to prevent the formation of negative attitudes.

Methods

Six focus group discussions were conducted with second, third, and fourth-year postgraduate medical students (n = 34) enrolled at The University of Melbourne Medical School in September – October 2021. Transcripts were analysed using inductive thematic analysis.

Results

In terms of where stigma presents, three main themes emerged – (1) through unpreparedness in dealing with patients with mental health conditions, (2) noticing mentors expressing stigma and (3) through the culture of medicine. The primary theme related to 'how best to support students to prevent negative attitudes from forming' was building stigma resistance to reduce the likelihood of perpetuating stigma towards patients with mental health conditions and therefore enhance patient care. The participants suggest six primary techniques to build stigma resistance, including (1) reflection, (2) skills building, (3) patient experiences, (4) examples and exemplars, (5) clinical application and (6) transforming structural barriers. We suggest these techniques combine to form the ReSPECT model for stigma resistance in the curriculum.

Conclusions

The ReSPECT model derived from our research could provide a blueprint for medical educators to integrate stigma resistance throughout the curriculum from year one to better equip medical students with the potential to reduce interpersonal stigma and perhaps self-stigma. Ultimately, building stigma resistance could enhance care towards patients with mental health conditions and hopefully improve patient outcomes.
Patient priorities for fulfilling the principle of respect in research: findings from a modified Delphi study
Authors: Kraft Stephanie A. , Duenas Devan M. , Shah Seema K.
Published: September 2023

Background

Standard interpretations of the ethical principle of respect for persons have not incorporated the views and values of patients, especially patients from groups underrepresented in research. This limits the ability of research ethics scholarship, guidance, and oversight to support inclusive, patient-centered research. This study aimed to identify the practical approaches that patients in community-based settings value most for conveying respect in genomics research.

Methods

We conducted a 3-round, web-based survey using the modified Delphi technique to identify areas of agreement among English-speaking patients at primary care clinics in Washington State and Idaho who had a personal or family history of cancer. In Round 1, respondents rated the importance of 17 items, identified in prior qualitative work, for feeling respected. In Round 2, respondents re-rated each item after reviewing overall group ratings. In Round 3, respondents ranked a subset of the 8 most highly rated items. We calculated each item’s mean and median rankings in Round 3 to identify which approaches were most important for feeling respected in research.

Results

Forty-one patients consented to the survey, 21 (51%) completed Round 1, and 18 (86% of Round 1) completed each of Rounds 2 and 3. Two sets of rankings were excluded from analysis as speed of response suggested they had not completed the Round 3 ranking task. Respondents prioritized provision of study information to support decision-making (mean ranking 2.6 out of 8; median ranking 1.5) and interactions with research staff characterized by kindness, patience, and a lack of judgment (mean ranking 2.8; median ranking 2) as the most important approaches for conveying respect.

Conclusions

Informed consent and interpersonal interactions are key ways that research participants experience respect. These can be supported by other approaches to respecting participants, especially when consent and/or direct interactions are infeasible. Future work should continue to engage with patients in community-based settings to identify best practices for research without consent and examine unique perspectives across clinical and demographic groups in different types of research.
SelANet: decision-assisting selective sleep apnea detection based on confidence score
Authors: Bark Beomjun , Nam Borum , Kim In Young
Published: September 2023

Background

One of the most common sleep disorders is sleep apnea syndrome. To diagnose sleep apnea syndrome, polysomnography is typically used, but it has limitations in terms of labor, cost, and time. Therefore, studies have been conducted to develop automated detection algorithms using limited biological signals that can be more easily diagnosed. However, the lack of information from limited signals can result in uncertainty from artificial intelligence judgments. Therefore, we performed selective prediction by using estimated respiratory signals from electrocardiogram and oxygen saturation signals based on confidence scores to classify only those sleep apnea occurrence samples with high confidence. In addition, for samples with high uncertainty, this algorithm rejected them, providing a second opinion to the clinician.

Method

Our developed model utilized polysomnography data from 994 subjects obtained from Massachusetts General Hospital. We performed feature extraction from the latent vector using the autoencoder. Then, one dimensional convolutional neural network—long short-term memory (1D CNN-LSTM) was designed and trained to measure confidence scores for input, with an additional selection function. We set a confidence score threshold called the target coverage and performed optimization only on samples with confidence scores higher than the target coverage. As a result, we demonstrated that the empirical coverage trained in the model converged to the target coverage.

Result

To confirm whether the model has been optimized according to the objectives, the coverage violation was used to measure the difference between the target coverage and the empirical coverage. As a result, the value of coverage violation was found to be an average of 0.067. Based on the model, we evaluated the classification performance of sleep apnea and confirmed that it achieved 90.26% accuracy, 91.29% sensitivity, and 89.21% specificity. This represents an improvement of approximately 7.03% in all metrics compared to the performance achieved without using a selective prediction.

Conclusion

This algorithm based on selective prediction utilizes confidence measurement method to minimize the problem caused by limited biological information. Based on this approach, this algorithm is applicable to wearable devices despite low signal quality and can be used as a simple detection method that determine the need for polysomnography or complement it.
Incidence of immune-mediated inflammatory diseases following COVID-19: a matched cohort study in UK primary care
Authors: Syed Umer , Subramanian Anuradhaa , Wraith David C. , Lord Janet M. , McGee Kirsty , Ghokale Krishna , Nirantharakumar Krishnarajah , Haroon Shamil
Published: September 2023

Background

Some patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) go on to experience post-COVID-19 condition or long COVID. Preliminary findings have given rise to the theory that long COVID may be due in part to a deranged immune response. In this study, we assess whether there is an association between SARS-CoV-2 infection and the incidence of immune-mediated inflammatory diseases (IMIDs).

Methods

Matched cohort study using primary care electronic health record data from the Clinical Practice Research Datalink Aurum database. The exposed cohort included 458,147 adults aged 18 years and older with a confirmed SARS-CoV-2 infection and no prior diagnosis of IMIDs. They were matched on age, sex, and general practice to 1,818,929 adults with no diagnosis of confirmed or suspected SARS-CoV-2 infection. The primary outcome was a composite of any of the following IMIDs: autoimmune thyroiditis, coeliac disease, inflammatory bowel disease (IBD), myasthenia gravis, pernicious anaemia, psoriasis, rheumatoid arthritis (RA), Sjogren’s syndrome, systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1DM), and vitiligo. The secondary outcomes were each of these conditions separately. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the primary and secondary outcomes, adjusting for age, sex, ethnic group, smoking status, body mass index, relevant infections, and medications.

Results

Six hundred and nighty six (0.15%) and 2230 (0.12%) patients in the exposed and unexposed cohort developed an IMID during the follow-up period over 0.29 person-years, giving a crude incidence rate of 4.59 and 3.65 per 1000 person-years, respectively. Patients in the exposed cohort had a 22% increased risk of developing an IMID, compared to the unexposed cohort (aHR 1.22, 95% CI 1.12 to 1.33). The incidence of three IMIDs was significantly associated with SARS-CoV-2 infection. These were T1DM (aHR 1.56, 1.09 to 2.23), IBD (aHR 1.36, 1.18 to 1.56), and psoriasis (1.23, 1.05 to 1.42).

Conclusions

SARS-CoV-2 was associated with an increased incidence of IMIDs including T1DM, IBD and psoriasis. However, these findings could be potentially due to ascertainment bias. Further research is needed to replicate these findings in other populations and to measure autoantibody profiles in cohorts of individuals with COVID-19.
Proposed protocol for utilising high-flow nasal oxygen therapy in treatment of dogs hospitalised due to pneumonia
Authors: Teppo Anna-Maija , Rossi Heini , Rajamäki Minna M. , Hyytiäinen Heli K.
Published: September 2023

Background

High-flow nasal oxygen (HFNO) therapy is a non-invasive respiratory support method that provides oxygen-enriched, warmed, and humidified air to respiratory-compromised patients. It is widely used in human medical care, but in veterinary medicine it is still a relatively new method. No practical guidelines exist for its use in canine pneumonia patients, although they could potentially benefit from HFNO therapy. This study aims to provide a new, safe, non-invasive, and effective treatment protocol for oxygen supplementation of non-sedated dogs with pneumonia.

Methods

Twenty privately owned dogs with pneumonia will receive HFNO therapy at a flow rate of 1–2 L/kg, and the fraction of inspired oxygen will be determined individually (ranging from 21% to 100%). HFNO therapy will continue as long as oxygen support is needed based on clinical evaluation. Patients will be assessed thrice daily during their hospitalisation, with measured primary outcomes including partial pressure of oxygen, oxygen saturation, respiratory rate and type, days in hospital, and survival to discharge.

Discussion

The proposed protocol aims to provide a practical guideline for applying HFNO to dogs hospitalised due to pneumonia. The protocol could enable more efficient and well-tolerated oxygenation than traditional methods, thus hastening recovery and improving survival of pneumonia patients.
Subclinical left ventricular deformation and microvascular dysfunction in T2DM patients with and without peripheral neuropathy: assessed by 3.0 T cardiac magnetic resonance imaging
Authors: Li Xue-Ming , Shi Rui , Shen Meng-Ting , Yan Wei-Feng , Jiang Li , Min Chen-Yan , Liu Xiao-Jing , Guo Ying-Kun , Yang Zhi-Gang
Published: September 2023

Background

Diabetic peripheral neuropathy (DPN) has been shown to be independently associated with cardiovascular events and mortality. This study aimed to evaluate changes in left ventricular (LV) microvascular perfusion and myocardial deformation in type 2 diabetes mellitus (T2DM) patients with and without DPN, as well as to investigate the association between myocardial perfusion and LV deformation.

Methods

Between October 2015 and July 2022, one hundred and twenty-three T2DM patients without DPN, fifty-four patients with DPN and sixty age‑ and sex‑matched controls who underwent cardiovascular magnetic resonance imaging were retrospectively analyzed. LV myocardial perfusion parameters at rest, including upslope, time to maximum signal intensity (TTM), max signal intensity (max SI), and myocardial strains, including global radial, circumferential and longitudinal strain (GRS, GCS and GLS, respectively), were calculated and compared among the groups with One‑way analysis of variance. Univariable and multivariable linear regression analyses were performed to explore the independent factors influencing LV myocardial perfusion indices and LV strains in diabetes.

Results

The LV GLS, upslope and max SI were significantly deteriorated from controls, through patients without DPN, to patients with DPN (all P < 0.001). Compared with controls, TTM was increased and LV GRS and GCS were decreased in both patient groups (all P < 0.05). Multivariable regression analyses considering covariates showed that DPN was independently associated with reduced upslope, max SI and LV GLS (β = − 0.360, − 2.503 and 1.113, p = 0.021, 0.031 and 0.010, respectively). When the perfusion indices upslope and max SI were included in the multivariable analysis for LV deformation, DPN and upslope (β = 1.057 and − 0.870, p = 0.020 and 0.018, respectively) were significantly associated with LV GLS.

Conclusion

In patients with T2DM, there was more severe LV microvascular and myocardial dysfunction in patients with complicated DPN, and deteriorated subclinical LV systolic dysfunction was associated with impaired myocardial circulation.
Cumulative exposure to high remnant-cholesterol concentrations increases the risk of cardiovascular disease in patients with hypertension: a prospective cohort study
Authors: Wu Weiqiang , Chen Guanzhi , Wu Kuangyi , Zheng Huancong , Chen Yanjuan , Wang Xianxuan , Huang Zegui , Cai Zefeng , Cai Zhiwei , Chen Zhichao , Lan Yulong , Chen Shuohua , Wu Shouling , Chen Youren
Published: September 2023

Background

The relationship of cumulative remnant-cholesterol (Cum-RC) concentration with the risk of cardiovascular disease (CVD) in patients with hypertension remains unclear.

Methods

We studied data for 28,698 individuals for whom three consecutive total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and triglyceride concentrations were available, and who did not have CVD (14,349 with hypertension and 14,349 without), that was collected between 2006 and 2010. Participants with hypertension were placed into four groups based on Cum-RC quartile: a Q1 group (< 26.40 mg/dl), a Q2 group (26.40–39.56 mg/dl), a Q3 group (39.57–54.65 mg/dl), and a Q4 group (≥ 54.66 mg/dl). Cox proportional hazards models were used to evaluate the relationship between Cum-RC and the risk of CVD.

Results

Over a median 10.9 (interquartile range, 10.5–11.3) years, 1,444 participants with hypertension developed CVD. After adjustment for multiple potential confounding factors, and compared with the Q1 Cum-RC group of the participants with hypertension, the adjusted hazard ratios for CVD for the Q2–Q4 groups were 1.07(0.92,1.26), 1.08(0.91,1.28), and 1.26(1.03,1.54) (P = 0.0405); those for myocardial infarction were 1.51(1.00,2.31), 2.02(1.22,3.27), and 2.08(1.41,3.28) (P < 0.0001); and those for ischemic stroke were 1.02(0.84,1.24), 1.04(0.86,1.25), and 1.29(1.02,1.62), respectively (P = 0.0336). However, no significant relationship was found between Cum-RC and the risk of hemorrhage stroke. At the same Cum-RC, the risk of CVD was significantly higher in participants with hypertension than in those without.

Conclusions

A consistently high remnant-cholesterol concentration increases the risk of CVD in individuals with hypertension. Therefore, the achievement of blood pressure and RC concentration targets should help reduce the risk of CVD in individuals with hypertension.
Association between the atherogenic index of plasma and adverse long-term prognosis in patients diagnosed with chronic coronary syndrome
Authors: Alifu Jiasuer , Xiang Lanqing , Zhang Wen , Qi Penglong , Chen Huiying , Liu Lu , Yin Guoqing , Mohammed Abdul-Quddus , Lv Xian , Shi Tingting , Abdu Fuad A. , Che Wenliang
Published: September 2023

Background

The Atherogenic Index of Plasma (AIP) is a newly identified biomarker associated with lipid metabolism, demonstrating significant prognostic capabilities in individuals diagnosed with cardiovascular disease. However, its impact within the context of chronic coronary syndromes (CCS) remains unexplored. Thus, the present investigation sought to examine the potential association between AIP levels and long-term clinical outcomes in patients diagnosed with CCS.

Methods

A total of 404 patients diagnosed with CCS and who underwent coronary angiography were included in this study. The AIP index was calculated as log (triglycerides / high-density lipoprotein-cholesterol). The patients were categorized into four groups based on their AIP values: Q1 (< -0.064), Q2 (-0.064 to 0.130), Q3 (0.130 to 0.328), and Q4 (> 0.328). The occurrence of major adverse cardiovascular events (MACE) was monitored during the follow-up period for all patients. Cox regression analysis and Kaplan-Meier curve analysis were employed to examine the relationship between AIP and MACE. Furthermore, ROC analysis was utilized to determine the optimal cut-off value of AIP for predicting clinical MACE.

Results

During the median 35 months of follow-up, a total of 88 patients experienced MACE. Notably, the group of patients with higher AIP values (Q4 group) exhibited a significantly higher incidence of MACE compared to those with lower AIP values (Q1, Q2, and Q3 groups) (31.7% vs. 16.8%, 15.7%, and 23.0% respectively; P = 0.023). The Kaplan-Meier curves illustrated those patients in the Q4 group had the highest risk of MACE relative to patients in the other groups (log-rank P = 0.014). Furthermore, the multivariate Cox regression analysis demonstrated that individuals in the Q4 group had a 7.892-fold increased risk of MACE compared to those in the Q1 group (adjusted HR, 7.892; 95% CI 1.818–34.269; P = 0.006). Additionally, the ROC curve analysis revealed an optimal AIP cut-off value of 0.24 for predicting clinical MACE in patients with CCS.

Conclusion

Our data indicate, for the first time, that AIP is independently associated with poor long-term prognosis in patients suffering from CCS. The optimal AIP cut-off value for predicting clinical MACE among CCS patients was 0.24.
High willingness to use overdose prevention sites among suburban people who use drugs who do not inject
Authors: Schneider Kristin E. , Urquhart Glenna J. , Rouhani Saba , Allen Sean T. , Morris Miles , Sherman Susan G.
Published: September 2023

Introduction

Overdose prevention sites (OPS) are evidence-based interventions to improve public health, yet implementation has been limited in the USA due to a variety of legal impediments. Studies in various US settings have shown a high willingness to use OPS among urban and rural people who inject drugs, but data among people who use drugs (PWUD) via non-injection routes of administration in suburban areas are lacking.

Methods

We utilized cross-sectional data from a sample of suburban PWUD who have not injected drugs in the past 3 months (N = 126) in Anne Arundel County, Maryland. We assessed PWUDs’ likelihood of using a hypothetical OPS and perceived potential barriers to accessing OPS. We tested for associations between sociodemographic characteristics, drug use, service access, and overdose experiences with willingness to utilize OPS.

Findings

Participants’ median age was 42, and the majority were men (67%) and non-Hispanic Black (79%). Sixty-six percent reported willingness to use an OPS. Concerns about confidentiality (29%), arrest (20%), and transportation costs (22%) were the most anticipated barriers to using OPS. Men (75% vs 55%, p = 0.015), participants who used heroin (53% vs 32%, p = 0.017), and participants who used multiple overdose prevention behaviors (e.g., using fentanyl test strips) (36% vs 19%, p = 0.006) were more likely to report willingness to use OPS.

Conclusion

Most suburban non-injecting PWUD in the sample were willing to use an OPS. OPS implementation strategies in suburban settings should be tailored to reach PWUD via non-injection routes of administration while meeting the unique needs of suburban contexts.
Acute myeloid leukemia-derived exosomes deliver miR-24-3p to hinder the T-cell immune response through DENN/MADD targeting in the NF-κB signaling pathways
Authors: Otmani Khalid , Rouas Redouane , Lagneaux Laurence , Krayem Mohammad , Duvillier Hugues , Berehab Mimoune , Lewalle Philippe
Published: September 2023

Background

microRNAs (miRNAs) are known as potent gene expression regulators, and several studies have revealed the prognostic value of miRNAs in acute myeloid leukemia (AML) patient survival. Recently, strong evidence has indicated that miRNAs can be transported by exosomes (EXOs) from cancer cells to recipient immune microenvironment (IME) cells.

Results

We found that AML blast-released EXOs enhance CD3 T-cell apoptosis in both CD4 and CD8 T cells. We hypothesized that miRNAs present in EXOs are key players in mediating the changes observed in AML T-cell survival. We found that miR-24-3p, a commonly overexpressed miRNA in AML, was present in released EXOs, suggesting that EXO-miR-24-3p was linked to the increased miR-24-3p levels detected in isolated AML T cells. These results were corroborated by ex vivo-generated miR-24-3p-enriched EXOs, which showed that miR-24-3p-EXOs increased apoptosis and miR-24-3p levels in T cells. We also demonstrated that overexpression of miR-24-3p increased T-cell apoptosis and affected T-cell proliferation by directly targeting DENN/MADD expression and indirectly altering the NF-κB, p-JAK/STAT, and p-ERK signaling pathways but promoting regulatory T-cell (Treg) development.

Conclusions

These results highlight a mechanism through which AML blasts indirectly impede T-cell function via transferred exosomal miR-24-3p. In conclusion, by characterizing the signaling network regulated by individual miRNAs in the leukemic IME, we aimed to discover new nonleukemic immune targets to rescue the potent antitumor function of T cells against AML blasts.
The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways
Authors: Bakhtiyari Maryam , Liaghat Mahsa , Aziziyan Fatemeh , Shapourian Hooriyeh , Yahyazadeh Sheida , Alipour Maedeh , Shahveh Shaghayegh , Maleki-Sheikhabadi Fahimeh , Halimi Hossein , Forghaniesfidvajani Razieh , Zalpoor Hamidreza , Nabi-Afjadi Mohsen , Pornour Majid
Published: September 2023

Acute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML.
Integrating single-nucleus sequence profiling to reveal the transcriptional dynamics of Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis
Authors: Fan Li-Yuan , Yang Jing , Liu Ruo-Yu , Kong Ying , Guo Guang-Yu , Xu Yu-Ming
Published: September 2023

Background

Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) are three nervous system diseases that partially overlap clinically and genetically. However, bulk RNA-sequencing did not accurately detect the core pathogenic molecules in them. The availability of high-quality single cell RNA-sequencing data of post-mortem brain collections permits the generation of a large-scale gene expression in different cells in human brain, focusing on the molecular features and relationships between diseases and genes. We integrated single-nucleus RNA-sequencing (snRNA-seq) datasets of human brains with AD, PD, and MS to identify transcriptomic commonalities and distinctions among them.

Methods

The snRNA-seq datasets were downloaded from Gene Expression Omnibus (GEO) database. The Seurat package was used for snRNA-seq data processing. The uniform manifold approximation and projection (UMAP) were utilized for cluster identification. The FindMarker function in Seurat was used to identify the differently expressed genes. Functional enrichment analysis was carried out using the Gene Set Enrichment Analysis (GSEA) and Gene ontology (GO). The protein‐protein interaction (PPI) analysis of differentially expressed genes (DEGs) was analyzed using STRING database (http://string-db.org). SCENIC analysis was performed using utilizing pySCENIC (v0.10.0) based on the hg19-tss-centered-10 kb-10species databases. The analysis of potential therapeutic drugs was analyzed on Connectivity Map (https://clue.io).

Results

The gene regulatory network analysis identified several hub genes regulated in AD, PD, and MS, in which HSPB1 and HSPA1A were key molecules. These upregulated HSP family genes interact with ribosome genes in AD and MS, and with immunomodulatory genes in PD. We further identified several transcriptional regulators (SPI1, CEBPA, TFE3, GRHPR, and TP53) of the hub genes, which has important implications for uncovering the molecular crosstalk among AD, PD, and MS. Arctigenin was identified as a potential therapeutic drug for AD, PD, and MS.

Conclusions

Together, the integrated snRNA-seq data and findings have significant implications for unraveling the shared and unique molecular crosstalk among AD, PD, and MS. HSPB1 and HSPA1A as promising targets involved in the pathological mechanisms of neurodegenerative diseases. Additionally, the identification of arctigenin as a potential therapeutic drug for AD, PD, and MS further highlights its potential in treating these neurological disorders. These discoveries lay the groundwork for future research and interventions to enhance our understanding and treatment of AD, PD, and MS.
Proteome-wide mendelian randomization study implicates therapeutic targets in common cancers
Authors: Ren Feihong , Jin Qiubai , Liu Tongtong , Ren Xuelei , Zhan Yongli
Published: September 2023

Background

The interest in targeted cancer therapies has been growing rapidly. While numerous cancer biomarkers and targeted treatment strategies have been developed and employed, there are still significant limitations and challenges in the early diagnosis and targeted treatment of cancers. Accordingly, there is an urgent need to identify novel targets and develop new targeted drugs.

Methods

The study was conducted using combined cis-Mendelian randomization (cis-MR) and colocalization analysis. We analyzed data from 732 plasma proteins to identify potential drug targets associated with eight site-specific cancers. These findings were further validated using the UK Biobank dataset. Then, a protein–protein interaction network was also constructed to examine the interplay between the identified proteins and the targets of existing cancer medications.

Results

This MR analysis revealed associations between five plasma proteins and prostate cancer, five with breast cancer, and three with lung cancer. Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. Our study indicatied that genetically predicted KDELC2 (OR: 0.89, 95% CI 0.86–0.93) and TNFRSF10B (OR: 0.74, 95% CI 0.65–0.83) are inversely associated with prostate cancer. Furthermore, we observed an inverse association between CPNE1 (OR: 0.96, 95% CI 0.94–0.98) and breast cancer, while PDIA3 (OR: 1.19, 95% CI 1.10–1.30) were found to be associated with the risk of breast cancer. In addition, we also propose that SPINT2 (OR: 1.05, 95% CI 1.03–1.06), GSTP1 (OR: 0.82, 95% CI 0.74–0.90), and CTSS (OR: 0.91, 95% CI 0.88–0.95) may serve as potential therapeutic targets in prostate cancer. Similarly, GDI2 (OR: 0.85, 95% CI 0.80–0.91), ISLR2 (OR: 0.87, 95% CI 0.82–0.93), and CTSF (OR: 1.14, 95% CI 1.08–1.21) could potentially be targets for breast cancer. Additionally, we identified SFTPB (OR: 0.93, 95% CI 0.91–0.95), ICAM5 (OR: 0.95, 95% CI 0.93–0.97), and FLRT3 (OR: 1.10, 95% CI 1.05–1.15) as potential targets for lung cancer. Notably, TNFRSF10B, GSTP1, and PDIA3 were found to interact with the target proteins of current medications used in prostate or breast cancer treatment.

Conclusions

This comprehensive analysis has highlighted thirteen plasma proteins with potential roles in three site-specific cancers. Continued research in this area may reveal their therapeutic potential, particularly KDELC2, TNFRSF10B, CPNE1, and PDIA3, paving the way for more effective cancer treatments.
Age, brood fate, and territory quality affect nest-site fidelity in white stork Ciconia ciconia
Authors: Bialas Joanna T. , Siekiera Joachim , Siekiera Artur , Chromik Wiesław , Dylewski Łukasz , Tobolka Marcin
Published: September 2023

Background

A particular type of site fidelity is faithfulness to the nest site, where birds are not only reoccupying breeding territories but also reusing nests built in previous breeding seasons. Staying faithful to the nest site is believed to be an adaptive strategy, and based on the ability to predict an individual's own breeding success, a hypothesis of “win-stay:loose-switch” was proposed. In this study, we aimed to resolve which factors affect the nest-site fidelity of white stork Ciconia ciconia, species known for reusing nests available in the breeding sites. Basing on ring recoveries from 31 years of studies in Western and Southern Poland, we analysed the impact of intrinsic and extrinsic factors on nest-site fidelity.

Results

We found that increasing age and breeding success (i.e. producing any fledglings or not) increased the probability of reusing the nest, but in the oldest individuals, the probability decreased. In turn, the probability of breeding success increased with age, the increasing number of reproductive events on the particular nest, and the presence on the nest in the previous year. However, the oldest individuals had lower probability of success, as the relationship was curvilinear. The number of fledglings, however, was influenced only by an individual's age. The number of reproductive events on the nest was, in turn, affected by age, with the youngest and oldest individuals using the current nest for the least number of years.

Conclusions

Our study shows that the decision process of whether to stay faithful to the nest or switch is based on the experience from the previous breeding event, consistently with the “win-stay:loose-switch” hypothesis. Our results also show that site fidelity benefits white storks, as the probability of breeding success increases if the nest is reused. Results also show the senescence effect that lowers breeding success and site fidelity probabilities.
Different states of stemness of glioblastoma stem cells sustain glioblastoma subtypes indicating novel clinical biomarkers and high-efficacy customized therapies
Authors: Visioli Alberto , Trivieri Nadia , Mencarelli Gandino , Giani Fabrizio , Copetti Massimiliano , Palumbo Orazio , Pracella Riccardo , Cariglia Maria Grazia , Barile Chiara , Mischitelli Luigi , Soriano Amata Amy , Palumbo Pietro , Legnani Federico , DiMeco Francesco , Gorgoglione Leonardo , Pesole Graziano , Vescovi Angelo L. , Binda Elena
Published: September 2023

Background

Glioblastoma (GBM) is the most malignant among gliomas with an inevitable lethal outcome. The elucidation of the physiology and regulation of this tumor is mandatory to unravel novel target and effective therapeutics. Emerging concepts show that the minor subset of glioblastoma stem cells (GSCs) accounts for tumorigenicity, representing the true target for innovative therapies in GBM.

Methods

Here, we isolated and established functionally stable and steadily expanding GSCs lines from a large cohort of GBM patients. The molecular, functional and antigenic landscape of GBM tissues and their derivative GSCs was highlited in a side-by-side comprehensive genomic and transcriptomic characterization by ANOVA and Fisher’s exact tests. GSCs’ physio-pathological hallmarks were delineated by comparing over time in vitro and in vivo their expansion, self-renewal and tumorigenic ability with hierarchical linear models for repeated measurements and Kaplan–Meier method. Candidate biomarkers performance in discriminating GBM patients’ classification emerged by classification tree and patients’ survival analysis.

Results

Here, distinct biomarker signatures together with aberrant functional programs were shown to stratify GBM patients as well as their sibling GSCs population into TCGA clusters. Of importance, GSCs cells were demonstrated to fully resemble over time the molecular features of their patient of origin. Furthermore, we pointed out the existence of distinct GSCs subsets within GBM classification, inherently endowed with different self-renewal and tumorigenic potential. Particularly, classical GSCs were identified by more undifferentiated biological hallmarks, enhanced expansion and clonal capacity as compared to the more mature, relatively slow-propagating mesenchymal and proneural cells, likely endowed with a higher potential for infiltration either ex vivo or in vivo. Importantly, the combination of DCX and EGFR markers, selectively enriched among GSCs pools, almost exactly predicted GBM patients’ clusters together with their survival and drug response.

Conclusions

In this study we report that an inherent enrichment of distinct GSCs pools underpin the functional inter-cluster variances displayed by GBM patients. We uncover two selectively represented novel functional biomarkers capable of discriminating GBM patients’ stratification, survival and drug response, setting the stage for the determination of patient-tailored diagnostic and prognostic strategies and, mostly, for the design of appropriate, patient-selective treatment protocols.
Higher sensitive selective spectrofluorometric determination of ritonavir in the presence of nirmatrelvir: application to new FDA approved co-packaged COVID-19 pharmaceutical dosage and spiked human plasma
Authors: Imam Mohamed S. , Abdelazim Ahmed H. , Ramzy Sherif , Almrasy Ahmed A. , Gamal Mohammed , Batubara Afnan S.
Published: September 2023

Background

Ritonavir was recently combined with nirmatrelvir in a new approved co-packaged medication form for the treatment of COVID-19. Quantitative analysis based on fluorescence spectroscopy measurement was extensively used for sensitive determination of compounds exhibited unique fluorescence features.

Objective

The main objective of this work was to develop higher sensitive cost effective spectrofluorometric method for selective determination of ritonavir in the presence of nirmatrelvir in pure form, pharmaceutical tablet as well as in spiked human plasma.

Methods

Ritonavir was found to exhibit unique native emission fluorescence at 404 nm when excited at 326 nm. On the other hand, nirmatrelvir had no emission bands when excited at 326 nm. This feature allowed selective determination of ritonavir without any interference from nirmatrelvir. The variables affecting fluorescence intensity of ritonavir were optimized in terms of sensitivity parameters and principles of green analytical chemistry. Ethanol was used a green solvent which provided efficient fluorescence intensity of the cited drug.

Results

The method was validated in accordance with the ICH Q2 (R1) standards in terms of linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and specificity. The described method was successfully applied for ritonavir assay over the concentration range of 2.0–20.0 ng/mL.

Conclusion

Ritonavir determination in the spiked human plasma was successfully done with satisfactory accepted results.
An exploratory study on the possibilities of microalgal biotechnology to obtain the essential 6Li isotope as fusion fuel
Authors: García-Balboa Camino , Martínez-Alesón Paloma , López-Rodas Victoria , Costas Eduardo Costas , Díaz Marta Fernández
Published: September 2023

Future energy supply needs to overcome two challenges: environmental impact and dependence on geopolitically unstable countries. A very promising alternative is based on lithium, an element for batteries, and whose isotope 6Li will be essential in nuclear fusion. The objective of this research has been to determine if it is possible to achieve isotopic fractionation of lithium through a process mediated by microalgae. For this purpose, Chlamydomonas reinhardtii was selected and grown in presence of 5 mg/L of lithium. Results revealed that this specie survives at the selected lithium concentration, discriminates isotopes and preferentially capture 6Li (6δ = 10.029 ± 3.307) through a process independent of the cellular growth. Concomitate recovered up 0.206 mg/L of lithium along a process of 21 days. The result of this study lets to affirm that Chlamydomonas reinhardtii might be used to obtain lithium enriched in the lighter isotope.
Influence of the timing of biological treatment initiation on Juvenile Idiopathic Arthritis long-term outcomes
Authors: Oliveira Ramos Filipa , Rodrigues Ana Maria , Melo Ana Teresa , Aguiar Francisca , Brites Luísa , Azevedo Soraia , Duarte Ana Catarina , Gomes José António Melo , Furtado Carolina , Mourão Ana Filipa , Sequeira Graça , Cunha Inês , Figueira Ricardo , Santos Maria José , Fonseca João Eurico
Published: September 2023

Background

Juvenile idiopathic arthritis (JIA) treatment is aimed at inducing remission to prevent joint destruction and disability. However, it is unclear what is the long-term impact on health-related outcomes of the timing of biological disease-modifying antirheumatic drug (bDMARD) initiation in JIA. Our aim was to evaluate the long-term impact of the time between JIA onset and the initiation of a bDMARD in achieving clinical remission, on physical disability and health-related quality of life (HRQoL).

Methods

Adult JIA patients registered in the Rheumatic Diseases Portuguese Register (Reuma.pt) and ever treated with bDMARD were included. Data regarding socio-demographic, JIA-related characteristics, disease activity, physical disability (HAQ-DI), HRQoL (SF-36), and treatments were collected at the last visit. Patients were divided into 3 groups (≤ 2 years, 2–5 years, or > 5 years), according to the time from disease onset to bDMARD initiation. Regression models were obtained considering remission on/off medication, HAQ-DI, SF-36, and joint surgeries as outcomes and time from disease onset to bDMARD start as an independent variable.

Results

Three hundred sixty-one adult JIA patients were evaluated, with a median disease duration of 20.3 years (IQR 12.1; 30.2). 40.4% had active disease, 35.1% were in remission on medication, and 24.4% were in drug-free remission; 71% reported some degree of physical disability. Starting a bDMARD > 5 years after disease onset decreased the chance of achieving remission off medication (OR 0.24; 95% CI 0.06, 0.92; p = 0.038). Patients who started a bDMARD after 5 years of disease onset had a higher HAQ and worse scores in the physical component, vitality, and social function domains of SF-36, and more joint surgeries when compared to an earlier start.

Conclusion

Later initiation of bDMARDs in JIA is associated with a greater physical disability, worse HRQoL, and lower chance of drug-free remission in adulthood.