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BMC Nephrology May 2024Protein carbamylation, a post-translational protein modification primarily driven by urea, independently associates with adverse clinical outcomes in patients with CKD.... (Comparative Study)
Comparative Study
BACKGROUND
Protein carbamylation, a post-translational protein modification primarily driven by urea, independently associates with adverse clinical outcomes in patients with CKD. Biomarkers used to quantify carbamylation burden have mainly included carbamylated albumin (C-Alb) and homocitrulline (HCit, carbamylated lysine). In this study, we aimed to compare the prognostic utility of these two markers in order to facilitate comparisons of existing studies employing either marker alone, and to inform future carbamylation studies.
METHODS
Both serum C-Alb and free HCit levels were assayed from the same timepoint in 1632 individuals with CKD stages 2-4 enrolled in the prospective Chronic Renal Insufficiency Cohort (CRIC) study. Adjusted Cox proportional hazard models were used to assess risks for the outcomes of death (primary) and end stage kidney disease (ESKD) using each marker. C-statistics, net reclassification improvement, and integrated discrimination improvement were used to compare the prognostic value of each marker.
RESULTS
Participant demographics included mean (SD) age 59 (11) years; 702 (43%) females; 700 (43%) white. C-Alb and HCit levels were positively correlated with one another (Pearson correlation coefficient 0.64). Higher C-Alb and HCit levels showed similar increased risk of death (e.g., the adjusted hazard ratio [HR] for death in the 4th carbamylation quartile compared to the 1st was 1.90 (95% confidence interval [CI] 1.35-2.66) for C-Alb, and 1.89 [1.27-2.81] for HCit; and on a continuous scale, the adjusted HR for death using C-Alb was 1.24 [1.11 to 1.39] per standard deviation increase, and 1.27 [1.10-1.46] using HCit). Both biomarkers also had similar HRs for ESKD. The C-statistics were similar when adding each carbamylation biomarker to base models (e.g., for mortality models, the C-statistic was 0.725 [0.707-0.743] with C-Alb and 0.725 [0.707-0.743] with HCit, both compared to a base model 0.723). Similarities were also observed for the net reclassification improvement and integrated discrimination improvement metrics.
CONCLUSIONS
C-Alb and HCit had similar performance across multiple prognostic assessments. The markers appear readily comparable in CKD epidemiological studies.
Topics: Humans; Female; Citrulline; Male; Protein Carbamylation; Biomarkers; Middle Aged; Renal Insufficiency, Chronic; Aged; Prospective Studies; Risk Assessment; Kidney Failure, Chronic; Prognosis; Proportional Hazards Models; Serum Albumin
PubMed: 38816682
DOI: 10.1186/s12882-024-03619-6 -
BMJ Open May 2024Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a...
INTRODUCTION
Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has been supported by a recent small case series.
METHODS AND ANALYSIS
SWIPED (Slow Wave Induction by Propofol to Eliminate Depression) phase I is an ongoing open-label, single-arm trial that assesses the safety and feasibility of using propofol to enhance SWS in older adults with LL-TRD. The study is enrolling 15 English-speaking adults over age 60 with LL-TRD. Participants will receive two propofol infusions 2-6 days apart. Propofol infusions are individually titrated to maximise the expression of EEG slow waves. Preinfusion and postinfusion sleep architecture are evaluated through at-home overnight EEG recordings acquired using a wireless headband equipped with dry electrodes. Sleep EEG recordings are scored manually. Key EEG measures include sleep slow wave activity, SWS duration and delta sleep ratio. Longitudinal changes in depression, suicidality and anhedonia are assessed. Assessments are performed prior to the first infusion and up to 10 weeks after the second infusion. Cognitive ability is assessed at enrolment and approximately 3 weeks after the second infusion.
ETHICS AND DISSEMINATION
The study was approved by the Washington University Human Research Protection Office. Recruitment began in November 2022. Dissemination plans include presentations at scientific conferences, peer-reviewed publications and mass media. Positive results will lead to a larger phase II randomised placebo-controlled trial.
TRIAL REGISTRATION NUMBER
NCT04680910.
Topics: Humans; Propofol; Cognitive Dysfunction; Aged; Sleep, Slow-Wave; Electroencephalography; Male; Anesthetics, Intravenous; Depressive Disorder, Treatment-Resistant; Female; Middle Aged; Clinical Trials, Phase I as Topic
PubMed: 38816055
DOI: 10.1136/bmjopen-2024-087516 -
BMJ Open May 2024Fluorine-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) CT imaging has been used in many inflammatory and infectious conditions to differentiate areas of...
Can FDG-PET/CT imaging be used to predict decline in quality of life in interstitial lung disease? A prospective study of the relationship between FDG uptake and quality of life in a UK outpatient setting.
BACKGROUND
Fluorine-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) CT imaging has been used in many inflammatory and infectious conditions to differentiate areas of increased metabolic activity. FDG uptake differs between areas of normal lung parenchyma and interstitial lung disease (ILD).
OBJECTIVES
In this study, we investigated whether FDG-PET/CT parameters were associated with a change in the quality of life (QoL) in patients with ILD over 4 years of follow-up.
METHODS
Patients underwent PET-CT imaging at diagnosis and were followed up with annual QoL assessment using the St George's Respiratory Questionnaire (SGRQ) until death or 4 years of follow-up. Maximum standard uptake value (SUVmax) and Tissue-to-Background Ratio (TBR) were assessed against SGRQ overall and subscale scores.
RESULTS
193 patients (94 patients in the idiopathic pulmonary fibrosis (IPF) subgroup and 99 patients in the non-IPF subgroup) underwent baseline FDG-PET/CT imaging and QoL assessment. Weak-to-moderate correlation was observed between baseline SUVmax and SGRQ scores in both ILD subgroups. No relationship was observed between baseline SUVmax or TBR and change in SGRQ scores over 4 years of follow-up. In the IPF subgroup, surviving patients reported a decline in QoL at 4 years post diagnosis whereas an improvement in QoL was seen in surviving patients with non-IPF ILD.
CONCLUSIONS
Weak-to-moderate positive correlation between baseline SUVmax and SGRQ scores was observed in both ILD subgroups (IPF:r=0.187, p=0.047, non-IPF: r=0.320, p=0.001). However, baseline SUVmax and TBR were not associated with change in QoL in patients with IPF and non-IPF ILD over 4 years of follow-up. At 4 years post diagnosis, surviving patients with IPF reported declining QoL whereas improvement was seen in patients with ILD who did not have IPF.
Topics: Humans; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Quality of Life; Male; Female; Lung Diseases, Interstitial; Prospective Studies; Aged; Middle Aged; United Kingdom; Radiopharmaceuticals; Surveys and Questionnaires; Idiopathic Pulmonary Fibrosis
PubMed: 38816048
DOI: 10.1136/bmjopen-2023-081103 -
BMJ Open May 2024Electronic health record (EHR) systems are used extensively in healthcare; their design can influence clinicians' behaviour. We conducted a systematic review of...
OBJECTIVES
Electronic health record (EHR) systems are used extensively in healthcare; their design can influence clinicians' behaviour. We conducted a systematic review of EHR-based interventions aimed at changing the clinical practice of general practitioners in the UK, assessed their effectiveness and applied behaviour change theory to identify lessons for other settings.
DESIGN
Mixed methods systematic review.
DATA SOURCES
MEDLINE, EMBASE, CENTRAL and APA PsycINFO were searched up to March 2023.
ELIGIBILITY CRITERIA
Quantitative and qualitative findings from randomised controlled trials (RCTs) controlled before-and-after studies and interrupted time series of EHR-based interventions in UK general practice were included.
DATA EXTRACTION AND SYNTHESIS
Quantitative synthesis was based on Cochrane's Synthesis without Meta-analysis. Interventions were categorised using the Behaviour Change Wheel and MINDSPACE frameworks and effectiveness determined by vote-counting using direction of effect. Inductive thematic synthesis was used for qualitative studies.
RESULTS
Database searching identified 3824 unique articles; 10 were included (from 2002 to 2021), comprising eight RCTs and two associated qualitative studies. Four of seven quantitative studies showed a positive effect on clinician behaviour and three on patient-level outcomes. Behaviour change techniques that may trigger emotions and required less cognitive engagement appeared to have positive effects. Qualitative findings indicated that interventions reassured clinicians of their decisions but were sometimes ignored.
CONCLUSION
Despite widespread use, there is little high quality, up-to-date experimental evidence evaluating the effectiveness of EHR-based interventions in UK general practice. The evidence suggested EHR-based interventions may be effective at changing behaviour. Persistent, simple action-oriented prompts appeared more effective than complex interventions requiring greater cognitive engagement. However, studies lacked detail in intervention design and theory behind design choices. Future research should seek to optimise EHR-based behaviour change intervention design and delineate limitations, providing theory-based justification for interventions. This will be of increasing importance with the growing use of EHRs to influence clinicians' decisions.
PROSPERO REGISTRATION NUMBER
CRD42022341009.
Topics: Humans; Electronic Health Records; United Kingdom; General Practitioners; Practice Patterns, Physicians'; General Practice; Behavior Therapy
PubMed: 38816046
DOI: 10.1136/bmjopen-2023-080546 -
The Journal of Biological Chemistry May 2024While the deubiquitinase ATXN3 has been implicated as a potential oncogene in various types of human cancers, its role in colon adenocarcinoma remains understudied....
While the deubiquitinase ATXN3 has been implicated as a potential oncogene in various types of human cancers, its role in colon adenocarcinoma remains understudied. Surprisingly, our findings demonstrate that ATXN3 exerts an anti-tumor effect in human colon cancers through potentiating Galectin-9-induced apoptosis. CRISPR-mediated ATXN3 deletion unexpectedly intensified colon cancer growth both in vitro and in xenograft colon cancers. At the molecular level, we identified ATXN3 as a bona fide deubiquitinase specifically targeting Galectin-9, as ATXN3 interacted with and inhibited Galectin-9 ubiquitination. Consequently, targeted ATXN3 ablation resulted in reduced Galectin-9 protein expression, thereby diminishing Galectin-9-induced colon cancer apoptosis and cell growth arrest. The ectopic expression of Galectin-9 fully reversed the growth of ATXN3-null colon cancer in mice. Furthermore, immunohistochemistry staining revealed a significant reduction in both ATXN3 and Galectin-9 protein expression, along with a positive correlation between them in human colon cancer. Our study identifies the first Galectin-9-specific deubiquitinase and unveils a tumor-suppressive role of ATXN3 in human colon cancer.
PubMed: 38815863
DOI: 10.1016/j.jbc.2024.107415 -
The Journal of Biological Chemistry May 2024Extracellular secretion is an essential mechanism for α-synuclein (α-syn) proteostasis. Although it was reported that neuronal activity affects α-syn secretion, the...
Extracellular secretion is an essential mechanism for α-synuclein (α-syn) proteostasis. Although it was reported that neuronal activity affects α-syn secretion, the underlying mechanisms remain unclear. Here, we investigated the autophagic processes that regulate the physiological release of α-syn in mouse primary cortical neurons and SH-SY5Y cells. Stimulating neuronal activity with glutamate or depolarization with high KCl enhanced α-syn secretion. This glutamate-induced α-syn secretion was blocked by a mixture of NMDA receptor antagonist AP5 and AMPA receptor antagonist NBQX, as well as by cytosolic Ca chelator BAPTA-AM. Additionally, mTOR inhibitor rapamycin increased α-syn and p62/SQSTM1 (p62) secretion, and this effect of rapamycin was reduced in primary cortical neurons deficient in the autophagy regulator beclin 1 (derived from BECN1 mice). Glutamate-induced α-syn and p62 secretion was suppressed by knockdown of ATG5, which is required for autophagosome formation. Glutamate increased LC3-II generation and decreased intracellular p62 levels, and the increase in LC3-II levels was blocked by BAPTA-AM. Moreover, glutamate promoted co-localization of α-syn with LC3-positive puncta, but not with LAMP1-positive structures in the neuronal somas. Glutamate-induced α-syn and p62 secretion was also reduced by knockdown of RAB8A, which is required for autophagosome fusion with the plasma membrane. Collectively, these findings suggest that stimulating neuronal activity mediates autophagic α-syn secretion in a cytosolic Ca-dependent manner, and autophagosomes may participate in autophagic secretion by functioning as α-syn carriers.
PubMed: 38815862
DOI: 10.1016/j.jbc.2024.107419 -
American Society of Clinical Oncology... Jun 2024The management of axillary lymph nodes in breast cancer is continually evolving. Recent data now support omitting axillary lymph node dissection (ALND) in most patients... (Review)
Review
Personalizing Locoregional Therapy in Patients With Breast Cancer in 2024: Tailoring Axillary Surgery, Escalating Lymphatic Surgery, and Implementing Evidence-Based Hypofractionated Radiotherapy.
The management of axillary lymph nodes in breast cancer is continually evolving. Recent data now support omitting axillary lymph node dissection (ALND) in most patients with metastases in up to two sentinel lymph nodes (SLNs) during upfront surgery and those with residual isolated tumor cells after neoadjuvant chemotherapy (NACT). In the upfront surgery setting, ALND is still indicated, however, in patients with clinically node-positive breast cancer or more than two positive SLNs and, after NACT, in case of residual micrometastases and macrometastases. Omission of the sentinel lymph node biopsy (SLNB) can be considered in many postmenopausal patients with small luminal breast cancer, particularly when axillary ultrasound is negative. Several randomized controlled trials (RCTs) are currently aiming at eliminating the remaining indications for ALND and also establishing omission of SLNB in a broader patient population. The movement to deescalate axillary staging is in part because of the association between ALND and lymphedema, which is swelling of an extremity because of lymphatic damage and obstructed lymphatic drainage. To reduce the risk of developing this condition, patients undergoing ALND can undergo reverse mapping of the axilla and immediate reconstruction or bypass of the lymphatics from the involved extremity. Decongestion and compression are the foundation of conservative treatment for established lymphedema, while lymphovenous bypass and lymph node transfer are surgical procedures to address the physiologic dysfunction. Radiotherapy is an essential component of breast locoregional therapy: more than three decades of radiation research has optimized treatment according to patient's risk of local recurrence while substantially reducing the number of treatment visits. High-quality RCTs have shown the efficacy and safety of hypofractionation-more than 2Gy radiation dose per treatment (fraction)-significantly reducing the burden of radiotherapy treatment for many patients with breast cancer. In 2024, guidelines recommend no more than 15-16 fractions for whole-breast and nodal radiotherapy, with some recommending five fractions for whole-breast radiotherapy. In addition, simultaneous integrated boost (SIB) has been shown to be noninferior to sequential boost with regards to ipsilateral breast tumor recurrence with similar or reduced long-term side effects, also reducing overall treatment length. Further RCTs are underway investigating other indications for five fractions, including SIB and regional node irradiation, such that, in future, it may be possible for the majority of breast radiotherapy patients to be treated with a 1-week course. This manuscript serves to outline the latest updates on axillary surgical staging, lymphatic surgery, and evidence-based radiotherapy in the treatment of breast cancer.
Topics: Humans; Breast Neoplasms; Female; Axilla; Lymph Node Excision; Radiation Dose Hypofractionation; Lymphatic Metastasis; Sentinel Lymph Node Biopsy; Combined Modality Therapy; Lymph Nodes; Neoplasm Staging; Neoadjuvant Therapy
PubMed: 38815195
DOI: 10.1200/EDBK_438776 -
PloS One 2024Non-small cell lung cancer (NSCLC) is one of the most common malignancies worldwide, and oxidative stress plays a crucial role in its development. Juglone, a naturally...
Non-small cell lung cancer (NSCLC) is one of the most common malignancies worldwide, and oxidative stress plays a crucial role in its development. Juglone, a naturally occurring naphthoquinone in J. mandshurica, exhibits significant cytotoxic activity against various cancer cell lines. However, whether the anticancer activity of juglone is associated with oxidative stress remains unexplored. In this study, mouse Lewis lung cancer (LLC) and human non-small cell lung cancer A549 cells were used to explore the anticancer mechanisms of juglone. Juglone inhibited LLC and A549 cells viability, with IC50 values of 10.78 μM and 9.47 μM, respectively, for 24 h, and substantially suppressed the migration and invasion of these two lung cancer cells. Additionally, juglone arrested the cell cycle, induced apoptosis, increased the cleavage of caspase 3 and the protein expression of Bax and Cyt c, and decreased the protein expression of Bcl-2 and caspase-3. Furthermore, juglone treatment considerably increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, but suppressed glutathione peroxidase 4 (GPX4) and superoxide dismutase (SOD) activities. It also inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which was attenuated by 1,3-diCQA (an activator of PI3K/Akt). Moreover, N-acetylcysteine (a ROS scavenger) partially reversed the positive effects of juglone in terms of migration, invasion, ROS production, apoptosis, and PI3K/Akt pathway-associated protein expression. Finally, in tumor-bearing nude mouse models, juglone inhibited tumor growth without any apparent toxicity and significantly induced apoptosis in NSCLC cells. Collectively, our findings suggest that juglone triggers apoptosis via the ROS-mediated PI3K/Akt pathway. Therefore, juglone may serve as a potential therapeutic agent for the treatment of NSCLC.
Topics: Naphthoquinones; Carcinoma, Non-Small-Cell Lung; Reactive Oxygen Species; Humans; Animals; Apoptosis; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Lung Neoplasms; Mice; Signal Transduction; A549 Cells; Cell Movement; Carcinoma, Lewis Lung; Cell Line, Tumor
PubMed: 38814975
DOI: 10.1371/journal.pone.0299921 -
PloS One 2024Women living with HIV (WLWH) have high risk of developing cervical cancer. High- risk Human papillomavirus (hrHPV) is the single most important cause of cervical cancer....
BACKGROUND
Women living with HIV (WLWH) have high risk of developing cervical cancer. High- risk Human papillomavirus (hrHPV) is the single most important cause of cervical cancer. Vaccination for and early detection of pre-malignant cervical changes, through cervical cancer screening contributes to prevention of cervical cancer. This study sought to determine the prevalence of HPV among WLWH, genotypes present and the risk factors associated with cervical cancer development.
METHODS AND FINDINGS
An analytical cross-sectional study of 250 sexually active women aged 18 years and above, attending HIV clinic at a tertiary health facility in Accra. Demographic data collection and risk factor assessments were done using interviewer-administered questionnaire, and patient records. Cervical swabs were collected and tested for HPV using real-time PCR assays. Genotype analysis was performed on 92 samples. Descriptive statistics and logistic regression analysis were used to establish associations between hrHPV and risk factors among WLWH. Approximately 60% of study participants tested positive for HPV. The prevalence of hr-HPV among WLH was 44.4%. Factors identified to be protective of hrHPV were employment (AOR = 0.19, 95% CI = 0.06, 0.56, p = 0.003) and highly active antiretroviral therapy (HAART) Tenofovir-Lamivudine-Ritonavir-Lopinavir (TLRL) (AOR = 0.30, 95% CI = 0.09, 0.95, p = 0.04). Women with HIV diagnosis within 6 to10 years (AOR = 4.89, 95% CI = 1.05, 22.70, p = 0.043) and diagnosis >10 years (AOR = 8.25, 95% CI = 1.24, 54.84, p = 0.029) had higher odds of hrHPV. Approximately 25% of samples analysed tested positive for hr-HPV group 1 (genotypes 16, 18, 31, 33, 35, 39, 45,51, 52, 56, 58, 69) and 46.8% for multiple HPV genotypes.
CONCLUSION
A high prevalence of genotypes that include high risk genotypes 16 and 18 and multiple HPV infections was found among WLWH. Almost half of the women screened had high-risk HPV and were prone to cervical cancer without their knowledge. Regular HPV screening is recommended for high-risk patient groups.
Topics: Humans; Female; Adult; Papillomavirus Infections; HIV Infections; Risk Factors; Prevalence; Ghana; Cross-Sectional Studies; Middle Aged; Young Adult; Uterine Cervical Neoplasms; Adolescent; Papillomaviridae; Tertiary Care Centers
PubMed: 38814956
DOI: 10.1371/journal.pone.0303535 -
PloS One 2024China is in a phase of high-quality development, where scientific and technological innovations are serving as the primary driving force for its development strategy....
China is in a phase of high-quality development, where scientific and technological innovations are serving as the primary driving force for its development strategy. This emphasis on innovations is expected to fuel the upgrading of the industrial structure. This study investigates the role of scientific and technological innovations in industrial upgradation in China using spatial econometric analysis. Leveraging the data of 31 provinces of China from 2005 to 2022, we employed a spatial Durbin model to determine the spatial spillover effects of scientific and technological innovations on industrial upgradation. Our findings reveal the significant positive spatial spillover effects, indicating that provinces with higher levels of scientific and technological innovations tend to experience greater industrial upgradation, which in turn contributes to regional economic development. Furthermore, the findings suggest a strong spatial correlation between innovation and the upgrading of industrial structures, indicating that regional innovations have the potential to drive China's industrial upgradation. These results underscore the critical role of scientific and technological innovations in promoting industrial upgradation and regional development in China.
Topics: China; Industrial Development; Inventions; Models, Econometric; Economic Development; Humans; Technology; Industry
PubMed: 38814955
DOI: 10.1371/journal.pone.0304344