Mast Cells and Their Related Gene HK-1 are Closely Associated with Discogenic Low Back Pain: A Bioinformatics and Clinical Sample Study.

Background: Low back pain (LBP) is primarily caused by intervertebral disc degeneration (IVDD). Immune cells penetrating nucleus pulposus (NP) tissues may play an important role in generating IVDD and LBP. Methods: The clinical data from 100 cases of IVDD patients was initially analyzed retrospectively. Subsequently, peripheral blood and NP tissues from 41 IVDD patients were gathered for a validated investigation. Among them, ribosome-removed-RNA sequencing (RNA-seq) was performed on 10 cases of NP tissues of specific classifications (VAS 3 and Pfirrmann 3 were used as the controls, while patients with VAS 6 and Pfirrmann 5 were used as the experimental group). Differentially expressed genes (DEGs) were identified for the subsequent bioinformatics analysis. Further methods to confirm the underlying cause of discogenic LBP included mast cell immunohistochemistry (IHC), 12 cytokine detection, Western blot (WB), and real-time polymerase chain reaction (RT-PCR). Results: Discogenic LBP and IVDD severity are strongly associated, and immunological cell infiltration has been demonstrated to be a significant factor in LBP by bioanalytical research. Tryptase-positive mast cells were found to be significantly more abundant in the VAS 6 NP tissues of IVDD patients than in the VAS 3 NP tissues. It was initially demonstrated that IVDD and LBP were significantly impacted by hemokinin-1 (HK-1), the mast cell-related gene. Furthermore, blood levels of interleukin 12 p70 (IL-12P70) are noticeably elevated and strongly correlated with HK-1, indicating that HK-1 may be involved in the regulation of mast cell activity and IL-12P70 production. Conclusion: The severity of LBP was observed to be positively correlated with the IVDD Pfirrmann grading. Further research indicates that patients with IVDD may experience persistent low back pain due to HK-1 activation of mast cells and the release of the cytokine IL12P70. This work will offer new insights into the diagnosis and treatment of discogenic LBP.

Automatic high-throughput and non-invasive selection of sperm at the biochemical level.

BACKGROUND: Sperm selection, a key step in assisted reproductive technology (ART), has long been restrained at the preliminary physical level (morphology or motility); however, subsequent fertilization and embryogenesis are complicated biochemical processes. Such an enormous "gap" poses tough problems for couples dealing with infertility, especially patients with severe/total asthenozoospermia . METHODS: We developed a biochemical-level, automatic-screening/separation, smart droplet-TO-hydrogel chip (BLASTO-chip) for sperm selection. The droplet can sense the pH change caused by sperm's respiration products and then transforms into a hydrogel to be selected out. FINDINGS: The BLASTO-chip system can select biochemically active sperm with an accuracy of over 90%, and its selection efficiency can be flexibly tuned by nearly 10-fold. All the substances in the system were proven to be biosafe via evaluating mice fertilization and offspring health. Live sperm down to 1% could be enriched by over 76-fold to 76%. For clinical application to patients with severe/total asthenozoospermia, the BLASTO-chip could select live sperm from human semen samples containing 10% live but 100% immotile sperm. The rates of fertilization, cleavage, early embryos, and blastocysts were drastically elevated from 15% to 70.83%, 10% to 62.5%, 5% to 37.5%, and 0% to 16.67%, respectively. CONCLUSIONS: The BLASTO-chip represents a real biochemical-level technology for sperm selection that is completely independent of sperm's motility. It can be a powerful tool in ART, especially for patients with severe/total asthenozoospermia. FUNDING: This work was funded by the Ministry of Science and Technology of China, the Ministry of Education of China, and the Shenzhen-Hong Kong Hetao Cooperation Zone.

Relationship of mTORC1 and ferroptosis in tumors.

Ferroptosis is a novel form of programmed death, dependent on iron ions and oxidative stress, with a predominant intracellular form of lipid peroxidation. In recent years, ferroptosis has gained more and more interest of people in the treatment mechanism of targeted tumors. mTOR, always overexpressed in the tumor, and controlling cell growth and metabolic activities, has an important role in both autophagy and ferroptosis. Interestingly, the selective types of autophay plays an important role in promoting ferroptosis, which is related to mTOR and some metabolic pathways (especially in iron and amino acids). In this paper, we list the main mechanisms linking ferroptosis with mTOR signaling pathway and further summarize the current compounds targeting ferroptosis in these ways. There are growing experimental evidences that targeting mTOR and ferroptosis may have effective impact in many tumors, and understanding the mechanisms linking mTOR to ferroptosis could provide a potential therapeutic approach for tumor treatment.

Late Positivity Correlates with Subjective Reports: Evidence from the Low-frequency and High-frequency Reporting Tasks.

Identifying the neural correlates of consciousness (NCCs) is an important way to understand the fundamental nature of consciousness. By recording event-related potentials (ERPs) using EEG, researchers have found three potential electrophysiological NCCs: early positive correlate of consciousness (enhanced P1), visual awareness negativity (VAN), and late positivity (LP). However, LP may reflect post-perceptual processing associated with subjective reports rather than consciousness per se. The present experiment investigated the relationship between LP and subjective reports. We adopted two subjective reporting tasks that differed in the requirement for subjective reports. In the low-frequency reporting task, participants needed to report whether they saw the target picture in 25% of trials, whereas in the high-frequency reporting task, participants needed to report whether they saw the target picture in each trial. Behavioral results showed that the hit rates were lower and false alarm rates were higher on reporting trials in low-frequency reporting tasks than on reporting trials in high-frequency reporting tasks. Unexpectedly, VAN was larger on reporting trials in the low-frequency reporting task than on reporting trials in the high-frequency reporting task. Importantly, our ERP results showed that LP was larger on reporting trials in the high-frequency reporting task than on reporting trials in the low-frequency reporting task. Thus, our findings indicated that when the frequency of reports was increased, the task relevance of the stimuli increased, which led to larger LP amplitudes. These findings suggest that LP correlates with subjective reports.

Electroacupuncture reduced airway inflammation by activating somatosensory-sympathetic pathways in allergic asthmatic rats.

BACKGROUND: Electroacupuncture (EA) treatment is efficacious in patients with respiratory disorders, although the mechanisms of its action in lung-function protection are poorly understood. This study aimed to explore the neuroanatomical mechanisms of EA stimulation at the BL13 acupoint (Feishu, EA-BL13) improvement in asthma. METHODS: Allergic asthma was induced by intranasal 2.0% ovalbumin (OVA) instillation combined with intraperitoneal injection of the 10.0% OVA. The levels of interleukin (IL)-4 and IL-5 were detected by enzyme-linked immunosorbent assay. Hematoxylin and eosin and periodic acid-schiff stain were used to evaluate inflammatory cell infiltration and mucus secretion. Cellular oncogene fos induction in neurons after EA stimulation was detected by immunofluorescent staining. The mRNA expression levels of adrenergic receptors were quantified with real-time polymerase chain reaction. RESULTS: EA improved airway inflammation and mucus secretion mainly by activating somatosensory-sympathetic pathways (P <0.001). Briefly, the intermediolateral (IML) nuclei of the spinal cord received signals from somatic EA stimulation and then delivered the information via the sympathetic trunk to the lung. Excited sympathetic nerve endings in lung tissue released large amounts of catecholamines that specifically activated the ß2 adrenergic receptor (ß2AR) on T cells (P <0.01) and further decreased the levels of IL-4 and IL-5 (P <0.001) through the cyclic adenosine monophosphate/protein kinase A signaling pathway. CONCLUSION: This study provided a new explanation and clinical basis for the use of EA-BL13 as a treatment for allergic asthma in both the attack and remission stages and other respiratory disorders related to airway inflammation.

TopDIA: A Software Tool for Top-Down Data-Independent Acquisition Proteomics.

Top-down mass spectrometry is widely used for proteoform identification, characterization, and quantification owing to its ability to analyze intact proteoforms. In the last decade, top-down proteomics has been dominated by top-down data-dependent acquisition mass spectrometry (TD-DDA-MS), and top-down data-independent acquisition mass spectrometry (TD-DIA-MS) has not been well studied. While TD-DIA-MS produces complex multiplexed tandem mass spectrometry (MS/MS) spectra, which are challenging to confidently identify, it selects more precursor ions for MS/MS analysis and has the potential to increase proteoform identifications compared with TD-DDA-MS. Here we present TopDIA, the first software tool for proteoform identification by TD-DIA-MS. It generates demultiplexed pseudo MS/MS spectra from TD-DIA-MS data and then searches the pseudo MS/MS spectra against a protein sequence database for proteoform identification. We compared the performance of TD-DDA-MS and TD-DIA-MS using Escherichia coli K-12 MG1655 cells and demonstrated that TD-DIA-MS with TopDIA increased proteoform and protein identifications compared with TD-DDA-MS.

Joint association and interaction of birth weight and lifestyle with hypertension: A cohort study in UK Biobank.

Low birth weight and unhealthy lifestyle are both associated with an increased risk of hypertension. The authors aimed to assess the joint association and interaction of birth weight and lifestyle with incident hypertension. The authors included 205 522 participants free of hypertension at baseline from UK Biobank. A healthy lifestyle score was constructed using information on body mass index, physical activity, diet, smoking status and alcohol intake. Cox proportional hazard models were used to investigate the impact of birth weight, healthy lifestyle score and their joint effect on hypertension. The authors documented 13 548 (6.59%) incident hypertension cases during a median of 8.6 years of follow-up. The multivariate adjusted hazard ratios and 95% confidence intervals were 1.12 (1.09, 1.15) per kg lower birth weight and 0.76 (0.75, 0.77) per score increment in healthy lifestyle score. Healthy lifestyle reduced the risk of hypertension in any category of different birth weight groups. The preventive effect of healthy lifestyle on hypertension was the most pronounced at lower birth weight with <2500 g and 2500-2999 g, respectively. Addictive interaction between birth weight and healthy lifestyle score was observed with the relative excess risk due to interaction of 0.04 (0.03, 0.05). Our findings emphasized the importance of healthy lifestyle for hypertension prevention, especially among the high-risk population with lower birth weight.

Lowering Entropic Barriers in Triplex DNA Switches Facilitating Biomedical Applications at Physiological pH.

Triplex DNA switches are attractive allosteric tools for engineering smart nanodevices, but their poor triplex-forming capacity at physiological conditions limited the practical applications. To address this challenge, we proposed a low-entropy barrier design to facilitate triplex formation by introducing a hairpin duplex linker into the triplex motif, and the resulting triplex switch was termed as CTNSds. Compared to the conventional clamp-like triplex switch, CTNSds increased the triplex-forming ratio from 30 % to 91 % at pH 7.4 and stabilized the triple-helix structure in FBS and cell lysate. CTNSds was also less sensitive to free-energy disturbances, such as lengthening linkers or mismatches in the triple-helix stem. The CTNSds design was utilized to reversibly isolate CTCs from whole blood, achieving high capture efficiencies (>86 %) at pH 7.4 and release efficiencies (>80 %) at pH 8.0. Our approach broadens the potential applications of DNA switches-based switchable nanodevices, showing great promise in biosensing and biomedicine.

Thiamine as a metabolic resuscitator after in-hospital cardiac arrest.

INTRODUCTION: Elevated lactate is associated with mortality after cardiac arrest. Thiamine, a cofactor of pyruvate dehydrogenase, is necessary for aerobic metabolism. In a mouse model of cardiac arrest, thiamine improved pyruvate dehydrogenase activity, survival and neurologic outcome. AIM: To determine if thiamine would decrease lactate and increase oxygen consumption after in-hospital cardiac arrest. METHODS: Randomized, double-blind, placebo-controlled phase II trial. Adult patients with arrest within 12 hours, mechanically ventilated, with lactate ≥ 3 mmol/L were included. Randomization was stratified by lactate > 5 or ≤ 5 mmol/L. Thiamine 500 mg or placebo was administered every 12 hours for 3 days. The primary outcome of lactate was checked at baseline, 6, 12, 24, and 48 hours, and compared using a linear mixed model, accounting for repeated measures. Secondary outcomes included oxygen consumption, pyruvate dehydrogenase, and mortality. RESULTS: Enrollments stopped after 36 patients due Data Safety and Monitoring Board concern about potential harm in an unplanned subgroup analysis. There was no overall difference in lactate (mean difference at 48 hours 1.5 mmol/L [95% CI -3.1-6.1], global p = 0.88) or any secondary outcomes. In those with randomization lactate > 5 mmol/L, mortality was 92% (11/12) with thiamine and 67% (8/12) with placebo (p = 0.32). In those with randomization lactate ≤ 5 mmol/L mortality was 17% (1/6) with thiamine and 67% (4/6) with placebo (p = 0.24). There was a significant interaction between randomization lactate and the effect of thiamine on survival (p = 0.03). CONCLUSIONS: In this single center trial thiamine had no overall effect on lactate after in-hospital cardiac arrest.

Corticosteroids to Reduce Inflammation in Severe Pancreatitis (CRISP) protocol and statistical analysis plan: a prospective, multicentre, double-blind, randomized, placebo controlled clinical trial.

INTRODUCTION: Acute pancreatitis is a common disease which, in its severe form, is associated with significant morbidity and mortality. Currently, there is no specific therapy known to attenuate organ failure in severe pancreatitis and treatment consists primarily of supportive care. Corticosteroids have been shown to be beneficial in disease processes associated with systemic inflammation and could potentially improve outcomes in severe acute pancreatitis. METHODS: The Corticosteroids to Reduce Inflammation in Severe Pancreatitis (CRISP) trial is a multi-centre, double-blind, randomized, placebo-controlled clinical trial that aims to determine the impact of corticosteroids versus placebo on organ injury in patients with severe acute pancreatitis. Patients are randomized to receive 100 mg of hydrocortisone parenterally versus matching placebo every 8 h for 3 days. Clinical and laboratory data are collected at the time of study enrollment, at 24, 48 and 72 h. The primary end-point for the trial is the difference in 72-h change in the Sequential Organ Failure Assessment (SOFA) score between hydrocortisone and placebo groups. Additional key secondary outcomes include ventilator free days and 28-day mortality. DISCUSSION: This study will add to the evidence base in the treatment of severe acute pancreatitis. The results will inform clinical practice and future studies in the field. Trial registration number The trial is registered on clinicaltrials.gov (NCT05160506). It was posted on December 16th, 2021. The study protocol was approved by the Beth Israel Deaconess Medical Center Committee on Clinical Investigation (CCI) (protocol 2021 P-000803).

Co-exposure to phthalates and polycyclic aromatic hydrocarbons and the risk of gestational hypertension in Chinese women.

Phthalates (PAEs) and polycyclic aromatic hydrocarbons (PAHs) are frequently detected in females of reproductive age. Many studies have found that environmental PAE and PAH levels are independent risk factors for gestational hypertension. However, exposure to both components is a more realistic scenario. To better assess the health effects of PAEs and PAHs in pregnant women, we explored the associations of exposure to both individual and combined PAEs and PAHs with gestational hypertension. This nested case-control study was a component of a prospective cohort study conducted in Beijing, China. We included 206 women with gestational hypertension and 214 pregnant controls. We used gas chromatography/tandem mass spectrometry (GC-MS/MS) to detect 8 PAEs and 13 PAHs in > 80 % of all collected hair samples. Multiple linear regression models were employed to test the individual associations between each component and gestational hypertension. A quantile-based g-computation (qgcomp) model and a weighted quantile sum (WQS) regression model were used to estimate whether exposure to both PAEs and PAHs increased the risk of gestational hypertension. The individual exposure analyses revealed that diethyl phthalate (DEP), diisobutyl phthalate (DIBP) (both PAEs), benzo(k)fluoranthene (BKF), anthracene, (ANT), and benzo(a)pyrene (BAP) (all PAHs) were positively associated with increased risk of gestational hypertension. In mixed-effect analyses, the qgcomp model indicated that co-exposure to PAEs and PAHs increased the risk of gestational hypertension (odds ratio = 2.01; 95 % confidence interval: 1.02, 3.94); this finding was verified by the WQS regression model. Our findings support earlier evidence that both PAEs and PAHs increase the risk of gestational hypertension, both individually and in combination. This suggests that reductions in exposure to endocrine system-disrupting chemicals such as PAEs and PAHs might reduce the risk of gestational hypertension.

Tonghua Liyan granules in the treatment of Laryngopharyngeal reflux disease with stagnation of phlegm and qi syndrome: a randomized, double-blind, placebo-controlled study.

Background: Laryngopharyngeal reflux disease (LPRD) is an extraesophageal syndromic manifestation of gastroesophageal reflux disease (GERD). Despite the increasing incidence of and concern about LPRD, treatment with proton pump inhibitors (PPIs) is unsatisfactory. Here, LPRD was treated with Tonghua Liyan (THLY) granules in combination with PPIs to evaluate treatment efficacy and possible adverse reactions. Methods: Seventy-six LPRD patients with stagnation of phlegm and qi syndrome (SPQS) were randomly divided into an experimental group and a control group. The experimental group received THLY granules combined with rabeprazole capsules. The control group received THLY granule placebo combined with rabeprazole capsules. A parallel, randomized, double-blind, placebo-controlled clinical trial was conducted with these two groups. The treatment cycle was 8 weeks. The reflux symptom index (RSI), clinical symptom score, salivary pepsin content, reflux finding score (RFS) and gastroesophageal reflux disease questionnaire (GerdQ) were used to evaluate clinical efficacy. The final efficacy rate was evaluated according to the RSI and clinical symptom score. Results: Compared with those at baseline, all the indicators in the experimental group and control group significantly improved (p < 0.01). In terms of the RSI, clinical symptom score, and RFS, the experimental group had a higher degree of improvement (p < 0.05), and the overall efficacy rate was higher (p < 0.05). In terms of the salivary pepsin concentration and GerdQ, there was no significant difference between the test group and the control group (p > 0.05). Both groups of safety indicators showed no abnormalities and did not cause any allergic reactions in the body. Conclusion: Compared with PPIs alone, THLY granules combined with PPIs are more effective in the treatment of LPRD patients with SPQS in terms of symptoms and signs. This combination treatment, because of its higher clinical efficacy and lack of obvious adverse reactions, is worthy of clinical promotion and further in-depth study. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2100046614.

A Comparative Study of Hearing Handicap Inventory and Pure-Tone Audiometry Scores in Unilateral Hearing Impaired Patients.

Objective: To investigate the consistency between the hearing handicap inventory (HHI) and pure-tone audiometry (PTA) scores in assessing hearing status to provide valuable insights for clinical application. Methods: Retrospective analysis of clinical data and the HHI reporting status of 6540 patients admitted between April 2020 and July 2022 for self-reported unilateral hearing loss who met the study inclusion and exclusion criteria. The kappa coefficient was used to evaluate the consistency of HHI and PTA in assessing the hearing status of the participants. Results: The PTA results showed that among the 6540 participants, 3895 exhibited normal hearing, 1434 showed mild hearing loss, 809 presented with moderate hearing loss, and 402 showed severe hearing loss. The mean hearing thresholds from 0.5 to 4 kHz in healthy ears ranged from 3.65 to 18.45 dB HL, with a mean of 10.83 ± 5.29 dB HL; in ears affected by hearing loss, this ranged from 35 to 125 dB HL, with a mean of 69.63 ± 28.45 dB HL. The HHI scores showed that 4820 people had normal hearing, 1245 had mild-to-moderate hearing loss, and 475 had severe hearing loss. The kappa coefficients of normal, mild-to-moderate, and severe hearing loss were 0.312, 0.223, and 0.716, respectively (P = .001). The consistency between the 2 groups was particularly significant in the assessment of severe hearing loss. Using the PTA results as a benchmark, the sensitivity, specificity, positive predictive value, and negative predictive value of the HHI were found to be 73.08%, 87.83%, 95.60%, and 70.98%, respectively. Conclusion: The HHI and PTA results were consistent in the assessment of hearing status, particularly in the assessment of severe hearing loss, and the level of consistency between the 2 methods was high. The combined use of these tools can facilitate a comprehensive assessment of the auditory status of patients with hearing loss.

Thiamine as a metabolic resuscitator after out-of-hospital cardiac arrest.

INTRODUCTION: Thiamine is a key cofactor for aerobic metabolism, previously shown to improve mortality and neurological outcomes in a mouse model of cardiac arrest. We hypothesized that thiamine would decrease lactate and improve outcomes in post-arrest patients. METHODS: Single center, randomized, blinded, placebo-controlled, Phase II trial of thiamine in adults within 4.5 hours of return of spontaneous circulation after out-of-hospital cardiac arrest (OHCA), with coma and lactate ≥ 3 mmol/L. Participants received 500 mg IV thiamine or placebo twice daily for 2 days. Randomization was stratified by lactate > 5 or ≤ 5 mmol/L. The primary outcome of lactate was checked at baseline, 6, 12, and 24 hours, and compared using a linear mixed model to account for repeated measures. Secondary outcomes included SOFA score, pyruvate dehydrogenase, renal injury, neurological outcome, and mortality. RESULTS: Of 93 randomized patients, 76 were enrolled and included in the analysis. There was no difference in lactate over 24 hours (mean difference 0.34 mmol/L (95% CI: -1.82, 2.50), p = 0.43). There was a significant interaction between randomization lactate subgroup and the effect of the intervention on mortality (p = 0.01) such that mortality was higher with thiamine in the lactate > 5 mmol/L group and lower with thiamine in the < 5 mmol/L group. This subgroup difference prompted the Data and Safety Monitoring Board to recommend the study be terminated early. PDH activity increased over 72 hours in the thiamine group. There were no differences in other secondary outcomes. CONCLUSION: In this single-center randomized trial, thiamine did not affect lactate over 24 hours after OHCA.

The HN protein of Newcastle disease virus induces cell apoptosis through the induction of lysosomal membrane permeabilization.

Lysosomes are acidic organelles that mediate the degradation and recycling of cellular waste materials. Damage to lysosomes can cause lysosomal membrane permeabilization (LMP) and trigger different types of cell death, including apoptosis. Newcastle disease virus (NDV) can naturally infect most birds. Additionally, it serves as a promising oncolytic virus known for its effective infection of tumor cells and induction of intensive apoptotic responses. However, the involvement of lysosomes in NDV-induced apoptosis remains poorly understood. Here, we demonstrate that NDV infection profoundly triggers LMP, leading to the translocation of cathepsin B and D and subsequent mitochondria-dependent apoptosis in various tumor and avian cells. Notably, the released cathepsin B and D exacerbate NDV-induced LMP by inducing the generation of reactive oxygen species. Additionally, we uncover that the viral Hemagglutinin neuraminidase (HN) protein induces the deglycosylation and degradation of lysosome-associated membrane protein 1 (LAMP1) and LAMP2 dependent on its sialidase activity, which finally contributes to NDV-induced LMP and cellular apoptosis. Overall, our findings elucidate the role of LMP in NDV-induced cell apoptosis and provide novel insights into the function of HN during NDV-induced LMP, which provide innovative approaches for the development of NDV-based oncolytic agents.

Circulating MicroRNA-19 and cardiovascular risk reduction in response to weight-loss diets.

OBJECTIVE: MicroRNA-19 (miR-19) plays a critical role in cardiac development and cardiovascular disease (CVD). We examined whether change in circulating miR-19 was associated with change in CVD risk during weight loss. METHODS: This study included 509 participants with overweight or obesity from the 24-month weight-loss diet intervention study (the POUNDS Lost trial) and with available data on circulating miR-19a-3p and miR-19b-3p at baseline and 6 months. The primary outcome for this analysis was the change in atherosclerotic CVD (ASCVD) risk at 6 and 24 months, which estimates the 10-year probability of hard ASCVD events. Secondary outcomes were the changes in ASCVD risk score components. RESULTS: Circulating miR-19a-3p and miR-19b-3p levels significantly decreased during the initial 6-month dietary intervention period (P = 0.008, 0.0004, respectively). We found that a greater decrease in miR-19a-3p or miR-19b-3p was related to a greater reduction in ASCVD risk (ß[SE] = 0.33 [0.13], P = 0.01 for miR-19a-3p; ß[SE] = 0.3 [0.12], P = 0.017 for miR-19b-3p) over 6 months, independent of concurrent weight loss. Moreover, we found significant interactions between change in miR-19 and sleep disturbance on change in ASCVD risk over 24 months of intervention (P interaction = 0.01 and 0.008 for miR-19a-3p and miR-19b-3p, respectively). Participants with a greater decrease in miR-19 without sleep disturbance had a greater reduction of ASCVD risk than those with slight/moderate/great amounts of sleep disturbance. In addition, change in physical activity significantly modified the associations between change in miR-19 and change in ASCVD risk over 24 months (P interaction = 0.006 and 0.004 for miR-19a-3p and miR-19b-3p, respectively). A greater decrease in miR-19 was significantly associated with a greater reduction in ASCVD risk among participants with an increase in physical activity, while non-significant inverse associations were observed among those without an increase in physical activity. CONCLUSIONS: In conclusion, decreased circulating miR-19 levels during dietary weight-loss interventions were related to a significant reduction in ASCVD risk, and these associations were more evident in people with no sleep disturbance or increase in physical activity. TRIAL REGISTRATION: ClinicalTrials.gov NCT00072995.

Thiamine as adjunctive therapy for diabetic ketoacidosis (DKAT) trial protocol and statistical analysis plan: a prospective, single-centre, double-blind, randomised, placebo-controlled clinical trial in the USA.

INTRODUCTION: Diabetic ketoacidosis (DKA) is a potentially life-threatening diabetic complication. Despite the high prevalence of DKA and the substantial associated healthcare burden, limited research on strategies to improve outcomes currently exists.Thiamine (vitamin B1) is a cofactor of pyruvate dehydrogenase, which plays a key role in aerobic glucose metabolism. Thiamine deficiency is common in patients with DKA, resulting in a shift to anaerobic metabolism and hyperlactatemia, which can prolong and complicate recovery. Therefore, we hypothesise that thiamine administration will improve aerobic metabolism and lead to faster resolution of acidemia in patients with DKA. METHODS AND ANALYSIS: In this single centre, double-blind, randomised, placebo-controlled, parallel group interventional trial, 100 patients admitted to the hospital with DKA will be randomised to receive either intravenous thiamine (200 mg in 50 mL 0.9% saline) or placebo (0.9% saline identical in appearance and volume) two times per day for 2 days. The primary outcome will be the change in bicarbonate level over 24 hours as compared between the two treatment groups. Additional secondary outcomes include the change over time in anion gap, lactate levels, oxygen consumption by circulating mononuclear cells, intensive care unit and hospital length-of-stay and hospital resource usage when comparing the two study arms. ETHICS AND DISSEMINATION: This trial was approved by the Committee on Clinical Investigations, the institutional review board of Beth Israel Deaconess Medical Center (protocol number 2018P000475). Findings will be disseminated through peer-reviewed publications and professional conference presentations. TRIAL REGISTRATION NUMBER: NCT03717896; clinicaltrials.gov.

Pilot Evaluation of the Long-Term Reproducibility of Capillary Zone Electrophoresis-Tandem Mass Spectrometry for Top-Down Proteomics of a Complex Proteome Sample.

Mass spectrometry (MS)-based top-down proteomics (TDP) has revolutionized biological research by measuring intact proteoforms in cells, tissues, and biofluids. Capillary zone electrophoresis-tandem MS (CZE-MS/MS) is a valuable technique for TDP, offering a high peak capacity and sensitivity for proteoform separation and detection. However, the long-term reproducibility of CZE-MS/MS in TDP remains unstudied, which is a crucial aspect for large-scale studies. This work investigated the long-term qualitative and quantitative reproducibility of CZE-MS/MS for TDP for the first time, focusing on a yeast cell lysate. Over 1000 proteoforms were identified per run across 62 runs using one linear polyacrylamide (LPA)-coated separation capillary, highlighting the robustness of the CZE-MS/MS technique. However, substantial decreases in proteoform intensity and identification were observed after some initial runs due to proteoform adsorption onto the capillary inner wall. To address this issue, we developed an efficient capillary cleanup procedure using diluted ammonium hydroxide, achieving high qualitative and quantitative reproducibility for the yeast sample across at least 23 runs. The data underscore the capability of CZE-MS/MS for large-scale quantitative TDP of complex samples, signaling its readiness for deployment in broad biological applications. The MS RAW files were deposited in ProteomeXchange Consortium with the data set identifier of PXD046651.

Fibroblast activation protein-sensitive polymeric nanobeacon for early diagnosis of renal fibrosis.

Early diagnosis and treatment of renal fibrosis (RF) significantly affect the clinical outcomes of chronic kidney diseases (CKDs). As the typical fibrotic ailment, RF is characterized by remodeling of the extracellular matrix, and the activation of fibroblast activation protein (FAP) plays a crucial role in the mediation of extracellular matrix protein degradation. Therefore, FAP can serve as a biomarker for RF. However, up to now, no effective tools have been reported to diagnose early-stage RF via detecting FAP. In this work, a polymeric nanobeacon integrating an FAP-sensitive amphiphilic polymer and fluorophores was proposed, which was used to diagnose early RF by sensing FAP. The FAP can be detected in the range of 0 to 200 ng/mL with a detection limit of 0.132 ng/mL. Furthermore, the fluorescence imaging results demonstrate that the polymeric nanobeacon can sensitively image fibrotic kidneys in mice with unilateral ureteral occlusion (UUO), suggesting its potential for early RF diagnosis and guidance of FAP-targeted treatments. Importantly, when employed alongside with non-invasive diagnostic techniques like magnetic resonance imaging (MRI) and serological tests, this nanobeacon exhibits excellent biocompatibility, low biological toxicity, and sustained imaging capabilities, making it a suitable fluorescent tool for diagnosing various FAP-related fibrotic conditions. To our knowledge, this study represents the first attempt to image RF in early stage by detecting FAP, offering a promising fluorescent molecular tool for diagnosing various FAP-associated diseases in the future.

NIMEQ-SACNet: A novel self-attention precision medicine model for vision-threatening diabetic retinopathy using image data.

In the realm of precision medicine, the potential of deep learning is progressively harnessed to facilitate intricate clinical decision-making, especially when navigating multifaceted datasets encompassing Omics, Clinical, image, device, social, and environmental dimensions. This study accentuates the criticality of image data, given its instrumental role in detecting and classifying vision-threatening diabetic retinopathy (VTDR) - a predominant global contributor to vision impairment. The timely identification of VTDR is a linchpin for efficacious interventions and the mitigation of vision loss. Addressing this, This study introduces "NIMEQ-SACNet," a novel hybrid model by the prowess of the Enhanced Quantum-Inspired Binary Grey Wolf Optimizer (EQI-BGWO) with a self-attention capsule network. The proposed approach is characterized by two pivotal advancements: firstly, the augmentation of the Binary Grey Wolf Optimization through Quantum Computing methodologies, and secondly, the deployment of the enhanced EQI-BGWO to adeptly calibrate the SACNet's parameters, culminating in a notable uplift in VTDR classification accuracy. The proposed model's ability to handle binary, 5-stage, and 7-stage VTDR classifications adroitly is noteworthy. Rigorous assessments on the fundus image dataset, underscored by metrics such as Accuracy, Sensitivity, Specificity, Precision, F1-Score, and MCC, bear testament to NIMEQ-SACNet's pre-eminence over prevailing algorithms and classification frameworks.