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Gregory S Tentindo,1 Scott M Fishman,2 Chin-Shang Li,3 Qinlu Wang,4 Steven D Brass5,6 1Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA, USA; 2Department of Anesthesiology, Division of Pain Medicine, University of California Davis, Sacramento, CA, USA; 3Department of Public Health Sciences, Division of Biostatistics, University of California Davis, Sacramento, CA, USA; 4Department of Statistics, University of California Davis, Davis, CA, USA; 5Department of Neurology, University of California Davis, Sacramento, CA, USA; 6Department of Administration, Providence Little Company of Mary Medical Center San Pedro, San Pedro, CA, USA Purpose: Some patient subsets are at higher risk of sleep apnea, including patients with chronic pain. However, it is unclear whether patients and their caregivers are aware of the possibly increased risk of sleep apnea in this population. Chronic pain is often treated with opioids which may decrease both the central respiratory drive and the patency of the upper airway, potentially contributing to this sleep disorder. Using a self-reporting questionnaire approach in the chronic pain population, this study surveyed patient and caregiver awareness surrounding the risk of sleep apnea. In addition, we looked at the influence of opioid therapy on the prevalence of sleep apnea. Participants and methods: Consecutive patients presenting to a pain clinic were invited to participate anonymously in a survey that included the STOP-Bang sleep apnea questionnaire, which assesses patients’ knowledge, testing, diagnosis, or treatment of sleep apnea and whether their caregivers had discussed with them their increased risk of sleep apnea and opioid use. Results: Among 305 participating patients, 58.2% (n=173) screened positive for sleep apnea. Among the 202 patients on opioid therapy, 59.2% (116/202) were STOP-Bang positive (score ≥3). However, only 37.5% (n=72/173) of these patients had discussed their risk of sleep apnea with a caregiver and only 30.7% (n=59) underwent testing. Against expectation, opioids did not increase the prevalence of sleep apnea in our study population. Conclusion: Chronic pain patients had a high risk of sleep apnea, regardless of opioid prescription. Most patients were unaware of their increased risk and denied undergoing the necessary testing. Greater attention to screening, testing, and education for sleep apnea needs to be paid in chronic pain patients, especially given the potentially dangerous ramifications of opioid-induced sleep apnea. Keywords: sleep apnea, opioids, narcotics, STOP-Bang survey

Overdispersion models have been extensively studied for correlated normal and binomial data but much less so for correlated multinomial data. In this work, we describe a multinomial overdispersion model that leads to the specification of the first two moments of the outcome and allows the estimation of the global parameters using generalized estimating equations (GEE). We introduce a Global Blinding Index as a target parameter and illustrate the application of the GEE method to its estimation from (1) a clinical trial with clustering by practitioner and (2) a meta-analysis on psychiatric disorders. We examine the impact of a small number of clusters, high variability in cluster sizes, and the magnitude of the intraclass correlation on the performance of the GEE estimators of the Global Blinding Index using the data simulated from different models. We compare these estimators with the inverse-variance weighted estimators and a maximum-likelihood estimator, derived under the Dirichlet-multinomial model. Our results indicate that the performance of the GEE estimators was satisfactory even in situations with a small number of clusters, whereas the inverse-variance weighted estimators performed poorly, especially for larger values of the intraclass correlation coefficient. Our findings and illustrations may be instrumental for practitioners who analyze clustered multinomial data from clinical trials and/or meta-analysis.

Aim: We explored how acculturation and self-actualization affect depression in the HIV-positive Asians and Pacific Islanders immigrant population. Background: Asians and Pacific Islanders are among the fastest growing minority groups in the USA. Asians and Pacific Islanders are the only racial/ethnic group to show a significant increase in HIV diagnosis rate. Design: A mixed-methods study was conducted. Methods: Thirty in-depth interviews were conducted with HIV-positive Asians and Pacific Islanders in San Francisco and New York. Additionally, cross-sectional audio computer-assisted self-interviews were conducted with a sample of 50 HIV-positive Asians and Pacific Islanders. Content analysis was used to analyse the in-depth interviews. Also, descriptive, bivariate statistics and multivariable regression analysis was used to estimate the associations among depression, acculturation and self-actualization. The study took place from January-June 2013. Discussion: Major themes were extracted from the interview data, including self-actualization, acculturation and depression. The participants were then divided into three acculturation levels correlating to their varying levels of self-actualization. For those with low acculturation, there was a large discrepancy in the Center for Epidemiologic Studies Depression Scale scores between those who had totally lost their self-actualization and those who believed they could still achieve their 'American dreams'. Among those who were less acculturated, there was a significant difference in depression scores between those who felt they had totally lost their ability to self-actualize and those who still believed they could 'make their dreams come true.' Conclusion: Acculturation levels influence depression and self-actualization in the HIV-positive Asians and Pacific Islanders population. Lower acculturated Asian Americans achieved a lower degree of self-actualization and suffered from depression. Future interventions should focus on enhancing acculturation and reducing depression to achieve self-actualization.

Objective The purpose of this study was to examine the relationship between second-trimester maternal serum biomarkers and the development of early- and late-onset severe preeclampsia in euploid pregnancies. Study Design Included were 136,139 pregnancies that obtained second-trimester prenatal screening through the California Prenatal Screening Program with live births in 2006-2008. We identified severe preeclampsia diagnoses from hospital discharge records. We used log binomial regression to examine the association between abnormal second-trimester maternal serum biomarkers and the development of severe preeclampsia.

Xiaoyu Zhu,1 Ran Li,1 Yu Zhu,1 Jia Zhou,1 Junchao Huang,1 Yanfang Zhou,1 Jinghui Tong,1 Ping Zhang,1 Xingguang Luo,2 Song Chen,1 Yanli Li,1 Baopeng Tian,1 Shu-Ping Tan,1 Zhiren Wang,1 Xiaole Han,1 Li Tian,3 Chiang-Shan R Li,2 Yun-Long Tan1 1Psychosomatic Department, Beijing HuiLongGuan Hospital, Beijing, People’s Republic of China; 2Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; 3Institute of Biomedicine and Translational Medicine, Department of Physiology, Faculty of Medicine, University of Tartu, Tartu, EstoniaCorrespondence: Yun-Long Tan, Psychosomatic Department, Beijing HuiLongGuan Hospital, Beijing, People’s Republic of China, Tel +86-10-83024319, Fax +86-10-62710156, Email yltan21@126.comObjective: Accumulating evidence suggested that immune system activation might be involved in the pathophysiology of schizophrenia. The neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) can measure inflammation. This study aimed to investigate the inflammatory state in patients with schizophrenia by using these indicators.Methods: In this study, the complete blood count data for 187 continuing hospitalized patients with schizophrenia and 187 age- and sex-matched healthy participants was collected annually from 2017 to 2019. Platelet (PLT), lymphocyte (LYM), monocyte (MON) and neutrophil (NEU) counts were aggregated and NLR, MLR, PLR, and SII were calculated. Using a generalized linear mixed model, we assessed the impact of age, sex, diagnosis, and sampling year on the above indicators and evaluated the interaction between the factors.Results: According to the estimation results of the generalized linear mixed model, the NLR increased by 0.319 (p = 0.004), the MLR increased by 0.037 (p < 0.001), and the SII increased by 57.858 (p = 0.018) in patients with schizophrenia. Data after two years of continuous antipsychotic treatment showed that the NLR and MLR were higher in patients with schizophrenia than those in healthy controls, while the PLT and LYM counts were decreased in patients with schizophrenia. The schizophrenia diagnosis was correlated to the MON and LYM count, NLR, MLR, and SII (p < 0.05).Conclusion: The differences in these markers were stable and cannot be eliminated by a full course of treatment. This study provides impetus for the inflammatory hypothesis of schizophrenia.Keywords: schizophrenia, systemic immune-inflammation index, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, platelet/lymphocyte ratio

OBJECTIVE: To evaluate the effects of hypothermia on cerebral edema and metabolism, a porcine model of cardiac arrest was assessed by magnetic resonance imaging during the first 72 hours after restoration of spontaneous circulation (ROSC). METHODS: Ventricular fibrillation was induced in 33 pigs. After 8 minutes of untreated ventricular fibrillation, 30:2 cardiopulmonary resuscitation was performed. After ROSC, 30 survival animals were randomly divided into normothermia group (n = 15) and hypothermia group (n = 15). The hypothermia group immediately received endovascular cooling to regulate temperature to 33°C, which was maintained for 12 hours, followed by passive rewarming at 0.5°C/h to 37°C. Diffusion-weighted imaging and (1)hydrogen proton magnetic resonance spectroscopy were acquired for each group at 6, 12, 24, and 72 hours after ROSC. RESULTS: Compared with the normothermia group, the hypothermia group exhibited a higher 72-hour survival (73.3% vs. 33.3%, P = .028) and a superior neurological deficit score (P = .031). Cerebral injury was found in both groups, but a lesser decrease in the apparent diffusion coefficient and N-acetyl aspartate/creatinine (P < .05) and a greater increase in choline/creatinine (P < .05) were found in the hypothermia group. CONCLUSIONS: Magnetic resonance imaging could effectively detect the dynamic trend of cerebral injury in a porcine model of cardiac arrest within the first 72 hours after ROSC. Hypothermia produced a protective effect on neurological function by reducing brain edema and formation of adverse metabolites. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to provide a realistic comparison of 3 different extracorporeal compression methods during cardiopulmonary resuscitation on intrathoracic pressure (ITP), hemodynamics, and oxygen metabolism in a swine model of ventricular fibrillation (VF). METHODS: Eight minutes after the development of VF, pigs were subjected to 3 different extracorporeal compression methods: traditional artificial manual compression, mechanical compression using an AutoPulse apparatus, or manual sucker. Heart rhythm was assessed by electrocardiography after 5 cycles of extracorporeal compression. If VF still occurred, electrical defibrillation was performed. After defibrillation, an additional 5 cycles of extracorporeal compression were performed. Resuscitation was considered to have failed if the above procedure was continued for 30 minutes without return of spontaneous circulation. Hemodynamics and ITP waveforms were monitored continuously. Oxygen metabolism indices were measured, and success rates were compared among the groups. RESULTS: Manual compression showed advantages over both of the other methods in terms of maximal ITP and fluctuation amplitude, hemodynamic and oxygen dynamic changes, convenience of administration, and duration of treatment. Survival rates and cerebral performance category scores for the manual compression group were significantly higher than that for the other groups. CONCLUSIONS: Mechanical compression cannot replace traditional artificial manual compression, which remains the preferred method for cardiopulmonary resuscitation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Postresuscitation myocardial dysfunction contributes to the low survival rate after successful resuscitation, but its mechanism remains poorly understood. This study investigated whether caspase 3-mediated apoptosis is activated in the heart after postresuscitation myocardial dysfunction. METHODS: After pigs were subjected to 8 minutes of electrically induced cardiac arrest (CA), standard cardiopulmonary resuscitation was performed. Animals in the post-return of spontaneous circulation (ROSC) group were randomly assigned to be killed (n = 6 per group) at 12 and 24 hours after ROSC, and myocardial specimens were analyzed with electron microscopy, Western blotting, quantitative real-time polymerase chain reaction, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. RESULTS: Myocardial function was significantly impaired after ROSC. Expression of Bcl-2, Bax, and caspase 3 protein was markedly increased in the post-ROSC group compared with the sham-operated group (P < .05) at 12 and 24 hours after ROSC, whereas Bcl-2/Bax was significantly reduced in the post-ROSC group compared with the sham-operated group (P < .05). The messenger RNA levels of caspase 3 were significantly elevated at 12 and 24 hours after ROSC, and increases in caspase 3 activity indicated activation of the mitochondrial apoptotic pathway. Typical apoptotic nuclei were observed in cardiomyocytes 24 hours after ROSC. More apoptotic cells were observed in animals that had undergone CA compared with sham-operated animals (P < .05). CONCLUSION: Caspase 3-mediated apoptosis may be one of the main pathologic mechanisms of postresuscitation myocardial injury in a porcine model of CA. [ABSTRACT FROM AUTHOR]

Purpose: The primary purpose of this study was to demonstrate intraobserver/interobserver reproducibility for novel semiautomated measurements of hepatic volume used for Yttrium-90 dose calculations as well as whole-liver and necrotic-liver (hypodense/nonenhancing) tumor volume after radioembolization. The secondary aim was to provide initial comparisons of tumor volumetric measurements with linear measurements, as defined by Response Evaluation Criteria in Solid Tumors criteria, and survival outcomes.Methods: Between 2006 and 2009, 23 consecutive radioembolization procedures were performed for 14 cases of hepatocellular carcinoma and 9 cases of hepatic metastases. Baseline and follow-up computed tomography obtained 1 month after treatment were retrospectively analyzed. Three observers measured liver, whole-tumor, and tumor-necrosis volumes twice using semiautomated software.Results: Good intraobserver/interobserver reproducibility was demonstrated (intraclass correlation [ICC] > 0.9) for tumor and liver volumes. Semiautomated measurements of liver volumes were statistically similar to those obtained with manual tracing (ICC = 0.868), but they required significantly less time to perform (p < 0.0001, ICC = 0.088). There was a positive association between change in linear tumor measurements and whole-tumor volume (p < 0.0001). However, linear measurements did not correlate with volume of necrosis (p > 0.05). Dose, change in tumor diameters, tumor volume, and necrotic volume did not correlate with survival (p > 0.05 in all instances). However, Kaplan-Meier curves suggest that a >10% increase in necrotic volume correlated with survival (p = 0.0472).Conclusion: Semiautomated volumetric analysis of liver, whole-tumor, and tumor-necrosis volume can be performed with good intraobserver/interobserver reproducibility. In this small retrospective study, measurements of tumor necrosis were suggested to correlate with survival. [ABSTRACT FROM AUTHOR]

This investigation aimed to evaluate patient characteristics and procedural factors associated with abnormal nephrograms encountered on noncontrast computed axial tomography (CAT) obtained 24-h after transarterial chemoembolization (TACE) for primary and metastatic hepatic malignancies. Sixty hepatic chemoembolization procedures were performed in 29 patients who had a median age of 63 years (range 42-79). The male-to-female ratio was 16:13. Noncontrast CAT scans were obtained approximately 24 h after TACE as part of our institutional protocol and were examined for persistent renal nephrograms. These findings were compared with clinical and procedural parameters to determine whether there was any association with these factors or with the occurrence of acute renal failure (ARF). Abnormally persistent CAT nephrograms were observed 24 h after 28 of 60 (46.7%) TACE procedures, of which 14 (23.3%) were persistent, bilaterally dense, global nephrograms, and 14 (23.3%) were small, wedge-shaped, and focal nephrograms. The change in serum creatinine from baseline to 24 h was significantly greater (p=0.031) in the global nephrogram group. The presence of cirrhosis, Child-Pugh score, procedure time, baseline renal insufficiency, and lower periprocedural mean arterial blood pressure were also statistically significantly associated with the occurrence of bilateral globally dense nephrograms. The procedure time was statistically significantly associated with the occurrence of wedge-like focally persistent nephrograms. Global, persistently dense nephrograms and wedge-shaped focally persistent nephrograms are not infrequently observed after TACE. Persistent global nephrograms can be an important clinical indicator of ARF. The wedge nephrogram may represent focal renal ischemia. [ABSTRACT FROM AUTHOR]

We report an unusual case of veno-caliceal fistula that developed because of high ureteric pressure caused by graft ureteric stricture after kidney transplantation in a 60-year-old patient. We further confirmed its presence with radiological images. Recirculation of creatinine and other uremic toxins resulted in a biochemical picture of renal failure in the presence of normal kidney function, confirmed by normal scintigraphy findings. Drainage of the pelvi-caliceal system could not be assessed accurately by means of diuretic renogram using technetium-99m diethylenetriaminepentaacetic acid with frusemide because of the rapid clearance of tracer activity from the system in the presence of a veno-caliceal fistula. The patient's renal function improved rapidly after interrupting urine recirculation by using percutaneous drainage, confirming 'pseudo renal failure' as the cause of his persistently increased serum creatinine concentration. The ureter was re-implanted later, and the veno-caliceal fistula was not seen in the nephrostogram after the operation. He remains well with stable renal function at 3 years' follow-up. Clinicians should exercise judgment when evaluating patients with allograft dysfunction, especially when the investigation and clinical findings show contradicting results.Copyright © 2007 by National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Background: Our previous work described the neural processes of motor response inhibition during a stop signal task (SST). Employing the race model, we computed the stop signal reaction time (SSRT) to index individuals' ability in inhibitory control. The pre-supplementary motor area (preSMA), which shows greater activity in individuals with short as compared to those with long SSRT, plays a role in mediating response inhibition. In contrast, the right inferior prefrontal cortex (rIFC) showed greater activity during stop success as compared to stop error. Here we further pursued this functional differentiation of preSMA and rIFC on the basis of an intra-subject approach.Results: Of 65 subjects who participated in four sessions of the SST, we identified 30 individuals who showed a difference in SSRT but were identical in other aspects of stop signal performance between the first ("early") and last two ("late") sessions. By comparing regional brain activation between the two sessions, we confirmed greater preSMA but not rIFC activity during short as compared to long SSRT session within individuals. Furthermore, putamen, anterior cerebellum and middle/posterior cingulate cortex also showed greater activity in association with short SSRT.Conclusion: These results are consistent with a role of medial prefrontal cortex in controlled action and inferior frontal cortex in orienting attention. We discussed these findings with respect to the process of attentional monitoring and inhibitory motor control during stop signal inhibition. [ABSTRACT FROM AUTHOR]

Polymeric microwave actuators combining tissue-like softness with programmable microwave-responsive deformation hold great promise for mobile intelligent devices and bionic soft robots. However, their application is challenged by restricted electromagnetic sensitivity and intricate sensing coupling. In this study, a sensitized polymeric microwave actuator is fabricated by hybridizing a liquid crystal polymer with Ti 3 C 2 T x (MXene). Compared to the initial counterpart, the hybrid polymer exhibits unique space-charge polarization and interfacial polarization, resulting in significant improvements of 230% in the dielectric loss factor and 830% in the apparent efficiency of electromagnetic energy harvest. The sensitized microwave actuation demonstrates as the shortened response time of nearly 10 s, which is merely 13% of that for the initial shape memory polymer. Moreover, the ultra-low content of MXene (up to 0.15 wt%) benefits for maintaining the actuation potential of the hybrid polymer. An innovative self-powered sensing prototype that combines driving and piezoelectric polymers is developed, which generates real-time electric potential feedback (open-circuit potential of ~ 3 mV) during actuation. The polarization-dominant energy conversion mechanism observed in the MXene-polymer hybrid structure furnishes a new approach for developing efficient electromagnetic dissipative structures and shows potential for advancing polymeric electromagnetic intelligent devices., Competing Interests: Declarations Conflict of interest The authors declare no interest conflict. They have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024. The Author(s).)

Iron nitrides with the merits of high theoretical capacities, cost-effectiveness, and good electronic/ionic conductivity have been recognized as attractive anode candidates for lithium-ion batteries (LIBs). Carbon compositing, pore engineering, and nanostructure construction have proved to be effective strategies to prepare high-performance metal nitride anodes for LIBs. Herein, we synthesized a series of Fe 3 N-embedded and N-doped carbon nanorods (Fe 3 N@NCNR) with a hierarchical porous system and controllable topography by metal-catalyzed graphitization-nitridization of the Fe(III)-triazole framework (Fe-MOF) and thermal evaporation of the triblock copolymer F127 template assembled in Fe-MOF via hydrogen bonding interaction, followed by the air oxidation and urea-assisted ammonolysis processes. The Fe 3 N@NCNR as anodes for LIBs display extraordinary lithium storage capabilities with a high reversible capacity of 830 mA h g -1 at 0.1 C, a good rate performance of 576 mAh g -1 at 5 C, and a long-term cycling stability of 742 mA h g -1 over 600 cycles at 1 C. Such outstanding performance benefits from the spongy carbon nanorods with rich macropores for rapid electronic/ionic transport and effective accommodation of electrode volume expansion, abundant N-doped meso-/microporous carbon for the additional storage of Li + via capacitive effect, and the efficient utilization of Fe 3 N nanoparticles uniformly distributed through carbon nanorods. Importantly, this work introduces an effective strategy to construct superior performance nitride anodes from MOF surfactants based on hydrogen bonding-driven interface self-assembly and provides insight into the preparation of highly efficient nanoarchitectures for Li + storage.

Tuberculosis is the leading cause of death from an infectious disease, and is caused by Mycobacterium tuberculosis (M.tb). More than 1 billion people worldwide are thought to harbor an M.tb infection. The multidrug therapy that represents the current standard of care requires a minimum of four months of dosing and drug resistant Mycobacterium tuberculosis treatment regimens are significantly longer. Inosine-5'-monophosphate dehydrogenase (GuaB) is the enzyme that performs the rate-limiting step in de novo guanine nucleotide biosynthesis that is critical for growth and viability of bacteria including M.tb. The development of a novel antibiotic that inhibits GuaB could combine with existing therapies in novel ways and thereby contribute to effective therapeutic regimens for the treatment of tuberculosis. Here we describe the discovery of structurally distinct small molecule GuaB inhibitors that are potent against M.tb H37Ra and H37Rv strains and have desirable safety and AMDE profiles., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Y.Z., I. A., S. W., C. B., D. J. B., K. C., T.D., J. F., A. G., H. G., E. H., S. F. H., C. H., S. K., M. K., J. L., X. L., F. M., J. M., J. N., J. S., S. U., G. W., P. W., Y. X., C. W. Y., T. F. E., M. W. T., E. M. K., T. D. C., are either current or former employees of Genentech or Roche and may hold stock in Roche Holding AG. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background and Objective: This study focuses on investigating the role of CDKN1A in cisplatin-induced AKI (acute kidney injury, AKI) and its potential as a biomarker for early diagnosis and therapeutic intervention by integrating bioinformatics analysis, machine learning, and experimental validation., Methods: We analyzed the GSE85957 dataset to find genes that changed between control and cisplatin-treated rats. Using bioinformatics and machine learning, we found 13 important genes related to ferroptosis and the P53 pathway. The key gene, CDKN1A, was identified using various algorithms. We then tested how reducing CDKN1A in human kidney cells affected cell health, ROS, and iron levels. We also checked how CDKN1A changes the levels of proteins linked to ferroptosis using Q-PCR and Western Blot., Results: CDKN1A was found to negatively regulate the G1/S phase transition and was associated with ferroptosis in p53 signaling. Experiments in human renal tubular epithelial cells (HK-2) and rat NRK-52E cells showed that CDKN1A knockdown mitigated cisplatin-induced cell injury by reducing oxidative stress and ferroptosis., Conclusion: Our integrated approach identified CDKN1A as a biomarker for cisplatin-induced AKI. Its regulation could be key in AKI pathogenesis, offering new therapeutic insights and aiding in early diagnosis and intervention., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people of organizations that can inappropriately influence our work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, with more than 800,000 deaths each year, and its 5-year survival rate is less than 12%. The role of the HN1 gene in HCC has remained elusive, despite its upregulation in various cancer types. In our investigation, we identified HN1's heightened expression in HCC tissues, which, upon overexpression, fosters cell proliferation, migration, and invasion, unveiling its role as an oncogene in HCC. In addition, silencing HN1 diminished the viability and metastasis of HCC cells, whereas HN1 overexpression stimulated their growth and invasion. Gene expression profiling revealed HN1 silencing downregulated 379 genes and upregulated 130 genes, and suppressive proteins associated with the lipogenic signaling pathway networks. Notably, suppressing HN1 markedly decreased the expression levels of SREBP1 and SREBP2, whereas elevating HN1 had the converse effect. This dual modulation of HN1 affected lipid formation, hindering it upon HN1 silencing and promoting it upon HN1 overexpression. Moreover, HN1 triggers the Akt pathway, fostering tumorigenesis via SREBP1-mediated lipogenesis and silencing HN1 effectively curbed HCC tumor growth in mouse xenograft models by deactivating SREBP-1, emphasizing the potential of HN1 as a therapeutic target, impacting both external and internal factors, it holds promise as an effective therapeutic strategy for HCC., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate The human study was conducted following approval from the Ethics Committee of the University of Texas MD Anderson Cancer Center (LAB09-0687) in accordance with the Helsinki Declaration of 1975. Written informed consent was obtained from all patients prior to their inclusion in the study. All animal care procedures and sacrifices were carried out in strict accordance with protocols approved by the Institutional Animal Care and Use Committee (IACUC) and the Center for Animal Experiments at Jeonbuk National University (CBNU 2020-072)., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Competing Interests: Disclosures The authors have no conflicts of interest to report.

Inosine 5'-monophosphate dehydrogenase (IMPDH), known as GuaB in bacteria, catalyzes the rate-limiting step in de novo guanine biosynthesis and is conserved from humans to bacteria. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here, we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important Gram-negative pathogens: Acinetobacter baumannii and Escherichia coli . Specifically, the GuaB inhibitor G6 rapidly kills A. baumannii but only kills E. coli after 24 h. After exposure to G6, the expression of genes involved in purine biosynthesis and stress responses change in opposite directions while siderophore biosynthesis is downregulated in both species. Our results suggest that different species respond to GuaB inhibition using distinct regulatory programs and possibly explain the different bactericidal kinetics upon GuaB inhibition. The comparison highlights opportunities for developing GuaB inhibitors as novel antibiotics.IMPORTANCE A. baumannii is a priority bacterial pathogen for which development of new antibiotics is urgently needed due to the emergence of multidrug resistance. We recently developed a series of specific inhibitors against GuaB, a bacterial inosine 5'-monophosphate dehydrogenase, and achieved sub-micromolar minimum inhibitory concentrations against A. baumannii . GuaB catalyzes the rate-limiting step of de novo guanine biosynthesis and is highly conserved across bacterial pathogens. This study shows that inhibition of GuaB induced a bacterial morphological profile distinct from that of other classes of antibiotics, highlighting a novel mechanism of action. Moreover, our transcriptomic analysis showed that regulation of de novo purine biosynthesis and stress responses of A. baumannii upon GuaB inhibition differed significantly from that of E. coli ., Competing Interests: The authors declare no conflict of interest.

Guanine nucleotides are required for growth and viability of cells due to their structural role in DNA and RNA, and their regulatory roles in translation, signal transduction, and cell division. The natural antibiotic mycophenolic acid (MPA) targets the rate-limiting step in de novo guanine nucleotide biosynthesis executed by inosine-5´-monophosphate dehydrogenase (IMPDH). MPA is used clinically as an immunosuppressant, but whether in vivo inhibition of bacterial IMPDH (GuaB) is a valid antibacterial strategy is controversial. Here, we describe the discovery of extremely potent small molecule GuaB inhibitors (GuaBi) specific to pathogenic bacteria with a low frequency of on-target spontaneous resistance and bactericidal efficacy in vivo against Acinetobacter baumannii mouse models of infection. The spectrum of GuaBi activity includes multidrug-resistant pathogens that are a critical priority of new antibiotic development. Co-crystal structures of A. baumannii, Staphylococcus aureus , and Escherichia coli GuaB proteins bound to inhibitors show comparable binding modes of GuaBi across species and identifies key binding site residues that are predictive of whole-cell activity across both Gram-positive and Gram-negative clades of Bacteria. The clear in vivo efficacy of these small molecule GuaB inhibitors in a model of A. baumannii infection validates GuaB as an essential antibiotic target., Importance: The emergence of multidrug-resistant bacteria worldwide has renewed interest in discovering antibiotics with novel mechanism of action. For the first time ever, we demonstrate that pharmacological inhibition of de novo guanine biosynthesis is bactericidal in a mouse model of Acinetobacter baumannii infection. Structural analyses of novel inhibitors explain differences in biochemical and whole-cell activity across bacterial clades and underscore why this discovery may have broad translational impact on treatment of the most recalcitrant bacterial infections., Competing Interests: All authors were employed by Genentech, Inc., a member of the Roche Group.

The purpose of this study was to identify the correlates of depressive symptoms and the prevalence of depression, distress, and demoralization among patients with cancer in Taiwan in relation to their sociodemographics. A cross-sectional study design with convenience sampling was used to recruit 191 consecutive patients with cancer from the Cancer Center of a teaching hospital in northern Taiwan. Multiple linear regression was applied to analyze the determinants of depressive symptoms. The prevalence rates of depression (including suspected cases), distress, and demoralization were 17.8%, 36.1%, and 32.5%, respectively. The regression model explained 42.2% of the total variance, with significant predictors including marital status, life dependence, comorbidity, demoralization, and distress. The results demonstrated that higher levels of distress and demoralization were associated with more depressive symptoms. Demoralization and distress played vital roles in moderating depressive symptoms among patients with cancer. Nursing interventions should integrate appropriate mental health services, such as alleviating distress and demoralization, to prevent the occurrence of depression in patients with cancer.

Background: Chemotherapy adversely affects physical well-being and inflammation may be related to changes in physical well-being. We evaluated the association of systemic inflammation with changes in physical well-being., Methods: In a prospective study of 580 patients with stages I-III breast cancer we assessed immune cell counts, neutrophil:lymphocyte ratio (NLR), lymphocyte:monocyte ratio (LMR), and platelet:lymphocyte ratio (PLR) within 7 days before chemotherapy (pre-chemotherapy). Physical well-being was assessed using the Functional Assessment of Cancer Therapy: General-Physical Well-being subscale (FACT-PWB) pre-chemotherapy and 1 month and 6 months post-chemotherapy. Clinically meaningful decline in physical well-being was determined as decreasing FACT-PWB by more than one point from pre-chemotherapy level, and non-resilience defined as having decline post-chemotherapy and not returning to within one-point of pre-chemotherapy FACT-PWB by 6 months post-chemotherapy. Multivariable logistic regressions examined the association between inflammation and changes in physical well-being, adjusting for sociodemographic and clinical characteristics., Results: Fifty-nine percent (310/529) and 36% (178/501) of participants had physical well-being decline post-chemotherapy and 6 months post-chemotherapy, respectively. Fifty percent (147/294) were non-resilient. Low NLR and PLR were associated with 1.78 (P = .01) and 1.66 (P = .02) fold greater odds of having a decline in physical well-being 6 months post-chemotherapy compared to those with high NLR and PLR, respectively. Low NLR and PLR were associated with 1.92 (P = .02) and 2.09 (P = 0.01) fold greater odds of being non-resilient 6 months post-chemotherapy compared to those with high NLR and PLR, respectively., Conclusion: Low NLR and PLR were associated with chemotherapy-induced changes in physical well-being independent of sociodemographic and clinical risk factors., (© The Author(s) 2024. Published by Oxford University Press.)

To understand the karst groundwater hydrochemical characteristics and ion sources of the Jinan Baotu Spring area, this study focused on the three functional zones as an indirect recharge area, direct recharge area, and discharge area. Through water sample collection and testing, the spatial variability of groundwater chemical characteristics in different functional zones and the formation mechanism were analyzed using hydrochemistry parameter statistics, multivariate statistics, self-organizing map, hydrochemistry graphical analysis, ion ratios, and other methods, guided by the theory of groundwater flow system and combined with regional physical geography and hydrogeological conditions. The results showed that： the groundwater of each functional zone was alkaline as is typical in the dissolution of carbonate minerals. Owing to the different groundwater runoff pathways, the variability of water chemistry parameters in different functional areas was obvious. The groundwater of the discharge area was recharged by both the direct recharge area and the indirect recharge area. The hydrochemistry type changed from HCO 3 -Ca type to HCO 3 ·SO 4 -Ca type through the indirect recharge area to the discharge area. The presence of a small amount of gypsum dissolution within the aquifer generated Ca 2+ and SO 4 2- . The ions in groundwater mainly came from the dissolution and filtration of aquifer rock minerals, and at the same time, they were affected by cation exchange, mineral dissolution equilibrium, and the combined effects of human activities. The groundwater in the Baotu Spring area was greatly influenced by human activities, which to some extent affected the evolution of groundwater hydrochemistry in the spring area.

Background: Globally, fall-related injuries are a substantial problem, and 80% of fatal falls occur in low-income and middle-income countries. We aimed to measure time from injury to hip-fracture surgery in people aged 50 years or older living in low-income and middle-income regions, as well as to measure the proportion of patients with surgical stabilisation of their hip fracture within 72 h of admission to hospital and to identify risk factors associated with surgical delay., Methods: For this secondary analysis, we analysed data collected from Africa, Latin America, China, India, and Asia (excluding China and India) for the International Orthopaedic Multicentre Study in Fracture Care (INORMUS) between March 29, 2014, and June 15, 2022. Patients from INORMUS were included in this analysis if they were aged 50 years or older and had an isolated, primary hip fracture sustained from a ground-level fall. Staff at participating hospitals identified patients with musculoskeletal injury and referred them for assessment of eligibility. We report time from injury to surgery as three distinct time periods: time from injury to hospital admission, time from admission to surgery, and a total time from injury to surgery. Date and time of injury were self-reported by patients at the time of study recruitment. If time to hospital admission after injury exceeded 24 h, patients reported the primary reason for delayed admission. Reasons for surgery, no surgery, and surgical delay were reported by the treating team. For patients undergoing surgery, multivariable regression analyses were used to identify risk factors for surgical delay., Findings: 4486 adults aged 50 years or older with an isolated, primary hip fracture were enrolled in INORMUS from 55 hospitals in 24 countries. Countries were grouped into five regions: Africa (418 [9·3%] of 4486), Latin America (558 [12·4%]), China (1680 [37·4%]), India (1059 [23·6%]) and Asia (excluding China and India; 771 [17·2%]). Of 4486 patients, 3805 (84·8%) received surgery. The rate of surgery was similar in all regions except in Africa, where only 193 (46·3%) of 418 patients had surgery. Overall, 2791 (62·2%) of 4486 patients were admitted to hospital within 24 h of injury. However, 1019 (22·7%) of 4486 patients had delayed hospital admission of 72 h or more from injury. The two most common reasons for delayed admission of more than 24 h were transfer from another hospital (522 [36·2%] of 1441) and delayed care-seeking because patients thought the injury would heal on its own (480 [33·3%]). Once admitted to hospital, 1451 (38·1%) of 3805 patients who received surgery did so within 72 h (median 4·0 days [IQR 1·7-6·0]). Regional variation was seen in the proportion of patients receiving surgery within 72 h of hospital admission (92 [17·9%] of 514 in Latin America, 53 [27·5%] of 193 in Africa, 454 [30·9%] of 1471 in China, 318 [44·4%] of 716 in Asia [excluding China and India], and 534 [58·6%] of 911 in India). Of all 3805 patients who received operative treatment, 2353 (61·8%) waited 72 h or more from hospital admission. From time of injury, the proportion of patients who were surgically stabilised within 72 h was 889 (23·4%) of 3805 (50 [9·7%] of 517 in Latin America, 31 [16·1%] of 193 in Africa, 277 [18·8%] of 1471 in China, 189 [26·4%] of 716 in Asia [excluding China and India], and 342 [37·5%] of 911 in India)., Interpretation: Access to surgery within 72 h of hospital admission was poor, with factors that affected time to surgery varying by region. Data are necessary to understand existing pathways of hip-fracture care to inform the local development of quality-improvement initiatives., Funding: The National Health and Medical Research Council of Australia, the Canadian Institutes of Health Research, McMaster Surgical Associates, Hamilton Health Sciences, and the US National Institutes of Health., Competing Interests: Declaration of interests MB receives financial support from McMaster Surgical Associates and the Canadian Orthopaedic Association; grant support from Smith and Nephew, Huxley Health, Sonex, the US Department of Defense, the Canadian Institutes of Health Research, the US National Institutes of Health via the Institute of Arthritis and Musculoskeletal and Skin Diseases, Physician Services, and the Patient-Centered Outcomes Research Institute. PJD receives grant funding from Abbott Diagnostics, Roche Diagnostics, and Siemans; is a consultant to Abbott Canada, Renibus, Roche Canada, and Trimedic; is a speaker for Velocity Canada; is a member of a data safety monitoring board for the Pulmonary Embolism Prevention after Hip and Knee Replacement (PEPPER) study; is President of the Society for Perioperative Research and Care; and has been provided with medical devices for studies by CloudDX and Phillips Healthcare. RI is supported by an Australian National Health and Medical Research Council senior research fellowship. EA receives an Australian Government Research Training Programme scholarship, grant funding from the UK National Institute of Health and Care Research (NIHR 203194), and has previously received grant funding from the Australian Government Department of Health and Aged Care. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)