The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8+ T cells against cancer.

Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon1,2. A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer3,4. Here we show that an interleukin-4 fusion protein (Fc-IL-4), a typical type 2 cytokine, directly acts on CD8+ T cells and enriches functional terminally exhausted CD8+ T (CD8+ TTE) cells in the tumour. Consequently, Fc-IL-4 enhances antitumour efficacy of type 1 immunity-centric adoptive T cell transfer or immune checkpoint blockade therapies and induces durable remission across several syngeneic and xenograft tumour models. Mechanistically, we discovered that Fc-IL-4 signals through both signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) pathways, augmenting the glycolytic metabolism and the nicotinamide adenine dinucleotide (NAD) concentration of CD8+ TTE cells in a lactate dehydrogenase A-dependent manner. The metabolic modulation mediated by Fc-IL-4 is indispensable for reinvigorating intratumoural CD8+ TTE cells. These findings underscore Fc-IL-4 as a potent type 2 cytokine-based immunotherapy that synergizes effectively with type 1 immunity to elicit long-lasting responses against cancer. Our study not only sheds light on the synergy between these two types of immune responses, but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors.

Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8+ T Cell Responses.

Systemic immunosuppression greatly affects the chemotherapeutic antitumor effect. Here, we showed that CD19+ extracellular vesicles (EVs) from B cells through CD39 and CD73 vesicle-incorporated proteins hydrolyzed ATP from chemotherapy-treated tumor cells into adenosine, thus impairing CD8+ T cell responses. Serum CD19+ EVs were increased in tumor-bearing mice and patients. Patients with fewer serum CD19+ EVs had a better prognosis after chemotherapy. Upregulated hypoxia-inducible factor-1α (HIF-1α) promoted B cells to release CD19+ EVs by inducing Rab27a mRNA transcription. Rab27a or HIF-1α deficiency in B cells inhibited CD19+ EV production and improved the chemotherapeutic antitumor effect. Silencing of Rab27a in B cells by inactivated Epstein-Barr viruses carrying Rab27a siRNA greatly improved chemotherapeutic efficacy in humanized immunocompromised NOD PrkdcscidIl2rg-/- mice. Thus, decreasing CD19+ EVs holds high potential to improve the chemotherapeutic antitumor effect.

E3 ubiquitin ligase Hul6 modulates iron-dependent metabolism by regulating Php4 stability.

Schizosaccharomyces pombe Php4 is the regulatory subunit of the CCAAT-binding complexes and plays an important role in the regulation of iron homeostasis and iron-dependent metabolism. Here, we show that Php4 undergoes ubiquitin-dependent degradation in the late logarithmic and stationary phases. The degradation and ubiquitination of Php4 could be attenuated by deletion of hul6, a gene encoding a putative HECT-type E3 ubiquitin ligase. The expression levels of Hul6 and Php4 are oppositely regulated during cell growth. Hul6 interacts with the C-terminal region of Php4. Two lysine residues (K217 and K274) located in the C-terminal region of Php4 are required for its polyubiquitination. Increasing the levels of Php4 by deletion of hul6 or overexpression of php4 decreased expression of Php4 target proteins involved in iron-dependent metabolic pathways such as the tricarboxylic cycle and mitochondrial oxidative phosphorylation, thus causing increased sensitivity to high-iron and reductions in succinate dehydrogenase and mitochondrial complex II activities. Hul6 is located primarily in the mitochondrial outer membrane and most likely targets cytosolic Php4 for ubiquitination and degradation. Taken together, our data suggest that Hul6 regulates iron-dependent metabolism through degradation of Php4 under normal growth conditions. Our results also suggest that Hul6 promotes iron-dependent metabolism to help the cell to adapt to a nutrient-starved growth phase.

Fasting-mimicking diet potentiates anti-tumor effects of CDK4/6 inhibitors against breast cancer by suppressing NRAS- and IGF1-mediated mTORC1 signaling.

AIMS: Acquired resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) frequently emerges, and CDK4/6i-containing therapies in triple-negative breast cancer (TNBC) remain to be determined. METHODS: RNA-sequencing, cell viability analysis, immunoblotting, siRNA transfection et al. were used to investigate and verify the resistance mechanism. BALB/c nude mice xenograft models and spontaneous MMTV-PyMT models were used to explore in vivo efficacy. RESULTS: The mTOR pathway was activated in acquired CDK4/6i-resistant cells and inhibition of mTORC1 restored the sensitivity. While fasting-mimicking diet (FMD) enhances the activity of anticancer agents by inhibiting the mTORC1 signaling, we assessed FMD and found that FMD restored the sensitivity of CDK4/6i-resistant cells to abemaciclib and potentiated the anti-tumor activity of CDK4/6i in TNBC. The anti-tumor effects of FMD and/or CDK4/6i were accompanied by the downregulation of S6 phosphorylation. FMD cooperated with CDK4/6i to suppress the levels of IGF1 and RAS. The combination of FMD and abemaciclib also led to a potent inhibition of tumor growth in spontaneous transgenic MMTV-PyMT mouse models. CONCLUSIONS: Our data demonstrate that FMD overcomes resistance and potentiates the anti-tumor effect of CDK4/6i by inhibiting mTORC1 signaling via lowering the levels of IGF1 and RAS, providing the rationale for clinical investigation of a potential FMD-CDK4/6i strategy in breast cancer.

Impacted spike frequency adaptation associated with reduction of KCNQ2/3 exacerbates seizure activity in temporal lobe epilepsy.

Numerous epilepsy-related genes have been identified in recent decades by unbiased genome-wide screens. However, the available druggable targets for temporal lobe epilepsy (TLE) remain limited. Furthermore, a substantial pool of candidate genes potentially applicable to TLE therapy awaits further validation. In this study, we reveal the significant role of KCNQ2 and KCNQ3, two M-type potassium channel genes, in the onset of seizures in TLE. Our investigation began with a quantitative analysis of two publicly available TLE patient databases to establish a correlation between seizure onset and the downregulated expression of KCNQ2/3. We then replicated these pathological changes in a pilocarpine seizure mouse model and observed a decrease in spike frequency adaptation due to the affected M-currents in dentate gyrus granule neurons. In addition, we performed a small-scale simulation of the dentate gyrus network and confirmed that the impaired spike frequency adaptation of granule cells facilitated epileptiform activity throughout the network. This, in turn, resulted in prolonged seizure duration and reduced interictal intervals. Our findings shed light on an underlying mechanism contributing to ictogenesis in the TLE hippocampus and suggest a promising target for the development of antiepileptic drugs.

Phosphatidylserine-mediated uptake of extracellular vesicles by hepatocytes ameliorates liver ischemia-reperfusion injury.

Compelling evidence suggests that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) promote regeneration in animal models of liver injury by delivering signaling molecules. However, their target cells and uptake mechanism remain elusive. In this study, MSC-EVs were intravenously administered in a mouse model of liver ischemia-reperfusion injury (IRI). Our results revealed that MSC-EVs exhibit enhanced liver targeting in IRI mice, and injured hepatocytes display a greater capacity for MSC-EV uptake. We found that phosphatidylserine (PS) displayed on the exterior of injured hepatocytes promotes MSC-EV internalization, possibly by binding to MFGE8, a protein expressed on the MSC-EV membrane. Furthermore, the therapeutic effect of MSC-EVs on liver IRI is highly dependent on this PS-mediated uptake pathway. Our findings provide evidence that MSC-EVs preferentially target injured hepatocytes, relying on a PS-dependent uptake route to exert hepatoprotective effects, which are critical for the future design of EV-based therapeutic strategies for liver IRI.

Postoperative radiotherapy with docetaxel versus cisplatin for high-risk oral squamous cell carcinoma: a randomized phase II trial with exploratory analysis of ITGB1 as a potential predictive biomarker.

BACKGROUND: Oral squamous cell carcinoma (OSCC) causes significant mortality and morbidity worldwide. Surgical resection with adjuvant radiotherapy remains the standard treatment for locally advanced resectable OSCC. Results from landmark trials have established postoperative concurrent cisplatin-radiotherapy (Cis-RT) as the standard treatment for OSCC patients with high-risk pathologic features. However, cisplatin-related toxicity limits usage in clinical practice. Given the need for effective but less toxic alternatives, we previously conducted a single-arm trial showing favorable safety profiles and promising efficacy of concurrent docetaxel-radiotherapy (Doc-RT). METHODS: In this randomized phase 2 trial, we aimed to compare Doc-RT with the standard Cis-RT in postoperative OSCC patients. Eligible patients had AJCC stage III-IV resectable OSCC with high-risk pathologic features. Two hundred twenty-four patients were enrolled and randomly assigned to receive concurrent Doc-RT or Cis-RT. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints included overall survival (OS), locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), and adverse events (AEs). Integrin ß1 (ITGB1) expression was analyzed as a biomarker for efficacy. RESULTS: After a median 28.8-month follow-up, 2-year DFS rates were 63.7% for Doc-RT arm and 56.1% for Cis-RT arm (p = 0.55). Meanwhile, Doc-RT demonstrated comparable efficacy to Cis-RT in OS, LRFS, and DMFS. Doc-RT resulted in fewer grade 3 or 4 hematological AEs. Low ITGB1 was associated with improved Doc-RT efficacy versus Cis-RT. CONCLUSIONS: This randomized trial directly compared Doc-RT with Cis-RT for high-risk postoperative OSCC patients, with comparable efficacy and less toxicity. ITGB1 merits further validation as a predictive biomarker to identify OSCC patients most likely to benefit from Doc-RT. Findings indicate docetaxel may be considered as a concurrent chemoradiation option in this setting. TRIAL REGISTRATION: www. CLINICALTRIALS: gov . NCT02923258 (date of registration: October 4, 2016).

A multidimensional analysis of the impact of obesity on immune checkpoint inhibitor therapy efficacy.

BACKGROUND: Obesity is a well-known risk factor for developing malignant tumors and promoting tumor cell growth and spread. However, recent studies have shown that obese cancer patients, who typically have a worse prognosis than nonobese cancer patients, show a significant improvement in survival after receiving immune checkpoint inhibitor (ICI) therapy. This phenomenon is known as the "obesity paradox". However, this phenomenon is influenced by tumor type and sex. Therefore, this study aimed to explore the impact of obesity on immunotherapy efficacy from multiple perspectives, aiming to verify this paradox and provide new scientific evidence on the effect of obesity on ICI efficacy. METHODS: This retrospective study evaluated the data of patients who received ICI therapy between June 2019 and August 2023. Automatic segmentation of skeletal muscle, subcutaneous fat, and visceral fat was performed using Slice-O-Matic software, and the corresponding skeletal muscle index (SMI), subcutaneous fat index (SFI) and visceral fat index (VFI) were calculated. The neutrophil-to-lymphocyte ratio (NLR) was determined by dividing the neutrophil count by the lymphocyte count. Univariate and multivariate Cox regression analyses were used to evaluate the correlation between body mass index (BMI), body composition parameters, and the NLR with overall survival (OS) and progression-free survival (PFS) in obese patients receiving ICI therapy. RESULTS: We analyzed 219 patients with a median age of 60 years (IQR 53-69 years; 155 men and 64 women). Obese patients, particularly those with visceral fat accumulation, exhibited extended OS after ICI therapy (log-rank P = 0.027). Cox multivariate analysis revealed that the NLR (HR = 1.036; 95% CI: 0.996 to 1.078; P = 0.002) was independently associated with OS. Patients with a high NLR had worse OS than those with a low NLR. CONCLUSIONS: This study corroborates the veracity of the "obesity paradox" under specific conditions and identifies NLR as an independent prognostic factor, with elevated NLR indicative of a poor prognosis.

Cohort profile: Beijing Healthy Aging Cohort Study (BHACS).

The Beijing Healthy Aging Cohort Study (BHACS) was established to supplement the limited data of a large representative cohort of older people based on the general population and was designed to evaluate the prevalence, incidence, and natural history of cognitive decline, functional disability, and conventional vascular risk factors. The aim was to determine the evolution of these conditions by estimating the rates and determinants of progression and regression to adverse outcomes, including dementia, cardiovascular events, cancer, and all-cause death. It can therefore provide evidence to help policy makers develop better policies to promote healthy aging in China. BHACS consisted of three cohorts (BLSA, CCHS-Beijing, and BECHCS) in Beijing with a total population of 11 235 (6281 in urban and 4954 in rural areas) and an age range of 55 years or older (55-101 years) with a mean age of 70.35 ± 7.71 years (70.69 ± 7.62 years in urban and 69.92 ± 7.80 years in rural areas). BHACS-BLSA conducted the baseline survey in 2009 with a multistage stratification-random clustering procedure for people aged 55 years or older; BHACS-CCHS-Beijing conducted the baseline survey in 2013-2015 with a stratified multistage cluster random sampling method for people aged 55 years or older; and BHACS-BECHCS conducted the baseline survey in 2010-2014 with two-stage cluster random sampling method for people aged 60 years or older. Data were collected through questionnaires, physical measurements, and laboratory analyses. Topics covered by BHACS include a wide range of physical and mental health indicators, lifestyles and personal, family, and socio-economic determinants of health. There are no immediate plans to make the cohort data freely available to the public, but specific proposals for further collaboration are welcome. For further information and collaboration, please contact the corresponding author Yao He (e-mail: yhe301@x263.net).

Metabolic processes drive spatio-temporal variations of carbon sink/source in a karst river.

Riverine carbon dioxide (CO2) exchange is a crucial component of the global carbon cycle. However, the changes in the CO2 sink/source in karst rivers caused by differences in lithological features and climate, hindered the resolution of the spatio-temporal heterogeneity of global inland water carbon emissions. Here, we use hydrochemical data and CO2 gas isotopic data to reveal the spatio-temporal variations of CO2 sink/source in karst rivers and their controlling mechanisms. Fifty-two monitoring transects were set up in the subtropical Lijiang River in southwest China in June and December 2019. Our results indicated that the CO2 flux across the water-air interface (FCO2) in the Lijiang River basin ranged from -43.77 to 519.67 mmol/(m2·d). In June, the Lijiang River acted as an atmospheric carbon source due to higher water temperatures (Twater). However, driven by hydrodynamic conditions and the metabolism of aquatic photosynthesis, the river shifts from being an atmospheric carbon source in June to an atmospheric carbon sink in December. The stable isotopes of CO2 (δ13C-CO2) show significant differences in the spatio-temporal variations of CO2 sink/source. In December, the transects of the Lijiang River basin with a negative CO2 flux are significantly negatively correlated with dissolved oxygen (DO) and chlorophyll-a (Chl-a) concentration (p < 0.05). This confirms that the enhancement of aquatic photosynthesis efficiency increased water DO concentrations, which resulted in the positive movement of water δ13C-CO2 and a decrease in the partial pressure of CO2 (pCO2) and FCO2. Comparative analysis with global river FCO2 indicates that under the combined driving forces of metabolic processes of aquatic photosynthetic organisms and hydrodynamic conditions, rivers tend to act more frequently as CO2 sinks, particularly in subtropical and temperate rivers. In conclusion, this study represents a new example focusing on CO2 dynamics to address the spatio-temporal heterogeneity of carbon emissions in inland waters on a global scale.

Aquatic photosynthetic carbon pump driven by periodic temperature variations affects dissolved inorganic carbon and hydrochemical characteristics in a groundwater-fed reservoir.

Under the influence of periodic temperature variations, biogeochemical cycling in water bodies is markedly affected by the periodic thermal stratification processes in subtropical reservoirs or lakes. In current studies, there is insufficient research on the influence and mechanism of dissolved inorganic carbon (DIC) distribution in karst carbon-rich groundwater-fed reservoirs under the coupled effects of thermal structure stratification and the biological carbon pump (BCP) effect. To address this issue, the Dalongdong (DLD) reservoir in the subtropical region of southern China was chosen as the site for long-term monitoring and research on relevant physicochemical parameters of water, DIC, and its stable carbon isotope (δ13CDIC), CO2 emission flux, as well as the reservoir's thermal stratification index. The results show that: (1) the DLD reservoir is a typical warm monomictic reservoir, which exhibits regular variations of mixing period-stratification period-mixing period on a yearly scale due to thermal structure changes; (2) DIC was consumed by aquatic photosynthetic organisms in the epilimnion during the stratification period, leading to a decrease in DIC concentration, partial pressure of CO2 (pCO2) and CO2 emission flux, and an increase in stable carbon isotope (δ13CDIC). During the mixing period, the trend was reversed; (3) During the thermal stratification, aquatic photosynthesis and water temperature were the primary factors controlling DIC variations in both the epilimnion and thermocline. Regarding the hypolimnion, calcite dissolution, organic matter decomposition, and water temperature were the dominant controlling factors. These results indicate that although carbon-rich karst groundwater provides a plentiful supply of DIC in the DLD reservoir, its availability is still influenced by variations in the reservoir's thermal structure and the metabolic processes of aquatic photosynthetic organisms. Therefore, to better estimate the regional carbon budget in a reservoir or lake, future studies should especially consider the combined effects of BCP and thermal structure variations on carbon variations.

High-frequency dynamics of CO2 emission flux and its influencing factors in a subtropical karst groundwater-fed reservoir, south China.

Revealing the magnitude, dynamics, and influencing factors of CO2 emissions across the water-air interface in karst water with high frequency is crucial for accurately assessing the carbon budget in a karst environment. Due to the limitations of observation methods, the current research is still very insufficient. To solve the above problems and clarify the main influencing factors of CO2 emission in karst water, this study selected Dalongdong (DLD) Reservoir, located in the typical karst peak and valley area in southwest China, to carry out a multi-parameter high-frequency monitoring study from January to December 2021, and used the thin boundary model method to estimate the CO2 flux across the water-air interface (CF). The average annual flux of DLD reservoir is 84.48 mmol·(m2·h)-1, which represents a CO2 source overall. However, during the stratification period in August, there is a transient carbon sink due to negative CO2 emission. The alteration of thermal stratification in water is crucial in regulating the seasonal variation of CF. Meanwhile, the diurnal variation is significantly influenced by changes in hydrochemical parameters during the thermal stratification stage. Compared to low wind speeds (<3 m/s), high wind speeds (≥3 m/s) have a greater impact on the CO2 flux. Furthermore, high-frequency continuous data revealed that the reservoir triggered a CO2 pulse emission during the turnover process, primarily at night, leading to unusually high CO2 flux values. It is of great significance to monitor and reveal the process, flux, and control factors of CO2 flux in land water at a high-frequency strategy. They will help improve the accuracy of regional or watershed carbon budgets and clarify the role of global land water in the global carbon budget.

Abnormalities of retinal function in type 2 diabetes mellitus patients without clinical diabetic retinopathy detected by multifocal electroretinogram.

OBJECTIVE: To study the changes of retinal function in type 2 diabetes mellitus(DM) patients without apparently diabetic retinopathy via multifocal electroretinogram. METHODS: Thirty-six type 2 DM patients (72 eyes) without visible diabetic retinopathy were selected as the experimental group, and thirty-five healthy subjects (70 eyes) were selected as the control group. All subjects were underwent multifocal electroretinogram (mf- ERG). RESULTS: Compared with the control group, the implicit time delay of the P1 wave in the first ring, third ring, fourth ring, and fifth ring of the experimental group was significant (t = -3.154, p = 0.004, t = -8.21, p = 0.000, t = -3.067, p = 0.004, t = -4.443, p = 0.000, respectively). The implicit time of the N1 wave in the fourth- and fifth-ring were also significantly delayed compared with the control group (t = -3.549, p = 0.001, t = 2.961, p = 0.005, respectively). Compared with the control group, the implicit time of the P1 wave and N1 wave in the temporal region of the experimental group were delayed (t = -2.148, p = 0.037, t = -2.834, p = 0.007, respectively). There were no significant difference between the experimental group and the control group of the temporal area in the amplitude density of P1 wave, N1 wave. There was no difference in the implicit time and amplitude density of the N1 and P1 waves in the nasal region between the experimental group and the control group. The multifocal electroretinogram complex parameters showed better specificity and sensitivity in the diagnosis of diabetic retinopathy. CONCLUSION: The multifocal electroretinogram can detect abnormal changes in the retina of type 2 DM patients without visible diabetic retinopathy. The multifocal electroretinogram complex parameter is a potential indicator for the early diagnosis of diabetic retinopathy.

The application of Chinese version of SARC-F and SARC-CalF in sarcopenia screening against five definitions: a diagnostic test accuracy study.

BACKGROUND: SARC-F questionnaire is a simple and convenient tool for sarcopenia screening, and SARC-CalF is a modified version of it. The developments of their Chinese versions are warranted for the clinical use for Chinese population. This study aimed to culturally adapt the SARC-F questionnaire into Chinese using standardized methods, validate the reliability and diagnostic accuracy of the Chinese version SARC-F and SARC-CalF against five sarcopenia diagnosis criteria, and determine optimal cut-off values for clinical practice in Chinese population. METHODS: The translation and cross-cultural adaptation of SARC-F into Chinese were conducted following the methodological report from European Union Geriatric Medicine Society Sarcopenia Special Interest Group. The Chinese version of SARC-F was validated through a diagnostic test, using diagnostic criteria of sarcopenia recommended by the revised 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) consensus, Asian Working Group for Sarcopenia (AWGS2019) consensus, the International Working Group on Sarcopenia (IWGS), the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium and the Sarcopenia Definition and Outcomes Consortium (SDOC). Additional analysis was done against the criteria of severe sarcopenia according to the revised EWGSOP2 and AWGS2019. RESULTS: The Chinese version of SARC-F was well translated and demonstrated good reliability and acceptability. The diagnostic test included 1859 community-dwelling older individuals from two medical centers. Against five different definitions of sarcopenia, the Chinese version of SARC-F showed reasonable diagnostic accuracy for sarcopenia screening (AUC 0.614-0.821), and was demonstrated low sensitivity (13.7-37.9%) but high specificity (94.8-97.7%) with a cut-off value of ≥ 4. SARC-CalF significantly enhanced the diagnostic accuracy of SARC-F when using definitions of EWGSOP2, AWGS2019 and IWGS (all P ≤ 0.001). A score of ≥ 2 for SARC-F and ≥ 7 for SARC-CalF were established as optimal cut-off points for identifying older individuals as at risk of sarcopenia in Chinese population. CONCLUSIONS: The Chinese version SARC-F is of reasonable reliability and validity for sarcopenia screening. Despite its low sensitivity, it proves to be a useful tool to identify severe cases in community taking advantage of its simplicity. SARC-CalF appears to be a more suitable screening tool for clinical use in detecting sarcopenia.

Smoking cessation and mortality risk reduction in older adults with long-term smoking history.

BACKGROUND: The association between smoking cessation and decreased mortality existed among former smokers has been well documented. However, evidence is limited for smokers with long-term exposure. This study aims to quantify the association between smoking cessation and mortality by years since quitting in older adults with long-term smoking history. METHODS: Data from Beijing Healthy Aging Cohort Study (BHACS), conducted among communities aged over 55 years old at recruitment, were collected via questionnaire between July 2009 and September 2015 and followed up for all-cause and cancer mortality until March 2021. Self-reported smoking status and years since quitting were collected at baseline. Cox proportional hazards models were used to examine the association between smoking cessation and all-cause and cancer mortality. RESULTS: A total of 11 235 participants (43.9% male) were included, with a mean age of 70.35 (SD 7.71) years. Former smokers comprised 31.7% of the cohort, with a median smoking duration of 43 (IQR: 34-50) years. During 71 573 person-years of follow-up, there were 1 617 deaths (14.4% of the total cohort), of which 872 (17.7%) occurred among male participants. Compared with never smokers, HR (95%CI) for participants who current smoked was 2.898 (2.092-4.013); quit smoking less than 10 years (medians [quartiles] 4 [1, 7] years) before recruitment was 2.738(1.972-3.802); 10 to 20 years (16 [13, 20] years), 1.807(1.286-2.540); and 20 years or more (30 [25, 37] years), 1.293(0.981-1.705). The risk of all-cause and cancer mortality decreased gradually over years since quitting. Quitting less than 10 years, 10 to 20 years and 20 years or more, former smokers avoided an estimated 8.4%, 57.5% and 84.6% of excess all-cause mortality associated with current smoking, respectively. The association between smoking cessation and decreased mortality was observed among former smokers regardless of smoking history. CONCLUSIONS: In this study, current smoking was associated with nearly triple the mortality risk compared to never smoking. Smoking cessation, even after a long-term smoking history, was associated with significant decreases in the relative excess mortality linked to continuing smoking. The association were more pronounced in men.

Classic ketogenic diet-induced ketoacidosis in the treatment of pyruvate dehydrogenase deficiency: a case report and literature review.

BACKGROUND: As a rare mitochondrial disorder, the pyruvate dehydrogenase complex (PDC) deficiency is a rare inborn disease characterized with glucose metabolism defects, which leads to neurological dysfunction, serum lactic acid buildup and a resultant trend of metabolic acidosis. Although the ketogenic diet (KD) is the first-line treatment for PDC deficiency, there is currently no widely accepted consensus on specific implementation of KD for this condition. Due to the combined effect of pre-existing hyperlactacidemia and KD-induced ketoacidosis that can further exacerbate metabolic disturbances, maintaining metabolic homeostasis should be prioritized during the implementation of KD. CASE PRESENTATION: Herein, the authors present a 6-year-old boy with lactic acidosis, ataxia, hypotonia and neuromotor development retardation. The KD was started after the patient was diagnosed with PDC deficiency based on genetic testing. The initiation with classic KD resulted in severe non-diabetic ketoacidosis with elevated anion gap, which was promptly alleviated by dextrose supplementation and dietary modification to a less-restrictive KD. Long-term supervision demonstrated the efficacy of a modified KD in improving both clinical course and metabolic acidosis of the patient. CONCLUSIONS: This rare case adds to the limited evidence of KD application in PDC deficiency, and provides valuable insights into the importance of reasonably lowering the ketogenic ratio of KD at the start of treatment to reduce the risk of metabolic acidosis.

Association Between Pornography Use, Sexism, and Sexual Violence Myth Acceptance in Chinese Men: The Moderating Effect of Perceived Realism.

Pornography is spreading more and more widely due to websites, applications, and social media. It has attracted the attention of a large number of researchers who are sometimes divided on the impact of pornography. However, the relationship between pornography and sexual violence myths has received little scholarly attention in China. Based on the 3AM model and previous research, the study examined hostile sexism (HS) as a mediator and perceived realism as a moderator in the links between pornography use frequency and sexual violence myths in a sample of Chinese men (N = 376). The results showed that although pornography use and sexual violence myths did not directly correlate with one another, there was an indirect correlation through HS. Further, perceived realism moderated the relationship between pornography use frequency and HS. When participants' perceived realism was high (i.e. +1 SD), the indirect effect of HS was strong; when participants' perceived realism was low (i.e. -1 SD), the indirect effect of HS was not significant. Taken together, the findings reveal the cross-cultural consistency of the 3AM theory in China, and the findings provide new insight into the potential impact of pornography on sexism. At the same time, the results suggest an increase in appropriate education and interventions to reduce the incidence of sexual violence.

Co-design and evaluation of an audio podcast about sustainable development goals for undergraduate nursing and midwifery students.

BACKGROUND: Sustainable Development Goals (SDGs) are universally recognised targets designed to combat poverty, inequality, and climate change. However, there exists limited awareness and understanding of these goals among nursing and midwifery students. To address this knowledge gap, a co-designed audio podcast was introduced as an educational tool to enhance students' comprehension of SDGs and their relevance to the healthcare profession. METHODS: A prospective study was conducted at Queen's University Belfast, involving 566 first-year nursing and midwifery students. A 60-minute SDG podcast, co-designed with students and stakeholders, was made accessible within the university's learning management system. Pre- and post-test questionnaires were administered to assess changes in students' knowledge levels and attitudes toward SDGs. Additionally, 37 participants engaged in focus group interviews six months after listening to the podcast to explore their experiences and reflections. Quantitative data was analysed using paired t-tests and descriptive statistics, while qualitative data was analysed thematically. RESULTS: The podcast significantly increased students' awareness of SDGs and their understanding of the goals' relevance to their profession and personal lives. Post-test scores showed substantial improvements across all three sub-scales: knowledge, professional relevance, and personal relevance. Moreover, participants rated the podcast as a valuable learning resource with high acceptability, although some expressed uncertainty about replay intentions. Focus group interviews revealed three themes, including 1) More than you know', which described how participants developed new knowledge and understanding about SDGs, 2) 'Nurse-Midwife Nudges', which illuminated how participants made minor changes to their behaviour and 3) 'Fitting Format', which highlighted how participants favoured the use of an audio podcast to learn about SDGs. DISCUSSION: This study demonstrates the potential of audio podcasts as an effective and engaging tool for increasing awareness and understanding of SDGs among nursing and midwifery students. The results suggest that such interventions can positively impact students' knowledge, attitudes, and behavioural intentions regarding the SDGs. The findings also emphasise the importance of co-design in developing educational resources tailored to the specific needs and preferences of students.

Correction of Thin Cirrus Absorption Effects in Landsat 8 Thermal Infrared Sensor Images Using the Operational Land Imager Cirrus Band on the Same Satellite Platform.

Data from the Operational Land Imager (OLI) and the Thermal Infrared Sensor (TIRS) instruments onboard the Landsat 8 and Landsat 9 satellite platforms are subject to contamination by cloud cover, with cirrus contributions being the most difficult to detect and mask. To help address this issue, a cirrus detection channel (Band 9) centered within the 1.375-µm water vapor absorption region was implemented on OLI, with a spatial resolution of 30 m. However, this band has not yet been fully utilized in the Collection 2 Landsat 8/9 Level 2 surface temperature data products that are publicly released by U.S. Geological Survey (USGS). The temperature products are generated with a single-channel algorithm. During the surface temperature retrievals, the effects of absorption of infrared radiation originating from the warmer earth's surfaces by ice clouds, typically located in the upper portion of the troposphere and re-emitting at much lower temperatures (approximately 220 K), are not taken into consideration. Through an analysis of sample Level 1 TOA and Level 2 surface data products, we have found that thin cirrus cloud features present in the Level 1 1.375-µm band images are directly propagated down to the Level 2 surface data products. The surface temperature errors resulting from thin cirrus contamination can be 10 K or larger. Previously, we reported an empirical and effective technique for removing thin cirrus scattering effects in OLI images, making use of the correlations between the 1.375-µm band image and images of any other OLI bands located in the 0.4-2.5 µm solar spectral region. In this article, we describe a variation of this technique that can be applied to the thermal bands, using the correlations between the Level 1 1.375-µm band image and the 11-µm BT image for the effective removal of thin cirrus absorption effects. Our results from three data sets acquired over spatially uniform water surfaces and over non-uniform land/water boundary areas suggest that if the cirrus-removed TOA 11-µm band BT images are used for the retrieval of the Level 2 surface temperature (ST) data products, the errors resulting from thin cirrus contaminations in the products can be reduced to about 1 K for spatially diffused cirrus scenes.

Validity of the modified versions of SARC-F+EBM for sarcopenia screening and diagnosis in China: the PPLSS study.

BACKGROUND AND OBJECTIVES: It is recommended by Asian Working Group for Sarcopenia to early identify people at risk for sarcopenia using simple screening tools like SARC-F. The modified version SARC-F+EBM showed higher diagnostic performance. However, this cut-off value of body mass index (BMI) remained uncertain to be used in Chinese population. In this study, we used appropriate BMI recommended for Chinese older population and further modified SARC-F+EBM by combining calf circumference. METHODS AND STUDY DESIGN: Diagnostic tests were performed and the receiver operating characteristics analyses were conducted between the SARC-F, SARC-F+EBM (cut-off of BMI: ≤ 21 kg/m2), SARC-F+EBM (CN) (cut-off of BMI: ≤ 22 kg/m2), SARC-CalF and SARC-CalF+EBM (CN) (cut-off of BMI: ≤ 22 kg/m2) in 1660 community-dwelling participants aged ≥ 65 years from China. RESULTS: The participants had an average age of 71.7±5.1 years, of which 56.8% were women. All the modified models could enhance the areas under the receiver operating characteristic curve (AUC) of original SARC-F (all p<0.001). The SARC-F+EBM (CN) also showed a significantly higher sensitivity of 47.4% (p<0.001) and an AUC of 0.809 (p=0.005) than SARC-F+EBM. SARC-CalF+EBM (CN) was validated to be of great diagnostic value of the highest AUC of 0.88 among these sarcopenia screening tools, including SARC-F, SARC-CalF and SARC-F+EBM (CN) (all p<0.001). Using this study population as a reference, the optimal cut-off value of SARC-CalF+EBM (CN) is ≥12 points, with a sensitivity of 79.3% and a specificity of 80.7%. CONCLUSIONS: The SARC-F+EBM (CN) and SARC-CalF+EBM (CN) could enhance the diagnostic performance of SARC-F and SARC-F+EBM and are suitable sarcopenia screening tools for Chinese population.