Regulating oxygen vacancies by Zn atom doping to anchor and disperse promoter Ba on MgO support to improve Ru-based catalysts activity for ammonia synthesis.

In heterogeneous catalysis, surface defects are widely regarded as an effective means to enhance the catalytic performance of catalysts. In this study, the oxygen vacancy-rich Mg(1-X)ZnXO solid solution support was successfully prepared by doping a small amount of Zn into MgO nanocrystals. Based on this support, Ru/Ba-Mg(1-X)ZnXO catalyst for ammonia synthesis was prepared. Characterization using TEM, EPR, XPS, and DFT calculations confirmed the successful substitution of Zn atoms for Mg atoms leading to the formation of more oxygen vacancies (OVs). N2-TPD, SEM and TEM analyses revealed that a small amount of Zn had minimal influence on the surface morphology and the size of Ru nanoparticles. The abundance of OVs in the support was identified as the primary factor enhancing the catalytic activity. XPS, H2-TPD and kinetics experiment studies further elucidated the mechanism by which OVs promote the reaction, with OVs serving as an anchor point for the promoter Ba on the MgO support and promoted the dispersion of Ba. This anchoring effect not only enhanced the electron density on Ru, favoring the dissociation of the N[triple bond, length as m-dash]N bond, but also mitigated hydrogen poisoning. As a result,the ammonia synthesis rate reached 1.73 mmol g-1 h-1. Furthermore, the CO2-TPD and H2-TPR analyses indicated that Zn doping effectively promotes the metal-support interaction (MSI) and surface alkalinity. The findings of this study offers valuable insights for the design of defective modified catalyst supports.

Effects of adjunctive Chinese patent medicine on outcome of viral encephalitis in children: A multicenter retrospective study in China.

BACKGROUND: Some patients with viral encephalitis in China seek treatment with Chinese patent medicine (CPM) to improve their symptoms, but few studies have focused on the impact of CPM on the prognosis of viral encephalitis (VE). The aim of this multicenter retrospective study was to assess the benefit of adjunctive CPM therapy on the outcome of children with VE in China. METHODS: This study retrospectively included 834 children with viral encephalitis who were hospitalized at five medical institutions from 2018 to 2021. Univariate and multivariate logistic regression was used to assess the effect of CPM on sequelae in patients with VE. 1:1 propensity score matching was used to exclude the effect of confounding factors. Forest plots were used to observe the effect of CPM on the prognosis of VE in different subgroups. RESULTS: There were fewer patients with sequelae in the group of patients using CPM regardless of whether they were matched or not. The results of multivariate logistic regression analysis showed that the use of CPM was an independent protective factor for the development of sequelae in VE patients (OR = 0.063, 95 % CI: 0.011-0.350, p = 0.002). Subgroup analyses showed that CPM was a protective factor for the development of sequelae regardless of the presence or absence of coma and comorbidities. In addition, we evaluated other outcome indicators and found shorter duration of illness, fever and headache in children with EV in the CPM group. CONCLUSION: Adjunctive CPM therapy may significantly reduce sequelae in children with VE, as well as effectively alleviate patients' clinical symptoms. However, more prospective studies and clinical trials are needed to further evaluate its efficacy and safety.

A cardiologist-like computer-aided interpretation framework to improve arrhythmia diagnosis from imbalanced training datasets.

Arrhythmias can pose a significant threat to cardiac health, potentially leading to serious consequences such as stroke, heart failure, cardiac arrest, shock, and sudden death. In computer-aided electrocardiogram interpretation systems, the inclusion of certain classes of arrhythmias, which we term "aggressive" or "bullying," can lead to the underdiagnosis of other "vulnerable" classes. To address this issue, a method for arrhythmia diagnosis is proposed in this study. This method combines morphological-characteristic-based waveform clustering with Bayesian theory, drawing inspiration from the diagnostic reasoning of experienced cardiologists. The proposed method achieved optimal performance in macro-recall and macro-precision through hyperparameter optimization, including spliced heartbeats and clusters. In addition, with increasing bullying by aggressive arrhythmias, our model obtained the highest average recall and the lowest average drop in recall on the nine vulnerable arrhythmias. Furthermore, the maximum cluster characteristics were found to be consistent with established arrhythmia diagnostic criteria, lending interpretability to the proposed method.

Diagnosis of generalized joint hypermobility with gait patterns using a deep neural network.

Generalized joint hypermobility (GJH) describes the situation that the range of joint motion exceeds the normal range. GJH is found to increase the risk of knee-related injury and osteoarthritis, challenging the athletic ability of the population. Gait signals are directly related to hip and knee athletic conditions, and have been shown to have significant changes with GJH by our previous research. But gait data are noisy, and vary with age, gender, weight, and ethnicity, which makes them hard to analyze with traditional statistical methods. In this study, we proposed an end-to-end deep learning model to recognize the patterns of the gait signals. The model consists of convolutional network blocks, residual network blocks, and attention blocks. Our dataset is composed of 452 samples of gait data obtained by a three-dimension motion capture system, with the six-degree-of-freedom kinematic data of hip, knee, and ankle joints during level walking, downhill, and uphill walking. The model achieves 95.77% accuracy and 98.68% specificity with a recall of 76.84% while is more efficient than traditional machine learning methods. The trained model can be run on economical friendly devices, and provide help for immediate and precise diagnosis of GJH. It is also meaningful to consider its application in large-scale GJH screening, which can contribute to sports medicine.

Dual active sites over Cu-ZnO-ZrO2 catalysts for carbon dioxide hydrogenation to methanol.

CO2 hydrogenation to methanol is a significant approach to tackle the problem of global warming and simultaneously meet the demand for the portable fuel. Cu-ZnO catalysts with various kinds of promoters have received wide attention. However, the role of promoter and the form of active sites in CO2 hydrogenation are still in debate. Here, various molar ratios of ZrO2 were added into the Cu-ZnO catalysts to tune the distributions of Cu0 and Cu+ species. A volcano-like trend between the ratio of Cu+/ (Cu+ + Cu0) and the amount of ZrO2 is presented, among which the CuZn10Zr (the molar ratio of ZrO2 is 10%) catalyst reaches the highest value. Correspondingly, the maximum value of space-time yield to methanol with 0.65 gMeOH/(gcat·hr) is obtained on CuZn10Zr at reaction conditions of 220°C and 3 MPa. Detailed characterizations demonstrate that dual active sites are proposed during CO2 hydrogenation over CuZn10Zr catalyst. The exposed Cu0 takes participate in the activation of H2, while on the Cu+ species, the intermediate of formate from the co-adsorption of CO2 and H2 prefers to be further hydrogenated to CH3OH than decomposing into the by-product of CO, yielding a high selectivity of methanol.

Identification of Distinct Clinical Phenotypes of Heterogeneous Mechanically Ventilated ICU Patients Using Cluster Analysis.

This retrospective study aimed to derive the clinical phenotypes of ventilated ICU patients to predict the outcomes on the first day of ventilation. Clinical phenotypes were derived from the eICU Collaborative Research Database (eICU) cohort via cluster analysis and were validated in the Medical Information Mart for Intensive Care (MIMIC-IV) cohort. Four clinical phenotypes were identified and compared in the eICU cohort (n = 15,256). Phenotype A (n = 3112) was associated with respiratory disease, had the lowest 28-day mortality (16%), and had a high extubation success rate (~80%). Phenotype B (n = 3335) was correlated with cardiovascular disease, had the second-highest 28-day mortality (28%), and had the lowest extubation success rate (69%). Phenotype C (n = 3868) was correlated with renal dysfunction, had the highest 28-day mortality (28%), and had the second-lowest extubation success rate (74%). Phenotype D (n = 4941) was associated with neurological and traumatic diseases, had the second-lowest 28-day mortality (22%), and had the highest extubation success rate (>80%). These findings were validated in the validation cohort (n = 10,813). Additionally, these phenotypes responded differently to ventilation strategies in terms of duration of treatment, but had no difference in mortality. The four clinical phenotypes unveiled the heterogeneity of ICU patients and helped to predict the 28-day mortality and the extubation success rate.

A Retrospective Study of Recurrent Bacterial Meningitis in Children: Etiology, Clinical Course, and Treatment.

Objectives: Recurrent bacterial meningitis (RBM) is a rare but life-threatening disease. This study aims to analyze the clinical features, potential causes, and therapeutic outcomes of RBM in children. Methods: This article retrospectively reviews the clinical characteristics, etiologies, and treatments in children with RBM hospitalized in Hebei children's hospital from 2012 to 2020. Results: A total of 10 children with RBM, five males and five females, were included in this study. The age of RBM in children spans from the neonatal stage to the childhood stage. The underlying illnesses were identified and classified as cerebrospinal fluid rhinorrhea (1 case), humoral immunodeficiency with Mondini dysplasia (1 case), common cavity deformity with cerebrospinal fluid ear leakage (1 case), Mondini malformations (2 cases), incomplete cochlear separation type I with a vestibular enlargement (2 cases), local inflammation of the sphenoid bone caused by cellulitis (1 case), congenital skull base defects (1 case), and congenital dermal sinus with intraspinal abscess (1 case). 6 patients chose targeted therapy for potential reasons. Conclusions: Congenital abnormalities or acquired injuries lead to intracranial communication with the outside world, which can quickly become a portal for bacterial invasion of the central nervous system, resulting in repeated infections.

Cost-effectiveness analysis of different screening strategies for colorectal cancer in Guangzhou, southern China: a Markov simulation analysis based on natural community screening results.

OBJECTIVES: To evaluate the cost-effectiveness of four different primary screening strategies: high-risk factor questionnaire (HRFQ) alone, single immunochemical faecal occult blood test (iFOBT), double iFOBT and HRFQ+double iFOBT for colorectal cancer (CRC) screening compared with no screening using the Markov model. METHODS: Treeage Pro V.2011 software was used to simulate the Markov model. The incremental cost-effectiveness ratio, which was compared with the willingness-to-pay (WTP) threshold, was used to reflect the cost-effectiveness of the CRC screening method. One-way sensitivity analysis and probabilistic sensitivity analysis were used for parameter uncertainty. RESULTS: All strategies had greater effectiveness because they had more quality-adjusted life years (QALYs) than no screening. When the WTP was ¥435 762/QALY, all screening strategies were cost-effective compared with no screening. The double iFOBT strategy was the best-buy option compared with all other strategies because it had the most QALYs and the least cost. One-way sensitivity analysis showed that the sensitivity of low-risk adenoma, compliance with colonoscopy and primary screening cost were the main influencing factors comparing single iFOBT, double iFOBT and HRFQ+double iFOBT with no screening. However, within the scope of this study, there was no fundamental impact on cost-effectiveness. Probabilistic sensitivity analysis showed that when the WTP was ¥435 762/QALY, the probabilities of the cost-effectiveness acceptability curve with HRFQ alone, single iFOBT, double iFOBT and HRFQ+double iFOBT were 0.0%, 5.3%, 69.3% and 25.4%, respectively. CONCLUSIONS: All screening strategies for CRC were cost-effective compared with no screening strategy. Double iFOBT was the best-buy option compared with all other strategies. The significant influencing factors were the sensitivity of low-risk polyps, compliance with colonoscopy and cost of primary screening.

A new indolizinium alkaloid from marine-derived Streptomyces sp. HNA39.

A new indolizinium alkaloid, named as cyclizidine J (1), was identified from Gause's liquid fermentation of marine-derived Streptomyces sp. HNA39. Its structure was elucidated by extensive NMR spectroscopic methods, HRESIMS data, and ECD calculations. To our best knowledge, compound 1 was a unique cyclizidine-type alkaloid that contain a chlorine atom substituted at position C-8. Unfortunately, biological evaluation of 1 exhibited no active against PC-3 cancer cell line, BRD4, and ROCK2 protein kinase.

Altered spontaneous brain activity in patients with childhood absence epilepsy: associations with treatment effects.

The study aims to detect resting-state functional MRI (RS-fMRI) changes and their relationships with the clinical treatment effects of anti-epileptic drugs (AEDs) for patients with childhood absence epilepsy (CAE) using the fractional amplitude of low-frequency fluctuation (fALFF). RS-fMRI data from 30 CAE patients were collected and compared with findings from 30 healthy controls (HCs) with matched sex and age. Patients were treated with first-line AEDs for 46.2 months before undergoing a second RS-fMRI scan. fALFF data were processed using DPABI and SPM12 software. Compared with the HCs, CAE patients at baseline showed increased fALFF in anterior cingulate cortex, inferior parietal lobule, inferior frontal lobule, supplementary motor area and reduced fALFF in putamen and thalamus. At follow-up, the fALFF showed a clear rebound which indicated a normalization of spontaneous brain activities in these regions. In addition, the fALFF changes within thalamus showed significant positive correlation with the seizure frequency improvements. Our results suggest that specific cortical and subcortical regions are involved in seizure generation and the neurological impairments found in CAE children and might shed new light about the AEDs effects on CAE patients.

How spatial accessibility to colonoscopy affects diagnostic adherences and adverse intestinal outcomes among the patients with positive preliminary screening findings.

BACKGROUND: Colonoscopy is an important procedure for early colorectal cancer (CRC) detection, however, patients with positive preliminary screening results in China may not seek for colonoscopy to confirm the diagnosis. We evaluated the spatial accessibility of colonoscopy among the residents with positive preliminary screening results in Guangzhou, China, and investigated how colonoscopy accessibility was associated with the population adherence and adverse intestinal outcomes. METHODS: This study was based on the Guangzhou community-based CRC screening program. Spatial accessibility was measured using three metrics including travel time from home to nearest colonoscopy hospital, physician-to-population ratio (PPR) and accessibility indicator estimated with enhanced two-step floating catchment area method (E2SFCA). We used Cox regression and logistic regression to assess the association of colonoscopy accessibility with population adherence and adverse intestinal outcomes, respectively. RESULTS: A total of 34 606 people were identified with positive preliminary screening findings. Central areas were reported with higher E2SFCA scores, higher PPR and less travel time. The model adjusting for potential individual level confounders found that PPR > 50 (Hazard Ratio (HR) = 1.88, 95% Confidence Interval (CI): 1.79-1.97) and higher scores of E2SFCA (HR = 3.78, 95% CI: 2.07-6.92) were associated with increased adherence, although estimates were not significant in the model adjusting for both individual and district-level confounders. For adverse intestinal outcomes, the final multilevel logistic model suggested a lower risk of intestinal lesions among the residents in areas with PPR > 50 (Odds Ratio (OR) = 0.49, 95% CI: 0.24-0.99) and higher scores of E2SFCA (OR = 0.20, 95% CI: 0.05-0.82). CONCLUSION: Significant inequality of colonoscopy accessibility was observed across Guangzhou. The increased incidence of intestinal lesions was associated with spatial inequalities of medical resources. Policies against the spatial inequality in medical resources should be developed.

Breast cancer mortality in Chinese women: does migrant status play a role?

PURPOSE: It is unclear whether migration would affect the mortality risk of breast cancer. In this study, we compared breast cancer mortality among three Chinese populations: Guangzhou (GZ)-born women, Hong Kong (HK)-born women, and HK residents who were born outside HK (HK immigrant), with the aim to explore the impact of migrant status on breast cancer mortality. METHODS: We applied an age-period-cohort model to annual age-specific mortality rates of breast cancer among GZ-born, HK-born, and HK-immigrant women from 2003 to 2016, respectively. We also projected mortality rates from 2017 to 2030. RESULTS: Annual age-standardized mortality rate of breast cancer in women aged 35 years or older was 9.18, 9.17, and 9.83 per 100,000 population, for GZ-born, HK-born, and HK-immigrant women, respectively. A decreasing trend was found in the post-1950s cohorts of GZ-born women and in the post-1960s cohorts of two HK populations. Annual mortality rates of breast cancer in these populations were projected to decrease among the 35-64 years age group and increase among the 65 years and older age group in 2017-2030. CONCLUSIONS: We found higher age-specific mortality rates of breast cancer in HK-immigrant women compared with HK- and GZ-born women, suggesting that immigration status might have an impact on breast cancer mortality.

Mass screening for colorectal cancer in a population of two million older adults in Guangzhou, China.

Screening is an effective measure to prevent and control colorectal cancer (CRC). A mass CRC screening programme was conducted in Guangzhou from 2015 to 2017. Public media and reminders from a mobile short message service were used to invite residents aged between 50 and 74 years. A high-risk factor questionnaire (HRFQ) and biennial faecal immunochemical testing (FIT) were chosen as the primary screening methods, and individuals with a positive test result were referred to a defined hospital for an assessment colonoscopy. During the 3 years, 350,581 residents of the total eligible population of 2,283,214 attended the free first stage of screening. In all, 91.0% of the participants finished the HRFQs and FITs. The total uptake rate was 15.4%, which increased with age, female sex, and rural location. There was 15.9% positivity in the first stage of screening, including 8.5% positive HRFQs, 6.2% positive FITs and 1.2% positive HRFQs and FITs. In total, 10,600 individuals with positive HRFQs/FITs completed an assessment colonoscopy. The total uptake rate of colonoscopies was 18.9%, which decreased with age and female sex. Three hundred fifty-one CRCs and 980 advanced adenomas (AAs) were diagnosed with positive predictive values (PPV) of 3.3% and 9.2%, respectively. The PPVs of CRCs in the exclusively FIT-positive population were 4.9%, which was 10 times greater than in the exclusively HRFQ-positive population (0.5%). The PPVs of CRCs and AAs increased with age and male sex. The detection ratio of localized CRCs (including stage I and stage II) increased 68.1% due to screening. Although the compliance rate was low, the PPVs for CRCs and AAs were high. More effective mobilization of the programme's needs and subsidies for colonoscopies should be taken into account to increase compliance.

High prevalence of hyperuricaemia and its impact on non-valvular atrial fibrillation: the cross-sectional Guangzhou (China) Heart Study.

OBJECTIVES: There are country and regional variations in the prevalence of hyperuricaemia (HUA). The prevalence of HUA and non-valvular atrial fibrillation (NVAF) in southern China is unknown. DESIGN: A cross-sectional study. SETTING AND PARTICIPANTS: A total of 11 488 permanent residents aged 35 or older from urban and rural areas of Guangzhou, China were enrolled. A questionnaire was used to compile each participant's demographic information and relevant epidemiological factors for HUA and NVAF. All participants were assessed using a panel of blood tests and single-lead 24-hour ECG. MAIN OUTCOME MEASURES: HUA was defined as serum uric acid level >420 µmol/L in men and >360 µmol/L in women. NVAF was diagnosed as per guidelines. RESULTS: The prevalence of HUA was 39.6% (44.8% in men and 36.7% in women), and 144 residents (1.25%) had NVAF. Prevalence of HUA increased with age in women but remained stably high in men. After adjusting for potential confounders, age, living in urban areas, alcohol consumption, central obesity, elevated fasting plasma glucose level, elevated blood pressure, lower high-density lipoprotein cholesterol level and elevated triglycerides level were associated with increased risk of HUA. Residents with HUA were at higher risk for NVAF. Serum uric acid level had a modest predictive value for NVAF in women but not men. CONCLUSIONS: HUA was highly prevalent among citizens of southern China and was a predictor of NVAF among women.

Effectiveness of a short message service intervention to motivate people with positive results in preliminary colorectal cancer screening to undergo colonoscopy: A randomized controlled trial.

BACKGROUND: Colonoscopy adherence among populations at high risk for colorectal cancer (CRC) is crucial for the early diagnosis and treatment of CRC, but the adherence rate has been found to be poor. A short message service (SMS) is effective in promoting cancer screening, but its effectiveness in promoting colonoscopy among populations at high risk for CRC has not been well studied. METHODS: In this randomized controlled trial conducted in Guangzhou, China, participants who had tested positive during preliminary CRC screening (a high-risk factor questionnaire and/or an immunochemical fecal occult blood test) but had not undergone colonoscopy were randomized into low-frequency (monthly) intervention, high-frequency (biweekly) intervention, and control groups. The 2 intervention groups received behavioral theory-based SMS for 6 months. Data were obtained from the CRC screening database. The outcome was undergoing a colonoscopy examination. RESULTS: For the 1362 participants, the rates of colonoscopy adherence were 5.2%, 6.0%, and 10.5% at month 3 and 7.1%, 9.6%, and 13.7% at month 6 in the control, low-frequency intervention, and high-frequency intervention groups, respectively. After adjustments for potential confounders, the high-frequency intervention group was approximately twice as likely as the control group to undergo colonoscopy (adjusted hazard ratio, 1.99; 95% confidence interval, 1.32-3.01), whereas the difference between the low-frequency intervention and control groups was not statistically significant. The cost of SMS to increase colonoscopy uptake by 1 in the high-frequency intervention group was US $2.7. CONCLUSIONS: Text messages sent biweekly for 6 months to patients with positive preliminary screening results could increase colonoscopy adherence. SMS could be a prioritized intervention for promoting colonoscopy in large community-based populations.

Defective graphene@diamond hybrid nanocarbon material as an effective and stable metal-free catalyst for acetylene hydrochlorination.

A defective nanodiamond-graphene material (ND@G) exhibits superior catalytic activity in acetylene hydrochlorination with an acetylene conversion of 50%, selectivity to vinyl chloride of up to 99.5% at 220 °C, and a C2H2 gas hourly space velocity of 300 h-1, which is the first example of a metal-free catalyst with comparable performance to that of the 0.25% Au/C catalyst.

Effect of nitrogen co-doping with ruthenium on the catalytic performance of Ba/Ru-N-MC catalysts for ammonia synthesis.

Nitrogen co-doping with ruthenium mesoporous carbons (Ru-N-MC) was prepared by co-impregnation of sucrose and urea on a RuCl3/SiO2 template followed by a thermal carbonization process. The turnover frequency (TOF) of the Ba/Ru-N-MC catalyst in ammonia synthesis is 0.16 s-1 under reaction conditions of 400 °C, pressure of 10 MPa and space velocity of 10 000 h-1. The superior catalytic performance of the Ba/Ru-N-MC is proposed to originate from the strong metal-support interaction between Ru nanoparticles (NPs) and carbon support. In addition to the activity, the Ba/Ru-N-MC catalyst exhibits a long-term stability for 35 h without significant deactivation.

Willingness to pay for colorectal cancer screening in Guangzhou.

AIM: To measure the willingness to pay for colorectal cancer screening in Guangzhou, and to identify those factors associated with it. METHODS: A face-to-face questionnaire survey for pre-screening population from free and non-free colonoscopy districts was used to collect information on demographic characteristics, health behaviours, the intention of the cancer screenings and willingness to pay for colorectal cancer screening. A total of 1243 participants who took part in the pre-screening for colorectal cancer in Guangzhou were collected in the study. Categorical data were compared using the χ2 test to analyse significant differences. Non-conditional logistic regression and multi-class logistic regression were also performed for multivariate analysis and to estimate the odds ratios. RESULTS: The percentage of participants willing to pay for colorectal cancer screening was 91.7%. "Unnecessary" was the dominant reason that participants gave for their unwillingness, accounting for 63.1%. Of those who were willing to pay, 29.2%, 20.7%, 14.8%, 13.0% and 22.4% of participants were willing to pay less than \100, \100-\199, \200-299, \300-\399 and more than \400, respectively. Non-logistic regression analysis showed that respondents who were male, had a high level of education, were from the family with more children/older to raise, and accepted colorectal cancer screening were willing to pay for this screening. Multi-class logistic regression analysis showed that respondents with higher annual household income per capita, from government and private enterprises, government agency/institution and peasants, and less family medical expenditure were willing to pay more. CONCLUSION: Willingness to pay for colorectal cancer screening in Guangzhou is high, but the amount of willing to pay is not much.

Wheat flour-derived N-doped mesoporous carbon extrudate as superior metal-free catalysts for acetylene hydrochlorination.

N-Doped mesoporous carbon extrudate with a major quaternary N species has been successfully prepared through direct carbonization of wheat flour/gluten with silica, which is a cheap and convenient method for scale-up production approach. The obtained carbon extrudate metal-free catalyst enables highly efficient production of vinyl chloride monomer through acetylene hydrochlorination, with a superior catalytic performance and excellent stability (>85% conversion and vinyl chloride selectivity over 99% at 220 °C).

One new indolocarbazole alkaloid from the Streptomyces sp. A22.

One new indolocarbazole alkaloid, 12-N-methyl-k252c, together with eight known indolocarbazoles were isolated from the rice solid fermentation of the marine-derived Streptomyces sp. A22. Their structures were elucidated on the basis of spectroscopic methods (UV, IR, HRESITOF MS, 1D NMR and 2D NMR). All of these compounds were evaluated for bromodomain-containing protein 4 (BRD4) inhibitory activities and cytotoxic activity assay, respectively. Compounds 4 and 5 showed moderate cytotoxic activity with an IC50 value of 3.52 and 3.93 µM, respectively. Additionally, compound 1 also was tested for enzyme inhibition activities of protein kinases and showed moderate activity with IC50 values of 0.91-1.84 µM.