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We lead multidisciplinary applied research and training to rethink the way health care is delivered in general practice and across the community.
Cannabis use and adherence to antipsychotic medication: a systematic review and meta-analysis
BACKGROUND: Substance use may increase the risk of non-adherence to antipsychotics, resulting in negative outcomes in patients with psychosis.
Association between continued cannabis use and risk of relapse in first-episode psychosis a quasi-experimental investigation within an observational study
IMPORTANCE Cannabis use after first-episode psychosis is associated with poor outcomes, but the causal nature of this association is unclear. OBJECTIVE To examine the precise nature of the association between continued cannabis use after the onset of psychosis and risk of relapse of psychosis. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study followed up for at least 2 years after the onset of psychosis 220 patients who presented to psychiatric services in South London, England, from April 12, 2002, to July 26, 2013, with first-episode psychosis. Longitudinal modeling (fixed-effects analysis, cross-lagged path analysis) was used to examine whether the association between changes in cannabis use and risk of relapse over time is the result of shared vulnerability between psychosis and cannabis use, psychosis increasing the risk of cannabis use (reverse causation), or a causal effect of cannabis use on psychosis relapse. INTERVENTIONS Exposure to cannabis within the first and second years after onset of psychosis. MAIN OUTCOMES AND MEASURES The main outcome measurewas relapse of psychosis, defined as subsequent hospitalization for psychosis. Effect of cannabis use status in the first year (Ct1) and second year (Ct2) and pattern of cannabis use continuation in the first year and second year were modeled for risk of relapse in the first year (Rt1) and risk of relapse in the second year (Rt2) after psychosis onset. RESULTS A total of 220 patients with first-episode psychosis were included in the analysis (mean [SD] age, 28.62 [8.58] years; age range, 18-65 years; 90 women [40.9%] and 130 men [59.1%]). Fixed-effects models that adjusted for time-variant (other illicit drug use, antipsychotic medication adherence) and time-invariant (eg, genetic or premorbid environment) unobserved confounders revealed that there was an increase in the odds of experiencing a relapse of psychosis during periods of cannabis use relative to periods of no use (odds ratio, 1.13; 95%CI, 1.03-1.24). Change in the pattern of continuation significantly increased the risk (odds ratio, 1.07; 95%CI, 1.02-1.13), suggesting a dose-dependent association. Cross-lagged analysis confirmed that this association reflected an effect of cannabis use on subsequent risk of relapse (Ct1→Rt2: β = 0.44, P = .04) rather than an effect of relapse on subsequent cannabis use (Rt1→Ct2: β = -0.29, P = .59). CONCLUSIONS AND RELEVANCE These results reveal a dose-dependent association between change in cannabis use and relapse of psychosis that is unlikely to be a result of self-medication or genetic and environmental confounding.
Effects of continuation, frequency, and type of cannabis use on relapse in the first 2 years after onset of psychosis: an observational study
Background Although cannabis use after a first episode of psychosis has been associated with relapse, little is known about the determinants of this most preventable risk factor for relapse of psychosis. Here we aimed to study whether the effects on outcome vary depending on the type of cannabis consumed and usage pattern. Methods In this observational study, we prospectively recruited and followed up patients aged 18–65 years who presented with their first episode of psychosis to psychiatric services in south London, London, UK. Relapse of psychosis within 2 years after onset of psychosis was defined as risk of subsequent admission to hospital. We classified patients into different patterns of cannabis use based on continuity of use after onset of psychosis, potency of cannabis consumed, and frequency of use after the onset of their illness. We used multiple regression analyses (logistic or binominal) to compare the different cannabis use groups and propensity score analysis to validate the results. Findings Between April 12, 2002, and July 26, 2013, 256 patients presented with a first episode of psychosis. We did follow-up assessments for these patients until September, 2015. Simple analyses showed that former regular users of cannabis who stopped after the onset of psychosis had the most favourable illness course with regards to relapse. In multiple analysis, continued high-frequency users (ie, daily use in all 24 months) of high-potency (skunk-like) cannabis had the worst outcome, indexed as an increased risk for a subsequent relapse (odds ratio [OR] 3·28; 95% CI 1·22–9·18), more relapses (incidence rate ratio 1·77; 95% CI 0·96–3·25), fewer months until a relapse occurred (b −0·22; 95% CI −0·40 to −0·04), and more intense psychiatric care (OR 3·16; 95% CI 1·26–8·09) after the onset of psychosis. Interpretation Adverse effects associated with continued use of cannabis after the onset of a first episode of psychosis depend on the specific patterns of use. Possible interventions could focus on persuading cannabis-using patients with psychosis to reduce use or shift to less potent forms of cannabis. Funding National Institute for Health Research (NIHR).
Impact of childhood trauma on risk of relapse requiring psychiatric hospital admission for psychosis
Relapse in psychosis typically necessitates admission to hospital placing a significant financial burden on the health service. Exposure to childhood trauma is associated with an increased risk of psychosis, however, the extent to which this influences relapse is unclear. This report summarises current research investigating the influence of childhood trauma on relapse requiring psychiatric hospital admission for psychosis. Seven studies were included; two revealed a positive association between childhood trauma and relapse admission, two studies found a negative relationship and three found no significant difference. Inconsistent current evidence suggests a need for further research in this area.
Continued versus discontinued cannabis use in patients with psychosis: A systematic review and meta-analysis
Background: Although the link between cannabis use and development of psychosis is well established, less is known about the effect of continued versus discontinued cannabis use after the onset of psychosis. We aimed to summarise available evidence focusing on the relationship between continued and discontinued cannabis use after onset of psychosis and its relapse. Methods: In this systematic review and meta-analysis, we searched MEDLINE for articles published in any language from the database inception date up until April 21, 2015 that included a sample of patients with a pre-existing psychotic disorder with a follow-up duration of at least 6 months. We used a combination of search terms for describing cannabis, the outcome of interest (relapse of psychosis), and the study population. We excluded studies if continued cannabis use or discontinued cannabis use could not be established. We compared relapse outcomes between those who continued (CC) or discontinued (DC) cannabis use or were non-users (NC). We used summary data (individual patient data were not sought out) to estimate Cohen's d, which was entered into random effects models (REM) to compare CC with NC, CC with DC, and DC with NC. Meta-regression and sensitivity analyses were used to address the issue of heterogeneity. Findings: Of 1903 citations identified, 24 studies (16 565 participants) met the inclusion criteria. Independent of the stage of illness, continued cannabis users had a greater increase in relapse of psychosis than did both non-users (dCC-NC=0·36, 95% CI 0·22-0·50, p<0·0001) and discontinued users (dCC-DC=0·28, 0·12-0·44, p=0·0005), as well as longer hospital admissions than non-users (dCC-NC=0·36, 0·13 to 0·58, p=0·02). By contrast, cannabis discontinuation was not associated with relapse (dDC-NC=0·02, -0·12 to 0·15; p=0·82). Meta-regression suggested greater effects of continued cannabis use than discontinued use on relapse (dCC-NC=0·36 vs dDC-NC=0·02, p=0·04), positive symptoms (dCC-NC=0·15 vs dDC-NC=-0·30, p=0·05) and level of functioning (dCC-NC=0·04 vs dDC-NC=-0·49, p=0·008) but not on negative symptoms (dCC-NC=-0·09 vs dDC-NC=-0·31, p=0·41). Interpretation: Continued cannabis use after onset of psychosis predicts adverse outcome, including higher relapse rates, longer hospital admissions, and more severe positive symptoms than for individuals who discontinue cannabis use and those who are non-users. These findings point to reductions in cannabis use as a crucial interventional target to improve outcome in patients with psychosis.
A pilot protocol for surveillance of infection and antibiotic prescribing in primary healthcare across the globe: Antibiotic Prescribing in Primary Healthcare Point Prevalence Survey (APC-PPS).
Little data is available from the primary healthcare setting in low- and middle-income countries to describe the burden of clinical infections and antibiotic prescribing proportions for those infections. The AWaRe Antibiotic Book provides a framework for assessing antibiotic prescribing in primary healthcare but requires understanding both frequency of clinical infections and their antibiotic prescribing proportions. The Antibiotic Prescribing in Primary Healthcare Point Prevalence Survey (APC-PPS) project is a series of point prevalence surveys conducted at primary healthcare facilities in LMICs to capture the frequency of consultation for different clinical infections and diagnoses and the frequency and type of antibiotic prescribing associated with these infections in primary healthcare facilities. This study aims to assess the feasibility of using a PPS methodology to collect data on clinical presentation and antibiotic prescribing in primary healthcare settings. The data collected are necessary to be able to summarise relative rates of presentation of different clinical infections and antibiotic prescribing practices to inform global estimates of antibiotic use and inform the development of surveillance methods and representative sampling frames. Each site will conduct 6-8 point prevalence surveys over the course of 12 months. Completely anonymous data on age, sex, relevant comorbidities, infection symptoms and diagnoses and antibiotic prescription are collected for patients of all ages with acute infection symptoms (up to 14 days of symptoms) who present to the facility on the day of the survey. No identifiable data will be collected from individuals. Data is collected via ODK Collect and stored in a secure ODK Cloud server hosted by City St. George's, University of London. Sites will be active between early 2023- end 2024, with regular interim data analysis scheduled and final data analysis planned by mid 2025. All required local and national ethical and regulatory approvals will be obtained prior to sites starting.
Identification of undetected SARS-CoV-2 infections by clustering of Nucleocapsid antibody trajectories
During the COVID-19 pandemic, numerous SARS-CoV-2 infections remained undetected. We combined results from routine monthly nose and throat swabs, and self-reported positive swab tests, from a UK household survey, linked to national swab testing programme data from England and Wales, together with Nucleocapsid (N-)antibody trajectories clustered using a longitudinal variation of K-means (N = 185,646) to estimate the number of infections undetected by either approach. Using N-antibody (hypothetical) infections and swab-positivity, we estimated that 7.4% (95%CI: 7.0–7.8%) of all true infections (detected and undetected) were undetected by both approaches, 25.8% (25.5–26.1%) by swab-positivity-only and 28.6% (28.4–28.9%) by trajectory-based N-antibody-classifications-only. Congruence with swab-positivity was respectively much poorer and slightly better with N-antibody classifications based on fixed thresholds or fourfold increases. Using multivariable logistic regression N-antibody seroconversion was more likely as age increased between 30–60 years, in non-white participants, those less (recently/frequently) vaccinated, for lower cycle threshold values in the range above 30, and in symptomatic and Delta (vs. BA.1) infections. Comparing swab-positivity data sources showed that routine monthly swabs were insufficient to detect infections and incorporating national testing programme/self-reported data substantially increased detection. Overall, whilst N-antibody serosurveillance can identify infections undetected by swab-positivity, optimal use requires fourfold-increase-based or trajectory-based analysis.
Knowledge and practice of healthy behaviors for dementia and stroke prevention in a United States cohort
At least 45% of dementia and 60% of stroke cases are due to modifiable risk factors and could in part be prevented through healthy behavior. This cross-sectional study clustered and characterized a U.S. cohort’s knowledge and practice of healthy behavior associated with dementia and stroke. A total of 1,478 participants (mean age: 45.5 years, 51.8% female) were included. A hierarchical cluster analysis was performed to identify clusters based on the level of knowledge and practice of healthy behavior. We defined knowledge as recognizing eight modifiable risk factors (alcohol, diet, smoking, physical activity, sleep, stress, social relationships, and purpose in life) as important. We defined practice as complying with validated recommendations for each healthy behavior. Three clusters emerged: (I) high knowledge and poor practice (II) high knowledge and good practice, and (III) lower knowledge and poor practice. Participants in the high knowledge and good practice cluster were statistically significantly older, more educated, perceived fewer barriers (financial and time limitations), and more facilitators (motivation or knowing someone with dementia or stroke) compared to the other clusters. Our findings could assist in tailoring preventative strategies to enhance knowledge, translating knowledge into practice, and addressing particular facilitators and barriers per identified cluster.
An electronic health record-wide association study to identify populations at increased risk of E. coli bacteraemia
Objectives: Escherichia coli bacteraemias have been under mandatory surveillance in the UK for fifteen years, but cases continue to rise. Systematic searches of all features present within electronic healthcare records (EHRs), described here as an EHR-wide association study (EHR-WAS), could potentially identify under-appreciated factors that could be targeted to reduce infections. Methods: We used data from Oxfordshire, UK, and an EHR-WAS method developed for use with large-scale COVID-19 data to estimate associations between E. coli bacteraemia cases, hospital-exposed controls, and 377 potential risk factors using Poisson regression models adjusted for potential confounders for three two-year financial year (FY) periods. Results: FY2022/23–2023/24 analysis included 757 (0.3%) cases and 276,758 (99.7%) controls. We identified six broad disease areas associated with increased or decreased E. coli bacteraemia risk. Renal/urological/urinary tract infection-related variables had the largest impact, with 47% of cases theoretically removed if these factors could be minimised. Cancer-related variables were associated with higher E. coli bacteraemia risk (1.20 times higher (95%CI 1.08–1.34) per three months closer to chemotherapy in the last year), as were gastrointestinal- and infectious disease-related variables. Cardiac/respiratory-related variables were associated with lower E. coli bacteraemia risk, whereas greater healthcare exposure showed no consistent effect. Associated factors varied across periods, but broad groups remained similar. Conclusions: Applying an EHR-WAS approach, we show E. coli bacteraemias are largely driven by known risk factors and frailty, highlighting the importance of monitoring these factors and targeting modifiable risks where possible.
Uncertainty quantification in cost-effectiveness analysis for stochastic-based infectious disease models: Insights from surveillance on lymphatic filariasis
Cost-effectiveness analyses (CEA) typically involve comparing the effectiveness and costs of one or more interventions compared to the standard of care, in order to determine which intervention should be optimally implemented to maximise population health within the constraints of the healthcare budget. Traditionally, cost-effectiveness evaluations are expressed using incremental cost-effectiveness ratios (ICERs), which are compared with a fixed willingness-to-pay (WTP) threshold. Due to the inherent uncertainty in intervention costs and the overall burden of disease, particularly with regard to diseases in populations that are difficult to study, it becomes important to consider uncertainty quantification while estimating ICERs. To tackle the challenges of uncertainty quantification in CEA, we propose an alternative paradigm utilizing the Linear Wasserstein framework combined with Linear Discriminant Analysis (LDA) using a demonstrative example of lymphatic filariasis (LF). This approach uses geometric embeddings of the overall costs for treatment and surveillance, disability-adjusted life-years (DALYs) averted for morbidity by quantifying the burden of disease due to the years lived with disability, and probabilities of local elimination over a time-horizon of 20 years to evaluate the cost-effectiveness of lowering the stopping thresholds for post-surveillance determination of LF elimination as a public health problem. Our findings suggest that reducing the stopping threshold from <1 % to <0.5 % microfilaria (mf) prevalence for adults aged 20 years and above, under various treatment coverages and baseline prevalences, is cost-effective. When validated on 20 % of test data, for 65 % treatment coverage, a government expenditure of WTP ranging from $500 to $3000 per 1 % increase in local elimination probability justifies the switch to the lower threshold as cost-effective. Stochastic model simulations often lead to parameter and structural uncertainty in CEA. Uncertainty may impact the decisions taken, and this study underscores the necessity of better uncertainty quantification techniques within CEA for making informed decisions.
Roux-en-Y gastric bypass, adjustable gastric banding, or sleeve gastrectomy for severe obesity (By-Band-Sleeve): a multicentre, open label, three-group, randomised controlled trial
Background: The health risks of severe obesity can be reduced with metabolic and bariatric surgery, but it is uncertain which operation is most effective or cost-effective. We aimed to compare Roux-en-Y gastric bypass, adjustable gastric banding, and sleeve gastrectomy in patients with severe obesity. Methods: By-Band-Sleeve is a pragmatic, multi-centre, open-label, randomised controlled trial conducted in 12 hospitals in the UK. Eligible participants were adults (aged ≥18 years) meeting national criteria for metabolic and bariatric surgery. Initially, a 2-group trial (Roux-en-Y gastric bypass versus adjustable gastric banding) became a 3-group trial to include sleeve gastrectomy at 2·6 years from study opening, when it became widely used in the UK. Co-primary endpoints were weight (proportion achieving ≥50% excess weight loss) and quality-of-life (EQ-5D utility score) at 3 years. If the proportion achieving at least 50% excess weight loss was non-inferior (<12% difference between groups) and quality-of-life was superior, sleeve gastrectomy and Roux-en-Y gastric bypass were considered more effective than adjustable gastric banding, and sleeve gastrectomy more effective than Roux-en-Y gastric bypass. Cost-effectiveness of the procedures was compared. This trial is registered with ClinicalTrials.gov, NCT02841527, and ISRCTN, 00786323. Results: Between Jan 16, 2013, and Sept 27, 2019, 1351 participants were randomly assigned; five withdrew consent and 1346 (mean age 47·3 [SD 10·6] years, 1020 [76%] women, 324 (24%) men, and two with missing data, mean weight of 129·7 kg [23·6] and mean BMI of 46·4 [6·9] kg/m2) were included in this report. Of 1346 participants, 462 (34%) were in the Roux-en-Y gastric bypass group, 464 (34%) in the adjustable gastric banding group, and 420 (31%) in the sleeve gastrectomy group. 1183 (88%) participants underwent surgery. 276 (68%) of 405 participants in the Roux-en-Y gastric bypass group, 97 (25%) of 383 participants in the adjustable gastric banding group and 141 (41%) of 342 participants in the sleeve gastrectomy group achieved at least 50% excess weight loss (adjusted risk difference: Roux-en-Y gastric bypass vs adjustable gastric banding 41% [98% CI 34 to 48]; sleeve gastrectomy vs adjustable gastric banding 15% [5 to 24]; sleeve gastrectomy vs Roux-en-Y gastric bypass, –26% [–36 to –16%]). Mean EQ-5D scores were 0·72 for Roux-en-Y gastric bypass, 0·62 for adjustable gastric banding, and 0·68 for sleeve gastrectomy (adjusted mean difference: Roux-en-Y gastric bypass vs adjustable gastric banding 0·08 [0·04 to 0·12], sleeve gastrectomy vs adjustable gastric banding 0·05 [0·01 to 0·09], and sleeve gastrectomy vs Roux-en-Y gastric bypass –0·03 [–0·07 to 0·01]). 1651 adverse events were reported following surgery (5·7 per year after sleeve gastrectomy, 6·0 per year after Roux-en-Y gastric bypass, and 4·6 per year after adjustable gastric banding). There were 11 deaths from randomisation to 3 years: one attributable to surgery (in the adjustable gastric bypass group, during the surgical admission) and ten not attributable to surgery (four each in the Roux-en-Y gastric bypass and adjustable gastric banding groups and two in the sleeve gastrectomy group). Roux-en-Y gastric bypass was most cost-effective. Interpretation: Roux-en-Y gastric bypass and sleeve gastrectomy are more effective than adjustable gastric banding. Sleeve gastrectomy has inferior weight loss and lower mean quality of life score compared with Roux-en-Y gastric bypass. Based on this evidence, it is recommended that patients electing to have metabolic and bariatric surgery are advised to have Roux-en-Y gastric bypass. Where contraindicated or unfeasible, sleeve gastrectomy should be offered. This evidence does not support adjustable gastric band as standard treatment for severe obesity. Funding: National Institute for Health and Care Research Health Technology Assessment Programme.
Umbrella review of economic evaluations of interventions for the prevention and management of healthcare-associated infections in adult hospital patients
Background: Healthcare-associated infections (HCAIs) result in worse outcomes for patients and greater financial burden. An estimated 4.8 million HCAIs occurred in hospitals across Europe in 2022–23. Sixty-four percent of antibiotic-resistant infections in Europe are associated with healthcare. It is therefore vital to identify cost-effective interventions. Aim: To summarize the cost-effectiveness evidence of interventions addressing HCAIs in hospitals. Methods: An umbrella review was conducted to identify evidence on the cost-effectiveness of antimicrobial stewardship, infection prevention and control, and microbiology and diagnostic stewardship interventions for the prevention and clinical management of HCAIs in adult hospital patients. Medline, Embase, and EconLit databases were searched. A qualitative synthesis was undertaken. Findings: Twenty-four systematic reviews met the inclusion criteria, with 101 separate analyses extracted and grouped into 10 intervention and 14 infection/organism categories, across various countries and settings. Most evidence focused on screening followed by contact precautions, isolation and/or decolonization, with selective screening most cost-effective. Most infection prevention and control bundles were cost-effective, although interventions were heterogeneous. The evidence base was sparse for the remaining intervention categories, with more research required. The limited evidence suggests that standalone environmental cleaning, hand hygiene, diagnostics, surveillance, antimicrobial stewardship, and decolonization interventions were mostly cost-effective. The cost-effectiveness of standalone personal protective equipment, and education and training interventions was mixed. Most interventions focused on meticillin-resistant Staphylococcus aureus and other Gram-positive infections, with more research needed on Gram-negative infections. The comparator was unclear in many extracted analyses. Conclusions: Cost-effective interventions to address HCAIs in hospitals exist, although more evidence is needed for most interventions.
General practice antibiotic prescriptions attributable to respiratory syncytial virus by age and antibiotic class: an ecological analysis of the English population
Background: Respiratory syncytial virus (RSV) may contribute to a substantial volume of antibiotic prescriptions in primary care. However, data on the type of antibiotics prescribed for such infections are only available for children <5 years in the UK. Understanding the contribution of RSV to antibiotic prescribing would facilitate predicting the impact of RSV preventative measures on antibiotic use and resistance. The objective of this study was to estimate the proportion of antibiotic prescriptions in English general practice attributable to RSV by age and antibiotic class. Methods: Generalized additive models examined associations between weekly counts of general practice antibiotic prescriptions and laboratory-confirmed respiratory infections from 2015 to 2018, adjusting for temperature, practice holidays and remaining seasonal confounders. We used general practice records from the Clinical Practice Research Datalink and microbiology tests for RSV, influenza, rhinovirus, adenovirus, parainfluenza, human metapneumovirus, Mycoplasma pneumoniae and Streptococcus pneumoniae from England’s Second Generation Surveillance System. Results: An estimated 2.1% of antibiotics were attributable to RSV, equating to an average of 640 000 prescriptions annually. Of these, adults ≥75 years contributed to the greatest volume, with an annual average of 149 078 (95% credible interval: 93 733–206 045). Infants 6–23 months had the highest average annual rate at 6580 prescriptions per 100 000 individuals (95% credible interval: 4522–8651). Most RSV-attributable antibiotic prescriptions were penicillins, macrolides or tetracyclines. Adults ≥65 years had a wider range of antibiotic classes associated with RSV compared with younger age groups. Conclusions: Interventions to reduce the burden of RSV, particularly in older adults, could complement current strategies to reduce antibiotic use in England.
Health impact and economic evaluation of the Expanded Program on Immunization in China from 1974 to 2024: a modelling study
Background: The Expanded Program on Immunization (EPI), initiated by WHO in 1974, is a cornerstone of public health. China's EPI covers more than a sixth of the world's population and includes eight routine vaccines with high coverage rates. This study aimed to estimate health and economic impacts of China's EPI over the past 50 years (1974–2024). Methods: This study mathematically modelled the impact of all eight routine vaccines in China's EPI against eight pathogens (measles, pertussis, hepatitis B, tuberculosis, hepatitis A, Japanese encephalitis, meningitis A, and poliomyelitis) based on data availability and their substantial disease burden, particularly accounting for non-linearities in vaccine impact. Health and economic outcomes were determined using mathematical models between a counterfactual scenario without vaccination (vaccine coverage set to zero) and the current vaccination scenario (routine vaccination scheduled at age 0–6 years), based on calendar year and birth cohort approaches. The health impact of China's EPI from 1974 to 2024 was measured in the number of cases, deaths, and disability-adjusted life-years (DALYs) averted. Findings: We estimated that China's EPI averted 703·02 million cases (95% credible interval 699·51–722·80) and 2·48 million deaths (2·14–2·97) in 1974–2024 based on the calendar year approach, equivalent to averting an estimated 160·22 million DALYs (145·05–196·99). Using the birth cohort approach, we predicted 707·41 million cases (703·93–727·03) and 7·01 million deaths (6·95–7·87) averted over the lifetime, corresponding to 279·02 million DALYs (265·78–316·12). From a societal perspective, the aggregated cost of vaccination was estimated to be US$124·06 billion (120·49–127·49), although the benefits amounted to $2417·85 billion (2359·38–2710·35). China's EPI yielded an aggregate benefit–cost ratio of 19·48 (18·82–22·08) from the societal perspective and 8·02 (7·64–8·80) from the provider's perspective. Interpretation: China's EPI has shown remarkable health and economic achievements, contributing to worldwide EPI success in the past 50 years. Further investment in EPI is warranted to sustain coverage and expand vaccine inclusion in China and globally. Funding: Beijing Natural Science Foundation. Translation: For the Chinese translation of the abstract see Supplementary Materials section.