The Chinese Parkinson's Disease Registry (CPDR): Study Design and Baseline Patient Characteristics.

BACKGROUND: There is a lack of large multicenter Parkinson's disease (PD) cohort studies and limited data on the natural history of PD in China. OBJECTIVES: The objective of this study was to launch the Chinese Parkinson's Disease Registry (CPDR) and to report its protocol, cross-sectional baseline data, and prospects for a comprehensive observational, longitudinal, multicenter study. METHODS: The CPDR recruited PD patients from 19 clinical sites across China between January 2018 and December 2020. Clinical data were collected prospectively using at least 17 core assessment scales. Patients were followed up for clinical outcomes through face-to-face interviews biennially. RESULTS: We launched the CPDR in China based on the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network (PD-MDCNC). A total of 3148 PD patients were enrolled comprising 1623 men (51.6%) and 1525 women (48.4%). The proportions of early-onset PD (EOPD, age at onset ≤50 years) and late-onset PD (LOPD) were 897 (28.5%) and 2251 (71.5%), respectively. Stratification by age at onset showed that EOPD manifested milder motor and nonmotor phenotypes and was related to increased probability of dyskinesia. Comparison across genders suggested a slightly older average age at PD onset, milder motor symptoms, and a higher rate of developing levodopa-induced dyskinesias in women. CONCLUSIONS: The CPDR is one of the largest multicenter, observational, longitudinal, and natural history studies of PD in China. It offers an opportunity to expand the understanding of clinical features, genetic, imaging, and biological markers of PD progression. © 2022 International Parkinson and Movement Disorder Society.

Dose-response relationship in non-pharmacological interventions for individuals with mild cognitive impairment: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Non-pharmacological interventions (NPIs) are important in cognitive decline prevention in individuals with mild cognitive impairment (MCI). However, the dose-response relationship remains unclear. DESIGN: Systematic review and meta-analysis of randomised controlled trials. METHODS: Seven databases were searched until April 2020. RCTs of NPIs in individuals with MCI were eligible for inclusion. Hedge's g was used to calculate the effect size. A random-effect meta-analysis was used to explore the impact of NPIs on cognition. Subgroup analysis was used to investigate the moderates. The dose was measured by prescription (frequency, intensity, type, time and volume) and intervention characteristics (period, energy expenditure, delivery mode and setting) in NPIs. RESULTS: Forty-two studies with 4401 participants were included. In the NPIs, cognitive intervention (g = 0.167), physical exercise (g = 0.536) and multicomponent intervention (g = 0.386) had significant effect on cognition in individuals with MCI. Dose-response results showed cognition could be significantly improved in 1-2 times/week (p < .05), 60-120 min/session (p < .05), ≥12 weeks (p < .05), supervised (p < .05), clinical setting (p < .05) in cognitive intervention. In physical exercise, cognition could be improved in ≥3 times/week (p < .05), vigorous-intensity (p < .05), muscle-strengthening activity (p < .05), 30-60 min/session (p < .05), 6-12 weeks (p < .05), unsupervised (p < .05), community setting (p < .05). In the multicomponent intervention, cognition could be improved in 1-2 times/week (p < .05), 30-60 min/session (p < .05), 8-16 weeks (p < .05), clinical (p < .05). In nutrition intervention, cognition could be better improved DHA (p < .05), >1000 mg/day (p < .05). CONCLUSIONS: The effectiveness of cognitive intervention is significantly influenced by frequency, time, period, delivery mode and setting. The effectiveness of physical exercise is significantly influenced by frequency, intensity, type, time, period, delivery mode and setting. The effectiveness of multicomponent intervention is significantly influenced by frequency, time, period and setting. The effectiveness of nutrition intervention is significantly influenced by dose and type. RELEVANCE TO CLINICAL PRACTICE: The research summarised the evidence to guide the best prescription of NPIs and helped clinicians design more effective interventions in individuals with MCI.

Impact of PD-1 gene polymorphism and its interaction with tea drinking on susceptibility to tuberculosis.

The aim of this study was to explore the impact of polymorphism of PD-1 gene and its interaction with tea drinking on susceptibility to tuberculosis (TB). A total of 503 patients with TB and 494 controls were enrolled in this case-control study. Three single-nucleotide polymorphisms of PD-1 (rs7568402, rs2227982 and rs36084323) were genotyped and unconditional logistic regression analysis was used to identify the association between PD-1 polymorphism and TB, while marginal structural linear odds models were used to estimate the interactions. Genotypes GA (OR 1.434), AA (OR 1.891) and GA + AA (OR 1.493) at rs7568402 were more prevalent in the TB patients than in the controls (P < 0.05). The relative excess risk of interaction (RERI) between rs7568402 of PD-1 genes and tea drinking was -0.3856 (95% confidence interval -0.7920 to -0.0209, P < 0.05), which showed a negative interaction. However, the RERIs between tea drinking and both rs2227982 and rs36084323 of PD-1 genes were not statistically significant. Our data demonstrate that rs7568402 of PD-1 genes was associated with susceptibility to TB, and there was a significant negative interaction between rs7568402 and tea drinking. Therefore, preventive measures through promoting the consumption of tea should be emphasised in the high-risk populations.

Development and application of a new framework for infectious disease management at the early stage of new epidemics: Taking COVID-19 outbreak in China as an example.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) rapidly spread across worldwide, posing a significant challenge to public health. Several shortcomings in the existing infectious disease management system were exposed during the pandemic, which hindered the control of the disease globally. To cope with this issue, we propose a window-period framework to reveal the general rule of the progression of management of infectious diseases and to help with decision making at the early stage of epidemics with a focus on healthcare provisions. METHODS: The framework has two significant periods (dark-window period and bright-window period). Outbreak of COVID-19 in China was used as an example for the application of the framework. RESULTS: The framework could reflect the progression of the epidemic objectively. The spread increased slowly in the dark-window period, but rocketed up in the bright-window period. The beginning of the bright-window period was the time when healthcare personnel were exposed to a substantially high risk of nosocomial infection. Additionally, proper and prompt preventive actions during the dark-window and bright-window periods were substantially important to reduce the future spreading of the disease. CONCLUSIONS: It was recommended that when possible healthcare provisions should upgrade to the highest level of alert for the control of an unknown epidemic in the dark-window period, while countermeasures in the bright-window period could be accordingly adjusted with full exploration and considerations. The framework may provide some insights into how to accelerate the control of future epidemics promptly and effectively.

A Risk Prediction Model Based on Machine Learning for Cognitive Impairment Among Chinese Community-Dwelling Elderly People With Normal Cognition: Development and Validation Study.

BACKGROUND: Identifying cognitive impairment early enough could support timely intervention that may hinder or delay the trajectory of cognitive impairment, thus increasing the chances for successful cognitive aging. OBJECTIVE: We aimed to build a prediction model based on machine learning for cognitive impairment among Chinese community-dwelling elderly people with normal cognition. METHODS: A prospective cohort of 6718 older people from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) register, followed between 2008 and 2011, was used to develop and validate the prediction model. Participants were included if they were aged 60 years or above, were community-dwelling elderly people, and had a cognitive Mini-Mental State Examination (MMSE) score ≥18. They were excluded if they were diagnosed with a severe disease (eg, cancer and dementia) or were living in institutions. Cognitive impairment was identified using the Chinese version of the MMSE. Several machine learning algorithms (random forest, XGBoost, naïve Bayes, and logistic regression) were used to assess the 3-year risk of developing cognitive impairment. Optimal cutoffs and adjusted parameters were explored in validation data, and the model was further evaluated in test data. A nomogram was established to vividly present the prediction model. RESULTS: The mean age of the participants was 80.4 years (SD 10.3 years), and 50.85% (3416/6718) were female. During a 3-year follow-up, 991 (14.8%) participants were identified with cognitive impairment. Among 45 features, the following four features were finally selected to develop the model: age, instrumental activities of daily living, marital status, and baseline cognitive function. The concordance index of the model constructed by logistic regression was 0.814 (95% CI 0.781-0.846). Older people with normal cognitive functioning having a nomogram score of less than 170 were considered to have a low 3-year risk of cognitive impairment, and those with a score of 170 or greater were considered to have a high 3-year risk of cognitive impairment. CONCLUSIONS: This simple and feasible cognitive impairment prediction model could identify community-dwelling elderly people at the greatest 3-year risk for cognitive impairment, which could help community nurses in the early identification of dementia.

Evaluation of quality improvement intervention with nurse training in nursing homes: A systematic review.

INTRODUCTION: Quality improvement may be a promising approach to improve the quality of care in nursing homes, and nurse training is a key step in a successful quality improvement practice. The implementation of training measures may be related to the quality of quality improvement practice. Little is known about the quality of quality improvement practice or effective nurse training measures that affect the quality of quality improvement interventions in nursing homes. AIMS: The aim of this review was to assess the quality of available quality improvement intervention designs and present effective nurse training measures that contribute to a high-quality quality improvement intervention. METHODS: We searched the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medline, Embase and the Cochrane Library for articles published before March 2019. quality improvement intervention quality was evaluated using a standardised assessment tool. Descriptive synthesis was used for the analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Checklist was used for transparency. RESULTS: We included 12 articles, 1 was rated as perfect quality and 7 good quality. Out of these 8 studies, 3 features primarily reflected differences in quality: compliance, sustainability and replication ability of the interventions. They were affected by measures included provision of advanced training, available training resources, feedback process, building quality improvement teams, setting up mentors and nursing leadership training. Other recommended measures included external cooperation and leadership empowerment. CONCLUSION: A high-quality quality improvement intervention should consider how to improve compliance, sustainability and replication ability. Adapting measures that are compatible with nurse training may ensure a successful implementation of quality improvement programmes that are conducive to the effective improvement of service quality. RELEVANCE TO CLINICAL PRACTICE: Quality improvement programmes should take into account measures that are compatible with nursing staff training. These measures should help improve the quality of interventions and promote care service of nursing homes.

Yoga for asthma.

BACKGROUND: Asthma is a common chronic inflammatory disorder affecting about 300 million people worldwide. As a holistic therapy, yoga has the potential to relieve both the physical and psychological suffering of people with asthma, and its popularity has expanded globally. A number of clinical trials have been carried out to evaluate the effects of yoga practice, with inconsistent results. OBJECTIVES: To assess the effects of yoga in people with asthma. SEARCH METHODS: We systematically searched the Cochrane Airways Group Register of Trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts. We also searched PEDro. We searched ClinicalTrials.gov and the WHO ICTRP search portal. We searched all databases from their inception to 22 July 2015, and used no restriction on language of publication. We checked the reference lists of eligible studies and relevant review articles for additional studies. We attempted to contact investigators of eligible studies and experts in the field to learn of other published and unpublished studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared yoga with usual care (or no intervention) or sham intervention in people with asthma and reported at least one of the following outcomes: quality of life, asthma symptom score, asthma control, lung function measures, asthma medication usage, and adverse events. DATA COLLECTION AND ANALYSIS: We extracted bibliographic information, characteristics of participants, characteristics of interventions and controls, characteristics of methodology, and results for the outcomes of our interest from eligible studies. For continuous outcomes, we used mean difference (MD) with 95% confidence interval (CI) to denote the treatment effects, if the outcomes were measured by the same scale across studies. Alternatively, if the outcomes were measured by different scales across studies, we used standardised mean difference (SMD) with 95% CI. For dichotomous outcomes, we used risk ratio (RR) with 95% CI to measure the treatment effects. We performed meta-analysis with Review Manager 5.3. We used the fixed-effect model to pool the data, unless there was substantial heterogeneity among studies, in which case we used the random-effects model instead. For outcomes inappropriate or impossible to pool quantitatively, we conducted a descriptive analysis and summarised the findings narratively. MAIN RESULTS: We included 15 RCTs with a total of 1048 participants. Most of the trials were conducted in India, followed by Europe and the United States. The majority of participants were adults of both sexes with mild to moderate asthma for six months to more than 23 years. Five studies included yoga breathing alone, while the other studies assessed yoga interventions that included breathing, posture, and meditation. Interventions lasted from two weeks to 54 months, for no more than six months in the majority of studies. The risk of bias was low across all domains in one study and unclear or high in at least one domain for the remainder.There was some evidence that yoga may improve quality of life (MD in Asthma Quality of Life Questionnaire (AQLQ) score per item 0.57 units on a 7-point scale, 95% CI 0.37 to 0.77; 5 studies; 375 participants), improve symptoms (SMD 0.37, 95% CI 0.09 to 0.65; 3 studies; 243 participants), and reduce medication usage (RR 5.35, 95% CI 1.29 to 22.11; 2 studies) in people with asthma. The MD for AQLQ score exceeded the minimal clinically important difference (MCID) of 0.5, but whether the mean changes exceeded the MCID for asthma symptoms is uncertain due to the lack of an established MCID in the severity scores used in the included studies. The effects of yoga on change from baseline forced expiratory volume in one second (MD 0.04 litres, 95% CI -0.10 to 0.19; 7 studies; 340 participants; I(2) = 68%) were not statistically significant. Two studies indicated improved asthma control, but due to very significant heterogeneity (I(2) = 98%) we did not pool data. No serious adverse events associated with yoga were reported, but the data on this outcome was limited. AUTHORS' CONCLUSIONS: We found moderate-quality evidence that yoga probably leads to small improvements in quality of life and symptoms in people with asthma. There is more uncertainty about potential adverse effects of yoga and its impact on lung function and medication usage. RCTs with a large sample size and high methodological and reporting quality are needed to confirm the effects of yoga for asthma.

Prospective Association between Diabetic Retinopathy and Cardiovascular Disease-A Systematic Review and Meta-analysis of Cohort Studies.

BACKGROUND: Diabetic retinopathy (DR) is linked to increased risk of cardiovascular (CV) disease. However, the effect size of the association was not consistent. In this study, we performed a systematic review and meta-analysis of available cohort studies to determine the association between DR and CV disease, and to investigate the factors that influence the association. METHODS: Terms related to DR and CV disease were searched from MEDLINE and EMBASE database. High-quality articles (Newcastle-Ottawa scales above 6) conducted in cohort studies reporting the association between DR and CV disease were identified. Study-specific estimates were pooled using random effects with inverse variance meta-analysis. Subgroup analysis was performed according to diabetes types. Heterogeneity of included studies was assessed using the I(2) test. The cause of the heterogeneity was examined using metaregression analyses. RESULTS: A total of 13 studies representing 17,611 patients without CV disease at baseline were included. At follow-up, there were 1457 CV disease-related incidences. Overall, DR was associated with increased risk of CV disease (relative risk [RR]: 2.42, 95% confidence interval [CI]: 1.77-3.31) in diabetes. Specifically, the RR was 3.59 (95% CI: 1.79-7.20) for type 1 diabetes and 1.81 (95% CI: 1.47-2.23) for type 2 diabetes. Significant heterogeneity was found in studies with type 1 diabetes. Metaregression analysis showed that baseline systolic blood pressure was a key factor leading to the heterogeneity. CONCLUSION: In conclusion, DR is significantly associated with CV disease incidence and CV disease-related mortality in diabetes. Patients with DR may need more intensive management to control future CV disease attacks.

Interleukin-2 as maintenance therapy for children and adults with acute myeloid leukaemia in first complete remission.

BACKGROUND: Acute myeloid leukaemia (AML) is a malignant cancer of hematopoietic stem cells. The treatment of AML consists of two treatment phases: the remission induction phase to achieve a rapid, complete remission (CR) and the consolidation phase to achieve a durable molecular remission. People in CR are at risk of AML relapse, and people with relapsed AML have poor survival prospects. Thus, there is a continuous need for treatments to further improve prognosis. Interleukin-2 (IL-2), an immune-stimulatory cytokine, is an alternative to standard treatment for people with AML to maintain the efficacy after consolidation therapy. Maintenance therapy is not an integral part of the standard treatment for AML. Studies have been conducted to evaluate the efficacy of IL-2 as maintenance therapy for people with AML in first CR, but the effect of IL-2 is not yet fully established. OBJECTIVES: To evaluate the efficacy and safety of IL-2 as maintenance therapy for children and adults with AML who have achieved first CR and have not relapsed. SEARCH METHODS: We systematically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 8), MEDLINE (1950 to August 2015), EMBASE (1950 to August 2015), LILACS (1982 to August 2015), CBM (1978 to August 2015), relevant conference proceedings (2000 to 2015), and metaRegister of Controlled Trials (since inception to August 2015) of ongoing and unpublished trials. In addition, we screened the reference lists of relevant trials and reviews. SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs) comparing IL-2 with no treatment in people with AML who had achieved first CR and had not relapsed. We did not identify studies comparing IL-2 versus best supportive care or maintenance chemotherapy or studies comparing IL-2 plus maintenance chemotherapy versus maintenance chemotherapy alone. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, extracted data with a predefined extraction form, and assessed risk of bias of included studies. We extracted data on the following outcomes: disease-free survival, overall survival, event-free survival, treatment-related mortality, adverse events, and quality of life. We measured the treatment effect on time-to-event outcomes and dichotomous outcomes with hazard ratio (HR) and risk ratio, respectively. We used inverse-variance method to combine HRs with fixed-effect model unless there was significant between-study heterogeneity. MAIN RESULTS: We included nine RCTs with a total of 1665 participants, comparing IL-2 with no treatment. Six studies included adult participants, and three studies included both adults and children. However, the latter three studies did not report data for children, thus we were unable to conduct subgroup analysis of children. One Chinese study did not report any outcomes of interest for this review. We included six trials involving 1426 participants in the meta-analysis on disease-free survival, and included five trials involving 1355 participants in the meta-analysis on overall survival. There is no evidence for difference between IL-2 group and no-treatment group regarding disease-free survival (HR 0.95; 95% CI 0.86 to 1.06, P = 0.37; quality of evidence: low) or overall survival (HR 1.05; 95% CI 0.95 to 1.16, P = 0.35; quality of evidence: moderate). Based on one trial of 161 participants, IL-2 exerted no effect on event-free survival (HR 1.02; 95% CI 0.79 to 1.32, P = 0.88; quality of evidence: low). Adverse events (including thrombocytopenia, neutropenia, malaise/fatigue, and infection/fever) were more frequent in participants receiving IL-2, according to one trial of 308 participants. No mortality due to adverse events was reported. None of the included studies reported treatment-related mortality or quality of life. AUTHORS' CONCLUSIONS: There is no evidence for a difference between IL-2 maintenance therapy and no treatment with respect to disease-free survival or overall survival of people with AML in first CR; however, the quality of the evidence is moderate or low, and further research is likely or very likely to have an important impact on the estimate or our confidence in the estimate. Adverse events seem to be more frequent in participants treated with IL-2, but the quality of the evidence is very low and our confidence in the estimates is very uncertain. Thus, further prospective randomised trials are needed before definitive conclusions can be drawn on these issues.

Chemotherapy with cetuximab versus chemotherapy alone for chemotherapy-naive advanced non-small cell lung cancer.

BACKGROUND: In advanced non-small cell lung cancer (NSCLC), the effectiveness of standard cytotoxic chemotherapy seems to have reached a 'plateau', and there is a continuous need for new treatments to further improve the prognosis. Cetuximab is a monoclonal antibody targeted at the epidermal growth factor receptor (EGFR) signalling pathway. Basically, it is designed to inhibit the growth and metastasis among other biological processes of cancer. In combination with chemotherapy, it has been evaluated as a first-line treatment for advanced NSCLC in some randomised controlled trials (RCTs), with inconsistent results. OBJECTIVES: To evaluate the efficacy and toxicity of chemotherapy plus cetuximab, compared with chemotherapy alone, for advanced non-small cell lung cancer (NSCLC) previously untreated with chemotherapy or epidermal growth factor receptor (EGFR)-targeted drugs. SEARCH METHODS: We systematically searched the Cochrane Lung Cancer Review Group's Specialized Register (from inception to 17 December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 12), MEDLINE (accessed through PubMed, 1966 to 17 December 2013), EMBASE (1980 to 17 December 2013), ClinicalTrials.gov (from inception to 17 December 2013), and the World Health Organization (WHO) International Clinical Trials Registry Platform (from inception to 17 December 2013). We also handsearched the proceedings related to lung cancer from the American Society of Clinical Oncology and European Society of Medical Oncology (2000 to 17 December 2013). We checked the reference lists of all eligible primary studies and review articles for additional potentially eligible studies. SELECTION CRITERIA: Eligible studies were RCTs that compared chemotherapy plus cetuximab with the same chemotherapy alone, in advanced NSCLC, previously untreated with chemotherapy or EGFR-targeted drugs, and measured at least one of the following: overall survival, progression-free survival, one-year survival rate, objective response rate, quality of life, or serious adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. We extracted the following data from each study: publication details, participant characteristics, regimens for intervention and control arms, outcome measures and effect size, and information related to the methodological quality of the study. We measured the treatment effects on dichotomous and time-to-event outcomes by risk ratio (RR) and hazard ratio (HR), with 95% confidence intervals (CIs), respectively. We conducted meta-analyses with Review Manager 5 using the random-effects model. We employed the Mantel-Haenszel method to combine RRs and the inverse-variance method to combine HRs. MAIN RESULTS: We included four trials, containing 2018 patients. The subjects were mostly white people (female: 26% to 56%), with a median age of 58 to 66 years. About half of them had histologically proven adenocarcinoma. Of the 2018 patients, 83% to 99% had their status measured using the Eastern Cooperative Oncology Group performance status, and had a score of 0 to 1 (which is usually considered as physically "fit").All four studies provided data on overall survival, progression-free survival, one-year survival rate, objective response rate, and serious adverse events, with two studies (1901 patients) investigating the effect of cetuximab on quality of life as well. The risk of bias was low for the data on overall survival and one-year survival rate, and high for the data on all other outcomes, mainly due to lack of blinding. Compared with chemotherapy alone, chemotherapy plus cetuximab improved overall survival (10.5 months versus 8.9 months; HR 0.87, 95% CI 0.79 to 0.96), one-year survival rate (45% versus 40%; RR 1.13, 95% CI 1.02 to 1.25), and objective response rate (30% versus 23%; RR 1.31, 95% CI 1.14 to 1.51). The difference in progression-free survival was at the limit of the statistical significance (4.9 months versus 4.4 months; HR 0.91, 95% CI 0.83 to 1.00). No significant difference in quality of life between the two treatment arms was reported by the two relevant studies. Patients in the cetuximab group experienced more acneiform rash (11.2% versus 0.3%; RR 37.36, 95% CI 10.66 to 130.95), hypomagnesemia (5.3% versus 0.8%; RR 6.57, 95% CI 1.13 to 38.12), infusion reaction (3.9% versus 1.1%; RR 3.50, 95% CI 1.76 to 6.94), diarrhoea (4.8% versus 2.3%; RR 2.10, 95% CI 1.26 to 3.48), hypokalaemia (6.3% versus 3.6%; RR 1.74, 95% CI 1.02 to 2.99), febrile neutropenia (10.6% versus 7.6%; RR 1.40, 95% CI 1.10 to 1.77), and leukopenia (58.1% versus 42.7%; RR 1.36, 95% CI 1.17 to 1.58) than did those in the control group. The difference in other adverse events did not reach statistical significance. According to the reports of original studies, the adverse events were generally manageable. There were no cetuximab-related deaths.The quality of the evidence is high for overall survival and one-year survival rate, but low for most secondary outcomes. AUTHORS' CONCLUSIONS: The combination of chemotherapy plus cetuximab is better than chemotherapy alone as the first-line treatment of advanced NSCLC in improving overall survival, while inducing higher rates of some reportedly manageable adverse events.

An internet-based epidemiological investigation of the outbreak of H7N9 Avian influenza A in China since early 2013.

BACKGROUND: In early 2013, a new type of avian influenza, H7N9, emerged in China. It quickly became an issue of great public concern and a widely discussed topic on the Internet. A considerable volume of relevant information was made publicly available on the Internet through various sources. OBJECTIVE: This study aimed to describe the outbreak of H7N9 in China based on data openly available on the Internet and to validate our investigation by comparing our findings with a well-conducted conventional field epidemiologic study. METHODS: We searched publicly accessible Internet data on the H7N9 outbreak primarily from government and major mass media websites in China up to February 10, 2014. Two researchers independently extracted, compared, and confirmed the information of each confirmed H7N9 case using a self-designed data extraction form. We summarized the epidemiological and clinical characteristics of confirmed H7N9 cases and compared them with those from the field study. RESULTS: According to our data updated until February 10, 2014, 334 confirmed H7N9 cases were identified. The median age was 58 years and 67.0% (219/327) were males. Cases were reported in 15 regions in China. Five family clusters were found. Of the 16.8% (56/334) of the cases with relevant data, 69.6% (39/56) reported a history of exposure to animals. Of the 1751 persons with a close contact with a confirmed case, 0.6% (11/1751) of them developed respiratory symptoms during the 7-day surveillance period. In the 97.9% (327/334) of the cases with relevant data, 21.7% (71/327) died, 20.8% (68/327) were discharged from a hospital, and 57.5% (188/327) were of uncertain status. We compared our findings before February 10, 2014 and those before December 1, 2013 with those from the conventional field study, which had the latter cutoff date of ours in data collection. Our study showed most epidemiological and clinical characteristics were similar to those in the field study, except for case fatality (71/327, 21.7% for our data before February 10; 45/138, 32.6% for our data before December 1; 47/139, 33.8% for the field study), time from illness onset to first medical care (4 days, 3 days, and 1 day), and time from illness onset to death (16.5 days, 17 days, and 21 days). CONCLUSIONS: Findings from our Internet-based investigation were similar to those from the conventional field study in most epidemiological and clinical aspects of the outbreak. Importantly, publicly available Internet data are open to any interested researchers and can thus greatly facilitate the investigation and control of such outbreaks. With improved efforts for Internet data provision, Internet-based investigation has a great potential to become a quick, economical, novel approach to investigating sudden issues of great public concern that involve a relatively small number of cases like this H7N9 outbreak.

Promising biomarkers for predicting the outcomes of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a systematic review with meta-analysis.

KRAS mutations have been established as a major predictive biomarker for resistance to the treatment of metastatic colorectal cancer (mCRC) with anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MoAbs). However, many patients with KRAS wild-type tumors still do not respond to the treatment. We conducted a systematic review with meta-analysis to assess whether BRAF mutations, PIK3CA mutations and PTEN loss can predict the outcomes of patients with KRAS wild-type mCRC treated with anti-EGFR MoAbs. Studies that explored the association of one or more of the three biomarkers with progression-free survival (PFS), overall survival (OS) and/or objective response rate (ORR) were identified through August 2012. Summary hazard ratios (HRs) and rate differences (RDs) and corresponding 95% confidence intervals (CIs) were calculated by using the random-effects model. BRAF mutations, PIK3CA exon 20 mutations and PTEN loss were all associated with shorter PFS (HR = 2.59, 95% CI 1.67-4.03; HR = 2.52, 95% CI 1.33-4.78 and HR = 1.75, 95% CI 1.19-2.56, respectively), shorter OS (HR = 2.74, 95% CI 1.79-4.19; HR = 3.29, 95% CI 1.60-6.75 and HR = 1.85, 95% CI 1.30-2.64, respectively) and lower ORR (RD = -36%, 95% CI -44 to -28%; RD = -38%, 95% CI -51 to -24% and RD = -41%, 95% CI -68 to -14%, respectively). PIK3CA exon 9 mutations were associated with none of the outcomes. Studies with relevant data consistently demonstrated a stronger predictive power of combined multiple biomarkers as compared to one alteration alone. These results suggest that BRAF mutations, PIK3CA exon 20 mutations and PTEN loss are predictive of worseoutcomes in KRAS wild-type mCRC treated with anti-EGFR MoAbs [corrected]. However, the quality of included studies varied, and some of the meta-analyses were limited by significant between-study heterogeneity. In the future, well-designed large randomized controlled trials conducted in KRAS wild-type mCRC patients with subgroup analysis according to BRAF, PIK3CA exon 20 and PTEN status are essential to fully assess the clinical relevance of these biomarkers.

Mycophenolate mofetil for primary focal segmental glomerulosclerosis: systematic review.

BACKGROUND: Current treatments for primary focal segmental glomerulosclerosis (FSGS), including corticosteroids and cyclosporine, are not satisfactory for all patients and may induce significant side effects. Antidotal benefits of mycophenolate mofetil (MMF) as an add-on to these immunosuppressive therapies have been reported. This review aims to systematically summarize the efficacy and safety of MMF as a treatment for primary FSGS. METHOD: Controlled and uncontrolled clinical trials evaluating the use of MMF in primary FSGS patients were identified from nine electronic databases and four clinical trial registries. Kidney failure was selected as the primary outcome. RESULTS: Three randomized controlled trials (RCT) and 18 uncontrolled pre-post studies were included. Results from RCTs revealed that MMF is no more effective than cyclosporine or cyclophosphamide for promoting kidney function preservation when corticosteroid is used as baseline treatment. One underpowered RCT reported that MMF provides no extra benefit on top of prednisolone, but the result is unlikely to be reliable. Amongst the small, uncontrolled pre-post studies, three of them used MMF as monotherapy, two of which reported successful prevention of kidney failure in all patients. The remaining 15 uncontrolled studies used MMF as add-on therapy and 11 reported kidney failure as an outcome. Amongst them, eight reported no patients developed kidney failure. MMF was generally well tolerated with mild adverse effects, including abdominal discomfort, diarrhea and infections. CONCLUSIONS: MMF tended to show beneficial effects in uncontrolled studies which recruited patients with resistance to routine treatments, but such favorable results have only been reported in small, uncontrolled trials. No RCT results suggested that MMF was a good alternative to cyclosporine or cyclophosphamide. The role of MMF as an add-on to current therapies, or as monotherapy, should further be evaluated.

Characteristics of fatigue in Parkinson's disease: A longitudinal cohort study.

Objective: To assess the prevalence, evolution, clinical characteristics, correlates and predictors of fatigue as well as to investigate the influence of comorbid fatigue on the longitudinal changes in motor and non-motor symptoms over a 2-year longitudinal follow-up period in a large cohort of patients with Parkinson's disease (PD). Materials and methods: A total of 2,100 PD patients were enrolled from the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC), and their motor and non-motor symptoms were assessed biennially using comprehensive scales, including the 16-item Parkinson Fatigue Scale (PFS-16). Each PD patient was categorized as PD with or without fatigue on the basis of a cut-off mean PFS-16 score of 3.3. Results: The prevalence of fatigue in our cohort was 36.8%. Compared to PD patients without fatigue, PD patients with fatigue were more likely to be older, have a longer disease duration, and higher baseline levodopa equivalent daily dose (all p < 0.05). Moreover, PD patients with fatigue showed more severe motor and non-motor phenotypes than those without fatigue. Overall, high total Unified Parkinson's Disease Rating Scale (UPDRS) score (odds ratio [OR] = 1.016, 95% confidence interval [CI]: 1.009-1.024), Non-Motor Symptoms Scale score (OR = 1.022, 95% CI: 1.015-1.029), postural instability and gait difficulty (PIGD) subtype (OR = 1.586, 95% CI: 1.211-2.079), presence of excessive daytime sleepiness (EDS; OR = 1.343, 95% CI: 1.083-1.666), and wearing-off (OR = 1.282, 95% CI: 1.023-1.607) were significantly associated with fatigue in PD patients (all p < 0.05). High total UPDRS score at baseline (OR = 1.014, 95% CI: 1.002-1.027, p = 0.028) increased the risk of developing fatigue during follow-up. Although significant, the odds ratios were low and confidence intervals were narrow. Analysis of disease progression showed significant group differences in motor and non-motor symptoms. In comparison with the never-fatigue group, the persistent-fatigue group showed significantly greater progression in motor, autonomic dysfunction, sleep, depression and cognitive symptoms (all p < 0.05). Conclusion: Increased disease severity, presence of the PIGD subtype, EDS, and wearing-off were associated with fatigue in PD patients. Significant subgroup-level differences were observed in the progression of motor and non-motor symptoms across different fatigue subgroups of PD patients.

A protocol of Chinese expert consensuses for the management of health risk in the general public.

Introduction: Non-communicable diseases (NCDs) represent the leading cause of mortality and disability worldwide. Robust evidence has demonstrated that modifiable lifestyle factors such as unhealthy diet, smoking, alcohol consumption and physical inactivity are the primary causes of NCDs. Although a series of guidelines for the management of NCDs have been published in China, these guidelines mainly focus on clinical practice targeting clinicians rather than the general population, and the evidence for NCD prevention based on modifiable lifestyle factors has been disorganized. Therefore, comprehensive and evidence-based guidance for the risk management of major NCDs for the general Chinese population is urgently needed. To achieve this overarching aim, we plan to develop a series of expert consensuses covering 15 major NCDs on health risk management for the general Chinese population. The objectives of these consensuses are (1) to identify and recommend suitable risk assessment methods for the Chinese population; and (2) to make recommendations for the prevention of major NCDs by integrating the current best evidence and experts' opinions. Methods and analysis: For each expert consensus, we will establish a consensus working group comprising 40-50 members. Consensus questions will be formulated by integrating literature reviews, expert opinions, and an online survey. Systematic reviews will be considered as the primary evidence sources. We will conduct new systematic reviews if there are no eligible systematic reviews, the methodological quality is low, or the existing systematic reviews have been published for more than 3 years. We will evaluate the quality of evidence and make recommendations according to the GRADE approach. The consensuses will be reported according to the Reporting Items for Practice Guidelines in Healthcare (RIGHT).

Age and Sex Affect Essential Tremor (ET) Plus: Clinical Heterogeneity in ET Based on the National Survey in China.

The new term essential tremor (ET) plus was proposed in the 2018 tremor consensus criteria. The National Survey of Essential Tremor Plus in China, a large multicenter registry study, aimed to evaluate the clinical features of pure ET and ET plus and explore possible factors related to ET plus. All patients with ET underwent neurological examination and neuropsychological assessment at 17 clinical sites. The diagnosis was made according to the 2018 consensus criteria. Clinicodemographic characteristics were analyzed. A total of 1160 patients were included, including 546 patients with pure ET and 614 patients with ET plus. The proportion of females was significantly higher in the ET plus than that in the pure ET (P = 0.001). The age at onset (AAO) of pure ET showed a bimodal distribution, with peaks in the 2nd and 5th decades. However, the AAO of the ET plus group demonstrated a skewed distribution, with a single peak in the 6th decade. Female sex (OR=1.645, P<0.001), older age (OR=1.023, P<0.001), lower educational level (OR=0.934, P<0.001), head tremor (OR=1.457, P<0.001), and higher the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-II scores (OR=1.134, P<0.001) were significantly associated with ET plus. Old age and female sex may contribute to ET plus development. Pure ET showed a bimodal distribution for AAO, whereas ET plus showed a unimodal distribution. It remains unclear whether pure ET and ET plus are merely different stages of a single disease or represent distinct disease entities.

Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson's disease in Chinese population.

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (Pcombined = 1.47 × 10-9) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P < 5 × 10-8) for PD in Chinese population. Moreover, of the reported genome-wide significant risk variants found mostly in European ancestry populations, the correlation coefficient (rb) of effect size accounting for sampling errors was 0.91 between datasets and 63.6% attained P < 0.05 in Chinese population. Accordingly, we estimated a heritability of 0.14-0.18 for PD, and a moderate genetic correlation between European ancestry and Chinese populations (rg = 0.47, se = 0.21). Polygenic risk score (PRS) analysis revealed that individuals with PRS values in the highest quartile had a 3.9-fold higher risk of developing PD than the lowest quartile. In conclusion, the present GWAS identified PD-associated variants in Chinese population, as well as genetic factors shared among distant populations. Our findings shed light on the genetic homogeneity and heterogeneity of PD in different ethnic groups and suggested WGS might continue to improve our understanding of the genetic architecture of PD.

Subtyping of early-onset Parkinson's disease using cluster analysis: A large cohort study.

Background: Increasing evidence suggests that early-onset Parkinson's disease (EOPD) is heterogeneous in its clinical presentation and progression. Defining subtypes of EOPD is needed to better understand underlying mechanisms, predict disease course, and eventually design more efficient personalized management strategies. Objective: To identify clinical subtypes of EOPD, assess the clinical characteristics of each EOPD subtype, and compare the progression between EOPD subtypes. Materials and methods: A total of 1,217 patients were enrolled from a large EOPD cohort of the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) between January 2017 and September 2021. A comprehensive spectrum of motor and non-motor features were assessed at baseline. Cluster analysis was performed using data on demographics, motor symptoms and signs, and other non-motor manifestations. In 454 out of total patients were reassessed after a mean follow-up time of 1.5 years to compare progression between different subtypes. Results: Three subtypes were defined: mild motor and non-motor dysfunction/slow progression, intermediate and severe motor and non-motor dysfunction/malignant. Compared to patients with mild subtype, patients with the severe subtype were more likely to have rapid eye movement sleep behavior disorder, wearing-off, and dyskinesia, after adjusting for age and disease duration at baseline, and showed a more rapid progression in Unified Parkinson's Disease Rating Scale (UPDRS) total score (P = 0.002), UPDRS part II (P = 0.014), and III (P = 0.001) scores, Hoehn and Yahr stage (P = 0.001), and Parkinson's disease questionnaire-39 item version score (P = 0.012) at prospective follow-up. Conclusion: We identified three different clinical subtypes (mild, intermediate, and severe) using cluster analysis in a large EOPD cohort for the first time, which is important for tailoring therapy to individuals with EOPD.

Constructing prediction models for excessive daytime sleepiness by nomogram and machine learning: A large Chinese multicenter cohort study.

Objective: Although risk factors for excessive daytime sleepiness (EDS) have been reported, there are still few cohort-based predictive models for EDS in Parkinson's disease (PD). This 1-year longitudinal study aimed to develop a predictive model of EDS in patients with PD using a nomogram and machine learning (ML). Materials and methods: A total of 995 patients with PD without EDS were included, and clinical data during the baseline period were recorded, which included basic information as well as motor and non-motor symptoms. One year later, the presence of EDS in this population was re-evaluated. First, the baseline characteristics of patients with PD with or without EDS were analyzed. Furthermore, a Cox proportional risk regression model and XGBoost ML were used to construct a prediction model of EDS in PD. Results: At the 1-year follow-up, EDS occurred in 260 of 995 patients with PD (26.13%). Baseline features analysis showed that EDS correlated significantly with age, age of onset (AOO), hypertension, freezing of gait (FOG). In the Cox proportional risk regression model, we included high body mass index (BMI), late AOO, low motor score on the 39-item Parkinson's Disease Questionnaire (PDQ-39), low orientation score on the Mini-Mental State Examination (MMSE), and absence of FOG. Kaplan-Meier survival curves showed that the survival prognosis of patients with PD in the high-risk group was significantly worse than that in the low-risk group. XGBoost demonstrated that BMI, AOO, PDQ-39 motor score, MMSE orientation score, and FOG contributed to the model to different degrees, in decreasing order of importance, and the overall accuracy of the model was 71.86% after testing. Conclusion: In this study, we showed that risk factors for EDS in patients with PD include high BMI, late AOO, a low motor score of PDQ-39, low orientation score of MMSE, and lack of FOG, and their importance decreased in turn. Our model can predict EDS in PD with relative effectivity and accuracy.

Extent, reasons and consequences of off-labeled and unlicensed drug prescription in hospitalized children: a narrative review.

BACKGROUND: Off-label and unlicensed prescriptions pose a severe safety concern among the pediatric population. We aimed to summarize the up-to-date evidence on the extent, reasons, and consequences of off-label and unlicensed drugs in hospitalized pediatric patients. METHODS: We systematically searched PubMed, EMBASE, SCOPUS, Web of Science and Google Scholar between 1990 and 2020 in which the last search was conducted on 12 February 2021. We included studies with the following inclusion criteria: (1) observational studies in design; (2) target population was hospitalized pediatric patients whether admitted in the intensive care unit or in the general ward; (3) study reporting the prevalence of off-label, unlicensed prescriptions or both; and (4) published in English. RESULTS: A total of 47 studies were eligible for inclusion. The proportion of off-label and unlicensed prescriptions ranged from 7.4% to 99.5% and 0.1% to 74.4%, respectively. The most frequent category of off-label prescriptions was prescription outside the age range, with the most commonly reported reason for off-label prescriptions being the lack of information specifically for pediatrics on the drug information leaflets. The consequences of off-label and unlicensed prescriptions ranged from minor and bearable skin reactions to debilitating renal failure, risking deaths. CONCLUSIONS: Off-label and unlicensed prescriptions are extensive and require progressively meditative interventions. However, the pediatric population is currently a "therapeutic orphan". Unless adequate pediatric clinical trials and licensed drugs become available, off-label and unlicensed drug prescription should not entirely be banned but rather promoted in an organized manner.