Antibody-Proteolysis Targeting Chimera Conjugate Enables Selective Degradation of Receptor-Interacting Serine/Threonine-Protein Kinase 2 in HER2+ Cell Lines.

Proteolysis targeting chimeras (PROTACs) are a family of heterobifunctional molecules that are now realizing their promise as a therapeutic strategy for targeted protein degradation. However, one limitation of existing designs is the lack of cell-selective targeting of the protein degrading payload. This manuscript reports a cell-targeted approach to degrade receptor-interacting serine/threonine-protein kinase 2 (RIPK2) in HER2+ cell lines. An antibody-PROTAC conjugate is prepared containing a protease-cleavable linkage between the antibody and the corresponding degrader. Potent RIPK2 degradation is observed in HER2+ cell lines, whereas an equivalent anti-IL4 antibody-PROTAC conjugate shows no degradation at therapeutically relevant concentrations. No RIPK2 degradation was observed in HER2- cell lines for both bioconjugates. This work demonstrates the potential for the cell-selective delivery of PROTAC scaffolds by engaging with signature extracellular proteins expressed on the surface of particular cell types.

Identifying and articulating the student experience in the Intercalated Enrichment Year.

BACKGROUND: Benefits of intercalation during an undergraduate medical degree are well-recognized. The University of Hong Kong implemented a compulsory Enrichment Year (EY) in its Bachelor of Medicine and Bachelor of Surgery degree programme (MBBS) in 2016. In their third year of study, students could work on an area of interest in any of three programme categories (i) intercalation/ university exchange (IC); (ii) research (RA); (iii) service/ humanitarian work (SH). This study aimed to explore the barriers, enablers, and overall student learning experiences from the first cohort of EY students in order to inform future development of the EY. METHODS: An exploratory sequential mixed-method study in 2019-20. Twenty students were purposively selected to attend three semi-structured focus group interviews. Conventional thematic analysis was employed and results assisted the design of a cross-sectional questionnaire. Sixty-three students completed the questionnaire. ANOVA or chi-square test was used to compare the difference in student's characteristics, barriers, enablers and perspectives on EY between programme categories. Adjusting student's characteristics, logistic regressions were conducted to identify the effect of programme categories on the EY experience. RESULTS: Most students (95% in the questionnaire) agreed that EY was worthwhile and more rewarding than expected. EY was positively regarded for enhancing personal growth and interpersonal relationships. The main barriers were financial difficulties, scholarship issues and insufficient information beforehand. A few students had practical (i.e. accommodation, cultural adaptation) problems. Potential enablers included better financial support, more efficient information exchange and fewer assignments and preparation tasks. Similar barriers were encountered by students across all three categories of EY activities. CONCLUSIONS: Personal growth was the most important benefit of the EY. Barriers were consistent with those identified in the literature except for cultural adaptation, which could be related to Hong Kong's unique historical context. Financial limitation was the most concerning barrier, as it could result in unequal access to educational opportunities. Better and timely access to scholarships and other funding sources need to be considered. TRIAL REGISTRATION: Ethics approval was obtained from the local Institutional Review Board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 19-585 ).

Evaluation of the outcomes of care of nurse-led continence care clinics for Chinese patients with lower urinary tract symptoms, a 2-year prospective longitudinal study.

AIM: The aim of this study was to evaluate the 24-month outcomes of a nurse-led continence care service for Chinese primary care patients with lower urinary tract symptoms. BACKGROUND: Most studies evaluating the outcomes of continence care services have had short follow-up durations with limited knowledge on whether benefits are sustained beyond 12 months. DESIGN: Twenty-four month cohort study. METHODS: Two comparison groups were recruited: (1) Patients with lower urinary tract symptoms attending a nurse-led community-based continence care programme; (2) Primary care patients with lower urinary tract symptoms identified by screening, receiving usual medical care. Self-reported symptom severity, health-related quality of life, patient enablement and general health perception were measured at baseline and 24 months. Data collection occurred from March 2013-August 2015. RESULTS: Baseline and 24-month data were available for 170 continence care and 158 usual care subjects. After controlling for baseline characteristics, the continence care group was observed to have greater reductions in symptom severity and larger improvements in disease-specific health-related quality of life, patient enablement and general health perception than the usual care group. Deterioration in the mental components of generic health-related quality of life was observed in the usual care group, but not in the continence care group. CONCLUSION: Over 24 months, when compared with usual medical care, nurse-led continence care services were effective in reducing symptom severity and improving health-related quality of life, patient enablement and general health perception and provided protection against deterioration in the mental components of health-related quality of life in patients with lower urinary tract symptoms.

Main predictors in health-related quality of life in Chinese patients with type 2 diabetes mellitus.

PURPOSE: This study aimed to identify the predictors of decline in health-related quality of life (HRQOL) in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: A prospective longitudinal observational study was conducted on 1826 Chinese T2DM patients managed in public primary care setting. HRQOL was measured at baseline, 1 and 2 years by the Short Form-12 Health Survey version 2 (SF-12v2) and Chinese (HK) Short Form-6 Dimensions (SF-6D). Linear mixed effect models with forward stepwise method were performed to select the factors associated with SF-12v2 physical (PCS) and mental component summary (MCS) scores and SF-6D value. RESULTS: Over a 2-year observation period, the HRQOL (PCS: -0.626; MCS: -1.869; and SF-6D: -0.017 per year) scores decreased significantly with time. Female, unmarried, current smoker, no regular exercise, obesity, comorbid hypertension, chronic kidney disease (CKD) or cardiovascular disease (CVD) and insulin use were predictors of one or more poorer HRQOL scores after 12 or 24 months. Older age had a negative impact on PCS score and SF-6D value, but had a positive impact on MCS score. CONCLUSIONS: The HRQOL of Chinese T2DM patients under primary care declined significantly over time. Obesity, smoking and no regular exercise were found to be modifiable risk factors of the decline in HRQOL in T2DM, which strengthened the importance of these lifestyle changes in diabetes care. More attention should be given to T2DM patients who are female, older, unmarried, or on anti-hypertensive drugs or insulin, or have comorbid hypertension, CKD or CVD in minimizing the negative impact of illness on their life.

Clinical and patient-reported outcomes of Chinese patients undergoing haemodialysis in hospital or in the community: A 1-year longitudinal study.

AIM: Little is known about the effect of haemodialysis (HD) setting on outcomes of patients with end stage renal disease (ESRD). The study aimed at comparing clinical outcomes and patient-reported outcomes (PRO) of patients on community-based (CBHD) and hospital-based haemodialysis (HBHD). METHODS: A prospective cohort of Chinese ESRD patients receiving HBHD (n = 89) or CBHD (n = 117) in Hong Kong were followed up for 12 months. Subjects were assessed on clinical outcomes of dialysis adequacy (Kt/V) and blood haemoglobin and PRO of health-related quality of life (SF-12v2), general health condition (Global Rating Scale (GRS)) and confidence to cope with their illness (Patient Enablement Instrument (PEI)). Differences between groups were analyzed by independent t-tests for the SF-12v2, GRS and PEI scores. χ(2) tests were used to analyze the difference in proportion of patients reaching the targets of Kt/V and blood haemoglobin and with GRS > 0 and PEI > 0. Multiple linear and logistic regressions were performed to assess the adjusted difference-in-difference estimation. RESULTS: The mean PEI and GRS scores of CBHD patients at 12 months were significantly higher than those of HBHD patients. CBHD patients had significantly greater improvement in self-efficacy and were more likely to be enabled after 12 months than the HBHD patients. CONCLUSION: The study showed similar clinical outcomes and PRO between CBHD and HBHD but CBHD was more effective than HBHD in promoting patient enablement over a 12-month period. The results suggest added value for patients receiving CBHD and support the transfer of HD care from the hospital to the community.

Evaluation of the quality of care of a haemodialysis public-private partnership programme for patients with end-stage renal disease.

BACKGROUND: Haemodialysis (HD) is one of the life-saving options for patients with end stage renal disease but demand for this treatment exceeds capacity in publicly funded hospitals. One novel approach to addressing this problem is through a shared-care model whereby government hospitals partner with qualified private HD service providers to increase the accessibility of HD for needy patients. The aim of this study is to evaluate and enhance the quality of care (QOC) provided in such a shared-care programme in Hong Kong, the Haemodialysis Public-Private Partnership Programme (HD-PPP). METHODS/DESIGN: This is a longitudinal study based on Action Learning and Audit Spiral methodologies to measure the achievement of pre-set target standards for the HD-PPP programme over three evaluation cycles. The QOC evaluation framework is comprised of structure, process and outcome criteria with target standards in each domain developed from review of the evidence and in close collaboration with the HD-PPP working group. During each evaluation cycle, coordinators of each study site complete a questionnaire to determine adherence with structural criteria of care. Process and clinical outcomes, such as adverse events and dialysis adequacy, are extracted from the patient records of consenting study participants while face-to-face interviews are conducted to ascertain patient-reported outcomes such as self-efficacy and health-related quality of life. DISCUSSION: The study relies on the successful implementation of partnership-based action research to develop an evidence-based and pragmatic framework for evaluation of quality of care in an iterative fashion, and to use it to identify possible areas of quality enhancements in a shared-care programme for HD patients. The approach we take in this study emphasizes partnership and engagement with the clinical and administrative programme team, a robust but flexible evaluation framework, direct observation and the potential to realize positive change. The experience will be useful to inform the process of coordinating research studies involving multiple stakeholders and results will help to guide service planning and policy decision making. TRIAL REGISTRATION: US Clinical Trial Registry NCT02307903.

Patterns of health-related quality of life and associated factors in Chinese patients undergoing haemodialysis.

BACKGROUND: Haemodialysis (HD) is a life-saving but burdensome therapy for patients with end-stage renal disease (ESRD) which can have a detrimental impact on patients' quality of life and outcomes. There is currently little data on the health related quality of life (HRQOL) of Chinese ESRD patients undergoing HD and this study sought to examine the patterns of HRQOL and its associated factors within this population, as well as in comparison with the general local population. METHODS: A cross-sectional study of 244 ESRD patients receiving HD in the hospital and in the community in Hong Kong was conducted using the Short Form-12 Health Survey version 2 (SF-12v2). All study subjects were one-to-one matched with subjects in a Hong Kong general population database by sex and exact age. Independent t-tests were performed to compare the mean SF-12v2 scores between HD patients and the general population, followed by one-way analysis of variance with post hoc Tukey's HSD tests to compare community-based haemodialysis, hospital-based haemodialysis and the general population. Multiple linear regressions were used to identify the factors (socio-demographic, clinical characteristics and comorbidities) associated with the HRQOL scores of ESRD patients receiving HD. RESULTS: The SF-12v2 Physical Functioning, Role Physical, Bodily Pain, General Health and Physical Component Summary scores of HD patients were significantly lower than the age-sex adjusted general population. However, the SF-12v2 Mental Health and Mental Component Summary scores of HD patients were significantly higher than the corresponding general population. Poorer HRQOL was associated with being female, smoking, unemployment and hospital-based haemodialysis. CONCLUSIONS: HD patients had substantially poorer physical HRQOL but better mental HRQOL than the age-sex adjusted general population. Patients receiving HD in the community setting had better HRQOL. Reasons for these observations will need to be further investigated. Those patients who are female, smokers and unemployed may warrant more attention as their poorer HRQOL may be associated with poorer outcomes.

Evaluation of the quality of care of a multi-disciplinary Risk Factor Assessment and Management Programme for Hypertension (RAMP-HT).

BACKGROUND: There is some evidence to support a risk-stratified, multi-disciplinary approach to manage patients with hypertension in primary care. The aim of this study is to evaluate the quality of care (QOC) of a multi-disciplinary Risk Assessment and Management Programme for Hypertension (RAMP-HT) for hypertensive patients in busy government-funded primary care clinics in Hong Kong. The objectives are to develop an evidence-based, structured and comprehensive evaluation framework on quality of care, to enhance the QOC of the RAMP-HT through an audit spiral of two evaluation cycles and to determine the effectiveness of the programme in reducing cardiovascular disease (CVD) risk. METHOD/DESIGN: A longitudinal study is conducted using the Action Learning and Audit Spiral methodologies to measure whether pre-set target standards of care intended by the RAMP-HT are achieved. A structured evaluation framework on the quality of structure, process and outcomes of care has been developed based on the programme objectives and literature review in collaboration with the programme workgroup and health service providers. Each participating clinic is invited to complete a structure of care evaluation questionnaire in each evaluation cycle. The data of all patients who have enrolled into the RAMP-HT in the pre-defined evaluation periods are used for the evaluation of the process and outcomes of care in each evaluation cycle. For evaluation of the effectiveness of RAMP-HT, the primary outcomes including blood pressure (both systolic and diastolic), low-density lipoprotein cholesterol and estimated 10-year CVD risk of RAMP-HT participants are compared to those of hypertensive patients in usual care without RAMP-HT. DISCUSSION: The QOC and effectiveness of the RAMP-HT in improving clinical and patient-reported outcomes for patients with hypertension in normal primary care will be determined. Possible areas for quality enhancement and standards of good practice will be established to inform service planning and policy decision making.

Systematic analysis of proteome turnover in an organoid model of pancreatic cancer by dSILO.

The role of protein turnover in pancreatic ductal adenocarcinoma (PDA) metastasis has not been previously investigated. We introduce dynamic stable-isotope labeling of organoids (dSILO): a dynamic SILAC derivative that combines a pulse of isotopically labeled amino acids with isobaric tandem mass-tag (TMT) labeling to measure proteome-wide protein turnover rates in organoids. We applied it to a PDA model and discovered that metastatic organoids exhibit an accelerated global proteome turnover compared to primary tumor organoids. Globally, most turnover changes are not reflected at the level of protein abundance. Interestingly, the group of proteins that show the highest turnover increase in metastatic PDA compared to tumor is involved in mitochondrial respiration. This indicates that metastatic PDA may adopt alternative respiratory chain functionality that is controlled by the rate at which proteins are turned over. Collectively, our analysis of proteome turnover in PDA organoids offers insights into the mechanisms underlying PDA metastasis.

Understanding family dynamics of obesity: Do parents and children lose and gain weight together?

BACKGROUND: Obesity is prevalent among children and adults. Yet, understanding the relationship between parent and child weight trajectories is limited. OBJECTIVE: (1) Examine the association between parent/child undesirable body mass index (BMI) category change. (2) Assess whether parental BMI category predicts child modified BMI z-score (mBMIz) annual change. METHODS: We conducted a cross-sectional study of weight trajectories of 3821 parent-child dyads between March 2020 and December 2021 within the NYC Health + Hospitals system. Undesirability of child and parental BMI category change and the magnitude of mBMIz change by parental BMI are analysed. RESULTS: Of 3821 children (mean [SD] baseline age, 9.84 [3.51]), 1889 were female. Of the 3220 parents (mean [SD] baseline age, 39.9 [8.51]), 2988 were female. Most children (53.52%) and parents (81.94%) presented with overweight and obesity. Undesirable BMI change in children was associated with concordant change in parents (adjusted OR: 1.7, 95% CI [1.45, 2.01], adjusted p < 0.001). Children of parents with obesity (adjusted coef: 0.076, 95% CI [0.004, 0.147], p < 0.038) and severe obesity (adjusted coef: 0.1317, 95% CI [0.024, 0.239], adjusted p < 0.016) demonstrated greater change in mBMIz than those of parents with normal weight or underweight. CONCLUSION: Parents and children have concordant weight trajectories, and public health interventions targeting both populations are essential.

Evening Chronotypes With Depression Report Poorer Outcomes of Selective Serotonin Reuptake Inhibitors: A Survey-Based Study of Self-Ratings.

BACKGROUND: Preliminary evidence suggests that evening chronotype is related to poorer efficacy of selective serotonin reuptake inhibitors. It is unknown whether this is specific to particular medications, self-rated chronotype, or efficacy. METHODS: In the Australian Genetics of Depression Study (n = 15,108; 75% women; 18-90 years; 68% with ≥1 other lifetime diagnosis), a survey recorded experiences with 10 antidepressants, and the reduced Morningness-Eveningness Questionnaire was used to estimate chronotype. A chronotype polygenic score was calculated. Age- and sex-adjusted regression models (Bonferroni-corrected) estimated associations among antidepressant variables (how well the antidepressant worked [efficacy], duration of symptom improvement, side effects, discontinuation due to side effects) and self-rated and genetic chronotypes. RESULTS: The chronotype polygenic score explained 4% of the variance in self-rated chronotype (r = 0.21). Higher self-rated eveningness was associated with poorer efficacy of escitalopram (odds ratio [OR] = 1.04; 95% CI, 1.02 to 1.06; p = .000035), citalopram (OR = 1.03; 95% CI, 1.01 to 1.05; p = .004), fluoxetine (OR = 1.03; 95% CI, 1.01 to 1.05; p = .001), sertraline (OR = 1.02; 95% CI, 1.01 to 1.04; p = .0008), and desvenlafaxine (OR = 1.03; 95% CI, 1.01 to 1.05; p = .004), and a profile of increased side effects (80% of those recorded; ORs = 0.93-0.98), with difficulty getting to sleep the most common. Self-rated chronotype was unrelated to duration of improvement or discontinuation. The chronotype polygenic score was only associated with suicidal thoughts and attempted suicide (self-reported). While our measures are imperfect, and not of circadian phase under controlled conditions, the model coefficients suggest that dysregulation of the phenotypic chronotype relative to its genetic proxy drove relationships with antidepressant outcomes. CONCLUSIONS: The idea that variation in circadian factors influences response to antidepressants was supported and encourages exploration of circadian mechanisms of depressive disorders and antidepressant treatments.

What's in a name? Role of verbal context in touch.

Can a name (i.e. verbal context) change how we react to and perceive an object? This question has been addressed several times for chemosensory objects, but appears unanswered for touch. To address this, two studies were run. In each, we allocated participants to a Positive, Neutral or Negative Group, and asked them to touch the same four objects, twice-first, named by the experimenter according to their Group-name, and second, named by the participant. Participants were timed as they touched and rated the objects on pleasantness and disgust. Negative-named objects were touched for shorter durations, and rated more negatively, than neutral-named objects, and positive-named objects were touched for the longest and rated most positively. In the second presentation, most objects (greater than 90%) were named by participants in accordance with their assigned Group-names. The similarity of these findings to chemosensory verbal context effects and their mechanistic basis is discussed.

Weight Loss Outcomes With Telemedicine During COVID-19.

Background: Amidst the COVID-19 pandemic, telemedicine was rapidly implemented to maintain patient care during quarantine. However, there is little data on how this transition may have impacted weight loss outcomes and interventions among patients with overweight or obesity. Methods: This was a retrospective observational study of adults who established care for medically managed obesity at the Weill Cornell Comprehensive Weight Control Center during September-November 2019 and May-July 2020 and who completed 6 months of follow-up. Weight loss outcomes and weight management interventions were explored and stratified by patient-provider interaction: in-person visits only, in-person and video visits, and video visits only. Results: Of 499 charts eligible for review, 245 (49%) returned for their 6-month follow-up visit and were included for analysis. Of 245 patients, 69 had in-person visits only ("in-person"), 85 started in-person and later switched to video visits ("hybrid"), and 91 had video visits only ("video"). All cohorts were predominantly white and female. Median ages were 56, 49, and 49 years; baseline median weights were 98.9, 96.8, and 93.0 kg; and baseline median BMIs were 35.3, 34.4, and 34.0 kg/m2 for in-person, hybrid, and video cohorts, respectively. The median percent weight changes over 6 months were not significantly different among cohorts: -4.3% [-8.5, -1.5] in the in-person cohort, -5.6% [-8.7, -2.2] in the hybrid group, and -5.8% [-9.7, -2.4] in the video cohort. The percent of patients who achieved ≥5% weight loss were also similar: 46.4%, 55.3%, and 59.3%, respectively. The median number of visits in the video cohort was more than in the in-person or hybrid groups (5 vs. 4). Median number of anti-obesity medications (AOMs) prescribed was similar among groups. The most common AOMs were metformin (all cohorts) followed by semaglutide 1.0 mg (in-person and video) or topiramate (hybrid). Conclusion: Patients on anti-obesity medications who were followed for 6 months via video or video plus in-person visits (hybrid) experienced clinically significant weight loss. Median number of AOMs were similar among groups, and the most common AOMs were metformin, semaglutide 1.0 mg, and topiramate. More investigation is required to compare telemedicine models with in-person care.

Herbal medicine for functional dyspepsia: Network meta-analysis of placebo-controlled randomised trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Conventional treatments for functional dyspepsia (FD) are limited. Herbal medicine (HM) use is prevalent despite unclear comparative effectiveness among different formulae. AIM OF THE STUDY: This network meta-analysis (NMA) aimed to evaluate the comparative effectiveness of HM formulae for FD against placebo. MATERIALS AND METHODS: Seven international and Chinese databases were searched for randomised controlled trials (RCTs) on HM versus placebo. Risk of bias among RCTs was assessed using Cochrane Risk-of-Bias Tool 2. Data from RCTs were extracted for random-effect pairwise meta-analyses. NMAs were performed to evaluate the comparative effectiveness of HM formulae. GRADE partially contextualised framework was adopted to facilitate NMA result interpretation. RESULTS: Twelve different HM formulae were identified from fifteen RCTs of mediocre quality. At 8-week follow-up, pairwise meta-analyses indicated that HM was superior to placebo in alleviating global symptoms (pooled risk difference (RD): 0.20; 95% confidence interval (CI): 0.11-0.29), with effect size larger than the minimally clinically important difference of 0.20 RD. Sensitivity analysis showed no significant impact on results attributable to risk of bias. NMAs demonstrated that Xiao Yao Pill and Modified Ban Xia Xie Xin Decoction probably have a large beneficial effect on alleviating global symptoms (RD: 0.37; 95% CI: 0.03-0.99) and postprandial fullness (standardised mean difference: -0.93; 95% credible interval: -1.61 to -0.06), respectively. No serious adverse events were reported. CONCLUSIONS: Xiao Yao Pill and Modified Ban Xia Xie Xin Decoction may be considered as an alternative among patients unresponsive to conventional treatments. The comparative effectiveness of these two formulae should be evaluated in future trials.

Medical weight management protects against weight gain during the COVID-19 pandemic.

Background: American adults have gained weight during the COVID-19 pandemic. Little is known about how patients who are medically managed for overweight and obesity, including patients who are prescribed antiobesity pharmacotherapy, have fared. Objective: To assess the COVID-19 pandemic's effect on weight, food choices, and health behaviors in patients receiving medical treatment for overweight or obesity. Methods: Adult patients treated at an urban academic weight management center between 1 May 2019 and 1 May 2020 were electronically surveyed between 23 February and 23 March 2021. The survey assessed changes in weight, eating, behaviors, and the use of antiobesity medications (AOMs) following issuance of social distancing/stay-at-home policies in March 2020. Results: In 970 respondents, median percent weight change for those taking AOMs was -0.459% [interquartile range -5.46%-(+3.73%)] compared to +2.33% [IQR -1.92%-(+6.52%)] for those not taking AOMs (p < 0.001). More participants achieved ≥5% weight loss if they were taking AOMs compared to those who were not (26.7% vs. 15.8%, p = 0.004), and weight gain ≥5% was also lower in those taking AOMs (19.8% vs. 30.3%, p = 0.004). Patients with pre-pandemic BMI ≥30 kg/m2 taking AOMs experienced the greatest weight reduction, and there was greater weight loss associated with increased physical activity. Conclusions and Relevance: Medical weight management protected against weight gain during this period of the COVID-19 pandemic. Increased physical activity, decreased alcohol intake, and use of AOMs were factors that contributed to this protective effect.

The nose is hungrier than the eyes.

Vision and olfaction are the main sensory channels for appraising food prior to eating. Motivational models often assume that these sensory channels function in an equivalent manner. We tested this notion by asking participants to rate their desire for some snacks only via smell and others only via vision. In the next phase, participants consumed a small sample of every snack, now with all of the senses available, rating liking and desire for more. After consuming a meal, participants repeated the desire/liking test. Sensing via olfaction, relative to vision, led to greater desire ratings irrespective of state. When hungry, judgments of liking and desire for more were higher for foods that were initially smelled relative to those that were initially seen. Across the meal, visually based desire ratings declined more than those based on smell, relative to ratings made when the snacks were tasted. Together, this suggests motivational equivalence does not hold for olfaction and vision. We suggest this may be due to a greater reliance on memory for generating visually based desire.

Chinese herbal medicine for functional dyspepsia: a network meta-analysis of prokinetic-controlled randomised trials.

BACKGROUND: Prokinetic is the first-line conventional treatment for functional dyspepsia (FD) in Asia despite potential adverse events. Chinese herbal medicine (CHM) may be an effective and safe substitution. This network meta-analysis (NMA) aimed to evaluate the comparative effectiveness of different CHM formulae for FD against prokinetics. METHODS: Seven international and Chinese databases were searched from their inception to July 2020 for randomised controlled trials (RCTs) on CHM versus prokinetics. Data from each RCT were first pooled using random-effect pairwise meta-analyses and illustrated as risk difference (RD) or standardised mean difference (SMD) with 95% confidence interval (CI). Random-effect NMAs were then performed to evaluate the comparative effectiveness of CHM formulae and displayed as RD with 95% CI or SMD with 95% credible interval (CrI). The GRADE partially contextualised framework was applied for NMA result interpretation. RESULTS: Twenty-six unique CHM formulae were identified from twenty-eight RCTs of mediocre quality. Pairwise meta-analyses indicated that CHM was superior to prokinetics in alleviating global symptoms at 4-week follow-up (pooled RD: 0.14; 95% CI: 0.10-0.19), even after trim and fill adjustment for publication bias. NMAs demonstrated that Modified Zhi Zhu Decoction may have a moderate beneficial effect on alleviating global symptoms at 4-week follow-up (RD: 0.28; 95% CI: - 0.03 to 0.75). Xiao Pi Kuan Wei Decoction may have a large beneficial effect on alleviating postprandial fullness (SMD: - 2.14; 95% CI: - 2.76 to 0.70), early satiety (SMD: - 3.90; 95% CI: - 0.68 to - 0.42), and epigastric pain (SMD: - 1.23; 95% CI: - 1.66 to - 0.29). No serious adverse events were reported. CONCLUSION: Modified Zhi Zhu Decoction and Xiao Pi Kuan Wei Decoction may be considered as an alternative for patients unresponsive to prokinetics. Confirmatory head-to-head trials should be conducted to investigate their comparative effectiveness against prokinetics.

Highlights of traditional Chinese medicine frontline expert advice in the China national guideline for COVID-19.

INTRODUCTION: The World Health Organization declared the coronavirus disease (COVID-19) as a pandemic on 11 March 2020, after the number of confirmed cases outside China increased 13-fold. As the epicentre of the initial outbreak, China has been updating the National COVID-19 Diagnostic and Treatment Guideline with up-to-date information about the disease. To facilitate the implementation of integrative Chinese-Western Medicine in COVID-19 management, Traditional Chinese medicine (TCM) has been recommended in recent editions of the national guideline. METHODS: The national guideline summarised the opinions and frontline experience of medical experts across the country to provide by far the best management for COVID-19. We extracted the case definition and clinical classifications of COVID-19 in China along with relevant TCM treatments cited in the seventh edition of the guideline, with an intent to disseminate practical information to TCM clinicians and researchers around the world. RESULTS: We present the most recent case definition, clinical classifications, and relevant TCM treatments of COVID-19 in accordance with the recommendations in the Chinese guideline. TCM treatments are stratified into two groups based on patients' disease status. Four types of Chinese patent medicines are recommended for suspected COVID-19 cases. Several herbal formulae are recommended for confirmed COVID-19 cases according to their clinical classification and TCM pattern diagnoses. Two herbal formulae are also recommended for rehabilitation of recovering cases. CONCLUSION: To control the waves of COVID-19 outbreak, countries must ensure the adherence of their citizens to local public health measures. Medical professionals should diagnose and treat patients according to up-to-date guidelines. Future evaluation of the outcomes of implementing TCM recommendations will strengthen the evidence base for COVID-19 management for the sake of public health and the internationalisation of TCM.

eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA.