Summary Lung cancer is a leading cause of cancer-related mortality worldwide, and is classically divided into two major histological subtypes: non-small-cell lung cancer (NSCLC) and small-cell lung ...cancer (SCLC). Although NSCLC and SCLC are considered distinct entities with different genomic landscapes, emerging evidence highlights a convergence in therapeutically relevant targets for both histologies. In adenocarcinomas with defined alterations such as EGFR mutations and ALK translocations, targeted therapies are now first-line standard of care. By contrast, many experimental and targeted agents remain largely unsuccessful for SCLC. Intense preclinical research and clinical trials are underway to exploit unique traits of lung cancer, such as oncogene dependency, DNA damage response, angiogenesis, and cellular plasticity arising from presence of cancer stem cell lineages. In addition, the promising clinical activity observed in NSCLC in response to immune checkpoint blockade has spurred great interest in the field of immunooncology, with the scope to develop a diverse repertoire of synergistic and personalised immunotherapeutics. In this Review, we discuss novel therapeutic agents for lung cancer that are in early-stage development, and how prospective clinical trials and drug development may be shaped by a deeper understanding of this heterogeneous disease.
Epimutations in the germline, such as methylation of the MLH1 gene, may contribute to hereditary cancer syndrome in human, but their transmission to offspring has never been documented. Here we ...report a family with inheritance, in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal or endometrial cancers, all with microsatellite instability and MSH2 protein loss. Clonal bisulfite sequencing and pyrosequencing showed different methylation levels in different somatic tissues, with the highest level recorded in rectal mucosa and colon cancer tissue, and the lowest in blood leukocytes. This mosaic state of germline methylation with different tissue distribution could act as the first hit and provide a mechanism for genetic disease inheritance that may deviate from the mendelian pattern and be overlooked in conventional leukocyte-based genetic diagnosis strategy.
A growing line of research has highlighted that e‐technologies may play a promising role in improving breastfeeding outcomes. The objective of this review was to synthesise the best of available ...evidence by conducting a meta‐analysis to evaluate whether e‐technologies have had any effect in improving breastfeeding outcomes among perinatal women. The review was conducted using nine electronic databases to search for English‐language research studies from 2007 to 2014. A ‘risk of bias’ table was used to assess methodological quality. Meta‐analysis was performed with the RevMan software. The Q test and I2 test was used to assess the heterogeneity. The test of overall effect was assessed using z‐statistics at P < 0.05. Of 1842 studies identified through electronic searches and reference lists, 16 experimental studies were selected after applying the inclusion and exclusion criteria. Half of the selected studies had a low risk of bias, from which a total of 5505 women in six countries in these studies were included. Meta‐analyses revealed that e‐technologies significantly improved exclusive breastfeeding initiation (z = 6.90, P < 0.00001), exclusive breastfeeding at 4 weeks (z = 2.12, P = 0.03) and 6 months (z = 3.2, P = 0.001), breastfeeding attitude (z = 3.01, P = 0.003) and breastfeeding knowledge (z = 4.54, P = < 0.00001) in subgroup analyses. This review provides support for the development of web‐based, texting messaging, compact disc read‐only memory, electronic prompts and interactive computer agent interventions for promoting and supporting breastfeeding.
Background
Cardiovascular disease (CVD) is a leading cause of death globally. Recently, dipeptidyl peptidase‐4 inhibitors (DPP4i), glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) and ...sodium‐glucose co‐transporter‐2 inhibitors (SGLT2i) were approved for treating people with type 2 diabetes mellitus. Although metformin remains the first‐line pharmacotherapy for people with type 2 diabetes mellitus, a body of evidence has recently emerged indicating that DPP4i, GLP‐1RA and SGLT2i may exert positive effects on patients with known CVD.
Objectives
To systematically review the available evidence on the benefits and harms of DPP4i, GLP‐1RA, and SGLT2i in people with established CVD, using network meta‐analysis.
Search methods
We searched CENTRAL, MEDLINE, Embase, and the Conference Proceedings Citation Index on 16 July 2020. We also searched clinical trials registers on 22 August 2020. We did not restrict by language or publication status.
Selection criteria
We searched for randomised controlled trials (RCTs) investigating DPP4i, GLP‐1RA, or SGLT2i that included participants with established CVD. Outcome measures of interest were CVD mortality, fatal and non‐fatal myocardial infarction, fatal and non‐fatal stroke, all‐cause mortality, hospitalisation for heart failure (HF), and safety outcomes.
Data collection and analysis
Three review authors independently screened the results of searches to identify eligible studies and extracted study data. We used the GRADE approach to assess the certainty of the evidence. We conducted standard pairwise meta‐analyses and network meta‐analyses by pooling studies that we assessed to be of substantial homogeneity; subgroup and sensitivity analyses were also pursued to explore how study characteristics and potential effect modifiers could affect the robustness of our review findings. We analysed study data using the odds ratios (ORs) and log odds ratios (LORs) with their respective 95% confidence intervals (CIs) and credible intervals (Crls), where appropriate. We also performed narrative synthesis for included studies that were of substantial heterogeneity and that did not report quantitative data in a usable format, in order to discuss their individual findings and relevance to our review scope.
Main results
We included 31 studies (287 records), of which we pooled data from 20 studies (129,465 participants) for our meta‐analysis. The majority of the included studies were at low risk of bias, using Cochrane's tool for assessing risk of bias. Among the 20 pooled studies, six investigated DPP4i, seven studied GLP‐1RA, and the remaining seven trials evaluated SGLT2i. All outcome data described below were reported at the longest follow‐up duration.
1. DPP4i versus placebo
Our review suggests that DPP4i do not reduce any risk of efficacy outcomes: CVD mortality (OR 1.00, 95% CI 0.91 to 1.09; high‐certainty evidence), myocardial infarction (OR 0.97, 95% CI 0.88 to 1.08; high‐certainty evidence), stroke (OR 1.00, 95% CI 0.87 to 1.14; high‐certainty evidence), and all‐cause mortality (OR 1.03, 95% CI 0.96 to 1.11; high‐certainty evidence). DPP4i probably do not reduce hospitalisation for HF (OR 0.99, 95% CI 0.80 to 1.23; moderate‐certainty evidence). DPP4i may not increase the likelihood of worsening renal function (OR 1.08, 95% CI 0.88 to 1.33; low‐certainty evidence) and probably do not increase the risk of bone fracture (OR 1.00, 95% CI 0.83 to 1.19; moderate‐certainty evidence) or hypoglycaemia (OR 1.11, 95% CI 0.95 to 1.29; moderate‐certainty evidence). They are likely to increase the risk of pancreatitis (OR 1.63, 95% CI 1.12 to 2.37; moderate‐certainty evidence).
2. GLP‐1RA versus placebo
Our findings indicate that GLP‐1RA reduce the risk of CV mortality (OR 0.87, 95% CI 0.79 to 0.95; high‐certainty evidence), all‐cause mortality (OR 0.88, 95% CI 0.82 to 0.95; high‐certainty evidence), and stroke (OR 0.87, 95% CI 0.77 to 0.98; high‐certainty evidence). GLP‐1RA probably do not reduce the risk of myocardial infarction (OR 0.89, 95% CI 0.78 to 1.01; moderate‐certainty evidence), and hospitalisation for HF (OR 0.95, 95% CI 0.85 to 1.06; high‐certainty evidence). GLP‐1RA may reduce the risk of worsening renal function (OR 0.61, 95% CI 0.44 to 0.84; low‐certainty evidence), but may have no impact on pancreatitis (OR 0.96, 95% CI 0.68 to 1.35; low‐certainty evidence). We are uncertain about the effect of GLP‐1RA on hypoglycaemia and bone fractures.
3. SGLT2i versus placebo
This review shows that SGLT2i probably reduce the risk of CV mortality (OR 0.82, 95% CI 0.70 to 0.95; moderate‐certainty evidence), all‐cause mortality (OR 0.84, 95% CI 0.74 to 0.96; moderate‐certainty evidence), and reduce the risk of HF hospitalisation (OR 0.65, 95% CI 0.59 to 0.71; high‐certainty evidence); they do not reduce the risk of myocardial infarction (OR 0.97, 95% CI 0.84 to 1.12; high‐certainty evidence) and probably do not reduce the risk of stroke (OR 1.12, 95% CI 0.92 to 1.36; moderate‐certainty evidence). In terms of treatment safety, SGLT2i probably reduce the incidence of worsening renal function (OR 0.59, 95% CI 0.43 to 0.82; moderate‐certainty evidence), and probably have no effect on hypoglycaemia (OR 0.90, 95% CI 0.75 to 1.07; moderate‐certainty evidence) or bone fracture (OR 1.02, 95% CI 0.88 to 1.18; high‐certainty evidence), and may have no impact on pancreatitis (OR 0.85, 95% CI 0.39 to 1.86; low‐certainty evidence).
4. Network meta‐analysis
Because we failed to identify direct comparisons between each class of the agents, findings from our network meta‐analysis provided limited novel insights. Almost all findings from our network meta‐analysis agree with those from the standard meta‐analysis. GLP‐1RA may not reduce the risk of stroke compared with placebo (OR 0.87, 95% CrI 0.75 to 1.0; moderate‐certainty evidence), which showed similar odds estimates and wider 95% Crl compared with standard pairwise meta‐analysis. Indirect estimates also supported comparison across all three classes. SGLT2i was ranked the best for CVD and all‐cause mortality.
Authors' conclusions
Findings from both standard and network meta‐analyses of moderate‐ to high‐certainty evidence suggest that GLP‐1RA and SGLT2i are likely to reduce the risk of CVD mortality and all‐cause mortality in people with established CVD; high‐certainty evidence demonstrates that treatment with SGLT2i reduce the risk of hospitalisation for HF, while moderate‐certainty evidence likely supports the use of GLP‐1RA to reduce fatal and non‐fatal stroke. Future studies conducted in the non‐diabetic CVD population will reveal the mechanisms behind how these agents improve clinical outcomes irrespective of their glucose‐lowering effects.
Many studies have shown the adverse effects of air pollution on respiratory health, but few have examined the effects of air pollution on service utilisation in the primary care setting. The aim of ...this study was to examine the association between air pollution and the daily number of consultations due to upper respiratory tract infections (URTIs) in general outpatient clinics (GOPCs) in Hong Kong.
Daily data on the numbers of consultations due to URTIs in GOPCs, the concentrations of major air pollutants, and the mean values of metrological variables were retrospectively collected over a 3-year period (2008-2010, inclusive). Generalised additive models were constructed to examine the association between air pollution and the daily number of consultations, and to derive the relative risks and 95% confidence intervals (95% CI) of GOPC consultations for a unit increase in the concentrations of air pollutants.
The mean daily consultations due to URTIs in GOPCs ranged from 68.4 to 253.0 over the study period. The summary relative risks (and 95% CI) of daily consultations in all GOPCs for the air pollutants PM10, NO2, O3, and SO2 were 1.005 (1.002, 1.009), 1.010 (1.006, 1.013), 1.009 (1.006, 1.012), and 1.004 (1.000, 1.008) respectively, per 10 µg/m(3) increase in the concentration of each pollutant.
Significant associations were found between the daily number of consultations due to URTIs in GOPCs and the concentrations of air pollutants, implying that air pollution incurs a substantial morbidity and increases the burden of primary health care services.
Aims: To assess any relationship between the levels of ambient air pollutants and hospital admissions for chronic obstructive pulmonary disease (COPD) in Hong Kong. Methods: A retrospective ...ecological study was undertaken. Data of daily emergency hospital admissions to 15 major hospitals in Hong Kong for COPD and indices of air pollutants (sulphur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), particulates with an aerodynamic diameter of <10 μm (PM10) and 2.5 μm (PM2.5)) and meteorological variables from January 2000 to December 2004 were obtained from several government departments. Analysis was performed using generalised additive models with Poisson distribution, adjusted for the effects of time trend, season, other cyclical factors, temperature and humidity. Autocorrelation and overdispersion were corrected. Results: Significant associations were found between hospital admissions for COPD with all five air pollutants. Relative risks for admission for every 10 μg/m3 increase in SO2, NO2, O3, PM10 and PM2.5 were 1.007, 1.026, 1.034, 1.024 and 1.031, respectively, at a lag day ranging from lag 0 to cumulative lag 0–5. In a multipollutant model, O3, SO2 and PM2.5 were significantly associated with increased admissions for COPD. SO2, NO2 and O3 had a greater effect on COPD admissions in the cold season (December to March) than during the warm season. Conclusion: Ambient concentrations of air pollutants have an adverse effect on hospital admissions for COPD in Hong Kong, especially during the winter season. This might be due to indoor exposure to outdoor pollution through open windows as central heating is not required in the mild winter. Measures to improve air quality are urgently needed.
EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of ...79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.
Chromosomal microarray (CMA) is recommended as a first tier investigation for patients with developmental delay (DD), intellectual disability (ID), autistic spectrum disorder (ASD), and multiple ...congenital anomalies (MCA). It is widely used in the prenatal and postnatal settings for detection of chromosomal aberrations. This is a retrospective review of all array comparative genomic hybridization (aCGH/ array CGH) findings ascertained in two major prenatal and postnatal genetic diagnostic centers in Hong Kong from June 2012 to December 2017. Medical records were reviewed for cases with pathogenic and variants of uncertain clinical significance (VUS). Classification of copy number variants (CNVs) was based on current knowledge and experience by August 2018. The aims of this review are to study the diagnostic yield of array CGH application in prenatal and postnatal settings in Hong Kong and to describe the spectrum of abnormalities found. Prenatal indications included abnormal ultrasound findings, positive Down syndrome screening, abnormal noninvasive prenatal test results, advanced maternal age and family history of chromosomal or genetic abnormalities. Postnatal indications included unexplained DD, ID, ASD, and MCA.
A total of 1,261 prenatal subjects and 3,096 postnatal patients were reviewed. The prenatal diagnostic yield of pathogenic CNV and VUS (excluding those detectable by karyotype) was 3.5%. The postnatal diagnostic yield of pathogenic CNV was 15.2%. The detection rates for well‐defined microdeletion and microduplication syndromes were 4.6% in prenatal and 6.1% (1 in 16 index patients) in postnatal cases, respectively. Chromosomes 15, 16, and 22 accounted for over 21 and 25% of pathogenic CNVs detected in prenatal and postnatal cohorts, respectively. This review provides the first large scale overview of genomic imbalance of mostly Chinese patients in prenatal and postnatal settings.
Mesenchymal epithelial transition factor ( MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancer (NSCLC) and can ...mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant-positive NSCLC.
MET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naïve EGFR-mutant-positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant-positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG.
Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to 15.0 months) for MET-high and -low, respectively ( P = .566), with no significant difference in response rate regardless of copy number thresholds. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, which is consistent with marked intratumoral heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response (TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET amplification (five 3.2% of 154).
Although up to 26% of TKI-naïve EGFR-mutant-positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to TKI, except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant-positive NSCLC.
A plethora of weight management apps are available, but many individuals, especially those living with overweight and obesity, still struggle to achieve adequate weight loss. An emerging area in ...weight management is the support for one's self-regulation over momentary eating impulses.
This study aims to examine the feasibility and effectiveness of a novel artificial intelligence-assisted weight management app in improving eating behaviors in a Southeast Asian cohort.
A single-group pretest-posttest study was conducted. Participants completed the 1-week run-in period of a 12-week app-based weight management program called the Eating Trigger-Response Inhibition Program (eTRIP). This self-monitoring system was built upon 3 main components, namely, (1) chatbot-based check-ins on eating lapse triggers, (2) food-based computer vision image recognition (system built based on local food items), and (3) automated time-based nudges and meal stopwatch. At every mealtime, participants were prompted to take a picture of their food items, which were identified by a computer vision image recognition technology, thereby triggering a set of chatbot-initiated questions on eating triggers such as who the users were eating with. Paired 2-sided t tests were used to compare the differences in the psychobehavioral constructs before and after the 7-day program, including overeating habits, snacking habits, consideration of future consequences, self-regulation of eating behaviors, anxiety, depression, and physical activity. Qualitative feedback were analyzed by content analysis according to 4 steps, namely, decontextualization, recontextualization, categorization, and compilation.
The mean age, self-reported BMI, and waist circumference of the participants were 31.25 (SD 9.98) years, 28.86 (SD 7.02) kg/m
, and 92.60 (SD 18.24) cm, respectively. There were significant improvements in all the 7 psychobehavioral constructs, except for anxiety. After adjusting for multiple comparisons, statistically significant improvements were found for overeating habits (mean -0.32, SD 1.16; P<.001), snacking habits (mean -0.22, SD 1.12; P<.002), self-regulation of eating behavior (mean 0.08, SD 0.49; P=.007), depression (mean -0.12, SD 0.74; P=.007), and physical activity (mean 1288.60, SD 3055.20 metabolic equivalent task-min/day; P<.001). Forty-one participants reported skipping at least 1 meal (ie, breakfast, lunch, or dinner), summing to 578 (67.1%) of the 862 meals skipped. Of the 230 participants, 80 (34.8%) provided textual feedback that indicated satisfactory user experience with eTRIP. Four themes emerged, namely, (1) becoming more mindful of self-monitoring, (2) personalized reminders with prompts and chatbot, (3) food logging with image recognition, and (4) engaging with a simple, easy, and appealing user interface. The attrition rate was 8.4% (21/251).
eTRIP is a feasible and effective weight management program to be tested in a larger population for its effectiveness and sustainability as a personalized weight management program for people with overweight and obesity.
ClinicalTrials.gov NCT04833803; https://classic.clinicaltrials.gov/ct2/show/NCT04833803.
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