Lipid Nanoparticle and Liposome Reference Materials: Assessment of Size Homogeneity and Long-Term -70 °C and 4 °C Storage Stability.

With recent advances and anticipated proliferation of lipid nanoparticle (LNP)-delivered vaccines and therapeutics, there is a need for the availability of internationally recognized reference materials of LNP systems. Accordingly, we developed six LNP and liposome (anionic, neutral, and cationic each) candidate reference material formulations and thoroughly characterized by dynamic light scattering their particle hydrodynamic size (Z-avr) and polydispersity. We also evaluated the particle size homogeneity and long-term -70 °C and 4 °C storage stability using multiple large sets of randomly selected vials for each formulation. The formulations stored at -70 °C remained stable and homogeneous for a minimum of 9 months. The Z-avr relative combined uncertainty and the long-term variability were both <1.3% for liposome formulations and anionic LNPs, (3.9% and 1.7%) for neutral LNPs, and (6.7% and 4.4%) for cationic LNPs. An inadvertent few-hour-long storage temperature increase to -35 °C due to a freezer malfunction resulted in a small change of the size and size distribution of anionic liposomes and LNPs but, unexpectedly, a larger size increase of the neutral and cationic liposomes (≤5%) and LNPs (≤25%). The mean Z-avr values of the LNPs stored at 4 °C appeared to slowly increase with t1/3, where t is the storage time, and the Z-avr between-vial heterogeneity and mean polydispersity index values appeared to decrease; no change was observed for liposomes. The size and size distribution evolution of LNPs stored at 4 °C was attributed to an incomplete equilibration of the formulations following the addition of sucrose prior to the initial freezing. Such a process of size increase and size distribution narrowing has not been previously discussed nor observed in the context of LNPs.

Can ship travel contain COVID-19 outbreak after re-opening: a Bayesian meta-analysis.

Large gatherings of people on cruise ships and warships are often at high risk of COVID-19 infections. To assess the transmissibility of SARS-CoV-2 on warships and cruise ships and to quantify the effectiveness of the containment measures, the transmission coefficient (ß), basic reproductive number (R0), and time to deploy containment measures were estimated by the Bayesian Susceptible-Exposed-Infected-Recovered model. A meta-analysis was conducted to predict vaccine protection with or without non-pharmaceutical interventions (NPIs). The analysis showed that implementing NPIs during voyages could reduce the transmission coefficients of SARS-CoV-2 by 50%. Two weeks into the voyage of a cruise that begins with 1 infected passenger out of a total of 3,711 passengers, we estimate there would be 45 (95% CI:25-71), 33 (95% CI:20-52), 18 (95% CI:11-26), 9 (95% CI:6-12), 4 (95% CI:3-5), and 2 (95% CI:2-2) final cases under 0%, 10%, 30%, 50%, 70%, and 90% vaccine protection, respectively, without NPIs. The timeliness of strict NPIs along with implementing strict quarantine and isolation measures is imperative to contain COVID-19 cases in cruise ships. The spread of COVID-19 on ships was predicted to be limited in scenarios corresponding to at least 70% protection from prior vaccination, across all passengers and crew.

Double-contrast barium enema is no longer justified as a backup examination for colonoscopy in the population screening program: Population study in an organized fecal immunochemical test-based screening program.

BACKGROUND AND AIM: Currently, some countries still acknowledge double-contrast barium enema (DCBE) as a backup confirmatory examination when colonoscopy is not feasible or incomplete in colorectal cancer (CRC) screening programs. This study aims to compare the performance of colonoscopy and DCBE in terms of the risk of incident CRC after negative results in the fecal immunochemical test (FIT)-based Taiwan Colorectal Cancer Screening Program. METHODS: Subjects who had positive FITs and received confirmatory exams, either colonoscopy or DCBE, without the findings of neoplastic lesions from 2004 to 2013 in the screening program comprised the study cohort. Both the colonoscopy and DCBE subcohorts were followed until the end of 2018 and linked to the Taiwan Cancer Registry to identify incident CRC cases. Multivariate analysis was conducted to compare the risk of incident CRC in both subcohorts after controlling for potential confounders. RESULTS: A total of 102 761 colonoscopies and 5885 DCBEs were performed after positive FITs without neoplastic findings during the study period. By the end of 2018, 2113 CRCs (2.7 per 1000 person-years) and 368 CRCs (7.6 per 1000 person-years) occurred in the colonoscopy and DCBE subcohorts, respectively. After adjusting for major confounders, DCBE had a significantly higher risk of incident CRC than colonoscopy, with an adjusted HR of 2.81 (95% CI = 2.51-3.14). CONCLUSIONS: In the FIT screening program, using DCBE as a backup examination was associated with a nearly threefold risk of incident CRC compared with colonoscopy, demonstrating that it is no longer justified as a backup examination for incomplete colonoscopy.

Deep Phenotyping by Mass Cytometry and Single-Cell RNA-Sequencing Reveals LYN-Regulated Signaling Profiles Underlying Monocyte Subset Heterogeneity and Lifespan.

RATIONALE: Monocytes are key effectors of the mononuclear phagocyte system, playing critical roles in regulating tissue homeostasis and coordinating inflammatory reactions, including those involved in chronic inflammatory diseases such as atherosclerosis. Monocytes have traditionally been divided into 2 major subsets termed conventional monocytes and patrolling monocytes (pMo) but recent systems immunology approaches have identified marked heterogeneity within these cells, and much of what regulates monocyte population homeostasis remains unknown. We and others have previously identified LYN tyrosine kinase as a key negative regulator of myeloid cell biology; however, LYN's role in regulating specific monocyte subset homeostasis has not been investigated. OBJECTIVE: We sought to comprehensively profile monocytes to elucidate the underlying heterogeneity within monocytes and dissect how Lyn deficiency affects monocyte subset composition, signaling, and gene expression. We further tested the biological significance of these findings in a model of atherosclerosis. METHODS AND RESULTS: Mass cytometric analysis of monocyte subsets and signaling pathway activation patterns in conventional monocytes and pMos revealed distinct baseline signaling profiles and far greater heterogeneity than previously described. Lyn deficiency led to a selective expansion of pMos and alterations in specific signaling pathways within these cells, revealing a critical role for LYN in pMo physiology. LYN's role in regulating pMos was cell-intrinsic and correlated with an increased circulating half-life of Lyn-deficient pMos. Furthermore, single-cell RNA sequencing revealed marked perturbations in the gene expression profiles of Lyn-/- monocytes with upregulation of genes involved in pMo development, survival, and function. Lyn deficiency also led to a significant increase in aorta-associated pMos and protected Ldlr-/- mice from high-fat diet-induced atherosclerosis. CONCLUSIONS: Together our data identify LYN as a key regulator of pMo development and a potential therapeutic target in inflammatory diseases regulated by pMos.

Systematic comparison of machine learning algorithms to develop and validate predictive models for periodontitis.

AIM: The aim of this study was to compare the validity of different machine learning algorithms to develop and validate predictive models for periodontitis. MATERIALS AND METHODS: Using national survey data from Taiwan (n = 3453) and the United States (n = 3685), predictors of periodontitis were extracted from the datasets and pre-processed, and then 10 machine learning algorithms were trained to develop predictive models. The models were validated both internally (bootstrap sampling) and externally (alternative country's dataset). The algorithms were compared across six performance metrics ([i] area under the curve for the receiver operating characteristic [AUC], [ii] accuracy, [iii] sensitivity, [iv] specificity, [v] positive predictive value, and [vi] negative predictive value) and two methods of data pre-processing ([i] machine-learning-based feature selection and [ii] dimensionality reduction into principal components). RESULTS: Many algorithms showed extremely strong performance during internal validation (AUC > 0.95, accuracy > 95%). However, this was not replicated in external validation, where predictive performance of all algorithms dropped off drastically. Furthermore, predictive performance differed according to data pre-processing methodology and the cohort on which they were trained. CONCLUSIONS: Larger sample sizes and more complex predictors of periodontitis are required before machine learning can be leveraged to its full potential.

Effectiveness of a 30-year periodontist's primary care for 1946 patients during five-year follow-up.

OBJECTIVE: To evaluate the effect of the periodontal primary care (PPC) on the improvement of periodontal probing depth based on a periodontist's 30-year practice. MATERIALS AND METHODS: We enrolled a total of 2,894 patients who underwent periodontal basic treatment between 1987 and 2017 with 84.5% retention rate. The study population was composed of 80% (n = 1,946) of retained patients with complete re-evaluation up to five-year follow-up. The outcome was measured by the improvement of probing depths (graded as 1:1-3 mm; 2:4-6 mm; 3: ≥7 mm) before and after PPC on both sextant and patient levels. Whether a better improvement was seen in the surgical group and the non-smoker group opposed to their comparators was assessed with various multi-variable regression models. RESULTS: On patient (sextant) level, 82% (38%) improved, 13% (59%) unchanged, and 5% (3%) deteriorated. Adjusted better improvement of probing depth was noted for the surgical group by 63% and non-smoker by 31% compared with their counterparts. The similar findings were found for the outcomes based on continuous probing depth scores. CONCLUSIONS: We demonstrate the improvement of probing depth scores with a periodontal primary care offered for the retained patients and larger effect for the surgical group and non-smoker patients.

Community-based multiple screening for metabolic syndrome by innovative theory: A longitudinal study.

The purpose of this research is to elucidate whether metabolic syndrome affects the rate of adoption of a new multiple cancer screening programme, based on the Diffusion of Innovation theory. The time to attend the screening programme, conducted in Keelung, Taiwan, within 10 years was assessed by innovativeness (innovators, early adaptors, early majority, late majority and laggard) using data from 79,303 residents, with the information on metabolic syndrome accrued from routine adult health check-ups. The median time of adopting the programme and the relative rates of early adoption by metabolic syndrome and its severity score were estimated. The results show that the estimated times to adopt the programme ranged from 3 months for innovators to 10 years for the laggard. The rate of early adoption was 34% higher for participants without metabolic syndrome than for those with the disease, and the gradient relationship of disease severity was noted. The adjusted median time to adopt innovativeness was 0.82 years earlier for participants who were disease-free than those with the disease. Meanwhile, the adjusted median time was wider by up to 2.25 years for those with severe disease. The study suggests that innovation should prioritise the potential risk of the metabolic syndrome population.

Long-term effectiveness of faecal immunochemical test screening for proximal and distal colorectal cancers.

OBJECTIVE: To measure the effects of faecal immunochemical test (FIT) for colorectal cancer (CRC) screening on overall and site-specific long-term effectiveness of population-based organised service screening. DESIGN: A prospective cohort study of Taiwanese nationwide biennial FIT screening was performed. A total of 5 417 699 eligible subjects were invited to attend screening from 2004 through 2009 and were followed up until 2014. We estimated the adjusted relative rates (aRRs) on the effectiveness of reducing advanced-stage CRC (stage II+) and CRC death by Bayesian Poisson regression models with the full adjustment for a cascade of self-selection factors (including the screening rate and the colonoscopy rate) and the completeness of colonoscopy together with demographic features. RESULTS: FIT screening (exposed vs unexposed) reduced the incidence of advanced-stage CRC (48.4 vs 75.7 per 100 000) and mortality (20.3 vs 41.3 per 100 000). Statistically significant reductions of both incidence of advanced-stage CRCs (aRR=0.66, 95% CI 0.63 to 0.70) and deaths from CRC (aRR=0.60, 95% CI 0.57 to 0.64) were noted. FIT screening was more effective in reducing distal advanced-stage CRCs (aRR=0.61, 95% CI 0.58 to 0.64) and CRC mortality (aRR=0.56, 95% CI 0.53 to 0.69) than proximal advanced CRCs (aRR=0.84, 95% CI 0.77 to 0.92) and CRC mortality (aRR=0.72, 95% CI 0.66 to 0.80). CONCLUSION: A large-scale population-based biennial FIT screening demonstrates 34% significant reduction of advanced-stage CRCs and 40% reduction of death from CRC with larger long-term effectiveness in the distal colon than the proximal colon. Our findings provide a strong and consistent evidence-based policy for supporting a sustainable population-based FIT organised service screening worldwide. The disparity of site-specific long-term effectiveness also provides an insight into the remedy for lower effectiveness of FIT screening in the proximal colon.

Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands.

OBJECTIVE: Although mass eradication of Helicobacter pylori has been proposed as a means to eliminate gastric cancer, its long-term effects remain unclear. DESIGN: Mass eradication of H. pylori infection was launched in 2004 and continued until 2018 for a high-risk Taiwanese population aged 30 years or older dwelling on Matsu Islands with prevalent H. pylori infection. Test positives for the 13C-urea breath test underwent eradication therapy. We evaluated the effectiveness of the mass eradication in reducing two main outcomes, incidence and mortality rates of gastric cancer, until the end of 2016 and 2018, respectively. RESULTS: After six rounds of mass screening and eradication, the coverage rate reached 85.5% (6512/7616). The referral rate for treatment was 93.5% (4286/4584). The prevalence rates of H. pylori fell from 64.2% to 15.0% with reinfection rates of less than 1% per person-year. The presence and severity of atrophic gastritis and intestinal metaplasia also decreased with time. Compared with the historical control period from 1995 to 2003, the effectiveness in reducing gastric cancer incidence and mortality during the chemoprevention period was 53% (95% CI 30% to 69%, p<0.001) and 25% (95% CI -14% to 51%, p=0.18), respectively. No significant changes were noted in the incidence rates of other digestive tract cancers or the antibiotic resistance rate of H. pylori. CONCLUSION: Population-based eradication of H. pylori has significantly reduced gastric cancer incidence with no increase in the likelihood of adverse consequences. A significant reduction in mortality is likely to be achieved with a longer follow-up period. TRIAL REGISTRATION NUMBER: NCT00155389.

Beneficial Effect of Consecutive Screening Mammography Examinations on Mortality from Breast Cancer: A Prospective Study.

Background Previously, the risk of death from breast cancer was analyzed for women participating versus those not participating in the last screening examination before breast cancer diagnosis. Consecutive attendance patterns may further refine estimates. Purpose To estimate the effect of participation in successive mammographic screening examinations on breast cancer mortality. Materials and Methods Participation data for Swedish women eligible for screening mammography in nine counties from 1992 to 2016 were linked with data from registries and regional cancer centers for breast cancer diagnosis, cause, and date of death (Uppsala University ethics committee registration number: 2017/147). Incidence-based breast cancer mortality was calculated by whether the women had participated in the most recent screening examination prior to diagnosis only (intermittent participants), the penultimate screening examination only (lapsed participants), both examinations (serial participants), or neither examination (serial nonparticipants). Rates were analyzed with Poisson regression. We also analyzed incidence of breast cancers proving fatal within 10 years. Results Data were available for a total average population of 549 091 women (average age, 58.9 years ± 6.7 [standard deviation]). The numbers of participants in the four groups were as follows: serial participants, 392 135; intermittent participants, 41 746; lapsed participants, 30 945; and serial nonparticipants, 84 265. Serial participants had a 49% lower risk of breast cancer mortality (relative risk [RR], 0.51; 95% CI: 0.48, 0.55; P < .001) and a 50% lower risk of death from breast cancer within 10 years of diagnosis (RR, 0.50; 95% CI: 0.46, 0.55; P < .001) than serial nonparticipants. Lapsed and intermittent participants had a smaller reduction. Serial participants had significantly lower risk of both outcomes than lapsed or intermittent participants. Analyses correcting for potential biases made little difference to the results. Conclusion Women participating in the last two breast cancer screening examinations prior to breast cancer diagnosis had the largest reduction in breast cancer death. Missing either one of the last two examinations conferred a significantly higher risk. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Stephen A. Feig in this issue.

Modular Lipid Nanoparticle Platform Technology for siRNA and Lipophilic Prodrug Delivery.

Successfully employing small interfering RNA (siRNA) therapeutics requires the use of nanotechnology for efficient intracellular delivery. Lipid nanoparticles (LNPs) have enabled the approval of various nucleic acid therapeutics. A major advantage of LNPs is the interchangeability of its building blocks and RNA payload, which allow it to be a highly modular system. In addition, drug derivatization approaches can be used to synthesize lipophilic small molecule prodrugs that stably incorporate in LNPs. This provides ample opportunities to develop combination therapies by co-encapsulating multiple therapeutic agents in a single formulation. Here, it is described how the modular LNP platform is applied for combined gene silencing and chemotherapy to induce additive anticancer effects. It is shown that various lipophilic taxane prodrug derivatives and siRNA against the androgen receptor, a prostate cancer driver, can be efficiently and stably co-encapsulated in LNPs without compromising physicochemical properties or gene-silencing ability. Moreover, it is demonstrated that the combination therapy induces additive therapeutic effects in vitro. Using a double-radiolabeling approach, the pharmacokinetic properties and biodistribution of LNPs and prodrugs following systemic administration in tumor-bearing mice are quantitatively determined. These results indicate that co-encapsulating siRNA and lipophilic prodrugs into LNPs is an attractive and straightforward plug-and-play approach for combination therapy development.

Elimination of Hepatitis C Virus in a Dialysis Population: A Collaborative Care Model in Taiwan.

RATIONALE & OBJECTIVE: Hemodialysis facilities are high-risk environments for the spread of hepatitis C virus (HCV). Eliminating HCV from all dialysis facilities in a community may be achieved more effectively under a collaborative care model. STUDY DESIGN: Quality improvement study of multidisciplinary collaborative care teams including nephrologists, gastroenterologists, and public health practitioners. SETTING & PARTICIPANTS: All dialysis patients in Changhua County, Taiwan were treated using an interdisciplinary collaborative care model implemented within a broader Changhua-Integrated Program to Stop HCV Infection (CHIPS-C). QUALITY IMPROVEMENT ACTIVITIES: Provision of an HCV care cascade to fill 3 gaps, including screening and testing, diagnosis, and universal direct-acting antiviral (DAA) treatment implemented by collaborating teams of dialysis practitioners and gastroenterologists working under auspices of Changhua Public Health Bureau. OUTCOME: Outcome measures included quality indicators pertaining to 6 steps in HCV care ranging from HCV screening to treatment completion to cure. ANALYTICAL APPROACH: A descriptive analysis. RESULTS: A total of 3,657 patients from 31 dialysis facilities were enrolled. All patients completed HCV screening. The DAA treatment initiation rate and completion rate were 88.9% and 94.0%, respectively. The collaborative care model achieved a cure rate of 166 (96.0%) of 173 patients. No virologic failure occurred. The cumulative treatment ratios for patients with chronic HCV infection increased from 5.3% before interferon-based therapy (2017) to 25.6% after restricted provision of DAA (2017-2018), and then to 89.1% after universal access to DAA (2019). LIMITATIONS: Unclear impact of this collaborative care program on incident dialysis patients entering dialysis facilities each year and on patients with earlier stages of chronic kidney disease. CONCLUSIONS: A collaborative care model in Taiwan increased the rates of diagnosis and treatment for HCV in dialysis facilities to levels near those established by the World Health Organization.

Scalable Production of Lipid Nanoparticles Containing Amphotericin B.

Lipid-based formulations have been developed to improve stability profiles, tolerability, and toxicity profiles of small molecule drugs. However, manufacture of such formulations involving lipophilic compounds can be labor-intensive and difficult to scale because of solubility and solvent compatibility issues. We have developed a rapid and scalable approach using rapid-mixing techniques to generate homogeneous lipid nanoparticle (LNP) formulations of siRNA, triglycerides, and hydrophilic weak-base drugs. Here, we used this approach to entrap a hydrophobic small molecule, Amphotericin B (AmpB), a hydrophobic drug not soluble in ethanol. The three prototypes presented in this study were derived from LNP-siRNA systems, triglyceride nanoparticles, and liposomal systems. Cryogenic transmission electron microscopy (cryo-TEM) revealed that all three LNP-AmpB formulations retain structural characteristics of the parent (AmpB-free) LNPs, with particles remaining stable for at least 1 month. All formulations showed similar in vitro toxicity profiles in comparison to AmBisome. Importantly, the formulations have a 2.5-fold improved IC50 for fungal growth inhibition as compared to AmBisome in in vitro efficacy studies. These results demonstrate that the rapid-mixing technology combined with dimethyl sulfoxide (DMSO) for drugs insoluble in other organic solvents can be a powerful manufacturing method for the generation of stable LNP drug formulations.

Characterization of Lipid Nanoparticles Containing Ionizable Cationic Lipids Using Design-of-Experiments Approach.

Lipid nanoparticles (LNPs) containing short-interfering RNA (LNP-siRNA systems) are a promising approach for silencing disease-causing genes in hepatocytes following intravenous administration. LNP-siRNA systems are generated by rapid mixing of lipids in ethanol with siRNA in aqueous buffer (pH 4.0) where the ionizable lipid is positively charged, followed by dialysis to remove ethanol and to raise the pH to 7.4. Ionizable cationic lipids are the critical excipient in LNP systems as they drive entrapment and intracellular delivery. A recent study on the formation of LNP-siRNA systems suggested that ionizable cationic lipids segregate from other lipid components upon charge neutralization to form an amorphous oil droplet in the core of LNPs. This leads to a decrease in intervesicle electrostatic repulsion, thereby engendering fusion of small vesicles to form final LNPs of increased size. In this study, we prepared LNP-siRNA systems containing four lipid components (hydrogenated soy phosphatidylcholine, cholesterol, PEG-lipid, and 1,2-dioleoyl-3-dimethylammonium propane) by microfluidic mixing. The effects of preparation parameters [lipid concentration, flow rate ratio (FRR), and total flow rate], dialysis process, and complex formation between siRNA and ionizable cationic lipids on the physicochemical properties [siRNA entrapment on the particle size and polydispersity index (PDI)] were investigated using a design of experiments approach. The results for the preparation parameters showed no impact on siRNA encapsulation, but lipid concentration and FRR significantly affected the particle size and PDI. In addition, the effect of FRR on the particle size was suppressed in the presence of anionic polymers such as siRNA as compared to the case of LNPs alone. More intriguingly, unlike empty LNPs, a decrease in the PDI and an increase in the particle size occurred after dialysis in the LNP-siRNA systems. Such changes by dialysis were suppressed at FRR = 1. These findings provide useful information to guide the development and manufacturing conditions for LNP-siRNA systems.

Modelling the impacts of COVID-19 pandemic on the quality of population-based colorectal cancer screening.

COVID-19 pandemic has severely affected regular public health interventions including population-based cancer screening. Impacts of such screening delays on the changes in structure and screening process and the resultant long-term outcomes are unknown. It is therefore necessary to develop a systematic framework to assess theses impacts related to these components of quality. Using population-based cancer screening with fecal immunochemical test (FIT) as an illustration, the main analysis was to assess how various scenarios of screening delays were associated with the capacity for primary screening and full time equivalent (FTE) for colonoscopy and impact long-term outcomes based on a Markov decision tree model on population level. The second analysis was to quantify how the extent of COVID-19 epidemic measured by social distancing index affected capacity and FTE that were translated to delays with an exponential relationship. COVID-19 epidemic led to 25%, 29%, 34%, and 39% statistically significantly incremental risks of late cancer for the delays of 0.5-year, 1-year,1.5-year, and 2-year, respectively compared with regular biennial FIT screening. The corresponding statistically findings of four delayed schedules for death from colorectal cancer (CRC) were 26%, 28%, 29%, and 30%, respectively. The higher social distancing index led to a lower capacity of uptake screening and a larger reduction of FTE, resulting in longer screening delay and longer waiting time, which further impacted long-term outcomes as above. In summary, a systematic modelling approach was developed for demonstrating the strong impact of screening delays caused by COVID-19 epidemic on long-term outcomes illustrated with a Taiwan population-based FIT screening of CRC.

Mitigating the impact of COVID-19 on colorectal cancer screening: Organized service screening perspectives from the Asia-Pacific region.

Colorectal cancer(CRC) is one of the most prevalent malignancies in the Asia-Pacific region, and many countries in this region have launched population CRC service screening. In this study, CRC screening key indicators, including the FIT(fecal immunochemical test) screening rate (or participation rate) and the rate of undergoing colonoscopy after positive FIT in 2019 and 2020, were surveyed in individual countries in the Asia-Pacific region. The impact of the pandemic on the effectiveness of CRC screening was simulated given different screening rates and colonoscopy rates and assuming the pandemic would persist or remain poorly controlled for a long period of time, using the empirical data from the Taiwanese program and the CRC natural history model. During the COVID-19 pandemic, most of the programs in this region were affected, but to different extents, which was largely influenced by the severity of the local pandemic. Most of the programs continued screening services in 2020, although a temporary pause occurred in some countries. The modeling study revealed that prolonged pauses of screening led to 6% lower effectiveness in reducing CRC mortality. Screening organizers should coordinate with health authorities to elaborate on addressing screening backlogs, setting priorities for screening, and applying modern technologies to overcome potential obstacles. Many novel approaches that were developed and applied during the COVID-19 pandemic, such as the risk-stratified approach that takes into account personal CRC risk and the local epidemic status, as well as new digital technologies, are expected to play important roles in CRC screening in the future.

Risk stratification for gastric cancer after Helicobacter pylori eradication: A population-based study on Matsu Islands.

BACKGROUND AND AIM: The reliable method to stratify the gastric cancer risk after Helicobacter pylori eradication remains an elusive goal. METHODS: Mass eradication of H. pylori began in 2004 in a high-risk population. After eradication, a screening program involving first-stage serological tests (pepsinogen-I, pepsinogen-II, H. pylori immunoglobin G, and gastrin-17) and second-stage endoscopic examination was launched in 2015-2018. Index lesions included gastric cancer or extensive premalignant lesions. We evaluated the performance of the serological tests to "rule in" and "rule out" the risk based on positive and negative likelihood ratios, respectively. The methylation levels of microRNA-124a-3 in the stomach were measured to indicate genetic damage. RESULTS: Among 6512 invited subjects, 3895 (59.6%) participated. Both gastrin-17 and pepsinogen tests were normal in 3560 (91.4%) subjects; 206 (5.3%) gastrin-17 and 129 (3.3%) pepsinogen tests were abnormal. Years after eradication, the severity of gastritis had fallen greatly, and extensive premalignant lesions or gastric cancer frequently occurred in newly non-atrophic-appearing mucosa. Pepsinogen testing could moderately predict atrophic gastritis (positive likelihood ratio: 4.11 [95% confidence interval: 2.92-5.77]; negative likelihood ratio: 0.14 [0.10-0.19]). Gastrin-17 was not useful (0.66 and 1.20, respectively). However, pepsinogen testing poorly predicted the index lesions (2.04 [1.21-3.42] and 0.57 [0.34-0.95]). DNA methylation levels in the post-eradication mucosa were more discriminative for predicting index lesions (3.89 [2.32-6.54] and 0.25 [0.15-0.42]). CONCLUSIONS: After eradication, pepsinogen false-negative results become more frequent because histology is improved but genetic damage may persist. Direct testing for genetic damage offers better discrimination.

Dental education changed by COVID-19: Student's perceptions and attitudes.

BACKGROUND: Dental students have encountered changes in the teaching format amid the SARS CoV-2 pandemic. This study aims to evaluate the attitudes of dental students of one medical university toward online courses and compare them with those of non-dental students amid the SARS CoV-2 pandemic. METHODS: A cross-sectional survey with a self-report online questionnaire was conducted at the medical university in May 2020 in Taipei. Students from the School of Dentistry, School of Dental Technology, and School of Oral Hygiene Study were enrolled in our survey. RESULTS: In total, 473 students responded to the survey, 318 (67.2%) of whom were dental students. Overall, 366 (77%) students agreed with the change to online learning. Only 10.4% of students thought that dental professional courses with a laboratory format could be changed to online courses. Dental students were significantly more worried than non-dental students about being infected with COVID-19 and about the COVID-19 pandemic continuing. CONCLUSIONS: In conclusion, changing to online learning seems to be perceived as feasible by students. However, more discussion about changing dental professional courses with a laboratory format to online courses considering the attitudes from students is needed.

Probabilistic forecasts of COVID-19 deaths with the progression rate from pneumonia to ARDS: An open-data-based global study.

BACKGROUND: Cumulative data of case-fatality rates (CFR) of COVID-19 varied across countries. A forecasting model generated based on detailed information from three countries during the initial phase of pandemic showed that progression rates from pneumonia to ARDS (PRPA) varied by country and were highly associated with CFR. We aim to elucidate the impact of the PRPA on COVID-19 deaths in different periods of pandemic. METHODS: We used the country-based, real-time global COVID-19 data through GitHub repository to estimate PRPA on the first period (January to June), second period (July to September), and third period (October to December) in 2020. PRPA was used for predicting COVID-19 deaths and assessing the reduction in deaths in subsequent two periods. RESULTS: The estimated PRPA varied widely from 0.38% to 51.36%, with an average of 15.99% in the first period. The PRPA declined to 8.44% and 6.35% in the second and third period. The CFR declined stepwise and was 4.94%, 2.61%, and 1.96%, respectively. Some countries exhibited a decrease in the PRPA from the second to the third period whereas others showed the opposite, particularly where selected viral mutants were prevalent. Overall, the number of observed deaths was lower than that of the predicted deaths in the second and third periods, suggesting an improvement in management of COVID-19 patients. Besides, the degree of improvement depends on the extent of change in PRPA. CONCLUSION: PRPA is a useful indicator to facilitate decision making and assess the improvement of clinical management and medical capacity by forecasting deaths.

Household transmission but without the community-acquired outbreak of COVID-19 in Taiwan.

BACKGROUND: Household transmission is responsible for the subsequent outbreak of community-acquired COVID-19. The aim of this study was to elucidate the household transmission mode and to further estimate effective and basic reproductive number with and without non-pharmaceutical interventions (NPIs). METHODS: A total of 26 households with 39 family clusters between January, 2020 and February, 2021 in Taiwan were enrolled for analysis. The Becker's chain binomial model was used to analyze the probabilities of being infected and escaping from SARS-COV-2 before and after January 1st, 2021, which were further converted to estimating basic reproductive numbers in the absence of NPIs. The likelihood of leading to the subsequent community-acquired outbreak given NPIs was further assessed. RESULTS: The secondary attack rate was 46.2%. Given the saturated Greenwood model selected as the best fitted model, the probability of being infected and escaping from COVID-19 within household was estimated as 44.4% (95% CI: 5.0%-53.7%) and 55.7% (95% CI: 46.3%-65.0%), respectively. In the second period of early 2021, the infected probability was increased to 58.3% (95% CI: 12.7%-90.0%) and the escape probability was lowered to 41.7% (95% CI: 0.0%-86.9%). The corresponding basic reproductive numbers (R0) increased from 4.29 in the first period to 6.73 in the second period without NPIs. However, none of subsequent community-acquired outbreak was noted in Taiwan given very effective NPIs in both periods. CONCLUSION: The proposed method and results are useful for designing household-specific containment measures and NPIs to stamp out a large-scale community-acquired outbreak as demonstrated in Taiwan.