Comparative analysis of atherosclerotic cardiovascular disease burden between ages 20-54 and over 55 years: insights from the Global Burden of Disease Study 2019.

BACKGROUND: To systematically analyze differences in atherosclerotic cardiovascular disease (ASCVD) burden between young and older adults. METHODS: We estimated the prevalence, mortality, and disability-adjusted life years (DALYs) of ASCVD, including ischemic heart disease (IHD), ischemic stroke (IS), and peripheral artery disease (PAD), in individuals aged 20-54 and > 55 years from 1990-2019, utilizing data from the 2019 Global Burden of Disease Study. The annual percentage changes (EAPCs) for age-specific prevalence, mortality, or DALY rates were calculated to quantify the temporal trends of ASCVD burden. We also analyzed population attribution fractions (PAF) of premature ASCVD mortality and DALYs for different risk factors and compared the burden of extremely premature, premature, and non-premature ASCVD cases based on clinical classifications. RESULTS: From 1990-2019, the global prevalence rates of IHD, IS, and PAD in the 20-54 years age group increased by 20.55% (from 694.74 to 837.49 per 100,000 population), 11.50% (from 439.48 to 490.03 per 100,000 population), and 7.38% (from 384.24 to 412.59 per 100,000 population), respectively. Conversely, the ASCVD prevalence in > 55years age group decreased. Adverse outcome burdens, including mortality and DALYs, varied among ASCVD subtypes. The decrease in the mortality/DALY burden of IHD and IS was lower in the 20-54 years group than in the > 55 years group. For PAD, DALYs among those aged 20-54 increased but decreased among those aged > 55 years. When grouped according to socio-demographic index (SDI) values, lower SDI regions exhibited a higher proportion of young ASCVD burden. The prevalence of young IHD, IS, and PAD in low SDI regions reached 20.70%, 40.05%, and 19.31% in 2019, respectively, compared with 12.14%, 16.32%, and 9.54%, respectively, in high SDI regions. Metabolic risks were the primary contributors to the ASCVD burden in both age groups. Increased susceptibility to ambient particulate matter pollution and inadequate control of high body-mass index and high fasting plasma glucose in young individuals may partially explain the differing temporal trends between young and older individuals. CONCLUSIONS: The ASCVD burden in young individuals may become a growing global health concern, especially in areas with lower socioeconomic development levels that require more effective primary prevention strategies.

Recurrent spontaneous pneumothorax secondary to lung cystic lesions in a case of convalescent COVID-19: a case report and literature review.

BACKGROUND: While spontaneous pneumothorax has been documented in COVID-19 patients, reports on recurrent spontaneous pneumothorax due to cystic lesions in convalescent COVID-19 patients are scarce. The progression of these lung cystic lesions remains inadequately explored. CASE PRESENTATION AND LITERATURE REVIEW: An 81-year-old male, a non-smoker with a history of rheumatoid arthritis, presented with fever, cough, and expectoration for 14 days. Initially diagnosed with moderate COVID-19, he deteriorated to severe COVID-19 despite adherence to local treatment guidelines. Successive identification of three cystic lesions termed "bulla" or "pneumatocele", and one cystic lesion with air-fluid level, referred to as "pneumo-hamatocele" (PHC), occurred in his lungs. Gradual improvement followed anti-inflammatory therapy and optimal supportive care. However, on day 42, sudden worsening dyspnea prompted a computed tomography (CT) scan, confirming a right spontaneous pneumothorax and subcutaneous emphysema, likely due to PHC rupture. Discharge followed chest tube implementation for pneumothorax resolution. On day 116, he returned to the hospital with mild exertional dyspnea. Chest CT revealed recurrent right pneumothorax from a remaining cyst in the right lung. Apart from our patient, literature retrieval identified 22 COVID-19 patients with spontaneous pneumothorax due to cystic lesions, with a male predominance (95.6%; 22/23). Diagnosis of pneumothorax and lung cystic lesions occurred around day 29.5 (range: 18-35) and day 26.4 (± 9.8) since symptom onset, respectively. Except for one patient whose pneumothorax occurred on day seven of illness, all patients eventually recovered. CONCLUSIONS: Recurrent spontaneous pneumothorax secondary to lung cystic lesions may manifest in convalescent COVID-19 patients, particularly males with COVID-19 pneumonia. Chest CT around 2 to 3 weeks post-symptom onset may be prudent to detect cystic lesion development and anticipate spontaneous pneumothorax.

Enhanced editing efficiency in Arabidopsis with a LbCas12a variant harboring D156R and E795L mutations.

Cas12a (Cpf1), a Class 2 Type V CRISPR/Cas nuclease, has several unique attributes for genome editing and may provide a valuable alternative to Cas9. However, a low editing efficiency due to temperature sensitivity and insufficient cleavage activity of the Cas12a nuclease are major obstacles to its broad application. In this report, we generated two variants, ttAsCas12 Ultra and ttLbCas12a Ultra harboring three (E174R, M537R, and F870L) or two (D156R and E795L) mutations, respectively, by combining the mutations from the temperature-tolerant variants ttAsCas12a (E174R) and ttLbCas12a (D156R), and those from the highly active variants AsCas12a Ultra (M537R and F870L) and LbCas12a Ultra (E795L). We compared editing efficiencies of the five resulting Cas12a variants (LbCas12a, ttLbCas12a, ttLbCas12a Ultra, AsCas12a Ultra, and ttAsCas12 Ultra) at six target sites of four genes in Arabidopsis (Arabidopsis thaliana). The variant ttLbCas12a Ultra, harboring the D156R and E795L mutations, exhibited the highest editing efficiency of all variants tested in Arabidopsis and can be used to generate homozygous or biallelic mutants in a single generation in Arabidopsis plants grown at 22 °C. In addition, optimization of ttLbCas12a Ultra, by varying nuclear localization signal sequences and codon usage, further greatly improved editing efficiency. Collectively, our results indicate that ttLbCas12a Ultra is a valuable alternative to Cas9 for editing genes or promoters in Arabidopsis. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00144-w.

PE6c greatly enhances prime editing in transgenic rice plants.

Prime editing is a versatile CRISPR/Cas-based precise genome-editing technique for crop breeding. Four new types of prime editors (PEs) named PE6a-d were recently generated using evolved and engineered reverse transcriptase (RT) variants from three different sources. In this study, we tested the editing efficiencies of four PE6 variants and two additional PE6 constructs with double-RT modules in transgenic rice (Oryza sativa) plants. PE6c, with an evolved and engineered RT variant from the yeast Tf1 retrotransposon, yielded the highest prime-editing efficiency. The average fold change in the editing efficiency of PE6c compared with PEmax exceeded 3.5 across 18 agronomically important target sites from 15 genes. We also demonstrated the feasibility of using two RT modules to improve prime-editing efficiency. Our results suggest that PE6c or its derivatives would be an excellent choice for prime editing in monocot plants. In addition, our findings have laid a foundation for prime-editing-based breeding of rice varieties with enhanced agronomically important traits.

Quantized ferroelectricity in multivalent ion conductors with non-polar point groups.

Ferroelectricity with switchable polarizations is generally associated with small ion-displacements and occurs only in 10 specific polar point groups, which is not a necessary requirement for ion conduction where the ions can also be electrically displaced but by much longer distances. Herein, through first-principles calculations, we predict the formation of unconventional ferroelectricity based on previous experimental reports on topotactic reaction with an aliovalent cation between trigonal layers of ion conductors. In such systems, the multivalent cations are surrounded by vacant sites that can simultaneously migrate by a much larger distance compared with conventional displacive ferroelectricity, giving rise to a quantized change in polarization even if the crystal lattices do not belong to the 10 polar groups. The deviation from classical principles can be attributed to the long ion displacements in ferroelectric ion conductors during switching that can lead to the transformation between multiple equivalent symmetrical stable states, which cannot be realized by the relatively small ion displacements in current ferroelectrics. The evenly distributed vacant sites due to Coulomb repulsion do not break the insulativity of the systems, while their inhomogeneous distribution under an electric field or in ferroelectric domain walls will give rise to high electrical conductance, which may be utilized for constructing nanoscale artificial ionic synapses that enable neuromorphic computing.

A smartphone-enabled colorimetric platform based on enzyme cascade amplification strategy for detection of Staphylococcus aureus in milk.

Staphylococcus aureus is a pathogenic bacterium contaminating milk and dairy foods causing food poisoning and foodborne pathogens. In this work, a smartphone-enabled enzyme cascade-triggered colorimetric platform was constructed using a cascade bio-nanozyme formed by immobilized glucose oxidase (GOx) on Fe3O4@Ag for rapid detection of S. aureus. Benefiting from reasonable experimental design, a bio-nanozyme cascade-triggered reaction was achieved through H2O2 produced by GOx oxidation of glucose, followed by in situ catalysis of 3,3',5,5'-tetramethylbenzidine (TMB) by the inherent peroxidase-like activity of Fe3O4@Ag to produce color signals. Staphylococcus aureus detection could be performed through naked-eye observation and smartphone measurement, and the developed assay can achieve quantitative and qualitative detection of S. aureus. The on-site nanoplatform had satisfactory specificity and sensitivity with a low detection limit of 6.9 cfu·mL-1 in 50 min. Moreover, the nanoplatform has good practicality in the detection of S. aureus in milk samples. Therefore, the assay has potential application prospects in food safety inspection.

Synergy detection: A practical guide to statistical assessment of potential drug combinations.

Combination treatments have been of increasing importance in drug development across therapeutic areas to improve treatment response, minimize the development of resistance, and/or minimize adverse events. Pre-clinical in-vitro combination experiments aim to explore the potential of such drug combinations during drug discovery by comparing the observed effect of the combination with the expected treatment effect under the assumption of no interaction (i.e., null model). This tutorial will address important design aspects of such experiments to allow proper statistical evaluation. Additionally, it will highlight the Biochemically Intuitive Generalized Loewe methodology (BIGL R package available on CRAN) to statistically detect deviations from the expectation under different null models. A clear advantage of the methodology is the quantification of the effect sizes, together with confidence interval while controlling the directional false coverage rate. Finally, a case study will showcase the workflow in analyzing combination experiments.

A matching-based machine learning approach to estimating optimal dynamic treatment regimes with time-to-event outcomes.

Observational data (e.g. electronic health records) has become increasingly important in evidence-based research on dynamic treatment regimes, which tailor treatments over time to patients based on their characteristics and evolving clinical history. It is of great interest for clinicians and statisticians to identify an optimal dynamic treatment regime that can produce the best expected clinical outcome for each individual and thus maximize the treatment benefit over the population. Observational data impose various challenges for using statistical tools to estimate optimal dynamic treatment regimes. Notably, the task becomes more sophisticated when the clinical outcome of primary interest is time-to-event. Here, we propose a matching-based machine learning method to identify the optimal dynamic treatment regime with time-to-event outcomes subject to right-censoring using electronic health record data. In contrast to the established inverse probability weighting-based dynamic treatment regime methods, our proposed approach provides better protection against model misspecification and extreme weights in the context of treatment sequences, effectively addressing a prevalent challenge in the longitudinal analysis of electronic health record data. In simulations, the proposed method demonstrates robust performance across a range of scenarios. In addition, we illustrate the method with an application to estimate optimal dynamic treatment regimes for patients with advanced non-small cell lung cancer using a real-world, nationwide electronic health record database from Flatiron Health.

Effect of black wolfberry anthocyanin and maltitol on the gelation and microstructural properties of curdlan/gellan gum hybrid gels.

BACKGROUND: Laboratory scale experiments have shown that curdlan and gellan gum gelled together as curdlan/gellan gum (CG) hybrid gels showed better gel properties than the individual curdlan and gellan gum. In this study, CG and black wolfberry anthocyanin (BWA), CG and maltitol (ML) hybrid gels were constructed using CG hybrid gel as matrix. The effects of BWA or ML on the gel properties and microstructure of CG hybrid gels were investigated and a confectionery gel was developed. RESULTS: The presence of BWA increased the storage modulus (G') value of CG at 0.1 Hz, whereas ML had little effect on the G' value of CG. The addition of BWA (5 g L-1 ) and ML (0.3 mol L-1 ) increased the melting and gelling temperatures of CG hybrid gels to 42.4 °C and 34.1 °C and 44.2 °C and 33.2 °C, respectively. Meanwhile, the relaxation time T22 in CG-ML and CG-BWA hybrid gels was reduced to 91.96 and 410.27 ms, indicating the strong binding between BWA and CG, ML and CG. The hydrogen bond interaction between BWA or ML and CG was confirmed by the shift in the hydroxyl stretching vibration peak. Moreover, the microstructures of CG-ML and CG-BWA hybrid gels were denser than that of CG. In addition, confectionery gel containing CG-BWA-ML has good chewing properties. CONCLUSION: These results indicated that the incorporation of BWA or ML could improve the structure of CG hybrid gels and assign a sustainability potential for the development of confectionery gels based on CG complex. © 2024 Society of Chemical Industry.

Variation in Treatment Charges and Reimbursement Among Individual Thoracic Surgeons.

BACKGROUND: Health care use and costs have undergone an increase in public scrutiny. Other specialties have evaluated practice patterns of their most highly reimbursed surgeons and found unique billing and procedure overuse. In this study, we evaluate Medicare payments to general thoracic surgeons and evaluate those with the highest reimbursements. METHODS: The 2018 Medicare Provider Utilization Data were queried to identify thoracic surgeons. Services were grouped into common categories: Evaluation and Management, Lung/Pleura, Foregut, Chest Wall, Airway, Diaphragm, Mediastinum, Endoscopy, and Transplant. Payment data were analyzed for surgeons receiving the top 1% of Medicare payments and the remainder of the workforce. RESULTS: In 2018, 2000 unique self-identified thoracic surgeons received a total of $54,734,736 in payments from Medicare for thoracic-related services. The top 1% of thoracic surgeons (n = 20) received $4,607,561, or 8.4% of total payments. Inpatient Evaluation and Management was the leading payment category for the top 1% (48.5% of payments), whereas Outpatient Evaluation and Management led for the remaining workforce (43.5% of payments). Whereas the surgical procedure code with overall highest reimbursement for both groups was Current Procedural Terminology (American Medical Association) 32663 (video-assisted thoracic surgery lobectomy), there was a difference with an increased use of high relative value unit unbundled Current Procedural Terminology codes in the highest earners. CONCLUSIONS: A disproportionate amount of Medicare reimbursement went to top 1%. The highest earners appeared to earn the most from inpatient treatment codes and also used unbundled codes more often. Because billing code use is not regulated and often subjective, a deeper evaluation by the major surgical societies may be warranted.

Veterans and Nonveterans Coping With Stress During 4 Months of COVID-19.

PURPOSE: Identifying how people have been coping with stress during the COVID-19 pandemic allows us to anticipate how the population may react to similar stressors over time. In this study, we assessed patterns of coping styles among veterans and nonveterans, and stability and change in these strategies at 3 time points during the pandemic. METHODS: Using an online survey platform, we circulated a questionnaire at 3 time points during the period when COVID-19 vaccines became widely available (December 2-27, 2020; January 21-February 6, 2021; and March 8-23, 2021). The questionnaire asked participants about their extent of use of 11 coping strategies, and symptoms of anxiety and depression. RESULTS: A total of 2,085 participants (50.8% veterans) completed the questionnaire at 1 or more time points and 930 participants (62.8% veterans) completed it at all 3 time points. Cluster analysis identified 3 distinct coping styles: adaptive, distressed, and disengaged. Compared with nonveterans, veterans more commonly had adaptive and disengaged coping styles, and less commonly had a distressed coping style. The majority of the cohort (71.3%) changed coping style at least once during the study period. Participants who used the same coping style across all 3 time points reported lower levels of anxiety and depression. CONCLUSIONS: Our data demonstrate a need to better understand the dynamic nature of coping with pandemic-level stressors across time. We did not find patterns of change in coping styles, but our findings point to potential advantages of stability in coping style. It is possible that less adaptive styles that are more stable may be advantageous for mental health. This research has implications for supporting patients dealing with stress in family medicine.

Adipose Tissue Distribution and Body Mass Index (BMI) Correlation With Daily Image-Guided Radiotherapy (IGRT) Shifts of Abdominal Radiation Therapy Patients.

Purpose There are several studies suggesting a correlation between image-guided radiotherapy (IGRT) setup errors and body mass index (BMI). However, abdominal fat content has visceral and subcutaneous components, which may affect setup errors differently. This study aims to analyze a potential workflow for characterizing adipose content and distribution in the region of the target that would allow a quickly calculated metric of abdominal fat content to stratify these patients. Methods IGRT shift data was retrospectively tabulated from daily fan-beam CT-on-rails pre-treatment alignment for 50 abdominal radiation therapy (RT) patients, and systematic and random errors in the daily setup were characterized by tabulating average and standard deviations of shift data for each patient and looking at differences for different distributions of adipose content. Visceral and subcutaneous fat content were defined by visceral fat area (VFA) and subcutaneous fat area (SFA) using a region-growing algorithm to contour adipose tissue on CT simulation scans. All contours were created for a single slice at the treatment isocenter, on which the VFA and SFA were calculated. A log-rank test was used to test trends in shifts over quartiles of adiposity. Results VFA ranged from 1.9-342.8c m2, and SFA from 11.8-756.0 cm2. The standard definition (SD) of random error (σ) in the lateral axis for Q1 vs. Q4 VFA was 0.10cm vs. 0.29cm, 0.12cm vs. 0.28cm for SFA, and 0.12cm vs. 0.31cm for BMI. The percentage of longitudinal shifts greater than 10mm for Q1 vs. Q4 VFA was 0% vs. 9%, 2% vs. 19% for SFA, and 0% vs. 20% for BMI. Statistically significant trends in shifts vs. the BMI quartile were seen for both pitch and the longitudinal direction, as well as for pitch corrections vs. the VFA quartile. Conclusion Within this dataset, abdominal cancer patients showed statistically significant trends in shift probability vs. BMI and VFA. Also, patients in the upper quartiles of all adiposity metrics showed an increased SD of σ in the lateral direction and increased shifts over 10 mm in the longitudinal direction. However, despite these relationships, neither VFA nor SFA offered discernible advantages in their relationship to shift uncertainty relative to BMI.

Variability in Excess Lobectomy Billing Among US Thoracic Surgeons.

BACKGROUND: Transparency in physician billing practices in the United States is lacking. Often, charges may vary substantially between providers and excess charges may be passed on to the patient. In this study, we evaluate Medicare charges and payments for minimally invasive lobectomy to obtain a sense of national billing practices and evaluate for predictors of higher charges. METHODS: The 2018 Medicare Provider Utilization Data was queried to identify surgeons submitting charges for Video-Assisted Thoracoscopic Lobectomy. Excess charges were determined by each provider. Additional demographic variables were collected including geographic region for general surgery and cardiothoracic surgery training, years in practice, and current practice setting. A multivariate gamma regression was utilized to determine predictors of high billing practices. RESULTS: A total of 307 unique providers submitted charges ranging from $1,104 to $25,128 with a median of $4,265. The average Medicare Payment amount ranged from $163 to $1,409, with a median of $1,056. Male surgeons were estimated to charge 1.3 times more than female surgeons, while those in an academic setting were estimated to charge 1.4 times more than private practice (p < 0.01). Surgeons practicing in the South or West were estimated to charge 0.76 and 0.81 times as much as those practicing in the Northeast (p < 0.01). CONCLUSIONS: Billing practices vary widely across the United States. Charges submitted to Medicare likely represent a provider's charges across all payers. In today's healthcare economy, it is important for patients to understand the true cost of care and for providers to be mindful of reasonable and appropriate charges.

Are people with diabetes getting the support they need? Deficits between support desired and received from family and friends relates to poorer health.

OBJECTIVE: To determine the mismatch of desired support versus support received and to evaluate the impact of these mismatches on health outcomes of people with diabetes. METHODS: This cross-sectional study is a secondary data analysis of medical record and survey data of participants with Type 1 and Type 2 diabetes from a diabetes care and education program. Biophysical metrics included HbA1c, body mass index, systolic blood pressure, diastolic blood pressure, triglycerides, and high- and low-density lipoproteins. Psychosocial and self-care survey outcomes included diabetes distress, diabetes self-care, and diabetes self-efficacy. Support mismatch was a difference score (support desired-support received). Descriptive statistics were computed for demographics, clinical characteristics, and primary outcomes. Multiple linear regressions were computed. RESULTS: The percentage of participants experiencing support mismatch (surplus/deficits) across six domains was: 15%/27% (foot care), 22%/24% (take medicine), 24%/23% (test blood sugar), 21%/29% (physical activity), and 18%/34% (follow meal plan). Greater support deficits were associated with higher triglyceride levels, increased diabetes distress, and lower diabetes self-efficacy. CONCLUSIONS: Findings indicate that greater support deficits can be a risk factor for some poorer physical and psychosocial health outcomes. PRACTICE IMPLICATIONS: Interventions to facilitate functional supportive behaviors are an avenue for future research and clinical practice.

Optimized prime editing efficiently generates heritable mutations in maize.

Low efficiency is the main obstacle to using prime editing in maize (Zea mays). Recently, prime-editing efficiency was greatly improved in mammalian cells and rice (Oryza sativa) plants by engineering prime-editing guide RNAs (pegRNAs), optimizing the prime editor (PE) protein, and manipulating cellular determinants of prime editing. In this study, we tested PEs optimized via these three strategies in maize. We demonstrated that the ePE5max system, composed of PEmax, epegRNAs (pegRNA-evopreQ. 1), nicking single guide RNAs (sgRNAs), and MLH1dn, efficiently generated heritable mutations that conferred resistance to herbicides that inhibit 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), acetolactate synthase (ALS), or acetyl CoA carboxylase (ACCase) activity. Collectively, we demonstrate that the ePE5max system has sufficient efficiency to generate heritable (homozygous or heterozygous) mutations in maize target genes and that the main obstacle to using PEs in maize has thus been removed.

Formation and characteristics of curcumin-loaded binary gels formed from large yellow croaker (Pseudosciaena crocea) roe protein isolate and gellan gum.

The aim of this study was to investigate the effect of gellan gum (GG) on the cold gelation of large yellow croaker roe protein isolate (pcRPI). The water-holding ability and storage modulus of the pcRPI-GG binary gels increased with the GG concentration, where the storage modulus of the pcRPI-0.2% GG gel was approximately 30.7 times that of the pure pcRPI gel. Compare to the other binary gels, pcRPI-0.2% GG gels exhibited a lower lacunarity and higher junction density, with a denser, more aggregated microstructure. Consequently, curcumin was embedded in pcRPI-0.2% GG gels, and simulated gastrointestinal digestion test results showed that GG addition effectively protected and slowed curcumin release in the gastrointestinal environment. These findings may contribute to elucidating the interaction of pcRPI with GG and demonstrate the potential of binary gels for the embedding and delivery of active substances.

Increasing Skin Cancer Prevention in Young Adults: the Cumulative Impact of Personalized UV Photography and MC1R Genetic Testing.

Skin cancer has become increasingly common among young adults; however, this population does not consistently adhere to recommended methods for preventing the disease. Interventions in college settings have relied on appearance-focused appeals and have not been able to examine the cumulative effect of multiple behavior change and skin cancer risk communication strategies. The goal of the current study was to examine the unique and combined impacts of personalized ultraviolet (UV) radiation photographs, genetic testing for skin cancer risk, and general skin cancer prevention education. Participants were randomly assigned to one of four conditions: (1) skin cancer prevention education, (2) education + UV photo, (3) education + genetic testing, and (4) education + UV photo + genetic testing. Self-reported sun protection, tanning, and sunburn were assessed at baseline, immediately post-intervention, and 1 month post-intervention. The findings indicated benefits of the interventions to skin cancer prevention behaviors in the overall sample; however, the combined (UV photo + genetic testing) intervention had the most consistent positive effects on behaviors. Intervention effects were distinct across seasons. These results suggest that interventions containing multiple skin cancer risk communication strategies hold promise in benefitting health-promoting behavior changes in an at-risk, young adult population.Trial Registration Number: NCT03979872; Registered 6/5/2019.

Unconventional Ferroelectricity with Quantized Polarizations in Ionic Conductors: High-Throughput Screening.

Ferroelectricity is generally a displacive phenomenon within a unit cell in which ions are placed asymmetrically. In ionic conductors, ions can also be electrically displaced but by much longer distances. They are mostly nonpolar with symmetrical lattices due to the nondirectional character of ionic bondings. Here we propose that the combination of two such displacive modes may give rise to unconventional ferroelectricity with quantized polarizations, where even one local vacancy may induce giant polarization in ubiquitous ionic conductors. Such systems should be insulating with ion vacancies inclined to aggregate at one side. Our high-throughput screening combined with ab initio calculations provided 35 candidates, from which we select KSnS4 and Na4SnS4 to show the existence of such long ion displacement ferroelectricity with a change in integer quantum number in polarizations during switching. The polarizations can be unprecedentedly large with a moderate density of ion vacancies that can be experimentally achieved via ion deintercalation.