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Background COVID-19 vaccines adapted to newly emerging circulating variants are necessary to better protect the population due to the evolving nature of the SARS-CoV-2 virus.Research Design and Methods The South African population was stratified by age and risk (defined by comorbidities such as diabetes, obesity, smoking, cancer, and asthma), and HIV status. The outcomes of different vaccination strategies based on age, risk, and HIV status were estimated using a Markov-decision tree model based on age-specific inputs derived from the literature and South African surveillance data.Results Vaccinating older adults and those with comorbidities was estimated to avert 111,179 infections 18,281 hospitalizations, and 3,868 deaths, resulting in savings of ZAR 1,260 million (USD 67 million) and ZAR 3,205 million (USD 170 million) in direct and indirect costs, respectively. Similar results were obtained when considering strategies targeting older adults and the HIV population. Expanding vaccination to 75% of the standard-risk population prevented more infections (401%), hospitalizations (167%), and deaths (67%) and increased the direct (232%) and indirect (455%) cost savings compared to the base case.Conclusions Implementing widespread vaccination strategies that utilize a vaccine adapted to the prevailing circulating variant in South Africa would result in significant public health and economic gains.

Background Updating vaccines is essential for combatting emerging coronavirus disease 2019 (COVID-19) variants. This study assessed the public health and economic impact of a booster dose of an adapted vaccine in the United Kingdom (UK).Methods A Markov-decision tree model estimated the outcomes of vaccination strategies targeting various age and risk groups in the UK. Age-specific data derived from published sources were used. The model estimated case numbers, deaths, hospitalizations, medical costs, and societal costs. Scenario analyses were conducted to explore uncertainty.Results Vaccination targeting individuals aged ≥ 65 years and the high-risk population aged 12–64 years was estimated to avert 701,549 symptomatic cases, 5,599 deaths, 18,086 hospitalizations, 56,326 post-COVID condition cases, and 38,263 lost quality-adjusted life years (QALYs), translating into direct and societal cost savings of £112,174,054 and £542,758,682, respectively. The estimated economically justifiable price at willingness-to-pay thresholds of £20,000 and £30,000 per QALY was £43 and £61, respectively, from the payer perspective and £64 and £82, respectively, from the societal perspective. Expanding to additional age groups improved the public health impact.Conclusions Targeting individuals aged ≥ 65 years and those aged 12–64 years at high risk yields public health gains, but expansion to additional age groups provides additional gains.

ABSTRACTBackground The aim of this study was to evaluate the public health and economic impact of the COVID-19 booster vaccination with BNT162b2 in Japan during an Omicron-dominant period from early 2022.Research design and methods A combined cohort Markov decision tree model estimated the cost-effectiveness of annual or biannual booster vaccination strategies compared to no booster vaccination for those aged 65 years and above, and those aged 60–64 years at high risk as the base case. The societal perspective was primarily considered. We also examined other target populations with different age and risk groups. Sensitivity and scenario analyses with alternative inputs were performed.Results Annual and biannual vaccination strategies were dominant from the societal perspective in the base case. Incremental Cost Effectiveness Ratios (ICERs) from the payer perspective were JPY 1,752,499/Quality Adjusted Life Year (QALY) for annual vaccination and JPY 2,831,878/QALY for biannual vaccination, both less than the threshold value in Japan (JPY 5 million/QALY). The results were consistent even when examining other target age and risk groups. All sensitivity and scenario analyses indicated that ICERs were below JPY 5 million/QALY.Conclusions Booster vaccination with the COVID-19 vaccine BNT162b2 is a dominant strategy and beneficial to public health in Japan.

ABSTRACTBackground Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 has been a dynamically changing virus, requiring the development of adapted vaccines. This study estimated the potential public health impact alternative vaccination strategies for COVID-19 in Singapore.Research Design and Methods The outcomes of alternative vaccination strategies with a future adapted vaccine were estimated using a combined Markov decision tree model. The population was stratified by high- and standard-risk. Using age-specific inputs informed by local surveillance data and published sources, the model estimated health (case numbers, hospitalizations, and deaths) and economic (medical costs and productivity losses) outcomes in different age and risk subpopulations.Results Booster vaccination in only the elderly and high-risk subpopulation was estimated to avert 278,614 cases 21,558 hospitalizations, 239 deaths, Singapore dollars (SGD) 277 million in direct medical costs, and SGD 684 million in indirect medical costs. These benefits increased as vaccination was expanded to other subpopulations. Increasing the booster vaccination coverage to 75% of the standard-risk population averted more deaths (3%), hospitalizations (29%), infections (145%), direct costs (90%), and indirect costs (192%) compared to the base case.Conclusions Broader vaccination strategies using an adapted booster vaccine could have substantial public health and economic impact in Singapore.

Abstract Background Diabetes, a health crisis afflicting millions worldwide, is increasing rapidly in prevalence. The microvascular complications triggered by diabetes have emerged as the principal cause of renal disease and blindness. The retinal microvascular network may be sensitive to early systemic vascular structural and functional changes. Therefore, this research endeavored to discern the systemic determinants influencing the retinal microvascular network in patients with and without diabetes. Methods The Kailuan Eye Study is a cross-sectional study based on the community-based cohort Kailuan Study. Participants underwent optical coherence tomography angiography (OCTA) (Zeiss Cirrus 5000; Carl Zeiss Meditec) and comprehensive systemic examination. Metrics such as perfusion density (PD), vascular density (VD), foveal avascular zone (FAZ) parameters of the superficial capillary plexus (SCP) in the macula were assessed. Results This study included 860 eligible participants (average age = 62.75 ± 6.52 years; 21.9% female), of which 449 were diabetics. People with diabetes had diminished PD and VD in the entire macular and parafoveal regions compared to people without diabetes. Reduced PD in the whole macular region was correlated with higher fasting plasma glucose (FPG, mmol/L) concentration (Beta = -0.19, 95% CI = -0.42 to -0.36, P

In the present review, we focused on recent translational and clinical discoveries in asthma immunology, facilitating phenotyping and stratified or personalized interventions for patients with this condition. The immune processes behind chronic inflammation in asthma exhibit marked heterogeneity, with diverse phenotypes defining discernible features and endotypes illuminating the underlying molecular mechanisms. In particular, two primary endotypes of asthma have been identified: “type 2-high,” characterized by increased eosinophil levels in the airways and sputum of patients, and “type 2-low,” distinguished by increased neutrophils or a pauci-granulocytic profile. Our review encompasses significant advances in both innate and adaptive immunities, with emphasis on the key cellular and molecular mediators, and delves into innovative biological and targeted therapies for all the asthma endotypes. Recognizing that the immunopathology of asthma is dynamic and continuous, exhibiting spatial and temporal variabilities, is the central theme of this review. This complexity is underscored through the innumerable interactions involved, rather than being driven by a single predominant factor. Integrated efforts to improve our understanding of the pathophysiological characteristics of asthma indicate a trend toward an approach based on disease biology, encompassing the combined examination of the clinical, cellular, and molecular dimensions of the disease to more accurately correlate clinical traits with specific disease mechanisms.

Introduction The COVID-19 pandemic triggered one of the largest global health and economic crises in recent history. COVID-19 vaccination (CV) has been the central tool for global health and macroeconomic recovery, yet estimates of CV’s global health and macroeconomic value remain scarce.Methods We used regression analyses to measure the impact of CV on gross domestic product (GDP), infections and deaths. We combined regression estimates of vaccine-averted infections and deaths with estimates of quality-adjusted life years (QALY) losses, and direct and indirect costs, to estimate three broad value components: (i) QALY gains, (ii) direct and indirect costs averted and (iii) GDP impacts. The global value is the sum of components over 148 countries between January 2020 and December 2021 for CV generally and for Pfizer-BioNTech specifically.Results CV’s global value was US$5.2 (95% CI US$4.1 to US$6.2) trillion, with Pfizer-BioNTech’s vaccines contributing over US$1.9 (95% CI US$1.5 to US$2.3) trillion. Varying key parameters results in values 10%–20% higher or lower than the base-case value. The largest value component was GDP impacts, followed by QALY gains, then direct and indirect costs averted. CV provided US$740 of value per dose, while Pfizer-BioNTech specifically provided >US$1600 per dose. We estimated conservative benefit-cost ratios of 13.9 and 30.8 for CV and Pfizer-BioNTech, respectively.Conclusions We provide the first estimates of the broad value of CV incorporating GDP, QALY and direct and indirect cost impacts. Through December 2021, CV produced significant health and economic value, represented strong value for money and produced significant macroeconomic benefits that should be considered in vaccine evaluation.

Abstract Introduction The delivery of COVID-19 vaccines was successful in reducing hospitalizations and mortality. However, emergence of the Omicron variant resulted in increased virus transmissibility. Consequently, booster vaccination programs were initiated to decrease the risk of severe disease and death among vulnerable members of the population. This study aimed to estimate the effects of the booster program and alternative vaccination strategies on morbidity and mortality due to COVID-19 in the UK. Method A Susceptible-Exposed-Infectious-Recovered (SEIR) model was used to assess the impact of several vaccination strategies on severe outcomes associated with COVID-19, including hospitalizations, mortality, National Health Service (NHS) capacity quantified by hospital general ward and intensive care unit (ICU) bed days, and patient productivity. The model accounted for age-, risk- and immunity-based stratification of the UK population. Outcomes were evaluated over a 48-week time horizon from September 2022 to August 2023 considering the actual UK autumn 2022/spring 2023 booster campaigns and six counterfactual strategies. Results The model estimated that the autumn 2022/spring 2023 booster campaign resulted in a reduction of 18,921 hospitalizations and 1463 deaths, compared with a no booster scenario. Utilization of hospital bed days due to COVID-19 decreased after the autumn 2022/spring 2023 booster campaign. Expanding the booster eligibility criteria and improving uptake improved all outcomes, including averting twice as many ICU admissions, preventing more than 20% additional deaths, and a sevenfold reduction in long COVID, compared with the autumn 2022/spring 2023 booster campaign. The number of productive days lost was reduced by fivefold indicating that vaccinating a wider population has a beneficial impact on the morbidities associated with COVID-19. Conclusion Our modelling demonstrates that the autumn 2022/spring 2023 booster campaign reduced COVID-19-associated morbidity and mortality. Booster campaigns with alternative eligibility criteria warrant consideration in the UK, given their potential to further reduce morbidity and mortality as future variants emerge.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 has continuously evolved, requiring the development of adapted vaccines. This study estimated the impact of the introduction and increased coverage of an Omicron-adapted bivalent booster vaccine in Thailand. Research Design and Methods The outcomes of booster vaccination with an Omicron-adapted bivalent vaccine versus no booster vaccination were estimated using a combined cohort Markov decision tree model. The population was stratified into high- and standard-risk subpopulations. Using age-specific inputs informed by published sources, the model estimated health (case numbers, hospitalizations, and deaths) and economic (medical costs and productivity losses) outcomes in different age and risk subpopulations. Results Booster vaccination in only the elderly and high-risk subpopulation was estimated to avert 97,596 cases 36,578 hospitalizations, 903 deaths, THB 3,119 million in direct medical costs, and THB 10,589 million in indirect medical costs. These benefits increased as vaccination was expanded to other subpopulations. Increasing the booster vaccination coverage to 75% of the standard-risk population averted more deaths (95%), hospitalizations (512%), infections (782%), direct costs (550%), and indirect costs (687%) compared to the base case. Conclusions Broader vaccination with an Omicron-adapted bivalent booster vaccine could have significant public health and economic benefits in Thailand.

Background We aimed to estimate the public health impact of booster vaccination against COVID-19 in the UK during an Omicron-predominant period. Research design and methods A dynamic transmission model was developed to compare public health outcomes for actual and alternative UK booster vaccination programs. Input sources were publicly available data and targeted literature reviews. Base case analyses estimated outcomes from the UK’s Autumn–Winter 2021–2022 booster program during January–March 2022, an Omicron-predominant period. Scenario analyses projected outcomes from Spring and in Autumn 2022 booster programs over an extended time horizon from April 2022–April 2023, assuming continued Omicron predominance, and explored hypothetical program alternatives with modified eligibility criteria and/or increased uptake. Results Estimates predicted that the Autumn–Winter 2021–2022 booster program averted approximately 12.8 million cases, 1.1 million hospitalizations, and 290,000 deaths. Scenario analyses suggested that Spring and Autumn 2022 programs would avert approximately 6.2 million cases, 716,000 hospitalizations, and 125,000 deaths; alternatives extending eligibility or targeting risk groups would improve these benefits, and increasing uptake would further strengthen impact. Conclusions Boosters were estimated to provide substantial benefit to UK public health during Omicron predominance. Benefits of booster vaccination could be maximized by extending eligibility and increasing uptake.

Background Limited data are available describing the global impact of COVID-19 vaccines. This study estimated the global public health and economic impact of COVID-19 vaccines before the emergence of the Omicron variant. Methods A static model covering 215 countries/territories compared the direct effects of COVID-19 vaccination to no vaccination during 13 December 2020–30 September 2021. After adjusting for underreporting of cases and deaths, base case analyses estimated total cases and deaths averted, and direct outpatient and productivity costs saved through averted health outcomes. Sensitivity analyses applied alternative model assumptions. Results COVID-19 vaccines prevented an estimated median (IQR) of 151.7 (133.7–226.1) million cases and 620.5 (411.1–698.1) thousand deaths globally through September 2021. In sensitivity analysis applying an alternative underreporting assumption, median deaths averted were 2.1 million. Estimated direct outpatient cost savings were $21.2 ($18.9–30.9) billion and indirect savings of avoided productivity loss were $135.1 ($121.1–206.4) billion, yielding a total cost savings of $155 billion globally through averted infections. Conclusions Using a conservative modeling approach that considered direct effects only, we estimated that COVID-19 vaccines have averted millions of infections and deaths, generating billions of cost savings worldwide, which underscore the continued importance of vaccination in public health response to COVID-19.

Background Coronavirus disease 2019 (COVID-19) case numbers have increased following the emergence of the Omicron variant. This study estimated the impact of introducing and increasing the coverage of an Omicron-adapted bivalent booster vaccine in Malaysia. Research Design and Methods A combined cohort Markov decision tree model was used to compare booster vaccination with an Omicron-adapted bivalent COVID-19 vaccine versus no booster vaccination in Malaysia. The model utilized age-specific data from January 2021 to March 2022 derived from published sources. The outcomes of interest included case numbers, hospitalizations, deaths, medical costs, and productivity losses. The population was stratified into high-risk and standard-risk subpopulations, and the study evaluated the benefits of increased coverage in different age and risk groups. Results Vaccinating only high-risk individuals and those aged ≥ 65 years was estimated to avert 274,313 cases, 33229 hospitalizations, 2,434 deaths, Malaysian ringgit (MYR) 576 million in direct medical costs, and MYR 579 million in indirect costs. Expanding vaccination coverage in the standard-risk population to 75% was estimated to avert more deaths (31%), hospitalizations (155%), infections (206%), direct costs (206%), and indirect costs (281%). Conclusions These findings support broader population Omicron-adapted bivalent booster vaccination in Malaysia with potential for significant health and economic gains.

The segmentation of fundus tumors is critical for ophthalmic diagnosis and treatment, yet it presents unique challenges due to the variability in lesion size and shape. Our study introduces Fundus Tumor Segmentation Network (FTSNet), a novel segmentation network designed to address these challenges by leveraging classification results and prompt learning. Our key innovation is the multiscale feature extractor and the dynamic prompt head. Multiscale feature extractors are proficient in eliciting a spectrum of feature information from the original image across disparate scales. This proficiency is fundamental for deciphering the subtle details and patterns embedded in the image at multiple levels of granularity. Meanwhile, a dynamic prompt head is engineered to engender bespoke segmentation heads for each image, customizing the segmentation process to align with the distinctive attributes of the image under consideration. We also present the Fundus Tumor Segmentation (FTS) dataset, comprising 254 pairs of fundus images with tumor lesions and reference segmentations. Experiments demonstrate FTSNet’s superior performance over existing methods, achieving a mean Intersection over Union (mIoU) of 0.8254 and mean Dice (mDice) of 0.9042. The results highlight the potential of our approach in advancing the accuracy and efficiency of fundus tumor segmentation.

Vaccination against infectious disease affords direct protection from vaccine-induced immunity and additional indirect protection for unvaccinated persons. A systematic review was conducted to estimate the indirect effect of COVID-19 vaccination. From PubMed and Embase, 31 studies were included describing the impact of original wild-type COVID-19 vaccines on disease transmission or viral load. Overall, study results showed the effectiveness of COVID-19 vaccination against SARS-CoV-2 transmission (range 16–95%), regardless of vaccine type or number of doses. The effect was apparent, but less pronounced against omicron (range 24–95% for pre-omicron variants versus 16–31% for omicron). Results from viral load studies were supportive, showing SARS-CoV-2 infections in vaccinated individuals had higher Ct values, suggesting lower viral load, compared to infections among the unvaccinated. Based on these findings, well-timed vaccination programs may help reduce SARS-CoV-2 transmission—even in the omicron era. Whether better-matched vaccines can improve effectiveness against transmission in the omicron era needs further study.

Methods Medline, EMBASE and the Cochrane Library were searched and supplemented with conference and grey literature searches. Eligible studies included individuals with (1) PCC or (2) a positive SARS-CoV-2 test or COVID-19 diagnosis who were followed over time. Included studies were published in English between 1 January 2020 and 14 November 2022.Findings Of 291 publications included, 175 (60%) followed individuals with confirmed COVID-19 over time for PCC and 116 (40%) used a prespecified PCC definition. There was substantial heterogeneity in study design, geography, age group, PCC conditions/symptoms assessed and their classification and duration of follow-up. Among studies using a prespecified PCC definition, author-defined criteria (51%) were more common than criteria recommended by major public health organisations (19%). Measurement periods for PCC outcomes from date of acute COVID-19 test were primarily 3 to

Objective To create case definitions for confirmed COVID-19 diagnoses, COVID-19 vaccination status and three separate definitions of high risk of severe COVID-19, as well as to assess whether the implementation of these definitions in a cohort reflected the sociodemographic and clinical characteristics of COVID-19 epidemiology in England.Design Retrospective cohort study.Setting Electronic healthcare records from primary care (Clinical Practice Research Datalink, CPRD) linked to secondary care data (Hospital Episode Statistics) data covering 24% of the population in England.Participants 2 271 072 persons aged 1 year and older diagnosed with COVID-19 in CPRD Aurum between 1 August 2020 and 31 January 2022.Main outcome measures Age, sex and regional distribution of COVID-19 cases and COVID-19 vaccine doses received prior to diagnosis were assessed separately for the cohorts of cases identified in primary care and those hospitalised for COVID-19 (primary diagnosis code of ICD-10 U07.1 ‘COVID-19’). Smoking status, body mass index and Charlson Comorbidity Index were compared for the two cohorts, as well as for three separate definitions of high risk of severe disease used in the UK (National Health Service Highest Risk, PANORAMIC trial eligibility, UK Health Security Agency Clinical Risk prioritisation for vaccination).Results Compared with national estimates, CPRD case estimates under-represented older adults in both the primary care (age 65–84: 6% in CPRD vs 9% nationally) and hospitalised (31% vs 40%) cohorts, and over-represented people living in regions with the highest median wealth areas of England (20% primary care and 20% hospital admitted cases in South East vs 15% nationally). The majority of non-hospitalised cases and all hospitalised cases had not completed primary series vaccination. In primary care, persons meeting high-risk definitions were older, more often smokers, overweight or obese, and had higher Charlson Comorbidity Index score.Conclusions CPRD primary care data are a robust real-world data source and can be used for some COVID-19 research questions, however, limitations of the data availability should be carefully considered. Included in this publication are supplemental files for a total of over 28 000 codes to define each of three definitions of high risk of severe disease.

Objectives To quantify direct costs and healthcare resource utilisation (HCRU) associated with acute COVID-19 in adults in England.Design Population-based retrospective cohort study using Clinical Practice Research Datalink Aurum primary care electronic medical records linked to Hospital Episode Statistics secondary care administrative data.Setting Patients registered to primary care practices in England.Population 1 706 368 adults with a positive SARS-CoV-2 PCR or antigen test from August 2020 to January 2022 were included; 13 105 within the hospitalised cohort indexed between August 2020 and March 2021, and 1 693 263 within the primary care cohort indexed between August 2020 and January 2022. Patients with a COVID-19-related hospitalisation within 84 days of a positive test were included in the hospitalised cohort.Main outcome measures Primary and secondary care HCRU and associated costs ≤4 weeks following positive COVID-19 test, stratified by age group, risk of severe COVID-19 and immunocompromised status.Results Among the hospitalised cohort, average length of stay, including critical care stays, was longer in older adults. Median healthcare cost per hospitalisation was higher in those aged 75–84 (£8942) and ≥85 years (£8835) than in those aged

Abstract Background To evaluate the prevalence and associated health and lifestyle factors of myopic maculopathy (MM) in a northern Chinese industrial city. Methods The cross-sectional Kailuan Eye Study included subjects who participated in the longitudinal Kailuan Study in 2016. Ophthalmologic and general examinations were performed on all the participants. MM was graded based on fundus photographs using the International Photographic Classification and Grading System. The prevalence of MM was evaluated. Univariate and multiple logistic regression were adopted to evaluated risk factors of MM. Results The study included 8330 participants with gradable fundus photographs for MM and ocular biometry data. The prevalence of MM was 1.11% (93/8330; 95% confidence interval [CI] 0.89–1.33%). Diffuse chorioretinal atrophy, patchy chorioretinal atrophy, macular atrophy, and plus lesions were observed in 72 (0.9%), 15 (0.2%), 6 (0.007%), and 32 eyes (0.4%), respectively. MM was more common in eyes with longer axial length (OR 4.517; 95%CI 3.273 to 6.235) and in participants with hypertension (OR 3.460; 95%CI 1.152 to 10.391), and older age (OR 1.084; 95%CI 1.036 to 1.134). Conclusions The MM was present in 1.11% of the northern Chinese individuals 21 years or older and the associate factors include longer axial length, older age, and hypertension.

IntroductionEpidemiological modeling is widely used to offer insights into the COVID-19 pandemic situation in Asia. We reviewed published computational (mathematical/simulation) models conducted in Asia that assessed impacts of pharmacological and non-pharmacological interventions against COVID-19 and their implications for vaccination strategy.MethodsA search of the PubMed database for peer-reviewed, published, and accessible articles in English was performed up to November 2022 to capture studies in Asian populations based on computational modeling of outcomes in the COVID-19 pandemic. Extracted data included model type (mechanistic compartmental/agent-based, statistical, both), intervention type (pharmacological, non-pharmacological), and procedures for parameterizing age. Findings are summarized with descriptive statistics and discussed in terms of the evolving COVID-19 situation.ResultsThe literature search identified 378 results, of which 59 met criteria for data extraction. China, Japan, and South Korea accounted for approximately half of studies, with fewer from South and South-East Asia. Mechanistic models were most common, either compartmental (61.0%), agent-based (1.7%), or combination (18.6%) models. Statistical modeling was applied less frequently (11.9%). Pharmacological interventions were examined in 59.3% of studies, and most considered vaccination, except one study of an antiviral treatment. Non-pharmacological interventions were also considered in 84.7% of studies. Infection, hospitalization, and mortality were outcomes in 91.5%, 30.5%, and 30.5% of studies, respectively. Approximately a third of studies accounted for age, including 10 that also examined mortality. Four of these studies emphasized benefits in terms of mortality from prioritizing older adults for vaccination under conditions of a limited supply; however, one study noted potential benefits to infection rates from early vaccination of younger adults. Few studies (5.1%) considered the impact of vaccination among children.ConclusionEarly in the COVID-19 pandemic, non-pharmacological interventions helped to mitigate the health burden of COVID-19; however, modeling indicates that high population coverage of effective vaccines will complement and reduce reliance on such interventions. Thus, increasing and maintaining immunity levels in populations through regular booster shots, particularly among at-risk and vulnerable groups, including older adults, might help to protect public health. Future modeling efforts should consider new vaccines and alternative therapies alongside an evolving virus in populations with varied vaccination histories.

Abstract Background For patients with malignant limb tumors, salvage surgery can be achieved using endoprosthesis or biological reconstructions like allograft or autograft. In carefully selected patients, resected bone can be recycled after sterilization using methods like autoclaving, irradiation, pasteurization or freezing with liquid nitrogen. We evaluated the clinical outcome and complications of malignant limb tumors treated with intercalary resection and frozen autograft reconstruction. Methods We reviewed 33 patients whose malignant bone tumors were treated by wide resection and reconstruction with recycling liquid nitrogen-treated autografts between 2006 and 2017. Limb function, bone union at the osteotomy site and complications were evaluated. Functional outcome was assessed using the Musculoskeletal Tumor Society (MSTS) scoring system. Results The cohort comprised 16 males and 17 females, with a mean age of 35.4 years (14–76 years). The most common tumor was osteosarcoma (7 cases). Tumors were located in the humerus (5), ulna (1), femur (10) and tibia (17). The mean follow-up was 49.9 months (range 12–127 months). Of the 33 patients, 16 remained disease-free, and 3 were alive with disease. The mean size of the defect after tumor resection was 11.6 cm (range 6–25 cm). Bone union was achieved in 32 patients, with a mean union time of 8.8 months (range 4–18 months). Complications included 1 graft nonunion, 2 infections (1 superficial, 1 deep infection), 1 leg length discrepancy, 2 graft fractures and 3 local recurrences. The mean MSTS score was 87.2% (range 70–100%). Conclusion Liquid nitrogen-treated tumor-bearing autograft is an effective option for biological reconstruction after meta-/diaphyseal tumor resection of long bones. This method has excellent clinical outcomes and is especially recommended for patients with no severe osteolytic bone tumors.

Objective: This study aims to evaluate the surgical morbidity and obstetric outcomes following in-pregnancy or pre-pregnancy laparoscopic abdominal cerclage (LAC) for patients who were diagnosed with refractory cervical insufficiency or had a short cervix. Methods: A retrospective study was conducted on patients undergoing LAC between May 2017 and May 2019 at the Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital. The patients were diagnosed with refractory cervical insufficiency based upon a previous failed transvaginal cervical cerclage (TVC), or had a short cervix who were considered unsuitable for a TVC after a previous cervical procedure. All patients were followed-up after surgery with transperineal ultrasonography until May 2020. Subsequently, surgical and obstetric data were collected and analyzed. Results: In total, 44 patients underwent LAC, with 8 patients in-pregnancy and 36 pre-pregnancy. For the patient with pre-pregancy LAC, the pregnancy rate was 80.6% (29/36), including 3 patients with first-trimester loss, 1 patient with an ectopic pregnancy, and 25 patients with a delivery. For the remaining 7 patients, 3 did not conceive, and another 4 had no pregnancy plans. All the patients with in-pregnancy LAC had a delivery. The “take-home baby” rate was 89.2% (33/37), with a live-birth rate of 100% and a neonatal survival rate of 100% for both patients with in-pregnancy and pre-pregnancy LAC. For patients with in-pregnancy LAC, 75.0% (6/8) patients delivered at ≥37 wk of gestation, 12.5% (1/8) delivered between 34 and 36+6 wk, and 12.5% (1/8) delivered between 28 and 33+6 wk. For patients with pre-pregnancy LAC, 80.0% (20/25) patients delivered at ≥37 wk of gestation, 16.0% (4/25) delivered between 34 and 36+6 wk, and 4.0% (1/25) delivered between 28 and 33+6 wk. No adverse-event intra-operative or post-operative sequelae were noted. Conclusions: LAC is an effective and safe procedure that results in remarkable obstetric outcomes for women with refractory cervical insufficiency, or with a short cervix who are considered unsuitable for a TVC. The success rate of in-pregnancy or pre-pregnancy LAC depends on a full evaluation of patients, a proper peri-operative management and close follow-up.

Abstract Breast cancer is the most common malignancy among women across the globe. Recent studies have revealed that many long non-coding RNAs (lncRNAs) regulate the Wnt/β-catenin signaling pathway in several types of cancer. Hyperactivation of the Wnt/β-catenin pathway has been extensively presented in breast cancer and is involved in breast cancer progression. However, the underlying molecular mechanism remains elusive. In the current study, we found lncRNA RBM5-AS1 was remarkably upregulated in breast cancer cells and tissues. Overexpression of RBM5-AS1 facilitated proliferation, migration, invasion, EMT, and stemness maintenance of breast cancer cells in vitro and in vivo. Mechanism studies suggested that RBM5-AS1 could be transcriptionally activated by hypoxia-induced RUNX2. Upregulated RBM5-AS1 further activated the Wnt/β-catenin signaling by preventing β-catenin degradation and by helping organize β-catenin-TCF4 transcriptional complex. These findings suggested that RBM5-AS1, a regulator of Wnt/β-catenin signaling, plays a vital role in breast cancer initiation and progression, implicating its potential as a new target for breast cancer treatment.

Abstract Background Pancreatic cancer (PC) is one of the most lethal cancer types with high degree of malignancy and poor prognosis. Recent studies have shown that long non-coding RNAs (lncRNAs) were associated with the initiation and progression of pancreatic cancer. In the current study, we have investigated the expression, biological function and mechanism of a lncRNA CTD-3252C9.4 in pancreatic cancer. Methods The expression of CTD-3252C9.4 in pancreatic cancer cells and tissues was measured by qRT-PCR. In vitro and in vivo functional experiments assays were implemented for identifying CTD-3252C9.4 function in pancreatic cancer. Molecular relationships among CTD-3252C9.4, IRF1 and IFI6 were investigated via luciferase reporter assay, pulldown assay and ChIP assays. Results CTD-3252C9.4 was found remarkably decreased in pancreatic cancer cells and tissues. Overexpression of CTD-3252C9.4 suppressed migration, invasion and proliferation, yet facilitated apoptosis of pancreatic cancer cells both in vitro and in vivo. Then, IFI6 was identified as a downstream target that could be down-regulated by CTD-3252C9.4 and IFI6 overexpression could counteract the effects of CTD-3252C9.4 upregulation on the survival and apoptosis of pancreatic cancer cells. Furthermore, mechanism experiments revealed that IRF1 was a transcriptional factor of IFI6 that can be blocked by CTD-3252C9.4 to inhibit IFI6 transcription. Conclusion Our data indicated that CTD-3252C9.4 could promote pancreatic cancer cell apoptosis and restrain cell growth via binding IRF1 and preventing the transcription of IFI6, which may become a potential therapeutic target for pancreatic cancer.

Abstract Ophiocordyceps sinensis has been a source of valuable materials in traditional Asian medicine for over two thousand years. With recent global warming and overharvest, however, the availability of these wild fungi has decreased dramatically. While fruiting body of O. sinensis has been artificially cultivated, the molecular mechanisms that govern the induction of fruiting body at the transcriptional and post-transcriptional levels are unclear. In this study, we carried out both mRNA and small RNA sequencing to identify crucial genes and miRNA-like RNAs (milRNAs) involved in the development of fruiting body. A total of 2875 differentially expressed genes (DEGs), and 71 differentially expressed milRNAs (DEMs) were identified among the mycoparasite complex, the sclerotium (ST) and the fruiting body stage. Functional enrichment and Gene Set Enrichment Analysis indicated that the ST had increased oxidative stress and energy metabolism and that mitogen-activated protein kinase signaling might induce the formation of fruiting body. Integrated analysis of DEGs and DEMs revealed that n_os_milR16, n_os_milR21, n_os_milR34, and n_os_milR90 could be candidate milRNAs that regulate the induction of fruiting body. This study provides transcriptome-wide insight into the molecular basis of fruiting body formation in O. Sinensis and identifies potential candidate genes for improving induction rate.

There are few reports of the successful delivery of unicornuate uterus pregnancy after laparoscopic cervical cerclage. Here, we report a 32-year-old woman, gravida 2 para 1, who had been admitted for unicornuate uterus pregnancy by a thawed frozen blastocyst transplantation. She accepted laparoscopic cervical cerclage for cervical insufficiency and delivered successfully via caesarean section at 35+3 weeks. Cervical cerclage may be used as an effective method of preventing abortion in unicornuate uterus pregnancy, while surgery by laparoscopy would be a better choice for patients with poor cervical condition. Obstetricians should pay due attention to complications such as uterine rupture for these high-risk patients.

Introduction The COVID-19 pandemic has created a huge social and economic burden, and the lifestyles of individuals have significantly changed. In addition, the diagnosis, treatment and management of patients with cancer were greatly affected. Studies have shown that patients with cancer are at a higher risk of COVID-19 infection-related complications, which require aggressive preventive measures. Different types of cancer may have different risks of COVID-19 infection and death, and different preventive care measures are needed for different types of patients with cancer. Here, we designed a protocol for systematic review and meta-analysis to explore the impact of cancer types on COVID-19 infection and mortality risk.Methods and analysis A systematic search plan will be performed to filter the eligible studies in the seven databases, namely PubMed, Cochrane search strategy, EMBASE search strategy, SinoMed, China National Knowledge Infrastructure, China Science and Technology Journals Database, and Wanfang database from 2019 to 10 August 2021. Two independent reviewers will choose the eligible studies and extract the data. The risk of bias will be evaluated based on the Newcastle-Ottawa Scale recommended by the Cochrane Collaboration. Finally, a systematic review and meta-analysis will be performed using Review Manager (V.5.3) statistical software.Ethics and dissemination Formal ethical approval is not required, and the findings will be published in a peer-reviewed journal.PROSPERO registration number CRD42021271108.

Objective Circulating tumor cells (CTCs) as novel biomarkers are widely investigated in various cancers, although most of the literature shows that CTCs have predictive value for recurrence, metastasis, and prognosis after CRC surgery, results remain controversial. We aimed to systematically evaluate the value of CTCs in monitoring of colorectal cancer (CRC) recurrence and metastasis after surgery. Method The PubMed, Cochrane Library, Embase, and other databases were searched from the establishment of the database to May 27, 2021. Relevant literature searches and data extraction were performed independently by two reviewers. The quality assessment was performed using the QUADAS2 scale developed by the Cochrane collaboration. The heterogeneity was checked using the Spearman correlation coefficient and the Cochran-Q test in the Meta-Disc1.4 software. Subgroup analysis was used to explore the source of heterogeneity. Considering that all the included papers were clinical studies with clinical heterogeneity, random effect model was adopted for analysis. And the sensitivity (Sen), specificity (Spe), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curves of CTCs, in monitoring recurrence and metastasis after CRC, were calculated. The publication bias of the included studies was assessed using Deek’s funnel figure. Result The literature included a total of 13 articles, comprising 1788 cases, and the overall quality of the literature was high. After summing up the indicators, the sensitivity pooled-value of the peripheral blood CTCs to monitor the recurrence and metastasis value of CRC after CRC was 0.67 [95%CI (0.62, 0.71)], specificity pooled-value was 0.71 [95%CI (0.67, 0.72)], PLR pooled-value was 2.37 [95%CI [1.52, 3.71]), NLR pooled into 0.53 [95%CI (0.36, 0.78)], DOR pooled into 4.97 [95%CI (2.11, 11.72)], AUC was 0.7395. Conclusion Peripheral blood CTCs have a moderate monitoring value for recurrence and metastasis after CRC; CTCs detected one week after surgery may be more correlated with recurrence and metastasis.

Health technology assessments (HTAs) of vaccines typically focus on the direct health benefits to individuals and healthcare systems. COVID-19 highlighted the widespread societal impact of infectious diseases and the value of vaccines in averting adverse clinical consequences and in maintaining or resuming social and economic activities. Using COVID-19 as a case study, this research work aimed to set forth a conceptual framework capturing the broader value elements of vaccines and to identify appropriate methods to quantify value elements not routinely considered in HTAs. A two-step approach was adopted, combining a targeted literature review and three rounds of expert elicitation based on a modified Delphi method, leading to a conceptual framework of 30 value elements related to broader health effects, societal and economic impact, public finances, and uncertainty value. When applying the framework to COVID-19 vaccines in post-pandemic settings, 13 value elements were consensually rated highly important by the experts for consideration in HTAs. The experts reviewed over 10 methods that could be leveraged to quantify broader value elements and provided technical forward-looking recommendations. Limitations of the framework and the identified methods were discussed. This study supplements ongoing efforts aimed towards a broader recognition of the full societal value of vaccines.

Native dental pulp extracellular matrix (DPEM) has proven to be an effective biomaterial for dental pulp regeneration. However, as a significant extracellular matrix glycoprotein, partial laminins were lost during the decellularization process, which were essential for odontoblast differentiation. Thereby, this study investigated the feasibility of LN supplementation to improve the surface of DPEM for odontoblast layer regeneration. The influences of laminin on cell adhesion and odontogenic differentiation were evaluated in vitro. Then, we fabricated laminin-modified DPEM based on the physical coating strategy and observed the location and persistency of laminin coating by immunofluorescent staining. Finally, laminin-modified DPEM combined with treated dentin matrix (TDM) was transplanted in orthotopic jaw bone of beagles (n = 3) to assess the effect of LNs on dental pulp tissue regeneration. The in vitro results showed that laminins could improve the adhesion of dental pulp stem cells (DPSCs) and promoted DPSCs toward odontogenic differentiation. Continuous odontoblastic layer-like structure was observed in laminin-modified DPEM group, expressing the markers for odontoblastogenesis, dentine matrix protein-1 (DMP-1) and dentin sialophosphoprotein (DSPP). Overall, these studies demonstrate that the supplementation of laminins to DPEM contributes to the odontogenic differentiation of cells and to the formation of odontoblast layer in dental pulp regeneration.

Background/Aims: Dysbiosis of the intestinal microbiota may accelerate the progression of chronic kidney disease (CKD) by increasing the levels of urea toxins. In recent years, probiotics have been recognized to maintain the physiological balance of the intestinal microbiota. In this study, we aim to assess the therapeutic effects of probiotics on CKD patients with and without dialysis via meta-analysis. Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) by searching the databases of Pubmed, EMBASE and Cochrane Library (No. CRD42018093080). Studies on probiotics for treatment of CKD adults lasting for at least 4 weeks were selected. The primary outcomes were the levels of urea toxins, and the second outcomes were the levels of interleukin (IL)-6, C-reactive protein (CRP) and hemoglobin (Hb). The risk of bias was assessed by Cochrane Collaboration’ tool, and the quality of evidence was appraised with the Grading of Recommendation Assessment. Means and standard deviations were analyzed by random effects analysis. Stratified analysis was done and sensitivity analysis was performed when appropriate. Results: Totally, eight studies with 261 patients at CKD stage 3 to 5 with and without dialysis were included. We found a decrease of p-cresyl sulfate (PCS) of 3 studies with 125 subjects (P = 0.01, SMD -0.57, 95% CI, -0.99 to -0.14, I2 = 25%) and an increase of IL-6 in 3 studies with 134 subjects (P = 0.03, 95% CI, SMD 0.37, 0.03 to 0.72, I2 = 0%) in the probiotics groups. Analysis of serum creatinine (P = 0.47), blood urine nitrogen (P = 0.73), CRP (P = 0.55) and Hb (P = 0.49) yielded insignificant difference. Conclusion: Limited number of studies and small sample size are limitations of our study. Probiotics supplementation may reduce the levels of PCS and elevate the levels of IL-6 whereby protecting the intestinal epithelial barrier of patients with CKD.

Aim: To compare air nicotine levels in public places in Ahmedabad, India, before (June 2008) and after (January, 2010) the implementation of a comprehensive smoking ban which was introduced in October 2008. Materials and Methods: Air nicotine concentrations were measured by sampling of vapor-phase nicotine using passive monitors. In 2008 (baseline), monitors were placed for 5-7 working days in 5 hospitals, 10 restaurants, 5 schools, 5 government buildings, and 10 entertainment venues, of which 6 were hookah bars. In 2010 (follow-up), monitors were placed in 35 similar venues for the same duration. Results: Comparison of the overall median nicotine concentration at baseline (2008) (0.06 μg/m 3 Interquartile range (IQR): 0.02-0.22) to that of follow-up (2010) (0.03 μg/m 3 IQR: 0.00-0.13), reflects a significant decline (% decline = 39.7, P = 0.012) in exposure to second-hand smoke (SHS). The percent change in exposure varied by venue-type. The most significant decrease occurred in hospitals, from 0.04 μg/m [3] at baseline to concentrations under the limit of detection at follow-up (%decline = 100, P < 0.001). In entertainment venues, government offices, and restaurants, decreases in SHS exposure also appeared evident. However, in hookah bars, air nicotine levels appeared to increase (P = 0.160). Conclusion: Overall, SHS exposure was significantly reduced in public places after the smoke-free legislation came into force. However, nicotine concentrations were still detected in most of the venues indicating imperfect compliance with the comprehensive ban.

BackgroundUnlike many other central nervous system (CNS) tumors, the surgical management of primary central nervous system lymphomas (PCNSL) is traditionally limited by diagnostic biopsy. Studies that predate the use of modern neurosurgical techniques have reported a prohibitive operative morbidity for this surgery. These early experiences have dictated the non-surgical management of PCNSL, whereas resection for cytoreduction is a mainstay of treatment in other CNS malignancies. Recent studies have suggested that craniotomy with the goal of cytoreduction might be associated with a favorable overall and progression-free survival for some patients with PCNSL. To challenge the traditional non-surgical paradigm, it is essential to first investigate the safety of resection for PCNSL.MethodsTo determine the operative morbidity of resection for this disease, we performed a population-based assessment of complications using the nationwide inpatient sample database for the years 1998–2013 for biopsies and open craniotomies for PCNSL and other brain tumors.ResultsAmong 95 patients who underwent biopsy and 34 patients who underwent craniotomy, we found no significant difference in complication rates between craniotomy for resection and biopsy procedures for PCNSL (23.16 versus 20.59%). The types of complications differ between diagnoses, with the PCNSL cohort suffering mainly medical complications and the non-PCNSL cohort suffering mainly from neurological complications.ConclusionThese findings support the safety of craniotomies in PCNSL and help provide a rationale for future prospective studies to evaluate the safety and efficacy of resection for this disease.

Comparative genome analyses have revealed a number of regions of difference (RD) among mycobacterial species. The functional consequences of most of these genome variations have not been studied. RD4, which encompasses Rv1506c-Rv1516c of Mycobacterium tuberculosis (M. tb) H37Rv, is absent in the closely related Mycobacterium bovis and M. bovis Bacille Calmette-Guérin (BCG). On the other hand, we previously found that Mycobacterium marinum has an extended RD4 which includes a number of genes involved in the biosynthesis of lipooligosaccharides (LOSs). As such, there appears to be a gradual decay of RD4 in mycobacterial genomes in the order of M. marinum, M. tb, and M. bovis (including BCG). To understand the potential effect of RD4 on mycobacterial virulence, in this study, we cloned the entire (Rv1501–1516c) and partial (Rv1501–1508c) RD4 into an integrating vector. These constructs were introduced to M. bovis BCG and M. marinum and the virulence of the RD4 knock-in strains were evaluated in the SCID mice and zebrafish infection models, respectively. BCG containing the entire RD4 exhibited similar levels of virulence to the parental strain but BCG containing partial RD4 (Rv1501–Rv1508c) was more attenuated. Similarly, zebrafish infection experiments showed that addition of partial RD4 also appeared to attenuate the virulence of M. marinum. However, M. marinum containing entire RD4 was more virulent than the wild type strain. Interestingly, BCG strains containing the entire or partial RD4 exhibited better protection of zebrafish against M. marinum challenge than the parental BCG. Taken together, our data suggest that RD4 plays a role in mycobacterial virulence and that RD4 knock-in BCG strains confer improved protection. Our study has provided new insights into the biological function of RD4 and evolution of mycobacterial genomes.

Objective. The lung allocation score (LAS) resulted in a lung transplantation (LT) selection process guided by clinical acuity. We sought to evaluate the relationship between LAS and outcomes. Methods. We analyzed Scientific Registry of Transplant Recipient (SRTR) data pertaining to recipients between 2005 and 2012. We stratified them into quartiles based on LAS and compared survival and predictors of mortality. Results. We identified 10,304 consecutive patients, comprising 2,576 in each LAS quartile (quartile 1 (26.3–35.5), quartile 2 (35.6–39.3), quartile 3 (39.4–48.6), and quartile 4 (48.7–95.7)). Survival after 30 days (96.9% versus 96.8% versus 96.0% versus 94.8%), 90 days (94.6% versus 93.7% versus 93.3% versus 90.9%), 1 year (87.2% versus 85.0% versus 84.8% versus 80.9%), and 5 years (55.4% versus 54.5% versus 52.5% versus 48.8%) was higher in the lower groups. There was a significantly higher 5-year mortality in the highest LAS group (HR 1.13, p=0.030, HR 1.17, p=0.01, and HR 1.17, p=0.02) comparing quartiles 2, 3, and 4, respectively, to quartile 1. Conclusion. Overall, outcomes in recipients with higher LAS are worse than those in patients with lower LAS. These data should inform more individualized evidence-based discussion during pretransplant counseling.

Objective: The aim of the study is to estimate COVID-19 absenteeism and indirect costs, by care setting. Methods: A population-based retrospective cohort study using data from the German Statutory Health Insurance (SHI) database to define outpatient (April 2020-December 2021) and hospitalized (April 2020-October 2022) cohorts of employed working-aged individuals. Results: In the outpatient cohort (N = 369,220), median absenteeism duration and associated cost was 10.0 (Q1, Q3: 5.0, 15.0) days and €1061 (530, 1591), respectively. In the hospitalized cohort (n = 20,687), median absenteeism and associated cost was 15.0 (7.0, 32.0) days and €1591 (743, 3394), respectively. Stratified analyses showed greater absenteeism in older workers, those at risk, and those with severe disease. Conclusions: The hospitalized cohort had longer absenteeism resulting in higher productivity loss. Being older, at risk of severe COVID-19 and higher disease severity during hospitalization were important drivers of higher absenteeism duration. [ABSTRACT FROM AUTHOR]