Suppression of the alpha, delta, and omicron variants of SARS-Cov-2 in Taiwan.

BACKGROUND: Taiwan was a coronavirus disease 2019 (COVID-19) outlier, with an extraordinarily long transmission-free record: 253 days without locally transmitted infections while the rest of the world battled wave after wave of infection. The appearance of the alpha variant in May 2021, closely followed by the delta variant, disrupted this transmission-free streak. However, despite low vaccination coverage (<1%), outbreaks were well-controlled. METHODS: This study analyzed the time to border closure and conducted one-sample t test to compare between Taiwan and Non-Taiwan countries prior to vaccine introduction. The study also collected case data to observe the dynamics of omicron transmission. Time-varying reproduction number,Rt, was calculated and was used to reflect infection impact at specified time points and model trends of future incidence. RESULTS: The study analyzed and compare the time to border closure in Taiwan and non-Taiwan countries. The mean times to any border closure from the first domestic case within each country were -21 and 5.98 days, respectively (P < .0001). The Taiwanese government invested in quick and effective contact tracing with a precise quarantine strategy in lieu of a strict lockdown. Residents followed recommendations based on self-discipline and unity. The self-discipline in action is evidenced in Google mobility reports. The central and local governments worked together to enact non-pharmaceutical interventions (NPIs), including universal masking, social distancing, limited unnecessary gatherings, systematic contact tracing, and enhanced quarantine measures. The people cooperated actively with pandemic-prevention regulations, including vaccination and preventive NPIs. CONCLUSIONS: This article describes four key factors underlying Taiwan's success in controlling COVID-19 transmission: quick responses; effective control measures with new technologies and rolling knowledge updates; unity and cooperation among Taiwanese government agencies, private companies and organizations, and individual citizens; and Taiwanese self-discipline.

Kaposi sarcoma herpesvirus/human herpesvirus 8-positive diffuse large B-cell lymphoma characterized by malignant ascites: A case report.

Herein, we report a rare case of Kaposi sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8)-positive diffuse large B-cell lymphoma (DLBCL), which is characterized by malignant ascites and complex karyotypes. A 72-year-old male patient who tested negative for human immunodeficiency virus presented with thrombocytopenia and lymphadenopathies. He was diagnosed with KSHV/HHV8-associated multicentric Castleman disease (MCD). After three years, he developed progressive lymphadenopathies and massive ascites. The lymphoma cells in the ascitic fluid presented with characteristic immunophenotype and monoclonality, which support the diagnosis of KSHV/HHV8-positive DLBCL. Lymphadenopathies and massive splenomegaly are common manifestations of KSHV/HHV8-positive DLBCL. Nevertheless, peritoneal involvement, as observed in this case, is a rare presentation. This emphasizes the diagnostic complexities of KSHV/HHV8-associated lymphoproliferative disorders. Within the context of preexisting KSHV/HHV8-associated multicentric Castleman disease, the differential diagnosis of this disorder can be challenging.

Tight junction protein cingulin variant is associated with cancer susceptibility by overexpressed IQGAP1 and Rac1-dependent epithelial-mesenchymal transition.

BACKGROUND: Cingulin (CGN) is a pivotal cytoskeletal adaptor protein located at tight junctions. This study investigates the link between CGN mutation and increased cancer susceptibility through genetic and mechanistic analyses and proposes a potential targeted therapeutic approach. METHODS: In a high-cancer-density family without known pathogenic variants, we performed tumor-targeted and germline whole-genome sequencing to identify novel cancer-associated variants. Subsequently, these variants were validated in a 222 cancer patient cohort, and CGN c.3560C > T was identified as a potential cancer-risk allele. Both wild-type (WT) (c.3560C > C) and variant (c.3560C > T) were transfected into cancer cell lines and incorporated into orthotopic xenograft mice model for evaluating their effects on cancer progression. Western blot, immunofluorescence analysis, migration and invasion assays, two-dimensional gel electrophoresis with mass spectrometry, immunoprecipitation assays, and siRNA applications were used to explore the biological consequence of CGN c.3560C > T. RESULTS: In cancer cell lines and orthotopic animal models, CGN c.3560C > T enhanced tumor progression with reduced sensitivity to oxaliplatin compared to the CGN WT. The variant induced downregulation of epithelial marker, upregulation of mesenchymal marker and transcription factor, which converged to initiate epithelial-mesenchymal transition (EMT). Proteomic analysis was conducted to investigate the elements driving EMT in CGN c.3560C > T. This exploration unveiled overexpression of IQGAP1 induced by the variant, contrasting the levels observed in CGN WT. Immunoprecipitation assay confirmed a direct interaction between CGN and IQGAP1. IQGAP1 functions as a regulator of multiple GTPases, particularly the Rho family. This overexpressed IQGAP1 was consistently associated with the activation of Rac1, as evidenced by the analysis of the cancer cell line and clinical sample harboring CGN c.3560C > T. Notably, activated Rac1 was suppressed following the downregulation of IQGAP1 by siRNA. Treatment with NSC23766, a selective inhibitor for Rac1-GEF interaction, resulted in the inactivation of Rac1. This intervention mitigated the EMT program in cancer cells carrying CGN c.3560C > T. Consistently, xenograft tumors with WT CGN showed no sensitivity to NSC23766 treatment, but NSC23766 demonstrated the capacity to attenuate tumor growth harboring c.3560C > T. CONCLUSIONS: CGN c.3560C > T leads to IQGAP1 overexpression, subsequently triggering Rac1-dependent EMT. Targeting activated Rac1 is a strategy to impede the advancement of cancers carrying this specific variant.

Glofitamab as a salvage treatment for B-cell lymphomas in the real world: A multicenter study in Taiwan.

BACKGROUND: Glofitamab is a bispecific antibody with promise for treating relapsed/refractory B-cell lymphoma according to a phase 1/2 clinical trial. This study examined its real-world effectiveness. METHODS: This was an investigator-initiated, multicenter retrospective study including 34 patients who had relapsed/refractory B-cell lymphomas after at least three prior lines of therapy and received glofitamab monotherapy in a compassionate use program in Taiwan between January 2021 and October 2022. RESULTS: At a median follow-up of 15.9 months, 56% of patients responded to glofitamab and 23% achieved complete remission. Response to the previous line of therapy significantly correlated with response to glofitamab (p = .020). Most responses were durable; only five out of the 19 responders had documented disease recurrence at the data cutoff date. The estimated progression-free survival (PFS) was 3.2 months, and the estimated 1-year PFS was 33% for the entire cohort. PFS was better for responders than nonresponders (median PFS, 16.9 vs. 1.8 months; 1-year PFS, 60% vs. 0%). Forty-three cytokine release syndrome (CRS) events were observed, three of which were grade 3; all were manageable without glofitamab discontinuation. No immune effector cell-associated neurotoxicity was reported. Among seven hepatitis B virus (HBV) carriers (six had antiviral prophylaxis) and 14 patients with remote HBV (four had antiviral prophylaxis), no HBV reactivation was observed. CONCLUSIONS: In this real-world cohort, glofitamab exhibited effectiveness comparable to trial results without excessive CRS or new safety issues. With appropriate prophylaxis, glofitamab-treated patients with chronic or remote HBV infection are unlikely to experience virus reactivation.

Beyond the waves: Unraveling pandemic outcomes with genomic insights and immunity analysis - Evidence from 14 countries.

OBJECTIVE: Although the World Health Organization and many governments have recategorized COVID-19 as a generally mild to moderately severe disease, consecutive pandemic waves driven by immune escape variants have underscored the need for timely and accurate prediction of the next outbreak. Nevertheless, little attention has been paid to translating genomic data and infection- and vaccine-induced immunity into direct estimates. METHODS: We retrieved epidemiologic and genomic data shortly before pandemic waves across 14 developed countries from late 2021 to mid-2022 and examined associations between early-stage variant competition, infection- and vaccine-induced immunity, and the time intervals between wave peaks. We applied regression analysis and the generalized estimating equation method to construct an inferential model. RESULTS: Each per cent increase in the proportion of a new variant was associated with a 1.0% reduction in interpeak intervals on average. Curvilinear associations between vaccine-induced immunity and outcome variables were observed, suggesting that reaching a critical vaccine distribution rate may decrease the caseload of the upcoming wave. CONCLUSIONS: By leveraging readily accessible pre-outbreak genomic and epidemiologic data, our results not only substantiate the predictive potential of early variant fractions but also propose that immunity acquired through infection alone may not sufficiently mitigate transmission. Conversely, a rapid and widespread vaccination initiative appears to be correlated with a decrease in disease incidence.

Real-time forecasting of COVID-19 spread according to protective behavior and vaccination: autoregressive integrated moving average models.

BACKGROUND: Mathematical and statistical models are used to predict trends in epidemic spread and determine the effectiveness of control measures. Automatic regressive integrated moving average (ARIMA) models are used for time-series forecasting, but only few models of the 2019 coronavirus disease (COVID-19) pandemic have incorporated protective behaviors or vaccination, known to be effective for pandemic control. METHODS: To improve the accuracy of prediction, we applied newly developed ARIMA models with predictors (mask wearing, avoiding going out, and vaccination) to forecast weekly COVID-19 case growth rates in Canada, France, Italy, and Israel between January 2021 and March 2022. The open-source data was sourced from the YouGov survey and Our World in Data. Prediction performance was evaluated using the root mean square error (RMSE) and the corrected Akaike information criterion (AICc). RESULTS: A model with mask wearing and vaccination variables performed best for the pandemic period in which the Alpha and Delta viral variants were predominant (before November 2021). A model using only past case growth rates as autoregressive predictors performed best for the Omicron period (after December 2021). The models suggested that protective behaviors and vaccination are associated with the reduction of COVID-19 case growth rates, with booster vaccine coverage playing a particularly vital role during the Omicron period. For example, each unit increase in mask wearing and avoiding going out significantly reduced the case growth rate during the Alpha/Delta period in Canada (-0.81 and -0.54, respectively; both p < 0.05). In the Omicron period, each unit increase in the number of booster doses resulted in a significant reduction of the case growth rate in Canada (-0.03), Israel (-0.12), Italy (-0.02), and France (-0.03); all p < 0.05. CONCLUSIONS: The key findings of this study are incorporating behavior and vaccination as predictors led to accurate predictions and highlighted their significant role in controlling the pandemic. These models are easily interpretable and can be embedded in a "real-time" schedule with weekly data updates. They can support timely decision making about policies to control dynamically changing epidemics.

Vaccine-Induced Immune Thrombotic Thrombocytopenia following BNT162b2 mRNA COVID-19 Booster: A Case Report.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a life-threatening complication caused by platelet activation via platelet factor 4 (PF4) antibodies. We report a healthy 28-year-old man who developed hemoptysis, bilateral leg pain, and headaches three weeks after his third dose of the COVID-19 vaccine with the first BNT162b2 (from Pfizer-BioNTech) injection. He had previously had the first and second doses with ChAdOx1 nCov-19 without any discomfort. Serial investigations demonstrated pulmonary embolisms, cerebral sinus, and deep iliac venous thrombosis. Positive PF4 antibody assay (ELISA) confirmed the diagnosis of VITT. He had a prompt response to intravenous immunoglobulins (IVIGs) at a total dose of 2 g/kg and his symptoms are now in remission with anticoagulant. Although the definite mechanism is unknown, the VITT was most likely triggered by his COVID-19 vaccine. We report this case of VITT following BNT162b2, a mRNA-based vaccine, and suggest that VITT could still happen without the adenoviral vector vaccines.

Cognitive function and breast cancer molecular subtype before and after chemotherapy.

Chemotherapy-related cognitive impairment has been reported in patients with breast cancer and received growing attention due to increased survival rate. However, cognitive outcome according to pathological tumor features, especially human epidermal growth factor receptor (HER2) status, has not been clearly elucidated. Despite its potential link with cognitive status through neuroinflammatory response, existing research is sparse and limited to cross-sectional studies. In this observational cohort study, 52 breast cancer patients received a series of neuropsychological examinations before and after chemotherapy. Patients' performances were compared with normative data, and analyzed with Reliable Change Indices and mixed-model analysis of covariance. Results showed that there was a higher percentage of HER2+ patients than HER2- patients who showed defective attention and processing speed before chemotherapy, and that there were more patients with HER2+ status showing cognitive decline on tests of attention and executive functions following chemotherapy. Group-wise analyses confirmed the foregoing pattern and further revealed that patients with HER2+ status also tended to deteriorate more in verbal memory after chemotherapy. These findings indicate that HER2 overexpression may serve as prognostic factors that help explain the heterogeneous cognitive outcome in breast cancer survivors. Further studies are needed to replicate this finding and delineate the underlying mechanisms.

Electrical Sympathetic Neuromodulation Protects Bone Marrow Niche and Drives Hematopoietic Regeneration during Chemotherapy.

The sympathetic nervous system (SNS) of the bone marrow regulates the regeneration and mobilization of hematopoietic stem cells. Chemotherapy can damage bone marrow SNS, which impairs hematopoietic regeneration and aggravates hematologic toxicities. This leads to long-term bone marrow niche damage and increases mortality in patients undergoing chemotherapy. Electrical neuromodulation has been used to improve functional recovery after peripheral nerve injury. This study demonstrates that electrical sympathetic neuromodulation (ESN) of bone marrow can protect the bone marrow niche from chemotherapy-induced injury. Using carboplatin-treated rats, the SNS via the sciatic nerve innervating the femoral marrow with the effective protocol for bone marrow sympathetic activation is electrically stimulated. ESN can mediate several hematopoietic stem cells maintenance factors and promote hematopoietic regeneration after chemotherapy. It also activates adrenergic signals and reduces the release of pro-inflammatory cytokines, particularly interleukin-1 ß, which contribute to chemotherapy-related nerve injury. Consequently, the severity of chemotherapy-related leukopenia, thrombocytopenia, and mortality can be reduced by ESN. As a result, in contrast to current drug-based treatment, such as granulocyte colony-stimulating factor, ESN can be a disruptive adjuvant treatment by protecting and modulating bone marrow function to reduce hematologic toxicity during chemotherapy.

Enhancing diagnosis of T-cell lymphoma using non-recombined T-cell receptor sequences.

Clonality assessment, which can detect neoplastic T cells by identifying the uniquely recombined T-cell receptor (TCR) genes, provides important support in the diagnosis of T-cell lymphoma (TCL). BIOMED-2 is the gold standard clonality assay and has proven to be effective in European TCL patients. However, we failed to prove its sensitivity in Taiwanese TCL patients, especially based on the TCRß gene. To explore potential impact of genetic background in the BIOMED-2 test, we analyzed TCRß sequences of 21 healthy individuals and two TCL patients. This analysis suggests that genetic variations in the BIOMED-2 primer sites could not explain the difference in sensitivity. The BIOMED-2 test results of the two TCL patients were positive and negative, respectively. Interestingly, a higher percentage (>81%) of non-recombined TCRß sequences was observed in the test-negative patient than those of the test-positive patient and all healthy individuals (13~66%). The result suggests a new TCR target for enhancing TCL diagnosis. To further explore the hypothesis, we proposed a cost-effective digital PCR assay that quantifies the relative abundance of non-recombined TCRß sequences containing a J2-2P~J2-3 segment. With the digital PCR assay, bone marrow specimens from TCL patients (n=9) showed a positive outcome (i.e., the relative abundance of the J2-2P~J2-3 sequences ≧5%), whereas non-TCL patients (n=6) gave a negative result. As five of nine TCL patients had a negative BIOMED-2 test result, the J2-2P~J2-3 sequences may improve TCL detection. This is the first report showing the capability of characterizing non-recombined TCR sequences as a supplementary strategy for the BIOMED-2 clonality test.

Contribution of Testing Strategies and Contact Tracing towards COVID-19 Outbreaks Control: A Mathematical Modeling Study.

This modeling study considers different screening strategies, contact tracing, and the severity of novel epidemic outbreaks for various population sizes, providing insight into multinational containment effectiveness of emerging infectious diseases, prior to vaccines development. During the period of the ancestral SARS-Cov-2 virus, contact tracing alone is insufficient to achieve outbreak control. Although universal testing is proposed in multiple nations, its effectiveness accompanied by other measures is rarely examined. Our research investigates the necessity of universal testing when contact tracing and symptomatic screening measures are implemented. We used a stochastic transmission model to simulate COVID-19 transmission, evaluating containment strategies via contact tracing, one-time high risk symptomatic testing, and universal testing. Despite universal testing having the potential to identify subclinical cases, which is crucial for non-pharmaceutical interventions, our model suggests that universal testing only reduces the total number of cases by 0.0009% for countries with low COVID-19 prevalence and 0.025% for countries with high COVID-19 prevalence when rigorous contact tracing and symptomatic screening are also implemented. These findings highlight the effectiveness of testing strategies and contact tracing in reducing COVID-19 cases by identifying subclinical cases.

Low expression of cytosolic NOTCH1 predicts poor prognosis of breast cancer patients.

The incidence of breast cancer is increasing, and is one of the leading causes of cancer death worldwide. Dysregulation of NOTCH1 signaling is reported in breast cancer. In present study, bioinformatics was utilized to study the expression of NOTCH1 gene in breast cancer from public databases, including the Kaplan-Meier Plotter, PrognoScan, Human Protein Atlas, and cBioPortal. The relationship between NOTCH1 mRNA expression and survival of patients was inconsistent in public databases. In addition, we performed immunohistochemistry (IHC) staining of 135 specimens from our hospital. Lower cytoplasmic staining of NOTCH1 protein was correlated with cancer recurrence, bone metastasis, and a worse disease-free survival of patients, especially those with estrogen receptor-positive and human epidermal growth factor receptor 2-positive (HER2+) cancers. In TCGA breast cancer dataset, lower expression of NOTCH1 in breast cancer specimens was correlated with higher level of CCND1 (protein: cyclin D1). Decreased expression of NOTCH1 was correlated with lower level of CCNA1 (protein: cyclin A1), CCND2 (protein: cyclin D2), CCNE1 (protein: cyclin E1), CDK6 (protein: CDK6), and CDKN2C (protein: p18). In conclusion, NOTCH1 mRNA expression is not consistently correlated with clinical outcomes of breast cancer patients. Low cytoplasmic expression of NOTCH1 in IHC study is correlated with poor prognosis of breast cancer patients. Cytoplasmic localization of NOTCH1 protein failed to initial oncogenic signaling in present study. Expression of NOTCH1 mRNA was discordant with cell cycle-related genes. Regulation of NOTCH1 in breast cancer involves gene expression, protein localization and downstream signaling.

A comprehensive evaluation of COVID-19 policies and outcomes in 50 countries and territories.

The COVID-19 pandemic struck the world unguarded, some places outperformed others in COVID-19 containment. This longitudinal study considered a comparative evaluation of COVID-19 containment across 50 distinctly governed regions between March 2020 and November 2021. Our analysis distinguishes between a pre-vaccine phase (March-November 2020) and a vaccinating phase (December 2020-November 2021). In the first phase, we develop an indicator, termed lockdown efficiency (LE), to estimate the efficacy of measures against monthly case numbers. Nine other indicators were considered, including vaccine-related indicators in the second phase. Linear mixed models are used to explore the relationship between each government policy & hygiene education (GP&HE) indicator and each vital health & socioeconomic (VH&SE) measure. Our ranking shows that surveyed countries in Oceania and Asian outperformed countries in other regions for pandemic containment prior to vaccine development. Their success appears to be associated with non-pharmaceutical interventions, acting early, and adjusting policies as needed. After vaccines have been distributed, maintaining non-pharmacological intervention is the best way to achieve protection from variant viral strains, breakthrough infections, waning vaccine efficacy, and vaccine hesitancy limiting of herd immunity. The findings of the study provide insights into the effectiveness of emerging infectious disease containment policies worldwide.

Application of PLASMIC Score in Risk Prediction of Thrombotic Thrombocytopenic Purpura: Real-World Experience From a Tertiary Medical Center in Taiwan.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency (activity <10%). Urgent intervention based on the timely evaluation of ADAMTS13 level is crucial to guide optimal therapy. The recently developed PLASMIC score based on seven items allows the rapid identification of patients at high risk for TTP due to severe ADAMTS13 deficiency. This retrospective study included 31 hospitalized patients with suspicious thrombotic microangiopathy in National Cheng Kung University Hospital from December 2016 to July 2021. Data on ADAMTS13 activity and medical and laboratory information were retrieved from medical records. The PLASMIC score could be calculated in 24 of the 31 patients with available data, and the final cohort was stratified according to the 7-point PLASMIC score. All patients with high PLASMIC score (6-7) exhibited severe ADAMTS13 deficiency (activity ≤10%). One patient with a brain tumor and a PLASMIC score of 6 did not have severe ADAMTS13 activity of ≤10%. The patients in the intermediate- and low risk groups (PLASMIC scores of 5 and 0-4, respectively) exhibited ADAMTS13 activities of above 10%. Given the role of prompt diagnosis in the timely delivery of appropriate therapy, these findings confirm and strengthen the predictive value of the PLASMIC score in patients at high risk for TTP due to severe ADAMTS13 deficiency.

The Value of Artificial Intelligence-Assisted Imaging in Identifying Diagnostic Markers of Sarcopenia in Patients with Cancer.

Sarcopenia is defined as the loss of skeletal muscle mass and muscle function. It is common in patients with malignancies and often associated with adverse clinical outcomes. The presence of sarcopenia in patients with cancer is determined by body composition, and recently, radiologic technology for the accurate estimation of body composition is under development. Artificial intelligence- (AI-) assisted image measurement facilitates the detection of sarcopenia in clinical practice. Sarcopenia is a prognostic factor for patients with cancer, and confirming its presence helps to recognize those patients at the greatest risk, which provides a guide for designing individualized cancer treatments. In this review, we examine the recent literature (2017-2021) on AI-assisted image assessment of body composition and sarcopenia, seeking to synthesize current information on the mechanism and the importance of sarcopenia, its diagnostic image markers, and the interventions for sarcopenia in the medical care of patients with cancer. We concluded that AI-assisted image analysis is a reliable automatic technique for segmentation of abdominal adipose tissue. It has the potential to improve diagnosis of sarcopenia and facilitates identification of oncology patients at the greatest risk, supporting individualized prevention planning and treatment evaluation. The capability of AI approaches in analyzing series of big data and extracting features beyond manual skills would no doubt progressively provide impactful information and greatly refine the standard for assessing sarcopenia risk in patients with cancer.

A case of acquired hemophilia A and bullous pemphigoid following SARS-CoV-2 mRNA vaccination.

Acquired hemophilia is a rare disease resulting from autoantibodies against endogenous factor VIII (FVIII), which associates with bleeding and a high mortality rate. The pathophysiology is still unclear. Recent studies suggest genetic and environmental factors trigger the breakdown of immune tolerance. We report a 77-year-old Taiwanese man presented with multiple ecchymoses and some hemorrhagic blisters three weeks after SARS-CoV-2 mRNA (Moderna) vaccination. Isolated activated partial thromboplastin time (aPTT) prolongation was found. Acquired hemophilia A (AHA) was confirmed by low factor VIII (FVIII) activity and high titer of FVIII inhibitor. The pathohistology of skin biopsy further supported the concomitant diagnosis of bullous pemphigoid. To date, 6 cases of acquired hemophilia A following SARS-CoV-2 mRNA vaccination were reported worldwide. We reviewed and summarized the characteristics of these cases. We also discussed the rare finding of concomitant acquired hemophilia A and bullous pemphigoid. Bullous pemphigoid results from autoantibody against epithelial basement membrane zone of skin. In this article, we proposed possibility of SARS-CoV-2 mRNA vaccine associated autoimmunity against FVIII and epithelial basement membrane zone.

A Case Report of Posttransplant Lymphoproliferative Disorder After AstraZeneca Coronavirus Disease 2019 Vaccine in a Heart Transplant Recipient.

We report a case of a heart transplant recipient who presented with a rapidly growing Epstein-Barr virus (EBV)-positive, diffuse large B-cell lymphoma 7 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. Because of the atypical radiologic presentation, the initial tentative diagnosis was a mediastinal abscess. This observation indicates a potential risk of EBV reactivation after coronavirus disease 2019 (COVID-19) vaccination, which might lead to or aggravate the presentation of posttransplant lymphoproliferative disorder in transplantation patients. Transplant surgeons should be aware of the potential immunomodulatory effects of the COVID-19 vaccination.