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BACKGROUND: The effect of standardizing an insertion and removal protocol for pVAD devices has not been previously described. OBJECTIVES: We sought to evaluate clinical outcomes in patients who underwent pVAD insertion pre- and post-protocol standardization. METHODS: All patients who underwent pVAD insertion that remained in place at index procedure completion between January 2017 and September 2023 at a single academic center for both high-risk PCI and cardiogenic shock indications were included in the study. The primary outcome was the incidence of limb ischemia and major bleeding before and after the protocol initiation. Secondary outcomes included in-hospital and 30-day MACCE rate (death, myocardial infarction, stroke, emergent CABG), and how often the operators followed the protocol. RESULTS: A total of 89 patients had pVAD left in place (29 pre-protocol initiation and 60 post-protocol initiation). There was a significant decrease in incidence of limb ischemia post-protocol initiation compared to pre (17.2 % vs 1.7 %, p = 0.01) but no difference in bleeding incidence (13.8 % vs 20.0 %, p = 0.47). Adherence increased in all components of the protocol except for right heart catheterization. CONCLUSION: Standardization of an insertion and removal protocol for pVAD devices led to a statistically significant decrease in limb ischemia in a high-risk patient population.
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Ebolavirus disease (EVD) outbreaks have intermittently occurred since the first documented case in the 1970s. Due to its transmission characteristics, large outbreaks have not been observed outside Africa. However, within the continent, significant outbreaks have been attributed to factors such as endemic diseases with similar symptoms and inadequate medical infrastructure, which complicate timely diagnosis. In this study, we employed a stochastic modeling approach to analyze the spread of EVD during the early stages of an outbreak, with an emphasis on inherent risks. We developed a model that considers healthcare workers and unreported cases, and assessed the effect of non-pharmaceutical interventions (NPIs) using actual data. Our results indicate that the implementation of NPIs led to a decrease in the transmission rate and infectious period by 30% and 40% respectively, following the declaration of the outbreak. We also investigated the risks associated with delayed outbreak recognition. Our simulations suggest that, when accounting for NPIs and recognition delays, prompt detection could have resulted in a similar outbreak scale, with approximately 50% of the baseline NPIs effect. Finally, we discussed the potential effects of a vaccination strategy as a follow-up measure after the outbreak declaration. Our findings suggest that a vaccination strategy can reduce both the burden of NPIs and the scale of the outbreak.
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Surtos de Doenças , Doença pelo Vírus Ebola , Vacinação , Humanos , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/prevenção & controle , Surtos de Doenças/prevenção & controle , Vacinação/estatística & dados numéricos , Processos Estocásticos , Modelos Estatísticos , Ebolavirus/imunologiaRESUMO
As coronavirus disease-2019 (COVID-19) becomes an endemic disease, the virus continues to evolve and become immunologically distinct from previous strains. Immune imprinting has raised concerns about bivalent mRNA vaccines containing both ancestral virus and Omicron variant. To increase efficacy against the predominant strains as of the second half of 2023, the updated vaccine formulation contained only the mRNA of XBB.1.5 sublineage. We conducted a multicenter, test-negative, case-control study to estimate XBB.1.5 monovalent vaccine effectiveness (VE) and present the results of an interim analysis with data collected in November 2023. Patients who underwent COVID-19 testing at eight university hospitals were included and matched based on age (19-49, 50-64, and ≥65 years) and sex in a 1:1 ratio. VE was calculated using the adjusted odds ratio derived from multivariable logistic regression. Of the 992 patients included, 49 (5.3%) received the XBB.1.5 monovalent vaccine at least 7 days before COVID-19 testing. Patients with COVID-19 (cases) were less likely to have received the XBB.1.5 monovalent vaccine (case 3.5% vs. control 7.2%, p=0.019) and to have a history of COVID-19 within 6 months (2.2% vs. 4.6%, p=0.068). In contrast, patients with COVID-19 were more likely to be healthcare workers (8.2% vs. 3.0%, p=0.001) and to have chronic neurological diseases (16.7% vs. 11.9%, p=0.048). The adjusted VE of the XBB.1.5 monovalent mRNA vaccine was 56.8% (95% confidence interval: 18.7-77.9%). XBB.1.5 monovalent mRNA vaccine provided significant protection against COVID-19 in the first one to two months after vaccination.
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Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Eficácia de Vacinas , Humanos , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/virologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , SARS-CoV-2/imunologia , SARS-CoV-2/genética , Estudos de Casos e Controles , República da Coreia/epidemiologia , Vacinas de mRNA , Adulto Jovem , Vacinas Sintéticas/imunologiaRESUMO
BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) account for a large proportion of healthcare-associated infections and have a significant impact on morbidity, length of hospital stay, and mortality. Adherence to the recommended infection prevention practices can effectively reduce the incidence of CAUTIs. This study aimed to assess the characteristics of CAUTIs and the efficacy of prevention programs across hospitals of various sizes. METHODS: Intervention programs, including training, surveillance, and monitoring, were implemented. Data on the microorganisms responsible for CAUTIs, urinary catheter utilization ratio, rate of CAUTIs per 1,000 device days, and factors associated with the use of indwelling catheters were collected from 2017 to 2019. The incidence of CAUTIs and associated data were compared between university hospitals and small- and medium-sized hospitals. RESULTS: Thirty-two hospitals participated in the study, including 21 university hospitals and 11 small- and medium-sized hospitals. The microorganisms responsible for CAUTIs and their resistance rates did not differ between the two groups. In the first quarter of 2018, the incidence rate was 2.05 infections/1,000 device-days in university hospitals and 1.44 infections/1,000 device-days in small- and medium-sized hospitals. After implementing interventions, the rate gradually decreased in the first quarter of 2019, with 1.18 infections/1,000 device-days in university hospitals and 0.79 infections/1,000 device-days in small- and medium-sized hospitals. However, by the end of the study, the infection rate increased to 1.74 infections/1,000 device-days in university hospitals and 1.80 infections/1,000 device-days in small- and medium-sized hospitals. CONCLUSION: We implemented interventions to prevent CAUTIs and evaluated their outcomes. The incidence of these infections decreased in the initial phases of the intervention when adequate support and personnel were present. The rate of these infections may be reduced by implementing active interventions such as consistent monitoring and adherence to guidelines for preventing infections.
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Infecções Relacionadas a Cateter , Infecções Urinárias , Humanos , Infecções Urinárias/prevenção & controle , Infecções Urinárias/epidemiologia , Infecções Relacionadas a Cateter/prevenção & controle , Infecções Relacionadas a Cateter/epidemiologia , Infecção Hospitalar/prevenção & controle , Infecção Hospitalar/epidemiologia , Incidência , Controle de Infecções/métodos , Cateterismo Urinário/efeitos adversos , Cateteres de Demora/efeitos adversos , Hospitais Universitários , Cateteres Urinários/efeitos adversosRESUMO
In the 2023-2024 season, the influenza epidemic in South Korea peaked earlier than in recent years. In this study, we aimed to estimate the interim vaccine effectiveness (VE) of the influenza vaccination to prevent influenza during the early season. From November 1, 2023, to December 31, 2023, we enrolled 2,632 subjects with influenza-like illness from eight hospitals participating in hospital-based influenza morbidity and mortality surveillance. A retrospective test-negative case-control study was conducted to estimate the VE. The results showed an adjusted VE of 22.5% (95% confidence interval [CI], 6.6 to 35.8) for the total population. The adjusted VE was 22.3% (95% CI, 6.1 to 35.7) for influenza A and 9.4% (95% CI, -51.3 to 45.7) for influenza A/H1N1. Full results of the analysis will be reported.
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Vacinas contra Influenza , Influenza Humana , Estações do Ano , Humanos , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Influenza Humana/epidemiologia , República da Coreia/epidemiologia , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Estudos de Casos e Controles , Vírus da Influenza A Subtipo H1N1/imunologia , Adulto Jovem , Eficácia de Vacinas , VacinaçãoRESUMO
Neuroscience research underscores the critical impact of adverse experiences on brain development. Yet, there is limited understanding of the specific pathways linking adverse experiences to accelerated or delayed brain development and their ultimate contributions to psychopathology. Here, we present new longitudinal data demonstrating that neurocognitive functioning during adolescence, as affected by adverse experiences, predicts psychopathology during young adulthood. The sample included 167 participants (52% male) assessed in adolescence and young adulthood. Adverse experiences were measured by early maltreatment experiences and low family socioeconomic status. Cognitive control was assessed by neural activation and behavioral performance during the Multi-Source Interference Task. Psychopathology was measured by self-reported internalizing and externalizing symptomatology. Results indicated that higher maltreatment predicted heightened frontoparietal activation during cognitive control, indicating delayed neurodevelopment, which, in turn predicted higher internalizing and externalizing symptomatology. Furthermore, higher maltreatment predicted a steeper decline in frontoparietal activation across adolescence, indicating neural plasticity in cognitive control-related brain development, which was associated with lower internalizing symptomatology. Our results elucidate the crucial role of neurocognitive development in the processes linking adverse experiences and psychopathology. Implications of the findings and directions for future research on the effects of adverse experiences on brain development are discussed.
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"Long COVID" is a term used to describe a condition when the symptoms and signs associated with coronavirus disease 2019 (COVID-19) persist for more than three months among patients infected with COVID-19; this condition has been reported globally and poses a serious public health issue. Long COVID can manifest in various forms, highlighting the need for appropriate evaluation and management by experts from various fields. However, due to the lack of clear clinical definitions, knowledge of pathophysiology, diagnostic methods, and treatment protocols, it is necessary to develop the best standard clinical guidelines based on the scientific evidence reported to date. We developed this clinical guideline for diagnosing and treating long COVID by analyzing the latest research data collected from the start of the COVID-19 pandemic until June 2023, along with the consensus of expert opinions. This guideline provides recommendations for diagnosis and treatment that can be applied in clinical practice, based on a total of 32 key questions related to patients with long COVID. The evaluation of patients with long COVID should be comprehensive, including medical history, physical examination, blood tests, imaging studies, and functional tests. To reduce the risk of developing long COVID, vaccination and antiviral treatment during the acute phase are recommended. This guideline will be revised when there is a reasonable need for updates based on the availability of new knowledge on the diagnosis and treatment of long COVID.
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BACKGROUND: In Korea, there are no surveillance programs for vaccines that are not included in the national immunization program (NIP), and vaccine safety monitoring in the adult population is inadequate. This study aimed to establish a safety monitoring system for non-NIP vaccines in adults. METHODS: Frequently administered non-NIP vaccines were selected. Individuals were included if they received at least one of the selected vaccines at a participating institution and provided informed consent. Solicited and unsolicited adverse events were monitored using questionnaires sent through text messages on days 1, 3, 7, 28, and 90 post-vaccination. Selected adverse events of special interest (AESIs) were monitored monthly by retrospective review of electronic medical records. Causality was assessed according to the Korea Disease Control and Prevention Agency guidelines. RESULTS: Four vaccines (tetanus-diphtheria-pertussis [Tdap], pneumococcal conjugate 13-valent [PCV13], live zoster vaccine [ZVL], and recombinant zoster vaccine [RZV]) were selected, and their safety profiles were monitored at four tertiary hospitals and 10 primary care clinics. The response rates of the questionnaires on post-vaccination days 1, 7, 28, and 90 were 99.2%, 93.6%, 81.0%, and 48.7%, respectively. Of 555 AESI identified over 10 months, 10 cases received one of the selected non-NIP vaccines within 90 days of the event. CONCLUSION: We are establishing the first safety monitoring system for selected non-NIP vaccines in Korea since September 2022 and report its progress as of July 2023. However, continuous government support is essential for its maintenance and improvement.
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Vacina contra Herpes Zoster , Tétano , Adulto , Humanos , Vacinas Pneumocócicas , Vacinação/efeitos adversos , Vacinas Sintéticas , Programas de Imunização , República da CoreiaRESUMO
OBJECTIVES: To assess the association of primary and third doses of vaccination with the risk of post-acute sequelae of COVID-19. METHODS: This retrospective cohort study utilized a combined database of nationwide health care claims data, COVID-19 patient registry, and vaccination records from South Korea. Individuals diagnosed with COVID-19 in the Omicron variant-dominant period of January-March 2022 were tracked for 30-120 days post-infection. The exposure of interest was the receipt of primary and third doses of the SARS-CoV-2 vaccine. The occurrence of 26 specific conditions in eight domains was compared using Cox regression with inverse probability of treatment weighting. RESULTS: This study included 394 773 unvaccinated individuals and 7 604 081 individuals receiving ≥2 doses of vaccine. Compared with unvaccinated individuals, vaccination with at least two doses was associated with a reduced risk (adjusted hazard ratio; 95% CI) of several conditions, including ischaemic heart disease (0.73; 0.57-0.94), heart failure (0.55; 0.48-0.63), cardiac dysrhythmia (0.72; 0.61-0.85), cardiac arrest (0.41; 0.33-0.51), pulmonary embolism (0.66; 0.52-0.84), venous thromboembolism (0.54; 0.44-0.66), acute renal failure (0.56; 0.46-0.67), new dialysis (0.45; 0.34-0.59), chronic obstructive pulmonary disease (0.74; 0.65-0.84), acute pancreatitis (0.64; 0.51-0.80), and diabetes (0.82; 0.71-0.95). The risks of heart failure, cardiac dysrhythmias, cardiac arrest, pulmonary embolism, and new dialysis were lower in those who were vaccinated with three doses compared with those who were vaccinated with two doses. DISCUSSION: Vaccination was associated with a decreased risk of post-acute sequelae of COVID-19, suggesting its potential role in mitigating the indirect impacts of COVID-19.
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Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Vacinação , Humanos , COVID-19/prevenção & controle , COVID-19/epidemiologia , Masculino , Feminino , Estudos Retrospectivos , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/administração & dosagem , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Idoso , Vacinação/efeitos adversos , Adulto , Fatores de RiscoRESUMO
BACKGROUND: With the global increase in the older population, the proportion of those receiving care in long-term care facilities (LTCFs) has also been increasing. We assessed the epidemiology, antibiotic susceptibility, and colonization status of drug-resistant organisms in patients transferred from LTCFs. METHODS: We retrospectively reviewed the medical records of patients transferred from LTCFs between 2017 and 2022. The reasons for admission, antimicrobial susceptibility, and colonization rates of carbapenem-resistant Enterobacterales (CRE), methicillin-resistant Staphylococcus aureus (MRSA), and carbapenem-resistant Acinetobacter baumannii (CRAB) were recorded. We analyzed the susceptibility and colonization rates by year to identify trends. RESULTS: Of the 936 patients transferred from LTCFs, 54.3% were admitted to the intensive care unit and 12.5% died. The most common reason for admission was infection (n = 573, 61.2%), followed by gastrointestinal bleeding (n = 67, 7.2%) and cerebrovascular disorder (n = 65, 6.9%). A total of 452 Enterobacterales strains were isolated, and their susceptibility rates to ciprofloxacin and cefotaxime were 33.3% and 35.6%, respectively. A total of 54.9% were extended-spectrum beta-lactamase-producing strains, and 4.9% of them were carbapenem-resistant, both of which showed an increasing trend (P = 0.024 and P < 0.001, respectively). The prevalence rates of CRE, CRAB, and MRSA colonization were 9.2%, 7.1%, and 23.1%, respectively. CRE colonization showed a significant increase (P < 0.001), with carbapenemase-producing Enterobacterales accounting for 75.9% of cases. CONCLUSIONS: Patients transferred from LTCFs are primarily affected by infections and exhibit high resistance rates. The increasing trend in CRE colonization rates each year highlights the need for the implementation of rigorous infection control measures for effective management.
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Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Humanos , Estudos Transversais , Estudos Retrospectivos , Assistência de Longa Duração , Farmacorresistência Bacteriana Múltipla , Carbapenêmicos/farmacologia , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêuticoRESUMO
BACKGROUND: Bivalent booster mRNA vaccines containing the omicron-variant strains have been introduced worldwide in the autumn of 2022. Nevertheless, the omicron subvariants evoked another large coronavirus disease 2019 (COVID-19) pandemic wave in late 2022 and early 2023. METHODS: A retrospective, test-negative, case-control study was conducted to estimate the vaccine effectiveness (VE) of bivalent COVID-19 vaccines in 8 university hospitals between January and February 2023. The case and control groups were divided based on nasopharyngeal COVID-19 real-time polymerase chain reaction results and matched based on age, sex, hospital, and date (week) of the test performed. The VE of the BA.1- or BA.4/BA.5-based mRNA vaccines were estimated. VE was calculated using the 1-adjusted odds ratio from multivariable logistic regression. RESULTS: In total, 949 patients and 947 controls were enrolled in this study. VE for the BA.4/BA.5-based bivalent mRNA vaccine was 43% (95% confidence interval [CI], 17, 61%). In subgroup analysis based on age and underlying medical conditions, BA.4/BA.5-based bivalent mRNA vaccine was effective against old adults aged ≥ 65-years (VE, 55%; 95% CI, 23, 73%) and individuals with comorbidities (VE, 54%; 95% CI, 23, 73%). In comparison, the BA.1-based bivalent mRNA vaccine did not demonstrate statistically significant effectiveness (VE, 25%; 95% CI, -8, 49%). CONCLUSION: The BA.4/BA.5-based bivalent mRNA booster vaccine provided significant protection against COVID-19 in the Korean adults, especially in the older adults aged ≥ 65 years and in individuals with underlying medical conditions.
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COVID-19 , Humanos , Idoso , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Estudos de Casos e Controles , Estudos Retrospectivos , Vacinas de mRNA , Hospitais Universitários , RNA Mensageiro/genética , República da Coreia/epidemiologiaRESUMO
Antiviral treatment reduces the severity and mortality of SARS-CoV-2 infection; however, its effectiveness against long COVID-19 is unclear. This study aimed to evaluate the effectiveness of antiviral drugs in preventing long COVID and related hospitalizations/deaths. Scientific and medical databases were searched from 1 January 2020 to 30 June 2023. We included observational cohort studies comparing individuals receiving early antiviral therapy for COVID-19 and those receiving supportive treatment. A fixed-effects model was used to merge the effects reported in two or more studies. The risk of post-acute sequelae of COVID-19 (PASC) was combined as an odds ratio (OR). Six studies were selected, including a total of 3,352,235 participants. The occurrence of PASC was 27.5% lower in patients who received antiviral drugs during the early stages of SARS-CoV-2 infection (OR = 0.725; 95% confidence interval [CI] = 0.409-0.747) than in the supportive treatment group. Moreover, the risk of PASC-associated hospitalization and mortality was 29.7% lower in patients receiving early antiviral therapy than in the supportive treatment group (OR = 0.721; 95% CI = 0.697-0.794). Early antiviral therapy was associated with a reduced risk of PASC and related hospitalization or death. Thus, early antiviral therapy is recommended for at-risk individuals.
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BACKGROUND: Targeted risk population has been highly vaccinated against pneumococcal diseases in South Korea. Despite this, the pneumococcal serotype distribution is evolving, which impedes efficient roll-out of vaccines. METHODS: This prospective cohort study included patients aged ≥ 19 years with community-acquired pneumonia (CAP) from five university hospitals in South Korea between September 2018 and July 2021. The outcomes of interest were the demographic and clinical characteristics of patients with CAP, pneumococcal serotype distribution, and risk factors of 30-day mortality in patients with pneumococcal CAP (pCAP). Considering the high seroprevalence, we analyzed the clinical characteristics of serotype 3 pCAP. RESULTS: A total of 5,009 patients hospitalized with CAP was included (mean age ± standard deviation, 70.3 ± 16.0 years; 3,159 [63.1%] men). Streptococcus pneumoniae was the leading causative agent of CAP (11.8% overall, 17.7% in individuals aged < 65 years with chronic medical conditions). Among the 280 serotyped Streptococcus pneumococcus, serotype 3 was the most common (10.0%), followed by serotypes 19A (8.9%), 34 (8.9%), and 35B (8.9%). Non-vaccine serotypes (serotype 35B [13.9%] and 34 [12.0%]) were the most prevalent in 108 individuals vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23). Serotype 3 was prevalent, irrespective of PPSV23 vaccination status, and more common in individuals with chronic lung disease (P = 0.008). Advanced age (adjusted odds ratio [aOR], 1.040; 95% confidence interval [CI], 1.011-1.071), long-term care facility residence (aOR, 2.161; 95% CI, 1.071-4.357), and bacteremia (aOR, 4.193; 95% CI, 1.604-10.962) were independent risk factors for 30-day mortality in patients with pCAP. PPSV23 vaccination reduced the risk of mortality (aOR, 0.507; 95% CI, 0.267-0.961). CONCLUSION: Serotype 3 and 19A were still the most common serotypes of pCAP in South Korea despite the national immunization program of 13-valent pneumococcal conjugated vaccine in children and PPSV23 in old adults. PPSV23 vaccination might reduce the risk of mortality in patients with pCAP.
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Infecções Comunitárias Adquiridas , Infecções Pneumocócicas , Pneumonia Pneumocócica , Adulto , Masculino , Criança , Humanos , Feminino , Streptococcus pneumoniae , Sorogrupo , Pneumonia Pneumocócica/epidemiologia , Pneumonia Pneumocócica/prevenção & controle , Estudos Prospectivos , Estudos Soroepidemiológicos , Vacinas Conjugadas , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/uso terapêutico , Infecções Comunitárias Adquiridas/epidemiologia , VacinaçãoRESUMO
BACKGROUND: In this study, we aimed to compare the effectiveness and adverse reactions of nirmatrelvir/ritonavir and molnupiravir in high-risk outpatients with coronavirus disease 2019 (COVID-19). METHODS: This multicenter prospective observational study evaluated the rate of hospitalization, death, and adverse events within 28 days of oral antiviral agent prescription (molnupiravir, n = 240; nirmatrelvir/ritonavir, n = 240) to 480 nonhospitalized adult patients with COVID-19 from August 2, 2022 to March 31, 2023. RESULTS: Patients receiving molnupiravir had a higher prevalence of comorbidities (85.8% vs. 70.4%; P < 0.001) and a higher Charlson comorbidity index (2.8 ± 1.4 vs. 2.5 ± 1.5; P = 0.009) than those receiving nirmatrelvir/ritonavir. Three patients required hospitalization (nirmatrelvir/ritonavir group, n = 1 [0.4%]; molnupiravir group, n = 2 [0.8%]; P = 1.000). Nirmatrelvir/ritonavir was associated with a higher risk of adverse events than molnupiravir (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.27-3.03), especially for patients aged 65 years and older (OR, 3.04; 95% CI, 1.71-5.39). The severity of adverse events in both groups was mild to moderate and improved after discontinuation of medication. In the molnupiravir group, age ≥ 65 years (OR, 0.43 95% CI, 0.22-0.86) and appropriate vaccination (OR, 0.37; 95% CI, 0.15-0.91) reduced the occurrence of adverse events. CONCLUSION: The rates of hospitalization and death were low and not significantly different between high-risk patients who received either nirmatrelvir/ritonavir or molnupiravir. Although adverse events were more frequent with nirmatrelvir/ritonavir than with molnupiravir, none were severe. Nirmatrelvir/ritonavir can be safely used to treat COVID-19, while molnupiravir could be considered as an alternative treatment option for high-risk groups.
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COVID-19 , Pacientes Ambulatoriais , Adulto , Humanos , Ritonavir/efeitos adversos , Tratamento Farmacológico da COVID-19 , Antivirais/efeitos adversosRESUMO
Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo mutations in Lysine(K) acetyltransferase 6A (KAT6A). ARTHS is clinically heterogeneous and characterized by several common features, including intellectual disability, developmental and speech delay, and hypotonia, and affects multiple organ systems. KAT6A is the enzymatic core of a histone-acetylation protein complex; however, the direct histone targets and gene regulatory effects remain unknown. In this study, we use ARTHS patient (n = 8) and control (n = 14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused by KAT6A mutations. We identified differential chromatin accessibility within the promoter or gene body of 23% (14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posterior HOXC gene cluster (HOXC10, HOXC11, HOXC-AS3, HOXC-AS2, and HOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene-body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression. Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation. Our multi-omics assays have identified novel histone and gene regulatory roles of KAT6A in a large group of ARTHS patients harboring diverse pathogenic mutations. This work provides insight into the role of KAT6A on the epigenomic regulation in somatic cell types.
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Epigênese Genética , Histonas , Humanos , Histonas/genética , Histonas/metabolismo , Proteômica , Cromatina , Mutação , Fatores de Transcrição/genética , Proteínas de Homeodomínio/genética , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismoRESUMO
Background: GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) in healthy adults aged ≥18 years, up to 6 months after the second dose. Methods: This was a randomised, active-controlled, observer-blinded, parallel group, phase 3 study, conducted at 38 sites across six countries (South Korea, Philippines, Thailand, Vietnam, Ukraine and New Zealand). Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination) was randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety), while Cohort 2 (regardless of baseline serostatus) was randomised 5:1 (safety). Primary objectives were to demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; ≥4-fold rise from baseline) of GBP510/AS03 vs. ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity (long-term 6 months cut-off date: 09 August 2022). This study was registered on ClinicalTrials.gov (NCT05007951). Findings: Between 30 August 2021 and 11 January 2022, a total of 4913 participants were screened and 4036 participants (1956 in Cohort 1 and 2080 in Cohort 2) who met eligibility criteria were enrolled and randomised to receive 2 doses of GBP510/AS03 (n = 3039) or ChAdOx1-S (n = 997). Most participants were Southeast Asian (81.5%) and aged 18-64 years (94.7%). The primary objectives assessed in per-protocol set included 877 participants in GBP510/AS03 and 441 in ChAdOx1-S group: at 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03/ChAdOx1-S) in per-protocol set was 2.93 (95% CI 2.63-3.27), demonstrating superiority (95% CI lower limit >1) of GBP510/AS03; the between-group SCR difference of 10.8% (95% CI 7.68-14.32) also satisfied the non-inferiority criterion (95% CI lower limit > -5%). Neutralizing antibody titres sustained higher for the GBP510/AS03 group compared to the ChAdOx1-S group through 6 months after the second vaccination. In Safety analysis (Cohort 1 & 2), the proportion of participants with adverse events (AEs) after any vaccination was higher with GBP510/AS03 vs. ChAdOx1-S for solicited local AEs (56.7% vs. 49.2%), but was similar for solicited systemic AEs (51.2% vs. 53.5%) and unsolicited AEs (13.3% vs. 14.6%) up to 28 days after the second vaccination. No safety concerns were identified during follow-up for 6 months after the second vaccination. Interpretation: Our interim findings suggested that GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.
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Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo truncating mutations in Lysine(K) acetyltransferase 6A (KAT6A). ARTHS is clinically heterogeneous and characterized by several common features including intellectual disability, developmental and speech delay, hypotonia and affects multiple organ systems. KAT6A is highly expressed in early development and plays a key role in cell-type specific differentiation. KAT6A is the enzymatic core of a histone-acetylation protein complex, however the direct histone targets and gene regulatory effects remain unknown. In this study, we use ARTHS patient (n=8) and control (n=14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused by KAT6A mutations. We identified differential chromatin accessibility within the promoter or gene body of 23%(14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posterior HOXC gene cluster (HOXC10, HOXC11, HOXC-AS3, HOXC-AS2, HOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene-body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression. Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation. Our multi-omics assays have identified novel histone and gene regulatory roles of KAT6A in a large group of ARTHS patients harboring diverse pathogenic mutations. This work provides insight into the role of KAT6A on the epigenomic regulation in somatic cell types.
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Background: More than half of the population in Korea had a prior COVID-19 infection. In 2022, most nonpharmaceutical interventions, except mask-wearing indoors, had been lifted. And in 2023, the indoor mask mandates were eased. Methods: We developed an age-structured compartmental model that distinguishes vaccination history, prior infection, and medical staff from the rest of the population. Contact patterns among hosts were separated based on age and location. We simulated scenarios with the lifting of the mask mandate all at once or sequentially according to the locations. Furthermore, we investigated the impact of a new variant assuming that it has higher transmissibility and risk of breakthrough infection. Results: We found that the peak size of administered severe patients may not exceed 1100 when the mask mandate is lifted everywhere, and 800 if the mask mandate only remains in the hospital. If the mask mandate is lifted in a sequence (except hospital), then the peak size of administered severe patients may not exceed 650. Moreover, if the new variant has both higher transmissibility and immune reduction, the effective reproductive number of the new variant is approximately 3 times higher than that of the current variant, and additional interventions may be needed to keep the administered severe patients from exceeding 2,000, which is the critical level we set. Conclusion: Our findings showed that the lifting of the mask mandate, except in hospitals, would be more manageable if implemented sequentially. Considering a new variant, we found that depending on the population immunity and transmissibility of the variant, wearing masks and other interventions may be necessary for controlling the disease.
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As the COVID-19 situation changes because of emerging variants and updated vaccines, an elaborate mathematical model is essential in crafting proactive and effective control strategies. We propose a COVID-19 mathematical model considering variants, booster shots, waning, and antiviral drugs. We quantify the effects of social distancing in the Republic of Korea by estimating the reduction in transmission induced by government policies from February 26, 2021 to February 3, 2022. Simulations show that the next epidemic peak can be estimated by investigating the effects of waning immunity. This research emphasizes that booster vaccination should be administered right before the next epidemic wave, which follows the increasing waned population. Policymakers are recommended to monitor the waning population immunity using mathematical models or other predictive methods. Moreover, our simulations considering a new variant's transmissibility, severity, and vaccine evasion suggest intervention measures that can reduce the severity of COVID-19.
Assuntos
COVID-19 , Epidemias , Humanos , Distanciamento Físico , COVID-19/epidemiologia , COVID-19/prevenção & controle , Imunização Secundária , Antivirais/farmacologia , Antivirais/uso terapêutico , VacinaçãoRESUMO
Adverse childhood experiences are common and have long-term consequences for biological and psychosocial adjustment. We used a person-centered approach to characterize distinct profiles of adversity in early adolescence and examined associations with later cognitive control and psychopathology. The sample included 167 adolescents (47% female) and their primary caregivers who participated in a longitudinal study across four time points (approximately one year between assessments). At Time 1 (Mage = 14 years), we measured seven indicators of adversity: socioeconomic disadvantage, abuse, neglect, household chaos, parent substance use, parent depression, and negative life events. At Times 2-4, adolescents' behavioral performance and functional activation during a cognitive control task were measured. At Time 5, adolescents and their caregiver reported on adolescent internalizing and externalizing symptomatology. Using latent profile analysis, we identified four distinct adversity subgroups: a low exposure group, a neglect group, a household instability group, and a poly-adversity group. These groups significantly differed on subsequent levels of psychopathology, but not cognitive control. Specifically, the poly-adversity group reported significantly higher levels of both internalizing and externalizing symptomatology relative to the low exposure group, and the household instability group demonstrated elevated risk for externalizing symptomatology. When using a cumulative risk approach, higher levels of adversity exposure were associated with significantly worse cognitive control performance (but not neural activation). These results suggest that psychopathology outcomes may be differentially predicted by distinct patterns of risk, and that cognitive control impairment may be more strongly predicted by cumulative risk.