RESUMO
Drug addiction, a phenomenon where cancer cells paradoxically depend on continuous drug treatment for survival, has uncovered cell signaling mechanisms and cancer codependencies. Here we discover mutations that confer drug addiction to inhibitors of the transcriptional repressor polycomb repressive complex 2 (PRC2) in diffuse large B-cell lymphoma. Drug addiction is mediated by hypermorphic mutations in the CXC domain of the catalytic subunit EZH2, which maintain H3K27me3 levels even in the presence of PRC2 inhibitors. Discontinuation of inhibitor treatment leads to overspreading of H3K27me3, surpassing a repressive methylation ceiling compatible with lymphoma cell survival. Exploiting this vulnerability, we show that inhibition of SETD2 similarly induces the spread of H3K27me3 and blocks lymphoma growth. Collectively, our findings demonstrate that constraints on chromatin landscapes can yield biphasic dependencies in epigenetic signaling in cancer cells. More broadly, we highlight how approaches to identify drug addiction mutations can be leveraged to discover cancer vulnerabilities.
Assuntos
Linfoma , Neoplasias , Humanos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Histonas/metabolismo , Linfoma/genética , Metilação , Neoplasias/genética , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismoRESUMO
Understanding how antibiotic use drives resistance is crucial for guiding effective strategies to limit the spread of resistance, but the use-resistance relationship across pathogens and antibiotics remains unclear. We applied sinusoidal models to evaluate the seasonal use-resistance relationship across 3 species (Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae) and 5 antibiotic classes (penicillins, macrolides, quinolones, tetracyclines, and nitrofurans) in Boston, Massachusetts. Outpatient use of all 5 classes and resistance in inpatient and outpatient isolates in 9 of 15 species-antibiotic combinations showed statistically significant amplitudes of seasonality (false discovery rate (FDR) < 0.05). While seasonal peaks in use varied by class, resistance in all 9 species-antibiotic combinations peaked in the winter and spring. The correlations between seasonal use and resistance thus varied widely, with resistance to all antibiotic classes being most positively correlated with use of the winter peaking classes (penicillins and macrolides). These findings challenge the simple model of antibiotic use independently selecting for resistance and suggest that stewardship strategies will not be equally effective across all species and antibiotics. Rather, seasonal selection for resistance across multiple antibiotic classes may be dominated by use of the most highly prescribed antibiotic classes, penicillins and macrolides.
Assuntos
Antibacterianos , Farmacorresistência Bacteriana , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias , Escherichia coli/genética , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , Penicilinas , Estações do AnoRESUMO
BACKGROUND: Group A Streptococcus (GAS) causes an estimated 5.2 million outpatient visits for pharyngitis annually in the United States, with incidence peaking in winter, but the annual spatiotemporal pattern of GAS pharyngitis across the United States is poorly characterized. METHODS: We used outpatient claims data from individuals with private medical insurance between 2010 and 2018 to quantify GAS pharyngitis visit rates across U.S. census regions, subregions, and states. We evaluated seasonal and age-based patterns of geographic spread and the association between school start dates and the summertime upward inflection in GAS visits. RESULTS: The South had the most visits per person (yearly average, 39.11 visits per 1000 people; 95% confidence interval, 36.21-42.01) and the West had the fewest (yearly average, 17.63 visits per 1000 people; 95% confidence interval, 16.76-18.49). Visits increased earliest in the South and in school-age children. Differences in visits between the South and other regions were most pronounced in the late summer through early winter. Visits peaked earliest in central southern states, in December to January, and latest on the coasts, in March. The onset of the rise in GAS pharyngitis visits correlated with, but preceded, average school start times. CONCLUSIONS: The burden and timing of GAS pharyngitis varied across the continental United States, with the South experiencing the highest overall rates and earliest onset and peak in outpatient visits. Understanding the drivers of these regional differences in GAS pharyngitis will help in identifying and targeting prevention measures.
Assuntos
Faringite , Estações do Ano , Infecções Estreptocócicas , Streptococcus pyogenes , Humanos , Faringite/microbiologia , Faringite/epidemiologia , Estados Unidos/epidemiologia , Infecções Estreptocócicas/epidemiologia , Infecções Estreptocócicas/microbiologia , Criança , Pré-Escolar , Adolescente , Feminino , Masculino , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Lactente , Incidência , Análise Espaço-Temporal , IdosoRESUMO
In a retrospective, ecological analysis of US medical claims, visit rates explained more of the geographic variation in outpatient antibiotic prescribing rates than per-visit prescribing. Efforts to reduce antibiotic use may benefit from addressing the factors that drive higher rates of outpatient visits, in addition to continued focus on stewardship.
Assuntos
Antibacterianos , Pacientes Ambulatoriais , Padrões de Prática Médica , Humanos , Antibacterianos/uso terapêutico , Estados Unidos , Estudos Retrospectivos , Padrões de Prática Médica/estatística & dados numéricos , Pacientes Ambulatoriais/estatística & dados numéricos , Gestão de Antimicrobianos/estatística & dados numéricos , Prescrições de Medicamentos/estatística & dados numéricos , Assistência Ambulatorial/estatística & dados numéricosRESUMO
SARS-CoV-2 infections are characterized by viral proliferation and clearance phases and can be followed by low-level persistent viral RNA shedding. The dynamics of viral RNA concentration, particularly in the early stages of infection, can inform clinical measures and interventions such as test-based screening. We used prospective longitudinal quantitative reverse transcription PCR testing to measure the viral RNA trajectories for 68 individuals during the resumption of the 2019-2020 National Basketball Association season. For 46 individuals with acute infections, we inferred the peak viral concentration and the duration of the viral proliferation and clearance phases. According to our mathematical model, we found that viral RNA concentrations peaked an average of 3.3 days (95% credible interval [CI] 2.5, 4.2) after first possible detectability at a cycle threshold value of 22.3 (95% CI 20.5, 23.9). The viral clearance phase lasted longer for symptomatic individuals (10.9 days [95% CI 7.9, 14.4]) than for asymptomatic individuals (7.8 days [95% CI 6.1, 9.7]). A second test within 2 days after an initial positive PCR test substantially improves certainty about a patient's infection stage. The effective sensitivity of a test intended to identify infectious individuals declines substantially with test turnaround time. These findings indicate that SARS-CoV-2 viral concentrations peak rapidly regardless of symptoms. Sequential tests can help reveal a patient's progress through infection stages. Frequent, rapid-turnaround testing is needed to effectively screen individuals before they become infectious.
Assuntos
Teste de Ácido Nucleico para COVID-19/estatística & dados numéricos , COVID-19/diagnóstico , RNA Viral/genética , SARS-CoV-2/genética , Replicação Viral/genética , Eliminação de Partículas Virais/genética , Adulto , Atletas , Basquetebol , COVID-19/epidemiologia , COVID-19/patologia , COVID-19/virologia , Convalescença , Humanos , Masculino , Estudos Prospectivos , Saúde Pública/métodos , SARS-CoV-2/crescimento & desenvolvimento , Índice de Gravidade de Doença , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: In the United States, children aged <5 years receive high volumes of antibiotics, which may contribute to antibiotic resistance. It has been unclear what role preventable illnesses and chronic comorbidities play in prompting antibiotic prescriptions. METHODS: We conducted an observational study with a cohort of 124 759 children aged <5 years born in the United States between 2008 and 2013 with private medical insurance. Study outcomes included the cumulative number of antibiotic courses dispensed per child by age 5 and the proportion of children for whom at least 1 antibiotic course was dispensed by age 5. We identified which chronic medical conditions predicted whether a child would be among the top 20% of antibiotic recipients. RESULTS: Children received a mean of 6.8 (95% confidence interval [CI]: 6.7-6.9) antibiotic courses by age 5, and 91% (95% CI: 90%-92%) of children had received at least 1 antibiotic course by age 5. Most antibiotic courses (71%; 95% CI: 70%-72%) were associated with respiratory infections. Presence of a pulmonary/respiratory, otologic, and/or immunological comorbidity substantially increase a child's odds of being in the top 20% of antibiotic recipients. Children with at least 1 of these conditions received a mean of 10.5 (95% CI: 10.4-10.6) antibiotic courses by age 5. CONCLUSIONS: Privately insured children in the United States receive many antibiotics early in life, largely due to respiratory infections. Antibiotic dispensing varies widely among children, with more antibiotics dispensed to children with pulmonary/respiratory, otologic, and/or immunological comorbidities.
Assuntos
Antibacterianos , Infecções Respiratórias , Criança , Humanos , Estados Unidos/epidemiologia , Antibacterianos/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/epidemiologia , Comorbidade , Prescrições , Resistência Microbiana a MedicamentosRESUMO
A consensus methodology for the pharmacometric assessment of candidate SARS-CoV-2 antiviral drugs would be useful for comparing trial results and improving trial design. The time to viral clearance, assessed by serial qPCR of nasopharyngeal swab samples, has been the most widely reported measure of virological response in clinical trials, but it has not been compared formally with other metrics, notably model-based estimates of the rate of viral clearance. We analyzed prospectively gathered viral clearance profiles from 280 infection episodes in vaccinated and unvaccinated individuals. We fitted different phenomenological pharmacodynamic models (single exponential decay, bi-exponential, penalized splines) and found that the clearance rate, estimated from a mixed effects single exponential decay model, is a robust pharmacodynamic summary of viral clearance. The rate of viral clearance, estimated from viral densities during the first week following peak viral load, provides increased statistical power (reduced type 2 error) compared with time to clearance. Antiviral effects approximately equivalent to those with currently used and recommended SARS-CoV-2 antiviral treatments, notably nirmatrelvir and molnupiravir, can be detected from randomized trials with sample sizes of only 35 to 65 patients per arm. We recommend that pharmacometric antiviral assessments should be conducted in early COVID-19 illness with serial qPCR samples taken over 1 week.
Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Cinética , Resultado do Tratamento , Carga ViralRESUMO
The sensitivity of genotype-based diagnostics that predict antimicrobial susceptibility is limited by the extent to which they detect genes and alleles that lead to resistance. As novel resistance variants are expected to emerge, such sensitivity is expected to decline unless the new variants are detected and incorporated into the diagnostic. Here, we present a mathematical framework to define how many diagnostic failures may be expected under varying surveillance regimes and thus quantify the surveillance needed to maintain the sensitivity of genotype-based diagnostics.
Assuntos
Farmacorresistência Bacteriana/genética , Resistência Microbiana a Medicamentos/genética , Genótipo , Monitoramento Epidemiológico , Marcadores Genéticos , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Reducing geographic disparities in antibiotic prescribing is a central public health priority to combat antibiotic resistance, but drivers of this variation have been unclear. METHODS: We measured how variation in outpatient visit rates (observed disease) and antibiotic prescribing rates per visit (prescribing practices) contributed to geographic variation in per capita antibiotic prescribing in Massachusetts residents younger than 65 years between 2011 and 2015. RESULTS: Of the difference in per capita antibiotic prescribing between high- and low-prescribing census tracts in Massachusetts, 45.2% was attributable to variation in outpatient visit rates, while 25.8% was explained by prescribing practices. Outpatient visits for sinusitis, pharyngitis, and suppurative otitis media accounted for 30.3% of the gap in prescribing, with most of the variation in visit rates concentrated in children younger than 10 years. Outpatient visits for these conditions were less frequent in census tracts with high social deprivation index. CONCLUSIONS: Interventions aimed at reducing geographic disparities in antibiotic prescribing should target the drivers of outpatient visits for respiratory illness and should account for possible underutilization of health services in areas with the lowest antibiotic consumption. Our findings challenge the conventional wisdom that prescribing practices are the main driver of geographic disparities in antibiotic use.
Assuntos
Antibacterianos , Infecções Respiratórias , Classe Social , Antibacterianos/uso terapêutico , Setor Censitário , Criança , Humanos , Massachusetts , Pacientes Ambulatoriais , Padrões de Prática Médica , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/epidemiologia , Privação SocialRESUMO
We estimated the fraction of antibiotic prescribing in the United States attributable to gonorrhea. Gonorrhea contributes to an outsized proportion of antibiotic prescriptions in young adults, males, and in the southern and western United States. A gonococcal vaccine could substantially reduce antibiotic prescribing in these populations.
Assuntos
Antibacterianos , Gonorreia , Antibacterianos/uso terapêutico , Vacinas Bacterianas , Gonorreia/tratamento farmacológico , Gonorreia/prevenção & controle , Humanos , Masculino , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: The mechanisms driving the recent decline in outpatient antibiotic prescribing are unknown. We estimated the extent to which reductions in the number of antibiotic prescriptions filled per outpatient visit (stewardship) and reductions in the monthly rate of outpatient visits (observed disease) for infectious disease conditions each contributed to the decline in outpatient antibiotic prescribing in Massachusetts between 2011 and 2015. METHODS: Outpatient medical and pharmacy claims from the Massachusetts All-Payer Claims Database were used to estimate rates of antibiotic prescribing and outpatient visits for 20 medical conditions and their contributions to the overall decline in antibiotic prescribing. Trends were compared with those in the National Ambulatory Medical Care Survey (NAMCS). RESULTS: Between 2011 and 2015, the January and July antibiotic-prescribing rates per 1000 individuals in Massachusetts declined by 18.9% and 13.6%, respectively. The monthly rate of outpatient visits per 1000 individuals in Massachusetts declined (Pâ <â .05) for respiratory infections and urinary tract infections. Nationally, outpatient visits for antibiotic-meriting medical conditions also declined between 2010 and 2015. Of the estimated 358 antibiotic prescriptions per 1000 individuals averted over the study period in Massachusetts, 59% (95% CI, 54-63%) were attributable to reduced observed disease and 41% (95% CI, 37-46%) to improved stewardship. CONCLUSIONS: The decline in antibiotic prescribing in Massachusetts was driven both by a decline in observed disease and improved antibiotic stewardship, in agreement with national trends. A focus on infectious disease prevention should be considered alongside antibiotic stewardship as a means to reduce antibiotic prescribing.
Assuntos
Gestão de Antimicrobianos , Infecções Respiratórias , Antibacterianos/uso terapêutico , Humanos , Prescrição Inadequada , Massachusetts/epidemiologia , Pacientes Ambulatoriais , Padrões de Prática Médica , Infecções Respiratórias/tratamento farmacológicoRESUMO
Public health surveillance for pathogens presents an optimization problem: we require enough sampling to identify intervention-triggering shifts in pathogen epidemiology, such as new introductions or sudden increases in prevalence, but not so much that costs due to surveillance itself outweigh those from pathogen-associated illness. To determine this optimal sampling frequency, we developed a general mathematical model for the introduction of a new pathogen that, once introduced, increases in prevalence exponentially. Given the relative cost of infection vs. sampling, we derived equations for the expected combined cost per unit time of disease burden and surveillance for a specified sampling frequency, and thus the sampling frequency for which the expected total cost per unit time is lowest.
Assuntos
Surtos de Doenças , Vigilância em Saúde PúblicaRESUMO
The COVID-19 pandemic has highlighted the need to upgrade systems for infectious disease surveillance and forecasting and modeling of the spread of infection, both of which inform evidence-based public health guidance and policies. Here, we discuss requirements for an effective surveillance system to support decision making during a pandemic, drawing on the lessons of COVID-19 in the U.S., while looking to jurisdictions in the U.S. and beyond to learn lessons about the value of specific data types. In this report, we define the range of decisions for which surveillance data are required, the data elements needed to inform these decisions and to calibrate inputs and outputs of transmission-dynamic models, and the types of data needed to inform decisions by state, territorial, local, and tribal health authorities. We define actions needed to ensure that such data will be available and consider the contribution of such efforts to improving health equity.
Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , Estados Unidos/epidemiologia , SARS-CoV-2 , Pandemias , Vigilância da População , Saúde PúblicaRESUMO
Background: Group A Streptococcus (GAS) causes an estimated 5.2 million outpatient visits for pharyngitis annually in the United States (U.S.) with incidence peaking in winter, but the annual spatiotemporal pattern of GAS pharyngitis across the U.S. is poorly characterized. Methods: We used outpatient claims data from individuals with private medical insurance between 2010-2018 to quantify GAS pharyngitis visit rates across U.S. census regions, subregions, and states. We evaluated seasonal and age-based patterns of geographic spread and the association between school start dates and the summertime upward inflection in GAS visits. Results: The South had the most visits per person (yearly average 39.11 visits per 1000 people, 95% CI: 36.21-42.01), and the West had the fewest (yearly average 17.63 visits per 1000 people, 95% CI: 16.76-18.49). Visits increased earliest in the South and in school-age children. Differences in visits between the South and other regions were most pronounced in the late summer through early winter. Visits peaked earliest in central southern states, in December to January, and latest on the coasts, in March. The onset of the rise in GAS pharyngitis visits correlated with, but preceded, average school start times. Conclusions: The burden and timing of GAS pharyngitis varied across the continental U.S., with the South experiencing the highest overall rates and earliest onset and peak in outpatient visits. Understanding the drivers of these regional differences in GAS pharyngitis will help in identifying and targeting prevention measures.
RESUMO
The impact of a prior SARS-CoV-2 infection on the progression of subsequent infections has been unclear. Using a convenience sample of 94,812 longitudinal RT-qPCR measurements from anterior nares and oropharyngeal swabs, we identified 71 individuals with two well-sampled SARS-CoV-2 infections between March 11th, 2020, and July 28th, 2022. We compared the SARS-CoV-2 viral kinetics of first vs. second infections in this group, adjusting for viral variant, vaccination status, and age. Relative to first infections, second infections usually featured a faster clearance time. Furthermore, a person's relative (rank-order) viral clearance time, compared to others infected with the same variant, was roughly conserved across first and second infections, so that individuals who had a relatively fast clearance time in their first infection also tended to have a relatively fast clearance time in their second infection (Spearman correlation coefficient: 0.30, 95% credible interval (0.12, 0.46)). These findings provide evidence that, like vaccination, immunity from a prior SARS-CoV-2 infection shortens the duration of subsequent acute SARS-CoV-2 infections principally by reducing viral clearance time. Additionally, there appears to be an inherent element of the immune response, or some other host factor, that shapes a person's relative ability to clear SARS-CoV-2 infection that persists across sequential infections.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Teste para COVID-19 , Projetos de Pesquisa , CinéticaRESUMO
Social gatherings can be an important locus of transmission for many pathogens including SARS-CoV-2. During an outbreak, restricting the size of these gatherings is one of several non-pharmaceutical interventions available to policy-makers to reduce transmission. Often these restrictions take the form of prohibitions on gatherings above a certain size. While it is generally agreed that such restrictions reduce contacts, the specific size threshold separating "allowed" from "prohibited" gatherings often does not have a clear scientific basis, which leads to dramatic differences in guidance across location and time. Building on the observation that gathering size distributions are often heavy-tailed, we develop a theoretical model of transmission during gatherings and their contribution to general disease dynamics. We find that a key, but often overlooked, determinant of the optimal threshold is the distribution of gathering sizes. Using data on pre-pandemic contact patterns from several sources as well as empirical estimates of transmission parameters for SARS-CoV-2, we apply our model to better understand the relationship between restriction threshold and reduction in cases. We find that, under reasonable transmission parameter ranges, restrictions may have to be set quite low to have any demonstrable effect on cases due to relative frequency of smaller gatherings. We compare our conceptual model with observed changes in reported contacts during lockdown in March of 2020.
Assuntos
COVID-19 , Doenças Transmissíveis , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Doenças Transmissíveis/epidemiologia , Humanos , Pandemias/prevenção & controle , SARS-CoV-2RESUMO
Social gatherings can be an important locus of transmission for many pathogens including SARS-CoV-2. During an outbreak, restricting the size of these gatherings is one of several non-pharmaceutical interventions available to policy-makers to reduce transmission. Often these restrictions take the form of prohibitions on gatherings above a certain size. While it is generally agreed that such restrictions reduce contacts, the specific size threshold separating "allowed" from "prohibited" gatherings often does not have a clear scientific basis, which leads to dramatic differences in guidance across location and time. Building on the observation that gathering size distributions are often heavy-tailed, we develop a theoretical model of transmission during gatherings and their contribution to general disease dynamics. We find that a key, but often overlooked, determinant of the optimal threshold is the distribution of gathering sizes. Using data on pre-pandemic contact patterns from several sources as well as empirical estimates of transmission parameters for SARS-CoV-2, we apply our model to better understand the relationship between restriction threshold and reduction in cases. We find that, under reasonable transmission parameter ranges, restrictions may have to be set quite low to have any demonstrable effect on cases due to relative frequency of smaller gatherings. We compare our conceptual model with observed changes in reported contacts during lockdown in March of 2020.
RESUMO
A key issue distinguishing prominent evolutionary models of human life history is whether prolonged childhood evolved to facilitate learning in a skill- and strength-intensive foraging niche requiring high levels of cooperation. Considering the diversity of environments humans inhabit, children's activities should also reflect local social and ecological opportunities and constraints. To better understand our species' developmental plasticity, the present paper compiled a time allocation dataset for children and adolescents from twelve hunter-gatherer and mixed-subsistence forager societies (n = 690; 3-18 years; 52% girls). We investigated how environmental factors, local ecological risk, and men and women's relative energetic contributions were associated with cross-cultural variation in child and adolescent time allocation to childcare, food production, domestic work, and play. Annual precipitation, annual mean temperature, and net primary productivity were not strongly associated with child and adolescent activity budgets. Increased risk of encounters with dangerous animals and dehydration negatively predicted time allocation to childcare and domestic work, but not food production. Gender differences in child and adolescent activity budgets were stronger in societies where men made greater direct contributions to food production than women. We interpret these findings as suggesting that children and their caregivers adjust their activities to facilitate the early acquisition of knowledge which helps children safely cooperate with adults in a range of social and ecological environments. These findings compel us to consider how childhood may have also evolved to facilitate flexible participation in productive activities in early life.