RESUMEN
Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work.
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Evolución Biológica , Sexo , Animales , Femenino , Humanos , Masculino , Caracteres Sexuales , Fenotipo , Células Germinativas/citología , Tamaño de la CélulaRESUMEN
AIM: There are no data on the performance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the staging and diagnosis of lung cancer in New Zealand. We aimed to assess the performance of EBUS-TBNA for lung cancer staging and diagnosis at our institution before and after the commencement of regular performance monitoring with comparison to published EBUS quality indicators. METHODS: The performance of EBUS-TBNA in the staging and diagnosis of lung cancer was assessed in two phases. Phase 1 consisted of a retrospective review of all lung cancer EBUS performed over a 2-year period. Published quality indicators were determined from the literature with relevant indicators being extracted and used to determine EBUS performance. Local reporting and education were undertaken and prospective data collection was commenced. Phase 2 consisted of prospective assessment of all lung cancer EBUS over the subsequent year. Performance of EBUS was then compared between phases 1 and 2 in order to determine the effect of performance monitoring and identify areas for service improvement. RESULTS: A total of 115 staging EBUS and 117 diagnostic EBUS were performed during the study period. Staging EBUS demonstrated good performance across phases 1 and 2 with high sensitivity and negative predictive values (NPV) for the detection of N2/3 disease, meeting published quality standards. During phase 2 there was evidence of a transition towards more guideline-concordant practice evidenced by more detailed nodal sampling during staging EBUS; however, this did not affect overall sensitivity or NPV. Diagnostic EBUS resulted in high rates of pathological confirmation meeting published quality standards across both phases. Pathway times were similar between phases 1 and 2, with reporting of molecular profiling being the predominant factor in delayed pathway times. CONCLUSION: Monitoring and reporting of local performance allows critical assessment of practice and can identify areas for quality improvement. This review demonstrated good overall performance but prompted a move towards more guideline-concordant practice with increased mediastinal nodal sampling during staging procedures. Consideration should be given to the adoption of routine EBUS performance monitoring within local and/or regional networks, which could be incorporated alongside the newly proposed Lung Cancer Clinical Quality Registry.
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Neoplasias Pulmonares , Estadificación de Neoplasias , Indicadores de Calidad de la Atención de Salud , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico por imagen , Nueva Zelanda , Masculino , Femenino , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/normas , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/métodos , Estudios Prospectivos , Broncoscopía/métodos , Anciano de 80 o más Años , Endosonografía/métodos , Endosonografía/normas , AdultoRESUMEN
OBJECTIVE: The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01649869.
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Antivirales , Infecciones por Citomegalovirus , Ganciclovir , Pérdida Auditiva Sensorineural , Valganciclovir , Humanos , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/complicaciones , Valganciclovir/uso terapéutico , Valganciclovir/administración & dosificación , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Pérdida Auditiva Sensorineural/virología , Pérdida Auditiva Sensorineural/etiología , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Masculino , Femenino , Método Doble Ciego , Lactante , Administración Oral , Ganciclovir/análogos & derivados , Ganciclovir/uso terapéutico , Ganciclovir/administración & dosificación , Preescolar , Resultado del Tratamiento , Carga Viral , Recién NacidoRESUMEN
BACKGROUND: Human cytomegalovirus (HCMV) is the most common and serious opportunistic infection after solid organ and hematopoietic stem cell transplantation. In this study, we used whole-genome HCMV data to investigate viral factors associated with the clinical outcome. METHODS: We sequenced HCMV samples from 16 immunocompromised pediatric patients with persistent viremia. Eight of the 16 patients died of complications due to HCMV infection. We also sequenced samples from 35 infected solid organ adult recipients, of whom 1 died with HCMV infection. RESULTS: We showed that samples from both groups have fixed variants at resistance sites and mixed infections. Next-generation sequencing also revealed nonfixed variants at resistance sites in most of the patients who died (6/9). A machine learning approach identified 10 genes with nonfixed variants in these patients. These genes formed a viral signature that discriminated patients with HCMV infection who died from those who survived with high accuracy (area under the curve = 0.96). Lymphocyte numbers for a subset of patients showed no recovery posttransplant in the patients who died. CONCLUSIONS: We hypothesize that the viral signature identified in this study may be a useful biomarker for poor response to antiviral drug treatment and indirectly for poor T-cell function, potentially identifying early those patients requiring nonpharmacological interventions.
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Infecciones por Citomegalovirus , Citomegalovirus , Huésped Inmunocomprometido , Humanos , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/mortalidad , Citomegalovirus/genética , Niño , Masculino , Femenino , Adulto , Preescolar , Antivirales/uso terapéutico , Adolescente , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Lactante , Trasplante de Órganos/efectos adversos , Secuenciación de Nucleótidos de Alto Rendimiento , Viremia , Genes Virales/genética , Variación Genética , Farmacorresistencia Viral/genética , Adulto Joven , Persona de Mediana EdadRESUMEN
BACKGROUND: Knowledge of the genetic basis of health conditions can influence how the public perceives their own and others' health. When there are known genetic associations for such conditions, genetic essentialist biases facilitate deterministic thinking and an over-emphasis of genetic causality. This study investigates the role that genetic essentialist biases play in medical decision-making. METHODS: Senior postgraduate medical students (N = 102) read a scenario in which a patient presents with gastroenterological symptoms. Half of the students were told that the patient tested positive for HLADQ2 - a gene implicated in, but not deterministic of, coeliac disease. The other half received no genetic information. Students were assessed on their recommendations for investigation and management using a multiple-choice questionnaire. Twenty-two of these students participated in a qualitative follow-up which used focus groups and semi-structured interviews to explore the reasoning behind students' responses. RESULTS: Management recommendations differed between the two groups, with those receiving genetic information more likely to recommend a gluten free diet. Recommendations for further investigation did not differ significantly between groups. Interviews suggested that these findings arose despite the students' good understanding of the common non-deterministic nature of genes, such as HLADQ2. CONCLUSION: Differences in management recommendations suggest that the inclusion of genetic information unduly biased students towards a premature diagnosis of a serious health condition, coeliac disease. Follow-up interviews introduced the possibility that observed manipulation-based differences may have been based on anticipated expectations of examiners, rather than perceived future clinical practice. Based on the present results it is unclear whether intentional exam-taking strategies fully account for medical students' decisions, or if they contribute in addition to the activation of genetic essentialist biases. Further research in clinical settings may ascertain whether genetic essentialist biases would truly influence medical student and doctors within their clinical practice environment.
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Enfermedad Celíaca , Estudiantes de Medicina , Humanos , Grupos Focales , Encuestas y CuestionariosRESUMEN
Cytomegalovirus (CMV) is the most common infectious cause of congenital malformation and a leading cause of developmental disabilities such as sensorineural hearing loss (SNHL), motor and cognitive deficits. The significant disease burden from congenital CMV infection (cCMV) led the US National Institute of Medicine to rank CMV vaccine development as the highest priority. An average of 6.7/1000 live births are affected by cCMV, but the prevalence varies across and within countries. In contrast to other congenital infections such as rubella and toxoplasmosis, the prevalence of cCMV increases with CMV seroprevalence rates in the population. The true global burden of cCMV disease is likely underestimated because most infected infants (85-90 %) have asymptomatic infection and are not identified. However, about 7-11 % of those with asymptomatic infection will develop SNHL throughout early childhood. Although no licensed CMV vaccine exists, several candidate vaccines are in development, including one currently in phase 3 trials. Licensure of one or more vaccine candidates is feasible within the next five years. Various models of CMV vaccine strategies employing different target populations have shown to provide substantial benefit in reducing cCMV. Although CMV can cause end-organ disease with significant morbidity and mortality in immunocompromised individuals, the focus of this vaccine value profile (VVP) is on preventing or reducing the cCMV disease burden. This CMV VVP provides a high-level, comprehensive assessment of the currently available data to inform the potential public health, economic, and societal value of CMV vaccines. The CMV VVP was developed by a working group of subject matter experts from academia, public health groups, policy organizations, and non-profit organizations. All contributors have extensive expertise on various elements of the CMV VVP and have described the state of knowledge and identified the current gaps. The VVP was developed using only existing and publicly available information.
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Infecciones por Citomegalovirus , Vacunas contra Citomegalovirus , Pérdida Auditiva Sensorineural , Lactante , Humanos , Preescolar , Citomegalovirus , Infecciones Asintomáticas , Estudios Seroepidemiológicos , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/prevención & control , Pérdida Auditiva Sensorineural/congénito , Pérdida Auditiva Sensorineural/epidemiologíaRESUMEN
Contemporary evolutionary medicine has unified the idea of 'evolutionary mismatch', derived from the older idea of 'adaptive lag' in evolution, with ideas about the mismatch in development and physiology derived from the Developmental Origins of Health and Disease (DOHaD) paradigm. A number of publications in evolutionary medicine have tried to make this theoretical framework explicit. The integrative theory of mismatch captures how organisms track environments across space and time on multiple scales in order to maintain an adaptive match to the environment, and how failures of adaptive tracking lead to disease. In this review, we try to present this complex body of theory as clearly and simply as possible with the aim of facilitating its application in new domains. We introduce terminology, which is as far as possible consistent with earlier usage, to distinguish the different forms of mismatch. Mismatch in its modern form is a productive organizing concept that can help researchers articulate how physiology, development and evolution interact with one another and with environmental change to explain health outcomes.
RESUMEN
Human cytomegalovirus (CMV) has infected humans since the origin of our species and currently infects most of the world's population. Variability between CMV genomes is the highest of any human herpesvirus, yet large portions of the genome are conserved. Here, we show that the genome encodes 74 regions of relatively high variability each with 2 to 8 alleles. We then identified two patterns in the CMV genome. Conserved parts of the genome and a minority (32) of variable regions show geographic population structure with evidence for African or European clustering, although hybrid strains are present. We find no evidence that geographic segregation has been driven by host immune pressure affecting known antigenic sites. Forty-two variable regions show no geographical structure, with similar allele distributions across different continental populations. These "nongeographical" regions are significantly enriched for genes encoding immunomodulatory functions suggesting a core functional importance. We hypothesize that at least two CMV founder populations account for the geographical differences that are largely seen in the conserved portions of the genome, although the timing of separation and direction of spread between the two are not clear. In contrast, the similar allele frequencies among 42 variable regions of the genome, irrespective of geographical origin, are indicative of a second evolutionary process, namely balancing selection that may preserve properties critical to CMV biological function. Given that genetic differences between CMVs are postulated to alter immunogenicity and potentially function, understanding these two evolutionary processes could contribute important information for the development of globally effective vaccines and the identification of novel drug targets.
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Infecciones por Citomegalovirus , Citomegalovirus , Humanos , Citomegalovirus/genética , Frecuencia de los Genes , GenómicaRESUMEN
Background: The COVID-19 pandemic has had a significant impact on delivery of NHS care. We have developed the OpenSAFELY Service Restoration Observatory (SRO) to develop key measures of primary care activity and describe the trends in these measures throughout the COVID-19 pandemic. Methods: With the approval of NHS England, we developed an open source software framework for data management and analysis to describe trends and variation in clinical activity across primary care electronic health record (EHR) data on 48 million adults.We developed SNOMED-CT codelists for key measures of primary care clinical activity such as blood pressure monitoring and asthma reviews, selected by an expert clinical advisory group and conducted a population cohort-based study to describe trends and variation in these measures January 2019-December 2021, and pragmatically classified their level of recovery one year into the pandemic using the percentage change in the median practice level rate. Results: We produced 11 measures reflective of clinical activity in general practice. A substantial drop in activity was observed in all measures at the outset of the COVID-19 pandemic. By April 2021, the median rate had recovered to within 15% of the median rate in April 2019 in six measures. The remaining measures showed a sustained drop, ranging from a 18.5% reduction in medication reviews to a 42.0% reduction in blood pressure monitoring. Three measures continued to show a sustained drop by December 2021. Conclusions: The COVID-19 pandemic was associated with a substantial change in primary care activity across the measures we developed, with recovery in most measures. We delivered an open source software framework to describe trends and variation in clinical activity across an unprecedented scale of primary care data. We will continue to expand the set of key measures to be routinely monitored using our publicly available NHS OpenSAFELY SRO dashboards with near real-time data. Funding: This research used data assets made available as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20058).The OpenSAFELY Platform is supported by grants from the Wellcome Trust (222097/Z/20/Z); MRC (MR/V015757/1, MC_PC-20059, MR/W016729/1); NIHR (NIHR135559, COV-LT2-0073), and Health Data Research UK (HDRUK2021.000, 2021.0157).
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COVID-19 , Medicina General , Humanos , Adulto , COVID-19/epidemiología , Estudios Retrospectivos , Pandemias , Inglaterra/epidemiología , Atención Primaria de SaludRESUMEN
Objective: To implement complex, PINCER (pharmacist led information technology intervention) prescribing indicators, on a national scale with general practice data to describe the impact of the covid-19 pandemic on safe prescribing. Design: Population based, retrospective cohort study using federated analytics. Setting: Electronic general practice health record data from 56.8 million NHS patients by use of the OpenSAFELY platform, with the approval of the National Health Service (NHS) England. Participants: NHS patients (aged 18-120 years) who were alive and registered at a general practice that used TPP or EMIS computer systems and were recorded as at risk of at least one potentially hazardous PINCER indicator. Main outcome measure: Between 1 September 2019 and 1 September 2021, monthly trends and between practice variation for compliance with 13 PINCER indicators, as calculated on the first of every month, were reported. Prescriptions that do not adhere to these indicators are potentially hazardous and can cause gastrointestinal bleeds; are cautioned against in specific conditions (specifically heart failure, asthma, and chronic renal failure); or require blood test monitoring. The percentage for each indicator is formed of a numerator of patients deemed to be at risk of a potentially hazardous prescribing event and the denominator is of patients for which assessment of the indicator is clinically meaningful. Higher indicator percentages represent potentially poorer performance on medication safety. Results: The PINCER indicators were successfully implemented across general practice data for 56.8 million patient records from 6367 practices in OpenSAFELY. Hazardous prescribing remained largely unchanged during the covid-19 pandemic, with no evidence of increases in indicators of harm as captured by the PINCER indicators. The percentage of patients at risk of potentially hazardous prescribing, as defined by each PINCER indicator, at mean quarter 1 (Q1) 2020 (representing before the pandemic) ranged from 1.11% (age ≥65 years and non-steroidal anti-inflammatory drugs) to 36.20% (amiodarone and no thyroid function test), while Q1 2021 (representing after the pandemic) percentages ranged from 0.75% (age ≥65 years and non-steroidal anti-inflammatory drugs) to 39.23% (amiodarone and no thyroid function test). Transient delays occurred in blood test monitoring for some medications, particularly angiotensin-converting enzyme inhibitors (where blood monitoring worsened from a mean of 5.16% in Q1 2020 to 12.14% in Q1 2021, and began to recover in June 2021). All indicators substantially recovered by September 2021. We identified 1 813 058 patients (3.1%) at risk of at least one potentially hazardous prescribing event. Conclusion: NHS data from general practices can be analysed at national scale to generate insights into service delivery. Potentially hazardous prescribing was largely unaffected by the covid-19 pandemic in primary care health records in England.
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Human cytomegalovirus (HCMV) remains an important cause of mortality in immune-compromised transplant patients and following congenital infection. Such is the burden, an effective vaccine strategy is considered to be of the highest priority. The most successful vaccines to date have focused on generating immune responses against glycoprotein B (gB) - a protein essential for HCMV fusion and entry. We have previously reported that an important component of the humoral immune response elicited by gB/MF59 vaccination of patients awaiting transplant is the induction of non-neutralizing antibodies that target cell-associated virus with little evidence of concomitant classical neutralizing antibodies. Here we report that a modified neutralization assay that promotes prolonged binding of HCMV to the cell surface reveals the presence of neutralizing antibodies in sera taken from gB-vaccinated patients that cannot be detected using standard assays. We go on to show that this is not a general feature of gB-neutralizing antibodies, suggesting that specific antibody responses induced by vaccination could be important. Although we can find no evidence that these neutralizing antibody responses are a correlate of protection in vivo in transplant recipients their identification demonstrates the utility of the approach in identifying these responses. We hypothesize that further characterization has the potential to aid the identification of functions within gB that are important during the entry process and could potentially improve future vaccine strategies directed against gB if they prove to be effective against HCMV at higher concentrations.
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Anticuerpos Neutralizantes , Vacunas , Humanos , Citomegalovirus , Temperatura , VacunaciónRESUMEN
Natural killer cells are considered to be important for control of human cytomegalovirus- a major pathogen in immune suppressed transplant patients. Viral infection promotes the development of an adaptive phenotype in circulating natural killer cells that changes their anti-viral function. In contrast, less is understood how natural killer cells that reside in tissue respond to viral infection. Here we show natural killer cells resident in the liver have an altered phenotype in cytomegalovirus infected individuals and display increased anti-viral activity against multiple viruses in vitro and identify and characterise a subset of natural killer cells responsible for control. Crucially, livers containing natural killer cells with better capacity to control cytomegalovirus replication in vitro are less likely to experience viraemia post-transplant. Taken together, these data suggest that virally induced expansion of tissue resident natural killer cells in the donor organ can reduce the chance of viraemia post-transplant.
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Infecciones por Citomegalovirus , Citomegalovirus , Humanos , Viremia , Células Asesinas Naturales , HígadoRESUMEN
BACKGROUND: The primary aim of the study is to test the null hypothesis that there are no statistically significant differences in intracranial volumes between male and female fetuses. Furthermore, we have studied the symmetry of the cerebral hemispheres in the cohort of low-risk fetuses. METHODS: 200 normal fetuses between 18 and 37 gestational weeks (gw) were included in the cohort and all had in utero MR, consisting of routine and 3D-volume imaging. The surfaces of the cerebral ventricles, brain and internal table of the skull were outlined manually and volume measurements were obtained of ventricles (VV), brain parenchyma (BPV), extraaxial CSF spaces (EAV) and the total intracranial volume (TICV). The changes in those values were studied over the gestational range, along with potential gender differences and asymmetries of the cerebral hemispheres. RESULTS: BPV and VV increased steadily from 18 to 37 gestational weeks, and as a result TICV also increased steadily over that period. TICV and BPV increased at a statistically significantly greater rate in male relative to female fetuses after 24gw. The greater VV in male fetuses was apparent earlier, but the rate of increase was similar for male and female fetuses. There was no difference between the genders in the left and right hemispherical volumes, and they remained symmetrical over the age range measured. CONCLUSIONS: We have described the growth of the major intracranial compartments in fetuses between 18 and 37gw. We have shown a number of statistically different features between male and female fetuses, but we have not detected any asymmetry in volumes of the fetal cerebral hemispheres.
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Encéfalo , Caracteres Sexuales , Embarazo , Femenino , Humanos , Masculino , Factores Sexuales , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodosRESUMEN
INTRODUCTION: In a previous study of classifying fetuses with cortical formation abnormalities (CFA) with fetal MR, we noticed a cluster of cases with unilateral CFA and complete agenesis of the corpus callosum (ACC). In this study, we provide a detailed morphological analysis of such fetuses using fetal MR to determine if there are indicators (such as the gender of the fetus) that could be used to delineate a genetic substrate of the phenotype in order to inform future studies. METHODS: We have studied 45 fetuses with the unilateral CFA/ACC phenotype and analysed through an expert consensus panel the location and fine detail of the CFA and the associated findings such as associated anomalies, head size, and sex of the fetus. RESULTS: The frontal lobe was significantly more frequently involved by CFA when compared with other lobes (p < 0.001) but no preference for the left or right hemisphere. CFA most often consisted of excessive/dysmorphic sulcation. The CFA/ACC phenotype was overwhelmingly more frequent in male fetuses (M:F 4.5:1-p < 0.0001). The most frequent associated findings were: ventriculomegaly (16/45 fetuses) and interhemispheric cysts (12/45 cases). CONCLUSIONS: This report highlights the specific phenotype of unilateral CFA/ACC that is much more common in male fetuses. This finding provides a starting point to study possible sex-linked genetic abnormalities that underpin the unilateral CFA/ACC phenotype. KEY POINTS: ⢠We collected fetuses with unilateral cortical formation abnormality and callosal agenesis. ⢠That distinctive neuroimaging phenotype has a strong male gender prevalence (over 80%). ⢠This observation forms the basis of studies about outcomes and genetic substrates.
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Cuerpo Calloso , Malformaciones del Sistema Nervioso , Masculino , Femenino , Embarazo , Humanos , Cuerpo Calloso/diagnóstico por imagen , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Feto/diagnóstico por imagen , Ultrasonografía Prenatal/métodosRESUMEN
Longitudinal deep sequencing of viruses can provide detailed information about intra-host evolutionary dynamics including how viruses interact with and transmit between hosts. Many analyses require haplotype reconstruction, identifying which variants are co-located on the same genomic element. Most current methods to perform this reconstruction are based on a high density of variants and cannot perform this reconstruction for slowly evolving viruses. We present a new approach, HaROLD (HAplotype Reconstruction Of Longitudinal Deep sequencing data), which performs this reconstruction based on identifying co-varying variant frequencies using a probabilistic framework. We illustrate HaROLD on both RNA and DNA viruses with synthetic Illumina paired read data created from mixed human cytomegalovirus (HCMV) and norovirus genomes, and clinical datasets of HCMV and norovirus samples, demonstrating high accuracy, especially when longitudinal samples are available.