RESUMEN
BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO PMWG) was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected on tumour-only sequencing, which were based on an analysis of 17 152 cancers. METHODS: We analysed an expanded dataset including 49 264 paired tumour-normal samples. We applied filters to tumour-detected variants based on variant allele frequency, predicted pathogenicity and population variant frequency. For 58 cancer-susceptibility genes, we then examined the proportion of filtered tumour-detected variants of true germline origin [germline conversion rate (GCR)]. We conducted subanalyses based on the age of cancer diagnosis, specific tumour types and 'on-tumour' status (established tumour-gene association). RESULTS: Analysis of 45 472 nonhypermutated solid malignancy tumour samples yielded 21 351 filtered tumour-detected variants of which 3515 were of true germline origin. 3.1% of true germline pathogenic variants were absent from the filtered tumour-detected variants. For genes such as BRCA1, BRCA2 and PALB2, the GCR in filtered tumour-detected variants was >80%; conversely for TP53, APC and STK11 this GCR was <2%. CONCLUSION: Strategic germline-focused analysis can prioritise a subset of tumour-detected variants for which germline follow-up will produce the highest yield of most actionable true germline variants. We present updated recommendations around germline follow-up of tumour-only sequencing including (i) revision to 5% for the minimum per-gene GCR, (ii) inclusion of actionable intermediate penetrance genes ATM and CHEK2, (iii) definition of a set of seven 'most actionable' cancer-susceptibility genes (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6 and RET) in which germline follow-up is recommended regardless of tumour type.
Asunto(s)
Neoplasias , Medicina de Precisión , Humanos , Frecuencia de los Genes , Mutación de Línea Germinal , Genes BRCA2 , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Breast cancer has a significant heritable basis, of which â¼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.
Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Adulto , Mutación de Línea Germinal , Neoplasias de la Mama/genética , Neoplasias de la Mama/diagnóstico , Estudios Retrospectivos , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/genéticaRESUMEN
PURPOSE: Where multiple in silico tools are concordant, the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) framework affords supporting evidence toward pathogenicity or benignity, equivalent to a likelihood ratio of ~2. However, limited availability of "clinical truth sets" and prior use in tool training limits their utility for evaluation of tool performance. METHODS: We created a truth set of 9,436 missense variants classified as deleterious or tolerated in clinically validated high-throughput functional assays for BRCA1, BRCA2, MSH2, PTEN, and TP53 to evaluate predictive performance for 44 recommended/commonly used in silico tools. RESULTS: Over two-thirds of the tool-threshold combinations examined had specificity of <50%, thus substantially overcalling deleteriousness. REVEL scores of 0.8-1.0 had a Positive Likelihood Ratio (PLR) of 6.74 (5.24-8.82) compared to scores <0.7 and scores of 0-0.4 had a Negative Likelihood Ratio (NLR) of 34.3 (31.5-37.3) compared to scores of >0.7. For Meta-SNP, the equivalent PLR = 42.9 (14.4-406) and NLR = 19.4 (15.6-24.9). CONCLUSION: Against these clinically validated "functional truth sets," there was wide variation in the predictive performance of commonly used in silico tools. Overall, REVEL and Meta-SNP had best balanced accuracy and might potentially be used at stronger evidence weighting than current ACMG/AMP prescription, in particular for predictions of benignity.
Asunto(s)
Genómica , Neoplasias , Simulación por Computador , Variación Genética , Humanos , Mutación Missense , Neoplasias/diagnóstico , Neoplasias/genéticaRESUMEN
Wearable camera photo review has successfully been used to enhance memory, yet very little is known about the underlying mechanisms. Here, the sequential presentation of wearable camera photos - a key feature of wearable camera photo review - is examined using behavioural and EEG measures. Twelve female participants were taken on a walking tour, stopping at a series of predefined targets, while wearing a camera that captured photographs automatically. A sequence of four photos leading to these targets was selected (â¼ 200 trials) and together with control photos, these were used in a recognition task one week later. Participants' recognition performance improved with the sequence of photos (measured in hit rates, correct rejections, & sensitivity), revealing for the first time, a positive effect of sequence of photos in wearable camera photo review. This has important implications for understanding the sequential and cumulative effects of cues on episodic remembering. An old-new ERP effect was also observed over visual regions for hits vs. correct rejections, highlighting the importance of visual processing not only for perception but also for the location of activated memory representations.
Asunto(s)
Memoria Episódica , Dispositivos Electrónicos Vestibles , Femenino , Humanos , Recuerdo Mental , Reconocimiento en Psicología , Percepción VisualRESUMEN
BACKGROUND: Cancer diagnostics and surgery have been disrupted by the response of health care services to the coronavirus disease 2019 (COVID-19) pandemic. Progression of cancers during delay will impact on patients' long-term survival. PATIENTS AND METHODS: We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of 3 and 6 months and periods of disruption of 1 and 2 years. Using health care resource costing, we contextualise attributable lives saved and life-years gained (LYGs) from cancer surgery to equivalent volumes of COVID-19 hospitalisations. RESULTS: Per year, 94 912 resections for major cancers result in 80 406 long-term survivors and 1 717 051 LYGs. Per-patient delay of 3/6 months would cause attributable death of 4755/10 760 of these individuals with loss of 92 214/208 275 life-years, respectively. For cancer surgery, average LYGs per patient are 18.1 under standard conditions and 17.1/15.9 with a delay of 3/6 months (an average loss of 0.97/2.19 LYGs per patient), respectively. Taking into account health care resource units (HCRUs), surgery results on average per patient in 2.25 resource-adjusted life-years gained (RALYGs) under standard conditions and 2.12/1.97 RALYGs following delay of 3/6 months. For 94 912 hospital COVID-19 admissions, there are 482 022 LYGs requiring 1 052 949 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5.08 LYG and 0.46 RALYGs. CONCLUSIONS: Modest delays in surgery for cancer incur significant impact on survival. Delay of 3/6 months in surgery for incident cancers would mitigate 19%/43% of LYGs, respectively, by hospitalisation of an equivalent volume of admissions for community-acquired COVID-19. This rises to 26%/59%, respectively, when considering RALYGs. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/epidemiología , Neoplasias/epidemiología , Neoplasias/cirugía , Pandemias/prevención & control , Neumonía Viral/epidemiología , Tiempo de Tratamiento/tendencias , Adulto , Anciano , Anciano de 80 o más Años , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/terapia , Femenino , Hospitalización/tendencias , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Neumonía Viral/diagnóstico , Neumonía Viral/terapia , SARS-CoV-2 , Resultado del TratamientoRESUMEN
BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. DISCUSSION AND CONCLUSION: Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.
Asunto(s)
Homocigoto , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias Testiculares/genética , Genoma , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focussed analysis' is carried out upon tumour sequencing data and for which variants follow-up analysis of a germline sample is carried out. Here we present analyses of paired sequencing data from 17 152 cancer samples, in which 1494 pathogenic sequence variants were identified across 65 cancer susceptibility genes. From these analyses, the European Society of Medical Oncology Precision Medicine Working Group Germline Subgroup has generated (i) recommendations regarding germline-focussed analyses of tumour-only sequencing data, (ii) indications for germline follow-up testing and (iii) guidance on patient information-giving and consent.
Asunto(s)
Biomarcadores de Tumor/genética , Pruebas Genéticas/normas , Neoplasias/diagnóstico , Medicina de Precisión/métodos , Análisis Mutacional de ADN , Unión Europea , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Consentimiento Informado/normas , Oncología Médica/métodos , Oncología Médica/normas , Neoplasias/genética , Guías de Práctica Clínica como Asunto , Medicina de Precisión/normas , Sociedades Médicas/normasRESUMEN
Positivity biases in autobiographical memory and episodic future thinking are considered important in mental wellbeing and are reduced in anxiety and depression. The inhibitory processes underlying retrieval-induced forgetting (RIF) have been proposed to contribute to these biases. This investigation found reduced positivity in past and future thinking to be associated with reduced memory specificity alongside greater levels of anxiety, depression, and rumination. Most notably, however, RIF was found to significantly predict memory valence. This indicates that RIF may be important in maintaining such biases, facilitating the forgetting of negative memories when a positive item is actively retrieved.
Asunto(s)
Ansiedad/fisiopatología , Depresión/fisiopatología , Memoria Episódica , Recuerdo Mental/fisiología , Pensamiento/fisiología , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The adrenal hormones cortisol and dehydroepiandrosterone (DHEA) share a common secretagogue: adrenocorticotropic hormone; however, secretion of these hormones can be dissociated suggesting subtle individual regulation at the level of the adrenal gland. We examined differences in the diurnal patterns of cortisol and DHEA secretion in healthy adolescent girls, with the aim of informing the possibility of exploiting these differences to aid interpretation of data from clinical populations in which these patterns can become dysregulated. Fifty-six healthy females aged 10-18 years provided saliva samples at 0 and 30 min (morning samples) and 12 h post-awakening on 2 consecutive weekdays. For morning salivary cortisol in relation to morning DHEA concentrations, correlational analysis revealed only a trend (p = 0.054). Similarly, the association between evening cortisol and DHEA was characterised as a trend (p = 0.084). Mean morning DHEA concentrations showed more day-to-day consistency than equivalent cortisol samples (r = 0.829 for DHEA and 0.468 for cortisol; z = 3.487, p < 0.0005). Unlike the cortisol pattern, characterised by a marked awakening response (cortisol awakening response, CAR), a significant rise in DHEA concentration post-awakening was not evident. Finally, there was a strong association between morning and evening concentrations of DHEA, not found for cortisol. The study shows differences in cortisol and DHEA secretion in the post-awakening period and informs work that seeks to examine correlates of dysregulated hypothalamic-pituitary-adrenal axis function. Parallel examination of both hormones enables enhanced interpretation of aberrant patterns of the CAR, i.e. an exploration of whether dysregulation affects both hormones (reflecting overall steroidogenic capacity) or cortisol alone (CAR-specific mechanisms).
Asunto(s)
Ritmo Circadiano/fisiología , Deshidroepiandrosterona/metabolismo , Hidrocortisona/metabolismo , Saliva/química , Adolescente , Niño , Femenino , HumanosRESUMEN
Associations between cognitive performance and cortisol have variously been reported for measures of both cortisol level and change, and for some domains of cognitive functioning more than others. In this study, associations between cortisol secretion measures and cognitive performance were examined in 50 healthy older people (mean age 74 years; 34 F /16 M). Participants provided 16 accurately timed saliva samples over 2 consecutive days to determine diurnal profiles of cortisol secretion. Overall cognitive performance (OCP) was measured as the principal component of a comprehensive battery of cognitive tests. Across a 30 year age range, there was a strong inverse correlation between age and OCP. Age and poorer OCP were also associated with an attenuated cortisol awakening response (CAR), defined as the rise from 0-30 min after awakening, and a subsequent less steep fall in cortisol level over the rest of the day. Partialling analyses, suggested that the correlation between fall in cortisol over the day and OCP was independent of age. Both older age and less cortisol change were particularly related to poorer performance on tests of declarative memory and executive functioning. Our conclusions are that during the short post-awakening period, an exception exists to the generally pertaining association between higher levels of cortisol and poorer cognitive performance. Consequentially dynamic measures reflecting the rise (CAR) and fall from the post-awakening peak may be particularly salient in helping to explain links between cortisol and cognitive performance. Finally our pattern of results across different cognitive tests suggests an association between cortisol and those domains of cognitive functioning which depend crucially on the integrity of the hippocampus and pre-frontal cortex.
Asunto(s)
Anciano/fisiología , Ritmo Circadiano/fisiología , Cognición/fisiología , Hidrocortisona/metabolismo , Anciano de 80 o más Años , Función Ejecutiva/fisiología , Femenino , Humanos , Aprendizaje/fisiología , Masculino , Memoria/fisiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Desempeño Psicomotor/fisiología , Saliva/metabolismo , Caracteres Sexuales , Prueba de Secuencia Alfanumérica , Conducta Verbal/fisiologíaRESUMEN
BACKGROUND: Information about patterns of HIV-1 drug resistance among treatment-exposed patients is crucial for the development of novel effective drugs. Currently no system exists that monitors patterns of resistance in patients failing therapy. METHODS: The study included 1,988 HIV-1 sequences from patients experiencing therapy failure collected between 2000 and 2004 in 15 European countries. Genotypic resistance was interpreted using the ANRS algorithm. Phenotypic resistance was predicted using the Virco geno- to phenotype system. RESULTS: 80.7% of the sequences included at least one drug-resistance mutation. Mutations were found for NRTIs (73.5%), NNRTIs (48.5%), and protease inhibitors (35.8%). Ninety percent of sequences with genotypic resistance harbored M184V, M41L, K103N, D67N, and/or T215Y. Among NRTIs, resistance was most frequently predicted for lamivudine. About half of all sequences had reduced susceptibility for NNRTIs. Resistance to most boosted protease inhibitors was found in < 25%. No sequence had resistance to all currently available drugs. CONCLUSION: Levels of resistance among patients with therapy failure were high. The patterns of resistance reflect resistance to drugs available for a longer time. Fully suppressive regimens can be designed even for the most mutated HIV because boosted protease inhibitors have remained active against most circulating viruses and new drug classes have become available.
Asunto(s)
Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Adulto , Sustitución de Aminoácidos , Europa (Continente) , Femenino , Genotipo , Infecciones por VIH/virología , Proteasa del VIH/genética , Inhibidores de la Proteasa del VIH/uso terapéutico , Transcriptasa Inversa del VIH/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Análisis de Secuencia de Proteína , Insuficiencia del TratamientoRESUMEN
When examining the diurnal profile of the hormone cortisol in children and adolescents developmental issues are particularly relevant. Previous findings regarding relationships between cortisol secretory activity and reproductive (pubertal) maturation lack clarity and may reflect methodological inconsistencies between studies. This study examined the diurnal cortisol profile across female adolescence, with a particular focus on an obvious and unique marker of development: menarche. In a cross-sectional design, 61 healthy female adolescents aged 9-18 years (mean age 13.89 years, S.D.+/-2.72) collected eight saliva samples per day on two consecutive weekdays. Samples were collected at awakening, 15, 30 and 45min and 3, 6, 9 and 12h post-awakening in order to capture both the cortisol awakening response (CAR) and the subsequent period of decline. Demographic information was recorded and participants also completed the Spielberger State-Trait Anxiety Inventory. Patterns of cortisol secretion exhibited good intra-individual stability across the two sampling days. Participants evidenced a robust diurnal pattern, with cortisol levels peaking approximately 30-45min post-awakening (the CAR) and steadily declining concentrations over the remainder of the day. Differences according to developmental status (in terms of whether or not participants had experienced first menses: menarche) were observed in the time of peak secretion of the CAR, and these distinct patterns could not be accounted for by group differences in demographic, situational or psychological characteristics measured in this study. This effect for the CAR was associated with the onset of menarche alone, unlike cortisol levels over the remainder of the day. For those who had undergone menarche, were older and of greater BMI, cortisol levels remained higher over the day. There was a significant difference in cortisol concentrations at 6h post-awakening between pre- and post-menarche groups. Again, these differences in daytime cortisol secretory activity could not be attributed to situational or psychological factors. Establishing patterns of cortisol secretion in healthy female adolescents provides an important baseline from which to investigate hypothalamic-pituitary-adrenal (HPA) physiology, measured via salivary cortisol, in adolescent populations with known or suspected psychopathology.
Asunto(s)
Desarrollo del Adolescente/fisiología , Ritmo Circadiano/fisiología , Hidrocortisona/metabolismo , Saliva/metabolismo , Adolescente , Nivel de Alerta , Niño , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/fisiología , Menarquia/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Psicología del Adolescente , Factores de TiempoRESUMEN
OBJECTIVES: To assess the clinical utility of phenotypic resistance testing in addition to genotypic resistance testing among HIV-1-infected patients experiencing virologic failure and with limited therapeutic options. DESIGN: Multicenter randomized trial. METHODS: Patients were eligible if a decision had been made to switch antiretroviral therapy, the most recent HIV-1 RNA plasma viral load (VL) exceeded 2000 copies/mL, and the clinician was unable to select a potent regimen of 3 or more drugs without access to a resistance test. Subjects were randomized to genotypic resistance testing alone (G arm) or to genotypic plus phenotypic testing (G + P arm). Patients had access to resistance testing at any time during follow-up (minimum of 1 year) according to the original allocation. The primary end point was change in plasma VL from baseline at 12 months. RESULTS: Three hundred eleven patients were recruited between February 2000 and July 2001. At baseline, mean VL and CD4 count were 4.23 log10 copies/mL and 275 cells/mm, respectively, and subjects had previous exposure to a mean of 7.7 antiretroviral drugs. There was no appreciable difference between the study arms in the drug regimens prescribed after randomization. Mean reduction in VL load at 12 months was similar in the 2 arms (G: 1.37 log10 reduction, G + P: 1.28 log10 reduction; P = 0.77), as was the proportion of subjects with VL <50 copies/mL (G: 35%, G + P: 27%). CONCLUSION: The study did not demonstrate added value of phenotypic resistance testing in conjunction with genotypic resistance testing in patients with limited therapeutic options.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/virología , Farmacorresistencia Viral , VIH-1/genética , VIH/genética , Adulto , Recuento de Linfocito CD4 , Farmacorresistencia Viral/genética , Genotipo , VIH/efectos de los fármacos , VIH-1/aislamiento & purificación , Humanos , Fenotipo , ARN Viral/sangre , Reproducibilidad de los Resultados , Reino Unido , Carga ViralRESUMEN
Normal pressure hydrocephalus (NPH) accounts for one of the few known forms of reversible dementia. Varied aetiology and clinical presentation contribute to difficulties with early or differential diagnoses, and delayed surgical treatment may be less efficacious. Clinical neuropsychology provides a means of determining a cognitive profile for NPH, assisting in differential diagnosis, tracking the disorder's progression and assessing the efficacy of treatment. This article will review possible applications of clinical neuropsychology and propose a clinical assessment protocol for NPH.
Asunto(s)
Trastornos del Conocimiento/diagnóstico , Hidrocéfalo Normotenso/diagnóstico , Protocolos Clínicos , Cognición/fisiología , Trastornos del Conocimiento/fisiopatología , Demencia/diagnóstico , Demencia/fisiopatología , Humanos , Hidrocéfalo Normotenso/fisiopatología , Hidrocéfalo Normotenso/psicología , Presión Intracraneal , Pruebas Neuropsicológicas , Desempeño Psicomotor/fisiología , Calidad de Vida , InvestigaciónRESUMEN
OBJECTIVES: To determine the relative impact of hydrocephalus and spinal dysraphism in young adults on intellectual and cognitive functioning. Sub-groups of patients with congenital hydrocephalus and/or spina bifida were assessed between 1995 and 2003. The entry criteria were that individuals should have (i) intact global function, (ii) average verbal intelligence (or above), and (iii) should not have clinical depression. There were three sub-groups: patients with hydrocephalus and spina bifida, patients with hydrocephalus without spina bifida, and patients with spina bifida without hydrocephalus. METHODS: Patients were neuropsychologically assessed as part of their normal clinical assessment during their annual medical review. Each individual completed a screening battery assessing global functioning, verbal intelligence, and mood. In addition they completed additional tests including measures of emotional intelligence, memory, attention, and executive function. Results were analysed to compare the performance of the patient sub-groups and to compare them to a healthy control group. RESULTS: Patients with hydrocephalus (with or without spina bifida) were significantly impaired on the vast majority of all test scores as compared to patients with spina bifida and healthy controls. They were particularly poor on measures assessing executive function. By contrast for patients with spina bifida with no associated hydrocephalus, the significant majority of all test scores fell within the average range or above. CONCLUSIONS: The neuropsychological profile of patients with hydrocephalus is one of relative impairment and this is so whether or not spina bifida is present. In spina bifida alone, in the absence of hydrocephalus, cognitive function is relatively spared.
Asunto(s)
Trastornos del Conocimiento/etiología , Hidrocefalia/etiología , Hidrocefalia/psicología , Inteligencia , Disrafia Espinal/complicaciones , Disrafia Espinal/psicología , Adulto , Atención , Estudios de Casos y Controles , Femenino , Humanos , Pruebas de Inteligencia , Masculino , MemoriaAsunto(s)
Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/economía , Terapia Antirretroviral Altamente Activa/efectos adversos , Farmacorresistencia Viral , Seropositividad para VIH/tratamiento farmacológico , Humanos , Cooperación del Paciente , Inhibidores de Proteasas/uso terapéutico , Terapia Recuperativa/métodosRESUMEN
OBJECTIVE: To use a stochastic model to gain insights into the consequence for resistance development of different drug use patterns. METHODS: We consider use of three drugs (A, B and C) where for each drug one and only one viral mutation is associated with ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. For drug A mutation is a, etc. We define eight populations of short-lived infected cells that live 1 day: Vo with no mutations a, b, c; Va with mutation a only, Vab with mutations a and b, etc. A random number generator was used to determine whether mutations occur in any one round of replication and to sample from a Poisson distribution to determine for each cell the number of cells of the same population created in the next generation, using the R operative at that time. Values of R depended on drug exposure, cost of resistance and availability of target cells. RESULTS: Treatment strategies and the resulting percentage (over 100 runs) developing full "resistance" in 1500 days (Vabc not equal 0) were: (i) ABC 1500 days 0%; (ii) A 300 days, AB 300 days, ABC 900 days 100%; (iii) AB 300 days, ABC 1200 days 33%; (iv) ABC 2/3 1500 days 15%; (v) ABC 1/2 1500 days 100%; (vi) ABC 50 days, no drugs 50 days, for 1500 days 1%, where ABC 2/3 means on-drug for 2 days in every 3, ABC 1/2 represents on-drug for 1 day in every 2, and represents suboptimal adherence. CONCLUSIONS: This model helps to develop understanding of key principles concerning development of resistance under different patterns of treatment use.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Simulación por Computador , Farmacorresistencia Viral Múltiple , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Modelos Estadísticos , Procesos Estocásticos , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral , VIH-1/genética , Humanos , MutaciónRESUMEN
PURPOSE: This study investigated the factors that may affect adherence to antiretroviral therapy in people with HIV infection and compared the use of three self-report tools to determine client adherence. METHOD: A descriptive, cross-sectional study of 260 HIV-infected clients attending nine HIV outpatient centers in England was conducted using researcher-administered instruments. Self-reports of adherence were assessed using the Morisky Medication Adherence Scale (MMAS), Reported Adherence to Medication Scale (RAM), and the Patient Adjustment to Medication Scale (PAM). RESULTS: Univariate analysis of clients' self-reports indicated a number of associations with adherence. Significant associations with less adherent behavior identified by two or more self-report tools were the reported use of recreational drugs, p =.001; living alone, p =.041; feeling depressed, p =.02; being influenced by the media, p =.037; and lack of a close confidant, p =.037. Greater adherence was associated with clients reporting a positive mental attitude to HIV infection, p =.038. Principal component analysis (PCA) of each self-report tool identified two well-recognized constructs: intentional nonadherence and unintentional nonadherence. In addition, a third construct of following instructions was identified from PAM, a scale developed by the authors. Subsequent regression analysis failed to confirm the associations with adherence suggested by the univariate analysis. CONCLUSION: This study suggests that the design and use of self-report tools to identify client's adherence to complex antiretroviral regimens may need to measure individual constructs of adherence to accurately assess adherence behavior.