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1.
BMJ Open ; 10(11): e043828, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33203640

RESUMEN

OBJECTIVES: To estimate the impact of the COVID-19 pandemic on cancer care services and overall (direct and indirect) excess deaths in people with cancer. METHODS: We employed near real-time weekly data on cancer care to determine the adverse effect of the pandemic on cancer services. We also used these data, together with national death registrations until June 2020 to model deaths, in excess of background (pre-COVID-19) mortality, in people with cancer. Background mortality risks for 24 cancers with and without COVID-19-relevant comorbidities were obtained from population-based primary care cohort (Clinical Practice Research Datalink) on 3 862 012 adults in England. RESULTS: Declines in urgent referrals (median=-70.4%) and chemotherapy attendances (median=-41.5%) to a nadir (lowest point) in the pandemic were observed. By 31 May, these declines have only partially recovered; urgent referrals (median=-44.5%) and chemotherapy attendances (median=-31.2%). There were short-term excess death registrations for cancer (without COVID-19), with peak relative risk (RR) of 1.17 at week ending on 3 April. The peak RR for all-cause deaths was 2.1 from week ending on 17 April. Based on these findings and recent literature, we modelled 40% and 80% of cancer patients being affected by the pandemic in the long-term. At 40% affected, we estimated 1-year total (direct and indirect) excess deaths in people with cancer as between 7165 and 17 910, using RRs of 1.2 and 1.5, respectively, where 78% of excess deaths occured in patients with ≥1 comorbidity. CONCLUSIONS: Dramatic reductions were detected in the demand for, and supply of, cancer services which have not fully recovered with lockdown easing. These may contribute, over a 1-year time horizon, to substantial excess mortality among people with cancer and multimorbidity. It is urgent to understand how the recovery of general practitioner, oncology and other hospital services might best mitigate these long-term excess mortality risks.

2.
Open Forum Infect Dis ; 6(1): ofy333, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30648127

RESUMEN

Background: There are no host biomarkers of risk for HIV-associated cryptococcal meningitis (CM) except CD4+ T-cell deficiency. At present, serum cryptococcal antigen (CrAg) screening of those with CD4 <100 cells/µL is used to identify persons at risk for HIV-associated CM. We determined if plasma antibody profiles could discriminate CrAg+ from CrAg- patients. Methods: We performed serological analyses of 237 HIV-infected asymptomatic Zimbabwean patients with CD4 <100 cells/µL; 125 CrAg- and CrAg+ but cerebrospinal fluid CrAg- by CrAg lateral flow assay. We measured plasma immunoglobulin M (IgM), immunoglobulin G (IgG) 1, and IgG2 concentrations by Luminex, and titers of Cryptococcus neoformans (Cn) glucuronoxylomannan (GXM) polysaccharide and naturally occurring Laminarin (natural Lam, a ß-(1-3)-glucan linked polysaccharide)-binding IgM and IgG by enzyme-linked immunosorbent assay. Results: GXM-IgG, -IgM, and -IgG2 levels were significantly higher in CrAg+ patients, whereas natural Lam-IgM and Lam-IgG were higher in CrAg- patients before and after adjustment for age, sex, and CD4 T-cell count, despite overlap of values. To address this variability and better discriminate the groups, we used Akaike Information Criteria to select variables that independently predicted CrAg+ status and included them in a receiver operating characteristic curve to predict CrAg status. By inclusion of CD4, GXM-IgG, GXM-IgM, and Lam-IgG, -IgG2, and -IgM, this model had an 80.4% probability (95% confidence interval, 0.75-0.86) of predicting CrAg+ status. Conclusions: Statistical models that include multiple serological variables may improve the identification of patients at risk for CM and inform new directions in research on the complex role that antibodies may play in resistance and susceptibility to CM.

3.
J Law Med ; 25(4): 1106-1118, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29978688

RESUMEN

Through preimplantation genetic diagnosis (PGD), individuals can now reliably choose the sex of their baby. However, PGD is largely prohibited for individuals seeking to sex select for non-medical reasons. This article argues that to protect reproductive autonomy, individuals should be allowed to make reproductive choices, regardless of their motivations, unless those choices would cause serious harms to others. It follows that social sex selection should not be prohibited on the basis of moral objections, only when it will cause serious harm. This article considers the opposing ethical framework of parental virtues. A reproductive autonomy framework is preferred, given the challenges of determining and applying parental virtues to social sex selection. This article examines three potential harms identified by opponents to sex selection, and argues that while these remain speculative they do not justify the curtailing of reproductive autonomy.


Asunto(s)
Diagnóstico Preimplantación , Preselección del Sexo , Conducta de Elección , Femenino , Humanos , Principios Morales , Padres , Autonomía Personal , Embarazo
4.
PLoS One ; 11(7): e0157546, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27388763

RESUMEN

INTRODUCTION: Enumeration of CD4+ T lymphocytes is important for pre-ART disease staging and screening for opportunistic infections, however access to CD4 testing in resource limited settings is poor. Point of care (POC) technologies can facilitate improved access to CD4 testing. We evaluated the analytical performance of a novel POC device the FACSPresto compared to the FACSCalibur as a reference standard and to the PIMA, a POC device in widespread use in sub-Saharan Africa. METHOD: Specimens were obtained from 253 HIV infected adults. Venous blood samples were analyzed on the FACSPresto and the FACSCalibur, in a subset of 41 samples additional analysis was done on the PIMA. RESULTS: The absolute CD4 count results obtained on the FACSPresto were comparable to those on the FACSCalibur with low absolute (9.5cells/µl) and relative bias (3.2%). Bias in CD4% values was also low (1.06%) with a relative bias of 4.9%. The sensitivity was lower at a CD4 count threshold of ≤350cells/µl compared with ≤500cells/µl (84.9% vs. 92.8%) resulting in a high upward misclassification rate at low CD4 counts. Specificity at thresholds of ≤350cells/µl and ≤500cells/µl were 96.6% and 96.8% respectively. The PIMA had a high absolute (-68.6cells/µl) and relative bias (-10.5%) when compared with the FACSCalibur. At thresholds of ≤350cells/µl and ≤500cells/µl the sensitivity was 100% and 95.5% respectively; specificity was 85.7% and 84.2% respectively. The coefficients of repeatability were 4.13%, 5.29% and 9.8% respectively. DISCUSSION: The analytic performance of the FACSPresto against the reference standard was very good with better agreement and precision than the PIMA. The FACSPresto had comparable sensitivity at a threshold of 500 cells/µl and better specificity than the PIMA. However the FACSPresto showed reduced sensitivity at low CD4 count thresholds. CONCLUSION: The FACSPresto can be reliably used as a POC device for enumerating absolute CD4 count and CD4% values.


Asunto(s)
Recuento de Linfocito CD4/métodos , Linfocitos T CD4-Positivos/virología , Separación Celular , Citometría de Flujo , Infecciones por VIH/virología , Sistemas de Atención de Punto , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
5.
AIDS Res Hum Retroviruses ; 31(5): 504-7, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25560566

RESUMEN

African infants with vertically acquired HIV infection progress rapidly, with only 50% surviving beyond 2 years in the absence of treatment. Despite this high initial mortality, recent reports describe a substantial burden of older children living with untreated vertically acquired HIV infection in Southern Africa. The immunological and genetic factors associated with long-term survival following vertical infection are poorly understood. We performed medium-to-high resolution HLA typing on DNA samples obtained from a cohort of presumed vertically HIV-1-infected children and age-matched uninfected controls in Harare, Zimbabwe. Overall, 93 HLA class I alleles were detected in the study population with a significant enrichment of HLA-C*08:02 and -C*08:04 in the HIV-1-infected long-term survivor group. Conversely, HLA-A*02:01, A*34:02, and -B*58:02 were overrepresented in the uninfected control group. Our data indicate that HLA alleles may have differential effects against HIV acquisition and disease progression in vertical HIV-1 infection.


Asunto(s)
Resistencia a la Enfermedad , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Sobrevivientes de VIH a Largo Plazo , Antígenos HLA/genética , Adolescente , Niño , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Humanos , Masculino , Zimbabwe
6.
Blood ; 115(18): 3664-70, 2010 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-20197551

RESUMEN

Enteropathy associated T-cell lymphoma (EATL) is a rare type of peripheral T-cell lymphoma. At present, there are no standardized diagnostic or treatment protocols for EATL. We describe EATL in a population-based setting and evaluate a new treatment with aggressive chemotherapy and autologous stem cell transplantation (ASCT). From 1979 onward the Scotland and Newcastle Lymphoma Group prospectively collected data on all patients newly diagnosed with lymphoma in the Northern Region of England and Scotland. Between 1994 and 1998, records of all patients diagnosed with EATL were reviewed, and 54 patients had features of EATL. Overall incidence was 0.14/100 000 per year. Treatment was systemic chemotherapy (mostly anthracycline-based chemotherapy) with or without surgery in 35 patients and surgery alone in 19 patients. Median progression-free survival (PFS) was 3.4 months and overall survival (OS) was 7.1 months. The novel regimen IVE/MTX (ifosfamide, etoposide, epirubicin/methotrexate)-ASCT [corrected] was piloted from 1998 for patients eligible for intensive treatment, and 26 patients were included. Five-years PFS and OS were 52% and 60%, respectively, and were significantly improved compared with the historical group treated with anthracycline-based chemotherapy (P = .01 and P = .003, respectively). EATL is a rare lymphoma with an unfavorable prognosis when treated with conventional therapies. The IVE/MTX-ASCT regimen is feasible with acceptable toxicity and significantly improved outcome.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad Celíaca/terapia , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células T Periférico/terapia , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Celíaca/complicaciones , Terapia Combinada , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Linfoma de Células T Periférico/complicaciones , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Estudios Prospectivos , Escocia/epidemiología , Tasa de Supervivencia , Trasplante Autólogo , Resultado del Tratamiento , Vincristina/administración & dosificación
7.
Blood ; 107(2): 733-41, 2006 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-16204320

RESUMEN

Myeloid leukemias in AKXD23 mice contain proviral insertions at Evi1, resulting in transcriptional activation. Although Evi1 is clearly involved in leukemia, gene transfer studies in mice with Evi1 fail to cause leukemia, arguing that cooperating events are necessary. We reanalyzed AKXD-23 tumors for cooperating proviral insertion and found that each tumor had a proviral insertion in Sox4, which encodes an HMG-box transcription factor. RNA analysis revealed these insertions cause increased Sox4 expression. Overexpression of Sox4 in 32Dcl3 cells markedly inhibited cytokine-induced granulocyte maturation, as documented by morphologic and mRNA analysis. Sox4-expressing cells had higher levels of transcripts associated with proliferation, including Evi1. Conversely, in leukemic cells that express Sox4 and bear provirally activated Evi1, suppression of Sox4 with short hairpin RNAs resulted in down-regulation of both Sox4 and Evi1. By cotransfection studies, Sox4 is able to transactivate the AKV long terminal repeat, which likely explains how Sox4 transcriptionally up-regulates provirally activated Evi1; however, Sox4 does not appear to regulate the native Evi1 promoter. We propose that Sox4 proviral activation is selected for in the setting of prior proviral activation of Evi1, because it transactivates the relatively weak LTR of AKV leading to higher Evi1 expression and consequent block to differentiation.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Leucemia Mieloide/metabolismo , Provirus , Secuencias Repetidas Terminales , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Activación Transcripcional , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Diferenciación Celular , Proliferación Celular , Citocinas/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Regulación hacia Abajo , Perfilación de la Expresión Génica , Granulocitos/citología , Granulocitos/efectos de los fármacos , Granulocitos/metabolismo , Proteínas del Grupo de Alta Movilidad/antagonistas & inhibidores , Proteínas del Grupo de Alta Movilidad/genética , Leucemia Mieloide/genética , Proteína del Locus del Complejo MDS1 y EV11 , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Proto-Oncogenes/genética , ARN Mensajero/análisis , ARN Interferente Pequeño/farmacología , Factores de Transcripción SOXC , Transactivadores/antagonistas & inhibidores , Transactivadores/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Transfección
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