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1.
J Med Genet ; 2024 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-39327040

RESUMEN

PURPOSE AND SCOPE: The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times. METHODS OF STATEMENT DEVELOPMENT: A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute. RESULTS AND CONCLUSIONS: We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources.

2.
Am J Hum Genet ; 106(2): 272-279, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32004445

RESUMEN

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data.


Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/genética , Colesterol/metabolismo , Duplicación de Gen , Recombinación Homóloga , Proteínas de la Membrana/genética , Mitocondrias/patología , Enfermedades Mitocondriales/patología , Proteínas Mitocondriales/genética , ATPasas Asociadas con Actividades Celulares Diversas/química , Secuencia de Aminoácidos , Encefalopatías/etiología , Encefalopatías/metabolismo , Encefalopatías/patología , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Opacidad de la Córnea/etiología , Opacidad de la Córnea/metabolismo , Opacidad de la Córnea/patología , Variaciones en el Número de Copia de ADN , Femenino , Reordenamiento Génico , Humanos , Lactante , Recién Nacido , Masculino , Proteínas de la Membrana/química , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Proteínas Mitocondriales/química , Hipotonía Muscular/etiología , Hipotonía Muscular/metabolismo , Hipotonía Muscular/patología , Mutación , Conformación Proteica , Convulsiones/etiología , Convulsiones/metabolismo , Convulsiones/patología , Homología de Secuencia
3.
J Craniofac Surg ; 33(2): 669-671, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34292242

RESUMEN

STUDY DESIGN: Technique Description with clinical presentation Correlates. PURPOSE: Revisit and discuss the advantages of the cervicodeltopectoral flap (CDP) as an alternative to microvascular reconstruction for head and neck cutaneous defects. METHODS: Retrospective chart review was performed on 2 patients with prior large cutaneous facial defects after tumor resection followed by cervicodeltopectoral flap reconstruction. These cases were performed at a single institution. The tumor resections, flap reconstructions, and postoperative management were led by the listed senior author (SPK). RESULTS: A 78-year-old (Clinical presentation 1) and 62-year-old (Clinical presentation 2) were evaluated for large nonmelanoma skin cancers of the face. Due to significant comorbidities, neither patient was an ideal candidate for microsurgical reconstruction. In both cases, lesion resection and CDP flap reconstruction was performed. The reconstruction allowed for successful coverage without significant donor site morbidity for each patient. CONCLUSIONS: The authors propose the addition of the CDP flap to the armamentarium of the head and neck reconstructive surgeon as a safe and reliable alternative to microvascular reconstruction.


Asunto(s)
Neoplasias de Cabeza y Cuello , Procedimientos de Cirugía Plástica , Anciano , Humanos , Neoplasias de Cabeza y Cuello/cirugía , Procedimientos de Cirugía Plástica/métodos , Estudios Retrospectivos , Colgajos Quirúrgicos/irrigación sanguínea
4.
Am J Hum Genet ; 102(1): 27-43, 2018 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-29276006

RESUMEN

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.


Asunto(s)
Anomalías Craneofaciales/genética , Enanismo/genética , Heterogeneidad Genética , Deformidades Congénitas de las Extremidades/genética , Anomalías Urogenitales/genética , Vía de Señalización Wnt/genética , Adolescente , Adulto , Secuencia de Bases , Niño , Preescolar , Segregación Cromosómica/genética , Anomalías Craneofaciales/diagnóstico , Diagnóstico Diferencial , Enanismo/diagnóstico , Femenino , Genes Dominantes , Estudios de Asociación Genética , Humanos , Deformidades Congénitas de las Extremidades/diagnóstico , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Fenotipo , Anomalías Urogenitales/diagnóstico
5.
BMC Health Serv Res ; 21(1): 305, 2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33823842

RESUMEN

BACKGROUND: Cryptococcal meningitis in HIV-infected patients in sub-Saharan Africa accounts for three-quarters of the global cases and 135,000 deaths per annum. Current treatment includes the use of fluconazole and amphotericin B. Recent evidence has shown that the synergistic use of flucytosine improves efficacy and reduces toxicity, however affordability and availability has hampered access to flucytosine in many countries. This study investigated the evidence and cost implications of introducing flucytosine as induction therapy for cryptococcal meningitis in HIV-infected adults in South Africa. METHODS: A decision analytic cost-effectiveness and cost impact model was developed based on survival estimates from the ACTA trial and local costs for flucytosine as induction therapy in HIV-infected adults with cryptococcal meningitis in a public sector setting in South Africa. The model considered five treatment arms: (a) standard of care; 2-week course amphotericin B/fluconazole (2wk AmBd/Flu), (b) 2-week course amphotericin B/flucytosine (2wk AmBd/5FC), (c) short course; 1-week course amphotericin B/flucytosine (1wk AmBd/5FC) (d) oral course; 2-week oral fluconazole/flucytosine (oral) and e) 1-week course amphotericin B/fluconazole (1wk AmBd/Flu). A sensitivity analysis was conducted on key variables. RESULTS: The highest total treatment costs are in the 2-week AmBd/5FC arm followed by the 2-week oral regimen, the 1-week AmBd/5FC, then standard of care with the lowest cost in the 1-week AmBd/Flu arm. Compared to the lowest cost option the 1-week flucytosine course is most cost-effective at USD119/QALY. The cost impact analysis shows that the 1-week flucytosine course has an incremental cost of just over USD293 per patient per year compared to what is currently spent on standard of care. Sensitivity analyses suggest that the model is most sensitive to life expectancy and hospital costs, particularly infusion costs and length of stay. CONCLUSIONS: The addition of flucytosine as induction therapy for the treatment of cryptococcal meningitis in patients infected with HIV is cost-effective when it is used as a 1-week AmBd/5FC regimen. Savings could be achieved with early discharge of patients as well as a reduction in the price of flucytosine.


Asunto(s)
Infecciones por VIH , Meningitis Criptocócica , Adulto , Antifúngicos/uso terapéutico , Análisis Costo-Beneficio , Quimioterapia Combinada , Flucitosina/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Quimioterapia de Inducción , Meningitis Criptocócica/tratamiento farmacológico , Sudáfrica
6.
Prenat Diagn ; 38(1): 33-43, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29096039

RESUMEN

OBJECTIVE: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. RESULTS: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. CONCLUSION: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.


Asunto(s)
Anomalías Congénitas/genética , Secuenciación del Exoma , Enfermedades Genéticas Congénitas/diagnóstico , Padres , Diagnóstico Prenatal/métodos , Femenino , Genes Recesivos , Humanos , Masculino , Embarazo
7.
Am J Emerg Med ; 36(6): 1126.e1-1126.e4, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29598889

RESUMEN

We describe the case of a previously healthy 33year-old male pilot recently arrived to the United States from Africa. The patient presented to our ED febrile and disoriented, with projectile coffee-ground emesis. He was later found to have severe malaria and cerebral parasitemia. Due to the severity of his illness, the patient received the anti-malarial medication Artesunate as well as several exchange transfusions. Within 48h his parasitic load was reduced from 42% to 0.4%. The following is an account of a collaborative effort that spans the specialties of emergency medicine, infectious disease, and critical care medicine.


Asunto(s)
Antimaláricos/administración & dosificación , Artesunato/administración & dosificación , Cuidados Críticos , Servicios Médicos de Urgencia , Infectología , Malaria Cerebral/tratamiento farmacológico , Parasitemia/tratamiento farmacológico , Adulto , Antimaláricos/farmacología , Artesunato/farmacología , Recambio Total de Sangre , Humanos , Colaboración Intersectorial , Malaria Cerebral/parasitología , Masculino , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
8.
J Am Soc Nephrol ; 28(8): 2529-2539, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28373276

RESUMEN

Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.


Asunto(s)
Hiperinsulinismo Congénito/complicaciones , Hiperinsulinismo Congénito/genética , Mutación , Fosfotransferasas (Fosfomutasas)/genética , Enfermedades Renales Poliquísticas/complicaciones , Enfermedades Renales Poliquísticas/genética , Regiones Promotoras Genéticas/genética , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino
9.
Pediatr Transplant ; 21(6)2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28639398

RESUMEN

Prediction of PTLD after pediatric lung transplant remains difficult. Use of EBV VL in WB has been poorly predictive, while measurement of VL in BAL fluid has been suggested to have enhanced utility. The NIH-sponsored Clinical Trials in Organ Transplantation in Children (CTOTC-03) prospectively obtained serial quantitative measurements of EBV PCR in both WB and BAL fluid after pediatric lung transplantation. Descriptive statistics, contingency analyses, and Kaplan-Meier analyses evaluated possible association between EBV and PTLD. Of 61 patients, 34 (56%) had an EBV+PCR (at least once in WB or BAL). EBV donor (D)+patients more often had a positive PCR (D+/recipient (R)-: 13/18; D+/R+: 14/23) compared to EBV D- patients (6/17). Several D-/R- (5/12) patients developed EBV, but none developed PTLD. All four PTLD patients were D+/R- with EBV+PCR. Neither the time to first EBV+PCR nor the CT for PCR positivity in BAL or WB was statistically different between those with and without PTLD. Having an EBV-seropositive donor was associated with increased risk of EBV+PCR in WB. EBV load in BAL was not predictive of PTLD.


Asunto(s)
Herpesvirus Humano 4/aislamiento & purificación , Trasplante de Pulmón , Trastornos Linfoproliferativos/virología , Complicaciones Posoperatorias/virología , Carga Viral , Adolescente , Líquido del Lavado Bronquioalveolar/virología , Niño , Preescolar , ADN Viral/análisis , Femenino , Herpesvirus Humano 4/genética , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , Factores de Riesgo , Adulto Joven
11.
Health Syst Reform ; 9(3): 2327098, 2023 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-38715202

RESUMEN

While South Africa has some experience in various forms of health technology assessment (HTA), it is currently fragmented across numerous players. Additionally, there is a lack of systematic and consistently applied HTA processes that inform priority-setting and budget allocations. To address this, the country is journeying toward more institutionalized use of HTA. This will begin with the establishment of a Ministerial Advisory Committee on HTA for National Health Insurance (NHI) and will gradually embed HTA processes in decision-making. The goal is to create an independent HTA agency. Although these reforms will be intrinsically linked to the wider health financing reforms envisaged under NHI, such as formulating the benefits package, they will also assist in strengthening South Africa's health system. As a country facing a highly constrained fiscal environment, with limited space for additional funding for the health sector, evidence-based priority-setting will be critical to ensure that value for money is achieved in the government's investments in health care services in NHI.


Asunto(s)
Programas Nacionales de Salud , Evaluación de la Tecnología Biomédica , Sudáfrica , Evaluación de la Tecnología Biomédica/métodos , Humanos , Reforma de la Atención de Salud/métodos , Reforma de la Atención de Salud/tendencias , Comités Consultivos , Prioridades en Salud/tendencias
12.
BMJ Open ; 12(3): e058761, 2022 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-35304402

RESUMEN

OBJECTIVES: This study assesses the cumulative incidence of SARS-CoV-2 infection among healthcare workers (HCWs) during South Africa's first wave and examines the associated demographic, health-related and occupational risk factors for infection. METHODS: Multistage cluster sampling was used in a cross-sectional study to recruit 1309 HCWs from two academic hospitals in the Eastern Cape, South Africa over 6 weeks in November and December 2020. Prior test results for SARS-CoV-2 PCR and participants' characteristics were recorded while a blood sample was drawn for detection of IgG antibodies against SARS-CoV-2 nucleocapsid protein. The primary outcome measure was the SARS-CoV-2 cumulative incidence rate, defined as the combined total of positive results for either PCR or IgG antibodies, divided by the total sample. The secondary outcome was significant risk factors associated with infection. RESULTS: Of the total participants included in the analysis (n=1295), the majority were women (81.5%), of black race (78.7%) and nurses (44.8%). A total of 390 (30.1%) HCWs had a positive SARS-CoV-2 PCR result and SARS-CoV-2 antibodies were detected in 488 (37.7%), yielding a cumulative incidence of 47.2% (n=611). In the adjusted logistic regression model, being overweight (adjusted OR (aOR)=2.15, 95% CI 1.44 to 3.20), obese (aOR=1.37, 95% CI 1.02 to 1.85) and living with HIV (aOR=1.78, 95% CI 1.38 to 2.08) were independently associated with SARS-CoV-2 infection. There was no significant difference in infection rates between high, medium and low COVID-19 exposure working environments. CONCLUSIONS: The high SARS-CoV-2 cumulative incidence in the cohort was surprising this early in the epidemic and probably related to exposure both in and outside the hospitals. To mitigate the impact of SARS-CoV-2 among HCWs, infection prevention and control strategies should target community transmission in addition to screening for HIV and metabolic conditions.


Asunto(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , COVID-19/epidemiología , Estudios Transversales , Femenino , Personal de Salud , Humanos , Incidencia , Masculino , Factores de Riesgo , Sudáfrica/epidemiología
13.
Artículo en Inglés | MEDLINE | ID: mdl-33466227

RESUMEN

Healthcare workers (HCWs) are at increased risk of infection by the virulent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Though data exist on the positivity rate of the SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) test as well as COVID-19-related deaths amongst HCWs in South Africa, the overall infection rate remains underestimated by these indicators. It is also unclear whether the humoral immune response after SARS-CoV-2 infection offers durable protection against reinfection. This study will assess the SARS-CoV-2 seroprevalence amongst HCWs in the Eastern Cape (EC) and examine the longitudinal changes (rate of decay) in the antibody levels after infection in this cohort. Using a multi-stage cluster sampling of healthcare workers in selected health facilities in the EC, a cross-sectional study of 2250 participants will be recruited. In order to assess the community infection rate, 750 antenatal women in the same settings will be recruited. Relevant demographic and clinical characteristics will be obtained by a self-administered questionnaire. A chemiluminescent microparticle immunoassay (CMIA) will be used for the qualitative detection of IgG antibodies against SARS-CoV-2 nucleocapsid protein. A nested cohort study will be conducted by performing eight-weekly antibody assays (X2) from 201 participants who tested positive for both SARS-CoV-2 RT-PCR and serology. Logistic regression models will be fitted to identify the independent risk factors for SARS-CoV-2 infection. The cumulative SARS-CoV-2 infection rate and infection fatality rate among the frontline HCWs will be estimated. In addition, the study will highlight the overall effectiveness of infection prevention and control measures (IPC) per exposure sites/wards at the selected health facilities. Findings will inform the South African Department of Health's policies on how to protect HCWs better as the country prepares for the second wave of the SARS-CoV pandemic.


Asunto(s)
COVID-19/diagnóstico , Personal de Salud , Exposición Profesional/estadística & datos numéricos , Proyectos de Investigación , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Embarazo , Estudios Seroepidemiológicos , Sudáfrica/epidemiología
14.
Vaccines (Basel) ; 9(6)2021 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-34207018

RESUMEN

BACKGROUND: This study assesses the perceptions and acceptance of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination. It also examines its influencing factors among the healthcare workers (HCWs) in the Eastern Cape, South Africa. METHODS: In this cross-sectional study performed in November and December 2020, a total of 1308 HCWs from two large academic hospitals participated in the Eastern Cape Healthcare Workers Acquisition of SARS-CoV-2 (ECHAS) study. Validated measures of vaccine hesitancy were explored using a questionnaire. Logistic regression was used to identify the determinants of vaccine hesitancy. RESULTS: The majority were nurses (45.2%), and at risk for unfavourable Covid-19 outcome, due to obesity (62.9%) and having direct contact with individuals confirmed to have Covid-19 (77.1%). The overall acceptance of SARS-CoV-2 vaccine was 90.1%, which differed significantly by level of education. Individuals with lower educational attainment (primary and secondary education) and those with prior vaccine refusal were less likely to accept the SARS-CoV-2 vaccine. However, positive perceptions about the SARS-CoV-2 vaccine were independently associated with vaccine acceptance. CONCLUSIONS: The high level of acceptance of SARS-CoV-2 vaccine is reassuring; however, HCWs with a lower level of education and those with prior vaccine refusal should be targeted for further engagements to address their concerns and fears.

18.
AIDS ; 28(10): 1463-72, 2014 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-24681417

RESUMEN

OBJECTIVE: The objective of the present study was to determine the diagnostic performance of the symptom-based tuberculosis (TB) screening questionnaire recommended by WHO for people living with HIV (PLWH) in resource-limited settings, among adults off and on antiretroviral therapy (ART). DESIGN: Cross-sectional study at two HIV clinics in South Africa. METHODS: A total of 825 PLWH completed the screening questionnaire and underwent investigations [chest radiography (CXR) and microbiologic testing of sputa]. A positive screen was defined as presence of cough, fever, night sweats, or weight loss. Pulmonary tuberculosis (PTB) was defined as sputum smear positive for acid-fast bacilli or growth of Mycobacterium tuberculosis. RESULTS: Of 737 participants with at least one diagnostic sputum specimen, PTB was diagnosed in 31 of 522 (5.9%) on ART, and 34 of 215 (15.8%) not on ART. The questionnaire missed 15 of 31 (48.4%) PTB cases on ART, and three of 34 (8.8%) not on ART. Among participants on ART, post-test probability of PTB diagnosis (95% confidence interval) was 6.8% (4.0-10.9%) if screening positive, and 5.2% (2.9-8.4%) if screening negative, whereas among participants not on ART, post-test probabilities were 20.3% (14.2-27.5%) and 4.8% (1.0-13.5%), respectively. Among participants diagnosed with PTB, those on ART were significantly less likely to screen positive (adjusted odds ratio 0.04, 95% confidence interval: 0.01-0.39). In both groups (ART and no ART), screening was more sensitive when CXR was incorporated. CONCLUSION: For case detection and exclusion of PTB, the WHO-recommended questionnaire performed adequately among PLWH not on ART, and poorly among those on ART. Further research is needed to identify feasible and effective TB screening strategies for PLWH in resource-limited settings.


Asunto(s)
Medicina Clínica/métodos , Infecciones por VIH/complicaciones , Tamizaje Masivo/métodos , Tuberculosis/diagnóstico , Tuberculosis/patología , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Estudios Transversales , Países en Desarrollo , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Microscopía/métodos , Persona de Mediana Edad , Sudáfrica , Encuestas y Cuestionarios , Tuberculosis/microbiología
19.
JIMD Rep ; 10: 103-6, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23430810

RESUMEN

Autosomal recessive disorders affecting pyridoxine (vitamin B6) metabolism are a rare but well-recognized cause of neonatal seizures. Antiquitin deficiency, caused by mutations in ALDH7A1, is a disorder of the lysine degradation pathway causing accumulation of an intermediate that complexes with pyridoxal phosphate. Reports of long-term follow-up of neonatal pyridoxine-dependent seizures (PDS) remain scarce and prognostic information is varied. We report a case of PDS in a 47-year-old lady who originally presented shortly after birth in 1964. Pyridoxine replacement was successful and diagnostic confirmation was obtained later in life, initially by biochemical analysis of serum pipecolic acid. Subsequently we organized genetic analysis of ALDH7A1, which revealed compound heterozygous mutations. To our knowledge, this represents the longest duration of follow-up published to date.

20.
Diabetes ; 57(4): 1034-42, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18162506

RESUMEN

OBJECTIVE: Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood. RESEARCH DESIGN AND METHODS: The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed <45 years). None had a molecular genetic diagnosis of monogenic diabetes. RESULTS: We identified heterozygous INS mutations in 33 of 141 probands diagnosed at <6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K(+) channel mutation carriers (11 vs. 8 weeks, P < 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant. CONCLUSIONS: We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age.


Asunto(s)
Análisis Mutacional de ADN , Diabetes Mellitus Tipo 1/genética , Insulina/genética , Mutación , Adulto , Sustitución de Aminoácidos , Niño , Humanos , Lactante , Recién Nacido
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