Cortical oxygen extraction fraction using quantitative BOLD MRI and cerebral blood flow during vasodilation.

Introduction: We aimed to demonstrate non-invasive measurements of regional oxygen extraction fraction (OEF) from quantitative BOLD MRI modeling at baseline and after pharmacological vasodilation. We hypothesized that OEF decreases in response to vasodilation with acetazolamide (ACZ) in healthy conditions, reflecting compensation in regions with increased cerebral blood flow (CBF), while cerebral metabolic rate of oxygen (CMRO2) remained unchanged. We also aimed to assess the relationship between OEF and perfusion in the default mode network (DMN) regions that have shown associations with vascular risk factors and cerebrovascular reactivity in different neurological conditions. Material and methods: Eight healthy subjects (47 ± 13 years, 6 female) were scanned on a 3 T scanner with a 32-channel head coil before and after administration of 15 mg/kg ACZ as a pharmacological vasodilator. The MR imaging acquisition protocols included: 1) A Gradient Echo Slice Excitation Profile Imaging Asymmetric Spin Echo scan to quantify OEF, deoxygenated blood volume, and reversible transverse relaxation rate (R2 ') and 2) a multi-post labeling delay arterial spin labeling scan to measure CBF. To assess changes in each parameter due to vasodilation, two-way t-tests were performed for all pairs (baseline versus vasodilation) in the DMN brain regions with Bonferroni correction for multiple comparisons. The relationships between CBF versus OEF and CBF versus R2' were analyzed and compared across DMN regions using linear, mixed-effect models. Results: During vasodilation, CBF significantly increased in the medial frontal cortex (P=0.004), posterior cingulate gyrus (pCG) (P=0.004), precuneus cortex (PCun) (P=0.004), and occipital pole (P=0.001). Concurrently, a significant decrease in OEF was observed only in the pCG (8.8%, P=0.003) and PCun (8.7%,P=0.001). CMRO2 showed a trend of increased values after vasodilation, but these differences were not significant after correction for multiple comparisons. Although R2' showed a slightly decreasing trend, no statistically significant changes were found in any regions in response to ACZ. The CBF response to ACZ exhibited a stronger negative correlation with OEF (ß=-0.104±0.027; t=-3.852,P<0.001), than with R2' (ß=-0.016±0.006; t=-2.692,P=0.008). Conclusion: Quantitative BOLD modeling can reliably measure OEF across multiple physiological conditions and captures vascular changes with higher sensitivity than R2' values. The inverse correlation between OEF and CBF across regions in DMN, suggests that these two measurements, in response to ACZ vasodilation, are reliable indicators of tissue health in this healthy cohort.

Is effective patient support missing in the global response to multidrug-resistant tuberculosis?

Multidrug-resistant tuberculosis (MDR-TB) is a threat to the achievement of the global targets to the World Health Organization (WHO) End TB by 2030 Strategy. The WHO consolidated guidelines for the treatment of drug-resistant TB emphasise the importance of addressing health systems issues, including supporting patients during treatment, contributing to improved adherence, reduced catastrophic costs and better treatment outcomes. The recently published results of the STREAM (Standardised Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB) clinical trial and the Delamanid 213 Trial suggest that the implementation of a proper patient-centred approach to the clinical and programmatic management of MDR-TB as per the WHO guidelines is key to improving treatment outcomes in MDR-TB patients.

No universal access to drug-resistant tuberculosis care without engaging all health care providers.

Should the engagement of all health care providers in all aspects of programmatic management of drug-resistant tuberculosis (PMDT) become a priority in the national strategic plans for tuberculosis (TB), progress towards universal access to diagnosis, treatment and care of drug-resistant tuberculosis (DR-TB) would accelerate. This would be especially crucial in countries where the private sector is a significant provider of health services. Proven successful interventions to engage all health care providers and partners in the cascade of prevention, diagnosis, treatment and care of DR-TB patients need to be urgently scaled up. Such engagement should not be limited to the diagnosis and treatment of DR-TB, but extended also to all the aspects of PMDT, including approaches ensuring that patient-centred care, social support, pharmacovigilance and surveillance. Integral to the End TB Strategy, PMDT should be embedded in all public-private mix initiatives for TB and vice versa.

An assessment of current tuberculosis patient care and support policies in high-burden countries.

CONTEXT: Adherence to treatment for tuberculosis (TB) is an important predictor of treatment outcomes. The World Health Organization guidelines recommend a patient-centred approach to adherence support; however, the extent to which policies in high-burden countries facilitate this approach remains uncertain.DESIGN: A cross-sectional survey of current national patient care and support policies in high TB burden countries was performed.RESULT: Responses were provided by TB care programmes in 23 of the 30 high TB burden countries, comprising 77.4% of TB cases globally. Clinic-based and household adherence support and patient education were recommended in all countries, while policies for digital technologies and social supports have been adopted in a small minority of countries. Financial or material support (such as reimbursement for transportation) and psychological support to patients-if included in the policies-was mainly recommended only for specific sub-groups of patients.CONCLUSION: National policies in many countries have not yet fully adopted global recommendations for patient care and support. Further scale-up of evidence-based approaches to care is required to improve quality of care for patients in high TB burden settings.

Radiographic predictors of subsequent reactivation of tuberculosis.

SETTING: A cohort of migrants to Australia (n = 7265) selected to be at increased risk of tuberculosis (TB) were assessed at the Liverpool Chest Clinic, Sydney, between 1984 and 2003. OBJECTIVE: To assess the reproducibility and predictive value of various radiographic criteria for predicting the subsequent development of TB. METHODS: A nested case control study was conducted. Cases were those who had a confirmed diagnosis of TB during follow-up (n = 60). A random sample of 107 controls was selected. Initial chest X-rays were read independently and blinded to case vs. control status by two readers according to two classification systems. Agreement was quantified as weighted kappa (kappaw). Sensitivity and specificity for subsequent TB were estimated. RESULTS: There was moderate agreement between readers for both classification systems (kappaw 0.67 and 0.60, respectively). The presence of calcified nodular densities or fibrosis together with non-calcified nodular densities in mid and/or upper lung zones or the presence of a pulmonary infiltrate typical of TB had a sensitivity of 66% for subsequent pulmonary TB and a specificity of 82%. Minor abnormalities or findings consistent with past primary TB infection alone were not predictive of subsequent TB. CONCLUSIONS: Radiographic screening can be helpful in identifying individuals at increased risk of subsequent TB.

Evaluation of sputum smear microscopy in the National Tuberculosis Control Programme in the north of Vietnam.

OBJECTIVE: To assess the yield of sputum smear microscopy and sex differences in the National Tuberculosis Control Programme in the north of Vietnam. METHODS: Review of registers of 30 randomly selected laboratories (26 district, 4 provincial level). RESULTS: The average daily workload per technician was 4.4 examinations in district and 5.3 examinations in provincial laboratories. To find one smear-positive case, 9.7 suspects were examined and 29.3 smears done. The smear-positive rate (mean 10.3%) was higher among men (11.6%) than among women (8.4%, P < 0.001). There were more men than women among tuberculosis (TB) suspects (male:female ratio 1.36, 95%CI 1.19-1.54), but even more so among smear-positive patients (1.89, 95%CI 1.64-2.14), irrespective of specimen quality and number of smears examined. Three smears were examined for 18,055 suspects (61.7%). The incremental gain was 33.5% and 4.9% for the second and third smear examination, respectively; 186 (95%CI 160-221) smears needed to be examined to find one additional case of TB with a third serial examination. CONCLUSION: The diagnostic process seemed generally efficient. The male:female ratios suggest higher TB incidence in men rather than lower access to TB facilities for women. The third smear examination could be omitted.

Typhoid fever. Studies of blood coagulation, bacteremia, and endotoxemia.

Patients with typhoid fever were studied to determine whether disseminated intravascular coagulation (DIC), circulating bacteria, and endotoxemia were responsible for the signs and symptoms of their illnesses. Coagulation tests in 28 patients detected thrombocytopenia in 17, hypofibrinogenemia in nine, and elevated titers of fibrinogen-related antigens in 20. Repeated testing during convalescence showed a return toward normal values. Intestinal bleeding, however, did not correlate with abnormalities of coagulation tests. Thus, DIC occurred commonly but appeared to be a subclinical event in these patients. In 25 patients with positive blood cultures for Salmonella typhi, quantitative cultures detected from less than 10 to 9 x 10(2) bacteria/ml. Limulus tests for endotoxin in plasma were negative in all 21 patients tested. These results indicated that the concentrations of circulating bacteria and endotoxin in typhoid fever are lower than in other Gram-negative bacterial infections and suggested that circulating bacteria and endotoxin do not play a major role in the pathogenesis of typhoid fever.

The trend of tuberculosis cases over 60 years in Fiji's largest treatment centre: 1950-2010.

SETTING: P J Twomey Hospital, National Tuberculosis Programme, Fiji. OBJECTIVES: To review the trend in numbers of tuberculosis (TB) cases registered each year from 1950 to 2010 at P J Twomey Hospital, Fiji's largest TB treatment centre and central TB unit, and to consider trends in the context of key TB control events in Fiji. DESIGN: Descriptive study of data from medical records and TB registers, including age, sex, ethnicity, TB diagnosis and smear result. RESULTS: Between 1950 and 2010, 14 616 cases were registered at P J Twomey Hospital. Of these, 58% were male, 70% were indigenous Fijians (i-taukei) and 64% were aged 15-49 years. The caseload dropped sharply in the 1960s, and has fallen steadily since 1990. Smear results were available for the majority of cases (91%). Between 1950 and 1985, smear-positive cases accounted for 19% of cases overall; this increased to 41% after 1985 following laboratory training. The numbers of sputum smear-positive cases recorded each year has been increasing in the last decade. CONCLUSION: There have been marked changes in TB caseload over the last 60 years at Fiji's largest TB treatment centre. The recent increase in smear-positive cases while total TB cases have been falling needs further evaluation.

Contexte : Hôpital P J Twomey, Programme National contre la Tuberculose, Fidji.Objectifs : Revoir les tendances des nombres de cas de tuberculose (TB) enregistrés chaque année de 1950 à 2010 à l'Hôpital P J Twomey, le plus grand centre de traitement de la TB et l'unité centrale du pays. Les tendances sont interprétées en fonction des différentes étapes de la lutte contre la TB.Schéma : Etude descriptive des données des dossiers médicaux et des registres de TB, notamment l'âge, le sexe, l'origine ethnique, le diagnostic et le résultat du frottis.Résultats : Entre 1950 et 2010, 14 616 cas ont été enregistrés à l'Hôpital P J Twomey. Parmi eux, 58% étaient de sexe masculin, 70% étaient des indigènes des îles Fidji (i-taukei) et 64% étaient âgés entre 15 et 49 ans. Le nombre de cas a chuté de façon brutale dans les années 1960 et a poursuivi sa descente progressive depuis 1990. Des résultats de frottis étaient disponibles dans 91% des cas. Entre 1950 et 1985, 19% des cas avaient un frottis positif ; cette proportion est passée à 41% après 1985 à la suite du recyclage des laborantins. Le nombre de cas à frottis de crachats positifs enregistré chaque année a augmenté au cours de la dernière décennie.Conclusion : Il y a eu des changements marquants du volume des cas dans le plus grand centre de traitement de la TB au Fidji au cours des 60 dernières années. L'accroissement récent des cas à frottis de crachats positifs alors que le nombre total de cas a diminué requiert de plus amples investigations.

Marco de referencia: El Programa Nacional contra la Tuberculosis de Fiyi y el Hospital P J Twomey.Objetivos: Analizar la tendencia del número de casos de tuberculosis (TB) registrados cada año entre 1950 y el 2010 en el Hospital P J Twomey, que representa el principal centro de tratamiento antituberculoso y la unidad central de atención de la enfermedad en Fiyi, y considerar las tendencias en el contexto de las actividades clave en el control de la TB en el país.Métodos: Se llevó a cabo un estudio descriptivo con datos provenientes de las historias clínicas y los registros de TB, entre ellos la edad, el sexo, la etnia, el tipo de TB y el resultado de la baciloscopia.Resultados: Entre 1950 y el 2010, se registraron 14 616 casos en el Hospital P J Twomey; de estos casos, el 58 % eran de sexo masculino, el 70% eran indígenas fiyianos (i-taukei) y el 64% pertenecía al grupo entre los 15 y los 49 años de edad. En los años sesenta disminuyó de manera drástica el número de casos de TB y a partir de 1990 ha disminuido constantemente. La mayoría de los casos contaba con resultados de la baciloscopia (91%). Entre 1950 y 1985, los casos con baciloscopia positiva representaron el 19% de todos los casos y esta proporción aumentó a 41% después de 1985 tras la capacitación en técnicas de laboratorio. El número de casos con baciloscopia positiva registrados cada año ha ido aumentando en el último decenio.Conclusión: En los últimos 60 años se han observado cambios notables en la carga de morbilidad por TB en el principal centro de tratamiento de la enfermedad en Fiyi. El aumento reciente de los casos con baciloscopia positiva, pese a una disminución en el número total de casos, precisa una consideración más detallada.

Building operational research capacity in the Pacific.

Operational research (OR) in public health aims to investigate strategies, interventions, tools or knowledge that can enhance the quality, coverage, effectiveness or performance of health systems. Attention has recently been drawn to the lack of OR capacity in public health programmes throughout the Pacific Islands, despite considerable investment in implementation. This lack of ongoing and critical reflection may prevent health programme staff from understanding why programme objectives are not being fully achieved, and hinder long-term gains in public health. The International Union Against Tuberculosis and Lung Disease (The Union) has been collaborating with Pacific agencies to conduct OR courses based on the training model developed by The Union and Médecins Sans Frontières Brussels-Luxembourg in 2009. The first of these commenced in 2011 in collaboration with the Fiji National University, the Fiji Ministry of Health, the World Health Organization and other partners. The Union and the Secretariat of the Pacific Community organised a second course for participants from other Pacific Island countries and territories in 2012, and an additional course for Fijian participants commenced in 2013. Twelve participants enrolled in each of the three courses. Of the two courses completed by end 2013, 18 of 24 participants completed their OR and submitted papers by the course deadline, and 17 papers have been published to date. This article describes the context, process and outputs of the Pacific courses, as well as innovations, adaptations and challenges.

En santé publique, la recherche opérationnelle (RO) vise à identifier des stratégies, des interventions, des outils et des connaissances susceptibles d'améliorer la qualité, la couverture, l'efficacité ou la performance de systèmes de santé. L'attention a récemment été attirée sur le manque de capacités en recherche opérationnelle des programmes de santé publique dans toutes les îles du Pacifique malgré des investissements considérables dans leur mise en œuvre. Ce manque de réflexion critique pourrait empêcher le personnel des programmes de santé de comprendre pourquoi les objectifs ne sont pas totalement atteints et entraver des progrès à long terme en santé publique. L'Union Internationale contre la Tuberculose et les Maladies Respiratoires (L'Union) a collaboré avec les agences du Pacifique pour offrir des cours de RO basés sur un modèle de formation élaboré par L≈os;Union et Médecins Sans Frontières Bruxelles-Luxembourg en 2009. Le premier a débuté en 2011 en collaboration avec l'Université nationale de Fidji, le Ministère de la santé de Fidji, l'Organisation Mondiale de la Santé et d'autres partenaires. L'Union et le Secrétariat de la Communauté Pacifique ont organisé un deuxième cours pour les participants des autres îles du Pacifique en 2012 et un cours supplémentaire destiné aux participants Fidjiens a commencé en 2013. Douze participants ont été enrôlés dans chacun des trois cours. En ce qui concerne les deux cours terminés avant la fin de 2013, 18 participants sur 24 ont terminé leur RO et soumis leurs articles avant la date limite. A ce jour, 17 articles ont été publiés. Cet article décrit le contexte, l'organisation et les résultats des cours du Pacifique ainsi que les innovations, adaptations et défis.

La meta de la investigación operativa en salud pública consiste en estudiar las estrategias, las intervenciones, los instrumentos o los conocimientos que fortalecen la calidad, la cobertura, la eficacia y el desempeño de los sistemas de salud. En tiempos recientes, se ha llamado la atención sobre la falta de capacidad de realizar investigación operativa en los programas de salud pública en todas las Islas del Pacífico, pese a una inversión considerable en la ejecución. La falta de una reflexión crítica permanente impide que el personal del programa de salud comprenda las razones por las cuales no se cumple a cabalidad con los objetivos y dificulta además el logro de beneficios a largo plazo en materia de salud pública. La Unión Internacional contra la Tuberculosis y las Enfermedades Respiratorias (La Unión) ha colaborado con entidades del Pacífico a fin de llevar a cabo cursos de investigación operativa, con base en un modelo de capacitación elaborado por La Unión y Médicos Sin Fronteras de Bruselas y Luxemburgo en el 2009. El primero de estos cursos comenzó en el 2011, en colaboración con la Universidad Nacional Fiji, el Ministerio de Salud de Fiji, la Organización Mundial de la Salud y otros asociados. La Unión y la Secretaría de la Comunidad del Pacífico organizaron un segundo curso dirigido a participantes de otros países y territorios de las Islas del Pacífico en el 2012 y en el 2013 comenzó un nuevo curso, destinado a participantes de las Islas Fiji. Cada uno de los tres cursos contó con 12 participantes. En los dos cursos terminados antes del fin de 2013, 18 de los 24 participantes completaron la investigación operativa, presentaron sus artículos dentro del término previsto en el curso y hasta la fecha, se han publicado 17 artículos científicos. En el presente artículo se describen el contexto, los procedimientos y los resultados de los cursos de las Islas del Pacífico y se comentan además las innovaciones, las adaptaciones y las dificultades encontradas.

Nurses graduating in Fiji between 2001 and 2010: sufficient supply for Fiji's health service demands?

SETTING: Fiji's schools of nursing and government health services, 2001-2010. OBJECTIVES: To report on 1) the number and characteristics of nurses who graduated in Fiji, 2) the proportion of vacant nursing positions in the government health services and 3) attrition among nurses. DESIGN: Descriptive study involving a retrospective record review of Ministry of Health annual reports and nursing registers. RESULTS: Over the period 2001-2010, a total of 1500 nurses graduated, with the overall trend being a gradual increase in newly qualified nurses year on year. Available data from 2007 onwards showed relatively low vacancy rates (range 0.4-2%), with a sharp rise to 15% in 2009. Complete data on nurse attrition were available only from 2007 onwards, with rates of attrition ranging from 4% to 10%; the most common reason for attrition was resignation. CONCLUSION: While it was unable to directly assess whether Fiji's supply of nursing graduates has been meeting the country's health service demands, this study provides a series of baseline data on Fiji's nurse graduate and nursing workforce. In addition, it identifies some of the challenges and gaps that need to be considered to better assess and address nursing staff shortages.

Sputum smear examination and time to diagnosis in patients with smear-negative pulmonary tuberculosis in the Pacific.

SETTING: National tuberculosis programmes (NTPs) in Kiribati and the Marshall Islands, 2006-2010. OBJECTIVE: To determine the proportion of all tuberculosis (TB) cases that were pulmonary smear-negative, and for these patients to determine how many sputum smears were examined and the time from sputum smear examination to registration. DESIGN: A retrospective cross-sectional study involving a record review of national TB and laboratory registers. RESULTS: Of 2420 TB cases identified, 709 (29%) were registered as smear-negative pulmonary TB. Of the 695 (98%) with information on smear examination, 222 (32%) had no smear recorded, 61 (9%) had one smear, 86 (12%) two smears and 326 (47%) three smears. Among the 473 patients who had at least one smear, 238 (50%) were registered before sputum examination, 131 (28%) within 1 week, 72 (15%) between 1 and 4 weeks, and 34 (7%) >4 weeks after sputum examination. CONCLUSION: NTPs in Kiribati and the Marshall Islands are diagnosing 29% of all TB patients as smear-negative pulmonary TB. Many patients do not have smears done or are registered before undergoing smear examination. Corrective measures are needed.

Yersinia pestis infection in Vietnam. II. Quantiative blood cultures and detection of endotoxin in the cerebrospinal fluid of patients with meningitis.

Quantitative blood cultures were obtained from 42 patients with acute Yersinia pestis infection to determine whether the concentration of bacteria in blood influenced the clinical severity and outcome of illness. In 17 bacteremic patients, colony counts in blood cultures ranged from less than 10 to 4 X 10(7)/ml. Three of five patients with colony counts of greater than 10(2)/ml died, and two patients survived episodes of hypotension. Results from plasma limulus tests were positive at the time of admission in three of 10 patients tested, and these three patients had bacteremia with colony counts of greater than 10(2)/ml. Meningitis developed in three patients and pneumonia in two patients; these five patients a-l had buboes in the axillary region. Endotoxin was detected with the limulus test in the cerebrospinal fluid in the three patients with meningitis. Ten patients randomly assigned to receive streptomycin or trimethoprim-sulfamethoxazole survived. Those treated with streptomycin had a shorter median duration of fever and a lower incidence of complications than did the patients treated with trimethoprim-sulfamethoxazole.

Oxolinic acid in the treatment of typhoid fever due to chloramphenicol-resistant strains of Salmonella typhi.

Of 28 strains of Salmonella typhosa collected in late 1972 in Vietnam, 4 had minimum inhibitory concentrations to chloramphenicol of >100 mug/ml. Median minimum inhibitory concentrations of all strains to oxolinic acid were 0.39 mug/ml; ampicillin, 6.25 mug/ml; amoxicillin, 0.39 mug/ml. Widespread typhoid fever appeared in mid-1973 with more than three-fourths of strains found to be resistant to chloramphenicol. Peak serum concentrations of oxolinic acid average 3.0 mug/ml after the oral ingestion of 1.0 g. In July 1974, a pilot study was begun to evaluate the efficacy of oxolinic acid in vivo, recognizing the discrepancy between in vitro and in vivo results with many agents evaluated in the treatment of typhoid fever. Seven patients with typhoid fever, six with positive blood cultures, were treated with oxolinic acid (1.5 g twice daily by mouth, a daily dose that averaged 75 mg/kg per day) for 5 to 12 days. In four of six patients, blood cultures became negative at 2 to 3 days, with another being negative at 6 days. Despite negative blood cultures, all but one patient remained clinically ill with temperatures of >39.5 C at 4 to 9 days. All strains were susceptible to 0.19 mug of oxolinic acid per ml, and resistant strains did not occur. One patient died after being changed to ampicillin, one left against advice, three responded to amoxicillin, and one died with pseudomonas bacteremia. Toxicity to oxolinic acid did not occur.

Therapy of antimicrobial-resistant typhoid fever.

Antimicrobial-resistant typhoid fever in Saigon was studied by examining in vitro antimicrobial susceptibilities of Salmonella typhi strains and conducting a randomized clinical trial of ampicillin and trimethoprim-sulfamethoxazole (TMP-SMZ). Isolates of S. typhi were obtained from blood or stool cultures of 90 patients. Of 87 isolates tested for antimicrobial susceptibility, 65 (75%) were resistant (R) to chloramphenicol, streptomycin, sulfonamide, and tetracycline, and 22 (25%) were susceptible (S). The drug resistance was transferable to Escherichia coli and was found in 11 different Vi-phage types. All isolates were susceptible to ampicillin and to TMP-SMZ. Agar dilution studies of TMP and SMZ showed synergistic inhibition of growth in all 18 S isolates and in 12 of 48 R isolates tested. The clinical trial of ampicillin and TMP-SMZ showed that both drugs were equally effective. Treatment failure with both drugs was more frequent in patients with S isolates than in patients with R isolates. Therefore, in an area where antimicrobial-resistant typhoid fever exists, patients with R isolates should receive either ampicillin or TMP-SMZ, but patients with S isolates should be treated with chloramphenicol.