Publications by authors named "Juan Carlos Hurtado"

33 Publications

High within-host diversity found from direct genotyping on post-mortem tuberculosis specimens in a high-burden setting.

Clin Microbiol Infect 2021 Jun 11. Epub 2021 Jun 11.

Barcelona Institute for Global Health (ISGlobal), Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain; Department of Microbiology, Hospital Clinic de Barcelona, Barcelona, Spain. Electronic address:

Objectives: To characterize the clonal complexity in Mycobacterium tuberculosis (MTB) infections considering factors that help maximize the detection of coexisting strains/variants.

Methods: Genotypic analysis by Mycobacterial Interspersed Repetitive-Unit-Variable-Number Tandem-Repeats (MIRU-VNTR) was performed directly on 70 biopsy specimens from two or more different tissues involving 28 tuberculosis cases diagnosed post-mortem in Mozambique, a country with a high tuberculosis burden.

Results: Genotypic data from isolates collected from two or more tissues were obtained for 23 of the 28 cases (82.1%), allowing the analysis of within-patient diversity. MIRU-VNTR analysis revealed clonal diversity in ten cases (35.7%). Five cases showed allelic differences in three or more loci, suggesting mixed infection with two different strains. In half of the cases showing within-host diversity, one of the specimens associated with clonal heterogeneity was brain tissue.

Conclusions: Direct MTB genotyping from post-mortem tissue samples revealed a frequent within-host Mycobacterium tuberculosis diversity, including mixed and polyclonal infections. Most of this diversity would have been overlooked if only standard analysis of respiratory specimens had been performed.
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http://dx.doi.org/10.1016/j.cmi.2021.05.038DOI Listing
June 2021

Klebsiella spp. cause severe and fatal disease in Mozambican children: antimicrobial resistance profile and molecular characterization.

BMC Infect Dis 2021 Jun 5;21(1):526. Epub 2021 Jun 5.

Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique.

Background: Klebsiella spp. are important pathogens associated with bacteremia among admitted children and is among the leading cause of death in children < 5 years in postmortem studies, supporting a larger role than previously considered in childhood mortality. Herein, we compared the antimicrobial susceptibility, mechanisms of resistance, and the virulence profile of Klebsiella spp. from admitted and postmortem children.

Methods: Antimicrobial susceptibility and virulence factors of Klebsiella spp. recovered from blood samples collected upon admission to the hospital (n = 88) and postmortem blood (n = 23) from children < 5 years were assessed by disk diffusion and multiplex PCR.

Results: Klebsiella isolates from postmortem blood were likely to be ceftriaxone resistant (69.6%, 16/23 vs. 48.9%, 43/88, p = 0.045) or extended-spectrum β-lactamase (ESBL) producers (60.9%, 14/23 vs. 25%, 22/88, p = 0.001) compared to those from admitted children. bla was the most frequent ESBL gene: 65.3%, 9/14 in postmortem isolates and 22.7% (5/22) from admitted children. We found higher frequency of genes associated with hypermucoviscosity phenotype and invasin in postmortem isolates than those from admitted children: rmpA (30.4%; 7/23 vs. 9.1%, 8/88, p = 0.011), wzi-K1 (34.7%; 8/23 vs. 8%; 7/88, p = 0.002) and traT (60.8%; 14/23 vs. 10.2%; 9/88, p < 0.0001), respectively. Additionally, serine protease auto-transporters of Enterobacteriaceae were detected from 1.8% (pic) to 12.6% (pet) among all isolates. Klebsiella case fatality rate was 30.7% (23/75).

Conclusion: Multidrug resistant Klebsiella spp. harboring genes associated with hypermucoviscosity phenotype has emerged in Mozambique causing invasive fatal disease in children; highlighting the urgent need for prompt diagnosis, appropriate treatment and effective preventive measures for infection control.
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http://dx.doi.org/10.1186/s12879-021-06245-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178901PMC
June 2021

Accuracy of verbal autopsy, clinical data and minimally invasive autopsy in the evaluation of malaria-specific mortality: an observational study.

BMJ Glob Health 2021 06;6(6)

ISGLOBAL, Hospital Clinic, University of Barcelona, Barcelona, Spain

Background: Global malaria mortality estimates are hindered by the low reliability of the verbal autopsy (VA) and the clinical records, the most common sources of information used to estimate malaria-specific mortality. We aimed to determine the accuracy of these tools, as well as of the minimally invasive autopsy (MIA), a needle-based postmortem sampling method, to identify malaria-specific mortality in a large series of deceased patients from Mozambique, using complete autopsy as the gold standard.

Methods: Observational study that included 264 deaths, occurring at a tertiary level hospital in Mozambique, from 1 November 2013 to 31 March 2015 (17 months-long period). Clinical data were abstracted, a computer coded VA was completed using the clinical data as source of information, and an MIA followed by a complete autopsy were performed. Screening for malaria infection was conducted postmortem to all participants using molecular and histological techniques (PCR and immunohistochemistry).

Findings: Malaria infection was considered the cause of death in 6/264 (2.3%) cases: 2/54 children (3.7%, both less than 5 years old) and 4/57 (7.0%) maternal deaths. The sensitivity and specificity of the VA, the clinical data and the MIA to identify malaria-specific deaths were 33.3% and 96.1%, 66.7% and 96.1%, and 100% and 100%, respectively. In addition, malaria was identified as a possible contributor in 14 additional patients who died of other diseases. These cases were also accurately identified by the MIA (sensitivity 82.4%, specificity 100%).

Interpretation: The high sensitivity and specificity of the MIA in identifying malaria may help to improve current estimates of malaria-specific mortality in endemic areas.
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http://dx.doi.org/10.1136/bmjgh-2021-005218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183227PMC
June 2021

Limitations to current methods to estimate cause of death: a validation study of a verbal autopsy model.

Gates Open Res 2020 5;4:55. Epub 2021 May 5.

Barcelona Institute for Global Health (ISGlobal), Hospital Clinic of Barcelona, Universitat de Barcelona, Barcelona, Spain.

: Accurate information on causes of death (CoD) is essential to estimate burden of disease, track global progress, prioritize cost-effective interventions, and inform policies to reduce mortality. In low-income settings, where a significant proportion of deaths take place at home or in poorly-resourced peripheral health facilities, data on CoD often relies on verbal autopsies (VAs). Validations of VAs have been performed against clinical diagnosis, but never before against an acceptable gold standard: the complete diagnostic autopsy (CDA). We have validated a computer-coded verbal autopsy method -the InterVA- using individual and population metrics to determine CoD against the CDA, in 316 deceased patients of different age groups who died in a tertiary-level hospital in Maputo, Mozambique between 2013 and 2015. We found a low agreement of the model across all age groups at the individual (kappa statistic ranging from -0.030 to 0.232, lowest in stillbirths and highest in adults) and population levels (chance-corrected cause-specific mortality fraction accuracy ranging from -1.00 to 0.62, lowest in stillbirths, highest in children). The sensitivity in identifying infectious diseases was low (0% for tuberculosis, diarrhea, and disseminated infections, 32% for HIV-related infections, 33% for malaria and 36% for pneumonia). Of maternal deaths, 26 were assigned to eclampsia but only four patients actually died of eclampsia. These findings do not lead to building confidence in current estimates of CoD. They also call to the need to implement autopsy methods where they may be feasible, and to improve the quality and performance of current VA techniques.
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http://dx.doi.org/10.12688/gatesopenres.13132.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590499.3PMC
May 2021

Minimally Invasive Autopsy Practice in COVID-19 Cases: Biosafety and Findings.

Pathogens 2021 Apr 1;10(4). Epub 2021 Apr 1.

ISGlobal, Barcelona Institute for Global Health, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain.

Postmortem studies are crucial for providing insight into emergent diseases. However, a complete autopsy is frequently not feasible in highly transmissible diseases due to biohazard challenges. Minimally invasive autopsy (MIA) is a needle-based approach aimed at collecting samples of key organs without opening the body, which may be a valid alternative in these cases. We aimed to: (a) provide biosafety guidelines for conducting MIAs in COVID-19 cases, (b) compare the performance of MIA versus complete autopsy, and (c) evaluate the safety of the procedure. Between October and December 2020, MIAs were conducted in six deceased patients with PCR-confirmed COVID-19, in a basic autopsy room, with reinforced personal protective equipment. Samples from the lungs and key organs were successfully obtained in all cases. A complete autopsy was performed on the same body immediately after the MIA. The diagnoses of the MIA matched those of the complete autopsy. In four patients, COVID-19 was the main cause of death, being responsible for the different stages of diffuse alveolar damage. No COVID-19 infection was detected in the personnel performing the MIAs or complete autopsies. In conclusion, MIA might be a feasible, adequate and safe alternative for cause of death investigation in COVID-19 cases.
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http://dx.doi.org/10.3390/pathogens10040412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065952PMC
April 2021

High prevalence and mortality due to Histoplasma capsulatum in the Brazilian Amazon: An autopsy study.

PLoS Negl Trop Dis 2021 04 5;15(4):e0009286. Epub 2021 Apr 5.

ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Background: Histoplasmosis is acquired by inhalation of spores of the dimorphic fungus Histoplasma spp. Although this pathogen is distributed worldwide, it is more prevalent in the Americas. However, the real burden of histoplasmosis remains undefined in many endemic regions.

Methodology: We conducted a series of 61 autopsies to individuals who died in a hospital in the Brazilian Amazon focused on infectious diseases. We performed a detailed histological and microbiological evaluation with genetic characterization of Histoplasma strains with the aim to evaluate the contribution of histoplasmosis to morbidity and mortality. Additionally, we assessed the clinicopathological correlation.

Principal Findings: Evidence of Histoplasma infection was detected in 21 patients (34%). Eight cases were disseminated infections, all of them occurred in HIV-positive patients. Six cases were localized histoplasmosis, limited to the lungs. In seven patients Histoplasma DNA was detected by PCR in patients with no histological lesions. Histoplasma infection was detected in 38% of HIV-positive patients and was a major contributor to death in 22% of them. Lungs, liver and spleen were affected in all cases of disseminated histoplasmosis. Phylogenetic analysis of the strains suggested a high diversity of Histoplasma species circulating in the Brazilian Amazon. Histoplasmosis was clinically missed in 75% of the disseminated infections.

Conclusions: The high incidence of histoplasmosis, the low index of clinical suspicion, and the severity of the disseminated disease highlight the need of proactively implementing sensitive routine screening methods for this pathogen in endemic areas. Antifungal prophylaxis against Histoplasma should be encouraged in the severely immunocompromised HIV patients in these areas. In conclusion, substantial mortality is associated with disseminated histoplasmosis among HIV-positive patients in the Brazilian Amazon.
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http://dx.doi.org/10.1371/journal.pntd.0009286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049479PMC
April 2021

Malacoplakia of the Uterine Cervix: A Case Report.

Pathogens 2021 Mar 15;10(3). Epub 2021 Mar 15.

Department of Pathology, Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain.

Malacoplakia is an uncommon chronic granulomatous inflammation that rarely affects the female genital tract. A case of a 78-year-old woman with malacoplakia involving the uterine cervix and the vagina is described. The patient complained of vaginal bleeding. Clinically, a 13-mm mass was detected in the cervix, which was confirmed by ultrasound scan and magnetic resonance imaging. Histological examination showed a dense histiocytic infiltrate with abundant Michaelis-Gutmann bodies involving the uterine cervix and the upper vagina. The presence of was confirmed in the lesion by immunohistochemistry and polymerase chain reaction. Only 12 cases of cervical malacoplakia have been reported to date. This condition should be included in the differential diagnosis of cervical tumors.
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http://dx.doi.org/10.3390/pathogens10030343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000235PMC
March 2021

Lack of efficacy of standard doses of ivermectin in severe COVID-19 patients.

PLoS One 2020 11;15(11):e0242184. Epub 2020 Nov 11.

Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.

Ivermectin has recently shown efficacy against SARS-CoV-2 in-vitro. We retrospectively reviewed severe COVID-19 patients receiving standard doses of ivermectin and we compared clinical and microbiological outcomes with a similar group of patients not receiving ivermectin. No differences were found between groups. We recommend the evaluation of high-doses of ivermectin in randomized trials against SARS-CoV-2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242184PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657540PMC
November 2020

Quality of care and maternal mortality in a tertiary-level hospital in Mozambique: a retrospective study of clinicopathological discrepancies.

Lancet Glob Health 2020 07;8(7):e965-e972

ISGlobal, Hospital Clinic-Universitat de Barcelona, Barcelona, Spain; Department of Pathology, Hospital Clinic-Universitat de Barcelona, Barcelona, Spain.

Background: Although an increasing number of pregnant women in resource-limited areas deliver in health-care facilities, maternal mortality remains high in these settings. Inadequate diagnosis and management of common life-threatening conditions is an important determinant of maternal mortality. We analysed the clinicopathological discrepancies in a series of maternal deaths from Mozambique and assessed changes over 10 years in the diagnostic process. We aimed to provide data on clinical diagnostic accuracy to be used for improving quality of care and reducing maternal mortality.

Methods: We did a retrospective analysis of clinicopathological discrepancies in 91 maternal deaths occurring from Nov 1, 2013, to March 31, 2015 (17 month-long period), at a tertiary-level hospital in Mozambique, using complete diagnostic autopsies as the gold standard to ascertain cause of death. We estimated the performance of the clinical diagnosis and classified clinicopathological discrepancies as major and minor errors. We compared the findings of this analysis with those of a similar study done in the same setting 10 years earlier.

Findings: We identified a clinicopathological discrepancy in 35 (38%) of 91 women. All diagnostic errors observed were classified as major discrepancies. The sensitivity of the clinical diagnosis for puerperal infections was 17% and the positive predictive value was 50%. The sensitivity for non-obstetric infections was 48%. The sensitivity for eclampsia was 100% but the positive predictive value was 33%. Over the 10-year period, the performance of clinical diagnosis did not improve, and worsened for some diagnoses, such as puerperal infection.

Interpretation: Decreasing maternal mortality requires improvement of the pre-mortem diagnostic process and avoidance of clinical errors by refining clinical skills and increasing the availability and quality of diagnostic tests. Comparison of post-mortem information with clinical diagnosis will help monitor the reduction of clinical errors and thus improve the quality of care.

Funding: Bill & Melinda Gates Foundation and Instituto de Salud Carlos III.
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http://dx.doi.org/10.1016/S2214-109X(20)30236-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303952PMC
July 2020

Comparison of Commensal and Clinical Isolates for Diversity of Plasmids in Escherichia coli and Klebsiella pneumoniae.

Antimicrob Agents Chemother 2020 04 21;64(5). Epub 2020 Apr 21.

Department of Microbiology, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain

In this study, the plasmid content of clinical and commensal strains was analyzed and compared. The replicon profile was similar in both populations, except for L, M, A/C, and N (detected only in clinical strains) and HI1 (only in commensal strains). Although I1 and F were the most frequent replicons, only IncI1, sequence type 12 (ST12) was associated with in both populations. In contrast, the widespread resistant IncF plasmids were not linked to a single epidemic plasmid.
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http://dx.doi.org/10.1128/AAC.02064-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179601PMC
April 2020

Clinico-pathological discrepancies in the diagnosis of causes of death in adults in Mozambique: A retrospective observational study.

PLoS One 2019 6;14(9):e0220657. Epub 2019 Sep 6.

Department of Pathology, Maputo Central Hospital, Maputo, Mozambique.

Background: Clinico-pathological discrepancies are more frequent in settings in which limited diagnostic techniques are available, but there is little information on their actual impact.

Aim: We assessed the accuracy of the clinical diagnoses in a tertiary referral hospital in sub-Saharan Africa by comparison with post-mortem findings. We also identified potential risk factors for misdiagnoses.

Methods: One hundred and twelve complete autopsy procedures were performed at the Maputo Central Hospital (Mozambique), from November 2013 to March 2015. We reviewed the clinical records. Major clinico-pathological discrepancies were assessed using a modified version of the Goldman and Battle classification.

Results: Major diagnostic discrepancies were detected in 65/112 cases (58%) and were particularly frequent in infection-related deaths (56/80 [70%] major discrepancies). The sensitivity of the clinical diagnosis for toxoplasmosis was 0% (95% CI: 0-37), 18% (95% CI: 2-52) for invasive fungal infections, 25% (95% CI: 5-57) for bacterial sepsis, 34% (95% CI: 16-57), for tuberculosis, and 46% (95% CI: 19-75) for bacterial pneumonia. Major discrepancies were more frequent in HIV-positive than in HIV-negative patients (48/73 [66%] vs. 17/39 [44%]; p = 0.0236).

Conclusions: Major clinico-pathological discrepancies are still frequent in resource constrained settings. Increasing the level of suspicion for infectious diseases and expanding the availability of diagnostic tests could significantly improve the recognition of common life-threatening infections, and thereby reduce the mortality associated with these diseases. The high frequency of clinico-pathological discrepancies questions the validity of mortality reports based on clinical data or verbal autopsy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220657PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730941PMC
March 2020

Unmasking the hidden tuberculosis mortality burden in a large study in Maputo Central Hospital, Mozambique.

Eur Respir J 2019 09 1;54(3). Epub 2019 Oct 1.

ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain

Sensitive tools are needed to accurately establish the diagnosis of tuberculosis (TB) at death, especially in low-income countries. The objective of this study was to evaluate the burden of TB in a series of patients who died in a tertiary referral hospital in sub-Saharan Africa using an in-house real time PCR (TB-PCR) and the Xpert MTB/RIF Ultra (Xpert Ultra) assay.Complete diagnostic autopsies were performed in a series of 223 deaths (56.5% being HIV-positive), including 54 children, 57 maternal deaths and 112 other adults occurring at the Maputo Central Hospital, Mozambique. TB-PCR was performed in all lung, cerebrospinal fluid and central nervous system samples in HIV-positive patients. All samples positive for TB-PCR or showing histological findings suggestive of TB were analysed with the Xpert Ultra assay.TB was identified as the cause of death in 31 patients: three out of 54 (6%) children, five out of 57 (9%)maternal deaths and 23 out of 112 (21%) other adults. The sensitivity of the main clinical diagnosis to detect TB as the cause of death was 19.4% (95% CI 7.5-37.5) and the specificity was 97.4% (94.0-99.1) compared to autopsy findings. Concomitant TB (TB disease in a patient dying of other causes) was found in 31 additional cases. Xpert Ultra helped to identify 15 cases of concomitant TB. In 18 patients, DNA was identified by TB-PCR and Xpert Ultra in the absence of histological TB lesions. Overall, 62 (27.8%) cases had TB disease at death and 80 (35.9%) had TB findings.The use of highly sensitive, easy to perform molecular tests in complete diagnostic autopsies may contribute to identifying TB cases at death that would have otherwise been missed. Routine use of these tools in certain diagnostic algorithms for hospitalised patients needs to be considered. Clinical diagnosis showed poor sensitivity for the diagnosis of TB at death.
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http://dx.doi.org/10.1183/13993003.00312-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769353PMC
September 2019

Sneathia amnii and Maternal Chorioamnionitis and Stillbirth, Mozambique.

Emerg Infect Dis 2019 08;25(8):1614-1616

We report a case of Sneathia amnii as the causative agent of maternal chorioamnionitis and congenital pneumonia resulting in a late fetal death in Mozambique, with strong supportive postmortem molecular and histopathologic confirmation. This rare, fastidious gram-negative coccobacillus has been reported to infrequently cause abortions, stillbirths, and neonatal infections.
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http://dx.doi.org/10.3201/eid2508.190526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649333PMC
August 2019

Performance of the minimally invasive autopsy tool for cause of death determination in adult deaths from the Brazilian Amazon: an observational study.

Virchows Arch 2019 Nov 14;475(5):649-658. Epub 2019 Jun 14.

Fundação de Medicina Tropical Dr. Heitor Viera Dourado, Manaus, 69040-000, Brazil.

The uncertainty about the real burden of causes of death (CoD) is increasingly recognized by the international health community as a critical limitation for prioritizing effective public health measures. The minimally invasive autopsy (MIA) has shown to be a satisfactory substitute of the complete diagnostic autopsy (CDA), the gold standard for CoD determination in low- and middle-income countries. However, more studies are needed to confirm its adequate performance in settings with different epidemiology. In this observational study, the CoD obtained with the MIA were compared with the clinical diagnosis and the results of the CDA in 61 deaths that occurred in an infectious diseases referral hospital in Manaus, Brazilian Amazon. Concordance between the categories of diseases obtained by the three methods was evaluated by the Kappa statistic. Additionally, we evaluated discrepancies between clinical and complete diagnostic autopsy diagnoses. The MIA showed a substantial concordance with the CDA (Kappa = 0.777, 95% CI 0.608-0.946), and a perfect or almost perfect coincidence in specific diagnosis (ICD-10 code) between MIA and CDA was observed in 85% of the cases. In contrast, the clinical diagnosis showed a fair concordance with the CDA (Kappa = 0.311, 95% CI 0.071-0.552). Major clinico-pathological discrepancies were identified in 49% of cases. In conclusion, the MIA showed a substantial performance for CoD identification. Clinico-pathological discrepancies remain high and justify the need for post-mortem studies, even in referral hospitals. The MIA is a robust substitute of the CDA for CoD surveillance and quality improvement of clinical practice in low- and middle-income settings.
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http://dx.doi.org/10.1007/s00428-019-02602-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861203PMC
November 2019

Mortality due to Cryptococcus neoformans and Cryptococcus gattii in low-income settings: an autopsy study.

Sci Rep 2019 05 16;9(1):7493. Epub 2019 May 16.

ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.

Cryptococcosis is a major opportunistic infection and is one of the leading causes of death in adults living with HIV in sub-Saharan Africa. Recent estimates indicate that more than 130,000 people may die annually of cryptococcal meningitis in this region. Although complete diagnostic autopsy (CDA) is considered the gold standard for determining the cause of death, it is seldom performed in low income settings. In this study, a CDA was performed in 284 deceased patients from Mozambique (n = 223) and Brazil (n = 61). In depth histopathological and microbiological analyses were carried out in all cases dying of cryptococcosis. We determined the cryptococcal species, the molecular and sero-mating types and antifungal susceptibility. We also described the organs affected and reviewed the clinical presentation and patient management. Among the 284 cases included, 17 fatal cryptococcal infections were diagnosed. Cryptococcus was responsible for 16 deaths among the 163 HIV-positive patients (10%; 95%CI: 6-15%), including four maternal deaths. One third of the cases corresponded to C. gattii (VGI and VGIV molecular types, Bα and Cα strains) and the remaining infections typed were caused by C. neoformans var. Grubii (all VNI and Aα strains). The level of pre-mortem clinical suspicion was low (7/17, 41%), and 7/17 patients (41%) died within the first 72 hours of admission. Cryptococcosis was responsible for a significant proportion of AIDS-related mortality. The clinical diagnosis and patient management were inadequate, supporting the need for cryptococcal screening for early detection of the disease. This is the first report of the presence of C. gattii infection in Mozambique.
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http://dx.doi.org/10.1038/s41598-019-43941-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522501PMC
May 2019

Training through malaria research: building capacity in good clinical and laboratory practice in Liberia.

Malar J 2019 Apr 17;18(1):136. Epub 2019 Apr 17.

ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Background: Limited health research capacities (HRC) undermine a country's ability to identify and adequately respond to local health needs. Although numerous interventions to strengthen HRC have been conducted in Africa, there is a need to share the lessons learnt by funding organizations, institutes and researchers. The aim of this report is to identify best practices in HRC strengthening by describing a training programme conducted between 2016 and 2017 at the Saint Joseph's Catholic Hospital (SJCH) in Monrovia (Liberia).

Methods: A call for trainees was launched at the SJCH, the Liberia Medicines and Health Products Regulatory Authority (LMHRA), the Ministry of Health and Social Welfare, the Mother Pattern College of Health Sciences (MPCHS) and community members. Selected trainees participated in four workshops on Good Clinical Laboratory Practice (GCLP), standard operating procedures (SOP) and scientific communication, as well as in a 5-months eLearning mentoring programme. After the training, a collectively-designed research project on malaria was conducted.

Results: Twenty-one of the 28 trainees (14 from the SJCH, 3 from LMHRA, one from MPCHS, and 10 community representatives) completed the programme satisfactorily. Pre- and post-training questionnaires completed by 9 of the trainees showed a 14% increase in the percentage of correct answers. Trainees participated in a mixed-methods cross-sectional study of Plasmodium falciparum infection among pregnant women at the SJCH. Selected trainees disseminated activities and research outcomes in three international meetings and three scientific publications.

Conclusion: This training-through-research programme successfully involved SJCH staff and community members in a practical research exercise on malaria during pregnancy. The challenge is to ensure that the SJCH remains active in research. Harmonization of effectiveness indicators for HRC initiatives would strengthen the case for investing in such efforts.
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http://dx.doi.org/10.1186/s12936-019-2767-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471755PMC
April 2019

Evaluation of the Magicplex™ Sepsis Real-Time Test for the Rapid Diagnosis of Bloodstream Infections in Adults.

Front Cell Infect Microbiol 2019 12;9:56. Epub 2019 Mar 12.

Department of Microbiology, ISGlobal, Barcelona Centre for International Health Research, Hospital Clinic, University of Barcelona, Barcelona, Spain.

Sepsis is a serious health condition worldwide, affecting more than 30 million people globally each year. Blood culture (BC) is generally used to diagnose sepsis because of the low quantity of microbes occurring in the blood during such infections. However, ~50% of bloodstream infections (BSI) give negative BC, this figure being higher for sepsis, which delays the start of appropriate antimicrobial therapy. This prospective study evaluated a multiplex real-time polymerase chain reaction, the Magicplex Sepsis test (MP), for the detection of pathogens from whole blood, comparing it to routine BC. We analyzed 809 blood samples from 636 adult patients, with 132/809 (16.3%) of the samples positive for one or more relevant microorganism according to BC and/or MP. The sensitivity and specificity of MP were 29 and 95%, respectively, while the level of agreement between BC and MP was 87%. The rate of contaminated samples was higher for BC (10%) than MP (4.8%) ( < 0.001). Patients with only MP-positive samples were more likely to be on antimicrobial treatment (47%) than those with only BC-positive samples (18%) ( = 0.002). In summary, the MP test could be useful in some clinical setting, such as among patients on antibiotic therapy. Nevertheless, a low sensitivity demonstrated impairs its use as a part of a routine diagnostic algorithm.
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http://dx.doi.org/10.3389/fcimb.2019.00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423426PMC
November 2019

Contribution of the clinical information to the accuracy of the minimally invasive and the complete diagnostic autopsy.

Hum Pathol 2019 03 27;85:184-193. Epub 2018 Nov 27.

ISGlobal, Hospital Clinic, Universitat de Barcelona, 08036 Barcelona, Spain; Centro de Investigação em Saúde de Manhiça, 1100 Maputo, Mozambique; Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain.

Although autopsy diagnosis includes routinely, a thorough evaluation of all available pathological results and also of any available clinical data, the contribution of this clinical information to the diagnostic yield of the autopsy has not been analyzed. We aimed to determine to which degree the use of clinical data improves the diagnostic accuracy of the complete diagnostic autopsy (CDA) and the minimally invasive autopsy (MIA), a simplified pathological postmortem procedure designed for low-income sites. A total of 264 coupled MIA and CDA procedures (112 adults, 57 maternal deaths, 54 children, and 41 neonates) were performed at the Maputo Hospital, Mozambique. We compared the diagnoses obtained by the MIA blind to clinical data (MIAb), the MIA adding the clinical information (MIAc), and the CDA blind to clinical information (CDAb), with the results of the gold standard, the CDA with clinical data, by comparing the International Classification of Diseases, Tenth Revision codes and the main diagnostic classes obtained with each evaluation strategy (MIAb, MIAc, CDAb, CDAc). The clinical data increased diagnostic coincidence to the MIAb with the gold standard in 30 (11%) of 264 cases and modified the CDAb diagnosis in 20 (8%) of 264 cases. The increase in concordance between MIAb and MIAc with the gold standard was significant in neonatal deaths (κ increasing from 0.404 to 0.618, P = .0271), adult deaths (κ increasing from 0.732 to 0.813, P = .0221), and maternal deaths (κ increasing from 0.485 to 0.836, 0.;P < .0001). In conclusion, the use of clinical information increases the precision of MIA and CDA and may strengthen the performance of the MIA in resource-limited settings.
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http://dx.doi.org/10.1016/j.humpath.2018.10.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478426PMC
March 2019

High seroprevalence of Strongyloides stercoralis among individuals from endemic areas considered for solid organ transplant donation: A retrospective serum-bank based study.

PLoS Negl Trop Dis 2018 11 29;12(11):e0007010. Epub 2018 Nov 29.

ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.

Background: Strongyloides stercoralis is a worldwide disseminated parasitic disease that can be transmitted from solid organ transplant (SOT) donors to recipients. We determined the serological prevalence of S. stercoralis among deceased individuals from endemic areas considered for SOT donation, using our institution's serum bank.

Methodology: Retrospective study including all deceased potential donors from endemic areas of strongyloidiasis considered for SOT between January 2004 and December 2014 in a tertiary care hospital. The commercial serological test IVD-Elisa was used to determine the serological prevalence of S. stercoralis.

Principal Findings: Among 1025 deceased individuals during the study period, 90 were from endemic areas of strongyloidiasis. There were available serum samples for 65 patients and 6 of them tested positive for S. stercoralis (9.23%). Only one of the deceased candidates was finally a donor, without transmitting the infection.

Conclusions: Among deceased individuals from endemic areas considered for SOT donation, seroprevalence of strongyloidiasis was high. This highlights the importance of adhering to current recommendations on screening for S. stercoralis among potential SOT donors at high risk of the infection, together with the need of developing a rapid diagnostic test to fully implement these screening strategies.
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http://dx.doi.org/10.1371/journal.pntd.0007010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289465PMC
November 2018

Postmortem Interval and Diagnostic Performance of the Autopsy Methods.

Sci Rep 2018 10 31;8(1):16112. Epub 2018 Oct 31.

Department of Molecular Microbiology, University Hospital Sant Joan de Déu (University of Barcelona), Barcelona, Spain.

Postmortem studies, including the complete diagnostic autopsy (CDA) and the minimally invasive autopsy (MIA), an innovative approach to post-mortem sampling and cause of death investigation, are commonly performed within 24 hours after death because the quality of the tissues deteriorates over time. This short timeframe may hamper the feasibility of the procedure. In this study, we compared the diagnostic performance of the two postmortem procedures when carried out earlier and later than 24 hours after death, as well as the impact of increasing postmortem intervals (PMIs) on the results of the microbiological tests in a series of 282 coupled MIA/CDA procedures performed at the Maputo Central Hospital in Mozambique between 2013 and 2015. 214 procedures were conducted within 24 hours of death (early autopsies), and 68 after 24 hours of death (late autopsies). No significant differences were observed in the number of non-conclusive diagnoses (2/214 [1%] vs. 1/68 [1%] p = 0.5645 for the CDA; 27/214 [13%] vs. 5/68 [7%] p = 0.2332 for the MIA). However, increasing PMIs were associated with a raise in the number of bacteria identified (rate: 1.014 per hour [95%CI: 1.002-1.026]; p = 0.0228). This increase was mainly due to rising numbers of bacteria of the Enterobacteriaceae family and Pseudomonas genus strains. Thus, performing MIA or CDA more than 24 hours after death can still render reliable diagnostic results, not only for non-infectious conditions but also for many infectious diseases, although, the contribution of Enterobacteriaceae and Pseudomonas spp. as etiological agents of infections leading to death may be overestimated.
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http://dx.doi.org/10.1038/s41598-018-34436-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208334PMC
October 2018

Fatal multi-drug-resistant Acinetobacter baumannii pneumonia in Maputo, Mozambique: A case report.

Enferm Infecc Microbiol Clin (Engl Ed) 2019 Aug - Sep;37(7):485-487. Epub 2018 Aug 3.

ISGlobal, Hospital Clínic-Universitat de Barcelona, Barcelona, Spain; Department of Clinical Microbiology, Hospital Clinic of Barcelona, Universitat de Barcelona, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.eimc.2018.06.016DOI Listing
September 2020

Antibiotic resistance genes in phage particles isolated from human faeces and induced from clinical bacterial isolates.

Int J Antimicrob Agents 2018 Mar 24;51(3):434-442. Epub 2017 Nov 24.

Department of Genetics, Microbiology and Statistics, University of Barcelona, Diagonal 643, Annex, Floor 0, E-08028 Barcelona, Spain. Electronic address:

Phage particles have emerged as elements with the potential to mobilise antibiotic resistance genes (ARGs) in different environments, including the intestinal habitat. This study aimed to determine the occurrence of ARGs in phage particles present in faecal matter and induced from strains isolated from faeces. Nine ARGs (bla, bla, bla, bla, qnrA, qnrS, mecA, sul1 and armA) were quantified by qPCR in the phage DNA fractions of 150 faecal samples obtained from healthy individuals who had not received antibiotic treatment or travelled abroad in the 3 months prior to sample collection. On the suspicion that the detected particles originated from bacterial flora, 82 Escherichia coli and Klebsiella pneumoniae isolates possessing at least one identified ARG (bla, bla, bla, armA, qnrA, qnrS and sul1) were isolated and their capacity to produce phage particles carrying these ARGs following induction was evaluated. Of 150 samples, 72.7% were positive for at least one ARG, with bla and bla being the most prevalent and abundant. Of the 82 isolates, 51 (62%) showed an increase in the number of copies of the respective ARG in the phage fraction following induction, with bla, bla, bla and sul1 being the most abundant. Phages induced from the isolates were further purified and visualised using microscopy and their DNA showed ARG levels of up to 10 gene copies/mL. This study highlights the abundance of phage particles harbouring ARGs and indicates that bacterial strains in the intestinal habitat could be source of these particles.
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http://dx.doi.org/10.1016/j.ijantimicag.2017.11.014DOI Listing
March 2018

Validity of a minimally invasive autopsy for cause of death determination in maternal deaths in Mozambique: An observational study.

PLoS Med 2017 Nov 8;14(11):e1002431. Epub 2017 Nov 8.

ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clinic of Barcelona, Universitat de Barcelona, Barcelona, Spain.

Background: Despite global health efforts to reduce maternal mortality, rates continue to be unacceptably high in large parts of the world. Feasible, acceptable, and accurate postmortem sampling methods could provide the necessary evidence to improve the understanding of the real causes of maternal mortality, guiding the design of interventions to reduce this burden.

Methods And Findings: The validity of a minimally invasive autopsy (MIA) method in determining the cause of death was assessed in an observational study in 57 maternal deaths by comparing the results of the MIA with those of the gold standard (complete diagnostic autopsy [CDA], which includes any available clinical information). Concordance between the MIA and the gold standard diagnostic categories was assessed by the kappa statistic, and the sensitivity, specificity, positive and negative predictive values and their 95% confidence intervals (95% CI) to identify the categories of diagnoses were estimated. The main limitation of the study is that both the MIA and the CDA include some degree of subjective interpretation in the attribution of cause of death. A cause of death was identified in the CDA in 98% (56/57) of cases, with indirect obstetric conditions accounting for 32 (56%) deaths and direct obstetric complications for 24 (42%) deaths. Nonobstetric infectious diseases (22/32, 69%) and obstetric hemorrhage (13/24, 54%) were the most common causes of death among indirect and direct obstetric conditions, respectively. Thirty-six (63%) women were HIV positive, and HIV-related conditions accounted for 16 (28%) of all deaths. Cerebral malaria caused 4 (7%) deaths. The MIA identified a cause of death in 86% of women. The overall concordance of the MIA with the CDA was moderate (kappa = 0.48, 95% CI: 0.31-0.66). Both methods agreed in 68% of the diagnostic categories and the agreement was higher for indirect (91%) than for direct obstetric causes (38%). All HIV infections and cerebral malaria cases were identified in the MIA. The main limitation of the technique is its relatively low performance for identifying obstetric causes of death in the absence of clinical information.

Conclusions: The MIA procedure could be a valuable tool to determine the causes of maternal death, especially for indirect obstetric conditions, most of which are infectious diseases. The information provided by the MIA could help to prioritize interventions to reduce maternal mortality and to monitor progress towards achieving global health targets.
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http://dx.doi.org/10.1371/journal.pmed.1002431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695595PMC
November 2017

Validity of a minimally invasive autopsy tool for cause of death determination in pediatric deaths in Mozambique: An observational study.

PLoS Med 2017 Jun 20;14(6):e1002317. Epub 2017 Jun 20.

ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clinic of Barcelona, Universitat de Barcelona, Barcelona, Spain.

Background: In recent decades, the world has witnessed unprecedented progress in child survival. However, our knowledge of what is killing nearly 6 million children annually in low- and middle-income countries remains poor, partly because of the inadequacy and reduced precision of the methods currently utilized in these settings to investigate causes of death (CoDs). The study objective was to validate the use of a minimally invasive autopsy (MIA) approach as an adequate and more acceptable substitute for the complete diagnostic autopsy (CDA) for pediatric CoD investigation in a poor setting.

Methods And Findings: In this observational study, the validity of the MIA approach in determining the CoD was assessed in 54 post-neonatal pediatric deaths (age range: ≥1 mo to 15 y) in a referral hospital of Mozambique by comparing the results of the MIA with those of the CDA. Concordance in the category of disease obtained by the two methods was evaluated by the Kappa statistic, and the sensitivity, specificity, and positive and negative predictive values of the MIA diagnoses were calculated. A CoD was identified in all cases in the CDA and in 52/54 (96%) of the cases in the MIA, with infections and malignant tumors accounting for the majority of diagnoses. The MIA categorization of disease showed a substantial concordance with the CDA categorization (Kappa = 0.70, 95% CI 0.49-0.92), and sensitivity, specificity, and overall accuracy were high. The ICD-10 diagnoses were coincident in up to 75% (36/48) of the cases. The MIA allowed the identification of the specific pathogen deemed responsible for the death in two-thirds (21/32; 66%) of all deaths of infectious origin. Discrepancies between the MIA and the CDA in individual diagnoses could be minimized with the addition of some basic clinical information such as those ascertainable through a verbal autopsy or clinical record. The main limitation of the analysis is that both the MIA and the CDA include some degree of expert subjective interpretation.

Conclusions: The MIA showed substantial concordance with CDA for CoD identification in this series of pediatric deaths in Mozambique. This minimally invasive approach, simpler and more readily acceptable than the more invasive CDA, could provide robust data for CoD surveillance, especially in resource-limited settings, which could be helpful for guiding child survival strategies in the future.
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http://dx.doi.org/10.1371/journal.pmed.1002317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478091PMC
June 2017

Validity of a minimally invasive autopsy for cause of death determination in stillborn babies and neonates in Mozambique: An observational study.

PLoS Med 2017 Jun 20;14(6):e1002318. Epub 2017 Jun 20.

ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clinic of Barcelona, Universitat de Barcelona, Barcelona, Spain.

Background: Over 5 million stillbirths and neonatal deaths occur annually. Limited and imprecise information on the cause of these deaths hampers progress in achieving global health targets. Complete diagnostic autopsies (CDAs)-the gold standard for cause of death determination-are difficult to perform in most high-burden settings. Therefore, validation of simpler and more feasible methods is needed.

Methods And Findings: In this observational study, the validity of a minimally invasive autopsy (MIA) method in determining the cause of death was assessed in 18 stillbirths and 41 neonatal deaths by comparing the results of the MIA with those of the CDA. Concordance between the categories of diseases obtained by the 2 methods was assessed by the Kappa statistic, and the sensitivity, specificity, positive, and negative predictive values of the MIA diagnoses were calculated. A cause of death was identified in 16/18 (89%) and 15/18 (83%) stillborn babies in the CDA and the MIA, respectively. Fetal growth restriction accounted for 39%, infectious diseases for 22%, intrapartum hypoxia for 17%, and intrauterine hypoxia for 11% of stillborn babies. Overall, the MIA showed in this group a substantial concordance with the CDA (Kappa = 0.78, 95% CI [0.56-0.99]). A cause of death was identified in all (100%) and 35/41 (85%) neonatal deaths in the CDA and the MIA, respectively. In this group, the majority of deaths were due to infectious diseases (66%). The overall concordance of the MIA with the CDA in neonates was moderate (Kappa = 0.40, 95% CI [0.18-0.63]). A high percentage of accuracy was observed for the MIA in all the diagnostic categories in both stillbirths and neonates (>75%). The main limitation of this study is that some degree of subjective interpretation is inherent to cause-of-death attribution in both the MIA and the CDA; this is especially so in stillbirths and in relation to fetal growth restriction.

Conclusions: The MIA could be a useful tool for cause-of-death determination in stillbirths and neonatal deaths. These findings may help to accelerate progress towards meeting global health targets by obtaining more accurate information on the causes of death in these age groups, which is essential in guiding the design of new interventions and increasing the effectiveness of those already implemented.
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http://dx.doi.org/10.1371/journal.pmed.1002318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478138PMC
June 2017

Prevalence of Extended-Spectrum-β-Lactamase- and/or Carbapenemase-Producing Escherichia coli Isolated from Yellow-Legged Gulls from Barcelona, Spain.

Antimicrob Agents Chemother 2017 02 24;61(2). Epub 2017 Jan 24.

Hospital Clínic, Universitat de Barcelona, Barcelona, Spain

Seventy-two (54.5%) out of 132 fecal samples from a group of yellow-legged gulls in Barcelona, Spain, were positive for Escherichia coli producing either extended-spectrum β-lactamases (ESBL) (51.5%), carbapenemase (1.5%), or cephamycinase (1.5%). The isolation of two carbapenemase-producing E. coli strains is a matter of concern.
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http://dx.doi.org/10.1128/AAC.02071-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278720PMC
February 2017

Validity of a Minimally Invasive Autopsy for Cause of Death Determination in Adults in Mozambique: An Observational Study.

PLoS Med 2016 Nov 22;13(11):e1002171. Epub 2016 Nov 22.

ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clinic of Barcelona, Universitat de Barcelona, Barcelona, Spain.

Background: There is an urgent need to identify tools able to provide reliable information on the cause of death in low-income regions, since current methods (verbal autopsy, clinical records, and complete autopsies) are either inaccurate, not feasible, or poorly accepted. We aimed to compare the performance of a standardized minimally invasive autopsy (MIA) approach with that of the gold standard, the complete diagnostic autopsy (CDA), in a series of adults who died at Maputo Central Hospital in Mozambique.

Methods And Findings: In this observational study, coupled MIAs and CDAs were performed in 112 deceased patients. The MIA analyses were done blindly, without knowledge of the clinical data or the results of the CDA. We compared the MIA diagnosis with the CDA diagnosis of cause of death. CDA diagnoses comprised infectious diseases (80; 71.4%), malignant tumors (16; 14.3%), and other diseases, including non-infectious cardiovascular, gastrointestinal, kidney, and lung diseases (16; 14.3%). A MIA diagnosis was obtained in 100/112 (89.2%) cases. The overall concordance between the MIA diagnosis and CDA diagnosis was 75.9% (85/112). The concordance was higher for infectious diseases and malignant tumors (63/80 [78.8%] and 13/16 [81.3%], respectively) than for other diseases (9/16; 56.2%). The specific microorganisms causing death were identified in the MIA in 62/74 (83.8%) of the infectious disease deaths with a recognized cause. The main limitation of the analysis is that both the MIA and the CDA include some degree of expert subjective interpretation.

Conclusions: A simple MIA procedure can identify the cause of death in many adult deaths in Mozambique. This tool could have a major role in improving the understanding and surveillance of causes of death in areas where infectious diseases are a common cause of mortality.
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http://dx.doi.org/10.1371/journal.pmed.1002171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119723PMC
November 2016

Economic Impact of a New Rapid PCR Assay for Detecting Influenza Virus in an Emergency Department and Hospitalized Patients.

PLoS One 2016 20;11(1):e0146620. Epub 2016 Jan 20.

ISGlobal Barcelona Institute for Global Health, Barcelona, Spain.

Seasonal influenza causes significant morbidity and mortality and has a substantial economic impact on the healthcare system. The main objective of this study was to compare the cost per patient for a rapid commercial PCR assay (Xpert® Flu) with an in-house real-time PCR test for detecting influenza virus. Community patients with influenza like-illness attending the Emergency Department (ED) as well as hospitalized patients in the Hospital Clínic of Barcelona were included. Costs were evaluated from the perspective of the hospital considering the use of resources directly related to influenza testing and treatment. For the purpose of this study, 366 and 691 patients were tested in 2013 and 2014, respectively. The Xpert® Flu test reduced the mean waiting time for patients in the ED by 9.1 hours and decreased the mean isolation time of hospitalized patients by 23.7 hours. This was associated with a 103€ (or about $113) reduction in the cost per patient tested in the ED and 64€ ($70) per hospitalized patient. Sensitivity analyses showed that Xpert® Flu is likely to be cost-saving in hospitals with different contexts and prices.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146620PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720278PMC
July 2016

In vitro time-kill curves study of three antituberculous combinations against Mycobacterium tuberculosis clinical isolates.

Int J Antimicrob Agents 2016 Jan 21;47(1):97-100. Epub 2015 Nov 21.

Servei de Microbiologia, CDB, Hospital Clínic de Barcelona-ISGlobal, Universitat de Barcelona, c/Villarroel 170, 08036 Barcelona, Spain. Electronic address:

The objective of this study was to examine the in vitro synergism of three-drug combinations against Mycobacterium tuberculosis (levofloxacin/linezolid/ethambutol, levofloxacin/amikacin/ethambutol and levofloxacin/linezolid/amikacin) using the time-kill curves method. In total, 8 multidrug-resistant and 12 drug-susceptible M. tuberculosis isolates were used. Minimum inhibitory concentrations (MICs) of the isolates for each drug were determined by the proportions method. Time-kill curves were studied for the three combinations proposed over 14 days using two different protocols. In protocol 1, 0.5× MIC for each drug was used. In protocol 2, 0.5× MIC for levofloxacin and linezolid and 0.25× MIC for amikacin and ethambutol were used. The MICs for all of the isolates studied were 0.5 mg/L for levofloxacin and linezolid and 2.5 mg/L for ethambutol and amikacin. All of the combinations displayed an additive activity compared with the most active individual drug. In conclusion, these results demonstrate that the three combinations tested were equally effective against M. tuberculosis isolates. The study of antituberculous combinations using in vitro methods is an excellent first step to predict their effect in clinical development phases as well as to test new regimens of the antituberculous drugs currently available.
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http://dx.doi.org/10.1016/j.ijantimicag.2015.10.016DOI Listing
January 2016