In-hospital safety in field conditions of Nifurtimox Eflornithine Combination Therapy (NECT) for T. B. Gambiense Sleeping Sickness

Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2(nd) stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use

Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense sleeping sickness in nine Médecins Sans Frontières programmes.

This paper describes the effectiveness of first-line regimens for stage 2 human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense infection in nine Médecins Sans Frontières HAT treatment programmes in Angola, Republic of Congo, Sudan and Uganda. Regimens included eflornithine and standard- and short-course melarsoprol. Outcomes for 10461 naïve stage 2 patients fitting a standardised case definition and allocated to one of the above regimens were analysed by intention-to-treat analysis. Effectiveness was quantified by the case fatality rate (CFR) during treatment, the proportion probably and definitely cured and the Kaplan-Meier probability of relapse-free survival at 12 months and 24 months post admission. The CFR was similar for the standard- and short-course melarsoprol regimens (4.9% and 4.2%, respectively). The CFR for eflornithine was 1.2%. Kaplan-Meier survival probabilities varied from 71.4-91.8% at 1 year and 56.5-87.9% at 2 years for standard-course melarsoprol, to 73.0-91.1% at 1 year for short-course melarsoprol, and 79.9-97.4% at 1 year and 68.6-93.7% at 2 years for eflornithine. With the exception of one programme, survival at 12 months was >90% for eflornithine, whilst for melarsoprol it was <90% except in two sites. Eflornithine is recommended where feasible, especially in areas with low melarsoprol effectiveness

Prevalence and under-detection of gambiense human African trypanosomiasis during mass screening sessions in Uganda and Sudan

Abstract Background: Active case detection through mass community screening is a major control strategy against human African trypanosomiasis (HAT, sleeping sickness) caused by T. brucei gambiense. However, its impact can be limited by incomplete attendance at screening sessions (screening coverage) and diagnostic inaccuracy. Methods: We developed a model-based approach to estimate the true prevalence and the fraction of cases detected during mass screening, based on observed prevalence, and adjusting for incomplete screening coverage and inaccuracy of diagnostic algorithms for screening, confirmation and HAT stage classification. We applied the model to data from three Médecins Sans Frontières projects in Uganda (Adjumani, Arua-Yumbe) and Southern Sudan (Kiri). Results: We analysed 604 screening sessions, targeting about 710 000 people. Cases were about twice as likely to attend screening as non-cases, with no apparent difference by stage. Past incidence, population size and repeat screening rounds were strongly associated with observed prevalence. The estimated true prevalence was 0.46% to 0.90% in Kiri depending on the analysis approach, compared to an observed prevalence of 0.45%; 0.59% to 0.87% in Adjumani, compared to 0.92%; and 0.18% to 0.24% in Arua-Yumbe, compared to 0.21%. The true ratio of stage 1 to stage 2 cases was around two-three times higher than that observed, due to stage misclassification. The estimated detected fraction was between 42.2% and 84.0% in Kiri, 52.5% to 79.9% in Adjumani and 59.3% to 88.0% in Arua-Yumbe

Nifurtimox plus Eflornithine for Late-Stage Sleeping Sickness in Uganda: A Case Series

African sleeping sickness (Human African Trypanosomiasis, or HAT), due to the parasite Trypanosoma brucei gambiense, threatens millions across remote and conflict-affected regions of sub-Saharan Africa, and causes about 15 000 reported cases every year. Untreated HAT progresses from stage 1 (infection of the blood and lymph) to stage 2 (invasion of the central nervous system), and ultimately death. Drugs for stage 2 are few. The historical mainstay, melarsoprol, is highly toxic and inefficacious in some areas due to parasite resistance. Eflornithine is the only viable alternative, already established as safe and efficacious, but difficult to administer and at risk of resistance if used in monotherapy. This paper reports on a series of 48 Ugandan patients treated with a novel combination of nifurtimox (a drug registered for Chagas disease) and eflornithine, 17 as part of a terminated trial, and 31 in a subsequent case series study. Despite the low sample size, findings are promising: no cases of treatment failure, no treatment terminations, and no HAT- or treatment-related deaths. Nifurtimox plus eflornithine may be the best treatment hope for stage 2 HAT patients in the next decade, while new drugs are developed. A larger, multi-centric trial of the combination is ongoing

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Abstract:&nbsp; Studies show that patients with type 2 diabetes (DM2) have a higher risk of developing some type of cancer. Objective:&nbsp;to analyze the incidence and association between DM2 and cancer in patients from the “San Ricardo Pampuri” health center in Villa Carlos Paz. A retrospective observational study was carried out analyzing the medical records of 42,948 patients (years 2000-2018), 17,109 (39.8%) had DM2 and 332 had cancer (186M and 146H). The data analyzed were age, sex, type of cancer and suffering from DM2. Incidence ratios between sexes (RS = incidence in Men / incidence in Women) were calculated for some types of cancer. The work has ethical approval and corresponding confidentiality. Data were statistically analyzed with Infostat. Average age was 72 (DS 11) years for men and 68.5 (DS 12) for women (56% of the patients). 162 patients who developed cancer had DM2 (93M and 69H). In women with DM2 the incidences were: breast (51.6%), endometrium (7.5%), colon, pancreas and cervix (all with 6.5%). In women without DM2: breast (41.1%), colon (14.4%), cervix (7.8%), ovary and thyroid (both with 5.6%). In men with DM2 the incidences: prostate (27.9%), colon (19.1%), pancreas (8.8%), kidney (7.4%), Non-Hodgkin\u27s Lymphoma and bladder (both with 5.9 %). In those without DM2 they were: prostate (40%), colon (18.8%), bladder (12.5%) and melanoma (5%). The highest incidence rates between sexes (SR) for patients with DM2 were: lung (4.1), colon (3), Non-Hodgkin\u27s Lymphoma (2.7), kidney (2.3) and myeloma (2); in patients without DM2 they were bladder (3.8) and leukemia (2.3). It was observed that diabetic patients have a higher risk for pancreatic cancer (OR = 6.96; p = 0.01) and kidney (OR = 4.96; p = 0.01). Men showed a slightly increased risk for: colon (OR = 0.49; p = 0.02), bladder (OR = 0.16; p = 0.05) and kidney (OR = 0.29; p = 0 , 05). It was observed that patients without DM2 showed a slightly elevated risk for bladder cancer (OR = 0.33; p = 0.05) and melanoma (OR = 0.13; p = 0.05). Conclusions: Positive correlations were observed between cancer and age, for some tumors it could also be established with sex and DM2. Patients with DM2 showed an increased risk for pancreatic and kidney cancer and a small decrease in risk for bladder and melanoma.Resumen:&nbsp; Numerosos estudios demuestran que pacientes con diabetes tipo 2 (DM2) tienen mayor riesgo de desarrollar algún tipo&nbsp;de cáncer. Objetivo del estudio:&nbsp;analizar la incidencia y asociación entre DM2 y cáncer en pacientes del centro de salud “San Ricardo Pampuri” de Villa Carlos Paz.&nbsp; Se realizó un estudio observacional retrospectivo analizando historias clínicas de 42948 pacientes &nbsp;(años 2000-2018), 17109 (39,8%) padecían DM2 y 332 &nbsp;presentaron &nbsp;cáncer (186M y 146H). Los datos analizados fueron edad, sexo, tipo de cáncer y padecer DM2. Se calcularon ratios de incidencia entre sexos (RS=incidencia Hombres/incidencia Mujeres) para algunos tipos de cáncer.&nbsp; El trabajo cuenta con&nbsp; aprobación ética y confidencialidad correspondiente. Se analizaron los datos estadísticamente con Infostat. Edad promedio fue 72(DS 11)&nbsp;años hombres y 68,5 (DS 12) mujeres (56% de los pacientes). 162 pacientes que desarrollaron cáncer tenían DM2 (93M y 69H). En mujeres con DM2&nbsp; incidencias fueron: mama (51,6%), endometrio (7,5%), colon, páncreas y cuello de útero (todos con 6,5%). En mujeres sin DM2: mama (41,1%), colon (14,4%), cuello de útero (7,8%) ovario y tiroides (ambos con 5,6%). En hombres con DM2 las incidencias: próstata (27,9%), colon (19,1%), páncreas (8,8%), riñón (7,4%), Linfoma No Hodgkin y vejiga (ambos con 5,9%). En aquellos sin DM2 fueron: próstata (40%), colon (18,8%), vejiga (12,5%) y melanoma (5%). Las ratios de incidencia entre sexos (RS) más altos para pacientes con DM2 fueron: pulmón (4,1), colon (3), Linfoma No Hodgkin (2,7), riñón (2,3) y mieloma (2); en pacientes sin DM2 fueron vejiga (3,8) y leucemia (2,3). Se observó que pacientes diabéticos tienen un riesgo mayor para cáncer de páncreas (OR=6,96; p=0,01) y riñón (OR=4,96; p=0,01). Los hombres mostraron un riesgo levemente aumentado para: colon (OR=0,49; p=0,02), vejiga (OR=0,16; p=0,05) y riñón (OR=0,29; p=0,05). Se observó que pacientes sin DM2 mostraron un riesgo ligeramente elevado para cáncer de vejiga (OR=0,33; p=0,05) y melanoma (OR=0,13; p=0,05).&nbsp; Conclusiones:&nbsp; Se observaron correlaciones positivas entre cáncer y edad, para algunos tumores también se pudieron establecer con sexo y DM2.&nbsp; Los pacientes con DM2 mostraron un riesgo mayor para cáncer de páncreas y riñón y una pequeña disminución del riesgo para vejiga y melanoma.

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Abstract:&nbsp; Type 2 diabetes (DBT2) affects the central nervous system (CNS) and vision. Environmental enrichment (EA), allows to develop greater physical activity and neurocognitive stimulation, being able to help in experimental animals in the treatment of CNS pathologies.&nbsp;Objective: To study the effect of exposure to EA&nbsp;on the ultrastructure of the optic nerve and metabolic markers in diabetic animals. We used 24 12-month-old male Wistar rats, divided into 6 groups, 4 with a diet with 30% saturated fat (HFD) and / or moderate consumption (0.42 g / kg weight / day) of alcohol (Alc). The 2 non-diabetic control groups (C), consumed a standard chow diet. The EA groups were housed in large cages, with treadmills and ramps, the other groups in standard animal cages. The trial lasted 16 months. Metabolic markers (lipidemia, glycemia and weight) were measured. At the end of the test, the optic nerves were extracted, fixed and processed for electron microscopy. The data obtained were analyzed by ANOVA, p≤0.05. The animals presented DBT2 at 7 months of the test, in groups HFD, Alc, HFD + Alc, hypertriglyceridemia and hypercholesterolemia and obesity were observed. Animals with EA at the end of the trial decreased their glycemic values ​​(118 ± 5 mg / dl) and had a normal weight. In the optic nerves, signs of atrophy, alteration of the shape of mitochondria and their crests were observed in the animals on the HFD and / or Alcohol diet, compared with the control groups (C and C + AE). The HFD, Alc, HFD + Alc and HFD + Alc + AE groups showed thickening of the myelin sheaths (between 39 and 233%, p = 0.01). In the animals with the HFD diet, more intracytoplasmic electrodense deposits were found, in HFD + Alc and HFD + Alc + AE the myelin sheath was observed with a greater separation of the axon (75 and 50% more, p = 0.05) than in the group C. In the Alc group, larger mitochondria were observed (119 vs 107 nm, p = 0.05) than in C. Diet and lack of physical activity led the animals to develop DBT2. This condition affected the ultrastructure of the optic nerve. Exposure to an enriched environment partially improved metabolic and ultrastructural alterations.Resumen:&nbsp; La diabetes tipo 2 (DBT2) afecta el sistema nervioso central (SNC) y la visión. El enriquecimiento ambiental (AE), permite desarrollar mayor actividad física y estímulo neurocognitivo, pudiendo ayudar en animales experimentales en el tratamiento de patologías del SNC.&nbsp;Objetivo: Estudiar el efecto de la exposición a un AE sobre la ultraestructura del nervio óptico y marcadores metabólicos en animales diabéticos. Utilizamos 24 ratas Wistar macho de 12 meses, divididas en 6 grupos, 4 con una dieta con 30% de grasas saturadas (HFD) y/o consumo moderado (0,42 g/kg peso/día) de alcohol (Alc). Los 2 grupos controles no diabéticos (C), consumieron una dieta chow estándar. Los grupos con AE se alojaron en&nbsp;jaulas grandes, con ruedas de correr y rampas, los otros grupos en jaulas estándar de bioterio.&nbsp;El ensayo duró 16 meses. Se midieron marcadores metabólicos (lipidemia, glucemia y peso). Al finalizar el ensayo los nervios ópticos fueron extraídos, fijados y procesados para microscopía electrónica. Los datos obtenidos se analizaron mediante ANOVA, p≤0,05. Los animales presentaron DBT2 a los 7 meses del ensayo, en grupos HFD, Alc, HFD+Alc se observó hipertrigliceridemia e hipercolesterolemia y obesidad. Los animales con AE al final del ensayo disminuyeron sus valores glucémicos (118 ±5 mg/dl) y tuvieron un peso normal. &nbsp;En los nervios ópticos se observaron signos de atrofia, alteración de la forma de mitocondrias y sus crestas en los animales con dieta HFD y/o Alcohol, comparados con los grupos control (C y C+AE). Los grupos HFD, Alc, HFD+Alc y HFD+Alc+AE mostraron engrosamientos de las vainas de mielina (entre 39 y 233%, p=0.01). En los animales con dieta HFD se hallaron más depósitos electrodensos intracitoplasmáticos, en HFD+Alc y HFD+Alc+AE la vaina de mielina se observó con una mayor separación del axón (75 y 50% más,&nbsp;p=0.05) que en el grupo C. En el grupo Alc se observaron mitocondrias de mayor tamaño (119 vs 107 nm,&nbsp;p=0.05) que en C.&nbsp; La dieta y falta de actividad física llevaron a los animales a desarrollar DBT2. Esta condición afectó la ultraestructura del nervio óptico. La exposición a un ambiente enriquecido logró mejorar parcialmente las alteraciones metabólicas y ultraestructurales.

Identification of sVSG117 as an immunodiagnostic antigen and evaluation of a dual-antigen lateral flow test for the diagnosis of human african trypanosomiasis

The diagnosis of human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense relies mainly on the Card Agglutination Test for Trypanosomiasis (CATT). There is no immunodiagnostic for HAT caused by T. b. rhodesiense. Our principle aim was to develop a prototype lateral flow test that might be an improvement on CATT.Pools of infection and control sera were screened against four different soluble form variant surface glycoproteins (sVSGs) by ELISA and one, sVSG117, showed particularly strong immunoreactivity to pooled infection sera. Using individual sera, sVSG117 was shown to be able to discriminate between T. b. gambiense infection and control sera by both ELISA and lateral flow test. The sVSG117 antigen was subsequently used with a previously described recombinant diagnostic antigen, rISG65, to create a dual-antigen lateral flow test prototype. The latter was used blind in a virtual field trial of 431 randomized infection and control sera from the WHO HAT Specimen Biobank.In the virtual field trial, using two positive antigen bands as the criterion for infection, the sVSG117 and rISG65 dual-antigen lateral flow test prototype showed a sensitivity of 97.3% (95% CI: 93.3 to 99.2) and a specificity of 83.3% (95% CI: 76.4 to 88.9) for the detection of T. b. gambiense infections. The device was not as good for detecting T. b. rhodesiense infections using two positive antigen bands as the criterion for infection, with a sensitivity of 58.9% (95% CI: 44.9 to 71.9) and specificity of 97.3% (95% CI: 90.7 to 99.7). However, using one or both positive antigen band(s) as the criterion for T. b. rhodesiense infection improved the sensitivity to 83.9% (95% CI: 71.7 to 92.4) with a specificity of 85.3% (95% CI: 75.3 to 92.4). These results encourage further development of the dual-antigen device for clinical use

Human African Trypanosomiasis in South Sudan: How Can We Prevent a New Epidemic?

Human African trypanosomiasis (HAT) has been a major public health problem in South Sudan for the last century. Recurrent outbreaks with a repetitive pattern of responding-scaling down activities have been observed. Control measures for outbreak response were reduced when the prevalence decreased and/or socio-political crisis erupted, leading to a new increase in the number of cases. This paper aims to raise international awareness of the threat of another outbreak of sleeping sickness in South Sudan. It is a review of the available data, interventions over time, and current reports on the status of HAT in South Sudan. Since 2006, control interventions and treatments providing services for sleeping sickness have been reduced. Access to HAT diagnosis and treatment has been considerably diminished. The current status of control activities for HAT in South Sudan could lead to a new outbreak of the disease unless 1) the remaining competent personnel are used to train younger staff to resume surveillance and treatment in the centers where HAT activities have stopped, and 2) control of HAT continues to be given priority even when the number of cases has been substantially reduced. Failure to implement an effective and sustainable system for HAT control and surveillance will increase the risk of a new epidemic. That would cause considerable suffering for the affected population and would be an impediment to the socioeconomic development of South Sudan