EClinicalMedicine

BACKGROUND: As mortality remains high for patients with Ebola virus disease (EVD) despite new treatment options, the ability to level up the provided supportive care and to predict the risk of death is of major importance. This analysis of the EVISTA cohort aims to describe advanced supportive care provided to EVD patients in the Democratic Republic of the Congo (DRC) and to develop a simple risk score for predicting in-hospital death, called PREDS. METHODS: In this prospective cohort (NCT04815175), patients were recruited during the 10(th) EVD outbreak in the DRC across three Ebola Treatment Centers (ETCs). Demographic, clinical, biological, virological and treatment data were collected. We evaluated factors known to affect the risk of in-hospital death and applied univariate and multivariate Cox proportional-hazards analyses to derive the risk score in a training dataset. We validated the score in an internal-validation dataset, applying C-statistics as a measure of discrimination. FINDINGS: Between August 1(st) 2018 and December 31(th) 2019, 711 patients were enrolled in the study. Regarding supportive care, patients received vasopressive drug (n = 111), blood transfusion (n = 101), oxygen therapy (n = 250) and cardio-pulmonary ultrasound (n = 15). Overall, 323 (45%) patients died before day 28. Six independent prognostic factors were identified (ALT, creatinine, modified NEWS2 score, viral load, age and symptom duration). The final score range from 0 to 13 points, with a good concordance (C = 86.24%) and calibration with the Hosmer-Lemeshow test (p = 0.12). INTERPRETATION: The implementation of advanced supportive care is possible for EVD patients in emergency settings. PREDS is a simple, accurate tool that could help in orienting early advanced care for at-risk patients after external validation. FUNDING: This study was funded by ALIMA

Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation

Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy

Mortality associated with COVID‐19 and hypertension in sub‐Saharan Africa. A systematic review and meta‐analysis

Abstract Hypertension is a common comorbidity in COVID‐19 patients. However, little data is available on mortality in COVID‐19 patients with hypertension in sub‐Saharan Africa (SSA). Herein, the authors conducted a systematic review of research articles published from January 1, 2020 to July 1, 2021. Our aim was to evaluate the magnitude of COVID‐19 mortality in patients with hypertension in SSA. Following the PRISMA guidelines, two independent investigators conducted the literature review to collect relevant data. The authors used a random effect model to estimate the odds ratio, or hazard ratio, with a 95% confidence interval (CI). Furthermore, the authors used Egger's tests to check for publication bias. For mortality analysis, the authors included data on 29 945 COVID‐19 patients from seven publications. The authors assessed the heterogeneity across studies with the I2 test. Finally, the pooled analysis revealed that hypertension was associated with an increased odds of mortality among COVID‐19 inpatients (OR 1.32; 95% CI, 1.13–1.50). Our analysis revealed neither substantial heterogeneity across studies nor a publication bias. Therefore, our prespecified results provided new evidence that hypertension could increase the risk of mortality from COVID‐19 in SSA

Human Immunodeficiency Virus Viral Load Monitoring and Rate of Virologic Suppression Among Patients Receiving Antiretroviral Therapy in Democratic Republic of the Congo, 2013-2020.

peer reviewedBACKGROUND: Antiretroviral therapy (ART) expansion and viral load as a treatment monitoring approach have increased the demand for viral load testing. Many hurdles affect the coverage, quality, and use of viral load results. Estimates of viral load monitoring and viral suppression rates are needed to assess the performance of ART programs and improve human immunodeficiency virus (HIV) management outcomes. METHODS: People with HIV (PWH) viral load monitoring data were routinely collected in 84 health facilities in Kinshasa, Democratic Republic of the Congo (DRC), between 2013 and 2020. The number of PWH under ART, the number of participants with at least 1 viral load test result, the rate of viral suppression (defined as ≤1000 HIV ribonucleic acid copies per mL), and the mean turnaround time from sample collection to release of viral load test results were collected together with clinical data. RESULTS: A total of 14 057 PWH were included in the analysis. People with HIV were mainly enrolled after the "test and treat" implementation. The patients were followed for a median period of 27 months. The proportion of PWH with at least 1 available viral load largely increased in recent years. The delay from sample collection to release of viral load test results decreased overtime, from 35 days in 2018 to 16 days in 2020. Pregnancy and advanced HIV disease were associated with a lower chance of viral suppression. CONCLUSIONS: There has been considerable success in increasing viral load access for all PWH under therapy in DRC. Nevertheless, viral load testing should be intensified with a particular effort to be made in groups at higher risk of viral failure

Epidemiological, clinical Characteristics and mortality of patients Infected with SARS-CoV-2 Admitted to Kinshasa University Hospital (KUH), the Democratic Republic of the Congo from March 24th, 2020, to January 30th, 2021: Two waves, two faces?

Context and objective: Like all epidemics, the COVID-19 pandemic occurs in several highly diverse waves. The objective of the present study was to  compare the demographic and clinical characteristics and mortality of patients between the first and second waves of COVID-19. Methods: This was a historical follow-up study conducted at the Kinshasa University Hospital (KUH) between March 2020 and January 2021. We used  the χ² test to compare proportions. Survival was described by the Kaplan Meier method. Cox regression was used to identify independent  predictors of mortality. Results: A total of 411 COVID-19 patients were enrolled. Compared to wave 1 patients, wave 2 patients were significantly  older (52.4 ±17.5 vs. 58.1 ±15.7; p=0.026). The death rate of patients in the first wave was higher than in the second wave (p=0.009). Survival was  more reduced in the first wave compared with the second wave. Predictors of mortality present in both the first and second waves were respiratory  distress and severe COVID-19 stage. Conclusion: The first wave was more lethal than the second wave with respiratory distress and severe COVID-19  stage as independent predictors in both waves. Strengthening the health system and raising awareness of preventive measures including  vaccination should continue to sustain gains.    French title: Caractéristiques épidémiologiques, cliniques et mortalité des patients infectés par le SRAS-CoV-2 admis aux Cliniques Universitaires  de Kinshasa, République démocratique du Congo du 24 mars 2020 au 30 janvier 2021 : Deux vagues, deux visages ? Contexte et objectif: Comme toutes les épidemies, la pandémie à COVID-19 sévit en plusieurs vagues très diversifiées. L’étude a comparé les  caractéristiques démographiques et cliniques ainsi que la mortalité des patients entre la 1ère et la 2ème vague de COVID-19. Méthodes: Il s’agissait  d’une étude de suivi historique réalisée aux Cliniques Universitaires de Kinshasa entre mars 2020 et janvier 2021. Le test de χ² a permis la  comparaison des proportions, et la la survie a été étudiée par la méthode de Kaplan Meier. L’identification dess prédicteurs indépendants de la  mortalité a été déterminée par la régression de Cox. Résultats: Des 411 patients enrôlés, ceux de la 2ème vague étaient beaucoup plus âgés ((58,1 ±15,7 vs 52,4 ±17,5 ; p=0,026). La 1ère vague a été  plus meurtrière que la seconde (p=0,009). La survie était plus réduite dans la première vague par rapport à la seconde. Les facteurs prédictifs de  mortalité présents à la fois dans la première et la deuxième vague étaient la détresse respiratoire et le stade COVID-19 sévère. Conclusion: La 1ère  vague était plus meutrière que la 2ème avec comme prédicteurs indépendants la détresse respiratoire et le stade COVID-19 sévère dans les deux  vagues. Le renforcement du système de santé et la sensibilisation sur les mésures préventives dont la vaccination devraient continuer à maintenir  les gains

A Multidisciplinary Investigation of the First Chikungunya Virus Outbreak in Matadi in the Democratic Republic of the Congo

Early March 2019, health authorities of Matadi in the Democratic Republic of the Congo alerted a sudden increase in acute fever/arthralgia cases, prompting an outbreak investigation. We collected surveillance data, clinical data, and laboratory specimens from clinical suspects (for CHIKV-PCR/ELISA, malaria RDT), semi-structured interviews with patients/caregivers about perceptions and health seeking behavior, and mosquito sampling (adult/larvae) for CHIKV-PCR and estimation of infestation levels. The investigations confirmed a large CHIKV outbreak that lasted February–June 2019. The total caseload remained unknown due to a lack of systematic surveillance, but one of the two health zones of Matadi notified 2686 suspects. Of the clinical suspects we investigated (n = 220), 83.2% were CHIKV-PCR or IgM positive (acute infection). One patient had an isolated IgG-positive result (while PCR/IgM negative), suggestive of past infection. In total, 15% had acute CHIKV and malaria. Most adult mosquitoes and larvae (>95%) were Aedes albopictus. High infestation levels were noted. CHIKV was detected in 6/11 adult mosquito pools, and in 2/15 of the larvae pools. This latter and the fact that 2/6 of the CHIKV-positive adult pools contained only males suggests transovarial transmission. Interviews revealed that healthcare seeking shifted quickly toward the informal sector and self-medication. Caregivers reported difficulties to differentiate CHIKV, malaria, and other infectious diseases resulting in polypharmacy and high out-of-pocket expenditure. We confirmed a first major CHIKV outbreak in Matadi, with main vector Aedes albopictus. The health sector was ill-prepared for the information, surveillance, and treatment needs for such an explosive outbreak in a CHIKV-naïve population. Better surveillance systems (national level/sentinel sites) and point-of-care diagnostics for arboviruses are needed

A multidisciplinary investigation of the first Chikungunya Virus outbreak in Matadi in the Democratic Republic of the Congo

Early March 2019, health authorities of Matadi in the Democratic Republic of the Congo alerted a sudden increase in acute fever/arthralgia cases, prompting an outbreak investigation. We collected surveillance data, clinical data, and laboratory specimens from clinical suspects (for CHIKV-PCR/ELISA, malaria RDT), semi-structured interviews with patients/caregivers about perceptions and health seeking behavior, and mosquito sampling (adult/larvae) for CHIKV-PCR and estimation of infestation levels. The investigations confirmed a large CHIKV outbreak that lasted February–June 2019. The total caseload remained unknown due to a lack of systematic surveillance, but one of the two health zones of Matadi notified 2686 suspects. Of the clinical suspects we investigated (n = 220), 83.2% were CHIKV-PCR or IgM positive (acute infection). One patient had an isolated IgG-positive result (while PCR/IgM negative), suggestive of past infection. In total, 15% had acute CHIKV and malaria. Most adult mosquitoes and larvae (>95%) were Aedes albopictus. High infestation levels were noted. CHIKV was detected in 6/11 adult mosquito pools, and in 2/15 of the larvae pools. This latter and the fact that 2/6 of the CHIKV-positive adult pools contained only males suggests transovarial transmission. Interviews revealed that healthcare seeking shifted quickly toward the informal sector and self-medication. Caregivers reported difficulties to differentiate CHIKV, malaria, and other infectious diseases resulting in polypharmacy and high out-of-pocket expenditure. We confirmed a first major CHIKV outbreak in Matadi, with main vector Aedes albopictus. The health sector was ill-prepared for the information, surveillance, and treatment needs for such an explosive outbreak in a CHIKV-naïve population. Better surveillance systems (national level/sentinel sites) and point-of-care diagnostics for arboviruses are needed

Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation

Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy

Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche

The adipocyte-rich microenvironment forms a niche for ovarian cancer metastasis, but the mechanisms driving this process are incompletely understood. Here we show that salt-inducible kinase 2 (SIK2) is overexpressed in adipocyte-rich metastatic deposits compared with ovarian primary lesions. Overexpression of SIK2 in ovarian cancer cells promotes abdominal metastasis while SIK2 depletion prevents metastasis in vivo. Importantly, adipocytes induce calcium-dependent activation and autophosphorylation of SIK2. Activated SIK2 plays a dual role in augmenting AMPK-induced phosphorylation of acetyl-CoA carboxylase and in activating the PI3K/AKT pathway through p85α-S154 phosphorylation. These findings identify SIK2 at the apex of the adipocyte-induced signaling cascades in cancer cells and make a compelling case for targeting SIK2 for therapy in ovarian cancer.</p