Potential for a large-scale newborn screening strategy for sickle cell disease in Mali: A comparative diagnostic performance study of two rapid diagnostic tests (SickleScan® and HemotypeSC®) on cord blood.

Sickle cell disease (SCD) is a life-threatening disease requiring reliable early diagnosis. We assessed the acceptability and diagnostic performances of two rapid diagnostic tests (RDTs) to identify SCD (HbSS, HbSC, HbS/ß-thalassaemia) or SCD carrier (HbS/HbC) in a pilot SCD newborn screening (NBS) strategy in Mali. All consenting delivering women were offered SCD NBS using cord blood sampling on two RDTs (SickleScan® and HemotypeSC®) compared to the high-performance liquid chromatography (HPLC) gold standard to detect SCD states. From April 2021 to August 2021, 4333 delivering women were eligible of whom 96.1% were offered NBS: 1.6% refused, 13.8% delivered before consenting and 84.6% consented; 3648 newborns were diagnosed by HPLC; 1.64% had SCD (0.63% HbSS, 0.85% HbSC, 0.16 HbS/ß-plus-thalassaemia); 21.79% were SCD carrier. To detect accurately SCD, SickleScan® had a sensitivity of 81.67% (95% confidence interval [CI]: 71.88-91.46) and a negative predictive value (NPV) of 99.69% (95% CI: 99.51-99.87); HemotypeSC® had a sensitivity of 78.33% (95% CI: 67.91-88.76) and a NPV of 99.64% (95% CI: 99.44-99.83). To detect SCD carrier: SickleScan® sensitivity was 96.10% (95% CI: 94.75-97.45) and NPV, 98.90% (95% CI: 98.51-99.29); HemotypeSC® sensitivity was 95.22% (95% CI: 93.74-96.70) and NPV, 98.66% (95% CI: 98.24-99.03). Routine SCD NBS was acceptable. Compared with HPLC, both RDTs had reliable diagnostic performances to exclude SCD-free newborns and to identify SCD carriers to be further confirmed. This strategy could be implemented in large-scale NBS programmes.

Evaluation of the tele-expertise project in the management of common dermatoses in Togo / Évaluation du projet de téléexpertise dans la prise en charge des dermatoses courantes au Togo

Introduction: Tele-expertise in dermatology represents an opportunity to change medical practice in response to the need for cost savings in the health sector. The aim of this study was to evaluate the medical activities of the pilot phase of the tele-expertise project in Togo. Method: A cross-sectional study was conducted in October 2020 on the 20 sites of the pilot phase. This evaluation consisted of a literature review and analysis of data posted on the tele-expertise platform. Results: A total of 738 (10.8%) of the 6810 dermatological consultations were posted on the tele-expertise platform. Of the 738 cases, the dermatologist's expertise did not allow a diagnosis to be made in 119 cases (16.1%). This expertise confirmed the single clinical hypothesis proposed by the health worker in 275 cases (37.3%) and allowed a diagnosis to be made among several clinical hypotheses in 30 cases (4.1%). On the contrary, the dermatologist's diagnosis was not included in the health worker's hypotheses in 201 cases (27.2%), and no clinical hypothesis was formulated in 113 cases (15.3%). The concordance between the clinical hypothesis proposed by the health worker and the diagnosis of the dermatologist was 48.8%. Regarding the acceptability of the tele-expertise, only one refusal was recorded. All patients were very satisfied with this practice. Conclusions: The results show the feasibility and acceptability of tele-expertise by health care personnel and patients. The diagnostic concordance of 48.8% shows the relative efficiency of task delegation.

Introduction: La téléexpertise en dermatologie représente une piste pour modifier l'exercice médical en réponse aux besoins d'économies de la santé. Le but de cette étude était d'évaluer les activités médicales de la phase pilote du projet de téléexpertise en dermatologie au Togo. Méthode: Il s'agit d'une étude transversale menée en octobre 2020 sur les 20 sites de la phase pilote. Cette évaluation consistait en une revue documentaire et l'analyse des données postées sur la plateforme de téléexpertise. Résultats: Au total, 738 (10,8 %) des 6 810 consultations dermatologiques ont été postées sur la plateforme de téléexpertise. Sur les 738 cas, l'expertise du dermatologue n'a pas permis de poser un diagnostic dans 119 cas (16,1 %). Cette expertise a confirmé l'hypothèse clinique unique proposée par l'agent de santé dans 275 cas (37,3 %) et a permis de conclure à un diagnostic parmi plusieurs hypothèses cliniques dans 30 cas (4,1 %). Au contraire, le diagnostic du dermatologue ne figurait pas dans les hypothèses de l'agent de santé dans 201 cas (27,2 %), et aucune hypothèse clinique n'avait été formulée dans 113 cas (15,3 %). La concordance entre l'hypothèse clinique proposée par l'agent de santé et le diagnostic du dermatologue était de 48,8 %. Concernant l'acceptabilité de la téléexpertise, un seul refus a été enregistré. Tous les patients étaient très satisfaits de cette pratique. Conclusions: Les résultats montrent la faisabilité et l'acceptabilité de la téléexpertise par les personnels de santé et les patients. La concordance diagnostique de 48,8 % montre la relative efficacité de la délégation de tâches.

A Comprehensive Study on the Hematological Progression of Sickle Cell Disease Patients with COVID-19 at the Center for Research and Control of Sickle Cell Disease, Bamako.

The Coronavirus disease 2019 pandemic is a real crisis that has exposed the unpreparedness of many healthcare systems worldwide. Several underlying health conditions have been identified as risk factors, including sickle cell disease, a chronic illness with various complications that can increase the risk of severe COVID-19 infection. Our study aimed to investigate the profile of sickle cell patients diagnosed with COVID-19 and explore any potential relationship between these two conditions. We analyzed data from 11 sickle cell patients who contracted COVID-19 between June and December 2020 and were treated at the CRLD (Center for Sickle Cell Disease and Research). The patients' COVID-19 diagnosis was confirmed using the (Real-Time Reverse Transcriptase-Polymerase Chain Reaction) RT-PCR technique on nasopharyngeal swab samples and/or based on clinical and radiological findings, including CT scans. The patients consisted of 7 males and 4 females, with a mean age of 40 ± 12 years. The sickle cell phenotypes observed were SC (45.4%), SS (36.37%), and Sß± thalassemia (18.2%). During the COVID-19 infection, we observed a slight increase in white blood cell and platelet counts, but a decrease in mean hemoglobin levels and red blood cells. Only 3 out of 11 patients (28%) had a fever at the time of diagnosis. Three patients required red blood cell transfusions due to severe anemia, and 7 out of 11 patients (63.6%) were hospitalized, with one patient admitted to the intensive care unit due to pulmonary embolism. All patients recovered from COVID-19.

Diagnostic accuracy in field conditions of the sickle SCAN® rapid test for sickle cell disease among children and adults in two West African settings: the DREPATEST study.

BACKGROUND: Sickle cell disease (SCD) accounts for 5% of mortality in African children aged < 5 years. Improving the care management and quality of life of patients with SCD requires a reliable diagnosis in resource-limited settings. We assessed the diagnostic accuracy of the rapid Sickle SCAN® point-of-care (POC) test for SCD used in field conditions in two West-African countries. METHODS: We conducted a case-control study in Bamako (Mali) and Lomé (Togo). Known cases of sickle cell disease (HbSS, HbSC), trait (HbAS), HbC heterozygotes (HbAC) and homozygous (HbCC), aged ≥6 months were compared to Controls (HbAA), recruited by convenience. All subjects received both an index rapid POC test and a gold standard (high-performance liquid chromatography in Bamako; capillary electrophoresis in Lomé). Personnel conducting tests were blinded from subjects' SCD status. Sensitivity and specificity were calculated for each phenotype. Practicality was assessed by local healthcare professionals familiar with national diagnostic methods and their associated constraints. RESULTS: In Togo, 209 Cases (45 HbAS, 39 HbAC, 41 HbSS, 44 HbSC and 40 HbCC phenotypes) were compared to 86 Controls (HbAA). 100% sensitivity and specificity were observed for AA Controls and HbCC cases. Estimated sensitivity was 97.7% [95% confidence interval: 88.0-99.9], 97.6% [87.1-99.9%], 95.6% [84.8-99.5%], and 94.9% [82.7-99.4], for HbSC, HbSS, HbAS, and HbAC, respectively. Specificity exceeded 99.2% for all phenotypes. Among 160 cases and 80 controls in Mali, rapid testing was 100% sensitive and specific. Rapid testing was well accepted by local healthcare professionals. CONCLUSION: Rapid POC testing is 100% accurate for homozygote healthy people and excellent (Togo) or perfect (Mali) for sickle cell trait and disease patients. In addition to its comparable diagnostic performance, this test is cheaper, easier to implement, and logistically more convenient than the current standard diagnostic methods in use. Its predictive value indicators and diagnostic accuracy in newborns should be further evaluated prior to implementation in large-scale screening programs in resource-limited settings where SCD is prevalent.

Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model.

The Hedgehog (HH) pathway has been linked to the formation of basal cell carcinoma (BCC), medulloblastoma, and other cancers. The recently approved orally active drugs vismodegib (GDC-0449) and sonidegib (LDE-225) were not only efficacious for the treatment of advanced or metastatic BCC by antagonizing the smoothened (SMO) receptor, but also produced important side effects, limiting their use for less invasive BCC. Herein, we compared a large series of SMO antagonists, including GDC-0449 and LDE-225, the clinically tested BMS-833923, CUR-61414, cyclopamine, IPI-926 (saridegib), itraconazole, LEQ-506, LY-2940680 (taladegib), PF-04449913 (glasdegib), and TAK-441 as well as preclinical candidates (PF-5274857, MRT-83) in two SMO-dependent cellular assays and for G-protein activation. We report marked differences in inhibitor potencies between compounds as well as a notable disparity between the G-protein assay and the cellular tests, suggesting that classification of drugs is assay dependent. Furthermore, we explored topical efficacies of SMO antagonists on depilated mice using Gli1 and Ptch1 mRNA quantification in skin as biomarkers of the HH signaling inhibition. This topical model rapidly discriminated drugs in terms of efficacies and potencies for inhibition of both biomarkers. SMO antagonists showed also a large variation in their blood and skin partition, suggesting that some drugs are more favorable for topical application. Overall, our data suggested that in vitro and in vivo efficacious drugs such as LEQ-506 and TAK-441 may be of interest for topical treatment of less invasive BCC with minimal side effects.

Does endoplasmic reticulum stress participate in APD-induced hepatic metabolic dysregulation?

Metabolic side effects caused by certain antipsychotic drugs (APDs), in particular clozapine and olanzapine, are now clinically well-documented. However, the potential mechanisms implicated in the metabolic disturbances of these drugs on peripheral tissues remain obscure. Here, we investigated the effects of five frequently prescribed APDs on the Sterol Regulatory Element Binding Protein (SREBP) transcription factor pathways which control lipogenesis and cholesterogenesis, using the Immortalized Human Hepatocyte cell model (IHH). First, clozapine, haloperidol, olanzapine and risperidone activated, at different levels, SREBP-1 activity reflected by an increased expression of SREBP-1 target genes involved in fatty acid biosynthesis (SREBP-1, FAS and/or SCD1) resulting in an accumulation of intracellular lipids. Second, clozapine and haloperidol also stimulated the SREBP-2 pathway associated with an increase in HMGCoAR expression. In contrast, quetiapine did not affect either the SREBP-1 or -2 pathways, but induced a slight accumulation of intracellular lipids. Interestingly, clozapine, haloperidol and olanzapine induced Endoplasmic Reticulum (ER) stress and, more precisely, initiation of the ER stress-activated eIF2α kinase (PERK) branch of the Unfolded Protein Response (UPR). Furthermore, treatment with thapsigargin, which increases intracellular calcium release, induced both ER stress and SREBP-1 and -2 pathway activation, whereas Ca(2+) chelation by BAPTA completely reversed the lipogenic effects and ER stress induction produced by clozapine. Based on these results, we propose that certain APDs induce ER stress via changes in Ca(2+) homeostasis in hepatocytes. This phenomenon potentially underlies a part of their known undesirable hepatic metabolic side effects. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Overweight induced by chronic risperidone exposure is correlated with overexpression of the SREBP-1c and FAS genes in mouse liver.

Weight gain and metabolic disturbances, such as dyslipidemia and hyperglycaemia, are common side effects of most antipsychotic drugs, including risperidone. The aim of this study was to investigate the effects of chronic treatment with risperidone on body weight, fat accumulation, liver weight, and hepatic expression of key genes involved in lipid metabolism in female mice. We also addressed the mechanism of risperidone induction of metabolic side effects by exploring its effect on lipid and cholesterol metabolism in primary cultures of rat hepatocytes. Eleven weeks of treatment with long-acting risperidone (12.5 mpk/week) resulted in a significant weight gain associated with an increase of liver and adipose tissue weight. These effects were positively correlated with hepatic mRNA induction of two key genes involved in lipogenesis: sterol regulatory element binding protein-1c (SREBP-1c) and fatty acid synthase (FAS). Furthermore, in line with these in vivo results, risperidone elicited significant inductions of SREBP-1 maturation and FAS mRNA expression in primary cultures of rat hepatocytes associated with an increase of free fatty acid, triacylglycerol, and phospholipid synthesis as assessed by acetate incorporation. The current investigations underscore the usefulness of a mouse model to study the weight gain observed with risperidone treatment in humans. This study shows that risperidone induces similar effects in the liver (in vivo) and in hepatocyte cell cultures (in vitro) on the expression of key genes and/or proteins that control lipid metabolism. This suggests that risperidone could alter lipid metabolism in the liver and induce weight gain in a way that is partly independent of its action on the central nervous system.

Antipsychotic drug action on SREBPs-related lipogenesis and cholesterogenesis in primary rat hepatocytes.

The use of some of antipsychotic drugs (APDs) in humans has been hampered by the induction of metabolic disorders such as weight gain, dyslipidemia, and diabetes. In primary rat hepatocytes, we investigated the actions of several APDs on lipid and cholesterol metabolism using [(14)C]acetate incorporation, quantitative reverse transcription-polymerase chain reaction, and western blotting. Clozapine and olanzapine, known to have significant metabolic side effects in man, strongly increased de novo lipid and cholesterol synthesis in rat hepatocytes. Haloperidol, which has less impact in metabolic disorders, enhanced lipogenesis without altering cholesterol production. By contrast, quetiapine, which exhibits few metabolic side effects in man, did not affect lipid and cholesterol synthesis. Interestingly, aripiprazole, which has not yet been reported to induce metabolic disorders in humans, strongly decreases cholesterol synthesis. Furthermore, these inductions of lipid and cholesterol synthesis observed with clozapine and olanzapine were also associated with up-regulation of the transcription factors sterol regulatory element-binding protein (SREBP)-1 and/or SREBP-2 and their associated target genes. Part of the APD-induced metabolic disorders in humans may be due to direct effects on liver metabolism. Our model may also be of interest to assess the action of future drugs on metabolic parameters.