Articular chondrocytes are responsible for the maintenance of healthy articulations; indeed, dysregulation of their functions, including the production of matrix proteins and matrix-remodeling proteases, may result in fraying of the tissue and development of osteoarthritis (OA). To explore transcriptional mechanisms that contribute to the regulation of chondrocyte homeostasis and may be implicated in OA development, we compared the gene expression profile of a set of zinc finger proteins potentially linked to the control of chondrocyte differentiation and/or functions (ZNF423, ZNF470, ZNF521, and ZNF780B) in chondrocytes from patients affected by OA and from subjects not affected by OA. This analysis highlighted a significantly lower expression of the transcript encoding ZNF423 in chondrocytes from OA, particularly in elderly patients. Interestingly, this decrease was mirrored by the similarly reduced expression of PPARγ, a known target of ZNF423 with anti-inflammatory and chondroprotective properties. The ZNF521 mRNA instead was abundant in all primary chondrocytes studied; the RNAi-mediated silencing of this gene significantly altered the COL2A/COL1 expression ratio, associated with the maintenance of the differentiated phenotype, in chondrocytes cultivated in alginate beads. These results suggest a role for ZNF423 and ZNF521 in the regulation of chondrocyte homeostasis and warrant further investigations to elucidate their mechanism of action.

The ketogenic diet (KD), a high-fat low-carbohydrate diet, has shown some efficacy in the treatment of certain types of tumors such as brain tumors and neuroblastoma. These tumors are characterized by the Warburg effect. Because renal cell carcinoma (RCC) presents similar energetic features as neuroblastoma, KD might also be effective in the treatment of RCC. To test this, we established xenografts with RCC 786-O cells in CD-1 nu/nu mice and then randomized them to a control diet or to KDs with different triglyceride contents. Although the KDs tended to reduce tumor growth, mouse survival was dramatically reduced due to massive weight loss. A possible explanation comes from observations of human RCC patients, who often experience secondary non-metastatic hepatic dysfunction due to secretion of high levels of inflammatory cytokines by the RCCs. Measurement of the mRNA levels of tumor necrosis factor alpha (TNFα) and interleukin-6 revealed high expression in the RCC xenografts compared to the original 786-O cells. The expression of TNFα, interleukin-6 and C-reactive protein were all increased in the livers of tumor-bearing mice, and KD significantly boosted their expression. KDs did not cause weight loss or liver inflammation in healthy mice, suggesting that KDs are per se safe, but might be contraindicated in the treatment of RCC patients presenting with Stauffer's syndrome, because they potentially worsen the associated hepatic dysfunction.

Maize (Zea mays L.) is an important source of carbohydrates and protein in the diet in sub-Saharan Africa. The objectives of this study were to (i) estimate general (GCA) and specific combining abilities (SCA) of 13 new quality protein maize (QPM) lines in a diallel under stress and non-stress conditions, (ii) compare observed and predicted performance of QPM hybrids, (iii) characterize genetic diversity among the 13 QPM lines using single nucleotide polymorphism (SNP) markers and assess the relationship between genetic distance and hybrid performance, and (iv) assess diversity and population structure in 116 new QPM inbred lines as compared to eight older tropical QPM lines and 15 non-QPM lines. The GCA and SCA effects were significant for most traits under optimal conditions, indicating that both additive and non-additive genetic effects were important for inheritance of the traits. Additive genetic effects appeared to govern inheritance of most traits under optimal conditions and across environments. Non-additive genetic effects were more important for inheritance of grain yield but additive effects controlled most agronomic traits under drought stress conditions. Inbred lines CKL08056, CKL07292, and CKL07001 had desirable GCA effects for grain yield across drought stress and non-stress conditions. Prediction efficiency for grain yield was highest under optimal conditions. The classification of 139 inbred lines with 95 SNPs generated six clusters, four of which contained 10 or fewer lines, and 16 lines of mixed co-ancestry. There was good agreement between Neighbor Joining dendrogram and Structure classification. The QPM lines used in the diallel were nearly uniformly spread throughout the dendrogram. There was no relationship between genetic distance and grain yield in either the optimal or stressed environments in this study. The genetic diversity in mid-altitude maize germplasm is ample, and the addition of the QPM germplasm did not increase it measurably.

Snakebite envenoming is a public health concern in many countries affected by humanitarian crises. Its magnitude was recognized internationally but associations between snakebite peaks and humanitarian crises were never clearly established or analysed. This scoping review searched any available evidence of this hypothesized association between snakebite types of crises, through PubMed/Medline by two researchers. The search also included hand searching, and reports from humanitarian organizations working in this area. The scoping review yielded 41 results. None described a robust epidemiological link or evidence of causality. There is an evidence gap regarding our research question. Several publications however point or hint towards the occurrence of snakebite outbreaks during conflict, displacement, floods, and migration of impoverished agricultural workers. Non-systematic screening yielded another 11 publications (52 in total). We found Médecins Sans Frontières routine reports showing that 6469 patients were admitted in 2019 throughout its projects in 17 countries. The impact of snakebite was the highest in four countries particularly affected by humanitarian crises, South Sudan, Ethiopia, Central African Republic, and Yemen, with some hospitals receiving more than 1000 annual admissions. Time correlations with conflict and events are shown in Figures. We found no published epidemiological data formally showing any associations between humanitarian crises and snakebite incidence. However, the search publications showing peaks during crises, and monitoring curves in four countries point towards an increased risk during humanitarian crises. We call for urgent population-based studies and surveillance. Stakeholders should consider upgrading snakebite care and antivenom supply during humanitarian crises in snakebite-endemic countries.

In 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a rapidly emerging virus causing the coronavirus disease 2019 (COVID-19) pandemic, had no known effective prophylaxis and no widely available proven effective antiviral treatment. Hydroxychloroquine/Chloroquine was identified as an early potential therapeutic candidate drawing on evidence from reports of both in vitro and in vivo testing. A multicountry placebo-controlled randomized trial was set to evaluate the use of hydroxychloroquine/chloroquine to prevent infection in healthcare workers and staff working in a health facility involved in COVID-19 management. One of the sites of this trial was in Niger. In Niger, of the 240 persons who were provided information about the study and with whom participation was discussed, only five participants provided their informed consent. In this article, we describe the key difficulties encountered in the conduct of this trial from the perspective of the site study team. Among the difficulties, we recognize that the epidemic context, controversy surrounding hydroxychloroquine, vaccine rollout, participants' perspectives, and trial design had a major impact on participation.

Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option.

We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support.

Maize (Zea mays L.) yield in sub-Saharan Africa (SSA) is low because of both abiotic and biotic constraints, and limited availability or use of improved seed in some areas. This study was conducted (i) to estimate combining ability and heterosis among seven stress-tolerant populations, and (ii) to assess diversity among the populations and the relationship between diversity and heterosis. Twenty-one hybrids developed from diallel crosses of seven populations, parents, and two checks were evaluated in 10 optimal and 11 stressed environments (drought, low N, and random stress) in Kenya, Ethiopia, Uganda, and Zimbabwe for 2 yr. Analysis II of Gardner and Eberhart showed that variety and heterosis were significant for grain yield (GY) under optimal and managed stress, and across environments. Heterosis accounted for most of the variation for GY among populations under optimal conditions (67%) and drought stress (53%), which suggested the importance of dominance in inheritance of GY under these conditions. Genetic distance (GD) among populations ranged from 0.328 to 0.477 (mean = 0.404). The correlation between GD and heterosis was low (r = 0.14-0.40) in all environments. The simple sequence repeat (SSR) marker-based and GY-based clustering of parental populations showed similar patterns, with three populations distinct from the rest, suggesting significant differentiation of allelic variation in these three populations. The SSR-based diversity and phenotypic analysis results should be useful in defining breeding strategies and maintaining heterotic patterns among these populations.

Human mpox is a viral disease caused by an Orthopoxvirus, human mpox virus (hMPXV), typically causing fever and a rash. Mpox has historically been endemic to parts of Central and West Africa, with small numbers of imported cases reported elsewhere, but starting May 2022 an unprecedented global outbreak caused by clade IIb hMPXV was reported outside traditionally endemic countries. This prompted the initiation of MOSAIC, a cohort study implemented in Europe and Asia that aims to describe clinical and virologic outcomes of PCR-confirmed hMPXV disease, including those who receive antiviral therapy. The focus of this article, however, is on describing the study protocol itself with implementation process and operational challenges.

The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support.

Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancer strategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Here we use genetic ablation of this enzyme to induce indolence in two cancer types, and show this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha (HIF-1α). We further show that on the long run CI-deficient tumors re-adapt to their inability to respond to hypoxia, concordantly with the persistence of human oncocytomas. We demonstrate that CI-deficient tumors survive and carry out angiogenesis, despite their inability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated macrophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneous pharmacological inhibition of CI function through metformin and macrophage infiltration through PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basis for an efficient combinatorial adjuvant therapy in clinical trials.

The ketogenic diet (KD), a high-fat/low-carbohydrate/adequate-protein diet, has been proposed as a treatment for a variety of diseases, including cancer. KD leads to generation of ketone bodies (KBs), predominantly acetoacetate (AcAc) and 3-hydroxy-butyrate, as a result of fatty acid oxidation. Several studies investigated the antiproliferative effects of lithium acetoacetate (LiAcAc) and sodium 3-hydroxybutyrate on cancer cells in vitro. However, a critical point missed in some studies using LiAcAc is that Li ions have pleiotropic effects on cell growth and cell signaling. Thus, we tested whether Li ions per se contribute to the antiproliferative effects of LiAcAc in vitro. Cell proliferation was analyzed on neuroblastoma, renal cell carcinoma, and human embryonic kidney cell lines. Cells were treated for 5 days with 2.5, 5, and 10 mM LiAcAc and with equimolar concentrations of lithium chloride (LiCl) or sodium chloride (NaCl). LiAcAc affected the growth of all cell lines, either negatively or positively. However, the effects of LiAcAc were always similar to those of LiCl. In contrast, NaCl showed no effects, indicating that the Li ion impacts cell proliferation. As Li ions have significant effects on cell growth, it is important for future studies to include sources of Li ions as a control.

Small ncRNAs (sncRNAs) offer great hope as biomarkers of disease and response to treatment. This has been highlighted in the context of several medical conditions such as cancer, liver disease, cardiovascular disease, and central nervous system disorders, among many others. Here we assessed several steps involved in the development of an ncRNA biomarker discovery pipeline, ranging from sample preparation to bioinformatic processing of small RNA sequencing data.

We present six draft genome sequences of Salmonella enterica serovar Bovismorbificans from isolates associated with the 2011 hummus-borne multistate outbreak. All six genome sequences indicate the presence of two plasmids, one of which demonstrates similarity to the 93-kb pSLT2 IncF-type plasmid of Salmonella enterica serovar Typhimurium.

Although real-life results of sofosbuvir/simeprevir have been extensively reported from the United States, data from other geographical areas are limited. In the French observational cohort, ANRS CO22 HEPATHER, 9432 patients were given the new oral antivirals from December 2013 to June 30, 2018. We report the results of sofosbuvir/simeprevir in genotypes 1- and 4-infected patients.

The Ebola virus disease (EVD) outbreak in 2014-2016 in West Africa was the largest on record and provided an opportunity for large clinical trials and accelerated efforts to develop an effective and safe preventative vaccine. Multiple questions regarding the safety, immunogenicity, and efficacy of EVD vaccines remain unanswered. To address these gaps in the evidence base, the Partnership for Research on Ebola Vaccines (PREVAC) trial was designed. This paper describes the design, methods, and baseline results of the PREVAC trial and discusses challenges that led to different protocol amendments.

The current COVID-19 pandemic was an exceptional health situation, including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different drug candidates were proposed. In this article, we present the challenges for an academic Safety Department to manage the global safety of a European trial during the pandemic. The National Institute for Health and Medical Research (Inserm) conducted a European multicenter, open-label, randomized, controlled trial involving three repurposed and one-in development drugs (lopinavir/ritonavir, IFN-β1a, hydroxychloroquine, and remdesivir) in adults hospitalized with COVID-19. From 25 March 2020 to 29 May 2020, the Inserm Safety Department had to manage 585 Serious Adverse Events (SAEs) initial notification and 396 follow-up reports. The Inserm Safety Department's staff was mobilized to manage these SAEs and to report Expedited safety reports to the competent authorities within the legal timeframes. More than 500 queries were sent to the investigators due to a lack of or incoherent information on SAE forms. At the same time, the investigators were overwhelmed by the management of patients suffering from COVID-19 infection. These particular conditions of missing data and lack of accurate description of adverse events made evaluation of the SAEs very difficult, particularly the assessment of the causal role of each investigational medicinal product. In parallel, working difficulties were accentuated by the national lockdown, frequent IT tool dysfunctions, delayed implementation of monitoring and the absence of automatic alerts for SAE form modification. Although COVID-19 is a confounding factor per se, the delay in and quality of SAE form completion and the real-time medical analysis by the Inserm Safety Department were major issues in the quick identification of potential safety signals. To conduct a high-quality clinical trial and ensure patient safety, all stakeholders must take their roles and responsibilities.