GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.</p

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Study of Cynara cardunculus L. enzymes potential in cheese technology

L’objectif des travaux entrepris au cours de cette thèse visait à identifier, extraire et caractériser les enzymes coagulants des fleurs de Cynara cardunculus L., en vue de les valoriser dans la technologie des produits laitiers. Dans une première étape, deux lots de fleurs, collectés à deux stades de maturation, ont été comparés d’un point de vue biochimique et enzymatique, afin de sélectionner le lot approprié pour une meilleure production d’enzymes coagulants. Les fleurs collectées au milieu du stade de maturation (fin du mois de juin) ont alors été sélectionnées pour la suite des travaux. Les critères de sélection étaient basés sur la composition chimique des fleurs, les activités enzymatiques des extraits coagulants, ainsi que sur les propriétés texturales des caillés produits. Dans une deuxième étape, le contenu enzymatique des fleurs a été identifié par une approche protéomique. L’étude a révélé la présence de 4 cardosines (A, E, G et H), dont la cardosine A qui a une spécificité d’action similaire à celle de la chymosine. L’absence des autres cardosines (B, C, D et F) constitue un avantage pour la réduction de l’activité protéolytique excessive, responsable de l’amertume et des défauts de texture des fromages. La partie suivante de la thèse a concerné l’étude de l’extraction de la présure de C. cardunculus et son application dans le processus de coagulation du lait. Cette étude était divisée en deux parties complémentaires. Dans un premier temps, nous nous sommes intéressés à évaluer l’effet du pH d’extraction sur les propriétés techno-fonctionnelles des extraits bruts des fleurs. Dans un deuxième temps, les conditions d’extraction de la présure ont été optimisées par méthodologie des surfaces de réponses, en vue de maximiser son activité coagulante. Les conditions optimales étaient alors sélectionnées. L’efficacité de l’extrait coagulant a été testée dans la coagulation de deux types de laits bovins (cru et reconstitué), en appliquant deux doses d’extrait coagulant (0,5 mg et 1 mg/10 mL de lait). Les résultats ont montré des propriétés viscoélastiques et des fermetés des gels élevées, similaires à ceux d’une chymosine commerciale. Pour terminer, l’étude des propriétés technologiques des gels était accompagnée d’une évaluation de la qualité des fromages produits, afin de confirmer l’aptitude de la présure extraite dans les conditions optimisées, à remplacer avec succès la chymosine. Cette dernière partie visait également à sélectionner une concentration en sel appropriée au cours du saumurage, pour obtenir une meilleure qualité du produit final. Par conséquent, les propriétés physico-chimiques, texturales et rhéologiques, ainsi que le niveau de protéolyse dans les fromages, saumurés à différentes concentrations en sel, ont été déterminés. Les résultats ont permis de sélectionner une concentration en sel de 15 %, pour la quelle d’excellentes propriétés ont été obtenues, en termes de rendement fromager, texture et viscoélasticité après 28 jours de stockage (4°C). En conclusion, la présente thèse a contribué par l’optimisation des conditions d’extraction, à la production d’un extrait enzymatique doté d’une activité spécifique maximale, permettant de produire d’excellentes qualités de coagulums et des fromages saumurés. Ces résultats satisfaisants pourraient offrir de nouvelles opportunités de production d’une « présure végétale » compétitive, par rapport aux enzymes animales ou microbiennes.Etude du potentiel des enzymes de Cynara cardunculus L. en technologie fromagère

Milk-clotting properties of plant rennets and their enzymatic, rheological and sensory role in cheese making: a Review

Plant rennets hold an important position amongst various coagulants used in cheese technology. The selection of a suitable plant coagulant is important due to the increasing global demands of cheese alongside reduced supply of calf rennet. Thus, a literature synthesis is presented to investigate recent achievements on their functional properties and enzymatic role in cheese making. Efforts have also been done to compare certain rheological and sensory properties of final products, arising from some plant and animal based rennets. In fact, some coagulants such as actinidin or dubiumin produce cheeses with sensory qualities similar to those produced by animal rennet. Others, like ginger, cucumisin or hieronymain proteases contribute to develop very different textures and flavors, due to excessive proteolytic activity and production of bitter peptides. For milk-clotting enzymes with high non-specific action, several improvement strategies have been developed to produce cheeses with sensory properties close to those of animal rennet. For example, the mixture of coagulants (cardosins/chymosin), the selection of appropriate milk or its ultrafiltration, as well as the increase of salting time of cheese during ripening could be efficient ways to improve texture and reduce bitterness. Concerning cheeses with high yield loss, the whey could be used for a traditional production of whey cheese. To conclude, the selection of appropriate plant rennet with high MCA/PA ratio and the optimization of all coagulation parameters play a central role in manufacturing cheese with superior rheological and sensory properties

Combinatorial effect of Bacillus thuringiensis kurstaki and Photorhabdus luminescens against Spodoptera littoralis (Lepidoptera: Noctuidae).

Spodoptera littoralis, one of the major pests of many important crop plants, is more susceptible to Bacillus thuringiensis aizawai delta-endotoxins than to those of Bacillus thuringiensis kurstaki. Within the framework of the development of efficient bioinsecticides and the prevention against insect resistance, we tested the effect of mixing B. thuringiensis kurstaki delta-endotoxins and Photorhabdus luminescens cells on S. littoralis growth. The obtained results showed that the growth inhibition of this insect was more effective when B. thuringiensis kurstaki spore-crystal mixture and Photorhabdus luminescens cells were used in combination. Furthermore, this synergism is mainly due to the presence of Cry1Ac, which is one of the three delta-endotoxins that form the crystal of B. thuringiensis kurstaki strain BNS3 in addition to Cry1Aa and Cry2Aa. This work shows a possibility to use B. thuringiensis as a delivery means for Photorhabdus bacteria in order to infect the insect hemocoel and to reduce the risk of developing resistance in the target organism

Physicochemical, thermal and rheological properties of prickly pear peel flours and fibers

peer reviewedPrickly pear peel flour (PPF) byproduct is an attractive source of fibers. Fiber concentrates (PFC) were obtained using an aqueous extraction from PPF derived from different Tunisian varieties: Opuntia ficus-indica (yellow color and purple-pink color ecotypes) and Opuntia stricta (OS). Results showed that the extraction process increased fiber content from ~ 42 to 67% for the pink ecotype. Fiber concentrate obtained from the yellow ecotype presented high water holding capacity (9.18 g/g). Thermogravimetric analyses revealed that fibers were thermally more stable than their corresponding flours, at temperatures up to 230 °C and 150 °C, respectively, for OS variety. Rheological properties of aqueous suspensions of PFC or PPF showed a shear-thinning behavior at 4% concentration. Apparent viscosity increased with concentration and decreased with temperature. All suspensions showed a closed hysteresis loop at 6% concentration, with highest thixotropic property for PFC obtained from the yellow ecotype. These promising properties of PFC provided their possible use in many food formulations