A Triassic stem lepidosaur illuminates the origin of lizard-like reptiles.

The early evolution of diapsid reptiles is marked by a deep contrast between our knowledge of the origin and early evolution of archosauromorphs (crocodiles, avian and non-avian dinosaurs) to that of lepidosauromorphs (squamates (lizards, snakes) and sphenodontians (tuataras)). Whereas the former include hundreds of fossil species across various lineages during the Triassic period1, the latter are represented by an extremely patchy early fossil record comprising only a handful of fragmentary fossils, most of which have uncertain phylogenetic affinities and are confined to Europe1-3. Here we report the discovery of a three-dimensionally preserved reptile skull, assigned as Taytalura alcoberi gen. et sp. nov., from the Late Triassic epoch of Argentina that is robustly inferred phylogenetically as the earliest evolving lepidosauromorph, using various data types and optimality criteria. Micro-computed tomography scans of this skull reveal details about the origin of the lepidosaurian skull from early diapsids, suggesting that several traits traditionally associated with sphenodontians in fact originated much earlier in lepidosauromorph evolution. Taytalura suggests that the strongly evolutionarily conserved skull architecture of sphenodontians represents the plesiomorphic condition for all lepidosaurs, that stem and crown lepidosaurs were contemporaries for at least ten million years during the Triassic, and that early lepidosauromorphs had a much broader geographical distribution than has previously been thought.

Levan Production by Suhomyces kilbournensis Using Sugarcane Molasses as a Carbon Source in Submerged Fermentation.

The valorization of byproducts from the sugarcane industry represents a potential alternative method with a low energy cost for the production of metabolites that are of commercial and industrial interest. The production of exopolysaccharides (EPSs) was carried out using the yeast Suhomyces kilbournensis isolated from agro-industrial sugarcane, and the products and byproducts of this agro-industrial sugarcane were used as carbon sources for their recovery. The effect of pH, temperature, and carbon and nitrogen sources and their concentration in EPS production by submerged fermentation (SmF) was studied in 170 mL glass containers of uniform geometry at 30 °C with an initial pH of 6.5. The resulting EPSs were characterized with Fourier-transform infrared spectroscopy (FT-IR). The results showed that the highest EPS production yields were 4.26 and 44.33 g/L after 6 h of fermentation using sucrose and molasses as carbon sources, respectively. Finally, an FT-IR analysis of the EPSs produced by S. kilbournensis corresponded to levan, corroborating its origin. It is important to mention that this is the first work that reports the production of levan using this yeast. This is relevant because, currently, most studies are focused on the use of recombinant and genetically modified microorganisms; in this scenario, Suhomyces kilbournensis is a native yeast isolated from the sugar production process, giving it a great advantage in the incorporation of carbon sources into their metabolic processes in order to produce levan sucrose, which uses fructose to polymerize levan.

Early Prediction of Response of Hepatocellular Carcinoma to Yttrium-90 Radiation Segmentectomy Using a Machine Learning MR Imaging Radiomic Approach.

PURPOSE: To assess the accuracy of a machine learning (ML) approach based on magnetic resonance (MR) imaging radiomic quantification obtained before treatment and early after treatment for prediction of early hepatocellular carcinoma (HCC) response to yttrium-90 transarterial radioembolization (TARE). MATERIALS AND METHODS: In this retrospective single-center study of 76 patients with HCC, baseline and early (1-2 months) post-TARE MR images were collected. Semiautomated tumor segmentation facilitated extraction of shape, first-order histogram, and custom signal intensity-based radiomic features, which were then trained (n = 46) using a ML XGBoost model and validated on a separate cohort (n = 30) not used in training to predict treatment response assessed at 4-6 months (based on modified Response and Evaluation Criteria in Solid Tumors criteria). Performance of this ML radiomic model was compared with those of models comprising clinical parameters and standard imaging characteristics using area under the receiver operating curve (AUROC) analysis for prediction of complete response (CR). RESULTS: Seventy-six tumors with a mean (±SD) diameter of 2.6 cm ± 1.6 were included. Sixty, 12, 1, and 3 patients were classified as having CR, partial response, stable disease, and progressive disease, respectively, at 4-6 months posttreatment on the basis of MR images. In the validation cohort, the radiomic model showed good performance (AUROC, 0.89) for prediction of CR, compared with models comprising clinical and standard imaging criteria (AUROC, 0.58 and 0.59, respectively). Baseline imaging features appeared to be more heavily weighted in the radiomic model. CONCLUSIONS: The use of ML modeling of radiomic data combining baseline and early follow-up MR imaging could predict HCC response to TARE. These models need to be investigated further in an independent cohort.

Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles.

Spontaneous recovery after a stroke accounts for a significant part of the neurological recovery in patients. However limited, the spontaneous recovery is mechanistically driven by axonal restorative processes for which several molecular cues have been previously described. We report the acceleration of spontaneous recovery in a preclinical model of ischemia/reperfusion in rats via a single intracerebroventricular administration of extracellular vesicles released from primary cortical astrocytes. We used magnetic resonance imaging and confocal and multiphoton microscopy to correlate the structural remodeling of the corpus callosum and striatocortical circuits with neurological performance during 21 days. We also evaluated the functionality of the corpus callosum by repetitive recordings of compound action potentials to show that the recovery facilitated by astrocytic extracellular vesicles was both anatomical and functional. Our data provide compelling evidence that astrocytes can hasten the basal recovery that naturally occurs post-stroke through the release of cellular mediators contained in extracellular vesicles.

Using small angle x-ray scattering to examine the aggregation mechanism in silica nanoparticle-based ambigels for improved optical clarity.

Silica-based aerogels are a promising low-cost solution for improving the insulation efficiency of single-pane windows and reducing the energy consumption required for space heating and cooling. Two key material properties required are high porosity and small pore sizes, which lead to low thermal conductivity and high optical transparency, respectively. However, porosity and pore size are generally directly linked, where high porosity materials also have large pore sizes. This is unfavorable as large pores scatter light, resulting in reduced transmittance in the visible regime. In this work, we utilized preformed silica colloids to explore methods for reducing pore size while maintaining high porosity. The use of preformed colloids allows us to isolate the effect of solution conditions on porous gel network formation by eliminating simultaneous nanoparticle growth and aggregation found when using typical sol-gel molecular-based silica precursors. Specifically, we used in situ synchrotron-based small-angle x-ray scattering during gel formation to better understand how pH, concentration, and colloid size affect particle aggregation and pore structure. Ex situ characterization of dried gels demonstrates that peak pore widths can be reduced from 15 to 13 nm, accompanied by a narrowing of the overall pore size distribution, while maintaining porosities of 70%-80%. Optical transparency is found to increase with decreasing pore sizes while low thermal conductivities ranging from 95 +/- 13 mW/m K are maintained. Mechanical performance was found to depend primarily on effective density and did not show a significant dependence on solution conditions. Overall, our results provide insights into methods to preserve high porosity in nanoparticle-based aerogels while improving optical transparency.

Variable Baseline and Flexible Configuration Stereo Vision Using Two Aerial Robots.

In this work, a new method for aerial robot remote sensing using stereo vision is proposed. A variable baseline and flexible configuration stereo setup is achieved by separating the left camera and right camera on two separate quadrotor aerial robots. Monocular cameras, one on each aerial robot, are used as a stereo pair, allowing independent adjustment of the pose of the stereo pair. In contrast to conventional stereo vision where two cameras are fixed, having a flexible configuration system allows a large degree of independence in changing the configuration in accordance with various kinds of applications. Larger baselines can be used for stereo vision of farther away targets while using a vertical stereo configuration in tasks where there would be a loss of horizontal overlap caused by a lack of suitable horizontal configuration. Additionally, a method for the practical use of variable baseline stereo vision is introduced, combining multiple point clouds from multiple stereo baselines. Issues from using an inappropriate baseline, such as estimation error induced by insufficient baseline, and occlusions from using too large a baseline can be avoided with this solution.

Mutational Landscape of Bladder Cancer in Mexican Patients: KMT2D Mutations and chr11q15.5 Amplifications Are Associated with Muscle Invasion.

Bladder cancer (BC) is the most common neoplasm of the urinary tract, which originates in the epithelium that covers the inner surface of the bladder. The molecular BC profile has led to the development of different classifications of non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). However, the genomic BC landscape profile of the Mexican population, including NMIBC and MIBC, is unknown. In this study, we aimed to identify somatic single nucleotide variants (SNVs) and copy number variations (CNVs) in Mexican patients with BC and their associations with clinical and pathological characteristics. We retrospectively evaluated 37 patients treated between 2012 and 2021 at the National Cancer Institute-Mexico (INCan). DNA samples were obtained from paraffin-embedded tumor tissues and exome sequenced. Strelka2 and Lancet packages were used to identify SNVs and insertions or deletions. FACETS was used to determine CNVs. We found a high frequency of mutations in TP53 and KMT2D, gains in 11q15.5 and 19p13.11-q12, and losses in 7q11.23. STAG2 mutations and 1q11.23 deletions were also associated with NMIBC and low histologic grade.

Protamine Sulfate Is a Potent Inhibitor of Human Papillomavirus Infection In Vitro and In Vivo.

Human papillomavirus (HPV) infections are transmitted through sexual or other close contact and are etiologically associated with epithelial warts, papillomas, and intraepithelial lesions that may progress to cancer. Indeed, 4.8% of the global cancer burden is linked to HPV infection. Highly effective vaccines protect against two to nine of the most medically important HPV genotypes, yet vaccine uptake is inadequate and/or cost prohibitive in many settings. With HPV-related cancer incidence expected to rise over the coming decades, there is a need for effective HPV microbicides. Herein, we demonstrate the strong inhibitory activity of the heparin-neutralizing drug protamine sulfate (PS) against HPV infection. Pretreatment of cells with PS greatly reduced infection, regardless of HPV genotype or virus source. Vaginal application of PS prevented infection of the murine genital tract by HPV pseudovirions. Time-of-addition assays where PS was added to cells before infection, during infection, or after viral attachment demonstrated strong inhibitory activities on early infection steps. No effect on virus infection was found for cell lines deficient in heparan sulfate expression, suggesting that PS binds to heparan sulfate on the cell surface. Consistent with this, prophylactic PS exposure prevented viral attachment, including under low-pH conditions akin to the human vaginal tract. Our findings suggest PS acts dually to prevent HPV infection: prophylactic treatment prevents HPV attachment to host cells, and postattachment administration alters viral entry. Clinical trials are warranted to determine whether protamine-based products are effective as topical microbicides against genital HPVs.

Diagnostic performance of IQ·SPECT with high-speed scanning: A preliminary quality control study in obese patients.

BACKGROUND: IQ·SPECT is a recently introduced collimator design for myocardial perfusion imaging (MPI). Little data exist on use of this collimator type in obese patients, particularly Class 2 or 3 [body mass index (BMI) > 35 kg/m2]. METHODS: Two consecutive rest-stress MPI scans were prospectively acquired using a conventional collimator and IQ·SPECT (acquisition times of 20 and 7 minutes, respectively) in 20 patients with a BMI of >30 kg/m2. Assigned by two blinded, independent readers, image quality (on a 5-point scale) and metrics of myocardial perfusion [summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS)] were compared. Software-based left ventricular ejection fraction (EF) was also correlated. RESULTS: Mean BMI was 39.6 ± 7.6 kg/m2. Class 2 or 3 obesity was present in 12 patients (BMI, 44.1 ± 6.8 kg/m2). Gated/non-gated images from IQ·SPECT revealed fair to good quality scores (median ≥ 3.25), which were inferior to the conventional collimator (median ≥ 4.0; P ≤ 0.01). Significant correlative indices were achieved when comparing IQ·SPECT and conventional collimators for EF values (r = 0.86, P < 0.01), SSS (r = 0.75, P < 0.0001) and SRS (r = 0.60, P < 0.005), but not for SDS (r = 0.15). CONCLUSION: IQ·SPECT was comparable to conventional SPECT in obese patients. The reduced acquisition time of IQ·SPECT may allow for improved throughput with no loss in diagnostic accuracy.

Transient production of receptor-binding domain of SARS-CoV-2 in Nicotiana benthamiana plants induces specific antibodies in immunized mice.

BACKGROUND: The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus has currently affected millions of people around the world. To combat the rapid spread of COVID-19 there is an urgent need to implement technological platforms for the production of vaccines, drugs and diagnostic systems by the scientific community and pharmaceutical companies. The SARS-CoV-2 virus enters the cells by the interaction between the receptor-binding domain (RBD) present in the viral surface spike protein and its human receptor ACE2. The RBD protein is therefore considered as the target for potential subunit-based vaccines. METHODS AND RESULTS: We evaluate the use of Nicotiana benthamiana plants as the host to transiently-producing recombinant RBD (RBDr) protein. The identity of the plant-produced RBDr was confirmed by immune assays and mass spectrometry. Immunogenicity was confirmed through the specific antibodies generated in all of the immunized mice compared to the PBS treated group. CONCLUSIONS: In conclusions, the immunogenicity of the RBDr produced in N. benthamiana was confirmed. These findings support the use of plants as an antigen expression system for the rapid development of vaccine candidates.

Medical management and resolution of perinatal bilateral exophthalmia and secondary corneal ulcers in an Antillean manatee (Trichechus manatus manatus) neonate from Puerto Rico.

OBJECTIVE: To present a novel case of perinatal bilateral exophthalmos and corneal ulcers in a neonate Antillean manatee and describe the medical treatment that led to the resolution of the observed clinical signs and vision restoration. ANIMAL STUDIED: A manatee stranded alone in Puerto Rico on July 5, 2020. RESULTS: The manatee was found in critical condition with pronounced exophthalmos, lagophthalmos, and corneal opacification of both eyes (OU). Vision impairment was evident due to the lack of ocular menace reflex and bumping into the tank's walls. Biomicroscopy revealed conjunctival hyperemia and chemosis, limited third eyelid movement, but had viscous tears present OU. Dense, full-thickness, white to cream-colored cellular infiltrates affected 70% of the cornea with peripheral active vascularization OU. Rubeosis iridis was also present OU. Treatment consisted of supportive medical management, including nutritional support and topical treatment for ulcerative keratitis. Resolution of the corneal ulcers and functional vision were achieved after 6 weeks of therapy. Currently, bilateral, mild, intermittent exophthalmos is observed with no adverse clinical signs, and the calf is in good health. CONCLUSIONS: The extent of bilateral corneal disease on a neonatal calf may be a result of an intrauterine infection or possible trauma at or right after birth. While the latter may have led to exophthalmia and consequent corneal disease, the exact cause could not be determined. Supportive therapy and medical management of infectious keratitis were successful and led to vision recovery. This is the first report of ocular pathology in a neonatal manatee.

4-Phenylcoumarin (4-PC) Glucoside from Exostema caribaeum as Corrosion Inhibitor in 3% NaCl Saturated with CO2 in AISI 1018 Steel: Experimental and Theoretical Study.

The corrosion inhibition of 5-O-ß-D-glucopyranosyl-7-methoxy-3',4'-dihydroxy-4-phenylcoumarin (4-PC) in AISI 1018 steel immersed in 3% NaCl + CO2 was studied by electrochemical impedance spectroscopy (EIS). The results showed that, at just 10 ppm, 4-PC exerted protection against corrosion with Õ² = 90% and 97% at 100 rpm. At static conditions, the polarization curves indicated that, at 5 ppm, the inhibitor presented anodic behavior, while at 10 and 50 ppm, there was a cathodic-type inhibitor. The inhibitor adsorption was demonstrated to be chemisorption, according to the Langmuir isotherm for 100 and 500 rpm. By means of SEM-EDS, the corrosion inhibition was demonstrated, as well as the fact that the organic compound was effective for up to 72 h of immersion. At static conditions, dispersion-corrected density functional theory results reveal that the chemical bonds established by the phenyl group of 4-PC are responsible of the chemisorption on the steel surface. According with Fukui reactivity indices, the molecules adsorbed on the metal surface provide a protective cover against nucleophilic and electrophilic attacks, pointing to the corrosion inhibition properties of 4-PC.

Routine systematic prostate biopsies not replaced by magnetic resonance imaging-targeted biopsy.

Background: Multiparametric magnetic resonance imaging improves the performance of prostate cancer (PCa) diagnostics through a better selection of patients. Objectives: The aim of the study was to study the detection rate (DR) of systematic and targeted cognitive biopsies in a cohort with the previous negative systematic biopsies. A secondary objective was to describe the value of prostate-specific antigen density (PSAd) in the detection of clinically significant PCa (CSPCa). Methods: We designed a prospective, single-center, and comparative study to determine the DR of systematic and targeted cognitive biopsies. The clinical and pathological characteristics of each patient were described. Results: A total of 111 patients with Prostate Imaging Reporting and Data System lesions > 3 were included in the study. PCa was detected in 41.4% (46 of 111 patients); 42 (91.3%) were detected by systematic biopsy and 30 (65.2%) by targeted biopsy. CSPCa was detected in 26 (23.4%), 23 (88.5%) by systematic biopsy, and 21 (76.9%) by targeted biopsy. PSAd > 0.15 was directly associated with CSPCa. Conclusion: The detection of PCa by systematic biopsy in this series was higher than 80%; hence, its routine use should not be replaced by targeted biopsy, since it continues to be the cornerstone of the diagnosis in patients with prior negative biopsies.

An axiomatic approach towards pandemic performance indicators.

During a pandemic, each country (or region) is characterized by a status matrix indicating its positive cases, hospitalizations and deaths. A pandemic performance indicator is a real-valued mapping from the set of status matrices to the set of non-negative real numbers, whereby lower values stand for better performance. We show that four axioms together characterize a family of indicators arising from a weighted average of the incidence rate, morbidity rate and mortality rate. We use these indicators to evaluate the impact of COVID-19 in major countries worldwide.

Internet health information seeking by primary care patients.

INTRODUCTION: As patients seek health information more frequently on the internet, the impact on their health status and their relationship with doctors could be a matter of concern. The objective of this study is to know how frequently rural primary care patients seek health information on the internet and the factors associated with it. METHODS: This cross-sectional study surveyed 850 patients aged over 15 years who attended two rural health centers in Cuenca (Spain). Consecutive case sampling was done. The participants were invited to answer a survey with sociodemographic and clinical aspects, and questions about possible internet searches for health information. The statistical analysis included the description of the variables and a bivariate analysis, and was completed with a logistic regression analysis. RESULTS: Patients' median age was 54 years, interquartile range 39-67 years; 60.9% were female. Of those surveyed, 49.8% (95% confidence interval 46.3-53.2) stated that they used the internet to seek health information. Statistically significant differences were apparent for gender, age, level of education, disease and attendance (p<0.0001). A logistic regression analysis showed an independent relationship with health information seeking on the internet for the variables gender, age, level of education (p<0.0001) and having a chronic disease (p=0.004). CONCLUSION: Roughly half the primary care patients in the rural area sought health information on the internet. Females, young people, those with a higher level of education and a chronic disease background did so more frequently.

Patterns of differentiation of renin lineage cells during nephrogenesis.

Developmentally heterogeneous renin-expressing cells serve as progenitors for mural, glomerular, and tubular cells during nephrogenesis and are collectively termed renin lineage cells (RLCs). In this study, we quantified different renal vascular and tubular cell types based on specific markers and assessed proliferation and de novo differentiation in the RLC population. We used kidney sections of mRenCre-mT/mG mice throughout nephrogenesis. Marker positivity was evaluated in whole digitalized sections. At embryonic day 16, RLCs appeared in the developing kidney, and the expression of all stained markers in RLCs was observed. The proliferation rate of RLCs did not differ from the proliferation rate of non-RLCs. RLCs expanded mainly by de novo differentiation (neogenesis). Fractions of RLCs originating from the stromal progenitors of the metanephric mesenchyme (renin-producing cells, vascular smooth muscle cells, and mesangial cells) decreased during nephrogenesis. In contrast, aquaporin-2-positive RLCs in the collecting duct system, which embryonically emerges almost exclusively from the ureteric bud, expanded postpartum. The cubilin-positive RLC fraction in the proximal tubule, deriving from the cap mesenchyme, remained constant. In summary, RLCs were continuously detectable in the vascular and tubular compartments of the kidney during nephrogenesis. Therein, various patterns of RLC differentiation that depend on the embryonic origin of the cells were identified.NEW & NOTEWORTHY The unifying feature of the renal renin lineage cells (RLCs) is their origin from renin-expressing progenitors. RLCs evolve to an embryologically heterogeneous large population in structures with different ancestry. RLCs are also targets for the widely used renin-angiotensin-system blockers, which modulate their phenotype. Unveiling the different differentiation patterns of RLCs in the developing kidney contributes to understanding changes in their cell fate in response to homeostatic challenges and the use of antihypertensive drugs.

Resection of Cavity Shave Margins in Stage 0-III Breast Cancer Patients Undergoing Breast Conserving Surgery: A Prospective Multicenter Randomized Controlled Trial.

OBJECTIVE: Single-center studies have demonstrated that resection of cavity shave margins (CSM) halves the rate of positive margins and re-excision in breast cancer patients undergoing partial mastectomy (PM). We sought to determine if these findings were externally generalizable across practice settings. METHODS: In this multicenter randomized controlled trial occurring in 9 centers across the United States, stage 0-III breast cancer patients undergoing PM were randomly assigned to either have resection of CSM ("shave" group) or not ("no shave" group). Randomization occurred intraoperatively, after the surgeon had completed their standard PM. Primary outcome measures were positive margin and re-excision rates. RESULTS: Between July 28, 2016 and April 13, 2018, 400 patients were enrolled in this trial. Four patients (2 in each arm) did not meet inclusion criteria after randomization, leaving 396 patients for analysis: 196 in the "shave" group and 200 to the "no shave" group. Median patient age was 65 years (range; 29-94). Groups were well matched at baseline for demographic and clinicopathologic factors. Prior to randomization, positive margin rates were similar in the "shave" and "no shave" groups (76/196 (38.8%) vs. 72/200 (36.0%), respectively, P = 0.604). After randomization, those in the "shave" group were significantly less likely than those in the "no shave" group to have positive margins (19/196 (9.7%) vs. 72/200 (36.0%), P < 0.001), and to require re-excision or mastectomy for margin clearance (17/196 (8.7%) vs. 47/200 (23.5%), P < 0.001). CONCLUSION: Resection of CSM significantly reduces positive margin and re-excision rates in patients undergoing PM.

Ear and Hearing Care Workforce: Current Status and its Implications.

OBJECTIVE: This study aimed to provide comprehensive global evidence on the availability of ear and hearing care (EHC) professionals and real-life examples that showcase the impact of workforce shortages on the workload faced by existing professionals. METHODS: Six sources of data were used to estimate availability of EHC workforce: a scoping literature review, World Health Organization (WHO) National Health Workforce Accounts platform, WHO Member States survey and regional consultations, hearing care organizations survey, and official government statistics. EHC professionals' workload undertaking common interventions was estimated through the WHO workload indicators of staffing need human resource management tool. RESULTS: With data on otolaryngologists from 138, audiologists from 102, speech and language therapists from 124, and teachers of the deaf from 86 countries, this study revealed large gaps in availability of EHC cadres. The majority of countries in the African region had less than one professional in each cadre per million in comparison with most European countries having up to 50 times higher densities. Workload indicators of staffing need calculations revealed the challenging workload faced by existing EHC professionals, with ratios between existing and required staff of 0.01-0.86. CONCLUSION: There is an enormous shortage of EHC professionals and urgent actions are needed to ensure sufficient and equitable access to services. Task sharing, a novel approach for improving access to hearing care alongside the development of new cadres, can be a vital strategy in overcoming the shortage of highly qualified providers in many settings, even in well-resourced health systems, to facilitate equitable access to required EHC services.

Serum or plasma ferritin concentration as an index of iron deficiency and overload.

BACKGROUND: Reference standard indices of iron deficiency and iron overload are generally invasive, expensive, and can be unpleasant or occasionally risky. Ferritin is an iron storage protein and its concentration in the plasma or serum reflects iron stores; low ferritin indicates iron deficiency, while elevated ferritin reflects risk of iron overload. However, ferritin is also an acute-phase protein and its levels are elevated in inflammation and infection. The use of ferritin as a diagnostic test of iron deficiency and overload is a common clinical practice. OBJECTIVES: To determine the diagnostic accuracy of ferritin concentrations (serum or plasma) for detecting iron deficiency and risk of iron overload in primary and secondary iron-loading syndromes. SEARCH METHODS: We searched the following databases (10 June 2020): DARE (Cochrane Library) Issue 2 of 4 2015, HTA (Cochrane Library) Issue 4 of 4 2016, CENTRAL (Cochrane Library) Issue 6 of 12 2020, MEDLINE (OVID) 1946 to 9 June 2020, Embase (OVID) 1947 to week 23 2020, CINAHL (Ebsco) 1982 to June 2020, Web of Science (ISI) SCI, SSCI, CPCI-exp & CPCI-SSH to June 2020, POPLINE 16/8/18, Open Grey (10/6/20), TRoPHI (10/6/20), Bibliomap (10/6/20), IBECS (10/6/20), SCIELO (10/6/20), Global Index Medicus (10/6/20) AIM, IMSEAR, WPRIM, IMEMR, LILACS (10/6/20), PAHO (10/6/20), WHOLIS 10/6/20, IndMED (16/8/18) and Native Health Research Database (10/6/20). We also searched two trials registers and contacted relevant organisations for unpublished studies. SELECTION CRITERIA: We included all study designs seeking to evaluate serum or plasma ferritin concentrations measured by any current or previously available quantitative assay as an index of iron status in individuals of any age, sex, clinical and physiological status from any country. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. We designed the data extraction form to record results for ferritin concentration as the index test, and bone marrow iron content for iron deficiency and liver iron content for iron overload as the reference standards. Two other authors further extracted and validated the number of true positive, true negative, false positive, false negative cases, and extracted or derived the sensitivity, specificity, positive and negative predictive values for each threshold presented for iron deficiency and iron overload in included studies. We assessed risk of bias and applicability using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. We used GRADE assessment to enable the quality of evidence and hence strength of evidence for our conclusions. MAIN RESULTS: Our search was conducted initially in 2014 and updated in 2017, 2018 and 2020 (10 June). We identified 21,217 records and screened 14,244 records after duplicates were removed. We assessed 316 records in full text. We excluded 190 studies (193 records) with reasons and included 108 studies (111 records) in the qualitative and quantitative analysis. There were 11 studies (12 records) that we screened from the last search update and appeared eligible for a future analysis. We decided to enter these as awaiting classification. We stratified the analysis first by participant clinical status: apparently healthy and non-healthy populations. We then stratified by age and pregnancy status as: infants and children, adolescents, pregnant women, and adults. Iron deficiency We included 72 studies (75 records) involving 6059 participants. Apparently healthy populations Five studies screened for iron deficiency in people without apparent illness. In the general adult population, three studies reported sensitivities of 63% to 100% at the optimum cutoff for ferritin, with corresponding specificities of 92% to 98%, but the ferritin cutoffs varied between studies. One study in healthy children reported a sensitivity of 74% and a specificity of 77%. One study in pregnant women reported a sensitivity of 88% and a specificity of 100%. Overall confidence in these estimates was very low because of potential bias, indirectness, and sparse and heterogenous evidence. No studies screened for iron overload in apparently healthy people. People presenting for medical care There were 63 studies among adults presenting for medical care (5042 participants). For a sample of 1000 subjects with a 35% prevalence of iron deficiency (of the included studies in this category) and supposing a 85% specificity, there would be 315 iron-deficient subjects correctly classified as having iron deficiency and 35 iron-deficient subjects incorrectly classified as not having iron deficiency, leading to a 90% sensitivity. Thresholds proposed by the authors of the included studies ranged between 12 to 200 µg/L. The estimated diagnostic odds ratio was 50. Among non-healthy adults using a fixed threshold of 30 µg/L (nine studies, 512 participants, low-certainty evidence), the pooled estimate for sensitivity was 79% with a 95% confidence interval of (58%, 91%) and specificity of 98%, with a 95% confidence interval of (91%, 100%). The estimated diagnostic odds ratio was 140, a relatively highly informative test. Iron overload We included 36 studies (36 records) involving 1927 participants. All studies concerned non-healthy populations. There were no studies targeting either infants, children, or pregnant women. Among all populations (one threshold for males and females; 36 studies, 1927 participants, very low-certainty evidence): for a sample of 1000 subjects with a 42% prevalence of iron overload (of the included studies in this category) and supposing a 65% specificity, there would be 332 iron-overloaded subjects correctly classified as having iron overload and 85 iron-overloaded subjects incorrectly classified as not having iron overload, leading to a 80% sensitivity. The estimated diagnostic odds ratio was 8. AUTHORS' CONCLUSIONS: At a threshold of 30 micrograms/L, there is low-certainty evidence that blood ferritin concentration is reasonably sensitive and a very specific test for iron deficiency in people presenting for medical care. There is very low certainty that high concentrations of ferritin provide a sensitive test for iron overload in people where this condition is suspected. There is insufficient evidence to know whether ferritin concentration performs similarly when screening asymptomatic people for iron deficiency or overload.

Mathematical indices for the influence of risk factors on the lethality of a disease.

We develop a theoretical model to measure the relative relevance of different pathologies of the lethality of a disease in society. This approach allows a ranking of diseases to be determined, which can assist in establishing priorities for vaccination campaigns or prevention strategies. Among all possible measurements, we identify three families of rules that satisfy a combination of relevant properties: neutrality, irrelevance, and one of three composition concepts. One of these families includes, for instance, the Shapley value of the associated cooperative game. The other two families also include simple and intuitive indices. As an illustration, we measure the relative relevance of several pathologies in lethality due to COVID-19.