Ethical considerations for Forensic Genetic Frequency databases: First Report conception and development.

The Forensic Databases Advisory Board (FDAB), an independent board that assists the International Society for Forensic Genetics (ISFG), has presented a First Report on ethical aspects of the following Forensic Genetic Frequency Databases (FGFD): EMPOP, STRidER and YHRD. The FDAB designed an ethical framework to evaluate the content of these FGFD, and the factors to be considered for retention and acceptance of submissions. The FDAB framework proposes to categorize submissions according to the risk of having contravened the universal ethical principles outlined by international organizations, and the guidelines adopted by the ISFG. The report has been open to discussion by the scientific community since 2023. Herein we present the conception and development of the First Report along with a summary of its content, with consideration of the feedback received.

Successful centralisation technique for treatment of post-traumatic absence of the radial shaft in a dog.

This report describes a centralisation procedure for the treatment of a radial non-union, characterised by extensive bone loss and an intact ulna, in an 18-month-old toy poodle. A lateral approach to the radius/ulna shafts was realised and, after debridement of the non-union site, an ulnar osteotomy was performed proximal to the styloid process of the ulna. Transposition of the distal fragment of the radius to the distal end of the osteotomised proximal segment of the ulna was performed and the stabilisation was obtained using a locking plate with proximal screws in the ulnar shaft and distal screws in the radius epiphysis. The patient achieved bone union in 10 weeks and the last evaluation, performed 112 weeks postoperatively, showed a full return to pre-injury function. Based on the results of this report, the centralisation was effective in the treatment of post-traumatic absence of the radial shaft in a dog.

Long-term outcomes of atrophic/oligotrophic non-unions in dogs and cats treated with autologous iliac corticocancellous bone graft and circular external skeletal fixation: 19 cases (2014-2021).

OBJECTIVES: To determine the short- and long-term outcomes and complications in dogs and cats undergoing surgical treatment for viable oligotrophic and nonviable atrophic non-unions using circular external skeletal fixation and autologous corticocancellous bone graft. MATERIALS AND METHODS: In this case series, the medical records and radiographs of all dogs and cats with radius/ulna and tibia/fibula viable oligotrophic and nonviable atrophic non-unions treated with corticocancellous bone graft and circular external skeletal fixation at two referral veterinary hospitals between 2014 and 2021 were retrospectively reviewed. The long-term follow-up was 1 year or greater. RESULTS: Thirteen dogs and six cats with 19 non-union fractures met the inclusion criteria for the study. Eighteen non-union fractures (94.7%) healed and one did not. Five patients (26%) had minor perioperative period complications (<3 months). The patient that did not achieve bone union underwent revision surgery with internal fixation (plate and screws) and autologous cancellous bone graft. Fifteen (78.9%) cases returned to full function and three (15.8%) cases returned to acceptable function in the long-term follow-up period. CLINICAL SIGNIFICANCE: The use of circular external skeletal fixation associated with autologous corticocancellous bone graft for the treatment of radius/ulna and tibia/fibula atrophic/oligotrophic non-union fractures in dogs and cats was considered successful in the majority of patients and was free of major or catastrophic complications.

The genetic landscape of South African males: A Y-STR perspective.

The profiles of 2188 SA males obtained with 10 Y-STR highly informative markers were analyzed for their information content for forensic and population studies. The samples comprised a total of 16 populations, represented by Bantu-speaking groups, KhoeSan descendants, out-of-Africa descendants and admixed groups. The country hosts approximately 58 million inhabitants, 80% native and the remaining with ancestry external to Africa and admixed. The forensic parameters indicated high levels of diversity in all populations and lower in the Nguni, who showed elevated number of repeated haplotypes, thus displaying the lowest DC values. Population comparative analysis with MDS showed concordant results with the historical record. Non-hierarchical and hierarchical AMOVA over ethnolinguistic groups and administrative divisions showed significant variation in all cases, with higher differences due to ethnicity than to geopolitical subdivision. The haplotypes were further analyzed by hierarchical kmeans clustering. The identified clusters differed in their relative contribution to the gene pool of the 16 analyzed populations. Geostatistical analysis of the clusters evidenced areas of higher density for some clusters in correspondence with language, while other clusters were more homogeneously distributed. In addition, a few rare microvariants were identified with very restricted geographic occurrence. The results emphasize the forensic value of a highly informative set of markers in a country with high genetic diversity and complex population history.

The prevalence of sleep impairments and predictors of sleep quality among patients with asthma.

BACKGROUND: Sleep is a significant dimension of daily life. However, only a few studies have examined the sleep quality of asthmatics in a real-world clinical settings. OBJECTIVE: This study is aimed to estimate the prevalence of sleep impairments among asthmatic patients and examine the relationship between sleep quality, asthma control, rhinitis symptoms, and sociodemographic characteristics. METHODS: The present study adopted the observational cross-sectional research design that has been designed by the Italian Respiratory Society and used valid assessments to measure the study variables. RESULTS: Data from 1150 asthmatic patients (mean age 51.01 years ± 16.03) were subjected to analysis. 58.3% of the patients had impaired sleep quality (Pittsburgh Sleep Quality Index [PSQI] total scores > 5), and their mean PSQI score was 5.68 (SD = 3.4). A significant correlation emerged between sleep quality and asthma control (p = 0.0001) and a significant albeit weak correlation emerged between PSQI total scores and Total 5 Symptoms Score (r = 0.24, p = 0.0001). Sleep quality was significantly associated health-related quality of life [HRQoL]. (r = 0.50, p < 0.001). After exclusion of patients at risk for Obstructive Sleep Apnea Syndrome (OSAS) and Gastro Esophageal Reflux Disease (GERD), the most important determinants of PSQI score were HRQoL, In the entire sample asthma control is the strongest predictor of both sleep quality and HRQoL. CONCLUSIONS: The results of this real-world study highlight the prevalence, impact and predictors of sleep disturbances in asthmatic patients and suggest the need for physicians to detect poor sleep quality.

Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease.

BACKGROUND: Success in personalized medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay [PEA] to identify diagnostic and prognostic biomarkers in inflammatory bowel disease [IBD]. METHODS: We conducted a prospective case-control study in an inception cohort of 552 patients [328 IBD, 224 non-IBD], profiling proteins recruited across six centres. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross-validation was used to examine the performance of diagnostic and prognostic proteins. RESULTS: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls, including matrix metallopeptidase-12 [MMP-12; Holm-adjusted p = 4.1 × 10-23] and oncostatin-M [OSM; p = 3.7 × 10-16]. Nine of these proteins are associated with cis-germline variation [59 independent single nucleotide polymorphisms]. Fifteen proteins, all members of tumour necrosis factor-independent pathways including interleukin-1 (IL-1) and OSM, predicted escalation, over a median follow-up of 518 [interquartile range 224-756] days. Nested cross-validation of the entire data set allowed characterization of five-protein models [96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7 and IL8], which define a high-risk subgroup in IBD [hazard ratio 3.90, confidence interval: 2.43-6.26], or allowed distinct two- and three-protein models for ulcerative colitis and Crohn's disease respectively. CONCLUSION: We have characterized a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings.

Efficacy and safety of the first-in-class imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial.

OBJECTIVE: CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes. DESIGN: This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain received CR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0-100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes. RESULTS: 213 patients were treated with CR4056 (92 women; 52 men) or placebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P = 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ≥ 27.5 kg/m2, N = 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12-18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache. CONCLUSIONS: Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2015-001136-37.

Allergy in adolescent population (14-18 years) living in Campania region (Southern Italy). A multicenter study.

Summary: Adolescents (Ad) constitute a difficult to manage population among individuals suffering from asthma. The aim of our study was to assess the prevalence, clinical characteristics and age of onset of allergic sensitization and clinical symptoms in a sample of atopic Ad living in the Campania region (Southern Italy). Sixteen Allergy units or Centers belonging to the Italian Association of Hospital and Territorial Allergologists (AAIITO, Campania region) participated in this cross-sectional study. A case report form (CRF) was specifically designed for this study and commercial allergen extracts used for screening SPTs were provided by ALK-Abelló Group (Milan, Italy). A total of 443 patients were examined (females, f 220, 49.6 %; males, m 223, 50.3%). Dust mites represent the most common sensitizing agents in allergic Ad living in Campania region (Dermatoph. pteronyssinus 67.4% and Dermatoph. farinae 66.5%), followed by Parietaria (58.9%), grasses (45.8%), Artemisia vulgaris (16.7%), Olea Europaea (32.2%), dog dander (17.1%), cat dander (20.0%), Alternaria alternata (8.1%), Cupressus sempervirens (4.9%), Betula pendula (4.7%), other allergens (19.4%). An interesting comparison has been made between clinical data of our Ad with data of elderly patients (E). The role of allergic sensitization is significantly higher in Ad compared to E. Dermatophagoides pteronyssinus is the first sensitizing allergen in Ad and the last in E. Parietaria constitutes the first sensitizing pollen both in Ad and E, the percentage of sensitization is higher in Ad. Another important difference is the higher prevalence of As, as only symptom, in E compared to Ad (19.7% versus 7.6%). In conclusion, our findings confirm the high prevalence and clinical significance of airway allergic sensitization in the adolescents living in Campania region.

A GWAS meta-analysis from 5 population-based cohorts implicates ion channel genes in the pathogenesis of irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) shows genetic predisposition, however, large-scale, powered gene mapping studies are lacking. We sought to exploit existing genetic (genotype) and epidemiological (questionnaire) data from a series of population-based cohorts for IBS genome-wide association studies (GWAS) and their meta-analysis. METHODS: Based on questionnaire data compatible with Rome III Criteria, we identified a total of 1335 IBS cases and 9768 asymptomatic individuals from 5 independent European genotyped cohorts. Individual GWAS were carried out with sex-adjusted logistic regression under an additive model, followed by meta-analysis using the inverse variance method. Functional annotation of significant results was obtained via a computational pipeline exploiting ontology and interaction networks, and tissue-specific and gene set enrichment analyses. KEY RESULTS: Suggestive GWAS signals (P ≤ 5.0 × 10-6 ) were detected for 7 genomic regions, harboring 64 gene candidates to affect IBS risk via functional or expression changes. Functional annotation of this gene set convincingly (best FDR-corrected P = 3.1 × 10-10 ) highlighted regulation of ion channel activity as the most plausible pathway affecting IBS risk. CONCLUSION & INFERENCES: Our results confirm the feasibility of population-based studies for gene-discovery efforts in IBS, identify risk genes and loci to be prioritized in independent follow-ups, and pinpoint ion channels as important players and potential therapeutic targets warranting further investigation.

Allergic sensitization to common pets (cats/dogs) according to different possible modalities of exposure: an Italian Multicenter Study.

BACKGROUND: The query "are there animals at home?" is usually administered for collecting information on anamnesis. This modality to consider exposure to pet allergens constitutes a potential bias in epidemiological studies and in clinical practice. The aim of our study was to evaluate/quantify different modalities of exposure to cat/dog in inducing allergic sensitization. METHODS: Thirty Italian Allergy units participated in this study. Each centre was required to collect the data of at least 20 consecutive outpatients sensitized to cat/dog allergens. A standardized form reported all demographic data and a particular attention was paid in relieving possible modalities of exposure to cat/dog. RESULTS: A total 723 patients sensitized to cat/dog were recorded, 359 (49.65%) reported direct pet contact, 213 patients (29.46%) were pet owners, and 146 subjects (20.19%) were exposed to pets in other settings. Other patients were sensitized by previous pet ownership (150-20.75%) or indirect contact (103-14.25%), in 111 subjects (15.35%) any contact was reported. CONCLUSIONS: Only 213 patients (29.46%) would be classified as "exposed to animals" and 510 (70.54%) as "not exposed" according to usual query. Our classification has shown that many "not-exposed" subjects (399-55.19%) were "really exposed". The magnitude of exposure to pet allergens at home is not related exclusively to pet ownership. These considerations should be taken into account during the planning of epidemiological studies and in clinical practice for the management of pet allergic individuals.

News on Climate Change, Air Pollution, and Allergic Triggers of Asthma.

The rising frequency of obstructive respiratory diseases during recent years, in particular allergic asthma, can be partially explained by changes in the environment, with the increasing presence in the atmosphere of chemical triggers (particulate matter and gaseous components such as nitrogen dioxide and ozone) and biologic triggers (aeroallergens). In allergic individuals, aeroallergens stimulate airway sensitization and thus induce symptoms of bronchial asthma. Over the last 50 years, the earth's temperature has risen markedly, likely because of growing concentrations of anthropogenic greenhouse gas. Major atmospheric and climatic changes, including global warming induced by human activity, have a considerable impact on the biosphere and on the human environment. Urbanization and high levels of vehicle emissions induce symptoms of bronchial obstruction (in particular bronchial asthma), more so in people living in urban areas compared than in those who live in rural areas. Measures need to be taken to mitigate the future impact of climate change and global warming. However, while global emissions continue to rise, we must learn to adapt to climate variability.

A GHEP-ISFG collaborative study on the genetic variation of 38 autosomal indels for human identification in different continental populations.

A collaborative effort was carried out by the Spanish and Portuguese Speaking Working Group of the International Society for Forensic Genetics (GHEP-ISFG) to promote knowledge exchange between associate laboratories interested in the implementation of indel-based methodologies and build allele frequency databases of 38 indels for forensic applications. These databases include populations from different countries that are relevant for identification and kinship investigations undertaken by the participating laboratories. Before compiling population data, participants were asked to type the 38 indels in blind samples from annual GHEP-ISFG proficiency tests, using an amplification protocol previously described. Only laboratories that reported correct results contributed with population data to this study. A total of 5839 samples were genotyped from 45 different populations from Africa, America, East Asia, Europe and Middle East. Population differentiation analysis showed significant differences between most populations studied from Africa and America, as well as between two Asian populations from China and East Timor. Low FST values were detected among most European populations. Overall diversities and parameters of forensic efficiency were high in populations from all continents.

News on climate change, air pollution, and allergic triggers of asthma

The rising frequency of obstructive respiratory diseases during recent years, in particular allergic asthma, can be partially explained by changes in the environment, with the increasing presence in the atmosphere of chemical triggers (particulate matter and gaseous components such as nitrogen dioxide and ozone) and biologic triggers (aeroallergens). In allergic individuals, aeroallergens stimulate airway sensitization and thus induce symptoms of bronchial asthma. Over the last 50 years, the earth’s temperature has risen markedly, likely because of growing concentrations of anthropogenic greenhouse gas. Major atmospheric and climatic changes, including global warming induced by human activity, have a considerable impact on the biosphere and on the human environment. Urbanization and high levels of vehicle emissions induce symptoms of bronchial obstruction (in particular bronchial asthma), more so in people living in urban areas compared than in those who live in rural areas. Measures need to be taken to mitigate the future impact of climate change and global warming. However, while global emissions continue to rise, we must learn to adapt to climate variability

La creciente frecuencia de enfermedades respiratorias obstructivas, en particular del asma alérgica, observada en los últimos años, puede explicarse parcialmente por diversos cambios ocurridos en el medio ambiente, con presencia creciente en la atmósfera de sustancias químicas (material particulado y componentes gaseosos como dióxido de nitrógeno y ozono) y por factores desencadenantes biológicos (aeroalérgenos). Los aeroalérgenos son capaces de estimular, en sujetos alérgicos, la reactividad de las vías respiratorias, induciendo síntomas de asma bronquial. En los últimos 50 años, la temperatura global de la tierra ha aumentado notablemente debido a la creciente emisión de concentraciones de gases de efecto invernadero generados por la actividad humana. Los principales cambios que afectan a la atmósfera y al clima, incluido el calentamiento global, tienen un gran impacto en la biosfera y en nuestro entorno. El incremento de las áreas residenciales y los altos niveles de emisiones vehiculares inducen síntomas de enfermedades que cursan con obstrucción bronquial (en particular asma bronquial), con mayor prevalencia en personas que viven en áreas urbanas en comparación con aquellos que viven en áreas rurales. Se deben aplicar medidas que mitiguen estos factores para reducir los impactos futuros del cambio climático y el calentamiento global en nuestro planeta. Mientras que las emisiones globales continúen aumentando, deberemos adaptarnos a los impactos de la variabilidad climática futura

Three-dimensional patellar tendon fibre kinematics in navigated TKA with and without patellar resurfacing.

PURPOSE: Physiological elongation and orientation of patellar tendon fibres are among the scopes of total knee arthroplasty, but little is known in the three dimensions. The study aims to assess in vitro these variations at the intact and replaced knee, with and without patellar resurfacing. It was hypothesised that fibre patterns differ before and after prosthesis implantation, and between specific prosthesis designs. It was also expected that patellar resurfacing would affect relevant results. METHODS: Measurements from 16 intact cadaver knees free from anatomical defects are here reported using a surgical navigation system. Data were collected at the intact joint and after implantation with cruciate-retaining or posterior-stabilised prosthesis designs, with and without patellar resurfacing. Relevant anatomical landmarks and patellar tendon attachments were digitised. Anatomical reference frames in the femur, tibia and patella were defined to measure component implantation parameters. Representative tendon fibres were defined as the straight line segments joining the two extremities. Changes in length and orientation of these fibres were calculated and reported versus flexion at the intact knee and after prosthesis implantation, both with and without patellar resurfacing. RESULTS: A good intra- and inter-specimen repeatability was found at the intact and replaced knees. In both prosthesis designs, the patterns of fibre lengthening were similar to those in the intact knee, though significant differences were observed before and after patellar resurfacing. Corresponding fibre orientations in the frontal and sagittal planes showed significantly smaller ranges than those in the corresponding intact joints. More natural patterns were observed in the knees implanted with the posterior-stabilised design. Significant correlations were identified between patellar component implantation parameters and both patellar tendon fibre elongation and orientation. CONCLUSIONS: Differences, however small, in patellar tendon fibre elongation and orientation were observed after total knee arthroplasty. The posterior-stabilised design provided better results, whereas patellar resurfacing affected significantly normal patellar function. In the clinical practice, the present findings can contribute to the understanding of current prosthesis designs and patellar resurfacing, recommending also enhanced care during this surgery.

A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population.

BACKGROUND: Gastroesophageal reflux disease (GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism (SNP) genotypes. METHODS: We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis (GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map (cMap). KEY RESULTS: We identified 30 GERD suggestive risk loci (P≤5×10-5 ), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds. CONCLUSIONS: We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities.

Near fatal asthma: treatment and prevention.

Near-fatal asthma (NFA) is described as acute asthma associated with a respiratory arrest or arterial carbon dioxide tension greater than 50 mmHg, with or without altered consciousness, requiring mechanical ventilation. Risk factors for near fatal asthma have not been fully elucidated. In 80-85% of all fatal events, a phenotype, characterized by eosinophilic inflammation associated with gradual deterioration occurring in patients with severe and poorly controlled asthma, has been identified. Regarding to the management, acute severe asthma remains a significant clinical problem, which needs to be identified to facilitate early and appropriate therapeutic interventions. The assessment relies on clinical signs, but additional information might be obtained from chest radiography or blood gas analysis. No investigation should delay the initiation of appropriate therapy. The goals of therapy are the maintenance of oxygenation, relief of airflow obstruction, reduction of airways edema and mucus plugging (with Increased use of medications such as beta-agonists via metered dose inhalers and nebulizers, oral and/or intravenous (other than by inhalation) corticosteroids and oral or intravenous theophylline) whereas supporting ventilation as clinically indicated. Of course, the emergency physician needs to consider the wide range of potential complications, as attention to these problems when managing severe acute asthma might significantly improve outcome. An understanding of the available agents and potential pitfalls in the management of NFA is mandatory for the emergency physician.