Using implementation science to evaluate a population-wide genomic screening program: Findings from the first 20,000 In Our DNA SC participants.

We use the implementation science framework RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) to describe outcomes of In Our DNA SC, a population-wide genomic screening (PWGS) program. In Our DNA SC involves participation through clinical appointments, community events, or at home collection. Participants provide a saliva sample that is sequenced by Helix, and those with a pathogenic variant or likely pathogenic variant for CDC Tier 1 conditions are offered free genetic counseling. We assessed key outcomes among the first cohort of individuals recruited. Over 14 months, 20,478 participants enrolled, and 14,053 samples were collected. The majority selected at-home sample collection followed by clinical sample collection and collection at community events. Participants were predominately female, White (self-identified), non-Hispanic, and between the ages of 40-49. Participants enrolled through community events were the most racially diverse and the youngest. Half of those enrolled completed the program. We identified 137 individuals with pathogenic or likely pathogenic variants for CDC Tier 1 conditions. The majority (77.4%) agreed to genetic counseling, and of those that agreed, 80.2% completed counseling. Twelve clinics participated, and we conducted 108 collection events. Participants enrolled at home were most likely to return their sample for sequencing. Through this evaluation, we identified facilitators and barriers to implementation of our state-wide PWGS program. Standardized reporting using implementation science frameworks can help generalize strategies and improve the impact of PWGS.

A Unique Role for Protocadherin γC3 in Promoting Dendrite Arborization through an Axin1-Dependent Mechanism.

The establishment of a functional cerebral cortex depends on the proper execution of multiple developmental steps, culminating in dendritic and axonal outgrowth and the formation and maturation of synaptic connections. Dysregulation of these processes can result in improper neuronal connectivity, including that associated with various neurodevelopmental disorders. The γ-Protocadherins (γ-Pcdhs), a family of 22 distinct cell adhesion molecules that share a C-terminal cytoplasmic domain, are involved in multiple aspects of neurodevelopment including neuronal survival, dendrite arborization, and synapse development. The extent to which individual γ-Pcdh family members play unique versus common roles remains unclear. We demonstrated previously that the γ-Pcdh-C3 isoform (γC3), via its unique "variable" cytoplasmic domain (VCD), interacts in cultured cells with Axin1, a Wnt-pathway scaffold protein that regulates the differentiation and morphology of neurons. Here, we confirm that γC3 and Axin1 interact in the cortex in vivo and show that both male and female mice specifically lacking γC3 exhibit disrupted Axin1 localization to synaptic fractions, without obvious changes in dendritic spine density or morphology. However, both male and female γC3 knock-out mice exhibit severely decreased dendritic complexity of cortical pyramidal neurons that is not observed in mouse lines lacking several other γ-Pcdh isoforms. Combining knock-out with rescue constructs in cultured cortical neurons pooled from both male and female mice, we show that γC3 promotes dendritic arborization through an Axin1-dependent mechanism mediated through its VCD. Together, these data identify a novel mechanism through which γC3 uniquely regulates the formation of cortical circuitry.SIGNIFICANCE STATEMENT The complexity of a neuron's dendritic arbor is critical for its function. We showed previously that the γ-Protocadherin (γ-Pcdh) family of 22 cell adhesion molecules promotes arborization during development; it remained unclear whether individual family members played unique roles. Here, we show that one γ-Pcdh isoform, γC3, interacts in the brain with Axin1, a scaffolding protein known to influence dendrite development. A CRISPR/Cas9-generated mutant mouse line lacking γC3 (but not lines lacking other γ-Pcdhs) exhibits severely reduced dendritic complexity of cerebral cortex neurons. Using cultured γC3 knock-out neurons and a variety of rescue constructs, we confirm that the γC3 cytoplasmic domain promotes arborization through an Axin1-dependent mechanism. Thus, γ-Pcdh isoforms are not interchangeable, but rather can play unique neurodevelopmental roles.

Epicardial deletion of Sox9 leads to myxomatous valve degeneration and identifies Cd109 as a novel gene associated with valve development.

Epicardial-derived cells (EPDCs) are involved in the regulation of myocardial growth and coronary vascularization and are critically important for proper development of the atrioventricular (AV) valves. SOX9 is a transcription factor expressed in a variety of epithelial and mesenchymal cells in the developing heart, including EPDCs. To determine the role of SOX9 in epicardial development, an epicardial-specific Sox9 knockout mouse model was generated. Deleting Sox9 from the epicardial cell lineage impairs the ability of EPDCs to invade both the ventricular myocardium and the developing AV valves. After birth, the mitral valves of these mice become myxomatous with associated abnormalities in extracellular matrix organization. This phenotype is reminiscent of that seen in humans with myxomatous mitral valve disease (MVD). An RNA-seq analysis was conducted in an effort to identify genes associated with this myxomatous degeneration. From this experiment, Cd109 was identified as a gene associated with myxomatous valve pathogenesis in this model. Cd109 has never been described in the context of heart development or valve disease. This study highlights the importance of SOX9 in the regulation of epicardial cell invasion-emphasizing the importance of EPDCs in regulating AV valve development and homeostasis-and reports a novel expression profile of Cd109, a gene with previously unknown relevance in heart development.

GPA-Tree: statistical approach for functional-annotation-tree-guided prioritization of GWAS results.

MOTIVATION: In spite of great success of genome-wide association studies (GWAS), multiple challenges still remain. First, complex traits are often associated with many single nucleotide polymorphisms (SNPs), each with small or moderate effect sizes. Second, our understanding of the functional mechanisms through which genetic variants are associated with complex traits is still limited. To address these challenges, we propose GPA-Tree and it simultaneously implements association mapping and identifies key combinations of functional annotations related to risk-associated SNPs by combining a decision tree algorithm with a hierarchical modeling framework. RESULTS: First, we implemented simulation studies to evaluate the proposed GPA-Tree method and compared its performance with existing statistical approaches. The results indicate that GPA-Tree outperforms existing statistical approaches in detecting risk-associated SNPs and identifying the true combinations of functional annotations with high accuracy. Second, we applied GPA-Tree to a systemic lupus erythematosus (SLE) GWAS and functional annotation data including GenoSkyline and GenoSkylinePlus. The results from GPA-Tree highlight the dysregulation of blood immune cells, including but not limited to primary B, memory helper T, regulatory T, neutrophils and CD8+ memory T cells in SLE. These results demonstrate that GPA-Tree can be a powerful tool that improves association mapping while facilitating understanding of the underlying genetic architecture of complex traits and potential mechanisms linking risk-associated SNPs with complex traits. AVAILABILITY AND IMPLEMENTATION: The GPATree software is available at https://dongjunchung.github.io/GPATree/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Extending an Antiracism Lens to the Implementation of Precision Public Health Interventions.

Precision public health holds promise to improve disease prevention and health promotion strategies, allowing the right intervention to be delivered to the right population at the right time. Growing concerns underscore the potential for precision-based approaches to exacerbate health disparities by relying on biased data inputs and recapitulating existing access inequities. To achieve its full potential, precision public health must focus on addressing social and structural drivers of health and prominently incorporate equity-related concerns, particularly with respect to race and ethnicity. In this article, we discuss how an antiracism lens could be applied to reduce health disparities and health inequities through equity-informed research, implementation, and evaluation of precision public health interventions. (Am J Public Health. 2023;113(11):1210-1218. https://doi.org/10.2105/AJPH.2023.307386).

HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry.

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/ß allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is a complex disease of unknown aetiology in which inflammation and fibrosis lead to multiple organ damage. There is currently no effective therapy that can halt the progression of fibrosis or reverse it, thus studies that provide novel insights into disease pathogenesis and identify novel potential therapeutic targets are critically needed. METHODS: We used global gene expression and genome-wide DNA methylation analyses of dermal fibroblasts (dFBs) from a unique cohort of twins discordant for SSc to identify molecular features of this pathology. We validated the findings using in vitro, ex vivo and in vivo models. RESULTS: Our results revealed distinct differentially expressed and methylated genes, including several transcription factors involved in stem cell differentiation and developmental programmes (KLF4, TBX5, TFAP2A and homeobox genes) and the microRNAs miR-10a and miR-10b which target several of these deregulated genes. We show that KLF4 expression is reduced in SSc dFBs and its expression is repressed by TBX5 and TFAP2A. We also show that KLF4 is antifibrotic, and its conditional knockout in fibroblasts promotes a fibrotic phenotype. CONCLUSIONS: Our data support a role for epigenetic dysregulation in mediating SSc susceptibility in dFBs, illustrating the intricate interplay between CpG methylation, miRNAs and transcription factors in SSc pathogenesis, and highlighting the potential for future use of epigenetic modifiers as therapies.

Diclidophora luscae (Monogenea: Diclidophoridae) in pouting, Trisopterus luscus (Linnaeus, 1758) from the northeast Atlantic; epidemiology, morphology, molecular and phylogenetic analysis.

Diclidophora (Monogenea) species are gill parasites with a stenoxenic specificity occurring only in Gadiformes. Epidemiological, morphological, molecular and phylogenetic studies were performed on 594 Diclidophora specimens collected from 213 Trisopterus luscus captured in the northeast Atlantic off the Portuguese coast during 2012, 2013 and 2020. Prevalence, parasite abundance and infection intensity were determined. Positive correlation between fish weight and length and infection intensity was observed. The effects of preservation on the parasite morphological features were studied, highlighting that specimen's identification should be reinforced by molecular studies. A sequence of D. luscae capelanii from T. capelanus captured in the Mediterranean Sea included in the 28S rDNA molecular analysis was nested within a robust D. luscae clade. Data analysis suggested that this species is in fact D. luscae, which is compatible with T. luscus and T. capelanus. The identity of fish hosts was confirmed by barcoding. For the first time, data on the infection parameters is shown, highlighting the importance of including this parasite in the monitoring plans for a holistic approach with possible effects for the management of pouting resources aiming of attaining sustainable development and biodiversity conservation measures, according to the 14th objective of the 2030 agenda.

Integrating genetic and social factors to understand health disparities in lupus.

PURPOSE OF REVIEW: Both social and genetic factors are associated with health outcomes in systemic lupus erythematosus (SLE), thus playing a role in its health disparities. Despite the growing list of social and genetic factors associated with SLE outcomes, studies integrating sociocultural and individual determinants of health to understand health disparities in SLE are lacking. We review the contributions of different social and genetic factors to the disparities in SLE, and propose a socioecological model to integrate and examine the complex interactions between individual and social factors in SLE outcomes. RECENT FINDINGS: Multiple studies collecting comprehensive social data and biospecimens from diverse populations are underway, which will contribute to the elucidation of the interplay and underlying mechanisms by which positive and negative social determinants of health influence epigenomic variation, and how the resulting biological changes may contribute to the lupus health disparities. SUMMARY: There is growing awareness of the need to integrate genomic and health disparities research to understand how social exposures affect disease outcomes. Understanding the contributions of these factors to the SLE health disparity will inform the development of interventions to eliminate risk exposures and close the health disparity gap.

Genetic landscape of Gullah African Americans.

OBJECTIVES: Gullah African Americans are descendants of formerly enslaved Africans living in the Sea Islands along the coast of the southeastern U.S., from North Carolina to Florida. Their relatively high numbers and geographic isolation were conducive to the development and preservation of a unique culture that retains deep African features. Although historical evidence supports a West-Central African ancestry for the Gullah, linguistic and cultural evidence of a connection to Sierra Leone has led to the suggestion of this country/region as their ancestral home. This study sought to elucidate the genetic structure and ancestry of the Gullah. MATERIALS AND METHODS: We leveraged whole-genome genotype data from Gullah, African Americans from Jackson, Mississippi, African populations from Sierra Leone, and population reference panels from Africa and Europe to infer population structure, ancestry proportions, and global estimates of admixture. RESULTS: Relative to non-Gullah African Americans from the Southeast US, the Gullah exhibited higher mean African ancestry, lower European admixture, a similarly small Native American contribution, and increased male-biased European admixture. A slightly tighter bottleneck in the Gullah 13 generations ago suggests a largely shared demographic history with non-Gullah African Americans. Despite a slightly higher relatedness to populations from Sierra Leone, our data demonstrate that the Gullah are genetically related to many West African populations. DISCUSSION: This study confirms that subtle differences in African American population structure exist at finer regional levels. Such observations can help to inform medical genetics research in African Americans, and guide the interpretation of genetic data used by African Americans seeking to explore ancestral identities.

Age-Related Changes in Lipidome of Rat Frontal Cortex and Cerebellum Are Partially Reversed by Methionine Restriction Applied in Old Age.

Lipids are closely associated with brain structure and function. However, the potential changes in the lipidome induced by aging remain to be elucidated. In this study, we used chromatographic techniques and a mass spectrometry-based approach to evaluate age-associated changes in the lipidome of the frontal cortex and cerebellum obtained from adult male Wistar rats (8 months), aged male Wistar rats (26 months), and aged male Wistar rats submitted to a methionine restriction diet (MetR)-as an anti-aging intervention-for 8 weeks. The outcomes revealed that only small changes (about 10%) were observed in the lipidome profile in the cerebellum and frontal cortex during aging, and these changes differed, in some cases, between regions. Furthermore, a MetR diet partially reversed the effects of the aging process. Remarkably, the most affected lipid classes were ether-triacylglycerols, diacylglycerols, phosphatidylethanolamine N-methylated, plasmalogens, ceramides, and cholesterol esters. When the fatty acid profile was analyzed, we observed that the frontal cortex is highly preserved during aging and maintained under MetR, whereas in the cerebellum minor changes (increased monounsaturated and decreased polyunsaturated contents) were observed and not reversed by MetR. We conclude that the rat cerebellum and frontal cortex have efficient mechanisms to preserve the lipid profile of their cell membranes throughout their adult lifespan in order to maintain brain structure and function. A part of the small changes that take place during aging can be reversed with a MetR diet applied in old age.

The Cdc14 Phosphatase Controls Resolution of Recombination Intermediates and Crossover Formation during Meiosis.

Meiotic defects derived from incorrect DNA repair during gametogenesis can lead to mutations, aneuploidies and infertility. The coordinated resolution of meiotic recombination intermediates is required for crossover formation, ultimately necessary for the accurate completion of both rounds of chromosome segregation. Numerous master kinases orchestrate the correct assembly and activity of the repair machinery. Although much less is known, the reversal of phosphorylation events in meiosis must also be key to coordinate the timing and functionality of repair enzymes. Cdc14 is a crucial phosphatase required for the dephosphorylation of multiple CDK1 targets in many eukaryotes. Mutations that inactivate this phosphatase lead to meiotic failure, but until now it was unknown if Cdc14 plays a direct role in meiotic recombination. Here, we show that the elimination of Cdc14 leads to severe defects in the processing and resolution of recombination intermediates, causing a drastic depletion in crossovers when other repair pathways are compromised. We also show that Cdc14 is required for the correct activity and localization of the Holliday Junction resolvase Yen1/GEN1. We reveal that Cdc14 regulates Yen1 activity from meiosis I onwards, and this function is essential for crossover resolution in the absence of other repair pathways. We also demonstrate that Cdc14 and Yen1 are required to safeguard sister chromatid segregation during the second meiotic division, a late action that is independent of the earlier role in crossover formation. Thus, this work uncovers previously undescribed functions of the evolutionary conserved Cdc14 phosphatase in the regulation of meiotic recombination.

Parasites in fishery products - Laboratorial and educational strategies to control.

The presence of parasites, including Anisakis spp. larvae in fishery products jeopardizes their safety and quality, which is a matter of concern and a challenge for official authorities, as well as for food businesses operators, and a potential health risk to consumers. In the last ten years, a total of 2367 samples from different seafood products, whole fish (n = 1022), fish steaks (n = 417), fish fillets (n = 46), roes (n = 11), canned fish fillets (n = 35), fish fingers (n = 705), and ready-made Japanese dishes (n = 131) were analysed at the Laboratory of Pathology of Aquatic Animals of IPMA. From the fishery products analysed, a total of 4643 visible Anisakis larvae were collected from eighteen different species of whole fish and there were two cases with numerous larvae, although live larvae were only found in fresh fish. Anisakis larvae (n = 523) were collected from fish steaks, (n = 20) from frozen fish fillets, (n = 7) from five different brands of fish fingers, (n = 2) from two cans of cod fillets and numerous viable larvae were collected from the serosae of European hake fresh roes. The great majority of the larvae were identified as L3 Anisakis larvae. Plerocercoids of Gymnorhynchus gigas and Hepatoxylon trichiuri and the myxosporean, Kudoa spp. were also observed and led to the withdrawal of the fish from the supply chain. No Anisakis larvae were collected from the farmed fish as well as from the ready-made Japanese dishes. However, Kudoa hexapunctata spores were observed in the tuna muscle from one sashimi meal. The data shows that fresh fish with live Anisakis larvae have been marketed. Educational strategies concerning parasites were implemented with workshops, "Parasites in Fishery Products" to train and instruct professionals within the fish supply chain and training activities for target groups, including children, were promoted, to raise awareness of this issue. One of the most relevant outcomes obtained was the improvement of implementation of parasite identification techniques in the industry, including private labs, and consequently: (1) decrease in the parasitological analysis number of common parasites and (2) reduction in the analysis of anatomical structures confused with parasites requested to IPMA's Laboratory of Pathology. In addition, the practice of freezing trash fish used to feed farmed fish, and the placement of nets at the water entry points of the earth ponds, in order to avoid wild fish introduction, were simple and important measures that were implemented to prevent Anisakis and other parasites entering fish farms. The two complementary parts of this work, laboratorial activities used to support the fish supply chain, and the educational strategies concerning parasites, have made an essential contribution towards the availability of data for assessing and minimizing the level of risk associated with fish consumption, and have particularly increased and improved awareness, regarding foodborne parasites.

Calpains mediate isoproterenol-induced hypertrophy through modulation of GRK2.

Inhibition of the Ca2+-dependent proteases calpains attenuates post-infarction remodeling and heart failure. Recent data suggest that calpain activity is elevated in non-ischemic cardiomyopathies and that upregulation of the key cardiac G-protein-coupled receptor kinase 2 (GRK2) signaling hub promotes cardiac hypertrophy. However, the functional interactions between calpains and GRK2 in this context have not been explored. We hypothesized that calpain modulates GRK2 levels in myocardial hypertrophy of non-ischemic cause, and analyzed the mechanisms involved and the potential therapeutic benefit of inhibiting calpain activity in this situation. The oral calpain inhibitor SNJ-1945 was administered daily to male Sprague-Dawley rats or wild-type and hemizygous GRK2 mice treated with 5 mg/Kg/day isoproterenol intraperitoneally for 1 week. In isoproterenol-treated animals, calpains 1 and 2 were overexpressed in myocardium and correlated with increased calpain activity and ventricular hypertrophy. Oral co-administration of SNJ-1945 attenuated calpain activation and reduced heart hypertrophy as assessed using morphological and biochemical markers. Calpain activation induced by isoproterenol increased GRK2 protein levels, while genetic downregulation of GRK2 expression prevented isoproterenol-mediated hypertrophy independently of calpain inhibition. GRK2 upregulation was associated to calpain-dependent degradation of the GRK2 ubiquitin ligase MDM2 and to enhanced NF-κB-dependent GRK2 gene expression in correlation with calpain-mediated IĸB proteolysis. These results demonstrate that calpain mediates isoproterenol-induced myocardial hypertrophy by modulating GRK2 protein content through mechanisms involving the control of GRK2 stability and expression. Sustained calpain inhibition attenuates isoproterenol-induced myocardial hypertrophy and could be an effective therapeutic strategy to limit ventricular remodeling of non-ischemic origin.

Auditory Skills following Cochlear Implantation in Children with the Charge Syndrome.

OBJECTIVES: To assess the auditory outcomes and skills of pediatric cochlear implant (CI) users with the CHARGE syndrome. To determine the influence of inner ear malformations on the surgical procedure and speech understanding outcomes in this population. STUDY DESIGN: Observational, retrospective study. MATERIALS AND METHODS: Imaging, auditory testing, intraoperative findings, complications, and postoperative auditory skills and outcomes of pediatric CI users with CHARGE syndrome were recorded. RESULTS: 6 children (8 ears) were included, 5 of whom had prelingual deafness. Their mean age at implantation was 37 months. Six of the 8 ears presented cochlear malformation; the most frequent was hypoplasia type III. Intraoperatively, the transmastoid facial recess approach was used in 5 ears, and abnormalities of facial nerve anatomy were found in 5 ears. All electrode insertions were complete. All children were, to a varying degree, able to detect and identify sound. Verbalization skills were developed by 2 children, 1 of whom used oral language as his primary mode of communication. CONCLUSIONS: Cochlear implantation performed by an experienced surgeon in patients with the CHARGE syndrome is a safe procedure with adequate treatment planning. All children had improved auditory skills although the improvement was variable.

Aggressive curettage of a chondroblastoma-like osteosarcoma of the proximal end of the tibia. A case report with seven-year follow-up.

A chondroblastoma-like osteosarcoma (CLO) in the proximal epiphysis and metaphysis of the tibia in a 30-year-old male is presented. With a wrong diagnosis of chondroblastoma, an aggressive curettage was performed. Later, the patient refused en-bloc resection. Seven years after surgery, there has been no local recurrence, and the patient is living an ordinary and active life. CLO is a very uncommon and controversial histologic subtype of osteosarcoma that can be misdiagnosed as chondroblastoma and therefore incorrectly treated. However, aggressive curettage with its functional advantages could be a reasonable option in selected cases.

Nonsurgical Treatment as Alternative to Surgical Treatment in Enchondromas of the Distal Phalanx. Analysis of a Series of 11 Cases.

PURPOSE: To describe the results of nonsurgical and surgical treatment of enchondromas of the distal phalanx of the hand. METHODS: Eleven enchondromas of the distal phalanx were retrospectively reviewed. Five patients underwent surgery (curettage and autogenous cancellous bone graft from the iliac crest) and 6 patients were treated nonsurgically. Clinical records and radiographs were reviewed for each patient. We recorded complications and cosmetic and functional results. Radiographic healing in surgical patients was scored according to the classification of Tordai and to the criteria of Wilhelm and Feldmeier. The average follow-up of the nonsurgical and surgical cases was 45 and 62 months, respectively. RESULTS: Eight patients were women. Average age at diagnosis was 40 years. Nine patients presented with a pathological fracture. The demographic characteristics of the surgical group and nonsurgical group were similar. Among the cases treated nonsurgically (6), 1 had 2 pathological fractures after diagnosis. At final follow-up, the average pain on a visual analog scale was 2.8. With the exception of 1 patient, the range of motion of the fingers was normal or minimally reduced. Among the surgical cases (5), there were no complications in the bone graft donor site, 2 patients developed infections in the operated finger, and no postoperative pathological fractures were found. At final follow-up, the average pain was 3.2. Joint mobility was normal in 3 patients. Postoperative radiological examination revealed complete bone healing in all patients (grade I in the Tordai classification). No local recurrence was seen. According to the criteria of Wilhelm and Feldmeier, there were 3 excellent, 1 good, and 1 satisfactory results in the surgical group, and 2 excellent, 3 good, and 1 satisfactory results in the nonsurgical group. CONCLUSIONS: Surgical and nonsurgical treatment in distal phalanx enchondromas appear to be associated with satisfactory results, although each has their own advantages and disadvantages. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Tolerance to multiple metal stressors in emerging non-typhoidal MDR Salmonella serotypes: a relevant role for copper in anaerobic conditions.

OBJECTIVES: Factors driving the expansion of particular MDR Salmonella serotypes/clones are not completely understood. We assessed if emergent MDR Salmonella serotypes/clones were more enriched in metal tolerance genes (e.g. to Cu/Ag) than other less frequent ones, as an additional feature to survive in environments contaminated with metals. METHODS: Metal (Cu pco/Ag,Cu sil/Hg mer/As ars/Te ter) tolerance genes screening (PCR/sequencing), MICs of CuSO4/AgNO3 (aerobiosis/anaerobiosis), genetic element characterization (S1/I-CeuI PFGE) and conjugation assays were performed in a well-characterized Salmonella collection (n = 275 isolates; 2000-14; 49 serotypes/clones). RESULTS: The sil ±â€Špco genes were detected in 37% of isolates from diverse serotypes, mainly in emergent Rissen/ST469 and Typhimurium/ST34 European clone (100%), which are mostly associated with pig settings where Cu is highly used. These genes were frequently co-located with merA ±â€ŠterF and/or antibiotic resistance genes in plasmids (100-270 kb; IncHI2/IncHI1/IncN/IncFIIA; mostly transferable by conjugation) or in the chromosome. Most sil ±â€Špco(+) isolates (77%) were MDR contrasting with sil ±â€Špco(-) ones (48%). The sil ±â€Špco(+) isolates presented significantly higher MICCuSO4 under anaerobiosis (MIC50/MIC90 = 28/32 mM) and MICAgNO3 after previous Ag contact (MIC50/MIC90 > 3 mM) than sil(-) ones (MIC50/MIC90 = 2/8 mM to CuSO4; MIC50/MIC90 = 0.125/0.16 mM to AgNO3). Use of these modified methodological approaches allowed the establishment of CuSO4/AgNO3 tolerance cut-offs to differentiate sil(+) and sil(-) isolates, here firstly proposed. CONCLUSIONS: This study demonstrates that acquisition of Cu/Ag tolerance genes (sil/pco genes) might contribute to the emergence of particular clinically relevant MDR Salmonella serotypes/clones by facilitating their survival in diverse metal-contaminated settings, particularly in pig production. Assessment of control measures for the use and/or accumulation of metals in diverse environments are needed to prevent a wider expansion of such strains or the emergence of new ones.

Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study.

Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 × 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62 × 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 × 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10(-8) < p(meta-Euro) < 9.99 × 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.