The influence of socioeconomic deprivation on outcomes in transplant patients infected with SARS-CoV-2 in Wales.

INTRODUCTION: SARS-CoV-2 infection has had a significant impact on vulnerable individuals including transplant patients. Socioeconomic deprivation negatively affects outcomes of many health conditions. The aim of this study was to evaluate the effect of socioeconomic deprivation on the incidence and severity of SARS-CoV-2 infection among Welsh transplant patients. METHODS: This study is a retrospective, cross-sectional study on the transplant population of Wales. The Welsh Index of Multiple Deprivation (WIMD) was used to assess the influence of socioeconomic deprivation on outcomes of Welsh transplant patients who developed SARS-CoV-2 infection. Outcome measures were the incidence of SARS-CoV-2 infection, rates of hospital and ICU admission, development of acute kidney injury (AKI) and mortality. A logistic binomial regression analysis was used to correlate the various risk factors with the incidence of SARS-CoV-2 infection. RESULTS: Two hundred and sixty-six (25%) of regular follow up patients had SARS-CoV-2 infection; of these 55 (20.7%) were admitted, 15 (5.6%) to ICU, 37 (13.9%) developed AKI, and 23 (8.6%) died. In a regression analysis, patients of younger age were associated with more (p = .001) and those with SPK (simultaneous pancreas kidney) transplant less chance of infection (p = .038), whereas social deprivation was not associated with the chance of infection (p = .14). In regression analysis increased social deprivation was associated with higher chance of AKI post SARS-CoV-2 (p = .049). CONCLUSIONS: Socioeconomic deprivation did not affect the rates or severity of SARS-CoV-2 infection apart from the degree of AKI in Welsh Transplant patients. Adherence to the preventive measures for this high-risk population must continue to remain a priority.

Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments. OBJECTIVE: We sought to identify microbiome and metabolome signatures that can distinguish individuals with CGD and CGD-IBD. METHODS: We conducted a cross-sectional observational study of 79 patients with CGD, 8 pathogenic variant carriers, and 19 healthy controls followed at the National Institutes of Health Clinical Center. We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 patients with CGD recruited through the Primary Immune Deficiency Treatment Consortium. RESULTS: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp, Sellimonas spp, and Lachnoclostridium spp in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the 2 cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD. CONCLUSION: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets.

Outcomes of Selective Arthrodesis Based on Joints Affected in 33 Feet With Müller-Weiss Disease.

No consensus exists regarding operative treatment of Müller-Weiss disease (MWD). Its only classification is based solely on Méary's angle and serves neither as guide to management nor prognosis. We report on 33 feet that underwent surgery following failed conservative management. Treatment was directed towards joint(s) involved, as determined by clinical examination, plain radiography and SPECT-CT. Thus, surgery consisted of isolated talonavicular in 6 feet, triple in 8, subtalar and talonavicular in 7, talonaviculocuneiform in 4, talonaviculocuneiform with interpositional tricortical iliac crest graft in 6 and pantalar arthrodesis in 2. PROMIS scores for pain interference and depression decreased significantly (p < .001) with significant accompanying increase in physical function (p = .003). Union occurred in 31 of 33 feet (94%) with complete resolution of pain at an average follow-up of 84 months. Of the 2 nonunions, 1 had fracture through the lateral navicular, and the other marked sclerosis and avascularity of the lateral navicular. We describe our pathways for selecting arthrodesis based on the joints affected. Isolated talonavicular arthrodesis was performed in early stages of MWD, which begins at the talonavicular articulation. When disease extended to both sides of the navicular, we performed talonaviculocuneiform arthrodesis. When considering isolated talonavicular, double medial or triple arthrodesis, there should be adequate cancellous bone stock remaining in the lateral part of the navicular, as determined on medial oblique radiographs and CT scan. In case of inadequate bone stock or fracture through the lateral navicular, talonaviculocuneiform arthrodesis with interpositional iliac crest bone graft is recommended.

Comparative evolutionary analyses of eight whitefly Bemisia tabaci sensu lato genomes: cryptic species, agricultural pests and plant-virus vectors.

BACKGROUND: The group of > 40 cryptic whitefly species called Bemisia tabaci sensu lato are amongst the world's worst agricultural pests and plant-virus vectors. Outbreaks of B. tabaci s.l. and the associated plant-virus diseases continue to contribute to global food insecurity and social instability, particularly in sub-Saharan Africa and Asia. Published B. tabaci s.l. genomes have limited use for studying African cassava B. tabaci SSA1 species, due to the high genetic divergences between them. Genomic annotations presented here were performed using the 'Ensembl gene annotation system', to ensure that comparative analyses and conclusions reflect biological differences, as opposed to arising from different methodologies underpinning transcript model identification. RESULTS: We present here six new B. tabaci s.l. genomes from Africa and Asia, and two re-annotated previously published genomes, to provide evolutionary insights into these globally distributed pests. Genome sizes ranged between 616-658 Mb and exhibited some of the highest coverage of transposable elements reported within Arthropoda. Many fewer total protein coding genes (PCG) were recovered compared to the previously published B. tabaci s.l. genomes and structural annotations generated via the uniform methodology strongly supported a repertoire of between 12.8-13.2 × 103 PCG. An integrative systematics approach incorporating phylogenomic analysis of nuclear and mitochondrial markers supported a monophyletic Aleyrodidae and the basal positioning of B. tabaci Uganda-1 to the sub-Saharan group of species. Reciprocal cross-mating data and the co-cladogenesis pattern of the primary obligate endosymbiont 'Candidatus Portiera aleyrodidarum' from 11 Bemisia genomes further supported the phylogenetic reconstruction to show that African cassava B. tabaci populations consist of just three biological species. We include comparative analyses of gene families related to detoxification, sugar metabolism, vector competency and evaluate the presence and function of horizontally transferred genes, essential for understanding the evolution and unique biology of constituent B. tabaci. s.l species. CONCLUSIONS: These genomic resources have provided new and critical insights into the genetics underlying B. tabaci s.l. biology. They also provide a rich foundation for post-genomic research, including the selection of candidate gene-targets for innovative whitefly and virus-control strategies.

Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Tumor necrosis factor-α inhibitor-induced morphea and psoriasiform dermatitis in a pediatric patient with Crohn's disease.

Tumor necrosis factor-alpha inhibitor therapy for inflammatory bowel disease may be associated with paradoxical cutaneous adverse events, most commonly psoriasiform eruptions. We present the case of a pediatric female patient with Crohn's disease who developed multiple concurrent cutaneous eruptions while on infliximab treatment, including morphea, psoriasiform dermatitis, and genital lichen sclerosus. Although refractory to skin-directed treatments, all three conditions resolved upon discontinuation of infliximab, supporting their development as a paradoxical reaction to infliximab therapy.

Towards understanding Müller-Weiss disease from an analysis of 95 cases.

BACKGROUND: The single existing classification of Müller-Weiss Disease (MWD), based solely upon Méary's angle, serves neither as guide for prognosis nor treatment. This accounts for lack of gold standard in its management. METHODS: Navicular compression, medial extrusion, metatarsal lengths, Kite's, lateral and dorsoplantar talo-first metatarsal angles were measured in 95 feet with MWD. Joints involved, presence and location of navicular fracture were recorded. RESULTS: Group 1 "early-onset" MWD feet (n = 11) had greatest compression and medial extrusion, and lowest Kite's angles. All except 1 were index minus and had lateral navicular fracture. Only 1 had moderate degeneration at the talonavicular joint (TNJ) with none requiring surgery yet. Group 2 "Müller-Weissoid" feet (n = 23) had radiologically normal navicular in their fifties and developed MWD on average 5 years later. They had the lowest compression and extrusion, and highest Kite's angles. None had complete fracture. All had TNJ arthritis, with early changes at lateral naviculocuneiform joint (NCJ) in 43%. Group 3 "late-onset" MWD presented in the sixth decade. Only TNJ was involved in Group 3 A (n = 16). Group 3B (n = 20) affected TNJ more than NCJ and had the greatest number of Maceira stage V disease. Group 3 C "reverse Müller-Weiss disease", which affected NCJ more than TNJ (n = 25), had greatest midfoot abduction and overlength of the second metatarsal. No fracture occurred in group 3 A compared to 65% and 32% in groups 3B and 3 C, respectively. CONCLUSIONS: With need to compare like-for-like pathology, the proposed classification provides a common platform for reporting outcomes of different treatments. We theorize pathogenetic pathways in the various groups.

Utilization of Antitumor Necrosis Factor Biologics in Very Early Onset Inflammatory Bowel Disease: A Multicenter Retrospective Cohort Study From North America.

BACKGROUND: Research on the utilization and effectiveness of antitumor necrosis factor (TNF) biologics in children with very early onset inflammatory bowel disease (VEOIBD) is urgently needed. Here we describe anti-TNF use and durability in a multicenter cohort. METHODS: We performed a retrospective cohort study of patients diagnosed with VEOIBD (<6 years) between 2008 and 2013 at 25 North American centers. We performed chart abstraction at diagnosis and 1, 3, and 5 years after diagnosis. We examined the rate of initiation and durability of infliximab and adalimumab and evaluated associations between treatment durability and the following covariates with multivariate Cox proportional hazard regression: age at diagnosis, sex, disease duration, disease classification, and presence of combined immunomodulatory treatment versus monotherapy. RESULTS: Of 294 children with VEOIBD, 120 initiated treatment with anti-TNF therapy and 101 had follow-up data recorded [50% Crohn disease (CD), 31% ulcerative colitis (UC), and 19% IBD unclassified (IBD-U)]. The cumulative probability of anti-TNF treatment was 15% at 1 year, 30% at 3 years, and 45% at 5 years from diagnosis; 56 (55%) were treated between 0 and 6 years old. Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years. The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children. Children with UC/IBD-U had lower durability than those with CD (hazard ratio [HR] 0.17; 95% confidence interval [CI], 0.06-0.51; P = 0.001). CONCLUSIONS: Utilization and durability of anti-TNF in VEOIBD is relatively high and comparable with older children. Having Crohn disease (compared with UC/IBD-U) is associated with greater durability.

Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation.

BACKGROUND & AIMS: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. METHODS: We obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. RESULTS: We identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. CONCLUSIONS: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.

Verruciform xanthoma in a patient with recessive dystrophic epidermolysis bullosa: Case report and literature review.

Verruciform xanthoma (VX) is a rare finding thought to be caused by epidermal damage from trauma or inflammation and has been reported in a limited number of patients with recessive dystrophic epidermolysis bullosa (RDEB). Herein, we describe a 20-year-old woman with RDEB who developed a large, verrucous, pink plaque on the posterior thigh that was histologically proven to be a VX. We review cases of VX in patients with RDEB and summarize the clinical features, pathophysiology, and management principles.