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Diabetic foot ulcers (DFUs) are the fastest growing chronic complication of diabetes mellitus, with more than 400 million people diagnosed globally, and the condition is responsible for lower extremity amputation in 85% of people affected, leading to high-cost hospital care and increased mortality risk. Neuropathy and peripheral arterial disease trigger deformities or trauma, and aggravating factors such as infection and edema are the etiological factors for the development of DFUs. DFUs require identifying the etiology and assessing the co-morbidities to provide the correct therapeutic approach, essential to reducing lower-extremity amputation risk. This review focuses on the current treatment strategies for DFUs with a special emphasis on tissue engineering techniques and regenerative medicine that collectively target all components of chronic wound pathology.

•Racial disparities affect patients with metastatic spine disease.•African-American patients are more likely to present with cord compression and paralysis.•African-American patients are less likely to receive surgical intervention.•African-American patients are more likely to develop a complication, prolonged length of stay, and non-routine discharge. Race is an important determinant of cancer outcome. The purpose of this study was to identify disparities in clinical presentation, treatment use, and in-hospital outcomes of patients with spinal metastases. The United States National Inpatient Sample database (2004–2014) was queried to identify patients with metastatic disease and cord compression (MSCC) or spinal pathological fracture. Clinical presentation, type of intervention, and in-hospital outcomes were compared between races/ethnicities. Multivariate logistic regression analyses were performed and adjusted for differences in patient age, sex, insurance status, income quartile, hospital teaching status and size, Charlson comorbidity index, smoking status, tumor type, and neurological status. A total of 145,809 patients were identified – 74.8 % Caucasian, 14.1 % African-American, 7.9 % Hispanic, and 3.2 % Asian. Over one-third of patients (38.1 %) presented with MSCC; 35.7 % of Caucasians, 50.3 % of AAs, 41.1 % of Hispanics, and 39.8 % of Asians (p < 0.001). Paralysis affected 8.4 % of all patients; 7.4 % of Caucasians, 12.7 % of AAs, 10.5 % of Hispanics, and 10.0 % of Asians (p < 0.001). For patients with MSCC, multivariate analysis showed that AAs were less likely to undergo surgical intervention (OR 0.71; 95 % CI, 0.62 – 0.82; p < 0.001), significantly more likely to experience a complication (OR 1.25; 95 % CI, 1.12–1.40; p < 0.001), significantly more likely to experience prolonged length of stay (OR 1.22; 95 % CI, 1.08–1.36; p = 0.001), and significantly more likely to experience a non-routine discharge (OR 1.19; 95 % CI, 1.05–1.35; p = 0.007) compared to Caucasians. Minority groups with spinal metastatic disease may be at a disadvantage compared to Caucasians, with significant disparities found in presenting characteristics, type of intervention, and in-hospital outcomes. Continued efforts to overcome these differences are needed.

Background Pathogenic variants in BRCA1 and BRCA2 ( BRCA1/2 ) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked Bio Me Biobank in New York City. Methods Exome sequence data from 30,223 adult Bio Me participants were evaluated for pathogenic variants in BRCA1/2 . Prevalence estimates were made in population groups defined by genetic ancestry and self-report. EHR data were used to evaluate clinical characteristics of variant-positive individuals. Results There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. The highest prevalence was in individuals with Ashkenazi Jewish (AJ; 1 in 49), Filipino and other Southeast Asian (1 in 81), and non-AJ European (1 in 103) ancestry. Among 218 variant-positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants ( BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 8 had a Puerto Rican founder variant ( BRCA2 c.3922G>T), and 24 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar or that had uncertain or conflicting evidence for pathogenicity (uncertain/conflicting). Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion of African genetic ancestry and the likelihood of harboring an uncertain/conflicting variant. Approximately 28% of variant-positive individuals had a personal history, and 45% had a personal or family history of BRCA1/2- associated cancers. Approximately 27% of variant-positive individuals had prior clinical genetic testing for BRCA1/2 . However, individuals with AJ founder variants were twice as likely to have had a clinical test (39%) than those with other pathogenic variants (20%). Conclusions These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.

Abstract Background Vector-borne diseases have an adverse impact on health of dogs, and infected dogs can be sentinels for human infection. Infection with Trypanosoma cruzi, an agent of Chagas disease, causes fatal heart disease in dogs across the southern United States but has been neglected from wide-scale prevalence studies. Objectives To determine the prevalence of exposure to T. cruzi, Ehrlichia spp., Anaplasma spp., Borrelia burgdorferi, and infection with Dirofilaria immitis among dogs in shelters across Texas and to identify risk factors for T. cruzi seropositivity. Animals Six hundred and eight dogs. Methods This repeated cross-sectional study was performed by collecting blood from ~30 dogs during each of the 3 visits to 7 shelters. We tested serum for antibodies to T. cruzi using 2 tests in series and for antibodies to Ehrlichia spp., Anaplasma spp., and B. burgdorferi and D. immitis antigen using the IDEXX SNAP 4DX Plus point-of-care test. DNA was extracted from blood clots and tested for T. cruzi DNA and strain type via quantitative polymerase chain reactions (qPCR). We used logistic regression to assess risk factors. Results One hundred ten (18.1%) of 608 dogs were seropositive for T. cruzi. Prevalence of exposure to the other vector-borne agents was: Ehrlichia spp. 3.6%; Anaplasma spp. 6.9%; B. burgdorferi 0.2%; and D. immitis infection 16.0%. Six of 559 (1.1%) dogs were qPCR-positive for T. cruzi. Conclusions and Clinical Importance T. cruzi seroprevalence was comparable to D. immitis prevalence and higher than seroprevalence of the tick-borne pathogens. T. cruzi is an underrecognized health threat to dogs across Texas and possibly other southern states where triatomine vectors are endemic.

Background Population-based genomic screening has the predicted ability to reduce morbidity and mortality associated with medically actionable conditions. However, much research is needed to develop standards for genomic screening and to understand the perspectives of people offered this new testing modality. This is particularly true for non-European ancestry populations who are vastly underrepresented in genomic medicine research. Therefore, we implemented a pilot genomic screening program in the Bio Me Biobank in New York City, where the majority of participants are of non-European ancestry. Methods We initiated genomic screening for well-established genes associated with hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), and familial hypercholesterolemia (FH). We evaluated and included an additional gene ( TTR ) associated with hereditary transthyretin amyloidosis (hATTR), which has a common founder variant in African ancestry populations. We evaluated the characteristics of 74 participants who received results associated with these conditions. We also assessed the preferences of 7461 newly enrolled Bio Me participants to receive genomic results. Results In the pilot genomic screening program, 74 consented participants received results related to HBOC ( N  = 26), LS ( N  = 6), FH ( N  = 8), and hATTR ( N  = 34). Thirty-three of 34 (97.1%) participants who received a result related to hATTR were self-reported African American/African (AA) or Hispanic/Latinx (HL), compared to 14 of 40 (35.0%) participants who received a result related to HBOC, LS, or FH. Among the 7461 participants enrolled after the Bio Me protocol modification to allow the return of genomic results, 93.4% indicated that they would want to receive results. Younger participants, women, and HL participants were more likely to opt to receive results. Conclusions The addition of TTR to a pilot genomic screening program meant that we returned results to a higher proportion of AA and HL participants, in comparison with genes traditionally included in genomic screening programs in the USA. We found that the majority of participants in a multi-ethnic biobank are interested in receiving genomic results for medically actionable conditions. These findings increase knowledge about the perspectives of diverse research participants on receiving genomic results and inform the broader implementation of genomic medicine in underrepresented patient populations.

Head and neck squamous cell carcinoma (HNSCC) tumor phenotypes and clinical outcomes are significantly influenced by etiological agents, such as HPV infection, smoking, and alcohol consumption. Accordingly, the intratumor microbiome has been increasingly implicated in cancer progression and metastasis. However, few studies characterize the intratumor microbial landscape of HNSCC with respect to these etiological agents. In this study, we aimed to investigate the bacterial and fungal landscape of HNSCC in association with HPV infection, smoking, and alcohol consumption. RNA-sequencing data were extracted from The Cancer Genome Atlas (TCGA) regarding 449 tissue samples and 44 normal samples. Pathoscope 2.0 was used to extract the microbial reads. Microbe abundance was compared to clinical variables, oncogenic signatures, and immune-associated pathways. Our results demonstrated that a similar number of dysregulated microbes was overabundant in smokers and nonsmokers, while heavy drinkers were characterized by an underabundance of dysregulated microbes. Conversely, the majority of dysregulated microbes were overabundant in HPV+ tumor samples when compared to HPV- tumor samples. Moreover, we observed that many dysregulated microbes were associated with oncogenic and metastatic pathways, suggesting their roles in influencing carcinogenesis. These microbes provide insights regarding potential mechanisms for tumor pathogenesis and progression with respect to the three etiological agents.

Background Borrelia burgdorferi and Anaplasma phagocytophilum are transmitted by Ixodes spp., with antibodies having been detected in cats in endemic areas. The combination of selamectin plus sarolaner (Revolution ® Plus/Stronghold ® Plus; Zoetis; RP) is effective against Ixodes spp. for 1 month. The objective of this study was to determine whether RP protects cats against transmission of B. burgdorferi from Ixodes scapularis by killing the ticks before transmission occurs. Transmission of A. phagocytophilum was also monitored. Methods Ten cats per group were treated once topically either with placebo solution (0.1 ml/kg) or with the minimum label dose of RP (6.0 mg/kg selamectin plus 1.0 mg/kg sarolaner). Thirty days post-treatment, cats were infested with 50 wild-caught adult I. scapularis . Ticks were counted, categorized, and removed on day 35. Blood collections for serology occurred on days −6, 30 (prior to infestation), 49, 63, 77, 91, and 104. Serum antibody assay results ( B. burgdorferi and A. phagocytophilum ) and polymerase chain reaction (PCR) of skin biopsies ( B. burgdorferi ) were used to define infection rates in the cats. Results Treatment with RP resulted in a 100% reduction of I. scapularis ticks compared with placebo-treated cats. In placebo-treated cats, antibodies against B. burgdorferi , A. phagocytophilum , both agents, and B. burgdorferi DNA in skin (five, nine, six, and three cats, respectively) were detected by day 104. In contrast, none of the RP-treated cats developed B. burgdorferi antibodies or DNA in skin biopsies, and A. phagocytophilum antibodies were detected in only two cats, significantly lower than in placebo-treated cats. Conclusions Results suggest that a single application of RP at the minimum label dose reduces the risk of infection by both B. burgdorferi and A. phagocytophilum, when infected at the end of the dosing interval. Graphical Abstract

Background Haemaphysalis longicornis (Asian longhorned tick) is an invasive species now established in the Northeastern and Mid-Atlantic USA. It feeds on mammalian wildlife, livestock, birds, cats, dogs, and humans. Simparica ® and Simparica Trio ® contain sarolaner, a drug in the isoxazoline class, with activity against fleas, ticks, and mites. Methods Two laboratory studies were conducted using 30 dogs each, randomized into three groups ( n  = 10/group): placebo (Pet Tabs ® ), Simparica Trio (minimum dose: 1.2 mg/kg sarolaner, 24 µg/kg moxidectin, 5 mg/kg pyrantel, as pamoate salt), and Simparica (minimum dose: 2.0 mg/kg sarolaner). Treatments were administered once orally on Day 0 according to the approved commercial dosing directions. Each dog was infested with 50 (± 5) unfed viable adult female H. longicornis on Days -2, 7, 14, 21, 30, 37, 49, and 63, and ticks were counted with removal and categorization at 48 h after treatment and each subsequent infestation. Ectoparasitic efficacy was calculated on the basis of the reduction in arithmetic mean of live and dead tick counts in each of the treated groups versus the untreated control group for every time point post infestation. Results Adequate challenge was demonstrated in both studies on the basis of live tick counts at each time point. For all sarolaner-treated groups, mean live counts were significantly ( P  ≤ 0.0005) lower than those for the placebo at all time points. For Simparica, in Study 1, the percentage reductions were 100% for all time points up to Day 39. On Days 51 and 65, the percentage reductions were 98.9% and 82.4%, respectively. In Study 2, reductions were 99.7–100% up to Day 65. For Simparica Trio, in Study 1, percentage reductions were 100% up to Day 51. On Day 65, the percentage reduction was 78.4%. In Study 2, reductions were 99.6–100% up to Day 39 and 97.6% and 94.1% on Days 51 and 65, respectively. Conclusions Results from these controlled studies demonstrated high efficacy (78.4–100%) of Simparica and Simparica Trio in reducing existing and subsequent infestations of H. longicornis within 48 h for up to 65 days post treatment. Graphical Abstract

Understanding the molecular basis for immune recognition of SARS-CoV-2 spike glycoprotein antigenic sites will inform the development of improved therapeutics. We determined the structures of two human monoclonal antibodies–AZD8895 and AZD1061–which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor-binding domain (RBD) of SARS-CoV-2 to define the genetic and structural basis of neutralization. AZD8895 forms an ‘aromatic cage’ at the heavy/light chain interface using germ line-encoded residues in complementarity-determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain. These structural features explain why highly similar antibodies (public clonotypes) have been isolated from multiple individuals. AZD1061 has an unusually long LCDR1; the HCDR3 makes interactions with the opposite face of the RBD from that of AZD8895. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the crucial binding residues of both antibodies and identified positions of concern with regards to virus escape from antibody-mediated neutralization. Both AZD8895 and AZD1061 have strong neutralizing activity against SARS-CoV-2 and variants of concern with antigenic substitutions in the RBD. We conclude that germ line-encoded antibody features enable recognition of the SARS-CoV-2 spike RBD and demonstrate the utility of the cocktail AZD7442 in neutralizing emerging variant viruses. Structural analysis of two human monoclonal antibodies that conform the antibody cocktail AZD7442, in complex with the RBD of SARS-CoV-2, reveal strong neutralization of SARS-CoV-2 variants of concern.

Estimates of intestinal parasite prevalence in canine populations have largely been based on use of fecal flotation methods only. Dogs in animal shelters are likely at higher risk of intestinal parasite infection because of their previous exposure history. Our objectives were to estimate the prevalence of intestinal parasites among Texas shelter dogs using centrifugal fecal flotation and saline sedimentation techniques, to identify risk factors for infection, and to compare proportions of positive samples detected via fecal flotation vs. saline sedimentation for the most common parasites. Using a repeated cross-sectional study design, we collected fecal samples from dogs on three visits to each of seven Texas animal shelters between May 2013 and December 2014. Fecal flotation and/or saline sedimentation were used to identify parasites in samples. Fecal samples were collected from 529 dogs. The most frequently detected parasites were Ancylostoma caninum (26.4% via fecal flotation, 20.7% via saline sedimentation) and Trichuris vulpis (12.0% via fecal flotation, 14.1% via saline sedimentation). Risk factors for certain parasites were identified; for example, dogs with abnormal fecal consistency were more likely to be shedding T. vulpis eggs than dogs with normal fecal consistency (OR = 1.8, p  = 0.005). The addition of fecal sedimentation not only added to the number of parasite species detected in this study, but it also increased the number of dogs diagnosed with the common intestinal parasites that are primarily detected using fecal flotation methods. Texas shelter dogs carry a high burden of intestinal parasites, including those of zoonotic importance.