Increasing the Dye Payload of Cetuximab-IRDye800CW Enables Photodynamic Therapy.

Cetuximab (Cet)-IRDye800CW, among other antibody-IRDye800CW conjugates, is a potentially effective tool for delineating tumor margins during fluorescence image-guided surgery (IGS). However, residual disease often leads to recurrence. Photodynamic therapy (PDT) following IGS is proposed as an approach to eliminate residual disease but suffers from a lack of molecular specificity for cancer cells. Antibody-targeted PDT offers a potential solution for this specificity problem. In this study, we show, for the first time, that Cet-IRDye800CW is capable of antibody-targeted PDT in vitro when the payload of dye molecules is increased from 2 (clinical version) to 11 per antibody. Cet-IRDye800CW (1:11) produces singlet oxygen, hydroxyl radicals, and peroxynitrite upon activation with 810 nm light. In vitro assays on FaDu head and neck cancer cells confirm that Cet-IRDye800CW (1:11) maintains cancer cell binding specificity and is capable of inducing up to ∼90% phototoxicity in FaDu cancer cells. The phototoxicity of Cet-IRDye800CW conjugates using 810 nm light follows a dye payload-dependent trend. Cet-IRDye800CW (1:11) is also found to be more phototoxic to FaDu cancer cells and less toxic in the dark than the approved chromophore indocyanine green, which can also act as a PDT agent. We propose that antibody-targeted PDT using high-payload Cet-IRDye800CW (1:11) could hold potential for eliminating residual disease postoperatively when using sustained illumination devices, such as fiber optic patches and implantable surgical bed balloon applicators. This approach could also potentially be applicable to a wide variety of resectable cancers that are amenable to IGS-PDT, using their respective approved full-length antibodies as a template for high-payload IRDye800CW conjugation.

Cretaceous and Paleocene fossils reveal an extinct higher clade within Cornales, the dogwood order.

PREMISE: Characterization and phylogenetic integration of fossil angiosperms with uncertain affinities is relatively limited, which may obscure the diversity of extinct higher taxa in the flowering plant tree of life. The order Cornales contains a diversity of extinct taxa with uncertain familial affinities that make it an ideal group for studying turnover in angiosperms. Here, we describe a new extinct genus of Cornales unassignable to an extant family and conduct a series of phylogenetic analyses to reconstruct relationships of fossils across the order. METHODS: Two permineralized endocarps were collected from the Cedar District Formation (Campanian, 82-80 Ma) of Sucia Island, State of Washington, United States. Fossils were sectioned with the cellulose acetate peel technique and incorporated into a morphological dataset. To assess the utility of this dataset to accurately place taxa in their respective clades, we used a series of phylogenetic pseudofossilization analyses. We then conducted a total-evidence analysis and a scaffold-based approach to determine relationships of fossils. RESULTS: Based on their unique combination of characters, the fossils represent a new genus, Fenestracarpa washingtonensis gen. nov. et sp. nov. Pseudofossilization analyses indicate that our morphological dataset can be used to accurately recover taxa at the major clade to family level, generally with moderate to high support. The total-evidence and scaffold-based analyses recovered Fenestracarpa and other fossil genera in an entirely extinct clade within Cornales. CONCLUSIONS: Our findings increase the reported diversity of extinct Cornales and indicate that the order's initial radiation likely included the divergence of an extinct higher clade that endured the end-Cretaceous Mass extinction but perished during the Cenozoic.

Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2.

Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.

neoepiscope improves neoepitope prediction with multivariant phasing.

MOTIVATION: The vast majority of tools for neoepitope prediction from DNA sequencing of complementary tumor and normal patient samples do not consider germline context or the potential for the co-occurrence of two or more somatic variants on the same mRNA transcript. Without consideration of these phenomena, existing approaches are likely to produce both false-positive and false-negative results, resulting in an inaccurate and incomplete picture of the cancer neoepitope landscape. We developed neoepiscope chiefly to address this issue for single nucleotide variants (SNVs) and insertions/deletions (indels). RESULTS: Herein, we illustrate how germline and somatic variant phasing affects neoepitope prediction across multiple datasets. We estimate that up to ∼5% of neoepitopes arising from SNVs and indels may require variant phasing for their accurate assessment. neoepiscope is performant, flexible and supports several major histocompatibility complex binding affinity prediction tools. AVAILABILITY AND IMPLEMENTATION: neoepiscope is available on GitHub at https://github.com/pdxgx/neoepiscope under the MIT license. Scripts for reproducing results described in the text are available at https://github.com/pdxgx/neoepiscope-paper under the MIT license. Additional data from this study, including summaries of variant phasing incidence and benchmarking wallclock times, are available in Supplementary Files 1, 2 and 3. Supplementary File 1 contains Supplementary Table 1, Supplementary Figures 1 and 2, and descriptions of Supplementary Tables 2-8. Supplementary File 2 contains Supplementary Tables 2-6 and 8. Supplementary File 3 contains Supplementary Table 7. Raw sequencing data used for the analyses in this manuscript are available from the Sequence Read Archive under accessions PRJNA278450, PRJNA312948, PRJNA307199, PRJNA343789, PRJNA357321, PRJNA293912, PRJNA369259, PRJNA305077, PRJNA306070, PRJNA82745 and PRJNA324705; from the European Genome-phenome Archive under accessions EGAD00001004352 and EGAD00001002731; and by direct request to the authors. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Preoperative Risk Factors for Postoperative Urinary Tract Infection After Primary Total Hip and Knee Arthroplasties.

BACKGROUND: Establishing clear risk factors for complications such as urinary tract infection (UTI) after arthroplasty procedures helps guide clinical practice and provides more information to both surgeons and patients. This study aims to assess selected preoperative patient characteristics as risk factors for postoperative UTI after primary total hip and knee arthroplasties (THA and TKA). METHODS: This was a retrospective analysis using current procedural terminology codes to investigate the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for patients who underwent THA or TKA from 2010 to 2017. Patients were classified for UTI by NSQIP guidelines. Patient samples with all possible covariates were included for multivariate logistic regression analysis and assessed for independent associations. RESULTS: In a cohort of 983 identified patients (983 of 119,096; 0.83%): ages 57+ years, preoperative red blood cell (RBC) transfusion, perioperative RBC transfusion, bleeding disorders, operative time 110+ minutes, preoperative steroid use, diabetes, pulmonary comorbidities, body mass index 30+ kg/m2 were independent risk factors for postoperative UTI after THA. In a cohort of 1503 identified patients (1503 of 189,327; 0.8%): ages 60+ years, preoperative RBC transfusion, perioperative RBC transfusion, anemia, platelets less than 150k, preoperative steroid use, diabetes, and body mass index 30+ kg/m2 were independent risk factors for postoperative UTI after TKA. Male sex was associated with a decreased risk of UTI in both THA and TKA. CONCLUSION: This study provides novel evidence on risk factors associated with the development of UTI after THA or TKA. Clinicians should be aware of risk factors in the manifestation of postoperative UTI after primary THA or TKA procedures.

Pediatric cellular neurothekeoma: Seven cases and systematic review of the literature.

BACKGROUND/OBJECTIVES: Neurothekeoma is a rare, benign, cutaneous neoplasm consisting of Schwann cells and perineural cells in myxoid stroma. Cellular neurothekeoma (CNT) was previously thought to represent a morphologic variant of neurothekeoma, but recent studies have shown that CNTs are unrelated to neurothekeomas and are more likely of histiocytic lineage. METHODS: Herein, we describe seven cases of CNT in pediatric patients. A comprehensive search of PubMed was performed, and 71 cases of cellular neurothekeoma in pediatric patients were reviewed. RESULTS: The clinical differential diagnosis for these lesions included Spitz nevi, keloid, juvenile xanthogranuloma, cutaneous lymphoid hyperplasia, and lymphomatoid papulosis. All cases were treated by excision or excisional biopsy. Histopathologically, all demonstrated multilobular, primarily intradermal neoplasms composed of plump spindled or epithelioid mononuclear cells with abundant eosinophilic pale-staining cytoplasm. Immunophenotypic findings included CD68 and NKI/C3 positivity, and negative staining with cytokeratin, S-100, Melan-A, and SOX-10. CONCLUSION: Cellular neurothekeoma is distinguished from conventional neurothekeoma by increased cellularity, a lack of myxoid stroma, and a lack of neural expression with immunohistochemical stains. These uncommon neoplasms should be included in the differential diagnosis of dermal nodules in children. Accurate diagnosis of these lesions is essential, as they can be mistaken for malignancy leading to unnecessary treatment.

Population-level distribution and putative immunogenicity of cancer neoepitopes.

BACKGROUND: Tumor neoantigens are drivers of cancer immunotherapy response; however, current prediction tools produce many candidates requiring further prioritization. Additional filtration criteria and population-level understanding may assist with prioritization. Herein, we show neoepitope immunogenicity is related to measures of peptide novelty and report population-level behavior of these and other metrics. METHODS: We propose four peptide novelty metrics to refine predicted neoantigenicity: tumor vs. paired normal peptide binding affinity difference, tumor vs. paired normal peptide sequence similarity, tumor vs. closest human peptide sequence similarity, and tumor vs. closest microbial peptide sequence similarity. We apply these metrics to neoepitopes predicted from somatic missense mutations in The Cancer Genome Atlas (TCGA) and a cohort of melanoma patients, and to a group of peptides with neoepitope-specific immune response data using an extension of pVAC-Seq (Hundal et al., pVAC-Seq: a genome-guided in silico approach to identifying tumor neoantigens. Genome Med 8:11, 2016). RESULTS: We show neoepitope burden varies across TCGA diseases and HLA alleles, with surprisingly low repetition of neoepitope sequences across patients or neoepitope preferences among sets of HLA alleles. Only 20.3% of predicted neoepitopes across TCGA patients displayed novel binding change based on our binding affinity difference criteria. Similarity of amino acid sequence was typically high between paired tumor-normal epitopes, but in 24.6% of cases, neoepitopes were more similar to other human peptides, or bacterial (56.8% of cases) or viral peptides (15.5% of cases), than their paired normal counterparts. Applied to peptides with neoepitope-specific immune response, a linear model incorporating neoepitope binding affinity, protein sequence similarity between neoepitopes and their closest viral peptides, and paired binding affinity difference was able to predict immunogenicity (AUROC = 0.66). CONCLUSIONS: Our proposed prioritization criteria emphasize neoepitope novelty and refine patient neoepitope predictions for focus on biologically meaningful candidate neoantigens. We have demonstrated that neoepitopes should be considered not only with respect to their paired normal epitope, but to the entire human proteome, and bacterial and viral peptides, with potential implications for neoepitope immunogenicity and personalized vaccines for cancer treatment. We conclude that putative neoantigens are highly variable across individuals as a function of cancer genetics and personalized HLA repertoire, while the overall behavior of filtration criteria reflects predictable patterns.

Group B streptococcus (GBS) is an important pathogen in human disease- but what about in cystic fibrosis?

BACKGROUND: Group B Streptococcus (GBS) is a common commensal capable of causing severe invasive infections. Most GBS infections occur in neonates (often as pneumonia). GBS can also cause infection in adults with diabetes and other immunological impairments but rarely leads to pneumonia in adults. GBS has occasionally been found in the sputum of Cystic Fibrosis (CF) patients, an inherited condition known for progressive lung disease. However, the epidemiology and clinical significance of GBS in CF are not understood. METHODS: We retrospectively reviewed a large single-centre adult CF population with an associated comprehensive, prospectively collected bacterial biobank beginning in 1978. We identified all individuals with GBS isolated from their sputum on at least one occasion. The primary outcome was risk of pulmonary exacerbation (PEx) at the time of the first GBS isolate compared to the preceding visit. Secondary outcomes included determining: prevalence of GBS infection in a CF population, whether GBS infections where transient or persistent, whether GBS strains were shared among patients, change in % predicted FEV1 at the time of GBS isolate compared to the preceding visit, PEx frequency after the first GBS isolate, change in % predicted FEV1 after the first GBS isolate, and complications of GBS infection. RESULTS: GBS was uncommon, infecting 3.5% (11/318) adults within our cohort. Only three individuals developed persistent GBS infection, all lasting > 12 months. There were no shared GBS strains among patients. PEx risk was not increased at initial GBS isolation (RR 5.0, CI 0.69-36.1, p=0.10). In the two years preceding initial GBS isolation compared to the two following years, there was no difference in PEx frequency (median 2, range 0-4 vs 1, range 0 to 5, respectively, p=0.42) or lung function decline, as measured by % predicted FEV1, (median -1.0%, range -19 to 7% vs median -6.0%, range -18 to 22%, p=0.86). There were no invasive GBS infections. CONCLUSION: In adults with CF, GBS is uncommon and is generally a transient colonizer of the lower airways. Despite the presence of structural lung disease and impaired innate immunity in CF, incident GBS infection did not increase PEx risk, PEx frequency, rate of lung function decline, or other adverse clinical outcomes.

Clinical use of high mobility group box 1 and the receptor for advanced glycation end products in the prognosis and risk stratification of heart failure: a literature review.

Heart failure (HF) is a clinical syndrome that represents the end stage of heart disease and remains the leading cause of morbidity and mortality worldwide. As heart failure mortality rates remain elevated, additional biomarkers that facilitate early detection or risk stratification in HF is of particularly great interest. High mobility group box 1 (HMGB1) and receptor for advanced glycation end products (RAGE) cause the activation of intracellular signaling, gene expression, and production of inflammatory cytokines and have been linked to many inflammatory disease states such as diabetes mellitus and atherosclerosis. Few studies have investigated their role in the pathophysiology of HF and any significant correlation remains uncertain. Review of the available literature discussing HMGB1 and RAGE clinical values as independent prognostic variables in HF resulted in the inclusion of 11 studies, which enrolled a total of 2025 heart failure patients. Overall, the data suggests a statistically significant positive correlation between RAGE and HF, with increasing RAGE levels associated with increasing New York Heart Association (NYHA) functional class of heart failure. HMGB1 correlations were not as extensively studied, but there is evidence that both HMGB1 and RAGE have a definite potential as biomarkers for the prognosis and risk stratification of HF patients.

Augmented Renal Clearance Using Population-Based Pharmacokinetic Modeling in Critically Ill Pediatric Patients.

OBJECTIVES: The objectives of this study were to: 1) evaluate the prevalence of augmented renal clearance in critically ill pediatric patients using vancomycin clearance; 2) derive the pharmacokinetic model that best describes vancomycin clearance in critically ill pediatric patients; and 3) correlate vancomycin clearance with creatinine clearance estimated by modified Schwartz or Cockcroft-Gault. DESIGN: Retrospective, two-center, cohort study from 2003 to 2016. SETTING: Clinical drug monitoring services in the PICUs at two tertiary care, teaching hospitals. PATIENTS: Children from 1 to 21 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Identify patients with augmented renal clearance (vancomycin clearance ≥ 130 mL/min/1.73 m used as definition of augmented renal clearance). Derive final population-based pharmacokinetic model and estimate individual patient pharmacokinetic parameters. Compare estimated glomerular filtration rate (modified Schwartz or Cockcroft-Gault depending on age < or ≥ 17 yr) with vancomycin clearance. Augmented renal clearance was identified in 12% of 250 total subjects. The final population-based pharmacokinetic model for vancomycin clearance (L/hr) was 0.118 × weight (e). Median vancomycin clearance in those with versus without augmented renal clearance were 141.3 and 91.7 mL/min/1.73 m, respectively (p < 0.001). By classification and regression tree analysis, patients who were more than 7.9 years old were significantly more likely to experience augmented renal clearance (17% vs 4.6% in those ≤ 7.9 yr old; p = 0.002). In patients with augmented renal clearance, 79% of 29 had vancomycin trough concentrations less than 10 µg/mL, compared with 52% of 221 in those without augmented renal clearance (p < 0.001). Vancomycin clearance was weakly correlated to the glomerular filtration rate estimated by the modified Schwartz or Cockcroft-Gault method (Spearman R = 0.083). CONCLUSIONS: Augmented renal clearance was identified in one of 10 critically ill pediatric patients using vancomycin clearance, with an increase of approximately 50 mL/min/1.73 m in those with augmented renal clearance. As augmented renal clearance results in subtherapeutic antibiotic concentrations, optimal dosing is essential in those exhibiting augmented renal clearance.

Clinical Features and Treatment of Dermatofibrosarcoma Protuberans Affecting the Vulva: A Literature Review.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a low-to-intermediate grade cutaneous neoplasm with a low propensity for metastasis and a high rate of local recurrence. It typically presents as a dermal plaque or nodule on the trunk, limbs, or head and neck region. Vulvar DFSP has also been described, although it is less common. OBJECTIVE: To review the available literature and discuss the clinical course of DFSP affecting the vulva. MATERIALS AND METHODS: We reviewed the existing English-language literature on DFSP of the vulva with respect to clinical presentation, diagnosis, treatment, and outcome. RESULTS: Thirty three case reports and series were included (n = 54 patients). Vulvar DFSP most commonly presents as a slowly enlarging tender or asymptomatic mass on the labia majora, with histological findings of classic DFSP. Most patients were treated with wide local excision. Three patients were treated with Mohs micrographic surgery, which may decrease local recurrence and seems well suited for use in vulvar DFSP. CONCLUSION: This literature review comprehensively reviews and describes the clinical presentation of vulvar DFSP and the treatment options for this rare vulvar neoplasm.

The danger zone: Systematic review of the role of HMGB1 danger signalling in traumatic brain injury.

BACKGROUND: Traumatic brain injuries (TBI) are associated with complex inflammatory pathways that lead to the development of secondary injuries such as cerebral ischaemia, elevated intracranial pressure and cognitive deficits. The association between intracellular danger signalling involving nuclear chromatin-binding factor, high mobility group box-1 (HMGB1) and inflammatory pathways following TBI has not yet been fully understood. PRIMARY OBJECTIVE: To comprehensively review the available literature regarding the potential diagnostic, prognostic and therapeutic use of HMGB1 in TBI. METHODS: A systematic literature review of studies available in PubMed using human and animal subjects was performed. A total of eight studies were included in the results. CONCLUSIONS: A comprehensive review of these reports demonstrated that, following TBI, HMGB1 is released from damaged neurons and is elevated in patient's serum and CSF. Furthermore, these studies showed the potential for HMGB1 to serve as a prognostic biomarker and therapeutic target in patients with TBI. Thus, HMGB1 is a prospective candidate for future studies as it shows promise in treating and/or predicting the sequelae of TBI.

Light and laser treatment modalities for disseminated superficial actinic porokeratosis: a systematic review.

Treatment of disseminated superficial actinic porokeratosis (DSAP) is poorly standardized. The present review seeks to comprehensively discuss the potential for laser and light modalities in the treatment of DSAP. A systematic review of light and laser treatment modalities was conducted to include 26 cases of patients with DSAP. Systematic review resulted in 14 articles to be included. Photodynamic therapy (PDT) overall was the least successful treatment modality, with clinical improvement seen in a minority of patients (MAL-PDT: N = 9 patients, 33.3% showed improvement; ALA-PDT: N = 3 patients, 0% improvement; hypericin-PDT: N = 2 patients, 0% improvement) after numerous post-procedural side effects of hyperpigmentation, inflammation, erythema, and discomfort. Overall, in the available reports, PDT demonstrates poor outcomes with greater incidence of side effects. The response rates of DSAP lesions treated with lasers were as follows: (Q-switched ruby lasers: N = 2, 100%; CO2 laser: N = 1, 100%; PDT and CO2 combination therapy: N = 2, 0-50%; erbium and neodymium YAG lasers: N = 2, 100%; fractional 1927-nm thulium fiber lasers: N = 2, 100%; Grenz rays: N = 1, 100%; and fractional photothermolysis: N = 2, 100%). The side effects of laser therapy were minimal and included mild erythema, slight hyperpigmentation, and moderate edema. Laser therapy is a promising treatment option for DSAP with an excellent side effect profile. However, higher power studies are required to determine optimal guidelines for laser treatment of DSAP.

Laser therapy for the treatment of pearly penile papules.

Pearly penile papules (PPP) present as dome-shaped papules of no more than 3 mm in diameter that line the base of the glans of the penis. These benign lesions affect between 14.3 and 48 % of men. While often asymptomatic, PPP can cause a great deal of psychological distress that may warrant treatment. Current treatment options include cryotherapy, electrodessication, and curettage (ED&C). However, these modalities may have considerable adverse cosmetic effects, including scarring, pain, and pigmentary changes. Laser modalities offer clear potential for improved cosmetic outcome in PPP treatment, but is not routinely used. Thus, a systematic review of available literature using the National Library of Medicine database PubMed was completed to find articles relevant to the treatment of PPP with laser and light therapy. The systematic search and screening of articles resulted in inclusion of eight articles discussing a total of 55 patients with PPP treated by laser therapy. The present systematic review found that erbium:yttrium-aluminum-garnet (Er:YAG) and CO2 laser were the most commonly reported (n = 45 and 7, respectively). Furthermore, the use of CO2, Er:YAG, pulsed dye laser, and fractional photothermolysis therapies demonstrated complete clearance of PPP in all cases with minimal complications and discomfort. Thus, based on the currently available evidence, laser therapy is a well-tolerated and efficacious method for treating PPP with minimal long-term adverse effects and a cosmetically desirable outcome. Although the included studies are limited in power, this systematic review offers clinically relevant insight into the potential for laser therapy.

Laser and light therapies for the treatment of nail psoriasis.

Psoriatic involvement of the nail is notoriously refractory to conventional therapy. Nail psoriasis has a high incidence amongst patients with psoriasis. It remains a significant cosmetic problem and thus, has a significant impact on quality of life. More recently, light and laser therapies have emerged as modalities for treatment of nail psoriasis. In this study, the efficacies of light and laser therapies are systematically reviewed. Light therapies involve ultraviolet light (with or without photosensitizers) or intense pulsed light. Alternatively, laser therapy in nail psoriasis is primarily administered using a 595-nm pulsed dye laser. These modalities have demonstrated significant improvement in psoriatic nail lesions, and even complete resolution in some cases. Both laser and light modalities have also been tested in combination with other systemic or topical therapeutics, with variable improvement in efficacy. Both laser and light therapies are generally well tolerated. Side-effects of light therapies include hyperpigmentation, itching and erythema; whereas, side-effects of laser therapy are more frequent and include pain, purpura/petechiae and hyperpigmentation. Patterns of response to therapy were also seen based on presenting characteristics of the nail lesions: subungual hyperkeratosis and onycholysis appeared to be the most responsive to therapy, while nail pitting was the most resistant. Light or laser therapies have the potential to be an efficient and cost-effective in-office based treatment for nail psoriasis. However, more large-scale clinical trials are needed to assess their efficacy, particularly in combination with other therapeutic modalities.

Erythroplasia of Queyrat treated by laser and light modalities: a systematic review.

Erythroplasia of Queyrat (EOQ) is a squamous cell carcinoma in situ most commonly located on the glans penis or prepuce. EOQ accounts for roughly 10 % of all penile malignancies and may lead to invasive squamous cell carcinoma. Standard therapy includes local excision, partial or total penectomy, cryotherapy, and topical cytotoxic agents. Treatment of EOQ has proven to be challenging due to low response rates and recurrence. In addition, radical procedures can significantly affect sexual function and quality of life. Alternative laser treatments and photodynamic therapy (PDT) offer promising results for treating EOQ. A systemic review of the literature was performed for articles discussing laser and light therapy for EOQ. Among the patients treated with the CO2 laser, 81.4 % of cases had complete remission after one session of treatment. Patients treated with PDT presented with more variable results, where 62.5 % of those treated with methyl aminolevulinate photodynamic therapy (MAL-PDT) achieved complete remission. Aminolevulinic acid (ALA-PDT) treatment showed a similar rate of remission at 58.3 %. One study utilized the Nd:YAG laser, which resulted in a recurrence of the lesion in four of the five patients treated. Of the methods reviewed, the CO2 laser offered the most promising results with a cosmetically excellent prognosis. Further studies with larger power and longer follow-up times are needed to determine the optimal treatment regimen for this penile malignancy.

Association of high mobility group BOX-1 and receptor for advanced glycation endproducts with clinicopathological features of haematological malignancies: a systematic review.

High-mobility group box 1 (HMGB1) is a versatile protein with nuclear and extracellular functions. In the extracellular milieu, HMGB1 binds to several receptors, notably the receptor for advanced glycation end-products (RAGE). The expressions of HMGB1 and RAGE have been described in a variety of cancers. However, the clinical values of HMGB1 and RAGE in haematological malignancies have yet to be evaluated. A systematic search through PubMed and the Web of Science for articles discussing the role of HMGB1 and RAGE in haematological malignancies produced 15 articles. Overexpression of HMGB1 was reported to be associated with malignancy and, in certain studies, poor prognosis and tumour aggressiveness. Only one included study investigated the clinical value of RAGE, in which no significant difference was found between expression of RAGE in CLL neoplastic cells and nonmalignant controls. The discussed associations of HMGB1 and RAGE with clinicopathological characteristics of patients with haematological malignancies warrants further investigation into the prognostic and diagnostic value of both of these molecules.

Clinical implications and characterization of Group A Streptoccoccus infections in adults with cystic fibrosis.

BACKGROUND: Persistent airway infection is a hallmark feature of cystic fibrosis (CF). However, increasingly it has been observed that non-classical pathogens may transiently infect CF lower airways. Streptococcus pyogenes (Group A Streptococcus; (GAS)) is an uncommon but potentially dangerous cause of community-acquired pneumonia. Our aim was to determine the incidence, natural history, and clinical impact of GAS infections in CF and phenotypically and genotypically characterize the isolates. METHODS: We retrospectively evaluated the Calgary Adult CF Clinic biobank to identify adults with at least one GAS isolate. Patient demographics, medical and pulmonary exacerbation (PEx) histories were evaluated. The primary outcome was PEx occurrence at incident GAS culture. Secondary outcomes evaluated were changes in lung function and PEx frequency following GAS isolation. Isolates were assessed for extra-cellular virulence factor production capacity and ability to produce quorum sensing (AI-2). Isolates were genotyped using pulse-field gel electrophoresis (PFGE). RESULTS: Fifteen individuals who cultured GAS twenty times were identified. At the time of GAS isolation, 47% (7/15) of subjects experienced a PEx and half of these (4/7) were severe. Individuals were more likely to have a PEx at the time of the index GAS isolate compared to the preceding visit (RR = 6.0, 95% CI 0.82-43.0, p = 0.08), particularly if GAS was the numerically dominant sputum pathogen (RR = 6.5, 95% CI 1.00-43.0, p = 0.009). There were no changes in PEx frequency or rate of lung function decline following GAS. None of the patients developed chronic airways infection, bacteremia, necrotizing pneumonia or empyema. Susceptibility was universal to common anti-Streptococcal antibiotics and anti-Pseudomonal antibiotics commonly used in CF, with the exception of azithromycin. GAS isolates varied in their production of protease, DNase, and AI-2 but these did not correlate with PEx, and none produced elastase, chrondrotin sulfatase or H202. One patient had prolonged carriage with the same isolate and two patients had isolates with similar PFGE patterns. CONCLUSIONS: GAS was an uncommon lower respiratory pathogen of adults with CF. Identification of GAS in sputum was frequently associated with PEx, particularly when numerically dominant. However, transient GAS infection did not result in chronic infection nor appreciably change long-term disease trajectory.

Vancomycin monitoring in children using bayesian estimation.

BACKGROUND: Optimal monitoring of vancomycin in children needs evaluation using the exposure target with area under the curve (AUC) of the serum concentrations versus time over 24 hours. Our study objectives were to: (1) compare the accuracy and precision of vancomycin AUC estimations using 2 sampling strategies-1 serum concentration sample (1S, near trough) versus 2 samples (2S, near peak and trough) against the rich sample (RS) method; and (2) determine the performance of these strategies in predicting future AUC against an internal validation sample (VS). METHODS: This was a retrospective cohort study using population-based pharmacokinetic modeling with Bayesian post hoc individual estimations in nonlinear mixed effects modeling (version 7.2). Pediatric subjects 3 months-21 years of age who received vancomycin ≥48 hours and had more than 3 drug samples within the first ≤96 hours of therapy were enrolled. Outcome measures were the accuracy, precision, and internal predictive performance of AUC estimations using 2 monitoring strategies (ie, 1S versus 2S) against the RS (which was derived from modeling all serum vancomycin concentrations obtained anytime during therapy) and VS (from serum concentrations obtained after 96 hours of therapy). RESULTS: Analysis included 138 subjects with 712 vancomycin serum concentrations. Median age was 6.1 (interquartile range, 2.2-12.2) years, weight 22 (13-38) kg, and baseline serum creatinine 0.37 (0.30-0.50) mg/dL. Both accuracy and precision were improved with the 2S, compared with 1S, for AUC estimations (-2.0% versus -7.6% and 10.3% versus 12.8%, respectively) against the RS. Improved accuracy and precision were also observed for 2S when evaluated against VS in predicting future AUC. CONCLUSIONS: Compared with 1S, the 2S sampling strategy for vancomycin monitoring improved accuracy and precision in estimating and predicting future AUC. Evaluating 2 drug concentrations in children may be prudent to ensure adequate drug exposure.

Biomechanical analysis of complications following T10-Pelvis spinal fusion: A population based computational study.

Proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) are challenging complications of long fusion constructs for the treatment of adult spinal deformity. The objective of this study is to understand the biomechanical stresses proximal to the upper instrumentation of a T10-pelvis fusion in a large patient cohort. The pre-fusion models were subject-specific thoracolumbar spine models that incorporate the height, weight, spine curvature, and muscle morphology of 250 individuals from the Framingham Heart Study Multidetector CT Study. To create post-fusion models, the subject-specific models were further modified to eliminate motion between the intervertebral joints from T10 to the pelvis. OpenSim analysis tools were used to calculate the medial lateral shear force, anterior posterior shear force, and compressive force on the T9 vertebra during the static postures. Differences between pre-fusion and post-fusion T9 biomechanics were consistent between increased segmental mobility and unchanged segmental mobility conditions. For all static postures, compression decreased (p < 0. 0005). Anterior-posterior shear force significantly increased (p < 0. 0005) during axial twist and significantly increased (p < 0. 0005) during trunk flexion. Medial lateral shear force significantly increased (p < 0. 0005) during axial twist. This computational study provided the first use of subject-specific models to investigate the biomechanics of long spinal fusions. Patients undergoing T10-Pelvis fusion were predicted to have increased shear forces and decreased compressive force at the T9 vertebra, independent of change in segmental mobility. The computational model shows potential for the investigation of spinal fusion biomechanics to reduce the risk of PJK or PJF.