The Severity of Initial Unilateral Cleft Lip and Nasal Deformity Predicts Long-Term Postoperative Esthetic Outcome.

BACKGROUND: Infantile cleft lip and nasal severity influence the final esthetic result of the repair. Although various authors have described methods of cleft lip and nasal repair, there is a paucity of data that correlates cleft severity with esthetic outcomes. The aim of this study was to examine the correlation between presurgical severity of unilateral cleft deformity and long-term postoperative esthetic outcomes. METHODS: This retrospective study, based at a single institution, investigated patients with complete unilateral cleft lip, with or without cleft palate, who underwent repair by a single surgeon, had preoperative infantile facial casts, and had postoperative facial photographs at 6 to 11 years of age (N=31). Preoperative nostril width ratio and columellar angle measurements were taken from facial casts. Postoperative, long-term nasolabial appearance was rated by 5 blinded observers used a modified Kuijpers-Jagtman scale. Linear regression was used to determine the relationship between preoperative cleft severity and postoperative ratings. RESULTS: Preoperative nostril width ratio directly correlated with postoperative nasal form score (r=0.40; P=0.026); likewise, preoperative columellar angle predicted postoperative nasal form score (r=0.37; P=0.040). Preoperative cleft severity was not significantly correlated with vermillion border appearance. Cronbach α values of 0.91 (nasal form) and 0.79 (vermillion border) indicated good inter-rater reliability. Kappa values of 0.87 (nasal form) and 0.70 (vermillion border) indicated good intrarater reliability. CONCLUSIONS: Preoperative unilateral cleft nose severity directly correlates with long-term postoperative nasal appearance in childhood. Outcome studies should present and control for preoperative severity to allow more accurate assessment of repair techniques.

Analgesia for rib fractures: a narrative review.

PURPOSE: Rib fracture(s) is a common and painful injury often associated with significant morbidity (e.g., respiratory complications) and high mortality rates, especially in the elderly. Risk stratification and prompt implementation of analgesic pathways using a multimodal analgesia approach comprise a primary endpoint of care to reduce morbidity and mortality associated with rib fractures. This narrative review aims to describe the most recent evidence and care pathways currently available, including risk stratification tools and pharmacologic and regional analgesic blocks frequently used as part of the broadly recommended multimodal analgesic approach. SOURCE: Available literature was searched using PubMed and Embase databases for each topic addressed herein and reviewed by content experts. PRINCIPAL FINDINGS: Four risk stratification tools were identified, with the Study of the Management of Blunt Chest Wall Trauma score as most predictive. Current evidence on pharmacologic (i.e., acetaminophen, nonsteroidal anti-inflammatory drugs, gabapentinoids, ketamine, lidocaine, and dexmedetomidine) and regional analgesia (i.e., thoracic epidural analgesia, thoracic paravertebral block, erector spinae plane block, and serratus anterior plane block) techniques was reviewed, as was the pathophysiology of rib fracture(s) and its associated complications, including the development of chronic pain and disabilities. CONCLUSION: Rib fracture(s) continues to be a serious diagnosis, with high rates of mortality, development of chronic pain, and disability. A multidisciplinary approach to management, combined with appropriate analgesia and adherence to care bundles/protocols, has been shown to decrease morbidity and mortality. Most of the risk-stratifying care pathways identified perform poorly in predicting mortality and complications after rib fracture(s).

RéSUMé: OBJECTIF: Les fractures des côtes sont des blessures courantes et douloureuses souvent associées à une morbidité importante (p. ex., complications respiratoires) et à des taux de mortalité élevés, surtout chez les personnes âgées. La stratification des risques et la mise en œuvre rapide de voies analgésiques à l'aide d'une approche d'analgésie multimodale constituent un critère d'évaluation principal des soins visant à réduire la morbidité et la mortalité associées aux fractures des côtes. Ce compte rendu narratif a pour objectif de décrire les données probantes les plus récentes et les parcours de soins actuellement disponibles, y compris les outils de stratification des risques et les blocs analgésiques pharmacologiques et régionaux fréquemment utilisés dans le cadre de l'approche analgésique multimodale largement recommandée. SOURCES: La littérature disponible a été recherchée à l'aide des bases de données PubMed et Embase pour chaque sujet abordé dans le présent compte rendu et examinée par des expert·es en contenu. CONSTATATIONS PRINCIPALES: Quatre outils de stratification des risques ont été identifiés, le score de l'Étude de la prise en charge des traumatismes contondants de la paroi thoracique (Study of the Management of Blunt Chest Wall Trauma) étant le plus prédictif. Les données probantes actuelles sur les techniques d'analgésie pharmacologiques (c.-à-d. acétaminophène, anti-inflammatoires non stéroïdiens, gabapentinoïdes, kétamine, lidocaïne et dexmédétomidine) et d'analgésie régionale (c.-à-d. analgésie péridurale thoracique, bloc paravertébral thoracique, bloc du plan des muscles érecteurs du rachis et bloc du plan du muscle grand dentelé) ont été examinées, de même que la physiopathologie de la ou des fractures des côtes et de leurs complications associées, y compris l'apparition de douleurs chroniques et d'incapacités. CONCLUSION: Les fractures des côtes continuent d'être un diagnostic grave, avec des taux élevés de mortalité, de développement de douleurs chroniques et d'invalidité. Il a été démontré qu'une approche multidisciplinaire de la prise en charge, combinée à une analgésie appropriée et à l'adhésion aux ensembles et protocoles de soins, réduit la morbidité et la mortalité. La plupart des parcours de soins de stratification des risques identifiés sont peu performants pour prédire la mortalité et les complications après une ou plusieurs fractures de côtes.

Rat-Bite Fever in a 34-Year-Old Female.

Rat-bite fever (RBF) is a rare systemic infectious disease caused by Streptobacillus moniliformis, Spirillum minus, or Streptobacillus notomytis. As the name implies, the disease is typically transmitted by a rat bite. RBF usually presents as a combination of fever, arthritis, and rash. Definitive diagnosis of RBF may prove difficult, as the responsible bacteria are not easily identified with standard testing. We describe a case of RBF in a 34-year-old female who presented with fever, chills, polyarthralgia, and skin rash following a rat bite. Initial vital signs were remarkable for fever and tachycardia. Physical examination revealed an erythematous vesicular and papular rash involving her extremities, buttocks, and oral mucosa. Blood cultures were negative. A skin biopsy revealed leukocytoclastic vasculitis and was negative for Gram stain. Further analysis using specialized immunohistochemistry and polymerase chain reaction (PCR) identified S. moniliformis. A diagnosis of RBF was made, and the patient was successfully treated with a two-week course of doxycycline.

Differential CD4+ T-Cell Cytokine and Cytotoxic Responses Between Reactivation and Latent Phases of Herpes Zoster Infection.

Background: CD4+ T cells are a critical component of effective immune responses to varicella zoster virus (VZV), but their functional properties during the reactivation acute vs latent phase of infection remain poorly defined. Methods: Here we assessed the functional and transcriptomic properties of peripheral blood CD4+ T cells in persons with acute herpes zoster (HZ) compared to those with a prior history of HZ infection using multicolor flow cytometry and RNA sequencing. Results: We found significant differences between the polyfunctionality of VZV-specific total memory, effector memory, and central memory CD4+ T cells in acute vs prior HZ. VZV-specific CD4+ memory T-cell responses in acute HZ reactivation had higher frequencies of IFN-γ and IL-2 producing cells compared to those with prior HZ. In addition, cytotoxic markers were higher in VZV-specific CD4+ T cells than non-VZV-specific cells. Transcriptomic analysis of ex vivo total memory CD4+ T cells from these individuals showed differential regulation of T-cell survival and differentiation pathways, including TCR, cytotoxic T lymphocytes (CTL), T helper, inflammation, and MTOR signaling pathways. These gene signatures correlated with the frequency of IFN-γ and IL-2 producing cells responding to VZV. Conclusions: In summary, VZV-specific CD4+ T cells from acute HZ individuals had unique functional and transcriptomic features, and VZV-specific CD4+ T cells as a group had a higher expression of cytotoxic molecules including Perforin, Granzyme-B, and CD107a.

Acute zoster plasma contains elevated amyloid, correlating with Aß42 and amylin levels, and is amyloidogenic.

Herpes zoster is associated with an increased dementia and neovascular macular degeneration risk and a decline in glycemic control in diabetes mellitus. Because amyloid is present and pathogenic in these diseases, we quantified amyloid, Aß40, Aß42, and amylin in 14 zoster and 10 control plasmas. Compared with controls, zoster plasma had significantly elevated amyloid that correlated with Aß42 and amylin levels and increased amyloid aggregation with addition of exogenous Aß42 or amylin. These results suggest that zoster plasma contains factor(s) that promotes aggregation of amyloidogenic peptides, potentially contributing to the toxic amyloid burden and explaining accelerated disease progression following zoster.

Venous Flaps for Revascularization and Soft-Tissue Coverage in Traumatic Hand Injuries: A Systematic Review of the Literature.

BACKGROUND: The use of the venous flap for simultaneous revascularization and coverage of soft tissue defects has been documented in the literature for over 30 years. First described in 1981, Nakayama et al demonstrated that a vein and overlying skin, or a venous flap, may be transposed from one area of the body to another with complete survival of the graft. The aim of this study was to conduct a systematic review of the literature to determine predictors of venous flap survival in traumatic hand injuries. METHODS: A literature search of PubMed, MEDLINE, and Cochrane Library was performed with emphasis on venous flap use in traumatic hand injuries. MeSH terms included: vein graft, revascularization, venous flow through flap, arterialized venous flap, bypass, replantation, amputation, avulsion, trauma, injury, amputate, finger, hand, and thumb. RESULTS: Forty-three articles were collected that contained data on 626 free venous flaps. Most patients were males (73.9) and injured their right hand (52.3%). The forearm was the most commonly used venous flap donor site (83.6%), and most of the skin paddles were 10 to 25 cm2 (41.1%). Arterial inflow was used in 93.1% of the flaps. Most venous flaps (79.6%) healed without superficial tissue loss or necrosis. Ninety-two (14.7%) flaps had partial loss while 36 (5.8%) flaps did not survive. CONCLUSION: The use of venous flaps for concomitant revascularization and soft tissue coverage of the hand permits good results with limited morbidity. The overall flap survival rate is nearly 95%. Younger patients whose flaps have arterial inflow and skin paddles of medium size (10-25 cm2) have the best chance for survival.

Discovery of IgG4 Anti-Gliadin Autoantibody as a Potential Biomarker of Psoriasis Using an Autoantigen Array.

PURPOSE: Psoriasis is a complex immunological skin disease. However, whether humoral autoimmunity is involved in the pathogenesis of psoriasis remains unclear. The aim is to determine if there are autoantibodies associated with disease activity of psoriasis. EXPERIMENTAL DESIGN: A novel autoantigen array harboring 75 antigens is developed to discover autoantibodies in the serum of psoriasis patients (N = 12) compared to healthy controls (N = 12). Validation studies are performed in a larger cohort of psoriasis patients (N = 73) and healthy controls (N = 75) together with atopic dermatitis as disease controls (N = 10). RESULTS: The screening results demonstrate that immunoglobulin G4 (IgG4) anti-gliadin autoantibodies are significantly elevated in the serum of psoriasis patients, compared to healthy controls. Receiver operating characteristic (ROC) analysis indicates that IgG4 anti-gliadin autoantibody levels can clearly discriminate psoriasis patients from healthy controls with an AUC of 0.98 (p < 0.001). Also, IgG4 anti-gliadin autoantibody can reflect disease severity with the psoriasis area severity index score in a subpopulation of psoriasis patients. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggest that IgG4 anti-gliadin autoantibody may be a disease marker of psoriasis, and it may be useful in clinical diagnostics and disease monitoring of psoriasis. CLINICAL RELEVANCE: This work represents a relatively comprehensive screening of autoantibodies, that is, IgG4 autoantibodies in psoriasis using an in-house autoantigen array. This novel proteomic platform may be useful in clinical screening of IgG type or IgG4 subtype autoantibodies in psoriasis patients for disease monitoring or drug responses. Particularly, IgG4 anti-gliadin autoantibody, as a new potential disease marker of psoriasis, may be useful in clinical diagnostics or prognostics of related immunological disorders.

Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing.

BACKGROUND: DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed 'epigenetic clocks'. The deviation of predicted age from the actual age ('age acceleration residual', AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affects such association. METHODS: In this study, we build multiple predictors based on training DNA methylation samples selected from 13,661 samples (13,402 from blood and 259 from saliva). We use the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936) to examine whether the association between AAR (from these predictors) and death is affected by (1) improving prediction accuracy of an age predictor as its training sample size increases (from 335 to 12,710) and (2) additionally correcting for confounders (i.e., cellular compositions). In addition, we investigated the performance of our predictor in non-blood tissues. RESULTS: We found that in principle, a near-perfect age predictor could be developed when the training sample size is sufficiently large. The association between AAR and mortality attenuates as prediction accuracy increases. AAR from our best predictor (based on Elastic Net, https://github.com/qzhang314/DNAm-based-age-predictor ) exhibits no association with mortality in both LBC1921 (hazard ratio = 1.08, 95% CI 0.91-1.27) and LBC1936 (hazard ratio = 1.00, 95% CI 0.79-1.28). Predictors based on small sample size are prone to confounding by cellular compositions relative to those from large sample size. We observed comparable performance of our predictor in non-blood tissues with a multi-tissue-based predictor. CONCLUSIONS: This study indicates that the epigenetic clock can be improved by increasing the training sample size and that its association with mortality attenuates with increased prediction of chronological age.

The efficacy of omalizumab in Cutaneous Mastocytosis: A case series.

BACKGROUND: Mastocytosis describes a heterogeneous group of disorders arising from a clonal proliferation of mast cells. Given the lack of curative treatments for the cutaneous form, there is a significant need for superior therapies. Omalizumab is a recombinant DNA-derived humanized IgG monoclonal antibody that selectively binds to human immunoglobulin E (IgE). It represents a potential treatment for the management of cutaneous mastocytosis, which currently has no standard treatment. METHODS: Two patients were treated with subcutaneous omalizumab 300 mg every 4 weeks. DISCUSSION: Patient 1 experienced 50% reduction in cutaneous infiltration and moderate improvement in pruritus. Patient 2 underwent 90% complete clearance of cutaneous lesions and reported full resolution of pruritus. The median duration of treatment was 24 weeks and time to response was 8 weeks. No significant changes in tryptase levels were observed. Both patients experienced injection site reactions. CONCLUSION: We provide evidence from two cases supporting the efficacy of IgE-mediated therapy in the treatment of cutaneous mastocytosis. Even at a higher-than-standard dose (300 mg vs. 150 mg), the drug was well-tolerated. As we await the results of pivotal clinical trials, omalizumab appears to be a promising treatment option in patients with cutaneous mastocytosis unresponsive to traditional therapies.

Identification of Novel Autoantibodies Associated With Psoriatic Arthritis.

OBJECTIVE: The autoimmune etiology in psoriasis remains to be clarified. We therefore undertook this study to identify novel pathogenic autoantigens and autoantibodies in patients with psoriasis, with the aim of shedding light on the molecular and cellular basis of the pathogenesis of psoriasis and psoriatic arthritis (PsA). METHODS: In this study, we developed an autoantigen array system that harbors a variety of antigens, including typical autoantigens in rheumatic diseases as well as skin antigens, inflammatory mediators, and putative autoantigens in psoriasis. Serum samples from patients with psoriasis (n = 73) were used to interrogate the antigens on the array. In addition, enzyme-linked immunosorbent assays of individual autoantibodies were used in validation studies. RESULTS: Levels of several autoantibodies were found to be elevated in the serum of patients with psoriasis compared to healthy controls; in particular, IgG autoantibodies against 2 novel antigens, LL-37 and ADAMTS-L5, were significantly increased in patients with psoriasis. Importantly, serum levels of IgG autoantibodies against LL-37 and ADAMTS-L5 were correlated with the Psoriasis Area and Severity Index, and reflected disease progression in longitudinally collected serum samples from patients with psoriasis. Importantly, both anti-ADAMTS-L5 and anti-LL-37 autoantibody levels were also significantly elevated in psoriasis patients with PsA compared to those without PsA, suggesting that these molecules may be involved in the pathogenesis of PsA. CONCLUSION: Our findings indicate that these identified autoantibodies may be useful biomarkers and may serve as therapeutic targets in psoriasis and PsA.

Human oncoviruses: Mucocutaneous manifestations, pathogenesis, therapeutics, and prevention: Hepatitis viruses, human T-cell leukemia viruses, herpesviruses, and Epstein-Barr virus.

In 1964, the first human oncovirus, Epstein-Barr virus, was identified in Burkitt lymphoma cells. Since then, 6 other human oncoviruses have been identified: human papillomavirus, Merkel cell polyomavirus, hepatitis B and C viruses, human T-cell lymphotropic virus-1, and human herpesvirus-8. These viruses are causally linked to 12% of all cancers, many of which have mucocutaneous manifestations. In addition, oncoviruses are associated with multiple benign mucocutaneous diseases. Research regarding the pathogenic mechanisms of oncoviruses and virus-specific treatment and prevention is rapidly evolving. Preventative vaccines for human papillomavirus and hepatitis B virus are already available. This review discusses the mucocutaneous manifestations, pathogenesis, diagnosis, treatment, and prevention of oncovirus-related diseases. The first article in this continuing medical education series focuses on diseases associated with human papillomavirus and Merkel cell polyomavirus, while the second article in the series focuses on diseases associated with hepatitis B and C viruses, human T-cell lymphotropic virus-1, human herpesvirus-8, and Epstein-Barr virus.

Human oncoviruses: Mucocutaneous manifestations, pathogenesis, therapeutics, and prevention: Papillomaviruses and Merkel cell polyomavirus.

In 1964, the first human oncovirus, Epstein-Barr virus, was identified in Burkitt lymphoma cells. Since then, 6 other human oncoviruses have been identified: human papillomavirus, Merkel cell polyomavirus, hepatitis B and C viruses, human T-cell lymphotropic virus-1, and human herpesvirus-8. These viruses are causally linked to 12% of all cancers, many of which have mucocutaneous manifestations. In addition, oncoviruses are associated with multiple benign mucocutaneous diseases. Research regarding the pathogenic mechanisms of oncoviruses and virus-specific treatment and prevention is rapidly evolving. Preventative vaccines for human papillomavirus and hepatitis B virus are already available. This review discusses the mucocutaneous manifestations, pathogenesis, diagnosis, treatment, and prevention of oncovirus-related diseases. The first article in this continuing medical education series focuses on diseases associated with human papillomavirus and Merkel cell polyomavirus, while the second article in the series focuses on diseases associated with hepatitis B and C viruses, human T-cell lymphotropic virus-1, human herpesvirus-8, and Epstein-Barr virus.

Concise total syntheses of (-)-jorunnamycin A and (-)-jorumycin enabled by asymmetric catalysis.

The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong Gram-positive and Gram-negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein, we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of nonnatural analogs.

Cohort profile for the STratifying Resilience and Depression Longitudinally (STRADL) study: A depression-focused investigation of Generation Scotland, using detailed clinical, cognitive, and neuroimaging assessments.

STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS provides an important opportunity to study complex gene-environment interactions, incorporating linkage to existing datasets and inclusion of early-life variables for two longitudinal birth cohorts. Specifically, data collection in STRADL included: socio-economic and lifestyle variables; physical measures; questionnaire data that assesses resilience, early-life adversity, personality, psychological health, and lifetime history of mood disorder; laboratory samples; cognitive tests; and brain magnetic resonance imaging. Some of the questionnaire and cognitive data were first assessed at the GS:SFHS baseline assessment between 2006-2011, thus providing longitudinal measures of depression and resilience. Similarly, routine NHS data and early-life variables are linked to STRADL data, further providing opportunities for longitudinal analysis. Recruitment has been completed and we consented and tested 1,188 participants.

Serum vascular endothelial growth factor receptor 3 as a potential biomarker in psoriasis.

To discover novel biomarkers of psoriasis, a target-specific antibody array screening of serum samples from psoriasis patients was initially performed. The results revealed that vascular endothelial growth factor receptor 3 (VEGFR-3) was significantly elevated in the sera of psoriasis patients, compared to healthy controls. Next, ELISA validation studies in a larger cohort of psoriasis patients (N = 73) were conducted, which confirmed that serum VEGFR-3 was indeed significantly increased in patients with psoriasis compared to healthy controls (P < 0.001). Furthermore, receiver operating characteristic curve analysis demonstrated that serum VEGFR-3 exhibited potential in distinguishing healthy controls from psoriasis patients: area under the curve = 0.85, P < 0.001. In addition, serum levels of VEGFR-3 were correlated with Psoriasis Area Severity Index scores (R = 0.32, P = 0.008) in psoriasis patients. Interestingly, serum VEGFR-3 levels were significantly elevated in psoriatic arthritis compared to non-psoriatic arthritis (P = 0.026). A pilot longitudinal study demonstrated that serum levels of VEGFR-3 could reflect disease progression in psoriasis. Collectively, serum VEGFR-3 may have a clinical value in monitoring disease activity of psoriasis.

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.