Post-acute phase and sequelae management of epidermal necrolysis: an international, multidisciplinary DELPHI-based consensus.

BACKGROUND: Long-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking. OBJECTIVES: We conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae. METHODS: Participants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method. RESULTS: Fifty-two healthcare professionals participated. After the first round, a consensus was obtained for 100% of 54 initially proposed statements (disagreement index < 1). Among them, 50 statements were agreed upon as 'appropriate'; four statements were considered 'uncertain', and ultimately finally discarded. CONCLUSIONS: Our DELPHI-based expert consensus should help guide physicians in conducting a prolonged multidisciplinary follow-up of sequelae in SJS-TEN.

Surgical management and epidemiological trends of pediatric electrical burns.

Electrical burns are an uncommon yet devastating class of burn injuries. Shriners Hospitals for Children - Boston a pediatric burn center in New England and cares for both domestic and international patients. We utilized our experience over the past 13 years to review surgical management and evaluate historical trends for this unique patient group. A retrospective chart review was conducted on 68 patients aged 0-18 years admitted to our pediatric center with an electrical burn from January 2005 to December 2018. We collected and analyzed data pertaining to patient demographics, burn characteristics, clinical course, and surgical interventions. Our cohort included 31 patients from the US (46%) and 37 transferred from a variety of international countries (54%). The majority of US patients were admitted with low voltage burns (81%), whereas the majority of international patients were admitted with high voltage burns (95%). Acute and reconstructive surgical interventions were performed mainly for high voltage burns (94% and 89%). Based on our experience, epidemiology and surgical intervention varied based on voltage of the burn injury and residence of the patient. We have seen a reduction in US pediatric high voltage injuries over the past two decades, likely due to enhancement of electrical safety. It may be possible to use a similar strategy to reduce the frequency of severe high voltage electrical burn injuries in developing countries.

Investigation of 'stone fruit' aroma in Chardonnay, Viognier and botrytis Semillon wines.

Despite numerous studies, the identity of the compounds that are responsible for 'stone fruit' aroma in wine has not been conclusively established. This study focussed on wine varieties that often display peach and apricot characters, such as Chardonnay, Viognier and botrytis-affected sweet Semillon wines. Wines with high and low 'stone fruit' aroma were evaluated by gas chromatography-olfactometry-mass spectrometry (GC-O-MS) using extracts representative of the aroma of the wine in a glass. No aroma-active zone was described as 'stone fruit' aroma across all three wine varietals. However, for the individual varieties, terpenes, such as linalool and geraniol, in the Viognier wines, several esters in the Chardonnay wines, and γ-nonalactone in the botrytis Semillon were associated with 'stone fruit' aroma. Notably, this is the first study assessing the aroma profile of Viognier wine by GC-O. In addition, an extension study of Viognier grape monoterpene profiles clarified its classification as an aromatic variety.

Analysis, potency and occurrence of (Z)-6-dodeceno-γ-lactone in white wine.

(Z)-6-Dodeceno-γ-lactone is a potent aroma compound that has been little studied and its prevalence in wines is unknown. An efficient stable isotope dilution assay was developed using a simple, direct immersion solid-phase microextraction and gas chromatography-tandem mass spectrometry method suitable for routine use with a low ng/L limit of quantitation. Using this method, 99 out of 104 young white wines analysed were found to contain detectable (Z)-6-dodeceno-γ-lactone. The highest concentrations were found in Riesling and Viognier wines. (Z)-6-Dodeceno-γ-lactone was found to have an aroma detection threshold of 700 ng/L in a neutral white wine. This study established that (Z)-6-dodeceno-γ-lactone is widely present in Australia's most popular white wine varieties, but generally at concentrations below its aroma detection threshold.

Volatile Compounds Related to 'Stone Fruit' Aroma Attributes in Viognier and Chardonnay Wines.

A 'stone fruit' aroma is important in many white wine varieties and styles, but little is known about the chemical basis of this wine aroma attribute. A set of Viognier and Chardonnay wines that featured 'stone fruit' aroma attributes were selected by a panel of wine experts. The selected wines were characterized by sensory descriptive analysis and detailed volatile chemical composition analyses. This comprehensive data also allowed Viognier wine to be profiled for the first time. By partial least-squares regression, several esters and fatty acids and benzaldehyde were indicated as contributing to the 'peach' attribute; however, a reconstitution sensory study was unsuccessful in mimicking this attribute. A mixture of γ-lactones, monoterpenes, and aldehydes were positively correlated to the 'apricot' aroma, which were generally higher in the Viognier wines. Reconstitution studies confirmed that the monoterpenes linalool, geraniol, and nerol were the most important compounds for the mixture being perceived as having an 'apricot' aroma.

Hepatic Hilar Lymph Node Reactivity at Kasai Portoenterostomy for Biliary Atresia: Correlations With Age, Outcome, and Histology of Proximal Biliary Remnant.

We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.

Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans.

While progress has been made in characterizing humoral immunity to Zika virus (ZIKV) in humans, little is known regarding the corresponding T cell responses to ZIKV. Here, we investigate the kinetics and viral epitopes targeted by T cells responding to ZIKV and address the critical question of whether preexisting dengue virus (DENV) T cell immunity modulates these responses. We find that memory T cell responses elicited by prior infection with DENV or vaccination with tetravalent dengue attenuated vaccines (TDLAV) recognize ZIKV-derived peptides. This cross-reactivity is explained by the sequence similarity of the two viruses, as the ZIKV peptides recognized by DENV-elicited memory T cells are identical or highly conserved in DENV and ZIKV. DENV exposure prior to ZIKV infection also influences the timing and magnitude of the T cell response. ZIKV-reactive T cells in the acute phase of infection are detected earlier and in greater magnitude in DENV-immune patients. Conversely, the frequency of ZIKV-reactive T cells continues to rise in the convalescent phase in DENV-naive donors but declines in DENV-preexposed donors, compatible with more efficient control of ZIKV replication and/or clearance of ZIKV antigen. The quality of responses is also influenced by previous DENV exposure, and ZIKV-specific CD8 T cells from DENV-preexposed donors selectively upregulated granzyme B and PD1, unlike DENV-naive donors. Finally, we discovered that ZIKV structural proteins (E, prM, and C) are major targets of both the CD4 and CD8 T cell responses, whereas DENV T cell epitopes are found primarily in nonstructural proteins.IMPORTANCE The issue of potential ZIKV and DENV cross-reactivity and how preexisting DENV T cell immunity modulates Zika T cell responses is of great relevance, as the two viruses often cocirculate and Zika virus has been spreading in geographical regions where DENV is endemic or hyperendemic. Our data show that memory T cell responses elicited by prior infection with DENV recognize ZIKV-derived peptides and that DENV exposure prior to ZIKV infection influences the timing, magnitude, and quality of the T cell response. Additionally, we show that ZIKV-specific responses target different proteins than DENV-specific responses, pointing toward important implications for vaccine design against this global threat.

Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.

Eosinophilic esophagitis (EoE) is diagnosed by symptoms, and at least 15 intraepithelial eosinophils per high power field in an esophageal biopsy. Other pathologic features have not been emphasized. We developed a histology scoring system for esophageal biopsies that evaluates eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces (DIS), surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Severity (grade) and extent (stage) of abnormalities were scored using a 4-point scale (0 normal; 3 maximum change). Reliability was demonstrated by strong to moderate agreement among three pathologists who scored biopsies independently (P ≤ 0.008). Several features were often abnormal in 201 biopsies (101 distal, 100 proximal) from 104 subjects (34 untreated, 167 treated). Median grade and stage scores were significantly higher in untreated compared with treated subjects (P ≤ 0.0062). Grade scores for features independent of eosinophil counts were significantly higher in biopsies from untreated compared with treated subjects (basal zone hyperplasia P ≤ 0.024 and DIS P ≤ 0.005), and were strongly correlated (R-square >0.67). Principal components analysis identified three principal components that explained 78.2% of the variation in the features. In logistic regression models, two principal components more closely associated with treatment status than log distal peak eosinophil count (PEC) (R-square 17, area under the curve (AUC) 77.8 vs. R-square 9, AUC 69.8). In summary, the EoE histology scoring system provides a method to objectively assess histologic changes in the esophagus beyond eosinophil number. Importantly, it discriminates treated from untreated patients, uses features commonly found in such biopsies, and is utilizable by pathologists after minimal training. These data provide rationales and a method to evaluate esophageal biopsies for features in addition to PEC.

Placental fetal thrombotic vasculopathy in severe congenital anomalies prompting EXIT procedure.

OBJECTIVE: The ex-utero intrapartum treatment (EXIT) procedure is used to secure fetal airway, cannulate for extracorporeal membrane oxygenation (ECMO), or resect a tumor during partial delivery in a modified cesarean section. This is a retrospective study of placental pathology from EXIT procedures. METHODS: Placental reports and glass slides from 36 placentas delivered by EXIT procedure (study group SG) and 36 placentas from pregnancies without perinatal mortality and delivered by cesarean sections and matched for gestational age were blindly reviewed. Indications for EXIT procedures were: 11 cervical teratomas, 9 diaphragmatic hernias, 4 pulmonary airway malformations, 4 micrognathias, 3 vascular malformations, 3 CHAOS, and 2 aortic stenoses. 22 clinical and 43 gross and histological placental features were compared using the analysis of variance or Yates χ(2) with Holm-Bonferroni correction, where appropriate. RESULTS: The average gestational age in the SG and the CG was 34.9 weeks. Histological features of fetal thrombotic vasculopathy were more frequently seen in the SG. Of the placental features, statistically significant differences were found in, partial fibrosis of chorionic villi (9.7 ± 7.9 vs. 6.1 ± 5.3 villi per placental section) [p = 0.035], clusters of at least 3 avascular chorionic villi (33 v. 6%) [p = 0.042], and abnormal umbilical cord insertion (8% vs. 0% (p = 0.045), in the SG and the CG respectively. CONCLUSION: To the best of our knowledge, this is the first study to describe the placentas from EXIT procedures. The presence of increased frequency of fetal thrombotic vasculopathy on histology indicates an underlying chronic and on-going stasis in fetal circulation due to the presence of conditions which were indications for the EXIT procedures. The possibility of coagulopathy should be considered in management of the fetuses and neonates undergoing EXIT procedure. Detailed examination of the placenta is of utmost importance in order to recognize and treat potentially life-threatening complications.

A 5' leader sequence regulates expression of methanosarcinal CO dehydrogenase/acetyl coenzyme A synthase.

In vivo expression of CO dehydrogenase/acetyl coenzyme A synthase in Methanosarcina spp. is coordinately regulated in response to substrate by at least two mechanisms: differential transcription initiation and early elongation termination near the 3' end of a 371-bp leader sequence. This is the first report of regulation of transcription elongation in the Archaea.

The archetype gamma-class carbonic anhydrase (Cam) contains iron when synthesized in vivo.

A recombinant protein overproduction system was developed in Methanosarcina acetivorans to facilitate biochemical characterization of oxygen-sensitive metalloenzymes from strictly anaerobic species in the Archaea domain. The system was used to overproduce the archetype of the independently evolved gamma-class carbonic anhydrase. The overproduced enzyme was oxygen sensitive and had full incorporation of iron instead of zinc observed when overproduced in Escherichia coli. This, the first report of in vivo iron incorporation for any carbonic anhydrase, supports the need to reevaluate the role of iron in all classes of carbonic anhydrases derived from anaerobic environments.

Polony analysis of gene expression in ES cells and blastocysts.

Expression profiling of stem cells is challenging due to their small numbers and heterogeneity. The PCR colony (polony) approach has theoretical advantages as an assay for stem cells but has not been applied to small numbers of cells. An assay has been developed that is sensitive enough to detect mRNAs from small numbers of ES cells and from fractions of a single mouse blastocyst. Genes assayed include Oct3, Rex1, Nanog, Cdx2 and GLUT-1. The assay is highly sensitive so that multiple mRNAs from a single blastocyst were easily detected in the same assay. In its present version, the assay is an attractive alternative to conventional RT-PCR for profiling small populations of stem cells. The assay is also amenable to improvements that will increase its sensitivity and ability to analyze many cDNAs simultaneously.

Electromagnetic modelling of current flow in the heart from TASER devices and the risk of cardiac dysrhythmias.

Increasing use by law enforcement agencies of the M26 and X26 TASER electrical incapacitation devices has raised concerns about the arrhythmogenic potential of these weapons. Using a numerical phantom constructed from medical images of the human body in which the material properties of the tissues are represented, computational electromagnetic modelling has been used to predict the currents arising at the heart following injection of M26 and X26 waveforms at the anterior surface of the chest (with one TASER 'barb' directly overlying the ventricles). The modelling indicated that the peak absolute current densities at the ventricles were 0.66 and 0.11 mA mm(-2) for the M26 and X26 waveforms, respectively. When applied during the vulnerable period to the ventricular epicardial surface of guinea-pig isolated hearts, the M26 and X26 waveforms induced ectopic beats, but only at current densities greater than 60-fold those predicted by the modelling. When applied to the ventricles in trains designed to mimic the discharge patterns of the TASER devices, neither waveform induced ventricular fibrillation at peak currents >70-fold (for the M26 waveform) and >240-fold (for the X26) higher than the modelled current densities. This study provides evidence for a lack of arrhythmogenic action of the M26 and X26 TASER devices.

Auditory stream segregation in an insect.

Auditory stream segregation is the perceptual grouping of the acoustic mixture reaching the ear into coherent representations of sound sources. It has been described in a variety of vertebrates and underlies auditory scene analysis or auditory image formation. Here we describe a phenomenon in an invertebrate that bears an intriguing resemblance to auditory stream segregation observed in vertebrates: in Neoconocephalus retusus (Orthoptera, Tettigoniidae) an auditory interneuron segregates information about bat echolocation calls from background male advertisement songs. This process utilizes differences between the temporal and spectral characteristics of the two stimuli, a mechanism which is similar to those of auditory stream segregation in vertebrates. This similarity suggests that auditory stream segregation is a fundamental feature of auditory perception, widespread from invertebrates to humans.

NSAID use and BP in treated hypertensives: a retrospective controlled observational study.

The objective of this study was to investigate the association between NSAID use and blood pressure (BP) among a sample of treated hypertensive patients. A controlled observational study was designed in UK primary care setting. Patients with diagnosed hypertension and currently being prescribed antihypertensive medication registered with four general practices, comparing patients also prescribed NSAIDs (exposed) to those not prescribed NSAIDs (unexposed). Majority of the patients were elderly. Systolic and diastolic pressure were the outcome measures. Data were collected for 184 NSAID users and 762 nonusers with a mean age of 68 years. There was no difference in either systolic (adjusted difference 1.9 mmHg, 95% CI -0.7 to 4.5, P=0.15) or diastolic (adjusted difference 1.0 mmHg, 95% CI -0.3 to 2.3, P=0.15) blood pressure. There was no evidence of any interactions according to categories of age, sex, or number of antihypertensive drugs prescribed. Among NSAID users, there was no evidence of any differences in blood pressure according to NSAID type or dose. In conclusion we found no evidence for an association between NSAID usage and BP control in known hypertensive patients receiving antihypertensive medication in primary care. The reported association between NSAID use and BP control appears much less substantial than has been previously suggested.

Current management of purpura fulminans: a multicenter study.

Seven burn centers performed a 10-yr retrospective chart review of patients diagnosed with purpura fulminans. Patient demographics, etiology, presentation, medical and surgical treatment, and outcome were reviewed. A total of 70 patients were identified. Mean patient age was 13 yr. Neisseria meningitidis was the most common etiologic agent in infants and adolescents whereas Streptococcus commonly afflicted the adult population. Acute management consisted of antibiotic administration, volume resuscitation, ventilatory and inotropic support, with occasional use of corticosteroids (38%) and protein C replacement (9%). Full-thickness skin and soft-tissue necrosis was extensive, requiring skin grafting and amputations in 90% of the patients. One fourth of the patients required amputations of all extremities. Fasciotomies when performed early appeared to limit the level of amputation in 6 of 14 patients. Therefore, fasciotomies during the initial management of these patients may reduce the depth of soft-tissue involvement and the extent of amputations.

Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody.

The botulinum neurotoxins (BoNTs) cause the paralytic human disease botulism and are one of the highest-risk threat agents for bioterrorism. To generate a pharmaceutical to prevent or treat botulism, monoclonal antibodies (mAbs) were generated by phage display and evaluated for neutralization of BoNT serotype A (BoNT/A) in vivo. Although no single mAb significantly neutralized toxin, a combination of three mAbs (oligoclonal Ab) neutralized 450,000 50% lethal doses of BoNT/A, a potency 90 times greater than human hyperimmune globulin. The potency of oligoclonal Ab was primarily due to a large increase in functional Ab binding affinity. The results indicate that the potency of the polyclonal humoral immune response can be deconvoluted to a few mAbs binding nonoverlapping epitopes, providing a route to drugs for preventing and treating botulism and diseases caused by other pathogens and biologic threat agents.

Hemifacial microsomia, external auditory canal atresia, deafness and Mullerian anomalies associated with acro-osteolysis: a new autosomal recessive syndrome?

We report the combination of hemifacial microsomia, external auditory canal atresia, deafness and acro-osteolysis in several members of a highly consanguineous Asian family. In addition Mullerian anomalies have been found in two female members of the family. The external auditory canal stenosis and Mullerian anomalies in this family are similar to those reported by Winter et al. [(1968) J Pediatr 72 : 88-93] and overlap with those found in Goldenhar syndrome and Mullerian duct/renal aplasia/cervicothoracic somite dysplasia (MURCS), CHARGE and VATER associations. However, to the authors' knowledge, acro-osteolysis has not been reported in patients with any of these conditions. Overall, the findings in this family appear to be unique and the presence of consanguinity suggests an autosomal recessive condition with variable expression.

A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century.

Toxic epidermal necrolysis (TEN) is a potentially fatal disorder that involves large areas of skin desquamation. Patients with TEN are often referred to burn centers for expert wound management and comprehensive care. The purpose of this study was to define the presenting characteristics and treatment of TEN before and after admission to regional burn centers and to evaluate the efficacy of burn center treatment for this disorder. A retrospective multicenter chart review was completed for patients admitted with TEN to 15 burn centers from 1995 to 2000. Charts were reviewed for patient characteristics, non-burn hospital and burn center treatment, and outcome. A total of 199 patients were admitted. Patients had a mean age of 47 years, mean 67.7% total body surface area skin slough, and mean Acute Physiology and Chronic Health Evaluation (APACHE II) score of 10. Sixty-four patients died, for a mortality rate of 32%. Mortality increased to 51% for patients transferred to a burn center more than one week after onset of disease. Burn centers and non-burn hospitals differed in their use of enteral nutrition (70 vs 12%, respectively, P < 0.05), prophylactic antibiotics (22 vs 37.9%, P < 0.05), corticosteroid use (22 vs 51%, P < 0.05), and wound management. Age, body surface area involvement, APACHE II score, complications, and parenteral nutrition before transfer correlated with increased mortality. The treatment of TEN differs markedly between burn centers and non-burn centers. Early transport to a burn unit is warranted to improve patient outcome.