Κυριακή 5 Φεβρουαρίου 2023

Monkeypox keratoconjunctivitis with associated Wessley immune ring in an immunocompetent patient

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ABSTRACT

Monkeypox is a neglected zoonotic disease caused by Monkeypox virus (MPXV), a double-stranded DNA virus of the genus Orthopoxvirus. Here we present a case report of a 32-year-old man with MPXV infection who developed keratoconjunctivitis and Wessley immune ring with no identifiable cause other than ocular involvement by MPXV. We highlight the need of ophthalmologists exploring any ocular symptoms in MPXV-infected individuals.

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Discovery of Isojacareubin as a covalent inhibitor of SARS‐CoV‐2 main protease using structural and experimental approaches

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Abstract

The ongoing pandemic with the emergence of immune evasion potential and particularly the current omicron sub variants intensified the situation further. Although vaccine are available but the immune evasion capabilities of the recent variants demand further efficient therapeutic choices to control the SARS-CoV-2 pandemic. Hence, considering the necessity of the small molecule inhibitor we target the main protease (3CLpro) which is an appealing target for the development of anti-viral drugs against the SARS-CoV-2. High-throughput molecular in silico screening of South African natural compounds database (SANCDB) reported as Isojacareubin and Glabranin the potential inhibitors for main protease. The calculated docking scores were reported to be -8.47 kcal/mol and -8.03 kcal/mol respectively. Moreover, the structural-dynamic assessment reported that Isojacareubin in complex with 3CLpro exhibit more stable dynamic behaviour than Glabranin. Inhibition assay indicated that Isojacareubin could inhibit SARS-CoV-2 3CLpro in a time- and dose-dependent manner, with IC50 values of 16.00±1.35 μM (60-min incubation). Next, the covalent binding sites of Isojacareubin on SARS-CoV-2 3CLpro was identified by biomass spectrometry which reported that Isojacareubin can covalently bind to thiols or Cysteine through Michael addition. To evaluate the inactivation potency of Isojacareubin, the inactivation kinetics was further investigated. The inactivation kinetic curves were plotted according to various concentrations with gradient-ascending incubation times. The K I value of Isojacareubin was determined as 30.71 μM, while the K inact value was calculated as 0.054 min-1. These results suggest that Isojacareubin is a covalent inhibitor of SARS-CoV-2 3CLpro.

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Human Leukocyte Antigen Genotyping of Idiopathic Subglottic Stenosis

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Human Leukocyte Antigen Genotyping of Idiopathic Subglottic Stenosis

Idiopathic subglottic stenosis is a rare disease with incompletely understood pathophysiology. This study investigated for association with human leukocyte antigen allele variations, which have important contributions to other airway disease including granulomatosis with polyangiitis. There was no specific HLA association identified for idiopathic subglottic stenosis.


Objective

Despite recent scientific inquiry, idiopathic subglottic stenosis (iSGS) remains an enigmatic disease. The consistent demographics of the affected population suggest genetic factors may contribute to disease susceptibility. Given the inflammation observed in the affected proximal airway mucosa, we interrogated disease association with human leukocyte antigen (HLA) polymorphisms. Polymorphisms in the HLA locus have previously been shown to influence individuals' susceptibility to distinct inflammatory diseases.

Methods

High-resolution HLA typing of 37 iSGS patients was compared with 1,242,890 healthy Caucasian controls of European ancestry from the USA National Marrow Donor Program and 281 patients with granulomatosis with polyangiitis (GPA).

Results

Complete HLA genotyping of an iSGS population showed no significant associations when compared to a North American Caucasian control population. Unlike GPA patients, iSGS was not associated with allele DPB1*04:01 nor did allele homozygosity correlate with disease severity.

Conclusions

There was not a detectable HLA association observed in iSGS. These results support the concept that iSGS possesses a distinct genetic architecture from GPA. If genetic susceptibility exists in iSGS, it likely lies outside the HLA locus.

Level of Evidence

N/A, basic science Laryngoscope, 2023
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Characteristics of Adults Undergoing Soft Tissue and Orthognathic Surgery for Obstructive Sleep Apnea

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Characteristics of Adults Undergoing Soft Tissue and Orthognathic Surgery for Obstructive Sleep Apnea

Of those with obstructive sleep apnea, unique clinical and demographic characteristics were identified in those who underwent soft tissue and orthognathic sleep surgery. Trends in palate-related surgery, as well as the proportion that was female, were examined over time.


Objective

To identify clinical and demographic characteristics of adults with obstructive sleep apnea (OSA) undergoing soft tissue and orthognathic sleep surgery, assess temporal trends in surgery type and proportion of women undergoing surgery, and provide clinical perspective before wide-spread implementation of hypoglossal nerve stimulation (HGNS).

Methods

In a retrospective cohort study, adults diagnosed with OSA from 2009 to 2016 were identified in a large integrated healthcare system. Characteristics between cohort members who did and did not undergo sleep surgeries were compared. Multivariable logistic regression models examined associations of different characteristics with whether surgery was performed.

Results

Of 172,216 adults with OSA, 2,262 (1.3%) underwent sleep surgery during 2009–2017. The most common sleep surgery was palate surgery (56.9%), which decreased proportionately over time. In multivariable analysis, older age and obesity were associated with lower odds of undergoing surgery. Those who underwent tonsillectomy and adenoidectomy were more likely to have larger tonsils and not require additional surgery, whereas tongue reduction recipients were more likely to have severe OSA and require multiple surgery types. The proportion of women undergoing surgery increased over time (p < 0.001 from trend test).

Conclusion

Clinical and demographic characteristics associated with soft tissue and orthognathic sleep surgery were identified in a large adult cohort prior to widespread implementation of HGNS. An increase in sleep surgery among women and a decrease in palate surgery over time were observed. The findings provide clinical perspective on sleep surgery performed prior to implementation of HGNS and may inform future studies examining its associations with patient characteristics.

Level of Evidence

3 Laryngoscope, 2023
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α‐KG Up‐regulates Autophagic Activity in Peri‐implant Environment and Enhances Dental Implant Osseointegration in Osteoporotic Mice

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Abstract

Aim

The osseointegration of dental implants is impaired among patients with osteoporosis, leading to significantly higher failure rate. This study set out to investigate the potential effects of alpha-ketoglutarate (α-KG) on implant osseointegration in an osteoporotic mouse model.

Material and Methods

Female C57BL/6 mice received ovariectomy and bilateral first maxillary molars extraction at the age of seven weeks. Dental implants were inserted eight weeks after tooth extraction. In one of the groups, α-KG was administered via drinking water throughout the experiment period. Specimens were collected on post-implant day (PID) 3, 7, 14, and 21 for micro-CT, histological and immunohistochemical analyses. At the same time, bone marrow-derived mesenchymal stem cells (BMMSCs) treated with α-KG were interrogated for osteogenic differentiation, autophagic activity, and apoptosis.

Results

α-KG supplement in drinking water resulted in enhanced dental implant osseointegration in ovariectomized mice, with upregulated osteogenic and autophagic activity and downregulated osteoclast differentiation and cell apoptosis. α-KG treated BMMSCs demonstrated enhanced activity in proliferation, survival, colony formation, osteogenic differentiation, as well as autophagic activity.

Conclusions

Systemic α-KG supplement effectively prevents the failure of dental implant osseointegration in mice under an osteoporotic state.

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gyrA mutations in Mycoplasma genitalium and their contribution to moxifloxacin failure: time for the next generation of resistance-guided therapy

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Abstract
Background
While single nucleotide polymorphisms (SNPs) in Mycoplasma genitalium parC contribute to fluoroquinolone treatment failure, data are limited for the homologous gene, gyrA. This study investigated the prevalence of gyrA SNPs, and their contribution to fluoroquinolone failure.
Methods
Samples from 411 patients (male and female) undergoing treatment for M. genitalium infection (Melbourne Sexual Health Centre, March 2019–February 2020) were analyzed by Sanger sequencing (gyrA and parC). For patients treated with moxifloxacin (n=194), the association between SNPs and microbiologic treatment outcome was analyzed.
Results
The most common parC SNP was G248T/S83I (21.1% of samples), followed by D87N (2.3%). The most common gyrA SNP was G285A/M95I (7.1%). Dual parC/gyrA SNPs were found in 8.6% of cases. One third of infections harboring parC G248T/S83I SNP had a concurrent SNP in gyrA conferring M95I. SNPs in gyrA co-occurred with parC S83I variations. Treatment failure was higher in patients with parC S83I/gyrA dual SNPs, when compared to infections with single S83I SNP alone from analysis of (i) 194 cases in this study (81.2% vs 45.8%, p=0.047), and (ii) pooled analysis of a larger population of 535 cases (80.6% vs 43.2%; p=0.0027), indicating a strong additive ef fect.
Conclusions
Compared to parC S83I SNP alone, M. genitalium infections with dual mutations affecting parC/gyrA had twice the likelihood of failing moxifloxacin. While AMR varies by region globally, these data indicate that gyrA should be considered as a target for future resistance assays in Australasia. We propose a strategy for the next generation of resistance-guided therapy incorporating parC and gyrA testing.
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Adult intracranial ependymoma - relevance of DNA methylation profiling for diagnosis, prognosis and treatment

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Abstract
Background
A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas.
Methods
Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from eight diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS).
Results
The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6% and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratento rial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (p=0.009) and postoperative radiotherapy (p=0.007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of prognosis within molecularly defined ependymoma classes.
Conclusions
DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. Gross total resection and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.
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The AUGIS Survival Predictor: Prediction of Long-Term and Conditional Survival After Esophagectomy Using Random Survival Forests

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imageObjective: The aim of this study was to develop a predictive model for overall survival after esophagectomy using pre/postoperative clinical data and machine learning. Summary Background Data: For patients with esophageal cancer, accurately predicting long-term survival after esophagectomy is challenging. This study investigated survival prediction after esophagectomy using a Random Survival Forest (RSF) model derived from routine data from a large, well-curated, national dataset. Methods: Patients diagnosed with esophageal adenocarcinoma or squamous cell carcinoma between 2012 and 2018 in England and Wales who underwent an esophagectomy were included. Prediction models for overall survival were developed using the RSF method and Cox regression from 41 patient and disease characteristics. Calibration and discrimination (time-dependent area under the curve) were validated internally using bootstrap resampling. Results: The study analyzed 6399 patients, with 2625 deaths during follow-up. Median follow-up was 41 months. Overall survival was 47.1% at 5 years. The final RSF model included 14 variables and had excellent discrimination with a 5-year time-dependent area under the receiver operator curve of 83.9% [95% confidence interval (CI) 82.6%–84.9%], compared to 82.3% (95% CI 81.1%—83.3%) for the Cox model. The most important variables were lymph node involvement, pT stage, circumferential resection margin involvement (tumor at
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Longitudinal Trends in 30-Day Mortality Between Multi-Site and Single-Site Surgeons

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imageBackground: Quality leaders are concerned that creation of multi-hospital health systems may lead to surgeons traveling to and from distant hospitals and thus to more fragmented surgical care and worse outcomes for their patients. Despite this concern, little empirical data exist on outcomes of multi-site versus single-site surgeons. Methods: Using national Medicare data, we assessed trends in the number of multi-site vs. single-site surgeons from 2011 to 2016. We performed a multivariable regression analysis to compare overall 30-day mortality differences, stratified by system and rural status, and examined trends over time. Results: The number of multi-site surgeons and the percentage of multi-site surgeons per hospital decreased over time (24.2%–19.0%; 44.3%–41.8%). Overall, multi-site surgeons had lower 30-day mortality than single-site surgeons (2.24% vs 2.50%, P
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18F-FDG PET/CT Imaging Post Heart Transplantation Depicts High Accumulation at Sites of Previous Ventricular Assist Device Insertion

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imageA 37-year-old man with previous heart transplantation for dilated cardiomyopathy underwent screening for malignancy under posttransplantation immunosuppression. 18F-FDG PET/CT revealed uptake in 2 peritoneal sites of the pericardium that corresponded to the insertion sites of a left ventricular assist device that was used before transplantation. Additional abnormal uptake in the right axillary artery, aortic arch, and left femoral artery corresponded to the insertion sites for arterial inflow during cardiopulmonary bypass. Knowledge that FDG accumulation may occur at the insertion sites of an extracorporeal-circulatio n device enables unnecessary tests to be avoided.
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