Objectives The acute dissection of an ascending thoracic aortic aneurysm (ATAA) represents a devastating separation of elastic layers occurring when the hemodynamic loads on the diseased wall exceed ...the adhesive strength between layers. At present, the mechanics underlying aortic dissection are largely unclear, and the biomechanical delamination properties of the aneurysmal aorta are not defined. Individuals with bicuspid aortic valve (BAV) are particularly predisposed to ascending aortic aneurysm formation, with a marked risk of aortic dissection. The purpose of this study was to evaluate and compare the dissection properties of nonaneurysmal and aneurysmal human ascending thoracic aorta from patients with BAV morphology or normal tricuspid aortic valve (TAV) morphology using biomechanical delamination testing. Methods The influence on the delamination strength (Sd ) of the aorta associated with BAV was compared with that in patients with TAV. After complete delamination of ATAA tissue samples, tensile tests were performed on each delaminated half for comparison of their tensile strengths. Results The results showed that the aneurysmal aortas with BAV and TAV have lower Sd than nonaneurysmal aortas and that ATAA with BAV has a lower Sd than that with TAV. We have found a significant difference in Sd between longitudinal and circumferential directions of the nondiseased aorta, suggesting anisotropic dissection properties. Conclusions The tensile testing results suggest that the weaker intimal half of the aortic wall might fail before the outer adventitial half. Scanning electron microscope analyses suggest different failure modalities of dissection between the two morphologies, and the lower Sd in ATAAs appears to be associated with a disorganized microstructure. BAV ATAAs have a lower Sd than TAV ATAAs, suggesting a greater propensity for aortic dissection.
In Latin America, rabies virus has persisted in a cycle between Desmodus rotundus vampire bats and cattle, potentially enhanced by deforestation. We modeled bovine rabies virus outbreaks in Costa ...Rica relative to land-use indicators and found spatial-temporal relationships among rabies virus outbreaks with deforestation as a predictor.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy.
BACKGROUND:Surgical management of thyroid disease has evolved considerably over several decades ...leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the US.
METHODS:The medical literature from 1/1/1985 to 11/9/2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content.
RESULTS:These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches to Thyroidectomy, Laryngology, Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation.
CONCLUSIONS:Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.
Fecal microbiota transplantation (FMT) is effective for treating recurrent Clostridioides difficile infection (CDI), but there are concerns about its long-term safety. Understanding the mechanisms of ...the effects of FMT could help us design safer, targeted therapies. We aimed to identify microbial metabolites that are important for C difficile growth.
We used a CDI chemostat model as a tool to study the effects of FMT in vitro. The following analyses were performed: C difficile plate counts, 16S rRNA gene sequencing, proton nuclear magnetic resonance spectroscopy, and ultra-performance liquid chromatography and mass spectrometry bile acid profiling. FMT mixtures were prepared using fresh fecal samples provided by donors enrolled in an FMT program in the United Kingdom. Results from chemostat experiments were validated using human stool samples, C difficile batch cultures, and C57BL/6 mice with CDI. Human stool samples were collected from 16 patients with recurrent CDI and healthy donors (n = 5) participating in an FMT trial in Canada.
In the CDI chemostat model, clindamycin decreased valerate and deoxycholic acid concentrations and increased C difficile total viable counts and valerate precursors, taurocholic acid, and succinate concentrations. After we stopped adding clindamycin, levels of bile acids and succinate recovered, whereas levels of valerate and valerate precursors did not. In the CDI chemostat model, FMT increased valerate concentrations and decreased C difficile total viable counts (94% decrease), spore counts (86% decrease), and valerate precursor concentrations; concentrations of bile acids were unchanged. In stool samples from patients with CDI, valerate was depleted before FMT but restored after FMT. Clostridioides difficile batch cultures confirmed that valerate decreased vegetative growth, and that taurocholic acid was required for germination but had no effect on vegetative growth. Clostridioides difficile total viable counts were decreased by 95% in mice with CDI given glycerol trivalerate compared with phosphate buffered saline.
We identified valerate as a metabolite that is depleted with clindamycin and only recovered with FMT. Valerate is a target for a rationally designed recurrent CDI therapy.
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IMPORTANCE: Use of next-generation sequencing of RNA and machine learning algorithms can classify the risk of malignancy in cytologically indeterminate thyroid nodules to limit unnecessary diagnostic ...surgery. OBJECTIVE: To measure the performance of a genomic sequencing classifier for cytologically indeterminate thyroid nodules. DESIGN, SETTING, AND PARTICIPANTS: A blinded validation study was conducted on a set of cytologically indeterminate thyroid nodules collected by fine-needle aspiration biopsy between June 2009 and December 2010 from 49 academic and community centers in the United States. All patients underwent surgery without genomic information and were assigned a histopathology diagnosis by an expert panel blinded to all genomic information. There were 210 potentially eligible thyroid biopsy samples with Bethesda III or IV indeterminate cytopathology that constituted a cohort previously used to validate the gene expression classifier. Of these, 191 samples (91.0%) had adequate residual RNA for validation of the genomic sequencing classifier. Algorithm development and independent validation occurred between August 2016 and May 2017. EXPOSURES: Thyroid nodule surgical histopathology diagnosis by an expert panel blinded to all genomic data. MAIN OUTCOMES AND MEASURES: The primary end point was measurement of genomic sequencing classifier sensitivity, specificity, and negative and positive predictive values in biopsies from Bethesda III and IV nodules. The secondary end point was measurement of classifier performance in biopsies from Bethesda II, V, and VI nodules. RESULTS: Of the 183 included patients, 142 (77.6%) were women, and the mean (range) age was 51.7 (22.0-85.0) years. The genomic sequencing classifier had a sensitivity of 91% (95% CI, 79-98) and a specificity of 68% (95% CI, 60-76). At 24% cancer prevalence, the negative predictive value was 96% (95% CI, 90-99) and the positive predictive value was 47% (95% CI, 36-58). CONCLUSIONS AND RELEVANCE: The genomic sequencing classifier demonstrates high sensitivity and accuracy for identifying benign nodules. Its 36% increase in specificity compared with the gene expression classifier potentially increases the number of patients with benign nodules who can safely avoid unnecessary diagnostic surgery.
Transcatheter pulmonary valve placement is an emerging therapy for pulmonary regurgitation and right ventricular outflow tract obstruction in selected patients. The Melody valve was recently approved ...in the United States for placement in dysfunctional right ventricular outflow tract conduits.
From January 2007 to August 2009, 136 patients (median age, 19 years) underwent catheterization for intended Melody valve implantation at 5 centers. Implantation was attempted in 124 patients; in the other 12, transcatheter pulmonary valve placement was not attempted because of the risk of coronary artery compression (n=6) or other clinical or protocol contraindications. There was 1 death from intracranial hemorrhage after coronary artery dissection, and 1 valve was explanted after conduit rupture. The median peak right ventricular outflow tract gradient was 37 mm Hg before implantation and 12 mm Hg immediately after implantation. Before implantation, pulmonary regurgitation was moderate or severe in 92 patients (81% with data); no patient had more than mild pulmonary regurgitation early after implantation or during follow-up (>or=1 year in 65 patients). Freedom from diagnosis of stent fracture was 77.8+/-4.3% at 14 months. Freedom from Melody valve dysfunction or reintervention was 93.5+/-2.4% at 1 year. A higher right ventricular outflow tract gradient at discharge (P=0.003) and younger age (P=0.01) were associated with shorter freedom from dysfunction.
In this updated report from the multicenter US Melody valve trial, we demonstrated an ongoing high rate of procedural success and encouraging short-term valve function. All reinterventions in this series were for right ventricular outflow tract obstruction, highlighting the importance of patient selection, adequate relief of obstruction, and measures to prevent and manage stent fracture. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00740870.
•NURTURE is an ongoing study of nusinersen started in a presymptomatic stage of SMA.•All infants were ≥25 months old, and alive without permanent ventilation.•All infants achieved independent sitting ...and 88% (22/25) were walking alone.•Nusinersen demonstrated durability of effect with a median 2.9 years of follow up.•Nusinersen was well tolerated with no new safety concerns over extended follow up.
Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 25.7–45.4 months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.
OBJECTIVES:We quantified the length of recovery time by week in a cohort of pediatric sports–related concussion patients treated at concussion clinics, and examined patient and injury characteristics ...associated with prolonged recovery.
DESIGN:A retrospective, cohort design.
SETTING:Seven concussion clinics at a Midwest childrenʼs hospital.
PATIENTS:Patients aged 10 to 17 years with a diagnosed sports-related concussion presenting to the clinic within 30 days of injury.
MAIN OUTCOME MEASURES:Length of recovery by week.
METHODS:Unadjusted and adjusted multinomial logistic regression analyses were used to model the effect of patient and injury characteristics on length of recovery by week.
RESULTS:Median length of recovery was 17 days. Only 16.3% (299/1840) of patients recovered within one week, whereas 26.4% took longer than four weeks to recover. By 2 months postinjury, 6.7% of patients were still experiencing symptoms. Higher symptom scores at injury and initial visit were significantly associated with prolonged symptoms by week. Patients who presented to the clinic more than 2 weeks postinjury or who had 2 or more previous concussions showed increased risk for prolonged recovery. Females were at greater risk for prolonged recovery than males (odds ratio = 2.08, 95% confidence interval = 1.49-2.89). Age was not significantly associated with recovery length.
CONCLUSIONS:High symptom scores at injury and initial visit, time to initial clinical presentation, presence of 2 or more previous concussions, and female sex are associated with prolonged concussion recovery. Further research should aim to establish objective measures of recovery, accounting for treatment received during the recovery.
CLINICAL RELEVANCE:The median length of recovery is 17 days among pediatric sports–related concussion patients treated at concussion clinics. Only 16.3% of patients recovered within one week, whereas 26.4% took longer than 4 weeks to recover.
The development of subunit vaccine platforms has been of considerable interest due to their good safety profile and ability to be adapted to new antigens, compared to other vaccine typess. ...Nevertheless, subunit vaccines often lack sufficient immunogenicity to fully protect against infectious diseases. A wide variety of subunit vaccines have been developed to enhance antigen immunogenicity by increasing antigen multivalency, as well as stability and delivery properties, via presentation of antigens on protein nanoparticles. Increasing multivalency can be an effective approach to provide a potent humoral immune response by more strongly engaging and clustering B cell receptors (BCRs) to induce activation, as well as increased uptake by antigen presenting cells and their subsequent T cell activation. Proper orientation of antigen on protein nanoparticles is also considered a crucial factor for enhanced BCR engagement and subsequent immune responses. Therefore, various strategies have been reported to decorate highly repetitive surfaces of protein nanoparticle scaffolds with multiple copies of antigens, arrange antigens in proper orientation, or combinations thereof. In this review, we describe different chemical bioconjugation methods, approaches for genetic fusion of recombinant antigens, biological affinity tags, and enzymatic conjugation methods to effectively present antigens on the surface of protein nanoparticle vaccine scaffolds.
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