A subset of patients with coronavirus disease 2019 (COVID-19) become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in ...severely ill patients with COVID-19 are still emerging, but the coincidence of critical illness with the timing of the onset of adaptive immunity could implicate an excessive immune response. We hypothesized that platelets might be susceptible to activation by anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies and might contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike immunoglobulin G enhanced platelet-mediated thrombosis on von Willebrand factor in vitro, but only when the glycosylation state of the Fc domain was modified to correspond with the aberrant glycosylation previously identified in patients with severe COVID-19. Furthermore, we found that activation was dependent on FcγRIIA, and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by the therapeutic small molecules R406 (fostamatinib) and ibrutinib, which inhibit tyrosine kinases Syk and Btk, respectively, or by the P2Y12 antagonist cangrelor.
OBJECTIVES
Few studies examine the impact of frailty on long‐term patient‐oriented outcomes after emergency general surgery (EGS). We measured the prevalence of frailty among older EGS patients and ...examined the impact of frailty on 1‐year outcomes.
DESIGN
Retrospective cohort study using 2008 to 2014 Medicare claims.
SETTING
Acute care hospitals.
PARTICIPANTS
Patients 65 years or older who received one of the five EGS procedures with the highest mortality burden (partial colectomy, small bowel resection, peptic ulcer disease repair, adhesiolysis, or laparotomy).
MEASUREMENTS
A validated claims‐based frailty index (CFI) identified patients who were not frail (CFI < .15), pre‐frail (.15 ≤ CFI < .25), mildly frail (.25 ≤ CFI < .35), and moderately to severely frail (CFI ≥ .35). Multivariable Cox regression compared 1‐year mortality. Multivariable Poisson regression compared rates of post‐discharge hospital encounters (hospitalizations, intensive care unit stay, emergency department visit) and home time over 1 year after discharge. All regression models adjusted for age, sex, race, admission from facility, procedure, sepsis, inpatient palliative care delivery, trauma center designation, hospital bed size, and teaching status, and they were clustered by patient and hospital referral region.
RESULTS
Among 468 459 older EGS adults, 37.4% were pre‐frail, 12.4% were mildly frail, and 3.6% were moderately to severely frail. Patients with mild frailty experienced a higher risk of 1‐year mortality compared with non‐frail patients (hazard ratio = 1.97; confidence interval CI = 1.94‐2.01). In the year after discharge, patients with mild and moderate to severe frailty had more hospital encounters compared with non‐frail patients (7.8 and 11.5 vs 2.0 per person‐year; incidence rate ratio IRR = 4.01; CI = 3.93‐4.08 vs IRR = 5.89; CI = 5.70‐6.09, respectively). Patients with mild and moderate to severe frailty also had fewer days at home in the year after discharge compared with non‐frail patients (256 and 203 vs 302 mean days; IRR = .97; CI = .96‐.97 vs IRR = .95; CI = .94‐.95, respectively).
CONCLUSION
Older EGS patients with frailty are at increased risk for poor 1‐year outcomes and decreased home time. Targeted interventions for older EGS patients with frailty during the index EGS hospitalization are urgently needed to improve long‐term outcomes. J Am Geriatr Soc 68:1037–1043, 2020
Chromosomal insertions are genomic rearrangements with a chromosome segment inserted into a non-homologous chromosome or a non-adjacent locus on the same chromosome or the other homologue, ...constituting ~2% of nonrecurrent copy-number gains. Little is known about the molecular mechanisms of their formation. We identified 16 individuals with complex insertions among 56,000 individuals tested at Baylor Genetics using clinical array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). Custom high-density aCGH was performed on 10 individuals with available DNA, and breakpoint junctions were fine-mapped at nucleotide resolution by long-range PCR and DNA sequencing in 6 individuals to glean insights into potential mechanisms of formation. We observed microhomologies and templated insertions at the breakpoint junctions, resembling the breakpoint junction signatures found in complex genomic rearrangements generated by replication-based mechanism(s) with iterative template switches. In addition, we analyzed 5 families with apparently balanced insertion in one parent detected by FISH analysis and found that 3 parents had additional small copy-number variants (CNVs) at one or both sides of the inserting fragments as well as at the inserted sites. We propose that replicative repair can result in interchromosomal complex insertions generated through chromothripsis-like chromoanasynthesis involving two or three chromosomes, and cause a significant fraction of apparently balanced insertions harboring small flanking CNVs.
Introduction
Epithelial barrier function (EBF) disruption is a key mechanism underlying gastroesophageal reflux disease (GERD). Our aim was to assess whether two novel technologies, probe-based ...confocal laser endomicroscopy (pCLE) and mucosal integrity testing (MIT), could assess EBF.
Methods
We prospectively enrolled patients undergoing upper endoscopy for refractory GERD or non-GERD conditions. Patients underwent esophagogastroduodenoscopy, pCLE, MIT, esophageal biopsy at 2 cm and 6 cm above the esophagogastric junction, and wireless pH testing. To assess EBF in vitro, biopsies were mounted in a mini-Ussing chamber, 1 ml of fluorescein was instilled on the mucosal side, and concentration of fluorescein on the serosal side was measured at 3 h.
Results
We enrolled 54 subjects (28 GERD, 26 non-GERD based on Lyon consensus criteria). In vivo permeability assessed by pCLE did not differ significantly between GERD vs. non-GERD patients and did not correlate with in vitro permeability. Mean MIT at 2 cm was lower in GERD compared to non-GERD (1914 vs. 3727 ohms). MIT correlated inversely with in vitro permeability at 2 cm and at 6 cm. Using a predictive model that used slope and intercept of MIT at 2 cm and 6 cm, sensitivity and specificity of MIT at identifying GERD was 76% and 72%, respectively.
Conclusion
pCLE did not differentiate GERD vs non-GERD and did not correlate with EBF measured in vitro. MIT, on the other hand, may be more promising as it differentiated GERD vs non-GERD and correlated with EBF measured in vitro.
HCV infects approximately 2-3% of the global population and is a leading cause of end-stage liver disease and hepatocellular carcinoma. Treatment of HCV infection with Peg-IFN in combination with ...ribavirin can eradicate HCV infection in 40-90% of patients; however, a major barrier to treatment uptake and delivery is the association of this therapy with frequent and, at times, serious adverse effects. Recognition and effective management of these adverse effects are critical components of the successful treatment of chronic HCV infection. In clinical trials, approximately 10-15% of patients discontinue Peg-IFN and ribavirin therapy due to adverse effects; however, in clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The off-target effect of Peg-IFN and ribavirin impacts most, if not all, organ systems; the most common adverse effects are hematologic, dermatologic, neurologic, immunologic, gastrointestinal, pulmonary, cardiovascular, and ocular. Regional and global variability exists in the nature of these adverse effects and the strategies employed to ameliorate their impact. This article provides a comprehensive literature review that systematically describes the adverse effects of Peg-IFN-α and ribavirin on various organ systems and, more importantly, recommends consensus approaches to managing those effects.
To synthesise exercise therapy intervention data investigating patient rating outcomes for the management of tendinopathy.
A systematic review and meta-analysis of randomized controlled trials ...investigating exercise therapy interventions and reporting patient rating outcomes.
Any setting in any country listed as very high on the human development index.
People with a diagnosis of any tendinopathy of any severity or duration.
Exercise therapy for the management of tendinopathy comprising five different therapy classes: 1) resistance; 2) plyometric; 3) vibration; 4) flexibility, and 5) movement pattern retraining modalities, were considered for inclusion.
Outcomes measuring patient rating of condition, including patient satisfaction and Global Rating of Change (GROC).
From a total of 124 exercise therapy studies, 34 (Achilles: 41%, rotator cuff: 32%, patellar: 15%, elbow: 9% and gluteal: 3%) provided sufficient information to be meta-analysed. The data were obtained across 48 treatment arms and 1246 participants. The pooled estimate for proportion of satisfaction was 0.63 95%CrI: 0.53–0.73, and the pooled estimate for percentage of maximum GROC was 53 95%CrI: 38–69%. The proportion of patients reporting positive satisfaction and perception of change increased with longer follow-up periods from treatment onset.
Patient satisfaction and GROC appear similar and are ranked moderately high demonstrating that patients generally perceive exercise therapies positively. Further research including greater consistency in measurement tools is required to explore and where possible, identify patient- and exercise-related moderating factors that can be used to improve person-centred care.
PROSPERO ID=CRD42020168187
•Patient rating of condition is one of the least measured core outcome domains in studies investigating exercise therapy.•Patients are generally satisfied and report positive perceptions of change with exercise therapy for the management of tendinopathies.
The metabolic syndrome (MS) is a constellation of risk factors associated with diabetes and cardiovascular disease. This syndrome consists of at least 3 parameters assessing central obesity, ...hypertension, high-density lipoprotein cholesterol, triglycerides, and impaired glucose metabolism. Whether persons with 4 or 5 risk factors are at higher risk than those with 3 risk factors is unclear. Also unclear is whether those without the MS but with 1 or 2 risk factors warrant therapy. We assessed cardiovascular and all-cause mortality as a function of the number of these risk factors. We followed 30,365 men for a median follow-up of 13.6 years. During follow-up, 1,449 participants died, 527 from cardiovascular causes. All of the individual parameters defining the MS were significantly associated with both all-cause and cardiovascular mortality (p <0.001). After adjustment for age and the other MS variables, hypertension was the most potent risk factor whereas central obesity and hypertriglyceridemia remained associated with both all-cause and cardiovascular mortality. A highly significant trend was also noted between both all-cause or cardiovascular mortality and the number of risk factors (p <0.001 for trend). Risk increased incrementally, beginning at 1 risk factor for cardiovascular mortality and at 2 risk factors for all-cause mortality. In conclusion, there is a continuum of risk as the number of metabolic syndrome risk factors increases. These findings add to the growing evidence that central obesity can independently and adversely affect health.
We developed a microarray for clinical diagnosis of chromosomal disorders using large insert genomic DNA clones as targets for comparative genomic hybridization (CGH).
The array contains 362 ...FISH-verified clones that span genomic regions implicated in over 40 known human genomic disorders and representative subtelomeric clones for each of the 41 clinically relevant human chromosome telomeres. Three or four clones from almost all deletion or duplication genomic regions and three or more clones for each subtelomeric region were included. We tested chromosome microarray analysis (CMA) in a masked fashion by examining genomic DNA from 25 patients who were previously ascertained in a genetic clinic and studied by conventional cytogenetics. A novel software package implemented in the R statistical programming language was developed for normalization, visualization, and inference.
The CMA results were entirely consistent with previous cytogenetic and FISH findings. For clone by clone analysis, the sensitivity was estimated to be 96.7% and the specificity was 99.1%. Major advantages of this selected human genome array include the following: interrogation of clinically relevant genomic regions, the ability to test for a wide range of duplication and deletion syndromes in a single analysis, the ability to detect duplications that would likely be undetected by metaphase FISH, and ease of confirmation of suspected genomic changes by conventional FISH testing currently available in the cytogenetics laboratory.
The array is an attractive alternative to telomere FISH and locus-specific FISH, but it does not include uniform coverage across the arms of each chromosome and is not intended to substitute for a standard karyotype. Limitations of CMA include the inability to detect both balanced chromosome changes and low levels of mosaicism.
The impact of neurological disorders is recognised globally, with one in six people affected in their lifetime and few treatments to slow or halt disease progression. This is due in part to the ...increasing ageing population, and is confounded by the high failure rate of translation from rodent-derived therapeutics to clinically effective human neurological interventions. Improved translation is demonstrated using higher order mammals with more complex/comparable neuroanatomy. These animals effectually span this translational disparity and increase confidence in factors including routes of administration/dosing and ability to scale, such that potential therapeutics will have successful outcomes when moving to patients. Coupled with advancements in genetic engineering to produce genetically tailored models, livestock are increasingly being used to bridge this translational gap.
In order to aid in standardising characterisation of such models, we provide comprehensive neurological assessment protocols designed to inform on neuroanatomical dysfunction and/or lesion(s) for large animal species. We also describe the applicability of these exams in different large animals to help provide a better understanding of the practicalities of cross species neurological disease modelling.
We would encourage the use of these assessments as a reference framework to help standardise neurological clinical scoring of large animal models.
Purpose: To compare base-in prism reading glasses with placebo reading glasses for the treatment of symptomatic convergence insufficiency (CI) in children aged 9 to <18 years. Methods: In a ...randomised clinical trial, 72 children aged 9 to <18 years with symptomatic CI were assigned to either base-in prism glasses or placebo reading glasses. Symptom level, measured with a quantitative symptom questionnaire (CI Symptom Survey-V15), was the primary outcome measure. Near point of convergence and positive fusional vergence at near were secondary outcomes. Results: The mean (SD) CI Symptom Survey score decreased (that is, less symptomatic) in both groups (base-in prism glasses from 31.6 (10.4) to 16.5 (9.2); placebo glasses from 28.4 (8.8) to 17.5 (12.3)). The change in the CI Symptom Survey scores (p = 0.33), near point of convergence (p = 0.91), and positive fusional vergence (p = 0.59) were not significantly different between the two groups after 6 weeks of wearing glasses. Conclusions: Base-in prism reading glasses were found to be no more effective in alleviating symptoms, improving the near point of convergence, or improving positive fusional vergence at near than placebo reading glasses for the treatment of children aged 9 to <18 years with symptomatic CI.
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