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Underdiagnosis and diagnostic delay in chronic inflammatory demyelinating polyneuropathy.
No full textBACKGROUND
The frequency and causes of underdiagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) are uncertain. We aimed to assess the frequency and electroclinical features of pre-referral CIDP underdiagnosis and the duration of delay prior to diagnosis and treatment initiation in a tertiary specialist clinic.
METHODS
We retrospectively investigated 60 consecutive patients attending our Inflammatory Neuropathy Service, between 2015 and 2019, with a final diagnosis of treatment-responsive definite/probable CIDP. We reviewed the clinical and electrophysiological data in light of European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines and determined the frequency, causes and delay in diagnosis of CIDP.
RESULTS
An initial alternative diagnosis to that of CIDP had been made in 68.3% (41/60) of patients. The commonest alternative diagnosis was of Guillain-Barré syndrome (GBS) in 23.3% (14/60) patients. Non-GBS underdiagnoses (27/60; 45%) mainly consisted of genetic neuropathy (8/27; 29.6%), diabetic neuropathy (5/27; 18.5%) and chronic idiopathic axonal polyneuropathy (4/27; 14.8%). Non-GBS underdiagnoses were predominantly due to non-recognition of proximal weakness (70.4%), multifocal deficits (18.5%) or proprioceptive loss (7.4%). Electrophysiological misinterpretation was contributory to pre-referral non-GBS underdiagnoses of CIDP in 85% of patients. Mean diagnostic delay in patients with non-GBS underdiagnoses of CIDP was of 21.3 months (range 2-132 months).
CONCLUSION
Underdiagnosis of CIDP is frequent and may lead to significant diagnostic and treatment delay. We suggest that lack of comprehensive and precise attention to typical electroclinical features of CIDP and its diagnostic criteria at the time of initial evaluation are equally contributory to underdiagnoses
Multi-center real-world comparison of the fully automated Idylla™ microsatellite instability assay with routine molecular methods and immunohistochemistry on formalin-fixed paraffin-embedded tissue of colorectal cancer.
No full textMicrosatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests
Tumor necrosis is significantly associated with reduced recurrence-free survival after curative resection of gastrointestinal stromal tumors.
No full textBACKGROUND OBJECTIVES
The impact of tumor necrosis as a prognostic factor in gastrointestinal stromal tumor (GISTs) is still debated. The objective was to determine whether tumor necrosis is an independent risk factor for survival in patients with GISTs.
METHODS
Patients undergoing surgery for primary GIST from March 2003 to October 2018 at two sarcoma referral centers were retrospectively identified. Patients who received neoadjuvant imatinib were excluded. Multivariable Cox regression models were produced, to assess whether tumor necrosis was an independent predictor of either overall or recurrence-free survival.
RESULTS
Forty-one out of 195 (21.0%) patients had tumor necrosis. Tumor necrosis was associated with a significantly higher modified National Institute of Health risk score, with 29 out of 41 (70.7%) patients with necrosis classified as high risk, compared to 52 out of 153 (34.0%) without (p < .001). Tumor necrosis was found to be independently predictive of recurrence-free survival (hazard ratio: 5.26, 95% CI: 2.62-10.56, p < .001) on multivariable analysis. At 5 years, 44.3% of patients with necrosis had either died or developed recurrence, compared to 9.9% of those without.
CONCLUSION
Tumor necrosis is an independent predictor of recurrence-free survival in patients with operable GISTs. It should be routinely reported by pathologists, and used by clinicians when counseling patients and deciding on adjuvant therapy
Only eye study 2 (OnES 2): 'Am I going to be able to see when the patch comes off?' A qualitative study of patient experiences of undergoing high-stakes only eye surgery.
No full textOBJECTIVES
Ocular surgery is a source of significant concern for many patients, especially in high-stakes circumstances. The purpose of this study was to explore patient experiences of undergoing surgery on their only-seeing eye.
DESIGN
A qualitative investigation using semistructured face-to-face interviews. Transcripts were analysed using thematic analysis.
SETTING
Hospital eye service in the UK.
PARTICIPANTS
Twelve participants with a diagnosis of glaucoma with worse eye visual acuity <3/60± end-stage visual field loss. All participants had experience of undergoing surgery on their better-seeing (ie, 'only') eye.
RESULTS
Data were coded into three key themes relating to (1) emotional impact of surgery, (2) burden of visual loss and (3) coping with surgery. Patients reported depressive symptoms at all stages of their surgical journey; concern about poor visual outcomes was a common feature. Only eye surgery imposes an emotional burden due to the uncertainty regarding individuals' ability to continue daily activities and maintaining social roles. Burden extended to the inconvenience of frequent hospital visits and difficulties with follow-up care. Participants' ability to cope effectively with surgery appeared to be linked to extent of support from healthcare professionals. Key areas in developing trust and support were an open and transparent dialogue between surgeons and patients, continuity of care, patient inclusion in decision-making, and observable empathy.
CONCLUSIONS
The findings indicate a need for an enhanced model of care in only eye surgery to better target patient preferences and allay concerns inherent with these procedures
Intracranial Bleeding After Reperfusion Therapy in Acute Ischaemic Stroke Patients Randomized to Glyceryl Trinitrate vs. Control: An Individual Patient Data Meta-Analysis.
No full textThrombolysis, with or without thrombectomy, for acute ischaemic stroke is associated with an increased risk of intracranial bleeding. We assessed whether treatment with glyceryl trinitrate (GTN), a nitric oxide donor, may influence the associated bleeding risk. We searched for completed randomized controlled trials of GTN vs. no GTN in acute ischaemic stroke with data on reperfusion treatments (thrombolysis and/or thrombectomy). The primary efficacy outcome was functional status as assessed by the modified Rankin Scale (mRS) at day 90; the primary safety outcome was intracranial bleeding. Secondary safety outcomes included symptomatic intracranial hemorrhage and haemorrhagic transformation of infarction. Individual patient data were pooled and meta-analysis performed using ordinal or binary logistic regression with adjustment for trial and prognostic variables both overall and in those randomized within 6 h of symptom onset. Three trials met the eligibility criteria. Of 715 patients with ischaemic stroke who underwent thrombolysis (709, >99%) or thrombectomy (24, 3.4%), 357 (49.9%) received GTN and 358 (50.1%) received no GTN. Overall, there was no difference in the distribution of the mRS at day 90 between GTN vs. no GTN (OR 0.94, 95% CI 0.72-1.23; = 0.65); similarly, there was no difference in intracranial hemorrhage rates between treatment groups (OR 0.90, 95% CI 0.43-1.89; = 0.77). In those randomized to GTN vs. no GTN within 6 h of symptom onset, there were numerically fewer bleeding events, but these analyses did not reach statistical significance. In ischaemic stroke patients treated predominantly with thrombolysis, transdermal GTN was safe, but did not influence functional outcome at 90 days
A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.
No full textBACKGROUND
Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.
METHODS
We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.
RESULTS
In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed.
CONCLUSIONS
This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.)
Exacerbations of Lung Disease in Alpha-1 Antitrypsin Deficiency.
No full textAlpha-1 antitrypsin deficiency (AATD) is an important risk factor for development of chronic obstructive pulmonary disease (COPD). Patients with AATD classically develop a different pattern of lung disease from those with usual COPD, decline faster and exhibit a range of differences in pathogenesis, all of which may be relevant to phenotype and/or impact of exacerbations. There are a number of definitions of exacerbation, with the main features being worsening of symptoms over at least 2 days, which may be associated with a change in treatment. In this article we review the literature surrounding exacerbations in AATD, focussing in particular on ways in which they may differ from such events in usual COPD, and the potential impact on clinical management
Acute, non-COVID related medical admissions during the first wave of COVID-19: A retrospective comparison of changing patterns of disease.
No full textCOVID-19 may have altered the case-mix of non-COVID acute medical admissions. Retrospective analysis of acute medical admissions to University Hospitals Birmingham NHS Foundation Trust, showed that medical admissions decreased in April 2020 compared to April 2019. The proportion of young adults, non-cardiac chest pain, musculoskeletal conditions and self-discharges decreased. The proportion of admissions due to alcohol misuse, psychiatric conditions, overdoses and falls increased. There were a higher number of patients admitted to ICU and greater inpatient mortality but not once COVID diagnoses were excluded. There was a significant change in hospitalised case-mix with conditions potentially reflecting social isolation increasing and diagnoses which rarely require hospital treatment, reducing. This analysis will help inform service planning
A random forest based biomarker discovery and power analysis framework for diagnostics research.
No full textBACKGROUND
Biomarker identification is one of the major and important goal of functional genomics and translational medicine studies. Large scale -omics data are increasingly being accumulated and can provide vital means for the identification of biomarkers for the early diagnosis of complex disease and/or for advanced patient/diseases stratification. These tasks are clearly interlinked, and it is essential that an unbiased and stable methodology is applied in order to address them. Although, recently, many, primarily machine learning based, biomarker identification approaches have been developed, the exploration of potential associations between biomarker identification and the design of future experiments remains a challenge.
METHODS
In this study, using both simulated and published experimentally derived datasets, we assessed the performance of several state-of-the-art Random Forest (RF) based decision approaches, namely the Boruta method, the permutation based feature selection without correction method, the permutation based feature selection with correction method, and the backward elimination based feature selection method. Moreover, we conducted a power analysis to estimate the number of samples required for potential future studies.
RESULTS
We present a number of different RF based stable feature selection methods and compare their performances using simulated, as well as published, experimentally derived, datasets. Across all of the scenarios considered, we found the Boruta method to be the most stable methodology, whilst the Permutation (Raw) approach offered the largest number of relevant features, when allowed to stabilise over a number of iterations. Finally, we developed and made available a web interface ( https://joelarkman.shinyapps.io/PowerTools/ ) to streamline power calculations thereby aiding the design of potential future studies within a translational medicine context.
CONCLUSIONS
We developed a RF-based biomarker discovery framework and provide a web interface for our framework, termed PowerTools, that caters the design of appropriate and cost-effective subsequent future omics study