Abstract Background context The lumbar multifidus muscle provides an important contribution to lumbar spine stability, and the restoration of lumbar multifidus function is a frequent goal of ...rehabilitation. Currently, there are no reliable and valid physical examination procedures available to assess lumbar multifidus function among patients with low back pain. Purpose To examine the inter-rater reliability and concurrent validity of the multifidus lift test (MLT) to identify lumbar multifidus dysfunction among patients with low back pain. Study design/setting A cross-sectional analysis of reliability and concurrent validity performed in a university outpatient research facility. Patient sample Thirty-two persons aged 18 to 60 years with current low back pain and a minimum modified Oswestry disability score of 20%. Study participants were excluded if they reported a history of lumbar spine surgery, lumbar radiculopathy, medical red flags, osteoporosis, or had recently been treated with spinal manipulation or trunk stabilization exercises. Outcome measures Concurrent measures of lumbar multifidus muscle function at the L4–L5 and L5–S1 levels were obtained with the MLT (index test) and real-time ultrasound imaging (reference standard). Methods The inter-rater reliability of the MLT was examined by measuring the level of agreement between two blinded examiners. Concurrent validity of the MLT was investigated by comparing clinicians' judgments with real-time ultrasound imaging measures of lumbar multifidus function. Results Inter-rater reliability of the MLT was substantial to excellent (κ=0.75 to 0.81, p≤.01) and free from errors of bias and prevalence. When performed at L4–L5 or L5–S1, the MLT demonstrated evidence of concurrent validity through its relationship with the reference standard results at L4–L5 ( r bis =0.59–0.73, p≤.01). The MLT generally failed to demonstrate a relationship with the reference standard results from the L5–S1 level. Conclusions Our results provide preliminary evidence supporting the reliability and validity of the MLT to assess lumbar multifidus function at the L4–L5 spinal level. Additional research examining the measurement properties and utility of this test should be undertaken before confident implementation with patients.
We constructed error-correcting DNA barcodes that allow one run of a massively parallel pyrosequencer to process up to 1,544 samples simultaneously. Using these barcodes we processed bacterial 16S ...rRNA gene sequences representing microbial communities in 286 environmental samples, corrected 92% of sample assignment errors, and thus characterized nearly as many 16S rRNA genes as have been sequenced to date by Sanger sequencing.
The microbial mats of Guerrero Negro (GN), Baja California Sur, Mexico historically were considered a simple environment, dominated by cyanobacteria and sulfate-reducing bacteria. Culture-independent ...rRNA community profiling instead revealed these microbial mats as among the most phylogenetically diverse environments known. A preliminary molecular survey of the GN mat based on only ∼1500 small subunit rRNA gene sequences discovered several new phylum-level groups in the bacterial phylogenetic domain and many previously undetected lower-level taxa. We determined an additional ∼119,000 nearly full-length sequences and 28,000 >200 nucleotide 454 reads from a 10-layer depth profile of the GN mat. With this unprecedented coverage of long sequences from one environment, we confirm the mat is phylogenetically stratified, presumably corresponding to light and geochemical gradients throughout the depth of the mat. Previous shotgun metagenomic data from the same depth profile show the same stratified pattern and suggest that metagenome properties may be predictable from rRNA gene sequences. We verify previously identified novel lineages and identify new phylogenetic diversity at lower taxonomic levels, for example, thousands of operational taxonomic units at the family-genus levels differ considerably from known sequences. The new sequences populate parts of the bacterial phylogenetic tree that previously were poorly described, but indicate that any comprehensive survey of GN diversity has only begun. Finally, we show that taxonomic conclusions are generally congruent between Sanger and 454 sequencing technologies, with the taxonomic resolution achieved dependent on the abundance of reference sequences in the relevant region of the rRNA tree of life.
Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to ...examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy.
This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study.
The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib n=599 and vemurafenib plus cobimetinib n=240), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine n=207 and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab n=331), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine n=320 and n=221) were classified according to BMI as normal (694 36% patients), overweight (711 37%), or obese (513 27%). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio HR 0·77 95% CI 0·66–0·90 for progression-free survival and 0·74 0·58–0·95 for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 0·57–0·91 for progression-free survival and 0·60 0·45–0·79 for overall survival) and immunotherapy (HR 0·75 0·56–1·00 and 0·64 0·47–0·86). No associations were observed with chemotherapy (HR 0·87 0·65–1·17, pinteraction=0·61 for progression-free survival and 1·03 0·80–1·34, pinteraction=0·01 for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 0·40–0·70), but no associations observed in women (HR 0·85 0·61–1·18, pinteraction=0·03).
Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations.
ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.
Spinal pain has been previously linked with cardiovascular disease risk factors in children. This study investigated the prospective associations between cardiovascular disease risk factors and ...non-traumatic spinal pain occurrences in children, and examined the moderating role of sex and health-related physical activity in these relationships.
We used prospective data from the Childhood Health, Activity, and Motor Performance School Study Denmark (CHAMPS Study-DK). The exposure variables were a clustered cardiovascular risk score and homeostasis assessment model-estimated insulin resistance (HOMA-IR) score collected in 2008 and 2010. The spinal pain outcome comprised the number of weeks of non-traumatic spinal pain from 2008-2010 and 2010-2012. Potential confounders included age, sex, and time spent in moderate-to-vigorous intensity physical activity. We constructed age-adjusted mixed negative binominal regression models to investigate the prospective associations of cardiovascular disease risk factors and non-traumatic spinal pain, while considering the potential moderating roles of sex and physical activity in these relationships.
Girls with low HOMA-IR scores and boys with low clustered cardiovascular disease risk scores, who engaged in higher levels of moderate-to-vigorous physical activity, reported more weeks of spinal pain, compared to girls with high HOMA-IR scores (p = 0.001) and boys with high clustered cardiovascular disease risk scores (p = 0.024). whereas boys with higher clustered cardiovascular disease risk who had less time in moderate-to-vigorous physical activity reported more weeks of spinal pain than boys with low clustered cardiovascular disease risk score (p = 0.024).
Our results show that cardiovascular disease risk factors are related to future occurrences of non-traumatic spinal pain. However, these relationships appear complex and dependent on the nature of the interactions with sex and physical activity.
Sputum neutrophil elastase and serum desmosine, which is a linked marker of endogenous elastin degradation, are possible biomarkers of disease severity and progression in bronchiectasis. This study ...aimed to determine the association of elastase activity and desmosine with exacerbations and lung function decline in bronchiectasis.
This was a single-center prospective cohort study using the TAYBRIDGE (Tayside Bronchiectasis Registry Integrating Datasets, Genomics, and Enrolment into Clinical Trials) registry in Dundee, UK. A total of 433 patients with high-resolution computed tomography-confirmed bronchiectasis provided blood samples for desmosine measurement, and 381 provided sputum for baseline elastase activity measurements using an activity-based immunosassay and fluorometric substrate assay. Candidate biomarkers were tested for their relationship with cross-sectional markers of disease severity, and with future exacerbations, mortality and lung function decline over 3 years.
Elastase activity in sputum was associated with the bronchiectasis severity index (r = 0.49; P < 0.0001) and was also correlated with the Medical Research Council dyspnea score (r = 0.34; P < 0.0001), FEV
% predicted (r = -0.33; P < 0.0001), and the radiological extent of bronchiectasis (r = 0.29; P < 0.0001). During a 3-year follow-up, elevated sputum elastase activity was associated with a higher frequency of exacerbations (P < 0.0001) but was not independently associated with mortality. Sputum elastase activity was independently associated with FEV
decline (β coefficient, -0.139; P = 0.001). Elastase showed good discrimination for severe exacerbations with an area under the curve of 0.75 (95% confidence interval CI, 0.72-0.79) and all-cause mortality (area under the curve, 0.70; 95% CI, 0.67-0.73). Sputum elastase activity increased at exacerbations (P = 0.001) and was responsive to treatment with antibiotics. Desmosine was correlated with sputum elastase (r = 0.42; P < 0.0001) and was associated with risk of severe exacerbations (hazard ratio 2.7; 95% CI, 1.42-5.29; P = 0.003) but not lung function decline.
Sputum neutrophil elastase activity is a biomarker of disease severity and future risk in adults with bronchiectasis.
The COVID-19 pandemic has brought into sharp focus the need to harness and leverage our digital infrastructure for remote patient monitoring. As current viral tests and vaccines are slow to emerge, ...we see a need for more robust disease detection and monitoring of individual and population health, which could be aided by wearable sensors. While the utility of this technology has been used to correlate physiological metrics to daily living and human performance, the translation of such technology toward predicting the incidence of COVID-19 remains a necessity. When used in conjunction with predictive platforms, users of wearable devices could be alerted when changes in their metrics match those associated with COVID-19. Anonymous data localized to regions such as neighborhoods or zip codes could provide public health officials and researchers a valuable tool to track and mitigate the spread of the virus, particularly during a second wave. Identifiable data, for example remote monitoring of cohorts (family, businesses, and facilities) associated with individuals diagnosed with COVID-19, can provide valuable data such as acceleration of transmission and symptom onset. This manuscript describes clinically relevant physiological metrics which can be measured from commercial devices today and highlights their role in tracking the health, stability, and recovery of COVID-19+ individuals and front-line workers. Our goal disseminating from this paper is to initiate a call to action among front-line workers and engineers toward developing digital health platforms for monitoring and managing this pandemic.
Individual study results have demonstrated unclear relationships between neurocompressive disorders and paraspinal muscle morphology. This systematic review aimed to synthesize current evidence ...regarding the relationship lumbar neurocompressive disorders may have with lumbar paraspinal muscle morphology.
Searches were conducted in seven databases from inception through October 2017. Observational studies with control or comparison groups comparing herniations, facet degeneration, or canal stenosis to changes in imaging or biopsy-identified lumbar paraspinal muscle morphology were included. Data extraction and risk of bias assessment were performed by review author pairs independent of one another. Morphological differences between individuals with and without neurocompressive disorders were compared qualitatively, and where possible, standardised mean differences were obtained.
Twenty-eight studies were included. Lumbar multifidus fiber diameter was smaller on the side of and below herniation for type I SMD: -0.40 (95% CI = -0.70, -0.09) and type II fibers SMD: -0.38 (95% CI = -0.69, -0.06) compared to the unaffected side. The distribution of type I fibers was greater on the herniation side SMD: 0.43 (95% CI = 0.03, 0.82). Qualitatively, two studies assessing small angular fiber frequency and fiber type groupings demonstrated increases in these parameters below the herniation level. For diagnostic imaging meta-analyses, there were no consistent differences across the various assessment types for any paraspinal muscle groups when patients with herniation served as their own control. However, qualitative synthesis of between-group comparisons reported greater multifidus and erector spinae muscle atrophy or fat infiltration among patients with disc herniation and radiculopathy in four of six studies, and increased fatty infiltration in paraspinal muscles with higher grades of facet joint degeneration in four of five studies. Conflicting outcomes and variations in study methodology precluded a clear conclusion for canal stenosis.
Based on mixed levels of risk of bias data, in patients with chronic radiculopathy, disc herniation and severe facet degeneration were associated with altered paraspinal muscle morphology at or below the pathology level. As the variability of study quality and heterogeneous approaches utilized to assess muscle morphology challenged comparison across studies, we provide recommendations to promote uniform measurement techniques for future studies.
PROSPERO 2015: CRD42015012985.
Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too ...late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease.
We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with ≥ 10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90α, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES) that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC.
This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification of classifier performance provides evidence against over-fitting and is encouraging for the next development phase, independent validation. This careful study provides a solid foundation to develop tests sorely needed to identify early stage lung cancer.
Patients on hemodialysis have an elevated risk for COVID-19 but were not included in efficacy trials of SARS-CoV-2 vaccines.
We conducted a retrospective, observational study to estimate the ...real-world effectiveness and immunogenicity of two mRNA SARS-CoV-2 vaccines in a large, representative population of adult hemodialysis patients in the United States. In separate, parallel analyses, patients who began a vaccination series with BNT162b2 or mRNA-1273 in January and February 2021 were matched with unvaccinated patients and risk for outcomes were compared for days 1-21, 22-42, and ≥43 after first dose. In a subset of consented patients, blood samples were collected approximately 28 days after the second dose and anti-SARS-CoV-2 immunoglobulin G was measured.
A total of 12,169 patients received the BNT162b2 vaccine (matched with 44,377 unvaccinated controls); 23,037 patients received the mRNA-1273 vaccine (matched with 63,243 unvaccinated controls). Compared with controls, vaccinated patients' risk of being diagnosed with COVID-19 postvaccination became progressively lower during the study period (hazard ratio and 95% confidence interval for BNT162b2 was 0.21 0.13, 0.35 and for mRNA-1273 was 0.27 0.17, 0.42 for days ≥43). After a COVID-19 diagnosis, vaccinated patients were significantly less likely than unvaccinated patients to be hospitalized (for BNT162b2, 28.0% versus 43.4%; for mRNA-1273, 37.2% versus 45.6%) and significantly less likely to die (for BNT162b2, 4.0% versus 12.1%; for mRNA-1273, 5.6% versus 14.5%). Antibodies were detected in 98.1% (309/315) and 96.0% (308/321) of BNT162b2 and mRNA-1273 patients, respectively.
In patients on hemodialysis, vaccination with BNT162b2 or mRNA-1273 was associated with a lower risk of COVID-19 diagnosis and lower risk of hospitalization or death among those diagnosed with COVID-19. SARS-CoV-2 antibodies were detected in nearly all patients after vaccination. These findings support the use of these vaccines in this population.
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