The reliability of clinical judgments and criteria associated with mechanisms-based classifications of pain in patients with low back pain disorders: a preliminary reliability study

Mechanisms-based classifications of pain have been advocated for their potential to aid understanding of clinical presentations of pain and improve clinical outcomes. However, the reliability of mechanisms-based classifications of pain and the clinical criteria upon which such classifications are based are not known. The purpose of this investigation was to assess the inter- and intra-examiner reliability of clinical judgments associated with: (i) mechanisms-based classifications of pain; and (ii) the identification and interpretation of individual symptoms and signs from a Delphi-derived expert consensus list of clinical criteria associated with mechanisms-based classifications of pain in patients with low back (±leg) pain disorders. The inter- and intra-examiner reliability of an examination protocol performed by two physiotherapists on two separate cohorts of 40 patients was assessed. Data were analysed using kappa and percentage of agreement values. Inter- and intra-examiner agreement associated with clinicians’ mechanisms-based classifications of low back (±leg) pain was ‘substantial’ (kappa  = 0.77; 95% confidence interval (CI): 0.57–0.96; % agreement  = 87.5) and ‘almost perfect’ (kappa  = 0.96; 95% CI: 0.92–1.00; % agreement = 92.5), respectively. Sixty-eight and 95% of items on the clinical criteria checklist demonstrated clinically acceptable (kappa ⩾ 0.61 or % agreement ⩾ 80%) inter- and intra-examiner reliability, respectively. The results of this study provide preliminary evidence supporting the reliability of clinical judgments associated with mechanisms-based classifications of pain in patients with low back (±leg) pain disorders. The reliability of mechanisms-based classifications of pain should be investigated using larger samples of patients and multiple independent examiners.     

Gremlin 1 depletion in vivo causes severe enteropathy and bone marrow failure

The intestinal epithelium is perpetually renewed from a stem cell niche in the base of crypts to maintain a healthy bowel mucosa. Exit from this niche and maturation of epithelial cells requires tightly controlled gradients in BMP signalling, progressing from low BMP signalling at the crypt base to high signalling at the luminal surface. The BMP antagonist gremlin 1 (Grem1) is highly expressed by subepithelial myofibroblasts adjacent to the intestinal crypts but its role in regulating the stem cell niche and epithelial renewal in vivo has not been explored. To explore the effects of Grem1 loss in adulthood following normal growth and development, we bred mice (ROSA26CreER-Grem1 ^flx/flx) in which Grem1 could be deleted by tamoxifen administration. While Grem1 remained intact, these mice were healthy, grew normally, and reproduced successfully. Following Grem1 depletion, the mice became unwell and were euthanised (at 7–13 days). Post-mortem examination revealed extensive mucosal abnormalities throughout the small and large intestines with failure of epithelial cell replication and maturation, villous atrophy, and features of malabsorption. Bone marrow hypoplasia was also observed with associated early haematopoietic failure. These results demonstrate an essential homeostatic role for gremlin 1 in maintaining normal bowel epithelial function in adulthood, suggesting that abnormalities in gremlin 1 expression can contribute to enteropathies. We also identified a previously unsuspected requirement for gremlin 1 in normal haematopoiesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Prenatal hypoxia may aggravate the cognitive impairment and Alzheimer’s disease neuropathology in APP/PS1 transgenic mice

Most cases of Alzheimer's disease (AD) arise through interactions between genetic and environmental factors. It is believed that hypoxia is an important environmental factor influencing the development of AD. Our group has previously demonstrated that hypoxia increased β-amyloid (Aβ) generation in aged AD mice. Here, we further investigate the pathological role of prenatal hypoxia in AD. We exposed the pregnant APP^Swe/PS1^A246E transgenic mice to high-altitude hypoxia in a hypobaric chamber during days 7–20 of gestation. We found that prenatal hypoxic mice exhibited a remarkable deficit in spatial learning and memory and a significant decrease in synapses. We also documented a significantly higher level of amyloid precursor protein, lower level of the Aβ-degrading enzyme neprilysin, and increased Aβ accumulation in the brain of prenatal hypoxic mice. Finally, we demonstrated striking neuropathologic changes in prenatal hypoxic AD mice, showing increased phosphorylation of tau, decreased hypoxia-induced factor, and enhanced activation of astrocytes and microglia. These data suggest that although the characteristic features of AD appear later in life, hypoxemia in the prenatal stage may contribute to the pathogenesis of the disease, supporting the notion that environmental factors can trigger or aggravate AD.     

Polymorphisms in apoptosis- and proliferation-related genes, ionizing radiation exposure, and risk of breast cancer among U.S. Radiologic Technologists.

BACKGROUND: Although genes involved in apoptosis pathways and DNA repair pathways are both essential for maintaining genomic integrity, genetic variants in DNA repair have been thought to increase susceptibility to radiation carcinogenesis, but similar hypotheses have not generally been raised about apoptosis genes. For this reason, potential modification of the relationship between ionizing radiation exposure and breast cancer risk by polymorphic apoptosis gene variants have not been investigated among radiation-exposed women. METHODS: In a case-control study of 859 cases and 1,083 controls within the U.S. Radiologic Technologists cohort, we assessed breast cancer risk with respect to 16 candidate variants in eight genes involved in apoptosis, inflammation, and proliferation. Using carefully reconstructed cumulative breast dose estimates from occupational and personal diagnostic ionizing radiation, we also investigated the joint effects of these polymorphisms on the risk of breast cancer. RESULTS: In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the homozygous minor allele of CASP8 D302H [rs1045485, odds ratio (OR), 0.3; 95% confidence interval (95% CI), 0.1-0.8]. We found a significantly increased breast cancer risk with increasing minor alleles for IL1A A114S (rs17561); heterozygote OR 1.2 (95% CI, 1.0-1.4) and homozygote OR 1.5 (95% CI, 1.1-2.0), P(trend) = 0.008. Assuming a dominant genetic model, IL1A A114S significantly modified the dose-response relationship between cumulative personal diagnostic radiation and breast cancer risk, adjusted for occupational dose (P(interaction) = 0.004). CONCLUSION: The U.S. Radiologic Technologists breast cancer study provided a unique opportunity to examine the joint effects of common genetic variation and ionizing radiation exposure to the breast using detailed occupational and personal diagnostic dose data. We found evidence of effect modification of the radiation and breast cancer dose-response relationship that should be confirmed in studies with more cases and controls and quantified radiation breast doses in the low-to-moderate range.     

Mortality among Catholic nuns certified as radiologic technologists

BACKGROUND: Several studies have shown that Catholic nuns have a different mortality experience than women of similar age in the general population. We had a unique opportunity to evaluate mortality patterns of nuns identified in an occupational study of nearly 145,000 radiologic technologists (73% female). METHODS: A total of 1,103 women were classified as nuns based on their titles of "Sister" or "SR". Their mortality experience was compared to other female radiologic technologists and to U.S. white females. RESULTS: Five hundred eighty-three nuns (53%) were deceased as of January 1, 1995. Compared to other technologists, nuns were at significantly increased risk of dying from all causes (Standardized mortality ratio (SMR)=1.1; 95% Confidence interval (CI)=1.0-1.2, stomach cancer (SMR=2.7; 95% CI=1.2-5.4), diabetes (SMR=2.2; 95% CI=1.0-4.1), ischemic heart disease (SMR=1.2; 95% CI=1.1-1.4), all digestive diseases (SMR=2.0; 95% CI=1.3-3.0), and gastric and duodenal ulcers (SMR=8.3; 95% CI=2.3-21.3). In contrast, we observed a significant deficit in lung cancer (SMR=0.5; 95% CI=0.2-0.9), no deaths from cervical cancer, and a breast cancer risk 10% lower than expected (SMR=0.9; 95% CI=0.6-1.3). When compared to U.S. females, nuns experienced significantly reduced mortality from all causes (SMR=0.8; 95% CI=0.7-0.9), cervical cancer (SMR=0.0; 95% CI=0.0-0.7), all endocrine, metabolic and nutritional diseases (SMR=0.5; 95% CI=0.3-0.9), all circulatory diseases (SMR=0.7; 95% CI=0.7-0.8) including ischemic heart disease and cerebrovascular disease, and all respiratory diseases (SMR=0.5; 95% CI=0.3-0.8), and a nearly significant deficit of diabetes (SMR=0.6; 95% CI=0.3-1.0). In contrast, nuns had an almost 3-fold greater risk of tuberculosis (SMR=2.9; 95% CI=1.4-5.3) and a 20% excess of breast cancer (SMR=1. 2; 95% CI=0.8-1.7). The breast cancer excess was concentrated among nuns first certified before 1940 (SMR=2.0; CI=1.3-3.0), when radiation doses were possibly the highest, but the risk did not increase with increasing length of certification. CONCLUSIONS: Compared with the general population, the mortality experience of nuns was favorable and reflected the "healthy worker effect" commonly seen in occupational studies. Patterns observed for breast and cervical cancer possibly indicate differences in reproductive and sexual activities associated with belonging to a religious order. The possibility of a radiation-related excess for breast cancer among nuns certified before 1940 cannot be completely discounted, although there was no dose-response relationship with a surrogate measure of exposure (number of years certified). When their mortality experience was compared with other radiologic technologists, the influence of lifestyle factors was not apparent. Am. J. Ind. Med. 37:339-348, 2000. Published 2000 Wiley-Liss, Inc. dagger     

Breast cancer mortality among female radiologic technologists in the United States

We evaluated breast cancer mortality through 1997 among 69 525 female radiologic technologists who were certified in the United States from 1926 through 1982 and who responded to our questionnaire. Risk of breast cancer mortality was examined according to work history and practices and was adjusted for known risk factors. Breast cancer mortality risk was highest among women who were first employed as radiologic technologists prior to 1940 (relative risk [RR] = 2.92, 95% confidence interval [CI] = 1.22 to 7.00) compared with risk of those first employed in 1960 or later and declined with more recent calendar year of first employment (P for trend =.002). Breast cancer mortality risk increased with increasing number of years of employment as a technologist prior to 1950 (P for trend =.018). However, risk was not associated with the total number of years a woman worked as a technologist. Technologists who first performed fluoroscopy (RR = 1.69, 95% CI = 1.02 to 3.11) and multifilm procedures (RR = 1.87, 95% CI = 1.04 to 3.34) before 1950 had statistically significantly elevated risks compared with technologists who first performed these procedures in 1960 or later. The high risks of breast cancer mortality for women exposed to occupational radiation prior to 1950 and the subsequent decline in risk are consistent with the dramatic reduction in recommended radiation exposure limits over time.