Clinical & Investigative Medicine
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Purpose: To estimate the positive predictive value (PPV) of Canadian ICD-10 diagnostic coding for the identification of hospitalization related to a diabetic foot ulcer (DFU). Methods: Hospitalizations related to a neuropathic and/or ischemic DFU were identified from the Discharge Abstract Database (DAD) records of a single Canadian tertiary care hospital between April 1, 2002 and March 31, 2019. The first coding approach required a most responsible diagnosis (MRDx) code for diabetes-specific foot ulceration or gangrene (DSFUG group). Three alternative coding approaches were also considered: MRDx code for lower-limb osteomyelitis (osteomyelitis group); lower-limb ulceration (LLU group); or lower-limb atherosclerotic gangrene (atherosclerosis group)—each in conjunction with a non-MRDx DSFUG code on the same DAD record. From all eligible DAD records, random samples were drawn for each coding group. DAD records were independently compared by a masked reviewer who manually abstracted data from the entire hospital record (reference standard). The PPV and 95% CI were generated. Results: Out of 1,460 hospitalizations, a total of 300, 50, 33 and seven records were included from the DSFUG, osteomyelitis, LLU and atherosclerosis samples, respectively. Compared to the reference standard, the PPV for all 390 records was 88.5% (95% CI 84.9 to 91.5). The DSFUG group had the highest PPV (90.0%, 95% CI 86.0 to 93.2), followed by the atherosclerosis (85.7%, 95% CI 42.1 to 99.6), LLU (84.9%, 95% CI 68.1 to 94.9) and osteomyelitis (82.0%, 95% CI 68.6 to 91.4) groups. Conclusion: Based on data from a Canadian tertiary care hospital, the specified coding algorithms can be used to identify and study the management and outcomes of people hospitalized with a DFU in Ontario.

Purpose: To evaluate the distribution of the posterior-anterior corneal radius ratio (B/F ratio; posterior corneal radius/anterior corneal radius) in patients without corneal abnormalities, and to investigate which parameters affect this ratio. Methods: Five thousand eyes from 5,000 patients who underwent cataract surgery were recruited to this study. We explored the linear relationship between B/F ratio and 13 variables using Principal Component-Multivariate Linear Regression Analysis. Results: The B/F ratio was negatively correlated with the difference between simulated keratometry (SimK) and true net power (TNP), central corneal thickness, spherical aberration (SA), and posterior corneal astigmatism and positively correlated with posterior corneal radius, corneal posterior surface, axial length (AL) and anterior corneal radius. Several variables (central corneal thickness, difference between SimK and TNP and asphericity coefficient (Q-value) of the posterior corneal surface) had the highest loading on the final score. B/F ratio reflects the refractive state and anatomical structure of the cornea: thus, higher B/F ratios were associated with larger posterior corneal surface curvature radius, longer axial length, thinner central corneal thickness, lower high order aberrations of the cornea and SA, and the numerical difference between simK and TNP gradually reduced. In clinical practice, for patients with lower B/F ratio, special care should be taken in the choice of system used for intraocular lens (IOL) measurements.

For over 40 years the journal of Clinical and Investigative Medicine (CIM) has published articles of interest to clinician investigators in Canada and elsewhere. We strive for the highest standards and to remain relevant to our readers, but we cannot achieve this goal without the help of our reviewers, all of whom play a vital role in maintaining the integrity of the scientific process. Without their efforts, academic excellence would falter.

Purpose: The coronavirus disease 2019 (COVID-19) pandemic has placed major limitations on trauma health care systems. This survey aims to identify how Canadian trauma centres altered their processes to care for injured patients and protect their staff during the pandemic. Methods: A survey was distributed to trauma directors at level 1 Canadian adult trauma centres in July 2020. Questions included changes made to the trauma service in preparation for the pandemic, modification to clinical practice and expected lasting modifications after the pandemic. Results: The response rate was 68.4%. All trauma centres modified their treatment and investigation protocols for the pandemic. Most respondents adopted online platforms for meetings and educational activities and used simulation to prepare for COVID-19-infected trauma patients. The approach to who would intubate trauma patients, which trauma patients should be tested for COVID-19 and who should use N95 ventilators, varied among the sites surveyed. Conclusion: All centres modified some of their treatment and investigation protocols for the pandemic but not all modifications were adopted universally. Knowing these steps and comparing them with other global centres will help organize disaster plans for the current and future pandemics.

Purpose: The association between subclinical hypothyroidism (SCH) and cardiovascular risk, particularly with a TSH <10 µIU/ml, remains controversial. The objective of our study was to assess the association between SCH and cardiovascular risk through carotid intima-media thickness, and alternatively, to evaluate its change after treatment with levothyroxine. Methods: A total of 54 individuals were included in the study: 18 with SCH; 18 with overt hypothyroidism (OH); and 18 healthy controls (HC). The carotid intima-media thickness was measured in each group. In SCH, follow-up was performed at three and six months after the start of levothyroxine treatment. Results: The mean age of the total population at baseline was 35.8 years. The median TSH in SCH was 6.15 µIU/ml. The carotid intima-media thickness (mean and standard deviation) was greater in SCH in comparison to the HC group: right common carotid artery (RCCA), 0.486 ± 0.106 mm and 0.413 ± 0.075 mm in SCH and HC, respectively, p=0.01 and left common carotid artery (LCCA), 0.511 ± 0.144 mm and 0.427 mm ± 0.090 in SCH and HC, respectively, p=0.03). In patients with SCH, there was a decrease in the carotid intima-media thickness after treatment with levothyroxine (RCCA and LCCA, p <0.05 at three and six months). Conclusions: There was an association between increased carotid intima-media thickness in patients with SCH in comparison with HC, even with a TSH <10 µIU/ml. The increase was reversed with levothyroxine therapy. The association of this increased thickness with important cardiovascular outcomes remains uncertain and should be evaluated in future studies.

Purpose: To evaluate the relationship between the serum calcitonin gene-related peptide (CGRP) level and severity of coronary stenosis. Methods: A total of 233 eligible patients who underwent coronary angiography were divided into two groups: a control and a coronary heart disease (CHD) group. The angiographic severity of coronary stenosis was evaluated by SYNTAX and Gensini scores. The incidence of major adverse cardiovascular events within two years was collected. Results: A negative correlation between serum CGRP levels and Gensini scores was observed in all patients (r=-0.352, p<0.001), the control group (r=-0.422, p<0.001) and the CHD group (r=-0.393, p<0.001). Serum CGRP levels were negatively associated with SYNTAX scores in the CHD group (r=-0.522, p<0.001). The area under the curve of CGRP for identifying high SYNTAX scores (>22) was 0.772 [95% confidence interval (CI): 0.673-0.870, p<0.001], and for identifying high Gensini scores was 0.744 (95% CI: 0.646-0.842, p<0.001). A CGRP concentration of 25.05 pg/ml was selected as the cutoff point. A low CGRP level (<25.05 pg/ml) was an independent predictor of severe coronary stenosis, a SYNTAX score >22 [odds ratio (OR) =5.819, 95% CI: 2.240-15.116; p<0.001] and a high Gensini score (>64) (OR=4.943, 95% CI: 2.020-12.095; p<0.001). The low CGRP group had a higher incidence of major adverse cardiovascular events within two years (11.1 vs. 3.1%, p=0.031). Conclusion: In coronary atherosclerosis patients without acute myocardial injury, serum CGRP levels were negatively associated with the severity of coronary stenosis.

Purpose: Chronic inflammation of the nasal mucosal tissues plays an important role in the pathogenesis of allergic rhinitis (AR). Aberrantly-expressed micro ribonucleic acid (miRNA) has been found to have strong associations with the inflammatory reactions in allergic diseases; however, its functional significance and molecular mechanism in AR remains unclear. The purpose of this study is to determine the functional role and mechanism of miR-181a-5p in AR. Methods: Allergic inflammatory reaction was induced by ovalbumin in human nasal epithelial cell line RPMI2650. The anti-inflammatory effects of miR-181a-5p were evaluated by examining pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α)) in the culture of RPMI-2650 cells stimulated by ovalbumin, using quantitative real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Luciferase assay and gain-of-function assay were used to investigate the association of miR-181a-5p and IL-33/p38 MAPK axis. Results: MiR-181a-5p was significantly downregulated in mucosal tissues of AR patients and in RPMI-2650 cells treated with ovalbumin. The overexpression of miR-181a-5p showed prominent suppression of inflammatory cytokine production in RPMI-2650 cells with the stimulation of ovalbumin. MiR-181a-5p directly targeted, and negatively regulated IL-33 to suppress the activation of p38 MAPK signalling. Conclusion: The results suggest that miR-181a-5p restricted allergic inflammation through inhibition of IL-33/p38 MAPK pathway, indicating miR-181a-5p may play an anti-inflammatory role in AR.

Purpose: The coronavirus disease 2019 (COVID-19) pandemic has deeply altered social and working environments among health care workers. These health care workers are therefore at risk of additional psychosocial strain and ensuing metal health symptoms, which indirectly affects patient care. In this study, we aimed to assess the psychosocial and psychopathological impact of COVID-19 among acute care mental health and addictions staff. Methods: This study is a cross-sectional survey and contains a sample size of 60 mental health and addiction acute care workers recruited from within Nova Scotia Health Authority. The survey was constructed using the online survey system, Opinio, and consisted of three sections: demographic variables (gender, age group and profession); the DASS-21 Questionnaire (which provides dimensional measures of stress, anxiety and depression); and the MBI-HSS (MP) Questionnaire (which measures three dimensions of burnout—emotional exhaustion, depersonalization and personal achievement). Results: The majority of participants had at least one pathologic score on the DASS-21 and MBI-HSS (MP) sections (75.5% and 93.5%, respectively). The median severity on the DASS-21 and MBI-HSS (MP) were both moderate, with the younger age group (20-35 years) having more significant burnout scores (p = 0.0494). Simple logistic regression showed a significant relationship between burnout severity and pathologic distress, and simple linear regression showed significant correlation between DASS-21 and MBI-HSS (MP) scores, with a R2 value of 0.4633. Conclusion: More planning, programs, resources and further research are needed to support wellness and recovery of all health care professionals who work at the mental health and addictions acute care unit.

Purpose: This study aimed to screen hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC)-related feature ribonucleic acids (RNAs) and to establish a prognostic model. Methods: The transcriptome expression data of HBV-associated HCC were downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus database. Differential RNAs between HBV-associated HCC and normal controls were identified by a meta-analysis of TCGA, GSE55092 and GSE121248. Weighted gene co-expression network analysis was performed to identify key RNAs and modules. A prognostic score model was established using TCGA as a training set by Cox regression analysis and was validated in E-TABM-36 dataset. Additionally, independent prognostic clinical factors were screened, and the function of lncRNAs waspredicted through Gene Set Enrichment Analysis. Results: A total of 710 consistent differential RNAs between HBV-associated HCC and normal controls were obtained, including five lncRNAs and 705 mRNAs. An optimized combination of six differential RNAs (DSCR4, DBH, ECM1, GDAP1, MATR3 and RFC4) was selected and a prognostic score model was constructed. Kaplan-Meier analysis demonstrated that the prognosis of the high-risk and low-risk groups separated by this model was significantly different in the training set and the validation set. Gene Set Enrichment Analysis showed that the co-expression genes of DSCR4 were significantly correlated with neuroactive ligand receptor interactionpathway. Conclusion: A prognostic model based on DSCR4, DBH, ECM1, GDAP1, MATR3 and RFC4 was developed that can accurately predict the prognosis of patients with HBV-associated HCC. These genes, as well as histologic grade, may serve as independent prognostic factors in HBV-associated HCC.

Purpose: Incidence of contrast induced nephropathy (CIN) and related risk factors in patients with liver cancer and chronic kidney disease after trans-catheter arterial chemoembolization (TACE) is higher. The purpose of this study was to investigate the feasibility and safety of TACE therapy in such patients. Methods: A retrospective analysis was performed on 103 patients with liver cancer and chronic kidney disease who underwent TACE treatments. TACE was performed according to Seldinger’s technique of arterial embolization with minor modifications. Based on CIN diagnostic criteria, patients were divided into non-CIN (n=89) and CIN (n=14) groups. Multiple clinical parameters were assessed for the two groups after TACE. Serum creatinine levels were measured 48-72 h after TACE. Results: Tumor size (>5 cm), TACE frequency, contrast agent dosage, solitary kidney, volume of iodized oil used in the TACE (ml) and urea levels were significantly higher in CIN group in comparison with the non-CIN group, while serum albumin and haemoglobin levels were significantly lower. Multivariate logistic regression analysis confirmed that the volume of iodized oil and TACE frequency were significantly positively correlated, and serum albumin level was negatively correlated in the CIN group. Conclusion: Volume of iodized oil, TACE frequency and low serum albumin levels were found to be independent risk factors for CIN after TACE. Thus, it is safe and feasible for hepatocellular carcinoma patients with chronic kidney disease to receive TACE treatment, but adverse events management after TACE needs to be addressed.