Mechanisms Linking COPD to Type 1 and 2 Diabetes Mellitus: Is There a Relationship between Diabetes and COPD?

Chronic obstructive pulmonary disease (COPD) patients frequently suffer from multiple comorbidities, resulting in poor outcomes for these patients. Diabetes is observed at a higher frequency in COPD patients than in the general population. Both type 1 and 2 diabetes mellitus are associated with pulmonary complications, and similar therapeutic strategies are proposed to treat these conditions. Epidemiological studies and disease models have increased our knowledge of these clinical associations. Several recent genome-wide association studies have identified positive genetic correlations between lung function and obesity, possibly due to alterations in genes linked to cell proliferation; embryo, skeletal, and tissue development; and regulation of gene expression. These studies suggest that genetic predisposition, in addition to weight gain, can influence lung function. Cigarette smoke exposure can also influence the differential methylation of CpG sites in genes linked to diabetes and COPD, and smoke-related single nucleotide polymorphisms are associated with resting heart rate and coronary artery disease. Despite the vast literature on clinical disease association, little direct mechanistic evidence is currently available demonstrating that either disease influences the progression of the other, but common pharmacological approaches could slow the progression of these diseases. Here, we review the clinical and scientific literature to discuss whether mechanisms beyond preexisting conditions, lifestyle, and weight gain contribute to the development of COPD associated with diabetes. Specifically, we outline environmental and genetic confounders linked with these diseases.

LRP1 loss in airway epithelium exacerbates smoke-induced oxidative damage and airway remodeling.

The LDL receptor-related protein 1 (LRP1) partakes in metabolic and signaling events regulated in a tissue-specific manner. The function of LRP1 in airways has not been studied. We aimed to study the function of LRP1 in smoke-induced disease. We found that bronchial epithelium of patients with chronic obstructive pulmonary disease and airway epithelium of mice exposed to smoke had increased LRP1 expression. We then knocked out LRP1 in human bronchial epithelial cells in vitro and in airway epithelial club cells in mice. In vitro, LRP1 knockdown decreased cell migration and increased transforming growth factor ß activation. Tamoxifen-inducible airway-specific LRP1 knockout mice (club Lrp1-/-) induced after complete lung development had increased inflammation in the bronchoalveolar space and lung parenchyma at baseline. After 6 months of smoke exposure, club Lrp1-/- mice showed a combined restrictive and obstructive phenotype, with lower compliance, inspiratory capacity, and forced expiratory volume0.05/forced vital capacity than WT smoke-exposed mice. This was associated with increased values of Ashcroft fibrotic index. Proteomic analysis of room air exposed-club Lrp1-/- mice showed significantly decreased levels of proteins involved in cytoskeleton signaling and xenobiotic detoxification as well as decreased levels of glutathione. The proteome fingerprint created by smoke eclipsed many of the original differences, but club Lrp1-/- mice continued to have decreased lung glutathione levels and increased protein oxidative damage and airway cell proliferation. Therefore, LRP1 deficiency leads to greater lung inflammation and damage and exacerbates smoke-induced lung disease.

Blinding in Clinical Trials: Seeing the Big Picture.

Blinding mitigates several sources of bias which, if left unchecked, can quantitively affect study outcomes. Blinding remains under-utilized, particularly in non-pharmaceutical clinical trials, but is often highly feasible through simple measures. Although blinding is generally viewed as an effective method by which to eliminate bias, blinding does also pose some inherent limitations, and it behooves clinicians and researchers to be aware of such caveats. This article will review general principles for blinding in clinical trials, including examples of useful blinding techniques for both pharmaceutical and non-pharmaceutical trials, while also highlighting the limitations and potential consequences of blinding. Appropriate reporting on blinding in trial protocols and manuscripts, as well as future directions for blinding research, will also be discussed.

Foundational Statistical Principles in Medical Research: Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value.

Sensitivity, which denotes the proportion of subjects correctly given a positive assignment out of all subjects who are actually positive for the outcome, indicates how well a test can classify subjects who truly have the outcome of interest. Specificity, which denotes the proportion of subjects correctly given a negative assignment out of all subjects who are actually negative for the outcome, indicates how well a test can classify subjects who truly do not have the outcome of interest. Positive predictive value reflects the proportion of subjects with a positive test result who truly have the outcome of interest. Negative predictive value reflects the proportion of subjects with a negative test result who truly do not have the outcome of interest. Sensitivity and specificity are inversely related, wherein one increases as the other decreases, but are generally considered stable for a given test, whereas positive and negative predictive values do inherently vary with pre-test probability (e.g., changes in population disease prevalence). This article will further detail the concepts of sensitivity, specificity, and predictive values using a recent real-world example from the medical literature.

Foundational Statistical Principles in Medical Research: A Tutorial on Odds Ratios, Relative Risk, Absolute Risk, and Number Needed to Treat.

Evidence-based medicine is predicated on the integration of best available research evidence with clinical expertise and patient values to inform care. In medical research, several distinct measures are commonly used to describe the associations between variables, and a sound understanding of these pervasive measures is foundational in the clinician's ability to interpret, synthesize, and apply available evidence from the medical literature. Accordingly, this article aims to provide an educational tutorial/topic primer on some of the most ubiquitous measures of association and risk quantification in medical research, including odds ratios, relative risk, absolute risk, and number needed to treat, using several real-world examples from the medical literature.

Therapeutic Potential of Alpha-1 Antitrypsin in Type 1 and Type 2 Diabetes Mellitus.

Alpha-1 antitrypsin (AAT) has established anti-inflammatory and immunomodulatory effects in chronic obstructive pulmonary disease but there is increasing evidence of its role in other inflammatory and immune-mediated conditions, like diabetes mellitus (DM). AAT activity is altered in both developing and established type 1 diabetes mellitus (T1DM) as well in established type 2 DM (T2DM). Augmentation therapy with AAT appears to favorably impact T1DM development in mice models and to affect ß-cell function and inflammation in humans with T1DM. The role of AAT in T2DM is less clear, but AAT activity appears to be reduced in T2DM. This article reviews these associations and emerging therapeutic strategies using AAT to treat DM.

Primary Small Cell Carcinoma of the Kidney: Disease Characteristics and Treatment Outcomes.

Background: Primary small cell carcinoma of the kidney (PSCCK) is exceedingly rare and data on disease characteristics and outcomes are sparse. This study examines a nationally-representative cancer registry to better characterize PSCCK. Methods: We queried the National Cancer Database to identify patients with histology-confirmed PSCCK from 2004 to 2015. Adjusted Cox proportional hazards regression and Kaplan-Meier analyses were employed to assess predictors of mortality and estimate median survival time, respectively. Results: A total of 110 patients were included (47:53% female:male, 77% ≥60 years of age, 86% Caucasian). Significant predictors of mortality included female sex, age 60-69 years, treatment at an Integrated Network Cancer Program, stage cM1, and lack of surgical and chemoradiotherapy treatment. Independent protective factors were high socioeconomic status and treatment at an Academic Research Program. The estimated median overall survival time was 9.31 (95% CI 7.28-10.98) months for all patients. No differences in estimated survival time were observed across individual treatment modalities among those patients who underwent treatment (p = 0.214). Conclusions: PSCCK is an aggressive malignancy with a median survival time of less than one year. Future studies that correlate clinical tumor staging with specific treatment modalities are needed to optimize and individualize management.

Phenotyping the Association between Nocturia and Hypertension: A Systematic Review and Meta-Analysis.

PURPOSE: The association between nocturia and hypertension has been widely reported yet remains poorly characterized, precluding a more refined understanding of blood pressure as it relates to the clinical urology setting. We synthesized current evidence on the relationship between nocturia and hypertension as a function of nocturia severity, age, gender, race, body mass index and diuretic use. MATERIALS AND METHODS: We searched PubMed®, EMBASE® and Cochrane databases for studies published up to May 2020. Random effects meta-analyses were performed to identify pooled odds ratios for nocturia given the presence of hypertension. Meta-regression and subgroup analyses were performed to identify differences across study samples. RESULTS: Of 1,193 identified studies, 25 met the criteria for inclusion. The overall pooled OR for the association of nocturia with hypertension was 1.25 (95% CI 1.21-1.28, p <0.001). Pooled estimates were 1.20 (1.16-1.25, p <0.001) and 1.30 (1.25-1.36, p <0.001) using a 1-void and 2-void cutoff for nocturia, respectively (p <0.001 between cutoffs). The association was more robust in patient-based (1.74 [1.54-1.98], p <0.001) vs community-based (1.24 [1.24-1.29], p <0.001) study samples (p <0.001). The association was stronger in females compared to males (1.45 [1.32-1.58] vs 1.28 [1.22-1.35], p <0.001), and Black (1.56 [1.25-1.94]) and Asian (1.28 [1.23-1.33]) vs White subgroups (1.16 [1.08-1.24]; p <0.05 for both). No effect was observed for age or body mass index. Evidence on diuretics was limited. CONCLUSIONS: Hypertension is associated with a 1.2-fold to 1.3-fold higher risk of nocturia. This association is more robust at a higher nocturia cutoff, in patient-based study samples, among females and in Black and Asian patients, but unrelated to age or body mass index.

Cardiovascular risk independently predicts small functional bladder storage capacity.

PURPOSE: We aimed to determine the potential relationship between atherosclerotic cardiovascular disease (ASCVD) score, which equates to 10-year risk of atherosclerotic cardiovascular events, and functional bladder capacity (FBC) among men in the outpatient urology setting. METHODS: We secondarily analyzed voiding diaries from men aged 40 to 79 years with nocturia. Patients with a history of cardiovascular disease or who had nocturnal polyuria were excluded. Patients were stratified by whether they met the high-risk ASCVD threshold (≥ 20%) following current cardiology consensus guidelines and assessed for the presence of small FBC (24-h maximum voided volume ≤ 200 ml). Logistic regression analyses were employed to explore associations between small FBC and ASCVD. RESULTS: Eighty-four men (median ASCVD score 18.4 [IQR 12.8-26.9] %, age 66 [61-71] years, body mass index [BMI] 29.4 [26.4-32.7] kg/m2) were included, of whom 36 (42.9%) were high-risk and 48 (57.1%) fell below the high-risk threshold. High-risk patients were more likely to have small FBC (23 [63.9%] vs. 14 [29.2%], p = 0.002). ASCVD risk predicted small FBC on univariate analysis (p = 0.002). No such effect was observed with age (p = 0.116), BMI (p = 0.523), or benign prostatic obstruction (p = 0.180). The association between ASCVD risk and small FBC persisted on multivariate analysis after controlling for BMI and benign prostatic obstruction (p = 0.002). No significant predictors of small FBC were observed when age, a major determinant of ASCVD risk and independent correlate of small FBC, was substituted for ASCVD score (p = 0.108). CONCLUSIONS: Small FBC is related to a higher predicted cardiovascular event rate in men with nocturia.

Nocturia and electrocardiographic abnormalities among patients at an inner-city cardiology clinic.

AIMS: Nocturia has been increasingly recognized as a potential manifestation of cardiovascular disease. However, the relationship between nocturia and electrocardiographic (ECG) abnormalities has not been studied. This study aims to characterize the diagnostic utility of nocturia in identifying left ventricular hypertrophy (LVH), left atrial enlargement (LAE), and prolonged QTc on ECG. METHODS: Retrospective analysis of nocturnal voiding frequency and contemporaneous ECG data from consecutive patients evaluated at a university-based outpatient cardiology clinic. Three sets of three incremental binary multiple logistic regression models controlling for (1) age, (2) sex and race, and (3) body mass index, hypertension, diabetes mellitus, and diuretic utilization were performed to determine whether nocturia was predictive of LVH, LAE, and prolonged QTc. RESULTS: Included patients (n = 143, 77.6% nocturia) were predominantly African-American (89.5%), female (74.1%), and obese (61.5%), of whom 44.1%, 41.3%, and 27.3% had LVH, LAE, and prolonged QTc, respectively. Older age, African-American race, obesity, hypertension, diuretic use, LVH, and LAE were significantly associated with nocturia on univariate analysis. No significant differences were observed in the strength of associations between nocturia and LVH, LAE, or QTc prolongation based on age. Nocturia independently predicted LVH in Models I-III (odds ratios [ORs], 2.99-3.20; relative risks [RRs], 1.18 for all, p ≤ .046) and LAE in Models I-III (ORs, 4.24-4.72; RRs, 1.21 for all, p ≤ .015). No significant associations were observed between nocturia and prolonged QTc. CONCLUSIONS: Nocturia may be a risk marker for underlying structural cardiac abnormalities.

Assessing the role of race in pathological upstaging of renal cell carcinoma: Results from the National Cancer Database.

PURPOSE: Pathologic upstaging in renal cell carcinoma (RCC) is common and confers a significant risk of poor surgical and survival outcomes. Preoperative predictors of upstaging are of great clinical relevance but empirical evidence specific to racial minorities remains scarce. METHODS: National Cancer Database (NCDB) analysis of T3a-specific upstaging among White, African-American, Hispanic and Asian Pacific Islander (API) patients with AJCC cT1N0M0 RCC who underwent partial or radical nephrectomy between 2010 and 2015. Independent preoperative predictors of tumour upstaging were identified using multivariate logistic regression analyses. RESULTS: A total of 81 002 patients met the criteria for inclusion (5.6% T3a-specific upstaging). Increased age, increased Charlson-Deyo comorbidity index, clinical stages cT1b and unspecified cT1, and increased Fuhrman nuclear grade were identified as independent risk factors for upstaging. Independent protective factors for upstaging were younger age, female sex, African-American race and papillary, chromophobe, and unspecified RCC histologic subtypes. Significant risk factors and protective factors within individual racial subgroups were highly consistent with those observed in the overall study sample. All independent factors identified on race-specific subgroup analyses were significant in the same direction relative to the overall study sample. Variables found to be non-significant in the overall study sample remained non-significant across all racial subgroup analyses. CONCLUSION: The present study of nationally representative data found no clinically significant differences in upstaging risk across individual racial subgroups relative to the overall study sample. Preoperative factors that can be used to predict pT3a-specific tumour upstaging in CT1N0M0 RCC likely persist across different racial groups.

Nocturnal Urine Production in Women With Global Polyuria.

PURPOSE: Low nocturnal urine production (NUP) may be sufficient to rule out global polyuria (GP) in men. This study determines the sensitivity of indices for nocturnal polyuria (NP), defined as nocturnal polyuria index (NPi; nocturnal urine volume/24-hour urine volume) ≥0.33 or NUP ≥90 mL/hr, for detecting GP in women. METHODS: Data were analyzed from 2 prospective protocols involving subjects recruited from a urology ambulatory care unit and a continence clinic. Women ≥18 years with nocturia were included if they met either of 2 common criteria for GP: (1) ≥40 mL/kg/24 hr or (2) ≥3,000 mL/24 hr. RESULTS: Thirty-one women were included (NPi, 28.6 [21.3-40.7]; NUP, 100.8 [68.3-135.8] mL/hr). At the ≥40 mL/kg/24-hr cutoff, 40% and 63% of women reporting ≥1 nocturnal void(s) (n=30) had NPi ≥0.33 and NUP ≥90 mL/hr, respectively. Additionally, 53% and 71% of subjects reporting ≥2 nocturnal voids (n=17) had NPi ≥0.33 and NUP ≥90 mL/hr, respectively. At the ≥3,000 mL/24-hr cutoff, 38% and 69% of women reporting ≥1 nocturnal void(s) (n=13) had NPi ≥0.33 and NUP ≥90 mL/hr, respectively, and 63% and 88% of subjects reporting ≥2 nocturnal voids (n=8) had NPi ≥0.33 and NUP ≥90 mL/hr, respectively. By extension, 37%-62% of women with nocturia and GP did not have NP by NPi ≥0.33 criteria, and 12%-37% did not have NP by NUP ≥90 mL/hr criteria. CONCLUSION: Indices of excess nighttime urination do not reliably predict GP in women. A full-length voiding diary may be particularly important in the evaluation of women with nocturia. Nocturia in women merits further consideration as a distinct entity.

Alveolar lipids in pulmonary disease. A review.

Lung lipid metabolism participates both in infant and adult pulmonary disease. The lung is composed by multiple cell types with specialized functions and coordinately acting to meet specific physiologic requirements. The alveoli are the niche of the most active lipid metabolic cell in the lung, the type 2 cell (T2C). T2C synthesize surfactant lipids that are an absolute requirement for respiration, including dipalmitoylphosphatidylcholine. After its synthesis and secretion into the alveoli, surfactant is recycled by the T2C or degraded by the alveolar macrophages (AM). Surfactant biosynthesis and recycling is tightly regulated, and dysregulation of this pathway occurs in many pulmonary disease processes. Alveolar lipids can participate in the development of pulmonary disease from their extracellular location in the lumen of the alveoli, and from their intracellular location in T2C or AM. External insults like smoke and pollution can disturb surfactant homeostasis and result in either surfactant insufficiency or accumulation. But disruption of surfactant homeostasis is also observed in many chronic adult diseases, including chronic obstructive pulmonary disease (COPD), and others. Sustained damage to the T2C is one of the postulated causes of idiopathic pulmonary fibrosis (IPF), and surfactant homeostasis is disrupted during fibrotic conditions. Similarly, surfactant homeostasis is impacted during acute respiratory distress syndrome (ARDS) and infections. Bioactive lipids like eicosanoids and sphingolipids also participate in chronic lung disease and in respiratory infections. We review the most recent knowledge on alveolar lipids and their essential metabolic and signaling functions during homeostasis and during some of the most commonly observed pulmonary diseases.

Overlap between nocturnal polyuria, diurnal polyuria, and 24-h polyuria among men with nocturia.

PURPOSE: A recent update in International Continence Society (ICS) terminology now recognizes nocturnal polyuria (NP) and diurnal polyuria (DP) as related subcategories of "Polyuria (global symptom)". This study determines the real-world clinical overlap between NP, DP, and 24-h polyuria (24hP) among men with nocturia. METHODS: Analysis of frequency-volume charts from men ≥ 18 years with ≥ 1 nocturnal void(s). Three separate analyses were performed using different rate criteria for NP, DP, and 24hP: (1) urine production > 90 mL/h (extrapolated from a proposed definition for NP); (2) > 125 mL/h (extrapolated from a proposed definition for 24hP [3000 mL/24 h]); and (3) > 1.67 mL/kg/h (extrapolated from the current ICS definition for 24hP [> 40 mL/kg/24 h]). Subjects were categorized as having one of five mathematically permissible phenotypic combinations: (1) isolated NP, (2) isolated DP, (3) NP + 24hP, (4) DP + 24hP, and (5) NP + DP + 24hP. RESULTS: 167, 95, and 61 patients were included at criteria 1, 2, and 3, respectively, with 56%, 43%, and 30% of patients demonstrating overlapping phenotypes (i.e., phenotypic combinations 3-5) at cut-offs 1-3, respectively. The prevalence of NP was similar across cut-offs (81-87%), but the prevalence of NP without 24hP was highly threshold-dependent (43-73%). CONCLUSION: Consistent with current ICS terminology, there exists a substantial overlap between NP, DP, and 24hP. As demonstrated in the current study, absolute volume-based criteria for NP/DP/24hP are indeed conducive to the diagnosis of concurrent NP + 24hP, and may be preferred over proportion-based NP criteria when both NP + 24hP are suspected.

Correction to: Association between nocturia and frailty among elderly males in a veterans administration population.

In the original publication of the article, the author's name Jeffrey P. Weiss was misspelled as "Jeffry P. Weiss".

Decreased surfactant lipids correlate with lung function in chronic obstructive pulmonary disease (COPD).

Smoke exposure is known to decrease total pulmonary surfactant and alter its composition, but the role of surfactant in chronic obstructive pulmonary disease (COPD) remains unknown. We aimed to analyze the compositional changes in the surfactant lipidome in COPD and identify specific lipids associated with pulmonary function decline. Bronchoalveolar lavage (BAL) fluid was obtained from 12 former smokers with COPD and 5 non-smoking, non-asthmatic healthy control volunteers. Lipids were extracted and analyzed by liquid chromatography and mass spectrometry. Pulmonary function data were obtained by spirometry, and correlations of lung function with lipid species were determined. Wild-type C57BL/6 mice were exposed to 6 months of second-hand smoke in a full-body chamber. Surfactant lipids were decreased by 60% in subjects with COPD. All phospholipid classes were dramatically decreased, including ether phospholipids, which have not been studied in pulmonary surfactant. Availability of phospholipid, cholesterol, and sphingomyelin in BAL strongly correlated with pulmonary function and this was attributable to specific lipid species of phosphatidylcholine with surface tension reducing properties, and of phosphatidylglycerol with antimicrobial roles, as well as to other less studied lipid species. Mice exposed to smoke for six months recapitulated surfactant lipidomic changes observed in human subjects with COPD. In summary, we show that the surfactant lipidome is substantially altered in subjects with COPD, and decreased availability of phospholipids correlated with decreased pulmonary function. Further investigation of surfactant alterations in COPD would improve our understanding of its physiopathology and reveal new potential therapeutic targets.

Sodium restriction improves nocturia in patients at a cardiology clinic.

This study aims to determine whether dietary sodium restriction counseling decreases nocturnal voiding frequency in cardiology patients with concomitant nocturia. Patients who had established care at a cardiology clinic from 2015 to 2018 reporting ≥1 average nocturnal void(s) underwent a comprehensive sodium intake interview by their cardiologist, who provided them with individualized strategies for dietary sodium reduction and assessed adherence at follow-up. Average nocturnal voiding frequency and dietary adherence were documented in the medical record. A nocturia database was compiled for retrospective analysis. A total of 74 patients were included. Patients considered to be adherent with dietary sodium restriction at follow-up (n = 56) demonstrated a decrease in median nocturia frequency (2.5 [2.3-3.0] vs 1.0 [1.0-2.0] voids, P < .001). Among nonadherent patients (n = 18), median nocturia frequency did not significantly change from baseline to follow-up (2.0 [1.5-3.8] vs 2.0 [1.5-4.8] voids, P = .423). Median changes were significantly different between the adherent and nonadherent groups (P < .001). Examination of second follow-up available from 37 patients showed a continued effect. In conclusion, adherence with dietary sodium counseling appears to improve nocturia. Accordingly, dietary modification may represent an important adjunct therapy to lifestyle and pharmacologic interventions for decreasing nocturia frequency. Reduction in nocturnal voiding frequency may also reflect an additional benefit of dietary sodium restriction in accordance with best practice standards for cardiovascular disease.