Pain Manifestations of COVID-19 and Their Association With Mortality: A Multicenter Prospective Observational Study

ObjectivesTo determine the prevalence and breakdown of pain symptoms among patients with coronavirus disease 2019 (COVID-19) infection admitted for nonpain symptoms and the association between the presence of pain and intensive care unit (ICU) admission and death.Patients and MethodsIn this multicenter prospective study, data on the intensity and type of pain were collected on 169 patients with active severe acute respiratory syndrome coronavirus 2 infection at 2 teaching hospitals in the United States and Korea and on 8 patients with acute pain at another large teaching hospital between February 1, 2020, and June 15, 2020.ResultsSixty-five of 169 patients (38.5%) reported an active pain condition. Among the 73 patients with pain, the most common pain symptoms were headache (n=22; 30.1%), chest pain (n=17; 23.3%), spinal pain (n=18; 24.7%), myalgia (n=13; 17.8%), abdominal or pelvic pain (n=13; 17.8%), arthralgia (n=11; 15.1%), and generalized pain (n=9; 12.3%). Those reporting headache as their main symptom were less likely to require ICU admission (P=.003). Acetaminophen or nonsteroidal anti-inflammatory drugs were prescribed to 80.8% (n=59), opioids to 17.8% (n=13), adjuvants to 8.2% (n=6), and ketamine to 5.5% (n=4) of patients with pain. When age 65 years and older and sex were controlled for in multivariable analysis, the absence of pain was associated with ICU admission (odds ratio, 2.92; 95% CI, 1.42 to 6.28; P=.004) and death (odds ratio, 3.49; 95% CI, 1.40 to 9.76; P=.01).ConclusionAcute pain is common during active COVID-19 infection with the most common manifestations being headache, chest pain and spine pain. Individuals without pain were more likely to require intensive care and expire than those with pain. Reasons why pain may be associated with reduced mortality include that an intense systemic stimulus (eg, respiratory distress) might distract pain perception or that the catecholamine surge associated with severe respiratory distress might attenuate nociceptive signaling.     

Pituitary Adenoma Incidence,Management Trends,and Long-term Outcomes: A 30-Year Population-Based Analysis

ObjectiveTo perform a population-based study of pituitary adenoma epidemiology, including longitudinal trends in disease incidence, treatment patterns, and outcomes.Patients and MethodsIn this study of incident pituitary adenomas in Olmsted County, Minnesota, from January 1, 1989, through December 31, 2019, we identified 785 patients who underwent primary screening, 435 of whom were confirmed as harboring incident pituitary adenomas and were included. Primary outcomes of interest included demographic characteristics, presenting features, and disease outcomes (tumor control, biochemical control, and complications).ResultsAmong our 435 study patients, 438 unique pituitary adenomas were diagnosed at a median patient age of 39 years (interquartile range [IQR], 27 to 58 years). Adenomas were incidentally identified in 164 of the 438 tumors (37%). Common symptomatic presentations included hyperprolactinemia (188 of 438 [43%]) and visual field deficit (47 of 438 [11%]). Laboratory tests confirmed pituitary hormone hypersecretion in 238 of the 435 patients (55%), which was symptomatic in 222. The median tumor diameter was 8 mm (IQR, 5 to 17 mm). Primary management strategies were observation (156 of 438 tumors [36%]), medication (162 of 438 tumors [37%]), and transsphenoidal resection (120 of 438 tumors [27%]). Tumor and biochemical control were achieved in 398 (95%) and 216 (91%) secreting tumors, respectively. New posttreatment pituitary or visual deficits were noted in 43 (11%) and 8 (2%); apoplexy occurred in 28 (6%). Median clinical follow-up was 98 months (IQR, 47 to 189 months). Standardized incidence rates were 3.77 to 16.87 per 100,000 population, demonstrating linear expansion over time (R²=0.67). The mean overall standardized incidence rate was 10.1 per 100,000 population; final point prevalence was 175.1 per 100,000 population.ConclusionPituitary adenoma is a highly incident disease, with prolactin-secreting and incidental lesions representing the majority of tumors. Incidence rates and asymptomatic detection appear to be increasing over time. Presenting symptoms and treatment pathways are variable; however, most patients achieve favorable outcomes with observation or a single treatment modality.     

Survival and Progression in Synucleinopathy Phenotypes With Parkinsonism: A Population-Based Study

ObjectiveTo compare survival by the presenting parkinsonism symptoms at diagnosis among patients with incident clinically diagnosed synucleinopathies.Patients and MethodsUsing the Rochester Epidemiology Project medical records–linkage system, we identified all persons residing in Olmsted County, Minnesota, who received a diagnostic code of parkinsonism from January 1, 1991, through December 31, 2010. A movement disorder specialist reviewed the complete medical records of each individual to confirm the presence of parkinsonism, determine the type of synucleinopathy, and identify the onset dates of each cardinal symptom (tremor at rest, bradykinesia, rigidity, and impaired postural reflexes). We determined the median time from age at diagnosis to death or censoring (June 30, 2015) for each presenting symptom and the age- and sex-adjusted risk of death.ResultsFrom 1991 through 2010, a total of 433 individuals had a synucleinopathy diagnosed (301 [69.5%], Parkinson disease; 68 [15.7%], dementia with Lewy bodies; 52 [12.0%], Parkinson disease dementia; and 12 [2.8%], multiple systems atrophy with parkinsonism). Overall, the risk of death in the tremor-predominant group was less than that in the bradykinesia/rigidity-only group (hazard ratio [HR], 0.59; 95% CI, 0.40-0.87; P=.007). Similarly, risk of death in the bradykinesia/rigidity-only group was significantly greater than in the tremor-predominant group (HR, 1.75; 95% CI, 1.23-2.51; P=.002) and compared with tremor before bradykinesia (HR, 1.75; 95% CI, 1.24-2.47; P=.001).ConclusionPatients with tremor as a presenting symptom have longer survival. In contrast, the presence of bradykinesia/rigidity as a presenting symptom correlates with reduced survival across all types of synucleinopathies.     

Physical Activity and Mortality Across Levels of Adiposity: A Prospective Cohort Study From the UK Biobank

ObjectiveTo examine the combined and stratified associations of physical activity and adiposity measures, modelled as body mass index (BMI), abdominal adiposity (waist circumference), and body fat percentage (BF) with all-cause mortality.Patients and MethodsUsing the UK Biobank cohort, we extracted quintiles of self-reported weekly physical activity. Categories of measured BMI, waist circumference, and BF were generated. Joint associations between physical activity-adiposity categories and mortality were examined using Cox proportional hazards models adjusted for demographic, behavioral, and clinical covariates. Physical activity-mortality associations were also examined within adiposity strata. Participants were followed from baseline (2006 to 2010) through January 31, 2018.ResultsA total of 295,917 participants (median follow-up, 8.9 years, during which 6684 deaths occurred) were included. High physical activity was associated with lower risk of premature mortality in all strata of adiposity except for those with BMI ≥35 kg/m². Highest risk (HR, 1.54; 95% CI; 1.33 to 1.79) was observed in individuals with low physical activity and high BF as compared with the high physical activity–low BF referent. High physical activity attenuated the risk of high adiposity when using BF (HR, 1.24; 95% CI; 1.04 to 1.49), but the association was weaker with BMI (HR, 1.45; 95% CI; 1.21 to 1.73). Physical activity also attenuated the association between mortality and high waist circumference.ConclusionLow physical activity and adiposity were both associated with a higher risk of premature mortality, but high physical activity attenuated the increased risk with adiposity irrespective of adiposity metric, except in those with a BMI ≥35 kg/m².     

Shift Work,Genetic Factors,and the Risk of Heart Failure: A Prospective Study of the UK Biobank

ObjectiveTo quantify the association of combined shift work and genetic factors with the incidence of heart failure (HF).Participants and MethodsThis study included 242,754 participants with complete shift work information in the UK Biobank. Participants were followed from baseline (2006 to 2010) through January 31, 2018. The association between shift work and HF incidence was investigated separately in males and females using a Cox proportional hazards model adjusted for covariates. In addition, we established a polygenic risk score and assessed whether shift work alters genetic susceptibility to HF.ResultsThe results showed a significant association of permanent night shift work with incident HF among females (hazard ratio, 2.25; 95% CI, 1.34 to 3.76; P=.002) after adjusting for age, and the association was attenuated in the fully adjusted model. Among men, we did not detect an association between shift work and HF. In addition, we observed that the association between the risk of HF and shift work was strengthened by high genetic risk. Permanent night shift work paired with high genetic risk, compared with low genetic risk, was suggested to be associated with the risk of HF in females (hazard ratio, 2.89; 95% CI, 1.05 to 7.94) but not in males.ConclusionShift work, particularly permanent night shift work, may increase the risk of HF in females, especially in those with high genetic risk.     

Serum 25-Hydroxyvitamin D and Subsequent Cancer Incidence and Mortality: A Population-Based Retrospective Cohort Study

ObjectiveTo determine the relationship between 25-hydroxyvitamin D (25[OH]D) values and subsequent cancer incidence and mortality.Patients and MethodsWe identified all adult patients living in Olmsted County, Minnesota, between January 1, 2005, and December 31, 2011, who had at least 1 25(OH)D measurement and no prior diagnosis of cancer. Cancer outcomes were retrieved starting 30 days after 25(OH)D measurement and until patients’ final clinical visit as an Olmsted County resident; December 31, 2014; or death. Cox proportional hazards regression was used to analyze data.ResultsA total of 8700 individuals had a 25(OH)D measurement and no history of cancer, with a mean ± SD 25(OH)D value of 29.7±12.8 ng/mL (to convert to nmol/L, multiply by 2.496). The mean ± SD age was 51.5±16.4 years, and most were women (78.1%; n=6796) and White (85.7%; n=7460). A total of 761 individuals developed cancer (skin cancer, n=360; nonskin cancer, n=401) during a median follow-up of 4.6 (interquartile range, 3.4-6.1) years. Compared with participants with 25(OH)D values of 20 to 50 ng/mL (reference group), those with 25(OH)D values less than 12 ng/mL had a greater nonskin cancer incidence (hazard ratio [HR], 1.56; 95% CI, 1.03 to 2.36; P=.04) after adjustment. There was no association between 25(OH)D values and total cancer or skin cancer incidence. Compared with individuals from the reference group, 25(OH)D levels less than 12 ng/mL (HR, 2.35; 95% CI, 1.01 to 5.48; P=.047) and 12 to 19 ng/mL (HR, 2.10; 95% CI, 1.05 to 4.22; P=.04) were associated with increased cancer mortality.ConclusionLow 25(OH)D levels were associated with increased risk for incident nonskin cancer and cancer-related mortality.     

The Natural History of Chronic Unexplained Gastrointestinal Disorders and Gastroesophageal Reflux During 20 Years: A US Population-Based Study

ObjectiveTo explore the natural history of chronic unexplained gastrointestinal (GI) symptoms and to determine the longitudinal trends of prevalence during a 20-year period in a single US community.MethodsBetween January 1, 1990, and December 31, 2009, valid self-report questionnaires of GI symptoms were mailed to randomly selected cohorts of a community. The study used respondents who answered questions on 1 or more of 3 surveys (initial, 1990-1992; second, 2003-2004; and third, 2008-2009). The trends of prevalence of GI symptoms over time were analyzed in responders who completed 3 surveys, and the natural history or transition was evaluated.ResultsThe overall prevalence of major symptom groupings including gastroesophageal reflux disease was consistent among residents in a community on 3 survey time points (1990-1992, 2003-2004, and 2008-2009). The transitions of GI symptoms were common in 228 patients who responded to all 3 surveys; only 29% had the same symptom category in 3 surveys; otherwise, symptoms changed over time, resolving, recurring, or transitioning to another disorder. Observed proportions of symptom transitions were significantly different from expected during 20 years (P<.001). Higher non-GI somatic symptom scores were significantly associated with both symptom transitions (odds ratio, 3.9; 95% CI, 1.38 to 10.77) and having sustained symptoms (odds ratio, 12.7; 95% CI, 4.62 to 34.90).ConclusionThe overall population prevalence of chronic unexplained GI symptoms is stable, but in individuals, transitions seem to be the rule. As these various GI syndromes appear to be so intimately interconnected, the common underlying pathogenesis may account for a major subgroup of chronic unexplained GI disorders.     

Association Between Personal Activity Intelligence and Mortality: Population-Based China Kadoorie Biobank Study

ObjectiveTo prospectively investigate the association between personal activity intelligence (PAI) — a novel metabolic metric which translates heart rate during physical activity into a simple weekly score — and mortality in relatively healthy participants in China whose levels and patterns of physical activity in addition to other lifestyle factors are different from those in high-income countries.Patients and MethodsFrom the population-based China Kadoorie Biobank study, 443,792 healthy adults were recruited between June 2004 and July 2008. Participant’s weekly PAI score was estimated and divided into four groups (PAI scores of 0, ≤50, 51–99, or ≥100). Using Cox proportional hazard analyses, we calculated adjusted hazard ratios (AHRs) for cardiovascular disease (CVD) and all-cause mortality related to PAI scores.ResultsDuring a median follow-up of 8.2 (interquartile range, 7.3 to 9.1) years, there were 21,901 deaths, including 9466 CVD deaths. Compared with the inactive group (0 PAI score), a baseline weekly PAI score greater than or equal to 100 was associated with a lower risk of CVD mortality, an AHR of 0.87 (95% CI, 0.81 to 0.94) in men, and an AHR of 0.84 (95% CI, 0.78 to 0.92) in women, after adjusting for multiple confounders. Participants with a weekly PAI score greater than or equal to 100 also had a lower risk of all-cause mortality (AHR, 0.93; 95% CI, 0.89 to 0.97 in men, and AHR, 0.93; 95%, 0.88 to 0.98 in women). Moreover, this subgroup gained 2.7 (95% CI, 2.4 to 3.0) years of life, compared with the inactive cohort.ConclusionAmong relatively healthy Chinese adults, the PAI metric was inversely associated with CVD and all-cause mortality, highlighting the generalizability of the score in different races, ethnicities, and socioeconomic strata.     

A Population-Based Study of the Incidence and Natural History of Degenerative Thoracic Aortic Aneurysms

ObjectiveTo investigate the incidence and natural history of degenerative thoracic aortic aneurysms (TAAs) and compare results between ascending (aTAAs) and descending TAAs (dTAAs).Patients and MethodsThis population-based cohort study used the Rochester Epidemiology Project database from January 1, 1995, through December 31, 2015. Patients were classified as the aTAA or dTAA group.ResultsOf 238 Olmsted County residents studied, 131 (55.0%) were women; 154 (64.7%) were in the aTAA group, and 84 (35.3%) were in the dTAA group. Median age was 77.0 years (interquartile range, 69.1-83.8 years). The overall age- and sex-adjusted incidence rate was 13.8 per 100,000 person-years (95% CI, 12.1 to 15.6) and varied from 9.9 in 1995 to 1999 to 19.0 in 2005 to 2009. It was 9.0 (95% CI, 7.5 to 10.4) for the aTAA and 4.9 (95% CI, 3.8 to 5.9) for the dTAA group. Overall 5-year survival was 62.5%, lower than the expected survival of 73.7% for the US 2010 census population (P<.001). The 5-year survival was 42.9% for the aTAA and 73.4% for the dTAA group (P<.001). On multivariable analysis, advanced age and smoking status were associated with all-cause mortality. The 5-year estimate of freedom from an aortic-related event was 80.0%, lower for dTAAs (67.8%) than for aTAAs (85.2%; P<.001). Maximal aortic diameter and dTAAs were associated with aortic-related events.ConclusionThe incidence of TAAs was stable from 1995 to 2015 and mortality for those with TAAs remains higher than for the general population. Older age and smoking status were associated with overall mortality, whereas larger aneurysms and dTAAs were associated with aortic-related events.     

Population-Based Evaluation of Total Protein in Cerebrospinal Fluid

ObjectivesTo present a normal range of cerebrospinal fluid (CSF) protein levels in a community-based population and to evaluate factors that contribute to CSF protein level variability.Patients and MethodsSamples of CSF protein were obtained from participants aged 32 to 95 years who underwent lumbar puncture (LP) between November 1, 2007, and October 1, 2017, as part of the Mayo Clinic Study of Aging, a longitudinal, population-based study of residents of Olmsted County, Minnesota.ResultsA total of 633 participants (58.1% male; 99.1% White; mean ± SD age, 70.9±11.6 years) underwent LP with recorded CSF protein level. Mean ± SD CSF protein level was 52.2±18.4 mg/dL (to convert to mg/L, multiply by 10), with a 95% reference interval of 24.0 to 93.4 mg/dL (range, 14.0-148.0 mg/dL). Spinal stenosis and arterial hypertension were associated with higher CSF protein levels on univariable analysis (P<.001). Increasing age, male sex, and diabetes were all independently associated with higher CSF protein levels on multivariable analysis (P<.001). In the 66 participants with repeated LPs within 2.5 years, the coefficient of repeatability was 26.1 mg/dL. Eleven participants (16.7%) had a CSF protein level difference of 20 mg/dL or more between serial LPs, and 4 (6.1%) had a difference of 25 mg/dL or more. There was a trend toward greater CSF protein level variability in patients with spinal stenosis (P=.054).ConclusionThis large population-based study showed that CSF protein level can vary significantly among individuals. Elevated CSF protein level was independently associated with older age, male sex, and diabetes and is higher than listed in many laboratories. These findings emphasize the necessity of evidence-based reevaluation and standardization of CSF protein metrics.     

A Contemporary Population-Based Profile of Infective Endocarditis Using the Expanded Rochester Epidemiology Project

ObjectiveTo develop a contemporary profile of infective endocarditis (IE) among a population in 6 counties of Olmsted, Dodge, Mower, Steele, Waseca, and Freeborn in southern Minnesota between 2014 and 2018.Patients and MethodsAll possible and definite cases of IE (≥18 years) among residents of 6 counties in southern Minnesota, including Olmsted County, diagnosed between January 1, 2014, and December 31, 2018, were included in this retrospective, population-based investigation, using the Expanded Rochester Epidemiology Project (E-REP).ResultsOverall, 137 patients with IE developed incident IE in the 6-county region, corresponding to an age- and sex-adjusted incidence rate of 11.9 per 100,000 person-years. Men had a significantly higher incidence of IE (17.9 vs 6.8 per 100,000 person-years), and rates increased exponentially with age in both sexes. The median age of incident cases was 68.2 years, and 67.9% were male patients. The percentage of patients with histories of injection-drug use was low, at 6.7%. Bicuspid aortic valve was the most common (9.6%) native valve predisposing condition. Staphylococcus aureus was identified as the predominant pathogen in the overall group (34.8%), with viridans-group streptococci accounting for only 19.3% cases. Central nervous system and musculoskeletal complications were common. The 30-day readmission rate was 27.9%, and the 6-month mortality rate was 31.8%.ConclusionTo our knowledge, this is the first time that the population-based E-REP has been used to determine an age- and sex-adjusted IE incidence. Older male patients predominated, and S aureus was the most common pathogen. Based on these findings, it is not surprising that IE complications were frequently seen.     

Nonlinear Associations Between Cumulative Dietary Risk Factors and Cardiovascular Diseases,Cancer, and All-Cause Mortality: A Prospective Cohort Study From UK Biobank

ObjectiveTo develop a score from cumulative dietary risk factors and examine its nonlinear associations with cardiovascular disease (CVD) and cancer incidence and mortality, as well as all-cause mortality.Patients and MethodsThere were 422,702 participants from UK Biobank included in this prospective study. Cumulative dietary risk factors were represented using a score ranging from 0 (healthiest) to 9 (least healthy). This was derived from 9 food items based on current UK guidelines using baseline data. Associations between the cumulative score and health outcomes were investigated using nonlinear penalized cubic splines fitted in Cox proportional hazard models. Follow-up was conducted until June 2020 for mortality, and for incidence, up to June 2020 in England and March 2017 in Wales and Scotland.ResultsThe median follow-up period was 9.0 years for incidence outcomes and 9.3 years for mortality outcomes. Each 1-point increment in the cumulative dietary risk factors score was associated with higher risk for incidence and mortality of the outcomes studied. The highest risks were identified for mortality due to heart failure (8.0% higher), CVD, and ischemic heart disease (both 7.0% higher). In addition, a higher diet score accounted for 18.8% of all deaths, 4.47% of incident cases of CVD, 25.5% of CVD deaths, 7.7% of incident cancers, and 18.2% of all cancer deaths.ConclusionOur findings show that dietary risk factors contributed to a large proportion of CVD and cancer events, as well as deaths, among those who did not meet most dietary recommendations.     

Osteoporosis and Its Association With Cardiovascular Disease,Respiratory Disease,and Cancer: Findings From the UK Biobank Prospective Cohort Study

ObjectiveTo investigate sex-specific associations of osteoporosis with incidence of and mortality from cardiovascular disease (CVD), respiratory disease, and cancer as well as with all-cause mortality.MethodsIn total, 305,072 participants (53% [161,383] women) of UK Biobank were included in this study (2007-2010). Self-reported diagnosis of osteoporosis at baseline was the exposure of interest. The outcomes were CVD, respiratory disease, chronic obstructive pulmonary disease (COPD), all cancer, and prostate and breast cancer incidence and mortality and all-cause mortality. Associations between osteoporosis and outcomes were investigated using Cox proportional hazards models.ResultsIn men, osteoporosis was associated with a higher incident risk of all respiratory diseases (hazard ratio [HR], 1.26; 95% CI, 1.06 to 1.50) including COPD (HR, 1.82; 95% CI, 1.38 to 2.40). Men with osteoporosis also had a higher mortality risk from all causes (HR, 1.71; 95% CI, 1.38 to 2.11), CVD (HR, 1.68; 95% CI, 1.19 to 2.37), respiratory disease (HR, 2.35; 95% CI, 1.70 to 3.24), and COPD (HR, 3.64; 95% CI, 2.24 to 5.91). These associations persisted after adjustment for age, body mass index, and comorbidities. Women with osteoporosis had a higher risk of incident CVD (HR, 1.24; 95% CI, 1.97 to 1.44), respiratory disease (HR, 1.23; 95% CI, 1.13 to 1.33), and COPD (HR, 1.29; 95% CI, 1.10 to 1.52). Women with osteoporosis also had a higher mortality risk from respiratory disease (HR, 1.31; 95% CI, 1.00 to 1.72) and breast cancer (HR, 1.60; 95% CI, 1.14 to 2.26).ConclusionCompared with women, men with osteoporosis had a higher risk of all-cause mortality, mortality from respiratory diseases including COPD, and cancer incidence. Osteoporosis was strongly associated with respiratory disease and COPD in both sexes, even after full adjustment for covariates, although men with osteoporosis experienced a higher risk of adverse outcomes.