Overview of Lymphedema for Physicians and Other Clinicians: A Review of Fundamental Concepts

Lymphedema has historically been underrated in clinical practice, education, and scholarship to the detriment of many patients with this chronic, debilitating condition. The mechanical insufficiency of the lymphatic system causes the abnormal accumulation of protein-rich fluid in the interstitium, which triggers a cascade of adverse consequences such as fat deposition and fibrosis. As the condition progresses, patients present with extremity heaviness, itchiness, skin infections, and, in later stages, dermal fibrosis, skin papillomas, acanthosis, and other trophic skin changes. Correspondingly, lymphedema results in psychological morbidity, including anxiety, depression, social avoidance, and a decreased quality of life, encompassing emotional, functional, physical, and social domains. For this review, we conducted a literature search using PubMed and EMBASE and herein summarize the evidence related to the fundamental concepts of lymphedema. This article aims to raise awareness of this serious condition and outline and review the fundamental concepts of lymphedema.     

Development and Validation of a Multivariable Risk Prediction Model for COVID-19 Mortality in the Southern United States

ObjectiveTo evaluate clinical characteristics of patients admitted to the hospital with coronavirus disease 2019 (COVID-19) in Southern United States and development as well as validation of a mortality risk prediction model.Patients and MethodsSouthern Louisiana was an early hotspot during the pandemic, which provided a large collection of clinical data on inpatients with COVID-19. We designed a risk stratification model to assess the mortality risk for patients admitted to the hospital with COVID-19. Data from 1673 consecutive patients diagnosed with COVID-19 infection and hospitalized between March 1, 2020, and April 30, 2020, was used to create an 11-factor mortality risk model based on baseline comorbidity, organ injury, and laboratory results. The risk model was validated using a subsequent cohort of 2067 consecutive hospitalized patients admitted between June 1, 2020, and December 31, 2020.ResultsThe resultant model has an area under the curve of 0.783 (95% CI, 0.76 to 0.81), with an optimal sensitivity of 0.74 and specificity of 0.69 for predicting mortality. Validation of this model in a subsequent cohort of 2067 consecutively hospitalized patients yielded comparable prognostic performance.ConclusionWe have developed an easy-to-use, robust model for systematically evaluating patients presenting to acute care settings with COVID-19 infection.     

Pernio (Chilblains), SARS-CoV-2, and COVID Toes Unified Through Cutaneous and Systemic Mechanisms

Pernio or chilblains is characterized by erythema and swelling at acral sites (eg, toes and fingers), typically triggered by cold exposure. Clinical and histopathologic features of pernio are well described, but the pathogenesis is not entirely understood; vasospasm and a type I interferon (IFN-I) immune response are likely involved. During the coronavirus disease 2019 (COVID-19) pandemic, dermatologists have observed an increase in pernio-like acral eruptions. Direct causality of pernio due to COVID-19 has not been established in many cases because of inconsistent testing methods (often negative results) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a form of COVID-19?associated pernio (also called COVID toes) is probable because of increased occurrence, frequently in young patients with no cold exposure or a history of pernio, and reports of skin biopsies with positive SARS-CoV-2 immunohistochemistry. PubMed was searched between January 1, 2020, and December 31, 2020 for publications using the following keywords: pernio, chilblain, and acral COVID-19. On the basis of our review of the published literature, we speculate that several unifying cutaneous and systemic mechanisms may explain COVID-19?associated pernio: (1) SARS-CoV-2 cell infection occurs through the cellular receptor angiotensin-converting enzyme 2 mediated by transmembrane protease serine 2, subsequently affecting the renin-angiotensin-aldosterone system with an increase in the vasoconstricting, pro-inflammatory, and prothrombotic angiotensin II pathway. (2) Severe acute respiratory syndrome coronavirus 2 cell infection triggers an immune response with robust IFN-I release in patients predisposed to COVID-19?associated pernio. (3) Age and sex discrepancies correlated with COVID-19 severity and manifestations, including pernio as a sign of mild disease, are likely explained by age-related immune and vascular differences influenced by sex hormones and genetics, which affect susceptibility to viral cellular infection, the renin-angiotensin-aldosterone system balance, and the IFN-I response.     

Changes in Burnout and Satisfaction With Work-Life Integration in Physicians During the First 2 Years of the COVID-19 Pandemic

ObjectiveTo evaluate the prevalence of burnout and satisfaction with work-life integration (WLI) in US physicians at the end of 2021, roughly 21 months into the COVID-19 pandemic, with comparison to 2020, 2017, 2014, and 2011.MethodsBetween December 9, 2021, and January 24, 2022, we surveyed US physicians using methods similar to those of our prior studies. Burnout, WLI, depression, and professional fulfillment were assessed with standard instruments.ResultsThere were 2440 physicians who participated in the 2021 survey. Mean emotional exhaustion and depersonalization scores were higher in 2021 than those observed in 2020, 2017, 2014, and 2011 (all P<.001). Mean emotional exhaustion scores increased 38.6% (2020 mean, 21.0; 2021 mean, 29.1; P<.001), whereas mean depersonalization scores increased 60.7% (2020 mean, 6.1; 2021 mean, 9.8; P<.001). Overall, 62.8% of physicians had at least 1 manifestation of burnout in 2021 compared with 38.2% in 2020, 43.9% in 2017, 54.4% in 2014, and 45.5% in 2011 (all P<.001). Although these trends were consistent across nearly all specialties, substantial variability by specialty was observed. Satisfaction with WLI declined from 46.1% in 2020 to 30.2% in 2021 (P<.001). Mean scores for depression increased 6.1% (2020 mean, 49.54; 2021 mean, 52.59; P<.001).ConclusionA dramatic increase in burnout and decrease in satisfaction with WLI occurred in US physicians between 2020 and 2021. Differences in mean depression scores were modest, suggesting that the increase in physician distress was overwhelmingly work related. Given the association of physician burnout with quality of care, turnover, and reductions in work effort, these findings have profound implications for the US health care system.     

Real-World Experience of Angiotensin Receptor–Neprilysin Inhibition in Reduced Ejection Fraction Heart Failure Patients With Advanced Kidney Disease

ObjectiveTo investigate the effectiveness and safety of angiotensin receptor-neprilysin inhibitors (ARNIs) in real-world patients with heart failure with reduced ejection fraction (HFrEF) and advanced chronic kidney disease (estimated glomerular filtration rate [eGFR] < 30 mL/min per 1.73 m²), which have been excluded from the landmark trials.Patients and MethodsThis study examined 3281 patients pooled from two multicenter HFrEF cohorts, and 661 patients with baseline eGFR less than 30 mL/min per 1.73 m² were further analyzed (the Taiwan Society of Cardiology – Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry: May 1, 2013 to October 31, 2014, and the Treatment with Angiotensin Receptor neprilysin inhibitor fOr Taiwan Heart Failure patients (TAROT-HF) study: March 1, 2017, to December 31, 2018). Propensity score matching was performed to adjust for confounders. At 1-year follow-up, all-cause mortality, total heart failure hospitalizations, renal function, and left ventricular ejection fraction (LVEF) were used as the endpoints.ResultsAfter propensity score matching, 510 patients (age, 69.8±13.9 years; male, 61.0%; mean LVEF, 29.8±7.3%; mean eGFR, 19.8±9.0 mL/min per 1.73 m²) were included in the final analysis, including 278 patients receiving ARNI treatment (ARNI group) and 232 patients not on ARNI treatment (non-ARNI group). Baseline characteristics were comparable between the two groups. At 1 year, eGFR and LVEF measurements were significantly higher in the ARNI group than in the non-ARNI group (25.0±17.1 mL/min per 1.73 m² vs 21.4±17.5 mL/min per 1.73 m²; P=.04; and 40.1±12.9% vs. 33.1±10.8%, P<.001, respectively). The ARNI group had significantly lower risks of 1-year all-cause mortality (19.4 vs 30.9 per 100-person year; P=.02), and total HF rehospitalizations (70.0 vs 110.4 per 100-person year; P=.01) than non-ARNI users.ConclusionOur results show the effectiveness of ARNIs in HFrEF patients with advanced chronic kidney disease in a real-world setting.     

Development and Implementation of a Team-Based,Primary Care Delivery Model: Challenges and Opportunities

In this article, we describe the implementation of a team-based care model during the first 2 years (2016-2017) after Mayo Clinic designed and built a new primary care clinic in Rochester, Minnesota. The clinic was configured to accommodate a team-based care model that included complete colocation of clinical staff to foster collaboration, designation of a physician team manager to support a physician to advanced practice practitioner ratio of 1:2, expanded roles for registered nurses, and integration of clinical pharmacists, behavioral health specialists, and community specialists; this model was designed to accommodate the growth of nonvisit care. We describe the implementation of this team-based care model and the key metrics that were tracked to assess performance related to the quadruple aim of improving population health, improving patient experience, reducing cost, and supporting care team's work life.     

Changes in Burnout and Satisfaction With Work-Life Integration in Physicians and the General US Working Population Between 2011 and 2020

ObjectiveTo evaluate the prevalence of burnout and satisfaction with work-life integration (WLI) among physicians and US workers in 2020 relative to 2011, 2014, and 2017.MethodsBetween November 20, 2020, and March 23, 2021, we surveyed US physicians and a probability-based sample of the US working population using methods similar to our prior studies. Burnout and WLI were measured using standard tools. Information about specific work-related COVID-19 experiences was collected.ResultsThere were 7510 physicians who participated in the survey. Nonresponder analysis suggested that participants were representative of US physicians. Mean emotional exhaustion and depersonalization scores were lower in 2020 than in 2017, 2014, and 2011 (all P<.001). However, emotional exhaustion and depersonalization scores did not improve in specialties most heavily affected by COVID-19. Overall, 38.2% of physicians reported 1 or more symptoms of burnout in 2020 compared with 43.9% in 2017, 54.4% in 2014, and 45.5% in 2011 (all P<.001). Providing care without adequate personal protective equipment (odds ratio [OR], 1.53; 95% CI, 1.35 to 1.72) and having suffered disruptive economic consequences due to COVID-19 (OR, 1.49; 95% CI, 1.32 to 1.69) were independently associated with risk of burnout. On multivariable analysis, physicians were at increased risk for burnout (OR, 1.41; 95% CI, 1.25 to 1.58) and were less likely to be satisfied with WLI (OR, 0.71; 95% CI, 0.64 to 0.79) than other working US adults.ConclusionBurnout and satisfaction with WLI among US physicians improved between 2017 and 2020. The impact of the COVID-19 pandemic on physicians varies on the basis of professional characteristics and experiences. Physicians remain at increased risk for burnout relative to workers in other fields.     

Effectiveness of COVID-19 Booster on the Risk of Hospitalization Among Medicare Beneficiaries

ObjectiveTo determine the effectiveness of booster vaccinations on the risk of hospitalization with coronavirus disease 2019 (COVID-19) and how it varies by enrollee characteristics and interval from the initial vaccination to receipt of a booster.Patients and MethodsThis cohort study used 100% Medicare claims from January 1, 2020, through December 31, 2021, and matched 3,940,475 individuals who received boosters to 3,940,475 controls based on week and type of original COVID-19 vaccine and demographic and clinical characteristics. We compared the association of booster vs no booster with COVID-19 hospitalization using Cox proportional hazards regression models controlling for patient characteristics. We also determined the association of time from original vaccine to booster with COVID-19 hospitalization.ResultsOver a maximum of 130 days of follow-up, boosted enrollees had 8.20 (95% CI, 7.81 to 8.60) COVID-19 hospitalizations per million days vs 43.70 (95% CI, 42.79 to 44.64) for controls (81% effectiveness). Effectiveness varied by race, prior hospitalizations, and certain comorbidities, for example, leukemia/lymphoma (53% effectiveness), autoimmune disease (73%), and dementia (73%). Boosters received between 6 and 9 months after original vaccination varied between 81% and 85% effectiveness, while boosters received at 5 to 6 months (62%) or less than 5 months (58%) were less effective.ConclusionBoosters are highly effective in the Medicare population. Approximately 69,225 hospitalizations would be prevented by boosters in the 15 million individuals aged 65 years or older currently not boosted in a period similar to the September 2020 through January 2021 period studied. Boosters provided the greatest benefits if they were received between 6 and 9 months following original vaccinations. However, boosters were associated with substantial decreases in COVID-19 hospitalizations in all categories of enrollees.     

Management of the Patient With Patent Foramen Ovale in 2021: A Spectrum of Cases

Patients with patent foramen ovale can manifest in a variety of ways. These presentations and their resolution are discussed in this article.     

Suicidal Ideation and Attitudes Regarding Help Seeking in US Physicians Relative to the US Working Population

ObjectiveTo evaluate the prevalence of suicidal ideation (SI) and attitudes regarding help seeking among US physicians relative to the general US working population.Participants and MethodsA secondary analysis of a cross-sectional survey of US physicians and a probability-based sample of the US working population was conducted between October 12, 2017, and March 15, 2018. Among 30,456 invited physicians, 5197 (17.1%) completed the primary survey. Suicidal ideation in the last year, attitudes regarding help seeking, symptoms of depression, and burnout were assessed by standardized questions.ResultsAmong the 4833 physicians who responded regarding SI, 316 (6.5%) reported having suicidal thoughts in the last 12 months. Most physicians (3527 [72.9%]) reported that they would seek professional help if they had a serious emotional problem. Physicians with SI were less likely to report that they would seek help (203/316 [64.2%]) than physicians without SI (3318/4517 [73.5%]; P=.001). On multivariable analysis, symptoms of depression (odds ratio [OR], 4.42; 95% CI, 1.89 to 11.52), emotional exhaustion (OR, 1.07 each 1-point increase; 95% CI, 1.03 to 1.11), and self-valuation (OR, 0.84 each 1-point increase; 95% CI, 0.70 to 0.99) were associated with SI. Among individuals aged 29 to 65 years, physicians were more likely than workers in other fields to report SI (7.1% vs 4.3%; P<.001), a finding that persisted on multivariable analysis.ConclusionIn this national study conducted before the COVID-19 pandemic, 1 in 15 US physicians had thoughts of taking their own life in the last year, which exceeded the prevalence of SI among US workers in other fields.     

Incidence and Risk of Various Types of Arterial Thromboembolism in Patients With Cancer

ObjectiveTo describe the temporal association and identify risk factors between cancer diagnosis and various types of arterial thromboembolism (ATE).Patients and MethodsWe inquired an aggregated electronic health record database (Explorys, IBM Corp., Armonk, New York) and identified patients with cancer from January 1999 to October 2019, with various types of ATE, including myocardial infarction, acute ischemic stroke, acute limb ischemia, acute mesenteric ischemia, acute renal infarction, and retinal artery occlusion. We investigated the temporal relationship between cancer diagnosis and ATE events by examining the incidence ratio (IR) of ATE before and after diagnosis of cancer.ResultsWe identified 305,384 patients with cancer and ATE. The 30-day interval IR of total ATE was elevated shortly before and after cancer diagnosis, which was consistent among different ATE and cancer types. The incidence was highest within a 330-day window (90 days before and 240 days after cancer diagnosis), and IR peaked at 13.9 (95% confidence interval [CI], 13.6 to 14.2) in the first 30 days following diagnosis of cancer. Compared with patients with cancer who never developed ATE, patients with ATE had more cardiovascular risk factors at baseline. Patients with brain cancer, lung cancer, colorectal cancer, and pancreatic cancer had the highest risk of developing ATE, whereas ATE type was anatomically associated with cancer type.ConclusionIn this observational study of an aggregated US patient population, those with newly diagnosed cancer had increased risk of ATE events. This risk was most elevated in a 330-day window around cancer diagnosis and was consistent across different types of ATE and cancer.     

Racial Differences and Social Determinants of Health in Achieving Hypertension Control

ObjectiveTo investigate whether specific social determinants of health could be a “health barrier” toward achieving blood pressure (BP) control and to further evaluate any differences between Black patients and White patients.Patients and MethodsWe conducted a retrospective cohort study of 3305 patients with elevated BP who were enrolled in a hypertension digital medicine program for at least 60 days and followed up for up to 1 year. Patients were managed virtually by a dedicated hypertension team who provided guideline-based medication management and lifestyle support to achieve goal BP.ResultsCompared with individuals without any health barriers, the addition of 1 barrier was associated with lower probability of control at 1 year from 0.73 to 0.60 and to 0.55 in those with 2 or more barriers. Health barriers were more prevalent in Black patients than in those who were White (44.6% [482 of 1081] vs 31.3% [674 of 2150]; P<.001). There was no difference at all in BP control between Black individuals and those who were White if 2 or more barriers were present.ConclusionPatient-related health barriers are associated with BP control. Black patients with poorly controlled hypertension have a higher prevalence of health barriers than their White counterparts. When 2 or more health barriers were present, there was no differences in BP control between White and Black individuals.     

Sequence of Splenectomy and Rituximab for the Treatment of Steroid-Refractory Immune Thrombocytopenia: Does It Matter?

ObjectiveTo evaluate the impact of the sequence of treatment with rituximab and/or splenectomy on time to relapse for patients with steroid-refractory immune thrombocytopenia (ITP).Patients and MethodsPatients 18 years or older with steroid-refractory immune thrombocytopenia who underwent treatment with splenectomy or rituximab from January 1, 2002, through December 31, 2015, at Mayo Clinic. Evaluation included freedom from relapse (FFR) and response rates after treatment with rituximab or splenectomy as single or sequential interventions.ResultsA total of 218 eligible patients with ITP who were treated according to standard of care were included in this analysis. Patients failing steroids treated with splenectomy had a higher 5-year FFR than did those treated with rituximab (67.4% vs 19.2%; P<.001, propensity-score matched). Patients who failed splenectomy and were then treated with rituximab had a 2-year FFR similar to that of patients who failed rituximab and were then treated with splenectomy (73.4% vs 59.9%; P=.52). Patients treated with rituximab after splenectomy had a longer 2-year FFR than did patients treated with rituximab as a second-line treatment (73.4% vs 29.0%; P<.001).ConclusionFor patients with ITP that relapse after treatment with steroids, splenectomy provides longer FFR than rituximab as a second-line therapy. Among patients who fail second-line treatment with splenectomy or rituximab, those who end up receiving sequential splenectomy-rituximab or rituximab-splenectomy therapy seem to derive similar benefit in the long term. Patients who received rituximab after splenectomy seem to derive superior benefit than do those who are treated with rituximab with an intact spleen.     

Imposter Phenomenon in US Physicians Relative to the US Working Population

ObjectiveTo determine the prevalence of imposter phenomenon (IP) experiences among physicians and evaluate their relationship to personal and professional characteristics, professional fulfillment, burnout, and suicidal ideation.Participants and MethodsBetween November 20, 2020, and February 16, 2021, we surveyed US physicians and a probability-based sample of the US working population. Imposter phenomenon was measured using a 4-item version of the Clance Imposter Phenomenon Scale. Burnout and professional fulfillment were measured using standardized instruments.ResultsAmong the 3237 physician responders invited to complete the subsurvey including the IP scale, 3116 completed the IP questions. Between 4% (133) and 10% (308) of the 3116 physicians endorsed each of the 4 IP items as a “very true” characterization of their experience. Relative to those with a low IP score, the odds ratio for burnout among those with moderate, frequent, and intense IP was 1.28 (95% CI, 1.04 to 1.58), 1.79 (95% CI, 1.38 to 2.32), and 2.13 (95% CI, 1.43 to 3.19), respectively. A similar association between IP and suicidal ideation was observed. On multivariable analysis, physicians endorsed greater intensity of IP than workers in other fields in response to the item, “I am disappointed at times in my present accomplishments and think I should have accomplished more.”ConclusionImposter phenomenon experiences are common among US physicians, and physicians have more frequent experiences of disappointment in accomplishments than workers in other fields. Imposter phenomenon experiences are associated with increased burnout and suicidal ideation and lower professional fulfillment. Systematic efforts to address the professional norms and perfectionistic attitudes that contribute to this phenomenon are necessary.     

The Role of Biological Effective Dose in Predicting Obliteration After Stereotactic Radiosurgery of Cerebral Arteriovenous Malformations

ObjectiveTo determine whether biological effective dose (BED) was predictive of obliteration after stereotactic radiosurgery (SRS) for cerebral arteriovenous malformations (AVMs).Patients and MethodsWe studied patients undergoing single-session AVM SRS between January 1, 1990, and December 31, 2014, with at least 2 years of imaging follow-up. Excluded were patients with syndromic AVM, previous SRS or embolization, and patients treated with volume-staged SRS. Biological effective dose was calculated using a mono-exponential model described by Jones and Hopewell. The primary outcome was likelihood of total obliteration defined by digital subtraction angiography or magnetic resonance imaging (MRI). Variables were analyzed as continuous and dichotomous variables based on the maximum value of (sensitivity–[1–specificity]).ResultsThis study included 352 patients (360 AVM, median follow-up, 5.9 years). The median margin dose prescribed was 18.75 Gy (interquartile range [IQR]: 18 to 20 Gy). Two hundred fifty-nine patients (71.9%) had obliteration shown by angiography (n=176) or MRI (n=83) at a median of 36 months after SRS (IQR: 26 to 44 months). Higher BED was associated with increased likelihood of obliteration in univariate Cox regression analyses, when treated as either a dichotomous (≥133 Gy; hazard ratio [HR],1.52; 95% confidence interval [CI], 1.19 to 1.95; P<.001) or continuous variable (HR, 1.00, 95% CI, 1.0002 to 1.005; P=.04). In multivariable analyses including dichotomized BED and location, BED remained associated with obliteration (P=.001).ConclusionBiological effective dose ≥133 Gy was predictive of AVM obliteration after single-session SRS within the prescribed margin dose range 15 to 25 Gy. Further study is warranted to determine whether BED optimization should be considered as well as treatment dose for AVM SRS planning.     

Association of Self-reported Walking Pace With Type 2 Diabetes Incidence in the UK Biobank Prospective Cohort Study

ObjectiveTo investigate the association between self-reported walking pace and type 2 diabetes (T2D) incidence and whether it differed by physical activity levels and walking time.MethodsThere were 162,155 participants (mean age, 57.1 years; 54.9% women) from the UK Biobank prospective study, recruited between 2006 and 2010, included in the study. Walking pace was self-reported and classified as brisk, average, or slow. Total physical activity and walking time were self-reported using the International Physical Activity Questionnaire. Association between walking pace and T2D incidence and the potential moderating role of physical activity and walking time were investigated using Cox proportional hazards models.ResultsThe median follow-up was 7.4 (interquartile range, 6.7 to 8.2) years. There were 4442 participants in whom T2D developed during the follow-up period. In the fully adjusted model (sociodemographic factors, diet, body mass index, and physical activity), average walking pace (hazard ratio [HR], 1.28; 95% CI, 1.14 to 1.44) and slow walking pace (HR, 1.91; 95% CI, 1.62 to 2.24) were associated with a higher T2D risk compared with brisk walking among women. Among men, average walking pace (HR, 1.28; 95% CI, 1.17 to 1.40) and slow walking pace (HR, 1.73; 95% CI, 1.50 to 1.99) were also associated with higher T2D risk. Compared with slow walkers, brisk walkers have the same diabetes incidence rate 18.6 and 16.0 years later, for women and men, respectively.ConclusionAverage and slow walking pace was associated with a higher risk of incident T2D in both men and women, independent of major confounding factors. The associations were consistent across different physical activity levels and walking time.     

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.     

Pitfalls in Diagnosing Hypoglycemia Due to Exogenous Insulin: Validation and Utility of an Insulin Analog Assay

ObjectiveTo overcome the limitations of commercially available insulin immunoassays which have variable detection of analog insulin and can lead to clinically discordant results and misdiagnosis in the workup of factitious hypoglycemia.Patients and MethodsWe performed analytical validation of a liquid chromatography high resolution accurate mass (LC-HRAM) immunoassay to detect insulin analogs. We completed clinical assessment using a large cohort of human serum samples from 78 unique individuals, and subsequently used the assay in the evaluation of eight individuals with high diagnostic suspicion for factitious hypoglycemia.ResultsThe performance characteristics show that the LC-HRAM immunoassay can be applied to detect five commonly used synthetic insulin analogs (lispro, glulisine, aspart, glargine metabolite, and detemir) in human serum. Our clinical cases show that this assay could be used in the diagnosis of factitious hypoglycemia by identifying the analog insulin(s) in question.ConclusionThe LC-HRAM immunoassay reported here overcomes a gap in our diagnostic pathway for hypoglycemia. The results obtained from our studies suggest that this method is appropriate for use in clinical laboratories when factitious hypoglycemia is considered as a differential diagnosis.