JIM Reading List

Our Literature Review section continues with another installment of summaries from the medical literature. Our authors have found recent articles that have direct relevance to the practice of insurance medicine. The intent of the reading list is to provide highlights of articles, not an in-depth analysis. Contributions to the reading list are invited. Please forward your citation and summary to Michael L. Moore, MD, Deputy Editor, Literature Review at Moorem1@Nationwide.com. We will acknowledge all contributors in each issue’s installment.Concerns regarding the cardiovascular safety of testosterone replacement therapy (TRT) have been somewhat inconclusive based on previous trials with conflicting results. Before 2010, studies suggested that TRT maybe protective against cardiovascular (CV) disease, but then from 2010 to 2014, four studies came out suggesting increased risk for CV events, resulting in a decline in prescribing. Labeling of testosterone products in fact specifically have indicated that long term safety cannot be assessed. Limitations of these prior trials included smaller sample sizes and lack of randomization or placebo control. In 2015, the FDA thus required testosterone manufacturers to conduct a large clinical trial to assess CV safety, the (TRAVERSE Trial), resulting in a placebo-controlled study of 5,200 men, age range 45-80 randomized to receive testosterone gel or placebo, the results of which were published in NEJM in July, 2023.Enrollment criteria required two fasting serum testosterone levels <300 ng/dl and symptoms of hypogonadism (including decreased libido, ED, fatigue and low or depressed mood). A key point of this study is that enrollees had to have known CV disease or multiple CV risk factors (at least 3 out of 8). Participants received transdermal 1.62% topical gel or placebo and target testosterone levels were between 350-750 ng/dl. Mean duration of treatment and follow-up were 22 and 33 months respectively.The primary endpoint was first occurrence of any component of major adverse cardiovascular events, a composite of death from CV disease, nonfatal MI or nonfatal stroke. These primary end-point events occurred in 182 patients (7%) in the testosterone group and 190 patients (7.3%) in the placebo group. There was a slight increase in pulmonary embolism, 0.5% in placebo group vs 0.9% in TRT group. Prostate cancer occurred in 12 patients in the TRT group (0.5%) and 11 patients of placebo (0.4%).Overall, the results of this TRAVERSE trial appear to provide reassurance for men under TRT with known CV disease or with multiple CV risk factors and that TRT was noninferior compared to placebo with the occurrence of major CV events during the mean 22-month follow-up.Limitations of this study include the relatively short duration and longer-term studies will need to be conducted to assess if this safety data holds. As well it is unclear how well these results would carry over to the ‘insured-life’ population we assess as medical directors as it is not uncommon to see individuals who are treated more as lifestyle medicine and may not meet the more stringent diagnostic criteria noted above. As well the individuals in this study were closely monitored and managed and it is not unusual to see individuals under treatment with supratherapeutic testosterone levels, polycythemia and/or gaps in appropriate monitoring. Submitted by Ted W. Gossard, MDThere has been little long-term data to date regarding adolescent blood pressure levels and cardiovascular outcomes as this has been most extensively studied in the older adult population. This study from Sweden addresses this question and is remarkable in that it includes a very large sample size (1.4 million adolescents) with up to 50 years of follow-up.Participants of this retrospective cohort study are Swedish males, conscripted to the military from 1969 to 1997, with a mean age of 18 at onset, whose baseline BP was measured at the time of conscription. Median follow-up was 36 years. The primary outcome was a composite of CV death or first hospitalization for myocardial infarction, heart failure, ischemic stroke or intracerebral hemorrhage.Based on a single BP reading at the onset of the study, 17% of conscripts had normal BP (<120/80), 29% had elevated BP but not hypertension (120-129/<80), 35% had Stage-1 HTN and 19% had Stage-2. During the median follow-up of 36 years, almost 80,000 individuals experienced a primary outcome. The adjusted hazard ratio was 1.1 for elevated BP, 1.15 HR for isolated systolic HTN, 1.32 HR for Stage-1 HTN and 1.71HR for Stage-2 HTN. The cumulative risk for CV events increased gradually across these BP stages from 14.7% for normal BP to 24% for Stage-2 HTN by age 68 years.There are many self-evident limitations to this study including the narrow representative sample population of Swedish teenage males, the assessment of blood pressure and diagnosis of HTN with just a single initial BP reading and also a lack of information regarding who might have received treatment or follow-up care. But regardless, it is insightful that a single blood pressure measurement at age 18 in this large study population was predictive of future CV events over the next several decades. As high blood pressure is one of the most important modifiable CV risk factors, this study speaks to the importance of the identification of these individuals at a young age and managing appropriately. As well this study has potential relevance with the underwriting assessment of younger individuals with pediatric hypertension increasing and often underrecognized. Submitted by Ted W. Gossard, MDIn breast, lung, and colorectal cancer, decreased survival is associated with a delay in surgical intervention. However data is conflicting for less aggressive malignancies such as PTC.This study looked at disease specific and overall survival in PTC and time to surgery in three intervals: within 90 day, 91 to 180 days, >180 days.This observational population based cohort study used SEER Medicare data from 1999-2018. ICD codes were used to select patients. Exclusion criteria: prior PTC, age <65, nonpapillary types, no primary lesion, RAI or chemo prior to surgery.Among 8170 patients analyzed, mean age was 69.3 (SD+/− 11.4) years, and 69.6% were female. Individuals having 90 days or less between diagnosis and surgery made up 89.8% of the cohort, 7.8% made up the 91 to 180 days group, and 2.4% made up the more than 180 days group. Mean follow-up time for the cohort was 99.3 ± 53.0 months.For stage, 64% of patients had localized disease, 28% had regional disease, and 8% had distant disease; frequencies were similar across time groups. Nearly 50 percent of patients (49.7%) had a pathologic T stage of 1, 81.8% had N0 disease, and 97.6% had no distant metastases (M0). Eighty-three percent of the cohort underwent a total thyroidectomy. Patients had a mean of 1 positive node (SD+/− 3.4), and 45 percent of patients received radioactive treatment after surgery.Results. Overall survival: After adjusting for demographic and clinical covariables, increased time to surgery was associated with decreased overall survival in the > 180 day group only. When broken down by disease type, localized disease had progressive higher mortality in the 91-180 d and >180 d groups. No difference for regional or metastatic disease.Disease specific survival: no difference with overall time to surgery. However those with localized disease in the >180 d group had more than three times the rate of mortality. No association in the 91-180 d group. Regional disease- no association. Distant disease- decreased risk in both 91-180 d and >180 d group.They found that the extent to which time to surgery impacts DSS and OS in PTC is limited but may be important in localized disease, 24% increased mortality risk in OS and more than 3 times the estimated disease-specific mortality with delays greater than 180 days.The authors postulate that “there is a window of opportunity during which earlier intervention may impact survival for localized PTC. By the time the tumor has progressed in size or presents with nodal metastasis, it is possible that a small difference in time to surgery may not result in significant differences in survival.”Limitations: Observational StudyAge of participants (PTC tends to affect younger patients than this group)Low mortality in generalIn Summary. In a SEER Medicare population, patients with localized PTC would benefit from early surgical resection to avoid nodal metastasis. Stage at surgery may be more critical to survival than time of surgery in relation to diagnosis. Submitted by Rachna Relwani, MD, Clinical EndocrinologistIn this fascinating study, authors make extensive use of the Human Mortality Database and explore the difference between mortality rates in the United States and those in other wealthy nations (specifically Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Iceland, Ireland, Italy, Japan, Luxembourg, The Netherlands, new Zealand, Norway, Portugal, Spain, Sweden, Switzerland and the United Kingdom). Some small adjustments were needed due to the lack of availability of the data for some countries in some years. For each country and year age-standardized mortality rates (ASMRs) were collected. This technique accounts for differences between countries in the distributions of ages.The authors found that, between 1933 and about 1960, the US enjoyed a lower ASMR than the average of peer countries. Between 1960 and 1980, the US ASMR was similar to other countries. Beginning around 1980, the US began to accumulate significant excess deaths beyond those of peer nations. To describe this trend, authors created a measure called “missing Americans” - which is the number of American deaths that would have been avoided if the US had ASMRs similar to the average of the other nations. By 2015, the number of missing Americans had reached 500,000 and stayed there until a massive spike occurred in 2020 and 2021 due to the COVID-19 pandemic. Of course, all nations experienced a surge in deaths in these years, but the surge in American deaths was disproportionate to the others, such that the number of missing Americans reached over 1 million in 2020, and was nearly 1.1 million in 2021.These excess deaths occurred disproportionately black and Native Americans. The mortality ratio between the US and other nations was highest in the 20-40 age group (about 3 in 2019, and 3.7 in 2020 and 2021). In black Americans this ratio was nearly 5, and among Native Americans it was over 8. In life insurance underwriting terms, being a young (age 15-44) American carried a rating of 190 debits vs. similarly aged groups in peer nations. Before the pandemic, in 2019, this rating was 140 debits. These ratios for the 45-64 age group were 1.6 (60 debits) in 2019, 1.8 (80 debits) in 2020, and 2.0 (100 debits) in 2021.The authors go into a very detailed explanation of possible culprits in terms of the causes of this pre- and peri-pandemic excess mortality. High rates of obesity, diabetes, drug overdose, HIV and homicide account for much of the difference in the 1990s and early 2000s. After that, the large increases in mortality in the under-65 group were due to “drug overdoses, alcohol-related mortality, suicides, and cardiometabolic diseases. During the pandemic, the authors point out, the US had a disorganized response, which, when combined with the lack of universal access to healthcare, mistrust of the medical establishment, and many other factors, lead to the overall poor performance in controlling pandemic mortality compared to other nations.Some have pointed out that excess deaths during the late phases of the COVID pandemic and afterward were partially or mostly made up of non-COVID deaths. While this is true, when measuring “excess” deaths in this context, the comparator is the US pre-pandemic death rate. This article helps us to understand that that pre-pandemic level is, itself, abnormally high - and we should likely be paying more attention to the excess deaths vs. other peer nations than the month-to-month variability in COVID or non-COVID deaths. Submitted by Steven J. Rigatti, MD, Founder, Rigatti Risk Analytics, LLCIn a recent issue of the Journal of the American Medical Association (JAMA, July 3, 2023. Vol: 330, Issue: 1) researchers at the Beth Israel Deaconess Medical Center use a large language model AI (Chat GPT-4) to analyze a series of difficult cases. The cases were gathered from the New England Journal of Medicine - specifically the “Clinicopathologic Case Conference” series. These articles, published in most issues of the NEJM since the 1950s, discuss the initial presentation, lab tests, radiological tests and pathological findings of challenging cases from the Mass General Hospital. These findings are then discussed among the eminent clinicians, radiologists, and finally pathologists, to identify the underlying diagnosis.As an aside, I can remember seeing the NEJM for the first time as a first-year medical student. Because “case conference” was the only phrase I understood in the Table of Contents I attempted to read it. Within the first few sentences I was lost in an avalanche of medical terminology I did not yet understand. Two years later, as a third-year student, I read it again and was astounded by the fact that I understood it. I still had absolutely no idea how the diagnosis was made, but at least I could comprehend the words. It was, and has remained, my favorite feature of the NEJM or indeed any medical journal.In any case, researchers found that the AI obtained either the correct diagnosis or a list of diagnoses that contained the correct one about 64% of the time. This is fairly impressive given that the diagnoses included such enigmas as Erysipelothrix rhusiopathiae infection and encephalopathy due to Behcet disease.As promising as this it is important to that the into the AI was the of the the of will a more than the in these are the of medical the information is under of and there are many by the it would has will not but who use AI will who Submitted by Rigatti, Rigatti Risk authors from to 2020 on mortality in with and on and or ICD or compared to the population to of and mortality. 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