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 [email protected]. We will acknowledge all contributors in each issue’s installment.

  • 1. Lincoff AM, Bhasin Shalender, Flevaris Panagiotis, et al., for the TRAVERSE Study Investigators. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389:107-117.

Introduction. The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial was designed to determine the effects of testosterone-replacement therapy on the incidence of major adverse cardiac events among middle-aged and older men with hypogonadism and either preexisting or a high risk of cardiovascular disease.

Methods

  • -Men 45 to 80 years of age

  • -Symptoms of hypogonadism, (decreased libido, decreased spontaneous erections, fatigue, depressed mood, loss of body hair, or hot flashes)

  • -Two AM fasting serum testosterone levels <300 ng/dl

  • -Cardiovascular disease (clinical or angiographic evidence of CAD, CVD, or PAD) OR

  • -Increased cardiovascular risk (presence of three or more of the following risk factors:

    • HTN

    • Chol

    • Smoker

    • Stage 3 CKD

    • DM

    • Elev hs CRP

    • Age >65

    • Coronary calcium score >75th percentile for age and race

Results. Nearly half the patients enrolled in the current trial were 65 years of age or older, and more than half had preexisting cardiovascular disease. Most had obesity and/or diabetes. The 372 adjudicated primary end-point events that occurred in this trial were greater in number than those in all previous randomized trials of testosterone combined. (see Table 1)

Discussion. No apparent clinically meaningful differences in primary (3 point MACE) or secondary endpoints. The CI all crossed one, showing that there was no difference between the two groups. There was a higher incidence of PE, a tertiary endpoint.

The incidence of pulmonary embolism was higher with testosterone than with placebo. Although most reported cases of thrombosis associated with testosterone therapy have been in men with underlying thrombophilia, a meta-analysis of randomized trials did not show an association between venous thromboembolic events and testosterone use in wider populations.

There were more cases of nonfatal arrhythmias warranting intervention, atrial fibrillation, and acute kidney injury among patients who received testosterone than among those who received placebo; these adverse events were not expected.

In the current trial, the small increase in blood pressure observed in the testosterone group was similar to that reported previously with other testosterone formulations.

Limitations. Firstly, generalizability- this study was a high risk group. As a consequence the results should be biased to showing impact, so the noninferiority is more striking. Of note the study was done with transdermal testosterone- may not be generalizable to injections, which are known to carry more risk and side effects. Second, atherosclerotic cardiovascular disease evolves over decades, and the duration of therapy in the TRAVERSE trial was relatively short. Third, in the TRAVERSE trial, the increase in testosterone levels during therapy was modest; the median testosterone level in the testosterone group ranged from 326 to 386 ng per deciliter.

Finally, estradiol levels were also increased by testosterone supplementation in the current trial. In the Testosterone Trials, several effects of treatment were attributed primarily to the change in estradiol levels, and in women, estrogen-replacement therapy has been linked to an increased risk of thrombosis. It will be important to examine the relationship between estradiol levels and outcomes in the TRAVERSE trial as well. Most of the above section taken from Safety of Testosterone-Replacement Therapy in Older Men (E Orwoll. N Engl J Med. 2023;389:177-178).

Conclusion. Among men with hypogonadism and established cardiovascular disease or multiple risk factors for incident cardiac events, testosterone-replacement therapy was noninferior to placebo with respect to the occurrence of major adverse cardiac events during a mean 22-month follow-up, and the overall incidence of adverse events was low. Submitted by Rachna Relwani, MD.

  • 2. Um YJ, Chang Yoosoo, Yejin K, et al. Risk of CKD Following Detection of Microscopic Hematuria: A Retrospective Cohort Study. Am J Kidney Dis. 2023;81:425-433.

Microscopic hematuria is often an incidental finding in primary care practice as well as on life insurance labs and can present a challenge when assessing its potential significance. The authors of this study investigate the association between persistent or single episodes of microscopic hematuria and the future development of CKD.

This retrospective cohort study of 232,000 Korean adults (mean age 38) took place over a 4.8 year median follow-up period and categorized participants into 1 of 4 groups according to the presence of hematuria on 2 consecutive exams about two years apart:

  1. No hematuria at both exams (reference group).

  2. Hematuria followed by no hematuria (regressed hematuria group).

  3. No hematuria followed by hematuria (developed hematuria) and

  4. Hematuria at both exams. Participants were without CKD at baseline, CKD being defined as GFR <60ml/min/1.73m2 or proteinuria (1+ or more on dipstick). Hematuria was defined as >5 RBCs/HPF.

At the median follow-up of 5 years, the incidence of CKD was 1% in the reference group (no hematuria both exams). Multivariable adjusted hazard ratios for incident CKD compared to this group was about twofold, threefold and fivefold increased risk of CKD respectively in the first examination only hematuria, second examination only and both examination hematuria. These findings remained similar when excluding patients who developed GU malignancy during the follow-up period.

This study concludes that men and women with incidental microscopic hematuria may be at increased risk of CKD, in particular, if found on two separate occasions (about 5%). Limitations of this study include lack of assessment of albuminuria and inability to consider specific glomerular diseases. Submitted by Ted W Gossard, MD.

  • 3. Rico BMH, Aliberti MJR, Trajano da Silva NO, et al. Advancing cognitive assessment in telemedicine: Validity and reliability of the telephone 10-point cognitive screener. J Am Geriatr Soc. 2023;71:977-980.

The recent SARS-CoV-2 pandemic resulted in a marked increase in the utilization of telemedicine services. With this, the demand for diagnostic tools which can be used during a telephonic or video call has increased. In this article, the authors studied the effectiveness and accuracy of a telephonic assessment of cognition. According to the authors, the 10-point cognitive screener or “10-CS,” “combines temporal orientation, verbal fluency, and word recall tests.” It does not assess writing, drawing or motor function and is therefore a good candidate for telephonic implementation.

The study subjects were 84 consecutive patients over the age of 60 who were referred to a Memory Clinic in Sao Paulo, Brazil, and who met inclusion criteria. The presence of dementia or cognitive impairment without dementia was established by a 90-minute expert assessment, which included neuropsychiatric testing. An in-person 10-CS test was given at that visit. One week later, a telephonic version of the 10-CS was given to the same patients.

The telephonic test performed very well, essentially equalling the performance of the in-person test and achieving a sensitivity of 83% and specificity of 80% for the detection of dementia. The AUC was 0.8 for any impairment (CIND or dementia) and 0.88 for dementia alone.

The authors concluded that their study supported the validity of the telephonic 10-CS and that wider use could improve healthcare access and equity. In the insurance industry, this lends validity to the telephonic cognitive screens that have been used for decades in the underwriting of life and long-term care insurance. Submitted by Steven J Rigatti, MD.

  • 4. Nik-Ahd F, De Hoedt A, Butler C, et al. Prostate Cancer in Transgender Women in the Veterans Affairs Health System, 2000-2022. JAMA. 2023;329:1877-1879.

In the past decade, gender affirming surgery has become more commonplace. This study looking at patients at the Veterans Administration who had undergone transgender care was undertaken to look at the incidence of prostate cancer. In this particular study, a total of 155 were found to be transgender women with prostate cancer. At the time of diagnosis, the median age was 61 years, 88% were Caucasian and the median PSA was 6.8 ng/mL. 116 had never used estrogen supplementation, 17 formerly used estrogen, and 22 individuals were actively using estrogen at the time of diagnosis. Of the 155 in the study, 152 had not undergone bilateral orchiectomy.

The study does confirm that prostate cancer does occur in transgender women and is not as rare as previously thought. Although this is a small study in a relatively specific cohort, it does suggest that regular prostate screening is still warranted in transgender women who still have prostates. It also showed that the use of estrogen tended to produce more aggressive prostate cancer grades than those who had not used estrogen. The most aggressive being in those who were currently receiving estrogen.

As medical directors, we are always adapting to new areas of development that may affect risk selection and overall morbidity and mortality. This new area of transgender risk selection is proving to be just as challenging in dealing with not only the medical aspects of risk selection but the societal norms as to which screening tests are acceptable. Submitted by Michael L. Moore, MD.

  • 5. Hamdy C, Donovan JL, Hamby JAL, et al. Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. N Engl J Med. 2023;388:1547-1558.

In the United States in 2020, about 192,000 men received a diagnosis of prostate cancer, and 33,000 men died of the disease. The challenging aspects of risk stratification may drive both overtreatment and undertreatment of this cancer. Therefore, assessing the future mortality risk of prostate cancer based on the various treatment modalities available can present a challenge in life underwriting, in particular as active surveillance becomes more common place in efforts to minimize treatment associated morbidities. In this study, a randomized controlled trial from the UK, the authors enrolled 1643 persons between 50 and 69 years of age with a diagnosis of localized prostate cancer and randomly assigned them to one of three treatment arms: active monitoring, prostatectomy, and radiotherapy. The primary outcome was death from prostate cancer and secondary outcomes included death from any cause, development of metastasis, and disease progression.

Follow-up was completed for 1610 patients (98%) with a duration range from 11 to 21 years and median duration of 15 years. Death from prostate cancer occurred in 45 men (2.7% of the entire population). This consisted of 17 (or 3.1%) in the active monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group.

Death from any cause occurred in 356 patients (21.7%) overall, with similar numbers in all 3 groups (22.8% in the active monitoring group, 21% in the prostatectomy group and 21% in the radiotherapy group). Metastases developed in 51 men (9.4%) in the active monitoring group, 26 (4.7%) in the active-monitoring group and 27 (5%) in the radiotherapy group.

The authors conclude that, based on median duration of 15 years, their analysis shows evidence of a high percentage of long-term survival in this population with 97% survival from prostate cancer-specific death and 78% from death of any cause, regardless of the treatment group. The radical treatments (prostatectomy or radiotherapy) did reduce the incidence of metastasis, local progression and long-term androgen-deprivation theory by half compared with active monitoring however this did not translate into differences in mortality. No differences on cancer-specific mortality were noted relative to baseline PSA level, tumor stage or grade or risk-stratification scores. Based on these results, the choice of therapy involves the weighing the trade-offs of potential risks and benefits associated with treatments for localized prostate cancer. Submitted by Ted W Gossard, MD.

  • 6. Bommersbach T, McKean A, Olfson M, Rhee Taeho G. National Trends in Mental-Health Related Emergency Department Visits Among Youth. JAMA. 2023;329:1469-1477.

From 2002-2019 national suicide rates among youth increased by 57%, and COVID-19 has only increased concerns for mental health at all ages.

This study aimed to answer four questions:

  • What are national annual trends in pediatric mental health-related ED visits from 2011-2020, including trends from 2019-2020?

  • How do trends vary by age, sex, race, and ethnicity, and psychiatric dx?

  • Among pediatric mental health related ED visits, how have visit characteristics changed over the study period, including length of visits, urgency, and how often children see a mental health professional?

  • Which sociodemographic and diagnostic characteristics are most strongly associated with pediatric mental health related ED visits?

Methods. Study based on public data from 2011-2020 NHAMCS, a cross sectional survey of ED visits across the US conducted annually by the National Center for Health Statistics. They identified visits for children (age 6-11), adolescents (12-17), and young adults (18-24) with a total of 49,515 visits. Visits were considered mental health related if any of the 5 ICD discharge diagnosis codes or psychiatric RFV codes identified a mental health condition.

Results. (see Table 2)

Discussion. Going back to the 4 questions:

  1. What are national annual trends in pediatric mental health-related ED visits from 2011-2020, including trends from 2019-2020?

Although the total number of ED visits declined with COVID, the number of mental health ED visits stayed the same, leading to a greater proportion of ED visits (nearly double) for mental health reasons.

The proportion of all types of mental health related visits increased significantly, but suicide related visits demonstrated the largest increase, and across all age groups.

  • 2

    How do trends vary by age, sex, race, and ethnicity, and psychiatric dx?

Increase in all age groups, both sexes, all races, and all geographic regions. Mental health-related visits increased the most among 10- and 14-year-olds. Suicide related visits increased 5 fold and now are nearly 5% of all pediatric ED visits, and across all age groups. No other trend by specific psychiatric diagnosis.

  • 3

    Among pediatric mental health related ED visits, how have visit characteristics changed over the study period, including length of visits, urgency, and how often children see a mental health professional?

No change in that time period in terms of urgency or length of visit (>6 hours), and <20% include evaluation by a mental health professional.

  • 4

    Which sociodemographic and diagnostic characteristics are most strongly associated with pediatric mental health related ED visits?

Children: males

Adolescents: females

Young adults: males, white

Public insurance

Limitations. Data sampling- did not include urgent care centers or psychiatric facilities; in locales with the latter they may see a significant population of the mental health visits and that may skew both total number and demographics.

Age group breakdown: They used classification categories stated above but some of the data is for age 10-14 and other categories were 6-11, 12-17, so there may be some overlap.

Data was by visit not patient- repeated visits by same patient not taken into account.

In conclusion, this study confirmed the growing mental health crisis, especially in children, with a disproportionate increase in suicide attempts by 10- to 14-year-olds. “ED are critical mental health access points for children who face structural barriers, including racial and ethnic minorities and children who are undocumented or uninsured.” Submitted by Rachna Relwani.

  • 7. Fan Y, Støving RK, Ibraim SB, et al. The Gut Microbiota Contributes to the Pathogenesis of Anorexia Nervosa in Humans and Mice. Nat Microbiology. 2023;8:787–802.

It seems that nearly every month we are finding more and more connections between overall health and the gut microbiome. This study of 77 women from Europe and Scandinavia who had been diagnosed with anorexia nervosa was taken to analyze gut microbes and metabolites in the bloodstream vs 70 healthy female controls. One bacterial family, Cristensenellaceae, was found in abundance, whereas several Rosburia species were depleted in those with anorexia nervosa. In addition, 35 bacterial metabolites were present in the blood correlated with anorexia nervosa. Finally, stool samples were transplanted from those with anorexia to otherwise healthy mice. Those mice initially lost weight and had slower weight gain over time than those who had received transplants from controls.

This is one of many recent studies that continue to show an increasing prevalence of human conditions that appear to be directly related to the microbiota of the gut. It would appear that we are near the beginning of a whole new era of medical diagnosis and treatment related to maximizing the potential of gut bacteria. One only has to wonder at what the future will eventually bring. Submitted by Michael L Moore, MD.