Characterization of the literature informing health care of transgender and gender-diverse persons: A bibliometric analysis.

BACKGROUND AND OBJECTIVE: Transgender and gender-diverse (TGD) persons experience health inequities compared to their cisgender peers, which is in part related to limited evidence informing their care. Thus, we aimed to describe the literature informing care provision of TGD individuals. DATA SOURCE, ELIGIBILITY CRITERIA, AND SYNTHESIS METHODS: Literature cited by the World Professional Association of Transgender Health Standards of Care Version 8 was reviewed. Original research articles, excluding systematic reviews (n = 74), were assessed (n = 1809). Studies where the population of interest were only caregivers, providers, siblings, partners, or children of TGD individuals were excluded (n = 7). Results were synthesized in a descriptive manner. RESULTS: Of 1809 citations, 696 studies met the inclusion criteria. TGD-only populations were represented in 65% of studies. White (38%) participants and young adults (18 to 29 years old, 64%) were the most well-represented study populations. Almost half of studies (45%) were cross-sectional, and approximately a third were longitudinal in nature (37%). Overall, the median number of TGD participants (median [IQR]: 104 [32, 356]) included in each study was approximately one third of included cisgender participants (271 [47, 15405]). In studies where both TGD and cisgender individuals were included (n = 74), the proportion of TGD to cisgender participants was 1:2 [1:20, 1:1]. Less than a third of studies stratified results by sex (32%) or gender (28%), and even fewer included sex (4%) or gender (3%) as a covariate in the analysis. The proportion of studies with populations including both TGD and cisgender participants increased between 1969 and 2023, while the proportion of studies with study populations of unspecified gender identity decreased over the same time period. CONCLUSIONS: While TGD participant-only studies make up most of the literature informing care of this population, longitudinal studies including a diversity of TGD individuals across life stages are required to improve the quality of evidence.

The Vaginal Microbiome of Transgender and Gender Nonbinary Individuals.

Purpose: The goal of this preliminary study is to describe the vaginal microbiome of transgender and gender nonbinary (TGNB) individuals using nonculture-based techniques. TGNB individuals may undergo gender-affirming surgical procedures, which can include the creation of a neovagina. Little is known about microbial species that comprise this environment in states of health or disease. Methods: In this pilot study, vaginal swabs were self-collected from 15 healthy self-identified TGNB participants (age 26-69 years) and 8 cisgender comparator participants (age 27-50 years) between 2017 and 2018. Next-generation 16S ribosomal RNA sequencing was used to profile individual bacterial communities from all study samples. Results: The TGNB cohort demonstrated significantly higher intraindividual (alpha) diversity than the cisgender group (p=0.0003). Microbial species commensal to the gut and skin were identified only in specimens from TGNB participants. Although Lactobacillus species were dominant in all cisgender comparator samples, they were found at low relative abundance (≤3%) in TGNB samples. Conclusion: In this study, specimens collected from neovaginas showed increased alpha diversity and substantially different composition compared with natal vaginas. In contrast to natal vaginas, neovaginas were not dominated by Lactobacillus, but were hosts to many microbial species. Studies that help to improve our understanding of the neovaginal microbiome may enable clinicians to differentiate between healthy and diseased neovaginal states.

ChatGPT vs Medical Professional: Analyzing Responses to Laboratory Medicine Questions on Social Media.

BACKGROUND: The integration of ChatGPT, a large language model (LLM) developed by OpenAI, into healthcare has sparked significant interest due to its potential to enhance patient care and medical education. With the increasing trend of patients accessing laboratory results online, there is a pressing need to evaluate the effectiveness of ChatGPT in providing accurate laboratory medicine information. Our study evaluates ChatGPT's effectiveness in addressing patient questions in this area, comparing its performance with that of medical professionals on social media. METHODS: This study sourced patient questions and medical professional responses from Reddit and Quora, comparing them with responses generated by ChatGPT versions 3.5 and 4.0. Experienced laboratory medicine professionals evaluated the responses for quality and preference. Evaluation results were further analyzed using R software. RESULTS: The study analyzed 49 questions, with evaluators reviewing responses from both medical professionals and ChatGPT. ChatGPT's responses were preferred by 75.9% of evaluators and generally received higher ratings for quality. They were noted for their comprehensive and accurate information, whereas responses from medical professionals were valued for their conciseness. The interrater agreement was fair, indicating some subjectivity but a consistent preference for ChatGPT's detailed responses. CONCLUSIONS: ChatGPT demonstrates potential as an effective tool for addressing queries in laboratory medicine, often surpassing medical professionals in response quality. These results support the need for further research to confirm ChatGPT's utility and explore its integration into healthcare settings.

Point-of-care testing: state-of-the art and perspectives.

Point-of-care testing (POCT) is becoming an increasingly popular way to perform laboratory tests closer to the patient. This option has several recognized advantages, such as accessibility, portability, speed, convenience, ease of use, ever-growing test panels, lower cumulative healthcare costs when used within appropriate clinical pathways, better patient empowerment and engagement, and reduction of certain pre-analytical errors, especially those related to specimen transportation. On the other hand, POCT also poses some limitations and risks, namely the risk of lower accuracy and reliability compared to traditional laboratory tests, quality control and connectivity issues, high dependence on operators (with varying levels of expertise or training), challenges related to patient data management, higher costs per individual test, regulatory and compliance issues such as the need for appropriate validation prior to clinical use (especially for rapid diagnostic tests; RDTs), as well as additional preanalytical sources of error that may remain undetected in this type of testing, which is usually based on whole blood samples (i.e., presence of interfering substances, clotting, hemolysis, etc.). There is no doubt that POCT is a breakthrough innovation in laboratory medicine, but the discussion on its appropriate use requires further debate and initiatives. This collective opinion paper, composed of abstracts of the lectures presented at the two-day expert meeting "Point-Of-Care-Testing: State of the Art and Perspective" (Venice, April 4-5, 2024), aims to provide a thoughtful overview of the state-of-the-art in POCT, its current applications, advantages and potential limitations, as well as some interesting reflections on the future perspectives of this particular field of laboratory medicine.

Impact of sex used for assignment of reference intervals in a population of patients taking gender-affirming hormones.

Background: Gender-affirming hormone therapy with either estradiol or testosterone for transgender persons can significantly impact chemistry and hematology laboratory tests. The sex used for assignment of reference intervals (RIs) in the electronic health record (EHR) will influence normal/abnormal flagging of test results. Objective: To analyze common non-hormonal laboratory tests with sex-specific RIs ordered in patients with sexual orientation/gender identify (SOGI) field differences (one or more differences between legal sex, sex assigned at birth, and gender identity) in the EHR at an academic medical center in midwestern United States. Methods: We utilized a previously characterized data set of patients at our institution that included chart review information on gender identity and gender-affirming therapy. We focused on the subset of these patients that had orders for 18 common laboratory tests in calendar year 2021. Results: A total of 1336 patients with SOGI field differences (1218 or 91.2% identifying as gender-expansive; 892 or 66.8% receiving estradiol or testosterone as gender-affirming therapy) had a total of 9374 orders for 18 laboratory tests with sex-specific RIs. Hemoglobin, creatinine, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and high-density lipoprotein were the most frequently ordered tests. For patients taking estradiol, 128 of 970 (13.2%) creatinine and 39 of 193 (20.2%) hemoglobin measurements were within the RI for one sex but not the other. For those taking testosterone, 119 of 531 (22.4%) creatinine and 49 of 120 (40.8%) hemoglobin measurements were within the RI for one sex but not the other. Values above the cisgender female RI but within the cisgender male RI were common for hemoglobin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase in patients taking testosterone. Conclusions: Clinicians should be aware of the potential impact of gender-affirming therapy on laboratory tests and what sex/gender is being used in the EHR to assign RIs.

Association between serum estradiol and cardiovascular health among transgender adults using gender-affirming estrogen therapy.

Gender-affirming estrogen therapy (GAET) is commonly used for feminization in transgender and nonbinary (TNB) individuals, yet the optimal rate of change (ROC) in estradiol levels for cardiovascular health is unclear. We examined the association between serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Web of Science were systematically searched (inception-April 2023) for original articles reporting serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Data extraction was completed in duplicate following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Stratified random effect meta-analyses using serum estradiol ROC (serum estradiolbaseline - serum estradiolfollow-up/study duration) was used to assess longitudinal studies (low, 0 < ROC ≤ 1 pg/mL/mo; moderate, 1 < ROC ≤ 3 pg/mL/mo; high, ROC ≥ 3 pg/mL/mo). Thirty-five studies (13 cross-sectional, 19 cohort, and 3 trials) were included. Two studies collectively reported 50 cardiovascular-related deaths, and four collectively reported 23 adverse cardiovascular events. Nineteen studies reporting cardiovascular risk factors were meta-analyzed by ROC stratum (low = 5; moderate = 6; high = 8), demonstrating an association between moderate [0.40, 95% confidence interval (CI): 0.22, 0.59 kg/m2, I2 = 28.2%] and high (0.46, 95% CI: 0.15, 0.78 kg/m2; I2 = 0.0%) serum estradiol ROC and increased body mass index. High (-6.67, 95% CI: -10.65, -2.68 mg/dL; I2 = 0.0%) serum estradiol ROC was associated with decreased low-density lipoproteins. Low (-7.05, 95% CI: -10.40, -3.70 mmHg; I2 = 0.0%) and moderate (-3.69, 95% CI: -4.93, -2.45 mmHg; I2 = 0.0%) serum estradiol ROCs were associated with decreases in systolic blood pressure. In TNB adults using GAET, serum estradiol ROC may influence cardiovascular risk factors, which may have implications for clinical cardiovascular outcomes.NEW & NOTEWORTHY In this systematic review and meta-analysis of 35 studies involving 7,745 participants, high rates of serum estradiol change were associated with small increases in body mass index. Moderate to high rates of change were associated with decreases in low-density lipoprotein. Low rates of change were associated with small decreases in systolic blood pressure. Rate of serum estradiol change in adults using gender-affirming estrogen therapy may influence cardiovascular risk factors, though further research is warranted.

Reflex strategy to ensure accurate total testosterone results from consumer initiated, self-collected capillary samples.

BACKGROUND: Self-collected capillary samples are convenient for direct access testing (DAT), but exogenous testosterone use may cause falsely elevated total testosterone (TT) results. We designed a quality assurance workflow to differentiate between accurate or erroneous supraphysiological TT concentrations. METHODS: Clinical samples with TT > 1500 ng/dL were reflexed to luteinizing hormone (LH) and follicle stimulating hormone (FSH) and screened for exogenous testosterone use. Samples (n = 120) with normal TT were reflexed to LH/FSH as a control. RESULTS: A total of 8572 TT samples were evaluated, of which 533 (6.2 %) had TT > 1500 ng/dL and were reflexed. Of these, 441 (82.7 %) had significantly decreased LH/FSH (<0.85/<0.7mIU/mL, respectively), 72 (13.5 %) had normal or borderline normal LH/FSH, and 20 (3.8 %) had insufficient plasma volume. In patients with TT > 1500 ng/dL, injectable exogenous testosterone use was most commonly accompanied by significantly decreased LH/FSH, while topical testosterone use was most commonly accompanied by detectable LH/FSH. Control samples were almost all (99.2 %) within or above the LH/FSH reference intervals. Unique patients ordered 351 TT tests where at least one TT result was > 1500 ng/dL. Based on TT and LH/FSH results, we hypothesized that patients were intermittently or consistently overusing exogenous testosterone, resolved elevated TT with recollection, or repeatedly contaminated their sample. CONCLUSION: Self-collected capillary specimens are acceptable for TT testing. A quality assurance reflex to LH/FSH can determine the validity of supraphysiological TT results in a consumer initiated/DAT population.

Development and validation of an LC-MSMS method to quantify creatinine from dried blood spots.

Introduction: Screening for chronic kidney disease relies on accurate and precise creatinine measurements. Traditionally, creatinine is measured in serum or plasma using high-throughput chemistry analyzers. However, dried blood spots (DBS) can also be utilized to improve testing access. Methods: Samples were obtained from a 6 mm DBS punch, which was reconstituted in water before undergoing an acetonitrile crash. The resulting supernatant was diluted using an 80:20 acetonitrile: water before injection. Creatinine was identified using an isocratic gradient, and detected using an API 4000 triple quadrupole mass analyzer. Quantification relied on matrix-matched calibrators, with values harmonized to the Roche Cobas enzymatic assay. Validation studies assessing method performance included precision, linearity, accuracy, method comparison, stability, interference, and matrix effects. Results: The LC-MSMS assay was linear from 0.3 to 20 mg/dL (y = 1.02x-0.11; R2 = 0.996). Precision ranged from 5.2 to 8.1 % using matrix-matched controls (n = 4) that spanned the analytical measurement range. LC-MSMS results corresponded to the enzymatic assay (Roche) with a fitted line equation of y = 0.956x-0.07 (R2 = 0.995; n = 173). The Siemens and Roche enzymatic assays demonstrated higher accuracy in correlating to the DBS creatinine concentration (n = 40 paired venous/DBS collections) compared to the Beckman Jaffe assay (-2.5 % and -0.8 % versus -6.3 % and -4.1 %, respectively) or the iSTAT (-28.4 % and -27.1 %, respectively). Accuracy was unaffected by hematocrit, blood spot volume, excess IgG or IgA, or hypertriglyceridemia. No matrix effects were observed, and both extraction and processing efficiency were robust.Ambient stability extended to at least 10 days, and exposure to extreme temperature did not affect the creatinine results. Conclusion: We successfully developed an accurate and precise LC-MSMS method for quantifying creatinine in DBS.

Evaluation of Pre-Analytical Variables for Human Papillomavirus Primary Screening from Self-Collected Vaginal Swabs.

Human papillomavirus (HPV) primary screening is an effective approach to assessing cervical cancer risk. Self-collected vaginal swabs can expand testing access, but the data defining analytical performance criteria necessary for adoption of self-collected specimens are limited, especially for those occurring outside the clinic, where the swab remains dry during transport. Here, we evaluated the performance of self-collected vaginal swabs for HPV detection using the Cobas 6800. There was insignificant variability between swabs self-collected by the same individual (n = 15 participants collecting 5 swabs per participant), measured by amplification of HPV and human ß-globin control DNA. Comparison of self-collected vaginal swab and provider-collected cervical samples (n = 144 pairs) proved highly concordant for HPV detection (total agreement = 90.3%; positive percentage agreement = 84.2%). There was no relationship between the number of dry storage days and amplification of HPV (n = 68; range, 4 to 41 days). Exposure of self-collected dry swabs to extreme summer and winter temperatures did not affect testing outcomes. A second internal control (RNase P) demonstrated that lack of amplification for ß-globin from self-collected specimens was consistent with poor, but not absent, cellularity. These data suggest that self-collected vaginal samples enable accurate clinical HPV testing, and that extended ambient dry storage or exposure to extreme temperatures does not influence HPV detection. Furthermore, lack of ß-globin amplification in HPV-negative samples accurately identified participants who required recollection.

A Holistic Framework for the Evaluation of Kidney Function in a Gender-Diverse Landscape.

The most commonly used equations to estimate glomerular filtration rate incorporate a binary male-female sex coefficient, which has important implications for the care of transgender, gender-diverse, and nonbinary (TGD) people. Whether "sex assigned at birth" or a binary "gender identity" is most appropriate for the computation of estimated glomerular filtration rate (eGFR) is unknown. Furthermore, the use of gender-affirming hormone therapy (GAHT) for the development of physical changes to align TGD people with their affirmed gender is increasingly common, and may result in changes in serum creatinine and cystatin C, the biomarkers commonly used to estimate glomerular filtration rate. The paucity of current literature evaluating chronic kidney disease (CKD) prevalence and outcomes in TGD individuals on GAHT makes it difficult to assess any effects of GAHT on kidney function. Whether alterations in serum creatinine reflect changes in glomerular filtration rate or simply changes in muscle mass is unknown. Therefore, we propose a holistic framework to evaluate kidney function in TGD people. The framework focuses on kidney disease prevalence, risk factors, sex hormones, eGFR, other kidney function assessment tools, and the mitigation of health inequities in TGD people.

Optimizing the data in direct access testing: information technology to support an emerging care model.

Direct access testing (DAT) is an emerging care model that provides on-demand laboratory services for certain preventative, diagnostic, and monitoring indications. Unlike conventional testing models where health care providers order tests and where sample collection is performed onsite at the clinic or laboratory, most interactions between DAT consumers and the laboratory are virtual. Tests are ordered and results delivered online, and specimens are frequently self-collected at home with virtual support. Thus, DAT depends on high-quality information technology (IT) tools and optimized data utilization to a greater degree than conventional laboratory testing. This review critically discusses the United States DAT landscape in relation to IT to highlight digital challenges and opportunities for consumers, health care systems, providers, and laboratories. DAT offers consumers increased autonomy over the testing experience, cost, and data sharing, but the current capacity to integrate DAT as a care option into the conventional patient-provider model is lacking and will require innovative approaches to accommodate. Likewise, both consumers and health care providers need transparent information about the quality of DAT laboratories and clinical decision support to optimize appropriate use of DAT as a part of comprehensive care. Interoperability barriers will require intentional approaches to integrating DAT-derived data into the electronic health records of health systems nationally. This includes ensuring the laboratory results are appropriately captured for downstream data analytic pipelines that are used to satisfy population health and research needs. Despite the data- and IT-related challenges for widespread incorporation of DAT into routine health care, DAT has the potential to improve health equity by providing versatile, discreet, and affordable testing options for patients who have been marginalized by the current limitations of health care delivery in the United States.

The Role of Artificial Intelligence for Providing Scientific Content for Laboratory Medicine.

BACKGROUND: Artificial intelligence (AI) promises to become an important tool in the practice of laboratory medicine. AI programs are available online that can provide concise medical and laboratory information within seconds after a question is submitted. METHODS: We posed the following contemporary and relevant question for clinical chemists using an AI program: "Should labs eliminate CK-MB testing?" The results of this inquiry were critically reviewed by a cardiologist, emergency department physician, and clinical laboratorians for accuracy and appropriateness. RESULTS: An AI report answering this question was generated within 15 s. The experts felt that the information was inaccurate with the statements that CK-MB results are released earlier than cardiac troponin (cTn), and are more useful for detection of myocardial injury in patients with renal insufficiencies. The summary omitted discussion on the ongoing debate for periprocedural detection of acute myocardial infarction (MI), the perceived value for detection of reinfarction, the value in risk stratification compared to cTn, the economic justification for testing both CK-MB and cTn, and medicolegal aspects of testing when results are discordant. CONCLUSIONS: At this time, AI does not appear to be ready to be used by clinical laboratories for answering important practice questions.

Falsely elevated serum testosterone measurements resulting from testosterone topical gel contamination of the venipuncture site: Case Series and retrospective review.

Testosterone as replacement therapy for male hypogonadism or as gender-affirming hormone therapy for transgender and non-binary patients has increased worldwide. Commonly used formulations of testosterone include intramuscular, transdermal patch, and topical gel, each of which has differing pharmacokinetics and practical challenges. In monitoring testosterone serum concentrations, contamination of the phlebotomy site by testosterone topical gel can lead to supraphysiologic (>1000 ng/dL or 34.7 nmol/L) serum concentrations of testosterone, as demonstrated in a few published case reports. The frequency of this issue is currently not known. The present study involves a retrospective search over a 13-year period across all clinical sites at an academic medical center. Out of 578 unique patients using testosterone topical gel, a total of 48 patients had at least 1 testosterone serum concentration exceed 1000 ng/dL. Documentation in the electronic health record revealed 7 patients where contamination of the phlebotomy site by topical gel was strongly supported as the cause of supraphysiologic testosterone serum concentrations. These included 5 males with primary hypogonadism, 1 male with panhypopituitarism, and a non-binary patient with gender dysphoria. The high testosterone concentrations prompted further work-up, including retesting and endocrinology consultation. There were additional cases of high testosterone serum concentration that may have been falsely elevated due to gel contamination but without sufficient supporting evidence available in the health record. Overall, we present 7 cases of spuriously high testosterone concentrations strongly suspected to be due to venipuncture performed near or at the location of prior testosterone gel application. Gel contamination should be considered as a possible cause of otherwise unexplained high testosterone serum concentration in patients receiving topical testosterone gel formulations. Patient counseling and provider awareness of this potential cause of spuriously high testosterone serum concentrations is important.

Matrix-matched calibrators are necessary for robust and high-quality dried blood spots lead screening assays by inductively coupled plasma-mass spectrometry.

Background and aims: Reliable lead screening methods are necessary to support early identification of lead exposure in children. Sample collection using dried blood spots (DBS) offers advantages compared to traditional venipuncture and capillary collection. Here, we describe and compare three lead DBS inductively coupled plasma-mass spectrometry (ICP-MS) methods for lead screening. Materials and methods: Lead was extracted from Whatman 903 protein saver cards punches and analyzed by ICP-MS across three independent clinical laboratories. Each laboratory evaluated the performance of aqueous and matrix-matched DBS calibrators using external quality control samples (WI State of Laboratory of Hygiene Program). Leftover patient samples (n = 39) were used for an interlaboratory comparison of lead DBS. Lead DBS results were compared to whole blood methods. Results: The DBS ICP-MS methods using matrix-matched DBS calibrators had superior performance to the aqueous calibrations. There was a strong correlation between lead measured in DBS (matrix-matched) and whole blood for the three methods evaluated. Conclusion: Lead can be measured accurately by ICP-MS in DBS samples when matrix-matched calibrators are used. External quality control programs are valuable to assess the performance of DBS methods. DBS lead ICP-MS methods are a robust analytical option for lead screening even though the limitations of DBS are well recognized.

Patterns of gender identity data within electronic health record databases can be used as a tool for identifying and estimating the prevalence of gender-expansive people.

Objective: Electronic health records (EHRs) within the United States increasingly include sexual orientation and gender identity (SOGI) fields. We assess how well SOGI fields, along with International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes and medication records, identify gender-expansive patients. Materials and Methods: The study used a data set of all patients that had in-person inpatient or outpatient encounters at an academic medical center in a rural state between December 1, 2018 and February 17, 2022. Chart review was performed for all patients meeting at least one of the following criteria: differences between legal sex, sex assigned at birth, and gender identity (excluding blank fields) in the EHR SOGI fields; ICD-10 codes related to gender dysphoria or unspecified endocrine disorder; prescription for estradiol or testosterone suggesting use of gender-affirming hormones. Results: Out of 123 441 total unique patients with in-person encounters, we identified a total of 2236 patients identifying as gender-expansive, with 1506 taking gender-affirming hormones. SOGI field differences or ICD-10 codes related to gender dysphoria or both were found in 2219 of 2236 (99.2%) patients who identify as gender-expansive, and 1500 of 1506 (99.6%) taking gender-affirming hormones. For the gender-expansive population, assigned female at birth was more common in the 12-29 year age range, while assigned male at birth was more common for those 40 years and older. Conclusions: SOGI fields and ICD-10 codes identify a high percentage of gender-expansive patients at an academic medical center.

Reconsidering the use of race adjustments in maternal serum screening.

The use of race in maternal serum screening is problematic because race is a social construct rather than a distinct biological classifier. Nevertheless, laboratories offering this testing are encouraged to use race-specific cutoff values for maternal serum screening biomarkers to determine the risk of fetal abnormalities. Large cohort studies examining racial differences in maternal serum screening biomarker concentrations have yielded conflicting results, which we postulate may be explained by genetic and socioeconomic differences between racial cohorts in different studies. We recommend that the use of race in maternal serum screening should be abandoned. Further research is needed to identify socioeconomic and environmental factors that contribute to differences in maternal serum screening biomarker concentrations observed between races. A better understanding of these factors may facilitate accurate race-agnostic risk estimates for aneuploidy and neural tube defects.