搜索结果：JCEM case reports

The demographic change in submissions to JCEM over the last decade is very apparent and largely driven by the emergence of China as a scientific superpower. Propelled by increases to budgets for research and development and national infrastructure platforms, China has overtaken the United States and Europe in terms of the size of its research workforce and its published scientific outputs. The Nature Index 2024 Research Leaders lists the leading institutions and countries/territories in the natural and health sciences according to their output in Nature Index journals (1) and shows that in 2023 China surpassed the United States for the first time in biomedical and health disciplines. Perhaps not surprisingly, as the most-cited journal in our discipline and one that is very popular in China, JCEM has statistics that mirror those of Nature journals. Ten years ago, manuscripts from China accounted for 11% of all submissions; by 2019 this had increased to 21%. The data for 2024 show that this figure has now increased dramatically, to more than 50% of submissions. JCEM is totally committed to attracting and publishing the best research in our discipline from around the world. We embrace geographical diversity in our governance (we have editors from 12 countries and editorial board members from 25 countries, with China well represented). We publish outputs from submitting authors based in 42 countries (2023 data). So what is the problem? In a nutshell, quality. Acceptance rates for submissions from China through 2014-2019 were ∼10%, but despite the rapid increase in submissions, the numbers of accepted papers have only modestly increased, such that their acceptance rate is now 6%. We are processing thousands of manuscripts per year from China, the vast majority of them either out of scope or lacking a mechanistic or experimental basis. We commonly see submissions based on single association studies, drawn from analysis of large published datasets such as the UK Biobank or the National Health and Nutrition Examination Survey, exploring relationships between unexplained and biologically irrelevant variables. Consequently the “reject without review rate” is unacceptably high, bringing with it significant staff time implications as well as diverting editors to “fire-fighting” rather than focusing on content strategy and enhancement of the journal for readers. These problems aside, I want to reassure our community that we are maintaining the quality of our peer review process and what we publish; preliminary data indicate that citation rates for manuscripts published from China are comparable to those published from the United States and western Europe. A pressing global concern is the authenticity of what is submitted. The pressure on emerging researchers to publish, particularly in clinical medicine, is intense in some countries, including China. This has contributed to the growth of “paper mills”—commercial organizations that charge for researchers to be listed as authors on wholly or partly fabricated, ghost-written papers. It is a huge problem and one that is not specific to endocrinology and metabolism. Studies show that some 2% of all scientific papers published in 2022 resembled paper-mill productions (2, 3). China, Thailand, and Saudi Arabia have all come under the spotlight (4), but fraudulent commercial activities are not confined to any single country and solutions must be global. In January 2025 the Chinese government announced a crackdown on paper mills and we await with interest to see the impact that this may have. Identity theft and misuse of identification data are further issues that are eroding one of the bedrock principles of publishing—trust in an individual's identity as a researcher and in their claimed affiliation and publication record. I cannot say with confidence that JCEM has published no fraudulent papers or never been a victim of the paper-mill industry. There are well-validated pointers that raise alarm bells in screening for such malpractice, and we have rejected several manuscripts without review in recent years on the basis of such suspicions. Further stringency will follow as we work with our publishing partner, Oxford University Press, on software screening tools. I do want to reassure all authors and readers of JCEM that we are committed to action. We have tightened our guidance on what research is within scope for JCEM and added the requirement for source documentation on ethics approvals. We have given additional guidance on Mendelian randomization (MR) studies, requiring that authors adhere to the STROBE-MR (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines. We also encourage authors to follow STROBE guidelines for observational studies generally (5). A key underpinning issue that has been identified is the prolific use of noninstitutional email accounts, which allows false self-identification and facilitates identity manipulation by bad actors (6). Our experience from returning to authors literally hundreds of submitted manuscripts that list no author with an institutional email account is that few of them are subsequently returned. More than a year ago, we instigated the requirement that submissions should list at least 1 author with an institutional email account, and we will be tightening this requirement further during 2025. We accept that this will be unpopular in some countries where many junior researchers and PhD students do not currently have access to institutional accounts. This is especially the case for emerging clinical researchers employed by hospitals rather than universities. Of course, we will be mindful of exceptions, but with the understanding that change must be a two-way process. Academic centers of excellence across the world with hospital/healthcare organization partnerships must take greater ownership and accountability for what is submitted to JCEM. From February, either an institutional email address or signoff by all authors with credible identity validation will be required for all authors lacking such validation, so they collectively confirm the identity of those 1 or 2 authors of a paper who unavoidably lack an institutional email address. As always, the submitting author must attest to the authenticity of the research and should ensure that it falls within the scope of JCEM. In our societal move to a digitally driven, “user-friendly” economy, electronic submission systems, researchers, and institutions will have to adapt. The current publishing environment has far too many gaps that have allowed this unprecedented surge of poor-quality manuscripts, some of which are undoubtedly fraudulent. Because no significant original research in endocrinology can be produced without the support and infrastructure of an institution or organization, it is time for all to recognize that employers must take responsibility for the work of their employees—by providing them with the means to identify themselves as legitimate researchers employed by their institution or organization. In short, if the employer is not willing to trust a researcher with an identifier linking them to the organization, why should we at JCEM trust their research? Raising the bar on research quality, reproducibility, and accountability is a strong commitment that goes hand in hand with JCEM being a global platform for knowledge transfer and innovation. The quote “Houston we have a problem” was popularized by the 1995 film Apollo 13. Those of you with an ear for detail will know that this was actually a misquote. The phrase used in the 1970 real life episode by command module pilot John Swigert was “Houston we’ve had a problem here.” Hopefully, concerted action here from all of us will enable our immediate problem to become an issue of the past. The author wishes to acknowledge the support of Endocrine Society Publications Department staff for providing invaluable input to this editorial. The author is Editor-in-Chief of The Journal of Clinical Endocrinology & Metabolism.

BACKGROUND: Pituitary carcinoma is a rare type of malignancy that can be very difficult to diagnose and treat. Many cases were diagnosed at autopsy. Delays in diagnosis often adversely impact patients' outcomes. Even with prompt diagnosis, treatment decisions remain challenging in the absence of randomized controlled trials. CASE SUMMARY: We report two cases of pituitary carcinoma in men with a history of pituitary adenoma. In the first case, a 55-year-old man was initially diagnosed with pituitary macroadenoma. He underwent subtotal debulking of the tumor followed by adjuvant radiotherapy. Subsequently, he developed relapsed disease and multifocal intracranial metastases and a diagnosis of pituitary carcinoma was rendered. He passed away despite several lines of systemic therapies including temozolomide, lomustine and bevacizumab. Another 52-year-old man was diagnosed with atypical pituitary adenoma with presentation of sudden onset of vision loss in the right eye. He had recurrent pituitary carcinoma with spinal metastases, treated with surgery, radiation and temozolomide. CONCLUSION: Pituitary carcinoma is a rare neoplasm with poor prognosis that is difficult to diagnose and treat. The small number of cases restricts our ability to design randomized clinical trials. Management is largely driven by retrospective studies and case series. Establishing molecular biomarkers and comprehensive genomic profiling could help in decisions about diagnosis and management of pituitary carcinoma.

CONTEXT: The clinical phenotype of multiple endocrine neoplasia type 4 (MEN4) is undefined due to a limited number of published cases. Knowledge on disease manifestation in MEN4 is essential for developing prevention programs and treatment. OBJECTIVE: To expand current knowledge of the MEN4 phenotype including assessment of penetrance. DESIGN: This is a case report and a brief review of previously published MEN4 cases. PATIENTS: We report a large Danish family with multiple cases of endocrine tumors that segregated with a pathogenic variant in the CDKN1B gene. MAIN OUTCOME/RESULT: The medical history of the proband included primary hyperparathyroidism and Cushing disease. Genetic analysis identified a pathogenic variant in CDKN1B (c.121_122delTT, p.Leu41Asnfs*83). Among the family members, another 12 individuals were identified as carriers of the same variant, which segregated with development of endocrine tumors. Hypercalcemia due to primary hyperparathyroidism occurred in all 13 of the available carriers of the genetic variant, and 4 patients also had functioning or nonfunctioning pituitary adenomas, whereas 1 patient had a metastatic neuroendocrine tumor (carcinoid). Loss-of-heterozygosity was detected in two of five parathyroid adenomas, supporting that CDKN1B acts as a tumor suppressor gene. Thirty cases representing 16 different CDKN1B variants have previously been reported, and these cases presented primarily with primary hyperparathyroidism and functioning and nonfunctioning pituitary tumors. CONCLUSION: Hypercalcemia due to primary hyperparathyroidism and pituitary tumors are common in MEN4. Gastrointestinal neuroendocrine tumors appear to be less prevalent in MEN4 than in MEN1.

The move by the JCEM to mandate measurement of sex steroids by mass spectrometry (MS) in manuscripts to be published from the beginning of 2015 (1) sparked vigorous debate among clinicians and scientists working within the diverse subspecialties of endocrinology. In response, The Endocrine Society Council assembled a Sex Steroid Assays Reporting Task Force (SSARTF) to review current reporting polices laid out by the Journal (and sister journals) and to recommend through the Publications Core Committee a clear policy on the future reporting of sex steroid hormone measurements. We commend the SSARTF in broadening the scope of their new guideline not only to encompass sex steroid hormone measurement but also to address the measurement of all steroid hormones more generally. Such an inclusive policy will undoubtedly propel the field toward optimized measurement procedures. With this goal in mind, we wish to make the case that the limitations inherent in immunoassay (IA) and the opportunities afforded by MS are not confined to the measurement of sex steroids, but rather the argument for measurement of cortisol and related metabolites is equally as compelling. Here, we present the case for cortisol measurement as an exemplar for the wider adoption of MS. IAs for serum steroid measurement are afflicted with cross-reactivity, to varying and often clinically significant degrees, with both endogenous and exogenous steroid hormones and their metabolites (2). Examples of analytical interference in commercial IAs include cross-reactivity in T assay by the structurally similar oral contraceptive pill component norethisterone (3) and the impact of both sample matrix and gender on the measurement of cortisol, likely attributable to variations in both cortisol-binding globulin concentration, and the accumulation of structurally related steroids in various physiological and pathophysiological conditions (4) acts to illustrate the inherent and persistent obstacles encountered by IA-based methodologies regardless of measurand, be it androgen or glucocorticoid. Similarly, indirect interference in many cortisol IAs has been demonstrated in patients receiving the 11β-hydroxylase inhibitor metyrapone for the medical management of Cushing's syndrome (5, 6). Metyrapone therapy blocks the conversion of 11-deoxycortisol to cortisol, causing a >10-fold increase in circulating concentration of this precursor (7, 8), which cross-reacts significantly in cortisol IA. The consequent positive interference carries the very real risk of inappropriate dose escalation and unrecognized hypoadrenalism. Salivary cortisol measurement used routinely in the investigation of Cushing's syndrome, and as a measure of “stress” in psychological research, is often measured by IA. However, there is a failure to recognize that, because of the abundance in parotid tissue of the enzyme 11β-hydroxysteroid dehydrogenase type II, which converts cortisol to cortisone, the latter is the predominate glucocorticoid in saliva at levels between 4- and 9-fold greater than cortisol. Cortisone cross-reactivity may therefore confound the accurate measurement of salivary cortisol in many IAs. Some of these problems inherent in IAs may be resolved by extracting samples to remove cross-reacting compounds and alleviate matrix effects before measurement, but importantly, such preanalytical extraction adds additional costs and complexity. In recent decades, the great advantage with IA has been speed and simplicity; sample prepurification seriously derogates from this and would therefore need to be evaluated in view of potential gains in diagnostic efficiency (9). These common and clinically important interferences in IA can be surmounted by the use of MS, and at present there are no feasible methodological alternatives that provide equivalent analytical robustness for steroid assay. As well as eliminating cross-reactivity, a further crucial practical advantage of MS is the dynamic range of measurement that can be achieved, comfortably exceeding that possible by conventional competitive IA methodology for the quantification of small molecules such as steroid hormones. For competitive IA, the typical dynamic range of the sigmoidal dose-response curve is no more than two orders of magnitude in measurand concentration. Assay manufacturers must therefore consider the clinical requirement for analytical sensitivity and also the expected (patho)physiological concentrations of measurand when designing these assays. Further methodological advantages of MS include the lack of susceptibility to interference from antireagent antibodies and the capacity to multiplex measurements for steroid profiling. In other words, a female androgen profile consisting of T, androstenedione, and dehydroepiandrosterone sulfate may be simultaneously measured in a single assay at negligible extra cost compared to measuring any of the steroids individually. From a practical standpoint, rapid MS assays for the routine measurement of serum cortisol are now available; the high level of specificity conferred by this technology has the added benefit of identifying samples that show evidence of exogenous steroid use. Recently, one such assay used in a routine diagnostics laboratory detected exogenous steroid use in 33% of serum samples, many of these samples giving a falsely elevated cortisol value by IA with the potential to affect patient management (10). Historically, the high cost of MS instrumentation has been prohibitive. However, the falling cost of hardware and low running costs for consumables is shaping MS as a viable option for routine diagnostic laboratories. To advocate for the measurement of sex steroids alone, the JCEM risks underutilization of clinical MS. As the portfolio of clinical MS applications expands, not least through advances to enable routine quantitative multiplexing alongside therapeutic drug monitoring, vitamin D and cortisol measurements, the economics of ensuring sample throughput supports the MS infrastructure of the laboratory, thus extending the utility of existing instrumentation to keep hardware busy provides economy of scale. It is important to acknowledge that MS, in common with IA, is liable to interference that can compromise the analytical integrity of the method, and factors including matrix effects, choice of internal standard and solvent, mass-transition selection, and ionic cross-talk must be considered during method validation (11). Matrix-dependent signal enhancement (ion enhancement) or suppression (ion suppression) can directly affect the quantitative performance of a mass spectrometer. These phenomena are commonly referred to as matrix effects, defined as the combined effect of all components of a sample other than the analyte on the measurement of the quantity of interest (12). There are many strategies to overcome matrix effects in MS-based assays; of particular note is the use of the internal standard approach whereby variation in the measurand signal can be balanced by an equivalent perturbation in the internal standard signal, thus correcting for the degree of ion suppression/enhancement. This topic has been comprehensively reviewed by Trufelli et al (13). The adoption of MS therefore needs to be undertaken in conjunction with robust standards for hormone measurement that recognize the need for assay standardization, traceability, and quality control. The JCEM preliminary stance on mandating MS for sex steroid assay may well have been contentious; arguments against a requirement for a specific methodology have focused on the potential for such a stand to stifle development of new methodologies by industry and academia. In advocating for MS, we would not wish to exaggerate the limitations of IA, and we recognize that in most clinical settings it is more than adequate to assist in clinical decision making. The JCEM is a journal with global impact that attracts manuscripts from around the world from researchers with very diverse infrastructure support. It cannot be the intention to exclude good science from the Journal because of inaccessibility to MS and a consequent use of well-validated IA. Bias and intra- and interassay coefficients of variation are issues with MS, and support for purist approaches to assay development focusing on traceability to a certified standard shouldn't be compromised as we move to new technologies. However, the development of assays traceable to high-order reference material and methodology does not detract from the fact that IA is susceptible to a plethora of analytical pitfalls that may be completely overlooked during standard assay validation procedures and may only come to light on postmarket surveillance. When possible, novel assays must be validated against a reference method, be assessed with certified reference material, or be compared against a well-validated procedure using clinical samples. The current “limitation” of MS for clinical use now appears not to be a cost or technical expertise issue, but rather one of calibration. A fundamental consideration in this respect is the potential matrix effects exerted by calibration materials. Any matrix effects in the calibrator should approximate those manifest by patient samples. Such matrix-matched calibrators are now becoming available. However, it will remain vital that commutability of these reference materials is thoroughly validated and demonstrable across methodologies, an approach that will necessitate open dialogue between all stakeholders, including manufacturers of reference material, the in vitro diagnostics (IVD) industry, and clinical laboratories. Furthermore, comprehensively established reference intervals and clinical validation of new assays for existing measurands is a prerequisite for optimal analytical and diagnostic assay performance. Currently, the two largest areas for diagnostic MS are therapeutic drug monitoring and vitamin D measurement, and this has been realized through the availability of commercial calibration sets. In contrast, the progression to MS assays for steroids is at present impeded by the scarcity of commercially available calibration material, and many diagnostic laboratories are unable or unwilling to produce calibrator and quality control materials for their MS assays. This is a real issue that requires addressing. The Joint Committee for Traceability in Laboratory Medicine database, which provides information for manufacturers and laboratories to establish and confirm traceability for routine methods, holds information concerning a number of reference preparations for cortisol in human serum that are available to manufacturers. There is currently a drive by manufacturers of mass spectrometers and MS-based assay kits to move into the diagnostics market. Manufacturers are required to register their devices with regulatory bodies. For example, in the United States this is overseen by the Food and Drug Administration, which requires a 510(k) submission or more rigorous premarket notification process. In Europe, the IVD Directive 98/79/EC applies. Assays that are developed and validated by laboratories “in-house” are currently exempted from the European Directive in its current form as long as they are produced within health-institution laboratories for use in that environment and are not subject to commercial transactions. However, in view of the ongoing revisions in this area, these in-house assays are likely to face greater interrogation by regulatory bodies in the near future, and rightly so. Indeed, laboratory-developed tests in the United States are regulated by the Center of Medicare and Medicaid Services, based on the Clinical Laboratory Improvement Amendments (CLIA) regulations, and laboratories are assessed against defined requirements as part of annual inspection for CLIA-certified laboratories. The role of external quality assessment (EQA) cannot be overstated as an essential tool for monitoring both short- and long-term analytical performance of diagnostic assays, and developers of MS-based assays must be held to operating by the same standards as the established commercial IA kit manufacturers. The utility of EQA is constantly evolving, and now may be an opportune time to push the debate on target level-based EQA—specifically, the use of MS target means to enable EQA performance evaluation against the best estimate of the true result. Currently, however, the main barrier to the use of MS target means for serum cortisol is the lack of participating laboratories. For example, less than 3% of laboratories participating in the UK National External Quality Assessment Scheme for steroid hormones measure serum cortisol by MS, limiting the robustness of target means. Nonetheless, as the role of EQA for steroid hormones expands, so too will its influence. It is evident that not all MS-based methods are the same (14, 15), although meaningful research should be supported by a high-quality, fully validated method, and evidence for this should be presented within the resultant publication. At this juncture, The Endocrine Society is best placed to move on journal standards, making it a requirement for manuscripts submitted to Endocrine Society journals to document assay calibration procedures and traceability. Such a move will promote transparency and greatly facilitate meaningful comparison of study data. This also presents an opportunity for The Endocrine Society to lead on the adoption of matrix-matched traceable commercial calibrator materials that may even be incorporated within ready-to-use steroid assay kits for IVD use, removing the need for a time-consuming method development and validation. In conclusion, well-validated IAs continue to serve us well in the diagnosis of most steroid-related clinical disorders. There are, however, notable exceptions that increasingly support the assertion that the era of steroid IA is drawing to a close. We must recognize that to reap the full benefits of MS-based assays for the diverse repertoire of clinically relevant steroids, there needs to be defined assay standards including designated reference material and participation in EQA schemes. The Endocrine Society has the opportunity to define and drive the adoption of best practice as the move to MS-based steroid assays gains momentum. Disclosure Summary: P.J.M. and P.J.T. have received research funding from Immunodiagnostic Systems PLC. The other authors have nothing to declare. external quality assessment immunoassay in vitro diagnostics mass spectrometry.

We aimed to study the clinical and imaging characteristics of patients sustaining vertebral fractures after denosumab discontinuation. For this purpose, we conducted a computerized advanced literature search that identified 13 published cases, and we additionally included another 11 new cases from our centers. Twenty-four postmenopausal women with vertebral fracture(s) after denosumab discontinuation, experiencing 112 fractures in total, were analyzed. The mean number of fractures per patient was 4.7. The most commonly affected vertebrae were T12 and L1. All fractures occurred 8 to 16 months after the last denosumab injection. Eighty-three percent of the patients were treatment naïve, whereas 33% had prevalent vertebral fractures. Five (23%) patients were on concurrent aromatase inhibitor treatment. When patients were divided according to treatment duration with an arbitrary cut-off of 2 years, those with ≤2 years of denosumab treatment had fewer fractures compared with those with >2 years (mean ± SEM fractures 3.2 ± 0.7 versus 5.2 ± 1.4, p = 0.055). Vertebroplasty was used in 5 patients, resulting in additional clinical vertebral fractures in all cases. We conclude that vertebral fracture(s) after denosumab discontinuation are in the majority of patients multiples, and they occur a few months after the effect of the last dose is depleted. Therefore, patients should not delay or omit denosumab doses. Fractures are typically osteoporotic, located at the lower thoracic and the upper lumbar spine. Vertebroplasty is an unsuccessful treatment strategy for such patients. © 2017 American Society for Bone and Mineral Research.

CONTEXT AND OBJECTIVE: Thyroid autoimmunity has been reported to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the SARS-CoV-2 vaccination recently. We report a series of patients who presented with new onset or relapse of Graves' disease-related hyperthyroidism shortly after receiving the SARS-CoV-2 messenger RNA (mRNA) vaccine at a single tertiary institution in Singapore. METHODS AND RESULTS: We describe 12 patients who developed hyperthyroidism within a relatively short interval (median onset, 17 [range, 5-63] days) after receiving the SARS-CoV-2 mRNA vaccine. The majority were females (11/12) with median age of 35.5 (range, 22-74) years. Six patients had new-onset hyperthyroidism, whereas the other 6 had relapse of previously well-controlled Graves' disease. TSH receptor antibody concentrations ranged from 2.4 to 32 IU/L. The majority of the patients were able to go for the second dose of the vaccine without any further exacerbations. Literature review revealed 21 other similar cases reported from across the world. CONCLUSION: Our case series provides insight into the characteristics of individuals in whom Graves' disease was triggered by the SARS-CoV-2 vaccination. Clinicians need to be vigilant of precipitation or exacerbation of autoimmune thyroid disorders in predisposed individuals after exposure to the SARS-CoV-2 vaccination. Further epidemiological and mechanistic studies are required to elucidate the possible associations between the SARS-CoV-2 vaccines and the development of thyroid autoimmunity.

Non-functional parathyroid carcinoma is an exceedingly rare disease with 31 reported cases since 1909. Because of the scarce number of cases of non-functional parathyroid carcinoma, there are no evidence-based recommendations for its optimal treatment. Surgery, including en bloc resection of the carcinoma, ipsilateral thyroid lobe and isthmus together with a neck dissection only in case of lymph node involvement, is the main treatment for non-functioning parathyroid carcinoma. The patient usually has a poorer prognosis because of detection at advanced stages, the relative ineffectiveness of adjuvant treatment modalities and the lack of adequate parameters for clinical follow-up. In this report, we present a case of non-functional parathyroid carcinoma at our institution, and we review the previous literature to discuss the latest advances in the diagnosis and treatment of this rare disease.

CONTEXT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 18 million people worldwide and the pandemic is still spreading. After the first case we reported, we observed 4 additional cases of subacute thyroiditis (SAT) related to SARS-CoV-2 infection. OBJECTIVES: The objective of this work is to describe additional cases of SAT associated with SARS-CoV-2 infection to alert physicians that SAT may be a manifestation of SARS-CoV-2 infection. METHODS: We describe clinical, biochemical, and imaging features of 4 patients with SAT related to SARS-CoV-2 infection. RESULTS: All patients were female (age, 29-46 years). SAT developed 16 to 36 days after the resolution of coronavirus disease 2019 (COVID-19). Neck pain radiated to the jaw and palpitations were the main presenting symptoms and were associated with fever and asthenia. One patient was hospitalized because of atrial fibrillation. Thyroid function tests (available for 3 individuals) were suggestive of destructive thyroiditis, and inflammatory markers were high. At neck ultrasound the thyroid was enlarged, with diffuse and bilateral hypoechoic areas and (in 3 patients) absent vascularization at color Doppler. Symptoms disappeared a few days after commencement of treatment (prednisone in 3 patients and ibuprofen in 1). Six weeks after the onset of SAT, all patients were asymptomatic and inflammatory markers had returned to normal range. Two patients were euthyroid, whereas 2 were diagnosed with subclinical hypothyroidism. CONCLUSIONS: SAT may be an underestimated manifestation of COVID-19. Clinicians should keep in mind the possible occurrence of SAT during and after SARS-CoV-2 infection.

Benign metastasizing leiomyomas (BMLs) occur predominantly in women during reproductive years. The condition is characterized by uterine leiomyomas associated with the development, typically years later, of slow-growing metastatic lesions. The most commonly affected organs are the lungs, but BMLs have been reported in lymph nodes, deep soft tissues, mesentery, bones, the central nervous system, and the heart. In many cases, these lesions have an indolent course and are discovered rather incidentally. However, occasionally they can present with debilitating symptoms or even life-threatening complications. The presence of estrogen and progesterone receptors in these tumors supports their origin from uterine smooth muscle and, more importantly, makes them amenable to hormonal manipulation. Radical interventions, such as extensive tumor debulking and oophorectomy for hormonal control, although effective in many cases, are not always possible or desirable and carry significant morbidity. Here we present two cases of BMLs to illustrate the role of newer therapeutic agents, the estrogen receptor modulators and the aromatase inhibitors, in the hormonal manipulation of these tumors.

OBJECTIVE: Our objective was to develop clinical practice guidelines for the diagnosis and treatment of patients with primary aldosteronism. PARTICIPANTS: The Task Force comprised a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, six additional experts, one methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. EVIDENCE: Systematic reviews of available evidence were used to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations and "suggest" for weak recommendations. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions during one group meeting, several conference calls, and multiple e-mail communications. The drafts prepared by the task force with the help of a medical writer were reviewed successively by The Endocrine Society's CGS, Clinical Affairs Core Committee (CACC), and Council. The version approved by the CGS and CACC was placed on The Endocrine Society's Web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS: We recommend case detection of primary aldosteronism be sought in higher risk groups of hypertensive patients and those with hypokalemia by determining the aldosterone-renin ratio under standard conditions and that the condition be confirmed/excluded by one of four commonly used confirmatory tests. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend the presence of a unilateral form of primary aldosteronism should be established/excluded by bilateral adrenal venous sampling by an experienced radiologist and, where present, optimally treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia, or those unsuitable for surgery, optimally be treated medically by mineralocorticoid receptor antagonists.

Importance: The global patterns and distribution of case-fatality rates (CFRs) in pediatric severe sepsis and septic shock remain poorly described. Objective: We performed a systematic review and meta-analysis of studies of children with severe sepsis and septic shock to elucidate the patterns of CFRs in developing and developed countries over time. We also described factors associated with CFRs. Data Sources: We searched PubMed, Web of Science, Excerpta Medica database, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Central systematically for randomized clinical trials and prospective observational studies from earliest publication until January 2017, using the keywords "pediatric," "sepsis," "septic shock," and "mortality." Study Selection: Studies involving children with severe sepsis and septic shock that reported CFRs were included. Retrospective studies and studies including only neonates were excluded. Data Extraction and Synthesis: We conducted our systematic review and meta-analysis in close accordance to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled case-fatality estimates were obtained using random-effects meta-analysis. The associations of study period, study design, sepsis severity, age, and continents in which studies occurred were assessed with meta-regression. Main Outcomes and Measures: Meta-analyses to provide pooled estimates of CFR of pediatric severe sepsis and septic shock over time. Results: Ninety-four studies that included 7561 patients were included. Pooled CFRs were higher in developing countries (31.7% [95% CI, 27.3%-36.4%]) than in developed countries (19.3% [95% CI, 16.4%-22.7%]; P < .001). Meta-analysis of CFRs also showed significant heterogeneity across studies. Continents that include mainly developing countries reported higher CFRs (adjusted odds ratios: Africa, 7.89 [95% CI, 6.02-10.32]; P < .001; Asia, 3.81 [95% CI, 3.60-4.03]; P < .001; South America, 2.91 [95% CI, 2.71-3.12]; P < .001) than North America. Septic shock was associated with higher CFRs than severe sepsis (adjusted odds ratios, 1.47 [95% CI, 1.41-1.54]). Younger age was also a risk factor (adjusted odds ratio, 0.95 [95% CI, 0.94-0.96] per year of increase in age). Earlier study eras were associated with higher CFRs (adjusted odds ratios for 1991-2000, 1.24 [95% CI, 1.13-1.37]; P < .001) compared with 2011 to 2016. Time-trend analysis showed higher CFRs over time in developing countries than developed countries. Conclusions and Relevance: Despite the declining trend of pediatric severe sepsis and septic shock CFRs, the disparity between developing and developed countries persists. Further characterizations of vulnerable populations and collaborations between developed and developing countries are warranted to reduce the burden of pediatric sepsis globally.

CONTEXT: Polycystic ovary syndrome (PCOS) is associated with a higher frequency of cardiovascular risk factors. Apolipoprotein (apo) A-I and apoB are potent markers for cardiovascular risk. Data on apo levels in women with PCOS are scarce and contradictory. OBJECTIVE: Our objective was to identify changes in lipid metabolism in women with PCOS, and the relative impact of obesity, insulin resistance, and hyperandrogenism on lipid parameters. DESIGN: This was a case-control study. SETTING: The study was performed at a single referral center. SUBJECTS: PCOS was diagnosed according to the 2003 Rotterdam criteria. Healthy mothers with regular menstrual cycles served as controls. MAIN OUTCOME PARAMETERS: Fasting insulin, triglycerides (TGs), cholesterol, high-density lipoprotein (HDL)-cholesterol, apoA-I, and apoB were determined. Low-density lipoprotein (LDL)-cholesterol was calculated using the Friedewald formula. RESULTS: We included 557 women with PCOS and 295 controls. After correction for age and body mass index, PCOS women had higher median levels of insulin (10.1 vs. 6.9 mU/liter), TGs (95 vs. 81 mg/dl), cholesterol (196 vs. 178 mg/dl), and LDL-cholesterol (125 vs. 106 mg/dl) in combination with lower levels of HDL-cholesterol (46 vs. 55 mg/dl) and apoA-I (118 vs. 146 mg/dl) compared with controls (all P values < or = 0.01). apoB levels were similar in cases and controls. Free androgen index, body mass index, SHBG, and estradiol were independent predictors of apoA-I levels in women with PCOS. CONCLUSIONS: PCOS is associated with a more pronounced atherogenic lipid profile. Furthermore, obesity and hyperandrogenism contribute to an adverse lipid profile. Finally, PCOS seems to constitute an additional risk factor for an atherogenic lipid profile.

Context: Denosumab inhibits bone resorption, increases bone mineral density, and reduces fracture risk. Denosumab was approved for the treatment of osteoporosis and the prevention of bone loss in some oncological situations. Denosumab discontinuation is associated with a severe bone turnover rebound (BTR) and a rapid loss of bone mineral density. The clinical consequences of the BTR observed after denosumab discontinuation are not known. Cases Description: We report 9 women who presented 50 rebound-associated vertebral fractures (RAVFs) after denosumab discontinuation. A broad biological and radiological assessment excluded other causes than osteoporosis. These 9 cases are unusual and disturbing for several reasons. First, all vertebral fractures (VFs) were spontaneous, and most patients had a high number of VFs (mean = 5.5) in a short period of time. Second, the fracture risk was low for most of these women. Third, their VFs occurred rapidly after last denosumab injection (9-16 months). Fourth, vertebroplasty was associated with a high number of new VFs. All the observed VFs seem to be related to denosumab discontinuation and unlikely to the underlying osteoporosis or osteopenia. We hypothesize that the severe BTR is involved in microdamage accumulation in trabecular bone and thus promotes VFs. Conclusion: Studies are urgently needed to determine 1) the pathophysiological processes involved, 2) the clinical profile of patients at risk for RAVFs, and 3) the management and/or treatment regimens after denosumab discontinuation. Health authorities, physicians, and patients must be aware of this RAVF risk. Denosumab injections must be scrupulously done every 6 months but not indefinitely.

CONTEXT: Autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome) can be seen as a postvaccination phenomenon that occurs after exposure to adjuvants in vaccines that increase the immune responses. There are very limited data regarding ASIA syndrome following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. OBJECTIVES: This work aims to report cases of subacute thyroiditis related to the SARS-CoV-2 vaccine. METHODS: We describe the clinical, laboratory, and imaging features of 3 cases of subacute thyroiditis after inactivated SARS-CoV-2 vaccine (CoronaVac®). Three female healthcare workers have applied to our clinic with anterior neck pain and fatigue 4 to 7 days after SARS-CoV-2 vaccination. Two of them were in the breastfeeding period. They were negative for thyroid antibodies, and there was no previous history of thyroid disease, upper respiratory tract infection, or COVID-19. Laboratory test results and imaging findings were consistent with subacute thyroiditis. RESULTS: SARS-CoV-2 vaccination can lead to subacute thyroiditis as a phenomenon of ASIA syndrome. Subacute thyroiditis may develop within a few days after the SARS-CoV-2 vaccination. Being in the postpartum period may be a facilitating factor for the development of ASIA syndrome after the SARS-CoV-2 vaccination. CONCLUSIONS: This is the first report of subacute thyroiditis as a phenomenon of ASIA syndrome after inactivated COVID-19 vaccination. Clinicians should be aware that subacute thyroiditis may develop as a manifestation of ASIA syndrome after the inactive SARS-CoV-2 vaccine.

CONTEXT AND OBJECTIVE: Evidence that bacteria in the human gut may influence nutrient metabolism is accumulating. We investigated whether use of antibiotics influences the risk of developing type 2 diabetes and whether the effect can be attributed to specific types of antibiotics. METHODS: We conducted a population-based case-control study of incident type 2 diabetes cases in Denmark (population 5.6 million) between January 1, 2000, and December 31, 2012. Data from the Danish National Registry of Patients, the Danish National Prescription Registry, and the Danish Person Registry were combined. RESULTS: The odds ratio (OR) associating type 2 diabetes with exposure to antibiotics of any type was 1.53 (95% confidence interval 1.50-1.55) with redemption of more than or equal to 5 versus 0-1 prescriptions. Although no individual group of antibiotics was specifically associated with type 2 diabetes risk, slightly higher ORs for type 2 diabetes were seen with narrow-spectrum and bactericidal antibiotics (OR 1.55 and 1.48) compared to broad-spectrum and bacteriostatic types of antibiotics (OR 1.31 and 1.39), respectively. A clear dose-response effect was seen with increasing cumulative load of antibiotics. The increased use of antibiotics in patients with type 2 diabetes was found up to 15 years before diagnosis of type 2 diabetes as well as after the diagnosis. CONCLUSIONS: Our results could support the possibility that antibiotics exposure increases type 2 diabetes risk. However, the findings may also represent an increased demand for antibiotics from increased risk of infections in patients with yet-undiagnosed diabetes.

Objective: Our report describes a case of nonpuerperal induced lactation in a transgender woman. Methods: We present the relevant clinical and laboratory findings, along with a review of the relevant literature. Results: A 30-year-old transgender woman who had been receiving feminizing hormone therapy for the past 6 years presented to our clinic with the goal of being able to breastfeed her adopted infant. After implementing a regimen of domperidone, estradiol, progesterone, and breast pumping, she was able to achieve sufficient breast milk volume to be the sole source of nourishment for her child for 6 weeks. This case illustrates that, in some circumstances, modest but functional lactation can be induced in transgender women.