bluuebunny/crossref_metadata_2025 huggingface dataset:
Stereotactic Radiosurgery for Unruptured Versus Ruptured Pediatric Brain Arteriovenous Malformations
Authors: Chen Ching-Jen , Lee Cheng-Chia , Ding Dale , Tzeng Shih-Wei , Kearns Kathryn N. , Kano Hideyuki , Atik Ahmet , Ironside Natasha , Joshi Krishna , Huang Paul P. , Kondziolka Douglas , Mathieu David , Iorio-Morin Christian , Grills Inga S. , Quinn Thomas J. , Siddiqui Zaid , Marvin Kim , Feliciano Caleb , Faramand Andrew , Starke Robert M. , Barnett Gene , Lunsford L. Dade , Sheehan Jason P. ,   on behalf of the International Radiosurgery Research Foundation
Published: August 2019

Background and Purpose—

The effects of prior hemorrhage on stereotactic radiosurgery (SRS) outcomes for pediatric arteriovenous malformations (AVMs) are not well defined. The aim of this multicenter, retrospective cohort study is to compare the SRS outcomes for unruptured versus ruptured pediatric AVMs.

Methods—

The International Radiosurgery Research Foundation pediatric AVM database from 1987 to 2018 was reviewed retrospectively. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes. Associations between prior hemorrhage and outcomes were adjusted for baseline differences, inverse probability weights, and competing risks.

Results—

The study cohort comprised 153 unruptured and 386 ruptured AVMs. Favorable outcome was achieved in 48.4% and 60.4% of unruptured and ruptured AVMs, respectively (adjusted odds ratio, 1.353;
P
=0.190). Cumulative AVM obliteration probabilities were 51.2%, 59.4%, 64.2%, and 70.0% for unruptured and 61.0%, 69.3%, 74.0%, and 79.3% for ruptured AVMs at 4, 6, 8, and 10 years, respectively (subhazard ratio, 1.311;
P
=0.020). Cumulative post-SRS hemorrhage probabilities were 4.5%, 5.6%, 5.6%, and 9.8% for unruptured and 4.7%, 6.1%, 6.1%, and 10.6% for ruptured AVMs at 4, 6, 8, and 10 years, respectively (subhazard ratio, 1.086;
P
=0.825). Probabilities of AVM obliteration (adjusted subhazard ratio, 0.968;
P
=0.850) and post-SRS hemorrhage (adjusted subhazard ratio, 1.663;
P
=0.251) were comparable between the 2 cohorts after inverse probability weight adjustments. Symptomatic (15.8% versus 8.1%; adjusted odds ratio, 0.400;
P
=0.008) and permanent (9.2% versus 5.0%; adjusted odds ratio, 0.441;
P
=0.045) radiation-induced change were more common in unruptured AVMs.

Conclusions—

The overall outcomes after SRS for unruptured versus ruptured pediatric AVMs are comparable. However, symptomatic and permanent radiation-induced change occur more frequently in pediatric patients with unruptured AVMs.
The Revolution Will Be Teletyped: Cuba's Prensa Latina News Agency and the Cold War Contest over Information
Authors: Keller Renata
Published: August 2019

This article is the first in-depth study of Cuba's revolutionary news agency, Prensa Latina. Drawing on a wide variety of archival and published sources, including Cuban media and memoirs, declassified intelligence reports, U.S. State Department records, and newspaper articles from across Latin America, the article analyzes the agency's controversial creation, international reception, and significance. The evidence presented here shows that Prensa Latina was a powerful weapon in Fidel Castro's revolutionary arsenal because it provided a way for the Cuban government to gather and shape information and garner international support. Studying the history of Prensa Latina provides new insight into the production, circulation, reception, restriction, and manipulation of information during the Cold War. The Cuban agency's efforts to reshape the international flow of information posed a clear challenge both to the traditional media and to Castro's enemies across the Americas, spurring them to pursue a wide variety of tactics to silence Prensa Latina.
An Improved Estimate of the Coupled Arctic Energy Budget
Authors: Mayer Michael , Tietsche Steffen , Haimberger Leopold , Tsubouchi Takamasa , Mayer Johannes , Zuo Hao
Published: August 2019

This study combines state-of-the-art reanalyses such as the fifth-generation European Re-Analysis (ERA5) and the Ocean Reanalysis System 5 (ORAS5) with novel observational products to present an updated estimate of the coupled atmosphere–ocean–sea ice Arctic energy budget, including flux and storage terms covering 2001–17. Observational products provide independent estimates of crucial budget terms, including oceanic heat transport from unique mooring-derived data, radiative fluxes from satellites, and sea ice volume from merged satellite data. Results show that the time averages of independent estimates of radiative, atmospheric, and oceanic energy fluxes into the Arctic Ocean domain are remarkably consistent in the sense that their sum closely matches the observed rate of regional long-term oceanic heat accumulation of ~1 W m−2. Atmospheric and oceanic heat transports are found to be stronger compared to earlier assessments (~100 and ~16 W m−2, respectively). Data inconsistencies are larger when considering the mean annual cycle of the coupled energy budget, with RMS values of the monthly budget residual between 7 and 15 W m−2, depending on the employed datasets. This nevertheless represents an average reduction of ~72% of the residual compared to earlier work and demonstrates the progress made in data quality and diagnostic techniques. Finally, the budget residual is eliminated using a variational approach to provide a best estimate of the mean annual cycle. The largest remaining sources of uncertainty are ocean heat content and latent heat associated with sea ice melt and freeze, which both suffer from the lack of observational constraints. More ocean in situ observations and reliable sea ice thickness observations and their routinely assimilation into reanalyses are needed to further reduce uncertainty.
Parental Perceived Facilitators for and Barriers to Participating in a Lifestyle Intervention to Reduce Early Childhood Obesity: A Qualitative Evaluation
Authors: Zahry Nagwan R. , Ling Jiying
Published: August 2019

This study aimed to examine low-income mothers’ perceived facilitators for and barriers to participating in a lifestyle intervention. A phenomenography approach was used to individually interview 14 mothers from Midwestern U.S. The data were analyzed using content analysis. Drawing on the socio-ecological model, mothers’ perceived facilitators included (a) intrapersonal factors including providing helpful information, being accommodating, motivating, and novel; (b) interpersonal factors, including two-way communication between mothers and preschoolers, social connectedness among mothers, and a positive relationship between mothers and researchers; and (c) environmental factors, including kid-friendly, and pleasant and comfortable intervention sites. Mothers’ reported barriers were intrapersonal factors including (a) use of technology due to unreliable Wi-Fi access and unfamiliarity of electronic device, (b) being “busy moms” due to busy schedules and stressful daily lives, and (c) lack of reliable transportation. Future interventions to reduce early childhood obesity among low-income families should consider these identified facilitators and barriers.
Effects of teriparatide on bone formation in novel unidirectional porous beta-tricalcium phosphate
Authors: Kumagai Hiroshi , Funayama Toru , Sugaya Hisashi , Yoshioka Tomokazu , Makihara Takeshi , Tomaru Yohei , Arai Norihito , Sato Kosuke , Miura Kousei , Noguchi Hiroshi , Abe Tetsuya , Koda Masao , Mishima Hajime , Yamazaki Masashi
Published: August 2019

This study aimed to evaluate the effect of intermittent teriparatide treatment on changes in bone formation using unidirectional porous beta-tricalcium phosphate in a rabbit bone defect model. Twelve Japanese white rabbits were used in this study. A 5 × 8 mm2 rectangular area of periosteum was resected, followed by preparation of a cortical bone defect in a 4.5 × 7 mm2 rectangular area using a high-speed bur. Unidirectional porous beta-tricalcium phosphate was embedded in the defect in the direction of the pores, parallel to the axis of the tibia. Six rabbits in the teriparatide group were subcutaneously injected with 30 μg/kg of chemically synthesized teriparatide three times per week starting on the day of the operation, while six rabbits in the control group were injected with a hormone stock solution according to the same schedule. Tissue samples were harvested at six weeks after implantation. Newly formed bone was observed as a green area after using Villanueva–Goldner stain on sagittal sections. A region of interest with a height of 3 mm and width of 5 mm was set in the center of the artificial bone. A portion of the new bone in the region of interest was extracted using analysis software (BZ-X analyzer; Keyence, Japan), and the area ratio of the newly formed bone was calculated by dividing the area of the extracted portion by the area of the region of interest. As seen with sagittal Villanueva–Goldner staining, the percentage of new bone area in the region of interest was significantly larger in the teriparatide group (33 ± 9.0%) than in the control group (24 ± 3.9%). Unidirectional porous beta-tricalcium phosphate used alone sufficiently resulted in new bone formation, but as combined use of teriparatide further enhances new bone formation, promotion of bone fusion can be expected, leading to better clinical outcomes when applied to surgical procedures in real-world settings.
Influency of pentoxifylline treatment for neonatal sepsis: A meta‐analysis of randomized controlled studies
Authors: Peng Peiyun , Xia Yunfeng
Published: August 2019

Introduction:

Pentoxifylline may be an important approach to treat neonatal sepsis. However, its use has not been well established. We conduct a systematic review and meta‐analysis to evaluate the efficacy of pentoxifylline treatment for neonatal sepsis.

Methods:

PubMed, Embase, and the Cochrane Central Register of Controlled Trials are searched. Randomized controlled trials assessing the influence of pentoxifylline treatment on neonatal sepsis are included. Two investigators independently have searched articles, extracted data, and assessed the quality of included studies. This meta‐analysis is performed using the random‐effect model.

Results:

Seven randomized controlled trials involving 439 patients are included in the meta‐analysis. Compared with control intervention for neonatal sepsis, pentoxifylline treatment is associated with reduced hospital stay (standard mean differences = −0.61; 95% confidence interval = −0.93 to −0.29; p = 0.0002) and metabolic acidosis (risk ratio = 0.38; 95% confidence interval = 0.22 to 0.66; p = 0.0006), but has no remarkable impact on mortality (risk ratio = 0.59; 95% confidence interval = 0.30 to 1.16; p = 0.13), serum tumor necrosis factor‐α (standard mean differences = −0.38; 95% confidence interval = −1.29 to 0.52; p = 0.41), serum C‐reactive protein (standard mean differences = −0.25; 95% confidence interval = −0.92 to 0.42; p = 0.47), plasma interleukin‐6 (standard mean differences = −0.13; 95% confidence interval = −0.41 to 0.15; p = 0.37), disseminated intravascular coagulopathy (risk ratio = 0.55; 95% confidence interval = 0.25 to 1.21; p = 0.14), and oliguria/anuria (risk ratio = 0.77; 95% confidence interval = 0.28 to 2.16; p = 0.62).

Conclusion:

Pentoxifylline treatment may be associated with reduced mortality and hospital stay in neonatal sepsis with caution.
The American Academy of Pediatrics hypertension guidelines identify obese youth at high cardiovascular risk among individuals non-hypertensive by the European Society of Hypertension guidelines
Authors: Di Bonito Procolo , Licenziati Maria Rosaria , Baroni Marco G , Maffeis Claudio , Morandi Anita , Manco Melania , Miraglia del Giudice Emanuele , Di Sessa Anna , Campana Giuseppina , Moio Nicola , Gilardini Luisa , Chiesa Claudio , Pacifico Lucia , de Simone Giovanni , Valerio Giuliana ,   for the CARITALY Study on the behalf of the Childhood Obesity Study Group of the Italian Society of Pediatric Endocrinology and Diabetology
Published: August 2019

Background

Two different systems for the screening and diagnosis of hypertension (HTN) in children currently coexist, namely, the guidelines of the 2017 American Academy of Pediatrics (AAP) and the 2016 European Society for Hypertension (ESH). The two systems differ in the lowered cut-offs proposed by the AAP versus ESH.

Objectives

We evaluated whether the reclassification of hypertension by the AAP guidelines in young people who were defined non-hypertensive by the ESH criteria would classify differently overweight/obese youth in relation to their cardiovascular risk profile.

Methods

A sample of 2929 overweight/obese young people (6–16 years) defined non-hypertensive by ESH (ESH–) was analysed. Echocardiographic data were available in 438 youth.

Results

Using the AAP criteria, 327/2929 (11%) young people were categorized as hypertensive (ESH–/AAP+). These youth were older, exhibited higher body mass index, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), triglycerides, total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, blood pressure, left ventricular mass index and lower HDL-C (p <0.025–0.0001) compared with ESH–/AAP–. The ESH–/AAP+ group showed a higher proportion of insulin resistance (i.e. HOMA-IR ≥3.9 in boys and 4.2 in girls) 35% vs. 25% (p <0.0001), high TC/HDL-C ratio (≥3.8 mg/dl) 35% vs. 26% (p = 0.001) and left ventricular hypertrophy (left ventricular mass index ≥45 g/h2.16) 67% vs. 45% (p = 0.008) as compared with ESH–/AAP–.

Conclusions

The reclassification of hypertension by the AAP guidelines in young people overweight/obese defined non-hypertensive by the ESH criteria identified a significant number of individuals with high blood pressure and abnormal cardiovascular risk. Our data support the need of a revision of the ESH criteria.
The Association between Use of Online Social Networks to Find Sex Partners and Sexually Transmitted Infection Diagnosis among Young Men Who Have Sex with Men and Transgender Women Living with HIV
Authors: Saberi Parya , Neilands Torsten B. , Lally Michelle A. , Hosek Sybil G. , Hightow-Weidman Lisa
Published: August 2019

We conducted a cross-sectional analysis of baseline data from the Adolescent Trials Network for HIV/AIDS Interventions to examine the association between the use of social media sites to find sex partners and recent diagnosis of sexually transmitted infections (STIs) among 13- to 24-year-old men who have sex with men and transgender women living with HIV. We used linear regression to determine the relationship between the number of STIs and the number of social media sites used to find sex partners with each type of sex act included in the analysis. Secondary analyses substituted frequency of social media site use for number of social media sites. Among 741 participants, for every 1 social media account used to find sex partners, there was a 2.53% (95% confidence interval: 0.28-5.54) increase in STIs. This association was mediated through condomless receptive anal intercourse or condomless insertive anal intercourse but not barrierless oral intercourse. Similar but attenuated associations were found when frequency of social media site use was substituted for number of social media sites. Future research should examine innovative interventions on these social media sites with respect for its users.
circMYBL2, a circRNA from MYBL2, regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression
Authors: Sun Yu-Meng , Wang Wen-Tao , Zeng Zhan-Cheng , Chen Tian-Qi , Han Cai , Pan Qi , Huang Wei , Fang Ke , Sun Lin-Yu , Zhou Yan-Fei , Luo Xue-Qun , Luo Chengwei , Du Xin , Chen Yue-Qin
Published: August 2019

Sun et al identify a circular RNA, circMYBL2, that upregulates FLT3 translation to promote FLT3-ITD acute myeloid leukemia (AML) progression, suggesting a novel therapeutic target for FLT3-ITD AML.
Strong random noise attenuation by shearlet transform and time-frequency peak filtering
Authors: Zhang Chao , van der Baan Mirko
Published: August 2019

Directional wavelet transforms combined with coefficient thresholding are very competitive in denoising seismic signals. However, these techniques struggle when the coefficients of signal and noise have comparable magnitudes. To better address this problem, we have developed an improvement to this method by applying time-frequency peak filtering (TFPF) to the directional wavelet coefficients. TFPF consists of computing the instantaneous frequency of a frequency-modulated analytic signal. The use of a longer or shorter smoothing window helps to emphasize either signal or remove random noise. In our method, we use the shearlet transform as a directional wavelet transform and estimate signal dips based on the cumulative energy in each decomposition direction. TFPF is then applied to the fine-scale wavelet coefficients to enhance signal and remove high-frequency noise. Coefficient thresholding is applied to all other scales. Experimental results demonstrate that our algorithm can effectively eliminate strong random noise and preserve events of interest.
Joint imaging of angle-dependent reflectivity and estimation of the migration velocity model using multiple scattering
Authors: Davydenko Mikhail , Verschuur D. J.
Published: August 2019

Migration velocity analysis is an important method for providing an accurate velocity model for seismic imaging, which is crucial for correct focusing and localization of subsurface information. Conventionally, only primaries are considered as a source of information for both methods. The use of surface multiples in imaging is becoming more common due to the use of inversion-based approaches, which allow us to handle the crosstalk associated with multiples. However, including internal multiples in imaging and velocity estimation is not straightforward using the standard combination of reverse time migration in combination with image-domain velocity tomography. Incorporating internal multiples in imaging and velocity estimation is possible with the joint migration inversion (JMI) methodology, in which internal multiples are explicitly modeled using the estimated reflectivity via a data-domain objective function. However, to correctly match the observed data, the angle-dependent reflectivity and the migration velocity model need to be determined, which provide an over-parameterization of the inversion problem. Therefore, we have extended the JMI methodology to carry out velocity analysis via the extended image domain, in which the angle-dependent reflectivity is updated via data-domain matching. Examples of synthetic and field data with strong internal multiples demonstrate the validity of our method.
Activin A–Induced Cachectic Wasting Is Attenuated by Systemic Delivery of Its Cognate Propeptide in Male Mice
Authors: Walton Kelly L , Chen Justin L , Arnold Quinn , Kelly Emily , La Mylinh , Lu Louis , Lovrecz George , Hagg Adam , Colgan Timothy D , Qian Hongwei , Gregorevic Paul , Harrison Craig A
Published: August 2019

In cancer, elevated activin levels promote cachectic wasting of muscle, irrespective of tumor progression. In excess, activins A and B use the myostatin signaling pathway in muscle, triggering a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to atrophy. Recently, we demonstrated that local delivery of engineered activin and myostatin propeptides (natural inhibitors of these growth factors) could induce profound muscle hypertrophy in healthy mice. Additionally, the expression of these propeptides effectively attenuated localized muscle wasting in models of dystrophy and cancer cachexia. In this study, we examined whether a systemically administered recombinant propeptide could reverse activin A–induced cachectic wasting in mice. Chinese hamster ovary cells stably expressing activin A were transplanted into the quadriceps of nude mice and caused an 85-fold increase in circulating activin A levels within 12 days. Elevated activin A induced a rapid reduction in body mass (−16%) and lean mass (−10%). In agreement with previous findings, we demonstrated that adeno-associated virus–mediated delivery of activin propeptide to the tibialis anterior muscle blocked activin-induced wasting. In addition, despite massively elevated levels of activin A in this model, systemic delivery of the propeptide significantly reduced activin-induced changes in lean and body mass. Specifically, recombinant propeptide reversed activin-induced wasting of skeletal muscle, heart, liver, and kidneys. This is the first study to demonstrate that systemic administration of recombinant propeptide therapy effectively attenuates tumor-derived activin A insult in multiple tissues.
Contemporary Debates in Adult Papillary Thyroid Cancer Management
Authors: McLeod Donald S A , Zhang Ling , Durante Cosimo , Cooper David S
Published: August 2019

An ever-increasing population of patients with papillary thyroid cancer is engaging with health care systems around the world. Numerous questions about optimal management have arisen that challenge conventional paradigms. This is particularly the case for patients with low-risk disease, who comprise most new patients. At the same time, new therapies for patients with advanced disease are also being introduced, which may have the potential to prolong life. This review discusses selected controversial issues in adult papillary thyroid cancer management at both ends of the disease spectrum. These topics include: (i) the role of active surveillance for small papillary cancers; (ii) the extent of surgery in low-risk disease (lobectomy vs total thyroidectomy); (iii) the role of postoperative remnant ablation with radioiodine; (iv) optimal follow-up strategies in patients, especially those who have only undergone lobectomy; and (v) new therapies for advanced disease. Although our current management is hampered by the lack of large randomized controlled trials, we are fortunate that data from ongoing trials will be available within the next few years. This information should provide additional evidence that will decrease morbidity in low-risk patients and improve outcomes in those with distant metastatic disease.
Denosumab in Patients With Fibrous Dysplasia Previously Treated With Bisphosphonates
Authors: Majoor Bas C J , Papapoulos Socrates E , Dijkstra P D Sander , Fiocco Marta , Hamdy Neveen A T , Appelman-Dijkstra Natasha M
Published: August 2019

Context

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates, but clinical and biochemical responses may be incomplete.

Objective

To evaluate the efficacy and tolerability of the receptor activator of nuclear factor-κB ligand inhibitor denosumab in the treatment of patients with FD/MAS refractory to bisphosphonate therapy.

Design

Case series.

Setting

Academic center of expertise for rare bone diseases.

Patients

Data were collected from 12 consecutive patients with FD/MAS with persistent pain and increased biochemical markers of bone turnover (BTMs) after long-term treatment with bisphosphonates (median, 8.8 years) and were treated with subcutaneous denosumab 60 mg at 3- or 6-month intervals with a follow-up for at least 12 months.

Main outcome(s)

Sustained reduction of BTMs and bone pain.

Results

A 60 mg dose of denosumab once every 3 months, but not once every 6 months, induced a sustained reduction of BTMs. After a median treatment period of 15.5 months (range, 12 to 19) serum alkaline phosphatase activity and propeptide of type 1 procollagen levels were respectively reduced from 212 ± 39.4 IU/L to 79 ± 6.0 IU/L (P = 0.004) and from 346.2 ± 111.1 ng/mL to 55.7 ± 16.6 ng/mL (P = 0.023) and normalized in 70% and 75% of patients, respectively. Although not quantitavely measured, 10 patients reported a reduction in bone pain of whom 6 reported complete elimination of pain. Treatment with denosumab was well tolerated.

Conclusion

Our results indicate that 60 mg of denosumab every 3 months is a promising, well-tolerated treatment of most patients with FD/MAS refractory to bisphosphonate therapy. These results together with those of previously published case reports provide the necessary background for the design of a larger, controlled study.
The Incremental Risk of Pancreatic Cancer According to Fasting Glucose Levels: Nationwide Population-Based Cohort Study
Authors: Koo Dong-Hoe , Han Kyung-Do , Park Cheol-Young
Published: August 2019

Context

It has been unclear whether the risk of pancreatic cancer is different according to glucose levels.

Objective

To determine the association between fasting glucose levels and pancreatic cancer risk using prospectively collected nationwide population-based cohort data in Korea.

Design

The National Health Insurance Service database of claims and preventive health check-up data recorded was used between 2009 and 2015.

Setting and Participants

A total of 25.4 million patients who had participated in a preventive health check-up between 2009 and 2013 were evaluated for pancreatic cancer incidence rates according to fasting glucose level.

Main Outcomes Measures

The cumulative incidence rate for pancreatic cancer was calculated after grouping according to fasting glucose levels as follows: (i) low normal (<90 mg/dL), (ii) high normal (90 to 99 mg/dL), (iii) prediabetes level 1 (100 to 109 mg/dL), (iv) prediabetes level 2 (110 to 125 mg/dL), (v) diabetes (≥126 mg/dL), and (vi) diabetes on anti-diabetic medications.

Results

The 5-year cumulative incidence rates (per 100,000) were as follows: (i) low normal = 32; (ii) high normal = 41; (iii) prediabetes level 1 = 50; (iv) prediabetes level 2 = 64; (v) diabetes = 75; and (vi) on anti-diabetic medications = 121. The risk of pancreatic cancer increased continuously with elevating fasting glucose levels (P < 0.0001). The incidence of pancreatic cancer increased significantly with increasing fasting blood glucose levels even after adjusting for age, sex, smoking, drinking, exercise, body mass index, and diabetes duration (P < 0.0001).

Conclusions

The cumulative incidence rate of pancreatic cancer significantly increased as the fasting glucose level elevated, even in populations with a normal glucose level range.
The Steroid Profile of Adrenal Incidentalomas: Subtyping Subjects With High Cardiovascular Risk
Authors: Di Dalmazi Guido , Fanelli Flaminia , Zavatta Guido , Ricci Bitti Silvia , Mezzullo Marco , Repaci Andrea , Pelusi Carla , Gambineri Alessandra , Altieri Paola , Mosconi Cristina , Balacchi Caterina , Golfieri Rita , Cosentino Eugenio Roberto , Borghi Claudio , Vicennati Valentina , Pasquali Renato , Pagotto Uberto
Published: August 2019

Context

Steroid profiling by mass spectrometry has shown implications for diagnosis and subtyping of adrenal tumors.

Objectives

To investigate steroid profiles and their cardiovascular correlates in a large cohort of patients with nonsecreting (NS) adrenal incidentalomas and autonomous cortisol secretion (ACS).

Design

Cohort study.

Setting

University hospital.

Patients

Patients (n = 302) with incidentally discovered adrenal masses, divided into unilateral adenoma and hyperplasia with ACS (n = 46 and n = 52, respectively) and NS (n = 120 and n = 84, respectively). Post–dexamethasone suppression test (DST) cortisol <50 or >50 nmol/L defined NS and ACS, respectively.

Intervention

Analysis of 10-steroid panel by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and clinical data (mean follow-up 39 months).

Main Outcome Measures

Difference in baseline and post-DST steroid profiles between groups. Correlation with cardiovascular profile.

Results

Patients with unilateral adenomas and ACS showed higher cortisol, 11-deoxycortisol, and corticosterone and lower dehydroepiandrosterone than those with NS adenomas. Patients with ACS hyperplasia showed higher cortisol and lower androgens in women than those with NS. Patients with ACS had reduced suppression of post-DST cortisol, 11-deoxycortisol, and corticosterone, irrespective of adrenal morphology. Post-DST cortisol and corticosterone were associated with higher prevalence of severe/resistant hypertension. Patients with ACS unilateral adenomas showed higher incidence of worsening of hypertensive disease and novel cardiovascular events than those with NS, with post-DST cortisol [hazard ratio (HR) 1.02; 95% CI, 1.01 to 1.03; P < 0.001] and baseline corticosterone (HR 1.06; 95% CI, 1.01 to 1.12; P = 0.031) among the main predictors.

Conclusions

Patients with adrenal incidentalomas showed different steroid profiles, depending on functional status and adrenal morphology, with implications for their cardiovascular status.
Genetics of Congenital Isolated TSH Deficiency: Mutation Screening of the Known Causative Genes and a Literature Review
Authors: Sugisawa Chiho , Takamizawa Tetsuya , Abe Kiyomi , Hasegawa Tomonobu , Shiga Kentaro , Sugawara Hidenori , Ohsugi Koji , Muroya Koji , Asakura Yumi , Adachi Masanori , Daitsu Takashi , Numakura Chikahiko , Koike Akemi , Tsubaki Junko , Kitsuda Kazuteru , Matsuura Nobuo , Taniyama Matsuo , Ishii Sumiyasu , Satoh Tetsurou , Yamada Masanobu , Narumi Satoshi
Published: August 2019

Context

Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified.

Objectives

To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations.

Patients and Methods

Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed.

Results

Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap.

Conclusions

The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.
Trimethylamine N-Oxide Metabolites in Early Pregnancy and Risk of Gestational Diabetes: A Nested Case-Control Study
Authors: Huo Xiaoxu , Li Jing , Cao Yun-Feng , Li Sai-Nan , Shao Ping , Leng Junhong , Li Weiqin , Liu Jinnan , Yang Kai , Ma Ronald C W , Hu Gang , Fang Zhong-Ze , Yang Xilin
Published: August 2019

Objectives

This study aimed to investigate the associations between trimethylamine N-oxide (TMAO) and related metabolites in early pregnancy and the risk of gestational diabetes mellitus (GDM).

Design

A prospective cohort of 22,302 pregnant women from 2010 to 2012 in Tianjin, China, was used to perform a nested case-control study. A total of 243 women with GDM and 243 women without GDM matched by maternal age (±1 year) were used as cases and controls, respectively. Conditional logistic regression and restricted cubic spline were used to examine the full-range risk associations between individual TMAOs metabolites at the first antenatal care visit with GDM. Trimethylamine conversion ratio (TMAR) was defined as trimethylamine (TMA)/its precursors, and trimethylamine N-oxide conversion ratio (TMAOR) was defined as TMAO/TMA. An additive interaction between high TMAR and low TMAOR indicates a state of TMA accumulation, and a mathematical interaction between high TMAR and high TMAOR indicates accumulation of TMAO.

Results

TMA was linearly associated with GDM, whereas TMA precursors and TMAO were inversely associated with GDM with clear threshold effects, i.e., 16 nmol/mL for TMAO, 200 nmol/mL for betaine, 112 nmol/mL for l-carnitine, and 110 and 270 nmol/mL for cholinechloride (a U-shaped relationship). Copresence of TMAR >0.35 and TMAOR ≤0.15 was associated with a markedly higher OR (11.16; 95% CI, 5.45 to 22.8), compared with TMAR >0.35 only (OR = 1.71; 95% CI, 0.42 to 6.95) or TMAOR ≤0.15 only (OR = 2.06; 95% CI, 1.09 to 3.90), with a significant additive interaction. However, the mathematical interaction was nonsignificant.

Conclusions

TMAO metabolites in the early pregnancy were associated with the risk of GDM, whereas TMA was more likely to play a causal role in GDM.
Purine Metabolites and Carnitine Biosynthesis Intermediates Are Biomarkers for Incident Type 2 Diabetes
Authors: Ottosson Filip , Smith Einar , Gallo Widet , Fernandez Céline , Melander Olle
Published: August 2019

Context

Metabolomics has the potential to generate biomarkers that can facilitate understanding relevant pathways in the pathophysiology of type 2 diabetes (T2DM).

Methods

Nontargeted metabolomics was performed, via liquid chromatography–mass spectrometry, in a discovery case-cohort study from the Malmö Preventive Project (MPP), which consisted of 698 metabolically healthy participants, of whom 202 developed T2DM within a follow-up time of 6.3 years. Metabolites that were significantly associated with T2DM were replicated in the population-based Malmö Diet and Cancer–Cardiovascular Cohort (MDC-CC) (N = 3423), of whom 402 participants developed T2DM within a follow-up time of 18.2 years.

Results

Using nontargeted metabolomics, we observed alterations in nine metabolite classes to be related to incident T2DM, including 11 identified metabolites. N2,N2-dimethylguanosine (DMGU) (OR = 1.94; P = 4.9e-10; 95% CI, 1.57 to 2.39) was the metabolite most strongly associated with an increased risk, and beta-carotene (OR = 0.60; P = 1.8e-4; 95% CI, 0.45 to 0.78) was the metabolite most strongly associated with a decreased risk. Identified T2DM-associated metabolites were replicated in MDC-CC. Four metabolites were significantly associated with incident T2DM in both the MPP and the replication cohort MDC-CC, after adjustments for traditional diabetes risk factors. These included associations between three metabolites, DMGU, 7-methylguanine (7MG), and 3-hydroxytrimethyllysine (HTML), and incident T2DM.

Conclusions

We used nontargeted metabolomics in two Swedish prospective cohorts comprising >4000 study participants and identified independent, replicable associations between three metabolites, DMGU, 7MG, and HTML, and future risk of T2DM. These findings warrant additional studies to investigate a potential functional connection between these metabolites and the onset of T2DM.
Low-Normal Thyroid Function Predicts Incident Anemia in the General Population With Euthyroid Status
Authors: Gu Yeqing , Chi Vu Thi Quynh , Zhang Qing , Liu Li , Meng Ge , Wu Hongmei , Bao Xue , Zhang Shunming , Sun Shaomei , Wang Xing , Zhou Ming , Jia Qiyu , Song Kun , Niu Kaijun
Published: August 2019

Context

Thyroid hormones (THs) have direct and indirect effects on hematopoiesis. However, few studies have directly evaluated the effect of THs on incident anemia among euthyroid subjects. This cohort study aimed to explore whether THs under physiological conditions can affect the development of anemia in the general population.

Design

A total of 12,310 participants were enrolled in the cohort study (∼5-year follow-up period; mean, 3.1 years). A chemiluminescence immunoassay was used to measure free T3 (FT3), free T4 (FT4), and TSH, and anemia was defined according to the World Health Organization recommendation. THs, TSH, and Hb were assessed yearly during follow-up. Multivariable Cox proportional hazards regression models were used to assess the association between THs, TSH, and incident anemia.

Results

The fully adjusted hazards ratios (95% CI) of anemia per 1-unit change in FT3, FT4, and TSH concentrations were 0.70 (0.56, 0.87), 0.93 (0.88, 0.98), and 1.19 (0.94, 1.50) (P < 0.01, P < 0.01, and P = 0.14, respectively). Moreover, a significant and positive association between FT3, FT4, and annual changes in Hb (standard regression coefficients of 0.056 and 0.028, respectively; both P < 0.01) was observed. Similar associations were observed when the participants who had thyroid dysfunction upon follow-up were excluded.

Conclusions

The current study demonstrated that THs significantly predict future anemia and annual changes in Hb, even in the euthyroid population.
Augmented Corneal Nerve Fiber Branching in Painful Compared With Painless Diabetic Neuropathy
Authors: Püttgen Sonja , Bönhof Gidon J , Strom Alexander , Müssig Karsten , Szendroedi Julia , Roden Michael , Ziegler Dan
Published: August 2019

Context

The factors that determine the development of diabetic sensorimotor polyneuropathy (DSPN) as a painful or painless entity are unknown.

Objective

We hypothesized that corneal nerve pathology could be more pronounced in painful DSPN, indicating predominant small nerve fiber damage.

Design and Methods

In this cross-sectional study, we assessed 53 patients with painful DSPN, 63 with painless DSPN, and 46 glucose-tolerant volunteers by corneal confocal microscopy (CCM), nerve conduction (NC), and quantitative sensory testing. DSPN was diagnosed according to modified Toronto Consensus criteria. A cutoff at 4 points on the 11-point rating scale was used to differentiate between painful and painless DSPN.

Results

After adjustment for age, sex, body mass index, and smoking, corneal nerve fiber density, corneal nerve fiber length, and corneal nerve branch density (CNBD) were reduced in both DSPN types compared with the control group (P < 0.05). Only CNBD differed between the groups; it was greater in patients with painful DSPN compared with those with painless DSPN [55.8 (SD, 29.9) vs 43.8 (SD, 28.3) branches/mm2; P < 0.05]. Several CCM measures were associated with NC and cold perception threshold in patients with painless DSPN (P < 0.05) but not those with painful DSPN.

Conclusion

Despite a similarly pronounced peripheral nerve dysfunction and corneal nerve fiber loss in patients with painful and painless DSPN, corneal nerve branching was enhanced in those with painful DSPN, pointing to some susceptibility of corneal nerve fibers toward regeneration in this entity, albeit possibly not to a sufficient degree.
The Medical Therapy of Craniopharyngiomas: The Way Ahead
Authors: Alexandraki Krystallenia I , Kaltsas Gregory A , Karavitaki Niki , Grossman Ashley B
Published: August 2019

Context

Craniopharyngiomas, which are categorized as adamantinomatous (ACPs) or papillary (PCPs), have traditionally been treated with surgery and/or radiotherapy, although when the tumors progress or recur, therapeutic possibilities are very limited. Following recent advances in their molecular pathogenesis, new medical therapeutic options have emerged.

Evidence Acquisition

The search strategy that we selected to identify the appropriate evidence involved the following medical subject headings (MeSH) terms: (“Craniopharyngioma” [MeSH] AND “Craniopharyngioma/drug therapy” [MeSH]) NOT (“review” [Publication Type] OR “review literature as topic” [MeSH Terms] OR “review” [All Fields]) AND (“2009/05/01” [PDat]: “2019/04/28” [PDat]).

Evidence Synthesis

Mutations of β-catenin causing Wnt activation with alterations of the MEK/ERK pathway are encountered in the great majority of patients with ACPs; specific alterations also stratify patients to a more aggressive behavior. In most PCPs there is primary activation of the Ras/Raf/MEK/ERK pathway secondary to BRAF-V600E mutations. BRAF inhibitors, such as dabrafenib or vemurafenib, either alone or in combination with the MEK inhibitors trametinib and cobimetinib, have been administered to patients with PCPs producing clinically useful and, in some cases, sustained responses. In contrast to PCPs, drugs targeting β-catenin and its downstream MAPK pathway in ACPs have so far only been used in in vitro studies, but there appear to be promising new targets clinically.

Conclusions

The identification of specific genetic alterations in patients with craniopharyngiomas has expanded the therapeutic options, providing evidence for a customized approach using newer molecular agents. More studies including a larger number of carefully selected patients are required to evaluate the response to currently available and evolving agents alone and in combination.
Dysglycemia, Not Altered Sex Steroid Hormones, Affects Cognitive Function in Polycystic Ovary Syndrome
Authors: Jarrett Brittany Y , Vantman Natalie , Mergler Reid J , Brooks Eric D , Pierson Roger A , Chizen Donna R , Lujan Marla E
Published: August 2019

Context

Polycystic ovary syndrome (PCOS) is a complex endocrine condition characterized by multiple reproductive and metabolic abnormalities. Because individual reproductive and metabolic abnormalities modulate working memory in the general population, there is growing interest in whether cognitive function is dually and negatively affected in PCOS.

Objective

To examine the association of reproductive and metabolic features with cognitive function in women with and without PCOS.

Design

An observational, cross-sectional study was conducted at an academic clinical research center in North America between 2006 and 2009. Common tests of working memory (i.e., manual dexterity, perceptual speed, and visuospatial ability) were performed by women with PCOS (n = 40) and control subjects (n = 40). Markers of sex steroid hormones, ovulatory function, and cardiometabolic health were also assessed.

Results

Reduced visuospatial ability was observed in women with PCOS compared with control subjects (P < 0.01). Reduced visuospatial ability was linked to higher levels of hemoglobin A1c in the entire study cohort, independent of body mass index or PCOS status. No associations were observed between visuospatial ability and reproductive features, after controlling for confounding variables.

Conclusion

Our findings support a role for glycemic control, and not PCOS per se, in cognitive dysfunction in women of reproductive age. Additional studies are needed to understand the short- and long-term effects of dysglycemia on brain health in women with PCOS, given their increased propensity for metabolic comorbidities, compared with control subjects.
Glucocorticoid and Mineralocorticoid Receptors in the Brain: A Transcriptional Perspective
Authors: Koning Anne-Sophie C A M , Buurstede Jacobus C , van Weert Lisa T C M , Meijer Onno C
Published: August 2019

Adrenal glucocorticoid hormones are crucial for maintenance of homeostasis and adaptation to stress. They act via the mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs)—members of the family of nuclear receptors. MRs and GRs can mediate distinct, sometimes opposite, effects of glucocorticoids. Both receptor types can mediate nongenomic steroid effects, but they are best understood as ligand-activated transcription factors. MR and GR protein structure is similar; the receptors can form heterodimers on the DNA at glucocorticoid response elements (GREs), and they share a number of target genes. The transcriptional basis for opposite effects on cellular physiology remains largely unknown, in particular with respect to MR-selective gene transcription. In this review, we discuss proven and potential mechanisms of transcriptional specificity for MRs and GRs. These include unique GR binding to “negative GREs,” direct binding to other transcription factors, and binding to specific DNA sequences in conjunction with other transcription factors, as is the case for MRs and NeuroD proteins in the brain. MR- and GR-specific effects may also depend on specific interactions with transcriptional coregulators, downstream mediators of transcriptional receptor activity. Current data suggest that the relative importance of these mechanisms depends on the tissue and physiological context. Insight into these processes may not only allow a better understanding of homeostatic regulation but also the development of drugs that target specific aspects of disease.
Practice Variation in the Care of Subclinical Hypothyroidism During Pregnancy: A National Survey of Physicians in the United States
Authors: Toloza Freddy J K , Singh Ospina Naykky M , Rodriguez-Gutierrez Rene , O’Keeffe Derek T , Brito Juan P , Montori Victor M , Maraka Spyridoula
Published: August 2019

Evidence regarding the effects of subclinical hypothyroidism (SCH) on adverse pregnancy outcomes and the ability of levothyroxine (LT4) treatment to prevent them is unclear. Available recommendations for the management of SCH during pregnancy are inconsistent. We conducted a nationwide survey among physicians assessing their knowledge of and current practices in the care of SCH in pregnancy and compared these with the most recent American Thyroid Association (ATA) recommendations. In this cross-sectional study, an online survey was sent to active US members of the Endocrine Society. This survey included questions about current practices and clinical scenarios aimed at assessing diagnostic evaluation, initiation of therapy, and follow-up in pregnant women with SCH. In total, 162 physicians completed the survey. ATA guidelines were reviewed by 76%, of whom 53% indicated that these guidelines actually changed their practice. Universal screening was the preferred screening approach (54%), followed by targeted screening (30%). For SCH diagnosis, most respondents (52%) endorsed a TSH level >2.5 mIU/L as a cutoff, whereas 5% endorsed a population-based cutoff as recommended by the ATA. The decision to initiate treatment varied depending on the specific clinical scenario; however, when LT4 was initiated, respondents expected a small/very small reduction in maternofetal complications. In conclusion, despite recently updated guidelines, there is still wide variation in clinical practices regarding the care of women with SCH in pregnancy. Highly reliable randomized trials are required to evaluate the effectiveness of the most uncertain treatment practices on the care of pregnant women with SCH.