bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep learning-based analysis of macaque corneal sub-basal nerve fibers in confocal microscopy images
Authors: Oakley Jonathan D. , Russakoff Daniel B. , McCarron Megan E. , Weinberg Rachel L. , Izzi Jessica M. , Misra Stuti L. , McGhee Charles N. , Mankowski Joseph L.
Published: May 2020

Background

To develop and validate a deep learning-based approach to the fully-automated analysis of macaque corneal sub-basal nerves using in vivo confocal microscopy (IVCM).

Methods

IVCM was used to collect 108 images from 35 macaques. 58 of the images from 22 macaques were used to evaluate different deep convolutional neural network (CNN) architectures for the automatic analysis of sub-basal nerves relative to manual tracings. The remaining images were used to independently assess correlations and inter-observer performance relative to three readers.

Results

Correlation scores using the coefficient of determination between readers and the best CNN averaged 0.80. For inter-observer comparison, inter-correlation coefficients (ICCs) between the three expert readers and the automated approach were 0.75, 0.85 and 0.92. The ICC between all four observers was 0.84, the same as the average between the CNN and individual readers.

Conclusions

Deep learning-based segmentation of sub-basal nerves in IVCM images shows high to very high correlation to manual segmentations in macaque data and is indistinguishable across readers. As quantitative measurements of corneal sub-basal nerves are important biomarkers for disease screening and management, the reported work offers utility to a variety of research and clinical studies using IVCM.
Spontaneous regression of advanced transverse colon cancer with remaining lymph node metastasis
Authors: Nishiura Bunpei , Kumamoto Kensuke , Akamoto Shintaro , Asano Eisuke , Ando Yasuhisa , Suto Hironobu , Kishino Takayoshi , Oshima Minoru , Fujiwara Masao , Usuki Hisashi , Okano Keiichi , Suzuki Yasuyuki
Published: May 2020

Background

The observation of spontaneous regression (SR) has been well documented for many cancer types, including renal cell carcinoma, non-Hodgkin’s lymphoma, leukemia, neuroblastoma, and malignant melanoma. However, the SR frequency in colorectal cancer is very rare. Therefore, the accumulation of SR colorectal cancer cases might contribute to find the regression mechanism.

Case presentation

A 67-year-old woman received colonoscopy due to being positive for fecal occult blood testing and was diagnosed as having a transverse colon cancer at a local hospital. She was admitted to our institution for surgical treatment of the colon cancer. The colonoscopy revealed a type 2 tumor of 13 mm in diameter at the hepatic flexure of the transverse colon. The enhanced computed tomography (CT) showed an enlarged lymph node in the intermediate lymph node region. The 18F-fluorodeoxyglucose positron emission tomography/CT showed no abnormal accumulation on the transverse colon; however, an abnormal accumulation was found at the enlarged lymph node. The patient was preoperatively diagnosed as having advanced transverse colon cancer with lymph node metastasis and underwent laparoscopic right hemicolectomy with D3 lymph node dissection. Pathological examination showed only a scar-like tissue and no cancerous lesion in the transverse colon, while a metastatic lymph node was histologically confirmed in the intermediate lymph node region. Loss of MLH1 and PMS2 expression was observed in the cancer cells of both biopsy specimens and resected lymph nodes. No recurrence was seen for 5 years after surgery.

Conclusions

We reported a rare case of SR of the primary transverse colon cancer without regression of the metastatic regional lymph node. We considered that colorectal cancer with SR should be resected because even if SR of the primary lesion occurs, lymph node metastasis might have an inconsistent behavior as shown in the present case.
Strengthening health systems response to violence against women: protocol to test approaches to train health workers in India
Authors: Meyer Sarah R. , Rege Sangeeta , Avalaskar Prachi , Deosthali Padma , García-Moreno Claudia , Amin Avni
Published: May 2020

Background

Globally, including in low- and middle-income [LMIC] countries, there is increased attention to and investment in interventions to prevent and respond to violence against women; however, most of these approaches are delivered outside of formal or informal health systems. The World Health Organization published clinical and policy guidelines Responding to intimate partner violence and sexual violence against women in 2013. Further evidence is needed concerning implementation of the Guidelines, including how health care providers perceive training interventions, if the training approach meets their needs and is of relevance to them and how to ensure sustainability of changes in practice due to training. This manuscript describes a study protocol for a mixed methods study of the implementation of the Guidelines and related tools in tertiary hospitals in two districts in Maharashtra, India.

Methods

The study will employ a mixed-methods study design. A quantitative assessment of health care providers’ and managers’ knowledge, attitudes, and practices will be conducted pre, post, and 6 months after the training. Qualitative methods will include a participatory stakeholders’ meeting to inform the design of the training intervention design, in-depth interviews [IDIs] and focus-group discussions [FGDs] with health care providers and managers 3–6 months after training, and IDIs with women who have disclosed violence to a trained health care provider, approximately 6 months after training. The study will also validate two tools: a readiness assessment of health facilities and a health management information system form in a facility register format which will be used to document cases of violence.

Discussion

The multiple components of this study will generate data to improve our understanding of how implementation of the Guidelines works, what barriers and facilitators to implementation exist in this context, and how current implementation practices result in changes in terms of health services and providers’ practices of responding to women affected by violence. The results will be useful for governmental and non-governmental and United Nations Agency efforts to improve health systems and services for women affected by violence, as well as for researchers working on health systems responses to violence against women in India and possibly other contexts.
Tricuspid three-dimensional ring versus fashioned flexible band annuloplasty in management of functional tricuspid valve regurge: comparative long term study
Authors: Nosair Abdallah , Elkahely Mohamed , Nasr Sherif , Alkady Hesham
Published: May 2020

Background

Functional tricuspid valve regurgitation due to left sided valve lesions remains a common finding. Nowadays, different types of three-dimensional rings and flexible bands are considered to be the gold standard techniques for repair of such functional regurgitation. Our study aimed for long-term comparison of the durability and effectiveness of those techniques.

Results

The data of 170 adult patients with moderate or more functional tricuspid regurgitation secondary to mitral stenosis or regurgitation receiving tricuspid valve repair using either rigid 3D rings (contour 3D or MC3 ring) or prosthetic fashioned bands (Dacron or PTFE) and mitral valve surgery between March 2013 and September 2018 were collected and analysed. Patients were classified in two matched groups: ring group (group A) consisting of 90 cases and band group (group B) consisting of 80 cases. follow-up period ranged from 55.2 to 78 months (mean 67.2 ± 10.8), during this period New York heart association for dyspnea functional class evaluation and full echocardiographic assessment were done and was scheduled as following: before hospital discharge, after 6 months of surgery and finally, every 2 years. In-hospital mortality was 1(1.1%) and 2 (2.5%) with p value 0.49 after ring or band annuloplasty, respectively. No significant differences in both groups regarding hospital mortality and morbidities. There was statistically significant decrease in NYHA class, degree of TR, and PASP within the 2 groups postoperatively with p value of 0.03, 0.04, and 0.033, respectively, with no statistically significant difference between both groups (p value > 0.05). There was statistically significant difference in the freedom from recurrent TR and need for reoperation during the follow-up period between both groups with lower recurrence and reoperation rates in group A, (p value 0.03 and 0.001, respectively).

Conclusion

Tricuspid valve repair with different annuloplasty rigid three dimensional rings or fashioned flexible bands for functional tricuspid regurgitation offers good long-term outcome. Yet, the rigid rings maintain their benefits on the rate of recurrent TR and the need for reoperation.
In vitro antioxidant, anti-inflammatory, and anticancer activities of methanolic extract and its metabolites of whole plant Cardiospermum canescens Wall
Authors: Ketha Alekhya , Vedula Girija Sastry , Sastry A. V. S.
Published: May 2020

Background

Traditionally, the whole plant ofCardiospermum canescenshas wide applications in the management of oxidative stress and inflammation in Africa and Asia. The present study investigated the antioxidant, anti-inflammatory, xanthine oxidase (XO) inhibitory, and anticancer activities of metabolites present in the crude methanolic extract of whole plantC.canescens(CCE).

Results

Chemical examination ofCCErevealed the presence of six known compounds (1–6). From the results of in vitro studies, it can confirm thatCCEexhibited notably inhibition of DPPH and superoxide free radicals, along with COX-1, COX-2, 5-LOX, and XO enzymes. Compounds2and3showed significant inhibition of DPPH and superoxide free radicals. Also, compound2exhibited good inhibition of COX-1 and COX-2 enzyme with IC50of 87.0 and 88.0 μg/mL. Furthermore,CCEexhibited significant inhibition of 5-LOX and XO enzymes with IC50of 42.5 and 56.0 μg/mL, respectively, while standard with IC50of 42.5 and 56.0 μg/mL, respectively. Among the test series of cancer cell lines, compounds2,3, andCCEshowed a significant percentage of cell growth lysis of DLD-1 with IC50values of 52.5, 72.5, and 32.5 μg/mL, respectively. Besides, all the metabolites andCCEshowed a very weak degree of specificity against NHME, indicates less toxicity to normal cells.

Conclusion

To conclude, the results of the present study indicated that the methanolic extract from the whole plant ofC.canescensdisplayed antioxidant activity by inhibiting DPPH and superoxide free radicals; anti-inflammatory effects by regulating enzymes COX-1, COX-2, 5-LOX, and XO; and anticancer activity by inhibiting the growth of MCF-7, DLD-1, HeLa, and A549. These activities can link to natural active compounds2and3. This study supports the traditional uses of the root ofC.canescens. These data findings suggest thatC.canescenscan be a promising natural source of biological medicines for oxidative stress, inflammation, gout, and cancer.
Embedding neuroscience in psychiatry training
Authors: O'Loughlin Christopher
Published: May 2020

Training in neuroscience is vital to the future of psychiatry as a medical specialty. Trainees and trainers alike demonstrate a desire to keep up to date with developments in the associated scientific fields. Neuroscience increasingly underpins clinical assessments, treatment options and patients’ expectations. Psychiatry training in the UK can embrace neuroscience at many levels, from discussing patient presentations with supervisors, to teaching programmes supported by the Royal College of Psychiatrists’ activities. Although challenges remain, neuroscience literacy enhances the specialty and will improve patient care.
Children and young people who die by suicide: childhood-related antecedents, gender differences and service contact
Authors: Rodway Cathryn , Tham Su-Gwan , Ibrahim Saied , Turnbull Pauline , Kapur Nav , Appleby Louis
Published: May 2020

Background

Worldwide suicide is commonest in young people and in many countries, including the UK, suicide rates in young people are rising.

Aims

To investigate the stresses young people face before they take their lives, their contact with services that could be preventative and whether these differ in girls and boys.

Method

We identified a 3-year UK national consecutive case series of deaths by suicide in people aged 10–19, based on national mortality data. We extracted information on the antecedents of suicide from official investigations, primarily inquests.

Results

Between 2014 and 2016, there were 595 suicides by young people, almost 200 per year; 71% were male (n = 425). Suicide rates increased from the mid-teens, most deaths occurred in those aged 17–19 (443, 74%). We obtained data about the antecedents of suicide for 544 (91%). A number of previous and recent stresses were reported including witnessing domestic violence, bullying, self-harm, bereavement (including by suicide) and academic pressures. These experiences were generally more common in girls than boys, whereas drug misuse (odds ratio (OR) = 0.54, 95% CI 0.35–0.83, P = 0.006) and workplace problems (OR 0.52, 95% CI 0.28–0.96, P = 0.04) were less common in girls. A total of 329 (60%) had been in contact with specialist children's services, and this was more common in girls (OR 1.86, 95% CI 1.19–2.94, P = 0.007).

Conclusions

There are several antecedents to suicide in young people, particularly girls, which are important in a multiagency approach to prevention incorporating education, social care, health services and the third sector. Some of these may also have contributed to the recent rise.
Quality by Design–Based Assessment for Analytical Similarity of Adalimumab Biosimilar HLX03 to Humira®
Authors: Zhang Erhui , Xie Liqi , Qin Peilan , Lu Lihong , Xu Yanpeng , Gao Wenyuan , Wang Linlin , Xie Michael Hongwei , Jiang Weidong , Liu Scott
Published: May 2020

Quality by design (QbD) is an efficient but challenging approach for the development of biosimilar due to the complex relationship among process, quality, and efficacy. Here, the analytical similarity of adalimumab biosimilar HLX03 to Humira® was successfully established following a QbD quality study. Quality target product profile (QTPP) of HLX03 was first generated according to the public available information and initial characterization of 3 batches of Humira®. The critical quality attributes (CQAs) were then identified through risk assessment according to impact of each quality attribute on efficacy and safety. The anticipated range for each CQA was derived from similarity acceptance range and/or the corresponding regulatory guidelines. Finally, a panel of advanced and orthogonal physicochemical and functional tests and comparison of 6 batches of HLX03 and 10 batches of the reference standard demonstrated high similarity of HLX03 to Humira®, except for slightly lower percentage of high mannosylated glycans (%HM) in HLX03 which had no effect on FcγRIII binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity in human peripheral blood mononuclear cell (PBMC). All above demonstrated the feasibility and efficiency of QbD-based similarity assessment of a biosimilar monoclonal antibody (mAb).
SUN-092 Effect of Pubertal Induction with Gonadotropins and GnRH Therapy in Male Hypogonadotropic Hypogonadism: Meta-Analysis
Authors: Agarwal Swashti , Austin Paul , Wood Alexis C , Karaviti Lefkothea P
Published: May 2020

Background: The use of gonadotropins is a recent strategy for inducing puberty in adolescent males with hypogonadotropic hypogonadism (HH). Testosterone use has been discouraged in patients who desire to preserve fertility. Human chorionic gonadotropin (hCG) has been recommended for inducing puberty in HH; however, several clinicians administer hCG in combination with other gonadotropins. The benefits of using combination gonadotropin therapies (hCG+) over hCG monotherapy in pre-pubertal adolescent males with HH has not been clearly established. We performed a meta-analysis to assess the outcomes of hCG compared to hCG+ in terms of virilizing effects and testicular growth in peripubertal boys with HH.

Methods: We evaluated for heterogeneity among studies. We calculated pooled means for the post-treatment mean testicular volume (MTV), testosterone (T) level, and penile length for the hCG monotherapy and hCG+ treatment groups. We performed a meta-regression analysis to examine the contribution of various factors to post-treatment outcomes including baseline T level, age, treatment duration, and study quality.

Results: The meta-analysis included seven studies. All participants were prepubertal (age range: 13.3–25.9 years), with weighted mean treatment durations of 10.95 months for hCG monotherapy and 28.2 months for hCG. There was significant heterogeneity in baseline age (Q = 121.71; df = 1; P < 0.001) and T levels (Q = 436.74; df = 1; P < 0.001) between the two treatment groups. The hCG+ group had a larger post-treatment MTV, but it was not significantly different between the two groups (6.60 mL [95% CI, 3.18–10.02] for hCG monotherapy vs. 10.02 mL [95% CI, 8.30–11.75] for hCG+; P = 0.079). Post-treatment T levels differed significantly between the two groups (101.89 ng/dL [95% CI, 50.7–153.08] for hCG monotherapy vs. 424.10 ng/dL [95% CI, 304.59–543.62] for hCG+; P < 0.0001). A meta-regression analysis of post-treatment T levels showed that baseline age, baseline T level, and study grade did not contribute significantly to the difference between treatment groups. Treatment duration explained 3.04% of the difference between the two groups (P < 0.0001). After adjusting for treatment duration, the post-treatment T level remained significantly higher in the hCG+ group compared to the hCG monotherapy group. The hCG+ was also associated with better outcomes for post-treatment penile length, although these findings relied on data from only three studies.

Conclusion: Our study indicates that hCG+ therapies provide potential benefits over hCG monotherapy for pubertal induction in males with HH, regarding T levels and penile growth, with no difference in testicular growth between treatments. Prospective pediatric studies are needed to assess the benefits of these therapies in patients with HH and, ultimately, to establish guidelines for gonadotropin therapy in the adolescent population.
MON-355 Charge Syndrome: Unusual Cause of Hypogonadism Leading to Osteoporosis
Authors: Modi Ankur , Piziak Veronica
Published: May 2020

CHARGE syndrome is an unusual cause of hypogonadism; it is characterized by coloboma, heart defect, ateresia choanae, retarded growth and development, genital hypoplasia and ear anomalies. Two-thirds of affected patients have a mutation within the chromodomain helicase DNA-binding protein-7 gene, which is involved in embryonic development. The involvement of this gene in the pathogenesis of isolated idiopathic hypogonadotropic hypogonadism (HH) has been postulated. The reported incidence of this syndrome ranges from 0.1–0.2/10000 (1).

A 24 year old female presented to our facility for further management of her HH and osteoporosis in the setting of her CHARGE syndrome. She was born full-term and diagnosed with this condition at the age of 6. Formal genetic testing as an adult demonstrated mutation within the CHD7 gene (chr 8:61,757,970). She had delayed puberty secondary to her hypogonadism; she was not treated with HRT as benefits were not considered significantly sufficient. She subsequently developed osteoporosis at the age of 20 which was treated at an outside facility with pamidronate IV Q4 months along with calcium and Vitamin D supplementation. Her initial Dual-energy X-ray absorptiometry (DXA) showed scoliosis in the lumbar spine [bone mass density (BMD): 0.514,osteoporosis by Z-score] with total hip showing BMD: 0.738,osteopenia by Z-score. Follow-up DXA after 3 years showed statistically significant improvement in bone mineralization of her L-spine [BMD: 0.595, +16%] and total hip [BMD: 0.777, +13.5%]. She presented to our facility in 2018 with labs showing normal calcium and 25-OH D; treatment with pamidronate was continued. She had a repeat DXA in 2019 which showed Z-scores of 0 in the left and right femoral necks. She was given the option of continued treatment for her osteoporosis versus monitoring and chose the latter with follow-up DXA.

Hypogonadotropic hypogonadism is associated with delays in puberty or pubertal arrest. Luteinizing Hormone Releasing Hormone and HCG tests should be performed within the four months of life or at puberty in cases of hypogenitalism. GH deficiency should be investigated as a cause for growth retardation with GH stimulation levels. Hormone replacement is often required at puberty for females and is indicated for prevention of osteoporosis. Radiological testing with DXA scan should be included. Early proper endocrinological assessment and management is essential for adequate sexual development in these patients; this leads to improved overall quality of life along with prevention of serious morbidities, including bone demineralization (2).

1. Blake K D, Prasad C. CHARGE syndrome. Orphanet Journal of Rare Diseases 2006, 1:34.

2. Foppiani L, Maffe A. CHARGE syndrome as unusual cause of hypogonadism: endocrine and molecular evaluation. Andrologia (2010). 42: 326–330.
MON-359 Hollow Bones: A Case Report of Immobilization Osteoporosis in a Young Female
Authors: Bhat Salman Zahoor , Goyal Itivrita , Chaudhuri Ajay
Published: May 2020

Abstract

Introduction:

Osteoporosis is defined as decreased bone strength due to reduced bone mineral density (BMD) and/or abnormal bone architecture leading to bone fragility and increased risk of pathologic fractures. Typically a disease of post-menopausal females, osteoporosis is uncommon in the young. We present a case of a 34-year-old woman, who was diagnosed with severe osteoporosis in the setting of prolonged immobilization.

Clinical Case:

A 34-year-old woman was admitted for treatment of bacteremia in the setting of IV drug use and right hip septic arthritis leading to femoral head osteonecrosis requiring a long course of antibiotic treatment and resulting in prolonged immobilization. She was readmitted 2 months later with septic shock and bilateral septic arthritis needing right hip replacement for source control. She developed multiple contractures of lower extremities due to prolonged immobility and was immobile for a total of 11 months despite significant physical therapy (PT) involvement. A few months into her hospital stay, she developed acute onset right ankle pain with no falls or trauma. Xrays showed right tibial metaphyseal fracture and severe demineralization of bones of lower extremities. History and physical exam showed no signs/symptoms of malabsorption, hyperthyroidism or Cushing’s syndrome. Laboratory evaluation showed calcium (Ca) of 11.8 mg/dL (8.5–10.4), parathyroid hormone (PTH) < 3 ng/dL (12–72), C-telopeptide (Ctx) 1806 pg/ml (60–650) and normal phosphate, TSH, prolactin, 25-hydroxy and 1,25-dihydroxy vitamin D levels. PTHrP (parathyroid hormone related peptide) was < 2 pmol/L. 24-hour urine Ca was 414 mg (50–150). Serum and urine protein electrophoresis showed no monoclonal spike. Gonadal profile showed estrogen 42 pg/dL, FSH 1 mU /mL, LSH 0.1 mU /mL. DEXA scan showed severe osteoporosis with T-score of -3.2 at both the left femoral neck and lumbar spine. Osteoporosis and hypercalcemia were attributed to protracted immobilization. Therapy was initiated with alendronate 70 mg weekly along with vitamin D. Teriparatide was not used due to high serum Ca. Repeat labs at 6 months showed good response to alendronate with Ca 9.6, PTH 58, 24 hr urine Ca 96 and Ctx 1092. Mobilization of patient and regular PT were performed.

Conclusion:

Osteoporosis in a young adult is a rare entity and demands evaluation for secondary causes. An important and overlooked cause of bone loss is immobility and decreased load development on bones. Bone is a piezoelectric material and immobilization causes negative bone turnover. Early physical mobility and weight bearing is the most effective method of reducing bone loss. Teriparatide, due to anabolic effects has an advantage over bisphosphonates. Romosozumab (anti-sclerostin antibody) and whole body vibration are also being studied for disuse osteoporosis. Calcium and vitamin D supplementation are essential.
SUN-347 Glucagon-like Peptide 1 (GLP-1) Acts Directly On Human Osteoclasts To Increase Differentiation And Bone Resorptive Activity
Authors: Hansen Morten Steen , Søe Kent , Gorvin Caroline , Frost Morten
Published: May 2020

Glucagon-like peptide 1 (GLP-1) is an intestinal hormone released in response to nutrient intake that promotes glucose-dependent insulin secretion by acting upon the pancreatic GLP-1 receptor (GLP-1R). GLP-1R agonists (GLP-1RAs) are widely used in treatment of type 2 diabetes. Preclinical data indicate that GLP-1RAs could be repurposed to treat low bone mass as GLP-1R-depleted mice have higher bone resorption and thinner cortical bones, while insulinopenic and insulin resistant rats have improved bone formation and reduced bone mass deterioration when treated with GLP-1 or GLP-1RAs. However, the effect of GLP-1 and GLP-1RAs on human bone cells remains undetermined. We aimed to elucidate the effect of GLP-1 on primary human osteoclast (OC) and osteoblast (OB) cultures. OCs were differentiated over 10 days from human blood-derived CD14+ monocytes and OBs over 4–6 weeks from human bone. Cells were seeded on bovine bone slices and studies performed using fetal bovine serum, MCSF and RANKL (OC monocultures) or MCSF only (OB monocultures and OB+OC co-cultures). We first investigated the effect of GLP-1 on bone resorptive activity of mature OCs on bovine bone slices. GLP-1 increased the eroded bone surface percentage compared to vehicle in both OC monocultures (1nM P=0.002; 10nM P=0.023; n=8 donors) and OC+OB co-cultures (1nM P=0.013; 10nM P=0.012; n=8 donors). We then tested the effects of GLP-1 on osteoblast activity in OC+OB co-cultures by measuring alkaline phosphatase (ALP). We found that GLP-1 increased ALP in OC+OB cultures (1nM, P=0.049; 10nM, P=0.019) and these effects were reversed by the GLP-1R antagonist exendin 9–39 (1nM, P=0.93, 10nM, P=0.64). However, in OB monocultures GLP-1 had no effects on ALP (1nM P=0.93, 10nM P=0.64) indicating a GLP-1-driven increase in osteoblast activity through osteoclast-osteoblast coupling. We then assessed the effect of GLP-1 on OC differentiation by assessing TRAcP activity. Although there was a trend towards increased TRAcP activity upon stimulation with GLP-1 on day 10 of osteoclastogenesis, this was not statistically significant (1nM P=0.12; n=8 donors; 10nM P=0.29, n=4 donors). Our studies indicated GLP-1 may have a direct effect on osteoclasts, and we therefore sought to characterise GLP-1-mediated signalling in these cells. We assessed the effect of GLP-1 on cAMP signalling using LANCE assays and assessed phosphorylation of ERK proteins by Western blot analysis in human OC cultures. OCs treated with 10nM GLP-1 for 30 minutes had increased cAMP signaling (P=0.004, n=12 bone slices from 2 donors) when compared to vehicle. Furthermore, 10nM GLP-1 induced rapid increases in phosphorylated ERK (P=0.03 following 2 minutes exposure, n=4 blots). In conclusion, our studies reveal that GLP-1 increases activity in primary mature human OCs, and OBs, via OCs. Our signaling studies in OCs indicate this is mediated by direct action of GLP-1 on human bone cells.
MON-249 SDHD Mutation: Nonfunctional Paragangliomas Presenting as Bilateral Carotid Body Tumors with Syncope
Authors: LaChance David , Hoang Thanh Duc , Shakir Mohamed K M
Published: May 2020

SDHD Mutation: Nonfunctional paragangliomas presenting as bilateral carotid body tumors with syncope

Background:

A mutation of the SDHD gene is associated with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes which most commonly originate in the head and neck region, and usually form in the carotid body. Paragangliomas (PGL) can be secretory or non-secretory with about 95% of head and neck PGL being non-secretory. They can rarely present with symptoms due to compression, however, as in this case of a 29 year-old female presenting with syncope.

Clinical Case:

A 29 year-old female presented for evaluation after syncope. She had a syncopal event and fell down while walking in her home. Syncope was preceded by about 15 minutes of flushing, nausea and palpitations. She reported similar episodes once weekly in the preceding months, which generally lasted an hour. Initial workup included normal vital signs at presentation, normal ECG and echocardiogram, normal TFT, CBC, complete metabolic panel. Subsequent head/neck CT revealed bilateral masses in the carotid bifurcations consistent with carotid body tumors. Further history revealed a family history of bilateral carotid body tumors in her father which had never been evaluated. Plasma and urine metanephrines were normal. She underwent carotid body tumor excision. The left carotid body tumor was successfully excised and pathology revealed a paraganglioma with positive synaptophysin and chromogranin stains. Genetic testing revealed an SDHD (succinate dehydrogenase complex subunit D) gene mutation. Repeat biochemical assessment 4 months later was again negative and patient remained asymptomatic postoperatively.

Conclusion:

Paragangliomas can be secretory or non-secretory with about 95% of head and neck paragangliomas being non-secretory, as in this case. Symptoms can arise from catecholamine hypersecretion, which generally presents as hypertension, headaches, diaphoresis, flushing, anxiety or palpitations, and can be episodic or sustained, or mass effect. Syncope as a presenting symptom is rare, however, and has not been quantified but only reported in case reports. The exact etiology of syncope in our patient is not clear. Hereditary PGL/PCC syndromes should be suspected in any individual with multiple, recurrent, early-onset (age less than 45 years) or family history of PGL/PCC, as these syndromes are inherited in an autosomal dominant manner.
SUN-724 Associations of GPR174 and ITM2A Genes on X Chromosome with Early Onset Autoimmune Thyroid Disease in Korean
Authors: Lee Nayeong , Cho Wonkyoung , Shin Hyeri , Lee Yoonji , Kim Seulki , Lee Seonhwa , choi yujung , Ahn Moon Bae , Baek Incheol , Kim Shin-Hee , Cho Kyoungsoon , Jung Min-Ho , Kim Taigyu , Suh Byung-Kyu
Published: May 2020

Background: Autoimmune thyroid diseases (AITDs) are female predominant and the biology of sexual dimorphism is not clearly understood. Recently, GPR174 and ITM2A on X chromosome have been newly suggested as autoimmune thyroid disease susceptible loci.

Methods: Fourteen single nucleotide polymorphisms in immune related genes on X chromosome were analyzed in 108 Korean children (girls =90, boys =18) with AITD [Hashimoto disease (HD) = 40, Graves′ disease (GD) = 68, thyroid-associated ophthalmopathy (TAO) = 37, and non-TAO =60] with gender ratio matched normal control 106 controls (female = 43, male = 63).

Results: In AITD, the frequencies of GPR174 rs3810711 T allele (OR=6.0, cP =0.000), GRP174 rs3827440 T allele (OR=6.0, cP =0.000), ITM2A-GPR174 rs5912838 A allele (OR=2.7, cP =0.001) were increased and of GPR174 rs3810711 CC genotype (OR=0.2, cP =0.000), GRP174 rs3827440 CC genotype (OR=0.2, cP =0.000), ITM2A-GPR174 rs5912838 CC genotype (OR=0.4, cP =0.000)were lower than controls. In GD, the frequencies of GPR174 rs3810711 T allele (OR=8.4, cP =0.000), GRP174 rs3827440 T allele (OR=8.4, cP =0.000), ITM2A-GPR174 rs5912838 A allele (OR=3.3, cP =0.000) were increased and GPR174 rs3810711 CC genotype (OR=0.1, cP =0.000), C allele (OR=0.5, cP =0.044), GRP174 rs3827440 CC genotype (OR=0.2, cP =0.000), C allele (OR=0.5, cP =0.044), ITM2A-GPR174 rs5912838 CC genotype (OR=0.4, cP =0.000) were lower than controls. In HD, the frequencies of GPR174 rs3810711 T allele (OR=3.9, cP =0.003), GRP174 rs3827440 T allele(OR=3.9, cP =0.003) were increased and GPR174 rs3810711 CC genotype (OR=0.3, cP =0.004), rs3827440 CC genotype (OR=3.9, cP =0.003) were lower than controls. In thyroid-associated ophthalmopathy, the frequencies of GPR174 rs3810711 T allele (OR=7.9, cP =0.000), GRP174 rs3827440 T allele (OR=7.9, cP =0.000), ITM2A-GPR174 rs5912838 A allele (OR=3.1, cP =0.001) were increased and of GPR174 rs3810711 CC genotype (OR=0.1, cP =0.000), GRP174 rs3827440 CC genotype (OR=0.1, cP =0.000), ITM2A-GPR174 rs5912838 CC genotype (OR=0.3, cP =0.014)were lower than controls.

Conclusions. Our results suggest that polymorphisms of GPR174 and ITM2A genes on X chromosome might contribute to the pathogenesis of AITD.
SAT-196 The Use of 11C-metomidate PET-CT to Detect Unilateral Primary Hyperaldosteronism
Authors: Harjanto Sumitro , Maung Aye Chan , Puar Troy , Gardner Daphne
Published: May 2020

Background

Identifying causative adrenal lesions presents a significant diagnostic burden for physicians and radiologists. We describe the use of radiolabelled metomidate to lateralise primary hyperaldosteronism.

Case presentation

A 52-year old Chinese man with a 5-year history of hypertension was referred for hypokalemia [K 2.7 mmol/L (3.6 - 5.0)]. He had been on Telmisartan 80 mg and Amlodipine 10 mg daily and blood pressure at home ranged 110-120 / 70-80 mmHg. There was no history of poor oral intake, persistent diarrhea or vomiting, and he was not on any other prescription or alternative medications. There was no significant family history of hypertension or sudden cardiac death. Clinic blood pressure was 140/84 mmHg. There were no features suggestive of Cushing’s syndrome.

Repeat biochemical tests confirmed hypokalemia (K 3.1 mmol/L), and associated raised bicarbonate 37.3 mmol/L [19 - 29]. Magnesium and creatinine were normal. Aldosterone-renin Ratio was elevated at 8.1 (serum Aldosterone 611 pmol/L [97.3 - 834.0], active renin 2.7 pg/ml [1.8 – 59.4]). Post-saline infusion, non-suppressible serum aldosterone levels of 1137 pmol/L was demonstrated, consistent with autonomous aldosterone production.

A computed tomography of the adrenal revealed a 2.3 cm x 1.9 cm nodule on the left adrenal gland consistent with lipid rich adenoma.

Adrenal vein sampling (AVS) under continuous synacthen infusion was performed. Adrenal to peripheral cortisol ratio was ≥10 for either adrenal veins, confirming cannulation of the adrenal veins. Aldosterone-cortisol ratios showed lateralization to the left adrenal gland (lateralization ratio of 10.35). There was contralateral suppression of the right adrenal gland with ratio of 0.41.

11C-Metomidate PET-CT scan demonstrated a maximum standardised uptake value (SUVmax) of 26.8 over the left adrenal nodule, while the SUVmax of the right adrenal gland was 16.2. Ratio of the left to right adrenal gland SUVmax was 1.65 (above the threshold of 1.25); and was concordant with AVS. This confirmed that the patient had a left functional adrenal adenoma responsible for hyperaldosteronism.

Our patient underwent a left adrenalectomy, and histology was consistent with adrenal cortical adenoma. Prior to surgery he required 72 mmol/l of potassium supplementation daily to maintain K levels of 3.3 – 4.0 mmol/L. Two weeks post-operatively, he was normokalemic (K 4.9 mmol/L) without potassium supplementation. Serum aldosterone normalized to 159.3 pmol/L (active renin 9.3 pg/ml). Blood pressure is well controlled on amlodipine 5mg daily.

Conclusion

Targeted molecular imaging such as 11C-Metomidate PET-CT could aid localisation of functional adrenal disease to guide definitive surgical management. In the future, this could obviate the need for invasive and technically complex procedures like AVS.
SUN-516 Unplanned Pregnancy Post Thyroid RAI Ablation
Authors: Bhalodkar Arpita , Busta Agustin
Published: May 2020

A patient’s pregnancy and fetus are at an increased risk for complications secondary to history of recent RAI ablation and maternal secondary hypothyroidism.

A 31 year old female with a recent history of miscarriage presented with abnormal thyroid function tests and was history of low dose levothyroxine use. She complained of a 3 month history of extreme fatigue, palpitations and 18 pound weight loss at the time of presentation. Her thyroid stimulating immunoglobulin was 9.21 IU/L (0-0.55), free thyroxine 6.2ng/dL (0.9-1.8), free triiodothyronine 20.04 pg/mL (1.8-4.6) with a suppressed TSH 0.01 uIU/ml (0.27 - 4.2). She was started on methimazole. Her 24 hour radioactive iodine uptake was 60% and she subsequently underwent radioactive iodine-131 ablation in capsule form. She failed the ablation after 7 months and remained on methimazole during that duration. Her second radioactive iodine uptake was 58% and she underwent a second RAI ablation. Her TSH was 50 uIU/ml and her free thyroxine was 0.1 ng/dl. She was started on levothyroxine for replacement. Patient unexpectedly became pregnant approximately six weeks after her radioactive iodine treatment.

Studies have shown that with the exception of miscarriages, there is no evidence that exposure to radioiodine affects the outcome of subsequent pregnancies and offspring. Although the number of children born of mothers exposed to radioiodine is relatively small, the present data indicates that there is no reason for patients exposed to radioiodine to avoid pregnancy. The only adverse effect observed in the study series is an increased incidence of miscarriages in women exposed to therapeutic radioiodine during the year which preceded conception. The fetus would be at risk due to maternal hypothyroidism.

Discussion: Radioactive iodine exposure does not appear to be associated with an increased risk of miscarriage or abnormal subsequent pregnancies.

Conclusion: Pregnancies achieved after exposure to radioactive iodine treatment do not appear to be at increased risk for negative outcomes. Nevertheless, it is recommended that pregnancy be avoided for 1 year following radioactive iodine therapy to allow reproductive function to normalize.
SAT-130 The Intermediate Prolactin Receptor Is a Breast Cancer Oncogene
Authors: Grible Jacqueline M , Zot Patricija , Harrell J Chuck , Idowu Michael , Clevenger Charles V
Published: May 2020

Epidemiological, cellular, and genetic analyses indicate the hormone prolactin (PRL) and its cognate receptor in humans (hPRLr) are significantly involved in breast cancer pathogenesis. Recent evidence demonstrated that a truncated mouse PRLr (mPRLrT) is oncogenic when expressed with canonical long mPRLr (mPRLrL). mPRLrT shares significant sequence homology with a naturally-occurring and widely-expressed hPRLr isoform, the intermediate hPRLr (hPRLrI). As determined by tissue microarray (TMA), hPRLrI is expressed in >85% of breast cancer, with expression increasing as a function of both tumor grade and Ki67 status. To confirm the oncogenic potential of hPRLrI, isoform-specific hPRLrI knock-down (KD) was performed in breast cancer cell line MCF7. hPRLrI KD resulted in a significant decrease in proliferation, migration, and anchorage-independent growth. Given the homology between mPRLrT and hPRLrI, we hypothesized hPRLrI may similarly induce transformation, when expressed alongside wild-type long hPRLr (hPRLrL). hPRLrL/I co-expression in the immortalized but not transformed human breast cell line MCF10A resulted in a significant increase in proliferation, migration, and anchorage-independent growth. These results were not observed following overexpression of either isoform alone, demonstrating that hPRLrL/I co-expression is necessary to induce transformation of normal mammary epithelia. To test our hypothesis in vivo, we established MCF10A xenografts using female NSG mice. Following intraductal injection, we observed rapid tumor growth in the hPRLrL/I cohort, significantly over that of expressing either isoform alone. To determine mechanisms of transformation, we examined both differential protein stability and altered signaling events. In analyzing receptor degradation, a cycloheximide assay revealed hPRLrL stability is increased when heterodimerized with hPRLrI. hPRLrL turnover is impaired in breast cancer, indicating this phenomenon may be involved in the observed hPRLrI-mediated transformation. Regarding differential signaling, we examined the Jak2/Stat5a pathway. Jak2 is a promiscuous kinase whose oncogenic actions are well-characterized, while Stat5a is a transcription factor whose activities are critical in attenuating the oncogenicity of Jak2. Following PRL stimulation, it was observed that hPRLrL/I co-expression induced approximately two-fold greater Jak2-Y1007/1008 phosphorylation (pJak2) compared to that induced by hPRLrL expression alone. Further, it was observed that hPRLrL/I co-expression induced ten-fold less Stat5a-Y694 phosphorylation (pY-Stat5a) than hPRLrL expression alone. These data indicate unchecked pJak2 activity may also be a contributing mechanism in the observed transformation. Overall, these results demonstrate that hPRLrI, alongside hPRLrL, is sufficient for transformation of normal breast tissue.
SUN-722 Liver Leptin Receptor Gene Network Moderates the Effects of Early Life Adversity on Anxiety and Depression Problems in Children and Adolescents
Authors: Sobreira de Lima Randriely Merscher , Barth Barbara , Arcego Danusa Mar , Filho Euclides José de Mendonça , Patel Sachin , Wang Zihan , Pokhvisneva Irina , Sassi Roberto Britto , Hall Geoffrey B C , Bittencourt Ana Paula Santana de Vasconcellos , Meaney Michael Joseph , Dalmaz Carla , Silveira Patricia Pelufo
Published: May 2020

Leptin is a hormone involved in the regulation of food intake, with receptors largely expressed centrally and peripherally, in structures like the hypothalamus and the liver. Beyond its well-known actions as an energy-balance regulator, leptin is linked to psychiatric disorders. Considering that the association between genetic and early environmental factors contributes to psychopathology, disruptions of leptin signaling could be a key mechanism in this interaction. To investigate this possibility, we created an expression-based polygenic risk score (ePRS) reflecting variations in the function of the LepR gene network in the liver and hypothalamus, and investigated its interaction with postnatal adversity on Child Behavior Checklist in 4 years old children (main cohort: MAVAN, N=137) and 17 years old teenagers (Replication Cohort: ALSPAC, N=2630). There is an interaction effect between adversity exposure and liver-based LepR-ePRS, increasing depressive and anxiety problems on the MAVAN cohort (β=78.16, p=0.02, β=83.77, p=0.01). In ALSPAC, the results were replicated, showing an interaction between adversity exposure and liver-based LepR-ePRS, increasing the depression score and somatic symptoms (β=24.65, p=0.005; β=33.51, p=0.009). No significant interactions were found using the hypothalamus-based LepR-ePRS (p>0.05), suggesting specificity for the liver LepR gene network to predict these behavioral outcomes. A parallel-independent component analysis showed relationships between the SNPs from the liver ePRS-LepR and gray matter density in cortical areas involved in emotion regulation (middle frontal gyrus, inferior parietal lobule and anterior cingulate). Finally, the relationship between gene and MRI components in this analysis is moderated by the history of early life adversity exposure. Enrichment analysis of the liver LepR co-expression network shows that these genes are related to biological processes including regulation of glucose transport, cholesterol metabolism and cellular glucose homeostasis, which indicates possible underlying mechanisms linking peripheral metabolism-related gene expression and the development of emotional symptoms. Our data supports the hypothesis that exposure to early adversity affects emotional behavior, and the liver LepR gene network is an important moderator of these effects. Further studies on development of emotional symptoms should consider metabolic markers to understand these complex phenotypes.
SUN-625 The Impact of Age on Outcomes of Hyperosmolar Hyperglycemia Among Adult Patients with Diabetes. from the National Inpatient Sample
Authors: Ahmed Fatima , Abugroun Ashraf , Elhassan Manar , Seyoum Berhane
Published: May 2020

Objective: There is paucity of literature on the impact of age on outcomes hyperosmolar hyperglycemic state (HHS) among adult patients with diabetes. The aim of the study was to evaluate the effect of age on the outcome of patients admitted for the management of HHS. Methodology: The National Inpatient Sample (NIS) was queried for all patients who were admitted with a diagnosis of HHS during the years 2005-2014. The primary outcomes of the study were all-cause mortality, acute myocardial infarction (MI), and acute stroke. The secondary outcomes were acute kidney injury (AKI), rhabdomyolysis, acute respiratory failure (ARF), need for mechanical ventilation (MV) length of stay (LOS), and total cost of stay. Results: Overall, 188,725 patients were admitted for HHS. Mean age was 55.9, standard error of the mean (SEM): 0.1. Majority were of middle age. Females were (43.9%), Caucasians were 37.4% while African Americans were 35.2%. Total mortality was 1.1%, MI was 1.3% and stroke was 1.1%. Most common secondary outcome was AKI seen in 31.3% followed by ARF seen in 2.9% of total. The mean cost was 7887 $ (SEM: 84.6) and mean LOS was 4.1 days (SEM: 0.03). Young age was defined as age ≤ 35 years, middle age was > 35 and ≤ 65 years, old age was > 65 years. Mortality was 0.3 %, 0.6%, 2.5% in young, middle and older aged groups respectively. Similarly, higher age correlated with increased risk for MI, stroke and all secondary outcomes. On multivariable analysis, age was an independent predictor for all adverse outcomes. Compared to young patients, middle and older age groups had higher odds for mortality with adjusted odds ratio (aOR) 2.23 [95%CI:1.10-4.52], p=0.03 and aOR 7.35 [95%CI: 3.27-16.53], p<0.001 respectively, higher risk for stroke with aOR 9.32 [95%CI: 2.92-29.7], p<0.001 and aOR 17.46 [95%CI:5.23-58.3], p<0.001 and higher risk for MI aOR 5.18 [95%CI:2.15-12.51], p<0.00 and aOR 5.80 [95%CI:2.27-14.80], p<0.00 for middle and older age groups respectively. In addition, compared to the younge age group, the risk for rhabdomyolysis, AKI, ARF, MV, total cost and LOS was significantly higher among middle and older age groups respectively. Conclusion: Age is an important determinant for adverse outcomes among patients with hyperosmolar hyperglycemic sate.