bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence, clinical characteristics, risk factors and outcomes of patients with mixed Candida/bacterial bloodstream infections: a retrospective study
Authors: Zhong Li , Dong Zhaohui , Liu Fengqi , Li Haidong , Tang Kankai , Zheng Cheng , Wang Lifang , Zhang Kai , Cai Jiachang , Zhou Hongwei , Cui Wei , Gao Yanqiu , Zhang Gensheng
Published: November 2022

Purpose

The mixed Candida/bacterial bloodstream infections (mixed C/B-BSIs) is worthy of particular attention recently, and we analyzed the incidence, co-pathogens, clinical characteristics, risk factors, and outcomes of mixed C/B-BSIs compared with monomicrobial candidemia (mono-candidemia) in adult patients in China.

Methods

All hospitalized adults with candidemia were recruited for this retrospective observational study from January 1, 2013, to December 31, 2019.

Results

Of the 296 patients with candidemia, 78 cases (26.3%) were mixed C/B-BSIs. Candida albicans (C. albicans) was the most common Candida species among all candidemia, and Klebsiella pneumoniae (K. pneumoniae) was the most concomitant bacteria (30.6%), followed by Acinetobacter baumannii (A. baumannii) (12.9%) and Enterococcus faecium (E. faecium) (11.8%) in mixed C/B-BSIs. In the multivariable analysis, prior β-lactams exposure [adjusted odds ratio (aOR), 1.97; 95% confidence interval (CI), 1.01–3.87], burn injury (aOR, 6.35; 95% CI 1.82–22.21) and continuous renal replacement therapy (CRRT) (aOR, 3.00; 95% CI 1.46–6.17) were independent risk factors for mixed C/B-BSIs. Compared with mono-candidemia, patients with mixed C/B-BSIs developed with more proportion of septic shock (55.1% vs. 39.9%, P < 0.05), prolonged stay in ICU [22.0(12.0–57.0) vs. 9.5(0.0–37.0) days, P < 0.001] and longer mechanical ventilation time [19.0(4.5–40.8) vs. 6.0(0.0–24.8) days, P < 0.001]. The in-hospital mortality in patients with mixed C/B-BSIs was higher than those with mono-candidemia (59.0% vs. 34.9%, P < 0.001). Survival analysis revealed that 28-day and 60-day mortality were significantly higher in patients with mixed C/B-BSI than in those with mono-candidemia (57.7% vs. 31.7%, P < 0.001; 59.0% vs. 34.9%, P < 0.001; respectively).

Conclusions

There is a high rate of mixed C/B-BSIs cases among candidemia, and K. pneumoniae is the predominant coexisting species. Prior β-lactams exposure, burn injury, and CRRT are independent risk factors for mixed C/B-BSIs. The mortality of patients with mixed C/B-BSIs is significantly higher than those with mono-candidemia, this deserves further attention for clinicians.
Lp(a), oxidized phospholipids and oxidation-specific epitopes are increased in subjects with keloid formation
Authors: Ruder Sundeep , Mansfield Brett , Immelman Andrew Ronald , Varki Nissi , Miu Phuong , Raal Frederick , Tsimikas Sotirios
Published: November 2022

Background

Keloid formation following trauma or surgery is common among darkly pigmented individuals. Since lipoprotein(a) [Lp(a)] has been postulated to have a putative role in wound healing, and also mediates atherosclerotic cardiovascular disease, it was assessed whether Lp(a), its associated oxidized phospholipids and other oxidation-specific biomarkers were associated with keloid formation.

Methods

This case-control study included darkly pigmented individuals of African ancestry, 100 with keloid scarring and 100 non-keloid controls. The lipid panel, hsCRP, Lp(a), oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), IgG and IgM apoB-immune complexes and IgG and IgM autoantibodies to a malondialdehyde mimotope (MDA-mimotope) were measured. Immunohistochemistry of keloid specimens was performed for both Lp(a) and OxPL staining.

Results

Cases and controls were well matched for age, sex and lipid profile. Mean Lp(a) (57.8 vs. 44.2 mg/dL; P = 0.01, OxPL-apoB 17.4 vs. 15.7 nmol/L; P = 0.009) and IgG and IgM apoB-immune complexes and IgG and IgM MDA-mimotope levels were significantly higher in keloid cases. Keloid tissue stained strongly for OxPL.

Conclusion

Darkly pigmented individuals of African ancestry with keloids have higher plasma levels of Lp(a), OxPL-apoB and oxidation-specific epitopes. The commonality of excessive wound healing in keloids and chronic complications from coronary revascularization suggests avenues of investigation to define a common mechanism driven by Lp(a) and the innate response to oxidized lipids.
The impact of COVID-19 pandemic on hospital admissions for nine diseases in Iran: insight from an interrupted time series analysis
Authors: Ahmadi Sina , Kazemi-Karyani Ali , Badiee Nasim , Byford Sarah , Mohammadi Ali , Piroozi Bakhtiar , Rezaei Satar
Published: November 2022

Background

Associations between the COVID-19 pandemic and hospitalizations have not been studied Iran. This study aimed to examine the impact of the COVID-19 pandemic on hospital admissions for nine categories of disease in seven public hospitals in Kermsnahah city, the capital of Kermsnahah province, in the west of Iran.

Methods

Data on monthly hospitalization rates (number of hospitalizations per 100,000 population) were collected for nine categories of disease for a period of 40 months (23 months before and 17 months after the COVID-19 outbreak in Iran) from the health information systems of all seven public hospitals in Kermanshah city. Categories of disease included those related to pregnancy, childbirth and the puerperium period, neoplasms, diseases of the digestive, respiratory, circulatory, genitourinary and nervous systems, mental and behavioural disorders, and infectious and parasitic diseases. Population data were extracted from the Statistics Centre of Iran. An interrupted time series analysis with segmented regression was used to examine the impact of COVID-19 on hospital admissions.

Findings

Average monthly hospitalization rates fell for all nine categories of disease included in the study after the onset of the pandemic, with overall rates of 85.5 per 100,000 population in the period before the COVID-19 outbreak and 50.4 per 100,000 population after the outbreak began. The relative reduction in hospitalizations for the nine diseases was 56.4%. Regression analysis of monthly data indicated a sharp decrease in hospitalisations during the first month after the COVID-19 outbreak, which was statistically significant for all diseases (p < 0.001). After the initial reduction following onset of the pandemic, significant increases were observed for some diseases, including neoplasms (increase of 3.17 per 100,000 population; p < 0.001), diseases of the digestive system (increase of 1.17 per 100,000 population; p < 0.001) and diseases related to pregnancy, childbirth and the puerperium period (increase of 1.73 per 100,000 population). For other categories of disease, rates significantly declined, including infectious and parasitic diseases (decrease of 2.46 per 100,000 population; p < 0.001). Hospitalization rates did not increase to pre-pandemic levels for any disease, with the exception of those related to pregnancy, childbirth and the puerperium period.

Conclusions

Our study indicated that the COVID-19 pandemic had a significantly negative effect on hospitalizations in Iran. Although use of hospital care has gradually increased post-outbreak, it has yet to return to normal levels.
Diagnostic utility of CSF1 immunohistochemistry in tenosynovial giant cell tumor for differentiating from giant cell-rich tumors and tumor-like lesions of bone and soft tissue
Authors: Sugita Shintaro , Takenami Tomoko , Kido Tomomi , Aoyama Tomoyuki , Hosaka Michiko , Segawa Keiko , Sugawara Taro , Fujita Hiromi , Shimizu Junya , Murahashi Yasutaka , Emori Makoto , Hasegawa Tadashi
Published: November 2022

Background

Tenosynovial giant cell tumor (TSGCT) is a benign fibrohistiocytic tumor that affects the synovium of joints, bursa, and tendon sheaths and is categorized into localized TSGCT (LTSGCT) and diffuse TSGCT (DTSGCT). LTSGCT and DTSGCT are characterized by recurrent fusions involving the colony-stimulating factor 1 (CSF1) gene and its translocation partner collagen type VI alpha 3 chain. The fusion gene induces intratumoral overexpression of CSF1 mRNA and CSF1 protein. CSF1 expression is a characteristic finding of TSGCT and detection of CSF1 mRNA and CSF1 protein may be useful for the pathological diagnosis. Although there have been no effective anti-CSF1 antibodies to date, in situ hybridization (ISH) for CSF1 mRNA has been performed to detect CSF1 expression in TSGCT. We performed CSF1 immunohistochemistry (IHC) using anti-CSF1 antibody (clone 2D10) in cases of TSGCT, giant cell-rich tumor (GCRT), and GCRT-like lesion and verified its utility for the pathological diagnosis of TSGCT.

Methods

We performed CSF1 IHC in 110 cases including 44 LTSGCTs, 20 DTSGCTs, 1 malignant TSGCT (MTSGCT), 10 giant cell tumors of bone, 2 giant cell reparative granulomas, 3 aneurysmal bone cysts, 10 undifferentiated pleomorphic sarcomas, 10 leiomyosarcomas, and 10 myxofibrosarcomas. We performed fluorescence ISH (FISH) for CSF1 rearrangement to confirm CSF1 expression on IHC in TSGCTs. We considered the specimens to have CSF1 rearrangement if a split signal was observed in greater than 2% of the tumor cells.

Results

Overall, 50 of 65 TSGCT cases, including 35 of the 44 LTSGCTs and 15 of the 20 DTSGCTs, showed distinct scattered expression of CSF1 in the majority of mononuclear tumor cells. MTSGCT showed no CSF1 expression. Non-TSGCT cases were negative for CSF1. FISH revealed CSF1 rearrangement in 6 of 7 CSF1-positive cases on IHC. On the other hand, FISH detected no CSF1 rearrangement in all CSF1-negative cases on IHC. Thus, the results of IHC corresponded to those of FISH.

Conclusion

We revealed characteristic CSF1 expression on IHC in cases of TSGCT, whereas the cases of non-TSGCT exhibited no CSF1 expression. CSF1 IHC may be useful for differentiating TSGCTs from histologically mimicking GCRTs and GCRT-like lesions.
Label-free detection of leukemic myeloblasts in hyaluronic acid
Authors: Park Suhyun , Kim Hyueyun , Woo Minna , Kim Minsuk
Published: November 2022

Chronic myeloid leukemia is generally required bone marrow biopsy for diagnosis. Although examining peripheral blood is less invasive, it has not been fully validated as a routine diagnostic test due to suboptimal sensitivity. To overcome this limitation, a number of methodologies based on microfluidics have been developed for sorting circulating tumor cells from peripheral blood of patients with leukemia.

In order to develop a more convenient method, we designed an analysis protocol using motion microscopy that amplifies cellular micro motions in a captured video by re-rendering pixels to generate extreme magnified visuals. Intriguingly, no fluctuations around leukemic myeloblasts were observed with a motion microscope at any wavelength of 0–10 Hz. However, use of 0.05% hyaluronic acid, one type of non-newtonian fluid, demonstrated fluctuations around leukemic myeloblasts under conditions of 25 μm/s and 0.5–1.5 Hz with a motion microscope.

Thus, the non-invasive detection of leukemic myeloblasts can offer a valuable supplementary diagnostic tool for assessment of drug efficacy for monitoring patients with chronic myeloid leukemia.
A sterile insect technique pilot trial on Captiva Island: defining mosquito population parameters for sterile male releases using mark–release–recapture
Authors: Carvalho Danilo O. , Morreale Rachel , Stenhouse Steven , Hahn Daniel A. , Gomez Maylen , Lloyd Aaron , Hoel David
Published: November 2022

Background

The sterile insect technique (SIT), which involves area-wide inundative releases of sterile insects to suppress the reproduction of a target species, has proven to be an effective pest control method. The technique demands the continuous release of sterilized insects in quantities that ensure a high sterile male:wild male ratio for the suppression of the wild population over succeeding generations.

Methods

For these releases, it is important to determine several ecological and biological population parameters, including the longevity of the released males in the field, the dispersal of the released males and the wild pest population size. The Lee County Mosquito Control District initiated a study in a 47-ha portion of Captiva Island (Florida, USA), an island with a total area of 230 ha, to define biological SIT parameters for Aedes aegypti (L.), an invasive disease-vectoring mosquito known to be difficult to control due to a combination of daytime biting activity, use of cryptic breeding habitats that are difficult to target with conventional night-time ultra-low volume methods, and emerging resistance to commonly used insecticides. Another goal was to assess patterns of dispersal and survival for laboratory-reared sterile Ae. aegypti males released over time in the pilot site. These parameters will be used to evaluate the efficacy of a SIT suppression program for Ae. aegypti on Captiva Island.

Results

Over the course of seven mark-release-recapture studies using single- and multiple-point releases, 190,504 sterile marked males were released, for which the recapture rate was 1.5% over a mean period of 12 days. The mean distance traveled by sterile males of the local strain of Ae. aegypti that has colonized Captiva Island was 201.7 m from the release point, with an observed maximum traveled distance of 404.5 m. The released sterile mosquitoes had a probability of daily survival of 0.67 and an average life expectancy of ~ 2.46 days.

Conclusions

These data together with the population size estimate and sterile:wild ratio provide a solid basis for planning the SIT operational phase which is aimed at mosquito population suppression.

Graphical abstract
Melanoma differentiation-associated gene 5 amyopathic dermatomyositis following an acute Mycoplasma pneumoniae infection: a case report
Authors: Hoey Jessica , Solomon Jenny Lue , Kim Brandon , Carsons Steven , Nusbaum Julie
Published: November 2022

Background

A previously healthy young male of Southeast Asian descent presented with 6 weeks of fevers, cough, mucocutaneous ulcers, arthritis, and myalgias. Initial workup revealed positive Mycoplasma pneumoniae immunoglobulin M, and the patient was treated with antibiotics without relief of symptoms. Rheumatologic workup revealed highly positive melanoma differentiation-associated gene 5 antibody. Viral infections are thought to potentially trigger loss of self tolerance, and prompt the autoimmunity cascade that can result in conditions such as dermatomyositis. To our knowledge, this is the first case report demonstrating a non-viral infection, specifically Mycoplasma pneumoniae, as the inciting infectious trigger for the anti-melanoma differentiation-associated gene 5 dermatomyositis subtype.

Case presentation

A 20-year-old southeast Asian–American male with no significant past medical history presented with symptoms of intermittent fevers, nonproductive cough, dry eyes, oral ulcers, rash, arthritis, and myalgias. The patient was noted to have erythematous papules across the bilateral hands along the lateral digits and palms, as well as synovitis involving the bilateral hands and feet. Immunoglobulin M antibodies were positive for Mycoplasma pneumoniae. The patient was diagnosed with mycoplasma pneumonia. The patient did not respond to a course of antibiotics, leading to rheumatological testing that found highly positive melanoma differentiation-associated gene 5 autoantibody. Muscle enzyme and electromyography testing were normal, indicating clinically amyopathic disease. Methylprednisolone was initiated, with resolution of fevers and improvement of arthritis and myalgias. The cutaneous lesions on the digits and palms improved.

Conclusions

This patient presented with symptoms of fever, cough, oral ulcers, rashes, and arthritis, and blood work demonstrated the presence of immunoglobulin M antibodies to Mycoplasma pneumoniae. Despite antibiotic treatment for the presumed diagnosis of Mycoplasma pneumoniae infection, the patient did not improve, prompting rheumatological workup and revealing melanoma differentiation-associated gene 5 autoantibodies. This case suggests that infections, other than viral, can trigger the autoinflammatory cascade, leading to the development of amyopathic melanoma differentiation-associated gene 5 dermatomyositis.
Decision Analysis for the Influence of Incorporating Waste Materials on Green Concrete Properties
Authors: Bakhoum Emad S. , Mater Yasser M.
Published: November 2022

Concrete industry is challenged by sustainability and technical concerns. Sustainability includes minimization of raw material usage, energy consumption, and emission of greenhouse gases, while technical concerns comprise the enhancement of mechanical properties and durability such as compressive strength, resistance to chloride, acids, and elevated temperatures. Therefore, recycling of industrial waste in manufacturing of green concrete has become a robust viable alternative to disposal, due to the limited natural resources and raw materials which contribute to sustainable construction. Consequently, this research aims to develop an approach using a multicriteria decision-making algorithm based on Analytical Hierarchy Process (AHP), to select the most suitable industrial waste to achieve the desired green concrete properties. The research starts by determining the alternatives including 18 industrial wastes, and the criteria including 14 properties of concrete. After that, an experimental database for the influence of the alternatives on the criteria is established based on the literature. Then, an algorithm is developed using a python script to analyze the influence of incorporating each of the industrial waste alternative on both the mechanical and sustainable properties of concrete. Subsequently, the efficiency of the proposed algorithm is validated using three case studies that present different circumstances of concrete specifications. Based on the proposed approach, the decision-maker can assign the appropriate residual waste to be incorporated into the concrete mix according to its application in a user-friendly manner. Such approach can support both sustainable use of waste materials and enhancement of concrete properties.
A glimpse into the monetary supply network of the Tang empire in the seventh century CE: archaeometallurgical study of Kaiyuan Tongbao coins from Lafu Queke cemetery, Xinjiang, Northwest China
Authors: Ma Ding , Wang Yongqiang , Yang Jun , Bi Yanqi , Luo Wugan
Published: November 2022

The supply of coins and their metal materials is important for state governance. Many details about the monetary supply network in ancient China still need to be verified. In this paper, 15 early Tang dynasty Kaiyuan Tongbao 開元通寶 coins excavated from the Lafu Queke 拉甫却克 cemetery, Hami 哈密 city, were studied by combining scientific analyses (PXRF and MC-ICP-MS etc.) with the archaeological context and historical texts. The results show that all of these coins are made of Cu-Sn–Pb ternary alloy. The lead isotopes match with the isotopic signatures of some southwest China lead mines consistent with historical records, 14 coins are located in the range of Southern China geochemical province, and the lead of 5 coins could be considered as highly radiogenic lead (HRL). Combining these results with the archaeological context and historical texts, it can be inferred that the coins minted in southwest China were made from locally exploited raw metal, and supplied to the northwest borderland of the Tang dynasty in the seventh century CE.
Metallothionein synthesis increased by Ninjin-yoei-to, a Kampo medicine protects neuronal death and memory loss after exposure to amyloid β1-42
Authors: Tamano Haruna , Tokoro Haruna , Murakami Daichi , Tsujimoto Rin , Nishijima Yuka , Tsuda Erina , Watanabe Satoshi , Suzuki Miki , Takeda Atsushi
Published: November 2022

Background

It is possible that increased synthesis of metallothioneins (MTs), Zn2+-binding proteins is linked with the protective effect of Ninjin-yoei-to (NYT) on Zn2+ toxicity ferried by amyloid β1-42 (Aβ1-42).

Methods

Judging from the biological half-life (18-20 h) of MTs,
the effective period of newly synthesized MT on capturing Zn2+ is
estimated to be approximately 2 days. In the present paper, a diet containing
3% NYT was administered to mice for 2 days and then Aβ1-42 was injected
into the lateral ventricle of mice.

Results

MT level in the dentate granule cell layer was elevated 2 days after administration of NYT diet, while the administration reduced intracellular Zn2+ level increased 1 h after Aβ1-42 injection, resulting in rescuing neuronal death in the dentate granule cell layer, which was observed 14 days after Aβ1-42 injection. Furthermore, Pre-administration of NYT diet rescued object recognition memory loss via affected perforant pathway long-term potentiation after local injection of Aβ1-42 into the dentate granule cell layer of rats.

Conclusion

The present study indicates that pre-administration of NYT diet for 2 days increases synthesis of MTs, which reduces intracellular Zn2+ toxicity ferried by extracellular Aβ1-42, resulting in protecting neuronal death in the dentate gyrus and memory loss after exposure to Aβ1-42.
The Break-Fast study protocol: a single arm pre-post study to measure the effect of a protein-rich breakfast on autophagic flux in fasting healthy individuals
Authors: Bensalem Julien , Heilbronn Leonie K. , Gore Jemima R. , Hutchison Amy T. , Sargeant Timothy J. , Fourrier Célia
Published: November 2022

Background

Autophagy is a cellular process that cleanses cells and is particularly important during ageing. Autophagy has been extensively studied in vitro and in animal models and is known to be sensitive to nutrition. However, human data are limited because autophagic flux (autophagic degradative activity) has been challenging to measure in humans. This protocol paper describes the Break-Fast study, in which autophagic flux will be measured using a recently developed blood test, before and after ingestion of whey protein. This aims to determine whether an acute nutritional intervention can change autophagy in humans.

Methods

A minimum of forty healthy participants (both male and female) aged 20–50 years, BMI 18.5–29.9 kg/m2 will be recruited into this single arm pre-post study. Participants will visit the clinic after an overnight fast for a first blood collection after which they will consume a whey protein-rich drink. A second blood collection will be performed 60 minutes after consumption of the drink. The primary outcome is the change in autophagic flux at 60 minutes post drink. Secondary outcomes include changes in blood glucose, autophagy-related proteins and mRNA, plasma hormones (e.g. insulin, C-peptide, adiponectin, GLP-1, GIP, ghrelin), cytokines, amino acids and lipids, protein synthesis, and correlation between molecular cell damage and autophagic flux.

Discussion

This study will provide information about whether autophagy responds to nutrients in humans, and if nutritional strategies could be used to treat or prevent autophagy-related diseases such as Alzheimer’s disease or cancer.

Trial registration

Australian New Zealand Clinical Trials Registry (ANZCTR), anzctr.org.au ACTRN12621001029886. Registered on 5 August 2021.
Acrostichium aureum Linn: traditional use, phytochemistry and biological activity
Authors: Akinwumi Kazeem A. , Abam Esther O. , Oloyede Sofiat T. , Adeduro Mary N. , Adeogun Yusuf A. , Uwagboe Juanian E.
Published: November 2022

Background

Acrostichum aureum L is an edible mangrove plant fern that grows mainly in tropical and subtropical regions of the world. This review was conducted to provide in-depth information regarding the traditional uses, phytochemistry and biological activity of A. aureum.

Methods

Scientific literatures were systematically searched using databases including Google scholar, PubMed, Science Direct and ResearchGate for ethnobotany, phytochemistry and pharmacology of the plant. Its potential pharmaceutical and nutritional applications as well as knowledge gap in A. aureum research were also documented.

Results

The outcome revealed that A. aureum is used traditionally across the world to treat several ailments including, non-healing ulcers, boil, wounds, snakebite, bleeding, worm infection, asthma, sore throat, constipation and elephantiasis. Secondary metabolites including, sterols, glycosides, saponins, alkaloids, tannins, flavonoids, phthalates, and terpenoids have been identified in A. aureum. Beneficial phytochemicals including kaempferol, di-(2-methylheptyl) phthalate, β-sitosterol, (2S,3S)-sulfated pterosin C, (+)-pinoresinol-4-O-sulfate, lupeol, α-amyrin and phytol have been detected and/or isolated in the plant. In vitro and in vivo studies also proved that various extracts and phytochemicals in A. aureum have powerful antioxidant, anti-inflammatory, antiulcer, tyrosinase inhibiting, anthelmintic, anti-diarrheal, analgesic, anti-tumor, anti-fertility, anticancer, antibacterial, anti-viral and wound healing properties.

Conclusion

The A.aureum could be harnessed for novel bioactive compounds that can be useful in the treatment of various diseases. Consequently, metabolomic and chemoinformatic analyses could be deployed to fast-track drug discovery and development from the plant. Moreover, safety and activity guided bioassays as well as clinical trials are needed before it could be recommended for clinical use.
An automated survey design process to reduce the environmental impact of onshore seismic surveys
Authors: Dean Tim , Whitfield Jennifer , Miller Julia , Brady Peter
Published: November 2022

Land seismic surveys acquired in anything but the barest landscapes encounter obstacles that cause the planned survey points to be either shifted or skipped. Besides these forced changes, an increased awareness of the environmental impact of seismic surveys, coupled with a general lack of trust and even opposition to the traditional energy industry, has resulted in a demand to minimize the impacts of the clearing that is necessary to allow access to the survey lines. We present a method to reduce the environmental impact of seismic surveys without compromising seismic imaging. The process is straightforward and can be applied automatically using standard mathematical software (in this case, MATLAB). For the example shown here, where the line spacing was particularly dense, the impact on vegetation greater than 2 m in height was reduced by 55%. For less dense geometries, where there is more opportunity to offset points, the impact is likely to be larger.
LBODP005 Gper Modulates Multiple Functions In Adipose Tissue To Promote An Anti-obese Phenotype
Authors: Sharma Geetanjali , Woods Christine D , Rajkarnikar Resha , Hathaway Helen J , Prossnitz Eric R
Published: November 2022

Obesity and metabolic syndrome are major health issues of modern society and their incidence is increasing at alarming rates worldwide. Obesity and associated chronic diseases exhibit sexual disparity with pre-menopausal females displaying better protection compared to age-matched males. These beneficial effects on metabolism in females are predominantly attributed to the female hormone estrogen, specifically 17β-estradiol (E2). E2 exerts its actions via multiple receptors, nuclear and extra-nuclear estrogen receptor (ER) α and ERβ, and the G protein-coupled estrogen receptor (GPER). GPER is present in diverse cells types and tissues and has been implicated in numerous physiological processes via multiple cellular signaling pathways. We have combined in vivo studies in an ovariectomized (OVX) mouse model along with in vitro assays in 3T3-L1 cells to investigate the role of GPER in modulating adipocyte function. Our studies reveal that loss of GPER increased adiposity in female mice on high fat diet and activation of GPER by its selective agonist G-1 attenuates adiposity in OVX mice. G-1 activated AMPK, increased cellular respiration and expression of mitochondrial and antioxidant genes and reduced lipid deposition in adipocytes. Furthermore, G-1 treatment promoted an anti-inflammatory phenotype in mice. Thus, our findings establish a role of GPER agonist G-1 in exerting anti-lipogenic and anti-inflammatory effects in adipocytes, which may have potential therapeutic implications in treatment of obesity.

Presentation: No date and time listed
ODP605 Body Mass Index and Weight Reductions in Patients With SRC1 Genetic Variant Obesity After 1 Year of Setmelanotide
Authors: Martos-Moreno Gabriel Á , Argente Jesús , Scimia Cecilia , Ohayan Olga , Yuan Guojun , Farooqi Sadaf
Published: November 2022

Background

The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Steroid receptor coactivator 1 (SRC1; also known as NCOA1) is a transcriptional coactivator that regulates proopiomelanocortin (POMC) expression in the MC4R pathway. Certain SRC1 variants impair MC4R signaling and are associated with hyperphagia (pathologic insatiable hunger) and early-onset, severe obesity. Treatment with setmelanotide, an MC4R agonist, resulted in weight and hunger reductions after 3 months in patients with SRC1 variant obesity in a Phase 2 study. This analysis is the first to assess the continued efficacy of 1 year of setmelanotide treatment in patients with SRC1 variant obesity.

Methods

Patients with SRC1 variant obesity aged ≥6 years were eligible for this long-term extension (LTE) trial (NCT03651765) if they completed an index trial in which they received setmelanotide and demonstrated clinical benefit on the basis of efficacy and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of setmelanotide treatment as part of the index trial and began the LTE immediately following completion. Study visits occurred approximately every 3 months. Study objectives included evaluating changes in weight-related measures and tolerability. The current analysis reports outcomes after 1 year of setmelanotide treatment across the index and LTE trials, relative to index trial baseline.

Results

As of October 29, 2021, 30 patients (20 ≥18 years old and 10 <18 years old) with SRC1 variant obesity enrolled in the index trial. Seventeen patients entered the LTE; at the time of analysis, 16, 11, and 8 patients had received at least 6, 9, and 12 months of treatment, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all patients was 45.4 (11.3) kg/m2, body weight in patients ≥18 years old was 139.7 (25.1) kg, and BMI Z score in patients <18 years old was 2.99 (0.63). After 6, 9, and 12 months of treatment, mean (SD) percent change in BMI was −5.7% (5.6%; n=16), −7.8% (5.8%; n=11), and −10.1% (9.4%; n=8), respectively. Mean (SD) percent change in body weight in patients ≥18 years old at 6, 9, and 12 months was −6.7% (6.1%; n=11), −9.9% (7.4%; n=8), and −11. 0% (8.6%; n=7), respectively. The mean (SD) change in BMI Z score was −0.35 (0.35; n=7), −0.42 (0.23; n=5), and −0.67 (0.57; n=3) after 6, 9, and 12 months, respectively. No new safety concerns emerged during long-term treatment, and no patients discontinued because of an adverse event.

Conclusions

One year of setmelanotide treatment led to clinical weight benefits in patients with SRC1 variant obesity. These data support the continued investigation of setmelanotide in this population, which is underway in the Phase 3 EMANATE trial (NCT05093634).

Presentation: No date and time listed
ODP607 Long-term Efficacy of Setmelanotide in Patients With POMC or LEPR Deficiency Obesity
Authors: Clément Karine , Wabitsch Martin , Van den Akker Erica , Argente Jesús , Scimia Ceclila , Srinivasan Madhura , Yuan Guojun , Kühnen Peter
Published: November 2022

The melanocortin-4 receptor (MC4R) pathway in the brain is responsible for energy regulation, affecting appetite and body weight. Impairments of this pathway can result in hyperphagia (insatiable hunger) and obesity. The MC4R can be impacted by the POMC, PCSK1, or LEPR genes. Variants in these genes that are inherited from both parents (biallelic) can result in MC4R pathway signaling deficiencies. Setmelanotide is a drug that activates the MC4R. In earlier Phase 3 studies, setmelanotide was shown to improve hunger and reduce weight in patients with POMC, PCSK1, and LEPR biallelic deficiency. The present study aims to examine the long-term efficacy of ∼3 years of setmelanotide treatment in patients with POMC, PCSK1, and LEPR biallelic deficiency in a long-term extension after a previous trial. Setmelanotide treatment continued to provide sizable reductions in body weight and body mass index while being generally well tolerated. These findings provide strong support of the safe and effective long-term use of setmelanotide to treat obesity in patients with POMC, PCSK1, and LEPR biallelic deficiency.

Presentation: No date and time listed
OR23-1 FXR Regulates the Expansion and Metabolic Function of Adipose Tissue upon Caloric Excess
Authors: Akinrotimi Oludemilade , Anakk Sayeepriyadarshini , Dadlani Neal , Zhou Weinan
Published: November 2022

Obesity is a major risk factor for developing metabolic diseases. Adipose tissue stores excess calories during obesity. Nuclear receptor Farnesoid X receptor (FXR) is expressed in various tissues and transcriptionally regulates lipid and glucose metabolism. However, the role of FXR in regulating adipose expansion is unknown. We showed that Fxr transcript is expressed in mature adipocytes isolated from both white (WAT) and brown (BAT) adipose tissues. In adipocyte-specific Fxr knockout (Ad-FxrKO) mice, we found enlarged adipocytes and decreased expression of lipolytic genes upon 60% high fat diet (HFD) or high fat/high sucrose western diet challenge. Transcriptomic analysis of WAT from Ad-FxrKO and control mice upon chow or HFD revealed that many genes involved in glucose and lipid homeostasis are misregulated in Ad-FxrKO mice with distinct patterns under normal and obese conditions. Since WAT stores fat and BAT generates heat, we examined both these depots in Ad-FxrKO mice and found reductions in the expression of mitochondrial genes and energy expenditure. Intriguingly, we found ectopic fat accumulation in the liver and systemic glucose intolerance in Ad-FxrKO compared to the control mice during obesity. Overall, these findings implicate that FXR may regulate lipid metabolism and mitochondrial functions in the adipose tissue, which consequently impacts whole-body energy homeostasis.

Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.
PSUN114 Correlation of Percent Body Fat From Two-Electrode Bioelectric Impedance Analysis and Dual-Energy X-Ray Absorptiometry
Authors: Roongjiraroj Thanasate , Siriwan Chonpiti , Suwannahitatorn Picha
Published: November 2022

Background

The diagnosis of obesity by measuring body mass index (BMI) is limited in some populations. Moreover, BMI does not reflect body fat levels, which are the main factors causing metabolic-related disorders, including cardiovascular disease. There are various methods for measuring percent body fat, such as using a two-electrode bioelectric impedance analysis (BIA), which is considered a portable and easy-to-use tool. In Thailand, the studies on BIA compared to standard method, dual-energy X-ray absorptiometry (DEXA scan) are still limited.

Objective

To study a correlation of percent body fat from two-electrode BIA and DEXA scan Methods: In this cross-sectional study, percent body fat were measured using three of two-electrode BIA and DEXA scan within the same week. The subjects were categorized into 3 groups according to their BMI: normal group (18.5 - 22.9 kg/m2), overweight and obese group (23 - 29.9 kg/m2) and extreme obesity group (≥ 30 kg/m2).

Results

A total of 30 study participants, with an average age of 28.07 ± 5.81 years, correlation of percent body fat as measured two-electrode BIA and DEXA scan were Omron®HBF-222T = 0.801, Tanita®BC-730 = 0.922, and Xiaomi®Body Composition Scale 2 = 0.884. All three correlations were strong (r 3 0.75) and statistically significant (p-value <0.001). Moreover, the percent body fat measured by three of two-electrode BIA were no different (p-value = 0.167).

Conclusion

The percent body fat measured by three of two-electrode BIA and DEXA scan is highly correlated and not statistically difference between three brands. Therefore, two-electrode BIA can be used as alternative method to DEXA scan to measure percent body fat.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN119 Obesity As An Independent Factor In Outcome Of SIADH Hospitalizations
Authors: Maghari Ibrahim , Abusalim Abdul-rahman , Ojemolon Pius , Abusalim Abdul-rahman , Shaka Hafeez , Laswi Hisham
Published: November 2022

Introduction

Several comorbidities have been associated with the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). However, not much literature documents an association between SIADH and obesity, and there is a marked paucity of research documenting the impact of obesity on outcomes in patients hospitalized with SIADH.

Method

We extracted data from the US Nationwide Inpatient Sample (NIS) for 2019. The NIS contains hospital discharge information estimating yearly US hospitalizations. We included hospitalizations with a principal discharge diagnostic code for SIADH using the ICD-10-CM code (E22.2). The study excluded hospitalizations of patients less than 18 years. This cohort was divided based on the secondary diagnosis of obesity.

Outcomes included comparing inpatient mortality rates, mean length of hospital stay (LOS), mean hospitalization cost (THC), rates of septic shock, acute myocardial infarction (AMI), acute respiratory failure (ARF), acute renal failure (AKI), acute pulmonary edema (PE) between the subgroups. An adjustment was made for age, sex, race, primary payer, median household income by zip code, Carlson Comorbidity Index (CCI), hospital location, bed-size, and teaching status using multivariate regression analysis. Statistical significance was set at a p-value < 0.05.

Results

In 2019, a total of 39,110 hospitalizations involved patients with SIADH as the reason for the admission and 7.7% of these admissions had comorbid obesity. A higher proportion of hospitalizations involved females, with more of the obese cohort being females (65.7 vs 61.4%, p=0.034). Patients with obesity comparatively had a lower mean age (67.9±13.1 vs 73±13.3 years, p<0.001), a higher proportion of CCI >2, and a higher proportion of Whites.

In patients with SIADH, obesity was associated with no difference in mortality (1.1 vs 1.3%, p=0.589) or THC, but patients with obesity had higher odds of increased LOS (5.6 vs 4.9 days, p=0.007), AKI (20 vs 11.3%, aOR: 1.88, p<0.001), and ARF (11.2 vs 7%, aOR: 1.53, p=0.003). There was no significant difference in CVA, PE, septic shock or AMI odds.

Conclusions

Comorbid obesity was associated with higher LOS and odds of AKI and ARF, but there was no difference in mortality, THC, CVA, PE, septic shock or AMI compared to SIADH hospitalizations without obesity.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN82 The Gut Microbiome Regulates Healthy Adipose Tissue Expansion via the Action of FFA2
Authors: Nnyamah Christine , Wicksteed Barton , Layden Brian
Published: November 2022

The obesity pandemic is a major health concern driving Type 2 Diabetes (T2D) and cardiovascular disease (CVD). One novel pathogenetic factor of obesity is the gut microbiome (GM), that is the microbes that reside in the digestive tract. Changes in the GM have profound effects on the obesity. These symbiotic microbes break down dietary fiber that are otherwise indigestible, releasing nutrients (in particular, short chain fatty acids, SCFAs). Free Fatty Acid Receptor 2 (FFA2) is a G-protein coupled receptor (GPCR) that senses SCFAs and influences secretion of the appetite-regulating proteins GLP-1 and PYY from enteroendocrine cells. However, its role in adipose tissue is less clear. While highly expressed in adipose tissue, research using global knockouts (KOs) of FFA2 in mouse models has observed conflicting phenotypic results. Here, we use adipocytes isolated from FFA2-KO and WT mice and SCFA-supplemented media to demonstrate that acetate, a primary ligand of FFA2, leads to increased adipogenesis. This expansion of total adipocyte population rather than individual size has been shown to greatly decrease metabolic health complications in highly obese individuals. Our ongoing research aims to explore the in vitro effects of FFA2 on lipogenesis, lipolysis, and secretion of adipokines. Primarily, we are exploring these outcomes in vivo using novel adipose-specific FFA2 KO (AdFFA2-KO) mice which we show have no congenital defects and are metabolically similar to FFA2 floxxed control mice on a normal chow diet. Our ongoing research challenges the mice with obesogenic diets to observe the effects of metabolic strain on FFA2 function specifically in adipose tissue.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN83 Exploring the Role of PARP1-mediated ADP-ribosylation in Diet-induced Obesity
Authors: Lee Kraus W , Whitaker Amy
Published: November 2022

Poly(ADP-ribosyl)ation (PARylation) is a posttranslational modification that regulates various cellular processes, including the differentiation of preadipocytes. PARylation involves the covalent attachment of a chain of ADP-ribose units to proteins by poly(ADP-ribose) polymerases (PARPs), mainly PARP1. We previously found that PARP1 activity decreases precipitously upon differentiation of preadipocytes, including 3T3-L1 cells, a preadipocyte cell line. Upon knockout or knockdown of Parp1, or chemical inhibition of PARP1, adipogenesis is dramatically increased. We have previously used a mouse lineage tracing model to show that knockout of Parp1 in preadipocytes promotes adipogenesis by expanding the pool of precursors, ultimately leading to accumulation of fat. PARP1 controls adipogenesis, in part, by PARylating two sites (E135A and E139A) in the regulatory domain of C/EBPβ, a proadipogenic transcription factor. Mutation of these sites enhances chromatin binding and transcriptional activity of C/EBPβ, as well as promotes a proadipogenic gene expression program and differentiation, in 3T3-L1 cells. However, we still do not know the role of PARP1-mediated site-specific PARylation in diet-induced obesity. We recently created a set of PAR-Trackers (PAR-Ts) that can detect changes in PAR levels during physiological processes in cells. We used PAR-T NanoLuc to observe dynamic changes in PAR levels during the differentiation of 3T3-L1 cells. We are now modifying the system to investigate PAR levels in the tissues of live animals. To investigate the physiological impact of loss of C/EBPβ PARylation in adipocytes, we have generated a knock-in mouse model for inducible tissue-specific expression of a C/EBPβ PARylation site mutant (Cebpb/E135A/E139A or C/EBPβ PAR mut). Using this model, we will investigate the impact of site-specific PARylation of C/EBPβ in mice fed a high fat diet. With these studies, we hope to reveal the specific roles of PARP1-mediated ADP-ribosylation in diet-induced obesity.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN84 Chronic Adrenergic Stimulation in Humans Increases Plasma Bile Acids and Expression of Bile Acid Synthesis Enzymes in White Adipose Tissue
Authors: Zhu Alexander R , Pierce Anne E , Katz Jacqueline M , Cero Cheryl , Cypess Aaron M
Published: November 2022

Bile acids (BAs) are classically known as facilitators of fat digestion. Moreover, they are now known to be ligands for receptors involved in glucose and lipoprotein metabolism. BA synthesis was originally thought to be exclusive to hepatic tissue, but emerging evidence in rodents has demonstrated the expression of BA transporters and de novo synthetic enzymes in murine adipose tissue. We previously showed that chronic activation of brown adipose tissue (BAT) and white adipose tissue (WAT) in adult women via the β3-adrenergic receptor (ADRB3) agonist mirabegron increases total plasma BA levels. The largest increases were seen with primary unconjugated BAs. Overall, these data suggest that chronic adrenergic stimulation may increase the synthesis and activity of BA synthesis enzymes in human adipose tissue, which contributes to the increase in total plasma BAs. To confirm this hypothesis, we measured expression levels of BAT and BA synthesis enzymes in liver and adipose tissues collected from healthy patients and those with pheochromocytoma (pheo) who experienced chronic adrenergic activation. As expected, expression of thermogenic UCP1 and ADRB3 was higher in pheo peri-renal BAT than in liver tissue (76,000x, P<0.001; and 6,000x, P=0.02, respectively) or either healthy subcutaneous WAT or pheo subcutaneous WAT (≥1500x, P<0.001 for UCP1). Conversely, expression of the rate-determining enzyme in BA synthesis CYP7A1 was similar in liver and both WAT depots (P>0.05), and liver had slightly higher expression than BAT (3x, P=0.03). Otherwise, most of the principal BA synthesis genes’ expression levels demonstrated the following stepwise pattern: liver tissue > pheo WAT = subcutaneous WAT > BAT (CYP8B1, CYP27A1, AKR1D1, and BAAT). These results suggest that BA production in humans is not limited to the liver. Rather, human WAT in particular may contribute to the BA pool and could serve as a target for producing BA-mediated improvements in glucose and lipoprotein metabolism.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF10 | PMON205 LH/CG Receptor Activation Protects Mice from Diet-Induced Obesity and Modifies Adipose Tissue Immune Response
Authors: Lizneva Daria , Ievleva Kseniia , Gumerova Anisa , Shelly Eleanor , Korkmaz Funda , Muradova Valeriia , Netto Jessica , Kuo Tanchun , Sultana Farhath , Kumar Pushkar , Kramskiy Natan , Ryu Vitaly , Padilla Ashley , Hutchison Susan , Yuen Tony , Zaidi Mone
Published: November 2022

Menopause is associated with the loss of LH ovulatory surges and enhanced visceral adiposity. Visceral fat depots increase from 5-8% at premenopause to 15-20% of total body fat at postmenopause. Here, we report that high-dose LH, hCG, or small molecule LH/CGR agonist ORG43553 injected twice-a-week into 14-weeks-old C57BL/6 male mice protects them from diet-induced obesity. Testosterone levels were elevated in mice treated with LH or hCG, but not with ORG43553. Notably, the anti-obesity action of LH/hCG is independent of testosterone, as blocking the androgen receptor using flutamide yielded similar results. Importantly, male Lhcgr knockout mice on a high-fat diet treated with LH failed to display a reduction in adiposity, confirming the in vivo specificity of action. Furthermore, our data phenocopied Lhcgr haploinsufficiency in mice. We confirmed the presence of Lhcgr in mouse genital and inguinal fat pads, adipose-derived stromal vascular cells, as well as in differentiated and undifferentiated 3T3-L1 murine adipocytes by qPCR, RNAscope in situ hybridization, and immunohistochemistry. Sanger sequencing showed that the extracellular domain of Lhcgr in genital fat depot was identical to the ovarian receptor. Similarly, we identified LHCGR in human subcutaneous and visceral fat depots. Binding of intraperitoneally injected AlexaFluor-488-labeled hCG was found not only in mouse ovary, but also in genital and subcutaneous fat pad, further confirming the presence of LHCGR in adipose tissue. This binding could be competitively displaced in 3T3-L1 cells using unlabeled hCG. LH, hCG and ORG43553 activated ERK1/2 in a dose-dependent manner in undifferentiated and differentiated 3T3-L1 cells, suggesting that the adipose LHCGR is fully functional. LH, hCG, and ORG43553 reduced adipogenic differentiation in 3T3-L1 cells, which is further confirmed by RNA sequencing. Moreover, we observed, that LH and hCG also alters several aspects of immune response in adipose tissue, including inflammatory response and adaptive immunity. In conclusion, we demonstrated that LH/CG receptors are present and fully functional in adipose tissue, and that high-dose intermittent activation of LHCGR in mouse fat depots protects mice from diet-induced obesity and modifies adipose tissue immune response.

Presentation: Saturday, June 11, 2022 1:42 p.m. - 1:47 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.