bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphometric measurement of lumbar pedicle in different regions: a systematic review
Authors: Wang Yixi , Kahaer Alafate , Shi Wenjie , Guo Hailong , Rexiti Paerhati
Published: January 2023

Objective

To collect the data of pedicle width and height in different areas, and to investigate the difference and variation rule of pedicle width and height.

Methods

Comprehensive search of PubMed, Ovid Medline, and Web of science databases was performed. Collected data were imported into SPSS, and one-way ANOVA test and post hoc test were used to determine whether there were statistical differences in pedicle width and height between the different regions.

Results

Oceania had the largest pedicle width and height, followed by Americans. West Asian had the largest pedicle width in Asia, followed by East and Southeast Asian, and Chinese and South Asian had similar pedicle width. Different from the variation pattern of pedicle width, the pedicle height of Chinese, East and Southeast Asian and West Asian in Asian range is similar, but the pedicle height of South Asian is significantly smaller than the first three, and has statistical significance.

Conclusions

People in different regions have similar patterns of variation in pedicle width and height even though they belong to different ethnic groups. This phenomenon is particularly prominent and pronounced in populations in geographically close areas, which may be related to inter-ethnic integration due to population movement between adjacent areas. There is a relationship between the morphological characteristics of the human lumbar pedicle and geographical location.
Genetic analysis reveals the inconsistency of amorpha-4,11-diene synthase, a key enzyme in the artemisinin synthesis pathway, in asteraceae
Authors: Chen Shiyu , Liao Baosheng , Guo Shuai , Shen Xiaofeng , Meng Ying , Liang Yu , Xu Jiang , Chen Shilin
Published: January 2023

Background

Amorpha-4,11-diene synthase (ADS) is a key enzyme in the artemisinin biosynthetic pathway. ADS promotes the first step of artemisinin synthesis by cyclizing faresyl pyrophosphate to synthesize the sesquiterpene product amorpha-4,11-diene. Thanks to the continuous improvement of genomic information, its evolutionary trace can be analyzed in a genome view.

Methods

Phylogenetic analysis was used to identify ADS-like genes in other Asteraceae. Gene structure and motif analysis was used to analyze the structural similarity of these identified genes. Heterologous expression and GC–MS analysis were performed to determine whether the functions of ADS and Cna4666 are consistent. Validation of ADS genes evolutionary trajectories was achieved by selective pressure and synteny analysis.

Result

In this study, we extracted 8 ADS genes from the Artemisia annua L. genome annotation and 121 ADS similar genes from the genomes of Artemisia annua L. and other plants in the Asteraceae, and further exploring their evolutionary relationship. Phylogenetic analysis showed that the genes most closely related to ADS genes were found in the genome of Chrysanthemum nankingense. Among them, the gene structure and motif composition of Cna4666 is very similar to ADS, we wondered whether it has the potential to synthesize amorpha-4,11-diene. Therefore, we extracted the products of recombinant p0_ADS.1 and Cna4666 proteins by HS-SPME combined with GC–MS analysis, the results indicate that Cna4666 is an α-bisabolol synthase, which cannot synthesize amorpha-4,11-diene. Through synteny analysis, we did not find collinear blocks of ADS genes in the Helianthus annuus and C. nankingense genomes. Furthermore, Ka/Ks ratios indicated that the evolution of ADS genes from their similar genes principally underwent purifying selection, and there was a strong positive selection between ADS genes.

Conclusions

This study proved that ADS is a multi-copy gene in Artemisia annua L., and they are not widely distributed in Asteraceae. The data will increase our understanding of the evolutionary selection pressure on ADS genes. The results suggest that ADS genes are subject to strong positive selection internally, and it is possible that they are a recently evolved gene in the Artemisia.
Screening and treatment of brain metastasis from papillary thyroid carcinoma: a case series
Authors: Ha Le Ngoc , Khanh Le Quoc , Hanh Ngo Thi Minh , Seo Hyo Jung , Son Mai Hong
Published: January 2023

Background

The brain metastasis from differentiated thyroid carcinoma (DTC) is a rare condition and its prognosis is poor. The standard protocol for screening and treatment of patients with brain metastases from papillary thyroid cancer (PTC) remains controversial. This report aims to share the experience of a single center in the management of brain metastases from DTC.

Material and methods

Five patients with brain metastases were identified from 5000 patients with DTC attending the department of nuclear medicine, Hospital 108 between 2016 to 2022. The statistical software Statistical Package for Social Sciences (SPSS) 20.0 (SPSS Inc., Chicago, IL, USA) was used to analyze the data.

Results

Five patients with brain metastases from DTC were revealed by MRI,18F-FDG PET/CT with contrast enhancement, and131I-SPECT/CT. The median time of overall survival (OS) was 15 months, ranging from 10 to 65 months. Two out of the five patients underwent surgery, and futher 2 patients were treated with stereotactic surgery (SRS). All patients are still alive.

Conclusions

Brain metastases from DTC are rare. MRI is the preferred imaging mobility to screen brain lesions in DTC. The primary treatment modalities are surgery and SRS.
M2 macrophage-derived exosomal miR-193b-3p promotes progression and glutamine uptake of pancreatic cancer by targeting TRIM62
Authors: Zhang Ke , Li Yu-Jie , Peng Lin-Jia , Gao Hui-Feng , Liu Lu-Ming , Chen Hao
Published: January 2023

Background

Pancreatic cancer (PC) is a highly lethal malignancy that requires effective novel therapies. M2 macrophages are abundant in the PC microenvironment and promote cancer progression. Exosomes are emerging mediators of the crosstalk between cancer cells and the microenvironment. This study was conducted to explore the role of M2 macrophage-derived exosomes in PC.

Methods

Exosomes derived from M2 macrophages were extracted. miR-193b-3p and TRIM62 were overexpressed or silenced to examine their function in PC. Luminescence assays were used to investigate the interaction between miR-193b-3p and TRIM62. Cell proliferation was examined by EdU staining. Would healing and transwell assays were applied to evaluate cell migration and invasion. Co-immunoprecipitation was used to assess the interaction between TRIM62 and c-Myc. Gene and protein expressions were analyzed by quantitative RT-PCR and immunoblotting, respectively.

Results

M2 macrophage-derived exosomal miR-193b-3p promoted the proliferation, migration, invasion, and glutamine uptake of SW1990 cells. Mechanism study revealed that TRIM62 is a target of miR-193b-3p. TRIM62 inhibited the proliferation, migration, invasion, and glutamine uptake of SW1990 cells by promoting c-Myc ubiquitination. Our data also suggested that TRIM62 expression negatively correlated with miR-193b-3p and c-Myc expression. High-expression of miR-193b-3p and c-Myc predicts poor prognosis, whereas low-expression of TRIM62 predicts poor prognosis in patients with PC.

Conclusion

M2 macrophage-derived exosomal miR-193b-3p enhances the proliferation, migration, invasion, and glutamine uptake of PC cells by targeting TRIM62, resulting in the decrease of c-Myc ubiquitination. This study not only reveals the mechanism underlying the crosstalk between M2 macrophages and PC cells but also suggests a promising therapeutic target for PC.
Drugging the epigenome in the age of precision medicine
Authors: Feehley Taylor , O’Donnell Charles W. , Mendlein John , Karande Mahesh , McCauley Thomas
Published: January 2023

Background

Modulating the epigenome has long been considered a potential opportunity for therapeutic intervention in numerous disease areas with several approved therapies marketed, primarily for cancer. Despite the overall promise of early approaches, however, these drugs have been plagued by poor pharmacokinetic and safety/tolerability profiles due in large part to off-target effects and a lack of specificity.

Results

Recently, there has been marked progress in the field on a new generation of epigenomic therapies which address these challenges directly by targeting defined loci with highly precise, durable, and tunable approaches. Here, we review the promise and pitfalls of epigenetic drug development to date and provide an outlook on recent advances and their promise for future therapeutic applications.

Conclusions

Novel therapeutic modalities leveraging epigenetics and epigenomics with increased precision are well positioned to advance the field and treat patients across disease areas in the coming years.
Predictive models and early postoperative recurrence evaluation for hepatocellular carcinoma based on gadoxetic acid-enhanced MR imaging
Authors: Li Qian , Wei Yi , Zhang Tong , Che Feng , Yao Shan , Wang Cong , Shi Dandan , Tang Hehan , Song Bin
Published: January 2023

Background

The prognosis of hepatocellular carcinoma (HCC) is still poor largely due to the high incidence of recurrence. We aimed to develop and validate predictive models of early postoperative recurrence for HCC using clinical and gadoxetic acid-enhanced magnetic resonance (MR) imaging-based findings.

Methods

In this retrospective case-control study, 209 HCC patients, who underwent gadoxetic acid-enhanced MR imaging before curative-intent resection, were enrolled. Boruta algorithm and backward stepwise selection with Akaike information criterion (AIC) were used for variables selection Random forest, Gradient-Boosted decision tree and logistic regression model analysis were used for model development. The area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis were used to evaluate model’s performance.

Results

One random forest model with Boruta algorithm (RF-Boruta) was developed consisting of preoperative serum ALT and AFP levels and six MRI findings, while preoperative serum AST and AFP levels and four MRI findings were included in one logistic regression model with backward stepwise selection method (Logistic-AIC).The two predictive models demonstrated good discrimination performance in both the training set (RF-Boruta: AUC, 0.820; Logistic-AIC: AUC, 0.853), internal validation set (RF-Boruta: AUC, 0.857, Logistic-AIC: AUC, 0.812) and external validation set(RF-Boruta: AUC, 0.805, Logistic-AIC: AUC, 0.789). Besides, in both the internal validation and external validation sets, the RF-Boruta model outperformed Barcelona Clinic Liver Cancer (BCLC) stage (p < 0.05).

Conclusions

The RF-Boruta and Logistic-AIC models with good prediction performance for early postoperative recurrence may lead to optimal and comprehensive treatment approaches, and further improve the prognosis of HCC after resection.
Alpha-gal syndrome initially misdiagnosed as chronic spontaneous urticaria in a pediatric patient: a case report and review of the literature
Authors: Bellutti Enders Felicitas , Elkuch Marius , Wörner Andreas , Scherer Hofmeier Kathrin , Hartmann Karin
Published: January 2023

Introduction

Delayed allergy to red meat, also termed alpha-gal syndrome, is increasingly reported in adults and African communities, while pediatric cases remain rare.

Case presentation

Here, we report on a 7-year-old Caucasian boy presenting with recurrent wheals since the age of 5 years old. Episodes with hives occurred around every 3 weeks, mainly in the evening. One of these episodes was also associated with angioedema. No clear trigger was identified. At the first visit, after excluding an infection and autoimmune thyroiditis, chronic spontaneous urticaria was suspected and symptomatic treatment with antihistamines was prescribed. Six months later, the boy presented at the emergency room with generalized urticaria, dyspnoea, and emesis. Symptoms resolved after administration of epinephrine and antihistamines. A detailed medical history after this event revealed that he had eaten three sausages as well as jelly beans containing gelatine several hours prior to this episode. More precisely, after eating the sausages and jelly beans during the day, he had shown some hives before going to bed, and later developed the other symptoms in the middle of the night, suggesting alpha-gal syndrome. In his history, several tick bites are reported. Immunoglobulin E levels for alpha-gal were clearly elevated, confirming the diagnosis of a delayed-appearing immunoglobulin E-mediated allergic reaction to alpha-gal. Emergency medication was prescribed and avoidance of red meat and gelatine-containing foods was recommended. Under this exclusion diet, the boy remained asymptomatic, with the exception of two accidents in the follow up of 3 years, one developing during a barbecue and the second after exceptionally eating marshmallows.

Conclusion

A detailed clinical history led to the diagnosis of alpha-gal syndrome. Although alpha-gal syndrome is typically seen in adults, our case illustrates that children can also present with this potentially life-threatening allergy. Since alpha-gal syndrome is rare in Europe, the disease is not well known and often overlooked for several years, especially in children.
Atypical Kawasaki disease presenting with macroscopic hematuria in an infant: a case report
Authors: Thadchanamoorthy V. , Dayasiri Kavinda , Ragunathan I. R.
Published: January 2023

Background

Kawasaki disease is an acute febrile condition in children. It affects mainly children under 5 years old, and is known to cause coronary artery abnormalities if treatment is delayed. The diagnosis rests mainly on clinical criteria. However, it is also known that some infants do not have diagnostic criteria sufficient enough for the diagnosis of Kawasaki disease. Further, children may rarely present with unusual features, and this entity is recognized as “Atypical Kawasaki disease.”

Case presentation

We present the case of a 9-month-old Tamil boy who presented with sterile gross hematuria in association with prolonged fever, lymphadenopathy, and generalized maculopapular rash. He had high inflammatory markers and echocardiogram disclosed left coronary artery dilatation. The diagnosis of incomplete Kawasaki disease was confirmed based on clinical grounds supported by investigations and exclusion of differential diagnosis. The child showed a good response to intravenous immunoglobulin and aspirin.

Conclusion

Kawasaki disease is one of the important differential diagnoses of protracted fever of unknown origin in very young children. Since delayed treatment is associated with a high risk of complications, atypical Kawasaki disease needs to be suspected in children presenting with unusual features such as macroscopic hematuria that occurs in association with unexplained prolonged fever.
Prediction of survival time after terminal extubation: the balance between critical care unit utilization and hospice medicine in the COVID-19 pandemic era
Authors: Zheng Yun-Cong , Huang Yen-Min , Chen Pin-Yuan , Chiu Hsiao-Yean , Wu Huang-Pin , Chu Chien-Ming , Chen Wei-Siang , Kao Yu-Cheng , Lai Ching-Fang , Shih Ning-Yi , Lai Chien-Hong
Published: January 2023

Background

We established 1-h and 1-day survival models after terminal extubation to optimize ventilator use and achieve a balance between critical care for COVID-19 and hospice medicine.

Methods

Data were obtained from patients with end-of-life status at terminal extubation from 2015 to 2020. The associations between APACHE II scores and parameters with survival time were analyzed. Parameters with a p-value ≤ 0.2 in univariate analysis were included in multivariate models. Cox proportional hazards regression analysis was used for the multivariate analysis of survival time at 1 h and 1 day.

Results

Of the 140 enrolled patients, 76 (54.3%) died within 1 h and 35 (25%) survived beyond 24 h. No spontaneous breathing trial (SBT) within the past 24 h, minute ventilation (MV) ≥ 12 L/min, and APACHE II score ≥ 25 were associated with shorter survival in the 1 h regression model. Lower MV, SpO2 ≥ 96% and SBT were related to longer survival in the 1-day model. Hospice medications did not influence survival time.

Conclusion

An APACHE II score of ≥ 25 at 1 h and SpO2 ≥ 96% at 1 day were strong predictors of disposition of patients to intensivists. These factors can help to objectively tailor pathways for post-extubation transition and rapidly allocate intensive care unit resources without sacrificing the quality of palliative care in the era of COVID-19.

Trial registration They study was retrospectively registered. IRB No.: 202101929B0.
Comparison of telemonitoring combined with intensive patient support with standard care in patients with chronic cardiovascular disease - a randomized clinical trial
Authors: Öner Alper , Dittrich Hermann , Arslan Fatih , Hintz Sissy , Ortak Jasmin , Brandewiede Bernard , Mann Miriam , Krockenberger Katja , Thiéry Alexandre , Ziegler Andreas , Schmidt Christian ,   the CardioCare MV Study Group, Bleschke H , Buchner T , Buckow C , Bunge K , Duda S , El-Sourani H , Frey K , Greiner-Leben H , Henschel F , Hering R , Knispel O , Kram J , Martschewski A , Mitusch R , Plietzsch S , Rausch S , Rink A , Wejda M , Wißmann R , Wolf. B
Published: January 2023

Importance

Healthcare concepts for chronic diseases based on tele-monitoring have become increasingly important during COVID-19 pandemic.

Objective

To study the effectiveness of a novel integrated care concept (NICC) that combines tele-monitoring with the support of a call centre in addition to guideline therapy for patients with atrial fibrillation, heart failure, or treatment-resistant hypertension.

Design

A prospective, parallel-group, open-label, randomized, controlled trial.

Setting

Between December 2017 and August 2019 at the Rostock University Medical Center (Germany).

Participants

Including 960 patients with either atrial fibrillation, heart failure, or treatment-resistant hypertension.

Interventions

Patients were randomized to either NICC (n = 478) or standard-of-care (SoC) (n = 482) in a 1:1 ratio. Patients in the NICC group received a combination of tele-monitoring and intensive follow-up and care through a call centre.

Main outcomes and measures

Three primary endpoints were formulated: (1) composite of all-cause mortality, stroke, and myocardial infarction; (2) number of inpatient days; (3) the first plus cardiac decompensation, all measured at 12-months follow-up. Superiority was evaluated using a hierarchical multiple testing strategy for the 3 primary endpoints, where the first step is to test the second primary endpoint (hospitalization) at two-sided 5%-significance level. In case of a non-significant difference between the groups for the rate of hospitalization, the superiority of NICC over SoC is not shown.

Results

The first primary endpoint occurred in 1.5% of NICC and 5.2% of SoC patients (OR: 3.3 [95%CI 1.4–8.3], p = 0.009). The number of inpatient treatment days did not differ significantly between both groups (p = 0.122). The third primary endpoint occurred in 3.6% of NICC and 8.1% of SoC patients (OR: 2.2 [95%CI 1.2–4.2], p = 0.016). Four patients died of all-cause death in the NICC and 23 in the SoC groups (OR: 4.4 [95%CI 1.6–12.6], p = 0.006). Based on the prespecified hierarchical statistical analysis protocol for multiple testing, the trial did not meet its primary outcome measure.

Conclusions and relevance

Among patients with atrial fibrillation, heart failure, or treatment-resistant hypertension, the NICC approach was not superior over SoC, despite a significant reduction in all-cause mortality, stroke, myocardial infarction and cardiac decompensation.

Trial registration ClinicalTrials.gov Identifier: NCT03317951.
Unmet need for family planning among married women in sub-Saharan Africa: a meta-analysis of DHS data (1995 – 2020)
Authors: Phiri Million , Odimegwu Clifford , Kalinda Chester
Published: January 2023

Background

Closing the gap of unmet needs for family planning (FP) in sub-Saharan Africa remains critical in improving maternal and child health outcomes. Determining the prevalence of unmet needs for family planning among married women in the reproductive age is vital for designing effective sexual reproductive health interventions and programmes. Here, we use nationally representative data drawn from sub-Saharan countries to estimate and examine heterogeneity of unmet needs for family planning among currently married women of reproductive age.

Methods

This study used secondary data from Demographic and Health Surveys (DHS) conducted between January 1, 1995 to December 31, 2020 from 37 countries in sub-Saharan African. An Inverse Heterogeneity model (IVhet) in MetaXL application was used to estimate country and sub-regional level pooled estimates and confidence intervals of unmet needs for FP in SSA.

Results

The overall prevalence of unmet need for family planning among married women of reproductive age in the sub-region for the period under study was 22.9% (95% CI: 20.9–25.0). The prevalence varied across countries from 10% (95% CI: 10–11%) in Zimbabwe to 38% (95% CI: 35–40) and 38 (95% CI: 37–39) (I2 = 99.8% and p-value < 0.0001) in Sao Tome and Principe and Angola, respectively. Unmet needs due to limiting ranged from 6%; (95% CI: 3–9) in Central Africa to 9%; (95% CI: 8–11) in East Africa. On the other hand, the prevalence of unmet needs due to spacing was highest in Central Africa (Prev: 18; 95% CI: 16–21) and lowest in Southern Africa (Prev: 12%; 95% CI: 8–16). Our study indicates that there was no publication bias because the Luis Furuya-Kanamori index (0.79) was within the symmetry range of -1 and + 1.

Conclusion

The prevalence of unmet need for FP remains high in sub-Saharan Africa suggesting the need for health policymakers to consider re-evaluating the current SRH policies and programmes with the view of redesigning the present successful strategies to address the problem.
Optimal reduction and equilibrium carbon allowance price for the thermal power industry under China’s peak carbon emissions target
Authors: Sun Jiaojiao , Dong Feng
Published: January 2023

As the largest source of carbon emissions in China, the thermal power industry is the only emission-controlled industry in the first national carbon market compliance cycle. Its conversion to clean-energy generation technologies is also an important means of reducing CO2 emissions and achieving the carbon peak and carbon neutral commitments. This study used fractional Brownian motion to describe the energy-switching cost and constructed a stochastic optimization model on carbon allowance (CA) trading volume and emission-reduction strategy during compliance period with the Hurst exponent and volatility coefficient in the model estimated. We defined the optimal compliance cost of thermal power enterprises as the form of the unique solution of the Hamilton–Jacobi–Bellman equation by combining the dynamic optimization principle and the fractional Itô’s formula. In this manner, we obtained the models for optimal emission reduction and equilibrium CA price. Our numerical analysis revealed that, within a compliance period of 2021–2030, the optimal reductions and desired equilibrium prices of CAs changed concurrently, with an increasing trend annually in different peak-year scenarios. Furthermore, sensitivity analysis revealed that the energy price indirectly affected the equilibrium CA price by influencing the Hurst exponent, the depreciation rate positively impacted the CA price, and increasing the initial CA reduced the optimal reduction and the CA price. Our findings can be used to develop optimal emission-reduction strategies for thermal power enterprises and carbon pricing in the carbon market.
Genetic diversity of Plasmodium vivax populations from the China–Myanmar border identified by genotyping merozoite surface protein markers
Authors: Wang Xun , Bai Yao , Xiang Zheng , Zeng Weilin , Wu Yanrui , Zhao Hui , Zhao Wei , Chen Xi , Duan Mengxi , Li Xiaosong , Zhu Wenya , Sun Kemin , Wu Yiman , Zhang Yanmei , Li Xiaomei , Rosenthal Benjamin M. , Cui Liwang , Yang Zhaoqing
Published: January 2023

Background

Parasite diversity and population structure influence malaria control measures. Malaria transmission at international borders affects indigenous residents and migrants, defying management efforts and resulting in malaria re-introduction. Here we aimed to determine the extent and distribution of genetic variations in Plasmodium vivax populations and the complexity of infections along the China–Myanmar border.

Methods

We collected clinical P. vivax samples from local and migrant malaria patients from Laiza and Myitsone, Kachin State, Myanmar, respectively. We characterized the polymorphisms in two P. vivax merozoite surface protein markers, Pvmsp-3α and Pvmsp-3β, by PCR-restriction fragment length polymorphism (PCR–RFLP) analysis. We sought to determine whether these genetic markers could differentiate these two neighboring parasite populations.

Results

PCR revealed three major size variants for Pvmsp-3α and four for Pvmsp-3β among the 370 and 378 samples, respectively. PCR–RFLP resolved 26 fragment-size alleles by digesting Pvmsp-3α with Alu I and Hha I and 28 alleles by digesting Pvmsp-3β with Pst I. PCR–RFLP analysis of Pvmsp-3α found that infections in migrant laborers from Myitsone bore more alleles than did infections in residents of Laiza, while such difference was not evident from genotyping Pvmsp-3β. Infections originating from these two places contained distinct but overlapping subpopulations of P. vivax. Infections from Myitsone had a higher multiplicity of infection as judged by the size of the Pvmsp-3α amplicons and alleles after Alu I/Hha I digestion.

Conclusions

Migrant laborers from Myitsone and indigenous residents from Laiza harbored overlapping but genetically distinct P. vivax parasite populations. The results suggested a more diverse P. vivax population in Myitsone than in the border town of Laiza. PCR–RFLP of Pvmsp-3α offers a convenient method to determine the complexity of P. vivax infections and differentiate parasite populations.
An Assessment of the Feasibility and Utility of an ACCC-ASCO Implicit Bias Training Program to Enhance Racial and Ethnic Diversity in Cancer Clinical Trials
Authors: Barrett Nadine J. , Boehmer Leigh , Schrag Janelle , Benson Al B. , Green Sybil , Hamroun-Yazid Leila , Howson Alexandra , Matin Khalid , Oyer Randall A. , Pierce Lori , Jeames Sanford E. , Winkfield Karen , Yang Eddy S. , Zwicker Victoria , Bruinooge Suanna , Hurley Patricia , Williams Jen Hanley , Guerra Carmen E.
Published: January 2023

PURPOSE:

Cancer trial participants do not reflect the racial and ethnic diversity in the population of people with cancer in the United States. As a result of multiple system-, patient-, and provider-level factors, including implicit bias, cancer clinical trials are not consistently offered to all potentially eligible patients.

MATERIALS AND METHODS:

ASCO and ACCC evaluated the utility (pre- and post-test knowledge changes) and feasibility (completion rates, curriculum satisfaction metrics, survey questions, and interviews) of a customized online training program combined with facilitated peer-to-peer discussion designed to help research teams identify their own implicit biases and develop strategies to mitigate them. Discussion focused on (1) specific elements of the training modules; (2) how to apply lessons learned; and (3) key considerations for developing a facilitation guide to support peer-to-peer discussions in cancer clinical research settings. We evaluated discussion via a qualitative assessment.

RESULTS:

Participant completion rate was high: 49 of 50 participating cancer programs completed training; 126 of 129 participating individuals completed the training (98% response rate); and 119 completed the training and evaluations (92% response rate). Training increased the mean percentage change in knowledge scores by 19%-45% across key concepts (eg, causes of health disparities) and increased the mean percentage change in knowledge scores by 10%-31% about strategies/actions to address implicit bias and diversity concerns in cancer clinical trials. Knowledge increases were sustained at 6 weeks. Qualitative evaluation validated the utility and feasibility of facilitated peer-to-peer discussion.

CONCLUSION:

The pilot implementation of the training program demonstrated excellent utility and feasibility. Our evaluation affirms that an online training designed to raise awareness about implicit bias and develop strategies to mitigate biases among cancer research teams is feasible and can be readily implemented in cancer research settings.
Future Directions for Adrenal Insufficiency: Cellular Transplantation and Genetic Therapies
Authors: Graves Lara E , Torpy David J , Coates P Toby , Alexander Ian E , Bornstein Stefan R , Clarke Brigette
Published: January 2023

Primary adrenal insufficiency (PAI) occurs in 1 in 5 to 7000 adults. Leading etiologies are autoimmune adrenalitis in adults and congenital adrenal hyperplasia (CAH) in children. Oral replacement of cortisol is lifesaving, but poor quality of life, repeated adrenal crises, and dosing uncertainty related to lack of a validated biomarker for glucocorticoid sufficiency persists. Adrenocortical cell therapy and gene therapy may obviate many of the shortcomings of adrenal hormone replacement. Physiological cortisol secretion regulated by pituitary adrenocorticotropin could be achieved through allogeneic adrenocortical cell transplantation, production of adrenal-like steroidogenic cells from either stem cells or lineage conversion of differentiated cells, or for CAH, gene therapy to replace or repair a defective gene. The adrenal cortex is a high-turnover organ and thus failure to incorporate progenitor cells within a transplant will ultimately result in graft exhaustion. Identification of adrenocortical progenitor cells is equally important in gene therapy, for which new genetic material must be specifically integrated into the genome of progenitors to ensure a durable effect. Delivery of gene-editing machinery and a donor template, allowing targeted correction of the 21-hydroxylase gene, has the potential to achieve this. This review describes advances in adrenal cell transplants and gene therapy that may allow physiological cortisol production for children and adults with PAI.
Prevaccination Glucose Time in Range Correlates With Antibody Response to SARS-CoV-2 Vaccine in Type 1 Diabetes
Authors: Alhamar Ghadeer , Briganti Silvia , Maggi Daria , Viola Viola , Faraj Malak , Zannella Carla , Galdiero Massimiliano , Franci Gianluigi , Fusco Clorinda , Isgrò Camilla , Leanza Giulia , Malandrucco Ilaria , Spinelli Andrea , Tramontana Flavia , Iaria Domenico , Tortoriello Rachele , Pieralice Silvia , Rosati Milena , Matarese Giuseppe , Pozzilli Paolo , Galgani Mario , Strollo Rocky
Published: January 2023

Context

Poor glucose control has been associated with increased mortality in COVID-19 patients with type 1 diabetes (T1D).

Objective

This work aimed to assess the effect of prevaccination glucose control on antibody response to the SARS-CoV-2 vaccine BNT162b2 in T1D.

Methods

We studied 26 patients with T1D scheduled to receive 2 doses, 21 days apart, of BNT162b2, followed prospectively for 6 months with regular evaluation of SARS-CoV-2 antibodies and glucose control. Immunoglobulin G (IgG) to spike glycoprotein were assessed by enzyme-linked immunosorbent assay, and serum neutralization by a live SARS-CoV-2 assay (Vero E6 cells system). Glycated hemoglobin A1c (HbA1c) and continuous glucose monitoring (CGM), including time in range (TIR) and above range (TAR), were collected. The primary exposure and outcome measures were prevaccination glucose control, and antibody response after vaccination, respectively.

Results

Prevaccination HbA1c was unrelated to postvaccine spike IgG (r = −0.33; P = .14). Of note, the CGM profile collected during the 2 weeks preceding BNT162b2 administration correlated with postvaccine IgG response (TIR: r = 0.75; P = .02; TAR: r = −0.81; P = .008). Patients meeting the recommended prevaccination glucose targets of TIR (≥ 70%) and TAR (≤ 25%) developed stronger neutralizing antibody titers (P < .0001 and P = .008, respectively), regardless of HbA1c. Glucose control along the study time frame was also associated with IgG response during follow-up (TIR: r = 0.93; P < .0001; TAR: r = −0.84; P < .0001).

Conclusion

In T1D, glucose profile during the 2 weeks preceding vaccination is associated with stronger spike antibody binding and neutralization, highlighting a role for well-controlled blood glucose in vaccination efficacy.
Genomic Profiling Reveals the Variant Landscape of Sporadic Parathyroid Adenomas in Chinese Population
Authors: Tao Xiaohui , Xu Tian , Lin Xiaoyun , Xu Shuqin , Fan Youben , Guo Bomin , Deng Xianzhao , Jiao Qiong , Chen Lihui , Wei Zhe , Chen Chengkun , Yang Wendi , Zhang Zhenlin , Yu Xiangtian , Yue Hua
Published: January 2023

Objective

To define somatic variants of parathyroid adenoma (PA) and to provide novel insights into the underlying molecular mechanism of sporadic PA.

Methods

Basic clinical characteristics and biochemical indices of 73 patients with PA were collected. Whole-exome sequencing was performed on matched tumor-constitutional DNA pairs to detect somatic alterations. Functional annotation was carried out by ingenuity pathway analysis afterward. The protein expression of the variant gene was confirmed by immunohistochemistry, and the relationship between genotype and phenotype was analyzed.

Results

Somatic variants were identified in 1549 genes, with an average of 69 variants per tumor (range, 13-2109; total, 9083). Several novel recurrent somatic variants were detected, such as KMT2D (15/73), MUC4 (14/73), POTEH (13/73), CD22 (12/73), HSPA2 (12/73), HCFC1 (11/73), MAGEA1 (11/73), and SLC4A3 (11/73), besides the previously reported PA-related genes, including MEN1 (11/73), CASR (6/73), MTOR (4/73), ASXL3 (3/73), FAT1 (3/73), ZFX (5/73), EZH1 (2/73), POT1 (2/73), and EZH2 (1/73). Among them, KMT2D might be the candidate driver gene of PA. Crucially, 5 patients carried somatic mutations in CDC73, showed an aggressive phenotype similar to that of parathyroid carcinoma (PC), and had a decreased expression of parafibromin. Pathway analysis of recurrent potential PA-associated driver variant genes revealed functional enrichments in the signaling pathway of Notch.

Conclusion

Our study expanded the pathogenic variant spectrum of PA and indicated that KMT2D might be a novel candidate driver gene and be considered as a diagnostic biomarker for PA. Meanwhile, CDC73 mutations might be an early developmental event from PA to PC. The results provided insights into elucidating the pathogenesis of parathyroid tumorigenesis and a certain basis for clinical diagnosis and treatment.
Systemic Activation of the Kynurenine Pathway in Graves Disease With and Without Ophthalmopathy
Authors: Ueland Hans Olav , Ulvik Arve , Løvås Kristian , Wolff Anette S B , Breivik Lars Ertesvåg , Stokland Ann-Elin Meling , Rødahl Eyvind , Nilsen Roy Miodini , Husebye Eystein , Ueland Grethe Åstrøm
Published: January 2023

Context

Graves disease (GD) is one of the most common autoimmune disorders. Recent literature has shown an immune response involving several different inflammatory related proteins in these patients.

Objective

This work aimed to characterize the kynurenine pathway, activated during interferon-γ (IFN-γ)–mediated inflammation and cellular (T-helper type 1 [Th1] type) immunity, in GD patients with and without thyroid eye disease (TED).

Methods

We analyzed 34 biomarkers by mass spectrometry in serum samples from 100 patients with GD (36 with TED) and 100 matched healthy controls. The analytes included 10 metabolites and 3 indices from the kynurenine pathway, 6 microbiota-derived metabolites, 10 B-vitamers, and 5 serum proteins reflecting inflammation and kidney function.

Results

GD patients showed significantly elevated levels of 7 biomarkers compared with healthy controls (omega squared [ω2] > 0.06; P < .01). Of these 7, the 6 biomarkers with the strongest effect size were all components of the kynurenine pathway. Factor analysis showed that biomarkers related to cellular immunity and the Th1 responses (3-hydroxykynurenine, kynurenine, and quinolinic acid with the highest loading) were most strongly associated with GD. Further, a factor mainly reflecting acute phase response (C-reactive protein and serum amyloid A) showed weaker association with GD by factor analysis. There were no differences in biomarker levels between GD patients with and without TED.

Conclusion

This study supports activation of IFN-γ inflammation and Th1 cellular immunity in GD, but also a contribution of acute-phase reactants. Our finding of no difference in systemic activation of the kynurenine pathway in GD patients with and without TED implies that the local Th1 immune response in the orbit is not reflected systemically.
Longitudinal Trajectory and Early Life Determinant of Childhood Adipokines: Findings From a Racially Diverse Birth Cohort
Authors: Makker Kartikeya , Zhang Mingyu , Wang Guoying , Hong Xiumei , Aziz Khyzer , Brady Tammy M , Wang Xiaobin
Published: January 2023

Context

Leptin and adiponectin play important roles in systemic metabolic homeostasis, beginning in utero. Limited data exist on the levels and trajectories of these 2 hormones at birth and in childhood and their biological and social determinants.

Objective

We examined the longitudinal trajectories of leptin and adiponectin from birth to early childhood, along with influential prenatal and infancy factors, and whether the trajectories and risk factors differ by preterm birth status.

Methods

We included mother-infant pairs in the Boston Birth Cohort, a predominantly Black, indigenous, and people of color (BIPOC) study population. We measured infant plasma leptin and adiponectin levels at birth and in early childhood. We examined longitudinal trajectories and the associated prenatal maternal and infancy factors. We analyzed 716 infants (158 preterm) who had leptin and adiponectin measured at birth and in early childhood (mean corrected age 2.18 years [interquartile range, 0.4-10.4]).

Results

Cord leptin was higher in term infants (40 230 vs 20 481 in preterm, P < 0.0001) but childhood leptin did not differ by prematurity (4123 in term vs 4181 in preterm, P = 0.92). Adiponectin was higher in term infants at birth (18 416 vs 11 223, P < 0.0001) and in childhood (12 108 vs 10532, P = 0.04). In stepwise regression, Black race was associated with higher childhood leptin and lower childhood adiponectin. Female sex was associated with higher childhood leptin levels and lower childhood adiponectin levels in multivariable regression models.

Conclusion

Our results highlight preterm status, race, and biological sex as predictors of adipokine trajectory throughout childhood. These findings raise the possibility that early life programming of adipokines may contribute to higher metabolic risk in life, especially among Black children born preterm.
Suppression of Insulin Receptor Substrate 1 Inhibits Breast Cancer Growth In Vitro and in Female Athymic Mice
Authors: Zhang Xihong , Varma Sidhant , Yee Douglas
Published: January 2023

Targeting the type I insulin-like growth factor receptor (IGF-IR) has not been successful in breast cancer. Data suggest the highly homologous insulin receptor (IR) may be an alternate growth stimulatory pathway used by cancer cells. Since both receptors phosphorylate the insulin receptor substrate 1 (IRS-1) protein as an immediate consequence of ligand binding, disruption of both receptors could be accomplished by suppression of IRS-1. IRS-1 gene deletion by CRISPR/Cas9 editing resulted in suppression of IGF-I, insulin, and estrogen-stimulated growth in hormone-dependent MCF-7L breast cancer cells. A doxycycline-inducible IRS-1 shRNA lentiviral construct was also used to infect MCF-7L breast cancer cells. IRS-1 shRNA downregulation resulted in decreased responses to IGF-I, insulin, and estradiol in monolayer and anchorage-independent growth assays. Decreased IRS-1 levels also suppressed estradiol-stimulated gene expression and estrogen receptor binding to DNA. Xenograft growth was also inhibited by induction of IRS-1 shRNA. These data show that IRS-1 is a critical regulator of endocrine responsive breast cancer. Efforts to target this adaptor protein could have broader growth inhibitory effects and receptor targeting.
Bladder Paraganglioma Associated With Succinate Dehydrogenase A Mutation Presenting as Pelvic Pain
Authors: Hehar Gurbir , Rahmon Dalia , Banka Ajaz
Published: January 2023

A 21-year-old female presented to the hospital with acute onset left pelvic pain that began while urinating. Ultrasound of the pelvis revealed a 1.7 cm structure within the bladder wall. Follow-up imaging with magnetic resonance imaging confirmed a 1.9 cm mass in the urinary bladder wall. Cystoscopy with transurethral resection was performed. Histopathology of the obtained tissue confirmed the diagnosis of paraganglioma. Laboratory evaluation revealed evidence of catecholamine excess with elevated urine norepinephrine, urine normetanephrine, and plasma free normetanephrine. Functional imaging with Ga-DOTATATE positron emission tomography-computed tomography (PET-CT) revealed increased uptake in the region of the known mass without findings of metastasis. Genetic testing revealed succinate dehydrogenase A mutation, consistent with paraganglioma syndrome 5. The patient was treated with alpha-adrenergic blockade prior to partial cystectomy. Urinary bladder paraganglioma is a rare entity. The diagnosis requires a high index of clinical suspicion due to variable presentation. Hypertension and other signs of catecholamine excess, especially in relation to micturition, are important clues. Despite evidence of catecholamine excess in most patients with bladder paraganglioma, the majority are diagnosed after biopsy, indicating a need for improved diagnostic strategies in this patient population. Early diagnosis and treatment are essential to prevent potentially lethal cardiac complications and tumor metastasis.
Introduced species in Mediterranean marine caves: an increasing but neglected threat
Authors: GEROVASILEIOU VASILIS , BANCILA RALUCA IOANA , KATSANEVAKIS STELIOS , ZENETOS ARGYRO
Published: January 2023

Marine caves are protected habitats with high biodiversity and low ecological resilience, vulnerable to multiple pressures including biological invasions. Therefore, comprehensive lists of alien species in sea caves and assessments of their impacts are urgently needed. This study aimed to provide an updated and validated list of introduced species in marine caves of the Mediterranean Sea based on the latest available checklist (2014). The number of introduced species in the updated list (December 2022 status) has doubled in the last eight years. The updated checklist includes 126 species (107 alien, 15 cryptogenic, two crypto-expanding, and two questionable) belonging to 12 phyla. The highest number of introduced species in caves was evidenced in the eastern Mediterranean (105), specifically in the Levantine (99) and the Aegean (34) ecoregions. Most introduced species originated from the Indo-Pacific. Most species entered the Mediterranean Sea through the Suez Canal, followed by species transferred via vessels. Most introduced species were found at the entrance and in the semi-dark zone of caves (60 and 52 species, respectively), with only 19 species being reported from the dark zone. Approximately 28% of the introduced species have a high impact on ecosystems, including nine of the ten worst invasive species in the Mediterranean Sea. Despite the lack of data on the impact of introduced species on marine cave biodiversity, given their high species richness and the recently reported population explosions of some alien fish in the eastern Mediterranean, our results highlight the need for continuous inventorying and monitoring.
COMPUTER SIMULATOR GAME IN YOUTH CULTURE
Authors: Kudryashova Elizaveta M. , Lyubimtseva Ekaterina M. , Yushchenko Vera M. , Barinova Sof’ya G.
Published: January 2023

Purpose. The purpose of the study is to determine the place, meaning, perspectives of the computer game simulator “The Sims” in the cultural space of youth, supplemented by a new digital environment, and to establish the reasons for its 20-year success.

Methodology. The main theoretical and methodological approaches to the review of a computer game are systemic and complex. The specifics of the study revealed the need for a cause-and-effect analysis of the studied phenomenon.

Results. The sociocultural aspect of young people involvement in the computer game “The Sims” is primary. The esthetic aspect (graphics, technical characteristics, which have been getting better and worse over for 20 years) is secondary. Namely the experience of attempt “life situations”, building own world, relationships, yourself attracts young players. Gamers see the game as a unique philosophy and values, that they share with the creators of the game, which is a prerequisite for the emergence of a digital cultural community based on a particular game. Given the wide range of players and interest in computer games, it is important to study them in a cultural context, since psychological and other characteristics go by the wayside (a variety of people play computer games, which is not associated with any personal characteristics, for example, introversion, self-doubt).

Practical implications. The results of the study can be applied in philosophy, cultural studies and pedagogy.
THEORY OF BIOHAPPINESS AND GENETIC VIRTUE OF MARK WALKER
Authors: Khvastunova Julia V.
Published: January 2023

Mark Walker, one of the ideologists of modern transhumanism, developed a number of neuroethics provisions for the implementation of the “human enhancement” project. The basic elements of “making happy” are neurovirtues mediated by the introduction of genetic engineering (the creation of “happy-people-pills” (HPP)). The methodological basis or norm for genetic engineering is proposed to use the type of hyperthymic people. In the concept, there is some repetition of the ideas of O. Huxley’s novel “Brave New World”, where residents use soma, have the corrected nature of “genetic virtues”, and are in a state of controlled “ignorance”, happiness, and peace. M. Walker formulates his solution to O. Huxley’s dilemma (the choice between happiness and perfection) through the legalization and improvement of HPP. However, the interpretation of happiness itself is not satisfactory for transhumanists, since it comes down solely to neuroreduction and positive arguments for the use of radical technologies, including the programs which launch irreversible processes.