bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre-hyperglycemia immune cell trafficking underlies subclinical diabetic cataractogenesis
Authors: Ranaei Pirmardan Ehsan , Zhang Yuanlin , Barakat Aliaa , Naseri Marzieh , Russmann Christoph , Hafezi-Moghadam Ali
Published: January 2023

Background

This work elucidates the first cellular and molecular causes of cataractogenesis. Current paradigm presupposes elevated blood glucose as a prerequisite in diabetic cataractogenesis. Novel evidence in our model of diabetic cataract challenges this notion and introduces immune cell migration to the lens and epithelial-mesenchymal transformation (EMT) of lens epithelial cells (LECs) as underlying causes.

Methods

Paucity of suitable animal models has hampered mechanistic studies of diabetic cataract, as most studies were traditionally carried out in acutely induced hyperglycemic animals. We introduced diabetic cataract in the Nile grass rat (NGR) that spontaneously develops type 2 diabetes (T2D) and showed its closeness to the human condition. Specialized stereo microscopy with dual bright-field illumination revealed novel hyperreflective dot-like microlesions in the inner cortical regions of the lens. To study immune cell migration to the lens, we developed a unique in situ microscopy technique of the inner eye globe in combination with immunohistochemistry.

Results

Contrary to the existing paradigm, in about half of the animals, the newly introduced hyper reflective dot-like microlesions preceded hyperglycemia. Even though the animals were normoglycemic, we found significant changes in their oral glucose tolerance test (OGTT), indicative of the prediabetic stage. The microlesions were accompanied with significant immune cell migration from the ciliary bodies to the lens, as revealed in our novel in situ microscopy technique. Immune cells adhered to the lens surface, some traversed the lens capsule, and colocalized with apoptotic nuclei of the lens epithelial cells (LECs). Extracellular degradations, amorphous material accumulations, and changes in E-cadherin expressions showed epithelial-mesenchymal transformation (EMT) in LECs. Subsequently, lens fiber disintegration and cataract progression extended into cortical, posterior, and anterior subcapsular cataracts.

Conclusions

Our results establish a novel role for immune cells in LEC transformation and death. The fact that cataract formation precedes hyperglycemia challenges the prevailing paradigm that glucose initiates or is necessary for initiation of the pathogenesis. Novel evidence shows that molecular and cellular complications of diabetes start during the prediabetic state. These results have foreseeable ramifications for early diagnosis, prevention and development of new treatment strategies in patients with diabetes.
Activation of NLRP3 inflammasome in lung epithelial cells triggers radiation-induced lung injury
Authors: Rao Xinrui , Zhou Dong , Deng Huilin , Chen Yunshang , Wang Jian , Zhou Xiaoshu , Jie Xiaohua , Xu Yingzhuo , Wu Zilong , Wang Geng , Dong Xiaorong , Zhang Sheng , Meng Rui , Wu Chuangyan , Xing Shijie , Fan Kai , Wu Gang , Zhou Rui
Published: January 2023

Background

Radiation-induced lung injury (RILI) is the most common and serious complication of chest radiotherapy. However, reported radioprotective agents usually lead to radiation resistance in tumor cells. The key to solving this problem is to distinguish between the response of tumor cells and normal lung epithelial cells to radiation damage.

Methods

RNA-Seq was used to recognize potential target of alleviating the progression of RILI as well as inhibiting tumor growth. The activation of NLRP3 inflammasome in lung epithelial cells was screened by qRT-PCR, western blotting, immunofluorescence, and ELISA. An in vivo model of RILI and in vitro conditioned culture model were constructed to evaluate the effect of NLRP3/interleukin-1β on fibroblasts activation. ROS, ATP, and (NADP)+/NADP(H) level in lung epithelial cells was detected to explore the mechanism of NLRP3 inflammasome activation. The lung macrophages of the mice were deleted to evaluate the role of lung epithelial cells in RILI. Moreover, primary cells were extracted to validate the results obtained from cell lines.

Results

NLRP3 activation in epithelial cells after radiation depends on glycolysis-related reactive oxygen species accumulation. DPYSL4 is activated and acts as a negative regulator of this process. The NLRP3 inflammasome triggers interleukin-1β secretion, which directly affects fibroblast activation, proliferation, and migration, eventually leading to lung fibrosis.

Conclusions

Our study suggests that NLRP3 inflammasome activation in lung epithelial cells is essential for radiation-induced lung injury. These data strongly indicate that targeting NLRP3 may be effective in reducing radiation-induced lung injury in clinical settings.
The real-world safety profile of sodium-glucose co-transporter-2 inhibitors among older adults (≥ 75 years): a retrospective, pharmacovigilance study
Authors: Goldman Adam , Fishman Boris , Twig Gilad , Raschi Emanuel , Cukierman-Yaffe Tali , moshkovits Yonatan , Pomerantz Alon , Ben-Zvi Ilan , Dankner Rachel , Maor Elad
Published: January 2023

Background

As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults.

Methods

A retrospective, pharmacovigilance study of the FDA’s global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (< 75 years) and older adults (≥ 75), we performed a disproportionality analysis using the sex-adjusted reporting odds ratio (adj.ROR).

Results

We identified safety reports of 129,795 patients who received non-insulin anti-diabetic drugs (NIAD), including 24,253 who were treated with SGLT2i (median age 60 [IQR: 51–68] years, 2,339 [9.6%] aged ≥ 75 years). Compared to other NIAD, SGLT2i were significantly associated with amputations (adj.ROR = 355.1 [95%CI: 258.8 − 487.3] vs adj.ROR = 250.2 [79.3 − 789.5]), Fournier gangrene (adj.ROR = 45.0 [34.5 − 58.8] vs adj.ROR = 88.0 [27.0 − 286.6]), diabetic ketoacidosis (adj.ROR = 32.3 [30.0 − 34.8] vs adj.ROR = 23.3 [19.2 − 28.3]), genitourinary infections (adj.ROR = 10.3 [9.4 − 11.2] vs adj.ROR = 8.6 [7.2 − 10.3]), nocturia (adj.ROR = 5.5 [3.7 − 8.2] vs adj.ROR = 6.7 [2.8 − 15.7]), dehydration (adj.ROR = 2.5 [2.3 − 2.8] vs adj.ROR = 2.6 [2.1 − 3.3]), and fractures (adj.ROR = 1.7 [1.4 − 2.1] vs adj.ROR = 1.5 [1.02 − 2.1]) in both adults and older adults, respectively. None of these safety signals was significantly greater in older adults (Pinteractionthreshold of 0.05). Acute kidney injury was associated with SGLT2i in adults (adj.ROR = 1.97 [1.85 − 2.09]) but not in older adults (adj.ROR = 0.71 [0.59 − 0.84]). Falls, hypotension, and syncope were not associated with SGLT2i among either adults or older adults.

Conclusion

In this global post-marketing study, none of the adverse events was reported more frequently among older adults. Our findings provide reassurance regarding SGLT2i treatment in older adults, although careful monitoring is warranted.
Prenatal exposure to ambient air pollution is associated with neurodevelopmental outcomes at 2 years of age
Authors: Morgan Zachariah E. M. , Bailey Maximilian J. , Trifonova Diana I. , Naik Noopur C. , Patterson William B. , Lurmann Frederick W. , Chang Howard H. , Peterson Bradley S. , Goran Michael I. , Alderete Tanya L.
Published: January 2023

Background

Higher prenatal ambient air pollution exposure has been associated with impaired neurodevelopment in preschoolers and school-aged children. The purpose of this study was to explore the relationships between prenatal ambient air pollution exposure and neurodevelopment during infancy.

Methods

This study examined 161 Latino mother-infant pairs from the Southern California Mother’s Milk Study. Exposure assessments included prenatal nitrogen dioxide (NO2) and particulate matter smaller than 2.5 and 10 microns in diameter (PM2.5 and PM10, respectively). The pregnancy period was also examined as three windows, early, mid, and late, which describe the first, middle, and last three months of pregnancy. Infant neurodevelopmental outcomes at 2 years of age were measured using the Bayley-III Scales of Infant and Toddler Development. Multivariable linear models and distributed lag linear models (DLM) were used to examine relationships between prenatal exposures and neurodevelopmental scores, adjusting for socioeconomic status, breastfeeding frequency, time of delivery, pre-pregnancy body mass index, and infant birthweight and sex.

Results

Higher prenatal exposure to PM10 and PM2.5 was negatively associated with composite cognitive score (β = -2.01 [-3.89, -0.13] and β = -1.97 [-3.83, -0.10], respectively). In addition, higher average prenatal exposure to PM10 was negatively associated with composite motor (β = -2.35 [-3.95, -0.74]), scaled motor (β = -0.77 [-1.30, -0.24]), gross motor (β = -0.37 [-0.70, -0.04]), fine motor (β = -0.40 [-0.71, -0.09]), composite language (β = -1.87 [-3.52, -0.22]), scaled language (β = -0.61 [-1.18, -0.05]) and expressive communication scaled scores (β = -0.36 [-0.66, -0.05]). DLMs showed that higher prenatal air pollution exposure during mid and late pregnancy was inversely associated with motor, cognitive, and communication language scores.

Conclusions

Higher exposure to air pollutants during pregnancy, particularly in the mid and late prenatal periods, was inversely associated with scaled and composite motor, cognitive, and language scores at 2 years. These results indicate that prenatal ambient air pollution may negatively impact neurodevelopment in early life.
Molecular differences of angiogenic versus vessel co-opting colorectal cancer liver metastases at single-cell resolution
Authors: Fleischer Johannes Robert , Schmitt Alexandra Maria , Haas Gwendolyn , Xu Xingbo , Zeisberg Elisabeth Maria , Bohnenberger Hanibal , Küffer Stefan , Teuwen Laure-Anne , Karras Philipp Johannes , Beißbarth Tim , Bleckmann Annalen , Planque Mélanie , Fendt Sarah-Maria , Vermeulen Peter , Ghadimi Michael , Kalucka Joanna , De Oliveira Tiago , Conradi Lena-Christin
Published: January 2023

Background

Colorectal cancer liver metastases (CRCLM) are associated with a poor prognosis, reflected by a five-year survival rate of 14%. Anti-angiogenic therapy through anti-VEGF antibody administration is one of the limited therapies available. However, only a subgroup of metastases uses sprouting angiogenesis to secure their nutrients and oxygen supply, while others rely on vessel co-option (VCO). The distinct mode of vascularization is reflected by specific histopathological growth patterns (HGPs), which have proven prognostic and predictive significance. Nevertheless, their molecular mechanisms are poorly understood.

Methods

We evaluated CRCLM from 225 patients regarding their HGP and clinical data. Moreover, we performed spatial (21,804 spots) and single-cell (22,419 cells) RNA sequencing analyses to explore molecular differences in detail, further validated in vitro through immunohistochemical analysis and patient-derived organoid cultures.

Results

We detected specific metabolic alterations and a signature of WNT signalling activation in metastatic cancer cells related to the VCO phenotype. Importantly, in the corresponding healthy liver of CRCLM displaying sprouting angiogenesis, we identified a predominantly expressed capillary subtype of endothelial cells, which could be further explored as a possible predictor for HGP relying on sprouting angiogenesis.

Conclusion

These findings may prove to be novel therapeutic targets to the treatment of CRCLM, in special the ones relying on VCO.
North Carolina pharmacists’ willingness to sell fentanyl test strips: a survey study
Authors: Marley Grace T. , Ostrach Bayla , Carpenter Delesha
Published: January 2023

Background

Although fentanyl test strips (FTS) can accurately determine the presence of fentanyl in unregulated substances, access to FTS remains limited. This study aimed to examine North Carolina community pharmacists’ attitudes and willingness to engage in various behaviors related to FTS sales and distribution.

Methods

A convenience sample of community pharmacists completed an online survey that assessed: (1) comfort initiating an FTS conversation; (2) willingness to sell FTS, distribute FTS instructions, counsel on FTS, refer patients to harm reduction organizations, and advertise FTS; (3) perceived barriers and benefits of selling FTS; and (4) interest in FTS training. Data were collected from March to May 2022. Descriptive statistics were calculated.

Results

Of the 592 pharmacists who participated, most were somewhat or very willing to refer patients to harm reduction organizations for FTS (514, 86.9%), counsel on FTS (485, 81.9%), distribute FTS instructions (475, 80.2%), sell FTS (470, 79.3%), and advertise FTS for sale (372, 62.9%). The most commonly reported benefits of selling FTS were reducing overdose deaths in the community (n = 482, 81.4%) and participating in community harm reduction efforts (n = 455; 76.9%). Barriers commonly reported to selling FTS were: not knowing where to order FTS (n = 295, 49.8%) and discomfort initiating a conversation about FTS (n = 266, 44.9%). Most respondents (88.3%) were interested in FTS training.

Conclusion

North Carolina community pharmacists are willing to engage in various behaviors related to FTS sales and distribution. Most pharmacists were interested in receiving FTS training, which should be created to address pharmacist-reported barriers to FTS sales. Pharmacist distribution of FTS could increase access to FTS at the community level and has the potential to change drug use behavior and reduce overdose deaths.
Interpersonal violence and recurrent headache among adolescents with a history of psychiatric problems
Authors: Greger Hanne Klæboe , Kristianslund Sara Konstanse , Stensland Synne Øien
Published: January 2023

Background

Interpersonal violence (IPV) is found to be associated with mental health problems and pain disorders such as headache among children and adolescents. It is well-known that adolescents in need of mental health services have experienced IPV more often than adolescents in the general population. However, there has not been much focus on pain conditions in child and adolescent psychiatric populations.

Methods

Data from the current study are based on a 3-year follow-up of the CAP-survey, which is a study of adolescents in the child and adolescent psychiatric unit population of St. Olavs Hospital (Trondheim University Hospital). The baseline study was conducted between 2009 and 2011, with 717 participants between 13 and 18 years. All participants were enrolled, or newly referred to the child and adolescent psychiatric clinic. At follow-up, 570 participants completed questionnaire, and 550 completed a diagnostic interview. The participants were aged 16–21 years (mean age 18.6 years).

Results

A third of the adolescents reported frequent headaches (weekly or daily). Adolescents with more severe mental problems were more likely to experience frequent headaches. Adolescents exposed to unpleasant sexual acts or bullying, reported more frequent headaches than non-exposed participants. Participants exposed to three or more types of IPV seemed to be at particularly high risk of experiencing frequent headache.

Conclusions

Both experiences of interpersonal violence and headache are common in this clinical psychiatric population. Clinicians should assess for headache disorders in addition to psychiatric and trauma assessment and provide need-based treatment to enhance chance of recovery among adolescents in mental health services.
Association between COVID-19 risk-mitigation behaviors and specific mental disorders in youth
Authors: Conway Kevin P. , Bhardwaj Kriti , Michel Emmanuella , Paksarian Diana , Nikolaidis Aki , Kang Minji , Merikangas Kathleen R. , Milham Michael P.
Published: January 2023

Background

Although studies of adults show that pre-existing mental disorders increase risk for COVID-19 infection and severity, there is limited information about this association among youth. Mental disorders in general as well as specific types of disorders may influence the ability to comply with risk-mitigation strategies to reduce COVID-19 infection and transmission.

Methods

Youth compliance (rated as “Never,” “Sometimes,” “Often,” or “Very often/Always”) with risk mitigation was reported by parents on the CoRonavIruS Health Impact Survey (CRISIS) in January 2021. The sample comprised 314 female and 514 male participants from the large-scale Child Mind Institute Healthy Brain Network, a transdiagnostic self-referred, community sample of children and adolescents (ages 5–21). Responses were summarized using factor analysis of risk mitigation, and their associations with lifetime mental disorders (assessed via structured diagnostic interviews) were identified with linear regression analyses (adjusted for covariates). All analyses used R Project for Statistical Computing for Mac (v.4.0.5).

Results

A two-factor model was the best-fitting solution. Factor 1 (avoidance behaviors) included avoiding groups, indoor settings, and other peoples’ homes; avoidance scores were higher among youth with any anxiety disorder (p = .01). Factor 2 (hygiene behaviors) included using hand sanitizer, washing hands, and maintaining social distance; hygiene scores were lower among youth with ADHD (combined type) (p = .02). Mask wearing was common (90%), did not load on either factor, and was not associated with any mental health disorder.

Conclusion and relevance

Although most mental disorders examined were not associated with risk mitigation, youth with ADHD characterized by hyperactivity plus inattention may need additional support to consistently engage in risk-mitigation behaviors. Enhancing risk-mitigation strategies among at-risk groups of youth may help reduce COVID-19 infection and transmission.
LARP6 suppresses colorectal cancer progression through ZNF267/SGMS2-mediated imbalance of sphingomyelin synthesis
Authors: Long Xiaoli , Liu Xunhua , Deng Ting , Chen Jianxiong , Lan Jiawen , Zhang Sijing , Zhou Miao , Guo Dan , Zhou Jun
Published: January 2023

Background

With increasing incidence and mortality, colorectal cancer (CRC) seriously endangers human health.LARP6, a member of La-related protein (LARP) family, is a RNA binding protein and probably associates with CRC progression, but its specific roles and mechanisms in CRC still remain unknown.

Method

Quantitative real-time PCR (qPCR), western blot, and immunohistochemistry were employed to examine LARP6 expression in CRC tissues. Using the stableLARP6overexpression or interference CRC cell lines, the effect of LARP6 on CRC progression were evaluated. High-throughput RNA immunoprecipitation sequencing (RIP-seq) and a series of relevant experiments were conducted to explain how LARP6 functions. SPSS software was used for statistical analysis.

Result

In this study, we found thatLARP6expression is downregulated in CRC and correlates with patients’ overall survival and relapse-free survival. Furthermore, altered LARP6 expression influences CRC cells invasion and metastasis. Mechanically, we discovered that LARP6 bindZNF267mRNA and regulated its stability and translation. LARP6 inhibited expression ofSGMS2, a downstream target of ZNF267, resulting in ceramide and sphingomyelin imbalance in CRC cells. Interestingly, LARP6 also enhances autophagy activity of CRC cells, and the effect was at least partially determined by the inhibition of SGMS2-mediated sphingomyelin synthesis.

Conclusion

Our study showed howLARP6/ZNF267/SGMS2axis influence CRC progression, which contributes to further understanding of the molecular mechanisms underlying CRC development.
Implementing deep learning models for the classification of Echinococcus multilocularis infection in human liver tissue
Authors: Sulyok Mihaly , Luibrand Julia , Strohäker Jens , Karacsonyi Peter , Frauenfeld Leonie , Makky Ahmad , Mattern Sven , Zhao Jing , Nadalin Silvio , Fend Falko , Schürch Christian M.
Published: January 2023

Background

The histological diagnosis of alveolar echinococcosis can be challenging. Decision support models based on deep learning (DL) are increasingly used to aid pathologists, but data on the histology of tissue-invasive parasitic infections are missing. The aim of this study was to implement DL methods to classify Echinococcus multilocularis liver lesions and normal liver tissue and assess which regions and structures play the most important role in classification decisions.

Methods

We extracted 15,756 echinococcus tiles from 28 patients using 59 whole slide images (WSI); 11,602 tiles of normal liver parenchyma from 18 patients using 33 WSI served as a control group. Different pretrained model architectures were used with a 60–20–20% random splitting. We visualized the predictions using probability-thresholded heat maps of WSI. The area-under-the-curve (AUC) value and other performance metrics were calculated. The GradCAM method was used to calculate and visualize important spatial features.

Results

The models achieved a high validation and test set accuracy. The calculated AUC values were 1.0 in all models. Pericystic fibrosis and necrotic areas, as well as germinative and laminated layers of the metacestodes played an important role in decision tasks according to the superimposed GradCAM heatmaps.

Conclusion

Deep learning models achieved a high predictive performance in classifying E. multilocularis liver lesions. A possible next step could be to validate the model using other datasets and test it against other pathologic entities as well, such as, for example, Echinococcus granulosus infection.

Graphical Abstract
Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations
Authors: Xin Junyi , Du Mulong , Gu Dongying , Jiang Kewei , Wang Mengyun , Jin Mingjuan , Hu Yeting , Ben Shuai , Chen Silu , Shao Wei , Li Shuwei , Chu Haiyan , Zhu Linjun , Li Chen , Chen Kun , Ding Kefeng , Zhang Zhengdong , Shen Hongbing , Wang Meilin
Published: January 2023

Background

The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations.

Methods

A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle.

Results

In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10−8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10−53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk.

Conclusions

In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.
Generalizable transfer learning of automated tumor segmentation from cervical cancers toward a universal model for uterine malignancies in diffusion-weighted MRI
Authors: Lin Yu-Chun , Lin Yenpo , Huang Yen-Ling , Ho Chih-Yi , Chiang Hsin-Ju , Lu Hsin-Ying , Wang Chun-Chieh , Wang Jiun-Jie , Ng Shu-Hang , Lai Chyong-Huey , Lin Gigin
Published: January 2023

Purpose

To investigate the generalizability of transfer learning (TL) of automated tumor segmentation from cervical cancers toward a universal model for cervical and uterine malignancies in diffusion-weighted magnetic resonance imaging (DWI).

Methods

In this retrospective multicenter study, we analyzed pelvic DWI data from 169 and 320 patients with cervical and uterine malignancies and divided them into the training (144 and 256) and testing (25 and 64) datasets, respectively. A pretrained model was established using DeepLab V3 + from the cervical cancer dataset, followed by TL experiments adjusting the training data sizes and fine-tuning layers. The model performance was evaluated using the dice similarity coefficient (DSC).

Results

In predicting tumor segmentation for all cervical and uterine malignancies, TL models improved the DSCs from the pretrained cervical model (DSC 0.43) when adding 5, 13, 26, and 51 uterine cases for training (DSC improved from 0.57, 0.62, 0.68, 0.70, p < 0.001). Following the crossover at adding 128 cases (DSC 0.71), the model trained by combining data from adding all the 256 patients exhibited the highest DSCs for the combined cervical and uterine datasets (DSC 0.81) and cervical only dataset (DSC 0.91).

Conclusions

TL may improve the generalizability of automated tumor segmentation of DWI from a specific cancer type toward multiple types of uterine malignancies especially in limited case numbers.
Transfer of mesenchymal stem cell mitochondria to CD4+ T cells contributes to repress Th1 differentiation by downregulating T-bet expression
Authors: Akhter Waseem , Nakhle Jean , Vaillant Loïc , Garcin Geneviève , Le Saout Cécile , Simon Matthieu , Crozet Carole , Djouad Farida , Jorgensen Christian , Vignais Marie-Luce , Hernandez Javier
Published: January 2023

Background

Mesenchymal stem/stromal cells (MSCs) are multipotent cells with strong tissue repair and immunomodulatory properties. Due to their ability to repress pathogenic immune responses, and in particular T cell responses, they show therapeutic potential for the treatment of autoimmune diseases, organ rejection and graft versus host disease. MSCs have the remarkable ability to export their own mitochondria to neighboring cells in response to injury and inflammation. However, whether mitochondrial transfer occurs and has any role in the repression of CD4+ Th1 responses is unknown.

Methods and results

In this report we have utilized CD4+ T cells from HNT TCR transgenic mice that develop Th1-like responses upon antigenic stimulation in vitro and in vivo. Allogeneic bone marrow-derived MSCs reduced the diabetogenic potential of HNT CD4+ T cells in vivo in a transgenic mouse model of disease. In co-culture experiments, we have shown that MSCs were able to reduce HNT CD4+ T cell expansion, expression of key effector markers and production of the effector cytokine IFNγ after activation. This was associated with the ability of CD4+ T cells to acquire mitochondria from MSCs as evidenced by FACS and confocal microscopy. Remarkably, transfer of isolated MSC mitochondria to CD4+ T cells resulted in decreased T cell proliferation and IFNγ production. These effects were additive with those of prostaglandin E2 secreted by MSCs. Finally, we demonstrated that both co-culture with MSCs and transfer of isolated MSC mitochondria prevent the upregulation of T-bet, the master Th1 transcription factor, on activated CD4+ T cells.

Conclusion

The present study demonstrates that transfer of MSC mitochondria to activated CD4+ T cells results in the suppression of Th1 responses in part by downregulating T-bet expression. Furthermore, our studies suggest that MSC mitochondrial transfer might represent a general mechanism of MSC-dependent immunosuppression.
Politics of reproduction: a view from Israel on the Dobbs decision
Authors: Shalev Carmel
Published: January 2023

Background

This opinion piece looks at the recent decision of the United States Supreme Court in Dobbs v. Jackson Women's Health Organization and then compares the law on abortion in the USA to the law in Israel on reproductive medicine in general.

The Dobbs decision validated a Mississippi state law that restricted access to abortion, while overruling the landmark precedent of Roe v. Wade on women's constitutional right to safe abortion. It declared that the US constitution does not confer upon women any right to abortion, whether pre- or post-viability, sending shockwaves throughout the world. It also had an immediate effect on women's reproductive health in the US.

Main body

Women's right to reproductive freedom and to make decisions about their lives and their bodies is key to their hard-won equality. Still, abortion remains in ongoing controversy worldwide with legal barriers that impact upon the most vulnerable. In Israel, abortion is relatively available, accessible, affordable, and acceptable, in both law and practice. This is because of the lenient and nuanced stance of rabbinical authorities in the Jewish law tradition. This stance, together with Israel's post-Holocaust biblical culture of "be fruitful and multiply", also underlies its high rates of medically assisted reproduction for the treatment of infertility, including preimplantation genetic diagnosis of fertilized eggs. Women's bodies mediate all these repro-genetic technologies, in most cases for the benefit of others, not because of their own health needs. There is also concern about global practices and market forces that objectify women's bodies, exploit women and are harmful to their health, wellbeing, and dignity, carrying on outdated patriarchal patterns.

Conclusion

Reproductive health policy ought to be based on an ethic of care and responsibility first and foremost for the women, as well as the children they choose to bring to life, in the spirit of the Jewish tradition that her life is of greater value than the fetus'. Women deserve control of their bodies and their lives and respect for the choices they make to the best of their judgment, which when it comes to abortion are mostly hard ones. They have a right to reproductive choice, freedom, autonomy, and dignity.

The views expressed in this perspective are those of the author.
Assessing social competence and antisocial behaviors in children: item response theory analysis of the home and community social behavior scales
Authors: Hukkelberg Silje Sommer , Andersson Björn
Published: January 2023

Background

The Home and Community Social Behavior Scales (HCSBS) is a rating scale that assesses social competence and antisocial behavior among children and youths between ages 5–18. The present study aimed to investigate the psychometric properties of the HCSBS by applying item response theory (IRT).

Methods

The HCSBS was completed by parents of 551 Norwegian children refereed to three independent interventions towards problem behaviors. Data used in this study was collected before the interventions started. IRT was carried out in R version 4.0.0 to investigate HCSBS items, subscales and main scales.

Results

The results showed that the two-dimensional IRT models for social competence and antisocial behavior were the most appropriate. The measurement precision of the scales was high for a large range of the latent spectrum, and estimated reliabilities were satisfactory. Model evaluations indicated that the overall model fit for the scales were acceptable, but some misfit existed with respect to specific item pairs.

Conclusion

The results indicate that the HCSBS is a reliable measurement instrument although there is still a potential for improvement by revising some of the items.
Virtual cleaning of works of art using a deep generative network: spectral reflectance estimation
Authors: Maali Amiri Morteza , Messinger David W.
Published: January 2023

Generally applied to a painting for protection purposes, a varnish layer becomes yellow over time, making the painting undergo an appearance change. Upon this change, the conservators start a process that entails removing the old layer of varnish and applying a new one. As widely discussed in the literature, helping the conservators through supplying them with the probable outcome of the varnish removal can be of great value to them, aiding in the decision making process regarding varnish removal. This help can be realized through virtual cleaning, which in simple terms, refers to simulation of the cleaning process outcome. There have been different approaches devised to tackle the problem of virtual cleaning, each of which tries to develop a method that virtually cleans the artwork in a more accurate manner. Although successful in some senses, the majority of them do not possess a high level of accuracy. Prior approaches suffer from a range of shortcomings such as a reliance on identifying locations of specific colors on the painting, the need to access a large set of training data, or their lack of applicability to a wide range of paintings. In this work, we develop a Deep Generative Network to virtually clean the artwork. Using this method, only a small area of the painting needs to be physically cleaned prior to virtual cleaning. Using the cleaned and uncleaned versions of this small area, the entire unvarnished painting can be estimated. It should be noted that this estimation is performed in the spectral reflectance domain and herein it is applied to hyperspectral imagery of the work. The model is first applied to a Macbeth ColorChecker target (as a proof of concept) and then to real data of a small impressionist panel by Georges Seurat (known as ‘Haymakers at Montfermeil’ or just ‘Haymakers’). The Macbeth ColorChecker is simulated in both varnished and unvarnished forms, but in the case of the ‘Haymakers’, we have real hyperspectral imagery belonging to both states. The results of applying the Deep Generative Network show that the proposed method has done a better job virtually cleaning the artwork compared to a physics-based method in the literature. The results are presented through visualization in the sRGB color space and also by computing Euclidean distance and spectral angle (calculated in the spectral reflectance domain) between the virtually cleaned artwork and the physically cleaned one. The ultimate goal of our virtual cleaning algorithm is to enable pigment mapping and identification after virtual cleaning of the artwork in a more accurate manner, even before the process of physical cleaning.
Living on the edge: morphological, karyological and genetic diversity studies of the Hungarian Plantago maxima populations and established ex situ collection
Authors: Kovács Zsófia , Mlinarec Jelena , Höhn Mária
Published: January 2023

Background

The analysis of genetic diversity of protected plant species can greatly support conservation efforts.Plantago maximaJuss. ex Jacq. is a perennial species distributed along the Eurasian steppe. The westernmost range edge of the species’ distribution is located in the Pannonian basin, in Hungary where it is represented by a few, fragmented and highly endangered populations. We studied population diversity of all Hungarian range edge, natural populations, and one established ex situ population. One population from the centre of distribution (Kazakhstan) was implemented in the cpDNA haplotype study to compare the peripheral vs. central populations. We performed morphometric trait-based analysis, chromosome studies (morphometric analyses and FISH) and genetic diversity evaluations using inter simple sequence repeats (ISSR) and cpDNA trnL-trnF to evaluate differences between the in situ and ex situ populations as well as central vs. peripheral populations.

Results

Our results showed no obvious morphological differences among the in situ and ex situ populations in the period between 2018 and 2020. One ex situ subpopulation develops flowers three years in a row from 2019, which is a favourable indicator of the introduction success. Hungarian populations are exclusively diploids (2n = 2x = 12). The karyogram consists of 5 metacentric and 1 acrocentric chromosome pair.Plantago maximahas one 35S and two 5S rDNA loci, located on the acrocentric chromosome pair. Eight variable ISSR primers yielded 100 fragments, of which 74.6% were polymorphic (mean He = 0.220). A high level of genetic variation within population was observed (92%) while the genetic differentiation among the populations was only 8%. STRUCTURE analysis revealed that the largest Kunpeszér population separated from the rest of the Hungarian populations, indicating a high rate of admixture among the other ones. Based on the trnL-trnF sequence analysis the Hungarian populations represent a single haplotype, which can indicate a reduced diversity due to isolation and recent population decline. By contrast, Kazakh population represents a distinct haplotype compared to the Hungarian samples.

Conclusions

The present study draws the attention to the high conservation value of thePlantago maximapopulations from the westernmost range edge of the species’ distribution.
Doctoral advisor selection processes in science, math, and engineering programs in the United States
Authors: Artiles Mayra S. , Knight David B. , Matusovich Holly M.
Published: January 2023

Although advising relationships are key for doctoral student success, little research has addressed how they form. Understanding the formation of advising relationships can help contextualize their later development and ultimately support a student’s decision to persist in the doctorate. To understand relationship formation, the purpose of this qualitative study is to identify and describe the types of advisor–advisee selection processes that exist in engineering, science, and math doctoral programs and examine patterns across disciplines within those fields. We conducted interviews with doctoral program directors and engaged in document analysis of graduate student handbooks from 55 doctoral programs in the aforementioned fields in high research institutions across the United States. Using principal–agent theory as a theoretical lens, our findings showed that engineering programs tend to decentralize the advisor selection process by funding students across different funding sources upon enrollment. Contrariwise, science and math programs tended to fund all students in a cohort from a common funding source, which allowed students to have more time to gather information, meet, and select an advisor. These findings also show important nuances when comparing graduate education in these programs that directly impact the doctoral student experience and reiterates the necessity to study these fields separately.
Conscious connected breathing with breath retention intervention in adults with chronic low back pain: protocol for a randomized controlled pilot study
Authors: Pratscher Steven D. , Sibille Kimberly T. , Fillingim Roger B.
Published: January 2023

Background

Chronic pain is a major source of human suffering, and chronic low back pain (cLBP) is among the most prevalent, costly, and disabling of pain conditions. Due to the significant personal and societal burden and the complex and recurring nature of cLBP, self-management approaches that can be practiced at home are highly relevant to develop and test. The respiratory system is one of the most integrated systems of the body, and breathing is bidirectionally related with stress, emotion, and pain. Thus, the widespread physiological and psychological impact of breathing practices and breathwork interventions hold substantial promise as possible self-management strategies for chronic pain. The primary aim of the current randomized pilot study is to test the feasibility and acceptability of a conscious connected breathing with breath retention intervention compared to a sham control condition.

Methods

The rationale and procedures for testing a 5-day conscious connected breathing with breath retention intervention, compared to a deep breathing sham control intervention, in 24 adults (18–65 years) with cLBP is described. Both interventions will be delivered using standardized audio recordings and practiced over 5 days (two times in-person and three times at-home), and both are described as Breathing and Attention Training to reduce possible expectancy and placebo effects common in pain research. The primary outcomes for this study are feasibility and acceptability. Feasibility will be evaluated by determining rates of participant recruitment, adherence, retention, and study assessment completion, and acceptability will be evaluated by assessing participants’ satisfaction and helpfulness of the intervention. We will also measure other clinical pain, psychological, behavioral, and physiological variables that are planned to be included in a follow-up randomized controlled trial.

Discussion

This will be the first study to examine the effects of a conscious connected breathing with breath retention intervention for individuals with chronic pain. The successful completion of this smaller-scale pilot study will provide data regarding the feasibility and acceptability to conduct a subsequent trial testing the efficacy of this breathing self-management practice for adults with cLBP.

Trial registration

Clinicaltrials.gov, identifierNCT04740710. Registered on 5 February 2021.
Can mHealth bridge the digital divide in rheumatic and musculoskeletal conditions?
Authors: Schreurs L. , Steenhout I. , Bosmans J. , Buyl R. , De Cock D.
Published: January 2023

Background

The impact of rheumatic and musculoskeletal diseases is significant worldwide. Progress in disease management has put current care models under pressure. Mobile Health solutions may constitute a solution for these changes. However, vulnerable populations groups including people with a migration or ethnic background different from the host country, people with low socio-economic status and people with low (digital) literacy skills seem to be underrepresented in mHealth research and practice.

Main body

In this editorial, we propose tailored interventions with mobile health applications on three levels including patient-related strategies, healthcare provider-related strategies and healthcare system-related strategies to solve this unmet need for patients from vulnerable populations groups with rheumatic and musculoskeletal diseases. Patient-related mobile health strategies should focus on increasing self-efficacy and enabling peer-education. Gamification could be a solution to motivate patients to use mobile health. On the level of the healthcare provider, we propose strategies including technology-enhanced learning and adaptative communication strategies, to tailor mobile health towards vulnerable populations groups with rheumatic and musculoskeletal diseases. Regarding healthcare system-related strategies, the aim is to increase minority participation in research in a cost-effective manner by remote longitudinal data tracking, using teleconsultation or remote symptom monitoring devices to ensure quality care for all patients with rheumatic and musculoskeletal diseases, even in vulnerable populations groups that are normally hard to reach.

Conclusion

Vulnerable population groups in rheumatic and musculoskeletal diseases are underrepresented in mobile health research and practice. Evidence is sparce on the scale of the digital divide between patients using or not using mobile health. Interventions that directly attempt to reduce health disparities among vulnerable populations groups are needed to guarantee all patients with rheumatic and musculoskeletal diseases might be engaged in the rheumatology care of the future.
Association between polypharmacy and depression relapse in individuals with comorbid depression and type 2 diabetes: a UK electronic health record study
Authors: Jeffery Annie , Bhanu Cini , Walters Kate , Wong Ian C. K. , Osborn David , Hayes Joseph F.
Published: January 2023

Background

Individuals with physical comorbidities and polypharmacy may be at higher risk of depression relapse, however, they are not included in the ‘high risk of relapse’ group for whom longer antidepressant treatment durations are recommended.

Aims

In individuals with comorbid depression and type 2 diabetes (T2DM), we aimed to investigate the association and interaction between depression relapse and (a) polypharmacy, (b) previous duration of antidepressant treatment.

Method

This was a cohort study using primary care data from the UK Clinical Practice Research Datalink (CPRD) from years 2000 to 2018. We used Cox regression models with penalised B-splines to describe the association between restarting antidepressants and our two exposures.

Results

We identified 48 001 individuals with comorbid depression and T2DM, who started and discontinued antidepressant treatment during follow-up. Within 1 year of antidepressant discontinuation, 35% of participants restarted treatment indicating depression relapse. As polypharmacy increased, the rate of restarting antidepressants increased until a maximum of 18 concurrent medications, where individuals were more than twice as likely to restart antidepressants (hazard ratio (HR) = 2.15, 95% CI 1.32–3.51). As the duration of previous antidepressant treatment increased, the rate of restarting antidepressants increased – individuals with a previous duration of ≥25 months were more than twice as likely to restart antidepressants than those who previously discontinued in <7 months (HR = 2.36, 95% CI 2.25–2.48). We found no interaction between polypharmacy and previous antidepressant duration.

Conclusions

Polypharmacy and longer durations of previous antidepressant treatment may be associated with depression relapse following the discontinuation of antidepressant treatment.