bluuebunny/crossref_metadata_2025 huggingface dataset:
The ERK2 DBP domain opposes pathogenesis of a JAK2V617F-driven myeloproliferative neoplasm
Authors: Zhang Yong , Truong Billy , Fahl Shawn P , Martinez Esteban , Cai Kathy , Dulaimi Essel , Gong Yulan , Liebermann Dan A. , Soboloff Jonathan , Dunbrack Roland , Levine Ross L. , Fletcher Steven , Kappes Dietmar J. , Sykes Stephen , Shapiro Paul , Wiest David L
Published: April 2022

While Ras/mitogen-activated protein kinase (MAPK) signaling is activated in most human cancers, attempts to target this pathway using kinase active site inhibitors have not typically led to durable, clinical benefit. To address this shortcoming, we sought to test the feasibility of an alternative targeting strategy, focused on the ERK2 substrate binding domains, D and DBP. We found that disabling the ERK2-DBP domain in mice caused baseline erythrocytosis. Consequently, we investigated the role of the ERK2-D and -DBP domains in disease, using a JAK2-dependent model of polycythemia vera (PV). Importantly, inactivation of the ERK2-DBP domain promoted the progression of disease from PV to myelofibrosis (MF), suggesting that the ERK2-DBP domain normally opposes progression. ERK2-DBP inactivation also prevented oncogenic JAK2 kinase (JAK2V617F) from promoting oncogene-induced senescence (OIS) in vitro. The ERK2-DBP mutation attenuated JAK2-mediated OIS by preventing the physical interaction of ERK2 with the transcription factor, Egr1. Because inactivation of the ERK2-DBP created a functional ERK2 kinase limited to binding substrates through its D-domain, these data suggested that the D-domain substrates were responsible for promoting oncogene-induced progenitor growth and tumor progression, and that pharmacologic targeting of the ERK2-D domain might attenuate cancer cell growth. Indeed, pharmacologic agents targeting the ERK2-D domain were effective in attenuating the growth of JAK2-dependent myeloproliferative neoplasm cell lines. Taken together, these data indicate that the ERK-D and -DBP domains can play distinct roles in the progression of neoplasms and that the D-domain has the potential to be potent therapeutic target in Ras/MAPK dependent cancers.
Measuring dose-related efficacy of eptinezumab for migraine prevention: post hoc analysis of PROMISE-1 and PROMISE-2
Authors: Apelian Rami , Boyle Lee , Hirman Joe , Asher Divya
Published: April 2022

Background

Eptinezumab 100 mg and 300 mg met the primary efficacy endpoint in both PROMISE clinical trials, significantly reducing frequency of monthly migraine days over Weeks 1‒12. The objective of this analysis was to assess the clinical response to eptinezumab 100 mg and 300 mg within the pivotal phase 3 PROMISE-1 and PROMISE-2 studies to potentially identify subsets of patients with meaningful differences between doses.

Methods

Patients from PROMISE-1 (NCT02559895) and PROMISE-2 (NCT02974153) trials were divided into subgroups based on demographic and migraine characteristics, and baseline questionnaire responses. For each subgroup, the overall likelihood of achieving ≥ 50% migraine responder rate (MRR) over Weeks 1–12 and Weeks 13–24 with either eptinezumab 100 mg or 300 mg was calculated using odds ratios (with associated confidence intervals) and compared.

Results

In PROMISE-1 (episodic migraine) and PROMISE-2 (chronic migraine), the likelihood of achieving ≥ 50% MRR over Weeks 1–12 and Weeks 13–24 was roughly equivalent for patients receiving either dose level of eptinezumab. Given the number of comparisons performed, sporadic apparent differences were seen but no replicated patterns between studies emerged. In PROMISE-1, no differences were observed in any subgroup over Weeks 1–12. In PROMISE-2, patients reporting < 15 monthly migraine days at baseline, any problems with mobility per the EQ-5D-5L, or a social functioning score > 45.0 per the 36-item Short-Form Health Survey (SF-36), appeared more likely to achieve ≥ 50% MRR with 300 mg over Weeks 1–12, with none of these being apparent in PROMISE-1.

Conclusions

Overall, these data suggest that across PROMISE-1 and PROMISE-2, there were no meaningful differences in the likelihood of achieving ≥ 50% MRR between the eptinezumab dose levels in the majority of patient subgroups. In the few subgroups that displayed small, but potentially meaningful differences, patients were more likely to achieve ≥ 50% MRR with eptinezumab 300 mg; however, minimal consistency across both studies and time periods was noted.

Trial Registration

ClinicalTrials.gov.

PROMISE-1: NCT02559895.

PROMISE-2: NCT02974153.
Using mid-infrared spectroscopy to increase GWAS power to detect QTL associated with blood urea nitrogen
Authors: van den Berg Irene , Ho Phuong N. , Nguyen Tuan V. , Haile-Mariam Mekonnen , Luke Timothy D. W. , Pryce Jennie E.
Published: April 2022

Blood urea nitrogen (BUN) is an indicator trait for urinary nitrogen excretion. Measuring BUN level requires a blood sample, which limits the number of records that can be obtained. Alternatively, BUN can be predicted using mid-infrared (MIR) spectroscopy of a milk sample and thus records become available on many more cows through routine milk recording processes. The genetic correlation between MIR predicted BUN (MBUN) and BUN is 0.90. Hence, genetically, BUN and MBUN can be considered as the same trait. The objective of our study was to perform genome-wide association studies (GWAS) for BUN and MBUN, compare these two GWAS and detect quantitative trait loci (QTL) for both traits, and compare the detected QTL with previously reported QTL for milk urea nitrogen (MUN). The dataset used for our analyses included 2098 and 18,120 phenotypes for BUN and MBUN, respectively, and imputed whole-genome sequence data. The GWAS for MBUN was carried out using either the full dataset, the 2098 cows with records for BUN, or 2000 randomly selected cows, so that the dataset size is comparable to that for BUN. The GWAS results for BUN and MBUN were very different, in spite of the strong genetic correlation between the two traits. We detected 12 QTL for MBUN, on bovine chromosomes 2, 3, 9, 11, 12, 14 and X, and one QTL for BUN on chromosome 13. The QTL detected on chromosomes 11, 14 and X overlapped with QTL detected for MUN. The GWAS results were highly sensitive to the subset of records used. Hence, caution is warranted when interpreting GWAS based on small datasets, such as for BUN. MBUN may provide an attractive alternative to perform a more powerful GWAS to detect QTL for BUN.
A new strain of Neowestiellopsis (Hapalosiphonaceae): first observation of toxic soil cyanobacteria from agricultural fields in Iran
Authors: Nowruzi Bahareh , Hutárová Lenka , Absalón Itzel Becerra , Liu Liwei
Published: April 2022

Background

In the present research, challenges arose when many reports have been published on the poisoning of humans due to the ingestion of crops of Crataegus plants contaminated with cyanobacterial toxins. The discovery of several poisonings around agricultural zones prompted us to study the toxic compounds in a strain of Neowestiellopsis which is the most abundant in the agricultural zones of Kermanshah province of Iran, using a polyphasic approach. Molecular procedure was followed to study these strains deeply.

Material and methods

To elucidate their systematic position, besides the 16S rRNA gene, the analyses of molecular toxicity markers, namely nos, mcy G, mcy D and internal transcribed spacer (ITS), were also used.

Results

Based on the results, for the first time, we record the presence of a gene cluster coding for the biosynthesis of a bioactive compound (Nostopeptolides) that is very rare in this family and the presence of toxic compounds (microcystin), which might account for the poisoning of humans.

Conclusions

This case is the first observation of a toxic soil strain from the genus Neowestiellopsis from agricultural fields in Iran.
A comparison of ondansetron and lidocaine in reducing injection pain of propofol: a randomized controlled study
Authors: Wasinwong Wirat , Termthong Sarocha , Plansangkate Prae , Tanasansuttiporn Jutarat , Kosem Riam , Chaofan Surewan
Published: April 2022

Background

Direct stimulation of the afferent nerve endings in the venous endothelium is one explanation of propofol injection pain. Previous studies found that ondansetron can also block sodium channels. This effect is similar to that of lidocaine.

Objective

The primary outcome was the efficacy of ondansetron compared to lidocaine and placebo for the reduction of propofol injection pain.

Method

This trial was conducted in 240 patients, American Society of Anesthesiologists classification I-III and aged between 18–65 years old, undergoing elective surgery, and having a 20-gauge intravenous catheter at the hand dorsum. Each group of 80 patients received 8 mg. of ondansetron in the O Group, 40 mg. of lidocaine in the L Group and normal saline in the C Group. The study medications were blindly administered to the patients through a 20-gauge intravenous catheter placed on the hand dorsum, and then 1 min later, the small dose of propofol (50 mg.) was infused via the syringe pump at a rate of 600 ml/hr. for 30 s. Following that, the syringe pump of propofol was temporarily stopped, and the patients were asked to rate their pain at the injection site.

Result

The incidence of pain was lowest in the L group (66.2%) compared with the O (82.5%) and the C groups (85.0%) (P < 0.01). The median pain score in the L, O, and C groups were 2 (0–4), 4 (2–5), and 4.5 (2–6), respectively (P < 0.01). The incidences of no pain, mild, moderate, and severe pain were also significantly different in the L group (33.8%, 37.5%, 21.2%, and 7.5%, respectively) compared with those in the O group (17.5%, 31.2%, 31.2%, and 20.0%, respectively) and the C groups (15.0%, 22.5%, 40.0%, and 22.5%, respectively) (P < 0.01).

Conclusion

Pretreatment with intravenous lidocaine, rather than ondansetron, can reduce the incidence and intensity of propofol-induced pain.
The challenge for general practitioners to keep in touch with vulnerable patients during the COVID-19 lockdown: an observational study in France
Authors: Bouchez Tiphanie , Gautier Sylvain , Le Breton Julien , Bourgueil Yann , Ramond-Roquin Aline
Published: April 2022

Background

In France, the first COVID-19-related lockdown (17th March to 10th May 2020) resulted in a major decrease in healthcare service utilization. This raised concerns about the continuity of care for vulnerable patients.

Objectives

To identify individual and organizational factors associated with the initiatives taken by French GPs to contact vulnerable patients during the lockdown.

Methods

A national observational survey using an online questionnaire was conducted to document French GPs’ adaptations to the COVID-19 situation, their individual and organizational characteristics, including practice type (individual, group, multidisciplinary) and size. Data were collected from 7th to 20th May 2020 using mailing lists of GPs from the study partners and GPs who participated in a previous survey. This paper analysed answers to the question exploring whether and how GPs took initiatives to contact vulnerable patients. Responses were categorized in: no initiative; selection of patients to contact with a criteria-based strategy; initiative of contact without criteria-based strategy. Multivariate multinomial logistic regression identified factors associated with each category. Key components of the reported initiatives were described by inductive analysis of verbatim material.

Results

Among the 3012 participant GPs (~ 5.6% of French GPs), 1419 (47.1%) reported initiatives to contact some patients without criteria-based strategy, and 808 (26.8%) with a strategy using various clinical/psychological/social criteria. Women GPs more often declared initiatives of contacts with a criteria-based strategy (OR = 1.41, 95% CI [1.14-1.75]) as well as GPs with more than two patients who died due to COVID-19 in comparison with those having none (OR = 1.84, 95% CI [1.43-2.36]). Teaching GPs more often used criteria-based strategies than the other GPs (OR = 1.94, 95% CI [1.51-2.48]). Compared with those working in small monodisciplinary practice, GPs working alone were less likely to implement criteria-based initiatives of contacts (OR = 0.70, 95% CI [0.51-0.97]), while GPs working in multidisciplinary practice were more likely (OR = 1.94, 95% CI [1.26-2.98] in practices > 20 professionals).

Conclusion

French GPs took various initiatives to keep in touch with vulnerable patients, more frequently when working in group practices. These findings confirm the importance of primary care organization to ensure continuity of care for vulnerable people.
Changes in public satisfaction with GP services in Britain between 1998 and 2019: a repeated cross-sectional analysis of attitudinal data
Authors: Aljohani Motab , Donnelly Michael , O’Neill Ciaran
Published: April 2022

Background

Between 1998 and 2019, the structure and process of general practitioner services in Britain underwent a series of reforms and experienced distinct funding environments. This paper examines changes in satisfaction with GP services over time against this backdrop.

Methods

Data were extracted from the British Social Attitudes Survey for the period 1998–2019. Logistic regression analyses investigated changes in overall satisfaction and among specific population sub-groups differentiated by socio-demographic characteristics whilst taking account of time trend and interaction effects between sub-group membership and time trend.

Results

Sustained and significant changes in satisfaction coincided closely with changes to the funding environment. Distinct patterns were evident among sub-groups. Satisfaction appeared to fall more sharply during austerity for low income groups, older people and people who had fewer formal qualifications/years in education.

Conclusion

While a series of policy initiatives were adopted over the period examined, public satisfaction seemed to move in a manner consistent with levels of government expenditure rather than exhibiting distinct breaks that coincided with policy initiatives. As services recover from the pandemic it will be necessary to invest in a significant and sustained way to rebuild public satisfaction.
Homogeneous and heterogeneous risk and prognostic factors for lung metastasis in colorectal cancer patients
Authors: Wang Hongmei , Shan Xuefeng , Zhang Min , Qian Kun , Shen Zhengze , Zhou Weiying
Published: April 2022

Background

The lung is one of the most frequent distant metastasis sites in colorectal cancer (CRC) patients; however, lung metastasis risk and prognostic factors have not been comprehensively elucidated. This study aimed to identify the homogeneous and heterogeneous lung metastasis risk and prognostic factors in CRC patients using the Surveillance, Epidemiology, and End Results (SEER) database.

Methods

CRC patients registered in the SEER database between 2010 and 2016 were included to analyse risk factors for developing lung metastasis by using univariable and multivariable logistic regression. Patients diagnosed between 2010 and 2015 were selected to investigate prognostic factors for lung metastasis by conducting Cox regression. Kaplan–Meier analysis was used to estimate overall survival outcomes.

Results

A total of 10,598 (5.2%) patients with synchronous lung metastasis were diagnosed among 203,138 patients with CRC. The median survival time of patients with lung metastasis was 10.0 months (95% CI 9.6–10.5 months). Older age, unmarried status, uninsured status, poor histological differentiation, more lymphatic metastasis, CEA positivity, liver metastasis, bone metastasis and brain metastasis were lung metastasis risk and prognostic factors. Black patients and those with left colon, rectum, and stage T4 disease were more likely to develop lung metastasis, while patients with right colon cancer and no surgical treatment of the primary tumour had poor survival outcomes.

Conclusion

The incidence of lung metastasis in CRC patients was 5.2%. CRC patients with lung metastasis exhibited homogeneous and heterogeneous risk and prognostic factors. These results are helpful for clinical evaluation and individual treatment decision making.
Healthcare provider perspectives on integrating peer support in non-dialysis-dependent chronic kidney disease care: a mixed methods study
Authors: Love Shannan , Harrison Tyrone G. , Fox Danielle E. , Donald Maoliosa , Verdin Nancy , Hemmelgarn Brenda R. , Elliott Meghan J.
Published: April 2022

Background

Peer support complements traditional models of chronic kidney disease (CKD) care through sharing of peer experiences, pragmatic advice, and resources to enhance chronic kidney disease self-management and decision-making. As peer support is variably offered and integrated into multi-disciplinary CKD care, we aimed to characterize healthcare providers’ experiences and views on peer support provision for people with non-dialysis-dependent CKD within Canada.

Methods

In this concurrent mixed methods study, we used a self-administered online survey to collect information from multi-disciplinary CKD clinic providers (e.g., nurses, nephrologists, allied health professionals) on peer support awareness, program characteristics and processes, perceived value, and barriers and facilitators to offering peer support in CKD clinics. Results were analyzed descriptively. We undertook semi-structured interviews with a sample of survey respondents to elaborate on perspectives about peer support in CKD care, which we analyzed using inductive, content analysis.

Results

We surveyed 113 providers from 49 clinics. Two thirds (66%) were aware of formal peer support programs, of whom 19% offered in-house peer support through their clinic. Peer support awareness differed by role and region, and most referrals were made by social workers. Likert scale responses suggested a high perceived need of peer support for people with CKD. Top cited barriers to offering peer support included lack of peer support access and workload demands, while facilitators included systematic clinic processes for peer support integration and alignment with external programs. Across 18 interviews, we identified themes related to peer support awareness, logistics, and accessibility and highlighted a need for integrated support pathways.

Conclusions

Our findings suggest variability in awareness and availability of peer support among Canadian multi-disciplinary CKD clinics. An understanding of the factors influencing peer support delivery will inform strategies to optimize its uptake for people with advanced CKD.
Assessing changes in the food retail environment during the COVID-19 pandemic: opportunities, challenges, and lessons learned
Authors: Russo Rienna G. , Ali Shahmir H. , Mezzacca Tamar Adjoian , Radee Ashley , Chong Stella , Kranick Julie , Tsui Felice , Foster Victoria , Kwon Simona C. , Yi Stella S.
Published: April 2022

Background

COVID-19 mitigation strategies have had an untold effect on food retail stores and restaurants. Early evidence from New York City (NYC) indicated that these strategies, among decreased travel from China and increased fears of viral transmission and xenophobia, were leading to mass closures of businesses in Manhattan’s Chinatown. The constantly evolving COVID −19 crisis has caused research design and methodology to fundamentally shift, requiring adaptable strategies to address emerging and existing public health problems such as food security that may result from closures of food outlets.

Objective

We describe innovative approaches used to evaluate changes to the food retail environment amidst the constraints of the pandemic in an urban center heavily burdened by COVID-19. Included are challenges faced, lessons learned and future opportunities.

Methods

First, we identified six diverse neighborhoods in NYC: two lower-resourced, two higher-resourced, and two Chinese ethnic enclaves. We then developed a census of food outlets in these six neighborhoods using state and local licensing databases. To ascertain the status (open vs. closed) of outlets pre-pandemic, we employed a manual web-scraping technique. We used a similar method to determine the status of outlets during the pandemic. Two independent online sources were required to confirm the status of outlets. If two sources could not confirm the status, we conducted phone call checks and/or in-person visits.

Results

The final baseline database included 2585 food outlets across six neighborhoods.

Ascertaining the status of food outlets was more difficult in lower-resourced neighborhoods and Chinese ethnic enclaves compared to higher-resourced areas. Higher-resourced neighborhoods required fewer phone call and in-person checks for both restaurants and food retailers than other neighborhoods.

Conclusions

Our multi-step data collection approach maximized safety and efficiency while minimizing cost and resources. Challenges in remote data collection varied by neighborhood and may reflect the different resources or social capital of the communities; understanding neighborhood-specific constraints prior to data collection may streamline the process.
Comparative analysis of contraceptive use in Punjab and Manipur: exploring beyond women’s education and empowerment
Authors: Sharma Anjali , Kumar Abhishek , Mohanty S. K. , Mozumdar Arupendra
Published: April 2022

Background

Women’s education and empowerment are important predictors of contraceptive use across countries. However, two of the Indian states, namely, Punjab and Manipur, showed large variations in contraceptive use, despite the similar level of women’s educational attainment and empowerment. Therefore, this paper attempts to understand variation in contraceptive use between these states, despite having similar level of educational attainment and empowerment among the married women.

Methods

This study primarily used cross-sectional data of the National Family Health Survey (NFHS) 2015–16 and to some extent the District Level Household Survey (DLHS) 2012–13 data. The analytical sample includes 13,730 currently married women in Punjab and 8,872 in Manipur. Modern contraceptive prevalence rate (mCPR) is the key outcome variable of this study. Bivariate, multivariate, and multilevel regression analysis are applied to understand the differences in mCPR between these states and its determinants.

Results

Mean years of schooling was about 8 years among women of both the states, and about 34% of the women in Punjab and 27% of the women in Manipur have high level of autonomy. Despite this, use of modern method was 66% in Punjab and only 13% in Manipur. Coverage of family planning program indicators were significantly lower in Manipur than Punjab – frontline workers’ (FLWs) outreach for family planning was only 18% in Manipur compared to 52% in Punjab. Similarly, only 11% of the public health facilities in Manipur compared to 50% of the health facilities in Punjab were ready to provide at least one clinical method of family planning.

Conclusion

Despite the similar level of individual level characteristics across the two states, poor coverage of family planning programs – low outreach of FLWs, low level of facility readiness, as well as sociocultural norms discouraging contraceptive use – might be responsible for lower contraceptive use in Manipur than Punjab. This implies for strengthening the health system for family planning in Manipur to meet the contraception needs of women by addressing sociocultural barriers in the state.
Dysregulation of Wnt signaling in bone of type 2 diabetes mellitus and diabetic Charcot arthropathy
Authors: Gassel Laurens Christian , Schneider Sandra , Banke Ingo Jörg , Braun Karl Friedrich , Volkering Christoph , Zeeb Leonie , Burgkart Rainer Hans Hermann , von Eisenhart-Rothe Rüdiger , Biberthaler Peter , van Griensven Martijn , Haug Alexander Tobias
Published: April 2022

Background

Type 2 diabetes mellitus (T2DM) patients show a markedly higher fracture risk and impaired fracture healing when compared to non-diabetic patients. However in contrast to type 1 diabetes mellitus, bone mineral density in T2DM is known to be normal or even regionally elevated, also known as diabetic bone disease. Charcot arthropathy is a severe and challenging complication leading to bone destruction and mutilating bone deformities. Wnt signaling is involved in increasing bone mineral density, bone homeostasis and apoptotic processes. It has been shown that type 2 diabetes mellitus is strongly associated with gene variants of the Wnt signaling pathway, specifically polymorphisms of TCF7L2 (transcription factor 7 like 2), which is an effector transcription factor of this pathway.

Methods

Bone samples of 19 T2DM patients and 7 T2DM patients with additional Charcot arthropathy were compared to 19 non-diabetic controls. qPCR analysis for selected members of the Wnt-signaling pathway (WNT3A, WNT5A, catenin beta, TCF7L2) and bone gamma-carboxyglutamate (BGLAP, Osteocalcin) was performed and analyzed using the 2-ΔΔCt- Method. Statistical analysis comprised one-way analysis of variance (ANOVA).

Results

In T2DM patients who had developed Charcot arthropathy WNT3A and WNT5A gene expression was down-regulated by 89 and 58% compared to healthy controls (p < 0.0001). TCF7L2 gene expression showed a significant reduction by 63% (p < 0.0001) and 18% (p = 0.0136) in diabetic Charcot arthropathy. In all diabetic patients BGLAP (Osteocalcin) was significantly decreased by at least 59% (p = 0.0019).

Conclusions

For the first time with this study downregulation of members of the Wnt-signaling pathway has been shown in the bone of diabetic patients with and without Charcot arthropathy. This may serve as future therapeutic target for this severe disease.
Effects of dietary palmitoleic acid on vascular function in aorta of diabetic mice
Authors: Takenouchi Yasuhiro , Seki Yoshie , Shiba Sachiko , Ohtake Kazuo , Nobe Koji , Kasono Keizo
Published: April 2022

Background

Chronic hyperglycemia in diabetes causes atherosclerosis and progresses to diabetic macroangiopathy, and can lead to coronary heart disease, myocardial infarction and cerebrovascular disease. Palmitoleic acid (POA) is a product of endogenous lipogenesis and is present in fish and vegetable oil. In human and animal studies, POA is reported as a beneficial fatty acid related to insulin sensitivity and glucose tolerance. However, few studies have reported its effects on aortic function in diabetes. Here, we investigated the effects of POA administration on vascular function in KKAy mice, a model of type 2 diabetes.

Methods

Male C57BL/6 J (control) and KKAy (experimental) mice at the age of 14 weeks were used in the present study. For each mouse strain, one group was fed with reference diet and a second group was fed POA-containing diet for 2 weeks. The vascular reactivities of prepared aortic rings were then measured in an organ bath to determine if POA administration changed vascular function in these mice.

Results

KKAy mice treated with POA exhibited decreased plasma glucose levels compared with mice treated with reference diet. However, endothelium-dependent vasorelaxant responses to acetylcholine and protease-activated receptor 2 activating protein, which are attenuated in the aorta of KKAy mice compared to C57BL/6 J mice under a reference diet, were not affected by a 2-week POA treatment. In addition, assessment of vasoconstriction revealed that the phenylephrine-induced vasoconstrictive response was enhanced in KKAy mice compared to C57BL/6 J mice under a reference diet, but no effect was observed in KKAy mice fed a POA-containing diet. In contrast, there was an increase in vasoconstriction in C57BL/6 J mice fed the POA-containing diet compared to mice fed a reference diet. Furthermore, the vasoconstriction in aorta in both C57BL/6 J and KKAy mice fed a POA-containing diet were further enhanced under hyperglycemic conditions compared to normal glucose conditions in vitro. In the hyperinsulinemic, and hyperinsulinemic combined with hyperglycemic conditions, vasoconstriction was increased in KKAy mice fed with POA.

Conclusion

These results suggest that POA intake enhances vasoconstriction under hyperglycemic and hyperinsulinemic conditions, which are characteristics of type 2 diabetes, and may contribute to increased vascular complications in diabetes.
Serum adiponectin and cortisol levels are not affected by studied ADIPOQ gene variants: Tehran lipid and glucose study
Authors: Nezhadali Masoumeh , Mesbah-Namin Seyed Alireza , Hedayati Mehdi , Akbarzadeh Mahdi , Najd Hassan Bonab Leila , Daneshpour Maryam S.
Published: April 2022

Background

Obesity is a major public health concern in developed and even developing countries worldwide. Adiponectin is a protein secreted by adipose tissue that modulates many metabolic processes and plays a vital role in obesity. This study aimed to determine the association of four variants of the ADIPOQ gene with serum adiponectin, cortisol levels and obesity status.

Methods

This case-control study was performed on 164 obese individuals compared by 156 control from the Tehran Lipid and Glucose Study (TLGS). Standard procedures obtained anthropometric measures and metabolic parameters. Cortisol and adiponectin levels were measured by ELISA method. rs1501299, rs266729, rs17300539, and rs17366743 on the ADIPOQ gene were genotyped using the PCR-RFLP. The correlation between adiponectin gene SNPs and obesity were calculated by Additive, dominant, and recessive genetic models. Pearson’s or Spearman’s found correlations between adiponectin levels and metabolic and anthropometric variables. Data were analyzed using SPSS software Version 20.

Results

Adiponectin and cortisol levels were significantly lower in obese subjects compared to the control group (p < 0.05). There was a significant negative correlation between serum adiponectin level and BMI, waist circumference (WC), waist-hip ratio, hip circumference (HC), Fasting blood sugar (FBS) Triglyceride (TG), Total cholesterol (TC), Systolic blood pressure (SBP), Diastolic blood pressure (DBP) (r = − 0.147, r = − 0.324, r = 0.371, r = − 0.179, r = − 0.299, r = − 0.277, r = − 0.041, r = − 0.134, and r = − 0.149, respectively). A positive correlation was found between adiponectin and high-density lipoprotein cholesterol (HDL-C) (r = 0.29), but no significant correlations were found between adiponectin and Low-density lipoprotein cholesterol(LDL-C) and cortisol. ADIPOQ variant rs1501299 was significantly associated with cortisol levels in subjects with BMI ≥ 25 (P-value =0.039).

Conclusions

Adiponectin and cortisol levels were associated with obesity. No ADIPOQ gene variants and haplotypes were associated with cortisol, Adiponectin, and obesity.
Understanding concepts of generalism and specialism amongst medical students at a research-intensive London medical school
Authors: Misky Adam T. , Shah Ronak J. , Fung Chee Yeen , Sam Amir H. , Meeran Karim , Kingsbury Martyn , Salem Victoria
Published: April 2022

Background

Many prominent UK medical organisations have identified a need for more generalist clinicians to address the complex requirements of an aging society. We sought to clarify attitudes towards “Specialists” and “Generalists” amongst medical students and junior doctors at Imperial College School of Medicine.

Methods

A survey exploring medical students’ beliefs was followed up by qualitative analysis of focus groups of medical students and Imperial-graduate foundation year doctors.

Results

First year medical students associated specialists with academia and higher income, and generalists with ease of training and job availability. Senior (Years 5/6) medical students associated specialists even more firmly with broader influence and academic work, whilst generalists were assigned lower prestige but the same workload as specialists. The medical student focus group discussed concepts of Generalism pertaining only to Primary Care. In contrast, the foundation year doctor focus group revealed that Generalism was now seen to include some hospital care, and the perception that generalists sat lower in a knowledge hierarchy had been challenged.

Conclusion

Perceptions that Generalism is associated with lower prestige in the medical profession are already present at the very start of medical school and seem to be reinforced during undergraduate training. In early postgraduate clinical practice, the perceived knowledge and prestige hierarchy lessens. These findings can help inform curriculum redesign and the promotion of Generalism as a rewarding career aspiration.
Implementation of team-based learning (TBL) in a second year medical school course: does prior experience with TBL improve the impact of this pedagogy?
Authors: Carrasco Gonzalo A. , Gentile Matthew , Salvatore Michelle L. , Lopez Osvaldo J. , Behling Kathryn C.
Published: April 2022

Background

We have shown that use of Team-based learning (TBL) in a first-year Infectious Diseases (ID) course improved final examination and course performance. Therefore, we implemented TBL in the second-year Women’s Health (WH) course to improve acquisition of course content. We hypothesized that prior experience with TBL in the first-year of medical school would lead to a strong correlation between TBL performance in the first and second years.

Methods

Our study is a retrospective review of student TBL and final examination performance in the ID and WH courses. The ID course has weekly TBL exercises that cover all course material, while the WH course has one TBL that covers a small portion of the course material. Final examination and TBL individual readiness assurance test (iRAT) scores in the ID and WH courses from three classes (n = 226) were obtained with institutional review board approval. Statistical analyses were performed including comparisons of means and correlation studies.

Results

Average WH iRAT scores were significantly higher than ID iRAT scores (9.19 vs. 7.40,p < 0.01), and iRAT scores in both courses were highly correlated (r = 0.35,p < 0.01). When stratifying students based on WH course performance, in struggling students, iRAT but not final examination scores were higher in the WH course than the ID course (8.73 vs. 7.00,p < 0.01 and 82.45 vs. 80.51,p > 0.05, respectively).

Conclusions

Our results suggest that prior experience with TBL improves TBL iRAT scores, especially in struggling students. Prior TBL experience is also associated with consistent iRAT performance between first- and second-year courses in high performing students.
Participant recall and understandings of information on biobanking and future genomic research: experiences from a multi-disease community-based health screening and biobank platform in rural South Africa
Authors: Luthuli Manono , Ngwenya Nothando , Gumede Dumsani , Gunda Resign , Gareta Dickman , Koole Olivier , Siedner Mark J. , Wong Emily B. , Seeley Janet
Published: April 2022

Background

Limited research has been conducted on explanations and understandings of biobanking for future genomic research in African contexts with low literacy and limited healthcare access. We report on the findings of a sub-study on participant understanding embedded in a multi-disease community health screening and biobank platform study known as ‘Vukuzazi’ in rural KwaZulu-Natal, South Africa.

Methods

Semi-structured interviews were conducted with research participants who had been invited to take part in the Vukuzazi study, including both participants and non-participants, and research staff that worked on the study. The interviews were transcribed, and themes were identified from the interview transcripts, manually coded, and thematically analysed.

Results

Thirty-nine individuals were interviewed. We found that the research team explained biobanking and future genomic research by describing how hereditary characteristics create similarities among individuals. However, recollection and understanding of this explanation seven months after participation was variable. The large volume of information about the Vukuzazi study objectives and procedures presented a challenge to participant recall. By the time of interviews, some participants recalled rudimentary facts about the genetic aspects of the study, but many expressed little to no interest in genetics and biobanking.

Conclusion

Participant’s understanding of information related to genetics and biobanking provided during the consent process is affected by the volume of information as well as participant’s interest (or lack thereof) in the subject matter being discussed. We recommend that future studies undertaking biobanking and genomic research treat explanations of this kind of research to participants as an on-going process of communication between researchers, participants and the community and that explanatory imagery and video graphic storytelling should be incorporated into theses explanations as these have previously been found to facilitate understanding among those with low literacy levels. Studies should also avoid having broader research objectives as this can divert participant’s interest and therefore understanding of why their samples are being collected.
Would they accept it? An interview study to identify barriers and facilitators to user acceptance of a prescribing advice service
Authors: Yager Rachel Constance , Taylor Natalie , Stocker Sophie Lena , Day Richard Osborne , Baysari Melissa Therese , Carland Jane Ellen
Published: April 2022

Objectives

Few studies have explored the factors influencing user uptake of interventions designed to enhance therapeutic drug monitoring (TDM). This study aimed to identify barriers and facilitators to acceptance of a pilot intervention, the TDM Advisory Service (the Service), that provided prescribing advice for the antibiotic, vancomycin at an Australian public hospital.

Methods

A sample of prescribers and pharmacists who had interacted with the Service (n = 10), and a sample who had not (n = 13), participated in semi-structured interviews. Interviews were transcribed verbatim and analysed independently by two researchers for emerging themes. The Theoretical Domains Framework (TDF) was used to synthesise barriers and facilitators to Service acceptance.

Results

Key barriers reported by participants who had interacted with the Service aligned with two TDF domains: ‘Social Influences’ (prescribing hierarchy) and ‘Environmental Context and Resources’ (accessibility of dose advice). For participants who had not interacted with the Service, key barriers aligned with two TDF domains: ‘Knowledge’ (uncertainty of Service processes) and ‘Environmental Context and Resources’ (accessibility of dose advice). Key facilitators for both participant groups aligned with ‘Beliefs about Consequences’ (improved prescribing and patient outcomes) and ‘Environmental Context and Resources’ (accessibility of dose advice). A novel domain, ‘Trust’, was identified.

Conclusions

Independent of participant interaction with the Service, knowledge of Service processes, perceived beneficial outcomes, improved accessibility, and trust in Service capabilities were key determinants of acceptance. This evidence can be used to inform the adoption of strategies to adapt and enhance integration of the Service into clinical workflow.
Circulating inflammatory biomarkers, adipokines and breast cancer risk—a case-control study nested within the EPIC cohort
Authors: Cairat Manon , Rinaldi Sabina , Navionis Anne-Sophie , Romieu Isabelle , Biessy Carine , Viallon Vivian , Olsen Anja , Tjønneland Anne , Fournier Agnès , Severi Gianluca , Kvaskoff Marina , Fortner Renée T. , Kaaks Rudolf , Aleksandrova Krasimira , Schulze Matthias B. , Masala Giovanna , Tumino Rosario , Sieri Sabina , Grasso Chiara , Mattiello Amalia , Gram Inger T. , Olsen Karina Standahl , Agudo Antonio , Etxezarreta Pilar Amiano , Sánchez Maria-Jose , Santiuste Carmen , Barricarte Aurelio , Monninkhof Evelyn , Hiensch Anouk E. , Muller David , Merritt Melissa A. , Travis Ruth C. , Weiderpass Elisabete , Gunter Marc J. , Dossus Laure
Published: April 2022

Background

Inflammation has been hypothesized to play a role in the development and progression of breast cancer and might differently impact breast cancer risk among pre and postmenopausal women. We performed a nested case-control study to examine whether pre-diagnostic circulating concentrations of adiponectin, leptin, c-reactive protein (CRP), tumour necrosis factor-α, interferon-γ and 6 interleukins were associated with breast cancer risk, overall and by menopausal status.

Methods

Pre-diagnostic levels of inflammatory biomarkers were measured in plasma from 1558 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We used conditional logistic regression to estimate the odds ratios (ORs) of breast cancer at blood collection, per one standard deviation increase in biomarker concentration.

Results

Cases were diagnosed at a mean age of 61.4 years on average 8.6 years after blood collection. No statistically significant association was observed between inflammatory markers and breast cancer risk overall. In premenopausal women, borderline significant inverse associations were observed for leptin, leptin-to-adiponectin ratio and CRP [OR= 0.89 (0.77–1.03), OR= 0.88 (0.76–1.01) and OR= 0.87 (0.75–1.01), respectively] while positive associations were observed among postmenopausal women [OR= 1.16 (1.05–1.29), OR= 1.11 (1.01–1.23), OR= 1.10 (0.99–1.22), respectively]. Adjustment for BMI strengthened the estimates in premenopausal women [leptin: OR = 0.83 (0.68–1.00), leptin-to-adiponectin ratio: OR = 0.80 (0.66–0.97), CRP: OR = 0.85 (0.72–1.00)] but attenuated the estimates in postmenopausal women [leptin: OR = 1.09 (0.96–1.24), leptin-to-adiponectin ratio: OR = 1.02 (0.89–1.16), CRP: OR = 1.04 (0.92–1.16)].

Conclusions

Associations between CRP, leptin and leptin-to-adiponectin ratio with breast cancer risk may represent the dual effect of obesity by menopausal status although this deserves further investigation.
Intellectual disability associated with craniofacial dysmorphism due to POLR3B mutation and defect in spliceosomal machinery
Authors: Saghi Mostafa , InanlooRahatloo Kolsoum , Alavi Afagh , Kahrizi Kimia , Najmabadi Hossein
Published: April 2022

Background

Intellectual disability (ID) is a clinically important disease and a most prevalent neurodevelopmental disorder. The etiology and pathogenesis of ID are poorly recognized. Exome sequencing revealed a homozygous missense mutation in the POLR3B gene in a consanguineous family with three Intellectual disability with craniofacial anomalies patients. POLR3B gene encoding the second largest subunit of RNA polymerase III.

Methods

We performed RNA sequencing on blood samples to obtain insights into the biological pathways influenced by POLR3B mutation. We applied the results of our RNA-Seq analysis to several gene ontology programs such as ToppGene, Enrichr, KEGG.

Results

A significant decrease in expression of several spliceosomal RNAs, ribosomal proteins, and transcription factors was detected in the affected, compared to unaffected, family members.

Conclusions

We hypothesize that POLR3B mutation dysregulates the expression of some important transcription factors, ribosomal and spliceosomal genes, and impairments in protein synthesis and splicing mediated in part by transcription factors such as FOXC2 and GATA1 contribute to impaired neuronal function and concurrence of intellectual disability and craniofacial anomalies in our patients. Our study highlights the emerging role of the spliceosome and ribosomal proteins in intellectual disability.
Exosomal miR-301a-3p from esophageal squamous cell carcinoma cells promotes angiogenesis by inducing M2 polarization of macrophages via the PTEN/PI3K/AKT signaling pathway
Authors: Shou Yuwei , Wang Xiaoqian , Chen Chao , Liang Yinghao , Yang Chenbo , Xiao Qiankun , Li Hui , Wang Shuaiyuan , Shu Jiao , Tian Xiangyu , Chen Kuisheng
Published: April 2022

Background

Growing evidence has indicated that tumor-associated macrophages (TAMs) promote tumor angiogenesis. However, the mechanisms underlying the pro-angiogenic switch of TAMs remains unclear. Here, we examined how exosomal miR-301a-3p secreted by esophageal squamous cell carcinoma (ESCC) cells triggers the pro-angiogenic switch of TAMs.

Methods

We quantified miR-301a-3p levels in ESCC tumors using qRT-PCR. Macrophage phenotypes were identified using flow cytometry and qRT-PCR. The pro-angiogenic ability of TAMs was measured using the CCK-8 assay, scratch assay, Transwell migration and invasion assay, and tube formation assay. The mechanism by which exosomal miR-301a-3p secreted by ESCC cells triggers the pro-angiogenic switch of TAMs was elucidated using western blots, qRT-PCR, and a dual-luciferase reporter assay.

Results

We observed anomalous miR-301a-3p overexpression in ESCC tumor tissues and cell lines. Then, we verified that ESCC-derived exosomes promoted angiogenesis by inducing macrophage polarization into M2 type, and exosomal miR-301a-3p secreted by ESCC cells was responsible for this effect. Finally, we discovered that exosomal miR-301a-3p promoted M2 macrophage polarization via the inhibition of PTEN and activation of the PI3K/AKT signaling pathway, subsequently promoting angiogenesis via the secretion of VEGFA and MMP9.

Conclusion

The pro-angiogenic switch of TAMs is triggered by exosomal miR-301a-3p secreted from ESCC cells via the PTEN/PI3K/AKT signaling pathway. Although tumor angiogenesis can be regulated by a wide range of factors, exosomal miR-301a-3p could hold promise as a novel anti-angiogenesis target for ESCC treatment.
An analysis of the gender and social determinants of health in urban poor areas of the most populated cities of Pakistan
Authors: Ahmed Khawaja Aftab , Grundy John , Hashmat Lubna , Ahmed Imran , Farrukh Saadia , Bersonda Dexter , Shah Muhammad Akram , Yunus Soofia , Banskota Hari Krishna
Published: April 2022

Background

Recent surveys, studies and reviews in urban areas of Pakistan have highlighted the impacts of social inequities on access of women and children to health services for women and children in Pakistan.

Objectives

The Urban Slum Profiles and coverage surveys were conducted between 2017 and 2019. The objective of the profiles was to obtain an updated listing of slums and other underserved areas, and to better understand current vaccination and health service coverage in these areas. Utilising findings from these studies, this paper aims to better understand the gender and social determinants of health that are giving rise to health inequalities in the slums.

Methods

The Urban Slum Profiles adopted a mixed methods approach combining both qualitative and quantitative methods. The study was comprised of two main survey approaches of Urban Slum Profiles and Immunisation Coverage Survey in 4431 urban poor areas of the 10 most highly populated cities of Pakistan.

Results

Findings are classified into six analytic categories of (1) access to health services, (2) female workforce participation, (3) gender-friendly health services, (4) access to schools and literacy, (5) social connections, and (6) autonomy of decision making. Out of a national sample of 14,531 children in urban poor areas of 10 cities, the studies found that just over half of the children are fully immunised (54%) and 14% of children had received zero doses of vaccine. There are large shortages of health facilities and female health workforce in the slums, with significant gaps in the quality of health infrastructure, which all serve to limit both demand for, and supply of, health services for women and children. Results demonstrate low availability of schools, low levels of female literacy and autonomy over decision making, limited knowledge of the benefits of vaccination, and few social connections outside the home. All these factors interact and reinforce existing gender norms and low levels of health literacy and service access.

Conclusion

The Urban Slum profiles and coverage studies provide an opportunity to introduce gender transformative strategies that include expansion of a female health workforce, development of costed urban health action plans, and an enabling policy environment to support community organisation and more equitable health service delivery access.