bluuebunny/crossref_metadata_2025 huggingface dataset:
Gaining insight into the views of outpatients with Huntington’s disease regarding their future and the way they deal with their poor prognosis: a qualitative study
Authors: Ekkel Marina R. , Depla Marja F. I. A. , Verschuur Els M. L. , Veenhuizen Ruth B. , Hertogh Cees M. P. M. , Onwuteaka-Philipsen Bregje D.
Published: January 2021

Background

Huntington’s disease (HD) has a poor prognosis. Decision-making capacity and communication ability may become lost as the disease progresses. Therefore, HD patients are encouraged to engage in advance care planning (ACP). To improve ACP for HD patients, there is a need to better understand how these patients face their poor prognosis.

Aim

To gain insight into the views of HD patients who receive outpatient care regarding their future and the way they deal with the poor prognosis of their disease.

Methods

A qualitative study using semi-structured interviews with 12 patients with HD (7 outpatient clinic, 3 day care, 2 assisted living facility). Audio-recorded interviews were transcribed verbatim. Through reading and re-reading interviews, writing memos and discussions in the research team, strategies were identified.

Results

Three strategies emerged for facing a future with HD. Participants saw the future: 1) as a period that you have to prepare for; 2) as a period that you would rather not think about; 3) as a period that you do not have to worry about yet. Participants could adopt more than one strategy at a time. Even though participants realized that they would deteriorate and would need more care in the future, they tried to keep this knowledge ‘at a distance’, with the motivation of keeping daily life as manageable as possible.

Conclusions

Official ACP guidelines recommend discussing goals and preferences for future treatment and care, but patients tend to want to live in the present. Further research is needed to elucidate the best approach to deal with this discrepancy.
Chinese medical teachers’ cultural attitudes influence palliative care education: a qualitative study
Authors: Willemsen Antonia M. , Paal Piret , Zhang Silja , Mason Stephen , Elsner Frank
Published: January 2021

Background

China holds one fifth of the world’s population and faces a rapidly aging society. In its ambition to reach a health care standard comparable to developed countries by 2030, the implementation of palliative care gains special importance. Until now, palliative care education in China is limited and disparate. This study aims to explore and determine factors that have impeded the development and implementation of palliative care education in China.

Methods

We conducted semi-structured interviews with n=28 medical teachers from seven Chinese universities. Interviews were transcribed, and thematic analysis applied.

Results

Three themes with two subthemes were constructed from data analysis. Theme 1 covers the still ambivalent perception of palliative care and palliative care education among participants. The second theme is about cultural attitudes around death and communication. The third theme reflects participants’ pragmatic general understanding of teaching. All themes incorporate obstacles to further implementation of palliative care and palliative care education in China.

Conclusions

According to the study participants, palliative care implementation through palliative care education in China is hindered by cultural views of medical teachers, their perception of palliative care and palliative care education, and their understanding of teaching. The study demonstrates that current attitudes may work as an obstacle to the implementation of palliative care within the health care system. Approaches to changing medical teachers’ views on palliative care and palliative care education and their cultural attitudes towards death and dying are crucial to further promote the implementation of palliative care in China.
Communication of Pharmacogenomic test results and treatment plans in pediatric oncology: deliberative stakeholder consultations with parents
Authors: Longo Cristina , Rahimzadeh Vasiliki , Bartlett Gillian
Published: January 2021

Background

Effective communication in support of clinical decision-making is central to the pediatric cancer care experience for families. A new laboratory derived pharmacogenetic test (LDT) that can diagnose difficult-to-treat brain cancers has been developed to stratify children based on their ability to respond to available treatment; however, the potential implementation of the LDT may make effective communication challenging since it can potentially remove the option for curative treatment in those children identified as non-responders, i.e. those with a catastrophic diagnosis.

Objective

We solicited the perspectives of parents of children with difficult-to-treat brain cancer on communication preferences surrounding the potential implementation of the LDT in standard care using deliberative stakeholder consultations.

Methods

Eight bereaved parents of children who succumbed to difficult-to-treat brain cancer, and four parents of children currently undergoing treatment for similar cancers attended separate small-group deliberative consultations – a stakeholder engagement method that enables the co-creation of recommendations following the consideration of competing arguments and diverse opinions of parents with different experiences. In the small-group consultations (Phase I), parents discussed four questions about potential communication issues that may arise with the LDT in practice. In Phase II, a total of five parents from both stakeholder groups (4 bereaved and 1 in current treatment) attended a consultation, known as the ‘mixed’ consultation, with the purpose of co-developing concrete recommendations for implementation of the LDT.

Results

Explaining the risks, benefits, and accuracy of the LDT were considered essential to parents. Once an LDT-based diagnosis/prognosis can be made, parents valued honesty, empathy, and clarity in communication. Parents also requested that all results and treatment options be presented to them in measured doses, and in an unbiased manner over the course of several meetings. This communication strategy allowed sufficient time to understand and accept the diagnosis/prognosis, particularly if it was catastrophic. Continuous access to the appropriate psychological and social support or counselling at and post-diagnosis was also strongly recommended.

Conclusions

Deliberants co-created family-centered recommendations surrounding communication issues of the LDT, providing guidance to pediatric oncologists that could implement the test in practice.
Psychological well-being of infertile women and its relationship with demographic factors and fertility history: a cross-sectional study
Authors: Sohbati Farnaz , Hasanpoor-Azghady Seyedeh Batool , Jafarabadi Mina , Amiri-Farahani Leila , Mohebbi Marzieh
Published: January 2021

Background

Infertility leads to a wide range of psychological injuries that may reduce psychological well-being. This study aimed to determine the psychological well-being of infertile women and its relation with demographic factors and fertility history.

Methods

This cross-sectional study was conducted on 300 infertile women referred to three infertility centres, Tehran, Iran. The sampling was continuous. We collected data from a self-generated demographic and fertility questionnaire and Ryff's Psychological Well-being Scale (PWB). Data analysis was done by independent t-test, one way ANOVA. The significance level was set at P < 0.05.

Results

The results showed that there was no significant relationship between demographic variables including age, occupation of each couple, spousal’s education, economic status and place of residence with PWB, but the mean score of PWB was significantly different in women's educational levels (P = 0.03). There was also a significant difference between the mean score of PWB among different groups in the duration of marriage (P = 0.01). Fertility characteristics variables include the duration of infertility, duration of treatment of infertility, and current treatment were not the relation with PWB. However, the mean score of PWB in the number of IVF (P = 0.003) and the failed IVF pregnancies (P = 0.01) had a significant statistical difference.

Conclusion

The results showed that PWB related to several variables. Paying attention to these variables can help in the preparation and development of counseling or educational programs.
Can the dynamic spectral imaging (DSI) color map improve colposcopy examination for precancerous cervical lesions? A prospective evaluation of the DSI color map in a multi-biopsy clinical setting
Authors: Booth Berit Bargum , Petersen Lone Kjeld , Blaakaer Jan , Johansen Tonje , Mertz Henrik , Dahl Katja , Bor Pinar
Published: January 2021

Background

Colposcopy serves as a subjective examination of the cervix with low sensitivity to detect cervical intraepithelial dysplasia (CIN) grade 2 or worse (CIN2 +). Dynamic spectral imaging (DSI) colposcopy has been developed to provide an objective element to cervix examinations and has been proven to increase sensitivity of detecting CIN2 + . We aimed to assess the performance of the DSI color map and compared it to histological diagnoses of cervical biopsies in determining the CIN grade present.

Methods

Women were included in a consecutive, prospective manner at Randers Regional Hospital, Denmark. Women were eligible to participate if they were referred for colposcopy due to abnormal cervical smear (threshold:  ≥ ASCUS) or follow-up after previously diagnosed CIN. All women had four biopsies taken, one directed by colposcopists alone prior to viewing the DSI color map, one directed by the worst color on the respective DSI color map, and two additional biopsies. All biopsies were analyzed separately. We calculated sensitivity, specificity, positive predictive values, and negative predictive values (NPVs) with 95% confidence intervals (CIs).

Results

A total of 800 women were recruited. Of these, 529 (66.1%) were eligible for inclusion. The sensitivity of the DSI color map was found to be 48.1% (95% CI 41.1–55.1) in finding CIN grade 2 or worse (CIN2 +) when compared to the histological diagnosis of the DSI directed biopsy. This was 42.5% (95% CI 36.7–48.5) when compared to the final histological diagnosis of all four cervical biopsies and with an NPV of 53.5% (95% CI 50.5–56.5).

Conclusion

The worst color indicated by the DSI map might not consistently reflect the true grade of cervical dysplasia present. Thus, even though the DSI color map indicates low-grade changes, colposcopists should still consider taking biopsies from the area as high-grade changes might be present.

Trial registration: NCT04249856, January 31 2020 (retrospectively registered).
A qualitative study of Ghanaian pediatric oncology nurses’ care practice challenges
Authors: Nukpezah Ruth Nimota , Khoshnavay Fomani Fatemeh , Hasanpour Marzieh , Nasrabadi Alireza Nikbakht
Published: January 2021

Background

Pediatric cancer is a global problem, and some studies have emphasized that nurses caring for these children experience work-related challenges. This has caused many children diagnosed with cancer to have a prolonged hospital stay and suffer unnecessary pain. However, there is insufficient documentary evidence on this issue. This study aims to explore and understand the challenges faced by pediatric oncology nurses in caring for children in Ghana.

Methods

An exploratory qualitative research design study was conducted from August 2019 to April 2020. The study was conducted at the pediatric oncology unit which is located at the Tamale Teaching Hospital (TTH), Ghana. The study was conducted among 14 Ghanaian pediatric oncology nurses who were purposively sampled. A semi-structured interview guide was used to collect data. The interviews were recorded, transcribed verbatim, and analyzed inductively using Elo and Kyngas content analysis approach. The criteria proposed by Guba and Lincoln were used to ensure the validity of the study.

Results

From the analysis of participants transcripts, eight subcategories emerged from two major categories. The subcategories were; time-consuming care, low job motivations, inadequate logistics, work stress, reduced labour force, low knowledge level, lack of teamwork and the perception of contracting cancer.

Conclusions

The results point to several organizational and personal constraints experienced by the nurses who work at the pediatric oncology ward. It is hoped that by addressing these challenges, it would lead to further improvement in the care that is provided to children with cancer. There is the need for the administrative managers of hospitals, government and other stakeholders to invest in human, material and financial resources for delivering childhood cancer care services.
Evaluation of chromosomal abnormalities and copy number variations in fetuses with ultrasonic soft markers
Authors: Cai Meiying , Lin Na , Chen Xuemei , Fu Meimei , Guo Nan , Xu Liangpu , Huang Hailong
Published: January 2021

Background

Some ultrasonic soft markers can be found during ultrasound examination. However, the etiology of the fetuses with ultrasonic soft markers is still unknown. This study aimed to evaluate the genetic etiology and clinical value of chromosomal abnormalities and copy number variations (CNVs) in fetuses with ultrasonic soft markers.

Methods

Among 1131 fetuses, 729 had single ultrasonic soft marker, 322 had two ultrasonic soft markers, and 80 had three or more ultrasonic soft markers. All fetuses underwent conventional karyotyping, followed by single nucleotide polymorphism (SNP) array analysis.

Results

Among 1131 fetuses with ultrasonic soft markers, 46 had chromosomal abnormalities. In addition to the 46 fetuses with chromosomal abnormalities consistent with the results of the karyotyping analysis, the SNP array identified additional 6.1% (69/1131) abnormal CNVs. The rate of abnormal CNVs in fetuses with ultrasonic soft marker, two ultrasonic soft markers, three or more ultrasonic soft markers were 6.2%, 6.2%, and 5.0%, respectively. No significant difference was found in the rate of abnormal CNVs among the groups.

Conclusions

Genetic abnormalities affect obstetrical outcomes. The SNP array can fully complement conventional karyotyping in fetuses with ultrasonic soft markers, improve detection rate of chromosomal abnormalities, and affect pregnancy outcomes.
Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications
Authors: Trougakos Ioannis P. , Stamatelopoulos Kimon , Terpos Evangelos , Tsitsilonis Ourania E. , Aivalioti Evmorfia , Paraskevis Dimitrios , Kastritis Efstathios , Pavlakis George N. , Dimopoulos Meletios A.
Published: January 2021

Background

Gaining further insights into SARS-CoV-2 routes of infection and the underlying pathobiology of COVID-19 will support the design of rational treatments targeting the life cycle of the virus and/or the adverse effects (e.g., multi-organ collapse) that are triggered by COVID-19-mediated adult respiratory distress syndrome (ARDS) and/or other pathologies.

Main body

COVID-19 is a two-phase disease being marked by (phase 1) increased virus transmission and infection rates due to the wide expression of the main infection-related ACE2, TMPRSS2 and CTSB/L human genes in tissues of the respiratory and gastrointestinal tract, as well as by (phase 2) host- and probably sex- and/or age-specific uncontrolled inflammatory immune responses which drive hyper-cytokinemia, aggressive inflammation and (due to broad organotropism of SARS-CoV-2) collateral tissue damage and systemic failure likely because of imbalanced ACE/ANGII/AT1R and ACE2/ANG(1–7)/MASR axes signaling.

Conclusion

Here we discuss SARS-CoV-2 life cycle and a number of approaches aiming to suppress viral infection rates or propagation; increase virus antigen presentation in order to activate a robust and durable adaptive immune response from the host, and/or mitigate the ARDS-related “cytokine storm” and collateral tissue damage that triggers the severe life-threatening complications of COVID-19.
LncRNA SNHG16 contributes to tumor progression via the miR-302b-3p/SLC2A4 axis in pancreatic adenocarcinoma
Authors: Xu Hao , Miao Xin , Li Xin , Chen Haofei , Zhang Bo , Zhou Wence
Published: January 2021

Background

It has been reported that the lncRNA SNHG16 has significantly increased expression in pancreatic adenocarcinoma (PC). However, the functions and mechanisms of SNHG16 are not clear. The aim of this study was to explore the effects of SNHG16 on PC.

Methods

qRT-PCR analysis was applied to detect the expression levels of SNHG16, miR-302b-3p and SLC2A4 in PC tissues and cells. CCK8 and EdU assays were used to evaluate the proliferation of PC cells. Transwell assays were used to assess PC cell migration and invasion. Apoptosis was evaluated by flow cytometry, and the expression of apoptosis-related proteins (including Bax, Bcl-2, cleaved caspase-3 and cleaved caspase-9) was tested by western blotting. The interactions between miR-302b-3p and SNHG16 or miR-302b-3p and the 3’UTR of SLC2A4 mRNA were clarified by a dual luciferase reporter assay and RNA immunoprecipitation.

Results

SNHG16 expression was significantly elevated in PC tissues and cell lines and was associated with poor prognosis of PC patients. Knockdown of SNHG16 reduced PC cell proliferation, migration and invasion. SNHG16 acted as a sponge to regulate miR-302b-3p expression in PC cells. In addition, miR-302b-3p targeted SLC2A4 directly.

Conclusions

SNHG16 promoted the progression of PC via the miR-302b-3p/SLC2A4 axis and was expected to be a potential target for the early diagnosis and treatment of PC.
Empagliflozin protects against atherosclerosis progression by modulating lipid profiles and sympathetic activity
Authors: Liu Yihai , Xu Jiamin , Wu Mingyue , Xu Biao , Kang Lina
Published: January 2021

Background

Several large clinical trials have confirmed the cardioprotective role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes. However, whether empagliflozin, as an SGLT2i, could alleviate atherosclerosis progression in non-diabetic states remain unknown.

Methods

ApoE-/- mice were fed a Western diet for 12 weeks to induce atherosclerosis. On the 7th week, a group of mice were treated with drinking water containing empagliflozin (10 mg/kg/day), while another group was given normal water. At the 12th week, the whole aortas of each group were harvested. Oil Red O, HE and Movat staining were performed for atherosclerotic lesion area and size. Mouse serum lipid profiles (total cholesterol [TC], triglyceride [TG], low-density lipoprotein-c [LDL], and high-density lipoprotein-c [HDL]), systemic inflammation levels (IL-1β, IL-6 and IL-10), renin-angiotensin-aldosterone system (RAAS) components and sympathetic activity (norepinephrine and neuropeptide Y) indicators were measured by ELISA.

Results

Empagliflozin reduced the atherosclerotic lesion burden (-8.6 %,P = 0.004) at aortic root in ApoE-/- mice. In addition, empagliflozin decreased body weight (-3.27 g,P = 0.002), lipid profiles (TC: [-15.3 mmol/L,P = 0.011]; TG: [-2.4 mmol/L,P < 0.001]; LDL: [-2.9 mmol/L,P = 0.010]), RAAS (renin [-9.3 ng/L,P = 0.047]; aldosterone [-16.7 ng/L,P < 0.001]) and sympathetic activity (norepinephrine [-8.9 ng/L,P = 0.019]; neuropeptide Y [-8.8 ng/L,P = 0.002]). However, the anti-inflammatory effect of empagliflozin was not significantly evident.

Conclusions

The early atherosclerotic lesion size was less visible in empagliflozin-treated mice. Empagliflozin could decrease lipid profiles and sympathetic activity in atherosclerosis.
Genomic instability-derived plasma extracellular vesicle-microRNA signature as a minimally invasive predictor of risk and unfavorable prognosis in breast cancer
Authors: Bao Siqi , Hu Ting , Liu Jiaqi , Su Jianzhong , Sun Jie , Ming Yue , Li Jiaxin , Wu Nan , Chen Hongyan , Zhou Meng
Published: January 2021

Background

Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer-associated deaths in women. Recent studies have indicated that microRNA (miRNA) regulation in genomic instability (GI) is associated with disease risk and clinical outcome. Herein, we aimed to identify the GI-derived miRNA signature in extracellular vesicles (EVs) as a minimally invasive biomarker for early diagnosis and prognostic risk stratification.

Experimental design

Integrative analysis of miRNA expression and somatic mutation profiles was performed to identify GI-associated miRNAs. Then, we constructed a discovery and validation study with multicenter prospective cohorts. The GI-derived miRNA signature (miGISig) was developed in the TCGA discovery cohort (n = 261), and was subsequently independently validated in internal TCGA validation (n = 261) and GSE22220 (n = 210) cohorts for prognosis prediction, and in GSE73002 (n = 3966), GSE41922 (n = 54), and in-house clinical exosome (n = 30) cohorts for diagnostic performance.

Results

We identified a GI-derived three miRNA signature (MIR421, MIR128-1 and MIR128-2) in the serum extracellular vesicles of BC patients, which was significantly associated with poor prognosis in all the cohorts tested and remained as an independent prognostic factor using multivariate analyses. When integrated with the clinical characteristics, the composite miRNA-clinical prognostic indicator showed improved prognostic performance. The miGISig also showed high accuracy in differentiating BC from healthy controls with the area under the receiver operating characteristics curve (ROC) with 0.915, 0.794 and 0.772 in GSE73002, GSE41922 and TCGA cohorts, respectively. Furthermore, circulating EVs from BC patients in the in-house cohort harbored elevated levels of miGISig, with effective diagnostic accuracy.

Conclusions

We report a novel GI-derived three miRNA signature in EVs, as an excellent minimally invasive biomarker for the early diagnosis and unfavorable prognosis in BC.
Pancreatic ductal adenocarcinoma and distal cholangiocarcinoma: a proposal of preoperative diagnostic score for differential diagnosis
Authors: Muttillo Edoardo Maria , Ciardi Antonio , Troiano Raffaele , Saullo Paolina , Masselli Gabriele , Guida Marianna , Tortora Alessandra , Sperduti Isabella , Marinello Giulio , Chirletti Piero , Caronna Roberto
Published: January 2021

Purpose

The differential diagnosis between primary adenocarcinoma of the pancreas head and distal cholangiocarcinoma remains a clinical challenge. Recent studies have shown important differences in terms of survival between these tumors. Therefore, different treatments should be considered, but the preoperative histological diagnosis is still difficult. Aim of this study is to create a preoperative diagnostic score for differential diagnosis between primary pancreatic adenocarcinoma and primary distal cholangiocarcinoma.

Methods

One hundred eighty consecutive patients who underwent pancreaticoduodenectomy at Sapienza University of Rome from January 2010 to December 2019 were retrospectively analyzed. Inclusion criteria were pancreatic or biliary histologic origin obtained by definitive postoperative histological examination. Exclusion criteria were diagnosis of ampullary carcinoma, non-ampullary duodenal adenocarcinoma, pancreatic metastasis, and benign disease. One hundred one patients were considered eligible for the retrospective study. Preoperative biological, clinical, and radiological parameters were considered.

Results

CRP > 10 mg/dL (p = 0.001), modified Glasgow Prognostic Score 2 (p = 0.002), albumin < 35 g/L (p = 0.05), CA 19-9 > 230 U/mL (p = 0.001), and Wirsung diameter > 3 mm (p < 0.001) were significant at univariate logistic analysis. Multivariate logistic analysis has shown that parameters independently associated with primary pancreatic adenocarcinoma were CRP > 10 mg/dL (p = 0.012), CA 19-9 > 230 U/mL (p = 0.043), and diameter of the Wirsung > 3 mm (p = 0.005). Through these parameters, a diagnostic score has been developed to predict a primary pancreatic adenocarcinoma when > 1 and a primary distal cholangiocarcinoma when < 1.

Conclusion

This feasible and low-cost diagnostic score could have a potential impact to differentiate pancreatic cancer histologic origin and to improve target therapeutic strategy.
Cytokine profile during occult hepatitis B virus infection in chronic hepatitis C patients
Authors: Ribeiro Camilla Rodrigues de Almeida , de Almeida Nathalia Alves Araújo , Martinelli Katrini Guidolini , Pires Marcia Amendola , Mello Carlos Eduardo Brandao , Barros José J. , de Paula Vanessa Salete
Published: January 2021

Background

The hepatitis B virus (HBV) is one of the leading causes of acute, chronic and occult hepatitis (OBI) representing a serious public health threat. Cytokines are known to be important chemical mediators that regulate the differentiation, proliferation and function of immune cells. Accumulating evidence indicate that the inadequate immune responses are responsible for HBV persistency. The aim of this study were to investigate the cytokines IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10 and IL-17A in patients with OBI and verify if there is an association between the levels of these cytokines with the determination of clinical courses during HBV occult infection.

Methods

114 patients with chronic hepatitis C were investigated through serological and molecular tests, the OBI coinfected patients were subjected to the test for cytokines using the commercial human CBA kit. As controls, ten healthy donors with no history of liver disease and 10 chronic HBV monoinfected patients of similar age to OBI patients were selected.

Results

Among 114 HCV patients investigated, 11 individuals had occult hepatitis B. The levels of cytokines were heterogeneous between the groups, most of the cytokines showed higher levels of production detection among OBI/HCV individuals when compared to control group and HBV monoinfected pacients. We found a high level of IL-17A in the HBV monoinfected group, high levels of TNF-α, IL-10, IL-6, IL-4 and IL-2 in OBI/HCV patients.

Conclusion

These cytokines could be involved in the persistence of HBV DNA in hepatocytes triggers a constant immune response, inducing continuous liver inflammation, which can accelerate liver damage and favor the development of liver cirrhosis in other chronic liver diseases.
TCF7L2 polymorphisms, nut consumption, and the risk of metabolic syndrome: a prospective population based study
Authors: Hosseinpour-Niazi Somayeh , Bakhshi Bahar , Zahedi Asiyeh-Sadat , Akbarzadeh Mahdi , Daneshpour Maryam S. , Mirmiran Parvin , Azizi Fereidoun
Published: January 2021

Background

The aim of this study was to investigate whether two variants of the TCF7L2 (rs7903146 and rs12255372) modify the association between nut consumption and the risk of metabolic syndrome (MetS). Additionally, the modifying effect of weight change during follow-up on these associations was investigated.

Material and methods

We prospectively studied 1423 participants of the Tehran Lipid and Glucose study aged 19–74 years who were followed-up for dietary assessment using a validated, semi-quantitative food frequency questionnaire. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for MetS events. Genotyping was performed by Human Omni Express-24-v1-0 chip.

Results

Over a median 8.9 years of follow-up, 415 new cases of MetS were documented. The median nut consumption was 20.0 g/week (Interquartile Range (IQR): 8.6–38.9 g/week). Regarding the rs7903146 genotype, in carriers of T allele (CT + TT), highest tertile of nut consumption was associated with a reduced risk of MetS after adjusting for confounders (HR: 0.67 (0.50–0.91)). Regarding the rs12255372 genotype, highest versus lowest tertile of nut consumption in participants with T allele (GT + TT) resulted in 34% reduction of MetS risk after adjustment for confounders (HR: 0.66 (0.49–0.69)). After stratification by weigh change (< 7% or ≥ 7% weight gain), in individuals with ≥ 7% weight gain, highest tertile of nut consumption was associated with reduced risk of MetS among the risk allele of rs7903146. In the risk allele of rs12255372, among individuals with < 7% weight gain, third tertile of nuts intake reduced the risk of MetS, after adjustment for confounders.

Conclusion

Higher consumption of nuts may reduces the risk of MetS in T-risk allele of the TCF7L2 rs7903146 and rs12255372 variants and weight change may modify this association.
Three-month outcomes from a patient-centered program to treat opioid use disorder in Iowa, USA
Authors: Lynch Alison C. , Weber Andrea N. , Hedden Suzy , Sabbagh Sayeh , Arndt Stephan , Acion Laura
Published: January 2021

Background

Opioid use disorder (OUD), a chronic disease, is a major public health problem. Despite availability of effective treatment, too few people receive it and treatment retention is low. Understanding barriers and facilitators of treatment access and retention is needed to improve outcomes for people with OUD.

Objectives

To assess 3-month outcomes pilot data from a patient-centered OUD treatment program in Iowa, USA, that utilized flexible treatment requirements and prioritized engagement over compliance.

Methods

Forty patients (62.5% female: mean age was 35.7 years, SD 9.5) receiving medication, either buprenorphine or naltrexone, to treat OUD were enrolled in an observational study. Patients could select or decline case management, counseling, and peer recovery groups. Substance use, risk and protective factors, and recovery capital were measured at intake and 3 months.

Results

Most participants reported increased recovery capital. The median Assessment of Recovery Capital (ARC) score went from 37 at enrollment to 43 (p < 0.01). Illegal drug use decreased, with the median days using illegal drugs in the past month dropping from 10 to 0 (p < 0.001). Cravings improved: 29.2% reported no cravings at intake and 58.3% reported no cravings at 3 months (p < 0.001). Retention rate was 92.5% at 3 months. Retention rate for participants who were not on probation/parole was higher (96.9%) than for those on probation/parole (62.5%, p = 0.021).

Conclusion

This study shows preliminary evidence that a care model based on easy and flexible access and strategies to improve treatment retention improves recovery capital, reduces illegal drug use and cravings, and retains people in treatment.
Distribution of the T12 erector spinal muscle plane block in the dorsal region guided by ultrasound
Authors: Zhang Jin-Feng , Zhang Wei-Wei , Wang Jia , Guo Hao , Wang Ting
Published: January 2021

Background

This study aimed to explore the distribution of the erector spinal muscle plane block of the thoracic 12 vertebral body (T12) in the dorsal region guided by ultrasound.

Methods

A total of 28 patients, who underwent elective lumbar surgery, were enrolled in the present study. These patients were aged between 18 and 65 years, and the American Society of Anesthesiologists (ASA) grade was 1 or 2. The block of the T12 transverse process erector spinal muscle was performed under the guidance of ultrasound, and each side was injected with 25 ml of 0.4% ropivacaine hydrochloride + 2 mg of dexamethasone. The back areas were measured using the cold-warm method (the back area was divided into 11 areas [T7–S1] with the body surface marker). At 10, 20, 30, 40, 50, and 60 min after the drug injection, the effectiveness of the regional block was recorded. The presence of puncture hematoma, local anesthesia drug poisoning, nausea, vomiting, headache, and dizziness after the block was recorded.

Results

The range of the T12 transverse process block was basically fixed at 30 min after the single injection. No pneumothorax, hematoma, or local anesthetic poisoning occurred in any of the patients.

Conclusion

The effective longitudinal plane of the T12 transverse process erector spinal muscle block was mainly distributed in the T9–L5 dorsal cutaneous branches, and the distribution of the block area was safe and stable.
Stakeholder perspectives on clinical research related to therapies for rare diseases: therapeutic misconception and the value of research
Authors:   In collaboration with the Canadian Inherited Metabolic Diseases Research Network, Tingley Kylie , Coyle Doug , Graham Ian D. , Chakraborty Pranesh , Wilson Kumanan , Potter Beth K.
Published: January 2021

Background

For many rare diseases, few treatments are supported by strong evidence. Patients, family members, health care providers, and policy-makers thus have to consider whether to accept, recommend, or fund treatments with uncertain clinical effectiveness. They must also consider whether and how to contribute to clinical research that may involve receiving or providing the therapy being evaluated.

Objective

To understand why and how patients and families with rare metabolic diseases, specialist metabolic physicians, and health policy advisors choose whether to participate in studies and how they use and value research.

Methods

We conducted separate focus group interviews with each stakeholder group (three groups in total); two groups were conducted by telephone and the third was held in-person. Participants were recruited using purposive sampling. We analyzed each interview transcript sequentially using a qualitative description approach to inductively identify key themes. Several strategies to ensure credibility and trustworthiness were used including debriefing sessions after each focus group and having multiple team members review transcripts.

Results

Four patients/caregivers, six physicians, and three policy advisors participated. Our findings did not support conventional perspectives that therapeutic misconception (gaining access to treatment) is the main motivating factor for patients/caregivers to participate in clinical research. Rather, patients’/caregivers’ expressed reasons for participating in research included advancing science for the next generation and having an opportunity to share their experiences. Patients/caregivers and physicians described the difficulties in weighing risks versus benefits of accepting treatments not well-supported by evidence. Physicians also reported feeling conflicted in their dual role as patient advisor/advocate and evaluator of the evidence. Policy advisors were primarily focused on critically appraising the evidence to make recommendations for the health system.

Conclusions

Stakeholders differ in their perspectives on rare disease research but share concerns about the risks versus benefits of therapies when making individual- and population-level decisions.
Scaling‐up school mental health services in low resource public schools of rural Pakistan: the Theory of Change (ToC) approach
Authors: Hamdani Syed Usman , Huma Zill-e- , Suleman Nadia , Warraitch Azza , Muzzafar Naila , Farzeen Midhat , Minhas Fareed Aslam , Rahman Atif , Wissow Lawrence S.
Published: January 2021

Background

Ninety percent of children with mental health problems live in low or middle-income countries (LMICs). School-based programs offer opportunities for early identification and intervention, however implementation requires cross-sector collaboration to assure sustainable delivery of quality training, ongoing supervision, and outcomes monitoring at scale. In Pakistan, 35% of school-aged children are reported to have emotional and behavioral problems. As in many other LMICs, the government agencies who must work together to mount school-based programs have limited resources and a limited history of collaboration. The “Theory of Change” (ToC) process offers a way for new partners to efficiently develop mutual goals and long-term prospects for sustainable collaboration.

Objective

Develop a model for scale-up of school based mental health services in public schools of Pakistan.

Methods

We used ToC workshops to develop an empirically supported, ‘hypothesized pathway’ for the implementation of WHO’s School Mental Health Program in the public schools of rural Pakistan. Three workshops included 90 stakeholders such as policy makers from education and health departments, mental health specialists, researchers, head teachers, teachers and other community stakeholders including non-governmental organizations.

Results

The ToC process linked implementers, organizations, providers and consumers of school mental health services to develop common goals and relate them (improved child socioemotional wellbeing, grades and participation in activities) to interventions (training, monitoring and supervision of teachers; collaboration with parents, teachers and primary health care facilities and schools). Key testable assumptions developed in the process included buy-in from health care providers, education officials and professionals, community-based organizations and families. For example, teachers needed skills for managing children’s problems, but their motivation might come from seeking improved school performance and working conditions. Poverty, stigma and lack of child mental health literacy among teachers, administration, and parents were identified as key hypothesized barriers. Children and their families were identified as key stakeholders to make such a program successful.

Discussion

ToC workshops assisted in team building and served as a stakeholders’ engagement tool. They helped to develop and support testable hypotheses about the structures, collaborations, and knowledge most important to scaling-up school based mental health services in Pakistan.
Distinct role of 5′UTR sequences in dendritic trafficking of BDNF mRNA: additional mechanisms for the BDNF splice variants spatial code
Authors: Colliva Andrea , Tongiorgi Enrico
Published: January 2021

The neurotrophin Brain-derived neurotrophic factor (BDNF) is encoded by multiple bipartite transcripts. Each BDNF transcript is composed by one out of 11 alternatively spliced exons containing the 5′untranslated region (UTR), and one common exon encompassing the coding sequence (CDS) and the 3′UTR with two variants (short and long). In neurons, BDNF mRNA variants have a distinct subcellular distribution, constituting a “spatial code”, with exon 1, 3, 5, 7 and 8 located in neuronal somata, exon 4 extending into proximal dendrites, and exon 2 and 6 reaching distal dendrites. We previously showed that the CDS encodes constitutive dendritic targeting signals (DTS) and that both the 3′UTR-short and the 3′UTR-long contain activity-dependent DTS. However, the role of individual 5′UTR exons in mRNA sorting remains unclear. Here, we tested the ability of each different BDNF 5′UTRs to affect the subcellular localization of the green fluorescent protein (GFP) reporter mRNA. We found that exon 2 splicing isoforms (2a, 2b, and 2c) induced a constitutive dendritic targeting of the GFP reporter mRNA towards distal dendritic segments. The other isoforms did not affect GFP-mRNA dendritic trafficking. Through a bioinformatic analysis, we identified five unique cis-elements in exon 2a, 2b, and 2c which might contribute to building a DTS. This study provides additional information on the mechanism regulating the cellular sorting of BDNF mRNA variants.
Efficacy and safety of geptanolimab (GB226) for relapsed or refractory peripheral T cell lymphoma: an open-label phase 2 study (Gxplore-002)
Authors: Shi Yuankai , Wu Jianqiu , Wang Zhen , Zhang Liling , Wang Zhao , Zhang Mingzhi , Cen Hong , Peng Zhigang , Li Yufu , Fan Lei , Guo Ye , Ma Liping , Cui Jie , Gao Yuhuan , Yang Haiyan , Zhang Hongyu , Wang Lin , Zhang Weihua , Zhang Huilai , Xie Liping , Jiang Ming , Zhou Hui , Shuang Yuerong , Su Hang , Ke Xiaoyan , Jin Chuan , Du Xin , Du Xin , Liu Li , Xi Yaming , Ge Zheng , Feng Ru , Zhang Yang , Zhou Shengyu , Xie Fan , Wang Qian
Published: January 2021

Background

Peripheral T cell lymphoma (PTCL) is a rare disease and recent approved drugs for relapsed/refractory (r/r) PTCL provided limited clinical benefit. We conducted this study to evaluate the efficacy and safety of geptanolimab (GB226), an anti-PD-1 antibody, in r/r PTCL patients.

Methods

We did this single-arm, multicenter phase 2 study across 41 sites in China. Eligible patients with r/r PTCL received geptanolimab 3 mg/kg intravenously every 2 weeks until disease progression or intolerable toxicity. All patients who received at least one dose of geptanolimab and histological confirmed PTCL entered full analysis set (FAS). The primary endpoint was objective response rate (ORR) in FAS assessed by the independent radiological review committee (IRRC) per Lugano 2014 criteria.

Results

Between July 12, 2018, and August 15, 2019, 102 patients were enrolled and received at least one dose of geptanolimab. At the data cutoff date (August 15, 2020), the median follow-up was 4.06 (range 0.30–22.9) months. For 89 patients in FAS, 36 achieved objective response (40.4%, 95% CI 30.2–51.4), of which 13 (14.6%) were complete response and 23 (25.8%) had partial response assessed by IRRC. The median duration of response (DOR) was 11.4 (95% CI 4.8 to not reached) months per IRRC. Patients with PD-L1 expression ≥ 50% derived more benefit from geptanolimab treatment compared to < 50% ones (ORR, 53.3% vs. 25.0%, p = 0.013; median PFS 6.2 vs. 1.5 months, p = 0.002). Grade ≥ 3 treatment-related adverse events occurred in 26 (25.5%) patients, and the most commonly observed were lymphocyte count decreased (n = 4) and platelet count decreased (n = 3). Serious adverse events were observed in 45 (44.1%) patients and 19 (18.6%) were treatment related.

Conclusions

In this study, geptanolimab showed promising activity and manageable safety profile in patients with r/r PTCL. Anti-PD-1 antibody could be a new treatment approach for this patient population.

Trial registration: This clinical trial was registered at the ClinicalTrials.gov (NCT03502629) on April 18, 2018.
The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials
Authors: Saeed Anwaar , Park Robin , Sun Weijing
Published: January 2021

Several targeted therapies have shown efficacy in patients with advanced gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJC), including anti-angiogenic agents and immune checkpoint inhibitors. Ramucirumab, an anti-VEGFR2 antibody, has shown efficacy in GC, but the benefits are limited, in part due to MET-mediated resistance. Other VEGF targeted agents like VEGF tyrosine kinase inhibitors (TKIs) with broad multi-kinase inhibitory spectrum like regorafenib and cabozantinib have also shown modest single agent activity in early phase trials. For immune checkpoint inhibitors, pembrolizumab (anti-PD-1) monotherapy confers survival advantage as 3rd line therapy for the PD-L1 expressing GC and GEJC population and has been approved for use in this setting. Extensive tumor microenvironment immune modulatory effects from antiangiogenic agents have been demonstrated from preclinical data which support the clinical study rationale of dual blockade of VEGF and immune checkpoint. In addition, FDA has approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in hepatocellular carcinoma and renal cell carcinoma. Promising clinical activity has been demonstrated in patients with refractory GC/GEJC when treated with dual blockade combination with antiangiogenic agents and immune checkpoint inhibitors like PD-1/PD-L1 inhibitors in several phase I/II trials. This review highlights the trials investigating these novel combinations as well as their preclinical rationale.
A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway
Authors: Xie Wei , Zhao Huijie , Wang Fengxian , Wang Yiyun , He Yuan , Wang Tong , Zhang Kunchi , Yang Hao , Zhou Zhaoli , Shi Haibin , Wang Jin , Huang Gang
Published: January 2021

Background

Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents.

Methods

Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity.

Results

The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7+ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling.

Conclusion

SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.
Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway
Authors: Wang Xuehui , Ji Changle , Hu Jiashu , Deng Xiaochong , Zheng Wenfang , Yu Yunhe , Hua Kaiyao , Zhou Xiqian , Fang Lin
Published: January 2021

Background

Circular RNAs (circRNAs), a novel class of endogenous RNAs, have shown to participate in the development of breast cancer (BC). Hsa_circ_0005273 is a circRNA generated from several exons of PTK2. However, the potential functional role of hsa_circ_0005273 in BC remains largely unknown. Here we aim to evaluate the role of hsa_circ_0005273 in BC.

Methods

The expression level of hsa_circ_0005273 and miR-200a-3p were examined by RT-qPCR in BC tissues and cell lines. The effect of knocking down hsa_circ_0005273 in BC cell lines were evaluated by examinations of cell proliferation, migration and cell cycle. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0005273 in BC. RNA immunoprecipitation assay, RNA probe pull-down assay, luciferase reporter assay and fluorescence in situ hybridization were conducted to confirm the relationship between hsa_circ_0005273, miR-200a-3p and YAP1.

Results

Hsa_circ_0005273 is over-expressed in BC tissues and cell lines, whereas miR-200a-3p expression is repressed. Depletion of hsa_circ_0005273 inhibited the progression of BC cells in vitro and in vivo, while overexpression of hsa_circ_0005273 exhibited the opposite effect. Importantly, hsa_circ_0005273 upregulated YAP1 expression and inactivated Hippo pathway via sponging miR-200a-3p to promote BC progression.

Conclusions

Hsa_circ_0005273 regulates the miR-200a-3p/YAP1 axis and inactivates Hippo signaling pathway to promote BC progression, which may become a potential biomarker and therapeutic target.