bluuebunny/crossref_metadata_2025 huggingface dataset:
Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction
Authors: Selli Mehmet Emrah , Landmann Jack , Terekhova Marina , Lattin John , Heard Amanda , Hsu Yu-Sung , Chang Tien-Ching , Chang Ju-fang , Warrington John M , Ha Helen , Kingston Natalie L , Hogg Graham , Slade Michael , Berrien-Elliott Melissa M , Foster Mark , Kersting-Schadek Samantha , Gruszczynska Agata , DeNardo David , Fehniger Todd A , Artyomov Maxim , Singh Nathan
Published: May 2023

T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have demonstrated impressive activity against relapsed or refractory B cell cancers yet fail to induce durable remissions for nearly half of patients treated. Enhancing the efficacy of this therapy requires detailed understanding of the molecular circuitry that restrains CAR-driven anti-tumor T cell function. We developed and validated an in vitro model that drives T cell dysfunction through chronic CAR activation and interrogated how CAR costimulatory domains, central components of CAR structure and function, contribute to T cell failure. We found that chronic activation of CD28-based CARs results in activation of classical T cell exhaustion programs and development of dysfunctional cells that bear the hallmarks of exhaustion. In contrast, 41BB-based CARs activate a divergent molecular program and direct differentiation of T cells into a novel cell state. Interrogation of CAR T cells from a patient with progressive lymphoma confirmed activation of this novel program in a failing clinical product. Further, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is directly responsible for impairing CAR T cell function. These findings identify that costimulatory domains are critical regulators of CAR-driven T cell failure and that targeted interventions are required to overcome costimulation-dependent dysfunctional programs.
Melatonin and erastin emerge synergistic anti-tumor effects on oral squamous cell carcinoma by inducing apoptosis, ferroptosis, and inhibiting autophagy through promoting ROS
Authors: Wang Leilei , Wang Chuan , Li Xuan , Tao Zhuoying , Zhu Wangyong , Su Yuxiong , Choi Wing Shan
Published: May 2023

Background

Oral squamous cell carcinomas are one of the most common cancers worldwide with aggressive behavior and poor prognosis. Reactive oxygen species (ROS) are associated with cancer and cause various types of regulated cell death (RCD). Inducing the RCD pathway by modulating ROS levels is imperative to conquer cancers. The aim of this study is to investigate the synergistic anticancer effects of melatonin and erastin on ROS modulation and subsequent RCD induction.

Methods

Human tongue squamous cell carcinoma cell lines (SCC-15 cells) were treated with melatonin, erastin, or their combination. Cell viability, ROS levels, autophagy, apoptosis, and ferroptosis levels were tested according to the results of the PCR array, which were verified with/without the induction and inhibition of ROS by H2O2 and N-acetyl-L-cysteine, respectively. In addition, a mouse-based subcutaneous oral cancer xenograft model was constructed to identify the effects of melatonin, erastin, and their combination on the autophagy, apoptosis, and ferroptosis levels in isolated tumor tissues.

Results

ROS levels were increased by the administration of melatonin at high concentrations (mM), and the combination of melatonin with erastin enhanced the levels of malonic dialdehyde, ROS, and lipid ROS, and reduced the levels of glutamate and glutathione. SQSTM1/p62, LC3A/B, cleaved caspase-3, and PARP1 protein levels in SCC-15 cells were also increased by melatonin plus erastin treatment, which further increased as ROS accumulated, and decreased as ROS levels were suppressed. Combined treatment of melatonin and erastin markedly reduced the tumor size in vivo, demonstrated no obvious systemic side effects, and significantly enhanced the apoptosis and ferroptosis levels in the tumor tissues, in parallel with decreased autophagy levels.

Conclusions

Melatonin combined with erastin exhibits synergistic anticancer effects without adverse reactions. Herein, this combination might become a promising alternative strategy for oral cancer treatment.

Graphical Abstract
Three QTL from Oryza meridionalis Could Improve Panicle Architecture in Asian Cultivated Rice
Authors: Yang Ying , Zhang Yu , Li Jing , Xu Peng , Wu Zhijuan , Deng Xianneng , Pu Qiuhong , Lv Yonggang , Elgamal Walid Hassan Ali Soliman , Maniruzzaman Sheikh , Deng Wei , Zhou Jiawu , Tao Dayun
Published: May 2023

Rice panicle architecture is directly associated with grain yield and is also the key target in high-yield rice breeding program. In this study, three BC6F2segregation populations derived from the crosses between two accessions ofOryza meridionalisand aO. sativaspp.japonicacultivar Dianjingyou 1, were employed to map QTL for panicle architecture. Three QTL,EP4.2,DEP7andDEP8were identified and validated using substitution mapping strategy on chromosome 4, 9 and 8, respectively. The three QTL showed pleiotropic phenotype on panicle length (PL), grain number per panicle (GNPP), number of primary branches (NPB), number of secondary branches (NSB), and grain width.DEP7andDEP8showed yield-enhancing potential by increasing GNPP, NPB and NSB, whileEP4.2exhibited wide grain, short stalk and panicle which can improve plant and panicle architecture, too. Moreover, epistatic interaction for PL was detected betweenEP4.2andDEP7, and epistatic analysis betweenDEP7andDEP8for GNPP and NPB also revealed significant two QTL interactions. The result would help us understand the molecular basis of panicle architecture and lay the foundation for using these three QTL in rice breeding.
Measurement of maternal morbidity during postpartum with the WHO-WOICE tools in Morocco
Authors: Hababa Hanane , Assarag Bouchra
Published: May 2023

Background

Maternal morbidity refers to any health problems or complications experienced by a woman during pregnancy, childbirth, or the postpartum period. Many studies have documented the, mostly negative, effects of maternal ill-health on functioning. Although, measurement of maternel morbidity remains underdeveloped. We aimed to evaluate the prevalence of non-severe maternal morbidities (including overall health, domestic and sexual violence, functionality, and mental health) in women during postpartum care and further analyze factors associated with compromised mental functioning and clinical health by administration of the WHO’s WOICE 2.0 instrument.

Methods

A cross-sectional study was conducted at 10 Health centers in Marrakech, Morocco with WOICE questionnaire included three sections: the first with maternal and obstetric history, sociodemographic data, risk and environment factors, violence and sexual health; the second considers functionality and disability, general symptoms and mental health; and the third includes data on physical and laboratory tests. This paper presents descriptive data on the distribution of functioning status among postpartum women.

Results

A total of 253 women averaging 30 years of age participated. For self-reported health status of women, more than 40% reported good health, and just 9.09% of women had a health condition reported by the attending physician. Among postpartum women with clinical diagnoses, 16.34% had direct (obstetric) conditions and 15.56% indirect (medical) problems. When screening for factors in the expanded morbidity definition, about 20.95% reported exposure to violence. Anxiety was identified in 29.24% of cases, and depression in 17.78%. Looking into gestational results, just 14.6% delivered by cesarean section and 15.02% had preterm birth. We found also that 97% reported “good baby health” in the postpartum evaluation, with 92% of exclusive breastfeeding.

Conclusion

Considering these results, improving the quality of care for women requires a multi-faceted approach, including increased research, better access to care, and improved education and resources for women and healthcare providers.
Vascular ring: prenatal diagnosis and prognostic management based on sequential cross-sectional scanning by ultrasound
Authors: Zhou Yi , Zhou Yuanyuan , Yu Tingting , Li Wanyan , Zhang Jingshu , Zhang Chaoxue
Published: May 2023

Background

In terms of embryonic origin, vascular ring is a congenital anomaly in which the aortic arch and its branches completely or incompletely encircle and compress the trachea or esophagus. Early and accurate diagnosis of a vascular ring is the key to treatment. Prenatal diagnosis mainly relies on fetal echocardiography, but the rate of missed diagnosis and misdiagnosis is still very high, and the prognosis has not been evaluated. The aim of this study was to investigate the accuracy of prenatal diagnosis and to evaluate the prognosis semi-quantitatively according to the shape of the ring and the distance between the vessel and the trachea.

Methods

From 2019 to 2021, 37,875 fetuses underwent prenatal ultrasound examination in our center. All fetal cardiac examinations were performed using the fetal echocardiography method proposed by the American Institute of Ultrasound in Medicine (AIUM) combined with dynamic sequential cross-sectional observation (SCS). For SCS, the standard abdominal section was taken as the initial section, and the probe was moved cephalically along the long axis of the body until the superior mediastinum had disappeared. If a vascular ring was found, the shape of the ring and the distance of the branch to the airway were observed. The distance relationship with the airway was divided into three grades: I-III; the closer the distance, the lower the grade. The vascular rings were monitored every 4 weeks before birth. All were monitored before surgery or 1 year after birth.

Results

A total of 418 cases of vascular rings were detected. There was no missed diagnoses or misdiagnoses by SCS. The vessels formed different shaped rings according to their origin and route. Grade I, “入” and “O” rings have a poor prognosis and are associated with the highest risk of respiratory symptoms.

Conclusions

SCS can accurately diagnose vascular rings before delivery, evaluate the shape and size of the rings to conduct prenatal monitoring of children until birth, which plays a guiding role in airway compression after birth.
“I am not really into the government telling me what I need to eat”: exploring dietary beliefs, knowledge, and practices among ethnically diverse communities in England
Authors: Ojo Abimbola S. , Nnyanzi Lawrence A. , Giles Emma L. , Ells Louisa , Okeke Sylvester R. , Ajayi Kobi V. , Bolarinwa Obasanjo Afolabi
Published: May 2023

Background

Communities with diverse ethnicity in high-income countries are disproportionately affected by poor diet-related health outcomes. In England, the United Kingdom’s government’s healthy eating dietary resources are not well accepted and are underutilised among this population. Thus, this study explored perceptions, beliefs, knowledge, and practices around dietary intake among communities with African and South Asian ethnicity residing in Medway, England.

Methods

This qualitative study generated data from 18 adults aged 18 and above using a semi-structured interview guide. These participants were sampled using purposive and convenience sampling strategies. All the interviews were conducted in English over the telephone, and responses were thematically analysed.

Results

Six overarching themes were generated from the interview transcripts: eating patterns, social and cultural factors, food preferences and routines, accessibility and availability, health and healthy eating, and perceptions about the United Kingdom government’s healthy eating resources.

Conclusion

The results of this study indicate that strategies to improve access to healthy foods are required to improve healthy dietary practices among the study population. Such strategies could help address this group’s structural and individual barriers to healthy dietary practices. In addition, developing a culturally responsive eating guide could also enhance the acceptability and utilisation of such resources among communities with ethnic diversity in England.
The effects of melissa officinalis on depression and anxiety in type 2 diabetes patients with depression: a randomized double-blinded placebo-controlled clinical trial
Authors: Safari Mostafa , Asadi Akbar , Aryaeian Naheed , Huseini Hasan Fallah , shidfar Farzad , Jazayeri Shima , Malek Mojtaba , Hosseini Agha Fateme , hamidi Zahra
Published: May 2023

Background

Depression is more common in diabetic patients, with a 1.5-fold increased risk of death.Melissa officinalis(M. officinalis) have anti-diabetic and anti-depression activities. The study aimed to determine the efficacy ofM. officinalisextract on depression, anxiety, and sleep quality in patients with type 2 diabetes with depressive symptoms.

Methods

In this double-blind clinical trial, 60 volunteer patients (age range 20–65 years) with type 2 diabetes mellitus with symptoms of depression were randomized into the intervention (received 700 mg/day hydroalcoholic extract;n = 30) or control group (received 700 mg/day toasted flour;n = 30). Dietary intake, physical activity, anthropometric indices, FBS (Fasting blood sugar), hs-CRP(High-sensitivity C-reactiveprotein), depression, anxiety, and sleep quality were determined at the beginning and end of the study. Depression and anxiety were assessed by Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI), respectively; sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI).

Results

Sixty participants receivedM. officinalisextract or placebo, of which 44 patients completed the 12-week double-blind clinical trial. After 12-week the mean change of depression and anxiety scores were statistically significant between the two groups (p < 0.001 and p = 0.04, respectively), but no significant differences were observed in FBS, hs-CRP, anthropometric indices, sleep quality, and blood pressure.In the intervention group, there was a significant decrease in depression and anxiety severity(p < 0.001 andp = 0.01, respectively) at the end of the study compared to the baseline.

Trial registration

All protocols in this study were followed in accordance with the Helsinki Declaration (1989 revision). Ethical approval for this study was obtained from the Iran University of Medical Sciences Ethics committee (IR.IUMS.FMD.REC 1396.9413468004; research.iums.ac.ir). The study was registered at the Iranian Registry of Clinical Trials (IRCT201709239472N16); Registration date: 09/10/2017.
Healthcare students’ prevention training in a sanitary service: analysis of health education interventions in schools of the Grenoble academy
Authors: Kuenemann Marie , Gaillet Mélanie , Shankland Rebecca , Fournier Joey , Boussat Bastien , François Patrice
Published: May 2023

Background

The sanitary service is a mandatory prevention training programme for all French healthcare students. Students receive training and then have to design and carry out a prevention intervention with various populations. The aim of this study was to analyse the type of health education interventions carried out in schools by healthcare students from one university in order to describe the topics covered and the methods used.

Method

The 2021–2022 sanitary service of University Grenoble Alpes involved students in maieutic, medicine, nursing, pharmacy and physiotherapy. The study focused on students who intervened in school contexts. The intervention reports written by the students were read doubly by independent evaluators. Information of interest was collected in a standardised form.

Results

Out of the 752 students involved in the prevention training program, 616 (82%) were assigned to 86 schools, mostly primary schools (58%), and wrote 123 reports on their interventions. Each school hosted a median of 6 students from 3 different fields of study. The interventions involved 6853 pupils aged between 3 and 18 years. The students delivered a median of 5 health prevention sessions to each pupil group and spent a median of 25 h (IQR: 19–32) working on the intervention. The themes most frequently addressed were screen use (48%), nutrition (36%), sleep (25%), harassment (20%) and personal hygiene (15%). All students used interactive teaching methods such as workshops, group games or debates that was addressed to pupils’ psychosocial (mainly cognitive and social) competences. The themes and tools used differed according to the pupils’ grade levels.

Conclusion

This study showed the feasibility of conducting health education and prevention activities in schools by healthcare students from five professional fields who had received appropriate training. The students were involved and creative, and they were focused on developing pupils’ psychosocial competences.
Effect of a curriculum transformation on pharmacy student self-efficacy, self-reported activities, and satisfaction in degree and career choice
Authors: Singh Harjit Kaur , Lyons Kayley Marie , Brock Tina Penick , Malone Daniel Thomas
Published: May 2023

Background

Curriculum revision in healthcare programs occurs frequently, but to undergo a whole degree transformation is less common. Also, the outcomes of curriculum redesign interventions on the selfreported clinical decision making, experiences, and perceptions of graduates of health education programs is unclear. This study evaluated these factors as an outcome of a pharmacy degree whole-curriculum transformation.

Methods

A 25-item cross-sectional end-of-course survey was developed to evaluate pharmacy student decisions, experiences, and perceptions upon completion of degree, pre- and post- curriculum transformation. A two-way analysis of variance (ANOVA) was used to determine whether the responses to the items classed within the main factors differed across the two cohorts. Independent t-tests were used to examine the student responses to the individual questions between the two cohorts.

Results

Graduates from the transformed degree had greater self-efficacy in clinical activities, were more satisfied with their education, found course activities more useful, and were more confident in their career choice. Transformed pharmacy degree students also reported spending more time on weekdays and weekends on activities such as attending lectures and working. Student satisfaction with their choice to attend pharmacy school was also significantly higher in transformed degree students.

Conclusions

Responses to the end of degree survey indicate that students who completed the transformed pharmacy curriculum have had positive experiences throughout their degree and felt more prepared for practice as pharmacists in comparison to students who completed the established degree. These results add value to those collected from other sources (e.g., student evaluations, assessment scores, preceptors focus groups, and other stakeholder inputs) consistent with a comprehensive quality improvement model.
Interprofessional peer-assisted learning for pharmacy and physical therapy students using inhalers and inhalation devices
Authors: Jones C. Allyson , Li Johnson Ching-hong , Hall Mark , Bertholet Renette , Turk Tarek , Sadowski Cheryl A.
Published: May 2023

Background

Peer-assisted learning (PAL) is exchanging knowledge between learners often from similar professional levels. Limited evidence exists on the effectiveness of PAL between different healthcare professions. The purpose of this study is to evaluate the knowledge, confidence, and perception of students engaged in an interprofessional PAL activity with pharmacy students instructing physical therapy students on the proper technique, cleaning/storage and therapeutic knowledge on inhaler devices for treatment of pulmonary conditions.

Methods

Pharmacy and physical therapy students completed a survey before and immediately after the PAL activity. As instructors, pharmacy students rated their experience with inhalers, their confidence if they were to assist clients on the use of inhaler devices and confidence in teaching peers. Physical therapy students completed surveys on inhaler knowledge with 10 scenario-based multiple-choice questions, and their confidence if they were to assist clients with inhaler devices. The knowledge questions were grouped into three categories: storage and cleaning of inhalers (3 questions), technique of using inhalers (4 questions), and therapeutic knowledge of drugs given by inhalation (3 questions).

Results

102 physical therapy and 84 pharmacy students completed the activity and surveys. For the physical therapy students, the mean improvement of the total score for knowledge-based questions was 3.6 ± 1.8 (p < 0.001). The question with the fewest number of correct answers (13%) before the PAL activity had the highest number of correct answers post-activity (95%). Prior to the activity, no physical therapy students felt certain/very certain about their knowledge on inhalers, yet after PAL activity this proportion increased to 35%. The percent of pharmacy students reporting their confidence as “certain” and “very certain” in teaching peers increased from 46% before the activity to 90% afterwards. Pharmacy students rated the monitoring and follow-up of inhaler devices as the lowest expectation for physical therapists to play a role. Steps taken to prepare for this PAL activity were also discussed.

Conclusions

Interprofessional PAL can increase knowledge and confidence of healthcare students reciprocally learning and teaching in joint activities. Allowing such interactions facilitate students to build interprofessional relationships during their training, which can increase communication and collaboration to foster an appreciation for each other’s roles in clinical practice.
Placental transcriptome analysis of hypertensive pregnancies identifies distinct gene expression profiles of preeclampsia superimposed on chronic hypertension
Authors: Hesson Ashley M. , Langen Elizabeth S. , Plazyo Olesya , Gudjonsson Johann E. , Ganesh Santhi K.
Published: May 2023

Background

The pathogenesis of preeclampsia superimposed on chronic hypertension (SI) is poorly understood relative to preeclampsia (PreE) occurring in pregnant people without chronic hypertension. Placental transcriptomes in pregnancies complicated by PreE and SI have not been previously compared.

Methods

We identified pregnant people in the University of Michigan Biorepository for Understanding Maternal and Pediatric Health with hypertensive disorders affecting singleton, euploid gestations (N = 36) along with non-hypertensive control subjects (N = 12). Subjects were grouped as: (1) normotensive (N = 12), (2) chronic hypertensive (N = 13), (3) preterm PreE with severe features (N = 5), (4) term PreE with severe features (N = 11), (5) preterm SI (N = 3), or (6) term SI (N = 4). Bulk RNA sequencing of paraffin-embedded placental tissue was performed. The primary analysis assessed differential gene expression relative to normotensive and chronic hypertensive placentas, where Wald adjusted P values < 0.05 were considered significant. Unsupervised clustering analyses and correlation analyses were performed between conditions of interest, and a gene ontology was constructed.

Results

Comparing samples from pregnant people with hypertensive diseases to non-hypertensive controls, there were 2290 differentially expressed genes. The log2-fold changes in genes differentially expressed in chronic hypertension correlated better with term (R = 0.59) and preterm (R = 0.63) PreE with severe features than with term (R = 0.21) and preterm (R = 0.22) SI. A relatively poor correlation was observed between preterm SI and preterm PreE with severe features (0.20) as well as term SI and term PreE with severe features (0.31). The majority of significant genes were downregulated in term and preterm SI versus normotensive controls (92.1%, N = 128). Conversely, most term and preterm PreE with severe features genes were upregulated compared to the normotensive group (91.8%, N = 97). Many of the upregulated genes in PreE with the lowest adjusted P values are known markers of abnormal placentation (e.g., PAAPA, KISS1, CLIC3), while the downregulated genes with the greatest adjusted P values in SI have fewer known pregnancy-specific functions.

Conclusions

We identified unique placental transcriptional profiles in clinically relevant subgroups of individuals with hypertension in pregnancy. Preeclampsia superimposed on chronic hypertension was molecularly distinct from preeclampsia in individuals without chronic hypertension, and chronic hypertension without preeclampsia, suggesting that preeclampsia superimposed on hypertension may represent a distinct entity.
Evaluation of the possible association of PDCD-1 and LAG3 gene polymorphisms with hepatocellular carcinoma risk
Authors: Wei Jiankai , Liao Zhangxiu , Tao Ying , Liu Shuaiting
Published: May 2023

Purpose

Programmed death-1 (PDCD-1) and lymphocyte activating 3 (LAG3), two important immunosuppressive molecules, play crucial roles in immune escape of tumor cells. This study evaluated the effects of PDCD-1 (rs10204525 and rs36084323), and LAG3 (rs870849 and rs1882545) gene polymorphisms on hepatocellular carcinoma (HCC) risk.

Methods

341 patients with HCC and 350 cancer-free controls in the South Chinese population were included in a population-based case-control study. DNAs were extracted from peripheral blood samples. Genotypes were analyzed using multiplex PCR and sequencing. SNPs were analyzed using multiple inheritance models (co-dominant, dominant, recessive, and over-dominant).

Results

The allele and genotype frequencies of neither of the four polymorphisms, adjusted for age and gender, differed between HCC patients and controls. The differences were also not significant after stratifying by gender and age. According to our results, HCC patients with rs10204525 TC genotype had significantly lower AFP levels than HCC patients with rs10204525 TT genotype (P = 0.004). Moreover, the frequency of PDCD-1 rs36084323 CT genotype reduced the risk of TNM grade (CT vs. C/C-T/T: OR = 0.57, 95%CI = 0.37–0.87, P = 0.049).

Conclusion

Our results demonstrated that the PDCD-1 (rs10204525 and rs36084323), and LAG3 (rs870849 and rs1882545) polymorphism did not influence the risk of HCC, PDCD-1 rs10204525 TC genotype was associated with the lower AFP levels and rs36084323 CT genotypes were related to HCC tumor grades in the South Chinese samples.
Does the presence of systemic artery–pulmonary circulation shunt during bronchial arterial embolization increase the recurrence of noncancer-related hemoptysis? A retrospective cohort study
Authors: Yan Hai-Tao , Lu Guang-Dong , Liu Jin , Liu Sheng , Shi Hai-Bin , Zhou Chun-Gao , Zu Qing-Quan
Published: May 2023

Background

The presence of systemic artery–pulmonary circulation shunt (SPS) during the bronchial arterial embolization (BAE) procedure, has been inferred to be a potential risk factor for recurrence. The aim of this study is to reveal the impact of SPS on the recurrence of noncancer-related hemoptysis after BAE.

Methods

In this study, 134 patients with SPS (SPS-present group) and 192 patients without SPS (SPS-absent group) who underwent BAE for noncancer-related hemoptysis from January 2015 to December 2020 were compared. Four different Cox proportional hazards regression models were used to clarify the impact of SPSs on hemoptysis recurrence after BAE.

Results

During the median follow-up time of 39.8 months, recurrence occurred in 75 (23.0%) patients, including 51 (38.1%) in the SPS-present group and 24 (12.5%) in the SPS-absent group. The 1-month, 1-year, 2-year, 3-year and 5-year hemoptysis-free survival rates in the SPS-present and SPS-absent groups were 91.8%, 79.7%, 70.6%, 62.3%, and 52.6% and 97.9%, 94.7%, 89.0%, 87.1%, and 82.3%, respectively (P < 0.001). The adjusted hazard ratios of SPSs in the four models were 3.37 [95% confidence intervals (CI), 2.07–5.47, P < 0.001 in model 1], 1.96 (95% CI, 1.11–3.49, P = 0.021 in model 2), 2.29 (95% CI, 1.34–3.92, P = 0.002 in model 3), and 2.39 (95% CI, 1.44–3.97, P = 0.001 in model 4).

Conclusions

The presence of SPS during BAE increases the recurrence probability of noncancer-related hemoptysis after BAE.
Surface-anchored microbial enzyme-responsive solid lipid nanoparticles enabling colonic budesonide release for ulcerative colitis treatment
Authors: Zhang Yipeng , Wang Liying , Wang Zi-Dan , Zhou Quan , Zhou Xuefei , Zhou Tianhua , Guan Yi-Xin , Liu Xiangrui
Published: May 2023

Colon-targeted oral drug delivery systems (CDDSs) are desirable for the treatment of ulcerative colitis (UC), which is a disease with high relapse and remission rates associated with immune system inflammation and dysregulation localized within the lining of the large bowel. However, the success of current available approaches used for colon-targeted therapy is limited. Budesonide (BUD) is a corticosteroid drug, and its rectal and oral formulations are used to treat UC, but the inconvenience of rectal administration and the systemic toxicity of oral administration restrict its long-term use. In this study, we designed and prepared colon-targeted solid lipid nanoparticles (SLNs) encapsulating BUD to treat UC by oral administration. A negatively charged surfactant (NaCS-C12) was synthesized to anchor cellulase-responsive layers consisting of polyelectrolyte complexes (PECs) formed by negatively charged NaCS and cationic chitosan onto the SLNs. The release rate and colon-specific release behavior of BUD could be easily modified by regulating the number of coated layers. We found that the two-layer BUD-loaded SLNs (SLN-BUD-2L) with a nanoscale particle size and negative zeta potential showed the designed colon-specific drug release profile in response to localized high cellulase activity. In addition, SLN-BUD-2L exhibited excellent anti-inflammatory activity in a dextran sulfate sodium (DSS)-induced colitis mouse model, suggesting its potential anti-UC applications.
How to exclude pulmonary embolism in patients hospitalized with COVID-19: a comparison of predictive scores
Authors: Vielhauer Jakob , Benesch Christopher , Pernpruner Anna , Johlke Anna-Lena , Hellmuth Johannes Christian , Muenchhoff Maximilian , Scherer Clemens , Fink Nicola , Sabel Bastian , Schulz Christian , Mayerle Julia , Mahajan Ujjwal Mukund , Stubbe Hans Christian
Published: May 2023

Background

Pulmonary embolism (PE) is an important complication of Coronavirus disease 2019 (COVID-19). COVID-19 is associated with respiratory impairment and a pro-coagulative state, rendering PE more likely and difficult to recognize. Several decision algorithms relying on clinical features and D-dimer have been established. High prevalence of PE and elevated Ddimer in patients with COVID-19 might impair the performance of common decision algorithms. Here, we aimed to validate and compare five common decision algorithms implementing age adjusted Ddimer, the GENEVA, and Wells scores as well as the PEGeD- and YEARS-algorithms in patients hospitalized with COVID-19.

Methods

In this single center study, we included patients who were admitted to our tertiary care hospital in the COVID-19 Registry of the LMU Munich. We retrospectively selected patients who received a computed tomography pulmonary angiogram (CTPA) or pulmonary ventilation/perfusion scintigraphy (V/Q) for suspected PE. The performances of five commonly used diagnostic algorithms (age-adjusted D-dimer, GENEVA score, PEGeD-algorithm, Wells score, and YEARS-algorithm) were compared.

Results

We identified 413 patients with suspected PE who received a CTPA or V/Q confirming 62 PEs (15%). Among them, 358 patients with 48 PEs (13%) could be evaluated for performance of all algorithms. Patients with PE were older and their overall outcome was worse compared to patients without PE. Of the above five diagnostic algorithms, the PEGeD- and YEARS-algorithms performed best, reducing diagnostic imaging by 14% and 15% respectively with a sensitivity of 95.7% and 95.6%. The GENEVA score was able to reduce CTPA or V/Q by 32.2% but suffered from a low sensitivity (78.6%). Age-adjusted D-dimer and Wells score could not significantly reduce diagnostic imaging.

Conclusion

The PEGeD- and YEARS-algorithms outperformed other tested decision algorithms and worked well in patients admitted with COVID-19. These findings need independent validation in a prospective study.
A mentored hands-on training model for scaling up implementation and intervention research in India: “connecting the dots”
Authors: Ransing Ramdas , Hawk Mary , McDonald Margaret , Jones Jacquelyn , Bhatia Triptish , Verma Vijay , Shah Gyan D. , Brar Jaspreet , Egan James Erin , Konsale Prasad , Kaur Jasmine , Singh Ravinder , Singh Harpreet , Dhaliwal R. S. , Wood Joel , Nimgaonkar Vishwajit , Deshpande Smita , Swaminathan Soumya
Published: May 2023

Despite the high burden of mental disorders in low- and middle-income countries (LMICs), less than 25% of those in need have access to appropriate services, in part due to a scarcity of locally relevant, evidence-based interventions and models of care. To address this gap, researchers from India and the United States and the Indian Council of Medical Research (ICMR) collaboratively developed a “Grantathon” model to provide mentored research training to 24 new principal investigators (PIs). This included a week-long didactic training, a customized web-based data entry/analysis system and a National Coordination Unit (NCU) to support PIs and track process objectives. Outcome objectives were assessed via scholarly output including publications, awards received and subsequent grants that were leveraged. Multiple mentorship strategies including collaborative problem-solving approaches were used to foster single-centre and multicentre research. Flexible, approachable and engaged support from mentors helped PIs overcome research barriers, and the NCU addressed local policy and day-to-day challenges through informal monthly review meetings. Bi-annual formal review presentations by all PIs continued through the COVID-19 pandemic, enabling interim results reporting and scientific review, also serving to reinforce accountability. To date, more than 33 publications, 47 scientific presentations, 12 awards, two measurement tools, five intervention manuals and eight research grants have been generated in an open-access environment. The Grantathon is a successful model for building research capacity and improving mental health research in India that could be adopted for use in other LMICs.
Clinical features, treatment, and outcomes of celiac-associated arthritis: a retrospective cohort study
Authors: Altaffer Ana Luiza , Weiss Pamela
Published: May 2023

Background

Although arthritis is recognized as an extra-intestinal manifestation of celiac disease, little is known about the clinical course and outcomes of pediatric celiac-associated arthritis. This study describes clinical characteristics, treatments, and outcomes of children with celiac-associated arthritis.

Methods

This was a retrospective cohort study of children with celiac disease seen in pediatric rheumatology clinic between 2004 and 2021 for joint complaints. Data was abstracted from electronic health records. Patient demographics and clinical manifestations were evaluated using standard descriptive statistics. Physician- and patient-reported outcomes were evaluated at the index visit, 6-month follow-up, and last recorded visit, and were compared using Wilcoxon signed-rank tests.

Results

Twenty-nine patients with celiac disease were evaluated for joint complaints, and 13 were diagnosed with arthritis. Their mean age was 8.9 years (SD 5.9), and 61.5% were female. Celiac disease diagnosis was made before arthritis diagnosis in only 2 cases (15.4%). Initial testing that led to the celiac disease diagnosis was obtained by the rheumatologist in 6 cases (46.2%). Only 8 patients (61.5%) had concomitant GI symptoms, and of these, 3 patients had BMI z-scores <-1.64 and 1 had impaired linear growth. Arthritis presentation was most often oligoarticular (76.9%) and asymmetric (84.6%). Most cases required systemic therapy (n = 11, 84.6%) with DMARDs, biologics, or both. Of the 10 patients who required systemic therapy and reported compliance with the gluten-free diet, 3 (30%) were able to stop systemic medications. Two of 3 patients who cleared celiac serologies came off systemic medications. Statistically significant improvement was noted in the number of joints involved (p = 0.02) and physician global assessment of disease activity (p = 0.03) between the index and final visit.

Conclusions

Rheumatologists play an important role in the identification of celiac disease, as arthritis was the presenting symptom in most cases and was not always associated with GI symptoms or poor growth. The arthritis was most often oligoarticular and asymmetric. Most children required systemic therapy. The gluten-free diet may not be sufficient to manage arthritis, but antibody clearance may be an indicator of higher likelihood of disease control off medications. Outcomes are promising with a combination of diet and medical therapy.
Role of macrophage autophagy in postoperative pain and inflammation in mice
Authors: Mitsui Kazuha , Hishiyama Sohei , Jain Aakanksha , Kotoda Yumi , Abe Masako , Matsukawa Takashi , Kotoda Masakazu
Published: May 2023

Background

Postoperative pain and inflammation are significant complications following surgery. Strategies that aim to prevent excessive inflammation without hampering natural wound-healing are required for the management of postoperative pain and inflammation. However, the knowledge of the mechanisms and target pathways involved in these processes is lacking. Recent studies have revealed that autophagy in macrophages sequesters pro-inflammatory mediators, and it is therefore being recognized as a crucial process involved in regulating inflammation. In this study, we tested the hypothesis that autophagy in macrophages plays protective roles against postoperative pain and inflammation and investigated the underlying mechanisms.

Methods

Postoperative pain was induced by plantar incision under isoflurane anesthesia in mice lacking macrophage autophagy (Atg5flox/flox LysMCre +) and their control littermates (Atg5flox/flox). Mechanical and thermal pain sensitivity, changes in weight distribution, spontaneous locomotor activity, tissue inflammation, and body weight were assessed at baseline and 1, 3, and 7 days after surgery. Monocyte/macrophage infiltration at the surgical site and inflammatory mediator expression levels were evaluated.

Results

Atg5flox/flox LysMCre + mice compared with the control mice exhibited lower mechanical and thermal pain thresholds and surgical/non-surgical hindlimb weight-bearing ratios. The augmented neurobehavioral symptoms observed in the Atg5flox/flox LysMCre + mice were associated with more severe paw inflammation, higher pro-inflammatory mediator mRNA expression, and more monocytes/macrophages at the surgical site.

Conclusion

The lack of macrophage autophagy augmented postoperative pain and inflammation, which were accompanied by enhanced pro-inflammatory cytokine secretion and surgical-site monocyte/macrophage infiltration. Macrophage autophagy plays a protective role in postoperative pain and inflammation and can be a novel therapeutic target.
A systematic review of the applications of markerless motion capture (MMC) technology for clinical measurement in rehabilitation
Authors: Lam Winnie W. T. , Tang Yuk Ming , Fong Kenneth N. K.
Published: May 2023

Background

Markerless motion capture (MMC) technology has been developed to avoid the need for body marker placement during motion tracking and analysis of human movement. Although researchers have long proposed the use of MMC technology in clinical measurement—identification and measurement of movement kinematics in a clinical population, its actual application is still in its preliminary stages. The benefits of MMC technology are also inconclusive with regard to its use in assessing patients’ conditions. In this review we put a minor focus on the method’s engineering components and sought primarily to determine the current application of MMC as a clinical measurement tool in rehabilitation.

Methods

A systematic computerized literature search was conducted in PubMed, Medline, CINAHL, CENTRAL, EMBASE, and IEEE. The search keywords used in each database were “Markerless Motion Capture OR Motion Capture OR Motion Capture Technology OR Markerless Motion Capture Technology OR Computer Vision OR Video-based OR Pose Estimation AND Assessment OR Clinical Assessment OR Clinical Measurement OR Assess.” Only peer-reviewed articles that applied MMC technology for clinical measurement were included. The last search took place on March 6, 2023. Details regarding the application of MMC technology for different types of patients and body parts, as well as the assessment results, were summarized.

Results

A total of 65 studies were included. The MMC systems used for measurement were most frequently used to identify symptoms or to detect differences in movement patterns between disease populations and their healthy counterparts. Patients with Parkinson’s disease (PD) who demonstrated obvious and well-defined physical signs were the largest patient group to which MMC assessment had been applied. Microsoft Kinect was the most frequently used MMC system, although there was a recent trend of motion analysis using video captured with a smartphone camera.

Conclusions

This review explored the current uses of MMC technology for clinical measurement. MMC technology has the potential to be used as an assessment tool as well as to assist in the detection and identification of symptoms, which might further contribute to the use of an artificial intelligence method for early screening for diseases. Further studies are warranted to develop and integrate MMC system in a platform that can be user-friendly and accurately analyzed by clinicians to extend the use of MMC technology in the disease populations.
Low-cost and automated phenotyping system “Phenomenon” for multi-sensor in situ monitoring in plant in vitro culture
Authors: Bethge Hans , Winkelmann Traud , Lüdeke Patrick , Rath Thomas
Published: May 2023

Background

The current development of sensor technologies towards ever more cost-effective and powerful systems is steadily increasing the application of low-cost sensors in different horticultural sectors. In plant in vitro culture, as a fundamental technique for plant breeding and plant propagation, the majority of evaluation methods to describe the performance of these cultures are based on destructive approaches, limiting data to unique endpoint measurements. Therefore, a non-destructive phenotyping system capable of automated, continuous and objective quantification of in vitro plant traits is desirable.

Results

An automated low-cost multi-sensor system acquiring phenotypic data of plant in vitro cultures was developed and evaluated. Unique hardware and software components were selected to construct a xyz-scanning system with an adequate accuracy for consistent data acquisition. Relevant plant growth predictors, such as projected area of explants and average canopy height were determined employing multi-sensory imaging and various developmental processes could be monitored and documented. The validation of the RGB image segmentation pipeline using a random forest classifier revealed very strong correlation with manual pixel annotation. Depth imaging by a laser distance sensor of plant in vitro cultures enabled the description of the dynamic behavior of the average canopy height, the maximum plant height, but also the culture media height and volume. Projected plant area in depth data by RANSAC (random sample consensus) segmentation approach well matched the projected plant area by RGB image processing pipeline. In addition, a successful proof of concept for in situ spectral fluorescence monitoring was achieved and challenges of thermal imaging were documented. Potential use cases for the digital quantification of key performance parameters in research and commercial application are discussed.

Conclusion

The technical realization of “Phenomenon” allows phenotyping of plant in vitro cultures under highly challenging conditions and enables multi-sensory monitoring through closed vessels, ensuring the aseptic status of the cultures. Automated sensor application in plant tissue culture promises great potential for a non-destructive growth analysis enhancing commercial propagation as well as enabling research with novel digital parameters recorded over time.
The genetic spectrum of congenital ocular motor apraxia type Cogan: an observational study, continued
Authors: Schröder Simone , Yigit Gökhan , Li Yun , Altmüller Janine , Büttel Hans-Martin , Fiedler Barbara , Kretzschmar Christoph , Nürnberg Peter , Seeger Jürgen , Serpieri Valentina , Valente Enza Maria , Wollnik Bernd , Boltshauser Eugen , Brockmann Knut
Published: May 2023

Background

The term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosological entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recognized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti–Boltshauser syndrome (PTBHS) and a tubulinopathy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient.

Results

Using a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identified forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causative variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI.

Conclusions

Our findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA.