bluuebunny/crossref_metadata_2025 huggingface dataset:
Study protocol for a randomized controlled trial evaluating the effectiveness of an internet-based self-help intervention to cope with psychological distress due to COVID-19 in the Italian general population: the RinasciMENTE project
Authors: Bertuzzi Vanessa , Semonella Michelle , Andersson Gerhard , Manzoni Gian Mauro , Castelnuovo Gianluca , Molinari Enrico , Pietrabissa Giada
Published: September 2022

Background

This study aims to evaluate the feasibility and effectiveness of the RinasciMENTE program, an Internet-based self-help intervention based on cognitive behavioral therapy (CBT) principles and techniques in supporting individuals experiencing psychological impairments during the COVID-19 pandemic. A randomized controlled trial (RCT) design with random allocation at the level of individual will be conducted to compare the impact of the RinasciMENTE program with a waiting list control in improving the psychological functioning of the general population during the COVID-19 pandemic.

Methods

A minimum sample of 128 participants experiencing mild/subthreshold levels of psychological symptoms during the COVID-19 pandemic will be recruited. After the initial screening, participants will be randomly assigned to either the experimental group or the control condition. The program will last 2 months, during which participants will receive 8 weekly CBT treatment modules. The impact of the RinasciMENTE program on selected primary and secondary psychological outcomes will be tested at the end of the intervention (2 months) and 6- and 12-month follow-ups.

Discussion

We expect people to show an increased level of psychological functioning and to acquire the skills and self-confidence necessary to deal with the psychological consequences of the COVID-19 outbreak and its related social isolation during and following the pandemic.

Trial registration

ClinicalTrials.gov NCT0497903 Registered on 28 May 2021
Effects of intravenous lidocaine on hypoxemia induced by propofol-based sedation for gastrointestinal endoscopy procedures: study protocol for a prospective, randomized, controlled trial
Authors: Qi Xiu-Ru , Sun Jing-Yi , An Li-Xin , Zhang Ke , Xue Fu-Shan
Published: September 2022

Background

Oxygen-desaturation episodes, blood pressure drops, and involuntary body movement are common problems that occur in propofol-based sedation in the procedure of painless gastrointestinal (GI) endoscopy. As a widely used analgesic adjuvant, intravenous lidocaine can reduce the consumption of propofol during ERCP or colonoscopy. However, it is still unknown how lidocaine affects the incidence of oxygen-desaturation episodes and cardiovascular events, and involuntary movement during painless GI endoscopy. Therefore, we aimed to assess the effectiveness and safety of intravenous lidocaine in propofol-based sedation for GI endoscopy.

Methods

We will conduct a single-center, prospective, randomized, double-blind, saline-controlled trial. A total number of 300 patients undergoing painless GI procedures will be enrolled and randomly divided into the lidocaine group (Group L) and the control group (Group C). After midazolam and sufentanil intravenous injection, a bolus of 1.5 mg/kg lidocaine was immediately injected and followed by a continuous infusion of 4 mg/kg/h in the lidocaine group, whereas the same volumes of saline solution in the control group. Then, propofol was titrated to produce unconsciousness during the procedure. The primary outcome will be the incidence of oxygen-desaturation episodes. Secondary outcomes will be the incidence of involuntary body movement, discomfort symptoms, propofol consumption, endoscopist, and patient satisfaction.

Discussion

Propofol-based deep sedation without intubation is widely used in painless GI endoscopy. However, adverse events such as hypoxemia often occur clinically. We expect to assess the effect of lidocaine on reducing the incidence of oxygen-desaturation episodes, cardiovascular events, and involuntary body movement. We believe that the results of this trial will provide an effective and safe method for painless GI endoscopy.

Trial registration

Chinese Clinical Trial Registry ChiCTR2100053818. Registered on 30 November 2021.
Optimal target blood pressure in elderly with septic shock (OPTPRESS) trial: study protocol for a randomized controlled trial
Authors: Endo Akira , Yamakawa Kazuma , Tagami Takashi , Umemura Yutaka , Takahashi Kyosuke , Nagasawa Hiroki , Araki Yuichi , Kojima Mitsuaki , Sera Toshiki , Yagi Masayuki , Yamamoto Ryo , Takahashi Jiro , Nakane Masaki , Takeda Chikashi , Narita Chihiro , Kazuma Satoshi , Okura Hiroko , Takahashi Hiroyuki , Wada Takeshi , Tahara Shu , Matsuoka Ayaka , Masaki Todani , Shiraishi Atsushi , Shimoyama Keiichiro , Yokokawa Yuta , Nakamura Rintaro , Sageshima Hisako , Yanagida Yuichiro , Takahashi Kunihiko , Otomo Yasuhiro
Published: September 2022

Background

Hemodynamic stabilization is a core component in the resuscitation of septic shock. However, the optimal target blood pressure remains debatable. Previous randomized controlled trials suggested that uniformly adopting a target mean arterial pressure (MAP) higher than 65 mmHg for all adult septic shock patients would not be beneficial; however, it has also been proposed that higher target MAP may be beneficial for elderly patients, especially those with arteriosclerosis.

Methods

A multicenter, pragmatic single-blind randomized controlled trial will be conducted to compare target MAP of 80–85 mmHg (high-target) and 65–70 mmHg (control) in the resuscitation of septic shock patients admitted to 28 hospitals in Japan. Patients with septic shock aged ≥65 years are randomly assigned to the high-target or control groups. The target MAP shall be maintained for 72 h after randomization or until vasopressors are no longer needed to improve patients’ condition. To minimize the adverse effects related to catecholamines, if norepinephrine dose of ≥ 0.1 μg/kg/min is needed to maintain the target MAP, vasopressin will be initiated. Other therapeutic approaches, including fluid administration, hydrocortisone use, and antibiotic choice, will be determined by the physician in charge based on the latest clinical guidelines. The primary outcome is all-cause mortality at 90 days after randomization.

Discussion

The result of this trial will provide great insight on the resuscitation strategy for septic shock in the era of global aged society. Also, it will provide the better understanding on the importance of individualized treatment strategy in hemodynamic management in critically ill patients.

Trial registration

UMIN Clinical Trials Registry; UMIN000041775. Registered 13 September 2020.
The effects of an integrated mindfulness-based tai chi chuan programme on sleep disturbance among community-dwelling elderly people: protocol for a randomized controlled trial
Authors: Chan Sunny Ho-Wan , Ng Siu-Man , Yu Chong-Ho , Chan Ching-Man , Wang Shu-Mei , Chan Wai-Chi
Published: September 2022

Background

Many elderly individuals who experience sleep disturbances would consider complementary and alternative medicine as an alternative therapeutic option in light of the limitations of traditional treatments. Mindfulness-based interventions (MBIs) and Tai Chi Chuan (TCC) are two alternative forms of complementary and alternative medicine. They both share the common feature of a focus on breathing but represent distinct approaches with different mechanisms and philosophical orientations. The trial described in this protocol aims to evaluate the effects of an integrated form of mindfulness-based Tai Chi Chuan (MBTCC) programme and the underlying mechanisms of the beneficial effects over a 12-month follow-up.

Methods

The planned study is a four-armed randomized controlled trial with repeated measures. A total of 256 community-dwelling older adults with sleep problems will be recruited and randomized into four groups: (1) an MBTCC group, (2) an MBI group, (3) a TCC group, and (4) a sleep hygiene education (SHE) control group. The outcome measures in terms of insomnia severity, interoception, sleep-wake pattern, health status, rumination, and hyperarousal level will be collected at four time points: at baseline (T1), after the 8-week intervention (T2), 6 months after the intervention (T3), and 1 year after the intervention (T4). In addition, qualitative evaluation through focus group interviews will be conducted at the end of the 12-month assessment period (T4).

Discussion

This trial will illuminate the synergetic effect of combining both MBIs and TCC on optimizing improvements in sleep disturbance. The findings from this study can provide empirical support for this integrated treatment, which provides an alternative for healthcare professionals in elderly service to select appropriate practices to treat elderly people with sleep disturbance. It can further help to lessen the growing public health burden of sleep disturbances among the elderly living in the community.

Trial registration

ClinicalTrials.gov. NCT05396092. Published on 24 May 2022
The haemostatic effect of deep-frozen platelets versus room temperature-stored platelets in the treatment of surgical bleeding: MAFOD—study protocol for a randomized controlled non-inferiority trial
Authors: Rijnhout Tim W. H. , Noorman Femke , van der Horst Robert A. , Tan Edward C. T. H. , Viersen Victor V. A. , van Waes Oscar J. F. , van de Watering Leo M. G. , van der Burg B. L. S. Borger , Zwaginga Jaap J. , Verhofstad Michael H. J. , Hoencamp Rigo
Published: September 2022

Background

The Netherlands Armed Forces have been successfully using deep-frozen (− 80 °C) thrombocyte concentrate (DTC) for the treatment of (massive) bleeding trauma patients in austere environments since 2001. However, high-quality evidence for the effectiveness and safety of DTCs is currently lacking. Therefore, the MAssive transfusion of Frozen bloOD (MAFOD) trial is designed to compare the haemostatic effect of DTCs versus room temperature-stored platelets (RSP) in the treatment of surgical bleeding.

Methods

The MAFOD trial is a single-blinded, randomized controlled non-inferiority trial and will be conducted in three level 1 trauma centres in The Netherlands. Patients 12 years or older, alive at hospital presentation, requiring a massive transfusion including platelets and with signed (deferred) consent will be included. The primary outcome is the percentage of patients that have achieved haemostasis within 6 h and show signs of life. Haemostasis is defined as the time in minutes from arrival to the time of the last blood component transfusion (plasma/platelets or red blood cells), followed by a 2-h transfusion-free period. This is the first randomized controlled study investigating DTCs in trauma and vascular surgical bleeding.

Discussion

The hypothesis is that the percentage of patients that will achieve haemostasis in the DTC group is at least equal to the RSP group (85%). With a power of 80%, a significance level of 5% and a non-inferiority limit of 15%, a total of 71 patients in each arm are required, thus resulting in a total of 158 patients, including a 10% refusal rate. The data collected during the study could help improve the use of platelets during resuscitation management. If proven non-inferior in civilian settings, frozen platelets may be used in the future to optimize logistics and improve platelet availability in rural or remote areas for the treatment of (massive) bleeding trauma patients in civilian settings.

Trial registration

ClinicalTrials.gov NCT05502809. Registered on 16 August 2022.
Improve the cervical cancer prevention behaviors through mobile-based educational intervention based on I-CHANGE model: study protocol for a randomized controlled trial
Authors: Kazemi Sara , Zarei Fatemeh , Heidarnia Alireza , Alhani Fatemeh
Published: September 2022

Background

Applications of mobile technologies (mHealth) have the potential to reduce health inequalities, give patients more control over their health, and improve health care’s cost-effectiveness. The widespread use of mobile phones offers us a new way to prevent cervical cancer. The objective of the study was to design and develop a mobile phone application (app) that aims to conduct a behavioral intervention for women and to evaluate the efficacy of the app-based intervention.

Methods

This study involves 5 phases. In the first phase, understanding women’s perspectives will be identified using a qualitative approach based on the I-Change model. In phase 2, the results from the qualitative approach and requirement prioritization through providing experts’ perspectives will be done. The main outputs of this phase will be resulted in prioritizing the main measurable effective variables of the I-Change model. Phase 3 will be processed for the development and psychometric of an assessment tool regarding selected constructs. In phase 4, the App framework and content development will be performed. In phase 5, a three-armed, parallel-design randomized controlled trial will be conducted on women. Two hundred ten women will be randomly assigned to three groups including two intervention groups and one control group. The intervention groups included the following: (1) a mobile application and (2) a digital book. The data will be evaluated using tools designed and constructed in phase 3 of the study at baseline in 3-month follow-up assessments. The impact of the two interventions on cervical cancer prevention behaviors through mobile-based educational intervention will then be evaluated.

Discussion

A theory-based health education program using a mobile app to improve cervical cancer-preventive behaviors will be implemented for the first time in Iran. With an effective health mobile-based educational design, it is very important to determine whether Iranian women will be motivated to adhere to preventive behavior related to CC.

Trial registration

Iranian Clinical Trial Register IRCT20181205041861N3. Registered V2.0 on 26 October 2021.
Impact of emergency physician-performed ultrasound for the evaluation of patients with acute abdominal pain, prospective randomized dual Centre study: study protocol for a diagnostic trial
Authors: Brau François , Martin Stéphanie , Le Bastard Quentin , Ricaud Patricia , Legrand Arnaud , Montassier Emmanuel , Le Conte Philippe
Published: September 2022

Background

Abdominal pain is frequent in patients consulting in emergency departments. The aim of this study is to determine the diagnosis efficacy of point-of-care ultrasound (POCUS) in patients consulting in the ED for acute abdominal pain by comparing the rate of exact diagnostic between the two arms (with or without POCUS), according to the index diagnostic established by an adjudication committee.

Methods

It is a randomized, controlled, open and interventional study in two emergency departments. The included patients will be adults admitted for acute abdominal pain. Exclusion criteria will be a documented end-of-life, an immediate need of life-support therapy and pregnant or breast-feeding women. Patients will be randomized in intervention (POCUS) or control groups. POCUS will only be performed by trained physicians and will be added to the diagnosis procedure in the intervention group. In the control group, the diagnosis will be established after clinical examination and reception of biological analysis results. In the interventional group, the diagnosis will be established after a clinical exam, biological analysis reception and POCUS. An adjudication committee will review all data from case report forms and will determine the index diagnosis which will be used for the analysis.

The primary endpoint will be the comparison of the rate of exact diagnostic between the two arms according to the adjudication committee diagnostic. Secondary endpoints will be the comparison between the two groups for diagnostic delay, duration of ED stay, diagnostic performances for non-specific abdominal pain and hospitalization rate. The primary endpoint will be compared between the two groups using a mixed model taking into account the recruiting centre. Delays will be compared by a mixed linear generalized model. Diagnostic performances will be estimated with their 95% confidence intervals. For a correct diagnostic rate of 57% in the control group and 74% in the intervention group with a 0.05 alpha risk and a 80% power, 244 patients will be required.

Discussion

POCUS diagnostic abilities have been mainly demonstrated in monocentric studies but the level of evidence of its diagnostic efficacy remains controversial in particular in Europe. The aim of this study is to address this question with a rigorous methodology.

Trial registration

ClinicalTrials.gov NCT04912206. Registered on June 3, 2021.
Enhanced productivity of extracellular free fatty acids by gene disruptions of acyl-ACP synthetase and S-layer protein in Synechocystis sp. PCC 6803
Authors: Eungrasamee Kamonchanock , Lindblad Peter , Jantaro Saowarath
Published: September 2022

Background

Based on known metabolic response to excess free fatty acid (FFA) products, cyanobacterium Synechocystis sp. PCC 6803 preferentially both recycles via FFA recycling process and secrets them into medium. Engineered cyanobacteria with well growth and highly secreted FFA capability are considered best resources for biofuel production and sustainable biotechnology. In this study, to achieve the higher FFA secretion goal, we successfully constructs Synechocystis sp. PCC 6803 mutants disrupting genes related to FFA recycling reaction (aas gene encoding acyl–acyl carrier protein synthetase), and surface layer protein (encoded by sll1951).

Results

Three Synechocystis sp. PCC 6803 engineered strains, including two single mutants lacking aas (KA) and sll1951 (KS), and one double mutant lacking both aas and sll1951 (KAS), significantly secreted FFAs higher than that of wild type (WT). Certain increase of secreted FFAs was noted when cells were exposed to nitrogen-deficient conditions, BG11-half N and BG11-N conditions, with the exception of strain KS. Under BG11-N condition at day 10, strain KAS strikingly secreted FFAs products up to 40%w/DCW or 238.1 mg/L, with trace amounts of PHB. Unexpectedly, strain KS, with S-layer disruption, appeared to have endured longer in BG11-N growth medium. This strain KS significantly acclimated to the BG11-N environment by accumulating a greater glycogen pool with lower FFA production, whereas strain KA favored higher PHB and intracellular lipid accumulations with moderate FFA secretion.

Conclusions

Mutations of both aas and sll1951 genes in Synechocystis sp. PCC 6803 significantly improved the productivity of secreted FFAs, especially under nitrogen deprivation.
Intratumor heterogeneity and T cell exhaustion in primary CNS lymphoma
Authors: Heming Michael , Haessner Svea , Wolbert Jolien , Lu I-Na , Li Xiaolin , Brokinkel Benjamin , Müther Michael , Holling Markus , Stummer Walter , Thomas Christian , Schulte-Mecklenbeck Andreas , de Faria Flavia , Stoeckius Marlon , Hailfinger Stephan , Lenz Georg , Kerl Kornelius , Wiendl Heinz , Meyer zu Hörste Gerd , Grauer Oliver M.
Published: September 2022

Background

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma of the central nervous system, usually of diffuse large B cell phenotype. Stereotactic biopsy followed by histopathology is the diagnostic standard. However, limited material is available from CNS biopsies, thus impeding an in-depth characterization of PCNSL.

Methods

We performed flow cytometry, single-cell RNA sequencing, and B cell receptor sequencing of PCNSL cells released from biopsy material, blood, and cerebrospinal fluid (CSF), and spatial transcriptomics of biopsy samples.

Results

PCNSL-released cells were predominantly activated CD19+CD20+CD38+CD27+ B cells. In single-cell RNA sequencing, PCNSL cells were transcriptionally heterogeneous, forming multiple malignant B cell clusters. Hyperexpanded B cell clones were shared between biopsy- and CSF- but not blood-derived cells. T cells in the tumor microenvironment upregulated immune checkpoint molecules, thereby recognizing immune evasion signals from PCNSL cells. Spatial transcriptomics revealed heterogeneous spatial organization of malignant B cell clusters, mirroring their transcriptional heterogeneity across patients, and pronounced expression of T cell exhaustion markers, co-localizing with a highly malignant B cell cluster.

Conclusions

Malignant B cells in PCNSL show transcriptional and spatial intratumor heterogeneity. T cell exhaustion is frequent in the PCNSL microenvironment, co-localizes with malignant cells, and highlights the potential of personalized treatments.
Gait parameters when walking with or without rollator on different surface characteristics: a pilot study among healthy individuals
Authors: Ekvall Hansson Eva , Akar Yara , Liu Tingting , Wang Cong , Malmgren Fänge Agneta
Published: September 2022

Objectives

Gait parameters can measure risks of falling and mortality and identify early stages of frailty. The use of walking aid changes gait parameters. The aim of this study was to describe differences in gait parameters among healthy adults when walking on different surfaces and under different conditions, with and without a rollator.

Results

Ten healthy participants walked first without and then with a rollator upslope, downslope and on flat surface, on bitumen and gravel respectively. Step length, walking speed and sideway deviation was measured using an inertial measurement unit. Walking up a slope using a rollator generated the longest step length and walking down a slope using a rollator the shortest. Fastest walking speed was used when walking up a slope with rollator and slowest when walking down a slope with rollator. Sideway deviation was highest when walking down a slope and lowest when walking on gravel, both without rollator. Highest walk ratio was found when walk up a slope without rollator and lowest when walking down a slope with rollator. Data from this study provides valuable knowledge regarding gait parameters among healthy individuals, useful for future clinical research relevant for rehabilitation and public health.
Associated changes in stiffness of collagen scaffolds during osteoblast mineralisation and bone formation
Authors: Bakkalci Deniz , Micalet Auxtine , Al Hosni Rawiya , Moeendarbary Emad , Cheema Umber
Published: September 2022

Objective

Engineering bone in 3D is important for both regenerative medicine purposes and for the development of accurate in vitro models of bone tissue. The changing material stiffness of bone tissue had not yet been monitored throughout the process of mineralisation and bone nodule formation by osteoblasts either during in vitro engineering or in development perspective.

Results

Within this short research note, stiffness changes (Young’s modulus) during in vitro bone formation by primary osteoblasts in dense collagen scaffolds were monitored using atomic force microscopy. Data analysis revealed significant stiffening of 3D bone cultures at day 5 and 8 that was correlated with the onset of mineral deposition (p < 0.00005).
Liquid biopsies based on DNA methylation as biomarkers for the detection and prognosis of lung cancer
Authors: Li Peilong , Liu Shibiao , Du Lutao , Mohseni Ghazal , Zhang Yi , Wang Chuanxin
Published: September 2022

Lung cancer (LC) is the main cause of cancer-related mortality. Most LC patients are diagnosed in an advanced stage when the symptoms are obvious, and the prognosis is quite poor. Although low-dose computed tomography (LDCT) is a routine clinical examination for early detection of LC, the false-positive rate is over 90%. As one of the intensely studied epigenetic modifications, DNA methylation plays a key role in various diseases, including cancer and other diseases. Hypermethylation in tumor suppressor genes or hypomethylation in oncogenes is an important event in tumorigenesis. Remarkably, DNA methylation usually occurs in the very early stage of malignant tumors. Thus, DNA methylation analysis may provide some useful information about the early detection of LC. In recent years, liquid biopsy has developed rapidly. Liquid biopsy can detect and monitor both primary and metastatic malignant tumors and can reflect tumor heterogeneity. Moreover, it is a minimally invasive procedure, and it causes less pain for patients. This review summarized various liquid biopsies based on DNA methylation for LC. At first, we briefly discussed some emerging technologies for DNA methylation analysis. Subsequently, we outlined cell-free DNA (cfDNA), sputum, bronchoalveolar lavage fluid, bronchial aspirates, and bronchial washings DNA methylation-based liquid biopsy for the early detection of LC. Finally, the prognostic value of DNA methylation in cfDNA and sputum and the diagnostic value of other DNA methylation-based liquid biopsies for LC were also analyzed.
Higher levels of myelin are associated with higher resistance against tau pathology in Alzheimer’s disease
Authors: Rubinski Anna , Franzmeier Nicolai , Dewenter Anna , Luan Ying , Smith Ruben , Strandberg Olof , Ossenkoppele Rik , Dichgans Martin , Hansson Oskar , Ewers Michael ,   the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: September 2022

Background

In Alzheimer’s disease (AD), fibrillar tau initially occurs locally and progresses preferentially between closely connected regions. However, the underlying sources of regional vulnerability to tau pathology remain unclear. Previous brain-autopsy findings suggest that the myelin levels—which differ substantially between white matter tracts in the brain—are a key modulating factor of region-specific susceptibility to tau deposition. Here, we investigated whether myelination differences between fiber tracts of the human connectome are predictive of the interregional spreading of tau pathology in AD.

Methods

We included two independently recruited samples consisting of amyloid-PET-positive asymptomatic and symptomatic elderly individuals, in whom tau-PET was obtained at baseline (ADNI:n = 275; BioFINDER-1:n = 102) and longitudinally in a subset (ADNI:n = 123, mean FU = 1.53 [0.69–3.95] years; BioFINDER-1:n = 39, mean FU = 1.87 [1.21–2.78] years). We constructed MRI templates of the myelin water fraction (MWF) in 200 gray matter ROIs and connecting fiber tracts obtained from adult cognitively normal participants. Using the same 200 ROI brain-parcellation atlas, we obtained tau-PET ROI values from each individual in ADNI and BioFINDER-1. In a spatial regression analysis, we first tested the association between cortical myelin and group-average tau-PET signal in the amyloid-positive and control groups. Secondly, employing a previously established approach of modeling tau-PET spreading based on functional connectivity between ROIs, we estimated in a linear regression analysis, whether the level of fiber-tract myelin modulates the association between functional connectivity and longitudinal tau-PET spreading (i.e., covariance) between ROIs.

Results

We found that higher myelinated cortical regions show lower tau-PET uptake (ADNI: rho =  − 0.267,p < 0.001; BioFINDER-1: rho =  − 0.175,p = 0.013). Fiber-tract myelin levels modulated the association between functional connectivity and tau-PET spreading, such that at higher levels of fiber-tract myelin, the association between stronger connectivity and higher covariance of tau-PET between the connected ROIs was attenuated (interaction fiber-tract myelin × functional connectivity: ADNI:β =  − 0.185,p < 0.001; BioFINDER-1:β =  − 0.166,p < 0.001).

Conclusion

Higher levels of myelin are associated with lower susceptibility of the connected regions to accumulate fibrillar tau. These results enhance our understanding of brain substrates that explain regional variation in tau accumulation and encourage future studies to investigate potential underlying mechanisms.
Impact of Litsea cubeba inter-row cover on the structure of bacterial community in the tea plantation
Authors: Hao Hai-Ping , Xia Fei , Bai Hong-Tong , Yan Xun-you , Cui Hong-xia , Xie Xiao-ming , Shi Lei
Published: September 2022

Purpose

The application of bio-control plants in the agricultural processes is one of the effective ways to solve the traditional agricultural synthetic pesticide residues. This study will investigate the effect of bio-control plant Litsea cubeba branch inter-row cover on soil bacterial community, soil-enriched metabolites, and soil mineral nutrition in tea plantation, which will provide a basis for the use of bio-control plant in agroecological farming systems.

Methods

The fruit-bearing (F-Pr) and vegetative (F-Ab) branches of Litsea cubeba were inter-row covered (the use of plants for partial coverage of soil between the rows) in the tea plantation. And we determined the soil microbial community, soil mineral nutriment, and soil-enriched metabolites composition with the methods of 16S rRNA gene sequencing, inductively coupled plasma-atomic emission spectroscopy (ICP-AEC), inductively coupled plasma-optical emission spectrometry (ICP-OES), and gas chromatography-mass spectrometry (GS-MS). We also predict the function of soil bacteria with the Tax4Fun software.

Results

Litsea cubeba inter-row cover modified the soil microbial structure and diversity; Litsea cubeba inter-row cover significantly decreased the relative abundance of Acidobacteria, Chloroflexi, and Planctomycetes while increased the relative abundance of Proteobacteria. Litsea cubeba inter-row cover significantly antagonized the plant pathogen community, and its OTUs number decreased from 907 ± 81 in the control to 337 ± 25 in F-Pr treatment; compared with F-Pr treatment, F-Ab treatment had weaker effect on the abundance of nutrition metabolism and transport, carbohydrate utilization, and nitrate reduction A. The aluminum element in the F-Pr treatment was significantly reduced, while phosphorus was increased. The soil-enriched metabolites of F-Pr treatment contained some antibacterial substance, including 14.2 ± 3.32% citronellol, 10.38 ± 4.79% alpha-terpineol, and 8.25 ± 2.62% (+)-2-bornanone, which was the main environment factor that affects the soil bacterial structure and diversity.

Conclusion

Litsea cubeba inter-row cover significantly affected bacterial structure and diversity, slightly increased the soil pH, and improved soil aluminum and phosphorus status; soil-enriched metabolites were the major environment factor affecting soil bacterial community and should be considered in the application of bio-control plants; Litsea cubeba vegetative branch inter-row cover will be a feasible measure for integrated pest management in tea plantation.
Effectiveness and safety of lanadelumab in ethnic and racial minority subgroups of patients with hereditary angioedema: results from phase 3 studies
Authors: Craig Timothy J. , Zaragoza-Urdaz Rafael H. , Li H. Henry , Yu Ming , Ren Hong , Juethner Salomé , Anderson John ,   the HELP and HELP OLE Study Investigators
Published: September 2022

Background

The COVID-19 pandemic has highlighted disparities in healthcare, particularly in the United States, even though disparities have existed since the organization of the modern healthcare system. Recruitment of patients from racial and ethnic minority groups is often minimal in phase 3 clinical trials, and is further exacerbated in the case of trials for rare diseases such as hereditary angioedema (HAE). This can lead to a gap in the understanding of minority patients’ experiences with these diseases and their response to potential treatment options.

Methods

We reviewed data from phase 3 double-blind (HELP) and open-label extension (HELP OLE) trials of lanadelumab, a monoclonal antibody developed for long-term prophylaxis against attacks of HAE. Efficacy (attack rate reduction) and safety (adverse events) results from White patients were compared descriptively to those from Hispanic/Latino patients, Black/African Americans, and other minority Americans.

Results

Not surprisingly, few minorities were recruited across both studies: 9.5% Black, 2.4% Asian, and 7.1% Hispanic/Latino versus 88.1% White and 91.7% non-Hispanic/non-Latino received lanadelumab in HELP, and 4.7% Black, 0.9% Asian, 0.9% other, and 6.1% Hispanic/Latino versus 93.4% White and 93.4% non-Hispanic/non-Latino were enrolled in HELP OLE. Although these studies were conducted in the United States, Canada, Europe, and Jordan, all minorities were from the United States. Despite the number of minority patients being far less than expected for the population, there was no evidence that either efficacy or adverse event profiles differed between ethnic or racial groups.

Conclusions

The HELP and HELP OLE studies described herein recruited far fewer minorities than would be ideal to represent these populations. However, evidence suggests that the effectiveness and tolerance of lanadelumab are similar between the groups. Nonetheless, the disparity in recruitment into research for minorities has significant room for improvement.

Trial registration NCT02586805, registered 26 October 2015, https://clinicaltrials.gov/ct2/show/record/NCT02586805. NCT02741596, registered 18 April 2016, https://clinicaltrials.gov/ct2/show/NCT02741596.
Integration of ultrasonography training into undergraduate medical education: catch up with professional needs
Authors: Teichgräber Ulf , Ingwersen Maja , Ehlers Claudia , Mentzel Hans-Joachim , Redies Christoph , Stallmach Andreas , Behringer Wilhelm , Guntinas-Lichius Orlando
Published: September 2022

Objective

Ultrasonography (US) has become the first-line imaging modality even for physicians who are not imaging specialists. The progress has not yet been sufficiently considered in medical education. The aim was to develop a curriculum that integrates US as a compulsory part into medical education directly from the start, to build up professional competencies toward residency.

Methods

Development was based on Kern’s six-step approach to identify problems, specify needs, define goals, outline strategies, and propose methods.

Results

The proposed curriculum follows a spiral course within which students should pass through four levels of training with increasing complexity. Students will be asked to independently prepare for courses by using learning videos. On the first training level, US should be closely linked to anatomy and physiology courses. Competency-centered courses should be held in small groups. On the second level, in the third year of education, students will apply point-of-care ultrasonography concerning multiple medical disciplines. On the third level, they will select a compulsory course in a specialty of their choice, held at five consecutive dates. From then on, US will be conducted in patients. Finally, during the final year, students are expected to use US under pro-active supervision with a large degree of independence and confidence. Throughout the curriculum, the discipline of radiology combines vertically with foundational sciences and horizontally with other medical specialties.

Conclusion

The conceptual proposal for a longitudinal US curriculum presented here has been developed by radiologists to equip students with competencies needed for contemporary patient care.
Dual-energy CT with virtual monoenergetic images and iodine maps improves tumor conspicuity in patients with pancreatic ductal adenocarcinoma
Authors: Liang Hongwei , Zhou Yang , Zheng Qiao , Yan Gaowu , Liao Hongfan , Du Silin , Zhang Xiaohui , Lv Fajin , Zhang Zhiwei , Li Yong-mei
Published: September 2022

Objectives

To evaluate the value of monoenergetic images (MEI [+]) and iodine maps in dual-source dual-energy computed tomography (DECT) for assessing pancreatic ductal adenocarcinoma (PDAC), including the visually isoattenuating PDAC.

Materials and methods

This retrospective study included 75 PDAC patients, who underwent contrast-enhanced DECT examinations. Conventional polyenergetic image (PEI) and 40–80 keV MEI (+) (10-keV increments) were reconstructed. The tumor contrast, contrast-to-noise ratio (CNR) of the tumor and peripancreatic vessels, the signal-to-noise ratio (SNR) of the pancreas and tumor, and the tumor diameters were quantified. On iodine maps, the normalized iodine concentration (NIC) in the tumor and parenchyma was compared. For subjective analysis, two radiologists independently evaluated images on a 5-point scale.

Results

All the quantitative parameters were maximized at 40-keV MEI (+) and decreased gradually with increasing energy. The tumor contrast, SNR of pancreas and CNRs in 40–60 keV MEI (+) were significantly higher than those in PEI (p < 0.05). For visually isoattenuating PDAC, 40–50 keV MEI (+) provided significantly higher tumor CNR compared to PEI (p < 0.05). The reproducibility in tumor measurements was highest in 40-keV MEI (+) between the two radiologists. The tumor and parenchyma NIC were 1.28 ± 0.65 and 3.38 ± 0.72 mg/mL, respectively (p < 0.001). 40–50 keV MEI (+) provided the highest subjective scores, compared to PEI (p < 0.001).

Conclusions

Low-keV MEI (+) of DECT substantially improves the subjective and objective image quality and consistency of tumor measurements in patients with PDAC. Combining the low-keV MEI (+) and iodine maps may yield diagnostically adequate tumor conspicuity in visually isoattenuating PDAC.
Radiochemotherapy-induced DNA repair promotes the biogenesis of gastric cancer stem cells
Authors: Lu Yu , Zhang Xiaobo
Published: September 2022

Background

Clinically, metastasis and recurrence occurred after routine radiochemotherapy in dozens of cases of gastric cancer, mainly attributed to the role of cancer stem cells (CSCs). Actually, radiochemotherapy could induce DNA damages, leading to activation of DNA repair which might be associated with acquisition of stem cell phenotype. Hitherto, the contribution made by active DNA repair to stemness induction has not been extensively explored.

Methods

Cisplatin/doxorubicin treatment and X-ray exposure were conducted in gastric cancer cell lines and gastric cancer cells derived from solid tumors to model clinical therapy. Quantitative real-time PCR, Western blot, and tumorsphere/tumor formation assay were further used to characterize CSCs and assess activation of DNA repair. RNA-seq was performed to identify which DNA repair genes were crucial for CSC traits induction, followed by the investigation of underlying mechanism and functional significance via in vitro and in vivo experiments.

Results

Here, we report a mechanism through which gastric cancer cells in response to radiochemotherapy were reprogrammed into gastric cancer stem cell-like cells. In this mechanism, radiochemotherapy triggers DNA damage response accompanied by elevated levels of EID3, a typical DNA repair gene, which interacts with NAMPT to promote stemness via upregulating Wnt signaling pathway, manifested by enhanced tumorsphere/tumor formation in gastric cancer. In addition to involvement of EID3 in stemness acquisition, it also shows impacts on proliferation, cell cycle, apoptosis and therapy resistance to maintain the characteristics of CSC populations.

Conclusion

Our study indicates that gastric cancer cells can be endowed with stemness traits via EID3-NAMPT-Wnt/β-catenin axis in response to radiochemotherapy. Blocking this axis (i.e., targeting EID3) along with radiochemotherapy might represent a potential strategy to sensitize CSCs to radiochemotherapy and further reinforce the anti-tumor effects of conventional treatments.
Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17+ regulatory T cell
Authors: Zhang Mingchao , Johnson-Stephenson Takerra K. , Wang Weiran , Wang Yang , Li Jing , Li Limin , Zen Ke , Chen Xi , Zhu Dihan
Published: September 2022

Background

Anti-inflammatory polarized macrophages are reported to alleviate systemic lupus erythematosus (SLE). Our previous studies have demonstrated that exosomes from adipose-derived stem cells promote the anti-inflammatory polarization of macrophages. However, the possible therapeutic effect of exosomes from stem cells on SLE remains unexplored.

Methods

Exosomes were isolated from the conditioned medium of bone marrow-derived mesenchymal stem cells using ultrafiltration and size-exclusion chromatography and were identified by nanoparticle tracking analysis and immunoblotting of exosomal-specific markers. Macrophages were collected from the MRL/lpr mouse kidney. The phenotype of macrophages was identified by immunoblotting for intracellular markers-inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1), and flow cytometry for macrophage markers F4/80, CD86, CD206, B7H4, and CD138. Pristane-induced murine lupus nephritis models were employed for in vivo study.

Results

When macrophages from the kidney of the MRL/lpr mice were treated with exosomes from bone marrow-derived mesenchymal stem cells (BM-MSCs), the upregulation of CD206, B7H4, CD138, Arg-1, CCL20, and anti-inflammatory cytokines was observed, which suggested that the macrophages were polarized to a specific anti-inflammatory phenotype. These anti-inflammatory macrophages produced low levels of reactive oxygen species (ROS) but had a high efferocytosis activity and promoted regulatory T (Treg) cell recruitment. Moreover, exosome injection stimulated the anti-inflammatory polarization of macrophages and increased the production of IL-17+ Treg cells in a pristane-induced murine lupus nephritis model. We observed that exosomes from BMMSCs depleted of microRNA-16 (miR-16) and microRNA-21 (miR-21) failed to downregulate PDCD4 and PTEN in macrophages, respectively, and attenuated exosome-induced anti-inflammatory polarization.

Conclusion

Our findings provide evidence that exosomes from BMMSCs promote the anti-inflammatory polarization of macrophages. These macrophages alleviate SLE nephritis in lupus mice by consuming apoptotic debris and inducing the recruitment of Treg cells. We identify that exosomal delivery of miR-16 and miR-21 is a significant contributor to the polarization of macrophages.

Graphical abstract
A homozygous PIWIL2 frameshift variant affects the formation and maintenance of human-induced pluripotent stem cell-derived spermatogonial stem cells and causes Sertoli cell-only syndrome
Authors: Wang Xiaotong , Li Zili , Qu Mengyuan , Xiong Chengliang , Li Honggang
Published: September 2022

Background

The most serious condition of male infertility is complete Sertoli cell-only syndrome (SCOS), which refers to the lack of all spermatogenic cells in the testes. The genetic cause of SCOS remains to be explored. We aimed to investigate the genetic cause of SCOS and assess the effects of the identified causative variant on human male germ cells.

Methods

Whole-exome sequencing was performed to identify potentially pathogenic variants in a man with complete SCOS, and Sanger sequencing was performed to verify the causative variant in this man and his father and brother. The pathogenic mechanisms of the causative variant were investigated by in vitro differentiation of human-induced pluripotent stem cells (hiPSCs) into germ cell-like cells.

Results

The homozygous loss-of-function (LoF) variant p.His244ArgfsTer31 (c.731_732delAT) in PIWIL2 was identified as the causative variant in the man with complete SCOS, and the same variant in heterozygosis was confirmed in his father and brother. This variant resulted in a truncated PIWIL2 protein lacking all functional domains, and no PIWIL2 expression was detected in the patient’s testes. The patient and PIWIL2−/− hiPSCs could be differentiated into primordial germ cell-like cells and spermatogonial stem cell-like cells (SSCLCs) in vitro, but the formation and maintenance of SSCLCs were severely impaired. RNA-seq analyses suggested the inactivation of the Wnt signaling pathway in the process of SSCLC induction in the PIWIL2−/− group, which was validated in the patient group by RT-qPCR. The Wnt signaling pathway inhibitor hindered the formation and maintenance of SSCLCs during the differentiation of normal hiPSCs.

Conclusions

Our study revealed the pivotal role of PIWIL2 in the formation and maintenance of human spermatogonial stem cells. We provided clinical and functional evidence that the LoF variant in PIWIL2 is a genetic cause of SCOS, which supported the potential role of PIWIL2 in genetic diagnosis. Furthermore, our results highlighted the applicability of in vitro differentiation models to function validation experiments.
TNFAIP6 defines the MSC subpopulation with enhanced immune suppression activities
Authors: Li Lingyun , Yang Lei , Chen Xian , Chen Xiangjuan , Diao Lianghui , Zeng Yong , Xu Jianyong
Published: September 2022

Background

Mesenchymal stromal/stem cells (MSCs) have been intensively investigated in both pre-clinical and clinical studies. However, the therapeutic efficacy varies resulting from the heterogenicity of MSCs. Therefore, purifying the specific MSC subpopulation with specialized function is necessary for their therapeutic applications.

Methods

The large-scale RNA sequencing analysis was performed to identify potential cell markers for the mouse MSCs. Then, the immune suppression activities of the purified MSC subpopulation were assessed in vitro and in vivo.

Results

The TNFAIP6 (tumor necrosis factor alpha-induced protein 6) has been identified as a potential cell marker for mouse MSCs, irrespective of tissue origin and laboratory origin. The TNFAIP6+mouse MSCs showed enhanced immune suppression activities and improved therapeutic effects on the mouse model of acute inflammation, resulting from faster response to immune stimulation.

Conclusions

Therefore, we have demonstrated that the TNFAIP6+MSC subpopulation has enhanced immune suppression capabilities.
Herpesviridae lung reactivation and infection in patients with severe COVID-19 or influenza virus pneumonia: a comparative study
Authors: Luyt Charles-Edouard , Burrel Sonia , Mokrani David , Pineton de Chambrun Marc , Luyt Domitille , Chommeloux Juliette , Guiraud Vincent , Bréchot Nicolas , Schmidt Matthieu , Hekimian Guillaume , Combes Alain , Boutolleau David
Published: September 2022

Background

Lung reactivations of Herpesviridae, herpes simplex virus (HSV) and cytomegalovirus (CMV) have been reported in COVID-19 patients. Whether or not those viral reactivations are more frequent than in other patients is not known.

Methods

Retrospective monocentric cohort study of 145 patients with severe COVID-19 pneumonia requiring invasive mechanical ventilation and who were tested for HSV and CMV in bronchoalveolar lavage performed during fiberoptic bronchoscopy for ventilator-associated pneumonia suspicion. Rates of HSV and CMV lung reactivations, and HSV bronchopneumonitis were assessed and compared with an historical cohort of 89 patients with severe influenza pneumonia requiring invasive mechanical ventilation.

Results

Among the 145 COVID-19 patients included, 50% and 42% had HSV and CMV lung reactivations, respectively, whereas among the 89 influenza patients, 63% and 28% had HSV and CMV lung reactivations, respectively. Cumulative incidence of HSV lung reactivation (taking into account extubation and death as competing events) was higher in influenza than in COVID-19 patients (p = 0.03), whereas the rate of HSV bronchopneumonitis was similar in both groups (31% and 25%, respectively). Cumulative incidence of CMV lung reactivation (taking into account extubation and death as competing events) was similar in COVID-19 and influenza patients (p = 0.07). Outcomes of patients with HSV or CMV lung reactivations were similar to that of patients without, whatever the underlying conditions, i.e., in COVID-19 patients, in influenza patients, or when all patients were grouped.

Conclusions

HSV and CMV lung reactivations are frequent in COVID-19 patients, but not more frequent than in patients with influenza-associated severe pneumonia, despite a higher severity of illness at intensive care unit admission of the latter and a longer duration of mechanical ventilation of the former. Although no impact on outcome of HSV and CMV lung reactivations was detected, the effect of antiviral treatment against these Herpesviridae remains to be determined in these patients.