bluuebunny/crossref_metadata_2025 huggingface dataset:
Engineering defected 2D Pd/H-TiO2 nanosonosensitizers for hypoxia alleviation and enhanced sono-chemodynamic cancer nanotherapy
Authors: Qiao Xiaohui , Xue Liyun , Huang Hui , Dai Xinyue , Chen Yu , Ding Hong
Published: April 2022

Background

Sonodynamic therapy (SDT) is a burgeoning modality for cancer therapy owing to its high tissue-penetrating capability, controllability and safety. Whereas, the undesirable reactive oxygen species (ROS) yield of sonosensitizers and tumor hypoxia are two vulnerable spots of SDT. Therefore, it is an advisable strategy to augment ROS level and simultaneously relieve hypoxia for SDT to arrive its full potential in cancer treatment.

Results

In this work, the defected two-dimensional (2D) Pd/H-TiO2 nanosheets (NSs) with triple antineoplastic properties were dexterously elaborated and engineered using a facile one-pot Pd-catalyzed hydrogenation tactic by loading a tiny amount of Pd and then inletting hydrogen flow at atmospheric pressure and temperature. The 2D black Pd/H-TiO2 NSs with oxygen defects exerted eximious SDT effect based on the decreased bandgap that made it easier for the separation of electrons and holes when triggered by ultrasound as theoretically guided by density functional theory calculations. Additionally, Pd/H-TiO2 NSs could serve as Fenton-like agents because of the presence of oxygen defects, facilitating the conversion of hydrogen peroxide into hydroxyl radicals for exerting the chemodynamic therapy (CDT). Simultaneously, the introduced tiny Pd component possessed catalase-like activity responsible for oxygen production to ameliorate hypoxic condition and thus contributed to improving SDT and CDT efficacies. Both in vitro and in vivo results provided compelling evidences of high ROS yield and aggrandized sono-chemodynamic effect of Pd/H-TiO2 nanosonosensitizers with the detailed underlying mechanism investigation by RNA sequencing.

Conclusion

This work delves the profound potential of Pd-catalyzed hydrogenated TiO2 on oncotherapy, and the effective antineoplastic performance and ignorable therapeutic toxicity make it a powerful competitor among a cornucopia of nanosonosensitizers.

Graphical Abstract
Integration of a community-based harm reduction program into a safety net hospital: a qualitative study
Authors: Khan Ghulam Karim , Harvey Leah , Johnson Samantha , Long Paul , Kimmel Simeon , Pierre Cassandra , Drainoni Mari-Lynn
Published: April 2022

Background

Community-based harm reduction programs reduce morbidity and mortality associated with drug use. While hospital-based inpatient addiction consult services can also improve outcomes for patients using drugs, inpatient clinical care is often focused on acute withdrawal and the medical management of substance use disorders. There has been limited exploration of the integration of community-based harm reduction programs into the hospital setting. We conducted a qualitative study to describe provider perspectives on the implementation of a harm reduction in-reach program.

Methods

We conducted 24 semi-structured interviews with providers from three different primary work sites within a safety net hospital in Boston, MA, in 2021. Interviews explored perceived facilitators and barriers to the implementation of the harm reduction in-reach program in the hospital setting and solicited recommendations for potential improvements to the harm reduction in-reach program. Interviews were analyzed using an inductive approach that incorporated principles of grounded theory methodology to identify prevailing themes.

Results

Twenty-four participants were interviewed from the harm reduction in-reach program, inpatient addiction consult service, and the hospital observation unit. Thematic analysis revealed seven major themes and multiple facilitators and barriers to the implementation of the harm reduction in-reach program. Participants highlighted the impact of power differences within the medical hierarchy on inter-team communication and clinical care, the persistence of addiction-related stigma, the importance of coordination and role delineation between care team members, and the benefits of a streamlined referral process.

Conclusions

Harm reduction programs offer accessible, patient-centered, low-barrier care to patients using drugs. The integration of community-based harm reduction programs into the inpatient setting is a unique opportunity to bridge inpatient and outpatient care and expand the provision of harm reduction services.

Trial registration: Not applicable.
The associations between interleukin-17 single-nucleotide polymorphism and colorectal cancer susceptibility: a systematic review and meta-analysis
Authors: Li Gaoming , Ma Jingfu , Zhang Ning , Li Xiaogang , Li Fangfang , Jiang Yuxing
Published: April 2022

Background

Numerous case-control studies have reported associations between interleukin-17 (IL-17) polymorphisms and colorectal cancer; however, the results were inconsistent. The aim of this meta-analysis was to further clarify the effects of IL-17 polymorphisms on colorectal cancer susceptibility.

Materials and method

Relevant studies were extracted from the electronic databases PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), and the Chinese Biomedical Literature Database (CMB) up to April 2021. The odds ratio and 95% confidence interval were used to estimate the strength of the associations.

Results

Ten articles including 2599 cases and 2845 controls were enrolled in our research after strict literature screening. Highly significant associations between the IL-17A rs2275913 polymorphism and increased colorectal cancer susceptibility were observed in all five gene models (allelic, dominant, recessive, homozygous, and heterozygous models), and subgroup analysis based on ethnicity revealed that these associations existed not only in the Asian population but also in the Caucasian population. However, the results showed no significantly elevated colorectal cancer risk correlated with the IL-17F rs763780 polymorphism, and a slightly lower colorectal cancer susceptibility for the Caucasian population was discovered in the recessive and homozygous models of this mutation.

Conclusion

The IL-17A rs2275913 polymorphism may be an independent risk factor contributing to colorectal cancer susceptibility, while the IL-17F rs763780 polymorphism may decrease susceptibility to colorectal cancer. Future studies with large-scale samples are warranted to identify these associations.
Risk factors for central venous catheter-associated deep venous thrombosis in pediatric critical care settings identified by fusion model
Authors: Li Haomin , Lu Yang , Zeng Xian , Feng Yuqing , Fu Cangcang , Duan Huilong , Shu Qiang , Zhu Jihua
Published: April 2022

Background

An increase in the incidence of central venous catheter (CVC)-related thrombosis (CRT) has been reported in pediatric intensive care patients over the past decade. Risk factors for the development of CRT are not well understood, especially in children. The study objective was to identify potential clinical risk factors associated with CRT with novel fusion machine learning models.

Methods

Patients aged 0–18 who were admitted to intensive care units from December 2015 to December 2018 and underwent at least one CVC placement were included. Two fusion model approaches (stacking and blending) were used to build a better performance model based on three widely used machine learning models (logistic regression, random forest and gradient boosting decision tree). High-impact risk factors were identified based on their contribution in both fusion artificial intelligence models.

Results

A total of 478 factors of 3871 patients and 3927 lines were used to build fusion models, one of which achieved quite satisfactory performance (AUC = 0.82, recall = 0.85, accuracy = 0.65) in 5-fold cross validation. A total of 11 risk factors were identified based on their independent contributions to the two fusion models. Some risk factors, such as D-dimer, thrombin time, blood acid-base balance-related factors, dehydrating agents, lymphocytes and basophils were identified or confirmed to play an important role in CRT in children.

Conclusions

The fusion model, which achieves better performance in CRT prediction, can better understand the risk factors for CRT and provide potential biomarkers and measures for thromboprophylaxis in pediatric intensive care settings.
Do German university medical centres promote robust and transparent research? A cross-sectional study of institutional policies
Authors: Holst M. R. , Faust A. , Strech D.
Published: April 2022

Background

In light of replication and translational failures, biomedical research practices have recently come under scrutiny. Experts have pointed out that the current incentive structures at research institutions do not sufficiently incentivise researchers to invest in robustness and transparency and instead incentivise them to optimize their fitness in the struggle for publications and grants. This cross-sectional study aimed to describe whether and how relevant policies of university medical centres in Germany support the robust and transparent conduct of research and how prevalent traditional metrics are.

Methods

For 38 German university medical centres, we searched for institutional policies for academic degrees and academic appointments as well as websites for their core facilities and research in general between December 2020 and February 2021. We screened the documents for mentions of indicators of robust and transparent research (study registration; reporting of results; sharing of research data, code and protocols; open access; and measures to increase robustness) and for mentions of more traditional metrics of career progression (number of publications; number and value of awarded grants; impact factors; and authorship order).

Results

While open access was mentioned in 16% of PhD regulations, other indicators of robust and transparent research were mentioned in less than 10% of institutional policies for academic degrees and academic appointments. These indicators were more frequently mentioned on the core facility and general research websites. Institutional policies for academic degrees and academic appointments had frequent mentions of traditional metrics.

Conclusions

References to robust and transparent research practices are, with a few exceptions, generally uncommon in institutional policies at German university medical centres, while traditional criteria for academic promotion and tenure still prevail.
Receptor activity‐modifying protein 1 regulates mouse skin fibroblast proliferation via the Gαi3-PKA-CREB-YAP axis
Authors: Yin Siyuan , Song Ru , Ma Jiaxu , Liu Chunyan , Wu Zhenjie , Cao Guoqi , Liu Jian , Zhang Guang , Zhang Huayu , Sun Rui , Chen Aoyu , Wang Yibing
Published: April 2022

Background

Skin innervation is crucial for normal wound healing. However, the relationship between nerve receptors and wound healing and the intrinsic mechanism remains to be further identified. In this study, we investigated the role of a calcitonin gene-related peptide (CGRP) receptor component, receptor activity‐modifying protein 1 (RAMP1), in mouse skin fibroblast (MSF) proliferation.

Methods

In vivo, Western blotting and immunohistochemical (IHC) staining of mouse skin wounds tissue was used to detect changes in RAMP1 expression. In vitro, RAMP1 was overexpressed in MSF cell lines by infection with Tet-On-Flag-RAMP1 lentivirus and doxycycline (DOX) induction. An IncuCyte S3 Live-Cell Analysis System was used to assess and compare the proliferation rate differences between different treatment groups. Total protein and subcellular extraction Western blot analysis, quantitative real-time-polymerase chain reaction (qPCR) analysis, and immunofluorescence (IF) staining analysis were conducted to detect signalling molecule expression and/or distribution. The CUT & RUN assay and dual-luciferase reporter assay were applied to measure protein-DNA interactions.

Results

RAMP1 expression levels were altered during skin wound healing in mice. RAMP1 overexpression promoted MSF proliferation. Mechanistically, total Yes-associated protein (YAP) and nuclear YAP protein expression was increased in RAMP1-overexpressing MSFs. RAMP1 overexpression increased inhibitory guanine nucleotide-binding protein (G protein) α subunit 3 (Gαi3) expression and activated downstream protein kinase A (PKA), and both elevated the expression of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and activated it, promoting the transcription of YAP, elevating the total YAP level and promoting MSF proliferation.

Conclusions

Based on these data, we report, for the first time, that changes in the total RAMP1 levels during wound healing and RAMP1 overexpression alone can promote MSF proliferation via the Gαi3-PKA-CREB-YAP axis, a finding critical for understanding RAMP1 function, suggesting that this pathway is an attractive and accurate nerve target for skin wound treatment.
The implications of exosomes in pregnancy: emerging as new diagnostic markers and therapeutics targets
Authors: Ghafourian Mehri , Mahdavi Roya , Akbari Jonoush Zahra , Sadeghi Mahvash , Ghadiri Nooshin , Farzaneh Maryam , Mousavi Salehi Abdolah
Published: April 2022

Extracellular vehicles (EVs) are a heterogeneous group of cell and membranous particles originating from different cell compartments. EVs participate in many essential physiological functions and mediate fetal-maternal communications. Exosomes are the smallest unit of EVs, which are delivered to the extracellular space. Exosomes can be released by the umbilical cord, placenta, amniotic fluid, and amniotic membranes and are involved in angiogenesis, endothelial cell migration, and embryo implantation. Also, various diseases such as gestational hypertension, gestational diabetes mellitus (GDM), preterm birth, and fetal growth restriction can be related to the content of placental exosomes during pregnancy. Due to exosomes' ability to transport signaling molecules and their effect on sperm function, they can also play a role in male and female infertility. In the new insight, exosomal miRNA can diagnose and treat infertilities disorders. In this review, we focused on the functions of exosomes during pregnancy.
CSF GFAP levels in double seronegative neuromyelitis optica spectrum disorder: no evidence of astrocyte damage
Authors: Hyun Jae-Won , Kim Yeseul , Kim Ki Hoon , Kim Su-Hyun , Olesen Mads Nikolaj , Asgari Nasrin , Siritho Sasitorn , Paul Friedemann , Kim Ho Jin
Published: April 2022

Background

Despite rigorous confirmation with reliable assays, some individuals showing the neuromyelitis optica spectrum disorder (NMOSD) phenotype remain negative for both aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies.

Objective

We aimed to investigate whether double seronegative NMOSD (DN-NMOSD) and NMOSD with AQP4 antibody (AQP4–NMOSD) share the same pathophysiological basis, astrocytopathy, by measurement of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) levels as a marker of astrocyte damage.

Methods

Seventeen participants who (1) satisfied the 2015 diagnostic criteria for NMOSD, and (2) tested negative for AQP4 and MOG antibodies confirmed with repeated cell-based assays, and (3) had available CSF samples obtained at the point of clinical attacks, were enrolled from 4 medical centers (South Korea, Germany, Thailand, and Denmark). Thirty age-matched participants with AQP4–NMOSD, 17 participants with MOG antibody associated disease (MOGAD), and 15 participants with other neurological disorders (OND) were included as controls. The concentration of CSF GFAP was measured using enzyme-linked immunosorbent assay.

Results

CSF GFAP levels in the DN-NMOSD group were significantly lower than those in the AQP4–NMOSD group (median: 0.49 versus 102.9 ng/mL; p < 0.001), but similar to those in the OND (0.25 ng/mL) and MOGAD (0.39 ng/mL) control groups. The majority (90% (27/30)) of participants in the AQP4–NMOSD group showed significantly higher CSF GFAP levels than the highest level measured in the OND group, while no participant in the DN-NMOSD and MOGAD groups did.

Conclusions

These results suggest that DN-NMOSD has a different underlying pathogenesis other than astrocytopathy, distinct from AQP4–NMOSD.
Role of lipocalin-2 in surgery-induced cognitive decline in mice: a signal from neuron to microglia
Authors: Xiang Xuwu , Tang Xiaodong , Yu Yang , Xie Shulan , Liu Lu , Chen ManLi , Zhang Rong , Kang Xianhui , Zheng Yueying , Yang Guang , Gan Shuyuan , Zhu Shengmei
Published: April 2022

Background

Perioperative neurocognitive disorders (PNDs) are common complications observed among surgical patients. Accumulating evidence suggests that neuroinflammation is one of the major contributors to the development of PNDs, but the underlying mechanisms remain unclear.

Methods

qPCR and ELISA analysis were used for detecting LCN2 and cytokine levels. cx3cr1CreER/−:: R26iDTR/− crossed mouse line was used for microglia depletion; intracranial injection of recombinant LCN2 (rLCN2) and adeno-associated viruses (AAV)-mediated shRNA silencing approaches were used for gain and loss of function, respectively. Combing with in vitro microglia cell culture, we have studied the role of LCN2 in surgery-induced cognitive decline in mice.

Results

We revealed that Lcn2 mRNA and protein levels were greatly increased in mouse hippocampal neurons after surgery. This surgery-induced elevation of LCN2 was independent of the presence of microglia. Gain of function by intracranial injection of rLCN2 protein into hippocampus disrupted fear memory in naive mice without surgery. Conversely, silencing LCN2 in hippocampus by AAV-shRNA protected mice from surgery-induced microglia morphological changes, neuroinflammation and cognitive decline. In vitro, application of rLCN2 protein induced the expression of several pro-inflammatory cytokines in both BV-2 and primary microglia culture.

Conclusions

These data suggest LCN2 acts as a signal from neuron to induce proinflammatory microglia, which contributes to surgery-induced neuroinflammation and cognitive decline in mice.
Barriers to sexual and reproductive care among cisgender, heterosexual and LGBTQIA + adolescents in the border region: provider and adolescent perspectives
Authors: Hubach Randolph D. , Zipfel Rebecca , Muñoz Fatima A. , Brongiel Ilana , Narvarte Annabella , Servin Argentina E.
Published: April 2022

Introduction

The United States (U.S.) has higher rates of sexually transmitted infections (STIs) and adolescent pregnancy than most other industrialized countries. Furthermore, health disparities persist among racial and ethnic minority adolescents (e.g., African American and Latinx) and in counties located along the U.S.–Mexico border region—they demonstrate the highest rates of STIs and unintended pregnancy among adolescents.

Methods

Qualitative data were collected as part of formative research for the development of a mobile app that provides gender-inclusive sexual education to adolescents living in the U.S.—Mexico border region. From August 2019 to March 2020, the study team conducted 11 in-depth interviews with healthcare providers and three focus groups with cisgender, heterosexual, and SGM adolescents ages 15–18 (n = 20).

Results

Providers and adolescents reported similar barriers to accessing SRH in this region such as transportation, lack of insurance and cost of services or accessing services without their parent’s knowledge. However, providers shared that some adolescents in this region face extreme poverty, family separation (i.e., parent has been deported), have a mixed family legal status or are binational and have to travel every day from Mexico to the U.S. for school. These challenges further limit their ability to access SRH.

Conclusions

Adolescents in the U.S.-Mexico border region face unique economic and social challenges that further limit their access to SRH care, making them uniquely vulnerable to STIs and unintended pregnancy. The prototype of the app was developed based on the needs expressed by providers and adolescents, including providing comprehensive Sex Ed and mapping of free comprehensive and confidencial SRH services available in the region and is being pilot tested. Our findings provide further evidence for the need for interventions and service delivery, programs tailored for residents in the border region.
Increased expression of TIGIT and KLRG1 correlates with impaired CD56bright NK cell immunity in HPV16-related cervical intraepithelial neoplasia
Authors: Nie You , Liu Dandan , Yang Wen , Li Yazhuo , Zhang Lihua , Cheng Xia , Chen Ruyu , Yuan Bingbing , Zhang Guangzheng , Wang Hongwei
Published: April 2022

Background

The onset and progression of cervical intraepithelial neoplasia (CIN) are closely associated with the persistent infection of high-risk HPV (especially type16), which is mainly caused by immune escape. Natural killer (NK) cells play an important role against virally infected cells and tumor cells through a fine balance of signals from multiple surface receptors. Overexpression of non-MHC-I specific inhibitory receptors TIGIT, KLRG1, Siglec-7, LAIR-1, and CD300a on NK cells correlates with cellular exhaustion and immune evasion, but these receptors have not been investigated in CIN. The aim of the present study was to examine the potential role of NK cell non-MHC-I specific inhibitory receptors expression in immune escape from HPV16(+)CIN patients.

Methods

The subset distribution, IFN-γ and TNF-α expression levels and immunophenotype of TIGIT, KLRG1, Siglec-7, LAIR-1, and CD300a of NK cells were investigated in peripheral blood mononuclear cell samples by flow cytometry from 82 women who were HPV16(+) with CIN grades 0, I, II–III or HPV(−) CIN 0. Immunohistochemistry was applied to detect the expression of ligands for NK receptors in the cervical tissues. HPV types were identified by PCR assays.

Results

The HPV16(+) subjects with high-grade lesions had an increased number of circulating peripheral blood CD56bright NK cells with reduced functionality and IFN-γ secretion. The expression levels of the inhibitory molecules TIGIT and KLRG1 on CD56bright NK cells increased in parallel with increasing CIN grade. In addition, TIGIT and KLRG1 related ligands, Poliovirus receptor (PVR), N-Cadherin and E-Cadherin expression level was also elevated with increasing CIN grade.

Conclusions

Our results suggest that up-regulation of the inhibitory TIGIT, KLRG1 and their ligands may negatively regulate cervical CD56bright NK-mediated immunity to HPV16 and contribute to the progression of CIN. These results may facilitate the development of early-warning immune predictors and therapeutic strategies for HPV16(+) CIN based on the TIGIT and KLRG1 inhibitory pathways of NK cells.
Three-dimensional assessment of the favorability of maxillary posterior teeth intrusion in different skeletal classes limited by the vertical relationship with the maxillary sinus floor
Authors: Abdulghani Ehab A. , Al-Sosowa Abeer A. , Alhammadi Maged Sultan , Al-fakeh Hanan , Al-Gumaei Waseem Saleh , Almashraqi Abeer A. , Sharhan Hasan M. , Cao BaoCheng
Published: April 2022

Background

Understanding the anatomical relationship between the maxillary sinus floor (MSF) and the posterior maxillary teeth (PMT) is important when planning the orthodontic intrusion of the posterior teeth. This study aimed to determine the vertical relationship between posterior maxillary teeth and maxillary sinus floor in different skeletal classes in the Chinese adult population.

Methods

This is a retrospective cross-sectional study involved cone beam computed tomography images of 298 adult patients (145 males and 153 females) between 20 and 45 years old. The sample was categorized according to A point, Nasion, B point (ANB) angle into 102 Class I, 102 Class II, and 94 Class III malocclusion. Non-parametric Wilcoxon Mann–Whitney U and Kruskal–Wallis tests were used to compare the studied groups. The Intra-class Correlation Coefficient (ICC) was used to assess the intra- and inter-observer reliability analysis.

Results

Overall, there was a statistically significant difference in the mean distance between both genders (P < 0.001). The measured distance increased with age in all posterior tooth roots (P < 0.001). The root apex in the sagittal view appeared to be closer to the maxillary sinus than in the coronal view; 2.2 ± 4.3 and 3.1 ± 5.5 mm, respectively. The most frequent root scores were Type 1 and Type 2P. In both sagittal and coronal views, Class I demonstrated a higher Type 2P prevalence, whereas Class III showed a lower prevalence. The second molars’ mesiobuccal root had the largest number of penetration in the three examined skeletal classes.

Conclusions

Maxillary molars of Class I malocclusion with the majority of Type 2P root-sinus relationship have the highest possible risk of root resorption during molar intrusion due to cortical bone encroachment, while Class III malocclusion showed the least possible risk.
The influence of ossification morphology on surgery outcomes in patients with thoracic ossification of ligamentum flavum (TOLF)
Authors: Du Peiyu , Ma Lei , Ding Wenyuan
Published: April 2022

Background

To determine whether there is a correlation between the type of ossification and radiological parameters, modified thoracic JOA scores, and complications in patients with thoracic ossification of ligamentum flavum treated by posterior thoracic surgery.

Methods

This retrospective cohort study included 48 patients with thoracic myelopathy caused by single-level thoracic ossification of ligamentum flavum who underwent thoracic posterior approach surgery in our Hospital o between December 2013 to December 2018. Patients were divided into unilateral, bilateral, and bridged groups in axial position, and beak and round groups in sagittal position. The differences were analyzed according to the ossification morphology.

Results

In axial myelopathy, there was no significant difference in preop and postop JOA scores and RR among the three groups in axial position (P = 0.884). In sagittal view, there was no significant difference in preoperative JOA score between the two groups (P = 0.710), while the postop JOA score and the recovery rate in the beak group were significantly lower than that of the round group (P = 0.010, P = 0.034). Two-way ANOVA showed that sagittal morphology had a significant effect on postop JOA score (P = 0.028), but axial morphology don’t (P = 0.431); there was no interaction between them (P = 0.444). For the recovery rate, sagittal morphology also had a significant effect (P = 0.043), but axial ossification don’t (P = 0.998); there was no interaction between them (P = 0.479).

Conclusion

Sagittal morphology had a significant adverse effect on postop JOA score and surgical outcome, while axial morphology had no effect on surgical outcome, and there was no interaction between sagittal morphology and axial morphology.
Electroacupuncture vs topical diclofenac sodium gel for patients with hand osteoarthritis: study protocol for a randomized controlled trial
Authors: Wang Weiming , Yu Shudan , Long Zilin , Liu Yan , Yan Yan , Sun Tianheng , Liu Zhishun
Published: April 2022

Background

Hand osteoarthritis (OA) is a prevalent joint disorder and a great burden to both patients and society. While electroacupuncture (EA) and topical diclofenac sodium gel (DSG) are both currently used to treat OA, no head-to-head study of EA and topical DSG for hand OA exists. Thus, it remains unknown whether one intervention offers improved outcomes over the other. This study aims to compare the effects of EA and topical DSG in patients with hand OA.

Methods

A total of 108 participants with hand OA according to the American College of Rheumatology criteria will be recruited and randomly assigned to the EA group or topical DSG group with a 1:1 allocation ratio. Participants in the EA group will receive EA treatment thrice weekly for 4 weeks, followed by a 12-week follow-up. In the topical DSG group, topical DSG at a dose of 2 g over the affected joints per hand will be applied four times per day for 4 weeks. The outcomes will be measured at weeks 4, 8, and 16. The primary outcome will be the change in average overall finger joint pain intensity in the dominant hand from baseline to week 4. All outcome variables will be analyzed on an intention-to-treat principle. All statistical tests will be two-sided.

Discussion

This study will help determine which of the two treatment protocols, EA or topical DSG, is more effective for the clinical treatment of hand OA.

Trial registration ClinicalTrials.gov identifier: NCT04402047. Registered 16 May 2020, https://clinicaltrials.gov/ct2/show/NCT04402047
Successful cases of percutaneous left ventricular assist device “Impella” to fulminant myocarditis
Authors: Hori Takayuki , Iida Mitsuru , Uchiyama Masateru , Shimokawa Tomoki
Published: April 2022

Background

Fulminant myocarditis (FM) is a form of severe inflammatory carditis with rapidly developing acute heart failure.

Case presentation

We report three cases of successful intensive treatment by Impella of FM without any complications. In all cases, impairment of microcirculation as measured by blood lactate level and the hemodynamic value as indicated by cardiac index were improved within 24–48 h and 7 days after Impella implantation, respectively. Interestingly, our data also suggested that treatment by Impella CP or 5.0 may lead to faster recovery of microcirculation and cardiac function than treatment by Impella 2.5.

Conclusion

Our findings demonstrate that the appropriate selection of Impella devices guided by body surface area measurements may help to improve clinical outcomes of severe heart failure including FM.
A rare case of right upper lung cancer with azygos lobe and partial anomalous pulmonary venous return
Authors: Su Xiaoyang , Huang Qianzhun , Luo Zhiqiang , Fang Ning , Huang Jian
Published: April 2022

Background

The azygos lobe (AL) combined with partial anomalous pulmonary venous return (PAPVR) is comparatively uncommon as well as in radical surgery for right lung cancer.

Case presentation

We herein present an extremely rare case of lung cancer coexisting with AL and asymptomatic PAPVR, which was diagnosed with preoperative contrast three-dimensional reconstruction and received radical surgery by thoracoscopy. During the surgery, we preserved azygos vein successfully and found a split type of PAPVR in right upper pulmonary vein.

Conclusions

AL combined with PAPVR may cause confusion on the vascular separation and disconnection of the right pulmonary hilar. However, preoperative 3D reconstruction is more conducive to the correct performing of this type of surgery.
VCP suppresses proteopathic seeding in neurons
Authors: Zhu Jiang , Pittman Sara , Dhavale Dhruva , French Rachel , Patterson Jessica N. , Kaleelurrrahuman Mohamed Salman , Sun Yuanzi , Vaquer-Alicea Jaime , Maggiore Gianna , Clemen Christoph S. , Buscher William J. , Bieschke Jan , Kotzbauer Paul , Ayala Yuna , Diamond Marc I. , Davis Albert A. , Weihl Conrad
Published: April 2022

Background

Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43.

Methods

We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice.

Results

One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons.

Conclusion

Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP.
Strand asymmetry influences mismatch resolution during single-strand annealing
Authors: Pokusaeva Victoria O. , Diez Aránzazu Rosado , Espinar Lorena , Pérez Albert Torelló , Filion Guillaume J.
Published: April 2022

Background

Biases of DNA repair can shape the nucleotide landscape of genomes at evolutionary timescales. The molecular mechanisms of those biases are still poorly understood because it is difficult to isolate the contributions of DNA repair from those of DNA damage.

Results

Here, we develop a genome-wide assay whereby the same DNA lesion is repaired in different genomic contexts. We insert thousands of barcoded transposons carrying a reporter of DNA mismatch repair in the genome of mouse embryonic stem cells. Upon inducing a double-strand break between tandem repeats, a mismatch is generated if the break is repaired through single-strand annealing. The resolution of the mismatch showed a 60–80% bias in favor of the strand with the longest 3′ flap. The location of the lesion in the genome and the type of mismatch had little influence on the bias. Instead, we observe a complete reversal of the bias when the longest 3′ flap is moved to the opposite strand by changing the position of the double-strand break in the reporter.

Conclusions

These results suggest that the processing of the double-strand break has a major influence on the repair of mismatches during single-strand annealing.
Within-subject effects of standardized prosthetic socket modifications on physical function and patient-reported outcomes
Authors: Anderst William , Fiedler Goeran , Onishi Kentaro , McKernan Gina , Gale Tom , Paulus Paige
Published: April 2022

Background

Among the challenges of living with lower limb loss is the increased risk of long-term health problems that can be either attributed directly to the amputation surgery and/or prosthetic rehabilitation or indirectly to a disability-induced sedentary lifestyle. These problems are exacerbated by poorly fit prosthetic sockets. There is a knowledge gap regarding how the socket design affects in-socket mechanics and how in-socket mechanics affect patient-reported comfort and function. The objectives of this study are (1) to gain a better understanding of how in-socket mechanics of the residual limb in transfemoral amputees are related to patient-reported comfort and function, (2) to identify clinical tests that can streamline the socket design process, and (3) to evaluate the efficacy and cost of a novel, quantitatively informed socket optimization process.

Methods

Users of transfemoral prostheses will be asked to walk on a treadmill wearing their current socket plus 8 different check sockets with designed changes in different structural measurements that are likely to induce changes in residual limb motion, skin strain, and pressure distribution within the socket. Dynamic biplane radiography and pressure sensors will be used to measure in-socket residual limb mechanics. Patient-reported outcomes will also be collected after wearing each socket. The effects of in-socket mechanics on both physical function and patient-reported outcomes (aim 1) will be assessed using a generalized linear model. Partial correlation analysis will be used to examine the association between research-grade measurements and readily available clinical measurements (aim 2). In order to compare the new quantitative design method to the standard of care, patient-reported outcomes and cost will be compared between the two methods, utilizing the Wilcoxon-Mann-Whitney non-parametric test (aim 3).

Discussion

Knowledge on how prosthetic socket modifications affect residual bone and skin biomechanics itself can be applied to devise future socket designs, and the methodology can be used to investigate and improve such designs, past and present. Apart from saving time and costs, this may result in better prosthetic socket fit for a large patient population, thus increasing their mobility, participation, and overall health-related quality of life.

Trial registration

ClinicalTrials.gov NCT05041998. Date of registration: Sept 13, 2021.
Single vs. double intracoronary injection of mesenchymal stromal cell after acute myocardial infarction: the study protocol from a randomized clinical trial: BOOSTER-TAHA7 trial
Authors: Attar Armin , Nouri Fatemeh , Yazdanshenas Arash , Hessami Kamran , Vosough Massoud , Abdi-Ardekani Alireza , Izadpanah Peyman , Ramzi Mani , Kojouri Javad , Pouladfar Gholamreza , Monabati Ahmad
Published: April 2022

Background

Meta-analysis from previous studies have shown that treatment with mesenchymal stromal cell (MCSs) may increase the left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) by 3.84%, and the effect is greater in those who are not aged and have developed a reduced LVEF. However, it seems that MSC transplantation does its effect through an indirect paracrine effect, and direct differentiation to the cardiomyocytes does not occur. Therefore, it can be hypothesized that this paracrine effect would be augmented if repeated doses of MSC are transplanted. This study is conducted to compare single vs. double injection of MSCs.

Methods

This is a single-blind, randomized, multicenter trial aiming to determine whether intracoronary infusion of double doses of umbilical cord-derived Wharton’s jelly MSCs (WJ-MSCs) improves LVEF more after AMI compared to single administration. Sixty patients 3 to 7 days after AMI will be enrolled. The patients should be under 65 years old and have a severe impairment in LV function (LVEF < 40%). They will be randomized to three arms receiving single or double doses of intracoronary infusion of WJ-MSCs or placebo. The primary endpoint of this study is assessment of improvement in LVEF at 6-month post intervention as compared to the baseline.

Discussion

This investigation will help to determine whether infusion of booster (second) dose of intracoronary WJ-MSCs in patients with AMI will contribute to increasing its effect on the improvement of myocardial function.

Trial registration

Iranian Registry of Clinical Trials (www.IRCT.ir) IRCT20201116049408N1. Registered on November 26 2020
Sensitivity of Haemonchus contortus to anthelmintics using different in vitro screening assays: a comparative study
Authors: Munguía Beatriz , Saldaña Jenny , Nieves Magdalena , Melian María Elisa , Ferrer Manuela , Teixeira Ramiro , Porcal Williams , Manta Eduardo , Domínguez Laura
Published: April 2022

Background

Helminthiasis and resistance to commercial anthelmintic compounds are major causes of economic losses for livestock producers, resulting in an urgent need for new drugs and reliable in vitro screening tests capable of detecting potentially active products. Considering this, a series of novel benzimidazole derivatives (5-methylbenzimidazole 1,2-disubstituted, 5-carboxybenzimidazole, 5-methylbenzimidazole 2-one) was screened on exsheathed L3 (xL3) and on the adult stage of Haemonchus contortus (Kirby anthelmintic-susceptible McMaster isolate).

Methods

This work presents the set-up of an automated motility assay on the xL3 stage of H. contortus using an infrared tracking device (WMicrotracker One) together with a larval development test (xL3 to L4) and a motility assay on the adult stage of H. contortus. A comparative study of the sensitivity of these in vitro assays using commercial anthelmintics with different mechanisms of action was carried out, also evaluating anthelmintic activity of a series of novel benzimidazole derivatives.

Results

The automated xL3 assay had the great advantage of being able to analyze many compounds simultaneously, but it showed the limitation of having lower sensitivity, requiring higher concentrations of the commercial anthelmintics tested compared to those needed for the adult motility or development assays. Although none of the novel 1,2,5-tri-substituted benzimidazole derivatives could significantly decrease the motility of xL3s, one of them (1e) significantly affected the development of xL3s to L4, and five new compounds (1b, 1d, 1e, 2a and 2c) reduced the motility of H. contortus adult stage.

Conclusions

The analysis of the results strongly suggests that the in vitro xL3 to L4 development test, particularly for the L4 stage, could be closer to the pharmacological sensitivity of the adult stage of H. contortus (target of interest) for commercial anthelmintic selected, with different mechanisms of action, and for the series of benzimidazole derivatives assayed. Therefore, an automated motility assay on L4 using the infrared tracking device is being set up. Further studies will be conducted to evaluate the in vivo anthelmintic activity of the most active novel benzimidazole derivatives.

Graphical Abstract
Bergmann’s rule is a “just-so” story of human body size
Authors: Bogin Barry , Hermanussen Michael , Scheffler Christiane
Published: April 2022

Carl Bergmann was an astute naturalist and physiologist. His ideas about animal size and shape were important advances in the pre-Darwinian nineteenth century. Bergmann’s rule claims that that in cold climates, large body mass increases the ratio of volume-to-surface area and provides for maximum metabolic heat retention in mammals and birds. Conversely, in warmer temperatures, smaller body mass increases surface area relative to volume and allows for greater heat loss. For humans, we now know that body size and shape are regulated more by social-economic-political-emotional (SEPE) factors as well as nutrition-infection interactions. Temperature has virtually no effect. Bergmann’s rule is a “just-so” story and should be relegated to teaching and scholarship about the history of science. That “rule” is no longer acceptable science and has nothing to tell us about physiological anthropology.
Reexamination of tsunami source models for the twentieth century earthquakes off Hokkaido and Tohoku along the eastern margin of the Sea of Japan
Authors: Murotani Satoko , Satake Kenji , Ishibe Takeo , Harada Tomoya
Published: April 2022

Large earthquakes around Japan occur not only in the Pacific Ocean but also in the Sea of Japan, and cause both damage from the earthquake itself and from the ensuing tsunami to the coastal areas. Recently, offshore active fault surveys were conducted in the Sea of Japan by the Integrated Research Project on Seismic and Tsunami Hazards around the Sea of Japan (JSPJ), and their fault models (length, width, strike, dip, and slip angles) have been obtained. We examined the causative faults of M7 or larger earthquakes in the Sea of Japan during the twentieth century, comprising events of 1940, 1964, 1983, and 1993, using seismic and tsunami data. The 1940 off Shakotan Peninsula earthquake (MJMA 7.5) appears to have been caused by the offshore active faults MS01, MS02, ST01, and ST02 as modeled by the JSPJ. The 1993 off the southwest coast of Hokkaido earthquake (MJMA 7.8) likely occurred on the offshore active faults OK03a, OK03b, and OK05, while the 1983 Central Sea of Japan earthquake (MJMA 7.7) probably related to MMS01, MMS04, and MGM01. For these earthquakes, the observed tsunami waveforms were basically reproduced by tsunami numerical simulation from the offshore active faults with the slip amounts obtained by the scaling relation with three stages between seismic moment and source area for inland earthquakes. However, the observed tsunami runup heights along the coast were not reproduced at certain locations, possibly because of the coarse bathymetry data used for the simulation. The 1983 west off Aomori (MJMA 7.1) and the 1964 off Oga Peninsula (MJMA 6.9) earthquakes showed multiple faults near the source area that could be used to reproduce the observed tsunami waveforms; therefore, we could not identify the causative faults. Further analysis using near-field seismic waveforms is required for their identification of their causative faults and their parameters. The scaling relation for inland earthquakes can be used to obtain the slip amounts for offshore active faults in the Sea of Japan and to estimate the coastal tsunami heights and inundation area which can be useful for disaster prevention and mitigation of future earthquakes and tsunamis.

Graphical Abstract
Fire severity and tree size affect post-fire survival of Afrotemperate forest trees
Authors: Giddey Brandon L. , Baard Johan A. , Kraaij Tineke
Published: April 2022

Background

Fire is recognized as an important factor in determining the distribution and composition of Southern Cape Afrotemperate Forest in South Africa, although comprehensive understanding of the resilience of these forests to fire is lacking. We investigated effects of fire severity and tree size on post-fire survival of Afrotemperate forest tree species.

Results

Fire severity was estimated from observed damage to the main stem of trees, and trees were considered to have survived if they resprouted from the main stem or had green foliage in the canopy. A total of 88 plots, 40 species, and 1 378 trees were surveyed 19–24 months post-fire. We assessed the survival response of all trees collectively and for 10 species (with sample size > 40) individually, using logistic regression. Relative to other forests of the world, the post-fire survival rate (45%) of Afrotemperate forest trees collectively was comparable to that in coniferous and tropical forests but lower than that in other temperate forests and in neighboring dune thicket. Fire severity had a significant negative effect on survival and tree size had a significant positive effect. Total variance explained by the model (for species collectively) was 40.8%, of which fire severity and tree size combined explained 13.2%, and species as random factor, 27.6%. Respective tree species showed differential survival responses—four species showed high survival (> 60%), while five species showed low survival (< 40%). Further, some species exhibited strong resprouting from the base or main stem while others rarely resprouted. The survival response and resprouting abilities of species which occur in both Afrotemperate forest and neighboring, more fire-exposed dune thicket, were generally poorer in forest. Such discrepancies imply that historical fire regimes associated with vegetation types likely drive species adaptions.

Conclusions

Our findings suggest that fire severity and fire frequency (in terms of how tree size relates to fire frequency) are important for maintaining species richness and diversity within and between forest types. Varying resilience to fire among species supports previous assertions that fire affects species composition and diversity in these forests and suggests that potential changes in fire regimes due to global change will have consequences for forest conservation.