bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 32 Low Incidence of Product Complaints and Adverse Events Support Safety of Cord Blood Units
Authors: O’Gara Erin , Regan Donna , Rice Lindsay , Bakken Ruth
Published: September 2022

Introduction

As an important cellular therapy source for many patients, the safe and timely delivery of cord blood units (CBU) is paramount. The National Marrow Donor Program (NMDP) investigates product complaints received for CBUs distributed under the 10-CBA investigational new drug application that may impact the safety, quality, identity, purity, or potency of the product. NMDP also receives reports of any patient adverse events or serious complications resulting from the transplantation of CBUs. Information on product complaints and adverse events provides insight into areas related to product integrity, patient safety, and customer satisfaction and highlights opportunities for improvement.

Objective

We analyzed all product complaints and adverse events reports submitted to NMDP for CBUs distributed under the NMDP 2010 Cord Blood Access Protocol (10-CBA) from October 2019 through March 2022. These investigations offer visibility into factors associated with product quality and integrity discovered after shipment.

Methods

A total of 1,578 CBUs from 38 cord blood banks were shipped from October 2019 through March 2022 (30 months). Data on CBU product complaints reported to NMDP were compiled and analyzed. Data were grouped into categories based upon the primary reason for the product complaint or adverse event. The outcome of NMDP investigations and resolutions is relayed quarterly to the Quality Subgroup of the Cord Blood Advisory Group.

Results

Of the 1,578 CBUs shipped between October 2019 and March 2022, 98% had no reported incidents (32 reports of product complaints and 4 of adverse events). The most common reasons for product complaints investigated by NMDP were related to shipping/transportation (n = 15, 47%), quality issues such as lower than expected potency or bag breaks (n = 11, 34%), and labeling errors (n = 3, 9%). Three of the four adverse events were associated with infusion (two hypertensive episodes and one anaphylaxis) and one was a secondary cancer following transplant.

Discussion

Transplant centers report very few quality incidents, product complaints, or adverse events when using cord blood units. We remain vigilant for opportunities to improve. Clinicians and patients can be assured that CBUs are a safe product with high likelihood of arriving to the transplant center without incident or causing adverse events once transplanted.
Long non-coding RNA OGFRP1 regulates cell proliferation and ferroptosis by miR-299-3p/SLC38A1 axis in lung cancer
Authors: Liu Liang , Su Shengtian , Ye Dan , Yu Zhigao , Lu Wenjing , Li Xiaoju
Published: September 2022

Lung cancer is devastating cancer that ranks as the leading cause of cancer-related death. Long noncoding RNA (lncRNA) opioid growth factor receptor pseudogene 1 (OGFRP1) was recognized as an oncogene in many cancers. However, the molecular mechanism of OGFRP1 in lung cancer is still poorly understood. The expression of target RNAs and genes was detected by quantitative real-time PCR and western blot. The interaction between miR-299-3p and OGFRP1 or solute carrier family 38 member 1 (SLC38A1) was predicted by StarbaseV3.0 and verified by dual-luciferase reporter assay and Pearson’s correlation coefficient. Besides, a transplantation model of human lung cancer in nude mice was established to evaluate the role of OGFRP1 in lung cancer. OGFRP1 and SLC38A1 were overexpressed, whereas miR-299-3p was lowly expressed in lung cancer tumors and cells. OGFRP1 knockdown suppressed cell proliferation and facilitated ferroptosis by promoting lipid peroxidation and iron accumulation in lung cancer. Besides, Furthermore, miR-299-3p inhibitor or SLC38A1 overexpression attenuated OGFRP1 depletion-induced suppression on cell proliferation and ferroptosis in lung cancer. Animal experiments indicated that OGFRP1 deficiency restrained tumor growth in vivo by regulating the miR-299-3p/SLC38A1 axis. OGFRP1 regulated cell proliferation and ferroptosis in lung cancer by inhibiting miR-299-3p to enhance SLC38A1 expression, providing a novel therapeutic strategy for lung cancer.
circRNA mannosidase alpha class 1A member 2 contributes to the proliferation and motility of papillary thyroid cancer cells through upregulating metadherin via absorbing microRNA-449a
Authors: Feng Yao , Yang Xinxin , Wang Yibo , Chi Nannan , Yu Jianan , Fu Xiandong
Published: September 2022

Papillary thyroid carcinoma (PTC) is a common malignancy in endocrine system globally. Accumulating articles have found that circular RNAs (circRNAs) were dysregulated, and they were involved in PTC development. The aim of this project was to explore the function and associated mechanism of circRNA mannosidase alpha class 1A member 2 (circMAN1A2) in PTC progression. The expression of RNA was determined by real-time quantitative PCR. Cell proliferation ability was analyzed by colony formation assay and 5-ethynyl-2′-deoxyuridine assay. Cell migration and invasion were assessed by wound healing assay and transwell invasion assay, respectively. Protein levels were determined by Western blot assay. Dual-luciferase reporter assay and RNA immunoprecipitation assay were applied to confirm the interaction between microRNA-449a (miR-449a) and circMAN1A2 or metadherin (MTDH). Xenograft tumor model was utilized to explore the effect of circMAN1A2 silencing on tumor growth in vivo. CircMAN1A2 expression was elevated in PTC specimens and three PTC cell lines relative to adjacent normal specimens and Nthy-ori 3-1 cell line. CircMAN1A2 silencing inhibited the proliferation and motility of PTC cells. CircMAN1A2 acted as a molecular sponge of miR-449a, and circMAN1A2 knockdown suppressed PTC development partly through upregulating miR-449a. MiR-449a bound to the 3′ untranslated region of MTDH, and miR-449a restrained PTC progression partly through down-regulating MTDH. CircMAN1A2 interference suppressed PTC progression in vivo. CircMAN1A2 contributed to the proliferation ability and motility of PTC cells through enhancing MTDH expression via sponging miR-449a.
Assessment in vitro of interactions between anti-cancer drugs and noncancer drugs commonly used by cancer patients
Authors: Andersson Claes R. , Ye Jiawei , Blom Kristin , Fryknäs Mårten , Larsson Rolf , Nygren Peter
Published: September 2022

Cancer patients often suffer from cancer symptoms, treatment complications and concomitant diseases and are, therefore, often treated with several drugs in addition to anticancer drugs. Whether such drugs, here denoted as ‘concomitant drugs’, have anticancer effects or interact at the tumor cell level with the anticancer drugs is not very well known. The cytotoxic effects of nine concomitant drugs and their interactions with five anti-cancer drugs commonly used for the treatment of colorectal cancer were screened over broad ranges of drug concentrations in vitro in the human colon cancer cell line HCT116wt. Seven additional tyrosine kinase inhibitors were included to further evaluate key findings as were primary cultures of tumor cells from patients with colorectal cancer. Cytotoxic effects were evaluated using the fluorometric microculture cytotoxicity assay (FMCA) and interaction analysis was based on Bliss independent interaction analysis. Simvastatin and loperamide, included here as an opioid agonists, were found to have cytotoxic effects on their own at reasonably low concentrations whereas betamethasone, enalapril, ibuprofen, metformin, metoclopramide, metoprolol and paracetamol were inactive also at very high concentrations. Drug interactions ranged from antagonistic to synergistic over the concentrations tested with a more homogenous pattern of synergy between simvastatin and protein kinase inhibitors in HCT116wt cells. Commonly used concomitant drugs are mostly neither expected to have anticancer effects nor to interact significantly with anticancer drugs frequently used for the treatment of colorectal cancer.
Rare Concurrence of Alopecia Areata in the Setting of the Lipedematous Scalp
Authors: Hu Danchen , Yang Shuxia
Published: September 2022

The lipedematous scalp (LS) is characterized by a thickened scalp because of the increased thickness of the subcutaneous fat layer. When the soft and boggy scalp is associated with shortened hairs and hair loss, it is referred to as lipedematous alopecia (LA). We report a case of alopecia areata with LS, which may be misdiagnosed as LA. However, the histopathologic features showed a thickened subcutaneous fat layer and hair bulb inflammation. Hair regrowth was appreciable after treatment with topical steroids, minoxidil, oral compound glycyrrhizin, and vitamin D. This case report aims to show that LS and alopecia areata may coexist, and histopathologic examination is necessary for precise diagnosis.
Climacteric status is associated with sexual dysfunction at the age of 46 years: a population-based study
Authors: Savukoski Susanna M. , Pinola Pekka A. , Pesonen Paula R. O. , Puukka Katri S. , Suvanto Eila T. J. , Niinimäki Maarit J.
Published: September 2022

Objective

Increasing age and menopausal transition increase the risk of sexual dysfunction. Sexual dysfunction is common in women experiencing menopause before the age of 40 years, whereas evidence on sexual function in women experiencing menopause in their mid-40s is scarce. We aimed to investigate sexual function in 46-year-old women in relation to their menopausal status.

Methods

This study cross-sectionally evaluated sexual function of women in a prospective population-based Northern Finland Birth Cohort 1966 (NFBC1966). A 46-year follow-up study of NFBC1966 included a broad questionnaire evaluating health, lifestyle, and life situation, as well as menstrual history and sexual function, and blood sampling analysis including follicle stimulating hormone and free androgen index (FAI). The participants were divided into two groups by their menopause status, defined by follicle-stimulating hormone and menstrual history. We performed logistic regression models in which parameters of sexual function were dependent factors and climacteric status, self-reported health, FAI, relationship status, smoking, and education level were independent variables.

Results

The study population included 2,661 women. In regression models, more advanced climacteric status was associated with higher frequency and difficulty level of low sexual desire and vaginal dryness (odds ratios with 95% confidence intervals: 2.80 [2.12-3.71], 3.22 [2.43-4.27], 3.83 [2.82-5.20], 3.75 [2.75-5.12], respectively), lower frequency of sexual thoughts (1.34 [1.02-1.75]), and higher frequency of problems with intercourse (2.35 [1.51-3.66]). Lower FAI and poorer health were associated with impaired sexual function.

Conclusions

The current study suggests that women experiencing menopausal transition in their mid-40s are at risk of impaired sexual function.
CHANGE IN CHORIOCAPILLARIS FLOW DEFICITS WITHIN TEARS OF THE RETINAL PIGMENT EPITHELIUM IMAGED WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY
Authors: Iyer Prashanth G. , Chu Zhongdi , Shen Mengxi , Shi Yingying , Trivizki Omer , Zhang Qinqin , Feuer William , Wang Ruikang K. , Gregori Giovanni , Rosenfeld Philip J.
Published: September 2022

Purpose:

Choriocapillaris (CC) flow deficits (FDs) were measured in the areas exposed by tears of the retinal pigment epithelium (RPE) before and after their onset to determine their change over time.

Methods:

Patients enrolled in a prospective, swept-source optical coherence tomography angiography (SS-OCTA) study were retrospectively reviewed for RPE tears, and scans were evaluated before and after RPE tear formation. Choriocapillaris flow deficits were measured within the bed of the tear and within a symmetric control region.

Results:

Three patients with RPE tears were imaged before tear formation and for at least 16 months afterward. When the baseline and first posttear visit were compared, CC FDs decreased by 1.0% in the tear region and 1.7% in the control region (P = 0.84). When the 16-month follow-up visits were compared with the first post-RPE tear visits, CC FDs decreased by 1.9% in tear regions and increased by 1.3% in control regions (P = 0.37).

Conclusion:

No significant changes in CC FDs were observed before and after RPE tear formation and for 16 months afterward, suggesting that CC FDs can be reliably detected in the presence of an intact RPE and the absence of the RPE did not affect CC perfusion for at least 16 months.
Decreases in Nephrotoxic Pain Medications Are Not Associated With Increased Opioid Utilization in Critically Ill Children
Authors: Stenson Erin K. , DeMasellis Gina , Shah Ananya , Reiter Pamela D. , Brinton John , Martin Sara , Iwanowski Melissa , Rannie Michael , Soranno Danielle E. , Gist Katja M.
Published: September 2022

OBJECTIVES:

Quality improvement initiatives to decrease rates of nephrotoxic medication exposure have reduced rates of acute kidney injury (AKI) in noncritically ill children. The objective of our study was to analyze the implementation of a similar program in critically ill children and to measure important balancing measures including opioid and benzodiazepine exposure.

DESIGN:

Prospective quality improvement study.

SETTING:

PICU at Children’s Hospital Colorado between 2018 and 2020.

PATIENTS:

All children admitted to PICU.

INTERVENTIONS:

Quality improvement initiative called Nephrotoxic Injury Negated by Just-In-Time Action (NINJA).

MEASUREMENT AND MAIN RESULTS:

Eight thousand eight hundred thirty-three PICU patient admissions were included. Mean rates of nephrotoxic medication exposure/1,000 PICU patient days decreased from 46 to 26, whereas rates of nephrotoxic AKI/1,000 PICU patient days did not change. Nonsteroidal anti-inflammatory drug dispenses per 1,000 patient days were reduced from 521 to 456. Similarly, opioid and benzodiazepine exposures per 1,000 patient days were reduced from 812 to 524 and 441 to 227, respectively, during the study observation period.

CONCLUSIONS:

The NINJA intervention was efficaciously implemented in our single-center PICU. Nephrotoxic exposure is a modifiable factor that did not inadvertently increase exposure to opioids and benzodiazepines.
Clinical and Epidemiologic Characteristics of a Cohort of HIV-Infected Mother–Infant Pairs During 21 Years
Authors: Illán Ramos Marta , Prieto Tato Luis Manuel , Guillén Martín Sara , Navarro Gómez Mᵃ Luisa , Escosa García Luis , Roa Francia Miguel Ángel , Beceiro Mosquera José , Olabarrieta Arnal Iciar , Muñoz Gálligo Eloy , Viñuela Benéitez Mᵃ Carmen , Regidor Sáez Francisco Javier , Mazariegos Orellana Diana , Fuentes Ferrer Manuel , Berzosa Sánchez Arantxa , Callejas Caballero Ignacio , Ramos Amador José Tomás ,   On Behalf of the Madrid Cohort of HIV-Infected Mother-Infant Pairs
Published: September 2022

Background:

HIV infection continues to be a worldwide public health problem. After the introduction of effective preventive measures, perinatal transmission dramatically decreased. Our aim was to assess the sociodemographic changes in pregnant women living with HIV infection and trends in perinatal transmission rates over time.

Setting:

The Madrid cohort of HIV-infected mother–infant pairs is a multicenter, prospective, observational, and cohort study that collects information on HIV-infected pregnant women and their children.

Methods:

Information on clinical–epidemiological characteristics of HIV-infected pregnant women until delivery and their children from 9 public hospitals was included. Data were collected from a standardized questionnaire from medical records. The results were classified in 3 periods: period 1 (P1) 2000–2006, period 2 (P2) 2007–2013, and period 3 (P3) 2014–2020.

Results:

A total of 1521 women living with HIV and 1548 newborns were included. In P1, most mothers (75.8%) were Spanish, whereas in P2 and P3 there was a predominance of foreign origin [62.8% and 70.5% respectively (P < 0.01)]. The percentage of women with antiretroviral treatment before pregnancy increased significantly in P3 (P < 0.01). The proportion of Caesarean sections decreased over time (P < 0.01): 66.2% (n = 472) in P1, 54.9% (n = 245) in P2, and 46.7% (n = 141) in P3. The percentage of preterm and low birth weight newborns showed a statistically significant decrease. Even though there were no statistically significant differences (P = 0.154), a decrease in cases of perinatal infection was observed (1.6% in P1, 1.3% in P2 and 0.3% in P3).

Conclusions:

The epidemiologic characteristics of pregnant women with HIV infection have changed over time in our setting, with an increase of non-Caucasian, heterosexual, and perinatally infected mothers. Although there are still perinatal infections, especially in vulnerable populations such as immigrant women, transmission rate has markedly decreased in recent years and is still of major concern. Prevention measures should be reinforced in the most socially disadvantaged groups.
Evaluating the Influence of Anatomical Accuracy and Electrode Positions on EEG Forward Solutions
Authors: Nielsen Jesper Duemose , Puonti Oula , Xue Rong , Thielscher Axel , Madsen Kristoffer Hougaard
Published: September 2022

Generating realistic volume conductor models for forward calculations in electroencephalography (EEG) is not trivial and several factors contribute to the accuracy of such models, two of which are its anatomical accuracy and the accuracy with which electrode positions are known. Here, we investigate effects of anatomical accuracy by comparing forward solutions from SimNIBS, a tool which allows state-of-the-art anatomical modeling, with well-established pipelines in MNE-Python and FieldTrip. We also compare different ways of specifying electrode locations when digitized positions are not available such as transformation of measured positions from standard space and transformation of a manufacturer layout.

Substantial effects of anatomical accuracy were seen throughout the entire brain both in terms of field topography and magnitude with SimNIBS generally being more accurate than the pipelines in MNE-Python and FieldTrip. Topographic and magnitude effects were particularly pronounced for MNE-Python which uses a three-layer boundary element method (BEM) model. We attribute these mainly to differences in skull and cerebrospinal fluid (CSF) modeling. Effects of electrode specification method were evident in occipital and posterior areas when using a transformed manufacturer layout whereas transforming measured positions from standard space generally resulted in smaller errors.

We suggest modeling the anatomy of the volume conductor as accurately possible and we hope to facilitate this by making it easy to export simulations from SimNIBS to MNE-Python and FieldTrip for further analysis. Likewise, if digitized electrode positions are not available, a set of measured positions on a standard head template may be preferable to those specified by the manufacturer.
Reactivation-induced memory integration prevents proactive interference in perceptual learning
Authors: Huang Zhibang , Niu Zhimei , Li Sheng
Published: September 2022

We acquire perceptual skills through experience to adapt ourself to the changing environment. Accomplishing an effective skill acquisition is a main purpose of perceptual learning research. Given the often observed learning effect specificity, multiple perceptual learnings with shared parameters could serve to improve the generalization of the learning effect. However, the interference between the overlapping memory traces of different learnings may impede this effort. Here, we trained human participants on an orientation discrimination task. We observed a proactive interference effect that the first training blocked the second training at its untrained location. This was a more pronounced effect than the well-known location specificity in perceptual learning. We introduced a short reactivation of the first training before the second training and successfully eliminated the proactive interference when the second training was inside the reconsolidation time window of the reactivated first training. Interestingly, we found that practicing an irrelevant task at the location of the second training immediately after the reactivation of the first training could also restore the effect of the second training but in a smaller magnitude, even if the second training was conducted outside of the reconsolidation window. We proposed a two-level mechanism of reactivation-induced memory integration to account for these results. The reactivation-based procedure could integrate either the previously trained and untrained locations or the two trainings at these locations, depending on the activated representations during the reconsolidation process. The findings provide us with new insight into the roles of long-term memory mechanisms in perceptual learning.
Longitudinal assessment of water-reaching reveals altered cortical activity and fine motor coordination defects in a Huntington Disease model
Authors: Wang Yundi , Sepers Marja D. , Xiao Dongsheng , Raymond Lynn A. , Murphy Timothy H.
Published: September 2022

Huntington Disease (HD), caused by dominantly inherited expansions of a CAG repeat results in characteristic motor dysfunction. Although gross motor and balance defects have been extensively characterized in multiple HD mouse models using tasks such as rotarod, beam walking and gait analysis, little is known about forelimb deficits. Here we use a high-throughput alternating reward/non-reward water-reaching task conducted daily over ∼2 months to simultaneously monitor forelimb impairment and mesoscale cortical changes in GCaMP activity, comparing female zQ175 (HD) and wildtype (WT) littermate mice, starting at ∼5.5 months of age. Behavioral analysis of the water-reaching task reveals that HD mice, despite learning the water-reaching task as proficiently as WT mice, take longer to learn the alternating event sequence. Although WT mice displayed no significant changes in cortical activity and reaching trajectory throughout the testing period, HD mice exhibited an increase in cortical activity – especially in the secondary motor and retrosplenial cortices – over time, as well as longer and more variable reaching trajectories by ∼7 months of age. HD mice also experienced a progressive reduction in successful performance rates. Tapered beam and rotarod tests before and/or after water-reaching assessment confirmed these early and manifest stages of HD characterized by the absence and presence of failed water-reaching trials, respectively. Reduced DARPP-32 (marker for striatal medium spiny neurons) expression in HD mice further confirmed disease pathology. The water-reaching task can be used to inform HD and potentially other movement disorder onset, therapeutic intervention windows and test drug efficacy.

Significance statement

The movement disorder, Huntington Disease (HD), has been extensively studied in preclinical settings using mouse models of disease examining gross motor and balance defects. Little however, is known regarding forelimb deficits and underlying cortical circuit changes. Using a high-throughput alternating reward/non-reward water-reaching task, we characterized early event sequence learning defects in HD mice aged ∼5.5 months. Progressive forelimb movement defects first become apparent at ∼6.5 months of age with corresponding increases in cortical activity associated with reaching observed over time. These forelimb defects revealed in the water-reaching task are coincident with gross motor defects characterized using the tapered beam and rotarod tasks, demonstrating the suitability of the water-reaching task in phenotyping HD motor deficits.
Microsaccades transiently lateralise EEG alpha activity
Authors: Liu Baiwei , Nobre Anna C. , van Ede Freek
Published: September 2022

The lateralisation of 8-12 Hz alpha activity is a canonical signature of human spatial cognition that is typically studied under strict fixation requirements. Yet, even during attempted fixation, the brain produces small involuntary eye movements known as microsaccades. Here we report how spontaneous microsaccades – made in the absence of incentives to look elsewhere – can themselves drive transient lateralisation of EEG alpha power according to microsaccade direction. This transient lateralisation of posterior alpha power occurs similarly following start and return microsaccades and is driven by increased alpha power ipsilateral to microsaccade direction. This reveals new links between spontaneous microsaccades and human electrophysiological brain activity, and highlights how microsaccades are an important factor to consider in studies relating alpha activity to spatial cognition.
An automated BIDS-App for brain segmentation of human fetal functional MRI data
Authors: Nichols Emily S. , Correa Susana , Van Dyken Peter , Kai Jason , Kuehn Tristan , de Ribaupierre Sandrine , Duerden Emma G. , Khan Ali R.
Published: September 2022

Fetal functional magnetic resonance imaging (fMRI) offers critical insight into the developing brain and could aid in predicting developmental outcomes. As the fetal brain is surrounded by heterogeneous tissue, it is not possible to use adult- or child-based segmentation toolboxes. Manually-segmented masks can be used to extract the fetal brain; however, this comes at significant time costs. Here, we present a new BIDS App for masking fetal fMRI, funcmasker-flex, that overcomes these issues with a robust 3D convolutional neural network (U-net) architecture implemented in an extensible and transparent Snakemake workflow. Open-access fetal fMRI data with manual brain masks from 159 fetuses (1103 total volumes) were used for training and testing the U-net model. We also tested generalizability of the model using 82 locally acquired functional scans from 19 fetuses, which included over 2300 manually segmented volumes. Dice metrics were used to compare performance of funcmasker-flex to the ground truth manually segmented volumes, and segmentations were consistently robust (all Dice metrics ≥0.74). The tool is freely available and can be applied to any BIDS dataset containing fetal bold sequences. funcmasker-flex reduces the need for manual segmentation, even when applied to novel fetal functional datasets, resulting in significant time-cost savings for performing fetal fMRI analysis.
Formulating a TMEM176B blocker in nanoparticles uncouples its paradoxical roles in innate and adaptive antitumoral immunity
Authors: Victoria Sabina , Castro Analía , Pittini Alvaro , Olivera Daniela , Russo Sofía , Cebrian Ignacio , Mombru Alvaro W. , Osinaga Eduardo , Pardo Helena , Segovia Mercedes , Hill Marcelo
Published: September 2022

The immunoregulatory cation channel TMEM176B plays a dual role in tumor immunity. On one hand, TMEM176B promotes antigen cross-presentation to CD8+ T cells by regulating phagosomal pH in dendritic cells (DCs). On the other hand, TMEM176B inhibits NLRP3 inflammasome activation through ionic mechanisms in DCs, monocytes and macrophages. Moreover, the TMEM176B blocker BayK8644 controls tumor progression through mechanisms involving inflammasome activation in prophylactic but not in therapeutic protocols. We speculated that the limited therapeutic efficacy of the compound may be linked to its potential capacity to inhibit antigen cross-presentation. Here we show that free BayK8644 inhibits antigen cross-presentation by splenic DCs. To prevent such inhibition, we reasoned that formulating BayK8644 in nanoparticles may delay the release of the compound in endosomes. Avoiding TMEM176B inhibition during the first 30 minutes of nanoparticle internalization by DCs may allow efficient cross-presentation to occur during this critical time frame. Indeed, we observed that NP-PEG-BayK8644 did not inhibit antigen cross-presentation, in contrast to the free compound. Moreover, NP-PEG-BayK8644 triggered inflammasome activation in a Tmem176b-dependent manner. We then injected eNP-PEG or NP-PEG-BayK8644 to mice bearing established tumors. NP-PEG-BayK8644 significantly controlled tumor growth and mice survival, as compared to eNP-PEG and free BayK8644, in a Tmem176b-dependent manner in mouse melanoma and lymphoma tumors. Responding animals treated with NP-PEG-BayK8644 showed reinforced tumor infiltration by total and tumor-specific CD8+ T cells. Overall, we rationally developed a formulating method of BayK8644 that improves its anti-tumoral therapeutic efficacy by uncoupling the dual role of TMEM176B on innate and adaptive immunity.
Tumor removal limits prostate cancer cell dissemination in bone and osteoblasts induce cancer cell dormancy through focal adhesion kinase
Authors: Liu Ruihua , Su Shang , Xing Jing , Liu Ke , Zhao Yawei , Stangis Mary , Jacho Diego P. , Yildirim-Ayan Eda D. , Gatto-Weis Cara M. , Chen Bin , Li Xiaohong
Published: September 2022

Background

Disseminated tumor cells (DTCs) can enter a dormant state and cause no symptoms in cancer patients. On the other hand, the dormant DTCs can reactivate and cause metastases progression and lethal relapses. In prostate cancer (PCa), relapse can happen after curative treatments such as primary tumor removal. The impact of surgical removal on PCa dissemination and dormancy remains elusive. Furthermore, as dormant DTCs are asymptomatic, dormancy-inducing can be an operational cure for preventing metastases and relapse of PCa patients.

Methods

We used a PCa subcutaneous xenograft model and species-specific PCR to survey the DTCs in various organs at different time points of tumor growth and in response to tumor removal. We developedin vitro2D and 3D co-culture models to recapitulate the dormant DTCs in the bone microenvironment. Proliferation assays, fluorescent cell cycle reporter, qRT-PCR, and Western Blot were used to characterize the dormancy phenotype. We performed RNA sequencing to determine the dormancy signature of PCa. A drug repurposing algorithm was applied to predict dormancy-inducing drugs and a top candidate was validated for the efficacy and the mechanism of dormancy induction.

Results

We found DTCs in almost all mouse organs examined, including bones, at week 2 post-tumor cell injections. Surgical removal of the primary tumor reduced the overall DTC abundance, but the DTCs were enriched only in the bones. We found that osteoblasts, but not other cells of the bones, induced PCa cell dormancy. RNA-Seq revealed the suppression of mitochondrial-related biological processes in osteoblast-induced dormant PCa cells. Importantly, the mitochondrial-related biological processes were found up-regulated in both circulating tumor cells and bone metastases from PCa patients’ data. We predicted and validated the dormancy-mimicking effect of PF-562271, an inhibitor of focal adhesion kinase (FAK)in vitro. Decreased FAK phosphorylation and increased nuclear translocation were found in both co-cultured and PF-271-treated C4-2B cells, suggesting that FAK plays a key role in osteoblast-induced PCa dormancy.

Conclusions

Our study provides the first insights into how primary tumor removal enriches PCa cell dissemination in the bones, defines a unique osteoblast-induced PCa dormancy signature, and identifies FAK as a PCa cell dormancy gatekeeper.
Gene interaction perturbation network deciphers a high-resolution taxonomy in colorectal cancer
Authors: Liu Zaoqu , Weng Siyuan , Dang Qin , Xu Hui , Ren Yuqing , Guo Chunguang , Xing Zhe , Sun Zhenqiang , Han Xinwei
Published: September 2022

Molecular subtypes of colorectal cancer (CRC) are currently identified via the snapshot transcriptional profiles, largely ignoring the dynamic changes of gene expressions. Conversely, biological networks remain relatively stable irrespective of time and condition. Here, we introduce an individual-specific gene interaction perturbation network-based (GIN) approach and identify six GIN subtypes (GINS1-6) with distinguishing features: (i) GINS1 (proliferative, 24%∼34%), elevated proliferative activity, high tumor purity, immune-desert,PIK3CAmutations, and immunotherapeutic resistance; (ii) GINS2 (stromal-rich, 14%∼22%), abundant fibroblasts, immune-suppressed, stem-cell-like,SMAD4mutations, unfavorable prognosis, high potential of recurrence and metastasis, immunotherapeutic resistance, and sensitive to fluorouracil-based chemotherapy; (iii) GINS3 (KRAS-inactivated, 13%∼20%), high tumor purity, immune-desert, activation ofEGFRand ephrin receptors, chromosomal instability (CIN), fewerKRASmutations,SMOC1methylation, immunotherapeutic resistance, and sensitive to cetuximab and bevacizumab; (iv) GINS4 (mixed, 10%∼19%), moderate level of stromal and immune activities, transit-amplifying-like, andTMEM106Amethylation; (v) GINS5 (immune-activated, 12%∼24%), stronger immune activation, plentiful tumor mutation and neoantigen burden, microsatellite instability and high CpG island methylator phenotype,BRAFmutations, favorable prognosis, and sensitive to immunotherapy andPARPinhibitors; (vi) GINS6, (metabolic, 5%∼8%), accumulated fatty acids, enterocyte-like, andBMPactivity. Overall, the novel high-resolution taxonomy derived from an interactome perspective could facilitate more effective management of CRC patients.
EFFORT TO ACHIEVE QUALITY JOB THROUGH INCREASING NURSE PERFORMANCE MOTIVATION
Authors: Masfi Achmad , Pandin Moses Glorino Rumambo
Published: September 2022

Objective

The era of globalization is a challenge for health companies to keep abreast of trends and issues in the health sector. The challenges of health companies are not only external factors, Human Resources is one of the challenges that must be solved by health companies, especially the motivation of nurses.

Method

The method in this research is Literature Review. The purpose of this research is to improve company performance through employee motivation. The search method uses the Prisma 2020 chart, the literature search for the authenticity of this research is carried out with a literature review using the keywords “Performance Motivation” AND “Quality Jobs”“ from 2020 to 2022. The search results obtained 8,430 articles but only 25 articles that match the criteria study. Articles obtained from Scopus, ScienceDirect, ProQuest and PubMed, google scholar

Findings

The results of 15 journal articles related to Performance Motivation, show that motivation affects employee performance, both motivation as an independent variable, dependent variable or intermediary variable, all show that there is a very strong relationship between motivation and employee performance in general. Based on previous research, there is a positive and significant influence between work motivation and employee performance

Conclusion

Based on the results of the Literature Review, it was found that there is a positive and strong relationship between Performance Motivation and Work Quality. As an effort to improve the quality of work, it is necessary to meet the variables that affect work motivation such as psychological motivation, safety motivation, social motivation, reward motivation, and actualization motivation, leadership, etc.
Molecular Simulations and NMR Reveal How Lipid Fluctuations Affect Membrane Mechanics
Authors: Doktorova Milka , Khelashvili George , Ashkar Rana , Brown Michael F.
Published: September 2022

Lipid bilayers form the main matrix of functional cell membranes, and their dynamics underlie a host of physical and biological processes. Here we show that elastic membrane properties and collective molecular dynamics are related by the mean-square amplitudes (order parameters) and relaxation rates (correlation times) of lipid acyl chain motions. We performed all-atom molecular dynamics simulations of liquid-crystalline bilayers to further interpret available NMR data. Our analysis entailed development of a theoretical framework that allows direct comparison of carbon-hydrogen (CH) bond relaxations as measured by simulations and NMR experiments. The new formalism enables validation of lipid force fields against NMR data by including a fixed bilayer normal (director axis) and restricted anisotropic motion of the CH bonds described by their segmental order parameters. The simulated spectral density of thermally excited CH bond fluctuations exhibited well-defined spin-lattice (Zeeman) relaxations analogous to those measured by solid-state NMR spectroscopy. Their frequency signature could be fit to a simple power-law function, indicative of collective dynamics of a nematic-like nature. The calculated spin-lattice relaxation rates scaled as the squared order parameters of the lipid acyl chains yielding an apparent bending modulus κC of the bilayer. Our results show a strong correlation with κC values obtained from solid-state NMR studies of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers with varying amounts of cholesterol as further validated by neutron spin-echo measurements of membrane elasticity. The simulations uncover a critical role of interleaflet coupling in membrane mechanics and thus provide insights into the molecular sites of emerging elastic properties within lipid bilayers.

STATEMENT OF SIGNIFICANCE

The lipid make-up of a bilayer determines its measurable properties but how the motions of individual molecules combine to produce these properties remains unclear. By exploiting the synergy between NMR spectroscopy and molecular dynamics (MD) simulations, we show that the lipid dynamics in a bilayer are collective yet segmental in nature and contribute directly to bilayer elasticity. Comparison between MD simulations and NMR entails an improved theoretical framework that allows the two techniques to be directly related. This study thus provides novel insights into the inner workings of lipid membranes while delivering a new tool for validating computational approaches against experimental data.
Community engagement to increase vaccine uptake: Quasi-experimental evidence from Islamabad and Rawalpindi, Pakistan
Authors: Abdullah Mujahid , Ahmad Taimoor , Kazmi Twangar , Sultan Faisal , Afzal Sabeen , Safdar Rana Muhammad , Khan Adnan Ahmad
Published: September 2022

Developing countries have been facing difficulties in reaching out to low-income and underserved communities for COVID-19 vaccination coverage. The rapidity of vaccine development caused a mistrust among certain subgroups of the population, and hence innovative approaches were taken to reach out to such populations. Using a sample of 1760 respondents in five low-income, informal localities of Islamabad and Rawalpindi, Pakistan, we evaluated a set of interventions involving community engagement by addressing demand and access barriers. We used multi-level mixed effects models to estimate average treatment effects across treatment areas. We found that our interventions increased COVID-19 vaccine willingness in two treatment areas that are furthest from city centers by 7.6% and 6.6% respectively, while vaccine uptake increased in one of the treatment areas by 17.1%, compared to the control area. Our results suggest that personalized information campaigns such as community mobilization help to increase COVID-19 vaccine willingness. Increasing uptake however, requires improving access to the vaccination services. Both information and access may be different for various communities and therefore a “one-size-fits-all” approach may need to be better localized. Such underserved and marginalized communities are better served if vaccination efforts are contextualized.
The prevalence of SARS-CoV-2 infection and long COVID in US adults during the BA.5 surge, June-July 2022
Authors: Qasmieh Saba A , Robertson McKaylee M , Teasdale Chloe A , Kulkarni Sarah G , Jones Heidi , McNairy Margaret , Borrell Luisa N. , Nash Denis
Published: September 2022

Due to changes in SARS-CoV-2 testing practices, passive case-based surveillance may be an increasingly unreliable indicator for monitoring the burden of SARS-CoV-2, especially during surges.

We conducted a cross-sectional survey of a population-representative sample of 3,042 U.S. adults between June 30 and July 2, 2022, during the Omicron BA.5 surge. Respondents were asked about SARS-CoV-2 testing and outcomes, COVID-like symptoms, contact with cases, and experience with prolonged COVID-19 symptoms following prior infection. We estimated the weighted age and sex-standardized SARS-CoV-2 prevalence, during the 14-day period preceding the interview. We estimated age and gender adjusted prevalence ratios (aPR) for current SARS-CoV-2 infection using a log-binomial regression model.

An estimated 17.3% (95% CI 14.9, 19.8) of respondents had SARS-CoV-2 infection during the two-week study period–equating to 44 million cases as compared to 1.8 million per the CDC during the same time period. SARS-CoV-2 prevalence was higher among those 18-24 years old (aPR 2.2, 95% CI 1.8, 2.7) and among non-Hispanic Black (aPR 1.7, 95% CI 1.4, 2.2) and Hispanic (aPR 2.4, 95% CI 2.0, 2.9). SARS-CoV-2 prevalence was also higher among those with lower income (aPR 1.9, 95% CI 1.5, 2.3), lower education (aPR 3.7 95% CI 3.0,4.7), and those with comorbidities (aPR 1.6, 95% CI 1.4, 2.0). An estimated 21.5% (95% CI 18.2, 24.7) of respondents with a SARS-CoV-2 infection more than 4 weeks prior reported long COVID symptoms.

The inequitable distribution of SARS-CoV-2 prevalence during the BA.5 surge will likely drive inequities in the future burden of long COVID.
STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria
Authors: Wang Yulin , De Labastida Rivera Fabian , Edwards Chelsea L. , Frame Teija C. M. , Engel Jessica A. , Bukali Luzia , Na Jinrui , Ng Susanna S. , Corvino Dillon , de Oca Marcela Montes , Bunn Patrick T. , Soon Megan S. F. , Andrew Dean , Loughland Jessica R. , Amante Fiona H. , Barber Bridget E. , McCarthy James S. , Lopez J. Alejandro , Boyle Michelle J. , Engwerda Christian R.
Published: September 2022

The development of highly effective malaria vaccines and improving drug treatment protocols to boost anti-parasitic immunity is critical for malaria elimination. However, these efforts are hampered by parasite-specific immunoregulatory networks that are rapidly established following exposure to malaria parasites. Here, we identify stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. STING activation by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription that promoted development of IL-10 and IFNγ co-producing CD4+ T (type I regulatory; Tr1) cells. CD4+ T cell sensitivity to STING phosphorylation increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. Finally, we found the JAK1/2 inhibitor ruxolitinib modulated this innate signalling axis in CD4+ T cells to increase parasite-specific Th1 and diminish Tr1 cell responses. These findings identify STING as a critical mediator of Tr1 cell development during malaria.
Erotic cue exposure increases physiological arousal, biases choices towards immediate rewards and attenuates model-based reinforcement learning
Authors: Mathar David , Wiebe Annika , Tuzsus Deniz , Knauth Kilian , Peters Jan
Published: September 2022

Computational psychiatry focuses on identifying core cognitive processes that appear altered across a broad range of psychiatric disorders. Temporal discounting of future rewards and model-based control during reinforcement learning have proven as two promising candidates. Despite its trait-like stability, temporal discounting has been suggested to be at least partly under contextual control. For example, highly arousing cues such as erotic pictures were shown to increase discounting, although overall evidence to date remains somewhat mixed. Whether model-based reinforcement learning is similarly affected by arousing cues is unclear. Here we tested cue-reactivity effects (erotic pictures) on subsequent temporal discounting and model-based reinforcement learning in a within-subjects design in n=39 healthy male participants. Self-reported and physiological arousal (cardiac activity and pupil dilation) were assessed before and during cue exposure. Arousal was increased during exposure of erotic vs. neutral cues both on the subjective and autonomic level. Erotic cue exposure nominally increased discounting as reflected by reduced choices of delayed options. Hierarchical drift diffusion modeling (DDM) linked increased discounting to a shift in the starting point bias of evidence accumulation towards immediate options. Model-based control during reinforcement learning was reduced following erotic cues according to model-agnostic analysis. Notably, DDM linked this effect to attenuated forgetting rates of unchosen options, leaving the model-based control parameter unchanged. Our findings replicate previous work on cue-reactivity effects in temporal discounting and for the first time show similar effects in model-based reinforcement learning. Our results highlight how environmental cues can impact core human decision processes and reveal that comprehensive drift diffusion modeling approaches can yield novel insights in reward-based decision processes.
Relationship between swimming velocity and trunk twist motion in short-distance crawl swimming
Authors: Hyodo Hiroki , Koga Daiki , Sengoku Yasuo , Wada Tadashi
Published: September 2022

This study aimed to estimate the trunk twist angle from the shoulder and hip rotation angles in short-distance crawl swimming and to elucidate the twist motion of the relationship between the trunk and the rotation angular velocity in response to changes in swimming speed. Swimming speed during the experimental trials was computed from the subject’s best times in the 50 and 100m crawl swims. Wireless self-luminous LED markers were attached to seven locations on the body. The actual coordinate values of the LED markers were obtained using 18 cameras for underwater movements and 4 on the water for above-water movements. A comparison of the rate of change between trials revealed a high correlation (r = 0.722, p < 0.01) between the twist angle and shoulder rotation angular velocity in the push phase. In the same phase, a high correlation (r =0.748, p < 0.01) was also found between the twist angle and the angular velocity of hip rotation. These results suggest that swimmers increase the twist angle of their trunks to obtain a higher swimming speed. Moreover, the trunk muscle group increases its activity before starting the main motion of the twist back motion, and stretch-shortening cycle (SSC) motion may be performed in the trunk.
Lexical Stability of Psychiatric Clinical Notes from Electronic Health Records over a Decade
Authors: Hansen Lasse , Enevoldsen Kenneth , Bernstorff Martin , Perfalk Erik , Danielsen Andreas A. , Nielbo Kristoffer L. , Østergaard Søren D.
Published: September 2022

Natural Language Processing methods hold promise for improving clinical prediction by utilising information otherwise hidden in the clinical notes of electronic health records. However, clinical practice—as well as the systems and databases in which clinical notes are recorded and stored—change over time. As a consequence, the content of clinical notes may also change over time, which could degrade the performance of prediction models. Despite its importance, the stability of clinical notes over time has rarely been tested. Therefore, in this study, we examined the lexical stability of clinical notes from the Psychiatric Services of the Central Denmark Region in the period from January 1, 2011, to November 22, 2021 (a total of 14,811,551 clinical notes describing 129,570 patients) by quantifying sentence length, readability, syntactic complexity and clinical content - and estimating changepoints in these metrics. We find lexical and syntactic stability over time, which bodes well for the use of Natural Language Processing for predictive modelling in clinical practice.