bluuebunny/crossref_metadata_2025 huggingface dataset:
The effective distance and cooling rate of liquid nitrogen-based adjunctive cryotherapy for bone tumors ex vivo
Authors: Chang Yu-Chuan , Chao Kuang-Yu , Chen Chao-Ming , Chen Cheng-Fong , Wu Po-Kuei , Chen Wei-Ming
Published: June 2022

Background:

Liquid nitrogen (LN) has been used as an adjuvant cryotherapy for bone tumors including giant-cell tumor of the bone (GCTB) to remove residual tumor cells after curettage. This study evaluated variables related to the efficacy of LN-based cryoablation in the context of adjuvant treatment of GCTB using porcine femur bone model.

Methods:

A porcine femur bone model was adopted to simulate intralesional cryotherapy. A LN-holding cavity (point 1, nadir) in the medial epicondyle, 4 holes (points 2–5) in the shaft situated 5, 10, 15, and 20 mm away from the proximal edge of the cavity, and 2 more holes (points 6 and 7) in the condyle cartilage (10 and 20 mm away from the distal edge of the cavity) were made. The cooling rate was compared between the 5 points. The cellular morphological changes and DNA damage in the GCTB tissue attributable to LN-based cryotherapy were determined by H&E stain and TUNEL assay. Cartilage tissue at points 6 and 7 was examined for the extent of tissue injury after cryotherapy.

Results:

The temperature kinetics at points 1, 2 reached the reference target and were found to be significantly better than the reference (both p < 0.05). The target temperature kinetics were not achieved at points 4 and 5, which showed a significantly lower cooling rate than the reference (both p < 0.001) without reaching the –60°C target. Compared with untreated samples, significantly higher proportion of shrunken or apoptotic cells were found at points 1–3; very small proportion were observed at points 4, 5. Significantly increased chondrocyte degeneration was observed at point 6, and was absent at point 7.

Conclusion:

The cryotherapy effective range was within 5 mm from nadir. Complications were restricted to within this distance. The cooling rate was unchanged after three repeated cycles of cryotherapy.
Effects of polyallylamine-coated nanoparticles on the optical and photochemical properties of rose bengal
Authors: Lin Kai-Ying , Tsay Yeou-Guang , Chang C. Allen
Published: June 2022

Background:

Inasmuch as optical and photochemical properties of a photosensitizer can be modified upon association with the nanoparticle (NP), we wondered whether the effectiveness of phototherapeutic rose bengal (RB) was affected upon tethering to the sodium lanthanide fluoride NP with an outer polyallylamine (PAH) coat.

Methods:

RB molecules were electrostatically bound to the NaYF4:Gd3+:Nd3+ NPs with inner silica and outer PAH coats. The products were analyzed for their size, shape and zeta potential using transmission electron microscopy and dynamic light scattering instrument. UV-Vis absorption spectrometry and fluorescence spectrometry were used to examine the spectral properties. Photodynamic effect in terms of singlet oxygen generation was quantitatively determined using the indicator 1,3-diphenylisobenzofuran (DPBF). Photocytotoxicity mediated by NP-bound RB was tested using A549 cells. (Student’s t test was used for statistical evaluation.)

Results:

NP-bound RB had the major absorbance peak at 561 nm, in comparison with 549 nm for free RB, accompanied with a significant decrease in absorptivity. The molar extinction coefficient becomes 36,000 M−1 cm−1, only ~35% of that for free RB. Fluorescence spectral analyses showed a paradoxical decrease in the emission with higher NP concentrations even at very low dilutions. Most importantly, the association of RB with these NPs drastically increased its singlet oxygen production upon irradiation. The interaction of RB with PAH coat could partly account for this enhancement, given our finding that PAH in solution also caused a drastic rise in DPBF reactivity by free RB. These NPs exhibited strong photocytotoxic effects, and their promise in photodynamic therapy was addressed.

Conclusion:

Our findings provide evidence that the PAH coat plays a key role in enhanced biological activities of RB delivered via nanoparticles, including the increase in singlet oxygen production and photocytotoxic effects.
The preparation, biodistribution, and human’s absorbed dose evaluation of Radio-Scandium-HYNIC-TOC for somatostatin-receptor-positive neuroendocrine tumors therapy by animal study
Authors: Deilami-nezhad Leila , Moghaddam-Banaem Leila , Sadeghi Mahdi
Published: June 2022

Background

Most of the neuroendocrine tumors (NETs) express Somatostatin receptors (SSTr), which are the main bases for the development of several radiopharmaceuticals for therapy and imaging of these types of tumors. In this study, 46Scandium nuclide was used to label a peptide compound via hydrazinonicotinyl-Tyr3-Octreotide (HYNIC-TOC) and researched further for somatostatin-receptor NETs treatment.

Methods and materials

The labeling procedure was conducted at 95°C for 10 min. The compound stability was tested in the environment of human serum at 37°C. The biodistribution of compound was investigated in balb/c normal mice and mice bearing AR4-2J tumor. Absorbed Doses of Human Organs were estimated by extrapolation of the biokinetics data of compound in mice to human’s organs and then the absorbed doses were estimated by application of MATLAB and MIRDOSE software.

Results

Labeling yield was more than 90% with 555 MBq/mg specific activity. The radio-labeled compound expressed well consistency in human serum. The tumor uptake reached 3.831 ID/g% until 4 h post-injection and increased to 5.564%ID/g until 24 h post-injection.

Conclusion

The main achievement of this study was high tumor uptake of 46Sc-HYNIC-TOC which may be therapeutically valuable for the therapy of NETs. The estimation of the absorbed dose of human from 47Scandium-HYNIC-TOC showed low absorbed doses in critical organs and the elimination of the radiopharmaceutical was through the gastrointestinal tract.
Pharmacokinetics of Budesonide Oral Suspension in Children and Adolescents With Eosinophilic Esophagitis
Authors: Gupta Sandeep K. , Hill Malcolm , Vitanza Joanne M. , Farber Robert H. , Desai Nirav K. , Williams James , Song Ivy H.
Published: June 2022

The pharmacokinetic (PK) profile of budesonide oral suspension (BOS) was evaluated during a phase 2, randomized, double-blind, placebo-controlled, dose-ranging study in pediatric patients with eosinophilic esophagitis (EoE) (MPI 101-01/NCT00762073).

Non-compartmental methods were used to calculate PK parameters in 37 patients after receiving morning doses of BOS, with volume and dose adjusted for age (low dose: 0.35 or 0.5 mg; high dose: 1.4 or 2.0 mg [2–9 or 10–18 years old, respectively]). Relationships between apparent oral clearance and volume of distribution, and bodyweight and body mass index were also evaluated.

Budesonide systemic exposure increased with BOS dose. After oral administration, time to maximum plasma budesonide concentration occurred ~1 hour post dose and the half-life of budesonide was 3.3–3.5 hours. PK parameters were similar between age groups for low- and high-dose BOS, indicating that volume and dose adjustments for age were appropriate for pediatric patients with EoE. BOS was well tolerated.
Does kinesiophobia obstacle to physical activity and quality of life in asthmatic patients?
Authors: Ozer Aysel Yildiz , Karaca Seda , Senocak Emre , Oguz Semra , Polat Mine Gulden
Published: June 2022

Kinesiophobia has been studied in musculoskeletal and neurological diseases. The aim of this descriptive study was to assess the level of kinesiophobia in stable asthmatic patients, and to determine whether it is an obstacle to physical activity and quality of life. A total of 62 asthmatic patients and 50 healthy control subjects were assessed using the tampa kinesiophobia scale (TSK) for kinesiophobia, International Physical Activity Questionnaire-Short Form (IPAQ-SF) for physical activity levels, and Asthma Quality of Life Questionnaire (AQLQ) for quality of life. A high degree of kinesiophobia was determined in 54.8% of the asthmatic patients. The TSK scores were significantly higher (P < 0.001), and the AQLQ scores were lower in the asthma group than in the control group (P < 0.001). The IPAQ-SF level and AQLQ score were lower (P < 0.001 for both) in the asthmatic group with a high kinesiophobia score. The TSK score was significantly associated with IPAQ-SF score (r = −0.889; P < 0.001) and AQLQ score (r = −0.820; P < 0.001) in asthmatic patients. According to linear regression analysis, kinesiophobia explained 84.40% of QoL and physical activity. Patients with a stable asthma were observed to have a high level of kinesiophobia compared with healthy subjects. High kinesiophobia levels may increase the disease burden by negatively affecting participation in physical activity and quality of life. While developing asthma education programs for asthma patients, it should be remembered that even in the stable period, kinesiophobia can develop. Preventive and therapeutic programs should include precautions to improve quality of life and physical activity against the effects of kinesiophobia.
Protein Profiling of Mechanically Processed Lipoaspirates: Discovering Wound Healing and Antifibrotic Biomarkers in Nanofat
Authors: Sanchez-Macedo Nadia , McLuckie Michelle , Grünherz Lisanne , Lindenblatt Nicole
Published: June 2022

Background:

Nanofat is an injectable oily emulsion, rich in adipose-derived stem cells and growth factors. It is prepared from lipoaspirates through mechanical emulsification and filtration. Despite being successfully used in several procedures in regenerative medicine such as scar attenuation, skin rejuvenation, and treatment of chronic wounds, little is known about exactly how nanofat induces regeneration in treated skin at the molecular level.

Methods:

Microfat and nanofat samples were isolated from 18 healthy patients. Proteomic profiling was performed through untargeted mass spectrometry proteomics and multiplex antibody arrays. Pathway enrichment analysis of differentially expressed proteins between microfat and nanofat was performed using Gene Ontology, Reactome, and Kyoto Encyclopaedia of Genes and Genomes as reference databases.

Results:

Untargeted proteomics showed that up-regulated genes in nanofat are involved in innate immunity responses, coagulation, and wound healing, whereas down-regulated genes were linked to cellular migration and extracellular matrix production. Secretome array screening of microfat and nanofat samples showed no significantly different expression, which strongly suggests that the mechanical emulsification step does not affect the concentration of tissue regeneration biomarkers. The identified proteins are involved in wound healing, cellular migration, extracellular matrix remodeling, angiogenesis, stress response, and immune response.

Conclusions:

Mechanical processing of lipoaspirates into nanofat significantly influences the proteome profile by enhancing inflammation, antimicrobial, and wound healing pathways. Nanofat is extremely rich in tissue repair and tissue remodeling factors. This study shows that the effects of microfat and nanofat treatment are based on up-regulated inflammation, antimicrobial, and wound healing pathways. Mechanical emulsification does not alter the concentration of tissue regeneration biomarkers.

Clinical Relevance Statement:

In addition to adipose-derived stems cells, nanofat contains distinct tissue repair and remodelling factors, which explains its beneficial effects on tissue regeneration.
Technique for Minimally Invasive Face and Neck Contouring with Bipolar Radiofrequency Devices
Authors: Rohrich Rod J. , Chamata Edward S. , Bellamy Justin L. , Alleyne Brendan
Published: June 2022

Radiofrequency devices have grown in popularity as minimally invasive options for the treatment of skin laxity in the face and neck. These treatments are often combined with liposuction procedures to provide enhanced tissue contraction alongside the reduction in adiposity. Proper patient selection and intraoperative technique are crucial to achieving the desired outcomes in a safe manner. In this article, the authors discuss their indications and technique for the treatment of the face and neck with bipolar radiofrequency devices.
Brief Report: Impact of COVID-19 on Cabotegravir Plus Rilpivirine Long-Acting Dosing Across 6 Ongoing Global Phase IIb and III Clinical Trials
Authors: Czarnogorski Maggie , Benn Paul , McCoig Cindy , Nwafor Toyin , Griffith Sandy , Sutton Ken , Harrington Conn , Saggu Parminder , Yague Itziar , Williams Will , Español Carlos M. , Goodchild Jessica , Fricker Jane , Patel Parul , D'Amico Ronald
Published: June 2022

Background:

Cabotegravir + rilpivirine long-acting (LA) is a novel antiretroviral therapy (ART) administered intramuscularly monthly or every 2 months by a health care provider. The COVID-19 pandemic presents a potential challenge to patients' ability to attend scheduled clinic visits for dosing administration.

Setting:

This analysis evaluated implementation fidelity across 6 phase IIb/III/IIIb cabotegravir + rilpivirine LA clinical trials in 16 countries during the COVID-19 pandemic.

Methods:

COVID-19-impacted visits were defined as modified dosing visits for which oral therapy was provided to participants unable to attend the clinic or injection visits that were rescheduled. Data from December 1, 2019, to March 1, 2021, were aggregated and analyzed using descriptive statistics.

Results:

Of 2127 participants in cabotegravir + rilpivirine LA trials, 1997 (94%) had LA dosing visits proceed as planned during the COVID-19 pandemic. Of 130 (6%) participants with injection visits affected by COVID-19, most were from North America (57%) and Europe (26%). Most participants with COVID-19-impacted visits used oral therapy with cabotegravir + rilpivirine (75%) or alternative oral standard-of-care ART (21%) to maintain continuous ART. The most common reasons for missed visits were clinic closure/staffing constraints (48%) and COVID-19-related travel restrictions (23%). Most (98%) participants who used oral ART maintained virologic suppression; 2 participants had viral load between 50 and 100 copies/mL.

Conclusion:

During the COVID-19 pandemic, most trial participants maintained their LA dosing schedules. Flexibility of the LA dosing regimen, with the ability to switch to oral therapy, facilitated continuous ART provision and implementation fidelity.
Drivers of melioidosis endemicity: epidemiological transition, zoonosis, and climate change
Authors: Birnie Emma , Biemond Jason J. , Wiersinga W. Joost
Published: June 2022

Purpose of review

Melioidosis, caused by the soil-dwelling bacterium Burkholderia pseudomallei, is a tropical infection associated with high morbidity and mortality. This review summarizes current insights into melioidosis’ endemicity, focusing on epidemiological transitions, zoonosis, and climate change.

Recent findings

Estimates of the global burden of melioidosis affirm the significance of hot-spots in Australia and Thailand. However, it also highlights the paucity of systematic data from South Asia, The Americas, and Africa. Globally, the growing incidence of diabetes, chronic renal and (alcoholic) liver diseases further increase the susceptibility of individuals to B. pseudomallei infection. Recent outbreaks in nonendemic regions have exposed the hazard from the trade of animals and products as potential reservoirs for B. pseudomallei. Lastly, global warming will increase precipitation, severe weather events, soil salinity and anthrosol, all associated with the occurrence of B. pseudomallei.

Epidemiological transitions, zoonotic hazards, and climate change are all contributing to the emergence of novel melioidosis-endemic areas. The adoption of the One Health approach involving multidisciplinary collaboration is important in unraveling the real incidence of B. pseudomallei, as well as reducing the spread and associated mortality.
Wireless interfaces for brain neurotechnologies
Authors: Kim Han-Joon , Ho John S.
Published: June 2022

Wireless interfaces enable brain-implanted devices to remotely interact with the external world. They are critical components in modern research and clinical neurotechnologies and play a central role in determining their overall size, lifetime and functionality. Wireless interfaces use a wide range of modalities—including radio-frequency fields, acoustic waves and light—to transfer energy and data to and from an implanted device. These forms of energy interact with living tissue through distinct mechanisms and therefore lead to systems with vastly different form factors, operating characteristics, and safety considerations. This paper reviews recent advances in the development of wireless interfaces for brain neurotechnologies. We summarize the requirements that state-of-the-art brain-implanted devices impose on the wireless interface, and discuss the working principles and applications of wireless interfaces based on each modality. We also investigate challenges associated with wireless brain neurotechnologies and discuss emerging solutions permitted by recent developments in electrical engineering and materials science.

This article is part of the theme issue 'Advanced neurotechnologies: translating innovation for health and well-being'.
COVID-19-Associated mucormycosis: Case series from a tertiary care hospital in South India
Authors: Rashbi K. Shafeedha , Ali T. M. Feroz , P. N. Deepthi , C. K. Saranya , Payyappilly Rajan Joseph
Published: June 2022

The pandemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is a global health problem. COVID-19 has given rise to a number of secondary bacterial or fungal infections. During the second wave of COVID-19, India experienced an epidemic of mucormycosis in COVID-19 patients. In this paper, we discuss the clinical features, investigations and management of four patients having COVID-19-associated mucormycosis (CAM), especially rhino-orbital mucormycosis (ROM) caused by Rhizopus arrhizus and Mucor species. We also compare the cases and their risk factors with previously reported CAM cases in India. Three patients had mucormycosis after recovering from COVID-19. They were successfully treated with surgical debridement and early initiation of anti-fungal therapy with systemic amphotericin B and other supportive measures such as broad-spectrum antibiotics, insulin infusion, antihypertensives and analgesics. The remaining patient had mucormycosis during COVID-19. He was admitted in the intensive care unit due to COVID-pneumonia and was on mechanical ventilation. In spite of all supportive measures, the patient succumbed to death due to cardiogenic shock. Three out of our four patients had diabetes mellitus. All patients were treated with systemic steroid during COVID-19 treatment. Diabetes mellitus and steroid treatment are the major risk factors for CAM. Early diagnosis of this life-threatening infection along with strict control of hyperglycemia is necessary for optimal treatment and better outcomes.
Nonomuraea aurantiaca sp. nov., a novel cellulase-producing actinobacterium isolated from soil
Authors: Lin Jiaying , Zhang Li , Qian Lulu , Yang Yanming , Xiang Wensheng , Zhao Junwei , Wang Xiangjing
Published: June 2022

A novel cellulase-producing actinobacterium, designated strain NEAU-L178T, was isolated from soil sample collected from Qiqihaer, Heilongjiang Province, PR China. A polyphasic study was carried out to determine the taxonomic status of the strain. On the basis of 16S rRNA gene sequence analysis, strain NEAU-L178T should be classified into the genus

Nonomuraea

and is closely related to

Nonomuraea cavernae

SYSU K10005T (99.31 % 16S rRNA gene sequence similarity),

Nonomuraea glycinis

NEAU-BB2C19T (98.75 %),

Nonomuraea guangzhouensis

NEAU-ZJ3T (98.75 %) and ‘Nonomuraea rhizosphaerae’ NEAU-mq18T (98.34 %). The digital DNA–DNA hybridization values between them are 27.1, 26.1, 42.0 and 30.9 %, and the whole-genome average nucleotide identity values between them are 83.1, 82.3, 90.3 and 85.8 %, respectively. The whole-cell hydrolysates contained glucose, ribose, arabinose and madurose. The menaquinones were identified as MK-9(H0), MK-9(H4) and MK-9(H2). The major fatty acids were C16 : 0, iso-C17 : 0 and C17 : 0 10-methyl. The detected polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, hydroxy-phosphatidylethanolamine, phosphatidylinositol and three unidentified phospholipids. The genomic DNA G+C content was 69.7 mol%. In addition, whole-genome analysis indicated that strain NEAU-L178T had the potential to degrade cellulose. Based on the phenotypic, genotypic, chemotaxonomic and phylogenetic data, strain NEAU-L178T can be differentiated from its close phylogenetic relatives and represents a novel species of the genus

Nonomuraea

, for which the name Nonomuraea aurantiaca sp. nov. is proposed. The type strain is NEAU-L178T (=JCM 34799T=CGMCC 4.7741T).
The interplay between sulfur assimilation and biodesulfurization phenotype in Rhodococcus qingshengii IGTS8: Insights into a regulatory role of the reverse transsulfuration pathway
Authors: Martzoukou Olga , Glekas Panayiotis , Avgeris Margaritis , Mamma Diomi , Scorilas Andreas , Kekos Dimitris , Amillis Sotiris , Hatzinikolaou Dimitris G.
Published: June 2022

Biodesulfurization (BDS) is a process that selectively removes sulfur from dibenzothiophene and its derivatives. Several mesophilic natural biocatalysts have been isolated, harboring the highly conserved desulfurization operon dszABC. Even though the desulfurization phenotype is known to be significantly repressed by methionine, cysteine, and inorganic sulfate, the available information on the metabolic regulation of gene expression is still limited. In this study, scarless knockouts of the sulfur metabolism-related cbs and metB genes are constructed in the desulfurizing strain Rhodococcus sp. IGTS8. We provide sequence analyses for both enzymes of the reverse transsulfuration pathway and report their involvement in the sulfate- and methionine-dependent repression of the biodesulfurization phenotype, based on desulfurization assays in the presence of different sulfur sources. Additionally, the positive effect of cbs and metB gene deletions on dsz gene expression in the presence of both sulfate and methionine, but not cysteine, is uncovered and highlighted.
Bridging the gap: A qualitative analysis of online public forum with healthcare professionals in bursting myths about weight management
Authors: Bhatti R , Joumaa M , Bereczky B
Published: June 2022

Background

Obesity has increased rapidly worldwide in last few decades. According to World Obesity Federation 2018, the prevalence of obesity in UAE amongst Emirati aged 18-69 years has been reported as 32.2% vs 38.5% living with obesity vs overweight in men and 41.8% vs 29.3% living with obesity vs overweight in women. There are many myths amongst general public about obesity.

Aim

The objective of the study was to address public questions through online forum regarding weight management.

Methods

In this cross-sectional observational study qualitative analysis was done. It was conducted quarterly at Mediclinic City and Parkview Hospital in Dubai from August 2020-September 2021. An online zoom meeting was made available to the public. People who wanted to attend the session registered via dedicated email address. A certified dietician, endocrinologist and bariatric surgeon were available to answer people’s questions.

Results

6 online forums have been conducted. 163 (range 10-90) people attended. Three themes were constructed during data analysis. 1-Diet: what’s the best diet and about caloric intake. 2-Insulin resistance or hormone imbalance is responsible for weight gain. 3-Misinformation and unrealistic expectations about bariatric surgery. Feedback from audience was ‘it was interactive, fun and informative session’, ‘it’s good to know that it’s not my fault and I need to get help’.

Conclusion

Our results show that patients need support throughout their weight management journey. Healthcare professionals need to be more aware of patient’s perceptions about weight management so that they can be addressed in consultations. We need more online support sessions facilitated by healthcare professionals.
Prosthesis hand grasp control following targeted muscle reinnervation in individuals with transradial amputation
Authors: Simon Ann M. , Turner Kristi L. , Miller Laura A. , Dumanian Gregory A. , Potter Benjamin K. , Beachler Mark D. , Hargrove Levi J. , Kuiken Todd A.
Published: June 2022

Transradial amputation is the most common level of major upper limb amputation. Despite the growing availability of multifunctional prosthetic hands, users’ control of these hands and overall functional abilities remain limited. The combination of pattern recognition control and targeted muscle reinnervation (TMR) surgery, an innovative technique where amputated nerves are transferred to reinnervate new muscle targets in the residual limb, has been used to improve prosthesis control of individuals with more proximal upper limb amputation levels (i.e., shoulder disarticulation and transhumeral amputation). The goal of this study was to determine if similar prosthesis control improvements could be seen for individuals with amputations at the transradial level. Participants controlled 3-5 grips with a multi-articulating hand prosthesis under myoelectric pattern recognition control for at least 8 weeks at home pre- and post-TMR surgery. Users gained some significant functional control benefits using a multi-articulating hand prosthesis with pattern recognition at 9-12 months post-TMR surgery. Additionally, a majority of subjects noted an improvement in their residual limb and phantom limb sensations post-TMR. An additional offline EMG analysis showed a decrease in grip classification error post-TMR surgery compared to pre-TMR surgery.
User-centred Design of a Clinical Decision Support System for Palliative Care: Insights from Healthcare Professionals
Authors: Blanes-Selva Vicent , Asensio-Cuesta Sabina , Doñate-Martínez Ascensión , Mesquita Felipe Pereira , García-Gómez Juan M.
Published: June 2022

Abstract

Clinical Decision Support Systems (CDSSs) could offer many benefits to clinical practice, but they present several adoption barriers regarding their acceptance and usability by professionals. Our objective in this study is to validate a Palliative Care CDSS, The Aleph, through a user-centred methodology, considering the predictions of the AI core, the usability, and the user experience. We performed two rounds of individual evaluation sessions with potential users. Each session included a model evaluation, a task test and a usability and user experience assessment. The Machine Learning predictive models outperformed the participants in the three predictive tasks. SUS reported 62.7± 14.1 and 65 ± 26.2 on a 100-point rating scale for both rounds, respectively, while UEQ-S scores were 1.42 and 1.5 on the –3 to 3 scale. Think-aloud methodology and the inclusion of the user-experience dimension allowed us to identify most of the workflow implementation issues.
Associations Between Depression, Anxiety, and Multiple Disease Outcomes: A Phenotype x Phenome-Wide Association Study in Electronic Health Records
Authors: Gao Y. Nina , Coombes Brandon , Ryu Euijung , Pazdernik Vanessa , Jenkins Gregory , Pendegraft Richard , Biernacka Joanna , Olfson Mark
Published: June 2022

Unstructured Abstract

Anxiety and depression are frequently comorbid yet phenotypically distinct. This study identifies differences in the clinically observable phenome across a wide variety of physical and mental disorders comparing patients with diagnoses of isolated depression, isolated anxiety, or both. Using electronic health records for 14,994 participants with depression and/or anxiety in the Mayo Clinic Biobank, a phenotype x phenome-wide association study (Phe2WAS) was performed to test for differences between these groups. Additional Phe2WAS were performed restricting analyses to diagnoses occurring before or after a diagnosis of depression or anxiety to determine the temporal sequencing of diagnoses. Compared to isolated anxiety, isolated depression was more strongly associated with obesity (OR=1.61; p=3e-22), sleep apnea (OR=1.71; p=1e-22), type II diabetes (OR=1.74; p=9e-18), and neurological disorders (OR=1.54; p=6e-10); these differences were most pronounced for medical diagnoses made after first depression or anxiety diagnosis. In relation to isolated depression, isolated anxiety was more strongly related to palpitations (OR=1.91; p=2e-25), skin neoplasms (OR=1.61; p=2e-17), cardiac dysrhythmias (OR=1.45; p=2e-12), and degenerative skin conditions (OR=1.41; p=1e-10); these differences were most pronounced for medical diagnoses made before a first depression or anxiety diagnosis. Patients with the comorbid depression and anxiety had stronger associations with other mental health disorders, substance use disorders, sleep problems, and digestive problems relative to those with isolated depression or anxiety. While depression and anxiety are closely related, this study suggests that improving phenotypic characterization within the broad categories of depression and anxiety could improve clinical care and provide future directions for research.
Tumor-immune metaphenotypes orchestrate an evolutionary bottleneck that promotes metabolic transformation
Authors: West Jeffrey , Rentzeperis Frederika , Adam Casey , Bravo Rafael , Luddy Kimberly A. , Robertson-Tessi Mark , Anderson Alexander R. A.
Published: June 2022

Metabolism plays a complex role in the evolution of cancerous tumors, including inducing a multifaceted effect on the immune system to aid immune escape. Immune escape is, by definition, a collective phenomenon by requiring the presence of two cell types interacting in close proximity: tumor and immune. The microenvironmental context of these interactions is influenced by the dynamic process of blood vessel growth and remodelling, creating heterogeneous patches of well-vascularized tumor or acidic niches. We present a multiscale mathematical model that captures the phenotypic, vascular, microenvironmental, and spatial heterogeneity which shapes acid-mediated invasion and immune escape over a biologically-realistic time scale. We model immune escape mechanisms such as i) acid inactivation of immune cells, ii) competition for glucose, and iii) inhibitory immune checkpoint receptor expression (PD-L1) under anti-PD-L1 and sodium bicarbonate buffer therapies. To aid in understanding immune escape as a collective cellular phenomenon, we define immune escape in the context of six collective phenotypes (termed "meta-phenotypes"): Self-Acidify, Mooch Acid, PD-L1 Attack, Mooch PD-L1, Proliferate Fast, and Starve Glucose. Fomenting a stronger immune response leads to initial benefits but this advantage is offset by increased cell turnover that accelerates the emergence of aggressive phenotypes by inducing an evolutionary bottleneck. This model helps to untangle the key constraints on evolutionary costs and benefits of three key phenotypic axes on tumor invasion and treatment: acid-resistance, glycolysis, and PD-L1 expression. The benefits of concomitant anti-PD-L1 and buffer treatments is a promising treatment strategy to limit the adverse effects of immune escape.
Community assessment of methods to deconvolve cellular composition from bulk gene expression
Authors: White Brian S. , de Reyniès Aurélien , Newman Aaron M. , Waterfall Joshua J. , Lamb Andrew , Petitprez Florent , Lin Yating , Yu Rongshan , Guerrero-Gimenez Martin E , Domanskyi Sergii , Monaco Gianni , Chung Verena , Banerjee Jineta , Derrick Daniel , Valdeolivas Alberto , Li Haojun , Xiao Xu , Wang Shun , Zheng Frank , Yang Wenxian , Catania Carlos A. , Lang Benjamin J. , Bertus Thomas J. , Piermarocchi Carlo , Caruso Francesca P. , Ceccarelli Michele , Yu Thomas , Guo Xindi , Bletz Julie , Coller John , Maecker Holden , Duault Caroline , Shokoohi Vida , Patel Shailja , Liliental Joanna E. , Simon Stockard ,   Tumor Deconvolution DREAM Challenge consortium, Saez-Rodriguez Julio , Heiser Laura M. , Guinney Justin , Gentles Andrew J.
Published: June 2022

We evaluate deconvolution methods, which infer levels of immune infiltration from bulk expression of tumor samples, through a community-wide DREAM Challenge. We assess six published and 22 community-contributed methods usingin vitroandin silicotranscriptional profiles of admixed cancer and healthy immune cells. Several published methods predict most cell types well, though they either were not trained to evaluate all functional CD8+ T cell states or do so with low accuracy. Several community-contributed methods address this gap, including a deep learning-based approach, whose strong performance establishes the applicability of this paradigm to deconvolution. Despite being developed largely using immune cells from healthy tissues, deconvolution methods predict levels of tumor-derived immune cells well. Our admixed and purified transcriptional profiles will be a valuable resource for developing deconvolution methods, including in response to common challenges we observe across methods, such as sensitive identification of functional CD4+ T cell states.
CRISPR/Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells
Authors: Hany Dina , Vafeiadou Vasiliki , Picard Didier
Published: June 2022

In breast cancer, resistance to endocrine therapies that target estrogen receptor α (ERα), such as tamoxifen and fulvestrant, remains a major clinical problem. Whether and how ERα+ breast cancers switch from being estrogen-dependent to -independent remains unclear. With a genome-wide CRISPR/Cas9 knockout screen, we identified new biomarkers and potential therapeutic targets of endocrine resistance. We demonstrate that high levels of PAICS, an enzyme involved in thede novobiosynthesis of purines, can shift the balance of ERα activity to be more estrogen-independent and tamoxifen-resistant. We indicate that this is due to an elevated activity of cAMP-activated protein kinase A and mammalian target of rapamycin, kinases known to phosphorylate ERα specifically and to stimulate its activity. Genetic or pharmacological targeting of PAICS sensitizes tamoxifen-resistant cells to tamoxifen. Based on these findings, we propose the combined targeting of PAICS and ERα as a new, effective, and potentially safe therapeutic regimen.
TransDFL: Identification of Disordered Flexible Linkers in Proteins by Transfer Learning
Authors: Pang Yihe , Liu Bin
Published: June 2022

Disordered flexible linkers (DFLs) are the functional disordered regions in proteins, which are the sub-regions of intrinsically disordered regions (IDRs) and play important roles in connecting domains and maintaining inter-domain interactions. Trained with the limited available DFLs, the existing DFL predictors based on the machine learning techniques tend to predict the ordered residues as DFLs leading to a high false-positive rate (FPR) and low prediction accuracy. Previous studies have shown that DFLs are the extremely flexible disordered regions, which are usually predicted as disordered residues with high confidence [P(D) > 0.9] by an IDR predictor. Therefore, transferring an IDR predictor to an accurate DFL predictor is of great significance for understanding the functions of IDRs. In this study, we proposed a new predictor called TransDFL for identifying DFLs by transferring the RFPR-IDP predictor for IDR identification to the DFL prediction. The RFPR-IDP was pre-trained with IDR sequences to learn the general features between IDRs and DFLs, which is helpful to reduce the false positives in the ordered regions. RFPR-IDP was fine-tuned with the DFL sequences to capture the specific features of DFLs so as to be transferred into the TransDFL. Experimental results of two application scenarios (prediction of DFLs only in the IDRs or prediction of DFLs in the entire proteins) showed that TransDFL consistently outperforms the other exiting DFL predictors with higher accuracy. The corresponding web server of TransDFL can be freely accessed from http://bliulab.net/TransDFL/.
Natural gradient enables fast sampling in spiking neural networks
Authors: Masset Paul , Zavatone-Veth Jacob A. , Connor J. Patrick , Murthy Venkatesh N. , Pehlevan Cengiz
Published: June 2022

For animals to navigate an uncertain world, their brains need to estimate uncertainty at the timescales of sensations and actions. Sampling-based algorithms afford a theoretically-grounded framework for probabilistic inference in neural circuits, but it remains unknown how one can implement fast sampling algorithms in biologically-plausible spiking networks. Here, we propose to leverage the population geometry, controlled by the neural code and the neural dynamics, to implement fast samplers in spiking neural networks. We first show that two classes of spiking samplers—efficient balanced spiking networks that simulate Langevin sampling, and networks with probabilistic spike rules that implement Metropolis-Hastings sampling—can be unified within a common framework. We then show that careful choice of population geometry, corresponding to the natural space of parameters, enables rapid inference of parameters drawn from strongly-correlated high-dimensional distributions in both networks. Our results suggest design prin-ciples for algorithms for sampling-based probabilistic inference in spiking neural networks, yielding potential inspiration for neuromorphic computing and testable predictions for neurobiology.
Virtual (Zoom) Interactions Alter Behavioral Cooperation, Neural Activation, and Dyadic Neural Coherence
Authors: Balters Stephanie , Miller Jonas G. , Li Rihui , Hawthorne Grace , Reiss Allan L.
Published: June 2022

The authors have withdrawn their manuscript because of a revised preprocessing pipeline. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Efficient Pangenome Construction through Alignment-Free Residue Pangenome Analysis (ARPA)
Authors: Lal Arnav , Moustafa Ahmed , Planet Paul J.
Published: June 2022

Protein sequences can be transformed into vectors composed of counts for each amino acid (vector of Residue Counts; vRC) that are mathematically tractable and retain information about homology. We use vRCs to perform alignment-free, residue-based, pangenome analysis (ARPA; https://github.com/Arnavlal/ARPA). ARPA is 70-90 times faster at identifying homologous gene clusters compared to standard techniques, and offers rapid calculation, visualization, and novel phylogenetic approaches for pangenomes.
Mothers’ experiences of using Facebook groups for local breastfeeding support: results of an online survey exploring midwife moderation
Authors: Morse H. , Brown A.
Published: June 2022

Problem

The use of Breastfeeding Support Facebook (BSF) groups that are aimed at supporting women in specific local areas, with links to face to face support, is under researched. The role that midwives play in offering support to local mothers through these groups has not been examined.

Background

Access to ongoing support from professionals assists mothers in meeting their breastfeeding goals. Social media is increasingly being used to offer this support, improving maternal knowledge, self-efficacy and breastfeeding duration.

Aim

To examine impacts of moderator type on mothers’ perceptions of online breastfeeding support, including when midwives play an active role in moderation.

Methods

An online mixed methods survey was conducted in January 2020. Quantitative data was analysed descriptively and for associations using SPSSv26. Qualitative data was analysed thematically.

Findings

Two thousand and twenty-eight mothers who used local BSF groups completed the survey. The experiences of those participating in groups moderated by midwives versus other moderators such as peer supporters, were compared. Moderation was an important factor in mothers’ experiences, with trained support associated with greater engagement and more frequent visits, impacting on perceptions of group ethos, reliability and inclusivity. Midwife moderation was uncommon but valued, and associated with viewing local face to face midwifery support for breastfeeding more positively.

Conclusion

Midwife moderated or supported Facebook groups have the potential to add value to local face to face services and improve breastfeeding experiences in communities. The findings have important implications to support the development of integrated online interventions to improve public health.

Statement of Significance

Problem

Low breastfeeding rates are connected to inconsistent access to quality local support. Mothers are frequently turning to social media groups for support but little is known about who runs and moderates them.

What is Already Known

Mothers have concerns about trustworthiness and reliability, despite finding Facebook groups useful for shared experience. There is insufficient evidence on moderation to recommend online models within maternity services.

What this Paper Adds

Evidence that Facebook groups linked to local face to face support are valued, and that trained moderators improves experiences. Access to local midwife support within Facebook groups improves perceptions of local midwifery support overall.
Personality traits are consistently associated with blood mitochondrial DNA copy number estimated from genome sequences in two genetic cohort studies
Authors: Oppong Richard F. , Terracciano Antonio , Picard Martin , Qian Yong , Butler Thomas J. , Tanaka Toshiko , Moore Ann Zenobia , Simonsick Eleanor M. , Opsahl-Ong Krista , Coletta Christopher , Sutin Angelina R. , Gorospe Myriam , Resnick Susan M. , Cucca Francesco , Scholz Sonja W. , Traynor Bryan J. , Schlessinger David , Ferrucci Luigi , Ding Jun
Published: June 2022

Background

Mitochondrial DNA copy number (mtDNAcn) in tissues and blood can be altered in conditions like diabetes and major depression and may play a role in aging and longevity. However, little is known about the association between mtDNAcn and personality traits linked to emotional states, metabolic health, and longevity. This study tests the hypothesis that blood mtDNAcn is related to personality traits and mediates the association between personality and mortality.

Methods

We assessed the big five personality domains and facets using the Revised NEO Personality Inventory (NEO-PI-R), assessed depressive symptoms with the Center for Epidemiologic Studies Depression Scale (CES-D), estimated mtDNAcn levels from whole-genome sequencing, and tracked mortality in participants from the Baltimore Longitudinal Study of Aging. Results were replicated in the SardiNIA Project.

Results

We found that mtDNAcn was negatively associated with the Neuroticism domain and its facets and positively associated with facets from the other four domains. The direction and size of the effects were replicated in the SardiNIA cohort and were robust to adjustment for potential confounders in both samples. Consistent with the Neuroticism finding, higher depressive symptoms were associated with lower mtDNAcn. Finally, mtDNAcn mediated the association between personality and mortality risk.

Conclusions

To our knowledge, this is the first study to show a replicable association between mtDNAcn and personality. Furthermore, the results support our hypothesis that mtDNAcn is a biomarker of the biological process that explains part of the association between personality and mortality.
Progression of prostate cancer reprograms MYC-mediated lipid metabolism via lysine methyltransferase 2A
Authors: Whitlock Nichelle C. , White Margaret E. , Capaldo Brian J. , Ku Anson T. , Agarwal Supreet , Fang Lei , Wilkinson Scott , Trostel Shana Y. , Shi Zhen-Dan , Basuli Falguni , Wong Karen , Jagoda Elaine M. , Kelly Kathleen , Choyke Peter L. , Sowalsky Adam G.
Published: June 2022

Background

The activities of MYC, the androgen receptor, and its associated pioneer factors demonstrate substantial reprogramming between early and advanced prostate cancer. Although previous studies have shown a shift in cellular metabolic requirements associated with prostate cancer progression, the epigenetic regulation of these processes is incompletely described. Here, we have integrated chromatin immunoprecipitation sequencing (ChIP-seq) and whole-transcriptome sequencing to identify novel regulators of metabolism in advanced prostate tumors characterized by elevated MYC activity.

Results

Using ChIP-seq against MYC, HOXB13, and AR in LNCaP cells, we observed redistribution of co-bound sites suggestive of differential KMT2A activity as a function of MYC expression. In a cohort of 177 laser-capture microdissected foci of prostate tumors, KMT2A expression was positively correlated with MYC activity, AR activity, and HOXB13 expression, but decreased with tumor grade severity. However, KMT2A expression was negatively correlated with these factors in 25 LuCaP patient-derived xenograft models of advanced prostate cancer and 99 laser-capture microdissected foci of metastatic castration-resistant prostate cancer. Stratified by KMT2A expression, ChIP-seq against AR and HOXB13 in 15 LuCaP patient-derived xenografts showed an inverse association with sites involving genes implicated in lipid metabolism, including the arachidonic acid metabolic enzyme PLA2G4F. LuCaP patient-derived xenograft models grown as organoids recapitulated the inverse association between KMT2A expression and fluorine-18 labeled arachidonic acid uptake in vitro.

Conclusions

Our study demonstrates that the epigenetic activity of transcription factor oncogenes exhibits a shift during prostate cancer progression with distinctive phenotypic effects on metabolism. These epigenetically driven changes in lipid metabolism may serve as novel targets for the development of novel imaging agents and therapeutics.
Functional connectivity fingerprints of the frontal eye fields and inferior frontal junction in the dorsal vs. ventral prefrontal cortex
Authors: Soyuhos Orhan , Baldauf Daniel
Published: June 2022

Neuroimaging evidence suggests that the frontal eye field (FEF) and inferior frontal junction (IFJ) govern the encoding of spatial and non-spatial (such as feature- or object-based) representations, respectively, both during visual attention and working memory tasks. However, it is still unclear whether such contrasting functional segregation is also reflected in their underlying functional connectivity patterns. Here, we hypothesized that FEF has predominant functional coupling with spatiotopically organized regions in the dorsal (‘where’) visual stream, whereas IFJ has predominant functional connectivity with the ventral (‘what’) visual stream. We applied seed-based functional connectivity analyses to temporally high-resolving resting-state magnetoencephalography (MEG) recordings. We parcellated the brain according to the multimodal Glasser atlas and tested, for various frequency bands, whether the spontaneous activity of each parcel in the ventral and dorsal visual pathway has predominant functional connectivity with FEF or IFJ. The results show that FEF has a robust power correlation with the dorsal visual pathway in beta and gamma bands. In contrast, anterior IFJ (IFJa) has a strong power coupling with the ventral visual stream in delta, beta, and gamma oscillations. Moreover, while FEF is directly phase-coupled with the superior parietal lobe in the beta band, IFJa is directly phase-coupled with the middle and inferior temporal cortex in delta and gamma oscillations. We argue that these intrinsic connectivity fingerprints are congruent with each brain region’s function. Therefore, we conclude that FEF and IFJ have dissociable connectivity patterns that fit their respective functional roles in spatial vs. non-spatial top-down attention and working memory control.