bluuebunny/crossref_metadata_2025 huggingface dataset:
Protocol: mixed-methods study of how implementation of US state medical cannabis laws affects treatment of chronic non-cancer pain and adverse opioid outcomes
Authors: McGinty Emma E. , Tormohlen Kayla N. , Barry Colleen L. , Bicket Mark C. , Rutkow Lainie , Stuart Elizabeth A.
Published: January 2021

Background

Thirty-three US states and Washington, D.C., have enacted medical cannabis laws allowing patients with chronic non-cancer pain to use cannabis, when recommended by a physician, to manage their condition. However, clinical guidelines do not recommend cannabis for treatment of chronic non-cancer pain due to limited and mixed evidence of effectiveness. How state medical cannabis laws affect delivery of evidence-based treatment for chronic non-cancer pain is unclear. These laws could lead to substitution of cannabis in place of clinical guideline-discordant opioid prescribing, reducing risk of opioid use disorder and overdose. Conversely, state medical cannabis laws could lead to substitution of cannabis in place of guideline-concordant treatments such as topical analgesics or physical therapy. This protocol describes a mixed-methods study examining the implementation and effects of state medical cannabis laws on treatment of chronic non-cancer pain. A key contribution of the study is the examination of how variation in state medical cannabis laws’ policy implementation rules affects receipt of chronic non-cancer pain treatments.

Methods

The study uses a concurrent-embedded design. The primary quantitative component of the study employs a difference-in-differences design using a policy trial emulation approach. Quantitative analyses will evaluate state medical cannabis laws’ effects on treatment for chronic non-cancer pain as well as on receipt of treatment for opioid use disorder, opioid overdose, cannabis use disorder, and cannabis poisoning among people with chronic non-cancer pain. Secondary qualitative and survey methods will be used to characterize implementation of state medical cannabis laws through interviews with state leaders and representative surveys of physicians who treat, and patients who experience, chronic non-cancer pain in states with medical cannabis laws.

Discussion

This study will examine the effects of medical cannabis laws on patients’ receipt of guideline-concordant non-opioid, non-cannabis treatments for chronic non-cancer pain and generate new evidence on the effects of state medical cannabis laws on adverse opioid outcomes. Results will inform the dynamic policy environment in which numerous states consider, enact, and/or amend medical cannabis laws each year.
Rationale and design of the Novel Uses of adaptive Designs to Guide provider Engagement in Electronic Health Records (NUDGE-EHR) pragmatic adaptive randomized trial: a trial protocol
Authors: Lauffenburger Julie C. , Isaac Thomas , Trippa Lorenzo , Keller Punam , Robertson Ted , Glynn Robert J. , Sequist Thomas D. , Kim Dae H. , Fontanet Constance P. , Castonguay Edward W. B. , Haff Nancy , Barlev Renee A. , Mahesri Mufaddal , Gopalakrishnan Chandrashekar , Choudhry Niteesh K.
Published: January 2021

Background

The prescribing of high-risk medications to older adults remains extremely common and results in potentially avoidable health consequences. Efforts to reduce prescribing have had limited success, in part because they have been sub-optimally timed, poorly designed, or not provided actionable information. Electronic health record (EHR)-based tools are commonly used but have had limited application in facilitating deprescribing in older adults. The objective is to determine whether designing EHR tools using behavioral science principles reduces inappropriate prescribing and clinical outcomes in older adults.

Methods

The Novel Uses of Designs to Guide provider Engagement in Electronic Health Records (NUDGE-EHR) project uses a two-stage, 16-arm adaptive randomized pragmatic trial with a “pick-the-winner” design to identify the most effective of many potential EHR tools among primary care providers and their patients ≥ 65 years chronically using benzodiazepines, sedative hypnotic (“Z-drugs”), or anticholinergics in a large integrated delivery system. In stage 1, we randomized providers and their patients to usual care (n = 81 providers) or one of 15 EHR tools (n = 8 providers per arm) designed using behavioral principles including salience, choice architecture, or defaulting. After 6 months of follow-up, we will rank order the arms based upon their impact on the trial’s primary outcome (for both stages): reduction in inappropriate prescribing (via discontinuation or tapering). In stage 2, we will randomize (a) stage 1 usual care providers in a 1:1 ratio to one of the up to 5 most promising stage 1 interventions or continue usual care and (b) stage 1 providers in the unselected arms in a 1:1 ratio to one of the 5 most promising interventions or usual care. Secondary and tertiary outcomes include quantities of medication prescribed and utilized and clinically significant adverse outcomes.

Discussion

Stage 1 launched in October 2020. We plan to complete stage 2 follow-up in December 2021. These results will advance understanding about how behavioral science can optimize EHR decision support to improve prescribing and health outcomes. Adaptive trials have rarely been used in implementation science, so these findings also provide insight into how trials in this field could be more efficiently conducted.

Trial registration

Clinicaltrials.gov (NCT04284553, registered: February 26, 2020)
Cost-effectiveness of a hybrid emergency room system for severe trauma: a health technology assessment from the perspective of the third-party payer in Japan
Authors: Kinoshita Takahiro , Moriwaki Kensuke , Hanaki Nao , Kitamura Tetsuhisa , Yamakawa Kazuma , Fukuda Takashi , Hunink Myriam G. M. , Fujimi Satoshi
Published: January 2021

Background

Hybrid emergency room (ER) systems, consisting of an angiography-computed tomography (CT) machine in a trauma resuscitation room, are reported to be effective for reducing death from exsanguination in trauma patients. We aimed to investigate the cost-effectiveness of a hybrid ER system in severe trauma patients without severe traumatic brain injury (TBI).

Methods

We conducted a cost-utility analysis comparing the hybrid ER system to the conventional ER system from the perspective of the third-party healthcare payer in Japan. A short-term decision tree and a long-term Markov model using a lifetime time horizon were constructed to estimate quality-adjusted life years (QALYs) and associated lifetime healthcare costs. Short-term mortality and healthcare costs were derived from medical records and claims data in a tertiary care hospital with a hybrid ER. Long-term mortality and utilities were extrapolated from the literature. The willingness-to-pay threshold was set at $47,619 per QALY gained and the discount rate was 2%. Deterministic and probabilistic sensitivity analyses were conducted.

Results

The hybrid ER system was associated with a gain of 1.03 QALYs and an increment of $33,591 lifetime costs compared to the conventional ER system, resulting in an ICER of $32,522 per QALY gained. The ICER was lower than the willingness-to-pay threshold if the odds ratio of 28-day mortality was < 0.66. Probabilistic sensitivity analysis indicated that the hybrid ER system was cost-effective with a 79.3% probability.

Conclusion

The present study suggested that the hybrid ER system is a likely cost-effective strategy for treating severe trauma patients without severe TBI.
Are vitamin D and vitamin D receptor levels different in children with developmental dysplasia of the hip?
Authors: Topak Duran , Seyithanoğlu Muhammet , Doğar Fatih , Karadeniz Ali Aydın , Tanrıverdi Burak , Ozan Fırat , Bilal Ökkeş
Published: January 2021

Introduction

Developmental dysplasia of the hip (DDH) is a common disorder and associated with significant morbidity of the hip joint. Several risk factors have been identified for DDH. The aim of this study is to investigate whether vitamin D and vitamin D receptor (VDR) levels differ in children with DDH and whether they have an effect on DDH development.

Materials and methods

A total of 40 (17 males, 23 females; 9 right hips, 16 left hips, 15 bilateral hips) children who were treated for developmental dysplasia and 40 (23 males, 17 females) healthy children without any musculoskeletal system and metabolic disorders were included in this study between January and June 2019. Blood samples from the DDH and control groups of children were collected to measure the serum levels of vitamin D, VDR, calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP). The levels of Ca, P, and ALP were analyzed using the automated standard spectrophotometric laboratory method. The levels of vitamin D and VDR in the samples were analyzed using enzyme-linked immunoassay.

Results

There were no significant differences in the serum levels of Ca, P, ALP, and vitamin D between the DDH and healthy groups (Ca 9.96 ± 0.47 vs. 9.92 ± 0.48 mg/dL, respectively, p = 0.721; P 5.3 ± 0.94 vs. 4.82 ± 0.88 mg/dL, respectively, p = 0.23; ALP 252.22 ± 170.15 vs. 245.3 ± 130.93 U/L, respectively, p = 0.839). However, serum VDR levels were significantly lower in children in the DDH group (5.77 ± 3.51 ng/mL) than in the healthy control group (9.25 ± 6.43 ng/mL) (p = 0.004).

Conclusions

In conclusion, we believe that low VDR levels can affect DDH regardless of the serum levels of Ca, P, ALP, and vitamin D. More comprehensive studies involving parents are needed to understand whether VDR levels mediate genetic transmission in DDH or not.
Inhibitory effects of Camellia japonica on cell inflammation and acute rat reflux esophagitis
Authors: Nam Hyeon Hwa , Nan Li , Choo Byung Kil
Published: January 2021

Background

Excessive and continuous inflammation may be the main cause of various immune system diseases. Reflux esophagitis (RE) is a common gastroesophageal reflux disease (GERD).Camellia japonicahas high medicinal value and has long been used as a traditional herbal hemostatic medicine in China and Korea. The purpose of this study is to explore the antioxidant and anti-inflammatory activities of CJE and its protective effect on RE.

Materials and methods

Buds fromC. japonicaplants were collected in the mountain area of Jeju, South Korea. DriedC. japonicabuds were extracted with 75% ethanol. DPPH and ABTS radical scavenging assay were evaluated according to previous method. The ROS production and anti-inflammatory effects ofC. japonicabuds ethanol extract (CJE) were evaluated on LPS-induced RAW 264.7 cell inflammation. The protective effects of CJE on RE were conducted in a RE rat model.

Results

CJE eliminated over 50% of DPPH and ABTS radical at concentration of 100 and 200 µg/mL, respectively. CJE alleviated changes in cell morphology, reduced production of ROS, NO and IL-1β. Also, down-regulated expression levels of iNOS, TNF-α, phosphorylated NF-κB, IκBα, and JNK/p38/MAPK. CJE reduced esophageal tissue damage ratio (40.3%) and attenuation of histological changes. In addition, CJE down-regulated the expression levels of TNF-α, IL-1β, COX-2 and phosphorylation levels of NF-κB and IκBα in esophageal tissue.

Conclusions

CJE possesses good anti-oxidation and anti-inflammatory activity, and can improve RE in rats caused by gastric acid reflux. Therefore, CJE is a natural material with good anti-oxidant and anti-inflammatory activity and has the possibility of being a candidate phytomedicine source for the treatment of RE.
Pharmacological activities and mechanisms of action of Pogostemon cablin Benth: a review
Authors: Junren Chen , Xiaofang Xie , Mengting Li , Qiuyun Xiong , Gangmin Li , Huiqiong Zhang , Guanru Chen , Xin Xu , Yanpeng Yin , Fu Peng , Cheng Peng
Published: January 2021

Patchouli (“Guanghuoxiang”) or scientifically known asPogostemon cablinBenth, belonging to the family Lamiaceae, has been used in traditional Chinse medicine (TCM) since the time of the Eastern Han dynasty. In TCM theory, patchouli can treat colds, nausea, fever, headache, and diarrhea. Various bioactive compounds have been identified in patchouli, including terpenoids, phytosterols, flavonoids, organic acids, lignins, glycosides, alcohols, pyrone, and aldehydes. Among the numerous compounds, patchouli alcohol, β-patchoulene, patchoulene epoxide, pogostone, and pachypodol are of great importance. The pharmacological impacts of these compounds include anti-peptic ulcer effect, antimicrobial effect, anti-oxidative effect, anti-inflammatory effect, effect on ischemia/reperfusion injury, analgesic effect, antitumor effect, antidiabetic effect, anti-hypertensive effect, immunoregulatory effect, and others.For this review, we examined publications from the previous five years collected from PubMed, Web of Science, Springer, and the Chinese National Knowledge Infrastructure databases. This review summarizes the recent progress in phytochemistry, pharmacology, and mechanisms of action and provides a reference for future studies focused on clinical applications of this important plant extract.
Regulation of PD-L1 expression in the tumor microenvironment
Authors: Yi Ming , Niu Mengke , Xu Linping , Luo Suxia , Wu Kongming
Published: January 2021

Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.
Comparison of 3D scanning versus traditional methods of capturing foot and ankle morphology for the fabrication of orthoses: a systematic review
Authors: Farhan Muhannad , Wang Joyce Zhanzi , Bray Paula , Burns Joshua , Cheng Tegan L.
Published: January 2021

Background

In the production of ankle‐foot orthoses and in‐shoe foot orthoses, lower leg morphology is traditionally captured using a plaster cast or foam impression box. Plaster‐based processes are a time‐consuming and labour‐intensive fabrication method. 3D scanning is a promising alternative, however how these new technologies compare with traditional methods is unclear. The aim of this systematic review was to compare the speed, accuracy and reliability of 3D scanning with traditional methods of capturing foot and ankle morphology for fabricating orthoses.

Methods

PRISMA guidelines were followed and electronic databases were searched to March 2020 using keywords related to 3D scanning technologies and traditional foot and ankle morphology capture methods. Studies of any design from healthy or clinical populations of any age and gender were eligible for inclusion. Studies must have compared 3D scanning to another form of capturing morphology of the foot and/or ankle. Data relating to speed, accuracy and reliability as well as study design, 3D scanner specifications and comparative capture techniques were extracted by two authors (M.F. and Z.W.). Study quality was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Consensus‐Based Standards for the Selection of Health Measurement Instruments (COSMIN).

Results

Six articles met the inclusion criteria, whereby 3D scanning was compared to five traditional methods (plaster cast, foam impression box, ink footprint, digital footprint and clinical assessment). The quality of study outcomes was rated low to moderate (GRADE) and doubtful to adequate (COSMIN). Compared to traditional methods, 3D scanning appeared to be faster than casting (2 to 11 min vs 11 to 16 min). Inter‐rater reliability (ICC 0.18–0.99) and intra‐rater reliability (ICCs 0.25–0.99) were highly variable for both 3D scanning and traditional techniques, with higher agreement generally dependent on the foot parameter measured.

Conclusions

The quality and quantity of literature comparing the speed, accuracy and reliability of 3D scanning with traditional methods of capturing foot and ankle morphology is low. 3D scanning appears to be faster especially for experienced users, however accuracy and reliability between methods is variable.
Morphological characteristics of the plantar calcaneocuboid ligaments
Authors: Edama Mutsuaki , Takabayashi Tomoya , Yokota Hirotake , Hrabayashi Ryo , Sekine Chie , Kageyama Ikuo
Published: January 2021

Background

The aim of this study was to clarify the differences in morphological features between the long plantar ligament (LPL) and the short plantar ligament (SPL).

Methods

This investigation examined 50 legs from 25 Japanese cadavers. The LPL and SPL of each leg were classified into one of three types based on the shape and number of fiber bundles. Then, fiber bundle length, fiber bundle width, and fiber bundle thickness were measured.

Results

The LPL was rectangular in shape (Type I) in 12%, hourglass shape (Type II) in 62%, and triangular in shape (Type III) in 26%. The SPL was a single fiber bundle (Type I‐a) in 26%, a surface fiber bundle and a deep fiber bundle (Type I‐b) in 60%, and a surface fiber bundle (medial and lateral) and a deep fiber bundle (Type II) in 14%. Regarding the morphological characteristics, there were no significant differences among the types in the LPL, but there were differences between types and between surface and deep fiber bundles in the SPL.

Conclusions

For the LPL, the hourglass shape is the most common type. However, there appeared to be no functional difference due to the difference in the shape of the LPL, since there were no significant differences among the types in the LPL. For the SPL, there were types of single, double and triple fiber bundles; there may be functional differences based on the number of fiber bundles and between superficial and deep fibers.
Exosomes secreted by chemoresistant ovarian cancer cells promote angiogenesis
Authors: Li Zhang , Yan-qing Wang , Xiao Yang , Shi-yi Liu , Meng-qin Yuan , Shu Xian , Dong-yong Yang , Ya-jing Zheng , Yan-xiang Cheng
Published: January 2021

Background

Ovarian cancer (OC) has the highest mortality rate in gynecologic tumors. Despite decades of continuous efforts, the survival rate of patients has not improved significantly, mostly due to drug resistance. Exosomes are hot topics in recent years. Cells can affect the biological behaviors of other cells by transferring exosomes. So far, numerous researchers have found that tumor cells can secrete exosomes which play a important role in the development of tumors. Solid tumors can promote angiogenesis. When drug resistance occurs, it seems that more blood vessels form. We suppose that exosomes derived from chemoresistant OC cells can also promote angiogenesis.

Results

We investigate whether exosomes secreted by chemoresistant SKOV3-DDP cells (SKOV3-DDP-exo) and sensitive SKOV3 cells (SKOV3-exo) influence angiogenesis. After exosomes were extracted, exosomes were co-cultured with HUVECs. We found that SKOV3-DDP-exo and SKOV3-exo are absorbed by endothelial cells and promote the proliferation, migration, invasion and tube formation of endothelial cells. Moreover, SKOV3-DDP-exo is more powerful in angiogenesis, suggesting that parts of the components of SKOV3-DDP-exo are significantly radical. We also found that miR-130a was highly expressed in drug-resistant OC cells. Also, we found that miR-130a in SKOV3-DDP-exo is higher than SKOV3-exo. Therefore, we suggest that miR-130a in exosomes is the main cause of chemoresistant OC cells promoting angiogenesis.
Injuries, treatment, and impairment caused by different types of fireworks; results of a 10 year multicenter retrospective cohort study
Authors: Van Yperen Daan T. , Van Lieshout Esther M. M. , Dijkshoorn J. Niels , Van der Vlies Cornelis H. , Verhofstad Michael H. J.
Published: January 2021

Objectives

The primary aim of this study was to evaluate the number of patients reported to a hospital with injuries from consumer fireworks in the months December–January in the past 10 years, and to describe the association between the type of fireworks, injury pattern, treatment, and permanent impairment.

Methods

A multicenter, retrospective, observational case series. Patients were selected from two hospitals in the Southwest Netherlands: a level 1 trauma center and a specialized burn center. All patients with any fireworks-related injuries treated between December 1 and January 31, during 2007 (December) to 2017 (January), were eligible for participation. The primary outcome was the number of patients with any type of injury caused by fireworks. The secondary outcome measures were patient and injury characteristics, treatment details, and whole person impairment (WPI). The percentage WPI expresses a patient’s degree of permanent impairments as a result of fireworks-related injuries.

Results

Of the 297 eligible patients, 272 patients were included. From 2007 to 2017, between 21 and 40 patients were treated, and no clear increase or decrease was observed in the number of patients and in the number of patients per type of fireworks. Explosive fireworks mainly caused upper extremity (N = 65; 68%) injuries, while rockets (N = 24; 41%) and aerials (N = 7; 41%) mainly affected the head/neck. Decorative fireworks predominantly resulted in burns (N = 82; 68%), and explosive fireworks in soft tissue lacerations (N = 24; 25%), fractures (N = 16; 17%), and amputations (N = 14; 15%). Patients injured by explosive and homemade fireworks were most often admitted to a hospital (respectively N = 24; 36% and N = 12; 80%), and resulted in the highest proportion undergoing surgical procedures (respectively N = 22; 33% and N = 7; 47%). WPI found in this study was between 0 to 95%, with a median of 0%. In 34 (14%) patients, the injuries resulted in a WPI of ≥1%, mostly as a result of explosive fireworks (N = 18; 53%).

Conclusion

This study found no increase or decrease in the number of patients treated in two specialized hospitals. Explosive and homemade fireworks could be considered as most dangerous, as they result into the most hospital admissions, surgical procedures, and into the most injuries with permanent impairment as a result.
Apnoeic oxygenation for emergency anaesthesia of pre-hospital trauma patients
Authors: Crewdson Kate , Heywoth Ainsley , Rehn Marius , Sadek Samy , Lockey David
Published: January 2021

Background

Efficient and timely airway management is universally recognised as a priority for major trauma patients, a proportion of whom require emergency intubation in the pre-hospital setting. Adverse events occur more commonly in emergency airway management, and hypoxia is relatively frequent. The aim of this study was to establish whether passive apnoeic oxygenation was effective in reducing the incidence of desaturation during pre-hospital emergency anaesthesia.

Methods

A prospective before-after study was performed to compare patients receiving standard care and those receiving additional oxygen via nasal prongs. The primary endpoint was median oxygen saturation in the peri-rapid sequence induction period, (2 minutes pre-intubation to 2 minutes post-intubation) for all patients. Secondary endpoints included the incidence of hypoxia in predetermined subgroups.

Results

Of 725 patients included; 188 patients received standard treatment and 537 received the intervention. The overall incidence of hypoxia (first recorded SpO2 < 90%) was 16.7%; 10.9% had SpO2 < 85%. 98/725 patients (13.5%) were hypoxic post-intubation (final SpO2 < 90% 10 minutes post-intubation).

Median SpO2 was 100% vs. 99% for the standard vs. intervention group. There was a statistically significant benefit from apnoeic oxygenation in reducing the frequency of peri-intubation hypoxia (SpO2 < =90%) for patients with initial SpO2 > 95%, p = 0.0001. The other significant benefit was observed in the recovery phase for patients with severe hypoxia prior to intubation.

Conclusion

Apnoeic oxygenation did not influence peri-intubation oxygen saturations, but it did reduce the frequency and duration of hypoxia in the post-intubation period. Given that apnoeic oxygenation is a simple low-cost intervention with a low complication rate, and that hypoxia can be detrimental to outcome, application of nasal cannulas during the drug-induced phase of emergency intubation may benefit a subset of patients undergoing emergency anaesthesia.
An estimation of the number of children requiring pediatric palliative care in Italy
Authors: Benini Franca , Bellentani Mariadonata , Reali Laura , Lazzarin Pierina , De Zen Lucia , Pellegatta Federico , Aprile Pierangelo Lora , Scaccabarozzi Gianlorenzo
Published: January 2021

Background

Pediatric palliative care (PPC) addresses the physical and psychological needs of children suffering from life-limiting diseases. To define prevention and educational plans and to properly allocate resources, a precise estimation of the PPC burden is required.

Objectives

To estimate the current number of children requiring PPC in Italy, useful to assist policy-makers and healthcare bodies in the organization and allocation of PPC resources.

Methods

Literature data, The Global Atlas of Palliative Care at the End of Life and Italian national databases have been consulted.

Results

According to our estimation, at present, a total of 20,540–32,864 children in Italy require PPC (34–54 children/100,000 inhabitants) of whom 18 children/100,000 inhabitants require specialized PPC.

Conclusions

The present work is a fundamental tool to be used by the institutions, the local networks of PPC and the health programmers when formulating organizational models and care plans consistent with the actual need for PPC.
Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report
Authors: Abe Kodai , Ueki Arisa , Urakawa Yusaku , Kitago Minoru , Yoshihama Tomoko , Nanki Yoshiko , Kitagawa Yuko , Aoki Daisuke , Kosaki Kenjiro , Hirasawa Akira
Published: January 2021

Background

Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants ofBRCA1and/orBRCA2(BRCA1/2),PALB2, orATM. Recently, some germline variants of familial pancreatic cancers (FPCs), includingPALB2,have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis.

Case presentation

Here, we present the case of a female patient harboring pathogenic variants ofPALB2andNBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored aPALB2pathogenic variant and her daughter harbored the sameNBNpathogenic variant. Given thePALB2andNBNvariants, we designed surveillance strategies for the pancreas, breast, and ovary.

Conclusions

Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.
Invasive lobular carcinoma of the breast: the increasing importance of this special subtype
Authors: McCart Reed Amy E. , Kalinowski Lauren , Simpson Peter T. , Lakhani Sunil R.
Published: January 2021

Invasive lobular carcinoma (ILC) is the most common of the breast cancer special types, accounting for up to 15% of all breast cancer cases. ILCs are noted for their lack of E-cadherin function, which underpins their characteristic discohesive growth pattern, with cells arranged in single file and dispersed throughout the stroma. Typically, tumours are luminal in molecular subtype, being oestrogen and progesterone receptor positive, and HER2 negative. Since last reviewing the lobular literature (McCart Reed et al., Breast Cancer Res 17:12, 2015), there has been a considerable increase in research output focused on this tumour type, including studies into the pathology and management of disease, a high-resolution definition of the genomic landscape of tumours as well as the evolution of several potential therapeutic avenues. There abounds a huge amount of new data, which we will review herein.
An interpretable bimodal neural network characterizes the sequence and preexisting chromatin predictors of induced transcription factor binding
Authors: Srivastava Divyanshi , Aydin Begüm , Mazzoni Esteban O. , Mahony Shaun
Published: January 2021

Background

Transcription factor (TF) binding specificity is determined via a complex interplay between the transcription factor’s DNA binding preference and cell type-specific chromatin environments. The chromatin features that correlate with transcription factor binding in a given cell type have been well characterized. For instance, the binding sites for a majority of transcription factors display concurrent chromatin accessibility. However, concurrent chromatin features reflect the binding activities of the transcription factor itself and thus provide limited insight into how genome-wide TF-DNA binding patterns became established in the first place. To understand the determinants of transcription factor binding specificity, we therefore need to examine how newly activated transcription factors interact with sequence and preexisting chromatin landscapes.

Results

Here, we investigate the sequence and preexisting chromatin predictors of TF-DNA binding by examining the genome-wide occupancy of transcription factors that have been induced in well-characterized chromatin environments. We develop Bichrom, a bimodal neural network that jointly models sequence and preexisting chromatin data to interpret the genome-wide binding patterns of induced transcription factors. We find that the preexisting chromatin landscape is a differential global predictor of TF-DNA binding; incorporating preexisting chromatin features improves our ability to explain the binding specificity of some transcription factors substantially, but not others. Furthermore, by analyzing site-level predictors, we show that transcription factor binding in previously inaccessible chromatin tends to correspond to the presence of more favorable cognate DNA sequences.

Conclusions

Bichrom thus provides a framework for modeling, interpreting, and visualizing the joint sequence and chromatin landscapes that determine TF-DNA binding dynamics.
Novel insights in dimethyl carbonate-based extraction of polyhydroxybutyrate (PHB)
Authors: Mongili Beatrice , Abdel Azim Annalisa , Fraterrigo Garofalo Silvia , Batuecas Esperanza , Re Angela , Bocchini Sergio , Fino Debora
Published: January 2021

Background

Plastic plays a crucial role in everyday life of human living, nevertheless it represents an undeniable source of land and water pollution. Polyhydroxybutyrate (PHB) is a bio-based and biodegradable polyester, which can be naturally produced by microorganisms capable of converting and accumulating carbon as intracellular granules. Hence, PHB-producing strains stand out as an alternative source to fossil-derived counterparts. However, the extraction strategy affects the recovery efficiency and the quality of PHB. In this study, PHB was produced by a genetically modified Escherichia coli strain and successively extracted using dimethyl carbonate (DMC) and ethanol as alternative solvent and polishing agent to chloroform and hexane. Eventually, a Life Cycle Assessment (LCA) study was performed for evaluating the environmental and health impact of using DMC.

Results

Extraction yield and purity of PHB obtained via DMC, were quantified, and compared with those obtained via chloroform-based extraction. PHB yield values from DMC-based extraction were similar to or higher than those achieved by using chloroform (≥ 67%). To optimize the performance of extraction via DMC, different experimental conditions were tested, varying the biomass state (dry or wet) and the mixing time, in presence or in absence of a paper filter. Among 60, 90, 120 min, the mid-value allowed to achieve high extraction yield, both for dry and wet biomass. Physical and molecular dependence on the biomass state and solvent/antisolvent choice was established. The comparative LCA analysis promoted the application of DMC/ethanol rather than chloroform/hexane, as the best choice in terms of health prevention. However, an elevated impact score was achieved by DMC in the environmental-like categories in contrast with a minor contribution by its counterpart.

Conclusion

The multifaceted exploration of DMC-based PHB extraction herein reported extends the knowledge of the variables affecting PHB purification process. This work offers novel and valuable insights into PHB extraction process, including environmental aspects not discussed so far. The findings of our research question the DMC as a green solvent, though also the choice of the antisolvent can influence the impact on the examined categories.
Culicoides biting midges involved in transmission of haemoproteids
Authors: Žiegytė Rita , Platonova Elena , Kinderis Egidijus , Mukhin Andrey , Palinauskas Vaidas , Bernotienė Rasa
Published: January 2021

Background

Culicoides biting midges (Diptera, Ceratopogonidae) are known vectors of avian Haemoproteus parasites. These parasites cause diseases, pathology and even mortality in birds. The diversity of biting midges in Europe is great, but only four Culicoides species are known to be vectors of avian Haemoproteus parasites. In general, our knowledge about the role of the particular Culicoides species in the transmission of Haemoproteus parasites remains insufficient. Information gaps hinder a better understanding of parasite biology and the epizootiology of parasite-caused diseases. The aim of this study was to determine new Culicoides species involved in the transmission of Haemoproteus parasites.

Methods

Biting midges were collected using a UV trap as well as sticky traps installed in bird nest boxes. Individual parous females were diagnosed for the presence of haemoproteids using both PCR-based and microscopic methods.

Results

We collected and dissected 232 parous Culicoides females from 9 species using a UV trap and 293 females from 11 species from bird nest boxes. Culicoides obsoletus was the dominant species collected using a UV trap, and Culicoides kibunensis dominated among midges collected in nest boxes. PCR-based screening showed that 5.2% of parous biting midges collected using a UV trap and 4.4% of midges collected from nest boxes were infected with avian haemosporidian parasites. Haemoproteid DNA was detected in C. kibunensis, Culicoides pictipennis, Culicoides punctatus, Culicoides segnis and Culicoides impunctatus females. The sporozoites of Haemoproteus minutus (genetic lineages hTURDUS2 and hTUPHI01) were detected in the salivary glands of two C. kibunensis females using microscopy, and this finding was confirmed by PCR.

Conclusions

Culicoides kibunensis was detected as a new natural vector of Haemoproteus minutus (hTURDUS2 and hTUPHI01). Haemoproteid DNA was detected in females from five Culicoides species. This study contributes to the epizootiology of avian Haemoproteus infections by specifying Culicoides species as vectors and species that are likely to be responsible for the transmission of haemoproteids in Europe.

Graphical Abstract
Next-generation tools to control biting midge populations and reduce pathogen transmission
Authors: Shults Phillip , Cohnstaedt Lee W. , Adelman Zach N. , Brelsfoard Corey
Published: January 2021

Biting midges of the genus Culicoides transmit disease-causing agents resulting in a significant economic impact on livestock industries in many parts of the world. Localized control efforts, such as removal of larval habitat or pesticide application, can be logistically difficult, expensive and ineffective if not instituted and maintained properly. With these limitations, a population-level approach to the management of Culicoides midges should be investigated as a means to replace or supplement existing control strategies. Next-generation control methods such as Wolbachia- and genetic-based population suppression and replacement are being investigated in several vector species. Here we assess the feasibility and applicability of these approaches for use against biting midges. We also discuss the technical and logistical hurdles needing to be addressed for each method to be successful, as well as emphasize the importance of addressing community engagement and involving stakeholders in the investigation and development of these approaches.

Graphical Abstract
Family history assessment significantly enhances delivery of precision medicine in the genomics era
Authors: Bylstra Yasmin , Lim Weng Khong , Kam Sylvia , Tham Koei Wan , Wu R. Ryanne , Teo Jing Xian , Davila Sonia , Kuan Jyn Ling , Chan Sock Hoai , Bertin Nicolas , Yang Cheng Xi , Rozen Steve , Teh Bin Tean , Yeo Khung Keong , Cook Stuart Alexander , Jamuar Saumya Shekhar , Ginsburg Geoffrey S. , Orlando Lori A. , Tan Patrick
Published: January 2021

Background

Family history has traditionally been an essential part of clinical care to assess health risks. However, declining sequencing costs have precipitated a shift towards genomics-first approaches in population screening programs rendering the value of family history unknown. We evaluated the utility of incorporating family history information for genomic sequencing selection.

Methods

To ascertain the relationship between family histories on such population-level initiatives, we analysed whole genome sequences of 1750 research participants with no known pre-existing conditions, of which half received comprehensive family history assessment of up to four generations, focusing on 95 cancer genes.

Results

Amongst the 1750 participants, 866 (49.5%) had high-quality standardised family history available. Within this group, 73 (8.4%) participants had an increased family history risk of cancer (increased FH risk cohort) and 1 in 7 participants (n = 10/73) carried a clinically actionable variant inferring a sixfold increase compared with 1 in 47 participants (n = 17/793) assessed at average family history cancer risk (average FH risk cohort) (p = 0.00001) and a sevenfold increase compared to 1 in 52 participants (n = 17/884) where family history was not available (FH not available cohort) (p = 0.00001). The enrichment was further pronounced (up to 18-fold) when assessing only the 25 cancer genes in the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes. Furthermore, 63 (7.3%) participants had an increased family history cancer risk in the absence of an apparent clinically actionable variant.

Conclusions

These findings demonstrate that the collection and analysis of comprehensive family history and genomic data are complementary and in combination can prioritise individuals for genomic analysis. Thus, family history remains a critical component of health risk assessment, providing important actionable data when implementing genomics screening programs.

Trial registration

ClinicalTrials.gov NCT02791152. Retrospectively registered on May 31, 2016.
An integrated in silico immuno-genetic analytical platform provides insights into COVID-19 serological and vaccine targets
Authors: Ward Daniel , Higgins Matthew , Phelan Jody E. , Hibberd Martin L. , Campino Susana , Clark Taane G.
Published: January 2021

During COVID-19, diagnostic serological tools and vaccines have been developed. To inform control activities in a post-vaccine surveillance setting, we have developed an online “immuno-analytics” resource that combines epitope, sequence, protein and SARS-CoV-2 mutation analysis. SARS-CoV-2 spike and nucleocapsid proteins are both vaccine and serological diagnostic targets. Using the tool, the nucleocapsid protein appears to be a sub-optimal target for use in serological platforms. Spike D614G (and nsp12 L314P) mutations were most frequent (> 86%), whilst spike A222V/L18F have recently increased. Also, Orf3a proteins may be a suitable target for serology. The tool can accessed from: http://genomics.lshtm.ac.uk/immuno (online); https://github.com/dan-ward-bio/COVID-immunoanalytics (source code).
Social purpose in an organization from the perspective of an employee: a self-determination outlook on the meaning of work
Authors: Puchalska-Kamińska Malwina , Łądka-Barańska Agnieszka , Roczniewska Marta
Published: January 2021

Objective

Advancing social purpose in organizations is usually studied from the macro perspective, i.e., how it benefits organizational business goals or society more broadly. In this paper, we focus on social purpose from the perspective of the employee and propose that advancing social purpose in an organization allows individuals to fulfil an important human need for the meaning of work (MW). This study’s objective was to assess whether a volunteering Corporate Social Responsibility (CSR) program in a manufacturing company allows employees to fulfil their basic psychological needs for relatedness, competence, and autonomy. The data was collected through in-depth interviews with 15 employees and an analysis of artifacts.

Results

In the analysis, three main themes describing different aspects of voluntary work at the company were identified. We found that across all groups of interviewed employees the voluntary activities served the needs of (1) relatedness, (2) competence, and (3) autonomy. We conclude that CSR programs have the most positive impact on MW when they allow employees to engage in prosocial actions and satisfy those needs.
Biomarker testing in MCI patients—deciding who to test
Authors: van Maurik Ingrid S. , Rhodius-Meester Hanneke F. M. , Teunissen Charlotte E. , Scheltens Philip , Barkhof Frederik , Palmqvist Sebastian , Hansson Oskar , van der Flier Wiesje M. , Berkhof Johannes
Published: January 2021

Background

We aimed to derive an algorithm to define the optimal proportion of patients with mild cognitive impairment (MCI) in whom cerebrospinal fluid (CSF) testing is of added prognostic value.

Methods

MCI patients were selected from the Amsterdam Dementia Cohort (n = 402). Three-year progression probabilities to dementia were predicted using previously published models with and without CSF data (amyloid-beta1-42 (Abeta), phosphorylated tau (p-tau)). We incrementally augmented the proportion of patients undergoing CSF, starting with the 10% patients with prognostic probabilities based on clinical data around the median (percentile 45–55), until all patients received CSF. The optimal proportion was defined as the proportion where the stepwise algorithm showed similar prognostic discrimination (Harrell’s C) and accuracy (three-year Brier scores) compared to CSF testing of all patients. We used the BioFINDER study (n = 221) for validation.

Results

The optimal proportion of MCI patients to receive CSF testing selected by the stepwise approach was 50%. CSF testing in only this proportion improved the performance of the model with clinical data only from Harrell’s C = 0.60, Brier = 0.198 (Harrell’s C = 0.61, Brier = 0.197 if the information on magnetic resonance imaging was available) to Harrell’s C = 0.67 and Brier = 0.190, and performed similarly to a model in which all patients received CSF testing. Applying the stepwise approach in the BioFINDER study would again select half of the MCI patients and yielded robust results with respect to prognostic performance.

Interpretation

CSF biomarker testing adds prognostic value in half of the MCI patients. As such, we achieve a CSF saving recommendation while simultaneously retaining optimal prognostic accuracy.
Left ventricular myocardial strain assessed by cardiac magnetic resonance feature tracking in patients with rheumatoid arthritis
Authors: Tański Wojciech , Gać Paweł , Chachaj Angelika , Mazur Grzegorz , Poręba Rafał , Szuba Andrzej
Published: January 2021

Purpose

The aim of the study was to assess a relationship between the occurrence of rheumatoid arthritis (RA) and its selected clinical parameters, and left ventricular myocardial strain.

Material and methods

Fifty-six subjects were qualified for the study: 30 RA patients and 26 subjects without rheumatoid diseases. The study design included taking medical history, assessment of the disease activity using selected scales of activity, collecting samples of venous blood to assess selected laboratory parameters and the assessment of cardiac magnetic resonance (CMR). Using the feature tracking method, the following parameters of the left ventricular myocardial strain were assessed: longitudinal strain (LS), radial strain (RS) and circumferential strain (CS).

Results

Regarding global values, peak LS and peak CS were statistically significantly lower in RA patients than in the control group. In the whole study group, the factors independently related to low global LS peaks were as follows: occurrence of RA, occurrence of arterial hypertension, increased activity of antibodies against cyclic citrullinated peptide and increased concentration of neutrophil gelatinase-associated lipocalin. The occurrence of RA, occurrence of diabetes, tobacco smoking, higher activity of antibodies against cyclic citrullinated peptide and current use of methotrexate are the risk factors for low peak of global CS. The current use of steroids constitutes a protecting factor against low global CS peaks.

Conclusion

In subjects with no clinically manifested cardiac damage, RA is associated with a deteriorated left ventricular systolic function assessed by left ventricular myocardial strain measured by CMR feature tracking.