bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of an integrated safer use space and safer supply program on non-fatal overdose among emergency shelter residents during a COVID-19 outbreak: a case study
Authors: Lew Brendan , Bodkin Claire , Lennox Robin , O’Shea Timothy , Wiwcharuk Gillian , Turner Suzanne 
Published: March 2022

Abstract
Background
Opioid-related harms, including fatal and non-fatal overdoses, rose dramatically during the COVID-19 pandemic and presented unique challenges during outbreaks in congregate settings such as shelters. People who are deprived of permanent housing have a high prevalence of substance use and substance use disorders, and need nimble, rapid, and portable harm reduction interventions to address the harms of criminalized substance use in an evidence-based manner.

Case study
In February 2021, a COVID-19 outbreak was declared at an emergency men’s shelter in Hamilton, Ontario, Canada. Building on pre-existing relationships, community and hospital-based addictions medicine providers and a local harm reduction group collaborated to establish a shelter-based opioid agonist treatment and safer supply program, and a volunteer run safer drug use space that also distributed harm reduction supplies. In the 4 weeks preceding the program, the rate of non-fatal overdoses was 0.93 per 100 nights of shelter bed occupancy. During the 26 days of program operation, there were no overdoses in the safer use space and the rate of non-fatal overdoses in the shelter was 0.17 per 100 nights of shelter bed occupancy. The odds ratio of non-fatal overdose pre-intervention to during intervention was 5.5 (95% CI 1.63–18.55, p = 0.0059). We were not able to evaluate the impact of providing harm reduction supplies and did not evaluate the impact of the program on facilitating adherence to public health isolation and quarantine orders. The program ended as the outbreak waned, as per the direction from the shelter operator.

Conclusions
There was a significant reduction in the non-fatal overdose rate after the safer drug use and safer supply harm reduction program was introduced. Pre-existing relationships between shelter providers, harm reduction groups, and healthcare providers were critical to implementing the program. This is a promising approach to reducing harms from the criminalization of substance use in congregate settings, particularly in populations with a higher prevalence of substance use and substance use disorders.
Parasagittal dural space and cerebrospinal fluid (CSF) flow across the lifespan in healthy adults
Authors: Hett Kilian , McKnight Colin D. , Eisma Jarrod J. , Elenberger Jason , Lindsey Jennifer S. , Considine Ciaran M. , Claassen Daniel O. , Donahue Manus J. 
Published: March 2022

Abstract
Background
Recent studies have suggested alternative cerebrospinal fluid (CSF) clearance pathways for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of these pathways is the anatomic region surrounding the superior sagittal sinus, which has been shown to have relevance to trans-arachnoid molecular passage. This so-called parasagittal dural (PSD) space may play a physiologically significant role as a distal intracranial component of the human glymphatic circuit, yet fundamental gaps persist in our knowledge of how this space changes with normal aging and intracranial bulk fluid transport.

Methods
We re-parameterized MRI methods to assess CSF circulation in humans using high resolution imaging of the PSD space and phase contrast measures of flow through the cerebral aqueduct to test the hypotheses that volumetric measures of PSD space (1) are directly related to CSF flow (mL/s) through the cerebral aqueduct, and (2) increase with age. Multi-modal 3-Tesla MRI was applied in healthy participants (n = 62; age range = 20–83 years) across the adult lifespan whereby phase contrast assessments of CSF flow through the aqueduct were paired with non-contrasted T1-weighted and T2-weighted MRI for PSD volumetry. PSD volume was extracted using a recently validated neural networks algorithm. Non-parametric regression models were applied to evaluate how PSD volume related to tissue volume and age cross-sectionally, and separately how PSD volume related to CSF flow (significance criteria: two-sided p < 0.05).

Results
A significant PSD volume enlargement in relation to normal aging (p < 0.001, Spearman’s-$$\rho$$
ρ
= 0.6), CSF volume (p < 0.001, Spearman’s-$$\rho$$
ρ
= 0.6) and maximum CSF flow through the aqueduct of Sylvius (anterograde and retrograde, p < 0.001) were observed. The elevation in PSD volume was not significantly related to gray or white matter tissue volumes. Findings are consistent with PSD volume increasing with age and bulk CSF flow.

Conclusions
Findings highlight the feasibility of quantifying PSD volume non-invasively in vivo in humans using machine learning and non-contrast MRI. Additionally, findings demonstrate that PSD volume increases with age and relates to CSF volume and bi-directional flow. Values reported should provide useful normative ranges for how PSD volume adjusts with age, which will serve as a necessary pre-requisite for comparisons to persons with neurodegenerative disorders.
Exploring ITM2A as a new potential target for brain delivery
Authors: Cegarra Céline , Chaves C. , Déon C. , Do T. M. , Dumas B. , Frenzel A. , Kuhn P. , Roudieres V. , Guillemot J. C. , Lesuisse D. 
Published: March 2022

Abstract
Background
Integral membrane protein 2A (ITM2A) is a transmembrane protein expressed in a variety of tissues; little is known about its function, particularly in the brain. ITM2A was found to be highly enriched in human brain versus peripheral endothelial cells by transcriptomic and proteomic studies conducted within the European Collaboration on the Optimization of Macromolecular Pharmaceutical (COMPACT) Innovative Medicines Initiative (IMI) consortium. Here, we report the work that was undertaken to determine whether ITM2A could represent a potential target for delivering drugs to the brain.

Methods
A series of ITM2A constructs, cell lines and specific anti-human and mouse ITM2A antibodies were generated. Binding and internalization studies in Human Embryonic Kidney 293 (HEK293) cells overexpressing ITM2A and in brain microvascular endothelial cells from mouse and non-human primate (NHP) were performed with these tools. The best ITM2A antibody was evaluated in an in vitro human blood brain barrier (BBB) model and in an in vivo mouse pharmacokinetic study to investigate its ability to cross the BBB.

Results
Antibodies specifically recognizing extracellular parts of ITM2A or tags inserted in its extracellular domain showed selective binding and uptake in ITM2A-overexpressing cells. However, despite high RNA expression in mouse and human microvessels, the ITM2A protein was rapidly downregulated when endothelial cells were grown in culture, probably explaining why transcytosis could not be observed in vitro. An attempt to directly demonstrate in vivo transcytosis in mice was inconclusive, using either a cross-reactive anti-ITM2A antibody or in vivo phage panning of an anti-ITM2A phage library.

Conclusions
The present work describes our efforts to explore the potential of ITM2A as a target mediating transcytosis through the BBB, and highlights the multiple challenges linked to the identification of new brain delivery targets. Our data provide evidence that antibodies against ITM2A are internalized in ITM2A-overexpressing HEK293 cells, and that ITM2A is expressed in brain microvessels, but further investigations will be needed to demonstrate that ITM2A is a potential target for brain delivery.
Perceived impact of the patent linkage system on pharmaceutical market from the viewpoint of the domestic manufacturers in South Korea
Authors: Choi Nahye , Son Kyung-Bok , Byun Joonsoo , Yang Dong-Wook 
Published: March 2022

Abstract
Background
The United States requires a patent linkage system in other countries as part of free trade agreements. However, introducing a patent linkage system could be a significant barrier to the timely approval of generic drugs. This study aimed to evaluate the perceived impact of the patent linkage system in South Korea held by domestic manufacturers and analyze variations in evaluating the system according to the characteristics of domestic manufacturers.

Methods
In 2020, we conducted a questionnaire survey of 39 domestic manufacturers. The survey consisted of perceptions of the system, factors affecting patent challenges, and the perceived impact of the system. A 5-point Likert scale was used to rate each item. Domestic manufacturers were categorized into three groups based on their experience of listing a patent and acquiring first generic exclusivity.

Results
More than half of the manufacturers surveyed had experience of listing a patent. The patent linkage system could protect the involved patents. However, manufacturers perceived that they could successfully challenge the validity of the involved patents and then obtained market approval for generic drugs. Manufacturers responded that market size, expectations for succeeding in litigation, and expectations for manufacturing the drug were the most relevant factors when they initiated patent challenges. Manufacturers reported that the system, in particular the first generic exclusivity, enhanced the research and development capability of generic manufacturers, increased their domestic sales, and improved access to generic drugs.

Conclusions
The perceived impact of the patent linkage system was limited to the domestic market and generic drugs. In narrowing the impact to the effects on the domestic industry, the system had positive impacts of the system on generic manufacturers. The first generic drug exclusivity lies at the center of this positive perception. However, manufacturers perceived that the current system did not provide enough incentives for domestic manufacturers to be granted first generic drug exclusivity through patent challenges.
Lactation in quarantine: The (in)visibility of human milk feeding during the COVID-19 pandemic in the United States
Authors: Cohen Mathilde , Botz Corinne 
Published: March 2022

AbstractBackgroundIn response to the COVID-19 pandemic, billions of people were asked by their state and local governments not to go to work and not leave the house unless they had to. The goal of this qualitative study was to collect the lived experiences of a small group of parents and lactation professionals in the United States about what it was like to feed babies human milk under these conditions of quarantine.MethodsThis project is a social constructionist analysis of lactation narratives of 24 parents feeding their children human milk and 13 lactation professionals. They were interviewed remotely in 2020–21 via videoconferencing about their experiences and perspectives on the pandemic’s effect on lactation. Additionally, photographs of 16 of the parents are provided to visualize their practices and how they chose to represent them.ResultsFour interrelated themes were identified in participants’ narratives about how they experienced and made sense of human milk feeding during the pandemic: the loneliness of lactation during the pandemic, the construction of human milk as a resource to cope with the crisis, the (in)visibility of lactation amidst heightened multitasking, and the sense of connection created by human milk feeding at a time of unprecedented solitude.ConclusionsWhile the pandemic may have had both positive and negative effects on lactation, it exposed continuing inequities in infant feeding, generating new forms of (in)visibility for lactating labor. Going forward, one lesson for policy and lawmakers may be that to adequately support lactation, they should take cues from the families who had positive experiences during the crisis. This would call for systemically overhauling of US laws and policies by guaranteeing: universal basic income, paid parental leave for at least six months, paid lactation leaves and breaks, affordable housing, universal health care, subsidized childcare programs, and equal access to high-quality, non-discriminatory, and culturally appropriate medical care—including lactation counseling—, among other initiatives.
Enablers and inhibitors of exclusive breastfeeding: perspectives from mothers and health workers in Accra, Ghana
Authors: Agyekum Martin Wiredu , Codjoe Samuel N. A. , Dake Fidelia A. A. , Abu Mumuni 
Published: March 2022

Abstract
Background
Despite the health and economic benefits of exclusive breastfeeding, there is evidence of a decline globally and in Ghana. Previous studies addressing this problem are mostly quantitative with only a few of such studies using qualitative or mixed methods to examine the predictors, benefits, ways of improving and managing exclusive breastfeeding, and the challenges associated with exclusive breastfeeding from the perspective of exclusive and nonexclusive breastfeeding mothers, and health workers. This study employs the health belief model to examine the experiences of mothers and health workers regarding exclusive breastfeeding to fill this gap in the literature.

Methods
A cross-sectional qualitative study involving in-depth interviews was conducted among health workers and mothers attending child welfare clinic at two polyclinics in Madina, Accra-Ghana in 2019. Purposive sampling was used to select health facilities and participants for the study. Twenty participants comprising ten exclusive breastfeeding mothers, six non-exclusive breastfeeding mothers and four health workers were interviewed for the study. The data were analyzed based on emerging themes from inductive and deductive coding.

Results
The decision to practice exclusive breastfeeding was based on mothers’ work, advertisement on exclusive breastfeeding and education on breastfeeding provided by health workers. Insufficient flow of breast milk, pressure from family and friends, and insufficient breast milk for infants were among the reasons for discontinuing exclusive breastfeeding. The factors that help improve exclusive breastfeeding include eating healthy food and breastfeeding on demand, while counselling and monitoring, restricting advertisement on infant formula and granting maternity leave for breastfeeding mothers were identified as factors that can facilitate the practice of exclusive breastfeeding.

Conclusion
Different levels of experience affect and shape exclusive breastfeeding practice in Ghana. The decision to practice exclusive breastfeeding, as well as the challenges and strategies employed in managing exclusive breastfeeding, emanates from mothers’ personal experiences and interactions with institutional factors. In view of this, there should be counselling on the management of challenges associated with exclusive breastfeeding and provision of accurate information on exclusive breastfeeding to enable mothers practice exclusive breastfeeding.
High-throughput estimation of allele frequencies using combined pooled-population sequencing and haplotype-based data processing
Authors: Schneider Michael , Shrestha Asis , Ballvora Agim , Léon Jens 
Published: March 2022

AbstractBackgroundIn addition to heterogeneity and artificial selection, natural selection is one of the forces used to combat climate change and improve agrobiodiversity in evolutionary plant breeding. Accurate identification of the specific genomic effects of natural selection will likely accelerate transfer between populations. Thus, insights into changes in allele frequency, adequate population size, gene flow and drift are essential. However, observing such effects often involves a trade-off between costs and resolution when a large sample of genotypes for many loci is analysed. Pool genotyping approaches achieve high resolution and precision in estimating allele frequency when sequence coverage is high. Nevertheless, high-coverage pool sequencing of large genomes is expensive.ResultsThree pool samples (n = 300, 300, 288) from a barley backcross population were generated to assess the population's allele frequency. The tested population (BC2F21) has undergone 18 generations of natural adaption to conventional farming practice. The accuracies of estimated pool-based allele frequencies and genome coverage yields were compared using three next-generation sequencing genotyping methods. To achieve accurate allele frequency estimates with low sequence coverage, we employed a haplotyping approach. Low coverage allele frequencies of closely located single polymorphisms were aggregated into a single haplotype allele frequency, yielding 2-to-271-times higher depth and increased precision. When we combined different haplotyping tactics, we found that gene and chip marker-based haplotype analyses performed equivalently or better compared with simple contig haplotype windows. Comparing multiple pool samples and referencing against an individual sequencing approach revealed that whole-genome pool re-sequencing (WGS) achieved the highest correlation with individual genotyping (≥ 0.97). In contrast, transcriptome-based genotyping (MACE) and genotyping by sequencing (GBS) pool replicates were significantly associated with higher error rates and lower correlations, but are still valuable to detect large allele frequency variations.ConclusionsThe proposed strategy identified the allele frequency of populations with high accuracy at low cost. This is particularly relevant to evolutionary plant breeding of crops with very large genomes, such as barley. Whole-genome low coverage re-sequencing at 0.03 × coverage per genotype accurately estimated the allele frequency when a loci-based haplotyping approach was applied. The implementation of annotated haplotypes capitalises on the biological background and statistical robustness.
Sensor-based phenotyping of above-ground plant-pathogen interactions
Authors: Tanner Florian , Tonn Sebastian , de Wit Jos , Van den Ackerveken Guido , Berger Bettina , Plett Darren 
Published: March 2022

AbstractPlant pathogens cause yield losses in crops worldwide. Breeding for improved disease resistance and management by precision agriculture are two approaches to limit such yield losses. Both rely on detecting and quantifying signs and symptoms of plant disease. To achieve this, the field of plant phenotyping makes use of non-invasive sensor technology. Compared to invasive methods, this can offer improved throughput and allow for repeated measurements on living plants. Abiotic stress responses and yield components have been successfully measured with phenotyping technologies, whereas phenotyping methods for biotic stresses are less developed, despite the relevance of plant disease in crop production. The interactions between plants and pathogens can lead to a variety of signs (when the pathogen itself can be detected) and diverse symptoms (detectable responses of the plant). Here, we review the strengths and weaknesses of a broad range of sensor technologies that are being used for sensing of signs and symptoms on plant shoots, including monochrome, RGB, hyperspectral, fluorescence, chlorophyll fluorescence and thermal sensors, as well as Raman spectroscopy, X-ray computed tomography, and optical coherence tomography. We argue that choosing and combining appropriate sensors for each plant-pathosystem and measuring with sufficient spatial resolution can enable specific and accurate measurements of above-ground signs and symptoms of plant disease.
Development of a controlled-environment assay to induce iron deficiency chlorosis in soybean by adjusting calcium carbonates, pH, and nodulation
Authors: Merry R. , Espina M. J. , Lorenz A. J. , Stupar R. M. 
Published: March 2022

Abstract
Background
Soybean iron deficiency chlorosis (IDC) is an important nutrient stress frequently found in high pH and/or soils high in calcium carbonates. To advance the understanding of IDC resistance in soybean, a rapid (21-day) controlled-environment assay was developed to investigate the effects of nodulation, pH, and calcium carbonate levels on soybean iron deficiency traits. This system was tested on four genotypes known to exhibit differences in iron efficiency, including two standard IDC check cultivars and a pair of near-isogenic lines exhibiting variation at an IDC resistance quantitative trait locus. Visual score, chlorophyll content, plant height, root dry mass, and shoot dry mass were measured to quantify iron stress.

Results
Calcium carbonate levels and nodulation were found to have the greatest effects on IDC severity. Increasing calcium carbonate levels worsened IDC symptoms, while nodulation reduced symptoms in all genotypes. Higher pH levels increased iron deficiency symptoms in check genotypes ‘Corsoy 79’ and ‘Dawson’, but did not induce iron deficiency symptoms in near-isogenic lines. A significant interaction was observed between genotype, nodulation, and calcium carbonate level, indicating that a specific treatment level could discern IDC symptoms between genotypes differing in resistance to IDC.

Conclusions
IDC symptoms were successfully induced in the Check Genotypes Experiment as well as the NIL Experiment, indicating the success of using this assay for inducing IDC in controlled environments. However, our results suggest that treatment levels that best differentiate genotypes for their IDC resistance may need to be determined for each experiment because of the unique way in which different genotypes display symptoms and respond to iron deficiency conditions.
Outcomes of proton therapy for non-small cell lung cancer in patients with interstitial pneumonia
Authors: Hashimoto Shingo , Iwata Hiromitsu , Hattori Yukiko , Nakajima Koichiro , Nomura Kento , Hayashi Kensuke , Toshito Toshiyuki , Yamamori Eiko , Akita Kenji , Mizoe Jun-etsu , Ogino Hiroyuki , Shibamoto Yuta 
Published: March 2022

AbstractBackgroundInterstitial pneumonia (IP) is a disease with a poor prognosis. In addition, IP patients are more likely to develop lung cancer. Since IP patients frequently develop toxicities during cancer treatment, minimally invasive cancer treatment is warranted for such patients to maintain their quality of life. This study retrospectively investigated the efficacy and safety of proton therapy (PT) for non-small cell lung cancer (NSCLC) in patients with IP.MethodsTwenty-nine NSCLC patients with IP were treated with PT between September 2013 and December 2019. The patients had stage IA to IIIB primary NSCLC. Ten of the 29 patients exhibited the usual interstitial pneumonia pattern. The prescribed dose was 66–74 Grays (relative biological effectiveness) in 10–37 fractions.ResultsThe median follow-up period was 21.1 months [interquartile range (IQR), 15.6–37.3] for all patients and 37.2 months (IQR, 24.0–49.9) for living patients. The median patient age was 77 years (IQR, 71–81). The median planning target volume was 112.0 ml (IQR, 56.1–246.3). The 2-year local control, progression-free survival, and overall survival rates were 85% (95% confidence interval: 57–95), 30% (15–47), and 45% (26–62), respectively. According to the Common Terminology Criteria for Adverse Events (version 4.0), grade 3 acute radiation pneumonitis (RP) was observed in 1 patient. Two patients developed grade 3 late RP, but no other patients experienced serious toxicities. The patients’ quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 and SF-36) scores had not changed after 3 months.Conclusions﻿PT may be a relatively safe treatment for NSCLC patients with IP, without deteriorating quality of life scores within 3 months.