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INTRODUCTION: The practice of supplementing standard infant formula with energy for infants with faltering growth has been widespread. This increases energy density but disturbs the protein : energy ratio, and increases risks of microbial contamination and errors in feed preparation. This study aimed to compare the effectiveness of a nutrient-dense formula (NDF) with an energy-supplemented formula (ESF) in infants with faltering growth. METHODS: In an open, parallel, randomized study, 49 infants with faltering growth were randomized to receive a NDF (4.2 kJ mL(-1)) or an ESF (4.2 kJ mL(-1)), for 6 weeks. Anthropometry, biochemistry, feed intake, stool and vomit frequency were collected. RESULTS: No significant differences in tolerance, feed volumes or energy intakes were recorded but the NDF group received 42% more protein and 15-40% more vitamins and minerals. Blood urea concentration in the ESF group fell by 50% over the trial period, suggesting a suboptimal protein : energy ratio in the ESF feed. The NDF group retained a normal mean blood urea concentration, a higher urinary potassium concentration and did not have the significant fall in length z-score seen in the ESF group. CONCLUSION: Increasing the energy content of normal infant formula without also increasing protein and micronutrients should not be practiced in infants with faltering growth. [ABSTRACT FROM AUTHOR]

Safe management of radioactive waste is challenging to waste producers and waste management organisations. Deployment of thermal treatment technologies can provide significant improvements: volume reduction, waste passivation, organics destruction, safety demonstration facilitation, etc. The EC-funded THERAMIN project enables an EU-wide strategic review and assessment of the value of thermal treatment technologies applicable to Low and Intermediate Level waste streams (ion exchange media, soft operational waste, sludges, organic waste, and liquids). THERAMIN compiles an EU-wide database of wastes, which could be treated by thermal technologies and documents available thermal technologies. Applicability and benefits of technologies to the identified waste streams will be evaluated through full-scale demonstration tests by project partners. Safety case implications will also be assessed through the study of the disposability of thermally treated waste products. This paper will communicate the strategic aims of the ongoing project and highlight some key findings and results achieved to date.

Abstract Background Over the last decades, converging forces in hospital care, including cost-containment policies, rising healthcare demands and nursing shortages, have driven the search for new operational models of nursing care delivery that maximize the use of available nursing resources while ensuring safe, high-quality care. Little is known, however, about the distinctive features of these emergent nursing care models. This article contributes to filling this gap by presenting a theoretically and empirically grounded taxonomy of nursing care organization models in the context of acute care units in Quebec and comparing their distinctive features. Methods This study was based on a survey of 22 medical units in 11 acute care facilities in Quebec. Data collection methods included questionnaire, interviews, focus groups and administrative data census. The analytical procedures consisted of first generating unit profiles based on qualitative and quantitative data collected at the unit level, then applying hierarchical cluster analysis to the units’ profile data. Results The study identified four models of nursing care organization: two professional models that draw mainly on registered nurses as professionals to deliver nursing services and reflect stronger support to nurses’ professional practice, and two functional models that draw more significantly on licensed practical nurses (LPNs) and assistive staff (orderlies) to deliver nursing services and are characterized by registered nurses’ perceptions that the practice environment is less supportive of their professional work. Conclusions This study showed that medical units in acute care hospitals exhibit diverse staff mixes, patterns of skill use, work environment design, and support for innovation. The four models reflect not only distinct approaches to dealing with the numerous constraints in the nursing care environment, but also different degrees of approximations to an “ideal” nursing professional practice model described by some leaders in the contemporary nursing literature. While the two professional models appear closer to this ideal, the two functional models are farther removed.

Lesion studies have historically been instrumental for establishing causal connections between brain and behavior. They stand to provide additional insight if integrated with multielectrode techniques common in systems neuroscience. Here, we present and test a platform for creating electrolytic lesions through chronically implanted, intracortical multielectrode probes without compromising the ability to acquire neuroelectrophysiology. A custom-built current source provides stable current and allows for controlled, repeatable lesions in awake-behaving animals. Performance of this novel lesioning technique was validated using histology from ex vivo and in vivo testing, current and voltage traces from the device, and measurements of spiking activity before and after lesioning. This electrolytic lesioning method avoids disruptive procedures, provides millimeter precision over the extent and submillimeter precision over the location of the injury, and permits electrophysiological recording of single-unit activity from the remaining neuronal population after lesioning. This technique can be used in many areas of cortex, in several species, and theoretically with any multielectrode probe. The low-cost, external lesioning device can also easily be adopted into an existing electrophysiology recording setup. This technique is expected to enable future causal investigations of the recorded neuronal population's role in neuronal circuit function, while simultaneously providing new insight into local reorganization after neuron loss., Competing Interests: IB, SC, KC, PN No competing interests declared, (© 2023, Bray, Clarke et al.)

Background: Perennial malaria chemoprevention (PMC) is a chemoprevention strategy endorsed by the World Health Organization (WHO) and is increasingly being adopted by National Malaria Programmes. PMC aims to reduce morbidity and mortality caused by malaria and anaemia in in young children through provision of antimalarial drugs at routine contact points with the local health system. This study aims to evaluate the impact of the programmatically-implemented country-tailored PMC programmes targeting children up to two years of age using sulfadoxine-pyrimethamine (SP) on the incidence of malaria and anaemia in children in Cameroon and Côte d'Ivoire., Methods: We will assess the impact of PMC using passive and active monitoring of a prospective observational cohort of children up to 36 months of age at recruitment in selected study sites in Cameroon and Côte d'Ivoire. The primary and secondary outcomes include malaria, anaemia and malnutrition incidence. We will also conduct a time-series analysis of passively detected malaria and anaemia cases comparing the periods before and after PMC introduction. This study is powered to detect a 30% and 40% reduction of malaria incidence compared to the standard of care in Cameroon and Côte d'Ivoire, respectively., Discussion: This multi-country study aims to provide evidence of the effectiveness of PMC targeting children in the first two years of life on malaria and anaemia and will provide important information to inform optimal operationalization and evaluation of this strategy., Trial Registration: Cameroon - NCT05889052; Côte d'Ivoire - NCT05856357., (© 2024. The Author(s).)

Anopheles stephensi is a highly competent urban malaria vector species, endemic in South Asia and the Persian Gulf, which has colonised eight countries in sub-Saharan Africa (SSA) since 2013 and is now spreading uncontrollably. In urban areas of Africa, where malaria transmission has previously been low or non-existent, the invasion of An. stephensi represents a significant problem, particularly to immunologically naïve populations. Despite this rapidly advancing threat, there is a paucity of information regarding the bionomics of An. stephensi in SSA. Here, we offer a critical synthesis of literature from An. stephensi's native range, focusing on the future of An. stephensi in a rapidly urbanising Africa, and highlighting key questions that warrant prioritisation by the global malaria vector control community., Competing Interests: Declaration of interests R. T. is also affiliated with the Medical Entomology and Zoonoses Ecology Team at the UK Health Security Agency, London. The remaining authors have no interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The behavior of fluid interfaces far from equilibrium plays central roles in nature and in industry. Active swimmers trapped at interfaces can alter transport at fluid boundaries with far reaching implications. Swimmers can become trapped at interfaces in diverse configurations and swim persistently in these surface adhered states. The self-propelled motion of bacteria makes them ideal model swimmers to understand such effects. We have recently characterized the swimming of interfacially trapped Pseudomonas aeruginosa PA01 moving in pusher mode. The swimmers adsorb at the interface with pinned contact lines, which fix the angle of the cell body at the interface and constrain their motion. Thus, swimmers become trapped at interfaces in diverse configurations and swim persistently in these surface adhered states. We observe that most interfacially trapped bacteria swim along circular paths. Fluid interfaces also typically form incompressible two-dimensional layers. These effects influence the flow generated by the swimmers. In our previous work, we have visualized the interfacial flow around a pusher bacterium and described the flow field using two dipolar hydrodynamic modes; one stresslet mode whose symmetries differ from those in bulk, and another bulk mode unique to incompressible fluid interfaces. Based on this understanding, swimmer-induced tracer displacements and swimmer-swimmer pair interactions are explored using analysis and experiment. The settings in which multiple interfacial swimmers with circular motion can significantly enhance interfacial transport of tracers or promote mixing of other swimmers on the interface are identified through simulations and compared to experiment. This study shows the importance of biomixing by swimmers at fluid interfaces and identifies important factors in the design of biomimetic active colloids to enhance interfacial transport.

We investigated the substance-specific and cross-substance risk associated with early onset (before age 15) of drunkenness and cannabis use in the subsequent development of alcohol (AUD) and cannabis use disorder (CUD) in Mexican American young adults. Survival analyses employed Cox proportional hazards models for AUD and CUD, separately. In cross-risk analyses, we modeled estimates for those participants reporting lifetime use of both substances. Early onset of drunkenness and early onset of cannabis use were associated with shorter time to AUD and CUD, respectively, even after accounting for psychiatric disorders. While there were no cross-risk associations, adjusting for psychiatric disorders and early onset cannabis use attenuated the association of early drunkenness with AUD.

Ethnic enclave residence is associated with decreased risk for drinking and related problems, but less is known about the mechanisms that explain this association. Informed by theories of social control, we used a multilevel framework to examine whether negative attitudes toward drinking mediated associations between ethnic enclave residence (i.e., neighborhood linguistic isolation) and alcohol outcomes among Mexican American young adults (N = 628) in Southern California. Model 1 assessed mediation effects in the pathways from linguistic isolation to current drinking and alcohol use disorder (AUD). Model 2 adjusted for parental drinking attitudes and neighborhood alcohol availability. There were differential associations by gender in direct effects of linguistic isolation and negative drinking attitudes on both drinking and AUD. Among women only, linguistic isolation was related to greater abstinence and decreased AUD after accounting for social control proxies of parent attitudes and alcohol availability. Young adults' own drinking attitudes did not mediate relationships between linguistic isolation and alcohol outcomes. This study offers evidence on the importance of disaggregating Hispanic national groups by gender to uncover social mechanisms within ethnic enclave settings for tailored supports in reducing risk of drinking and alcohol-related harms., (© 2024 Society for Community Research and Action.)

Background: The first dengue outbreak in Sao Tome and Principe was reported in 2022. Entomological investigations were undertaken to establish the typology of Aedes larval habitats, the distribution of Ae. aegypti and Ae. albopictus, the related entomological risk and the susceptibility profile of Ae. aegypti to insecticides, to provide evidence to inform the outbreak response., Methodology/principal Findings: Entomological surveys were performed in all seven health districts of Sao Tome and Principe during the dry and rainy seasons in 2022. WHO tube and synergist assays using piperonyl butoxide (PBO) and diethyl maleate (DEM) were carried out, together with genotyping of F1534C/V1016I/V410L mutations in Ae. aegypti. Aedes aegypti and Ae. albopictus were found in all seven health districts of the country with high abundance of Ae. aegypti in the most urbanised district, Agua Grande. Both Aedes species bred mainly in used tyres, discarded tanks and water storage containers. In both survey periods, the Breteau (BI > 50), house (HI > 35%) and container (CI > 20%) indices were higher than the thresholds established by WHO to indicate high potential risk of dengue transmission. The Ae. aegypti sampled were susceptible to all insecticides tested except dichlorodiphenyltrichloroethane (DDT) (9.2% mortality, resistant), bendiocarb (61.4% mortality, resistant) and alpha-cypermethrin (97% mortality, probable resistant). A full recovery was observed in Ae. aegypti resistant to bendiocarb after pre-exposure to synergist PBO. Only one Ae. aegypti specimen was found carrying F1534C mutation., Conclusions/significance: These findings revealed a high potential risk for dengue transmission throughout the year, with the bulk of larval breeding occurring in used tyres, water storage and discarded containers. Most of the insecticides tested remain effective to control Aedes vectors in Sao Tome, except DDT and bendiocarb. These data underline the importance of raising community awareness and implementing routine dengue vector control strategies to prevent further outbreaks in Sao Tome and Principe, and elsewhere in the subregion., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kamgang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Detection of del(17p) in myeloma is generally performed by fluorescence in situ hybridization (FISH) on a slide with analysis of up to 200 nuclei. The small cell sample analyzed makes this a low precision test. We report the utility of an automated FISH method, called "immuno-flowFISH", to detect plasma cells with adverse prognostic risk del(17p) in bone marrow and blood samples of patients with myeloma., Methods: Bone marrow (n = 31) and blood (n = 19) samples from 35 patients with myeloma were analyzed using immuno-flowFISH. Plasma cells were identified by CD38/CD138-immunophenotypic gating and assessed for the 17p locus and centromere of chromosome 17. Cells were acquired on an AMNIS ImageStreamX MkII imaging flow cytometer using INSPIRE software., Results: Chromosome 17 abnormalities were identified in CD38/CD138-positive cells in bone marrow (6/31) and blood (4/19) samples when the percent plasma cell burden ranged from 0.03% to 100% of cells. Abnormalities could be identified in 14.5%-100% of plasma cells., Conclusions: The "immuno-flowFISH" imaging flow cytometric method could detect del(17p) in plasma cells in both bone marrow and blood samples of myeloma patients. This method was also able to detect gains and losses of chromosome 17, which are also of prognostic significance. The lowest levels of 0.009% (bone marrow) and 0.001% (blood) for chromosome 17 abnormalities was below the detection limit of current FISH method. This method offers potential as a new means of identifying these prognostically important chromosomal defects, even when only rare cells are present and for serial disease monitoring., (© 2024 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide, but prevalence estimates in former professional athletes are limited., Objectives: HUDDLE (Heart Health: Understanding and Diagnosing Disease by Leveraging Echocardiograms) aimed to raise awareness and estimate the prevalence of CVD and associated risk factors among members of the National Football League (NFL) Alumni Association and their families through education and screening events., Methods: HUDDLE was a multicity, cross-sectional study of NFL alumni and family members aged 50 years and older. Subjects reported their health history and participated in CVD education and screening (blood pressure, electrocardiogram, and transthoracic echocardiogram [TTE] assessments). Phone follow-up by investigators occurred 30 days postscreening to review results and recommendations. This analysis focuses on former NFL athletes., Results: Of 498 participants screened, 57.2% (N = 285) were former NFL players, the majority of whom were African American (67.6%). The prevalence of hypertension among NFL alumni was estimated to be 89.8%, though only 37.5% reported a history of hypertension. Of 285 evaluable participants, 61.8% had structural cardiac abnormalities by TTE. Multivariable analysis showed that hypertension was a significant predictor of clinically relevant structural abnormalities on TTE., Conclusions: HUDDLE identified a large discrepancy between participant self-awareness and actual prevalence of CVD and risk factors, highlighting a significant opportunity for population health interventions. Structural cardiac abnormalities were observed in most participants and were independently predicted by hypertension, affirming the role of TTE for CVD screening in this population aged older than 50 years. (Heart Health: Understanding and Diagnosing Disease by Leveraging Echocardiograms [HUDDLE]; NCT05009589)., Competing Interests: Funding Support and Author Disclosures The HUDDLE trial was sponsored by Edwards Lifesciences, Irvine, California, USA. Drs Okoh and Amponsah have received consulting fees from Edwards Lifesciences. Dr Patel is a proctor for Edwards Lifesciences. Dr Brennan is the team physician for the NFL Tampa Bay Buccaneers. Dr Park is an employee of Edwards Lifesciences. Dr Gunnarsson is an employee of Edwards Lifesciences. Dr Snowden is an employee of Edwards Lifesciences. Dr Mootz is an employee of Edwards Lifesciences. Dr Koepnick is an employee of Edwards Lifesciences. Dr Wheeler is an employee of Edwards Lifesciences. Dr Clarke is an employee of Edwards Lifesciences. Dr Prince is an employee of Edwards Lifesciences. Dr Sannino has received research grants from CardioMech, Cardiovalve, Edwards Lifesciences (including the core lab contract for this study), and Restore Medical. Dr Grayburn has received research grants from Abbott Vascular, CardioMech, Cardiovalve, Edwards Lifesciences (including the core lab contract for this study), Medtronic, Neochord, Restore Medical, and 4C Medical; and has served on the Advisory Board as a consultant for Abbott Vascular, Edwards Lifesciences, Medtronic, and 4C Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess the impact on clinical management, potential for peer learning, and referring physician satisfaction with subspecialist reinterpretations of hepatopancreaticobiliary (HPB) imaging examinations., Materials and Methods: HPB CTs and MRIs from outside hospitals were reinterpreted by two subspecialty radiologists between March 2021 and August 2022. Reinterpretation reports were mailed to radiologists that issued primary reports. The electronic record was reviewed to assess for changes in clinical management based on the reinterpretations (yes/no/unavailable). To assess the potential for peer learning, a survey using a 5-point Likert scale was sent to radiologists who issued primary reports. A separate survey was sent to referring physicians to assess satisfaction with reinterpretations., Results: Two hundred fifty imaging examinations (122 CT, 128 MRI) were reinterpreted at the request of 19 referring physicians. Ninety-six radiologists issued primary reports. RADPEER scores 1-3 were assigned to 131/250 (52%), 86/250 (34%), and 33/250 (13%) examinations, respectively. Of 213 reinterpretations with adequate records for assessment, 75/213 (35%) were associated with a change in management; of these, 71/75 (95%) were classified as RADPEER 2 or 3. Most radiologists agreed or strongly agreed with the following: prefer to receive reinterpretations (34/36, 94%); reinterpretations changed practice of reporting HPB imaging examinations (23/36, 64%); and reinterpretations offer opportunities for peer learning (34/36, 94%). Referring physicians agreed or strongly agreed (7/7, 100%) that reinterpretations are valuable and often change or clarify management of patients with complex HPB disease, and offer an opportunity for peer learning., Conclusion: Radiologists and referring physicians strongly agree that HPB imaging reinterpretations help support peer learning and patient management, respectively., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: The United States (US) continues to experience unprecedented rates of overdose mortality and there is increased need to identify effective harm reduction practices. Research from Canada describes cannabis donation through harm reduction agencies as an adjunctive strategy to mitigate the negative consequences of more harmful drugs. This case study describes the operational logistics, feasibility, and potential benefits of a cannabis donation program that was operated through a harm reduction program in rural Michigan., Case Presentation: We applied a community driven research approach to gather information from harm reduction program staff about the implementation and evolution of cannabis donation efforts in Michigan. We also examined 20-months (September 2021 through May 2023) of administrative data from a cannabis company to compare the sale and donation of cannabis products. Ten cannabis-experienced harm reduction clients received cannabis donations, with clinical staff determining client interest and appropriateness, and providing weekly pick-up or delivery. To expand product availability and sustainability, we examined administrative data from a commercialcannabis company that volunteered to provide donations. This administrative data suggests that while flower products constitute most of the adult and medical sales, edible, oil, and topical products predominated donations. Further, cost analysis suggests that donations represent only 1% of total gross sales and account for much less than the expected yearly donation amount., Conclusions: Research suggests there is potential to reduce alcohol and drug use related harms of more dangerous substances through substitution with cannabis. This case study is the first to document cannabis donation as a harm reduction practice in the US and suggests potential for sustainability dependent on state laws. Findings from this case study provide a starting point for inquiry into cannabis donation as a harm reduction strategy in the US; future research is needed to fully understand the individual-level outcomes, public health impacts, necessary legal regulations, and best practices for cannabis donation programs through harm reduction organizations., (© 2024. The Author(s).)

Multiple myeloma is a plasma cell neoplasm driven by primary (e.g. hyperdiploidy; IGH translocations) and secondary (e.g. 1q21 gains/amplifications; del(17p); MYC translocations) chromosomal events. These are important to detect as they influence prognosis, therapeutic response and disease survival. Currently, cytogenetic testing is most commonly performed by interphase fluorescence in situ hybridisation (FISH) on aspirated bone marrow samples. A number of variations to FISH methodology are available, including prior plasma cell enrichment and incorporation of immunophenotypic plasma cell identification. Other molecular methods are increasingly being utilised to provide a genome-wide view at high resolution (e.g. single nucleotide polymorphism (SNP) microarray analysis) and these can detect abnormalities in most cases. Despite their wide application at diagnostic assessment, both FISH and SNP-array have relatively low sensitivity, limiting their use for identification of prognostically significant low-level sub-clones or for disease monitoring. Next-generation sequencing is increasingly being used to detect mutations and new FISH techniques such as by flow cytometry are in development and may address some of the current test limitations. Here we review the primary and secondary cytogenetic aberrations in myeloma and discuss the range of techniques available for their assessment., Competing Interests: Declaration of competing interest KAF and WNE are inventors of a patent application covering immuno-flowFISH, an imaging flow cytometry FISH technique. SEC declares no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The USA continues to face a fentanyl-driven overdose epidemic. Prior research has demonstrated users of illicit opioids are concerned about fentanyl exposure and overdose, but the strategies they report using to detect fentanyl's presence lack empirical support. This study compares self-report and biologically detected fentanyl use and investigates overdose risk and risk reduction behaviors among a sample of high-risk people who use opioids., Methods: Structured enrollment interviews conducted as part of a larger clinical trial assessed self-reported fentanyl exposure as well as strategies used to determine believed fentanyl exposure and prevent overdose among 240 participants enrolled at a Chicago, IL syringe service program. Urinalysis measured actual fentanyl exposure., Results: Most participants identified as African American (66.7%) and had considerable overdose experience (76.7% lifetime and 48% in the past year). Most also tested positive for fentanyl (93.75%) despite reporting no past year use of fentanyl or fentanyl-adulterated drugs (64.17%). The most utilized approaches reported for identifying fentanyl exposure were stronger effects of the drug (60.7%), sight or taste (46.9%), and being told by someone using the same drugs (34.2%). Few participants (14%) reported using fentanyl test strips. No significant associations were identified between self-report and urinalysis measures or urinalysis results and risk reduction strategies., Conclusion: This study adds to prior fentanyl exposure risk research. The disconnect between participants' fentanyl detection methods and reported overdose experiences supports the need for more research to identify and understand factors driving access and use of overdose prevention resources and strategies., (© 2023. The Author(s).)

Aims: Cytogenetic abnormalities involving the IGH gene are seen in up to 55% of patients with multiple myeloma. Current testing is performed manually by fluorescence in situ hybridisation (FISH) on purified plasma cells. We aimed to assess whether an automated imaging flow cytometric method that uses immunophenotypic cell identification, and does not require cell isolation, can identify IGH abnormalities., Methods: Aspirated bone marrow from 10 patients with multiple myeloma were studied. Plasma cells were identified by CD38 and CD138 coexpression and assessed with FISH probes for numerical or structural abnormalities of IGH . Thousands of cells were acquired on an imaging flow cytometer and numerical data and digital images were analysed., Results: Up to 30 000 cells were acquired and IGH chromosomal abnormalities were detected in 5 of the 10 marrow samples. FISH signal patterns seen included fused IGH signals for IGH/FGFR3 and IGH/MYEOV , indicating t(4;14) and t(11;14), respectively. In addition, three IGH signals were identified, indicating trisomy 14 or translocation with an alternate chromosome. The lowest limit of detection of an IGH abnormality was in 0.05% of all cells., Conclusions: This automated high-throughput immuno-flowFISH method was able to identify translocations and trisomy involving the IGH gene in plasma cells in multiple myeloma. Thousands of cells were analysed and without prior cell isolation. The inclusion of positive plasma cell identification based on immunophenotype led to a lowest detection level of 0.05% marrow cells. This imaging flow cytometric FISH method offers the prospect of increased precision of detection of critical genetic lesions involving IGH and other chromosomal defects in multiple myeloma., Competing Interests: Competing interests: HH, KF and WNE are inventors of a patent application covering the immuno-flowFISH technique. The remaining authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

As a global health problem, antimicrobial resistance (AMR) crosses national borders, leading UN (United Nations) multilateral agencies to call for all countries to improve the stewardship of antibiotics in humans and animals. South American countries have changed their regulations regarding antibiotic use in livestock production. This literature review examines how far the five largest meat-producing countries in South America (Argentina, Brazil, Chile, Colombia, and Uruguay) have come in terms of the relevant legislation. Rules on market entry (marketing authorization and official distribution systems) are already set in all countries examined. Four countries do not allow growth promoters based on critically important antibiotics, and countries have also begun to set guidelines and minimum welfare and biosecurity requirements to reduce the therapeutic demand for antibiotics. Nonetheless, there are aspects related to the distribution, use, and disposal of antibiotics that need to be developed further. In conclusion, legislation in South American countries is moving towards the goals set by UN multilateral agencies, but more can be done. Differences between countries' rules and the gold standards set by the World Organization for Animal Health (OIE), World Health Organization (WHO), and Food and Agriculture Organization of the United Nations (FAO) reveal possible adaptations to the countries' realities. Further studies must examine compliance with the legislation already set and investigate other tools that can be used alongside legislation as a driving force to change stakeholder behaviour.

Poor-quality medicines pose a significant challenge for health systems in low- to middle-income countries (LMICs),with recent deaths in multiple countries following ingestion of substandard cough syrups emphasising the need for quality-assurance of medicines in our increasingly interconnected global markets. Research also suggests that the source (country of manufacture) and type of medicine (generic/brand) are perceived to be associated with medicine quality. This study explores perceptions of medicines quality among national stakeholders of a medicines quality assurance system (MQAS) in sub-Saharan Africa. Through semi-structured interviews (n = 29) with managers from organisations responsible for the MQAS, public-sector doctors and nurses, and regulated private-sector pharmacists in three urban centres in Senegal in 2013. A thematic approach to analysis was undertaken with themes organised under three main categories, the source of drugs, the type of medicine, and medicines storage. A key emerging theme was the perception of the inferior quality of generic medicines, especially those produced in Asia and Africa, as they were lower in cost and thus believed to be less effective in alleviating symptoms than their brand versions. Medicines in Senegal's less regulated (informal) street markets were also thought to be of poor-quality as they were not subjected to national regulatory processes or stored appropriately, resulting in exposure to direct sunlight and high temperatures. In contrast, the interviewees expressed confidence in medicines quality within the regulated sectors (public and private retail pharmacies) attributed to stringent national medicines regulation, secure medicines supply chains and adequate technical capacity to survey and analyse for medicines quality. Also, the views expressed typically described a medicine's quality in terms of its effectiveness in alleviating the symptoms of ill health (efficacy of a medicine).These perceptions may have implications for developing national medicines policy, the procurement and supply of affordable medicines and consumers' decision-making when purchasing medicines. Indeed, a proclivity for supplying and purchasing more expensive brand medicines may act as a barrier to accessing essential medicines., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lalani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The medicines retail sector is an essential element of many health systems in Africa and Asia, but it is also well known for poor practice. In the literature, it is recognised that improvements in the sector can only be made if more effective forms of governance and regulation can be identified. Recent debate suggests that interventions responsive to structural constraints that shape and underpin poor practice is a useful way forward. This paper presents data from a mixed-methods study conducted to explore regulation and the professional, economic and social constraints that shape rule breaking among drug shops in one district in Uganda. Our findings show that regulatory systems are undermined by frequent informal payments, and that although drug shops are often run by qualified staff, many are unlicensed and sell medicines beyond their legal permits. Most shops have either a small profit or a loss and rely on family and friends for additional resources as they compete in a highly saturated market. We argue that in the current context, drug shop vendors are survivalist entrepreneurs operating in a market in which it is extremely difficult to abide by policy, remain profitable and provide a service to the community. Structural changes in the medicines market, including removing unqualified sellers and making adjustments to policy are likely prerequisite if drug shops are to become places where individuals can earn a living, abide by the rules and facilitate access to medicines for people living in some of the world's poorest countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Groin and neck injections are generally a last resort for people who inject drugs (PWID) who do not have easy access to functioning veins. These alternative injection practices can lead to an increased likelihood of adverse health outcomes. There is still much we do not know about groin and neck injections among PWID in the US, as the literature to-date comes from studies primarily focused on groin injections outside the US. We assessed prevalence, predictors, and associated behaviors of neck injection through a survey fielded in San Francisco, California, US., Methods: The sample comes from a longitudinal observational study that used targeted sampling to recruit PWID in San Francisco. The current study sample includes 239 PWID who completed their 12-month survey between June 2019 and June 2020., Results: About a third of the sample reported injecting in their neck in the past 30 days, with the most common reason being lack of available veins. Age, past 6-month abscess / soft tissue infection, and past 30-day use of opioids mixed with cocaine were significantly associated with past 30-day neck injection in the final multivariate model. Past 30-day neck injection was also significantly associated with being injected by another person in the past 30 days., Conclusions: PWID at higher risk for vein deterioration were more likely to inject into their neck. Harm reduction strategies such as safer injection counseling, safe smoking supplies, use of "street doctors," and safe consumption sites may reduce instances of neck injection and/or associated health risks., Competing Interests: Declaration of Competing Interest No author has any conflicts to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Prostate cancer is the most common malignancy and the third most common cause of death in Canadian men. In light of evolving diagnostic pathways for prostate cancer and the increased use of MRI, which now includes its use in men prior to biopsy, the Canadian Association of Radiologists established a Prostate MRI Working Group to produce a white paper to provide recommendations on establishing and maintaining a Prostate MRI Programme in the context of the Canadian healthcare system. The recommendations, which are based on available scientific evidence and/or expert consensus, are intended to maintain quality in image acquisition, interpretation, reporting and targeted biopsy to ensure optimal patient care. The paper covers technique, reporting, quality assurance and targeted biopsy considerations and includes appendices detailing suggested reporting templates, quality assessment tools and sample image acquisition protocols relevant to the Canadian healthcare context.

BACKGROUND. The clear cell likelihood score (ccLS) has been proposed for the noninvasive differentiation of clear cell renal cell carcinoma (ccRCC) from other renal neoplasms on multiparametric MRI (mpMRI), though further external validation remains needed. OBJECTIVE. The purpose of our study was to evaluate the diagnostic performance and interreader agreement of the ccLS version 2.0 (v2.0) for characterizing solid renal masses as ccRCC. METHODS. This retrospective study included 102 patients (67 men, 35 women; mean age, 56.9 ± 12.8 [SD] years) who underwent mpMRI between January 2013 and February 2018, showing a total of 108 (≥ 25% enhancing tissue) solid renal masses measuring 7 cm or smaller (83 cT1a [≤ 4 cm] and 25 cT1b [> 4 cm and ≤ 7 cm]), all with a histologic diagnosis. Three abdominal radiologists independently reviewed the MRI examinations using ccLS v2.0. Median reader sensitivity, specificity, and accuracy were computed for predicting ccRCC by ccLS of 4 or greater, and individual reader AUCs were derived. The percentage of masses that were ccRCC was calculated, stratified by ccLS. Interobserver agreement was assessed by the Fleiss kappa statistic. RESULTS. The sample included 45 ccRCCs (34 cT1a, 11 cT1b), 30 papillary renal cell carcinomas (RCCs), 13 chromophobe RCCs, 14 oncocytomas, and six fat-poor angiomyolipomas. Median reader sensitivity, specificity, and accuracy for predicting ccRCC by ccLS of 4 or greater were 85%, 82%, and 83% among cT1a masses and 82%, 100%, and 92% among cT1b masses. The three readers' AUCs for predicting ccRCC by ccLS for cT1a masses were 0.90, 0.84, and 0.89 and for cT1b masses were 0.99, 0.97, and 0.92. Across readers, the percentage of masses that were ccRCC among cT1a masses was 0%, 0%, 20%, 68%, and 93% for ccLS of 1, 2, 3, 4, and 5, respectively; among cT1b masses, the percentage of masses that were ccRCC was 0%, 0%, 32%, 90%, and 100% for ccLS of 1, 2, 3, 4, and 5, respectively. Interobserver agreement among cT1a and cT1b masses for ccLS of 4 or greater was 0.82 and 0.83 and for ccLS of 1-5 overall was 0.65 and 0.62, respectively. CONCLUSION. This study provides external validation of the ccLS, finding overall high measures of diagnostic performance and interreader agreement. CLINICAL IMPACT. The ccLS provides a standardized approach to the noninvasive diagnosis of ccRCC by MRI.

Background: Non-alcoholic fatty liver disease (NAFLD) is increasingly common worldwide and can lead to the development of cirrhosis, liver failure and cancer. Virtual magnetic resonance elastography (VMRE), which is based on a shifted apparent diffusion coefficient (sADC), is a potential noninvasive method to assess liver fibrosis without the specialized hardware and expertise required to implement traditional MR elastography (MRE). Although hepatic steatosis is known to confound ADC measurements, previous studies using VMRE have not corrected for hepatic fat fraction., Purpose: To compare VMRE, corrected for the confounding effects of unsuppressed fat signal, to MRE and biopsy in subjects with suspected NAFLD., Study Type: Prospective, cross-sectional., Population: A total of 49 adult subjects with suspected NAFLD (18 male; median age 55 years, range 33-74 years) who underwent liver biopsy., Field Strength/sequence: 3T, diffusion-weighted spin echo planar, chemical-shift encoded (IDEAL IQ) and MRE sequences., Assessment: Two observers drew regions of interest on sADC, proton density fat fraction and MRE-derived stiffness maps. Fat-corrected sADC values were used to calculate the diffusion-based shear modulus according to the VMRE method. Predicted fibrosis stage for MRE and VMRE was determined using previously published cut-off values., Statistical Tests: The relationship between VMRE and MRE was assessed with least-squares linear regression (coefficient of determination, R 2 ). Agreement between MRE and VMRE-predicted fibrosis stage was evaluated with a kappa coefficient and accuracy compared using McNemar's test. A one-way ANOVA determined if the fat-corrected sADC (VMRE) and MRE differed by fibrosis stage. A P value < 0.05 was considered statistically significant., Results: Least squares regression of VMRE vs. MRE revealed R 2  = 0.046 and a slope that was not significantly different from zero (P = 0.14). There was no agreement between MRE and VMRE-predicted fibrosis stage (kappa = -0.01). The proportion of correctly predicted fibrosis stage was significantly higher for MRE compared to VMRE. MRE was significantly associated with fibrosis stage, but fat-corrected sADC was not (P = 0.24)., Data Conclusion: Fat-corrected VMRE was not associated with fibrosis stage in NAFLD. Further investigation is required if VMRE is to be considered in subjects with NAFLD., Evidence Level: 1 TECHNICAL EFFICACY: Stage 2., (© 2022 International Society for Magnetic Resonance in Medicine.)

The airway epithelium is a protective barrier that is maintained by the self-renewal and differentiation of basal stem cells. Increasing age is a principle risk factor for chronic lung diseases, but few studies have explored age-related molecular or functional changes in the airway epithelium. We retrieved epithelial biopsies from histologically normal tracheobronchial sites from pediatric and adult donors and compared their cellular composition and gene expression profile (in laser capture-microdissected whole epithelium, fluorescence-activated cell-sorted basal cells, and basal cells in cell culture). Histologically, pediatric and adult tracheobronchial epithelium was similar in composition. We observed age-associated changes in RNA sequencing studies, including higher interferon-associated gene expression in pediatric epithelium. In cell culture, pediatric cells had higher colony formation ability, sustained in vitro growth, and outcompeted adult cells in a direct competitive proliferation assay. Our results demonstrate cell-intrinsic differences between airway epithelial cells from children and adults in both homeostatic and proliferative states., Competing Interests: The authors declare no competing interests relating to this manuscript. S.M.J. has attended advisory boards for Johnson and Johnson, BARD1 Life Sciences, and AstraZeneca. S.M.J. receives grant funding from GRAIL Inc. and Owlstone Medical., (© 2022 The Authors.)

Antibiotic use in animal agriculture contributes significantly to antibiotic use globally and is a key driver of the rising threat of antibiotic resistance. It is becoming increasingly important to better understand antibiotic use in livestock in low-and-middle income countries where antibiotic use is predicted to increase considerably as a consequence of the growing demand for animal-derived products. Antibiotic crossover-use refers to the practice of using antibiotic formulations licensed for humans in animals and vice versa. This practice has the potential to cause adverse drug reactions and contribute to the development and spread of antibiotic resistance between humans and animals. We performed secondary data analysis of in-depth interview and focus-group discussion transcripts from independent studies investigating antibiotic use in agricultural communities in Uganda, Tanzania and India to understand the practice of antibiotic crossover-use by medicine-providers and livestock-keepers in these settings. Thematic analysis was conducted to explore driving factors of reported antibiotic crossover-use in the three countries. Similarities were found between countries regarding both the accounts of antibiotic crossover-use and its drivers. In all three countries, chickens and goats were treated with human antibiotics, and among the total range of human antibiotics reported, amoxicillin, tetracycline and penicillin were stated as used in animals in all three countries. The key themes identified to be driving crossover-use were: (1) medicine-providers' and livestock-keepers' perceptions of the effectiveness and safety of antibiotics, (2) livestock-keepers' sources of information, (3) differences in availability of human and veterinary services and antibiotics, (4) economic incentives and pressures. Antibiotic crossover-use occurs in low-intensity production agricultural settings in geographically distinct low-and-middle income countries, influenced by a similar set of interconnected contextual drivers. Improving accessibility and affordability of veterinary medicines to both livestock-keepers and medicine-providers is required alongside interventions to address understanding of the differences between human and animal antibiotics, and potential dangers of antibiotic crossover-use in order to reduce the practice. A One Health approach to studying antibiotic use is necessary to understand the implications of antibiotic accessibility and use in one sector upon antibiotic use in other sectors.

Forkhead box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and pediatric cancer samples and found FOXR2 to be aberrantly upregulated in 70% of all cancer types and 8% of all individual tumors. The majority of tumors (78%) aberrantly expressed FOXR2 through a previously undescribed epigenetic mechanism that involves hypomethylation of a novel promoter, which was functionally validated as necessary for FOXR2 expression and proliferation in FOXR2-expressing cancer cells. FOXR2 promoted tumor growth across multiple cancer lineages and co-opted ETS family transcription circuits across cancers. Taken together, this study identifies FOXR2 as a potent and ubiquitous oncogene that is epigenetically activated across the majority of human cancers. The identification of hijacking of ETS transcription circuits by FOXR2 extends the mechanisms known to active ETS transcription factors and highlights how transcription factor families cooperate to enhance tumorigenesis., Significance: This work identifies a novel promoter that drives aberrant FOXR2 expression and delineates FOXR2 as a pan-cancer oncogene that specifically activates ETS transcriptional circuits across human cancers. See related commentary by Liu and Northcott, p. 2977., (©2022 The Authors; Published by the American Association for Cancer Research.)

In many countries, when health systems are examined from the bottom up medicine sellers emerge as critical actors providing care and access to commodities. Despite this, these actors are for the most part excluded from health systems and policy research. In this paper, we ask 'what happens to the conceptualisations of a health system when medicine sellers and their practices are foregrounded in research?' We respond by arguing that these sellers sit uncomfortably in the mechanical logic in which health systems are imagined as bounded institutions, tightly integrated and made up of intertwined and interconnected spaces, through which policies, ideas, capital and commodities flow. They challenge the functionalist holism that runs through the complex adaptive systems (CAS) approach. We propose that health systems are better understood as social fields in which unequally positioned social agents (the health worker, managers, patients, carers, citizens, politicians) compete and cooperate over the same limited resources. We draw on ethnographic research from Uganda (2018-2019) to analyse the responses of different actors to a new policy that sought to rationalise the medicines retail sector and exclude drug shops from urban centres. We examine the emergence of new lobby groups who contested the policy and secured the rights of 'drug shop vendors' to trade on the basis that these shops are increasingly populated by trained nurses and clinical officers, who are surplus to the capacity of the formal health system and so look to markets to make a living. The paper adds to the growing anthropological literature on health systems that allows for a focus on social change and a form of holism that enables phenomena to be connected to diverse elements of the context in which they emerge., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of cancer deaths worldwide, and is preceded by the appearance of progressively disorganised pre-invasive lesions in the airway epithelium. Yet the biological mechanisms underlying progression of pre-invasive lesions into invasive LUSC are not fully understood. LRIG1 (leucine-rich repeats and immunoglobulin-like domains 1) is downregulated in pre-invasive airway lesions and invasive LUSC tumours and this correlates with decreased lung cancer patient survival., Methods and Results: Using an Lrig1 knock-in reporter mouse and human airway epithelial cells collected at bronchoscopy, we show that during homeostasis LRIG1 is heterogeneously expressed in the airway epithelium. In basal airway epithelial cells, the suspected cell of origin of LUSC, LRIG1 identifies a subpopulation of progenitor cells with higher in vitro proliferative and self-renewal potential in both the mouse and human. Using the N-nitroso-tris-chloroethylurea (NTCU)-induced murine model of LUSC, we find that Lrig1 loss-of-function leads to abnormally high cell proliferation during the earliest stages of pre-invasive disease and to the formation of significantly larger invasive tumours, suggesting accelerated disease progression., Conclusion: Together, our findings identify LRIG1 as a marker of basal airway progenitor cells with high proliferative potential and as a regulator of pre-invasive lung cancer progression. This work highlights the clinical relevance of LRIG1 and the potential of the NTCU-induced LUSC model for functional assessment of candidate tumour suppressors and oncogenes., Competing Interests: Conflict of interest: L. Succony reports grants from Wellcome Trust and Cancer Research UK, during the conduct of the study. Conflict of interest: S. Gómez-López reports grants (Newton International Fellowship) from The Royal Society, during the conduct of the study. Conflict of interest: A. Pennycuick reports grants (reference 211161/Z/18/Z) from Wellcome Trust, during the conduct of the study; and has a United Kingdom patent application number 1819452.2 pending. Conflict of interest: A.S.N. Alhendi has nothing to disclose. Conflict of interest: D. Davies has nothing to disclose. Conflict of interest: S.E. Clarke reports grants from NIHR UCLH BRC, during the conduct of the study. Conflict of interest: K.H.C. Gowers has nothing to disclose. Conflict of interest: N.A. Wright reports grants from Cancer Research UK, outside the submitted work. Conflict of interest: K.B. Jensen has nothing to disclose. Conflict of interest: S.M. Janes reports grants from Wellcome, during the conduct of the study; personal fees for advisory board work from Jansen and AstraZeneca, grants from GRAIL Inc., outside the submitted work., (Copyright ©The authors 2022.)

Objectives: To evaluate the interobserver agreement between radiologists using the Ultrasound Liver Reporting And Data System (US LI-RADS) visualization score and assess association between visualization score and cause of liver disease, sex, and body mass index (BMI)., Methods: This retrospective, single institution, cross-sectional study evaluated 237 consecutive hepatocellular carcinoma surveillance US examinations between March 4, 2017 and September 4, 2017. Five abdominal radiologists independently assigned a US LI-RADS visualization score (A, no or minimal limitations; B, moderate limitations; C, severe limitations). Interobserver agreement was assessed with a weighted Kappa statistic. Association between US visualization score (A vs B or C) and cause of liver disease, sex, and BMI (< or ≥ 25 kg/m 2 ) was evaluated using univariate and multivariate analyses., Results: The average weighted Kappa statistic for all raters was 0.51. A score of either B or C was assigned by the majority of radiologists in 148/237 cases and was significantly associated with cause of liver disease ( P = 0.014) and elevated BMI ( P < 0.001). Subjects with viral liver disease were 3.32 times (95% CI: 1.44-8.38) more likely to have a score of A than those with non-alcoholic steatohepatitis ( P = 0.007). The adjusted odds ratio of visualization score A was 0.249 (95% CI: 0.13-0.48) among those whose BMI was ≥25 kg/m 2 vs. BMI < 25 kg/m 2 ., Conclusion: Interobserver agreement between radiologists using US LI-RADS score was moderate. The majority of US examinations were scored as having moderate or severe limitations, and this was significantly associated with non-alcoholic steatohepatitis and increased BMI.

The use of magnetic resonance imaging (MRI) during pregnancy is associated with concerns among patients and health professionals with regards to fetal safety. In this work, the Canadian Association of Radiologists (CAR) Working Group on MRI in Pregnancy presents recommendations for the use of MRI in pregnancy, derived from literature review as well as expert panel opinions and discussions. The working group, which consists of academic subspecialty radiologists and obstetrician-gynaecologists, aimed to provide updated, evidence-based recommendations addressing safety domains related to energy deposition, acoustic noise, and gadolinium-based contrast agent use based on magnetic field strength (1.5T and 3T) and trimester scanned, in addition to the effects of sedative use and occupational exposure.

Background: North America continues to face an opioid overdose epidemic, driven by persistent increases in illicit fentanyls and fluctuations in potency leading to uncertainty for consumers. This qualitative study was conducted to better understand how people who inject drugs (PWID) came to recognize fentanyl as a growing adulterant of heroin and the subsequent sensory discernment strategies they employed to continue injecting. Our main objective was to investigate how observations and knowledge are combined as homegrown techniques for detecting fentanyl and minimizing risk. Secondary objectives were to examine the impact of growing fentanyl adulteration on individual drug use behavior., Methods: Between April and May 2019, 28 PWID (18 men, 10 women; average age = 38.43 years, SD = 9.26) were purposely recruited from a needle services program in Greensboro, North Carolina. Study participants were interviewed in-person using a qualitative, semi-structured instrument. Interviews were analyzed with a general inductive approach using NVivo12., Results: Participants described methods for detecting fentanyl in illicit opioids. Sudden increases in the potency of the 'rush' and sharp decreases in the length of the 'high' were chief indicators along with changes in drug color and texture. Heavy sedation was associated with fentanyl use and histamine-releasing effects characterized as 'pins and needles' were ascribed to injecting fentanyl as a component of the rush. Fentanyl's short high helped explain higher injection frequency and heavy sedation was the leading reason for co-using fentanyl with cocaine/crack or methamphetamine., Conclusion: PWID have the capacity to recognize changes to the illicit opioid supply. Study participants navigated unpredictable fluctuations in the illicit opioid market by employing homegrown discernment techniques, modifying drug use behavior, and co-using non-opioid drugs. Researchers and policymakers should involve PWID as subject matter experts to help modernize harm reduction for the fentanyl age with practical strategies to boost resiliency and save lives., Competing Interests: Declarations of Interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Multiparametric MRI (mp-MRI) is a widely used tool for diagnosing and staging prostate cancer. The purpose of this study was to evaluate whether transfer learning, unsupervised pre-training and test-time augmentation significantly improved the performance of a convolutional neural network (CNN) for pixel-by-pixel prediction of cancer vs. non-cancer using mp-MRI datasets., Methods: 154 subjects undergoing mp-MRI were prospectively recruited, 16 of whom subsequently underwent radical prostatectomy. Logistic regression, random forest and CNN models were trained on mp-MRI data using histopathology as the gold standard. Transfer learning, unsupervised pre-training and test-time augmentation were used to boost CNN performance. Models were evaluated using Dice score and area under the receiver operating curve (AUROC) with leave-one-subject-out cross validation. Permutation feature importance testing was performed to evaluate the relative value of each MR contrast to CNN model performance. Statistical significance (p<0.05) was determined using the paired Wilcoxon signed rank test with Benjamini-Hochberg correction for multiple comparisons., Results: Baseline CNN outperformed logistic regression and random forest models. Transfer learning and unsupervised pre-training did not significantly improve CNN performance over baseline; however, test-time augmentation resulted in significantly higher Dice scores over both baseline CNN and CNN plus either of transfer learning or unsupervised pre-training. The best performing model was CNN with transfer learning and test-time augmentation (Dice score of 0.59 and AUROC of 0.93). The most important contrast was apparent diffusion coefficient (ADC), followed by Ktrans and T2, although each contributed significantly to classifier performance., Conclusions: The addition of transfer learning and test-time augmentation resulted in significant improvement in CNN segmentation performance in a small set of prostate cancer mp-MRI data. Results suggest that these techniques may be more broadly useful for the optimization of deep learning algorithms applied to the problem of semantic segmentation in biomedical image datasets. However, further work is needed to improve the generalizability of the specific model presented herein., Competing Interests: Conflict of Interest Drs. Guida, Bowen, Beyea and Clarke acknowledge research funding and support from GE Healthcare., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We performed an X-ray crystallographic study of complexes of protein kinase PIM-1 with three inhibitors comprising an adenosine mimetic moiety, a linker, and a peptide-mimetic (d-Arg) 6 fragment. Guided by the structural models, simplified chemical structures with a reduced number of polar groups and chiral centers were designed. The developed inhibitors retained low-nanomolar potency and possessed remarkable selectivity toward the PIM kinases. The new inhibitors were derivatized with biotin or fluorescent dye Cy5 and then applied for the detection of PIM kinases in biochemical solutions and in complex biological samples. The sandwich assay utilizing a PIM-2-selective detection antibody featured a low limit of quantification (44 pg of active recombinant PIM-2). Fluorescent probes were efficiently taken up by U2OS cells and showed a high extent of co-localization with PIM-1 fused with a fluorescent protein. Overall, the developed inhibitors and derivatives represent versatile chemical tools for studying PIM function in cellular systems in normal and disease physiology.

Background: The United States (U.S.) continues to witness an unprecedented increase in opioid overdose deaths driven by precipitous growth in the supply and use of illicitly-manufactured fentanyls (IMF). Fentanyl's growing market share of the illicit opioid supply in the U.S. has led to seismic shifts in the composition of the country's heroin supply. The growth in fentanyl supply has transformed illicit opioid markets once offering heroin with fairly consistent purity and potency to a supply overpopulated with fentanyl(s) of inconsistent and unpredictable potency. In response, people who inject drugs (PWID) have developed a number of sensory strategies to detect fentanyl in illicit opioids. The current study examined the accuracy of sensory discernment strategies by measuring study participants' descriptions of the last opioid injected and checked with a fentanyl test strip (FTS) by that test's positive/negative result. The primary objective was to determine associations between FTS results and descriptions of the illicit opioid's physical appearance and physiological effects., Methods: Between September-October 2017, a total of 129 PWID were recruited from a syringe services program in Greensboro, North Carolina and completed an online survey about their most recent use of FTS. Participants were instructed to describe the appearance and effects associated with the most recent opioid they injected and tested with FTS. We conducted bivariate and multivariate analyses to determine differences in positive vs negative FTS results and the physical characteristics and physiological experiences reported. An exploratory analysis was also conducted to describe the types and bodily locations of unusual sensations experienced by PWID reporting positive FTS results., Results: For physical characteristics, 32% reported that the drug was white before adding water and 38% reported the solution was clear after adding water. For physiological effects compared to heroin, 42% reported a stronger rush, 30% a shorter high, 30% a shorter time to the onset of withdrawal symptoms, and 42% experienced unusual sensations. In the multivariable model adjusting for demographics and polydrug correlates, white color of drug before adding water, stronger rush, shorter time to withdrawal, and unusual sensations were significantly associated with a positive FTS result. The most common unusual sensations were pins and needles (51%), warming of the head and face (35%), and lightheadedness (30%), and the most common locations where sensations occurred were face and neck (61%), arms/legs (54%), and chest (37%)., Conclusion: We found positive FTS results were significantly associated with the physical characteristics and physiological effects described by PWID. Descriptions concerning physical appearance were consistent with law enforcement profiles of illicitly-manufactured fentanyl and physiological effects were concomitant with scientific and clinical medical literature on iatrogenic fentanyl use. Taken together, these findings suggest sensory strategies for detecting fentanyl in illicit opioids may be an effective risk reduction tool to help consumers navigate unpredictable markets more safely., Competing Interests: Declarations of Interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)