bluuebunny/crossref_metadata_2025 huggingface dataset:
NLRP3 Inflammasome, NEK7 and Major Depressive Disorder
Authors: Ozel Fatih , Ozturk Bilge Targitay , Yaras Tutku , Ekinci Burcu , Oktay Yavuz , Alkin Tunc , Aysevener Elif Onur , Direk Nese
Published: July 2022

Background

Association between inflammation and depression has been known for a long time. Activation of pro-inflammatory molecular complexes such as inflammasomes in depression was suggested as the most relevant hypothesis among many others. Psychological stress is considered to cause sterile inflammation through inflammasomes, and the NLRP3 inflammasome was proposed as a crucial molecule for the pro-inflammatory response in depression.

Objective

In the current study, we aimed to explore the relationship of NLRP3 inflammasome and its regulatory protein NEK7 with major depressive disorder in a drug naïve study sample.

Methods

In total 58 patients with major depressive disorder and 58 age and gender-matched healthy persons were included. The mRNA expressions of NLRP3, ASC, caspase-1 and NEK7 coding proteins were evaluated with quantitative PCR, plasma IL-1β levels were detected by ELISA.

Results

Patients with major depressive disorder had higher gene expressions of NLRP3 (p= 0.03) and ASC (p= 0.002) compared to healthy persons. Higher gene expressions of NLRP3 (OR= 1.17, 95% CI= 1.01, 1.37, p= 0.04), ASC (OR= 1.45, 95% CI= 1.15, 1.82, p= 0.002) and NEK7 (OR= 1.33, 95% CI= 1.08, 1.63, p= 0.007) were related to the increased likelihood of having major depressive disorder.

Conclusion

The results of this study support the role of NLRP3 inflammasome in the increased risk for major depressive disorder.
Isolated correlates of somatosensory perception in the mouse posterior cortex
Authors: Sokoletsky Michael , Ungarish David , Katz Yonatan , Lampl Ilan
Published: July 2022

To uncover the neural correlates of stimulus perception, experimenters commonly use tasks in which subjects are repeatedly presented with a weak stimulus and instructed to report, via movement, if they perceived the stimulus. The difference in neural activity between reported stimulus (hit) and unreported stimulus (miss) trials is then seen as potentially perception-related. However, recent studies found that activity related to the report spreads throughout the brain, calling into question to what extent such tasks conflate perception-related activity with report-related activity. To isolate perception-related activity, we developed a paradigm in which the same mice were trained on both a regular go/no-go whisker stimulus detection task and a reversed contingencies version, in which they reported the absence of a whisker stimulus. By comparing no-report trials across the two tasks, we located perception-related activity within a posterior network of cortical regions contralateral to the stimulus. In addition, we found this activity was on average an order of magnitude lower than report-related activity and began after the low-level stimulus response. In summary, our study revealed the mouse cortical areas associated with the perception of a sensory stimulus independently of a perceptual report.
Genomic islands of divergence betweenDrosophila yakubasubspecies predominantly overlap with chromosomal inversions
Authors: Ferreira Erina A. , Moore Cathy C. , Ogereau David , Suwalski Arnaud , Prigent Stéphane R. , Rogers Rebekah L. , Yassin Amir
Published: July 2022

During the early stages of local adaptation and speciation, genetic differences tend to accumulate at certain regions of the genome leading to the formation of genomic islands of divergence (GIDs). This pattern may be due to selection and/or difference in the rate of recombination. Here, we investigate the possible causes of GIDs inDrosophila yakuba mayottensis, and reconfirm using field collection its association with toxic noni (Morinda citrifolia) fruits on the Mayotte island. Population genomics revealed lack of genetic structure on the island and identified 20 GIDs distinguishingD. y. mayottensisfrom generalist mainland populations ofD. y. yakuba. The GIDs were enriched with gene families involved in the metabolism of lipids, sugars, peptides and xenobiotics, suggesting a role in host shift. We assembled a new genome forD. y. mayottensisand identified five novel chromosomal inversions. Twelve GIDs (∼72% of outlier windows) fell close to or within subspecies-specific inversions. However, three GIDs were in collinear, high recombining regions indicating strong signal of hard selective sweeps. UnlikeD. y. mayottensis,D. sechellia, the only other noni-specialist, is homosequential with its generalist relatives. Thus, both selection and rearrangements shape GIDs and striking convergences can occur between species with distinct genomic architectures.
Reciprocal regulation between cell mechanics and ZO-1 guides tight junction assembly and epithelial morphogenesis
Authors: Haas Alexis J. , Zihni Ceniz , Krug Susanne M. , Maraspini Riccardo , Otani Tetsuhisa , Furuse Mikio , Honigmann Alf , Balda Maria , Matter Karl
Published: July 2022

Formation and maintenance of tissue barriers require the coordination of cell mechanics and cell-cell junction assembly. Here, we combined methods to modulate ECM stiffness and to measure mechanical forces on adhesion complexes to investigate how tight junctions regulate cell mechanics and epithelial morphogenesis. We found that depletion of the tight junction adaptor ZO-1 regulates cytoskeletal tension at cell-matrix and cell-cell interfaces in an ECM stiffness-regulated manner, possibly via differential organisation of the actin cytoskeleton. ZO-1 depletion inhibited junction assembly and disrupted morphogenesis in an ECM stiffness-dependent manner. Both processes were rescued by inhibition of cell contractility. Although ZO-1-deficient cells could assemble functional barriers at low tension, their tight junctions remained corrupted with strongly reduced and discontinuous recruitment of junctional components. Our results thus reveal that reciprocal regulation between ZO-1 and cell mechanics controls tight junction assembly and epithelial morphogenesis, and that tension-independent roles of ZO-1 control proper junction organisation.
Targeting c-Jun is a potential therapy of luminal breast cancer bone metastasis
Authors: Han Yuxuan , Futakuchi Mitsuru , Nakamichi Kazuya , Wakabayashi Yutaro , Sakamoto Mai , Nakayama Jun , Semba Kentaro
Published: July 2022

Luminal breast cancer has the highest bone metastasis frequency among all breast cancer subtypes, but its metastatic mechanism has not been elucidated because of the lack of appropriate metastatic cell lines. The study aim was to characterize high-osteolytic bone metastatic MCF7-BM cell lines and extract c-Jun, a novel bone metastasis marker. We found that c-Jun was upregulated in MCF7-BM cells, and its deficiency was associated with suppression of the cell migration, transformation, and stemness of BM cells. In vivo, c-Jun-deficient MCF7-TAM67 cells exhibited weaker bone metastatic ability. Additionally, c-Jun overexpression in MCF7-BM cells led to a tumor-migration promotion cycle in the bone microenvironment possibly by enhancing calcium-induced migration and releasing the osteoclast activator BMP5. Inhibition of c-Jun by JNK-IN-8, a JNK inhibitor, effectively reduced tumorigenesis activities and bone metastatic tumors. Our results indicate the potential benefits of a therapy that targets c-Jun to prevent or minimize luminal breast cancer bone metastasis.
AGO2 silences mobile transposons in the nucleus of quiescent cells
Authors: Sala Laura , Chandrasekhar Srividya , Cosby Rachel L. , La Rocca Gaspare , Macfarlan Todd S. , Awasthi Parirokh , Chari Raj , Kruhlak Michael , Vidigal Joana A.
Published: July 2022

Argonaute 2 (AGO2) is a cytoplasmic component of the miRNA pathway with essential roles in development and disease. Yet, little is known about its regulationin vivo. Here, we show that in quiescent mouse splenocytes, AGO2 localizes almost exclusively to the nucleus. AGO2 subcellular localization is modulated by the Pi3K-AKT-mTOR pathway, a well-established regulator of quiescence. Signaling through this pathway in proliferating cells promotes AGO2 cytoplasmic accumulation, at least in part by stimulating the expression of TNRC6, an essential AGO2 binding partner in the miRNA pathway. In quiescent cells where mTOR signaling is low, AGO2 accumulates in the nucleus where it binds to young mobile transposons co-transcriptionally to repress their expression via its catalytic domain. Our data point to an essential but previously unrecognized nuclear role for AGO2 during quiescence as part of a genome-defense system against young mobile elements and provide evidence of RNA interference in the soma of mammals.
In silico repurposed drugs against monkeypox virus
Authors: Lam Hilbert Yuen In , Guan Jia Sheng , Mu Yuguang
Published: July 2022

Monkeypox is an emerging epidemic of concern. The disease is caused by the monkeypox virus and an increasing global incidence with a 2022 outbreak that has spread to Europe amid the COVID-19 pandemic. The new outbreak is associated with novel, previously undiscovered mutations a nd variants. Currently the US Food and Drug Administration (FDA) approved poxvirus treatment involves use of tecovirimat. However, there is limited pharmacopoeia otherwise, and limited research interest in monkeypox. In this study, virtual screening and molecular dynamics were employed to explore the potential repurposing of multiple drugs previously approved by the FDA or other jurisdictions for other applications. Several drugs are predicted to tightly bind to viral proteins which are crucial in viral replication, including molecules which show high potential for binding the monkeypox D13L capsid protein, whose inhibition has previously been demonstrated to suppress viral replication.
Phyllosphere exudates select for distinct microbiome members in sorghum epicuticular wax and aerial root mucilage
Authors: Mechan-Llontop Marco E. , Mullet John , Shade Ashley
Published: July 2022

Phyllosphere exudates create specialized microhabitats that shape microbial community diversity. Here, we explore the microbiome associated with two sorghum phyllosphere exudates, the epicuticular wax and aerial root mucilage. We hypothesized that these exudates selectively enrich for microbiome members that support host resilience to stress. Thus, we assessed the microbiome associated with the epicuticular wax from sorghum plants under non-limiting and limiting water conditions, and the aerial root mucilage from nitrogen-fertilized and non-fertilized plants. In parallel, we isolated and characterized hundreds of bacteria from wax and mucilage, and integrated data from cultivation-independent and -dependent approaches to gain deeper insights into phyllosphere functions and phenotypes. We found thatSphingomonadaceaeandRhizobiaceaefamilies were the major taxa in the wax regardless of water availability to plants and that plant development only modestly affected wax bacterial community structure. The mucilage-associated bacterial microbiome contained several described diazotrophic species, and its structure was strongly influenced by sorghum development but only modestly influenced by fertilization. In contrast, the fungal community structure of mucilage was strongly affected by the year of sampling but not by fertilization or plant developmental stage, suggesting a decoupling of fungal-bacterial dynamics in the mucilage. Our bacterial isolate collection from wax and mucilage increased phylogenetic diversity of non-rhizosphere, plant-associated bacteria by ~20% from previous work, and several isolates matched 100% to detected amplicon sequence variants. This work expands our understanding of the microbiome of phyllosphere exudates and advances our long-term goal of translating microbiome research to support sorghum cultivation for biofuel production.
Aviation communication: the effect of critical factors on the rate of misunderstandings
Authors: Alharasees Omar , Jazzar Abeer , Kale Utku , Rohacs Daniel
Published: July 2022

Purpose

Ineffective communication consequences can be life-threatening and drastic. Communication misunderstandings are frequently reported in incidents, accidents and occurrences. This research paper aims to evaluate operator communication load in highly automated systems; distinguish and highlight the communication error factors during flight operations from different perspectives; and provide suggestions to operators to decrease the rate of misunderstandings in aviation communication.

Design/methodology/approach

This study is based on a questionnaire that investigated the critical communication load, including aviation training, standard phraseology, operators’ native language and cultural background. In addition to the effect of using controller–pilot data link communications will be discussed widely. In this research, 110 responses were obtained from pilots and air traffic controller (ATCOs) that vary in 44 countries; approximately 20% were ATCOs, and 75% were pilots.

Findings

This study was designed to assess the level of aviation operators communication load in highly automated systems, identify and illustrate the factors that contribute to communication errors during flight operations from multiple viewpoints, and offer recommendations to operators to minimize the rate of misunderstandings in aviation communication.

Originality/value

This research deals with evaluating the operators’ communication load, which is crucial for the air traffic safety and efficiency.
An analysis of fear factors predicting enterprise social media use in an era of communication visibility
Authors: Van Zoonen Ward , Treem Jeffrey W. , Sivunen Anu
Published: July 2022

Purpose

The benefits associated with visibility in organizations depend on employees' willingness to engage with technologies that utilize visible communication and make communication visible to others. Without the participation of workers, enterprise social media have limited value. This study develops a framework to assess what deters and drives employees' use of enterprise social media.

Design/methodology/approach

Data were collected from 753 employees of a global company using an online survey. The response rate was 24.5%. The authors used structural equation modeling to test the hypothesized framework.

Findings

The results show that various fears by workers may deter or motivate enterprise social media use. This offers an alternative viewpoint for examining the consequences of communication visibility in organizations. Specifically, the findings demonstrate that the fear of accountability and the fear of losing uniqueness reduce enterprise social media use through increased codification efforts. The fear of missing out is directly and positively related to collecting behaviors on enterprise social media.

Research limitations/implications

Expectations about participation in visible organizational communication environments are rising. However, as individuals may experience anxiety in such settings, the authors need to direct more analytical focus to the ways individuals manage communication visibility in organizing contexts and develop a deeper understanding of the consequences of fear in workplace communication.

Originality/value

The analysis recognizes that fear can play a key role in deterring or motivating workers' specific choices in navigating the challenges that occur when technology can make communication broadly visible. This study uses theorizing on communication visibility to bring together different fear mechanisms to predict enterprise social media use.
Supplier interfaces in digital transformation: an exploratory case study of a manufacturing firm and IoT suppliers
Authors: Ferreira Carla Cleri , Lind Frida
Published: July 2022

Purpose

The purpose of this paper is to characterize the interfaces between manufacturing companies and the Internet of Things (IoT) suppliers involved in their digital servitization.

Design/methodology/approach

This paper builds on an explorative case study of a manufacturing firm and its IoT suppliers. This paper relies on the Industrial Network Approach to study interfaces between buying firms and their suppliers.

Findings

This paper identifies three distinct types of supplier interfaces: connected, digital and digital-physical. They all contain technical resource interfaces with additional organizational and/or technical complexities that need to be managed. Connectivity, an Agile approach to software development and strong technical dependence emerged as key factors that impact the interactions between manufacturing firms and IoT suppliers and how their resources are combined.

Practical implications

This paper offers managerial implications regarding the importance of internal organization (such as appropriate cross-functional teams) to manage the dynamics of collaborations required by digital technologies, maintain interactions with IoT suppliers and identify and manage interdependences between IoT suppliers. Building close relationships with suppliers of crucial infrastructure (e.g. IoT cloud platform and data security systems) can also be beneficial for manufacturing firms to reduce risks. Finally, attention should be given to IoT technology strategy, which impacts both digital and digital-physical supplier interfaces.

Originality/value

In digital servitization, manufacturing firms are heavily reliant on external resources for IoT technology. Despite this, few studies have investigated the characteristics of their interfaces with IoT suppliers, how these can be managed and how resources are combined.
Keeping time: a taxonomy of temporal effects on employees at the workplace
Authors: Das Roshni
Published: July 2022

Purpose

In recent years, there has been a burgeoning interest around “time” or “temporality” as a subject of study in workplace behavior at the microlevel. This research is, however, not integrated systematically till date. The purpose of this study is to address this gap with a comprehensive review of this domain.

Design/methodology/approach

The present study conducts a large-scale bibliometric analysis of 1,120 papers, collected from Scopus, to decipher the structural patterns underlying this research domain.

Findings

The analysis unraveled the performance statistics (articles, journals, authors) and intellectual structure (themes, keywords, ontological position) of temporal research. The authors also present a matrix of extant and emergent thought in time studies and discuss how they fare on causality versus dynamicity dimensions.

Research limitations/implications

Future research directions are discussed extensively based on qualitative and quantitative insights.

Originality/value

This is a structured literature review combined with bibliometric analysis of a large corpus of research.
Modelling the factors in implementation of environmental sustainability in healthcare organisations
Authors: Vaishnavi V. , Suresh M.
Published: July 2022

Purpose

Environmental sustainability (ES) is an increasing tendency in the healthcare industry as it seeks to enhance the environmental friendliness and reduces waste in operations to save money. The objective of research article is to identify the factors that contribute to improving the performance of ES in hospitals. Understanding the factors that contribute to the improvement of healthcare services may be helpful for practitioners, who need to address and implement an effective framework to enable an environment-friendly practice in hospitals.

Design/methodology/approach

The current study utilised the technique called total interpretive structural modelling (TISM) to identify the factors and understand the interconnection between the identified factors. A literature review revealed 12 factors, which were then refined with the input of hospital experts. Based on a questionnaire survey, a planned interview is conducted in chosen Indian hospitals. The matrix impact cross multiplication applied to classification (MICMAC) study employs dependency and driving power to identify the hierarchical relationship between the detected factors.

Findings

Green building initiatives, water consumption, resource usage, and renewable energy were identified as key factors in the study. Other factors such as staff behaviour, procurement of goods and management of hazardous substance would be influenced by these fundamental components. With the implementation of green initiatives in the hospital, ES is primarily used to reduce the excessive use of scarce resources.

Practical implications

The ES programme begins at the hospital grounds, with awareness and specific training provided to all personnel, including doctors, nurses, and managers at all levels. The training programme is intended to raise awareness; sessions are divided into targeted groups; a new organisational structure is created; and a consultant agent is hired to commence ES.

Originality/value

Existing literature has focussed mostly on ES factors such as carbon emissions, water conservation, and effective waste disposal, while ignoring organisational viewpoints and their interrelationships. As a result, the current study used TISM to show the relationship between various organisational and environmental perspective components in order to comprehend the reasoning behind improving performance.
The impact of COVID-19 on people with intellectual disabilities
Authors: Warner Katie , Marrington Cathryn
Published: July 2022

Purpose

As Clinical Psychologists working in a tertiary Intellectual Disability (ID) service in the UK, this paper aims to address the impact of Covid-19 – and the subsequent transition out of Covid-19 restrictions – on individuals with an ID, and the clinicians working alongside them. Additionally, the paper reflects upon how Covid-19 has shaped and manipulated therapeutic communities and environments.

Design/methodology/approach

This paper is reflective in nature and reviews current evidence associated with how people with an ID experienced the impact of Covid-19. Clinicians reflect upon their shared experience in line with this evidence.

Findings

This paper highlights perpetuating inequalities and injustices on people with an ID as a result of Covid-19. Further, it is indicated that that there should be consideration of how people with an intellectual disability experience transitions back to their day-to-day environments and encourages clinicians to widely consider how to shape therapeutic communities and environments.

Originality/value

Multiple themes have been addressed in this paper, and the reflections add to an understanding of how those individuals specifically working in, or using intellectual disability services, have experienced the Covid-19 pandemic, though a critical lens.
Human DNA contamination of postmortem examination facilities: Impact of COVID‐19 cleaning procedure
Authors: Bini Carla , Giorgetti Arianna , Giovannini Elena , Pelletti Guido , Fais Paolo , Pelotti Susi
Published: July 2022

The DNA contamination of evidentiary trace samples, included those collected in the autopsy room, has significant detrimental consequences for forensic genetics investigation. After the COVID‐19 pandemic, methods to prevent environmental contamination in the autopsy room have been developed and intensified. This study aimed to evaluate the level of human DNA contamination of a postmortem examination facility before and after the introduction of COVID‐19‐related disinfection and cleaning procedures. Ninety‐one swabs were collected from the surfaces and the dissecting instruments, analyzed by real‐time quantitative PCR (q‐PCR) and typed for 21 autosomal STRs. Sixty‐seven out of 91 samples resulted in quantifiable human DNA, ranging from 1 pg/μl to 12.4 ng/μl, including all the samples collected before the implementation of COVID‐19 cleaning procedures (n = 38) and 29 out of 53 (54.7%) samples taken afterward. All samples containing human DNA were amplified, resulting in mixed (83.6%), single (13.4%), and incomplete (3%) profiles. A statistically significant decrease in DNA contamination was found for dissecting instruments after treatment with chlorhexidine and autoclave (p < 0.05). Environmental decontamination strategies adopted during COVID‐19 pandemic only partially solved the long‐standing issue of DNA contamination of postmortem examination facilities. The pandemic represents an opportunity to further stress the need for standardized evidence‐based protocols targeted to overcome the problem of DNA contamination in the autopsy room.
Conservation biological control of the fruit fly parasitoid Fopiusa arisanus (Hymenoptera: Braconidae)
Authors: Harris Colin , Bromley Emma , Clarke Linda K , Kay Bianca J , Schwenke Andrew C , Clarke Anthony R
Published: July 2022

Fopius arisanus is a parasitoid of Bactrocera fruit flies. In sub‐tropical Australia, it can cause >30% parasitism of Queensland fruit fly, Bactrocera tryoni. There has been minimal research effort globally, and none in Australia, to determine how the abundance of this species can be maintained and increased through conservation biological control. We carried out three research activities aimed at conserving this species in a landscape: (i) testing mesh sizes for augmentoria, devices into which fallen fruit can be placed that capture emergent flies while allowing parasitoid release; (ii) investigation of the suitability of wild tobacco, Solanum mauritianum, and wild tobacco fly, Bactrocera cacuminata, as a non‐crop refuge for the parasitoid; and (iii) the value of floral resources for companion planting to increase carbohydrate sources. We determined that a mesh size of approximately 2 mm2 retained near 100% of fruit flies while releasing ~90% of parasitoids. A readily obtainable 50% shade cloth maintained a mesh pore of this size and was confirmed as suitable for making augmentoria. In South East Queensland, the wild tobacco/wild tobacco fly system was demonstrated to host F. arisanus continuously through the year, with an annual parasitism rate of 31%, peaking in the spring at 60%. A second fruit fly parasitoid, Diachasmimorpha kraussii, was also collected from this system, but at lower levels. Fopius arisanus were able to move >120 m from a wild tobacco patch to parasitise fruit fly‐infested fruit. None of five floral resources trialled increased wasp longevity beyond the mean of 5.3 days achieved by a water‐only control. When five additional fruit juice/fruit pulp resources were tested, only one increased wasp longevity, by 1.3 days, over the water‐only control. In contrast, wasps fed on honey and water survived for a mean of nearly 40 days. We thus concluded that in the field F. arisanus does not gain its nutritional needs from either flowers or fruit. Augmentoria offer an easily scalable tool, suitable for backyard growers through to commercial producers, which provides the control benefits of crop hygiene while not disrupting the parasitoid cycle. Where wild tobacco can be maintained without impacting the quality of farm habitat, it has great potential as a year‐round reservoir of the wasp. Companion planting to increase nectar resources is not recommended for F. arisanus conservation biological control.
Perception of Somali pastoralists in Adadle woreda, Eastern Ethiopia, towards wildlife at the human‐animal interface, conservation and wildlife population change
Authors: Ibrahim Mohammed , Muhummed Abdifatah , Melaku Hamere , Mohammed Seid , Zinsstag Jakob , Tschopp Rea
Published: July 2022

Pastoralists and wildlife co‐exist in the Somali Regional State competing for habitat, food and water resources. A questionnaire survey conducted among 198 pastoralists, captured information on their perception of wildlife against the backdrop of wildlife population decrease, illegal wildlife trade and lack of quantitative and qualitative data in the area. The top perceived threats to livestock were drought (46%), wildlife attacks (33.8%) and diseases (20.2%). Daily encounters between wildlife and livestock were reported by 61.1% of respondents. Herbivores, including warthogs, accounted for the majority of these encounters (88.4%), whereas carnivores were rarely observed with livestock, except for jackals. The majority (92.9%) of the respondents did not think that wildlife could transmit diseases to livestock. Jackals were reported by 7.1% to transmit rabies. A strong dislike for wildlife was recorded in 99% of all respondents. All stated that wildlife should not be protected. Half of the respondents did not see any benefits in wildlife. Wildlife populations have decreased over the last 10 years, particularly lions and cheetahs. Pastoralist's attitudes and perceptions towards wildlife in the study area were negative, potentially affecting conservation efforts. There is an urgent need to improve awareness of the benefits of wildlife and to include wildlife in integrated human‐livestock‐environment surveillance systems.
Tilmanocept as a novel tracer for lymphatic mapping and sentinel lymph node biopsy in melanoma and oral cancer
Authors: Mwagiru Derek , Shivashankar Pranav , Wong Eva , Farlow David , Cambden Brad , Abdul‐Razak Muzib
Published: July 2022

Background

Sentinel lymph node biopsy (SLNB) has been pivotal for pathological assessment of nodal status in cutaneous melanoma (CM) and oral cavity squamous cell carcinoma (OCSCC) thus crucial for staging. An ideal agent for lymphatic mapping should have a standardized preparation, appropriate accumulation in first‐echelon nodes and no side effects. Tilmanocept, a CD206‐receptor targeted novel radiotracer fulfils these properties. This study investigated Tilmanocept for lymphoscintigraphy and intraoperative identification of sentinel lymph nodes (SLN) in CM and OCSCC.

Methods

This prospective cross sectional study examined patients who presented to Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney. Patients had biopsy proven tumours with clinically and radiologically negative regional lymph nodes. Tilmanocept guided lymphoscintigraphy was followed by intraoperative SLNs identification via handheld gamma probe. Primary endpoints were detection and retrieval rate of SLNs while secondary endpoints included pathological status of SLNs.

Results

Thirty‐five patients were included (26 with CM and 9 with OCSCC) with the most common primary tumour site for CM on the extremities (33.3%). Lymphoscintigraphy with Tilmanocept identified at least 1 SLN (sensitivity 100%) in all patients. SLNs were retrieved in all of patients intraoperatively (100% retrieval rate) with positive nodes found in 20% of patients. Tilmanocept also demonstrated 100% tissue specificity, with lymph nodal tissue confirmed histologically, with no false positives.

Conclusion

Tilmanocept is a reliable radiotracer for assessing the nodal status in patients with CM and OCSCC. Our group is the first to evaluate the use of Tilmanocept in the Australian setting, adding to the limited studies worldwide.
Women's interest in surgery as a career in the early postgraduate period: a national longitudinal study
Authors: Meyer Juliette A. , Connell Charlotte J. W. , Rennie Sarah , Verstappen Antonia C. , Poole Phillippa J.
Published: July 2022

Background

Women remain underrepresented in Surgery in Aotearoa New Zealand (AoNZ). This study described interest in surgical careers by gender in the early postgraduate period and associated influencing factors.

Methods

AoNZ medical graduates between 2012 and 2016 responding to an Exit Questionnaire (EQ) at graduation and 3 years later (PGY3) as part of the Medical Schools Outcomes Database and Longitudinal Tracking Project (MSOD) were included. Analyses of specialty preferences and influences by gender were performed.

Results

Of 992 participants, 58% were women. At EQ, 158 participants (16%) had a surgical preference: 21% of men and 14% of women (P < 0.01). By PGY3, this was 20% of men and 10% of women (P < 0.01). A logistic regression found women were half as likely as men to have a surgical preference at PGY3. Those with a surgical preference at EQ were over 23 times more likely to have a surgical preference at PGY3, irrespective of gender. There were significant differences in self‐reported career influencing factors between women and men at EQ and PGY3, as well as between PGY3 women with a surgical and those with a non‐surgical preference. These included nature of the specialty, training requirements, lifestyle, family and personal factors.

Conclusions

Increasing the proportion of women in Surgery requires a multifaceted approach starting during medical school and continuing through early postgraduate years. More needs to be done to make surgical experiences as an undergraduate and junior doctor appealing to women.
Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout
Authors: Kamel Bishoy , Abuhelwa Ahmad Y. , Foster David , Duong Janna K. , Graham Garry G. , Williams Kenneth M. , Pile Kevin D. , Day Richard O.
Published: July 2022

Aims

To investigate and characterise the pharmacokinetics of febuxostat and the effect of the covariates of renal function and body size descriptors on the pharmacokinetics of the drug.

Methods

Blood samples (n = 239) were collected using sparse and rich sampling strategies from healthy (n = 9) and gouty (n = 29) subjects. Febuxostat plasma concentrations were measured by a validated high‐performance liquid chromatography method. Population pharmacokinetic analysis was performed using NONMEM. A common variability on bioavailability (FVAR) approach was used to test the effect of fed status on absorption parameters. Covariates were modelled using a power model.

Results

The time course of the plasma concentrations of febuxostat is best described by a two‐compartment model. In the final model, the population mean for apparent clearance (CL/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption rate constant (ka) and apparent intercompartmental clearance (Q/F) were 6.91 l h−1, 32.8 l, 19.4 l, 3.6 h−1 and 1.25 l h−1, respectively. The population parmater variability (coefficient of variation) for CL/F, Vc/F and Vp/F were 13.6, 22 and 19.5%, respectively. Food reduced the relative biovailability and ka by 67% and 87%, respectively. Renal function, as assessed by creatinine clearance, was a significant covariate for CL/F while body mass index was a significant covariate for Vc/F.

Conclusions

Renal function and body mass index were significant covariates. Further work is warranted to investigate the clinical relevance of these results, notably as renal impairment and obesity are common occurrences in people with gout.
Identifying and addressing pill aversion in adults without physiological‐related dysphagia: A narrative review
Authors: McCloskey Alice P. , Penson Peter E. , Tse Yincent , Abdelhafiz Majadah A. , Ahmed Shah N. , Lim Emma J.
Published: July 2022

Solid oral dosage forms (SODFs) (often called pills by patients) are the default formulation to treat medical ailments. Beneficial therapeutic outcomes rely on patients taking them as directed. Up to 40% of the population experience difficulties swallowing SODFs, resulting in reduced adherence and impaired therapeutic efficacy. Often associated with children, this also presents in adults with dysphagia, and without any organic dysphagia (non‐physiological‐related or functional dysphagia). This review aims to identify and appraise current interventions used to screen for and overcome pill aversion in adults with functional dysphagia. A comprehensive search of the literature was conducted. Articles reporting pill aversion in adults aged ≥18 years with no underlying cause, history of, or existing dysphagia were included. Study quality was determined using the STROBE tool for observational studies. A narrative synthesis of the findings was prepared. We identified 18 relevant cohort studies, which demonstrate that pill aversion is a global problem. Perceived ease of and/or SODF swallowability appears to be influenced by female gender, younger age, co‐morbidities (e.g., depression), and physical SODF properties. Patients often modify their medicines rather than raise this issue with their healthcare team. Screening for pill aversion is haphazard but controlled postural adjustments, coating SODFs and behavioural interventions appear to be successful solutions. SODF swallowing difficulties are a barrier to effective medication use. Healthcare professionals must recognise that pill aversion is a problem requiring identification through effective screening and resolution by training interventions, appropriate formulation selection or specialist referral.
Making informed choices about cannabis use during pregnancy and lactation: A qualitative study of information use
Authors: Taneja Shipra , Panday Janelle , Popoola Anuoluwa , Greyson Devon , McDonald Sarah D. , Patel Tejal , Vanstone Meredith
Published: July 2022

Background

Cannabis use during pregnancy and lactation continues to increase as some perceive cannabis to be helpful for symptom management and coping. As such, pregnant and lactating people are faced with challenging decisions, weighing benefits against the potential risks of cannabis use. To help clinicians facilitate informed choices, we explored the self‐identified information needs of pregnant and lactating people who are deciding whether or not to use cannabis. We aimed to describe the modes and sources of their information‐seeking and their satisfaction with the information they found.

Methods

We interviewed 52 people in Canada who made the decision to start, stop, or continue using cannabis during pregnancy and lactation. Participants were recruited from advertisements in prenatal clinics and on social media. We utilized an inductive approach to analysis focused on information used in decision‐making about cannabis use, including the process of seeking and evaluating that information.

Results

Participants were deliberate in their search for information, most commonly seeking information on risks of use. Information sources were mainly online material or people in their social networks. Clinicians were not commonly described as a knowledgeable or supportive source of information. Overwhelmingly, participants described the information they found as insufficient and emphasized the need for more comprehensive and trustworthy sources of information.

Conclusions

Participants identified distinct and unmet information needs associated with their decision to use cannabis. They described a desire for clear evidence about the impact of cannabis use, including information about how to balance the benefits they perceived from cannabis use with the risks of harm.
Debate: Conduct disorder, like all psychiatric diagnoses, is not a diagnosis
Authors: Timimi Sami
Published: July 2022

Like all psychiatric diagnoses, conduct disorder (CD) relies on entirely subjective foundations. Without empirical anchors, we are left with descriptors that cannot help us identify cases that share universalisable commonalities beyond those imposed on them by the subjectivity of the diagnoser. This article highlights how mistaking a descriptive category for a diagnosis has resulted in, including for CD, a failure to improve scientific knowledge or clinical outcomes. For progress to occur the dominance of a technical diagnostic paradigm in psychiatry must be over‐turned and CD will then lie on the slag heap of history alongside the other consumable brands mis‐labelled as a psychiatric diagnosis.
Polarity switching of ovarian cancer cell clusters via SRC family kinase is involved in the peritoneal dissemination
Authors: Kawata Mayuko , Kondo Jumpei , Onuma Kunishige , Ito Yu , Yokoi Takeshi , Hamanishi Junzo , Mandai Masaki , Kimura Tadashi , Inoue Masahiro
Published: July 2022

Peritoneal dissemination is a predominant pattern of metastasis in patients with advanced ovarian cancer. Despite recent progress in the management strategy, peritoneal dissemination remains a determinant of poor ovarian cancer prognosis. Using various histological types of patient‐derived ovarian cancer organoids, the roles of the apicobasal polarity of ovarian cancer cell clusters in peritoneal dissemination were studied. First, it was found that both ovarian cancer tissues and ovarian organoids showed apicobasal polarity, where zonula occludens‐1 (ZO‐1) and integrin beta 4 (ITGB4) served as markers for apical and basal sides, respectively. The organoids in suspension culture, as a model of cancer cell cluster floating in ascites, showed apical‐out/basal‐in polarity status, while once embedded in extracellular matrix (ECM), the organoids switched their polarity to apical‐in/basal‐out. This polarity switch was accompanied by the SRC kinase family (SFK) phosphorylation and was inhibited by SFK inhibitors. SFK inhibitors abrogated the adherence of the organoids onto the ECM‐coated plastic surface. When the organoids were seeded on a mesothelial cell layer, they cleared and invaded mesothelial cells. In vivo, dasatinib, an SFK inhibitor, suppressed peritoneal dissemination of ovarian cancer organoids in immunodeficient mice. These results suggest SFK‐mediated polarity switching is involved in peritoneal metastasis. Polarity switching would be a potential therapeutic target for suppressing peritoneal dissemination in ovarian cancer.
Independent verification of circulating miRNA as diagnostic biomarkers for urothelial carcinoma
Authors: Urabe Fumihiko , Matsuzaki Juntaro , Takeshita Fumitaka , Kishida Takeshi , Ochiya Takahiro , Hirai Kotaro
Published: July 2022

Urothelial carcinoma (UC) is an umbrella term for bladder cancers (BCa) and upper‐tract urothelial carcinoma (UTUC), with BCa and UTUC sometimes detected concomitantly. The methods of detection for UC are often inaccurate or highly invasive, and, therefore, are thought to be unsatisfactory. Previously, we reported seven serum miRNAs as diagnostic markers for BCa. Here, we re‐evaluated potential diagnostic miRNAs in different institutions. We prospectively analyzed serum samples obtained from 126 UC patients (BCa: 106 samples; UTUC: 14 samples; UTUC with BCa: six samples) and 50 noncancer controls by microarray analysis. We randomly assigned these samples into a training or a validation set. Biomarker candidate miRNAs were selected based on cross‐validation scores in the training set of samples, with diagnostic power confirmed in the validation set. Among the diagnostic miRNAs identified in this way, miR‐1343‐5p and miR‐6087 had been identified as potential diagnostic miRNAs in our previous study. In addition, we evaluated the association between the serum levels of identified miRNAs and the presence of UC risk conditions. The expression levels of several miRNAs correlate with the risk factors in participants without UC, which may be explained by the presence of a microscopic tumor or a precancerous lesion. In conclusion, we identified two robust miRNA diagnostic markers for UC detection. Further functional analysis is required to elucidate the mechanism by which alterations in the expression of these miRNAs occur.
Mechanisms of resistance to immune checkpoint inhibitors
Authors: Nagasaki Joji , Ishino Takamasa , Togashi Yosuke
Published: July 2022

Immune checkpoint inhibitors (ICIs) are effective for various types of cancer, and their application has led to paradigm shifts in cancer treatment. While many patients can obtain clinical benefits from ICI treatment, a large number of patients are primarily resistant to such treatment or acquire resistance after an initial response. Thus, elucidating the resistance mechanisms is warranted to improve the clinical outcomes of ICI treatment. ICIs exert their antitumor effects by activating T cells in the tumor microenvironment. There are various resistance mechanisms, such as insufficient antigen recognition by T cells, impaired T‐cell migration and/or infiltration, and reduced T‐cell cytotoxicity, most of which are related to the T‐cell activation process. Thus, we classify them into three main mechanisms: resistance mechanisms related to antigen recognition, T‐cell migration and/or infiltration, and effector functions of T cells. In this review, we summarize these mechanisms of resistance to ICIs related to the T‐cell activation process and progress in the development of novel therapies that can overcome resistance.
Mechanisms of dermatological toxicities to immune checkpoint inhibitor cancer therapies
Authors: Seervai Riyad N. H. , Sinha Avilasha , Kulkarni Rajan P.
Published: July 2022

The discovery of immune checkpoint inhibition (ICI) sparked a revolution in the era of targeted anticancer therapy. However, although monoclonal antibodies targeting the cytotoxic T-lymphocyte antigen-4 and programmed death-1 axes have improved survival in patients with advanced cancers, these immunotherapies are associated with a wide spectrum of dermatological immune-related adverse events (irAEs), ranging from mild to life-threatening. Several publications have addressed the clinical and histopathological classification of these skin-directed irAEs, their impact on anti-tumour immunity and survival, and the critical role of supportive oncological dermatology in their management. In this paper, we review the current understanding of the mechanistic drivers of immune-related skin toxicities with a focus on inflammatory, immunobullous and melanocyte/pigment-related reactions. We detail the specific immune-based mechanisms that may underlie different cutaneous reactions. We also discuss potential mechanisms as they relate to extracutaneous irAEs and the lessons learned from these, the potential overlap with cutaneous irAEs, techniques to study differences in immune-related vs. de novo skin reactions, and how treatment of these AEs impacts cancer treatment, patient quality of life and overall survival. An improved understanding of the mechanistic basis of cutaneous irAEs will allow clinicians to develop and use blood-based biomarkers that could help ultimately predict onset and/or severity of these irAEs, and to implement rational mechanistic-based treatment strategies that are targeted to the irAEs while potentially avoiding reducing the anti-tumour effect of ICIs.