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The move toward early detection and treatment of cancer presents challenges for value assessment using traditional endpoints. Current cancer management rarely considers the full economic and societal benefits of therapies. Our study used a modified Delphi process to develop principles for defining and assessing value of cancer therapies that aligns with the current trajectory of oncology research and reflects broader notions of value. 24 experts participated in consensus-building activities across 5 months (16 took part in structured interactions, including a survey, plenary sessions, interviews, and off-line discussions, while 8 participated in interviews). Discussion focused on: 1) which oncology-relevant endpoints should be used for assessing treatments for early-stage cancer and access decisions for early-stage treatments, and 2) the importance of additional value components and how these can be integrated in value assessments. The expert group reached consensus on 4 principles in relation to the first area (consider oncology-relevant endpoints other than overall survival; build evidence for endpoints that provide earlier indication of efficacy; develop evidence for the next generation of predictive measures; use managed entry agreements supported by ongoing evidence collection to address decision-maker evidence needs) and 3 principles in relation to the second (routinely use patient reported outcomes in value assessments; assess broad economic impact of new medicines; consider other value aspects of relevance to patients and society).

The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c+CD5+ DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy. CD5+ DC numbers increased during ICB therapy, and low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T cells dampened tumor elimination in response to ICB therapy in vivo. Thus, CD5+ DCs are an essential component of optimal ICB therapy.

PurposeNeoadjuvant targeted therapy provides a brief, preoperative window of opportunity that can be exploited to individualize cancer care based on treatment response. We investigated whether response to neoadjuvant therapy during the preoperative window confers survival benefit in patients with operable head and neck squamous cell carcinoma (HNSCC).Patients and methodsA pooled analysis of treatment-naïve patients with operable HNSCC enrolled in one of three clinical trials from 2009 to 2020 (NCT00779389, NCT01218048, NCT02473731). Neoadjuvant regimens consisted of EGFR inhibitors (n = 83) or anti-ErbB3 antibody therapy (n = 9) within 28 days of surgery. Clinical to pathologic stage migration was compared with disease-free survival (DFS) and overall survival (OS) while adjusting for confounding factors using multivariable Cox regression. Circulating tumor markers validated in other solid tumor models were analyzed.Results92 of 118 patients were analyzed; all patients underwent surgery following neoadjuvant therapy. Clinical to pathologic downstaging was more frequent in patients undergoing neoadjuvant targeted therapy compared with control cohort (P = 0.048). Patients with pathologic downstage migration had the highest OS [89.5%; 95% confidence interval (CI), 75.7-100] compared with those with no stage change (58%; 95% CI, 46.2-69.8) or upstage (40%; 95% CI, 9.6-70.4; P = 0.003). Downstage migration remained a positive prognostic factor for OS (HR, 0.22; 95% CI, 0.05-0.90) while adjusting for measured confounders. Downstage migration correlated with decreased circulating tumor markers, SOX17 and TAC1 (P = 0.0078).ConclusionsBrief neoadjuvant therapy achieved pathologic downstaging in a subset of patients and was associated with significantly better DFS and OS as well as decreased circulating methylated SOX17 and TAC1.

Thwaites Glacier is one of the fastest-changing ice-ocean systems in Antarctica1-3. Much of the ice sheet within the catchment of Thwaites Glacier is grounded below sea level on bedrock that deepens inland4, making it susceptible to rapid and irreversible ice loss that could raise the global sea level by more than half a metre2,3,5. The rate and extent of ice loss, and whether it proceeds irreversibly, are set by the ocean conditions and basal melting within the grounding-zone region where Thwaites Glacier first goes afloat3,6, both of which are largely unknown. Here we show-using observations from a hot-water-drilled access hole-that the grounding zone of Thwaites Eastern Ice Shelf (TEIS) is characterized by a warm and highly stable water column with temperatures substantially higher than the in situ freezing point. Despite these warm conditions, low current speeds and strong density stratification in the ice-ocean boundary layer actively restrict the vertical mixing of heat towards the ice base7,8, resulting in strongly suppressed basal melting. Our results demonstrate that the canonical model of ice-shelf basal melting used to generate sea-level projections cannot reproduce observed melt rates beneath this critically important glacier, and that rapid and possibly unstable grounding-line retreat may be associated with relatively modest basal melt rates.

Thwaites Glacier represents 15% of the ice discharge from the West Antarctic Ice Sheet and influences a wider catchment1-3. Because it is grounded below sea level4,5, Thwaites Glacier is thought to be susceptible to runaway retreat triggered at the grounding line (GL) at which the glacier reaches the ocean6,7. Recent ice-flow acceleration2,8 and retreat of the ice front8-10 and GL11,12 indicate that ice loss will continue. The relative impacts of mechanisms underlying recent retreat are however uncertain. Here we show sustained GL retreat from at least 2011 to 2020 and resolve mechanisms of ice-shelf melt at the submetre scale. Our conclusions are based on observations of the Thwaites Eastern Ice Shelf (TEIS) from an underwater vehicle, extending from the GL to 3 km oceanward and from the ice-ocean interface to the sea floor. These observations show a rough ice base above a sea floor sloping upward towards the GL and an ocean cavity in which the warmest water exceeds 2 °C above freezing. Data closest to the ice base show that enhanced melting occurs along sloped surfaces that initiate near the GL and evolve into steep-sided terraces. This pronounced melting along steep ice faces, including in crevasses, produces stratification that suppresses melt along flat interfaces. These data imply that slope-dependent melting sculpts the ice base and acts as an important response to ocean warming.

The neurohormone oxytocin regulates many aspects of physiology primarily by binding to its receptor, the oxytocin receptor. The oxytocin receptor gene (Oxtr) has been shown to have alternative transcripts in the mouse brain which may each have different biological functions or be used in specific contexts. A popular animal model for studying oxytocin-dependent social behaviors is the prairie vole, a biparental and monogamous rodent. Alternative transcriptional capacity of Oxtr in prairie voles is unknown. We used 5 rapid amplification of cDNA ends to identify alternative Oxtr transcription start sites in prairie vole brain tissue and uterine tissue. We then validated expression of specific transcripts in fetal brains and assessed the impact of exogenous oxytocin administration in utero on offspring brain development. We identified seven distinct Oxtr transcripts, all of which are present in both brain and uterine tissue. We then demonstrated that maternal oxytocin administration alters expression of a specific subset of Oxtr transcripts and that these different transcripts are under unique epigenetic regulation, such that in the perinatal period only one of the alternative transcripts is associated with DNA methylation in the Oxtr promoter. These data establish the existence of multiple Oxtr transcripts in prairie vole brain and uterine tissue and implicate oxytocin in the regulation of alternative transcript expression. These data have significant implications for our understanding of null mutant models in both mice and voles and translation in human birth and behavior.

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus-negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53-mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or breakout groups, were tasked with developing clinical studies in both the locally advanced and recurrent and/or metastatic (R/M) disease settings as well as considering signal-seeking trial designs. A fourth breakout group was focused on identifying and standardizing biomarker integration into trial design; this information was provided to the other breakout groups prior to the meeting to aid in study development. A total of 4 concepts were prioritized to move forward for further development and implementation. This article summarizes the proceedings of the Clinical Trials Planning Meeting with the goal of developing clinical trials for patients with TP53-mutant HNSCC that can be conducted within the National Clinical Trials Network.

BackgroundThe effectiveness of MAPK pathway inhibitors (MAPKi) used to treat patients with BRAF-mutant melanoma is limited by a range of resistance mechanisms, including soluble TNF (solTNF)-mediated NF-kB signaling. solTNF preferentially signals through type-1 TNF receptor (TNFR1), however, it can also bind to TNFR2, a receptor that is primarily expressed on leukocytes. Here, we investigate the TNFR2 expression pattern on human BRAFV600E+ melanomas and its role in solTNF-driven resistance reprogramming to MAPKi.MethodsFlow cytometry was used to test TNFR1, TNFR2 and CD271 expression on, as well as NF-kB phosphorylation in human BRAF-mutant melanoma. The ability of melanoma cell lines to acquire MAPKi resistance in response to recombinant or macrophage-derived TNF was evaluated using the MTT cytotoxicity assay. Gene editing was implemented to knock out or knock in TNF receptors in melanoma cell lines. Knockout and knock-in cell line variants were employed to assess the intrinsic roles of these receptors in TNF-induced resistance to MAPKi. Multicolor immunofluorescence microscopy was utilized to test TNFR2 expression by melanoma in patients receiving MAPKi therapy.ResultsTNFR1 and TNFR2 are co-expressed at various levels on 4/7 BRAFV600E+ melanoma cell lines evaluated in this study. In vitro treatments with solTNF induce MAPKi resistance solely in TNFR2-expressing BRAFV600E+ melanoma cell lines. TNFR1 and TNFR2 knockout and knock-in studies indicate that solTNF-mediated MAPKi resistance in BRAFV600E+ melanomas is predicated on TNFR1 and TNFR2 co-expression, where TNFR1 is the central mediator of NF-kB signaling, while TNFR2 plays an auxiliary role. solTNF-mediated effects are transient and can be abrogated with biologics. Evaluation of patient specimens indicates that TNFR2 is expressed on 50% of primary BRAFV600E+ melanoma cells and that MAPKi therapy may lead to the enrichment of TNFR2-expressing tumor cells.ConclusionsOur data suggest that TNFR2 is essential to solTNF-induced MAPKi resistance and a possible biomarker to identify melanoma patients that can benefit from solTNF-targeting therapies.

Purpose: This study included two parts: a descriptive study followed by an integrative review. The purpose of the study was to converge finding from the descriptive study and summarize relevant findings from existent literature to identify potential culturally responsive early language and literacy intervention strategies for Native American caregivers and their children. Method: This study included a nonexperimental descriptive design and integrative review. The descriptive study analyzed the language behaviors and shared book interactions of Native American caregivers with their young children (N = 21) and included results from a caregiver teaching questionnaire. The integrative review evaluated relevant literature and identified strategies that were described in these sources. These findings were combined with the descriptive study findings to identify promising culturally consistent language and literacy strategies. Results: Caregivers' shared book behaviors were associated with caregivers' vocabulary usage and children's shared book behaviors. Caregivers reported a number of language and teaching strategies they frequently employed; this information was integrated with other sources to identify promising approaches. A total of 20 potential strategies were identified. Conclusions: The purpose of this study was to describe potential early language and literacy strategies for Native American families. It would be impossible to develop early language interventions to meet the needs of all Native American families and children; thus, this study is a preliminary step in identifying strategies that may be culturally responsive for some families. The integrative review supported the use of shared book reading with young Native American children. Promising language and early literacy strategies included play-based strategies, teaching new words, questioning strategies, using descriptive language, and other language and interaction enhancements. The effectiveness of these strategies should be further evaluated in future research or treatment studies.

Mental health problems in school-aged youth are a risk factor for poor outcomes in adulthood. Although these poor outcomes are well established, most youth with mental health problems continue to experience barriers to receiving appropriate services. Tier 2 interventions are sometimes provided to students who are at risk of developing a mental illness. The aim of this scoping review was to synthesize the peer-reviewed research regarding Tier 2 mental health interventions in primary and secondary school settings. A systematic search of published research was conducted in CINAHL, Education Research Complete, Embase, ERIC, Medline, PsycINFO and SocINDEX electronic databases. This scoping review followed a two-level screening process where articles were screened in duplicate by two blinded reviewers. A total of 288 articles were included in this scoping review. Tier 2 mental health interventions in schools have significantly increased since 1965, increasing to about 24 research publications per year. Interventions mainly targeted youth with behavioural problems (51.04%), social difficulties (21.88%), emotional problems (20.49%), and substance abuse (18.06%). Tier 2 interventions were administered by teachers (58.33%) and most often delivered in a group setting (42.01%). This scoping review demonstrated that Tier 2 mental health interventions in schools are gaining prominence in the literature and primarily target children with externalizing behavioural problems. The flexibility of Tier 2 interventions allows them to be implemented in a variety of settings and treat several symptoms making them ideal for broad-based mental health support in schools.

Abstract Recent advances in molecular analyses of ovarian cancer have revealed a wealth of promising tumour‐specific biomarkers, including protein, DNA mutations and methylation; however, reliably detecting such alterations at satisfactorily high sensitivity and specificity through low‐cost methods remains challenging, especially in early‐stage diseases. Here we present PapDREAM, a new approach that enables detection of rare, ovarian‐cancer‐specific aberrations of DNA methylation from routinely‐collected cervical Pap specimens. The PapDREAM approach employs a microfluidic platform that performs highly parallelized digital high‐resolution melt to analyze locus‐specific DNA methylation patterns on a molecule‐by‐molecule basis at or near single CpG‐site resolution at a fraction (

Coronaviruses have caused three severe epidemics since the start of the 21st century: SARS, MERS and COVID-19. The severity of the ongoing COVID-19 pandemic and increasing likelihood of future coronavirus outbreaks motivates greater understanding of factors leading to severe coronavirus disease. We screened ten strains from the Collaborative Cross mouse genetic reference panel and identified strains CC006/TauUnc (CC006) and CC044/Unc (CC044) as coronavirus-susceptible and resistant, respectively, as indicated by variable weight loss and lung congestion scores four days post-infection. We generated a genetic mapping population of 755 CC006xCC044 F2 mice and exposed the mice to one of three genetically distinct mouse-adapted coronaviruses: clade 1a SARS-CoV MA15 (n=391), clade 1b SARS-CoV-2 MA10 (n=274), and clade 2 HKU3-CoV MA (n=90). Quantitative trait loci (QTL) mapping in SARS-CoV MA15- and SARS-CoV-2 MA10-infected F2 mice identified genetic loci associated with disease severity. Specifically, we identified seven loci associated with variation in outcome following infection with either virus, including one, HrS43, that is present in both groups. Three of these QTL, including HrS43, were also associated with HKU3-CoV MA outcome. HrS43 overlaps with a QTL previously reported by our lab that is associated with SARS-CoV MA15 outcome in CC011xCC074 F2 mice and is also syntenic with a human chromosomal region associated with severe COVID-19 outcomes in humans GWAS. The results reported here provide: (a) additional support for the involvement of this locus in SARS-CoV MA15 infection, (b) the first conclusive evidence that this locus is associated with susceptibility across the Sarbecovirus subgenus, and (c) demonstration of the relevance of mouse models in the study of coronavirus disease susceptibility in humans.

IntroductionThis work presents a method to treat stereotactic body radiation therapy (SBRT) for pancreatic cancer on a magnetic resonance-guided linear accelerator (MR-linac) using daily adaptation, real-time motion monitoring, and abdominal compression.MethodsThe motion management and treatment planning process involves a magnetic resonance imaging (MRI) simulation with cine and 3D images, a computed tomography (CT) simulation with a breath-hold CT and a 4DCT, pre-treatment verification and planning MRI, and intrafraction MRI cine images.ResultsThe results from 26 patients were included in this work. Our motion management process results in consistent motion analysis on the CT simulation, MRI simulation, and each treatment fraction. The liver dome was found to be an overestimate of tumor superior/inferior (SI) motion for most patients. Adding compression reduced SI liver dome motion by 6.2 mm on average. Clinical outcomes are similar to those observed in the literature.ConclusionsIn this work, we demonstrate how pancreatic SBRT can be successfully treated on an MR-linac using abdominal compression. This allows for an increased duty cycle compared to gating and/or breath-hold techniques.

Coronavirus (CoV) cause considerable morbidity and mortality in humans and other mammals, as evidenced by the emergence of Severe Acute Respiratory CoV (SARS-CoV) in 2003, Middle East Respiratory CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. Although poorly characterized, natural genetic variation in human and other mammals modulate virus pathogenesis, as reflected by the spectrum of clinical outcomes ranging from asymptomatic infections to lethal disease. Using multiple human epidemic and zoonotic Sarbecoviruses, coupled with murine Collaborative Cross genetic reference populations, we identify several dozen quantitative trait loci that regulate SARS-like group-2B CoV pathogenesis and replication. Under a Chr4 QTL, we deleted a candidate interferon stimulated gene, Trim14 which resulted in enhanced SARS-CoV titers and clinical disease, suggesting an antiviral role during infection. Importantly, about 60 % of the murine QTL encode susceptibility genes identified as priority candidates from human genome-wide association studies (GWAS) studies after SARS-CoV-2 infection, suggesting that similar selective forces have targeted analogous genes and pathways to regulate Sarbecovirus disease across diverse mammalian hosts. These studies provide an experimental platform in rodents to investigate the molecular-genetic mechanisms by which potential cross mammalian susceptibility loci and genes regulate type-specific and cross-SARS-like group 2B CoV replication, immunity, and pathogenesis in rodent models. Our study also provides a paradigm for identifying susceptibility loci for other highly heterogeneous and virulent viruses that sporadically emerge from zoonotic reservoirs to plague human and animal populations.

Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision-making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the associated behavioral changes and increased vulnerability. Here, we utilized fast scan cyclic voltammetry and microdialysis to examine differences in dopamine release as well as mechanisms that underlie differential dopamine signaling in the nucleus accumbens (NAc) core of adolescent (P28-35) and adult (P70-90) male rats. We show baseline differences between adult and adolescent-stimulated dopamine release in male rats, as well as opposite effects of the α6 nicotinic acetylcholine receptor (nAChR) on modulating dopamine release. The α6-selective blocker, α-conotoxin, increased dopamine release in early adolescent rats, but decreased dopamine release in rats beginning in middle adolescence and extending through adulthood. Strikingly, blockade of GABAA and GABAB receptors revealed that this α6-mediated increase in adolescent dopamine release requires NAc GABA signaling to occur. We confirm the role of α6 nAChRs and GABA in mediating this effect in vivo using microdialysis. Results herein suggest a multisynaptic mechanism potentially unique to the period of development that includes early adolescence, involving acetylcholine acting at α6-containing nAChRs to drive inhibitory GABA tone on dopamine release.

Despite the shortage of physicians in the United States, there is no consensus among medical educators as to how to address the nation's unmet needs. A growing but unfulfilled argument is to revisit the configuration of medical education and the time required to complete medical training. Pilot programs, such as shortened programs or advancement-in-place structures to accelerate the practice capability of trainees, have been attempted. This manuscript addresses underlying economic and human considerations that medical educators must reconcile, drawing on lessons from international educational structures, as we advance toward a system that supports the needs of the communities that our graduates will serve.

Locomotor adaptation to abrupt and gradual perturbations are likely driven by fundamentally different neural processes. The aim of this study was to quantify brain dynamics associated with gait adaptation to a gradually introduced gait perturbation, which typically results in smaller behavioral errors relative to an abrupt perturbation. Loss of balance during standing and walking elicits transient increases in midfrontal theta oscillations that have been shown to scale with perturbation intensity. We hypothesized there would be no significant change in anterior cingulate theta power (4–7 Hz) with respect to pre-adaptation when a gait perturbation is introduced gradually because the gradual perturbation acceleration and stepping kinematic errors are small relative to an abrupt perturbation. Using mobile electroencephalography (EEG), we measured gait-related spectral changes near the anterior cingulate, posterior cingulate, sensorimotor, and posterior parietal cortices as young, neurotypical adults (n = 30) adapted their gait to an incremental split-belt treadmill perturbation. Most cortical clusters we examined (>70%) did not exhibit changes in electrocortical activity between 2–50 Hz. However, we did observe gait-related theta synchronization near the left anterior cingulate cortex during strides with the largest errors, as measured by step length asymmetry. These results suggest gradual adaptation with small gait asymmetry and perturbation magnitude may not require significant cortical resources beyond normal treadmill walking. Nevertheless, the anterior cingulate may remain actively engaged in error monitoring, transmitting sensory prediction error information via theta oscillations.

By phasing out production and consumption of most ozone-depleting substances (ODSs), the Montreal Protocol on Substances that Deplete the Ozone Layer (Montreal Protocol) has avoided consequences of increased ultraviolet (UV) radiation and will restore stratospheric ozone to pre-1980 conditions by mid-century, assuming compliance with the phaseout. However, several studies have documented an unexpected increase in emissions and suggested unreported production of trichlorofluoromethane (CFC-11) and potentially other ODSs after 2012 despite production phaseouts under the Montreal Protocol. Furthermore, because most ODSs are powerful greenhouse gases (GHGs), there are significant climate protection benefits in collecting and destroying the substantial quantities of historically allowed production of chemicals under the Montreal Protocol that are contained in existing equipment and products and referred to as ODS “banks”. This technical note presents a framework for considering offsets to ozone depletion, climate forcing, and other environmental impacts arising from occurrences of unexpected emissions and unreported production of Montreal Protocol controlled substances, as recently experienced and likely to be experienced again. We also show how this methodology could be applied to the destruction of banks of controlled ODSs and GHGs or to halon or other production allowed under a Montreal Protocol Essential Use Exemption or Critical Use Exemption. Further, we roughly estimate the magnitude of offset each type of action could provide for ozone depletion, climate, and other environmental impacts that Montreal Protocol Parties agree warrant remedial action.

Individuals with transtibial amputation can activate residual limb muscles to volitionally control robotic ankle prostheses for walking and postural control. Most continuous myoelectric ankle prostheses have used a tethered, pneumatic device. The Open Source Leg allows for myoelectric control on an untethered electromechanically actuated ankle. To evaluate continuous proportional myoelectric control on the Open Source Ankle, we recruited five individuals with transtibial amputation. Participants walked over ground with an experimental powered prosthesis and their prescribed passive prosthesis before and after multiple powered device practice sessions. Participants averaged five hours of total walking time. After the final testing session, participants indicated their prosthesis preference via questionnaire. Participants tended to increase peak ankle power after practice (powered $0.80~\pm ~1.02$ W/kg and passive $0.39~\pm ~0.31$ W/kg). Additionally, participants tended to generate greater ankle work with the powered prosthesis compared to their passive device ( $0.13~\pm $ .15 J/kg increase). Although work and peak power generation were not statistically different between the two prostheses, participants preferred walking with the prosthesis under myoelectric control compared to the passive prosthesis. These results indicate individuals with transtibial amputation learned to walk with an untethered powered prosthesis under continuous myoelectric control. Four out 5 participants generated larger magnitudes in peak power compared to their passive prosthesis after practice sessions. An additional important finding was participants chose to walk with peak ankle powers about half of what the powered prosthesis was capable of based on mechanical testing.

Abstract A wide range of critical infrastructures are connected via wide area networks as well as the Internet-of-Thing (IoT). Apart from natural disasters, these infrastructures, providing services such as electricity, water, gas, and Internet, are vulnerable to terrorist attacks. Clearly, damages to these infrastructures can have dire consequences on economics, health services, security and safety, and various business sectors. An infrastructure network can be represented as a directed graph in which nodes and edges denote operation entities and dependencies between entities, respectively. A knowledgeable attacker who plans to harm the system would aim to use the minimum amount of effort, cost, or resources to yield the maximum amount of damage. Their best strategy would be to attack the most critical nodes of the infrastructure. From the defender’s side, the strategy would be to minimize the potential damage by investing resources in bolstering the security of the critical nodes. Thus, in the struggle between the attacker and defender, it becomes important for both the attacker and defender to identify which nodes are most critically significant to the system. Identifying critical nodes is a complex optimization problem. In this paper, we first present the problem model and then propose a solution for computing the optimal cost attack while considering the failure propagation. The proposed model represents one or multiple interconnected infrastructures. While considering the attack cost of each node, the proposed method computes the optimal attack that a rational attacker would make. Our problem model simulates one of two goals: maximizing the damage for a given attack budget or minimizing the cost for a given amount of damage. Our technique obtains solutions to optimize the objective functions by utilizing integer-linear programming while observing the constraints for each of the specified goals. The paper reports an extensive set of experiments using various graphs. The results show the efficacy of our technique in terms of its ability to obtain solutions with fast turnaround times.

This study explored stakeholder experiences and attitudes regarding the use of ID scanners in licensed venues in Queensland, Australia. In July 2017, the Queensland Government introduced mandatory, networked ID scanners in licensed venues within designated nightlife districts (SNPs). After 10pm, people seeking to enter late-night licensed venues must provide identification, which is verified by the scanner. The scanner also checks whether the patron has any recorded banning notice/s that may preclude entry into the venue. Semi-structured interviews were conducted with 66 key stakeholders and analysed using thematic analysis. Stakeholders reported that ID scanners support the enforcement of patron bans. Their mandated use within SNPs allows for accurate and timely identification of patrons, and may offer benefits with respect to reducing and solving crime, and improving patron behaviours. Some concerns were expressed regarding data privacy and the need to ensure procedural fairness and consistent use. Overall, the study highlighted the importance of ongoing monitoring and refining of ID scanner policy, particularly with respect to where and when scanners are used.

Studies with dairy cows receiving mixed ration and grazing annual pastures, which have low tiller density, are scarce. This study examined the effect of partial replacement of a total mixed ration (TMR) with annual temperate pasture. Treatments were ad libitum TMR (TMR100), 75% ad libitum TMR + ryegrass (Lolium multiflorum ‘Maximus’) (pTMR75), and 50% ad libitum TMR + ryegrass (pTMR50). Twelve multiparous Holstein and F1 Jersey × Holstein cows were divided into six groups (experimental units), taking account of milk production (26.6 ± 4.55 kg/day), days-in-milk (129 ± 50.8) and body weight (546 ± 30.6 kg). Treatments were compared using two 3 × 3 Latin square arangements, comprising three 21-day periods (measurements during final 5 days). Herbage DM intake increased from 4.8 kg/day with pTMR75 to 6.7 kg/day with pTMR50. Total DM intake decreased from 19.4 kg/day (TMR100), to 18.1 and 15.8 kg/day (pTMR75 and pTMR50, respectively). Milk production, energy corrected milk production (ECM), and milk fat content were similar between treatments, averaging 25.6, 28.4 kg/day and 44.6 g/kg, respectively. Ryegrass pastures were able to replace up to 50% of TMR offered to mid lactation dairy cows with no adverse effects on ECM production.

Background: Older adults in residential aged care facilities (RACFs) experience disproportionate levels of poor oral health relative to other groups in the general population, affecting their physical and mental wellbeing. The Oral Health Assessment Tool (OHAT) is a validated and widely used dental assessment tool; however, recent systematic reviews have identified shortcomings with respect to its measurement properties. Objective: The objective of this protocol is to provide a detailed overview of a multidisciplinary qualitative study that aims to (a) co-design and develop a modified OHAT for RACFs and (b) inform the development of an OHAT training package and implementation strategies. Methods: This study will utilize a co-design methodology with aged care residents, caregivers, staff members, and health professionals. The co-design workshops will: (1) investigate the barriers to and enablers of optimal oral healthcare in RACFs; and (2) co-design a modified version of the Oral Health Assessment Tool and a referral to treatment pathway that is appropriate for use in RACFs. The co-design workshops will facilitate group discussion and involve interactive activities using, for example, mind mapping and Sticky Notes. Qualitative data (transcripts and artefacts from co-design activities) will be analyzed in NVivo using an inductive codebook thematic analysis, specifically a template analysis. Conclusion: The findings of this study will inform a modified OHAT (M-OHAT), as well as future study phases regarding training and implementation strategies. It is expected that the M-OHAT will have enhanced usability and relevance to RACFs, facilitating the identification of poor oral health and timely referral to dental treatment.

Background and objectivesIt is difficult to predict post-stroke outcome for people with severe motor impairment, as both clinical tests and corticospinal tract (CST) microstructure may not reliably indicate severe motor impairment. Here, we test whether imaging biomarkers beyond the CST relate to severe upper limb impairment post-stroke by evaluating white matter microstructure in the corpus callosum (CC). In an international, multisite hypothesis-generating observational study we determined if: a) CST asymmetry index can differentiate between individuals with mild-moderate and severe upper limb impairment; and b) CC biomarkers relate to upper limb impairment within individuals with severe impairment post-stroke. We hypothesised that CST asymmetry index would differentiate between mild-moderate and severe impairment, but CC microstructure would relate to motor outcome for individuals with severe upper limb impairment.MethodsSeven cohorts with individual diffusion imaging and motor impairment (Fugl Meyer-Upper Limb) data were pooled. Hand-drawn regions-of-interest were used to seed probabilistic tractography for CST (ipsilesional/contralesional) and CC (prefrontal/premotor/motor/sensory/posterior) tracts. Our main imaging measure was mean fractional anisotropy. Linear mixed-effect regression explored relationships between candidate biomarkers and motor impairment, controlling for observations nested within cohorts, as well as age, sex, time post-stroke and lesion volume.ResultsData from 110 individuals (30 mild-moderate, 80 with severe motor impairment) were included. In the full sample, greater CST asymmetry index (i.e., lower fractional anisotropy in the ipsilesional hemisphere, p

We explore privilege and its systemic intertwining with management education curricula. We take the view that "privilege as power and control" is intimately bound up with shareholder primacy as a foundation of mainstream management education (Lund Dean & Forray, 2021). In an attempt to tackle this, we provide a single case study of how we "appreciate" a broad concept of Indigenous stewardship in a brand-new foundation unit called "Responsible Business Mindset," as part of a Master of Commerce program at a large Australian university. By proactively engaging with Indigenous stewardship to tackle privilege we contribute to the literature on engaging with privilege in management education curricula. We highlight how a concept of Indigenous stewardship may help us to reimagine business, where business no longer ignores the interconnections and interdependencies it has with the communities and natural environments within which it operates. Such a concept may also be a means to bolster alternative narratives to shareholder primacy that currently exclude a meaningful debate about privilege. At the same time, the entire exercise of introducing a new concept into the curricula has brought about a deep and critical self-reflection of our own privilege and how we as educators can respectfully and meaningfully introduce such concepts with a sense of appreciation rather than appropriation.

This article explores the ways in which female teachers negotiate their developing teacher identities and educational reform. It provides interesting data from the case of India that reflects female teacher identity and agency in the context of educational reform. Few studies specifically reference gendered responses to education reform; fewer still focus on how female teachers respond and act upon these reforms. It is argued that educational reform efforts in India should take into account female teachers' lives and development. This small qualitative study explores through semi-structured interviews the emerging identities of eight female teachers who work in five different higher secondary schools in Chennai, Tamil Nadu. Their responses were analysed using the voice-centred relational approach. The findings point to the importance of understanding the different ways female teachers negotiate their developing teacher identities in response to the changing structural and cultural contexts in which they find themselves.

This article examines the historical backdrop to the involvement of teaching Sisters in convent schooling for girls in India and the Islamic Republic of Pakistan, since the late nineteenth century. It then explores how, as a consequence of a range of social changes, leadership in convent schools has changed in both countries, across the twentieth century. The Irish Sisters who founded and established these schools commenced "passing the baton" of convent school leadership to Indian and Pakistani women. The article draws on interviews to examine ways in which successive generations of women in the study refer to the legacy of the past, and the issue of women in education leadership.

During the dual pandemics of COVID-19 and continuing racial injustices, many literacy clinics pivoted to online instruction. Educators were now in students' homes for virtual literacy lessons. To understand how literacy clinics responded, teacher educators analyzed a national survey of clinic directors' perspectives. Analysis regarding family communication and participation led to six categories: parent involvement, communication, family presence, learning with families v. teaching families, diminished/enhanced experiences, and access/digital divide. Contrasting examples from these categories were chosen to create a research-based verbatim audio play. Teacher educators then used fieldnotes, artifacts, and transcripts from their clinical experiences to create vignettes of clinic instruction, which they then put into dialogue with survey findings to reconceptualize, animate, and (re)present these as navigating digital divides/access, challenging school-centric definitions of family literacy, and building community with families in online settings. Findings from this study highlight that as the technological landscape of literacy clinics changes, so must our understanding of engaging with families' literacy practices.

Organizational citizenship behavior refers to "individual behavior that is discretionary, not directly or explicitly recognized by the formal reward system, and that in the aggregate promotes the effective functioning of the organization" (Organ, 1988, p. 4). Previous research suggests organizational citizenship behavior can be a beneficial concept in a collaborative learning setting because it may affect learning outcomes, student satisfaction, and social loafing in organizations and teams. However, a measure of organizational citizenship behavior in the collaborative learning setting does not exist. This research aimed to adapt and validate the measurement of organizational citizenship behavior in a collaborative learning setting. 511 college students in Korea participated in this study. First, we conducted exploratory analysis, and as a result, four dimensions were extracted: altruism, conscientiousness, sportsmanship, and courtesy. Subsequently, we conducted confirmatory factor analysis to examine the stability of multidimensionality, and the result indicated the four-factor structure has a reasonable fit statistically. In addition, we examined convergent, discriminant and criterion validities. With this validated measurement, future studies can examine how organizational citizenship behavior in the collaborative learning is related to other learning constructs such as student engagement and academic achievement.

Professional development offerings for current and aspiring educational developers can be sparse and neither fully contextually appropriate nor personally relevant given the range of experiences people bring to the field. In the absence of suitable professionalization programs, we created a self-defined professional development approach to support us in our educational developer work. Using a framework for reflective writing, we describe our approach and the strategies we implemented, and we consider at a "meta" level what contributes to the viability or success of our self-defined professional development plan. Measures for assessing success were framed using utilization-focused evaluation. We outline implications for future practice and propose that a self-defined approach to professional development could be adopted and adapted by other current and aspiring educational developers.

Background: Inclusive STEM high schools employ a variety of instructional strategies, including PBL (problem and/or project-based learning) experiences, with the goals of building students' 21st century skills, facilitating long-term academic success, and encouraging pursuit of STEM careers. PBL approaches are central to the goals of inclusive STEM schools; however, at this writing, no description of the implementation of PBL at these schools exists. Material and Methods: The current study draws on classroom observations and teacher interviews to describe PBL implementation across schools and classrooms. We describe specific instructional practices and classroom behaviors that teachers and students engage in during PBL. Results: Results highlight the multifaceted and multidimensional nature of PBL implementation, and that consistencies in practice do exist across inclusive STEM schools. Additionally, quantitative results show increased use of particular strategies in PBL experiences, as compared with non-PBL classes. Conclusions: This paper provides an in-depth look at instructional practices used in PBL approaches at inclusive STEM schools across the country, and findings have implications for how researchers and practitioners understand and use PBL going forward.