Racial/Ethnic Trends in Virtual Mental Health Care Utilization Among Undergraduate Students: A Descriptive Study.

BACKGROUND: Undergraduate students are particularly in need of mental health support, but demand has far surpassed resources. This gap between mental health diagnoses and support is particularly large among Asian, Hispanic/Latinx, and Black students. Supplementing on-campus care with a virtual-only behavioral health partner may shift these trends. OBJECTIVE: This study is aimed at comparing the number of undergraduate students from different racial/ethnic groups (White, Asian, Islander, Hispanic/Latinx, Black, Native, and Multiracial) engaging in virtual mental health visits as part of a partnership with a company providing virtual-only care, with the total enrolled undergraduate students at the same 113 institutions. METHODS: We used de-identified visit data and self-reported race/ethnicity to define the "patient" population of undergraduates accessing care. We compared that to the full "student" population of undergraduates among the same schools, available as part of the Integrated Postsecondary Education Data System (IPEDS). RESULTS: Patient population race/ethnicity (N = 14,870) differed significantly from student population race/ethnicity (N = 619,459). A significant effect ( χ 26 = 2258, P < .001) indicated that patient demographics differed from student demographics. We found proportionally more Asian, Black, and Multiracial patients than students. At the same time, we found proportionally fewer White and Hispanic/Latinx patients than students. CONCLUSIONS: We conclude that, in contrast to prior literature in traditional mental health care, some racial/ethnic minority undergraduates (Asian, Black, and Multiracial) may actually access care at a higher rate under a fully virtual model. On the other hand, White and Hispanic/Latinx students may access care less frequently.

Advanced practice physiotherapy care in emergency departments for patients with musculoskeletal disorders: a pragmatic cluster randomized controlled trial and cost analysis.

BACKGROUND: Advanced practice physiotherapy (APP) models of care where physiotherapists are primary contact emergency department (ED) providers are promising models of care to improve access, alleviate physicians' burden, and offer efficient centered patient care for patients with minor musculoskeletal disorders (MSKD). OBJECTIVES: To compare the effectiveness of an advanced practice physiotherapist (APPT)-led model of care with usual ED physician care for persons presenting with a minor MSKD, in terms of patient-related outcomes, health care resources utilization, and health care costs. METHODS: This trial is a multicenter stepped-wedge cluster randomized controlled trial (RCT) with a cost analysis. Six Canadian EDs (clusters) will be randomized to a treatment sequence where patients will either be managed by an ED APPT or receive usual ED physician care. Seven hundred forty-four adults with a minor MSKD will be recruited. The main outcome measure will be the Brief Pain Inventory Questionnaire. Secondary measures will include validated self-reported disability questionnaires, the EQ-5D-5L, and other health care utilization outcomes such as prescription of imaging tests and medication. Adverse events and re-visits to the ED for the same complaint will also be monitored. Health care costs will be measured from the perspective of the public health care system using time-driven activity-based costing. Outcomes will be collected at inclusion, at ED discharge, and at 4, 12, and 26 weeks following the initial ED visit. Per-protocol and intention-to-treat analyses will be performed using linear mixed models with a random effect for cluster and fixed effect for time. DISCUSSION: MSKD have a significant impact on health care systems. By providing innovative efficient pathways to access care, APP models of care could help relieve pressure in EDs while providing efficient care for adults with MSKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05545917 . Registered on September 19, 2022.

Antimicrobial usage in farm animal practices in the UK: A mixed-methods approach.

Antimicrobial resistance (AMR) is a growing One Health problem. Monitoring antimicrobial usage in farm animals is crucial for tackling AMR. A cohort study using the electronic clinical records during 2019 from 23 farm animal veterinary practices across the UK belonging to two corporate groups, with a range of 2-14 veterinarians per practice, estimated the usage of antimicrobials and highest priority critically important antimicrobials (HP-CIAs). Risk factors for using HP-CIAs were evaluated using hierarchical mixed-effects logistic regression modelling with practice ID and farm ID added as random effects. Using a qualitative approach, veterinarians from one of the participating practice groups were recruited for a qualitative study to explore the barriers and facilitators in relation to antimicrobial use. Semi-structured interviews were conducted with participants and analysed thematically. During the year 2019, 98,824 antimicrobial prescribing events overall were recorded from the treatment records of the 23 participating practices. The median count of antimicrobial events per practice was 3226 (range 263-22,159). There were 17,111/98,824 (17.3%) HP-CIAs events overall, with a median of 15.4% at practice level (range 4.8-22.1%). Penicillins were the most frequently used antimicrobials 29,539/98,824 (29.9%) followed by tetracyclines 19,015/98,824 (19.2%). HP-CIA use was strongly clustered, with more clustering seen at the farm level (intraclass correlation coefficient (ICC)= 0.56) than at the practice level (ICC= 0.32). Country, route of administration, season and practice type were significantly associated with the usage of HP-CIAs. Four main themes were identified from the analysis of the veterinarians' interviews: pressure from the industry, drug-related factors, knowledge level of veterinarians and clinical factors. Supermarket contracts and farm assurance schemes were facilitators for reducing antimicrobial use and the use of HP-CIAs. Ease of administration and the withdrawal period of the antimicrobials influenced veterinarians' choice of antimicrobials. The clinical condition and clinical signs presented on farm were reported to influence participating veterinarians' prescribing decision. Participants showed a good understanding of AMR, responsible use of antimicrobials and the term 'critically important antimicrobials'. In conclusion, integrating the quantitative and qualitative findings can inform policymaking on antimicrobials stewardship in farm practice. By estimating the relative levels of clustering of antimicrobial use at the practice and farm level, as well as identifying major risk factors for using HP-CIAs, more targeted interventions can be designed to promote responsible antimicrobial use in farm practice. Furthermore, better understanding the industry pressures on farms to reduce antimicrobials usage could reduce the barriers for responsible antimicrobial use by veterinarians.

Social Isolation in Community-Dwelling Older Adults During COVID-19: Understanding the Role of Resilience.

The COVID-19 pandemic increased social isolation for many older adults, causing concern for their health and well-being. To enhance understanding of how community-dwelling older adults were impacted by prolonged social isolation during COVID-19, a qualitative descriptive study was conducted to: (1) explore the self-reported factors supporting their resilience during COVID-19 related social isolation, and (2) to help understand the intentional and unintentional outcomes of the government mandated health measures. A total of 19 community dwelling older adults were sampled. Factors that supported older adults' resilience during COVID-19 included maintaining positivity, drawing on historical experiences of resilience and finding opportunities to connect with their community. However, collective safety came with losses: such as time, freedom, opportunity, engagement, and initiative. The findings provide insight on contributing factors to resilience against social isolation in older adults and suggest the value of collective, community-based approaches to build resilience across variable contexts in this population.

A survey of calf management practices and farmer perceptions of calf housing in UK dairy herds.

Adoption of optimal management techniques for rearing dairy calves has significant effects on their health, welfare, and productivity. Despite much published literature on best practice, calf morbidity and mortality rates remain high. This survey aimed to establish current calf management practices in the United Kingdom, along with farmer perceptions surrounding different housing types. A survey containing 48 questions was distributed online to UK farmers via social media, online forums, and a convenience sample of veterinary practices and was completed by 216 participants. A descriptive analysis with frequency distributions was calculated, with chi-squared tests, linear regression and multinomial regression performed to assess associations between variables. There was a low level of regular veterinary involvement in day-to-day health decision making for calves (3/216, 1.4%), highlighting the need for appropriate staff training and standard operating procedures to ensure prudent antimicrobial usage. Restricted calf milk feeding remains highly prevalent in the United Kingdom, with most calves fed milk replacer (114/216, 52.8%), twice daily (189/216, 87.5%), initially given milk at 4 L/d (66/216, 30.6%) or 6 L/d (47/216, 21.8%). There was, however, a small number of farmers initially feeding only 2 to 3 L/d (28/216, 13.0%). Euthanasia of bull calves (5/216, 2.3%) and feeding antimicrobial waste milk to calves (8/216, 3.7%) both occurred on some farms. With regard to housing, use of individual calf pens has reduced from around 60% in 2010 to 38.4% in this study (83/216), with this reduction being partly driven by the policy of UK milk buyers. Farmer perceptions indicated that individual housing was thought to help to improve calf health and feed monitoring of calves, suggesting that successful use of group housing requires a higher level of stockmanship. The majority of farmers did not provide fresh bedding to calves on a daily basis (141/216, 65.3%), and relatively few disinfected both the calf housing (38.0%) and ground (47.7%) between calves, suggesting that hygiene practices may require additional attention in farm management protocols.

Influence of season, age, sex, and time of day on the endocrine profile of the common bottlenose dolphin (Tursiops truncatus).

Understanding baseline hormone levels, the magnitude of intra-individual variability, and their variation as a function of life history is difficult in toothed whales (e.g. dolphins and porpoises) because of the effects of capture stress. To determine the endocrine profile of the common bottlenose dolphin (Tursiops truncatus) as a function of season, time of day (TOD), age, sex, and reproductive status, blood corticosteroids, thyroid hormones, and catecholamines were repeatedly measured in a managed-care population exposed to ambient light and water temperatures of San Diego Bay. Additionally, fecal hormone metabolites were assessed for cortisol, aldosterone, and triiodothyronine. Samples were collected at two to four-week intervals over a period of two years, and multiple times within a day at monthly intervals over a year. Samples were collected through the voluntary participation of the dolphins in the blood draws and fecal collections in order to avoid the effects of handling stress. All serum hormones except aldosterone significantly varied with season and all serum hormones except total thyroxine significantly varied as a function of TOD. Fecal glucocorticoid metabolites significantly correlated with circulating cortisol levels, and there was a significant seasonal effect on triiodothyronine fecal metabolites. Strong seasonal effects demonstrated complex interactions with age and sex suggesting that contextual information is critical to interpreting differences in endocrine profiles. Strong circadian patterns further suggest that sampling design is important to the interpretation of blood or fecal collections, particularly since diurnal changes in some serum hormone levels are similar to the magnitude of seasonal differences. Despite potential impacts of feeding schedules on diurnal patterns, managed care populations can provide important insights into seasonal and age-related endocrine changes in toothed whales.

Immature stages, host plants and natural enemies of Henosepilachna implicata (Mulsant) (Coleoptera: Coccinellidae) with DNA sequence data and a new synonym and notes on some Indian species of Epilachnini.

Life stages of Henosepilachna implicata (Mulsant), an economically important species of Epilachnini in India, are documented and illustrated. Mitochondrial DNA sequence data is provided for the first time for H. implicata with additional details on its host plants, distribution, and natural enemies. Its similarities and differences with other common pestiferous Henosepilachna spp. in India such as H. vigintioctopunctata (F.), H. septima (Dieke) and H. pusillanima (Mulsant) are discussed. Epilachna circularis Korschefsky, 1933 is found to be conspecific with H. implicata and is reduced to a junior synonym of the latter (new synonym). Notes are given on the distribution and natural enemies of some other species of Epilachnini of the Indian region.

Removal of uterine polyps: clinical management and surgical approach.

Endometrial polyps have a reported prevalence from 7.8% up to 30% and are one of the most cost-consuming gynecological conditions for our specialty. There are strong practitioner beliefs that surgical removal of endometrial polyps is highly beneficial, particularly for those with abnormal uterine bleeding and infertility. Additionally, polypectomy is indicated to reduce the risk of malignancy. Transvaginal ultrasound is the first-line diagnostic option for detection of endometrial polyps, while sonohysterography has similar accuracy as hysteroscopy in the diagnostic confirmation. Blind dilatation and curettage is not recommended for polyp removal; rather, hysteroscopy in the operating room and office setting using small-diameter hysteroscopic equipment is the standard approach. This can be performed without anesthesia in most women. While hysteroscopy is an effective method for polypectomy with a low complication rate, it is unknown whether this is truly beneficial for reproductive-age women with infertility and prior assisted reproduction therapy. The risk of malignancy in women with postmenopausal bleeding justifies the necessity of polypectomy with histologic tissue examination. In asymptomatic women, the risk of malignancy is low, and there are no known benefits of polyp removal in the prevention of malignant transformation. Cost-effective studies remain to be done to provide us with the optimal approach to endometrial polyps including the management of asymptomatic and/or infertile women, ideal location including office-based or the operating room setting, complication prevention including intrauterine adhesions, and recurrence issues.

The role of intra-operative cell salvage in patient blood management for revision hip arthroplasty: a prospective cohort study.

Cell salvage is an important component of blood management in patients undergoing revision hip arthroplasty surgery. However concerns regarding efficacy and patient selection remain. The aims of this study were to describe intra-operative blood loss, cell salvage re-infusion volumes and red blood cell transfusion rates for revision hip procedures and to identify factors associated with the ability to salvage sufficient blood intra-operatively to permit processing and re-infusion. Data were collected from a prospective cohort of 664 consecutive patients undergoing revision hip surgery at a single tertiary centre from 31 March 2015 to 1 April 2018. Indications for revision surgery were aseptic (n = 393 (59%)) fracture (n = 160 (24%)) and infection (n = 111 (17%)). Salvaged blood was processed and re-infused when blood loss exceeded 500 ml. Mean (SD) intra-operative blood loss was 1038 (778) ml across all procedures. Salvaged blood was re-infused in 505 of 664 (76%) patients. Mean (SD) re-infusion volume was 253 (169) ml. In total, 246 of 664 (37%) patients received an allogeneic red blood cell transfusion within 72 h of surgery. Patients undergoing femoral component revision only (OR (95%CI) 0.41 (0.23-0.73)) or acetabular component revision only (0.53 (0.32-0.87)) were less likely to generate sufficient blood salvage volume for re-infusion compared with revision of both components. Compared with aseptic indications, patients undergoing revision surgery for infection (1.87 (1.04-3.36)) or fracture (4.43 (2.30-8.55)) were more likely to generate sufficient blood salvage volume for re-infusion. Our data suggest that cell salvage is efficacious in this population. Cases where the indication is infection or fracture and where both femoral and acetabular components are to be revised should be prioritised.

Inflation of 430-parsec bipolar radio bubbles in the Galactic Centre by an energetic event.

The Galactic Centre contains a supermassive black hole with a mass of four million Suns1 within an environment that differs markedly from that of the Galactic disk. Although the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings2. Also, although the levels of star formation in the Galactic Centre have been approximately constant over the past few hundred million years, there is evidence of increased short-duration bursts3, strongly influenced by the interaction of the black hole with the enhanced gas density present within the ring-like central molecular zone4 at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200-parsec region is characterized by large amounts of warm molecular gas5, a high cosmic-ray ionization rate6, unusual gas chemistry, enhanced synchrotron emission7,8, and a multitude of radio-emitting magnetized filaments9, the origin of which has not been established. Here we report radio imaging that reveals a bipolar bubble structure, with an overall span of 1 degree by 3 degrees (140 parsecs × 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 × 1052 ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities.

Risk factors and mitigation of influenza among Indigenous children in Australia, Canada, United States, and New Zealand: a scoping review.

AIM: This review considers prominent risk factors and mitigation strategies of influenza among Indigenous children. METHODS: Seven electronic databases were searched from the period of 2004-2017 to locate articles discussing influenza among Indigenous children in the developed circumpolar nations of Australia, Canada, United States, and New Zealand. Articles selected for inclusion discussed influenza among Indigenous children as either individuals or as a part of a community. Ancestry searches of articles meeting the review criteria were also undertaken to discern seminal research in this topic area. RESULTS: From the 39 primary research studies included, marked risk factors and mitigation strategies of influenza among Indigenous children were identified using inductive analysis. Notable risk factors included age under 2 years, cigarette smoke exposure, presence of a chronic illness, and crowded living conditions. Successful mitigation of influenza for Indigenous children included strategies to improve vaccine coverage, provision of health education, and policy change. CONCLUSION: In the past, the impact of influenza upon Indigenous communities has been devastating for both children and their families. By utilizing existing public health infrastructure and collaborating with culturally unique Indigenous groups, preventive action for Indigenous children at significant risk of contracting influenza can be realized.

Isolation of DNA from small amounts of elephant ivory: Sampling the cementum with total demineralization extraction.

Genotyping ivory samples can determine the geographic origin of poached ivory as well as the legality of ivory being sold in ivory markets. We conducted a series of experiments to determine where the DNA is most concentrated in ivory samples and how best to increase DNA yield from groups of samples likely to vary in DNA concentration. We examined variation in DNA amplification success from: the layer(s) of the tusk (cementum and/or dentine) being extracted, demineralization temperature and time, and the concentration of eluates. Since demineralization of the pulverized sample produces a pellet and supernatant, we also assessed DNA amplification success from the pellet, the supernatant, their combination, as well as variation in the respective amounts used for extraction. Our results show that the outer cementum layer of the tusk contains the highest concentration of DNA and should be separated and used exclusively as the source material of ivory processed for extraction, when available. Utilizing the combined demineralized lysate improves extraction efficiency, as does increasing demineralization time to 3 or more days, conducted at 4°C. The most significant improvements occurred for low template DNA ivory samples followed by medium quality samples. Amplification success of high quality samples was not affected by these changes. Application of this optimized method to 3068 ivory samples resulted in 81.2% of samples being confirmed for both alleles at a minimum of 10 out of 16 microsatellite loci, which is our threshold for inclusion in DNA assignment analyses.

Randomised positive control trial of NSAID and antimicrobial treatment for calf fever caused by pneumonia.

One hundred and fifty-four preweaning calves were followed between May and October 2015. Calves were fitted with continuous monitoring temperature probes (TempVerified FeverTag), programmed so a flashing light emitting diode (LED) light was triggered following six hours of a sustained ear canal temperature of ≥39.7°C. A total of 83 calves (61.9 per cent) developed undifferentiated fever, with a presumptive diagnosis of pneumonia through exclusion of other calf diseases. Once fever was detected, calves were randomly allocated to treatment groups. Calves in group 1 (NSAID) received 2 mg/kg flunixin meglumine (Allevinix, Merial) for three consecutive days and group 2 (antimicrobial) received 6 mg/kg gamithromycin (Zactran, Merial). If fever persisted for 72 hours after the initial treatment, calves were given further treatment (group 1 received antimicrobial and group 2 received NSAID). Calves in group 1 (NSAID) were five times more likely (P=0.002) to require a second treatment (the antimicrobial) after 72 hours to resolve the fever compared with the need to give group 2 (antimicrobial) calves a second treatment (NSAID). This demonstrates the importance of ongoing monitoring and follow-up of calves with respiratory disease. However, of calves with fever in group 1 (NSAID), 25.7 per cent showed resolution following NSAID-only treatment with no detrimental effect on the development of repeated fever or daily live weight gain. This suggests that NSAID alone may be a useful first-line treatment, provided adequate attention is given to ongoing monitoring to identify those cases that require additional antimicrobial treatment.

Assessing the impact of tailored biosecurity advice on farmer behaviour and pathogen presence in beef herds in England and Wales.

The term 'biosecurity' encompasses many measures farmers can take to reduce the risk of pathogen incursion or spread. As the best strategy will vary between settings, veterinarians play an important role in assessing risk and providing advice, but effectiveness requires farmer acceptance and implementation. The aim of this study was to assess the effectiveness of specifically-tailored biosecurity advice packages in reducing endemic pathogen presence on UK beef suckler farms. One hundred and sixteen farms recruited by 10 veterinary practices were followed for three years. Farms were randomly allocated to intervention (receiving specifically-tailored advice, with veterinarians and farmers collaborating to develop an improved biosecurity strategy) or control (receiving general advice) groups. A spreadsheet-based tool was used annually to attribute a score to each farm reflecting risk of entry or spread of bovine viral diarrhoea virus (BVDV), bovine herpesvirus-1 (BHV1), Mycobacterium avium subsp. paratuberculosis (MAP), Leptospira interrogans serovar hardjo (L. hardjo) and Mycobacterium bovis (M. bovis). Objectives of these analyses were to identify evidence of reduction in risk behaviours during the study, as well as evidence of reductions in pathogen presence, as indications of effectiveness. Risk behaviours and pathogen prevalences were examined across study years, and on intervention compared with control farms, using descriptive statistics and multilevel regression. There were significant reductions in risk scores for all five pathogens, regardless of intervention status, in every study year compared with the outset. Animals on intervention farms were significantly less likely than those on control farms to be seropositive for BVDV in years 2 and 3 and for L. hardjo in year 3 of the study. Variations by study year in animal-level odds of seropositivity to BHV1 or MAP were not associated with farm intervention status. All farms had significantly reduced odds of BHV1 seropositivity in year 2 than at the outset. Variations in farm-level MAP seropositivity were not associated with intervention status. There were increased odds of M. bovis on intervention farms compared with control farms at the end of the study. Results suggest a structured annual risk assessment process, conducted as a collaboration between veterinarian and farmer, is valuable in encouraging improved biosecurity practices. There were some indications, but not conclusive evidence, that tailored biosecurity advice packages have potential to reduce pathogen presence. These findings will inform development of a collaborative approach to biosecurity between veterinarians and farmers, including adoption of cost-effective strategies effective across pathogens.

Individuals with current suicidal ideation demonstrate implicit "fearlessness of death".

BACKGROUND AND OBJECTIVES: Suicidal behaviour has proved to be difficult to predict, due in part to the particular limitations of introspection within suicidality. In an effort to overcome this, recent research has demonstrated the utility of indirect measures of "implicit" attitudes within the study of suicidality. However, research to date has focused predominantly on implicit self-evaluations and self-death associations. No work has examined implicit evaluations of death, despite the theoretical importance of such evaluations; "fearlessness of death" is central to both the Interpersonal Theory of Suicide and the Integrated Motivational-Volitional model of suicide.. METHODS: Twenty-three psychiatric patients with current suicidal ideation and twenty-five normative university students completed two versions of the Implicit Relational Assessment Procedure (IRAP) that targeted evaluations of death. One task specified personal death (i.e., was self-focused) and the other targeted death in the abstract. RESULTS: Self-focused evaluations of death reliably distinguished between the two groups, correctly classifying 74% of cases, but evaluations of death in the abstract did not. The suicidal group produced specific biases indicating a rejection of the negativity of death. Results are consistent with the definition of suicidality as involving a self-focused wish to die.. LIMITATIONS: For ethical reason, suicidal behaviours were not assessed in the normative group. Groups were therefore not mutually exclusive. This may have decreased the specificity of the IRAP. CONCLUSIONS: Suicidal ideation is associated with an implicit "fearlessness of death". The utility of implicit death-evaluations should therefore be considered alongside self-evaluations and self-death associations in the future..

The age of anxiety? It depends where you look: changes in STAI trait anxiety, 1970-2010.

PURPOSE: Population-level surveys suggest that anxiety has been increasing in several nations, including the USA and UK. We sought to verify the apparent anxiety increases by looking for systematic changes in mean anxiety questionnaire scores from research publications. METHODS: We analyzed all available mean State-Trait Anxiety Inventory scores published between 1970 and 2010. We collected 1703 samples, representing more than 205,000 participants from 57 nations. RESULTS: Results showed a significant anxiety increase worldwide, but the pattern was less clear in many individual nations. Our analyses suggest that any increase in anxiety in the USA and Canada may be limited to students, anxiety has decreased in the UK, and has remained stable in Australia. CONCLUSIONS: Although anxiety may have increased worldwide, it might not be increasing as dramatically as previously thought, except in specific populations, such as North American students. Our results seem to contradict survey results from the USA and UK in particular. We do not claim that our results are more reliable than those of large population surveys. However, we do suggest that mental health surveys and other governmental sources of disorder prevalence data may be partially biased by changing attitudes toward mental health: if respondents are more aware and less ashamed of their anxiety, they are more likely to report it to survey takers. Analyses such as ours provide a useful means of double-checking apparent trends in large population surveys.

Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2.

Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.