PHARMACOKINETICS AND EFFICACY OF A SINGLE TOPICAL DOSE OF EPRINOMECTIN IN GIRAFFE (GIRAFFA SPP.).

Growing resistance to current antiparasitic medications, both in livestock and in zoological species under human care, makes it imperative to evaluate available drugs on the market, such as eprinomectin. In this prospective study, five males and one female of reticulated (Giraffa reticulata; n = 2), Masai (Giraffa tippelskirchii; n = 1), Nubian (Giraffa camelopardalis; n = 2), and hybrid subspecies (n = 1) of giraffe, received 1.5 mg/kg eprinomectin topically along the dorsum. Using high-performance liquid chromatography, concentrations of eprinomectin in plasma samples collected at 0, 4, 24, and 48 h, and 7, 14, 21, and 28 d were evaluated following drug administration. Complete blood cell counts and biochemistry panels were performed before (n = 6) and after (n = 3) eprinomectin administration. Samples for modified double centrifugal fecal flotation (n = 6) were evaluated prior to eprinomectin administration to evaluate for endoparasites and were repeated after the study (n = 5). Noncompartmental pharmacokinetic analysis was applied to the data. The observed maximum plasma concentration was 11.45 ng/ml and the time of observed maximum concentration was 2.67 d. The mean terminal half-life was 5.16 d. No adverse effects were observed related to eprinomectin administration and no blood work changes were observed. Parasite loads decreased (n = 3) or did not change (n = 2) after eprinomectin administration. The mean peak plasma concentration of eprinomectin in giraffe was similar to that achieved in cattle, despite using three times the dose.

Congenital and Neoplastic Cranial Deformities in Wild Giraffe (Giraffa spp.).

Congenital deformities and neoplasia are poorly documented in wildlife, owing to the difficulty of detection in wild populations. Congenital deformities may lead to premature mortality, thus reducing the chances of thorough documentation. Importantly, neoplasia diagnoses depend on either sampling suspicious lesions from living individuals or access to fresh, undisturbed carcasses, which can prove challenging. We describe five cases of suspected congenital cranial deformities (midfacial cleft, wry nose, and brachygnathia inferior) and two possible cases of cranial neoplasia (orbital bone mass and a soft tissue mass) opportunistically observed in wild giraffe (Giraffa spp.) across their range in Africa. Although cases are largely limited to subjective description because physical examination is often not possible, it is critical to document such observations to help identify and track potential health concerns in wild giraffe populations.

Ranging behaviours across ecological and anthropogenic disturbance gradients: a pan-African perspective of giraffe (Giraffa spp.) space use.

Animal movement behaviours are shaped by diverse factors, including resource availability and human impacts on the landscape. We generated home range estimates and daily movement rate estimates for 149 giraffe (Giraffa spp.) from all four species across Africa to evaluate the effects of environmental productivity and anthropogenic disturbance on space use. Using the continuous time movement modelling framework and a novel application of mixed effects meta-regression, we summarized overall giraffe space use and tested for the effects of resource availability and human impact on 95% autocorrelated kernel density estimate (AKDE) size and daily movement. The mean 95% AKDE was 359.9 km2 and the mean daily movement was 14.2 km, both with marginally significant differences across species. We found significant negative effects of resource availability, and significant positive effects of resource heterogeneity and protected area overlap on 95% AKDE size. There were significant negative effects of overall anthropogenic disturbance and positive effects of the heterogeneity of anthropogenic disturbance on daily movements and 95% AKDE size. Our results provide unique insights into the interactive effects of resource availability and anthropogenic development on the movements of a large-bodied browser and highlight the potential impacts of rapidly changing landscapes on animal space-use patterns.

Using open data and open-source software to develop spatial indicators of urban design and transport features for achieving healthy and sustainable cities.

Benchmarking and monitoring of urban design and transport features is crucial to achieving local and international health and sustainability goals. However, most urban indicator frameworks use coarse spatial scales that either only allow between-city comparisons, or require expensive, technical, local spatial analyses for within-city comparisons. This study developed a reusable, open-source urban indicator computational framework using open data to enable consistent local and global comparative analyses. We show this framework by calculating spatial indicators-for 25 diverse cities in 19 countries-of urban design and transport features that support health and sustainability. We link these indicators to cities' policy contexts, and identify populations living above and below critical thresholds for physical activity through walking. Efforts to broaden participation in crowdsourcing data and to calculate globally consistent indicators are essential for planning evidence-informed urban interventions, monitoring policy effects, and learning lessons from peer cities to achieve health, equity, and sustainability goals.

Giraffe skin disease: Clinicopathologic characterization of cutaneous filariasis in the critically endangered Nubian giraffe (Giraffa camelopardalis camelopardalis).

Giraffe skin disease (GSD) is an emerging disease of free-ranging giraffe recognized in the last 25 years in several species, including the critically endangered Nubian giraffe (Giraffa camelopardalis camelopardalis) of Uganda. Identifying the cause of GSD and understanding its impact on health were deemed paramount to supporting these vulnerable populations. Sixty-four giraffes were immobilized in Murchison Falls National Park, Uganda, from 2017 to 2019, and GSD lesions were opportunistically biopsied. Fifty-five giraffes (86%) had GSD lesions on the neck, axilla, chest, and cranial trunk. Lesions were categorized into early, intermediary, and dormant stages based on gross and histological characteristics. Early lesions were smaller, crusted nodules with eosinophilic and pyogranulomatous dermatitis and furunculosis. Intermediary lesions were thick plaques of proliferative and fissured hyperkeratosis and acanthosis with dense dermal granulation tissue and severe eosinophilic and granulomatous dermatitis. Lesions appeared to resolve to dormancy, with dormant lesions consisting of hairless plaques of hyperkeratosis with dermal scarring and residual inflammation. The periphery of early and intermediary lesions included follicular granulomas containing adult filarid nematodes, with myriad encysted microfilariae in the superficial dermis. Stage L3 larvae were common in early and intermediary lesions, and dormant lesions had remnant encysted microfilariae with no adult or stage L3 larvae. Nematodes were morphologically and genetically novel with close identity to Stephanofilaria spp. and Brugia malayi, which cause infectious filariasis. Identification of potential insect vectors, long-term monitoring of GSD lesions, and evaluating response to therapy is ongoing in the efforts to help conserve the Nubian giraffe.

Investigating the physical activity, health, wellbeing, social and environmental effects of a new urban greenway: a natural experiment (the PARC study).

BACKGROUND: Evidence for the health benefits of urban green space tends to stem from small, short-term quasi-experimental or cross-sectional observational research, whilst evidence from intervention studies is sparse. The development of an urban greenway (9 km running along 3 rivers) in Northern Ireland provided the opportunity to conduct a natural experiment. This study investigated the public health impact of the urban greenway on a range of physical activity, health, wellbeing, social, and perceptions of the environment outcomes. METHODS: A repeated cross-sectional household survey of adult residents (aged ≥16 years) who lived ≤1-mile radius of the greenway (intervention sample) and > 1-mile radius of the greenway (control sample) was conducted pre (2010/2011) and 6-months post implementation (2016/2017). We assessed changes in outcomes pre- and post-intervention follow-up including physical activity behaviour (primary outcome measure: Global Physical Activity Questionnaire), quality of life, mental wellbeing, social capital and perceptions of the built environment. Linear regression was used to calculate the mean difference between post-intervention and baseline measures adjusting for age, season, education, car ownership and deprivation. Multi-level models were fitted using a random intercept at the super output area (smallest geographical unit) to account for clustering within areas. The analyses were stratified by distance from the greenway and deprivation. We assessed change in the social patterning of outcomes over time using an ordered logit to make model-based outcome predictions across strata. RESULTS: The mean ages of intervention samples were 50.3 (SD 18.9) years at baseline (n = 1037) and 51.7 (SD 19.1) years at follow-up (n = 968). Post-intervention, 65% (adjusted OR 0.60, 95% CI 0.35 to 1.00) of residents who lived closest to the greenway (i.e., ≤400 m) and 60% (adjusted OR, 0.64 95% CI 0.41 to 0.99) who lived furthest from the greenway (i.e.,≥1200 m) met the physical activity guidelines - 68% of the intervention sample met the physical activity guidelines before the intervention. Residents in the most deprived quintiles had a similar reduction in physical activity behaviour as residents in less deprived quintiles. Quality of life at follow-up compared to baseline declined and this decline was significantly less than in the control area (adjusted differences in mean EQ5D: -11.0 (95% CI - 14.5 to - 7.4); - 30.5 (95% CI - 37.9 to - 23.2). Significant change in mental wellbeing was not observed despite improvements in some indicators of social capital. Positive perceptions of the local environment in relation to its attractiveness, traffic and safety increased. CONCLUSIONS: Our findings illustrate the major challenge of evaluating complex urban interventions and the difficulty of capturing and measuring the network of potential variables that influence or hinder meaningful outcomes. The results indicate at this stage no intervention effect for improvements in population-level physical activity behaviour or mental wellbeing. However, they show some modest improvements for secondary outcomes including positive perceptions of the environment and social capital constructs. The public health impact of urban greenways may take a longer period of time to be realised and there is a need to improve evaluation methodology that captures the complex systems nature of urban regeneration.

Four weeks of vitamin D supplementation improves nitric oxide-mediated microvascular function in college-aged African Americans.

Reduced nitric oxide (NO)-mediated cutaneous vasodilation, secondary to increased oxidative stress, presents in young African American (AA) compared with European American (EA) adults and may be modulated by vitamin D status. We assessed cutaneous microvascular function in 18 young, healthy (21 ± 2 yr; 9 men, 9 women) subjects before (pre, 8 AA, 10 EA) 4 wk of 2,000 IU/day oral vitamin D supplementation and in 13 subjects after (post, 7 AA, 6 EA) 4 wk of 2,000 IU/day oral vitamin D supplementation. Serum vitamin D concentrations [25(OH)D] were measured at each visit. Three intradermal microdialysis fibers placed in the ventral forearm were randomized for treatment with 10 µM Tempol, 100 µM apocynin, or lactated Ringer's solution (control). Local heating (39°C) induced cutaneous vasodilation; red cell flux was measured at each site (laser-Doppler flowmetry), and cutaneous vascular conductance (CVC = flux/MAP) was expressed as a percentage of maximum (28 mM sodium nitroprusside, +43°C) for each phase of local heating. After stable elevated blood flow was attained, 15 mM NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) was perfused at all sites to quantify the NO contribution to cutaneous vasodilation (%NO), calculated as the difference between local heating and l-NAME plateaus. Serum [25(OH)D], the magnitude of the local heating response, and %NO were all lower in AAs versus EAs (P < 0.01). Tempol (P = 0.01), but not apocynin (P ≥ 0.19), improved the local heating response and %NO. Four weeks of supplementation improved serum [25(OH)D], the local heating response, and %NO in AAs (P ≤ 0.04) but not in EAs (P ≥ 0.41). Vitamin D supplementation mitigated endothelial dysfunction, an antecedent to overt cardiovascular disease (CVD), in otherwise healthy, young AA adults.NEW & NOTEWORTHY Endothelial dysfunction, an antecedent to overt cardiovascular disease (CVD), is observed earlier and more frequently in otherwise healthy African Americans (AAs) when compared with other ethnic groups. Vitamin D may modulate endothelial function, and darkened skin pigmentation increases risk of vitamin D deficiency. We show that 4 wk of 2,000 IU/day vitamin D supplementation improves microvascular responses to local heating in AAs. Ensuring adequate vitamin D status may mitigate development of cardiovascular dysfunction in this at-risk population.

Considerations in Processing Accelerometry Data to Explore Physical Activity and Sedentary Time in Older Adults.

Processing decisions for accelerometry data can have important implications for outcome measures, yet little evidence exists exploring these in older adults. The aim of the current study was to investigate the impact of three potentially important criteria on older adults, physical activity, and sedentary time. Participants (n = 222: mean age 71.75 years [SD = 6.58], 57% male) wore ActiGraph GT3X+ for 7 days. Eight data processing combinations from three criteria were explored: low-frequency extension (on/off), nonwear time (90/120 min), and intensity cut points (moderate-to-vigorous physical activity ≥1,041 and >2,000 counts/min). Analyses included Wilcoxon signed-rank test, paired t tests, and correlation coefficients (significance, p < .05). Results for low-frequency extension on 90-min nonwear time and >1,041 counts/min showed significantly higher light and moderate-to-vigorous physical activity and lower sedentary time. Cut points had the greatest impact on physical activity and sedentary time. Processing criteria can significantly impact physical activity and/or sedentary time, potentially leading to data inaccuracies, preventing cross-study comparisons and influencing the accuracy of population surveillance.

Sunscreen or simulated sweat minimizes the impact of acute ultraviolet radiation on cutaneous microvascular function in healthy humans.

NEW FINDINGS: What is the central question of this study? Are ultraviolet radiation (UVR)-induced increases in skin blood flow independent of skin erythema? Does broad-spectrum UVR exposure attenuate NO-mediated cutaneous vasodilatation, and does sunscreen or sweat modulate this response? What are the main findings and their importance? Erythema and vascular responses to UVR are temporally distinct, and sunscreen prevents both responses. Exposure to UVR attenuates NO-mediated vasodilatation in the cutaneous microvasculature; sunscreen or simulated sweat on the skin attenuates this response. Sun over-exposure may elicit deleterious effects on human skin that are separate from sunburn, and sunscreen or sweat on the skin may provide protection. ABSTRACT: Exposure to ultraviolet radiation (UVR) may result in cutaneous vascular dysfunction independent of erythema (skin reddening). Two studies were designed to differentiate changes in erythema from skin vasodilatation throughout the 8 h after acute broad-spectrum UVR exposure with (+SS) or without SPF-50 sunscreen (study 1) and to examine NO-mediated cutaneous vasodilatation after acute broad-spectrum UVR exposure with or without +SS or simulated sweat (+SW) on the skin (study 2). In both studies, laser-Doppler flowmetry was used to measure red cell flux, and cutaneous vascular conductance (CVC) was calculated (CVC = flux/mean arterial pressure). In study 1, in 14 healthy adults (24 ± 4 years old; seven men and seven women), the skin erythema index and CVC were measured over two forearm sites (UVR only and UVR+SS) before, immediately after and every 2 h for 8 h post-exposure (750 mJ cm-2 ). The erythema index began to increase immediately post-UVR (P < 0.05 at 4, 6 and 8 h), but CVC did not increase above baseline for the first 4-6 h (P ≤ 0.01 at 6 and 8 h); +SS prevented both responses. In study 2, in 13 healthy adults (24 ± 4 years old; six men and seven women), three intradermal microdialysis fibres were placed in the ventral skin of the forearm [randomly assigned to UVR (450 mJ cm-2 ), UVR+SS or UVR+SW], and one fibre (non-exposed control; CON) was placed in the contralateral forearm. After UVR, a standardized local heating (42°C) protocol quantified the percentage of NO-mediated vasodilatation (%NO). The UVR attenuated %NO compared with CON (P = 0.01). The diminished %NO was prevented by +SS (P < 0.01) and +SW (P < 0.01). Acute broad-spectrum UVR attenuates NO-dependent dilatation in the cutaneous microvasculature, independent of erythema. Sunscreen protects against both inflammatory and heating-induced endothelial dysfunction, and sweat might prevent UVR-induced reductions in NO-dependent dilatation.

Bundled payment for actinic keratosis management: Pilot evaluation of developed models.

BACKGROUND: There is an opportunity to explore alternate payment models in dermatology. OBJECTIVE: To pilot 2 bundled payment models for actinic keratosis (AK) management. METHODS: A prospective cohort study was conducted during September 2013-June 2016. Consecutive patients were recruited from clinics of 5 dermatologists. Patients had to be adults, have ≥1 year of care at the department, and have a history of AK. A bundled payment strategy was prospectively piloted for 1 year and compared with costs in the prior year. RESULTS: Overall, 400 participants were enrolled, and complete data was collected for 254 participants. During the year of bundled payments, actual total annual spending on claims was $70,557, whereas model 1 and model 2 bundled payment models would have totaled $67,310 and $74,422, respectively, for the patient cohort. Patient satisfaction surveys showed no difference in the quality of care. LIMITATIONS: Single-center study and limited sample size. International Classification of Diseases 9 and 10 codes were used to identify claims and might be inaccurate. Costs were modeled rather than fully implemented. CONCLUSION: Dermatologists should be aware of bundled payment models. More work is needed to elucidate the optimal formulation of a bundled payment for AK management, including the services covered, time delimitation, and risk stratification factors.

Validity of the International Physical Activity Questionnaire (IPAQ) for assessing moderate-to-vigorous physical activity and sedentary behaviour of older adults in the United Kingdom.

BACKGROUND: In order to accurately measure and monitor levels of moderate-to-vigorous physical activity (MVPA) and sedentary behaviour (SB) in older adults, cost efficient and valid instruments are required. To date, the International Physical Activity Questionnaire (IPAQ) has not been validated with older adults (aged 60 years plus) in the United Kingdom. The current study aimed to test the validity of the IPAQ in a group of older adults for both MVPA and SB. METHODS: Participants wore an Actigraph GT3X+ for seven consecutive days and following the monitor wear participants were asked to complete the IPAQ. Statistical analysis included: Kolmogorov-Smirnov tests; descriptive analyses; Spearman's rho coefficients; and Bland-Altman analyses. RESULTS: A sample of 253 older adults were recruited (mean age 71.8 years (SD 6.6) and 57% male). In total, 226 had valid accelerometer and IPAQ data for MVPA and 228 had valid data for SB. Results showed the IPAQ had moderate/acceptable levels of validity (r = .430-.557) for MVPA. For SB, there was substantial levels of validity on weekdays (r = .702) and fair levels of validity (r = .257) on weekend days. Bland-Altman analysis showed inherent measurement error with the majority of participants tending to under-report both MVPA and SB. Results showed the majority of older adult's under-report their level of MVPA and SB when completing the IPAQ and the linear relationship above the mean shows an error from under to over reporting as the mean increases. CONCLUSIONS: Findings from the current study suggest that the IPAQ is better implemented in larger surveillance studies comparing groups within or between countries rather than on an individual basis. Findings also suggest that the IPAQ validity scores could be strengthened by providing additional detail of types of activities older adults might do on a daily basis, improving recall; and it may also be necessary to provide an example of a daily break down of typical activities performed. This may enable older adults to more fully comprehend the amount of time they may spend active, sitting and/or lying during waking hours.

Study protocol: healthy urban living and ageing in place (HULAP): an international, mixed methods study examining the associations between physical activity, built and social environments for older adults the UK and Brazil.

BACKGROUND: The ability to 'age in place' is dependent on a range of inter-personal, social and built environment attributes, with the latter being a key area for potential intervention. There is an emerging body of evidence that indicates the type of built environment features that may best support age friendly communities, but there is a need to expand and consolidate this, while generating a better understanding of how on how research findings can be most effectively be translated in to policy and practice. METHODS: The study is based on two case study cities, Curtiba (Brazil) and Belfast (UK), which have highly contrasting physical, social and policy environments. The study deploys a mix methods approach, mirrored in each city. This includes the recruitment of 300 participants in each city to wear GPS and accelerometers, a survey capturing physical functioning and other personal attributes, as well as their perception of their local environment using NEWS-A. The study will also measure the built environments of the cities using GIS and develop a tool for auditing the routes used by participants around their neighbourhoods. The study seeks to comparatively map the policy actors and resources involved in healthy ageing in the two cities through interviews, focus groups and discourse analysis. Finally, the study has a significant knowledge exchange component, including the development of a tool to assess the capacities of both researchers and research users to maximise the impact of the research findings. DISCUSSION: The HULAP study has been designed and implemented by a multi-disciplinary team and integrates differing methodologies to purposefully impact on policy and practice on healthy ageing in high and low-middle income countries. It has particular strengths in its combination of objective and self-reported measures using validated tools and the integration of GPS, accelerometer and GIS data to provide a robust assessment of 'spatial energetics'. The strong knowledge exchange strand means that the study is expected to also contribute to our understanding of how to maximise research impact in this field and create effective evidence for linking older adult's physical activity with the social, built and policy environments.

Endothelial function is impaired in the cutaneous microcirculation of adults with psoriasis through reductions in nitric oxide-dependent vasodilation.

Psoriasis is an independent risk factor for cardiovascular disease; however, the underlying mechanisms are not fully understood. Deficits in conduit arterial function are evident in patients with psoriasis, but potential impairments in microcirculatory endothelial function remain unclear. We hypothesized that cutaneous microvascular dysfunction would be detectable in otherwise healthy individuals with psoriasis. Two intradermal microdialysis fibers were placed in (nonlesional) forearm skin of nine patients (3 men and 6 women, 39 ± 5 yr) with moderate (16 ± 2% of body surface area) plaque psoriasis and nine healthy (nonpsoriatic) control subjects (3 men and 6 women, 38 ± 5 yr) for local delivery of 1) lactated Ringer solution (control) and 2) 10 mM l-ascorbate (a nonspecific antioxidant). An index of skin blood flow was measured using laser-Doppler flowmetry during local heating (42°C). Nitric oxide (NO)-dependent vasodilation was directly quantified after perfusion of the nonspecific NO synthase inhibitor NG-nitro-l-arginine methyl ester (15 mM). A third fiber was perfused with increasing concentrations (10-10 - 10-2 M) of norepinephrine to elicit adrenoreceptor-mediated cutaneous vasoconstriction. NO-dependent vasodilation was attenuated in patients with psoriasis (57 ± 5% and 39 ± 7% maximum cutaneous vascular conductance in control subjects and adults with psoriasis, respectively, P < 0.01). l-Ascorbate did not improve NO-dependent vasodilation ( P > 0.05). There was no group difference in maximal vasoconstriction or microvascular sensitivity to norepinephrine ( P > 0.05). These data suggest that NO bioavailability is reduced in otherwise healthy individuals with psoriasis, which contributes to systemic microvascular dysfunction. NEW & NOTEWORTHY In adults with psoriasis, reduced nitric oxide bioavailability mediates impaired endothelium-dependent vasodilation, independent of increases in oxidative stress. Furthermore, the degree of psoriatic symptomology is directly related to greater reductions in nitric oxide-dependent vasodilation.

COCCIDIAL INFECTION OF THE ADRENAL GLANDS OF LEATHERBACK SEA TURTLES (DERMOCHELYS CORIACEA).

Histologic lesions incidental to the cause of death were observed in the adrenal glands of 17 subadult and adult leatherback sea turtles ( Dermochelys coriacea ) found dead or moribund on or near shore in North America. Round bodies, 250-300 µm in diameter composed of an outer capsule and large multinucleated cells surrounding a central mass of acellular material were distributed throughout the affected glands. Protozoal etiology was suspected based on some resemblance to coccidia; however, features diagnostic for coccidial infection were lacking in all but one case, which had a focal area of adrenalitis containing zoites. A novel eucoccidian partial 18S rRNA genetic sequence was consistently detected in adrenal glands with lesions. With the use of quantitative PCR, a specific area of the V4 region of the coccidian 18S gene was quantified in affected adrenal glands and correlated significantly with density of the histologic lesions. A second distinct, but closely related, 18S sequence was also amplified from the adrenal gland of one turtle and from a fecal sample containing unsporulated coccidian oocysts. The two 18S sequences identified from leatherback sea turtles form a clade within the family Eimeriidae. Further investigation is required to understand better the morphology of the life stages, life cycle, and potential effects of this coccidian parasite on adrenal function.

Actinic Keratosis Clinical Practice Guidelines: An Appraisal of Quality.

Actinic keratosis (AK) is a common precancerous skin lesion and many AK management guidelines exist, but there has been limited investigation into the quality of these documents. The objective of this study was to assess the strengths and weaknesses of guidelines that address AK management. A systematic search for guidelines with recommendations for AK was performed. The Appraisal of Guidelines for Research and Evaluation (AGREE II) was used to appraise the quality of guidelines. Multiple raters independently reviewed each of the guidelines and applied the AGREE II tool and scores were calculated. Overall, 2,307 citations were identified and 7 fulfilled the study criteria. The Cancer Council of Australia/Australian Cancer Network guideline had the highest mean scores and was the only guideline to include a systematic review, include an evidence rating for recommendations, and report conflicts of interest and funding sources. High-quality, effective guidelines are evidence-based with recommendations that are concise and organized, so practical application is facilitated. Features such as concise tables, pictorial diagrams, and explicit links to evidence are helpful. However, the rigor and validity of some guidelines were weak. So, it is important for providers to be aware of the features that contribute to a high-quality, practical document.

Lentigo Maligna Melanoma With Local and Distant Blue Nevus-like Metastases.

Melanoma or melanoma metastases can rarely mimic blue nevi clinically and/or histologically, presenting a diagnostic pitfall for both the clinician and the dermatopathologist. We report a case of an invasive lentigo maligna melanoma with subsequent development of multiple, cutaneous blue nevus-like localized metastases followed by a distant metastasis, heralding widespread systemic metastases.