MC1R signaling through the cAMP-CREB/ATF-1 and ERK-NFκB pathways accelerates G1/S transition promoting breast cancer progression.

MC1R, a G-protein coupled receptor, triggers ultraviolet light-induced melanin synthesis and DNA repair in melanocytes and is implicated in the pathogenesis of melanoma. Although widely expressed in different tissue types, its function in non-cutaneous tissue is relatively unknown. Herein, we demonstrate that disruptive MC1R variants associated with melanomagenesis are less frequently found in patients with several cancers. Further exploration revealed that breast cancer tissue shows a significantly higher MC1R expression than normal breast tissue, and knocking down MC1R significantly reduced cell proliferation in vitro and in vivo. Mechanistically, MC1R signaling through the MC1R-cAMP-CREB/ATF-1 and MC1R-ERK-NFκB axes accelerated the G1-S transition in breast cancer cells. Our results revealed a new association between MC1R and breast cancer, which could be potentially targeted therapeutically. Moreover, our results suggest that MC1R-enhancing/activating therapies should be used cautiously, as they might be pro-tumorigenic in certain contexts.

An inverse relationship between asthma prevalence and medication dispensation trend: a 12-year spatial analysis of electronic health record data in Alberta, Canada.

Despite guideline-based asthma management in Alberta, an inverse trend between asthma prevalence and dispensation of asthma medications in the past 12 years possibly underscores the reason for a large number of emergency department visits https://bit.ly/3HQsBo8.

Temporal and Regional Trends in Obstructive Sleep Apnea Using Administrative Health Data in Alberta, Canada.

Rationale: Obstructive sleep apnea (OSA) is a common treatable condition with important health and societal consequences. Objectives: We aimed to assess the annual incidence and prevalence of clinically recognized and geographic clustering of OSA in Alberta, Canada, using administrative health data case definitions. Methods: We used two administrative health databases in Alberta to identify ICD-9 and ICD-10 (International Classification of Diseases, Ninth and 10th Revisions, respectively) diagnostic codes for adults and children at least 2 years old diagnosed with OSA between 2003 and 2020. We defined OSA using an algorithm developed and validated in Alberta: at least three claims or one hospitalization within 2 years. We mapped residential postal codes to 70 subregional health authorities (SRHAs). Crude, age group- and sex-specific incidence and prevalence, and age group- and sex-standardized rates were calculated for Alberta and SRHAs. Spatial scan statistics identified clusters of SRHAs in which OSA cases were higher (hot spots) or lower (cold spots) than expected. Results: Between 2003 and 2020, OSA prevalence increased from 0.14% to 4.59%. The annual incidence of OSA increased after 2013. Incidence and prevalence were higher in older adults and children aged 2-11 years compared with 12-17 years. Cluster analysis revealed regional variation in OSA incidence and prevalence over time with no consistent pattern except for cold spots in one large metropolitan center (Calgary). Conclusions: From 2003 to 2020, the incidence and prevalence of clinically recognized OSA increased but varied by geography. Administrative health data can be used to guide interventions aimed at improving health service delivery and the quality of OSA care.

Health Care Utilization in the Last Year of Life in Parkinson Disease and Other Neurodegenerative Movement Disorders.

Background and Objectives: Neurodegenerative movement disorders are rising in prevalence and are associated with high health care utilization. Generally, health care resources are disproportionately expended in the last year of life. Health care utilization by those with neurodegenerative movement disorders in the last year of life is not well-understood. The goal of this study was to assess the utilization of acute care in the last year of life among individuals with neurodegenerative movement disorders and determine whether outpatient neurology or palliative care affected acute care utilization and place of death. Methods: We conducted a retrospective cross-sectional study including health system administrative data in Alberta, Canada, from 2011 to 2017. Administrative data were used to determine place of death and quantify emergency department (ED) visits, hospitalizations, intensive care unit admissions, and outpatient generalist and specialist visits. Diagnoses were classified by 10th revision of the International Classification of Diseases codes. Stata 16v was used for statistical analyses. Results: Among 1439 individuals (60% male), Parkinson disease (n = 1226), progressive supranuclear palsy (n = 78), multiple system atrophy (n = 47), and Huntington disease (n = 58) were the most common diagnoses. The most frequent place of death was in hospital (45.9%), followed by long-term care (36.3%), home (7.9%), and residential hospice (4.0%). Most (64.2%) had >1 ED visit, and 14.4% had >3 emergency department visits. Fifty-five percent had >1 hospitalization, and 23.3% spent >30 days in hospital. Few (2.6%) were admitted to ICU. Only 37.2% and 8.8% accessed outpatient neurologist and specialist palliative care services, respectively. Multivariate logistic regression found the odds of dying at home was higher for those who received outpatient palliative consultation (OR, 2.49, 95% confidence interval [CI], 1.48-4.21, p < 0.001) and were with a longer duration of home care support (OR, 1.0007, 95% CI, 1.0004-1.0009, p < 0.001). Discussion: There are high rates of in-hospital death and acute care utilization in the year before death among those with neurodegenerative movement disorders. Most did not access specialist palliative or neurologic care in the last year of life. Outpatient palliative care and home care services were associated with increased odds of dying at home. Our results indicate the need for further research into the causes, costs, and potential modifiers to inform public health planning.

The Economic Burden of Food Allergy: What We Know and What We Need to Learn.

Purpose of Review: Food allergy management and treatment require dietary modification, are associated with significant burdens, and affect food choices and behaviours. Emerging therapies, such as oral immunotherapy (OIT), provide a glimmer of hope for those living with the condition. Some burdens have received substantial focus, whereas many knowledge gaps on the significance of other impacts, including economic burden, remain. Recent Findings: Evidence from many countries, but disproportionately from the United States, supports that food allergy carries significant healthcare and societal costs. Early introduction for the prevention of food allergies is theoretically cost-effective, but remains largely undescribed. Unique considerations, such as those to cow's milk protein allergy, which affects a substantial proportion of infants, and adrenaline autoinjectors, which have a high cost-per-use, require a balance between cost-effectiveness to the healthcare system and adverse outcomes. Household costs have largely been explored in two countries, but owing to different healthcare structures and costs of living, comparisons are difficult, as are generalisations to other countries. Stock epinephrine in schools may present a cost-effective strategy, particularly in economically disadvantaged areas. Costs relating to OIT must be examined within both immediate benefits, such as protection from anaphylaxis, and long-term benefits, such as sustained unresponsiveness. Summary: Although the absolute costs differ by region/country and type of food allergy, a consistent pattern persists: food allergy is a costly condition, to those who live with it, and the multiple stakeholders with which they interact. Supplementary Information: The online version contains supplementary material available at 10.1007/s40521-022-00306-5.

Recruitment of adults with moderate eczema for a randomised trial: Comparison of traditional versus modern methods.

BACKGROUND: Clinical trial recruitment is challenging for investigators who often overestimate the pool of qualified, willing subjects. Moreover, there is a paucity of literature, particularly in dermatology, regarding recruitment and the comparative success of advertising strategies. METHODS: Both 'traditional' (physician referral, newspaper and radio advertisements, letterbox drops, posters/flyers, word-of-mouth) and 'modern' (patient recruitment services, social media, Google advertisements, websites, email) recruitment methods were used to enrol 100 patients (>18 years) diagnosed with moderate eczema for a randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of a topical eczema treatment over 4 weeks. The relationships between recruitment method and patient age, sex, race, study completion and costs were analysed. RESULTS: The majority of patients recruited were young, with millennials and Gen Z comprising 77% of the study population. Both traditional and modern recruitment methods were equally successful in recruiting younger patients, with older patients predominately recruited by traditional methods. Eighty per cent more men were recruited by traditional compared to modern methods, whilst 67% more women than men were recruited by modern methods. Recruitment method neither appeared to be influenced by race, nor did it effect whether patients completed the study. Costs per enrolment were similar for both methods. CONCLUSIONS: This study shows that despite the high proportion of young patients and the rising popularity of social media and increased internet use, a combination of both traditional and modern recruitment methods was required to successfully meet the trial enrolment target of 100 adult patients with moderate eczema.

A daily regimen of a ceramide-dominant moisturizing cream and cleanser restores the skin permeability barrier in adults with moderate eczema: A randomized trial.

The dysfunctional skin barrier in eczema patients may be attributed to decreased levels of ceramides in the stratum corneum. The aim of this study was to determine whether a two-part system consisting of a ceramide-dominant physiological lipid-based moisturizing cream and cleanser could ameliorate the signs and symptoms of moderate eczema in adults over 28 days compared to placebo. Assessments were conducted at baseline and every 7 days thereafter. Eczema area severity index score decreased significantly across all time points in both groups compared to baseline (P < .0001), however, this decrease was not significant between groups at day 28 (P = .7804). In contrast, transepidermal water loss and skin hydration significantly improved over time in the active group, while it either stayed the same or worsened in the placebo group (P = .0342 and P < .0001, respectively). There was no difference in the use of mometasone furoate as rescue medication over time between groups (P = .1579). Dermatology life quality index scores improved significantly in both groups (P < .0001), with no difference between groups (P = .5256). However, patient satisfaction was greater in the active compared to the placebo group for several parameters including relief of itch, dry skin, skin softness and smoothness (all P < .05). No patients withdrew from the study due to adverse events (AEs) and there were no serious AEs. The ceramide-dominant moisturizing cream and cleanser safely restores skin permeability and improves the signs and symptoms of eczema in adults.

Hospital-based acute care in the last 30 days of life among patients with chronic disease that received early, late or no specialist palliative care: a retrospective cohort study of eight chronic disease groups.

OBJECTIVE: For eight chronic diseases, evaluate the association of specialist palliative care (PC) exposure and timing with hospital-based acute care in the last 30 days of life. DESIGN: Retrospective cohort study using administrative data. SETTING: Alberta, Canada between 2007 and 2016. PARTICIPANTS: 47 169 adults deceased from: (1) cancer, (2) heart disease, (3) dementia, (4) stroke, (5) chronic lower respiratory disease (chronic obstructive pulmonary disease (COPD)), (6) liver disease, (7) neurodegenerative disease and (8) renovascular disease. MAIN OUTCOME MEASURES: The proportion of decedents who experienced high hospital-based acute care in the last 30 days of life, indicated by ≥two emergency department (ED) visit, ≥two hospital admissions,≥14 days of hospitalisation, any intensive care unit (ICU) admission, or death in hospital. Relative risk (RR) and risk difference (RD) of hospital-based acute care given early specialist PC exposure (≥90 days before death), adjusted for patient characteristics. RESULTS: In an analysis of all decedents, early specialist PC exposure was associated with a 32% reduction in risk of any hospital-based acute care as compared with those with no PC exposure (RR 0.69, 95% CI 0.66 to 0.71; RD 0.16, 95% CI 0.15 to 0.17). The association was strongest in cancer-specific analyses (RR 0.53, 95% CI 0.50 to 0.55; RD 0.31, 95% CI 0.29 to 0.33) and renal disease-specific analyses (RR 0.60, 95% CI 0.43 to 0.84; RD 0.22, 95% CI 0.11 to 0.34), but a~25% risk reduction was observed for each of heart disease, COPD, neurodegenerative diseases and stroke. Early specialist PC exposure was associated with reducing risk of four out of five individual indicators of high hospital-based acute care in the last 30 days of life, including ≥two ED visit,≥two hospital admission, any ICU admission and death in hospital. CONCLUSIONS: Early specialist PC exposure reduced the risk of hospital-based acute care in the last 30 days of life for all chronic disease groups except dementia.

COX-2 Overexpression in Schneiderian Papillomas.

BACKGROUND: Schneiderian papillomas (SP) are aggressive sinonasal tumors that occasionally extend into areas that are surgically unresectable. OBJECTIVE: evaluate the signifcance of cyclo-oxygenase-2 (COX-2) expression in SP. METHODS: Immunohistochemistry for COX-2 was performed on SP samples and middle turbinates from chronic rhinosinusitis without nasal polyps controls obtained during surgical resection between 2009-2017. A positive stain was defined as having 10% or more cells exhibiting diffuse immunoreactivity. Comparisons were performed using Fisher Exact tests, t-tests, and ANOVA. RESULTS: The study included 67 tumor samples and 9 controls from two academic institutions. The mean age of the SP group was 55.4 years and 53.2 years in the control group (p = 0.71). Thirty-nine (58.2%) SP patients had previous surgery compared to 1 (11.1%) in the control group (p = 0.01). The most common tumor attachment sites were the maxillary (47.8%) and ethmoid (25.4%) sinuses. Fifteen (22.4%) SP samples stained strongly positive for COX-2 and 24 (35.8%) stained weakly positive compared to no positive stains in the control group (p < 0.01). When stratified by COX-2 intensity, there were no statistically significant differences in gender, smoking history, history of previous sinus surgery, site of attachment, papilloma subtype, or future recurrence between SP samples. CONCLUSION: COX-2 was overexpressed in 58.2% of SP cases, and strongly positive in 22.4% of cases, compared to no positive staining among controls. No significant differences in COX-2 expression were observed between SP subtypes or recurrent tumors. Further studies are warranted to evaluate COX-2 as a possible therapeutic target in tumors that overexpress the enzyme.

MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling.

MAPK pathway mutations affect one-fifth of head and neck squamous cell carcinoma (HNSCC). Unexpectedly, MAPK pathway aberrations are associated with remarkably long patient survival, even among patients with TP53 mutations (median ∼14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (A/BRAF, HRAS, MAPK1, and MAP2K1/2) all abrogated ErbB3 activation, a well-established HNSCC progression signal. Inhibitor studies functionally defined ERK activity negatively regulating phospho-ErbB3 in MAPK-mutants. Furthermore, pan-pathway immunoprofiling investigations identified MAPK-mutant tumors as the only "CD8+ T-cell-inflamed" tumors inherently bearing high-immunoreactive, constitutive cytolytic tumor microenvironments. Immunocompetent MAPK-mutant HNSCC models displayed active cell death and massive CD8+ T-cell recruitment in situ. Consistent with CD8+ T-inflamed phenotypes, MAPK-mutant HNSCC patients, independent of tumor-mutational burden, survived 3.3-4 times longer than WT patients with anti-PD1/PD-L1 immunotherapies. Similar prognosticity was noted in pan-cancers. We uncovered clinical, signaling, and immunological uniqueness of MAPK-mutant HNSCC with potential biomarker utilities predicting favorable patient survival.

Quality and access - Early experience of implementing a virtual stereotactic chart round across a national network.

INTRODUCTION: Stereotactic radiation therapy is a highly specialised technique which requires careful and structured implementation. As part of a national stereotactic programme implementation, protocols were developed and a national stereotactic chart round was formed, which strongly recommended attendance and presentation of all cases before treatment. Herein, we describe our experiences launching a national chart round and its importance in a stereotactic programme. METHOD: Stereotactic chart rounds were held via videoconference between July 2018 and July 2019. Data collected included attendances, patient-related information including, diagnosis, clinical background, treatment intent, prescribed dose and fractionation and technical approach. Consensus recommendations regarding changes to treatment approaches were also recorded. RESULTS: For the 12 months recorded, there were 1126 attendances, from 144 individual attendees, across 21 locations. In total, 285 cases (237 new cases, and 48 re-presentations) were presented by 27 radiation oncologists (ROs) from 13 different locations. From the cases presented, 65 changes were recommended from 53 patients (22.3%), including 27 (11.4%) changes to contours, 18 (7.6%) changes to dose prescription/fractionation, 9 (3.8%) changes to plan dosimetry, 1 (0.4%) changes to treatment technique and 10 (4.2%) recommendations for which stereotactic radiation therapy was not advised. A significant inverse relationship was found between frequency of recommended changes and the individual RO's stereotactic case load (P < 0.002). CONCLUSION: The implementation of a national stereotactic chart held via videoconference has ensured national protocol compliance across the network of locations. Furthermore, the chart rounds have allowed the entire multidisciplinary team to be provided with mentorship and guidance. Increasing number of cases presented was associated with lower rates of recommended changes highlighting the impact of experience and the need for continued mentorship.

Fatal refractory cardiac arrest as presentation of systemic amyloidosis.

Amyloidosis is a challenging diagnosis in the absence of clinical suspicion. The two patients reported here lacked any symptoms suggestive of amyloidosis. Instead, they presented with sudden, unexplained cardiac arrests that were persistent, treatment refractory, and ultimately fatal. Post-mortem examination unexpectedly revealed evidence of diffuse, systemic amyloidosis throughout multiple organ systems. We bring awareness to this unusual presentation of systemic amyloidosis that portends to poor outcome.

Skin testing with ultra-heat-treated (UHT) cow's milk in children with cow's milk allergy.

BACKGROUND: A large proportion of cow's milk (CM)-allergic children are able to tolerate extensively heated forms of CM such as baked goods. Little is known about whether ultra-heat-treated (UHT) forms of cow's milk are immunologically similar to extensively heated cow's milk and therefore may be tolerated by these children. OBJECTIVE: To determine whether skin test wheal size using UHT CM was significantly different from other forms of CM and CM extracts. METHODS: Children presenting for oral food challenges with either extensively heated or unheated cow's milk underwent skin prick test (SPT) to commercial CM, UHT CM, evaporated CM, and fresh whole CM. The results were compared between groups of children. RESULTS: At study exit, only 14% of children were avoiding all forms of CM, compared with 70% at study entry. No difference was seen in the mean SPT results for UHT CM between those children that could tolerate heated CM compared with those that could not. The mean SPT result for casein was significantly lower in those that could tolerate heated CM. However, within the group of heated milk-tolerant children, the mean SPT for UHT CM was significantly lower than the SPT for fresh whole CM. CONCLUSION: Ultra-heat-treated CM does not behave significantly differently from other forms of CM when evaluated by SPT in heated milk-allergic vs heated milk-tolerant children. This suggests that UHT CM is not sufficiently immunologically different from unheated CM to be tolerated by heated CM-tolerant children.

Implementing user-defined atlas-based auto-segmentation for a large multi-centre organisation: the Australian Experience.

INTRODUCTION: Contouring has become an increasingly important aspect of radiation therapy due to inverse planning, and yet is extremely time-consuming. To improve contouring efficiency and reduce potential inter-observer variation, the atlas-based auto-segmentation (ABAS) function in Velocity was introduced to ICON cancer centres (ICC) throughout Australia as a solution for automatic contouring. METHODS: This paper described the implementation process of the ABAS function and the construction of user-defined atlas sets and compared the contouring efficiency before and after the introduction of ABAS. RESULTS: The results indicate that the main limitation to the ABAS performance was Velocity's sub-optimal atlas selection method. Three user-defined atlas sets were constructed. Results suggested that the introduction of the ABAS saved at least 5 minutes of manual contouring time (P < 0.05), although further verification was required due to limitations in the data collection method. The pilot rollout adopting a 'champion' approach was successful and provided an opportunity to improve the user-defined atlases prior to the national implementation. CONCLUSION: The implementation of user-defined ABAS for head and neck (H&N) and female thorax patients at ICCs was successful, which achieved at least 5 minutes of efficiency gain.

Detection and Characterization of Silver Nanostructures in Consumer Products.

Silver (Ag) is one among the few nanomaterials which are widely used across several consumer products. However, there is limited research on detection and characterization of Ag nanostructures in complex matrices such as consumer products. Most previous studies for analytical method development were based on Ag liquid formulations or with standard materials. In this study, a total of fifteen commercial products including dietary supplements, deodorants, fabric, skin protectants, and toothpastes that declare nano or colloidal Ag ingredients were investigated. To characterize the quantity, size, size distribution, and morphology of Ag nanoparticles used in the products, several analytical instrumental techniques such as inductively coupled plasma-mass spectroscopy (ICPMS), dynamic light scattering (DLS), differential centrifugal sedimentation (DCS), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), and energy dispersive X-ray spectrometry (EDS) were employed. Study results showed that Ag nanoparticles were found in eleven of the fifteen investigated commercial products, where the majority of Ag nanoparticles were spherical and smaller than 50 nm. The advantages and limitations of size characterization techniques were discussed with respect to product type. A combination of characterization techniques was highly desired based on the product type and other ingredients used to confirm the presence of nanostructures in consumer products.

Estimating Bacterial Concentrations in Fibrous Substrates Through a Combination of Scanning Electron Microscopy and ImageJ.

Conventional signal-based microanalytical techniques for estimating bacterial concentrations are often susceptible to false signals. A visual quantification, therefore, may compliment such techniques by providing additional information and support better management decisions in the event of outbreaks. Herein, we explore a method that combines electron microscopy (EM) and image-analysis techniques and allows both visualization and quantification of pathogenic bacteria adherent even to complex nonuniform substrates. Both the estimation and imaging parameters were optimized to reduce the estimation error ( E, %) to close to ±5%. The method was validated against conventional microbiological techniques such as the use of optical density, flow cytometry, and quantitative real-time PCR (qPCR). It could easily be tailored to estimate different species of pathogens, such as Escherichia coli O157, Listeria innocua, Staphylococcus aureus, Enterococcus faecalis, and Bacillus anthracis, on samples similar to those in real-time contamination scenarios. The present method is sensitive enough to detect ∼100 bacterial CFU/mL but has the potential to estimate even lower concentrations with increased imaging and computation times. Overall, this imaging-based method may greatly complement any signal-based pathogen-detection technique, especially in negating false signals, and therefore may significantly contribute to the field of analytical microbiology and biochemistry.

Metastatic Acinic Cell Carcinoma to the Vagina: A First Reported Case.

This is a case of a 62-year-old woman with a remote history of acinic cell carcinoma of the parotid gland, who presented with a palpable vaginal mass, anterior vaginal wall prolapse, and stress urinary incontinence. A 2 cm firm mobile mass on the anterior vaginal wall was found on clinical examination. A computed tomographic scan revealed a mass between the vaginal vault and bladder that was eventually surgically excised. The histology, supported by the immunohistochemistry, revealed metastatic acinic cell carcinoma to the vagina after 37 years of her initial diagnosis. This is the first reported case in the literature to occur in the vagina.