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Abstract Liposome-based anticancer agents take advantage of the increased vascular permeability and transvascular pressure gradients for selective accumulation in tumors, a phenomenon known as the enhanced permeability and retention(EPR) effect. The EPR effect has motivated the clinical use of nano-therapeutics, with mixed results on treatment outcome. High interstitial fluid pressure (IFP) has been shown to limit liposome drug delivery to central tumour regions. Furthermore, high IFP is an independent prognostic biomarker for treatment efficacy in radiation therapy and chemotherapy for some solid cancers. Therefore, accurately measuring spatial liposome accumulation and IFP distribution within a solid tumour is crucial for optimal treatment planning. In this paper, we develop a model capable of predicting voxel-by-voxel intratumoral liposome accumulation and IFP using pre and post administration imaging. Our approach is based on physics informed machine learning, a novel technique combining machine learning and partial differential equations. through application to a set of mouse data and a set of synthetically-generated tumours, we show that our approach accurately predicts the spatial liposome accumulation and IFP for an individual tumour while relying on minimal information. This is an important result with applications for forecasting tumour progression and designing treatment.

Abstract Angiogenesis is an important process in the formation and maintenance of tissues which is driven by a complex system of intracellular and intercellular signaling mechanisms. Endothelial cells taking part in early angiogenesis must select their phenotype as either a tip cells (leading, migratory) or a stalk cells (following). Recent experiments have demonstrated that rapid calcium oscillations within active cells characterize this phenotype selection process and that these oscillations play a necessary role in governing phenotype selection and eventual vessel architecture. In this work, we develop a mathematical model capable of describing these oscillations and their role in phenotype selection then use it to improve our understanding of the biological mechanisms at play. We developed a model based on two previously published and experimentally validated mathematical models of calcium and angiogenesis then use our resulting model to simulate various multi-cell scenarios. We are able to capture essential calcium oscillation dynamics and intercellular communication between neighboring cells. The results of our model show that although the late DLL4 (a transmembrane protein that activates Notch pathway) levels of a cell are connected with its initial IP3 (Inositol 1,4,5-trisphosphate) level, cell-to-cell communication determines its eventual phenotype.

Vasopressin has traditionally been thought to be produced by the neurohypophyseal system and then released into the circulation where it regulates water homeostasis. The questions of whether vasopressin could be produced outside of the brain and if the kidney could be a source of vasopressin are raised by the syndrome of inappropriate antidiuretic hormone secretion (vasopressin). We found that mouse and human kidneys expressed vasopressin mRNA. Using an antibody that detects preprovasopressin, we found that immunoreactive preprovasopressin protein was found in mouse and human kidneys. Moreover, we found that murine collecting duct cells made biologically active vasopressin, which increased in response to NaCl-mediated hypertonicity, and that water restriction increased the abundance of kidney-derived vasopressin mRNA and protein expression in mouse kidneys. Thus, we provide evidence of biologically active production of kidney-derived vasopressin in kidney tubular epithelial cells.

Introduction: The purpose of this study was to evaluate whether kinematic assessments help to improve golf putting accuracy and precision, and increase the success rate of golf putts. Specifically, this study also investigated the differences in club head velocity and putter face angle at impact (°) between elite and amateur golfers. Methods: A total of 25 articles were used in this review. An initial, broad search of electronic databases including PubMed, SPORT discus, Scopus, Science Direct and Google Scholar was conducted for literature using the keywords “biomechanics” AND “golf putting”. The total number of studies screened for this review was n = 897. Among these articles, only n = 63 were assessed for eligibility. The number of articles were reduced further to n = 25 and included in the qualitative and quantitative synthesis. Results: Out of the initial n = 897, n = 834 records were excluded. After the articles were assessed for eligibility, n = 17 articles were excluded for not meeting the inclusion criteria. The studies included demonstrated that kinematic approaches can help improve accuracy and precision of golf putts which help to increase the success rate of putts and reduce overall scoring. Elite golfers have a more accurate direction and face angle when compared to amateur golfers. Conclusion: This systematic review and meta-analysis suggests that kinematic assessments of face angle at impact, putter path, the vertical spot and backswing are critical determinants of a golfer’s success and are useful indicators to help improve accuracy and precision of golf putts. This study also noted that elite golfers had slightly less velocity but more precise putter face angles at impact which increased their accuracy in completing more successful putts than amateur golfers.

Tumour hypoxia has been associated with increased resistance to various cancer treatments, particularly radiation therapy. Conversely, tumour hypoxia is a validated and ideal target for guided cancer drug delivery. For this reason, hypoxia-activated prodrugs (HAPs) have been developed, which remain inactive in the body until in the presence of tissue hypoxia, allowing for an activation tendency in hypoxic regions. We present here an experimentally motivated mathematical model predicting the effectiveness of HAPs in a variety of clinical settings. We first examined HAP effectiveness as a function of the amount of tumour hypoxia and showed that the drugs have a larger impact on tumours with high levels of hypoxia. We then combined HAP treatment with radiation to examine the effects of combination therapies. Our results showed radiation-HAP combination therapies to be more effective against highly hypoxic tumours. The analysis of combination therapies was extended to consider schedule sequencing of the combination treatments. These results suggested that administering HAPs before radiation was most effective in reducing total cell number. Finally, a sensitivity analysis of the drug-related parameters was done to examine the effect of drug diffusivity and enzyme abundance on the overall effectiveness of the drug. Altogether, the results highlight the importance of the knowledge of tumour hypoxia levels before administration of HAPs in order to ensure positive results.

The outbreak of SARS-CoV-2 is thought to have originated in Wuhan, China in late 2019 and has since spread quickly around the world. To date, the virus has infected tens of millions of people worldwide, compelling governments to implement strict policies to counteract community spread. Federal, provincial, and municipal governments have employed various public health policies, including social distancing, mandatory mask wearing, and the closure of schools and businesses. However, the implementation of these policies can be difficult and costly, making it imperative that both policy makers and the citizenry understand their potential benefits and the risks of non-compliance. In this work, a mathematical model is developed to study the impact of social behaviour on the course of the pandemic in the province of Ontario. The approach is based upon a standard SEIRD model with a variable transmission rate that depends on the behaviour of the population. The model parameters, which characterize the disease dynamics, are estimated from Ontario COVID-19 epidemiological data using machine learning techniques. A key result of the model, following from the variable transmission rate, is the prediction of the occurrence of a second wave using the most current infection data and disease-specific traits. The qualitative behaviour of different future transmission-reduction strategies is examined, and the time-varying reproduction number is analyzed using existing epidemiological data and future projections. Importantly, the effective reproduction number, and thus the course of the pandemic, is found to be sensitive to the adherence to public health policies, illustrating the need for vigilance as the economy continues to reopen.

Tumour hypoxia is a well-studied phenomenon with implications in cancer progression, treatment resistance, and patient survival. While a clear adverse prognosticator, hypoxia is also a theoretically ideal target for guided drug delivery. This idea has lead to the development of hypoxia-activated prodrugs (HAPs): a class of chemotherapeutics which remain inactive in the body until metabolized within hypoxic regions. In theory, these drugs have the potential for increased tumour selectivity and have therefore been the focus of numerous preclinical studies. Unfortunately, HAPs have had mixed results in clinical trials, necessitating further study in order to harness their therapeutic potential. One possible avenue for the improvement of HAPs is through the selective application of anti angiogenic agents (AAs) to improve drug delivery. Such techniques have been used in combination with other conventional chemotherapeutics to great effect in many studies. A further benefit is theoretically achieved through nanocell administration of the combination, though this idea has not been the subject of any experimental or mathematical studies to date. In the following, a mathematical model is outlined and used to compare the predicted efficacies of separate vs. nanocell administration for AAs and HAPs in tumours. The model is experimentally motivated, both in mathematical form and parameter values. Preliminary results of the model are highlighted throughout which qualitatively agree with existing experimental evidence. The novel prediction of our model is an improvement in the efficacy of AA/HAP combination therapies when administered through nanocells as opposed to separately. While this study specifically models treatment on glioblastoma, similar analyses could be performed for other vascularized tumours, making the results potentially applicable to a range of tumour types.

Epidermolysis bullosa (EB) is a group of genetic blistering diseases characterized by mechanically fragile skin and mucocutaneous involvement. Historically, disease management has focused on supportive care. The development of new genetic, cellular, and recombinant protein therapies has shown promise, and this review summarizes a unique gene and cell therapy phenomenon termed revertant mosaicism (RM). RM is the spontaneous correction of a disease-causing mutation. It has been reported in most EB subtypes, some with relatively high frequency, and has been observed in both keratinocytes and fibroblasts. RM manifests as identifiable patches of unaffected, blister-resistant skin and can occur through a variety of molecular mechanisms, including true back mutation, intragenic crossover, mitotic gene conversion, and second-site mutation. RM cells represent a powerful autologous platform for therapy, and leveraging RM cells as a therapeutic substrate may avoid the inherent mutational risks of gene therapy/editing. However, further examination of the genomic integrity and long-term functionality of RM-derived cells, as well in vivo testing of systemic therapies with RM cells, is required to realize the full therapeutic promise of naturally occurring RM in EB.

Although older persons (aged 65 years and older) experience stressful ethical problems involving their health, research is lacking about this phenomenon. The purpose of this study was to describe and examine the content and basic nature of older persons' ethical problems concerning their health. The conceptual framework and method combined ethical enquiry and phenomenology. The participants were 18 older persons and 12 of their children or grandchildren (for contextual understanding). The 19 women and 11 men, 73% of whom were Caucasian, described 184 ethical problems, from which emerged 10 content categories. The basic nature of the ethical problems consisted of conflict, resolution and rationale. The results could assist health professionals to promote older persons' ethical decision making, quality of life, and good death. [ABSTRACT FROM AUTHOR]

Using a conceptual framework and method combining ethical enquiry and phenomenology, we asked 73 senior baccalaureate nursing students to answer two questions: (1) What is nursing students' experience of an ethical problem involving nursing practice? and (2) What is nursing students' experience of using an ethical decision-making model? Each student described one ethical problem, from which emerged five content categories, the largest being that involving health professionals (44%). The basic nature of the ethical problems consisted of the nursing students' experience of conflict, resolution and rationale; 85% of the students stated that using an ethical decision-making model was helpful. Although additional research is needed, these findings have important implications for nursing ethics education and practice. [ABSTRACT FROM AUTHOR]

Glioblastomas are the most common primary brain tumours. They are known for their highly aggressive growth and invasion, leading to short survival times. Treatments for glioblastomas commonly involve a combination of surgical intervention, chemotherapy, and external beam radiation therapy (XRT). Previous works have not only successfully modelled the natural growth of glioblastomas in vivo, but also show potential for the prediction of response to radiation prior to treatment. This suggests that the efficacy of XRT can be optimized before treatment in order to yield longer survival times. However, while current efforts focus on optimal scheduling of radiotherapy treatment, they do not include a similarly sophisticated spatial optimization. In an effort to improve XRT, we present a method for the spatial optimization of radiation profiles. We expand upon previous results in the general problem and examine the more physically reasonable cases of 1-step and 2-step radiation profiles during the first and second XRT fractions. The results show that by including spatial optimization in XRT, while retaining a constant prescribed total dose amount, we are able to increase the total cell kill from the clinically-applied uniform case.

Abstract Chiropractic & Osteopathy changes its title to Chiropractic & Manual Therapies in January 2011. This change reflects the expanding base of submissions from clinical scientists interested in the discipline of manual therapy. It is also in accord with the findings of a review of the journal content and a joint venture between the original parent organisation the Chiropractic and Osteopathic College of Australasia and a new partner the European Academy of Chiropractic, which is a subsidiary body of the European Chiropractors' Union. The title change should encourage submissions from all professionals interested in manual therapy including chiropractors, osteopaths, physiotherapists, medical doctors and scientists interested in this field.

Background: Sixty percent of patients with esophageal cancer display signs of cachexia at diagnosis. Changes in body composition are common, and muscle mass and quality are measurable through imaging studies. Cachexia leads to functional impairments that complicate treatments, including surgery. We hypothesize that low muscle mass and quality associate with pulmonary function testing parameters, highlighting ventilatory deficits, and postoperative complications in patients receiving esophagectomy., Study Design: We performed a retrospective review of patients receiving esophagectomy between 2012 and 2021 at our facility. PET/CT scans were used to quantify skeletal muscle at the L3 and T4 levels. Patient characteristics were recorded, including pulmonary function testing parameters. Regression models were created to characterize predictive associations., Results: One hundred eight patients were identified. All were included in the final analysis. In linear regression adjusted for sex, age, and COPD status, low L3 muscle mass independently associated with low forced vital capacity (p < 0.005, β 0.354) and forced expiratory volume in 1 second (p < 0.001, β 0.392). Similarly, T4 muscle mass independently predicted forced vital capacity (p < 0.005, β 0.524) and forced expiratory volume in 1 second (p < 0.01, β 0.480). L3 muscle quality correlated with total lung capacity ( R 0.2463, p < 0.05). Twenty-six patients had pleural effusions postoperatively, associated with low muscle quality on L3 images (p < 0.05). Similarly, patients with hospitalization more than 2 weeks presented with lower muscle quality (p < 0.005)., Conclusions: Cachexia and low muscle mass are common. Reduced muscle mass and quality independently associate with impaired forced vital capacity, forced expiratory volume in 1 second, and total lung capacity. We propose that respiratory muscle atrophy occurs with weight loss. Body composition analyses may aid in stratifying patients. Pulmonary function testing may also serve as a functional endpoint for clinical trials. These findings highlight the need to study mechanisms that lead to respiratory muscle pathology and dysfunction in tumor-bearing hosts., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Pancreatic cancer is a deadly disease with limited diagnostic and treatment options. Not all populations are affected equally, as disparities exist in pancreatic cancer prevalence, treatment and outcomes. Recently, next-generation sequencing has facilitated a more comprehensive analysis of the human oral microbiome creating opportunity for its application in precision medicine. Oral microbial shifts occur in patients with pancreatic cancer, which may be appreciated years prior to their diagnosis. In addition, pathogenic bacteria common in the oral cavity have been found within pancreatic tumors. Despite these findings, much remains unknown about how or why the oral microbiome differs in patients with pancreatic cancer. As individuals develop, their oral microbiome reflects both their genotype and environmental influences. Genetics, race/ethnicity, smoking, socioeconomics and age affect the composition of the oral microbiota, which may ultimately play a role in pancreatic carcinogenesis. Multiple mechanisms have been proposed to explain the oral dysbiosis found in patients with pancreatic cancer though they have yet to be confirmed. With a better understanding of the interplay between the oral microbiome and pancreatic cancer, improved diagnostic and therapeutic approaches may be implemented to reduce healthcare disparities. Video Abstract., (© 2022. The Author(s).)

Studies of living children demonstrate that early life stress impacts linear growth outcomes. Stresses affecting linear growth may also impact later life health outcomes, including increased cardiometabolic disease risk. Palaeopathologists also assess the growth of children recovered from bioarchaeological contexts. Early life stresses are inferred to affect linear growth outcomes, and measurements of skeletal linear dimensions alongside other bioarchaeological information may indicate the types of challenges faced by past groups. In clinical settings, the impacts of stress on growing children are typically measured by examining height. Palaeopathologists are limited to examining bone dimensions directly and must grapple with incomplete pictures of childhood experiences that may affect growth. Palaeopathologists may use clinical growth studies to inform observations among past children; however, there may be issues with this approach. Here, we review the relationship between contemporary and palaeopathological studies of child and adolescent growth. We identify approaches to help bridge the gap between palaeopathological and biomedical growth studies. We advocate for: the creation of bone-specific growth reference information using medical imaging and greater examination of limb proportions; the inclusion of children from different global regions and life circumstances in contemporary bone growth studies; and greater collaboration and dialogue between palaeopathologists and clinicians as new studies are designed to assess linear growth past and present. We advocate for building stronger bridges between these fields to improve interpretations of growth patterns across human history and to potentially improve interventions for children living and growing today., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Background: Given the growing interest in using microRNAs (miRNAs) as biomarkers of early disease, establishment of robust protocols and platforms for miRNA quantification in biological fluids is critical., Objective: The goal of this multi-center pilot study was to evaluate the reproducibility of NanoString nCounter™ technology when analyzing the abundance of miRNAs in plasma and cystic fluid from patients with pancreatic lesions., Methods: Using sample triplicates analyzed across three study sites, we assessed potential sources of variability (RNA isolation, sample processing/ligation, hybridization, and lot-to-lot variability) that may contribute to suboptimal reproducibility of miRNA abundance when using nCounter™, and evaluated expression of positive and negative controls, housekeeping genes, spike-in genes, and miRNAs., Results: Positive controls showed a high correlation across samples from each site (median correlation coefficient, r> 0.9). Most negative control probes had expression levels below background. Housekeeping and spike-in genes each showed a similar distribution of expression and comparable pairwise correlation coefficients of replicate samples across sites. A total of 804 miRNAs showed a similar distribution of pairwise correlation coefficients between replicate samples (p= 0.93). After normalization and selecting miRNAs with expression levels above zero in 80% of samples, 55 miRNAs were identified; heatmap and principal component analysis revealed similar expression patterns and clustering in replicate samples., Conclusions: Findings from this pilot investigation suggest the nCounter platform can yield reproducible results across study sites. This study underscores the importance of implementing quality control procedures when designing multi-center evaluations of miRNA abundance.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest of all common malignancies. Treatment is difficult and often complicated by the presence of cachexia. The clinical portrait of cachexia contributes to the poor prognosis experienced by PDAC patients and worsens therapeutic outcomes. We propose that low bone mineral density is a component of cachexia, which we explore herein through a retrospective review of all patients at our facility that underwent surgery for PDAC between 2011 and 2018 and compared to sex-, age- and comorbidity-matched control individuals. Data were abstracted from the medical record and pre-operative computed tomography scans. Muscle mass and quality were measured at the L3 level and bone mineral density was measured as the radiation attenuation of the lumbar vertebral bodies. Patients with PDAC displayed typical signs of cachexia such as weight loss and radiologically appreciable deterioration of skeletal muscle. Critically, PDAC patients had significantly lower bone mineral density than controls, with 61.2% of PDAC patients categorized as osteopenic compared to 36.8% of controls. PDAC patients classified as osteopenic had significantly reduced survival (1.01 years) compared to patients without osteopenia (2.77 years). The presence of osteopenia was the strongest clinical predictor of 1- and 2-year disease-specific mortality, increasing the risk of death by 107% and 80%, respectively. Osteopenia serves as a test of 2-year mortality with sensitivity of 76% and specificity of 58%. These data therefore identify impaired bone mineral density as a key component of cachexia and predictor of postoperative survival in patients with PDAC. The mechanisms that lead to bone wasting in tumor-bearing hosts deserve further study., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background and Objectives: Pancreatic neuroendocrine tumors (PNETs) represent a rare form of pancreatic cancer. Racial/ethnic disparities have been documented in pancreatic ductal adenocarcinoma, but health disparities have not been well described in patients with PNETs., Methods: A retrospective review of patients with PNETs in the National Cancer Database was performed for 2004-2014. Approximately 16 605 patients with PNETs and available vital status were identified. Survival was compared by race/ethnicity and socioeconomic status using Kaplan-Meier methods and Cox regression., Results: There were no significant differences in survival between Non-Hispanic, White; Hispanic, White; or Non-Hispanic, Black patients on univariate analysis. Kaplan-Meier analysis showed that patients from communities with lower median household income and education level had worse survival (p < 0.001). Patients age less than 65 without insurance, similarly, had worse survival (p < 0.001). Multivariable modeling found no association between race/ethnicity and risk of mortality (p = 0.37). Lower median household income and lower education level were associated with increased mortality (p < 0.001)., Conclusions: Unlike most other malignancies, race/ethnicity is not associated with survival differences in patients with PNETs. Patients with lower socioeconomic status had worse survival. The presence of identifiable health disparities in patients with PNETs represents a target for intervention and opportunity to improve survival in patients with this malignancy., (© 2021 Wiley Periodicals LLC.)

Lessons Learned: Preclinical studies have demonstrated that Src inhibition through dasatinib synergistically enhances the antitumor effects of oxaliplatin. In this phase II, single-arm study, FOLFOX with dasatinib in previously untreated patients with mPC only showed only modest clinical activity, with a progressive-free survival of 4 months and overall survival of 10.6 months. Continued investigation is ongoing to better understand the role of Src inhibition with concurrent 5-fluorouracil and oxaliplatin in a subset of exceptional responders., Background: Src tyrosine kinase activity is overexpressed in many human cancers, including metastatic pancreatic cancer (mPC). Dasatinib is a potent inhibitor of Src family of tyrosine kinases. This study was designed to investigate whether dasatinib can synergistically enhance antitumor effects of FOLFOX regimen (FOLFOX-D)., Methods: In this single-arm, phase II study, previously untreated patients received dasatinib 150 mg oral daily on days 1-14, oxaliplatin 85 mg/m 2 intravenous (IV) on day 1 every 14 days, leucovorin (LV) 400 mg/m 2 IV on day 1 every 14 days, 5-fluorouracil (5-FU) bolus 400 mg/m 2 on day 1 every 14 days, and 5-FU continuous infusion 2,400 mg/m 2 on day 1 every 14 days. Primary endpoint was progression-free survival (PFS) with preplanned comparison to historical controls., Results: Forty-four patients enrolled with an estimated median PFS of 4.0 (95% confidence interval [CI], 2.3-8.5) months and overall survival (OS) of 10.6 (95% CI, 6.9-12.7) months. Overall response rate (ORR) was 22.7% (n = 10): one patient (2.3%) with complete response (CR) and nine patients (20.5%) with partial response (PR). Fifteen patients (34.1%) had stable disease (SD). Nausea was the most common adverse event (AE) seen in 35 patients (79.5%)., Conclusion: The addition of dasatinib did not appear to add incremental clinical benefit to FOLFOX in untreated patients with mPC., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Modern humans originated between 300 and 200 ka in structured populations throughout Africa, characterized by regional interaction and diversity. Acknowledgment of this complex Pleistocene population structure raises new questions about the emergence of phenotypic diversity. Holocene Southern African Later Stone Age (LSA) skeletons and descendant Khoe-San peoples have small adult body sizes that may reflect long-term adaptation to the Cape environment. Pleistocene Southern African adult body sizes are not well characterized, but some postcranial elements are available. The most numerous Pleistocene postcranial skeletal remains come from Klasies River Mouth on the Southern Cape coast of South Africa. We compare the morphology of these skeletal elements with globally sampled Holocene groups encompassing diverse adult body sizes and shapes (n = 287) to investigate whether there is evidence for phenotypic patterning. The adult Klasies River Mouth bones include most of a lumbar vertebra, and portions of a left clavicle, left proximal radius, right proximal ulna, and left first metatarsal. Linear dimensions, shape characteristics, and cross-sectional geometric properties of the Klasies River Mouth elements were compared using univariate and multivariate methods. Between-group principal component analyses group Klasies River Mouth elements, except the proximal ulna, with LSA Southern Africans. The similarity is driven by size. Klasies River Mouth metatarsal cross-sectional geometric properties indicate similar torsional and compressive strength to those from LSA Southern Africans. Phenotypic expressions of small-bodied adult morphology in Marine Isotope Stages 5 and 1 suggest this phenotype may represent local convergent adaptation to life in the Cape., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Disparities exist among patients with pancreatic ductal adenocarcinoma (PDAC). Non-White race is regarded as a negative predictor of expected treatment and overall survival. Data suggest that Academic Research Programs (ARP) provide better outcomes for minorities, but ethnic/minority outcomes are underreported. We hypothesize that outcomes among racially/ethnically diverse PDAC patients may be influenced by treatment facility., Methods: The National Cancer Database was used to identify 170,327 patients diagnosed with PDAC between 2004 and 2015. Cox proportional-hazard regression was used to compare survival between race/ethnic groups across facilities., Results: In unadjusted models, compared to non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB) had the worst overall survival (HR = 1.05, 95%CI: 1.03-1.06, P < .001) and Hispanics had the best overall survival (HR = 0.92, 95%CI: 0.90-0.94, P < .001). After controlling for socioeconomic and clinical covariates, NHB (HR = 0.95, 95%CI: 0.93-0.96, P < .001) had better overall survival compared to NHW, and Hispanics continued to have the best comparative outcomes (HR = 0.84, 95%CI: 0.82-0.86, P < .001). Among Hispanics, Dominicans and South/Central Americans lived the longest, at 10.25 and 9.82 months, respectively. The improved survival in Hispanics was most pronounced at ARP (HR = 0.80, 95%CI: 0.77-0.84, P < .001) and Integrated Network Cancer Programs (HR = 0.78, 95%CI: 0.73-0.84, P < .001). NHB had improved survival over NHW at Comprehensive Community Care Programs (HR = 0.96, 95%CI: 0.93-0.98, P = .002) and ARP (HR = 0.96, 95%CI: 0.94-0.98, P = .001), which was influenced by income, education, and surgical resection., Conclusion: Survival was improved at ARP for all populations. Hispanics had the best comparative overall survival. NHB had improved overall survival at higher volume centers, but this was dependent upon income, education, and surgical resection., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. SIGNIFICANCE: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia., (©2020 American Association for Cancer Research.)

Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets.

Cancer cachexia is a multifactorial syndrome defined by weight loss, muscle wasting, and systemic inflammation. It affects the majority of patients with advanced cancer and is associated with poor treatment response, early mortality and decreased quality of life. The microbiota has been implicated in cancer cachexia through pathways of systemic inflammation, gut barrier dysfunction and muscle wasting. The imbalance of the microbiota, known as dysbiosis, has been shown to influence cancer cachexia. Bacteria that play beneficial and detrimental roles in the disease pathogenesis have been identified. The phenotype of cancer cachexia is associated with decreased levels of Lactobacillales and increased levels of Enterobacteriaceae and Parabacteroides . Currently, there are no treatment options that demonstrate increased survival or the quality of life in patients suffering from cancer cachexia. Through the manipulation of beneficial bacteria in the gut microbiota, different treatment options have been explored. Prebiotics and probiotics have been shown to improve outcomes in animal models of cachexia. Expounding on this mechanism, fecal microbiota transplant (FMT) holds promise for a future treatment of cancer cachexia. Further research is necessary to address this detrimental disease process and improve the lives of patients suffering from cancer cachexia.

Objectives: The research explores whether the combined study of cortical bone histology, bone morphology, and dietary stable isotopes can expand insights into past human health and adaptations, particularly dietary sufficiency and life span., Materials and Methods: Midthoracic rib cortices from 54 South African Late Holocene adult skeletons (28 M, 24 F, two sex undetermined) are assessed by transmitted-light microscopy for cross-sectional area measurements, osteon area (On.Ar), osteon population density, and presence/absence of secondary osteon variants. Values for δ 13 C bone collagen , δ 15 N bone collagen , 14 C dates, Southwestern and Southern Cape geographic regions, body size measures, estimated ages-at-death from both morphological and histological methods are integrated into analyses, which include Spearman correlations, χ 2 tests and Kruskal-Wallis ANOVAs., Results: There is reduced On.Ar variability with higher δ 15 N (r = -.41, p = .005); rib %cortical area and δ 15 N are negatively correlated in the Southern Cape group (r = -.60, p = .03). Osteon variants are more common in older adults; histological ages at death are significantly older than those determined from gross morphology., Discussion: We found bone tissue relationships with measures of diet composition, but indicators of dietary adequacy remain elusive. Relationships of tissue quality and isotopes suggest that some Southern Cape adults lived long lives. Osteon variants are associated with age-at-death; some association with diet remains possible. Gross morphological methods appear to underestimate adult ages-at-death, at least among small-bodied adults., (© 2019 Wiley Periodicals, Inc.)

Pancreatic cancer (PC) is characterized by racial/ethnic disparities and the debilitating muscle-wasting condition, cancer cachexia. Florida ranks second in the number of PC deaths and has a large and understudied minority population. We examined the primary hypothesis that PC incidence and mortality rates may be highest among Black Floridians and the secondary hypothesis that biological correlates of cancer cachexia may underlie disparities. PC incidence and mortality rates were estimated by race/ethnicity, gender, and county using publicly available state-wide cancer registry data that included approximately 2700 Black, 25 200 Non-Hispanic White (NHW), and 3300 Hispanic/Latino (H/L) Floridians diagnosed between 2004 and 2014. Blacks within Florida experienced a significantly (P < 0.05) higher incidence (12.5/100 000) and mortality (10.97/100 000) compared to NHW (incidence = 11.2/100 000; mortality = 10.3/100 000) and H/L (incidence = 9.6/100 000; mortality = 8.7/100 000), especially in rural counties. To investigate radiologic and blood-based correlates of cachexia, we leveraged data from a subset of patients evaluated at two geographically distinct Florida Cancer Centers. In Blacks compared to NHW matched on stage, markers of PC-induced cachexia were more frequent and included greater decreases in core musculature compared to corresponding healthy control patients (25.0% vs 10.1% lower), greater decreases in psoas musculature over time (10.5% vs 4.8% loss), lower baseline serum albumin levels (3.8 vs 4.0 gm/dL), and higher platelet counts (332.8 vs 268.7 k/UL). Together, these findings suggest for the first time that PC and cachexia may affect Blacks disproportionately. Given its nearly universal contribution to illness and PC-related deaths, the early diagnosis and treatment of cachexia may represent an avenue to improve health equity, quality of life, and survival., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Early herders in eastern Africa built elaborate megalithic cemeteries ~ 5000 BP overlooking what is now Lake Turkana in northwestern Kenya. At least six 'pillar sites' were constructed during a time of rapid change: cattle, sheep, and goats were introduced to the basin as the lake was shrinking at the end of the African Humid Period. Cultural changes at this time include new lithic and ceramic technologies and the earliest monumentality in eastern Africa. Isolated human remains previously excavated from pillar sites east of Lake Turkana seemed to indicate that pillar site platforms were ossuaries for secondary burials. Recent bioarchaeological excavations at four pillar sites west of the lake have now yielded ≥49 individuals, most from primary and some from secondary interments, challenging earlier interpretations. Here we describe the mortuary cavities, and burial contexts, and included items such as adornments from Lothagam North, Lothagam West, Manemanya, and Kalokol pillar sites. In doing so, we reassess previous hypotheses regarding pillar site construction, use, and inter-site variability. We also present the first osteological analyses of skeletons buried at these sites. Although the human remains are fragmentary, they are nevertheless informative about the sex, age, and body size of the deceased and give evidence for health and disease processes. Periosteal moulds of long bone midshafts ( n  = 34 elements) suggest patterns of terrestrial mobility. Pillar site deposits provide important new insights into early herder lifeways in eastern Africa and the impact of the transition to pastoralism on past human populations., (© The Author(s) 2019.)

Membrane transporters fulfill essential roles in maintaining normal cellular function in health. In cancer, transporters likewise facilitate the aberrant characteristics typical of proliferating tumor cells. Pancreatic ductal adenocarcinoma is remarkable in its aggressiveness, and its metabolism is supported by a variety of membrane transporters. Glucose transporter 1 is upregulated in pancreatic cancer, enables rapid cellular uptake of glucose, and contributes to the invasiveness and metastatic ability of the disease. Likewise, the machinery of glycolysis, enzymes such as pyruvate kinase type M2 and hexokinase 2, is particularly active and ultimately leads to both lactate and tumor formation. Lactic acid channels and transporters include monocarboxylate transporters 1 and 4, connexin43, and CD147. In conjunction with glucose transporters and glycolytic metabolism, lactic acid transport helps perpetuate tumor cell metabolism and contributes to the formation of the unique tumor microenvironment in pancreatic cancer. These transporters may serve as potential therapeutic targets.

Background: Cancer cachexia is a catabolic condition characterized by skeletal muscle wasting, consequent to tumor burden, which negatively impacts tolerance to cancer therapies and contributes to increased mortality. Partly because of the limited knowledge of the underlying mechanisms of cancer cachexia derived from human studies, however, the ability to therapeutically intervene remains elusive. The purpose of the current study was therefore to better define the phenotype of skeletal muscle obtained from patients with pancreatic ductal adenocarcinoma (PDAC), which has one of the highest rates of cachexia., Methods: Morphological analyses were performed on rectus abdominis muscle biopsies obtained from resectable PDAC patients undergoing tumor resection surgery (N = 20) and from weight-stable non-cancer control subjects undergoing benign abdominal surgery (N = 16). PDAC patients with a body weight loss of greater than 5% during the previous 6 months were considered cachectic (N = 15). Statistical tests were two sided., Results: Skeletal muscle from cachectic PDAC patients had increased collagen content compared with non-cancer control subjects (1.43% vs 9.66%, P  = .0004, Dunn test). Across all PDAC patients, collagen content positively correlated with body weight loss (P  = .0016, r  = 0.672), was increased in patients with lymph node metastasis ( P  = .007, Mann-Whitney U test), and was associated with survival on univariate (HR = 1.08, 95% confidence interval [CI] = 1.02 to 1.04, P  = .008) and multivariable analyses (HR = 1.08, 95% CI = 1.00 to 1.17, P  = .038). Cachectic PDAC patients also displayed increased lipid deposition (2.63% vs 5.72%, P  = .042), infiltration of CD68+ macrophages (63.6 cells/mm 2 vs 233.8 cells/mm 2 , P  = .0238), calcium deposition (0.21% vs 2.51%, P  = .030), and evidence of deficient cellular quality control mechanisms (Mann-Whitney U test). Transcriptional profiling of all patients supported these findings by identifying gene clusters related to wounding, inflammation, and cellular response to TGF-β upregulated in cachectic PDAC patients compared with non-cancer control subjects., Conclusions: To our knowledge, this work is the first to demonstrate increased collagen content in cachectic PDAC patients that is associated with poor survival.

Anxiety disorders are the most prevalent mental health conditions. Although they are less visible than schizophrenia, depression, and bipolar disorder, they can be just as disabling. The diagnoses of anxiety disorders are being continuously revised. Both dimensional and structural diagnoses have been used in clinical treatment and research, and both methods have been proposed for the new classification in the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-5). However, each of these approaches has limitations. More recently, the emphasis in diagnosis has focused on neuroimaging and genetic research. This approach is based partly on the need for a more comprehensive understanding of how biology, stress, and genetics interact to shape the symptoms of anxiety. Anxiety disorders can be effectively treated with psychopharmacological and cognitive-behavioral interventions. These inter ventions have different symptom targets; thus, logical combinations of these strategies need to be further studied in order to improve future outcomes. New developments are forthcoming in the field of alternative strategies for managing anxiety and for treatment-resistant cases. Additional treatment enhancements should include the development of algorithms that can be easily used in primary care and with greater focus on managing functional impairment in patients with anxiety.

Proposals to address the needs of uninsured Californians take one of two broadly different emphases: assuring that the uninsured have access to health services by expanding community health centers and clinics; or by extending health insurance coverage to those without it. This policy brief examines literature on the effect of expanding access to safety net health services versus extending health insurance coverage to those who are currently uninsured. Based on this examination of the literature and analysis of the 2005 California Health Interview Survey (CHIS 2005), we conclude that both approaches are necessary to address access problems faced by the uninsured and underserved.

Synthetic feline facial pheromone (FFP) (Feliway; Ceva Animal Health) was assessed for the management of cats with recurrent feline idiopathic cystitis (FIC). Nine of 12 cats completed the randomised, double-blinded, placebo-controlled, crossover pilot study. They had their environment treated daily with either FFP or placebo for 2 months, after which time the treatment groups were reversed. Owners used visual analogue scales to define the severity of their cat's clinical signs and behavioural changes. Five (56%) of the owners stated that their cat's overall health was better when they were using FFP. Four (44%) of the owners noticed no difference between when using the FFP and when using the placebo. While there were no statistical differences between the two treatment groups there was a trend for the cats exposed to FFP to show fewer days with clinical signs of cystitis (FFP total, mean per cat+/-standard deviation, 30, 4.3+/-6.7; placebo 69, 9.9+/-19.1), a lower overall clinical score (1667, 238+/-476; 2009, 287+/-425), a reduced number of episodes of cystitis (9, 1.3+/-2.0; 10, 1.4+/-2.1) and reduced negative behavioural traits (e.g., less aggression and fear) (-128, -18.3+/-65.8; -73, -10.4+/-35.1).

The cause of cystitis in many cats remains unknown. The aim of this study was to determine whether or not any environmental or behavioural factors, particularly those that could be considered potentially stressful, were associated with feline idiopathic cystitis (FIC). The questionnaire-based study involved comparing 31 cats with FIC to 24 cats in the same households that did not have cystitis. They were also compared with a control population of 125 clinically healthy cats. Compared with the live-in controls and the control population, the cats with FIC were significantly more likely to be male, overweight and pedigree. Several stress factors were found to be associated with FIC. The factor that stood out most prominently was living with another cat with which there was conflict. The findings support the hypothesis that stress may be implicated in some cases of FIC.

This Korean study replicated a previously published American study. The conceptual framework and method combined ethical enquiry and phenomenology. The research questions were: (1) What is nursing students' experience of ethical problems involving nursing practice? and, (2) What is nursing students' experience of using an ethical decision-making model? The participants were 97 senior baccalaureate nursing students, each of whom described one ethical problem and chose to use one of five ethical decision-making models. From 97 ethical problems, five content categories emerged, the largest being health professionals (69%). The basic nature of the ethical problems was the students' experience of conflict, resolution and rationale. Using an ethical decision-making model helped 94% of the students. A comparison of the Korean and American results yields important implications for nursing ethics education, practice and research.