Psychosocial and palliative care in African national cancer control plans: A qualitative study.

OBJECTIVE: Low and middle income countries of Africa account for a disproportionate amount of the global health burden of cancer. Providing patients access to psychosocial oncology and palliative care through policy structures such as the National Cancer Control Plans (NCCP) is essential to improving the care provided to patients and their families. The first phase of this study sought to determine the extent to which palliative care and psychosocial oncology were integrated in NCCPs in African countries. METHODS: A qualitative thematic analysis of the plans was used using Nvivo, with two-raters coding and continuous team discussions. Data were organized into an infographic map showing the coverage of themes across African countries. RESULTS: Fifty-eight NCCPs and NCD plans were analyzed in the 54 countries in Africa. The findings illustrate a lack of standardization across countries' NCCPs in addressing psychosocial oncology and palliative care themes. Certain areas presented good coverage across several plans, such as barriers to access, education, awareness, and health behaviors, coordination of care, families, caregivers and community involvement, and palliative care. Other themes presented low coverage, such as doctor-patient communication, mental health, bereavement, psychosocial care, survivorship care, and traditional medicine. CONCLUSIONS: One may consider further developing NCCP areas as they pertain to psychosocial oncology and palliative care to ensure their proper place on the policy agenda for a healthier Africa.

Direct Cryo-ET observation of platelet deformation induced by SARS-CoV-2 spike protein.

SARS-CoV-2 is a novel coronavirus responsible for the COVID-19 pandemic. Its high pathogenicity is due to SARS-CoV-2 spike protein (S protein) contacting host-cell receptors. A critical hallmark of COVID-19 is the occurrence of coagulopathies. Here, we report the direct observation of the interactions between S protein and platelets. Live imaging shows that the S protein triggers platelets to deform dynamically, in some cases, leading to their irreversible activation. Cellular cryo-electron tomography reveals dense decorations of S protein on the platelet surface, inducing filopodia formation. Hypothesizing that S protein binds to filopodia-inducing integrin receptors, we tested the binding to RGD motif-recognizing platelet integrins and find that S protein recognizes integrin αvß3. Our results infer that the stochastic activation of platelets is due to weak interactions of S protein with integrin, which can attribute to the pathogenesis of COVID-19 and the occurrence of rare but severe coagulopathies.

Communicating bad news to patients and families in African oncology settings.

AIMS: To assess clinicians' self-reported knowledge of current policies in African oncology settings, of their personal communication practices around sharing bad news with patients, and to identify barriers to the sharing of serious news in these settings. METHODS: A cross-sectional study of cancer care providers in African oncology settings (N = 125) was conducted. Factor analysis was used to assess cross-cultural adaptation and uptake of an evidence-based protocol for disclosing bad news to patients with cancer and of providers' perceived barriers to disclosing bad news to patients with cancer. Analysis of Various (ANOVA) was used to assess strength of association with each dimension of these two measurement models by various categorical variables. RESULTS: Providers from Nigeria, Kenya, Ghana, and Rwanda represented 85% of survey respondents. Two independent, psychometrically reliable, multi-dimensional measurement models were derived to assess providers' personal communication practices and providers' perceived barriers to disclosing a cancer diagnosis. Forty percent (40%) of respondent nurses but only 20% of respondent physicians had had formal communications skills training. Approximately 20%-25% of respondent physicians and nurses reported having a consistent plan or strategy for communicating bad news to their cancer patients. CONCLUSIONS: Results show that effective communication about cancer diagnosis and prognosis requires an appreciation and clinical skill set that blends an understanding of cancer-related internalized stigmas harbored by patient and family, dilemmas posed by treatment affordability, and the need to navigate family wishes about cancer-related diagnoses in the context of African oncology settings. Findings underscore the need for culturally grounded communications research and program design.

Direct Cryo-ET observation of platelet deformation induced by SARS-CoV-2 Spike protein.

SARS-CoV-2 is a novel coronavirus responsible for the COVID-19 pandemic. Its high pathogenicity is due to SARS-CoV-2 spike protein (S protein) contacting host-cell receptors. A critical hallmark of COVID-19 is the occurrence of coagulopathies. Here, we report the direct observation of the interactions between S protein and platelets. Live imaging showed that the S protein triggers platelets to deform dynamically, in some cases, leading to their irreversible activation. Strikingly, cellular cryo-electron tomography revealed dense decorations of S protein on the platelet surface, inducing filopodia formation. Hypothesizing that S protein binds to filopodia-inducing integrin receptors, we tested the binding to RGD motif-recognizing platelet integrins and found that S protein recognizes integrin α v ß 3 . Our results infer that the stochastic activation of platelets is due to weak interactions of S protein with integrin, which can attribute to the pathogenesis of COVID-19 and the occurrence of rare but severe coagulopathies.

Inorganic-Organic Interpenetrating Network Hydrogels as Tissue-Integrating Luminescent Implants: Physicochemical Characterization and Preclinical Evaluation.

Sensors capable of accurate, continuous monitoring of biochemistry are crucial to the realization of personalized medicine on a large scale. Great strides have been made to enhance tissue compatibility of long-term in vivo biosensors using biomaterials strategies such as tissue-integrating hydrogels. However, the low level of oxygen in tissue presents a challenge for implanted devices, especially when the biosensing function relies on oxygen as a measure-either as a primary analyte or as an indirect marker to transduce levels of other biomolecules. This work presents a method of fabricating inorganic-organic interpenetrating network (IPN) hydrogels to optimize the oxygen transport through injectable biosensors. Capitalizing on the synergy between the two networks, various physicochemical properties (e.g., swelling, glass transition temperature, and mechanical properties) are shown to be independently adjustable while maintaining a 250% increase in oxygen permeability relative to poly(2-hydroxyethyl methacrylate) controls. Finally, these gels, when functionalized with a Pd(II) benzoporphyrin phosphor, track tissue oxygen in real time for 76 days as subcutaneous implants in a porcine model while promoting tissue ingrowth and minimizing fibrosis around the implant. These findings support IPN networks for fine-tuned design of implantable biomaterials in personalized medicine and other biomedical applications.

Tracing the Evolutionary Origin of Desmosomes.

Cadherin-based cell-cell junctions help metazoans form polarized sheets of cells, which are necessary for the development of organs and the compartmentalization of functions. The components of the protein complexes that generate cadherin-based junctions have ancient origins, with conserved elements shared between animals as diverse as sponges and vertebrates. In invertebrates, the formation and function of epithelial sheets depends on classical cadherin-containing adherens junctions, which link actin to the plasma membrane through α-, ß- and p120 catenins. Vertebrates also have a new type of cadherin-based intercellular junction called the desmosome, which allowed for the creation of more complex and effective tissue barriers against environmental stress. While desmosomes have a molecular blueprint that is similar to that of adherens junctions, desmosomal cadherins - called desmogleins and desmocollins - link intermediate filaments (IFs) rather than actin to the plasma membrane through protein complexes comprising relatives of ß-catenin (plakoglobin) and p120 catenin (plakophilins). In turn, desmosomal catenins interact with members of the IF-binding plakin family to create the desmosome-IF linking complex. In this Minireview, we discuss when and how desmosomal components evolved, and how their ability to anchor the highly elastic and tough IF cytoskeleton endowed vertebrates with robust tissues capable of not only resisting but also properly responding to environmental stress.

The significance of sponges for comparative studies of developmental evolution.

Sponges, ctenophores, placozoans, and cnidarians have key evolutionary significance in that they bracket the time interval during which organized animal tissues were first assembled, fundamental cell types originated (e.g., neurons and myocytes), and developmental patterning mechanisms evolved. Sponges in particular have often been viewed as living surrogates for early animal ancestors, largely due to similarities between their feeding cells (choanocytes) with choanoflagellates, the unicellular/colony-forming sister group to animals. Here, we evaluate these claims and highlight aspects of sponge biology with comparative value for understanding developmental evolution, irrespective of the purported antiquity of their body plan. Specifically, we argue that sponges strike a different balance between patterning and plasticity than other animals, and that environmental inputs may have prominence over genetically regulated developmental mechanisms. We then present a case study to illustrate how contractile epithelia in sponges can help unravel the complex ancestry of an ancient animal cell type, myocytes, which sponges lack. Sponges represent hundreds of millions of years of largely unexamined evolutionary experimentation within animals. Their phylogenetic placement lends them key significance for learning about the past, and their divergent biology challenges current views about the scope of animal cell and developmental biology. This article is characterized under: Comparative Development and Evolution > Evolutionary Novelties Comparative Development and Evolution > Body Plan Evolution.

Diverse cell junctions with unique molecular composition in tissues of a sponge (Porifera).

The integrity and organization of animal tissues depend upon specialized protein complexes that mediate adhesion between cells with each other (cadherin-based adherens junctions), and with the extracellular matrix (integrin-based focal adhesions). Reconstructing how and when these cell junctions evolved is central to understanding early tissue evolution in animals. We examined focal adhesion protein homologs in tissues of the freshwater sponge, Ephydatia muelleri (phylum Porifera; class Demospongiae). Our principal findings are that (1) sponge focal adhesion homologs (integrin, talin, focal adhesion kinase, etc.) co-precipitate as a complex, separate from adherens junction proteins; (2) that actin-based structures resembling focal adhesions form at the cell-substrate interface, and their abundance is dynamically regulated in response to fluid shear; (3) focal adhesion proteins localize to both cell-cell and cell-extracellular matrix adhesions, and; (4) the adherens junction protein ß-catenin is co-distributed with focal adhesion proteins at cell-cell junctions everywhere except the choanoderm, and at novel junctions between cells with spicules, and between cells with environmental bacteria. These results clarify the diversity, distribution and molecular composition of cell junctions in tissues of E. muelleri, but raise new questions about their functional properties and ancestry.

Long-Term In Vivo Oxygen Sensors for Peripheral Artery Disease Monitoring.

Tracking of tissue oxygenation around chronic foot wounds may help direct therapy decisions in patients with peripheral artery disease (PAD). Novel sensing technology to enable such monitoring was tested over 9 months in a Sinclair mini-pig model. No adverse events were observed over the entire study period. Systemic and acute hypoxia challenges were detected during each measurement period by the microsensors. The median time to locate the sensor signal was 13 s. Lumee Oxygen microsensors appear safe for long-term repeated oxygen measurements over 9 months.

Analysis of a vinculin homolog in a sponge (phylum Porifera) reveals that vertebrate-like cell adhesions emerged early in animal evolution.

The evolution of cell-adhesion mechanisms in animals facilitated the assembly of organized multicellular tissues. Studies in traditional animal models have revealed two predominant adhesion structures, the adherens junction (AJ) and focal adhesions (FAs), which are involved in the attachment of neighboring cells to each other and to the secreted extracellular matrix (ECM), respectively. The AJ (containing cadherins and catenins) and FAs (comprising integrins, talin, and paxillin) differ in protein composition, but both junctions contain the actin-binding protein vinculin. The near ubiquity of these structures in animals suggests that AJ and FAs evolved early, possibly coincident with multicellularity. However, a challenge to this perspective is that previous studies of sponges-a divergent animal lineage-indicate that their tissues are organized primarily by an alternative, sponge-specific cell-adhesion mechanism called "aggregation factor." In this study, we examined the structure, biochemical properties, and tissue localization of a vinculin ortholog in the sponge Oscarella pearsei (Op). Our results indicate that Op vinculin localizes to both cell-cell and cell-ECM contacts and has biochemical and structural properties similar to those of vertebrate vinculin. We propose that Op vinculin played a role in cell adhesion and tissue organization in the last common ancestor of sponges and other animals. These findings provide compelling evidence that sponge tissues are indeed organized like epithelia in other animals and support the notion that AJ- and FA-like structures extend to the earliest periods of animal evolution.

Antibiotic-induced changes in the microbiota disrupt redox dynamics in the gut.

How host and microbial factors combine to structure gut microbial communities remains incompletely understood. Redox potential is an important environmental feature affected by both host and microbial actions. We assessed how antibiotics, which can impact host and microbial function, change redox state and how this contributes to post-antibiotic succession. We showed gut redox potential increased within hours of an antibiotic dose in mice. Host and microbial functioning changed under treatment, but shifts in redox potentials could be attributed specifically to bacterial suppression in a host-free ex vivo human gut microbiota model. Redox dynamics were linked to blooms of the bacterial family Enterobacteriaceae. Ecological succession to pre-treatment composition was associated with recovery of gut redox, but also required dispersal from unaffected gut communities. As bacterial competition for electron acceptors can be a key ecological factor structuring gut communities, these results support the potential for manipulating gut microbiota through managing bacterial respiration.

Evidence of Signaling and Adhesion Roles for ß-Catenin in the Sponge Ephydatia muelleri.

ß-Catenin acts as a transcriptional coactivator in the Wnt/ß-catenin signaling pathway and a cytoplasmic effector in cadherin-based cell adhesion. These functions are ancient within animals, but the earliest steps in ß-catenin evolution remain unresolved due to limited data from key lineages-sponges, ctenophores, and placozoans. Previous studies in sponges have characterized ß-catenin expression dynamics and used GSK3B antagonists to ectopically activate the Wnt/ß-catenin pathway; both approaches rely upon untested assumptions about the conservation of ß-catenin function and regulation in sponges. Here, we test these assumptions using an antibody raised against ß-catenin from the sponge Ephydatia muelleri. We find that cadherin-complex genes coprecipitate with endogenous Em ß-catenin from cell lysates, but that Wnt pathway components do not. However, through immunostaining we detect both cell boundary and nuclear populations, and we find evidence that Em ß-catenin is a conserved substrate of GSK3B. Collectively, these data support conserved roles for Em ß-catenin in both cell adhesion and Wnt signaling. Additionally, we find evidence for an Em ß-catenin population associated with the distal ends of F-actin stress fibers in apparent cell-substrate adhesion structures that resemble focal adhesions. This finding suggests a fundamental difference in the adhesion properties of sponge tissues relative to other animals, in which the adhesion functions of ß-catenin are typically restricted to cell-cell adhesions.

Transcriptome sequencing and delimitation of sympatric Oscarella species (O. carmela and O. pearsei sp. nov) from California, USA.

The homoscleromorph sponge Oscarella carmela, first described from central California, USA is shown to represent two superficially similar but both morphologically and phylogenetically distinct species that are co-distributed. We here describe a new species as Oscarella pearsei, sp. nov. and re-describe Oscarella carmela; the original description was based upon material from both species. Further, we correct the identification of published genomic/transcriptomic resources that were originally attributed to O. carmela, and present new Illumina-sequenced transcriptome assemblies for each of these species, and the mitochondrial genome sequence for O. pearsei sp. nov. Using SSU and LSU ribosomal DNA and the mitochondrial genome, we report the phylogenetic relationships of these species relative to other Oscarella species, and find strong support for the placement of O. pearsei sp. nov. in a distinct clade within genus Oscarella defined by the presence of spherulous cells that contain paracrystalline inclusions; O. carmela lacks this cell type. Oscarella pearsei sp. nov and O. carmela can be tentatively distinguished based upon gross morphological differences such as color, surface texture and extent of mucus production, but can be more reliably identified using mitochondrial and nuclear barcode sequencing, ultrastructural characteristics of cells in the mesohyl, and the morphology of the follicle epithelium which surrounds the developing embryo in reproductively active individuals.

Injectable Phosphorescence-based Oxygen Biosensors Identify Post Ischemic Reactive Hyperoxia.

Novel injectable biosensors were used to measure interstitial oxygenation before, during, and after transient ischemia. It is well known that reactive hyperemia occurs following a period of ischemia. However, increased blood flow does not necessarily mean increased oxygen tension in the tissue. Therefore, the purpose of this study was to test the hypothesis that tissue reactive hyperoxia occurs following release of hind-limb tourniquet occlusions. Rats were injected with bilateral hind-limb biosensors and were simultaneously subjected to a unilateral femoral vessel ligation. After approximately one and three months, the rats underwent a series of oxygenation challenges, including transient hind-limb tourniquet occlusion. Along with the biosensors, near infrared spectroscopy was used to measure percent oxyhemoglobin in capillaries and laser Doppler flowmetry was used to measure blood flow. Post-occlusion reactive hyperemia was observed. It was accompanied by tissue reactive hyperoxia, affirming that the post-occlusion oxygen supply must have exceeded the expected increased oxygen consumption. The measurement of the physiologic phenomenon of reactive hyperoxia could prove clinically beneficial for both diagnosis and optimizing therapy.

Tissue-Integrating Oxygen Sensors: Continuous Tracking of Tissue Hypoxia.

We describe a simple method of tracking oxygen in real-time with injectable, tissue-integrating microsensors. The sensors are small (500 µm × 500 µm × 5 mm), soft, flexible, tissue-like, biocompatible hydrogel s that have been shown to overcome the foreign body response for long-term sensing. The sensors are engineered to change luminescence in the presence of oxygen or other analytes and function for months to years in the body. A single injection followed by non-invasive monitoring with a hand-held or wearable Bluetooth optical reader enables intermittent or continuous measurements. Proof of concept for applications in high altitude, exercise physiology, vascular disease, stroke, tumors, and other disease states have been shown in mouse, rat and porcine models. Over 90 sensors have been studied to date in humans. These novel tissue-integrating sensors yield real-time insights in tissue oxygen fluctuations for research and clinical applications.

Conserved expression of vertebrate microvillar gene homologs in choanocytes of freshwater sponges.

BACKGROUND: The microvillus is a versatile organelle that serves important functions in disparate animal cell types. However, from a molecular perspective, the microvillus has been well studied in only a few, predominantly vertebrate, contexts. Little is known about how differences in microvillar structure contribute to differences in function, and how these differences evolved. We sequenced the transcriptome of the freshwater sponge, Ephydatia muelleri, and examined the expression of vertebrate microvillar gene homologs in choanocytes-the only microvilli-bearing cell type present in sponges. Sponges offer a distant phylogenetic comparison with vertebrates, and choanocytes are central to discussions about early animal evolution due to their similarity with choanoflagellates, the single-celled sister lineage of modern animals. RESULTS: We found that, from a genomic perspective, sponges have conserved homologs of most vertebrate microvillar genes, most of which are expressed in choanocytes, and many of which exhibit choanocyte-specific or choanocyte-enriched expression. Possible exceptions include the cadherins that form intermicrovillar links in the enterocyte brush border and hair cell stereocilia of vertebrates and cnidarians. No obvious orthologs of these proteins were detected in sponges, but at least four candidate cadherins were identified as choanocyte-enriched and might serve this function. In contrast to the evidence for conserved microvillar structure in sponges and vertebrates, we found that choanoflagellates and ctenophores lack homologs of many fundamental microvillar genes, suggesting that microvillar structure may diverge significantly in these lineages, warranting further study. CONCLUSIONS: The available evidence suggests that microvilli evolved early in the prehistory of modern animals and have been repurposed to serve myriad functions in different cellular contexts. Detailed understanding of the sequence by which different microvilli-bearing cell/tissue types diversified will require further study of microvillar composition and development in disparate cell types and lineages. Of particular interest are the microvilli of choanoflagellates, ctenophores, and sponges, which collectively bracket the earliest events in animal evolution.

Preclinical Evaluation of Poly(HEMA-co-acrylamide) Hydrogels Encapsulating Glucose Oxidase and Palladium Benzoporphyrin as Fully Implantable Glucose Sensors.

BACKGROUND: Continuous glucose monitors (CGMs) require percutaneous wire probes to monitor glucose. Sensors based on luminescent hydrogels are being explored as fully implantable alternatives to traditional CGMs. Our previous work investigated hydrogel matrices functionalized with enzymes and oxygen-quenched phosphors, demonstrating sensitivity to glucose, range of response, and biofouling strongly depend on the matrix material. Here, we further investigate the effect of matrix composition on overall performance in vitro and in vivo. METHODS: Sensors based on three hydrogels, a poly(2-hydroxyethyl methacrylate) (pHEMA) homopolymer and 2 poly(2-hydroxyethyl methacrylate-co-acrylamide) (pHEMA-co-AAm) copolymers, were compared. These were used to entrap glucose oxidase (GOx), catalase, and an oxygen-sensitive benzoporphyrin phosphor. All sensor formulations were evaluated for glucose response and stability at physiological temperatures. Selected sensors were then evaluated as implanted sensors in a porcine model challenged with glucose and insulin. The animal protocol used in this study was approved by an IACUC committee at Texas A&M University. RESULTS: PHEMA-co-AAm copolymer hydrogels (75:25 HEMA:AAm) yielded the most even GOx and dye dispersion throughout the hydrogel matrix and best preserved GOx apparent activity. In response to in vitro glucose challenges, this formulation exhibited a dynamic range of 12-167 mg/dL, a sensitivity of 1.44 ± 0.46 µs/(mg/dL), and tracked closely with reference capillary blood glucose values in vivo. CONCLUSIONS: The hydrogel-based sensors exhibited excellent sensitivity and sufficiently rapid response to the glucose levels achieved in vivo, proving feasibility of these materials for use in real-time glucose tracking. Extending the dynamic range and assessing long-term effects in vivo are ongoing efforts.

Eucalyptus obliqua seedling growth in organic vs. mineral soil horizons.

Eucalyptus obliqua, the most widespread timber tree in Tasmania, is a pioneer after fire which can eliminate the organic layer of forest soil, exposing the underlying mineral soil. We compared seedling growth, mycorrhiza formation, and mineral nutrient limitation in organic layer vs. mineral soil. We grew E. obliqua seedlings separately in pots of organic layer and mineral soil in a glasshouse. Additional treatments of organic soil only, involved fully crossed methyl-bromide fumigation and fertilization. Fertilization comprised chelated iron for 121 days after transplant (DAT) followed by soluble phosphorus. At 357 DAT, whole plant dry weight was three times greater in ambient organic than in mineral soil. In organic soil, fumigation halved ectomycorrhiza abundance and reduced seedling growth at 149 DAT, but by 357 DAT when negative effects of fumigation on seedling growth had disappeared, neither fumigation nor fertilization affected mycorrhiza abundance. Iron fertilization diminished seedling growth, but subsequent phosphorus fertilization improved it. E. obliqua seedlings grow much better in organic layer soil than in mineral soil, although phosphorus remains limiting. The prevalent forestry practice of burning to mineral soil after timber harvest exposes a poor growth medium likely only partially compensated by fire-induced mineral soil alterations.

Crying and suicidal, but not depressed. Pseudobulbar affect in multiple sclerosis successfully treated with valproic acid: Case report and literature review.

OBJECTIVE: Pseudobulbar affect/emotional incontinence is a potentially disabling condition characterized by expressions of affect or emotions out of context from the normal emotional basis for those expressions. This condition can result in diagnostic confusion and unrelieved suffering when clinicians interpret the emotional expressions at face value. In addition, the nomenclature, etiology, and treatment for this condition remain unclear in the medical literature. METHOD: We report the case of a 60-year-old woman with multiple sclerosis who was referred to an inpatient psychiatry unit with complaints of worsening depression along with hopelessness, characterized by unrelenting crying. Our investigation showed that her symptoms were caused by pseudobulbar affect/emotional incontinence stemming from multiple sclerosis. RESULTS: The patient's history of multiple sclerosis and the fact that she identified herself as depressed only because of her incessant crying suggested that her symptoms might be due to the multiple sclerosis rather than to a depressive disorder. Magnetic resonance imaging demonstrated a new plaque consistent with multiple sclerosis lateral to her corpus callosum. Her symptoms resolved completely within three days on valproic acid but returned after she was cross-tapered to dextromethorphan plus quinidine, which is the FDA-approved treatment for this condition. SIGNIFICANCE OF RESULTS: This case provides important additional information to the current literature on pseudobulbar affect/emotional incontinence. The existing literature suggests a selective serotonin reuptake inhibitor (SSRI) and dextromethorphan/quinidine (Nuedexta) as first-line treatments; however, our patient was taking an SSRI at the time of presentation without appreciable benefit, and her symptoms responded to valproic acid but not to the dextromethorphan/quinidine. In addition, the case and the literature review suggest that the current nomenclature for this constellation of symptoms can be misleading.