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Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer that is driven by the fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). PKA activity is controlled through regulatory proteins that both inhibit catalytic activity and control localization, and an excess of regulatory subunits ensures PRKACA activity is inhibited. Here, we found an increase in the ratio of catalytic to regulatory units in FLC patient tumors driven by DNAJB1::PRKACA using mass spectrometry, biochemistry, and immunofluorescence, with increased nuclear localization of the kinase. Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA, or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes in primary human hepatocytes, recapitulating the changes observed in FLC. Consistently, tumors in patients missing a regulatory subunit or harboring an ATP1B1::PRKACA fusion were indistinguishable from FLC based on the histopathological, transcriptomic, and drug-response profiles. Together, these findings indicate that the DNAJB1 domain of DNAJB1::PRKACA is not required for FLC. Instead, changes in PKA activity and localization determine the FLC phenotype. Significance: Alterations leading to unconstrained protein kinase A signaling, regardless of the presence or absence of PRKACA fusions, drive the phenotypes of fibrolamellar hepatocellular carcinoma, reshaping understanding of the pathogenesis of this rare liver cancer.
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Carcinoma Hepatocelular , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico , Proteínas del Choque Térmico HSP40 , Neoplasias Hepáticas , Humanos , Proteínas del Choque Térmico HSP40/metabolismo , Proteínas del Choque Térmico HSP40/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/metabolismo , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Regulación Neoplásica de la Expresión Génica , ATPasa Intercambiadora de Sodio-PotasioRESUMEN
Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer caused by a dominant recurrent fusion of the heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PRKACA). Current therapies such as chemotherapy and radiation have limited efficacy, and new treatment options are needed urgently. We have previously shown that FLC tumors are dependent on the fusion kinase DNAJB1::PRKACA, making the oncokinase an ideal drug target. mRNA degrading modalities such as antisense oligonucleotides or small interfering RNAs (siRNAs) provide an opportunity to specifically target the fusion junction. Here, we identify a potent and specific siRNA that inhibits DNAJB1::PRKACA expression. We found expression of the asialoglycoprotein receptor in FLC to be maintained at sufficient levels to effectively deliver siRNA conjugated to the GalNAc ligand. We observe productive uptake and siRNA activity in FLC patient-derived xenografts (PDX) models in vitro and in vivo. Knockdown of DNAJB1::PRKACA results in durable growth inhibition of FLC PDX in vivo with no detectable toxicities. Our results suggest that this approach could be a treatment option for FLC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/metabolismo , ARN Interferente Pequeño/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , ARN Bicatenario , Proteínas del Choque Térmico HSP40/genética , Proteínas del Choque Térmico HSP40/metabolismo , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/genética , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/metabolismoRESUMEN
BACKGROUND: Virtual nurse-led care models designed with health care professionals (HCPs) and patients may support addressing unmet prostate cancer (PCa) survivor needs. Within this context, we aimed to better understand the optimal design of a service model for a proposed nurse-led PCa follow-up care platform (Ned Nurse). METHODS: A qualitative descriptive study exploring follow-up and virtual care experiences to inform a nurse-led virtual clinic (Ned Nurse) with an a priori convenience sample of 10 HCPs and 10 patients. We provide a health ecosystem readiness checklist mapping facilitators onto CFIR and Proctor's implementation outcomes. RESULTS: We show that barriers within the current standard of care include: fragmented follow-up, patient uncertainty, and long, persisting wait times despite telemedicine modalities. Participants indicate that a nurse-led clinic should be scoped to coordinate care and support patient self-management, with digital literacy considerations. CONCLUSION: A nurse-led follow-up care model for PCa is seen by HCPs as acceptable, feasible, and appropriate for care delivery. Patients value its potential to provide role clarity, reinforce continuity of care, enhance mental health support, and increase access to timely and targeted care. These findings inform design, development, and implementation strategies for digital health interventions within complex settings, revealing opportunities to optimally situate these interventions to improve care.
Prostate cancer (PCa) survivors in Canada receive follow-up care after treatment through a specialist-led model, which is currently straining to meet patient needs. We interviewed healthcare providers (HCPs) and patients to investigate the design and development of a healthcare service that uses technology, also known as virtual care, to provide nurse-led follow-up care. Mixed experiences with virtual care informed participant feedback and concerns, including impacts of the pandemic and digital literacy considerations. We show that HCPs and patients see potential benefit in virtual nurse-led follow-up care if it can increase access to resources, clarify patient and provider care roles, and improve access and continuity of care. This type of approach to follow-up care may help to improve survivor quality of life and PCa follow-up care while extending the reach of healthcare systems with limited resources.
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BACKGROUND: Comprehensive models of survivorship care are necessary to improve access to and coordination of care. New models of care provide the opportunity to address the complexity of physical and psychosocial problems and long-term health needs experienced by patients following cancer treatment. OBJECTIVE: This paper presents our expert-informed, rules-based survivorship algorithm to build a nurse-led model of survivorship care to support men living with prostate cancer (PCa). The algorithm is called No Evidence of Disease (Ned) and supports timelier decision-making, enhanced safety, and continuity of care. METHODS: An initial rule set was developed and refined through working groups with clinical experts across Canada (eg, nurse experts, physician experts, and scientists; n=20), and patient partners (n=3). Algorithm priorities were defined through a multidisciplinary consensus meeting with clinical nurse specialists, nurse scientists, nurse practitioners, urologic oncologists, urologists, and radiation oncologists (n=17). The system was refined and validated using the nominal group technique. RESULTS: Four levels of alert classification were established, initiated by responses on the Expanded Prostate Cancer Index Composite for Clinical Practice survey, and mediated by changes in minimal clinically important different alert thresholds, alert history, and clinical urgency with patient autonomy influencing clinical acuity. Patient autonomy was supported through tailored education as a first line of response, and alert escalation depending on a patient-initiated request for a nurse consultation. CONCLUSIONS: The Ned algorithm is positioned to facilitate PCa nurse-led care models with a high nurse-to-patient ratio. This novel expert-informed PCa survivorship care algorithm contains a defined escalation pathway for clinically urgent symptoms while honoring patient preference. Though further validation is required through a pragmatic trial, we anticipate the Ned algorithm will support timelier decision-making and enhance continuity of care through the automation of more frequent automated checkpoints, while empowering patients to self-manage their symptoms more effectively than standard care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2020-045806.
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Peripheral neuroblastic tumors of childhood exhibit 3 principal neural crest lineages: primitive neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. They are unique in undergoing maturation of neurons (ganglion cells) and Schwann cells, thereby recapitulating normal fetal neuronal development in the brain. Precision in estimating neurogenesis is enhanced by immunoreactivities of markers of neuronal maturation. Whether organ tissue factors in different sites of metastases influence rates of maturation and whether metastases are similar to their primary neuroblastic tumor are incompletely documented. Four young children, 1 with a mixed primary adrenal tumor and 3 with metastases were studied at surgery or autopsy. Immunocytochemical reactivities included microtubule-associated protein-2, synaptophysin, chromogranin-A, somatostatin, keratan sulfate, vimentin, S-100ß protein, and PHOX2B. Primary tumors were non-uniform with regions of either poor or enhanced maturation. Both neuronal and Schwannian lineages were represented in each tumor type but differed in proportions. Bi- or multi-nucleated ganglion cells matured equal to mononuclear forms. Ganglion cell maturation was similar in metastases regardless of the target organ. Metastases resembled primary tumors. Immunocytochemical markers of neuronal and of Schwann cell maturation provide greater diagnostic precision to supplement histological criteria. Interval between diagnosis of primary tumor and metastases, metastatic target tissues, and chemotherapy over an interval of time do not appear to influence neuroblastic or Schwann cell differentiation.
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Neuroblastoma , Humanos , Niño , Embarazo , Preescolar , Femenino , Encéfalo , Neuronas , Autopsia , Diferenciación CelularRESUMEN
BACKGROUND: Causalgia and complex regional pain syndrome (CRPS) type II with nerve injury can be difficult to treat. Surgical peripheral nerve denervation for causalgia has been largely abandoned by pain clinicians because of a perception that this may aggravate a central component (anesthesia dolorosa). METHODS: We selectively searched Pubmed, Cochrane, MEDLINE, EMBASE, CINAHL Plus, and Scopus from 1947 for articles, books, and book chapters for evidence of surgical treatments (nerve resection and amputation) and treatment related to autoimmunity and immune deficiency with CRPS. RESULTS: Reviews were found for the treatment of causalgia or CRPS type II (n = 6), causalgia relieved by nerve resection (n = 6), and causalgia and CRPS II treated by amputation (n = 8). Twelve reports were found of autoimmunity with CRPS, one paper of these on associated immune deficiency and autoimmunity, and two were chosen for discussion regarding treatment with immunoglobulin and one by plasma exchange. We document a report of a detailed and unique pathological examination of a CRPS type II affected amputated limb and related successful treatment with immunoglobulin. CONCLUSIONS: Nerve resection, with grafting, and relocation may relieve uncomplicated causalgia and CRPS type II in some patients in the long term. However, an unrecognized and treatable immunological condition may underly some CRPS II cases and can lead to the ultimate failure of surgical treatments.
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PURPOSE: Gene fusions are drivers of many pediatric tumors. In fibrolamellar hepatocellular carcinoma (FLC), a fusion of DNAJB1 and PRKACA is the dominant recurrent mutation. Expression of the DNAJB1-PRKACA fusion gene in mice results in a tumor that recapitulates FLC. However, it is not known whether transient expression of DNAJB1-PRKACA is sufficient only to trigger tumor formation or whether ongoing expression is necessary for maintenance and progression. EXPERIMENTAL DESIGN: We screened short hairpin RNAs (shRNA) tiled over the fusion junction and identified several potent and specific candidates in vitro and two independent FLC patient-derived xenografts (PDX). RESULTS: We show that continued DNAJB1-PRKACA expression is not only required for continued tumor growth, but additionally its inhibition results in cell death. Inhibition of DNAJB1-PRKACA by an inducible shRNA in cells of PDX of FLC resulted in cell death in vitro. Induction of the shRNA inhibits FLC tumors growing in mice with no effect on xenografts from a hepatocellular carcinoma cell line engineered to express DNAJB1-PRKACA. CONCLUSIONS: Our results validate DNAJB1-PRKACA as the oncogene in FLC and demonstrate both a continued requirement for the oncogene for tumor growth as well as an oncogenic addiction that can be exploited for targeted therapies. We anticipate our approach will be useful for investigations of other fusion genes in pediatric cancers and spur development of precision therapies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Dependencia del Oncogén , ARN Interferente Pequeño/genética , Proteínas del Choque Térmico HSP40/genética , Proteínas del Choque Térmico HSP40/metabolismo , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/genética , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/metabolismoRESUMEN
Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal liver cancer with no proven effective systemic therapy. Inhibition of the antiapoptotic protein BCL-XL was found to synergize with a variety of systemic therapies in vitro using cells dissociated from patient-derived xenografts (PDX) of FLC or cells dissociated directly from surgical patient resections. As BCL-XL is physiologically expressed in platelets, prior efforts to leverage this vulnerability in other cancers have been hampered by severe thrombocytopenia. To overcome this toxicity, we treated FLC models with DT2216, a proteolysis targeting chimera (PROTAC) that directs BCL-XL for degradation via the von Hippel-Lindau (VHL) E3 ligase, which is minimally expressed in platelets. The combination of irinotecan and DT2216 in vitro on cells directly acquired from patients or in vivo using several xenografts derived from patients with FLC demonstrated remarkable synergy and at clinically achievable doses not associated with significant thrombocytopenia.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombocitopenia , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , PiperazinasRESUMEN
Fibrolamellar carcinoma (FLC) is a rare, often lethal, liver cancer affecting adolescents and young adults, for which there are no approved therapeutics. The development of therapeutics is hampered by a lack of in vitro models. Organoids have shown utility as a model system for studying many diseases. In this study, tumor tissue and the adjacent non-tumor liver were obtained at the time of surgery. The tissue was dissociated and grown as organoids. We developed 21 patient-derived organoid lines: 12 from metastases, three from the liver tumor and six from adjacent non-tumor liver. These patient-derived FLC organoids recapitulate the histologic morphology, immunohistochemistry, and transcriptome of the patient tumor. Patient-derived FLC organoids were used in a preliminary high-throughput drug screen to show proof of concept for the identification of therapeutics. This model system has the potential to improve our understanding of this rare cancer and holds significant promise for drug testing and development.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adolescente , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/patología , Organoides/patologíaRESUMEN
PURPOSE: Industrial implementation of continuous oral solid dosage form manufacturing has been impeded by the poor powder flow properties of many active pharmaceutical ingredients (APIs). Microfluidic droplet-based particle synthesis is an emerging particle engineering technique that enables the production of neat or composite microparticles with precise control over key attributes that affect powder flowability, such as particle size distribution, particle morphology, composition, and the API's polymorphic form. However, the powder properties of these microparticles have not been well-studied due to the limited mass throughputs of available platforms. In this work, we produce spherical API and API-composite microparticles at high mass throughputs, enabling characterization and comparison of the bulk powder flow properties of these materials and greater understanding of how particle-scale attributes correlate with powder rheology. METHODS: A multi-channel emulsification device and an extractive droplet-based method are harnessed to synthesize spherical API and API-excipient particles of artemether. As-received API and API crystallized in the absence of droplet confinement are used as control cases. Particle attributes are characterized for each material and correlated with a comprehensive series of powder rheology tests. RESULTS: The droplet-based processed artemether particles are observed to be more flowable, less cohesive, and less compressible than conventionally synthesized artemether powder. Co-processing the API with polycaprolactone to produce composite microparticles reduces the friction of the powder on stainless steel, a common equipment material. CONCLUSIONS: Droplet-based extractive solidification is an attractive particle engineering technique for improving powder processing and may aid in the implementation of continuous solid dosage form manufacturing.
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Antimaláricos/química , Arteméter/química , Excipientes/química , Técnicas Analíticas Microfluídicas , Poliésteres/química , Cristalización , Composición de Medicamentos , Emulsiones , Fricción , Polvos , ReologíaRESUMEN
Upregulated expression of microRNA (miR)-221 is associated with downregulation of p27 and subsequent increased cell proliferation in a variety of human cancers. It is unknown whether miR-221 mimics could trigger neoplastic cellular proliferation. In vitro, we demonstrated miR-221 significantly downregulates the expression of P27 and increases proliferation of H9c2 and cardiac fibroblasts. The knockdown of PUM1 but not PUM2 abolished such effects by miR-221, as verified by RT-qPCR and western blot, direct binding of p27 3' UTR by luciferase reporter assay and cell proliferation by Ki67. In vivo expression of P27 in the rat liver, heart, kidney, spleen, and muscle were not affected by miR-221 at 1 and 4 mg/kg and concurrently full-length (FL) PUM1 (140 kDa) was not detected. Instead, isoforms of 105 and 90 kDa were observed and generated through alternative RNA slicing verified by cDNA cloning and sequencing and cathepsin K cleavage confirmed by studies with the inhibitor odanacatib. This is the first study to address the possible pro-proliferative effects of miR-221 mimic therapeutics in cardiovascular applications. Loss of FL PUM1 expression is a key factor abrogating miR-221-mediated p27 regulation, although other concurrent mechanisms cannot be excluded. Our findings provide essential insights into the context-dependent nature of miRNA functionality.
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To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. SIGNIFICANCE: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor.This article is highlighted in the In This Issue feature, p. 2355.
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Carcinoma Hepatocelular/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Compuestos de Anilina/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Benzofuranos/uso terapéutico , Carcinoma Hepatocelular/genética , Femenino , Humanos , Neoplasias Hepáticas/genética , Masculino , Ratones , Naftoquinonas/uso terapéutico , Sulfonamidas/uso terapéuticoRESUMEN
Kidney failure (KF) is associated with cardiac fibrosis and significantly increased mortality in heart failure. Thrombospondin-1 (TSP1), a key regulator of latent transforming growth factor-ß1 (L-TGF-ß1) activation, is a predicted target of miR-221. We hypothesized miR-221 attenuates severe KF-associated cardiac fibrosis via targeting of Thbs1 with subsequent inhibition of L-TGF-ß1 activation. Rat cardiac fibroblasts (cFB) were isolated and transfected with microRNA-221 (miR-221) mimics or mimic control (miR-221 and MC) with or without exposure to L-TGF-ß1. We demonstrate miR-221 downregulates Thbs1 via direct 3' untranslated region (3' UTR) targeting with consequent inhibition of L-TGF-ß1 activation in cFB as proven by the significant reduction of myofibroblast activation, collagen secretion, TGF-ß1 signaling, TSP1 secretion, and TGF-ß1 bioactivity measured by Pai1 promoter reporter. The 5/6 nephrectomy (Nx) model of cardiac fibrosis was used to test the in vivo therapeutic efficacy of miR-221 (i.v. 1 mg/kg ×3). miR-221 significantly inhibited Nx-induced upregulation of TSP1 and p-SMAD3 in the heart at day-7 and reduced cardiac fibrosis (picro-sirius), improved cardiac function (±dP/dt), and improved 8-week survival rate (60% versus 36%; p = 0.038). miR-221 mimic treatment improved survival and reduced cardiac fibrosis in a model of severe KF. miR-221 is a therapeutic target to address cardiac fibrosis originating from renal disease and other causes.
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The ILAE Neuroimaging Task Force aims to publish educational case reports highlighting basic aspects related to neuroimaging in epilepsy consistent with the educational mission of the ILAE. It is important to obtain MRI scans early in the clinical course of epilepsy, using an optimized protocol. Furthermore, it is critical that MRI scans are reviewed by experts who have been provided with all the clinical information and results from other investigations. We report a patient with a 21-year history of drug-resistant seizures who was admitted from another centre for presurgical evaluation. She had four previous MRI scans from this centre which were reported as unremarkable. However, a review of the MRI scan obtained on the day of admission, with the patient's ictal semiology in mind, resulted in identification of an epileptogenic lesion which was later confirmed by video-EEG monitoring and interictal PET. This lesion was present on all previous MRI scans and showed no change. The patient underwent lesionectomy, and histopathology of the resected specimen was consistent with a dysembryoplastic neuroepithelial tumour. The patient remains seizure-free, 2.5 years after surgery. This case highlights the importance of obtaining detailed descriptions of seizure semiology and considering them when reviewing MR images.
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Neoplasias Encefálicas/diagnóstico , Epilepsia Refractaria/diagnóstico , Neoplasias Neuroepiteliales/diagnóstico , Neuroimagen , Adulto , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Epilepsia Refractaria/patología , Epilepsia Refractaria/fisiopatología , Epilepsia Refractaria/cirugía , Electroencefalografía , Femenino , Humanos , Imagen por Resonancia Magnética , Neoplasias Neuroepiteliales/patología , Neoplasias Neuroepiteliales/cirugía , Tomografía de Emisión de PositronesAsunto(s)
Linfohistiocitosis Hemofagocítica , Piebaldismo , Enfermedades de Inmunodeficiencia Primaria , Proteínas rab27 de Unión a GTP/genética , Adolescente , Autoinjertos , Trasplante de Células Madre Hematopoyéticas , Humanos , Linfohistiocitosis Hemofagocítica/diagnóstico por imagen , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/patología , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Masculino , Piebaldismo/diagnóstico por imagen , Piebaldismo/genética , Piebaldismo/patología , Enfermedades de Inmunodeficiencia Primaria/diagnóstico por imagen , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/patologíaRESUMEN
Colchicine is a medication most commonly used in the treatment of gout and familial mediterannean fever. A rare complication of therapy is toxicity causing proximal myopathy and polyneuropathy. Colchicine myopathy has been associated with the coadministration of other medications with colchicine, such as statins or tacrolimus, and is more common in patients with renal impairment. Otherwise, it is unclear which patients are at greatest risk of developing this adverse drug reaction. ABCB1 is important to the metabolism of colchicine, so we speculated that it was possible that colchicine myopathy patients may have a particular genotype that is associated with this side effect. We describe two cases of colchicine myopathy which occurred with co-administration of rosuvastatin. From one case, we present the first published data on muscle MRI in this condition. We additionally present an analysis of four genetic polymorphisms in ABCB1 and transcript levels in muscle tissue, and demonstrate the descriptive finding of reduced ABCB1 transcript levels in the colchicine myopathy patients.
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BACKGROUND: Smartphones are positioned to transform the way health care services gather patient experience data through advanced mobile survey apps which we refer to as smart surveys. In comparison with traditional methods of survey data capture, smartphone sensing survey apps have the capacity to elicit multidimensional, in situ user experience data in real time with unprecedented detail, responsiveness, and accuracy. OBJECTIVE: This study aimed to explore the context and circumstances under which patients are willing to use their smartphones to share data on their service experiences. METHODS: We conducted in-person, semistructured interviews (N=24) with smartphone owners to capture their experiences, perceptions, and attitudes toward smart surveys. RESULTS: Analysis examining perceived risk revealed a few barriers to use; however, major potential barriers to adoption were the identity of recipients, reliability of the communication channel, and potential for loss of agency. The results demonstrate that the classical dimensions of perceived risk raised minimal concerns for the use of smartphones to collect patient service experience feedback. However, trust in the doctor-patient relationship, the reliability of the communication channel, the altruistic motivation to contribute to health service quality for others, and the risk of losing information agency were identified as determinants in the patients' adoption of smart surveys. CONCLUSIONS: On the basis of these findings, we provide recommendations for the design of smart surveys in practice and suggest a need for privacy design tools for voluntary, health-related technologies.
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BACKGROUND: Primary Angiitis of the Central Nervous System (PACNS) is a rare cause of CNS vasculitis that should be included as part complete differential diagnosis, especially in cases with suggestive imaging findings and an absence of secondary causes for CNS vasculitis. CASE PRESENTATION: We describe a case of a 47-year-old previously healthy Caucasian male presenting with rapid progression of encephalopathy and fevers. Extensive infectious, autoimmune, and imaging workups were unrevealing. A diagnosis of PACNS was made posthumously on histopathology. CONCLUSIONS: PACNS is a challenging diagnosis owing to frequent discrepancies between radiologic and histopathologic findings. Tissue biopsy is key to diagnosing PACNS.
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Vasculitis del Sistema Nervioso Central/líquido cefalorraquídeo , Vasculitis del Sistema Nervioso Central/diagnóstico por imagen , Edema Encefálico/líquido cefalorraquídeo , Edema Encefálico/diagnóstico por imagen , Edema Encefálico/etiología , Diagnóstico Diferencial , Resultado Fatal , Humanos , Masculino , Persona de Mediana Edad , Vasculitis del Sistema Nervioso Central/complicacionesRESUMEN
In recent decades, the demand for ready-to-eat (RTE) food items prepared by the food catering sector has increased together with the value of cook-serve, cook-chill, and cook-freeze food products. The technologies by which foods are cooked, chilled, refrigerated for storage, and reheated before serving are of prime importance to maintain safety. Packaging materials and food containers play an important role in influencing the cooling rate of RTE foods. Food items that are prepared using improper technologies and inappropriate packaging materials may be contaminated with foodborne pathogens. Numerous research studies have shown the impact of deficient cooling technologies on the survival and growth of foodborne pathogens, which may subsequently pose a threat to public health. The operating temperatures and cooling rates of the cooling techniques applied must be appropriate to inhibit the growth of pathogens. Food items must be stored outside the temperature danger zone, which is between 5 and 60 °C, in order to inhibit the growth of these pathogens. The cooling techniques used to prepare potentially hazardous foods, such as cooked meat, rice, and pasta, must be properly applied and controlled to ensure food safety. This paper critically reviews the effects of cooling and its relationship to food containers on the safety of RTE foods produced and sold through the food service industry.