Introduction For some people, ageing is associated with the experience of increased co-morbidity, functional impairment, poor resilience and heightened vulnerability to external stressors, resulting ...in reduced lifespan as well as health-span. This frailty phenomenon poses challenges to health care systems in the form of increased patient complexity and resource utilisation. The acute care setting, characterised by time-pressure and high patient turn-over, is under strain and struggles to recognise and subsequently reliably intervene, to prevent, reverse or halt the decline of this vulnerable cohort. Methods This mixed-methods study probes existing evidence and ‘real-world’ processes with a systematic review of frailty assessments developed or validated in the acute care setting and a survey of contemporaneous clinical practice in London Acute Medical Units. Content validation and understanding of contextual factors for ideal frailty assessment in acute care is explored using Delphi consensus and Focus Group methodology respectively. The resultant model is developed on existing retrospective national Hospital Episode Statistics data, and prospectively tested on observational data in a local Acute Medical Unit setting. Results Existing frailty scores are preponderantly biophysical in nature, and have poor predictive power for adverse outcomes in the acute care setting. In clinical practice, single-dimension assessment tools predominate. Frailty syndromes and previous high resource utilisation in the form of a simple, clinically relevant tool useful to the multidisciplinary team gain consensus as optimal assessment for the setting. Retrospective testing of the frailty model displays moderate predictive powers for adverse events (inpatient mortality, emergency readmission and institutionalisation) and prospective testing provides concurrent (Frailty Index, Age, Co-Morbidity) and comparative predictive validity (Frailty Index, Co-Morbidity, admission National Early Warning Score) with existing risk stratification models in this setting. Conclusions A risk prediction model based on frailty syndromes and previous high resource utilisation is a valid, feasible and useful for the acute care setting.
▪
RNA polymerase I (Pol I) transcription of the ribosomal RNA (rRNA) genes, a rate-limiting step for growth and proliferation, is a highly regulated process downstream of many oncogenic pathways. ...Dysregulation of ribosome biogenesis is a feature of numerous cancers (Bywater Nat Rev 2013 ).
CX-5461, a selective inhibitor of Pol I transcription (Senhwa Biosciences, San Diego, USA), has ~200-fold selectivity for inhibition of Pol I over Pol II (Drygin Can Res 2011 ). Inhibition of Pol I transcription by CX-5461 induces a p53 independent nucleolar stress response and a nucleolar specific DNA damage response (Quin Oncotarget 2016 ). CX-5461 provides survival benefit in mouse models of lymphoma, myeloid leukemia and myeloma (Hein Blood 2017) .
Methods: We initiated a first in class, first in human, phase I dose escalation study of CX-5461 in adult patients with advanced hematologic cancers, with no standard therapeutic options, adequate organ function and performance status to determine maximum tolerated dose (MTD), safety, pharmacokinetic (PK) profile and antitumor activity.
CX-5461 was administered by 1 hour IV infusion 3 weekly. Dose escalations were planned in 7 cohorts (25 - 450 mg/m2), in an accelerated design, with change to a 3+3 design based on predefined toxicity criteria.
Inhibition of Pol I transcription rate was measured via RNA-FISH, quantitating the abundance of 47S pre-rRNA levels in peripheral blood mononuclear cells (PBMC) and tumor tissue, at various time points following cycle 1. Skin biopsies from normal skin and rash areas were studied after the observation of photosensitivity in patients in cohort 1.
Results: 16 patients (6 myeloma, 2 Hodgkin lymphoma, 6 Non Hodgkin lymphoma (NHL), 1 TPLL, 1 CLL) were treated in 5 cohorts (25 - 250 mg/ m2), for a median of 2 (1 - 18) cycles. The MTD was 170 mg/ m2. The dose limiting toxicity was palmar plantar erythrodysaesthesia in 2 patients at 250 mg/ m2. One of these patients continued treatment for 17 further cycles at 170 mg/ m2. Eight patients (50%) had grade </=3 treatment related photosensitivity across all dose cohorts, this did not recur on re-exposure with appropriate protection. No other grade 3+ treatment related adverse events were observed.
The average terminal half-life (T1/2) showed an increasing trend with dose escalation, in a profile consistent with enterohepatic recycling. The maximum T1/2 noted was 92 hours in cohort 5. Linear behaviors were generally observed in Cmax and AUC exposure parameters.
The best response seen was an excellent prolonged partial response in 1 patient with anaplastic large cell lymphoma (18 cycles) and stable disease in 3 patients with myeloma (4 - 6 cycles) and 2 with diffuse large B-cell lymphoma (4 - 16 cycles). Clinical and radiologic response was noted in an area of high grade transformation in a patient with cutaneous T-Cell lymphoma (CTCL).
Consistent, significant decreases in Pol I transcription were observed at 1hr post-infusion in PBMC. The average level of inhibition was 49.0% (22.9 - 69.9%), 51.1% (34.4 - 64.4%), 19.6% (-72.0 - 69.7%), 47.3% (46.5 - 48.0%) and 38.6% (6.8 - 70.4%) in cohorts 1 - 5 respectively (Fig 1). On target activity at 24hrs was observed in most tumor biopsies, where the level of inhibition was variable (10/13; median range: 4.8 - 68.9 %) (Fig 2).
Targeted exon sequencing determined TP53 mutational status in selected patients (n=13). 4 patients with mutations experienced early disease progression. In TP53 wildtype patients, 4 achieved periods of stable disease. In a CTCL patient, stabilization of p53 protein levels and increase in the p53 target gene p21 occurred in an area of high grade transformation where response was observed (Fig 3).
A spongiotic or parakeratosis reaction pattern was observed in biopsies from the photosensitivity rash, with increase in p53 IHC expression in the epidermis of normal skin following CX-5461 exposure (Fig 4).
Conclusion: Our first in human study of the Pol I inhibitor CX-5461, has determined a MTD of 170 mg/ m2 every 3 weeks, with a predictable PK profile. The drug is well tolerated and compatible with a prolonged duration of treatment. Photosensitivity can be a significant adverse event independent of dose, which is manageable by careful attention to preventive measures. Durable periods of response or stability have been noted in heavily pretreated chemorefractory patients with NHL and myeloma. Further studies to explore weekly dosing regimens are planned.
Display omitted
Khot:Celgene: Consultancy; Janssen: Consultancy; Amgen: Other: Travel Grant. Lim:Senhwa Biosciences: Consultancy, Equity Ownership. Soong:Senwa Biosciences: Employment, Equity Ownership. Harrison:Celgene: Consultancy, Research Funding, Speakers Bureau.
Truly patient-centred care needs to be aligned with what patients consider important, and is highly desirable in the first 24 h of an acute admission, as many decisions are made during this period. ...However, there is limited knowledge on what matters most to patients in this phase of their hospital stay. The objective of this study was to identify what mattered most to patients in acute care and to assess the patient perspective as to whether their treating doctors were aware of this.
This was a large-scale, qualitative, flash mob study, conducted simultaneously in sixty-six hospitals in seven countries, starting November 14th 2018, ending 50 h later. One thousand eight hundred fifty adults in the first 24 h of an acute medical admission were interviewed on what mattered most to them, why this mattered and whether they felt the treating doctor was aware of this.
The most reported answers to "what matters most (and why)?" were 'getting better or being in good health' (why: to be with family/friends or pick-up life again), 'getting home' (why: more comfortable at home or to take care of someone) and 'having a diagnosis' (why: to feel less anxious or insecure). Of all patients, 51.9% felt the treating doctor did not know what mattered most to them.
The priorities for acutely admitted patients were ostensibly disease- and care-oriented and thus in line with the hospitals' own priorities. However, answers to why these were important were diverse, more personal, and often related to psychological well-being and relations. A large group of patients felt their treating doctor did not know what mattered most to them. Explicitly asking patients what is important and why, could help healthcare professionals to get to know the person behind the patient, which is essential in delivering patient-centred care.
NTR (Netherlands Trial Register) NTR7538 .
Circulatory shock Soong, John Tshon Yit; Soni, Neil
Medicine (Abingdon. 1995, UK ed.),
02/2013, Letnik:
41, Številka:
2
Journal Article
Recenzirano
Abstract Shock is a clinical state in which disparity of oxygen supply and demand at cell level results in tissue hypoxia and incipient failure of cell function. It leads to distinctive symptoms and ...signs, initially of compensation and later of failure. In effect, there is inadequate effective cardiac output (ECO) to provide the appropriate oxygen delivery. Shock can be categorized as hypodynamic (cardiogenic, obstructive and hypovolaemic) or hyperdynamic (distributive), with distinctive patterns of clinical presentation and aetiology evident with these subtypes. History and examination are invaluable in identifying the presence of shock (failed ECO), and should guide investigations of aetiology. The clinical picture, central venous pressure trends, serial lactate and ScvO2 measurements may yield sufficient information of severity and aid in guiding resuscitation, but other haemodynamic monitoring modalities are available. Circulatory shock is a medical emergency. Early identification leads to early intervention and prevention of secondary insults. Resuscitation, investigation and diagnosis need to happen in parallel and expediently. The aim of treatment is to restore and maintain oxygen delivery to the cell. Ensuring and maintaining an ECO is an immediate and urgent goal, via oxygen delivery, fluid resuscitation, and inotropes/vasopressors. Additionally, shock subtypes may necessitate specific investigations and treatment.
The aim of this study was to define and quantitate the normal anatomy of the extracranial head and neck with 2-fluorine-18fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). This ...information was used to study 12 patients with primary squamous cell carcinomas. In all cases, the lymphoid tissue of the Waldeyer ring and the palatine and lingual tonsils could be differentiated from the airway, striated muscle, osseous structures, and salivary glands. Striated muscle had markedly less activity than lymphoid or salivary gland tissue. In the 12 patients with primary tumors, FDG PET depicted the tumor as an area of increased activity significantly higher than that of normal tissue. In one instance, FDG PET allowed detection of a tumor not seen at magnetic resonance (MR) imaging or computed tomography. Of the 34 lymph nodes positive for carcinoma, 24 were positive according to MR size criteria and 25 were detected with FDG PET. FDG PET allowed detection of three nonenlarged metastatic nodes that were negative at MR imaging.
We suggested a unified system with core components of data augmentation, ImageNet-pretrained ResNet-50, cost-sensitive loss, deep ensemble learning, and uncertainty estimation to quickly and ...consistently detect COVID-19 using acoustic evidence. To increase the model's capacity to identify a minority class, data augmentation and cost-sensitive loss are incorporated (infected samples). In the COVID-19 detection challenge, ImageNet-pretrained ResNet-50 has been found to be effective. The unified framework also integrates deep ensemble learning and uncertainty estimation to integrate predictions from various base classifiers for generalisation and reliability. We ran a series of tests using the DiCOVA2021 challenge dataset to assess the efficacy of our proposed method, and the results show that our method has an AUC-ROC of 85.43 percent, making it a promising method for COVID-19 detection. The unified framework also demonstrates that audio may be used to quickly diagnose different respiratory disorders.
Angiosarcoma is a rare soft tissue tumor of the breast. It occurs in both a primary form without a known precursor, and a secondary form that has been associated to a history of irradiated breast ...tissue. These forms differ in many ways including median age, precipitating factors, and presentation. Both forms have a malignant behavior and a poor prognosis. The endeavor of this paper is to review what is known about the presentation, diagnostic and therapeutic modalities to date.
The proto-oncogene C-jun acts as a transcriptional activator or repressor for numerous cellular genes, and the overexpression of these genes may cause malignant transformation. JunB inhibits c-jun's ...transforming activities. We investigated the expression of jun genes in renal cell cancer (RCC) and their regulation by cytokines and transforming growth factor beta 1 (TGF-b1). The constitutive expression of c-jun was detected in 39 of 43 fresh frozen RCC, 5 of 10 normal kidneys, and the expression of junB detected in 28 of 34 RCC, 5 of 6 normal kidneys. C-jun was also found expressed in all 10 RCC tumor lines examined and junB was expressed at low levels in 6 of 10 renal tumor lines. TGF-b1 and tumor necrosis factor alpha (TNF-a) have been shown to alter the expression of jun genes in other tissue types. Additionally, TGF-b1, TNF-a, and gamma interferon (g-IFN) were shown to inhibit the growth of RCC. We found that TGF-b1 highly augmented the expression of junB (mean of 34 folds, p less than .05), but did not significantly alter the expression of c-jun, the transforming gene. In contrast, TNF-a significantly enhanced the expression of both c-jun (mean fold enhancement of 2.1, p less than .05) and junB (2.2 folds, p less than .05). Interleukin-2 (IL-2), interleukin-4 (IL-4) and g-IFN did not significantly alter jun expression. The findings presented suggest that c-jun may have a role in inducing malignant transformation in RCC and a novel mechanism by which TGF-b1 may exert its anti-tumor effects, via the activation of junB. Additionally, although TGF-b1, TNF-a, and g-IFN all have anti-proliferative actions on RCC in vitro, they were found to have different effects in altering jun expressions.
Introduction For some people, ageing is associated with the experience of increased co-morbidity, functional impairment, poor resilience and heightened vulnerability to external stressors, resulting ...in reduced lifespan as well as health-span. This frailty phenomenon poses challenges to health care systems in the form of increased patient complexity and resource utilisation. The acute care setting, characterised by time-pressure and high patient turn-over, is under strain and struggles to recognise and subsequently reliably intervene, to prevent, reverse or halt the decline of this vulnerable cohort. Methods This mixed-methods study probes existing evidence and ‘real-world’ processes with a systematic review of frailty assessments developed or validated in the acute care setting and a survey of contemporaneous clinical practice in London Acute Medical Units. Content validation and understanding of contextual factors for ideal frailty assessment in acute care is explored using Delphi consensus and Focus Group methodology respectively. The resultant model is developed on existing retrospective national Hospital Episode Statistics data, and prospectively tested on observational data in a local Acute Medical Unit setting. Results Existing frailty scores are preponderantly biophysical in nature, and have poor predictive power for adverse outcomes in the acute care setting. In clinical practice, single-dimension assessment tools predominate. Frailty syndromes and previous high resource utilisation in the form of a simple, clinically relevant tool useful to the multidisciplinary team gain consensus as optimal assessment for the setting. Retrospective testing of the frailty model displays moderate predictive powers for adverse events (inpatient mortality, emergency readmission and institutionalisation) and prospective testing provides concurrent (Frailty Index, Age, Co-Morbidity) and comparative predictive validity (Frailty Index, Co-Morbidity, admission National Early Warning Score) with existing risk stratification models in this setting. Conclusions A risk prediction model based on frailty syndromes and previous high resource utilisation is a valid, feasible and useful for the acute care setting.
PDF
