Heat shock protein 90 (Hsp90) is a molecular chaperone with many oncogenic client proteins. The small-molecule Hsp90 inhibitor alvespimycin, a geldanamycin derivative, is being developed for various ...malignancies. This phase 1 study examined the maximum-tolerated dose (MTD), safety and pharmacokinetic/pharmacodynamic profiles of alvespimycin in patients with advanced acute myeloid leukemia (AML). Patients with advanced AML received escalating doses of intravenous alvespimycin (8-32 mg/m(2)), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m(2) twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m(2) (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C(max) and area under the curve (AUC) from 8 to 32 mg/m(2) and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twice-weekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m(2).
Pneumoconiosis is a well-documented occupational disease that is linked to conditions such as chronic obstructive pulmonary disease (COPD), pneumonia and congestive heart failure. Pneumoconiosis ...prevalence has decreased in the United States, but it remains implicated in tens of thousands of deaths worldwide per year.
To provide a recent update on associations of pneumoconiosis and smoking status with various pulmonary diseases in the United States.
The CDC's National Vital Statistics System was analysed on the entity axis using ICD-10 codes for pulmonary disease and potential lung injury with a cohort of those aged 15 and older during the years 2010-2019. The cases of evaluated diseases were scaled to rates per 100 000 and compared through analysis of variance.
Pneumoconiosis and smoking history were each associated with an increased rate of COPD, but combined, were associated with an even higher rate of COPD than either factor alone. Smoking history was associated with an increased rate of lung cancer, but pneumoconiosis status was only linked to increased lung cancer prevalence in non-smokers. Both pneumoconiosis and smoking were associated with an increased rate of pneumonia, but combined, had no deviation from the pneumonia rate in those with pneumoconiosis alone. Finally, pneumoconiosis status was associated with decreased rates of non-lung cancers and sepsis.
Although pneumoconiosis has become less common in the United States through regulatory and industrial shifts, it is still a significant risk factor for co-occurring pulmonary diseases and will likely remain relevant as international demands for mining, construction and manufacturing change.
Summary
Concise guidelines are presented that recommend the method of choice for skin antisepsis before central neuraxial blockade. The Working Party specifically considered the concentration of ...antiseptic agent to use and its method of application. The advice presented is based on previously published guidelines, laboratory and clinical studies, case reports, and on the known properties of antiseptic agents.
Functional abdominal pain (FAP) is common in childhood, but is not often caused by disease. It is often the impact of the pain rather than the pain itself that results in referral to the clinician. ...In this review, we will summarise the currently available evidence and discuss the functional dimensions of the presentation, within the framework of commonly expressed parental questions. Using the Rome III criteria, we discuss how to classify the functional symptoms, investigate appropriately, provide reassurance regarding parental worries of chronic disease. We outline how to explain the functional symptoms to parents and an individualised strategy to help restore function.
Abstract
Objective
Sleep and pain-related experiences are consistently associated, but the pathways linking these experiences are not well understood. We evaluated whether pain catastrophizing and ...arthritis self-efficacy mediate the association between sleep disturbance and osteoarthritis (OA) symptom severity in patients with knee OA.
Methods
We analyzed cross-sectional baseline data collected from Veterans Affairs (VA) patients enrolled in a clinical trial examining the effectiveness of a positive psychology intervention in managing pain from knee OA. Participants indicated how often in the past two weeks they were bothered by trouble falling asleep, staying asleep, or sleeping too much. We used validated scales to assess the primary outcome (OA symptom severity) and potential mediators (arthritis self-efficacy and pain catastrophizing). To test the proposed mediation model, we used parallel multiple mediation analyses with bootstrapping, controlling for sociodemographic and clinical characteristics with bivariate associations with OA symptom severity.
Results
The sample included 517 patients (Mage = 64 years, 72.9% male, 52.2% African American). On average, participants reported experiencing sleep disturbance at least several days in the past two weeks (M = 1.41, SD = 1.18) and reported moderate OA symptom severity (M = 48.22, SD = 16.36). More frequent sleep disturbance was associated with higher OA symptom severity directly (b = 3.08, P <0.001) and indirectly, through higher pain catastrophizing (b = 0.60, 95% confidence interval CI = 0.20 to 1.11) and lower arthritis self-efficacy (b = 0.84, 95% CI = 0.42 to 1.42).
Conclusions
Pain catastrophizing and arthritis self-efficacy partially mediated the association between sleep disturbance and OA symptom severity. Behavioral interventions that address pain catastrophizing and/or self-efficacy may buffer the association between sleep disturbance and OA symptom severity.
Summary
Tumour necrosis factor receptor‐associated periodic syndrome (TRAPS) is a hereditary autoinflammatory disorder characterized by recurrent episodes of fever and inflammation. It is associated ...with autosomal dominant mutations in TNFRSF1A, which encodes tumour necrosis factor receptor 1 (TNF‐R1). Our aim was to understand the influence of TRAPS mutations on the response to stimulation of the pattern recognition Toll‐like receptor (TLR)‐9. Peripheral blood mononuclear cells (PBMCs) and serum were isolated from TRAPS patients and healthy controls: serum levels of 15 proinflammatory cytokines were measured to assess the initial inflammatory status. Interleukin (IL)‐1β, IL‐6, IL‐8, IL‐17, IL‐22, tumour necrosis factor (TNF)‐α, vascular endothelial growth factor (VEGF), interferon (IFN)‐γ, monocyte chemoattractant protein 1 (MCP‐1) and transforming growth factor (TGF)‐β were significantly elevated in TRAPS patients’ sera, consistent with constitutive inflammation. Stimulation of PBMCs with TLR‐9 ligand (ODN2006) triggered significantly greater up‐regulation of proinflammatory signalling intermediates TNF receptor‐associated factor (TRAF 3), IL‐1 receptor‐associated kinase‐like 2 (IRAK2), Toll interacting protein (TOLLIP), TRAF6, phosphorylated transforming growth factor‐β‐activated kinase 1 (pTAK), transforming growth factor‐β‐activated kinase‐binding protein 2 (TAB2), phosphorylated TAK 2 (pTAB2), IFN‐regulatory factor 7 (IRF7), receptor interacting protein (RIP), nuclear factor kappa B (NF‐κB) p65, phosphorylated NF‐κB p65 (pNF‐κB p65) and mitogen‐activated protein kinase kinase (MEK1/2) in TRAPS patients’ PBMCs. This up‐regulation of proinflammatory signalling intermediates and raised serum cytokines occurred despite concurrent anakinra treatment and no overt clinical symptoms at time of sampling. These novel findings further demonstrate the wide‐ranging nature of the dysregulation of innate immune responses underlying the pathology of TRAPS and highlights the need for novel pathway‐specific therapeutic treatments for this disease.
Stimulation of TRAPS patient PBMCs with TLR‐9 ligand (ODN2006) triggers significantly greater up‐regulation, relative to controls, of proinflammatory signalling intermediates TRAF3, IRAK2, TOLLIP, TRAF6, pTAK, TAB2, phosphorylated TAB2 (pTAB2), IRF7, RIP, NF‐κB p65, phosphorylated NFκB p65 and MEK1/2. This up‐regulation of proinflammatory signalling intermediates and raised serum cytokines occurred despite concurrent anakinra treatment and no overt clinical symptoms at time of sampling. These novel findings further demonstrate the wide‐ranging nature of the dysregulation of innate immune responses underlying the pathology of TRAPS.
Abstract Study objective Historically, the placement of internal jugular central venous lines has been accomplished by using external landmarks to help identify target-rich locations in order to ...steer clear of dangerous structures. This paradigm is largely being displaced, as ultrasound has become routine practice, raising new considerations regarding target locations and risk mitigation. Most human anatomy texts depict the internal jugular vein as a straight columnar structure that exits the cranial vault the same size that it enters the thoracic cavity. We dispute the notion that the internal jugulars are cylindrical columns that symmetrically descend into the thoracic cavity, and purport that they are asymmetric conical structures. Design The primary aim of this study was to evaluate 100 consecutive adult chest and neck computed tomography exams that were imaged at an inpatient hospital. We measured the internal jugular on the left and right sides at three different levels to look for differences in size as the internal jugular descends into the thoracic cavity. Main results We revealed that as the internal jugular descends into the thorax, the area of the vessel increases and geometrically resembles a conical structure. We also reconfirmed that the left internal jugular is smaller than the right internal jugular. Conclusions Understanding that the largest target area for central venous line placement is the lower portion of the right internal jugular vein will help to better target vascular access for central line placement. This is the first study the authors are aware of that depicts the internal jugular as a conical structure as opposed to the commonly depicted symmetrical columnar structure frequently illustrated in anatomy textbooks. This target area does come with additional risk, as the closer you get to the thoracic cavity, the greater the chances for lung injury.
Summary
Concise guidelines are presented that recommend the method of choice for skin antisepsis before central neuraxial blockade. The Working Party specifically considered the concentration of ...antiseptic agent to use and its method of application. The advice presented is based on previously published guidelines, laboratory and clinical studies, case reports, and on the known properties of antiseptic agents.
Objective: To determine whether certain patients are vulnerable to errant triage decisions immediately after major surgery and whether there are unique sociodemographic phenotypes within overtriaged ...and undertriaged cohorts. Background: In a fair system, overtriage of low-acuity patients to intensive care units (ICUs) and undertriage of high-acuity patients to general wards would affect all sociodemographic subgroups equally. Methods: This multicenter, longitudinal cohort study of hospital admissions immediately after major surgery compared hospital mortality and value of care (risk-adjusted mortality/total costs) across 4 cohorts: overtriage (N = 660), risk-matched overtriage controls admitted to general wards (N = 3077), undertriage (N = 2335), and risk-matched undertriage controls admitted to ICUs (N = 4774). K-means clustering identified sociodemographic phenotypes within overtriage and undertriage cohorts. Results: Compared with controls, overtriaged admissions had a predominance of male patients (56.2% vs 43.1%, P < 0.001) and commercial insurance (6.4% vs 2.5%, P < 0.001); undertriaged admissions had a predominance of Black patients (28.4% vs 24.4%, P < 0.001) and greater socioeconomic deprivation. Overtriage was associated with increased total direct costs $16.2K ($11.4K–$23.5K) vs $14.1K ($9.1K–$20.7K), P < 0.001 and low value of care; undertriage was associated with increased hospital mortality (1.5% vs 0.7%, P = 0.002) and hospice care (2.2% vs 0.6%, P < 0.001) and low value of care. Unique sociodemographic phenotypes within both overtriage and undertriage cohorts had similar outcomes and value of care, suggesting that triage decisions, rather than patient characteristics, drive outcomes and value of care. Conclusions: Postoperative triage decisions should ensure equality across sociodemographic groups by anchoring triage decisions to objective patient acuity assessments, circumventing cognitive shortcuts and mitigating bias.
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