Exploring generalizability in a study of costs for community-based palliative care

ContextPalliative care researchers face challenges recruiting and retaining study subjects.ObjectivesThis article investigates selection, study site, and participation biases to assess generalizability of a cost analysis of palliative care program (PCP) clients receiving care at home.MethodsStudy subjects’ sociodemographic, geographic, survival, disease, and treatment characteristics were compared for the same year and region with those of three populations. Comparison I was with nonstudy subjects enrolled in the PCP to assess selection bias. Comparison II was with adults who died of cancer to assess study site bias. Comparison III was with study-eligible persons who declined to participate in order to assess participation bias.ResultsComparison I: When compared with the other 1010 PCP clients, the 50 study subjects were on average 3.6 years younger (P = 0.03), enrolled 70 days longer in the PCP (P < 0.001), lived 6.7 km closer to the PCP (P < 0.0001), and were more likely to have cancer (96.0% vs. 86.4%, P = 0.05). Comparison II: Compared with all cancer decedents, the 45 study subjects who died of cancer were on average 7.0 years younger (P < 0.001), lived 2.7 km closer to the PCP (P < 0.001), and were more likely to have had radiotherapy (62.2% vs. 33.8%, P < 0.0001) and medical oncology (28.9% vs. 14.8%, P = 0.01) consultations. Comparison III: The 50 study subjects lived on average 42 days longer after their diagnosis (P = 0.03) and 2.6 km closer to the PCP (P = 0.01) than the 110 eligible persons who declined to participate.ConclusionIf the study findings are applied to populations that differ from the study subjects, inaccurate conclusions are possible.     

The PANDORA study: peripheral arterial disease in patients with non-high cardiovascular risk

Few studies are available with sufficient sample size to accurately describe the prevalence of low ankle-brachial index (ABI) in patients at ‘non-high’ cardiovascular (CV) risk. The aim of this study was to evaluate the prevalence of asymptomatic peripheral arterial disease (PAD), as determined by using ABI, in this patient population. A non-interventional, cross-sectional, pan-European study was conducted in patients with ≥1 CV risk factor in addition to age, evaluating the prevalence of asymptomatic PAD (ABI ≤ 0.90). Secondary objectives included assessing the prevalence and treatment of CV risk factors. Patients were consecutively recruited during scheduled visits to the physician’s office, or were randomly selected by the physician from a list of eligible patients. Patients with diabetes were excluded as this condition was deemed to be a secondary prevention risk. 10,287 patients were enrolled (9,816 evaluable: mean age 64.3 years; 53.5% male). Prevalence of asymptomatic PAD was 17.8% (99% CI 16.84–18.83). Factors significantly associated with asymptomatic PAD included hypertension, age, alcohol intake, family history of coronary heart disease, low levels of high-density lipoprotein-cholesterol, and smoking (p < 0.0001). Patients treated with statins were significantly less likely to have asymptomatic PAD than those who were not (odds ratio 0.62; 95% CI 0.50–0.76; p < 0.0001). Asymptomatic PAD was highly prevalent in patients with non-high CV risk, the majority of whom would not typically be candidates for ABI assessment. These patients should be carefully screened, and ABI measured, so that therapeutic interventions known to diminish their increased CV risk may be offered.     

Role of interleukin‐1β in NLRP12‐associated autoinflammatory disorders and resistance to anti–interleukin‐1 therapy

Objective

A new class of autoinflammatory syndromes called NLRP12‐associated disorders (NLRP12AD) has been associated with mutations in NLRP12. Conflicting data on the putative role of NLRP12 in interleukin‐1β (IL‐1β) signaling have been found in in vitro analyses. This prospective study was undertaken to assess the secretion of IL‐1β and 3 IL‐1β–induced cytokines (IL‐1 receptor antagonist [IL‐1Ra], IL‐6, and tumor necrosis factor α [TNFα]) in patients' peripheral blood mononuclear cells (PBMCs) cultured ex vivo and to evaluate the patients' response to IL‐1Ra (anakinra), a major drug used in the treatment of autoinflammatory disorders.

Methods

Patients' disease manifestations and cytokine measurements were recorded before anakinra treatment was started, during 14 months of therapy, and after discontinuation of anakinra treatment.

Results

Spontaneous secretion of IL‐1β by patients' PBMCs was found to be dramatically increased (80–175 fold) compared to healthy controls. Consistent with these findings, anakinra initially led to a marked clinical improvement and to a rapid near‐normalization of IL‐1β secretion. However, a progressive clinical relapse occurred secondarily, associated with an increase in TNFα secretion, persistent elevated levels of IL‐1Ra and IL‐6, and a reactivation of IL‐1β secretion. Anakinra was discontinued after 14 months of therapy.

Conclusion

Our findings provide in vivo evidence of the crucial role of IL‐1β in the pathophysiology of NLRP12AD. This is the first time anakinra has been used to treat this disorder. This study provides new insights into the mechanisms underlying resistance to anti–IL‐1 therapy observed in a few patients with autoinflammatory syndromes. Our data also point to the potential of ex vivo cytokine measurements as predictors of response to treatment.

     

Neuromelanin Activates Microglia and Induces Degeneration of Dopaminergic Neurons: Implications for Progression of Parkinson’s Disease

In Parkinson’s disease (PD), there is a progressive loss of neuromelanin (NM)-containing dopamine neurons in substantia nigra (SN) which is associated with microgliosis and presence of extracellular NM. Herein, we have investigated the interplay between microglia and human NM on the degeneration of SN dopaminergic neurons. Although NM particles are phagocytized and degraded by microglia within minutes in vitro, extracellular NM particles induce microglial activation and ensuing production of superoxide, nitric oxide, hydrogen peroxide (H₂O₂), and pro-inflammatory factors. Furthermore, NM produces, in a microglia-depended manner, neurodegeneration in primary ventral midbrain cultures. Neurodegeneration was effectively attenuated with microglia derived from mice deficient in macrophage antigen complex-1, a microglial integrin receptor involved in the initiation of phagocytosis. Neuronal loss was also attenuated with microglia derived from mice deficient in phagocytic oxidase, a subunit of NADPH oxidase, that is responsible for superoxide and H₂O₂ production, or apocynin, an NADPH oxidase inhibitor. In vivo, NM injected into rat SN produces microgliosis and a loss of tyrosine hydroxylase neurons. Thus, these results show that extracellular NM can activate microglia, which in turn may induce dopaminergic neurodegeneration in PD. Our study may have far-reaching implications, both pathogenic and therapeutic.     

Social cognition impairments in relapsing-remitting multiple sclerosis

Theory of Mind (ToM) is the ability to attribute independent mental states to self and others to explain and predict behavior. Impairment of ToM is well established in developmental pathologies. In neurological populations, investigation of ToM is still rare but data suggest that ToM impairment could contribute to behavioral and social disturbances. In addition to neurological signs, multiple sclerosis (MS) presents with disorders of cognition and behavior directly related to brain damage. The aim of this study was to assess ToM abilities and recognition of facial emotional expression in adults with MS. We compared 64 patients with relapsing MS and 30 matched healthy controls on three levels of ToM tasks, a facial emotion recognition task, and a neuropsychological assessment. MS patients performed significantly worse than controls in emotion recognition and all ToM tasks (p < .02). These deficits were not correlated with demographic variables or neuropsychological test performance. These findings underscore the importance of assessing ToM and facial recognition in MS, as dysfunction in these areas may impact upon social interaction and, thus, impair quality of life for both patients with MS and their families.     

18F‐FDG PET/CT and MRI in the follow‐up of head and neck squamous cell carcinoma

We evaluated the diagnostic performance of ¹⁸F‐FDG PET/CT and MRI for the assessment of head and neck squamous cell carcinoma (HNSCC) relapse. Since early treatment might prevent inoperable relapse, we also evaluated THE performance of early unenhanced ¹⁸F‐FDG PET/CT in residual tumor detection. The study was prospectively performed on 32 patients who underwent ¹⁸F‐FDG PET/CT and MRI before treatment and at 4 and 12 months after treatment. ¹⁸F‐FDG PET/CT was also performed 2 weeks after the end of radiotherapy. Histopathology or a minimum of 18 months follow‐up were used as gold standard. Before treatment ¹⁸F‐FDG PET/CT and MRI detected all primary tumors except for two limited vocal fold lesions (sensitivity 94%). MRI was more sensitive than ¹⁸F‐FDG PET/CT for the detection of local extension sites (sensitivity 75 vs 58%), but at the cost of a higher rate of false positive results (positive predictive value 74 vs 86%). For relapse detection at 4 months, sensitivity was significantly higher for ¹⁸F‐FDG PET/CT (92%) than for MRI (70%), but the diagnostic performances were not significantly different at 12 months. For the detection of residual malignant tissue 2 weeks post‐radiotherapy, sensitivity and specificity of ¹⁸F‐FDG PET/CT were respectively 86 and 85% (SUV cut‐off value 5.8). ¹⁸F‐FDG PET/CT is effective in the differentiation between residual tumor and radiation‐induced changes, as early as 2 weeks after treatment of a primary HNSCC. For follow‐up, performance of ¹⁸F‐FDG PET/CT and MRI are similar except for a higher sensitivity of ¹⁸F‐FDG PET/CT at 4 months. Copyright © 2011 John Wiley & Sons, Ltd.