The Two Faces of NF-κB Signaling in Cancer Development and Therapy

Constitutive activation of NF-κB signaling can promote oncogenesis, providing a rationale for anticancer strategies that inhibit NF-κB signaling. Two recent publications in Genes & Development provide evidence that, in contexts where prosurvival signals derive from other oncogenes, NF-κB activity instead enhances sensitivity to cytotoxic chemotherapy, thereby exerting a tumor-suppressor function.     

Strengthening of local vital events registration: lessons learnt from a voluntary sector initiative in a district in southern India

Problem

Birth and death registration rates are low in most parts of India. Poor registration rates are due to constraints in both the government system (supply-side) and the general population (demand-side).

Approach

We strengthened vital event registration at the local level within the existing legal framework by: (i) involving a non-profit organization as an interface between the government and the community; (ii) conducting supply-side interventions such as sensitization workshops for government officials, training for hospital staff and building data-sharing partnerships between stakeholders; (iii) monitoring for vital events by active surveillance through lay-informants; and (iv) conducting demand-side interventions such as publicity campaigns, education of families and assistance with registration.

Local setting

In the government sector, registration is given low priority and there is an attitude of blaming the victim, ascribing low levels of vital event registration to “cultural reasons/ignorance “. In the community, low registration was due to lack of awareness about the importance of and procedures for registration.

Relevant changes

This initiative helped improve registration of births and deaths at the subdistrict level. Vital event registration was significantly associated with local equity stratifiers such as gender, socioeconomic status and geography.

Lessons learnt

The voluntary sector can interface effectively between the government and the community to strengthen vital registration. With political support from the government, outreach activities can dramatically improve vital event registration rates, especially in disadvantaged populations. The potential relevance of the data and the data collection process to stakeholders at the local level is a critical factor for success.     

C3–C4 spondyloptosis without neurological deficit—a case report

Background contextTraumatic spondyloptosis of the cervical spine is usually associated with a complete, or rarely a partial, neurological deficit. Traumatic spondyloptosis with bipedicular fracture of the C3 vertebra is uncommon. To the best of the authors' knowledge, there is no report in the literature of bipedicular fracture of C3 with spondyloptosis of C3 over C4 with no neurological deficit. Literature is not clear about the role of preoperative traction in neurologically intact patients, and most authors advise both anterior and posterior fixation for cervical spondyloptosis.PurposeTo report a case of C3–C4 spondyloptosis with C1 and C2 posterior arch fractures with no neurological deficit and its management strategy and underline the fact that closed reduction and limited anterior fusion can preserve the motion segment of cervical spine at other fractured levels and give a stable cervical column with good long-term results.Study designA case report with review of the literature.MethodsA 35-year-old man fell from a height with hyperextension-compression injury to the cervical spine. The patient suffered fracture of the posterior elements of C1–C3 along with spondyloptosis of C3 over C4 without any neurological deficit. The patient was treated with an awake nasotracheal intubation with gradual cervical traction under fluoroscopic guidance to acceptable alignment followed by anterior cervical fusion at C3–C4.ResultsAt 24 months' follow-up, the C3–C4 level fused completely with fracture healing at C1 and C2. The patient remained asymptomatic with normal neurological examination and near complete cervical motion. The patient returned to his preinjury job and recreational activities.ConclusionsA case of C3–C4 spondyloptosis with associated C1–C2 posterior arch fracture is reported. The patient can present without neurological deficit if associated with a fracture of the posterior elements. Spondyloptosis without neurological deficit can be treated with gradual reduction under fluoroscopic guidance. A limited anterior-only fusion at the spondyloptosis level can provide good long-term results with preservation of other motion segments.     

Prognostic value of atherosclerotic burden and coronary vascular function in patients with suspected coronary artery disease

Purpose

To evaluate the prognostic value of coronary atherosclerotic burden, assessed by coronary artery calcium (CAC) score, and coronary vascular function, assessed by coronary flow reserve (CFR) in patients with suspected coronary artery disease (CAD).

Methods

We studied 436 patients undergoing hybrid ⁸²Rb positron emission tomography/computed tomography imaging. CAC score was measured according to the Agatston method, and patients were categorized into three groups (0, <400, and ≥400). CFR was calculated as the ratio of hyperemic to baseline myocardial blood flow, and it was considered reduced when <2.

Results

Follow-up was 94% complete during a mean period of 47±15 months. During follow-up, 17 events occurred (4% cumulative event rate). Event-free survival decreased with worsening of CAC score category (p < 0.001) and in patients with reduced CFR (p < 0.005). At multivariable analysis, CAC score ≥400 (p < 0.01) and CFR (p < 0.005) were independent predictors of events. Including CFR in the prognostic model, continuous net reclassification improvement was 0.51 (0.14 in patients with events and 0.37 in those without). At classification and regression tree analysis, the initial split was on CAC score. For patients with a CAC score < 400, no further split was performed, while patients with a CAC score ≥400 were further stratified by CFR values. Decision curve analyses indicate that the model including CFR resulted in a higher net benefit across a wide range of decision threshold probabilities.

Conclusions

In patients with suspected CAD, CFR provides significant incremental risk stratification over established cardiac risk factors and CAC score for prediction of adverse cardiac events.

     

Dose discrepancy between planning system estimation and measurement in spine stereotactic body radiation therapy: A case report

Stereotactic body radiation therapy (SBRT) to treat spinal metastases has shown excellent clinical outcomes for local control. High dose gradients wrapping around spinal cord make this treatment technically challenging. In this work, we present a spine SBRT case where a dosimetric error was identified during pre‐treatment dosimetric quality assurance (QA). A patient with metastasis in T7 vertebral body consented to undergo SBRT. A dual arc volumetric modulated arc therapy plan was generated on the Pinnacle treatment planning system (TPS) with a 6 MV Elekta machine using gantry control point spacing of 4°. Standard pre‐treatment QA measurements were performed, including ArcCHECK, ion chamber in CTV and spinal cord (SC) region and film measurements in multiple planes. While the dose measured at CTV region showed good agreement with TPS, the dose measured to the SC was significantly higher than reported by TPS in the original and repeat plans. Acceptable agreement was only achieved when the gantry control point spacing was reduced to 3°. A potentially harmful dose error was identified by pre‐treatment QA. TPS parameter settings used safely in conventional treatments should be re‐assessed for complex treatments.     

Weight Loss Interventions in Chronic Kidney Disease: A Systematic Review and Meta-analysis

Background and objectives: Obesity is an independent risk factor for development and progression of chronic kidney disease (CKD). We conducted a systematic review to assess the benefits of intentional weight loss in patients with non–dialysis-dependent CKD and glomerular hyperfiltration.Design, setting, participants, & measurements: We searched MEDLINE, SCOPUS, and conference proceedings for randomized, controlled trials and observational studies that examined various surgical and nonsurgical interventions (diet, exercise, and/or antiobesity agents) in adult patients with CKD. Results were summarized using random-effects model.Results: Thirteen studies were included. In patients with CKD, body mass index (BMI) decreased significantly (weighted mean difference [WMD] −3.67 kg/m²; 95% confidence interval [CI] −6.56 to −0.78) at the end of the study period with nonsurgical interventions. This was associated with a significant decrease in proteinuria (WMD −1.31 g/24 h; 95% CI −2.11 to −0.51) and systolic BP with no further decrease in GFR during a mean follow-up of 7.4 mo. In morbidly obese individuals (BMI >40 kg/m²) with glomerular hyperfiltration (GFR >125 ml/min), surgical interventions decreased BMI, which resulted in a decrease in GFR (WMD −25.56 ml/min; 95% CI −36.23 to −14.89), albuminuria, and systolic BP.Conclusions: In smaller, short-duration studies in patients with CKD, nonsurgical weight loss interventions reduce proteinuria and BP and seem to prevent further decline in renal function. In morbidly obese individuals with glomerular hyperfiltration, surgical interventions normalize GFR and reduce BP and microalbuminuria. Larger, long-term studies to analyze renal outcomes such as development of ESRD are needed.Nearly two thirds of US adults are overweight (body mass index [BMI] ≥25 kg/m²), and of these, one half are obese (BMI ≥30 kg/m²) (1). Obesity not only is associated with an increase in morbidity, mortality, and reduction in life expectancy but also leads to an increase in the incidence of diabetes, hypertension, and dyslipidemia that are independent risk factors for chronic kidney disease (CKD) and coronary artery disease (2–5). Multiple mechanisms by which obesity may initiate and exacerbate CKD exist, and recent observational studies have established obesity as an independent risk factor for CKD and the development of ESRD (6–8).Currently, >20 million Americans have CKD, and the projections for 2015 estimate that there will be >700,000 prevalent cases of ESRD in the United States (9). The health care costs that are associated with this increase are staggering. Diabetes and hypertension together account for >70% of the incident and prevalent cases of ESRD. Given the epidemic of obesity in the United States and around the world, the numbers of obesity-related cases of diabetes, hypertension, and kidney disease are expected to increase. Several treatment options to prevent the progression of CKD have been tested. To date, the major impact on the progression of CKD and the incidence of ESRD has been through the treatment of proteinuria and hypertension (10,11). Although weight loss has been shown to reduce proteinuria in obese patients, the impact on progression of CKD and development of ESRD is less clear (12). Especially, with the increasing number of weight reduction surgeries being performed, intentional weight loss might be a therapeutic option for CKD if its benefits are proved (13,14). Hence, we conducted a systematic review to analyze the impact of weight loss interventions in patients with preexisting CKD and in patients with obesity-related glomerular hyperfiltration.     

Your algorithm might think the hippocampus grows in Alzheimer's disease: Caveats of longitudinal automated hippocampal volumetry

Hippocampal atrophy rate—measured using automated techniques applied to structural MRI scans—is considered a sensitive marker of disease progression in Alzheimer's disease, frequently used as an outcome measure in clinical trials. Using publicly accessible data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we examined 1‐year hippocampal atrophy rates generated by each of five automated or semiautomated hippocampal segmentation algorithms in patients with Alzheimer's disease, subjects with mild cognitive impairment, or elderly controls. We analyzed MRI data from 398 and 62 subjects available at baseline and at 1 year at MRI field strengths of 1.5 T and 3 T, respectively. We observed a high rate of hippocampal segmentation failures across all algorithms and diagnostic categories, with only 50.8% of subjects at 1.5 T and 58.1% of subjects at 3 T passing stringent segmentation quality control. We also found that all algorithms identified several subjects (between 2.94% and 48.68%) across all diagnostic categories showing increases in hippocampal volume over 1 year. For any given algorithm, hippocampal “growth” could not entirely be explained by excluding patients with flawed hippocampal segmentations, scan–rescan variability, or MRI field strength. Furthermore, different algorithms did not uniformly identify the same subjects as hippocampal “growers,” and showed very poor concordance in estimates of magnitude of hippocampal volume change over time (intraclass correlation coefficient 0.319 at 1.5 T and 0.149 at 3 T). This precluded a meaningful analysis of whether hippocampal “growth” represents a true biological phenomenon. Taken together, our findings suggest that longitudinal hippocampal volume change should be interpreted with considerable caution as a biomarker. Hum Brain Mapp 38:2875–2896, 2017. © 2017 Wiley Periodicals, Inc.     

Safety of repetitive transcranial magnetic stimulation in patients with implanted cortical electrodes. An ex-vivo study and report of a case

Objective

To evaluate the safety of repetitive transcranial magnetic stimulation (rTMS) in patients with implanted subdural cortical electrodes.

“Set in Stone” or “Ray of Hope”: Parents’ Beliefs About Cause and Prognosis After Genomic Testing of Children Diagnosed with ASD

Despite increasing utilization of chromosomal microarray analysis (CMA) for autism spectrum disorders (ASD), limited information exists about how results influence parents’ beliefs about etiology and prognosis. We conducted in-depth interviews and surveys with 57 parents of children with ASD who received CMA results categorized as pathogenic, negative or variant of uncertain significance. Parents tended to incorporate their child’s CMA results within their existing beliefs about the etiology of ASD, regardless of CMA result. However, parents’ expectations for the future tended to differ depending on results; those who received genetic confirmation for their children’s ASD expressed a sense of concreteness, acceptance and permanence of the condition. Some parents expressed hope for future biomedical treatments as a result of genetic research.