Three-dimensional photon treatment planning for Hodgkin's disease

A multi-institutional study was undertaken using computerized planning systems to develop three-dimensional (3-D) radiotherapy plans for Hodgkin's disease (H.D.). Two patients, the first afflicted with bulky stage II disease and another one with early stage I H.D., were studied. Three main categories of plan were produced for each patient: a) a traditional plan which modelled a conventional mantle treatment on the 3-D system, b) a 3-D standard plan where anterior and posterior fields were designed to cover 3-D target volumes, and c) a 3-D unconstrained plan where innovational techniques were employed. Three-dimensional planning provides information about the dose distribution throughout the large volume irradiated in patients with H.D. that is not available with conventional mantle planning. The use of 3-D techniques resulted in improved tumor coverage, but by allowing for uncertainties such as motion, the doses to normal tissues tended to be higher. The use of unorthodox beam arrangements introduced added complexities, and further increased the lung doses. The most even dose distributions were obtained by incorporating compensating filters into anterior fields. Clinicians showed wide variations in their assessment of the plans, possible reasons for which are addressed in this paper. In addition, calculated probabilities from models of tumor control and normal tissue damage are also presented.     

Complementation of Lymphotoxin α Knockout Mice with Tumor Necrosis Factor–expressing Transgenes Rectifies Defective Splenic Structure and Function

Lymphotoxin (LT)α knockout mice, as well as double LTα/tumor necrosis factor (TNF) knockout mice, show a severe splenic disorganization with nonsegregating T/B cell zones and complete absence of primary B cell follicles, follicular dendritic cell (FDC) networks, and germinal centers. In contrast, as shown previously and confirmed in this study, LTβ-deficient mice show much more conserved T/B cell areas and a reduced but preserved capacity to form germinal centers and FDC networks. We show here that similar to the splenic phenotype of LTβ-deficient mice, complementation of LTα knockout mice with TNF-expressing transgenes leads to a p55 TNF receptor–dependent restoration of B/T cell zone segregation and a partial preservation of primary B cell follicles, FDC networks, and germinal centers. Notably, upon lipopolysaccharide challenge, LTα knockout mice fail to produce physiological levels of TNF both in peritoneal macrophage supernatants and in their serum, indicating a coinciding deficiency in TNF expression. These findings suggest that defective TNF expression contributes to the complex phenotype of the LTα knockout mice, and uncover a predominant role for TNF and its p55 TNF receptor in supporting, even in the absence of LTα, the development and maintenance of splenic B cell follicles, FDC networks, and germinal centers.     

Pectoral cardioverter defibrillators: comparison of prepectoral and submuscular implantation techniques

The purpose of this study was to compare the two techniques of pectoral ICD implantation, prepectoral and submuscular, performed by an electrophysiologist in the catheterization laboratory with use of general or local anesthesia in 45 consecutive patients. Over a period of 30 months, we implanted pectoral transvenous ICDs in 43 men and 2 women, aged 59 +/- 12 years, with use of general (n = 20) or local (n = 25) anesthesia in the catheterization laboratory. Patients had coronary (n = 30) or valvular (n = 4) disease, cardiomyopathy (n = 10) or no organic disease (n = 1), a mean left ventricular ejection fraction of 31%, and presented with ventricular tachycardia (n = 40) or fibrillation (n = 5). One-lead ICD systems (18 Endotak, 10 Transvene/8 Sprint, 2 EnGuard) were used in 38 patients, 2-lead (5 Transvene, 1 EnGuard) systems in 6 patients, and 1 atrioventricular lead ICD system in 1 patient. The prepectoral technique was employed in 29 patients with adequate subcutaneous tissue, while the submuscular technique was used in 16 patients who had a thin layer of subcutaneous tissue. The defibrillation threshold averaged 9-10 J in both groups and there were no differences in pace/sense thresholds. All implants were entirely transvenous with no subcutaneous patch. Biphasic ICD devices were employed in all patients. Active or hot can devices were used in 39 patients. There were no complications, operative deaths, or infections. Patients were discharged at a mean of 3 days. All devices functioned well at predis-charge testing. Over 14 +/- 8 months, 20 patients received appropriate device therapy (antitachycardia pacing or shocks). No late complications occurred. One patient died at 3 months of pump failure; there were no sudden deaths. In conclusion, for exclusive pectoral implantation of transvenous ICDs, electrophysiologists should master both prepectoral and submuscular techniques. One can thus avoid potential skin erosion or need for abdominal implantation in patients with a thin layer of subcutaneous tissue. Finally, there are no differences in pacing or defibrillation thresholds between the two techniques.     

Efficacy of Zofenopril vs. Irbesartan in Combination with a Thiazide Diuretic in Hypertensive Patients with Multiple Risk Factors not Controlled by a Previous Monotherapy: A Review of the Double-Blind,Randomized “Z” Studies

Combinations between an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) and hydrochlorothiazide (HCTZ) are among the recommended treatments for hypertensive patients uncontrolled by monotherapy. Four randomized, double-blind, parallel group studies with a similar design, including 1469 hypertensive patients uncontrolled by a previous monotherapy and with ≥1 cardiovascular risk factor, compared the efficacy of a combination of a sulfhydryl ACE inhibitor (zofenopril at 30 or 60 mg) or an ARB (irbesartan at 150 or 300 mg) plus HCTZ 12.5 mg. The extent of blood pressure (BP)-lowering was assessed in the office and over 24 h. Pleiotropic features of the treatments were evaluated by studying their effect on systemic inflammation, organ damage, arterial stiffness, and metabolic biochemical parameters. Both treatments similarly reduced office and ambulatory BPs after 18–24 weeks. In the ZODIAC study a larger reduction in high sensitivity C reactive protein (hs-CRP) was observed under zofenopril (?0.52 vs. +0.97 mg/dL under irbesartan, p = 0.001), suggesting a potential protective effect against the development of atherosclerosis. In the ZENITH study the rate of carotid plaque regression was significantly larger under zofenopril (32% vs. 16%; p = 0.047). In the diabetic patients of the ZAMES study, no adverse effects of treatments on blood glucose and lipids as well as an improvement of renal function were observed. In patients with isolated systolic hypertension of the ZEUS study, a slight and similar improvement in renal function and small reductions in pulse wave velocity (PWV), augmentation index (AI), and central systolic BP were documented with both treatments. Thus, the fixed combination of zofenopril and HCTZ may have a relevant place in the treatment of high-risk or monotherapy-treated uncontrolled hypertensive patients requiring a more prompt, intensive, and sustained BP reduction, in line with the recommendations of current guidelines.     

Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury

The inhibitor of NF-kappaB (I-kappaB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF-kappaB essential modulator (NEMO), and is involved in the activation of NF-kappaB by various stimuli. IKK2 or NEMO constitutive knockout mice die during embryogenesis as a result of massive hepatic apoptosis. Therefore, we examined the role of IKK2 in TNF-induced apoptosis and ischemia/reperfusion (I/R) injury in the liver by using conditional knockout mice. Hepatocyte-specific ablation of IKK2 did not lead to impaired activation of NF-kappaB or increased apoptosis after TNF-alpha stimulation whereas conditional NEMO knockout resulted in complete block of NF-kappaB activation and massive hepatocyte apoptosis. In a model of partial hepatic I/R injury, mice lacking IKK2 in hepatocytes displayed significantly reduced liver necrosis and inflammation than wild-type mice. AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and could therefore emerge as a new pharmacological therapy for liver resection, hemorrhagic shock, or transplantation surgery.     

“Heart failure in COVID-19 patients: Critical care experience”: A letter to the editor

Coronavirus disease 2019 (COVID-19) is associated with poor cardiovascular outcomes in patients with heart failure (HF) of all categories of ejection fraction (EF), but mainly in patients with HF with reduced EF. Moreover, cardiac transplant patients exhibit worse cardiovascular prognosis, high mortality, and more admissions to the intensive care unit. In general, COVID-19 seems to de-teriorate the clinical status of HF and favors the development of acute respiratory distress syndrome and multiorgan failure, especially in the presence of cardiovascular comorbidities such as diabetes mellitus, kidney dysfunction, and older age. COVID-19 may induce new-onset HF with complex mechanisms that involve myocardial injury. Indeed, myocardial injury comprises a large category of detrimental effects for the myocardium, such as myocardial infarction type 1 or type 2, Takotsubo cardiomyopathy, microvascular dysfunction and myocarditis, which are not easily distinguished by HF. The pathophysiologic mechanisms mainly involve direct myocardial damage by severe acute respiratory syndrome coronavirus 2, cytokine storm, hypercoagulation, inflammation, and endothelial dysfunction. The proper management of patients with COVID-19 involves careful patient evaluation and ongoing monitoring for complications such as HF.     

Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis

Development of obesity-associated insulin resistance and diabetes mellitus type 2 has been linked to activation of proinflammatory pathways in the liver, leading to impaired insulin signal transduction. To further define the role of hepatic NF-kappaB activation in this process, we have analyzed glucose metabolism in mice with liver-specific inactivation of the NF-kappaB essential modulator gene (NEMO(L-KO) mice) exposed to a high-fat diet (HFD). These animals are protected from the development of obesity-associated insulin resistance, highlighting the importance of hepatic NF-kappaB activation in this context. However, hepatic NEMO deficiency synergizes with HFD in the development of liver steatosis as a consequence of decreased peroxisome proliferator-activated receptor (PPAR-alpha) and increased PPAR-gamma expression. Steatosis interacts with increased inflammation, causing elevated apoptosis in the livers of these mice under HFD. These changes result in liver tumorigenesis of NEMO(L-KO) mice under normal diet, a process that is largely aggravated when these mice are exposed to HFD. These data directly demonstrate the interaction of hepatic inflammation, dietary composition, and metabolism in the development of liver tumorigenesis.     

Assessment of PCBs exposure in human hair using double focusing high resolution mass spectrometry and single quadrupole mass spectrometry

Polychlorinated biphenyls (PCBs) levels were assessed in human hair samples, originating from two main agricultural regions of Greece. The analysis was performed by gas chromatography-mass spectrometry (GC-MS) and gas chromatography-double focusing high resolution mass spectrometry (GC-DFHRMS). The main analytical procedure involved hair decontamination, solid-liquid extraction and cleanup steps. The recoveries of PCBs ranged from 71.2% to 101.6%, with accuracies greater than 87.5% and the between-run precisions (%RSD) lower than 25% for all analytes. Differences in the frequencies of detection and the median values of PCBs were detected between the examined regions and between the applied analytical techniques. All Peloponnesus' hair examined samples were found positive for each examined PCB, while the percentage of the total positive samples ranged from 86.1% (for PCB 138) to 94.4% (for PCB 28 and 153 congeners) using GC-DFHRMS. The Cretan hair samples were less contaminated (SUM PCBs=0.61 and 1.47pg/mg) unlike the Peloponnesus' samples (SUM PCBs=24.68 and 38.74pg/mg) measured by GC-DFHRMS and GC-MS, respectively. PCBs with high chlorination gave lower concentration values compared to low chlorination PCBs in both populations. No significant differences were observed between women and men. The GC-DFHRMS technique provided higher percentage of positive samples and low PCBs median values, due to higher sensitivity and interferences from isobaric ions in the GC-MS technique and is therefore considered as a powerful tool for such assessments in hair specimens.     

Organizational factors affecting successful adoption of innovative eHealth services: a case study employing the FITT framework

Objective

The paper presents an application of the “Fit between Individuals, Task and Technology” (FITT) framework to analyze the socio-organizational-technical factors that influence IT adoption in the healthcare domain.

Method

The FITT framework was employed as the theoretical instrument for a retrospective analysis of a 15-year effort in implementing IT systems and eHealth services in the context of a Regional Health Information Network in Crete. Quantitative and qualitative research methods, interviews and participant observations were employed to gather data from a case study that involved the entire region of Crete.

Results

The detailed analysis of the case study based on the FITT framework, showed common features, but also differences of IT adoption within the various health organizations. The emerging picture is a complex nexus of factors contributing to IT adoption, and multi-level interventional strategies to promote IT use.

Conclusion

The work presented in this paper shows the applicability of the FITT framework in explaining the complexity of aspects observed in the implementation of healthcare information systems. The reported experiences reveal that fit management can be viewed as a system with a feedback loop that is never really stable, but ever changing based on external factors or deliberate interventions. Management of fit, therefore, becomes a constant and complex task for the whole life cycle of IT systems.