Disability-Adjusted Life Years Averted Versus Quality-Adjusted Life Years Gained: A Model Analysis for Breast Cancer Screening

ObjectivesTo quantify the impact of mammography-based screening on the quality of life, disability-adjusted life years (DALYs) averted or quality-adjusted life years (QALYs) gained can be used. We aimed to assess whether the use of DALYs averted or QALYs gained will lead to different cost-effective screening strategies.MethodsUsing the microsimulation model MISCAN, we simulated different breast cancer screening strategies varying in starting age (starting at 45, 47, and 50 years), stopping age (stopping at 69, 72, and 74 years), and frequency (annual [A], biennial [B], combination of both [A + B], and triennial [T]). In total, we defined 24 different breast cancer screening strategies, including no screening as a reference strategy. We calculated incremental cost-effectiveness ratios (ICERs) and compared which strategies were on the efficiency frontiers for DALYs and QALYs.ResultsBreast cancer screening averted between 46.00 and 105.58 DALYs and gained between 28.69 and 64.50 QALYs per 1000 women. For DALYs there were 5 strategies on the efficiency frontier (T50-69, T50-74, T45-74, B45-74, and A45-74). The same strategies plus one (B45-72) were on the efficiency frontier for QALYs.ConclusionsUsing DALYs averted instead of QALYs gained to assess the effects on quality of life from breast cancer screening in the Dutch population yields differences in ICERs, but almost the same strategies were on the efficiency frontiers. Whether the choice in outcome measure leads to a difference in optimal policy depends on the cost-effectiveness threshold.     

Cystatin C predicts renal function impairment after partial or radical tumor nephrectomy

International Urology and Nephrology - To test the value of preoperative and postoperative cystatin C (CysC) as a predictor on kidney function after partial (PN) or radical nephrectomy (RN) in...     

The Effect of Functional Pelvic Tilt on the Three-Dimensional Acetabular Cup Orientation in Total Hip Arthroplasty Dislocations

BackgroundAnterior and posterior pelvic tilt appears to play a role in total hip arthroplasty (THA) stability. When changing from the standing to the sitting position, the pelvis typically rotates posteriorly while the hips flex and this affects the femoro-acetabular positions. This case-control study compares changes in 3-D acetabular cup orientation during functional pelvic tilt between posterior THA dislocations vs stable THAs.MethodsStanding and sitting 3-D cup orientation was compared between fifteen posterior dislocations vs 233 prospectively followed stable THAs. 3-D cup orientation was calculated using previously validated trigonometric algorithms on biplanar radiographs. Those algorithms combine the angles in the three anatomical planes (coronal inclination, transverse version, and sagittal ante-inclination) in the standing position with the change in sagittal pelvic tilt from standing to sitting to calculate the 3-D orientation in the sitting position.ResultsThe standing cup orientation of the dislocated THAs was only characterized by a lower coronal inclination (P = .039). Compared with the controls, from standing to sitting, they showed less posterior pelvic tilt (P < .001). This led to a significant lower coronal inclination (P < .001) and sagittal ante-inclination (P < .001) in the sitting position but similar transverse version (P = .366).ConclusionsComparing posterior THA dislocations to stable THAs, there is a lower increase of all three orientation angles from standing to sitting. This leads to a decreased sitting coronal inclination and sagittal ante-inclination which may lead to an increased risk of impingement ensued by THA instability. By contrast, the transverse version was not significantly different in both positions. This confirms the importance of biplanar data on functional cup orientation.Level of EvidenceDiagnostic, Level III.     

Placental Insulin/IGF-1 Signaling,PGC-1α, and Inflammatory Pathways Are Associated With Metabolic Outcomes at 4–6 Years of Age: The ECHO Healthy Start Cohort

An adverse intrauterine environment is associated with the future risk of obesity and type 2 diabetes. Changes in placental function may underpin the intrauterine origins of adult disease, but longitudinal studies linking placental function with childhood outcomes are rare. Here, we determined the abundance and phosphorylation of protein intermediates involved in insulin signaling, inflammation, cortisol metabolism, protein glycosylation, and mitochondrial biogenesis in placental villus samples from healthy mothers from the Healthy Start cohort. Using MANOVA, we tested the association between placental proteins and offspring adiposity (fat mass percentage) at birth (n = 109) and infancy (4–6 months, n = 104), and adiposity, skinfold thickness, triglycerides, and insulin in children (4–6 years, n = 66). Placental IGF-1 receptor protein was positively associated with serum triglycerides in children. GSK3β phosphorylation at serine 9, a readout of insulin and growth factor signaling, and the ratio of phosphorylated to total JNK2 were both positively associated with midthigh skinfold thickness in children. Moreover, peroxisome proliferator–activated receptor γ coactivator (PGC)-1α abundance was positively associated with insulin in children. In conclusion, placental insulin/IGF-1 signaling, PGC-1α, and inflammation pathways were positively associated with metabolic outcomes in 4- to 6-year-old children, identifying a novel link between placental function and long-term metabolic outcomes.     

Weightbearing and Activity Restriction Treatments and Quality of Life in Patients with Perthes Disease

BackgroundWeightbearing and activity restrictions are commonly prescribed during the active stages of Perthes disease. These restrictions, ranging from cast or brace treatment with nonweightbearing to full weightbearing with activity restrictions, may have a substantial influence on the physical, mental, and social health of a child. However, their impact on the patient’s quality of life is not well-described.Questions/purposesAfter controlling for confounding variables, we asked (1) are restrictions on weightbearing and activity associated with physical health measures (as expressed by the Patient-Reported Outcome Measurement Information System [PROMIS] mobility, PROMIS pain interference, and PROMIS fatigue) of children in the active stages of Perthes disease? (2) Are these restrictions associated with poorer scores for mental health measures (PROMIS depressive symptoms and PROMIS anxiety)? (3) Are these restrictions associated with poorer scores for social health measures (PROMIS peer relationships)?MethodsBetween 2013 and 2020, 211 patients with Perthes disease at a single institution were assigned six PROMIS measures to assess physical, mental, and social health. Patients who met the following eligibility criteria were analyzed: age 8 to 14 years old, completion of six PROMIS measures, English-speaking, and active stage of Perthes disease (Waldenstrom Stage I, II, or III). Weightbearing and activity restrictions were clinically recommended to patients in the initial through early reossification stages of Perthes disease when patients had increasing pain, loss of hip motion, loss of hip containment, progression of femoral head deformity, increased hip synovitis, and femoral head involvement on MRI or as a postoperative regimen. Patients were categorized into four intervention groups based on weightbearing and activity regimen. We excluded 111 patients who did not meet the inclusion criteria. The following six pediatric self-report PROMIS measures were assessed: mobility, pain interference, fatigue, depressive symptoms, anxiety, and peer relationships. Of the 100 patients, 36 were categorized into the no-restriction regimen, 27 into the mild-restriction regimen, 25 into the moderate-restriction regimen, and 12 into the severe-restriction regimen at the time of PROMIS administration. The median (range) age at diagnosis was 8 years old (range 2 to 13 years). There were 85 boys and 15 girls. Eleven patients had hips in Waldenstrom Stage I, 10 were in Stage II, and 79 were in Stage III. Forty-four patients had hips classified as lateral pillar B and 47 patients as lateral pillar C. Nine patients had not reached the mid-fragmentation stage for appropriate lateral pillar classification by the time they took the PROMIS survey. ANOVA was used to compare differences between the mean PROMIS T-scores of these weightbearing/activity regimens. Results were assessed with a significance of p < 0.05 and adjusted for Waldenstrom stage, gender, age at diagnosis, and history of major surgery using multivariate regression analysis.ResultsAfter controlling for confounding variables, the mild- (β regression coefficient -15 [95% CI -19 to -10]; p < 0.001), moderate- (β -19 [95% CI -24 to -14]; p < 0.001), and severe- (β -25 [95% CI -30 to -19]; p < 0.001) restriction groups were associated with worse mobility T-scores compared with the no-restriction group, but no association was detected for the pain interference or fatigue measures. Weightbearing and activity restrictions were not associated with mental health measures (depressive symptoms and anxiety). Weightbearing and activity restrictions were not associated with social health measures (peer relationships). Earlier Waldenstrom stage was associated with worse pain interference (β 10 [95% CI 2 to 17]; p = 0.01) and peer relationships scores (β -8 [95% CI -15 to -1]; p = 0.03); female gender was linked with worse depressive symptoms (β 7 [95% CI 2 to 12]; p = 0.005) and peer relationships scores (β -6 [95% CI -12 to 0]; p = 0.04); and earlier age at diagnosis was associated with worse peer relationships scores (β 1 [95% CI 0 to 2]; p = 0.03). History of major surgery had no connection to any of the six PROMIS measures.ConclusionWe found that weightbearing and activity restriction treatments are associated with poorer patient-reported mobility in the active stages of Perthes disease after controlling for Waldenstrom stage, gender, age at diagnosis, and history of surgery. Weightbearing/activity restrictions, however, are not associated with pain interference, fatigue, depressive symptoms, anxiety, and peer relationships. Understanding how these treatments are associated with quality of life in patients with Perthes disease can aid in decision-making for providers, help set expectations for patients and their parents, and provide opportunities for better education and preparation. Because of the chronic nature of Perthes disease, future studies may focus on longitudinal trends in patient-reported outcomes to better understand the overall impact of this disease and its treatment.Level of EvidenceLevel III, therapeutic study.     

Unfinished feticide: the ethical problems

Dr. Jansen's paper raises three main issues. The one with which he himself is most concerned is the question of which methods of abortion are ethically right, and whether methods which risk the birth of a damaged baby are wrong. But there are two others: first, how the (originally unintended) birth of a live but damaged child alters the moral situation, and secondly, whether the overcoming of sterility by inducing a multiple pregnancy in which some of the fetuses have to be killed in order for any of them to survive is at all morally acceptable.     

Pharmacokinetics of the antitumor antibiotic n-pentyl-sparsomycin in beagle dogs

Summary N-pentyl-sparsomycin (PSm) is a lipophilic analogue of sparsomycin (Sm), which is a well known inhibitor of protein synthesis. This compound was selected for preclinical pharmacokinetic studies because of its high in vitro and in vivo antitumor activity. In this study in which the drug was evaluated in beagle dogs under anaesthesia, the drug concentrations in plasma, urine and bile samples were determined using high performance liquid chromatography (HPLC). Plasma protein binding was approximately 54%. The mean t1/2 was 0.2 hours (12 minutes) and t1/2 was 0.75 ± 0.1 hours (45 ± 6 minutes). During continuous infusions up to 5.25 hours, the steady state was reached in 3 out of 6 experiments, suggesting that in some cases the real t1/2 was longer than measured. PSm was actively reabsorbed from the renal tubuli. This process was saturable at the higher doses. Tubular reabsorption played only a minor role in pharmacokinetics as most of the drug (67%) was eliminated by the non-renal clearance. The non-renal clearance was saturable at higher doses of PSm and was the reason for non-linearity of pharmacokinetics.     

Examiner Differences in the Mini-Cex

Objective: The objective of this study was to analyze whether faculty ratings of residents, using the mini-CEX oral exam format, differed in stringency or were influenced by the clinical setting. It also sought to learn whether the examiners were satisfied with the format.Method: A mini-CEX encounter consisted of a single faculty member observing a resident conduct a focused history and physical examination in an inpatient, outpatient, or emergency room setting. After asking the resident for a diagnosis and treatment plan, the faculty member rated the resident and provided educational feedback. The encounters were intended to be short and occur as a routine part of the training, so each resident would be evaluated on many occasions by different faculty.Sample: Sixty-four attending physicians evaluated residents from five internal medicine training programs; data were analyzed for 355 mini-CEX encounters involving 88 residents.Results: There were not large differences among the examiners in their ratings. Moreover, there were not great differences among the ratings in terms of the training program with which the examiner was associated, the setting of the mini-CEX, or the nature of the patient. The examiners were generally satisfied with the format and their level of satisfaction was correlated with the residents' perceptions of the format.Conclusion: The mini-CEX adapts itself to a broad range of clinical situations, and these results show that it should produce roughly comparable scores over examiners and settings. This makes it a worthwhile device for evaluation at the local level.This revised version was published online in September 2005 with corrections to the Cover Date.     

Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone,and in combination with Ro15-1788 (flumazenil)

Recent work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine (BDZ) agonist, decreases ethanol (ETOH) self-administration in rodents under fluid deprivation conditions. The present study further examined the effects of Ro15-4513 (2.5 and 5.0 mg/kg) alone and in combination with Ro15-1788, (flumazenil) (8.0 and 16.0 mg/kg), a BDZ receptor antagonist on ETOH self-administration in freely feeding and drinking rats. Animals were trained to consume ETOH (11% v/v) using a limited access procedure. Measurements were taken at 10- and 60-min intervals. Ro15-4513 (2.5 and 5.0 mg/kg) markedly attenuated ETOH consumption at both intervals. The antagonistic actions of Ro15-4513 were completely blocked by the higher dose of flumazenil at both intervals; the lower dose failed to antagonize the Ro15-4513-induced reduction of ETOH intake. When flumazenil was given alone, both doses reduced ETOH self-administration at 60 min; although the magnitude of the antagonism was comparable to that of Ro15-4513 only with the highest does of flumazenil (16.0 mg/kg). Neither Ro15-4513 nor flumazenil alone or in combination significantly altered water intake at any of the tested doses. Rats pretreated with Ro15-4513 showed a substantial reduction in blood ethanol concentration (BEC) compared with the Tween-80 vehicle condition at the 10-min interval. However, the BEC of animals given Ro15-4513 in combination with flumazenil were similar to rats given Tween-80 vehicle. The present study extends our previous research by demonstrating that Ro15-4513 and flumazenil attenuate ETOH self-administration in non-food or water deprived rats. These studies suggest that the suppressant effects of Ro15-4513 and flumazenil on ETOH self-administration are associated with actions at the BDZ site of the GABA_A receptor complex. These data are discussed in relation to the possible mechanism(s) by which Ro-15-4513 and flumazenil exert their antagonism on ETOH self-administration.Portions of this work were presented at the Annual Meeting of the Research Society on Alcoholism under the symposium entitled GABA/BDZ Receptor Update, Marco Island, FL, June 10, 1991.We would like to dedicate this paper to the late Dr. Richard G. Lister, a friend, teacher, colleague and exceptional scientist who contributed substantially to the area of alcohol abuse and alcoholism. Over the past years, Dr. Lister investigated the interactions of alcohol with inverse benzodiazepine agonists and benzodiazepine receptor antagonists. His seminal and more recent papers played an important role in delineating the GABA benzodiazepine systems in the neurobehavioral actions of alcohol. Richard, we will miss you.     

Selective incorporation of111In-labeled PHOTOFRIN™ by glioma tissuein vivo

The use of PHOTOFRIN for photodynamic therapy of human gliomas has been studied by i.v. administration and laser photosensitization. Defining the uptake of PHOTOFRIN in the patient's tumor in comparison with the surrounding normal brain tissue is highly desirable for patient selection and study ofin vivo kinetics. We utilized a non-invasive approach to the detection of PHOTOFRIN uptake in brain tumors with¹¹¹In-oxine radiolabeled PHOTOFRIN and external imaging and quantitation using a gamma camera. Biodistribution of¹¹¹In-labeled PHOTOFRIN in 13 organs was determined in four dogs and 15 mice with gliomas.^99mTc-DTPA was used as a control for nonspecific uptake. The greatest concentration of¹¹¹In-PHOTOFRIN in the brain tumor occurred at 24 hours post i.v. administration. The brain tumor PHOTOFRIN uptake was seven times greater than that of normal brain. The decreased blood background at 72 hours made this the optimum time for imaging. Specific tumor tissue uptake of¹¹¹In-PHOTOFRIN occurred, well beyond that resulting from blood-brain-barrier (BBB) breakdown.