A universal and structured way to derive dual optimization problem formulations

The dual problem of a convex optimization problem can be obtained in a relatively simple and structural way by using a well-known result in convex analysis, namely Fenchel’s duality theorem. This alternative way of forming a strong dual problem is the subject of this paper. We recall some standard results from convex analysis and then discuss how the dual problem can be written in terms of the conjugates of the objective function and the constraint functions. This is a didactically valuable method to explicitly write the dual problem. We demonstrate the method by deriving dual problems for several classical problems and also for a practical model for radiotherapy treatment planning, for which deriving the dual problem using other methods is a more tedious task. Additional material is presented in the appendices, including useful tables for finding conjugate functions of many functions

Regional Recurrence Risk Following a Negative Sentinel Node Procedure Does Not Approximate the False-Negative Rate of the Sentinel Node Procedure in Breast Cancer Patients Not Receiving Radiotherapy or Systemic Treatment

Background: Although the false-negative rate of the sentinel lymph node biopsy (SLNB) in breast cancer patients is 5–7%, reported regional recurrence (RR) rates after negative SLNB are much lower. Adjuvant treatment modalities probably contribute to this discrepancy. This study assessed the 5-year RR risk after a negative SLNB in the subset of patients who underwent breast amputation without radiotherapy or any adjuvant treatment.Methods: All patients operated for primary unilateral invasive breast cancer between 2005 and 2008 were identified in the Netherlands Cancer Registry. Patients with a negative SLNB who underwent breast amputation and who were not treated with axillary lymph node dissection, radiotherapy, or any adjuvant systemic treatment were selected. The cumulative 5-year RR rate was estimated by Kaplan–Meier analysis.Results: A total of 13,452 patients were surgically treated for primary breast cancer and had a negative SLNB, and 2012 patients fulfilled the selection criteria. Thirty-eight RRs occurred during follow-up. Multifocal disease was associated with a higher risk of developing RR (P = 0.04). The median time to RR was 27 months and was significantly shorter in patients with estrogen receptor-negative (ER−) breast cancer (9.5 months; P = 0.003). The 5-year RR rate was 2.4% in the study population compared with 1.1% in the remainder of 11,440 SLNB-negative patients (P = 0.0002).Conclusions: Excluding the effect of radiotherapy and systemic treatment resulted in a twofold 5-year RR risk in breast cancer patients with a tumor-free SLNB. This 5-year RR rate was still much lower than the reported false-negative rate of the SLNB procedure.</p

Growth of the thoracic aorta in the smoking population: The Danish Lung Cancer Screening Trial

Background: Although the descending aortic diameter is larger in smokers, data about thoracic aortic growth is missing. Our aim is to present the distribution of thoracic aortic growth in smokers and to compare it with literature of the general population. Methods: Current and ex-smokers aged 50–70 years from the longitudinal Danish Lung Cancer Screening Trial, were included. Mean and 95th percentile of annual aortic growth of the ascending aortic (AA) and descending aortic (DA) diameters were calculated with the first and last non-contrast computed tomography scans during follow-up. Determinants of change in aortic diameter over time were investigated with linear mixed models. Results: A total of 1987 participants (56% male, mean age 57.4 ± 4.8 years) were included. During a median follow-up of 48 months, mean AA and DA growth rates were comparable between males (AA 0.12 ± 0.31 mm/year and DA 0.10 ± 0.30 mm/year) and females (AA 0.11 ± 0.29 mm/year and DA 0.13 ± 0.27 mm/year). The 95th percentile ranged from 0.42 to 0.47 mm/year, depending on sex and location. Aortic growth was comparable between current and ex-smokers and aortic growth was not associated with pack-years. Our findings are consistent with aortic growth rates of 0.08 to 0.17 mm/years in the general population. Larger aortic growth was associated with lower age, increased height, absence of medication for hypertension or hypercholesterolemia and lower Agatston s

Automated 3D segmentation and diameter measurement of the thoracic aorta on non-contrast enhanced CT

Objectives To develop and evaluate a fully automatic method to measure diameters of the ascending and descending aorta on non-ECG-gated, non-contrast computed tomography (CT) scans. Material and methods The method combines multi-atlas registration to obtain seed points, aorta centerline extraction, and an optimal surface segmentation approach to extract the aorta surface around the centerline. From the extracted 3D aorta segmentation, the diameter of the ascending and descending aorta was calculated at cross-sectional slices perpendicular to the extracted centerline, at the level of the pulmonary artery bifurcation, and at 1-cm intervals up to 3 cm above and below this level. Agreement with manual annotations was evaluated by dice similarity coefficient (DSC) for segmentation overlap, mean surface distance (MSD), and intra-class correlation (ICC) of diameters on 100 CT scans from a lung cancer screening trial. Repeatability of the diameter measurements was evaluated on 617 baseline-one year follow-up CT scan pairs. Results The agreement between manual and automatic segmentations was good with 0.95 ± 0.01 DSC and 0.56 ± 0.08 mm MSD. ICC between the diameters derived from manual and from automatic segmentations was 0.97, with the per-level ICC ranging from 0.87 to 0.94. An ICC of 0.98 for all measurements and per-level ICC ranging from 0.91 to 0.96 were obtained for repeatability. Conclusion This fully automatic method can assess diameters in the thoracic aorta reliably even in non-ECG-gated, non-contrast CT scans. This could be a promising tool to assess aorta dilatation in screening and in clinical practice

Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia With Lewy Bodies

Background and Objectives: Recently, the US Food and Drug Administration approved the tau-binding radiotracer [18F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables. // Methods: We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE). // Results: We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91–0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (β = −0.52, CI −0.74 to −0.30, p < 0.001) and participants with AD (β = −0.30, CI −0.58 to −0.02, p = 0.04). // Discussion: The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population. // Classification of Evidence: This study provides Class II evidence that [18F]flortaucipir visual read accurately distinguishes patients with low tau-tracer binding from those with high tau-tracer binding and is associated with amyloid positivity and cognitive decline. // Glossary: Aβ=β-amyloid; AD=Alzheimer disease; CU=cognitively unimpaired; DLB=dementia with Lewy bodies; US FDA=US Food and Drug Administration; GMM=Gaussian mixture model; LMM=linear mixed model; MCI=mild cognitive impairment; MMSE=Mini-Mental State Examination; OR=odds ratio; ROI=region of interest; SCD=subjective cognitive decline; SUVr=standardized uptake value ratio

Modification and re-validation of the ethyl acetate-based multi-residue method for pesticides in produce

The ethyl acetate-based multi-residue method for determination of pesticide residues in produce has been modified for gas chromatographic (GC) analysis by implementation of dispersive solid-phase extraction (using primary–secondary amine and graphitized carbon black) and large-volume (20 μL) injection. The same extract, before clean-up and after a change of solvent, was also analyzed by liquid chromatography with tandem mass spectrometry (LC–MS–MS). All aspects related to sample preparation were re-assessed with regard to ease and speed of the analysis. The principle of the extraction procedure (solvent, salt) was not changed, to avoid the possibility invalidating data acquired over past decades. The modifications were made with techniques currently commonly applied in routine laboratories, GC–MS and LC–MS–MS, in mind. The modified method enables processing (from homogenization until final extracts for both GC and LC) of 30 samples per eight hours per person. Limits of quantification (LOQs) of 0.01 mg kg−1 were achieved with both GC–MS (full-scan acquisition, 10 mg matrix equivalent injected) and LC–MS–MS (2 mg injected) for most of the pesticides. Validation data for 341 pesticides and degradation products are presented. A compilation of analytical quality-control data for pesticides routinely analyzed by GC–MS (135 compounds) and LC–MS–MS (136 compounds) in over 100 different matrices, obtained over a period of 15 months, are also presented and discussed. At the 0.05 mg kg−1 level acceptable recoveries were obtained for 93% (GC–MS) and 92% (LC–MS–MS) of pesticide–matrix combinations

Hypertension in Sub-Saharan Africa: Cross-Sectional Surveys in Four Rural and Urban Communities

Background: Cardiovascular disease (CVD) is the leading cause of adult mortality in low-income countries but data on the prevalence of cardiovascular risk factors such as hypertension are scarce, especially in sub-Saharan Africa (SSA). This study aims to assess the prevalence of hypertension and determinants of blood pressure in four SSA populations in rural Nigeria and Kenya, and urban Namibia and Tanzania. Methods and Findings: We performed four cross-sectional household surveys in Kwara State, Nigeria; Nandi district, Kenya; Dar es Salaam, Tanzania and Greater Windhoek, Namibia, between 2009-2011. Representative population-based samples were drawn in Nigeria and Namibia. The Kenya and Tanzania study populations consisted of specific target groups. Within a final sample size of 5,500 households, 9,857 non-pregnant adults were eligible for analysis on hypertension. Of those, 7,568 respondents ≥18 years were included. The primary outcome measure was the prevalence of hypertension in each of the populations under study. The age-standardized prevalence of hypertension was 19.3% (95%CI:17.3-21.3) in rural Nigeria, 21.4% (19.8-23.0) in rural Kenya, 23.7% (21.3-26.2) in urban Tanzania, and 38.0% (35.9-40.1) in urban Namibia. In individuals with hypertension, the proportion of grade 2 (≥160/100 mmHg) or grade 3 hypertension (≥180/110 mmHg) ranged from 29.2% (Namibia) to 43.3% (Nigeria). Control of hypertension ranged from 2.6% in Kenya to 17.8% in Namibia. Obesity prevalence (BMI ≥30) ranged from 6.1% (Nigeria) to 17.4% (Tanzania) and together with age and gender, BMI independently predicted blood pressure level in all study populations. Diabetes prevalence ranged from 2.1% (Namibia) to 3.7% (Tanzania). Conclusion: Hypertension was the most frequently observed risk factor for CVD in both urban and rural communities in SSA and will contribute to the growing burden of CVD in SSA. Low levels of control of hypertension are alarming. Strengthening of health care systems in SSA to contain the emerging epidemic of CVD is urgently needed

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. Results: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] ¼ 0.99, 95% confidence interval [CI] ¼ 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc¼ 0.79, 95% CI ¼ 0.69 to 0.91; HRc¼ 0.70, 95% CI ¼ 0.59 to 0.82; HRc¼ 0.50, 95% CI ¼ 0.40 to 0.63, for 2, 3, and 4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend ¼ .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] ¼ 1.69, 95% CI ¼ 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc ¼ 1.33, 95% CI ¼ 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc¼ 0.72, 95% CI ¼ 0.54 to 0.98). Conclusions: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Structural characterization of the murine fourth component of complement and sex-limited protein and their precursors: Evidence for two loci in the S region of the H-2 complex

The S region of the murine major histocompatibility complex controls the expression of two related, serum substance-positive proteins; one (C4) has functional complement activity, whereas the other, the sex-limited protein (Slp), is hemolytically nonfunctional. The structural relationships of these molecules to each other and to their putative intracellular precursors have been examined. Radiolabeled intracellular C4 and Slp precursors were isolated from lysates of cultured peritoneal cells. The C4 and Slp precursors and their processed subunits were purified by immunoprecipitation and sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Antigenically distinct precursors for C4 and Slp were demonstrated by sequential immunoprecipitation experiments in which anti-Slp-reactive molecules were precleared by exhaustive immunoprecipitation and residual C4 molecules were precipitated by antibody to serum substance. Both molecules had apparent molecular weights of 185,000. Their molecular identities as precursors of the mature C4 and Slp proteins were established in pulse-chase studies and by comparisons of their tryptic peptide profiles with those of isolated subunits from the processed proteins. When isolated α- or β-subunits from C4 and Slp proteins were compared by peptide mapping, it was possible to detect multiple distinct and multiple shared peptides. This evidence indicates that the C4 and Slp proteins derive from distinct precursor polypeptides and suggests that the primary structures of the C4 and Slp α- and β-subunits are different. These results support the postulate that the S region contains two discrete structural loci that specify discrete C4 and Slp proteins