Cystatin C-Based Equation to Estimate GFR without the Inclusion of Race and Sex.

BACKGROUND: The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown. METHODS: We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex. RESULTS: On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 × (age - 50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone. CONCLUSIONS: The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.).

Species motif participation provides unique information about species risk of extinction.

Loss of species in food webs can set in motion a cascade of additional (secondary) extinctions. A species' position in a food web (e.g. its trophic level or number of interactions) is known to affect its ability to persist following disturbance. These simple measures, however, offer only a coarse description of how species fit into their community. One would therefore expect that more detailed structural measures such as participation in three-species motifs (meso-scale structures which provide information on a species' direct and indirect interactions) will also be related to probability of persistence. Disturbances affecting the basal resources have particularly strong effects on the rest of the food web. However, how disturbances branch out and affect consumer persistence depends on the structural pattern of species interactions in several steps. The magnitude, for example, the proportion of basal resources lost, will likely also affect the outcome. Here, we analyse whether a consumer's risk of secondary extinction after the removal of basal resources depends on the consumer's motif participation and how this relationship varies with the severity of disturbance. We show that consumer species which participate more frequently in the direct competition motif and less frequently in the omnivory motif generally have higher probability of persistence following disturbance to basal resources. However, both the strength of the disturbance and the overall network structure (i.e. connectance) affect the strength and direction of relationships between motif participation and persistence. Motif participation therefore captures important trends in species persistence and provides a rich description of species' structural roles in their communities, but must be considered in the context of network structure as a whole and of the specific disturbance applied.

Impact of breast density on diagnostic accuracy in digital breast tomosynthesis versus digital mammography: results from a European screening trial.

BACKGROUND: The diagnostic accuracy of digital breast tomosynthesis (DBT) and digital mammography (DM) in breast cancer screening may vary per breast density subgroup. The purpose of this study was to evaluate which women, based on automatically assessed breast density subgroups, have the greatest benefit of DBT compared with DM in the prospective Malmö Breast Tomosynthesis Screening Trial. MATERIALS AND METHODS: The prospective European, Malmö Breast Tomosynthesis Screening Trial (n = 14,848, Jan. 27, 2010-Feb. 13, 2015) compared one-view DBT and two-view DM, with consensus meeting before recall. Breast density was assessed in this secondary analysis with the automatic software Laboratory for Individualized Breast Radiodensity Assessment. DBT and DM's diagnostic accuracies were compared by breast density quintiles of breast percent density (PD) and absolute dense area (DA) with confidence intervals (CI) and McNemar's test. The association between breast density and cancer detection was analyzed with logistic regression, adjusted for ages < 55 and ≥ 55 years and previous screening participation. RESULTS: In total, 14,730 women (median age: 58 years; inter-quartile range = 16) were included in the analysis. Sensitivity was higher and specificity lower for DBT compared with DM for all density subgroups. The highest breast PD quintile showed the largest difference in sensitivity and specificity at 81.1% (95% CI 65.8-90.5) versus 43.2% (95% CI 28.7-59.1), p < .001 and 95.5% (95% CI 94.7-96.2) versus 97.2% (95% CI 96.6-97.8), p < 0.001, respectively. Breast PD quintile was also positively associated with cancer detected via DBT at odds ratio 1.24 (95% CI 1.09-1.42, p = 0.001). CONCLUSION: Women with the highest breast density had the greatest benefit from digital breast tomosynthesis compared with digital mammography with increased sensitivity at the cost of slightly lower specificity. These results may influence digital breast tomosynthesis's use in an individualized screening program stratified by, for instance, breast density. TRIAL REGISTRATION: Trial registration at https://www. CLINICALTRIALS: gov : NCT01091545, registered March 24, 2010.

The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous glomerular filtration rate (GFR)-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by the identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterized by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules <1 kDa dominating the glomerular filtrate, for example water, urea and creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterized by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.

Long-term outcomes and prognostic factors for survival of patients with ANCA-associated vasculitis.

BACKGROUND: Despite newer treatments with immunosuppressive agents, there still exists a considerable morbidity and mortality risk among patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Since 1994 the European Vasculitis Society (EUVAS) has aimed for an improved outcome for patients with AAV, conducting several prospective randomized controlled trials (RCTs). The aim for the present study was to further evaluate the long-term survival of patients with AAV included in seven RCTs conducted by the EUVAS as well as to identify potential prognostic factors. METHODS: Long-term follow-up data were collected from questionnaires sent to the principal investigators of the original RCTs (1995-2012): MEPEX, NORAM, CYCAZAREM, CYCLOPS, IMPROVE, RITUXVAS and MYCYC, comprising 848 patients, all newly diagnosed with AAV. Relative survival estimates are presented for the study cohorts. Demographic, clinical and laboratory characteristics at trial entry were studied as potential prognostic factors in multivariable models. RESULTS: A total of 478 (56%) patients had granulomatosis with polyangiitis (GPA) and 370 (44%) had microscopic polyangiitis (MPA) with a mean age at diagnosis of 58 ± 14 years. The median follow-up time was 8 years (interquartile range 2.9-13.6). During the observation period there were 305 deaths and the main causes were infections (26%), cardiovascular disease (14%) and malignancies (13%). When compared with a matched cohort (regarding country, age group and sex) from the background population there were 14.2% more deaths among our cohort of AAV patients at 5 years, 19.9% at 10 years, 28.8% at 15 years and 36.3% at 20 years. The excess mortality occurred in all age groups. The estimated median survival time (from diagnosis) was 17.8 years (95% confidence interval 15.7-20). Among variables measured at baseline, advanced age, male sex, low estimated glomerular filtration rate and low platelet count were identified as predictors of death in a multivariate Cox model. CONCLUSIONS: Patients with AAV still have an increased risk of mortality compared with the general population despite newer therapeutic regimens. Treatment complications and organ damage are the main causes of limited survival and infections remain the leading cause of mortality among patients with AAV.

Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil and Africa.

BACKGROUND: A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts. METHODS: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed. RESULTS: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males. CONCLUSION: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study.

Role of Mannose-binding Lectin and Association with Microbial Sensitization in a Cohort of Patients with Atopic Dermatitis.

Atopic dermatitis is a relapsing inflammatory skin condition, in which bacteria, fungi and viruses may colonize the skin and aggravate the condition. Mannose-binding lectin is part of the innate immune system. Polymorphism in the mannose-binding lectin gene can result in deficiency of mannose-binding lectin, which may affect defence against microbes. The aim of this study was to investigate whether polymorphisms in the mannose-binding lectin gene affect the extent of sensitization to common skin microbes, the skin barrier function, or the severity of the disease in a cohort of patients with atopic dermatitis. Genetic testing of mannose-binding lectin polymorphism was performed in 60 patients with atopic dermatitis. The disease severity, skin barrier function, and serum levels of specific immunoglobulin E against skin microbes were measured. In patients with low mannose-binding lectin genotype (group 1) 6 of 8 (75%) were sensitized to Candida albicans, compared to 14 of 22 (63.6%) patients with intermediate mannose-binding genotype  (group 2) and 10 of 30 (33.3%) patients with high mannose-binding genotype (group 3). Group 1 (low mannose-binding lectin) was more likely to be sensitized to Candida albicans compared with group 3 (high mannose-binding lectin) (odds ratio 6.34, p-value 0.045). In this cohort of patients with atopic dermatitis, mannose-binding lectin deficiency was associated with increased sensitization to Candida albicans.

Performance of creatinine-based equations to estimate glomerular filtration rate with a methodology adapted to the context of drug dosage adjustment.

AIM: The Cockcroft-Gault (CG) creatinine-based equation is still used to estimate glomerular filtration rate (eGFR) for drug dosage adjustment. Incorrect eGFR may lead to hazardous over- or underdosing. METHODS: In a cross-sectional analysis, CG was validated against measured GFR (mGFR) in 14 804 participants and compared with the Modification-of-Diet-in-Renal-Diseases (MDRD), Chronic-Kidney-Disease-Epidemiology (CKD-EPI), Lund-Malmö-Revised (LMR) and European-Kidney-Function-Consortium (EKFC) equations. Validation focused on bias, imprecision and accuracy (percentage of estimates within ±30% of mGFR, P30), overall and stratified for mGFR, age and body mass index at mGFR <60 mL/min, as well as classification in mGFR stages. RESULTS: The CG equation performed worse than the other equations, overall and in mGFR, age and BMI subgroups in terms of bias (systematic overestimation), imprecision and accuracy except for patients ≥65 years where bias and P30 were similar to MDRD and CKD-EPI, but worse than LMR and EKFC. In subjects with mGFR <60 mL/min and at BMI 18.5-25 kg/m2 , all equations performed similarly, and for BMI < 18.5 kg/m2 CG and LMR had the best results though all equations had poor P30-accuracy. At BMI ≥ 25 kg/m2 the bias of the CG increased with increasing BMI (+17.2 mL/min at BMI ≥ 40 kg/m2 ). The four more recent equations also classified mGFR stages better than CG. CONCLUSIONS: The CG equation showed poor ability to estimate GFR overall and in analyses stratified for mGFR, age and BMI. CG was inferior to correctly classify the patients in the mGFR staging compared to more recent creatinine-based equations.

Applicability of polygenic risk scores in endometriosis clinical presentation.

BACKGROUND: Risk prediction is an essential part of preventative medicine and in recent years genomic information has become an interesting factor in risk models. Polygenic risk scores (PRS) combine the effect of many genetic variations into a single score which has been shown to have predictive value for many diseases. This study aimed to investigate the association between PRS for endometriosis and the clinical presentation of the disease. METHODS: Women with endometriosis (N = 172) were identified at the Department of Gynecology. All participants answered questionnaires regarding sociodemographic factors, lifestyle habits and medical history, registered bowel symptoms on the Visual Analog Scale for Irritable Bowel Syndrome and passed blood samples. DNA was extracted and samples were genotyped, and a PRS was calculated based on previous genome-wide association studies of endometriosis. Inflammatory proteins and TSH receptor antibodies (TRAb) in serum were analyzed. RESULTS: Inverse associations were identified between PRS and spread of endometriosis, involvement of the gastrointestinal tract and hormone treatment. However, significance was lost when calculated as p for trend and the specificity and sensitivity were low. There were no correlations between PRS and TRAb or inflammatory proteins. CONCLUSION: The findings indicate that specific PRS should be developed to predict clinical presentations in patient with endometriosis.

Development and Validation of a Modified Full Age Spectrum Creatinine-Based Equation to Estimate Glomerular Filtration Rate : A Cross-sectional Analysis of Pooled Data.

BACKGROUND: The Chronic Kidney Disease in Children Study (CKiD) equation for children and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for adults are recommended serum creatinine (SCr)-based calculations for estimating glomerular filtration rate (GFR). However, these equations, as well as their combination, have limitations, notably the problem of implausible changes in GFR during the transition from adolescence to adulthood and overestimation of GFR in young adults. The full age spectrum (FAS) equation addresses these issues but overestimates GFR when SCr levels are low. OBJECTIVE: To develop and validate a modified FAS SCr-based equation combining design features of the FAS and CKD-EPI equations. DESIGN: Cross-sectional analysis with separate pooled data sets for development and validation. SETTING: Research and clinical studies (n = 13) with measured GFR available. PATIENTS: 11 251 participants in 7 studies (development and internal validation data sets) and 8378 participants in 6 studies (external validation data set). MEASUREMENTS: Clearance of an exogenous marker (reference method), SCr level, age, sex, and height were used to develop a new equation to estimate GFR. RESULTS: The new European Kidney Function Consortium (EKFC) equation is a FAS equation with low bias (-1.2 mL/min/1.73 m2 [95% CI, -2.7 to 0.0 mL/min/1.73 m2] in children and -0.9 mL/min/1.73 m2 [CI, -1.2 to -0.5 mL/min/1.73 m2] in adults) across the FAS (2 to 90 years) and SCr range (40 to 490 µmol/L [0.45 to 5.54 mg/dL]) and with fewer estimation errors exceeding 30% (6.5% [CI, 3.8% to 9.1%] in children and 3.1% [CI, 2.5% to 3.6%] in adults) compared with the CKiD and CKD-EPI equations. LIMITATION: No Black patients were included. CONCLUSION: The new EKFC equation shows improved accuracy and precision compared with commonly used equations for estimating GFR from SCr levels. PRIMARY FUNDING SOURCE: Swedish Research Council (Vetenskapsrådet).

Finger Joint Contractures 5 Years After Treatment for Dupuytren Disease: A Comparative Cohort Study of Collagenase Injection Versus Surgical Fasciectomy.

PURPOSE: To compare collagenase injection with surgical fasciectomy in Dupuytren disease (DD) for the prevalence of contracture in treated fingers 5 years after treatment. METHODS: This was a single-center, comparative cohort study comprising 2 cohorts of patients treated for DD in 1 or more of 3 ulnar fingers with collagenase injection (159 patients) or surgical fasciectomy (59 patients). At 5 years after treatment, 13 collagenase-treated and 8 fasciectomy-treated patients had undergone subsequent treatment on the treated fingers and were considered to have current contracture. Of the remaining patients, 112 collagenase-treated patients (128 hands, 180 fingers) and 46 fasciectomy-treated patients (49 hands, 63 fingers) attended follow-up evaluation performed by 2 independent examiners (participation rate 84% and 93%, respectively). We defined current contracture in a treated finger as an active extension deficit of ≥20° in the metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joint or a total (MCP + PIP) active extension deficit (TAED) of ≥30°. We used linear mixed models to analyze differences between the cohorts over time. RESULTS: In the collagenase cohort, current contracture was present in 45 (25%) MCP and 60 (33%) PIP joints, and in the fasciectomy cohort, current contracture was present in 12 MCP (19%) and 30 PIP (48%) joints; a TAED of ≥30° was present in 79 (44%) of the collagenase-treated and 30 (48%) of the fasciectomy-treated fingers. In MCP and PIP joints with ≥20° pretreatment contracture, complete correction was observed in 82 (56%) MCP and 30 (30%) PIP joints in the collagenase cohort and 23 (70%) MCP and 5 (16%) PIP joints in the fasciectomy cohort. There was no statistically significant difference between the 2 cohorts in the TAED change over time. CONCLUSIONS: In patients with DD, collagenase injection and surgical fasciectomy improved finger joint contracture over the pretreatment status but had a high prevalence of joint contracture in the treated fingers 5 years after treatment. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Interval Breast Cancer Rates and Tumor Characteristics in the Prospective Population-based Malmö Breast Tomosynthesis Screening Trial.

Background Interval cancer rates can be used to evaluate whether screening with digital breast tomosynthesis (DBT) contributes to a screening benefit. Purpose To compare interval cancer rates and tumor characteristics in DBT screening to those in a contemporary population screened with digital mammography (DM). Materials and Methods The prospective population-based Malmö Breast Tomosynthesis Screening Trial (MBTST) was designed to compare one-view DBT to two-view DM in breast cancer detection. The interval cancer rates and cancer characteristics in the MBTST were compared with an age-matched contemporary control group, screened with two-view DM at the same center. Conditional logistic regression was used for data analysis. Results There were 14 848 women who were screened with DBT and DM in the MBTST between January 2010 and February 2015. The trial women were matched with two women of the same age and screening occasion at DM screening during the same period. Matches for 13 369 trial women (mean age, 56 years ± 10 [standard deviation]) were found with 26 738 women in the control group (mean age, 56 years ± 10). The interval cancer rate in the MBTST was 1.6 per 1000 screened women (21 of 13 369; 95% CI: 1.0, 2.4) compared with 2.8 per 1000 screened women in the control group (76 of 26 738 [95% CI: 2.2, 3.6]; conditional odds ratio, 0.6 [95% CI: 0.3, 0.9]; P = .02). The invasive interval cancers in the MBTST and in the control group showed in general high Ki-67 (63% [12 of 19] and 75% [54 of 72]), and low proportions of luminal A-like subtype (26% [five of 19] and 17% [12 of 72]), respectively. Conclusion The reduced interval cancer rate after screening with digital breast tomosynthesis compared with a contemporary age-matched control group screened with digital mammography might translate into screening benefits. Interval cancers in the trial generally had nonfavorable characteristics. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Mann in this issue.

Development of MRI-defined Structural Tissue Damage after Anterior Cruciate Ligament Injury over 5 Years: The KANON Study.

Background MRI is used to evaluate structural joint changes after anterior cruciate ligament (ACL) injury, but no long-term data are available for comparing different treatment approaches. Purpose To describe structural joint damage with MRI over a 5-year period in the Knee Anterior Cruciate Ligament, Nonsurgical versus Surgical Treatment (KANON) study and to compare frequencies of such tissue damage for a nonsurgical versus a surgical treatment strategy. Materials and Methods In this secondary analysis of a prospective trial (ISRCTN 84752559), 119 participants with an acute ACL injury were evaluated. Participants were enrolled from 2002 through 2006, the 2-year follow-up started in 2008, and the 5-year follow-up started in 2011. A 1.5-T MRI examination was performed at baseline and at 2- and 5-year follow-up. MRI scans were read according to a validated scoring instrument. Kruskal-Wallis tests were used to assess whether the frequencies of structural damage differed between the three as-treated groups. Results Of 119 participants (mean age, 26 years ± 5 [standard deviation]), 91 men were evaluated. At 2- and 5-year follow-up, respectively, 13% (15 of 117) and 13% (15 of 115) of knees showed incident cartilage damage in the medial tibiofemoral joint, 11% (13 of 117) and 17% (20 of 115) of knees showed incident cartilage damage in the lateral tibiofemoral joint, and 4% (five of 117) and 8% (nine of 115) of knees showed incident cartilage damage in the patellofemoral joint. Osteophyte development was seen in 23% (27 of 117) and 29% (33 of 115) of knees in the medial tibiofemoral joint, in 36% (42 of 117) and 43% (49 of 115) of knees in the lateral tibiofemoral joint, and in 35% (41 of 117) and 37% (42 of 115) of knees in the patellofemoral joint. No major differences between the groups were found for incident or worsening cartilage damage, bone marrow lesions, and osteophytes at 2 or 5 years. The rehabilitation-alone group showed less Hoffa-synovitis at 2 (P = .02) and 5 (P = .008) years. Conclusion Young adults with anterior cruciate ligament injury showed no major difference in frequency of structural tissue damage on MRI scans at 2 and 5 years regardless of treatment. However, the rehabilitation-alone group had less inflammation at 2 and 5 years. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Andreisek in this issue.

Change in mammography screening attendance after removing the out-of-pocket fee: a population-based study in Sweden (2014-2018).

PURPOSE: To assess the change in mammography screening attendance in Sweden-overall and in sociodemographic groups at risk of low attendance-after removal of the out-of-pocket fee in 2016. METHODS: Individual-level data on all screening invitations and attendance between 2014 and 2018 were linked to sociodemographic data from Statistics Sweden. Odds ratios and 95% confidence intervals (CIs) for attendance by time period and sociodemographic factor were computed using mixed logistic regression to account for repeated measures within women. The study sample included 1.4 million women, aged 40-75, who had a mammography screening appointment in 2014-2015 and/or 2017-2018 in 14 of Sweden's 21 health care regions. RESULTS: Overall screening attendance was 83.8% in 2014-2015 and 84.1% in 2017-2018 (+ 0.3 percentage points, 95% CI 0.2-0.4). The greatest increase in attendance was observed in non-Nordic women with the lowest income, where attendance rose from 62.9 to 65.8% (+ 2.9 points, 95% CI 2.3-3.6), and among women with four or more risk factors for low attendance, where attendance rose from 59.2 to 62.0% (+ 2.8 points, 95% CI 2.2-3.4). CONCLUSION: Screening attendance did not undergo any important increase after implementing free screening, although attendance among some sociodemographic groups increased by almost three percentage points after the policy change.

Pituitary Function after High-Dose 177Lu-DOTATATE Therapy and Long-Term Follow-Up.

INTRODUCTION: The pituitary gland has a high expression of somatostatin receptors and is therefore a potential organ at risk for radiation-induced toxicity after 177Lu-DOTATATE treatment. OBJECTIVE: To study changes in pituitary function in patients with neuroendocrine tumors (NETs) treated with dosimetry-based 177Lu-DOTATATE to detect possible late toxicity. METHODS: 68 patients from a phase II clinical trial of dosimetry-based, individualized 177Lu-DOTATATE therapy were included in this analysis. Patients had received a median of 5 (range 3-9) treatment cycles of 7.4 GBq/cycle. Median follow-up was 30 months (range 11-89). The GH/IGF-1 axis, gonadotropins, and adrenal and thyroid axes were analyzed at baseline and on a yearly basis thereafter. Percent changes in hormonal levels over time were analyzed statistically using a linear mixed model and described graphically using box plots. The absorbed radiation dose to the pituitary was estimated based on post-therapeutic imaging, and the results analyzed versus percent change in IGF-1 levels over time. RESULTS: A statistically significant decrease in IGF-1 levels was found (p < 0.005), which correlated with the number of treatment cycles (p = 0.008) and the absorbed radiation dose (p = 0.03). A similar decrease, although non-significant, was seen in gonadotropins in postmenopausal women, while in men there was an increase during the first years after therapy, after which the levels returned to baseline. No change was observed in the adrenal or thyroid axes. CONCLUSIONS: No signs of severe endocrine disorders were detected, although a significant decrease in the GH/IGF-1 axis was found, where dosimetric analyses indicated radiation-induced damage to the pituitary gland as a probable cause.

Predictors of outcome in children with disorders of mitochondrial metabolism in the pediatric intensive care unit.

BACKGROUND: The aim of this study was to identify factors predicting outcome in patients with mitochondrial disease admitted to pediatric intensive care units (PICU). METHODS: Retrospective study of 2434 patients (age <21 years) admitted to a PICU from 1 January 2006 through 31 March 2016 and captured in the Virtual Pediatric Systems database with ICD9 diagnosis 277.87, disorders of mitochondrial metabolism. Factors influencing mortality and prolonged length of stay (≥14 days) were analyzed using logistic regression. RESULTS: Predictors independently affecting mortality (adjusted odds ratios and 95% confidence intervals, p < 0.05): age 1-23 months 3.4 (1.7-6.6) and mechanical ventilation 4.7 (2.6-8.6) were risk factors; post-operative 0.2 (0.1-0.6), readmission 0.5 (0.3-0.9), and neurologic reason for admittance 0.3 (0.1-0.9) were factors reducing risk. Predictors affecting prolonged length of stay: mechanical ventilation 7.4 (5.2-10.3) and infectious reason for admittance 2.0 (1.3-3.2) were risk factors, post-operative patients 0.3 (0.2-0.5) had lower risk. The utility of PRISM and PIM2 scores in this patient group was evaluated. CONCLUSIONS: The single most predictive factor for both mortality and prolonged length of stay is the presence of mechanical ventilation. Age 1-23 months is a risk factor for mortality, and infectious reason for admittance indicates risk for prolonged length of stay. IMPACT: Presence of mechanical ventilation is the factor most strongly associated with negative outcome in patients with mitochondrial disease in pediatric intensive care. Age 1-23 months is a risk factor for mortality, and infectious reason for admittance indicates risk for prolonged length of stay PRISM3 and PIM2 are not as accurate in patients with mitochondrial disease as in a mixed patient population.

Identifying normal mammograms in a large screening population using artificial intelligence.

OBJECTIVES: To evaluate the potential of artificial intelligence (AI) to identify normal mammograms in a screening population. METHODS: In this retrospective study, 9581 double-read mammography screening exams including 68 screen-detected cancers and 187 false positives, a subcohort of the prospective population-based Malmö Breast Tomosynthesis Screening Trial, were analysed with a deep learning-based AI system. The AI system categorises mammograms with a cancer risk score increasing from 1 to 10. The effect on cancer detection and false positives of excluding mammograms below different AI risk thresholds from reading by radiologists was investigated. A panel of three breast radiologists assessed the radiographic appearance, type, and visibility of screen-detected cancers assigned low-risk scores (≤ 5). The reduction of normal exams, cancers, and false positives for the different thresholds was presented with 95% confidence intervals (CI). RESULTS: If mammograms scored 1 and 2 were excluded from screen-reading, 1829 (19.1%; 95% CI 18.3-19.9) exams could be removed, including 10 (5.3%; 95% CI 2.1-8.6) false positives but no cancers. In total, 5082 (53.0%; 95% CI 52.0-54.0) exams, including 7 (10.3%; 95% CI 3.1-17.5) cancers and 52 (27.8%; 95% CI 21.4-34.2) false positives, had low-risk scores. All, except one, of the seven screen-detected cancers with low-risk scores were judged to be clearly visible. CONCLUSIONS: The evaluated AI system can correctly identify a proportion of a screening population as cancer-free and also reduce false positives. Thus, AI has the potential to improve mammography screening efficiency. KEY POINTS: • Retrospective study showed that AI can identify a proportion of mammograms as normal in a screening population. • Excluding normal exams from screening using AI can reduce false positives.

Markers of renal function at admission and mortality in hip fracture patients - a single center prospective observational study.

Plasma cystatin C and shrunken pore syndrome (SPS) are associated with increased mortality in older adults. The objective was to assess the association between these markers of kidney function at admission and mortality in hip fracture patients. Hip fracture patients presenting at Lund University Hospital were eligible for inclusion. Cox regression was used to assess association between plasma cystatin C, creatinine, cystatin C- or creatinine-based estimations of glomerular filtration rate (eGFRCYS and eGFRCREA), or SPS (defined as eGFRCYS/eGFRCREA < 0.7) and mortality during one year follow up. Improvement in discrimination relative to the Nottingham Hip fracture score was assessed by Receiver Operational Characteristics (ROC) analysis and calculation of Net Reclassification Index (NRI). 996 patients were included in the study. Cystatin C, creatinine, eGFRCYS and eGFRCREA were associated with one-year mortality in both unadjusted and adjusted analyses. The association with mortality was stronger for cystatin C and for eGFRCYS than for creatinine and eGFRCREA. Patients with SPS had doubled mortality compared with patients without SPS (43.7 and 20.2%, respectively, p < .001). Hazard ratio for SPS in the adjusted analysis was 1.66 (95%CI; 1.16-2.39, p = .006). None of the markers improved discrimination compared to the Nottingham Hip Fracture Score using ROC analysis whereas eGFRCYS and eGFRCREA improved NRI. Our conclusion is that plasma concentrations of creatinine or cystatin C, eGFRCYS or eGFRCREA or SPS at admission in hip fracture patients are associated with mortality when known risk factors are accounted for. Identification of high risk patients may be improved by eGFRCYS or eGFRCREA.

A novel method for creatinine adjustment makes the revised Lund-Malmö GFR estimating equation applicable in children.

The aim of this study was to establish creatinine growth curves separately for males and females that can be used to adjust childhood levels of serum creatinine to corresponding adult levels. Linear regression with fractional polynomials of age as independent variable was used to construct creatinine growth curves for a reference cohort (n = 83,157 samples from Belgium and Sweden, age 2-40 years). Adjusted creatinine obtained from the growth curves was used to improve accuracy of estimated glomerular filtration rate (eGFR) based on the Lund-Malmö revised (LMR) equation in children. The LMR equation based on creatinine values adjusted to age 18 years was validated against measured GFR (mGFR) in a separate cohort of 4005 children from four different European countries. Validation metrics included median bias, precision, and accuracy expressed as percentage of estimates within ±30% (P30) of mGFR. Remarkable improvements in bias and accuracy were observed; P30 increased from 56% to 74% after creatinine adjustments in children with mGFR <75 mL/min/1.73 m2 (n = 932), while P30 was relatively unchanged (89-90%) at mGFR ≥75 mL/min/1.73 m2 (n = 3073). The suggested approach with adjusted creatinine makes LMR applicable in children irrespective of their renal function.

Shrunken pore syndrome and mortality: a cohort study of patients with measured GFR and known comorbidities.

Shrunken pore syndrome (SPS) is defined by a cystatin C-based estimation of glomerular filtration rate (eGFRCYS) being less than 60% or 70% of a creatinine-based GFR estimation (eGFRCR) in the absence of extrarenal influences on cystatin C or creatinine concentrations. SPS has been associated with a substantial increase in mortality or morbidity in all investigated populations. However, in these studies, neither the diagnoses, nor causes of death were described, and only estimated GFR was available. The present study concerns 2781 individuals with measured GFR (mGFR), known diagnoses, and known causes of death during 5.6 years in median. Cox multivariate proportional hazards regression model was used to estimate hazard ratios (HR) for all-cause and cancer, cardiovascular, diabetes or chronic kidney disease (CKD) as cause-specific mortality among patients with SPS. At an eGFRCYS/eGFRCR-ratio <0.70, the adjusted SPS death risk in the total cohort (HR 3.0, 95% CI 2.4-3.7) was clearly higher than that for the other diagnosis groups. In a sub-cohort of 1300 persons with or without diagnosis, but with normal mGFR, the all-cause mortality of SPS was markedly increased (HR 4.1, 95% CI 2.6-6.5). In a sub-cohort of 567 persons with normal mGFR and no diagnosis, the all-cause mortality of SPS was even more increased (HR 7.3, 95% CI 2.3-23). The prevalence of SPS in the total cohort was 23% and in the sub-cohorts 17 and 12%, respectively. As SPS is associated with a high mortality, occurs in the absence of reduced mGFR and albuminuria, it expands the spectrum of kidney disorders.