The influence of explainable vs non-explainable clinical decision support systems on rapid triage decisions: a mixed methods study.

BACKGROUND: During the COVID-19 pandemic, a variety of clinical decision support systems (CDSS) were developed to aid patient triage. However, research focusing on the interaction between decision support systems and human experts is lacking. METHODS: Thirty-two physicians were recruited to rate the survival probability of 59 critically ill patients by means of chart review. Subsequently, one of two artificial intelligence systems advised the physician of a computed survival probability. However, only one of these systems explained the reasons behind its decision-making. In the third step, physicians reviewed the chart once again to determine the final survival probability rating. We hypothesized that an explaining system would exhibit a higher impact on the physicians' second rating (i.e., higher weight-on-advice). RESULTS: The survival probability rating given by the physician after receiving advice from the clinical decision support system was a median of 4 percentage points closer to the advice than the initial rating. Weight-on-advice was not significantly different (p = 0.115) between the two systems (with vs without explanation for its decision). Additionally, weight-on-advice showed no difference according to time of day or between board-qualified and not yet board-qualified physicians. Self-reported post-experiment overall trust was awarded a median of 4 out of 10 points. When asked after the conclusion of the experiment, overall trust was 5.5/10 (non-explaining median 4 (IQR 3.5-5.5), explaining median 7 (IQR 5.5-7.5), p = 0.007). CONCLUSIONS: Although overall trust in the models was low, the median (IQR) weight-on-advice was high (0.33 (0.0-0.56)) and in line with published literature on expert advice. In contrast to the hypothesis, weight-on-advice was comparable between the explaining and non-explaining systems. In 30% of cases, weight-on-advice was 0, meaning the physician did not change their rating. The median of the remaining weight-on-advice values was 50%, suggesting that physicians either dismissed the recommendation or employed a "meeting halfway" approach. Newer technologies, such as clinical reasoning systems, may be able to augment the decision process rather than simply presenting unexplained bias.

The Effect of Pulse Shape and Interphase Gaps on Speech Perception and Perceived Sound Quality in Electrical Hearing.

BACKGROUND: Stimulation with triphasic pulses has been shown to reduce the occurrence of unwanted facial nerve stimulation (FNS) with cochlear implants (CIs). However, there is little data available on how different pulse shapes affect the hearing outcome with electrical hearing in general. The aim of the study was to evaluate the effects of different stimulation pulse shapes on speech perception in noise, as well as loudness perception and subjective sound quality. METHODS: Twenty experienced cochlear-implant users not suffering from FNS participated in a prospective single-visit study. Based on the subjects' current clinical fitting, six fitting maps with different pulse shapes (biphasic and triphasic) and different interphase gap (IPG) durations (2.1 µs, 10 µs, and 20 µs) were created. First, the loudness was balanced for each configuration by adjusting the stimulation charge amount. Then, speech perception in noise was measured with a German matrix sentence test (Oldenburg Sentence test). The perception of particular sound attributes of speech and music, as well as overall preference, was evaluated with visual analog scales. RESULTS: Similar levels of speech perception were obtained with triphasic stimulation ( P = 0.891) and longer IPGs ( P = 0.361) compared to the subjects' clinical map settings. The stimulation amplitudes for equal loudness were significantly higher with triphasic stimulation compared to biphasic stimulation when keeping the IPG constant. Increasing the IPG had a significantly larger effect on perceived loudness ( P < 0.0001) and charge reduction for equal loudness with triphasic pulses compared to biphasic pulses. Triphasic configuration showed lower overall subjective sound quality ratings than biphasic for speech intelligibility, clarity, naturalness, and overall preference, as well as for music naturalness, and overall preference in the acute setting without adaptation time. Post-hoc pairwise comparisons against the clinical map revealed significantly lower speech naturalness ratings for triphasic with 2.1 µs IPG and for triphasic with 20 µs IPG only. CONCLUSION: Although some sound quality attributes were rated lower compared to the clinical map in the acute test setting, stimulation with triphasic pulses does not affect speech perception in noise and can be considered as a valuable option in CI fitting.

The adapted Heart Donor Score.

The Heart Donor Score (HDS) predicts donor organ discard for medical reasons and survival after heart transplantation (HTX) in the Eurotransplant allocation system. Our aim was to adapt the HDS for application in the United Network for Organ Sharing (UNOS) registry. To adjust for differences between the Eurotransplant and UNOS registries, the "adapted HDS" was created (aHDS) by exclusion of the covariates "valve function," "left-ventricular hypertrophy," and exclusion of "drug abuse" from the variable "compromised history." Two datasets were analyzed to evaluate associations of the aHDS with donor organ discard (n = 70 948) and survival (n = 19 279). The aHDS was significantly associated with donor organ discard [odds ratio 2.72, 95% confidence interval (CI) 2.68-2.76, P < 0.001; c-statistic: 0.937). The score performed comparably in donors <60 and ≥60 years of age. The aHDS was a significant predictor of survival as evaluated by univariate Cox proportional hazards analysis (hazard ratio 1.04, 95% CI 1.01-1.07, P = 0.023), although the association lost significance in a multivariable model. The aHDS predicts donor organ discard. Negative effects of most aHDS components on survival are likely eliminated by highly accurate donor selection processes.

Speech Segregation in Active Middle Ear Stimulation: Masking Release With Changing Fundamental Frequency.

OBJECTIVES: Temporal fine structure information such as low-frequency sounds including the fundamental frequency (F0) is important to separate different talkers in noisy environments. Speech perception in noise is negatively affected by reduced temporal fine structure resolution in cochlear hearing loss. It has been shown that normal-hearing (NH) people as well as cochlear implant patients with preserved acoustic low-frequency hearing benefit from different F0 between concurrent talkers. Though patients with an active middle ear implant (AMEI) report better sound quality compared with hearing aids, they often struggle when listening in noise. The primary objective was to evaluate whether or not patients with a Vibrant Soundbridge AMEI were able to benefit from F0 differences in a concurrent talker situation and if the effect was comparable to NH individuals. DESIGN: A total of 13 AMEI listeners and 13 NH individuals were included. A modified variant of the Oldenburg sentence test was used to emulate a concurrent talker scenario. One sentence from the test corpus served as the masker and the remaining sentences as target speech. The F0 of the masker sentence was shifted upward by 4, 8, and 12 semitones. The target and masker sentences were presented simultaneously to the study subjects and the speech reception threshold was assessed by adaptively varying the masker level. To evaluate any impact of the occlusion effect on speech perception, AMEI listeners were tested in two configurations: with a plugged ear-canal contralateral to the implant side, indicated as AMEIcontra, or with both ears plugged, indicated as AMEIboth. RESULTS: In both study groups, speech perception improved when the F0 difference between target and masker increased. This was significant when the difference was at least 8 semitones; the F0-based release from masking was 3.0 dB in AMEIcontra (p = 0.009) and 2.9 dB in AMEIboth (p = 0.015), compared with 5.6 dB in NH listeners (p < 0.001). A difference of 12 semitones revealed a F0-based release from masking of 3.5 dB in the AMEIcontra (p = 0.002) and 3.4 dB in the AMEIboth (p = 0.003) condition, compared with 5.0 dB in NH individuals (p < 0.001). CONCLUSIONS: Though AMEI users deal with problems resulting from cochlear damage, hearing amplification with the implant enables a masking release based on F0 differences when F0 between a target and masker sentence was at least 8 semitones. Additional occlusion of the ear canal on the implant side did not affect speech performance. The current results complement the knowledge about the benefit of F0 within the acoustic low-frequency hearing.

Increased serum neurofilament light chain concentration indicates poor outcome in Guillain-Barré syndrome.

BACKGROUND: Guillain-Barré syndrome (GBS) is an autoimmune disease that results in demyelination and axonal damage. Five percent of patients die and 20% remain significantly disabled on recovery. Recovery is slow in most cases and eventual disability is difficult to predict, especially early in the disease. Blood or cerebrospinal fluid (CSF) biomarkers that could help identify patients at risk of poor outcome are required. We measured serum neurofilament light chain (sNfL) concentrations from blood taken upon admission and investigated a correlation between sNfL and clinical outcome. METHODS: Baseline sNfL levels in 27 GBS patients were compared with a control group of 22 patients with diagnoses not suggestive of any axonal damage. Clinical outcome parameters for GBS patients included (i) the Hughes Functional Score (HFS) at admission, nadir, and discharge; (ii) the number of days hospitalised; and (iii) whether intensive care was necessary. RESULTS: The median sNfL concentration in our GBS sample on admission was 85.5 pg/ml versus 9.1 pg/ml in controls. A twofold increase in sNfL concentration at baseline was associated with an HFS increase of 0.6 at nadir and reduced the likelihood of discharge with favourable outcome by a factor of almost three. Higher sNfL levels upon admission correlated well with hospitalisation time (rs = 0.69, p < 0.0001), during which transfer to intensive care occurred more frequently at an odds ratio of 2.4. Patients with baseline sNfL levels below 85.5 pg/ml had a 93% chance of being discharged with an unimpaired walking ability. CONCLUSIONS: sNfL levels measured at hospital admission correlated with clinical outcome in GBS patients. These results represent amounts of acute axonal damage and reflect mechanisms resulting in disability in GBS. Thus, sNfL may serve as a convenient blood-borne biomarker to personalise patient care by identifying those at higher risk of poor outcome.

Correction to: The Prognostic Index Independently Predicts Survival in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Resection.

In the original article there are errors in the authors' affiliations.

The Prognostic Index Independently Predicts Survival in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Resection.

BACKGROUND: Cancer-related inflammation is associated with tumour proliferation, maintenance and dissemination. It therefore impacts pancreatic cancer survival. The goal of this study was to examine the Prognostic Index (PI) as a prognostic biomarker for survival in patients with pancreatic ductal adenocarcinoma (PDAC). In addition, we explored factors known to interact with the immune and inflammation cascade that might interfere with the PI's strength for prognostication. METHODS: Patients with PDAC undergoing resection were analysed retrospectively. The PI was calculated from preoperatively derived C-reactive protein levels and white blood count. Data were subject to correlation and survival analysis. RESULTS: Of 357 patients, 235 (65.8%) patients had a PI 0, 108 (30.3%) PI 1, and 14 (3.9%) PI 2. Median (quartiles) survival with a high PI (group 1 + 2) was 13.2 months (7.7-27.0), compared with 18.7 months (10.2-35.4) with a low PI (group 0; p = 0.012). The PI proved to be an independent prognostic factor for cancer-specific survival (p = 0.003) adjusted for conventional prognostic factors. Prognostic strength was influenced by the presence of a bile stent (p = 0.032). CONCLUSIONS: The PI is a strong and solid independent prognostic tool for survival in patients with PDAC undergoing resection. Preoperative survey of inflammatory activity as provided by the use of a biomarker like the PI may help to identify those patients at risk of a poor prognosis.

The pro-inflammatory marker soluble suppression of tumorigenicity-2 (ST2) is reduced especially in diabetic morbidly obese patients undergoing bariatric surgery.

BACKGROUND: High soluble suppression of tumorigenicity-2 (sST2) is a marker of poor prognosis in chronic inflammatory conditions. ST2 and its ligand interleukin (IL)-33 are elevated in adipose tissue of obese individuals. We aimed to evaluate circulating sST2 and IL-33 as possible markers of metabolic benefit in morbidly overweight patients after Roux-en-Y gastric bypass (RYGB) bariatric surgery. METHODS: sST2, IL-33, high sensitive IL-6, high sensitive C-reactive protein (hsCRP), leptin, cholesterol metabolism and liver parameters were measured in 80 morbidly obese individuals before and 1 year after bariatric surgery. RESULTS: sST2 was higher (P = 0.03) in diabetics as compared to individuals without diabetes. Baseline sST2 was also higher in males than in females (P= 0.0002). One year after bariatric surgery, sST2 levels were decreased (median 120, IQR 59-176 pg/mL) as compared to sST2 before surgery (median 141, IQR 111-181, P = 0.0024), and the diabetic group showed most pronounced reduction in sST2 (P = 0.0016). An association was found between sST2 and liver function parameters before and after bariatric surgery, and between baseline sST2 and total cholesterol, triglyceride, total low density lipoprotein (LDL), small dense LDL, Apolipoprotein B as well as with small dense high density lipoproteins (HDL). In the subgroup of diabetic patients positive correlation between IL-33 and sST2 (r = 0.44, P = 0.05) was noticed. CONCLUSIONS: Circulating sST2 is associated with markers of liver functions and lipid metabolism in severely obese patients and a reduction of sST2 was shown after successful bariatric surgery, most prominently in diabetic patients.

Treatment patterns and bleeding outcomes in persons with severe hemophilia A and B in a real-world setting.

The current standard of care treatment for severe hemophilia A and B (SHA and SHB) is the prophylactic intravenous replacement of coagulation factor VIII or IX (FVIII/FIX) to prevent spontaneous bleeding. Persons with hemophilia without prophylactic treatment receive therapy in case of bleeding, i.e., on demand. To assess treatment patterns, utilization of products, and bleeding outcomes in a real-world cohort of persons with SHA and SHB, defined as FVIII or FIX activity < 1%, data was retrospectively collected from hemophilia-specific patient diaries used for home treatment, medical records, and entries into the Austrian Hemophilia Registry from the year 2012 to 2017. Fifty-three male persons with SHA (n = 47) and SHB (n = 6) were included; 26 with SHA and 5 with SHB were on prophylaxis, 8 and 1 switched therapy regimen, and 13 and 0 received on-demand therapy. Persons on prophylaxis used a mean factor FVIII or FIX dose of 71.7 and 40.1 IU/kg/week. Median (IQR) annualized bleeding rates (ABR) in SHA were 28.0 (23.4-31.3) in the on-demand, 4.9 (1.6-13.5) in the prophylaxis group, and 3.0 (2.0-6.8) in the prophylactic group of SHB. Three persons with SHA had zero bleeds during the observation period. On-demand therapy and hepatitis B and C were associated with higher ABR but not age, weight, and HIV positivity. Bleeding rates and the proportion of on-demand therapy in persons with hemophilia were high in our real-world cohort. Further improvement is needed, which might be facilitated with the advent of factor products with extended half-life or non-factor therapies.

Biological properties of bone marrow plasma cells influence their recovery in aspirate specimens: impact on classification of plasma cell disorders and potential bias to evaluation of treatment response.

Methods to estimate bone marrow plasma cells (BMPC) basically include histopathology, cytomorphology, and flow cytometry. The present study compares the outcomes of these methods with special focus on the impact of BMPC-specific characteristics on their recovery by either method. Laboratory reports of diagnostic samples from 238 consecutive patients with suspected or known plasma cell disease were retrospectively analyzed. The median (IQR) proportion of BMPC was 30.0% (15.0-70.0%) by histological review (hBMPC), 7.0% (2.0-16.0%) by smear review (sBMPC), and 3.0% (0.8-10.0%) by flow cytometry (fBMPC). The disparity of results between core biopsy and aspirate smear was enhanced in case of poor quality of the smear, increased BM fiber content, higher grade cell atypia, expression of CD56 (all P < 0.0001), the number of cytogenetic aberrations (P = 0.0002), and abnormalities of the MYC gene (P = 0.0002). Conversely, expression of CD19 and a non-clonal plasma cell phenotype were associated with a lower difference between hBMPC and sBMPC (both P < 0.0001). The disparity between the percentages of sBMPC and fBMPC was associated with the quality of the smear (P = 0.0007) and expression of CD56 (P < 0.0001). Our results suggest that the recovery of BMPC in aspirate specimens not only is a matter of sampling quality but also depends on biological cell properties. Aspiration failure due to malignant type features of BMPC may lead to misclassification of plasma cell disorders and represent a bias for the detection of minimal residual disease after therapy.

Molecular-level HLA mismatch is associated with rejection and worsened graft survival in heart transplant recipients - a retrospective study.

The aim was to evaluate the association of molecular-level human leukocyte antigen (HLA) mismatching with post-transplant graft survival, rejection, and cardiac allograft vasculopathy (CAV). We retrospectively analyzed all primary cardiac transplant recipients between 01/1984-06/2016. 1167 patients fulfilled inclusion criteria and had HLA typing information available. In 312 donor-recipient pairs, typing at serological split antigen level was available. We used the Epitope MisMatch Algorithm to calculate the number of amino acid differences in antibody-verified HLA eplets (amino acid mismatch load (AAMM)) between donor and recipient. Patients with a higher HLA-DR AAMM load had inferior 1-year graft survival (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.01-1.28). The HLA-AB AAMM load showed no impact on graft survival. In the subgroup with available split-level information, we observed an inferior graft survival for a higher HLA-DR AAMM load 3 months after transplantation (HR, 1.22; 95% CI, 1.04-1.44) and a higher risk for rejection for an increasing HLA-AB (HR, 1.70; 95% CI, 1.29-2.24) and HLA-DR (HR, 1.32; 95% CI, 1.09-1.61) AAMM load. No impact on the development of CAV was found. Molecular-level HLA mismatch analysis could serve as a tool for risk stratification after heart transplantation and might take us one step further into precision medicine.

Does a Competing Risk Analysis Show Differences in the Cumulative Incidence of Revision Surgery Between Patients with Oncologic and Non-oncologic Conditions After Distal Femur Replacement?

BACKGROUND: Distal femur replacement is frequently used for limb salvage after bone tumor resections. It is also used in patients with severe bone loss because of traumatic conditions or revision TKA. Some studies on distal femur replacement reported on revision-free survival without distinguishing between patients with oncologic diagnoses and those without, although these patients might be incomparable because of their differences in important patient- and disease-specific characteristics. This may lead to an inaccurate and undifferentiated interpretation of the results of survival analyses. QUESTIONS/PURPOSES: (1) What is the overall cumulative incidence of revision surgery after cemented and cementless distal femoral replacement, as determined with a competing risk analysis? (2) Does the cumulative incidence of revision surgery change over time? (3) Are there differences in the cumulative incidence of revision surgery between patients with oncologic conditions and those without who are treated with cemented or cementless distal femoral replacement? METHODS: A total of 403 patients were possible candidates for distal femoral replacement. Of these, 56 patients elected to undergo different procedures, 83 were excluded because an expendable growing prosthesis was implanted, and 28 were lost to follow-up. Therefore, 229 patients who underwent distal femoral replacement for oncologic or non-oncologic reasons between 1983 and 2016 were retrospectively included in this study. The type of fixation method (cemented or cementless) was obtained from the patients' medical records, operation reports, and radiographic analyses from plain radiographs. All radiographs were standardized and obtained at standard time intervals in our institution. No algorithm regarding the fixation approach was followed. According to our data, patients receiving cementless fixation were younger and therefore likely to be more active than those receiving cemented fixation. The median follow-up duration of the overall cohort was 85 months (range 0.1-391 months). Patients who died or had revision surgery before the 2-year minimum follow-up interval were adequately considered using competing risk calculation. The reasons for revision surgery were classified using the classification system proposed by the International Society for Limb Salvage. A competing risk analysis was performed to estimate the cumulative incidence function of revision, accounting for death as a competing event. To evaluate the influence of potential prognostic factors, including diagnosis (oncologic versus non-oncologic), fixation (cemented versus cementless), year of distal femoral replacement, age, and sex on the occurrence of revision surgery, univariate and multivariable Fine and Gray models were applied. RESULTS: The competing risks analysis revealed cumulative incidences of revision surgery for any cause (Types 1 to 5) of 26% (95% CI, 20.3%-31.9%) at 12 months, 37.9% (95% CI, 31.3%-44.4%) at 24 months, 52.6% (95% CI, 45.1%-59.5%) at 5 years, and 58.2% (95% CI, 50.1%-65.4%) at 10 years for all patients. Rotating hinge-type prostheses showed a lower cumulative incidence of revision surgery (41.6%; 95% CI, 31.8%-51%) than fixed-hinge prostheses did (64%; 95% CI, 50.5%-74.5% ) at 5 years (Gray's test: p = 0.01). According to the multivariate Fine and Gray model, the year of surgery did not have any effect on the risk of revision surgery (1994 to 2003: hazard ratio 0.70; 95% CI, 0.46-1.07); 2004 to 2016: HR 0.83; 95% CI, 0.52-1.34; p = 0.26). The multivariate analysis, adjusted for disease, sex, age, cementation, and year of surgery, revealed a difference in the risk of revision surgery between patients with oncologic disease and those with non-oncologic disease (HR 0.44 for oncologic versus non-oncologic; 95% CI, 0.22-0.87; p = 0.02) and a reduction in the risk of overall revision with cemented fixation in patients with oncologic disease (HR 0.53; 95% CI, 0.29-0.98; p = 0.03). CONCLUSION: This study indicates that even with newer implants, there was a high incidence of revision surgery after distal femoral replacement. According to our analysis, patients with oncologic diagnoses have a lower likelihood of revision when the stem is cemented whereas the type of fixation did not impact patients with non-oncologic diagnoses. Because of differences in patient demographics (age, etiology of disease, and use of chemotherapy) and outcomes of fixation, oncologic and non-oncologic patients should be analyzed separately in survival studies about distal femoral replacement. LEVEL OF EVIDENCE: Level III, therapeutic study.

Neutrophil Gelatinase Associated Lipocalin (NGAL) for Identification of Unstable Plaques in Patients with Asymptomatic Carotid Stenosis.

OBJECTIVE: Neutrophil gelatinase associated lipocalin (NGAL) and matrix metalloproteinase (MMP)-9/NGAL complex were investigated in asymptomatic patients with carotid artery stenosis including gender specific differences aiming at vulnerable plaques prone to embolisation. METHODS: Serum NGAL and MMP-9/NGAL levels were analysed in 83 patients with asymptomatic carotid artery stenosis. Pre-operative ultrasound and post-endarterectomy histology of carotid atherosclerotic lesions were evaluated. RESULTS: Patients with vulnerable plaques, as determined by ultrasound (plaques with decreased echogenicity) and histological analysis (type VI according to the classification of the American Heart Association), displayed the highest levels of NGAL and MMP-9/NGAL complex (p = .0003 and p = .0078, respectively). Grade VI plaques were primarily detected in patients with "soft" plaques (12 type VI plaques in 25 patients), but also in patients with mixed (four of 19) and calcified (three of 39) plaques according to ultrasound. Higher grade carotid artery stenosis (≥90%) was not associated with elevated NGAL levels. The receiver operating characteristic curve analysis detecting grade VI lesions yields an area under the curve (AUC) = 0.85, with respect to soft plaque on ultrasound the AUC = 0.86. There were no gender specific differences in levels of NGAL 80.9 (37.7) ng/mL in women vs. 76.7 (36.3) ng/mL in men, p = .607) nor of MMP-9/NGAL 33.0 (18.2-55.5) ng/mL in women vs. 36.7 (20.2-54.0) ng/mL in men, p = .969. Likewise, there were no gender associated differences in vulnerable plaque characteristics: either for grade VI plaques (17.9% vs. 27.3%, p = .582) or for the presence of soft plaques as evaluated by ultrasound (35.9% vs. 25%, p = .503). CONCLUSION: Circulating NGAL and MMP-9/NGAL are significantly increased in asymptomatic patients with vulnerable carotid atherosclerotic plaques independent of gender. Accordingly, serum NGAL may be proposed as a valuable biomarker for the detection of unstable carotid plaques in asymptomatic patients, who can then be selected for early carotid endarterectomy or stenting.

GDF-15 is a better complimentary marker for risk stratification of arrhythmic death in non-ischaemic, dilated cardiomyopathy than soluble ST2.

Growth differentiation factor (GDF)-15 and soluble ST2 (sST2) are established prognostic markers in acute and chronic heart failure. Assessment of these biomarkers might improve arrhythmic risk stratification of patients with non-ischaemic, dilated cardiomyopathy (DCM) based on left ventricular ejection fraction (LVEF). We studied the prognostic value of GDF-15 and sST2 for prediction of arrhythmic death (AD) and all-cause mortality in patients with DCM. We prospectively enrolled 52 patients with DCM and LVEF ≤ 50%. Primary end-points were time to AD or resuscitated cardiac arrest (RCA), and secondary end-point was all-cause mortality. The median follow-up time was 7 years. A cardiac death was observed in 20 patients, where 10 patients had an AD and 2 patients had a RCA. One patient died a non-cardiac death. GDF-15, but not sST2, was associated with increased risk of the AD/RCA with a hazard ratio (HR) of 2.1 (95% CI = 1.1-4.3; P = .031). GDF-15 remained an independent predictor of AD/RCA after adjustment for LVEF with adjusted HR of 2.2 (95% CI = 1.1-4.5; P = .028). Both GDF-15 and sST2 were independent predictors of all-cause mortality (adjusted HR = 2.4; 95% CI = 1.4-4.2; P = .003 vs HR = 1.6; 95% CI = 1.05-2.7; P = .030). In a model including GDF-15, sST2, LVEF and NYHA functional class, only GDF-15 was significantly associated with the secondary end-point (adjusted HR = 2.2; 95% CI = 1.05-5.2; P = .038). GDF-15 is superior to sST2 in prediction of fatal arrhythmic events and all-cause mortality in DCM. Assessment of GDF-15 could provide additional information on top of LVEF and help identifying patients at risk of arrhythmic death.

The influence of brain iron and myelin on magnetic susceptibility and effective transverse relaxation - A biochemical and histological validation study.

Quantitative susceptibility mapping (QSM) and effective transverse relaxation rate (R2*) mapping are both highly sensitive to variations in brain iron content. Clinical Magnetic Resonance Imaging (MRI) studies report changes of susceptibilities and relaxation rates in various neurological diseases which are often equated with changes in regional brain iron content. However, these mentioned metrics lack specificity for iron, since they are also influenced by the presence of myelin. In this study, we assessed the extent to which QSM and R2* reflect iron concentration as well as histological iron and myelin intensities. Six unfixed human post-mortem brains were imaged in situ with a 7 T MRI scanner. After formalin fixation, the brains were sliced axially and punched. 671 tissue punches were subjected to ferrozine iron quantification. Subsequently, brain slices were embedded in paraffin, and histological double-hemispheric axial brain slices were stained for Luxol fast blue (myelin) and diaminobenzidine (DAB)-enhanced Turnbull blue (iron). 3331 regions of interest (ROIs) were drawn on the histological stainings to assess myelin and iron intensities, which were compared with MRI data in corresponding ROIs. QSM more closely reflected quantitative ferrozine iron values (r = 0.755 vs. 0.738), whereas R2* correlated better with iron staining intensities (r = 0.619 vs. 0.445). Myelin intensities correlated negatively with QSM (r = -0.352), indicating a diamagnetic effect of myelin on susceptibility. Myelin intensities were higher in the thalamus than in the basal ganglia. A significant relationship was nonetheless observed between quantitative iron values and QSM, confirming the applicability of the latter in this brain region for iron quantification.

Does the interval from tumour surgery to radiotherapy influence survival in paediatric high grade glioma?

PURPOSE: Paediatric high grade glioma (pHGG) are rare. Following maximum safe resection, children >3 years with HGG receive radiotherapy as standard of care. Whether the interval from tumour surgery to radiotherapy (ISRT) influences survival is disputed in adults with glioblastoma, data for children are lacking. This retrospective single-centre analysis investigates a possible impact of ISRT on survival in paediatric patients with HGG. METHODS: Survival was analysed in patients aged 3-19 years with non-pontine HGG. RESULTS: Thirty-eight patients were included (female:male 19:19) with a median age of 11.0 years (3.4-17.7). Seventeen patients had grade 3 and 21 grade 4 glioma. Gross total resection was achieved in 26.3%, partial resection in 36.8% and 36.8% underwent biopsy only. All patients received concomitant and adjuvant chemotherapy. Fifty percent (n = 19) started irradiation ≤17 days (median interval 12 days [range 5-17]), 50% thereafter (median 28 days [range 19-78]). More patients with grade 4 tumours were irradiated shortly after surgery. ISRT (as a continuous variable and dichotomised into two groups by the median ISRT of 18 days) did not significantly influence overall survival (OS) or progression-free survival (PFS). Higher extent of resection (EOR), lower tumour grade as well as chemotherapy with temozolomide had a significant positive impact on OS and PFS in univariate analysis and (except for the effect of temozolomide on PFS) also in multivariable analysis. CONCLUSIONS: ISRT did not influence survival in pHGG. In view of upcoming targeted treatment options in pHGG the present data suggest that it is safe to perform molecular analyses within a 4-week timeframe before radiotherapy.

Diminished impact of cytomegalovirus infection on graft vasculopathy development in the antiviral prophylaxis era - a retrospective study.

Evidence concerning an association between cytomegalovirus (CMV) infection and accelerated cardiac allograft vasculopathy (CAV) is inconclusive. Data were analyzed retrospectively from 297 consecutive heart transplants between 1.1.2002 and 31.12.2012. Patients ≤18 years of age, survival, and follow-up ≤1-year post-transplant and patients with early CAV were excluded. CMV-infection was diagnosed and monitored closely in the first year. CAV was diagnosed by coronary angiography via left heart catheterization, and results were categorized according to the International Society of Heart and Lung Transplantation (ISHLT) scoring system. Risk factors for CAV were tested in a multivariable model. Median follow-up was 7.5 years (IQR: 5.6-10.3). CMV infection in the first year after transplantation occurred in 26% of patients (n = 78), CMV disease in 5% (n = 15). CAV ≥1 ISHLT was detected in 36% (n = 108). Incidence of CAV >1 ISHLT and severity of CAV increased over time. No statistically significant association between CMV infection and disease within the first year and risk of CAV after 1-year post-HTx was detected in the univariate (P = 0.16) and multivariable [hazard ratio (HR), 1.36; confidence interval (CI), 0.89-2.07; P = 0.16] Cox regression. In the multivariable Cox regression, donor age (HR, 1.04; 95% CI, 1.02-1.06; P < 0.01) and acute cellular rejection (ACR) ≥2R in the first year after HTx (HR, 1.77; 95% CI, 1.06-2.95; P = 0.03) were independent risk factors for CAV development. In our cohort, CMV infection and disease in the first year after transplantation did not significantly influence the risk of CAV in the long-term follow-up.

Is Total Femur Replacement a Reliable Treatment Option for Patients With Metastatic Carcinoma of the Femur?

BACKGROUND: The majority of metastatic bone lesions to the femoral bone can be treated without surgery or with minimally invasive intramedullary nailing. In rare patients with extensive metastatic disease to the femur, total femur replacement may be the only surgical alternative to amputation; however, little is known about this approach. QUESTIONS/PURPOSES: In a highly selected small group of patients with metastatic carcinoma of the femur, we asked: (1) What was the patient survivorship after this treatment? (2) What was the implant survivorship free from all-cause revision and amputation, and what complications were associated with this treatment? (3) What functional outcomes were achieved by patients after total femur replacement for this indication? METHODS: Eleven patients (three men, eight women) with a mean age of 64 years (range, 41-78 years) received total femur replacements between 1986 and 2016; none were lost to followup. The most common primary disease was breast cancer. In general, during this period, our indications for this procedure were extensive metastatic disease precluding internal fixation or isolated proximal or distal femur replacement, and an anticipated lifespan exceeding 6 months. Our contraindication for this procedure during this time was expected lifespan less than 6 months. Patient survival was assessed by Kaplan-Meier analysis; implant survival free from revision surgery and amputation were assessed by competing risk analysis. Function was determined preoperatively and 6 to 12 weeks postoperatively with the Musculoskeletal Tumor Society (MSTS) score normalized to a 100-point scale, with higher scores representing better function from a longitudinally maintained institutional database. RESULTS: Eleven patients died at a median of 5 months (range, 1-31 months) after surgery. One-year revision-free and limb survival were 82% (95% CI, 51%-98%) and 91% (95% CI, 61%-99%), respectively. Reasons for reoperation were hip dislocation, infection and local recurrence in one patient each. The latter two complications resulted in amputation in two patients. The median MSTS score was 32 (range, 13-57). CONCLUSIONS: Despite attempts to select patients who might have anticipated greater life expectancy, eight of 11 patients died by 6 months after surgery, and an additional two patients had undergone an amputation at 8 and at 17 months postoperatively. Most patients undergoing total femur replacement in this series did not recover from the procedure by the time they died, despite our best attempts to perform the procedure in patients whom we thought would live at least 6 months. Based on this, we believe that most patients with extensive metastatic disease to the femur should be offered palliative care, rather than major reconstruction. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Cancer stage and pack-years, but not p16 or HPV, are relevant for survival in hypopharyngeal and laryngeal squamous cell carcinomas.

PURPOSE: Recently, p16 has been included in the TNM guideline for oropharyngeal carcinomas. The role of HPV and p16 in hypopharyngeal and laryngeal carcinomas has not yet been established sufficiently. METHODS: Hundred and thirty-four patients with hypopharyngeal and laryngeal carcinomas were included in this retrospective analysis. Only patients with known HPV status were eligible for the investigation. Survival probabilities were estimated for different risk factors. RESULTS: Eighty-five patients presented with laryngeal carcinoma and 49 patients with hypopharyngeal carcinoma. 8% were HPV positive (10.6% laryngeal, 4.1% hypopharyngeal carcinoma). Median follow-up time was 58 months. We observed a significantly better overall survival for patients with an early tumor stage compared to advanced carcinoma. One of the hypopharyngeal HPV positive carcinomas was also p16 positive and one was p16 negative. Of the nine HPV positive laryngeal carcinomas, four were p16 positive and five p16 negative. Neither patients who were HPV positive nor patients positive for p16 showed a significantly better outcome than HPV or p16 negative patients. In contrast, nicotine pack-years showed a highly significant correlation with survival in our patient collective. CONCLUSIONS: The data suggest that tumor stage and nicotine exposure seem to have the highest impact on survival in hypopharyngeal and laryngeal squamous cell carcinoma patients. There is no evidence for a better survival for p16 positive or HPV positive patients with hypopharyngeal or laryngeal squamous cell carcinoma. HPV seems to play a minor role in these entities of head and neck carcinoma.

Fibrinolysis in patients with a mild-to-moderate bleeding tendency of unknown cause.

In more than 50% of patients with a mild-to-moderate bleeding tendency, no underlying cause can be identified (bleeding of unknown cause, BUC). Data on parameters of fibrinolysis in BUC are scarce in the literature and reveal discrepant results. It was the aim of this study to investigate increased fibrinolysis as a possible mechanism of BUC. We included 270 patients (227 females, median age 44 years, 25-75th percentile 32-58) with BUC and 98 healthy controls (65 females, median age 47 years, 25-75thpercentile 39-55). Tissue plasminogen activator (tPA-) antigen and activity, plasminogen activator inhibitor type-1 (PAI-1), tPA-PAI-1 complexes, thrombin activatable fibrinolysis inhibitor (TAFI), α2-antiplasmin, and D-dimer were determined. While PAI-1 deficiency was equally frequent in patients with BUC and controls (91/270, 34%, and 33/98, 34%, p = 0.996), tPA activity levels were more often above the detection limit in patients than in controls (103/213, 48%, and 23/98, 23%, p < 0.0001). We found lower levels of tPA-PAI-1 complexes (6.86 (3.99-10.00) and 9.11 (7.17-13.12), p < 0.001) and higher activity of TAFI (18.61 (15.80-22.58) and 17.03 (14.02-20.02), p < 0.001) and α2-antiplasmin (102 (94-109) and 98 (90-106], p = 0.003) in patients compared to controls. Detectable tPA activity (OR 3.02, 95%CI 1.75-5.23, p < 0.0001), higher levels of TAFI (OR 2.57, 95%CI 1.48-4.46, p = 0.0008) and α2-antiplasmin (OR 1.03, 95%CI 1.01-1.05, p = 0.011), and lower levels of tPA-PAI-1 complexes (OR 0.90, 95%CI 0.86-0.95, p < 0.0001) were independently associated with BUC in sex-adjusted logistic regression analyses. We conclude that the fibrinolytic system can play an etiological role for bleeding in patients with BUC.