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The specific effect of donation after circulatory death (DCD) liver grafts on fibrinolysis, blood loss, and transfusion requirements after graft reperfusion is not well known. The aim of this study was to determine whether transplantation of controlled DCD livers is associated with an elevated risk of hyperfibrinolysis, increased blood loss, and higher transfusion requirements upon graft reperfusion, compared with livers donated after brain death (DBD).A retrospective single-center analysis of all adult recipients of primary liver transplantation between 2000 and 2019 was performed (total cohort n = 628). Propensity score matching was used to balance baseline characteristics for DCD and DBD liver recipients (propensity score matching cohort n = 218). Intraoperative and postoperative hemostatic variables between DCD and DBD liver recipients were subsequently compared. Additionally, in vitro plasma analyses were performed to compare the intraoperative fibrinolytic state upon reperfusion.No significant differences in median (interquartile range) postreperfusion blood loss (1.2 L [0.5-2.2] versus 1.3 L [0.6-2.2]; P = 0.62), red blood cell transfusion (2 units [0-4] versus 1.1 units [0-3]; P = 0.21), or fresh frozen plasma transfusion requirements (0 unit [0-2.2] versus 0 unit [0-0.9]; P = 0.11) were seen in DCD compared with DBD recipients, respectively. Furthermore, plasma fibrinolytic potential was similar in both groups.Transplantation of controlled DCD liver grafts does not result in higher intraoperative blood loss or more transfusion requirements, compared with DBD liver transplantation. In accordance with this, no evidence for increased hyperfibrinolysis upon reperfusion in DCD compared with DBD liver grafts was found.

OBJECTIVES: To explore the level and time course of patient-ventilator asynchrony in mechanically ventilated children and the effects on duration of mechanical ventilation, PICU stay, and Comfort Behavior Score as indicator for patient comfort.DESIGN: Secondary analysis of physiology data from mechanically ventilated children.SETTING: Mixed medical-surgical tertiary PICU in a university hospital.PATIENTS: Mechanically ventilated children 0-18 years old were eligible for inclusion. Excluded were patients who were unable to initiate and maintain spontaneous breathing from any cause.MEASUREMENTS AND MAIN RESULTS: Twenty-nine patients were studied with a total duration of 109 days. Twenty-two study days (20%) were excluded because patients were on neuromuscular blockade or high-frequency oscillatory ventilation, yielding 87 days (80%) for analysis. Patient-ventilator asynchrony was detected through analysis of daily recorded ventilator airway pressure, flow, and volume versus time scalars. Approximately one of every three breaths was asynchronous. The percentage of asynchronous breaths significantly increased over time, with the highest prevalence on the day of extubation. There was no correlation with the Comfort Behavior score. The percentage of asynchronous breaths during the first 24 hours was inversely correlated with the duration of mechanical ventilation. Patients with severe patient-ventilator asynchrony (asynchrony index > 10% or > 75th percentile of the calculated asynchrony index) did not have a prolonged duration of ventilation.CONCLUSIONS: The level of patient-ventilator asynchrony increased over time was not related to patient discomfort and inversely related to the duration of mechanical ventilation.

Context Whilst radioactive iodine (RAI) is often administered in the treatment for differentiated thyroid carcinoma (DTC), long-term data on male fertility after RAI are scarce. Objective To evaluate long-term male fertility after RAI for DTC, and to compare semen quality before and after RAI. Design, setting, and patients Multicenter study including males with DTC ≥2 years after their final RAI treatment with a cumulative activity of ≥3.7 GBq. Main outcome measure(s) Semen analysis, hormonal evaluation, and a fertility-focused questionnaire. Cut-off scores for ‘low semen quality’ were based on reference values of the general population as defined by the World Health Organization (WHO). Results Fifty-one participants had a median age of 40.5 (interquartile range (IQR): 34.0–49.6) years upon evaluation and a median follow-up of 5.8 (IQR: 3.0–9.5) years after their last RAI administration. The median cumulative administered activity of RAI was 7.4 (range: 3.7–23.3) GBq. The proportion of males with a low semen volume, concentration, progressive motility, or total motile sperm count did not differ from the 10th percentile cut-off of a general population (P = 0.500, P = 0.131, P = 0.094, and P = 0.500, respectively). Cryopreserved semen was used by 1 participant of the 20 who had preserved semen. Conclusions Participants had a normal long-term semen quality. The proportion of participants with low semen quality parameters scoring below the 10th percentile did not differ from the general population. Cryopreservation of semen of males with DTC is not crucial for conceiving a child after RAI administration but may be considered in individual cases.

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation. Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively. Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed. Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.

Background Pediatric differentiated thyroid cancer (DTC) has an excellent prognosis but unknown late effects of treatment. The initial cardiac evaluation showed subclinical diastolic dysfunction in 20% of adult survivors. The objective of this follow-up study was to determine the clinical course of this finding. Methods This multicenter study, conducted between 2018 and 2020, re-evaluated survivors after 5 years. The primary endpoint was echocardiographic diastolic cardiac function (depicted by the mean of the early diastolic septal and early diastolic lateral tissue velocity (e’ mean)). Secondary endpoints were other echocardiographic parameters and plasma biomarkers. Results Follow-up evaluation was completed in 47 (71.2%) of 66 survivors who had completed their initial evaluation. Of these 47 survivors, 87.2% were women. The median age was 39.8 years (range: 18.8–60.3), and the median follow-up after the initial diagnosis was 23.4 years (range: 10.2–48.8). Between the first and second evaluation, the e’ mean significantly decreased by 2.1 cm/s (s.d. 2.3 cm/s, P < 0.001). The median left ventricular ejection fraction did not significantly change (58.0% vs 59.0%, P= NS). In the best explanatory model of e’ mean, multivariate linear regression analysis showed that BMI and age were significantly associated with e’ mean (β coefficient: −0.169, 95% CI: −0.292; −0.047, P = 0.008 and β coefficient: −0.177, 95% CI: −0.240; −0.113, P < 0.001, respectively). Conclusions and relevance In these relatively young survivors of pediatric DTC, diastolic function decreased significantly during 5-year follow-up and is possibly more pronounced than in normal aging. This finding requires further follow-up to assess clinical consequences.

Background Extending the original criteria of the Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) in daily practice may increase the treatment outcome of esophageal cancer (EC) patients. This retrospective national cohort study assessed the impact on the pathologic complete response (pCR) rate and surgical outcome. Patients and Methods Data from EC patients treated between 2009 and 2017 were collected from the national Dutch Upper Gastrointestinal Cancer Audit database. Patients had locally advanced EC (cT1/N+ or cT2-4a/N0-3/M0) and were treated according to the CROSS regimen. CROSS (n = 1942) and the extended CROSS (e-CROSS; n = 1359) represent patients fulfilling the original or extended CROSS criteria, respectively. The primary outcome was total pCR (ypT0N0), while secondary outcomes were local esophageal pCR (ypT0), surgical radicality, and postoperative morbidity and mortality. Results Overall, CROSS and e-CROSS did not differ in total or local pCR rate, although a trend was observed (23.2% vs. 20.4%, p = 0.052; and 26.7% vs. 23.8%, p = 0.061). When stratifying by histology, the pCR rate was higher in the CROSS group compared with e-CROSS in squamous cell carcinomas (48.2% vs. 33.3%, p = 0.000) but not in adenocarcinomas (16.8% vs. 16.9%, p = 0.908). Surgical radicality did not differ between groups. Postoperative mortality (3.2% vs. 4.6%, p = 0.037) and morbidity (58.3% vs. 61.8%, p = 0.048) were higher in e-CROSS. Conclusion Extending the CROSS inclusion criteria for neoadjuvant chemoradiotherapy in routine clinical practice of EC patients had no impact on the pCR rate and on radicality, but was associated with increased postoperative mortality and morbidity. Importantly, effects differed between histological subtypes. Hence, in future studies, we should carefully reconsider who will benefit most in the real-world setting.

Introduction As survival rates of colon cancer increase, knowledge about functional outcomes is becoming ever more important. The primary aim of this systematic review and meta-analysis was to quantify functional outcomes after surgery for colon cancer. Secondly, we aimed to determine the effect of time to follow-up and type of colectomy on postoperative functional outcomes. Materials and methods A systematic literature search was performed to identify studies reporting bowel function following surgery for colon cancer. Outcome parameters were bowel function scores and/or prevalence of bowel symptoms. Additionally, the effect of time to follow-up and type of resection was analyzed. Results In total 26 studies were included, describing bowel function between 3 to 178 months following right hemicolectomy (n = 4207), left hemicolectomy/sigmoid colon resection (n = 4211), and subtotal/total colectomy (n = 161). In 16 studies (61.5%) a bowel function score was used. Pooled prevalence for liquid and solid stool incontinence was 24.1% and 6.9%, respectively. The most prevalent constipation-associated symptoms were incomplete evacuation and obstructive, difficult emptying (33.3% and 31.4%, respectively). Major Low Anterior Resection Syndrome was present in 21.1%. No differences between time to follow-up or type of colectomy were found. Conclusion Bowel function problems following surgery for colon cancer are common, show no improvement over time and do not depend on the type of colectomy. Apart from fecal incontinence, constipation-associated symptoms are also highly prevalent. Therefore, more attention should be paid to all possible aspects of bowel dysfunction following surgery for colon cancer and targeted treatment should commence promptly.

Background Ventilator liberation is one of the most challenging aspects in patients with respiratory failure. Most patients are weaned through a transition from full to partial respiratory support, whereas some advocate using a continuous spontaneous ventilation (CSV). However, there is little scientific evidence supporting the practice of pediatric ventilator liberation, including the timing of onset of and the approach to weaning mode. We sought to explore differences in patient effort between a pressure controlled continuous mode of ventilation (PC-CMV) [in this cohort PC assist/control (PC-A/C)] with a reduced ventilator rate and CSV, and to study changes in patient effort with decreasing PS. Methods In this prospective physiology cross-over study, we randomized children Campbell), and by pressure–rate-product (PRP) and pressure–time-product (PTP). Respiratory inductance plethysmography (RIP) was used to calculate the phase angle. Measurements were obtained at baseline, during PC-A/C and CPAP + PS, and during decreasing set PS (maximum -6 cmH2O). Results Thirty-six subjects with a median age of 4.4 (IQR 1.5–11.9) months and median ventilation time of 4.9 (IQR 3.4–7.0) days were included. Nearly all patients (94.4%) were admitted with primary respiratory failure. WOBCampbell during baseline [0.67 (IQR 0.38–1.07) Joules/L] did not differ between CSV [0.49 (IQR 0.17–0.83) Joules/L] or PC-A/C [0.47 (IQR 0.17–1.15) Joules/L]. Neither PRP, PTP, ∆Pes nor phase angle was different between the two ventilator modes. Reducing pressure support resulted in a statistically significant increase in patient effort, albeit that these differences were clinically negligible. Conclusions Patient effort during pediatric ventilation liberation was not increased when patients were in a CSV mode of ventilation compared to a ventilator mode with a ventilator back-up rate. Reducing the level of PS did not lead to clinically relevant increases in patient effort. These data may aid in a better approach to pediatric ventilation liberation. Trial registration clinicaltrials.gov NCT05254691. Registered 24 February 2022

OBJECTIVES: Driving pressure (ratio of tidal volume over respiratory system compliance) is associated with mortality in acute respiratory distress syndrome. We sought to evaluate if such association could be identified in critically ill children.DESIGN: We studied the association between driving pressure on day 1 of mechanical ventilation and ventilator-free days at day 28 through secondary analyses of prospectively collected physiology data.SETTING: Medical-surgical university hospital PICU.PATIENTS: Children younger than 18 years (stratified by Pediatric Mechanical Ventilation Consensus Conference clinical phenotype definitions) without evidence of spontaneous respiration.INTERVENTIONS: Inspiratory hold maneuvers.MEASUREMENTS AND MAIN RESULTS: Data of 222 patients with median age 11 months (2-51 mo) were analyzed. Sixty-five patients (29.3%) met Pediatric Mechanical Ventilation Consensus Conference criteria for restrictive and 78 patients (35.1%) for mixed lung disease, and 10.4% of all patients had acute respiratory distress syndrome. Driving pressure calculated by the ratio of tidal volume over respiratory system compliance for the whole cohort was 16 cm H2O (12-21 cm H2O) and correlated with the static airway pressure gradient (plateau pressure minus positive end-expiratory pressure) (Spearman correlation coefficient = 0.797; p < 0.001). Bland-Altman analysis showed that the dynamic pressure gradient (peak inspiratory pressure minus positive end-expiratory pressure) overestimated driving pressure (levels of agreement -2.295 to 7.268). Rematching the cohort through a double stratification procedure (obtaining subgroups of patients with matched mean levels for one variable but different mean levels for another ranking variable) showed a reduction in ventilator-free days at day 28 with increasing driving pressure in patients ventilated for a direct pulmonary indication. Competing risk regression analysis showed that increasing driving pressure remained independently associated with increased time to extubation (p < 0.001) after adjusting for Pediatric Risk of Mortality III 24-hour score, presence of direct pulmonary indication jury, and oxygenation index.CONCLUSIONS: Higher driving pressure was independently associated with increased time to extubation in mechanically ventilated children. Dynamic assessments of driving pressure should be cautiously interpreted.

Background cognitive impairment is highly prevalent among older patients attending the Emergency Department (ED) and is associated with adverse outcomes. Methods we conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of cognitive screening instruments to rule out cognitive impairment in older patients in the ED. A comprehensive literature search was performed in MEDLINE, EMBASE, CINAHL and CENTRAL. A risk of bias assessment using QUADAS-2 was performed. Results 23 articles, examining 18 different index tests were included. Only seven index tests could be included in the meta-analysis. For ruling out cognitive impairment irrespective of aetiology, Ottawa 3 Day Year (O3DY) (pooled sensitivity 0.90; (95% CI) 0.71–0.97) had the highest sensitivity. Fourteen articles focused on screening for cognitive impairment specifically caused by delirium. For ruling out delirium, the 4 A’s Test (4AT) showed highest sensitivity (pooled sensitivity 0.87, 95% confidence interval (95% CI) 0.74–0.94). Conclusions high clinical and methodological heterogeneity was found between included studies. Therefore, it is a challenge to recommend one diagnostic test for use as a screening instrument for cognitive impairment in the ED. The 4AT and O3DY seem most promising for ruling out cognitive impairment in older patients attending the ED. The review protocol was registered in PROSPERO (CRD42018082509).

Contains fulltext : 225882.pdf (Publisher’s version ) (Closed access) Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged

Objectives: We sought to investigate factors that affect the difference between the peak inspiratory pressure measured at the Y-piece under dynamic flow conditions and plateau pressure measured under zero-flow conditions (resistive pressure) during pressure controlled ventilation across a range of endotracheal tube sizes, respiratory mechanics, and ventilator settings. Design: In vitro study. Setting: Research laboratory. Patients: None. Interventions: An in vitro bench model of the intubated respiratory system during pressure controlled ventilation was used to obtain the difference between peak inspiratory pressure measured at the Y-piece under dynamic flow conditions and plateau pressure measured under zero-flow conditions across a range of endotracheal tubes sizes (3.0–8.0 mm). Measurements were taken at combinations of pressure above positive end-expiratory pressure (10, 15, and 20 cm H2O), airway resistance (no, low, high), respiratory system compliance (ranging from normal to extremely severe), and inspiratory time at constant positive end-expiratory pressure (5 cm H2O). Multiple regression analysis was used to construct models predicting resistive pressure stratified by endotracheal tube size. Measurements and Main Results: On univariate regression analysis, respiratory system compliance (β –1.5; 95% CI, –1.7 to –1.4; p < 0.001), respiratory system resistance (β 1.7; 95% CI, 1.5–2.0; p < 0.001), pressure above positive end-expiratory pressure (β 1.7; 95% CI, 1.4–2.0; p < 0.001), and inspiratory time (β –0.7; 95% CI, –1.0 to –0.4; p < 0.001) were associated with resistive pressure. Multiple linear regression analysis showed the independent association between increasing respiratory system compliance, increasing airway resistance, increasing pressure above positive end-expiratory pressure, and decreasing inspiratory time and resistive pressure across all endotracheal tube sizes. Inspiratory time was the strongest variable associated with a proportional increase in resistive pressure. The contribution of airway resistance became more prominent with increasing endotracheal tube size. Conclusions: Peak inspiratory pressures measured during pressure controlled ventilation overestimated plateau pressure irrespective of endotracheal tube size, especially with decreased inspiratory time or increased airway resistance.

Background In phenylketonuria, treatment and subsequent lowering of phenylalanine levels usually occur within the first month of life. This study investigated whether different indicators of metabolic control during the neonatal period were associated with IQ during late childhood/early adolescence. Methods Overall phenylalanine concentration during the first month of life (total "area under the curve"), proportion of phenylalanine concentrations above upper target level (360 mu mol/L) and proportion below lower target level (120 mu mol/L) during this period, diagnostic phenylalanine levels, number of days until phenylalanine levels were 360 mu mol/L during the first month of life negatively correlated with IQ in late childhood/early adolescence. Separately, phenylalanine concentrations during different periods within the first month of life (0-10 days, 11-20 days, 21-30 days) were negatively correlated with later IQ as well, but correlation strengths did not differ significantly. No further significant associations were found. Conclusions In phenylketonuria, achievement of target-range phenylalanine levels during the neonatal period is important for cognition later in life, also when compared to other indicators of metabolic control. Impact In phenylketonuria, it remains unclear during which age periods or developmental stages metabolic control is most important for later cognitive outcomes. Phenylalanine levels during the neonatal period were clearly and negatively related to later IQ, whereas no significant associations were observed for other indices of metabolic control. This emphasizes the relative importance of this period for cognitive development in phenylketonuria. No further distinctions were observed in strength of associations with later IQ between different indicators of metabolic control during the neonatal period. Thus, achievement of good metabolic control within 1 month after birth appears "safe" with respect to later cognitive outcomes.

Background The use of (val)ganciclovir is complicated by toxicity, slow response to treatment and acquired resistance. Objectives To evaluate a routine therapeutic drug monitoring (TDM) programme for ganciclovir in a transplant patient population. Methods An observational study was performed in transplant recipients from June 2018 to February 2020. Dose adjustments were advised by the TDM pharmacist as part of clinical care. For prophylaxis, a trough concentration (Cmin) of 1–2 mg/L and an AUC24h of >50 mg·h/L were aimed for. For treatment, a Cmin of 2–4 mg/L and an AUC24h of 80–120 mg·h/L were aimed for. Results Ninety-five solid organ and stem cell transplant patients were enrolled. Overall, 450 serum concentrations were measured; with a median of 3 (IQR = 2–6) per patient. The median Cmin and AUC24h in the treatment and prophylaxis groups were 2.0 mg/L and 90 mg·h/L and 0.9 mg/L and 67 mg·h/L, respectively. Significant intra- and inter-patient patient variability was observed. The majority of patients with an estimated glomerular filtration rate of more than 120 mL/min/1.73 m2 and patients on continuous veno-venous haemofiltration showed underexposure. The highest Cmin and AUC24h values were associated with the increase in liver function markers and decline in WBC count as compared with baseline. Conclusions This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir Cmin and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study.

Background In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. Methods This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor 2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. Conclusions The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. Trial registration ClinicalTrials.gov: NCT03797196, registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

Background: Isolated local recurrent or persistent esophageal cancer (EC) after curative intended definitive (dCRT) or neoadjuvant chemoradiotherapy (nCRT) with initially omitted surgery, is a potential indication for salvage surgery. We aimed to evaluate safety and efficacy of salvage surgery in these patients. Material and methods: A systematic literature search following PRISMA guidelines was performed using databases of PubMed/Medline. All included studies were performed in patients with persistent or recurrent EC after initial treatment with dCRT or nCRT, between 2007 and 2017. Survival analysis was performed with an inverse-variance weighting method. Results: Of the 278 identified studies, 28 were eligible, including a total of 1076 patients. Postoperative complications after salvage esophagectomy were significantly more common among patients with isolated persistent than in those with locoregional recurrent EC, including respiratory (36.6% versus 22.7%; difference in proportion 10.9 with 95% confidence interval (CI) [3.1; 18.7]) and cardiovascular complications (10.4% versus 4.5%; difference in proportion 5.9 with 95% CI [1.5; 10.2]). The pooled estimated 30-and 90-day mortality was 2.6% [1.6; 3.6] and 8.0% [6.3; 9.8], respectively. The pooled estimated 3-year and 5-year overall survival (OS) were 39.0% (95% CI: [35.8; 42.2]) and 19.4% [95% CI:16.5; 22.4], respectively. Patients with isolated persistent or recurrent EC after initial CRT had similar 5-year OS (14.0% versus 19.7%, difference in proportion -5.7, 95% CI [-13.7; 2.3]). Conclusions: Salvage surgery is a potentially curative procedure in patients with locally recurrent or persistent esophageal cancer and can be performed safely after definitive or neoadjuvant chemoradiotherapy when surgery was initially omitted. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

BACKGROUND: High-frequency oscillatory ventilation (HFOV) is a common but unproven management strategy in paediatric critical care. Oscillator settings have been traditionally guided by patient age and/or weight rather than by lung mechanics, thereby potentially negating any beneficial effects. We have adopted an open-lung HFOV strategy based on a corner frequency approach using an initial incremental-decremental mean airway pressure titration manoeuvre, a high frequency (8-15 Hz), and high power to initially target a proximal pressure amplitude (∆Pproximal) of 70-90 cm H2O, irrespective of age or weight.METHODS: We reviewed prospectively collected data on patients RESULTS: Data from 115 non-cardiac patients were analysed, of whom 53 had moderate-to-severe paediatric acute respiratory distress syndrome (PARDS). Sixteen patients (13.9%) died. Frequencies≥ 8 Hz and high ∆Pproximal were achieved in all patients irrespective of age or PARDS severity. Patients with severe PARDS showed the greatest improvement in oxygenation. pH and PaCO2 normalized in all patients. Haemodynamic parameters, cumulative amount of fluid challenges, and daily fluid balance did not deteriorate after transitioning to HFOV in any age or PARDS severity group. We observed a transient increase neuromuscular blocking agent use after switching to HFOV, but there was no increase in the daily cumulative amount of continuous midazolam or morphine in any age or PARDS severity group. No patients experienced clinically apparent barotrauma.CONCLUSIONS: This is the first study reporting the feasibility of an alternative, individualized, physiology-based open-lung HFOV strategy targeting high F and high ∆Pproximal. No adverse effects were observed with this strategy. Our findings warrant further systematic evaluation.

BackgroundImprovement in depression within the first 2 weeks of antidepressant treatment predicts good outcomes, but non-improvers can still respond or remit, whereas improvers often do not.AimsWe aimed to investigate whether early improvement of individual depressive symptoms better predicts response or remission.MethodWe obtained individual patient data of 30 trials comprising 2184 placebo-treated and 6058 antidepressant-treated participants. Primary outcome was week 6 response; secondary outcomes were week 6 remission and week 12 response and remission. We compared models that only included improvement in total score by week 2 (total improvement model) with models that also included improvement in individual symptoms.ResultsFor week 6 response, the area under the receiver operating characteristic curve and negative and positive predictive values of the total improvement model were 0.73, 0.67 and 0.74 compared with 0.77, 0.70 and 0.71 for the item improvement model. Model performance decreased for week 12 outcomes. Of predicted non-responders, 29% actually did respond by week 6 and 43% by week 12, which was decreased from the baseline (overall) probabilities of 51% by week 6 and 69% by week 12. In post hoc analyses with continuous rather than dichotomous early improvement, including individual items did not enhance model performance.ConclusionsExamining individual symptoms adds little to the predictive ability of early improvement. Additionally, early non-improvement does not rule out response or remission, particularly after 12 rather than 6 weeks. Therefore, our findings suggest that routinely adapting pharmacological treatment because of limited early improvement would often be premature.Declaration of interestNone.

PURPOSE: To analyse the effects of interdisciplinary pain rehabilitation programmes with different dosages; care as usual versus short form.METHODS: A single blinded, two armed, randomised controlled trial, with non-inferiority design was performed. All patients with chronic musculoskeletal pain referred to an outpatient multidisciplinary pain rehabilitation programme were eligible for this study. Only dosage differed, content was similar. The difference on Pain Disability Index was the primary outcome measure. Four points difference on Pain Disability Index was applied as a non-inferiority margin. Treatment effects within groups were expressed in standardised mean difference and effect sizes were calculated between the groups.RESULTS: Because care as usual was frequently extended, the difference in dosage between groups was limited. The study was stopped prematurely because of an a-priori stopping rule. Interim analyses are presented. Both groups (care as usual n = 58, short form n = 54) improved significantly (mean Pain Disability Index change care as usual: -10.8; short form: -8.3). Mean difference between groups was 2.5 points (95% confidence interval was -2.2 to 7.3). Effect size between groups was 0.2.CONCLUSIONS: The 95% confidence interval for the difference in mean pain disability reduction exceeded the upper limit of the non-inferiority margin. The results of the primary analyses of this trial are, therefore, inconclusive. Ancillary analyses revealed that programme dosage was not associated with differences in the disability outcomes. Implications for rehabilitation Optimum dosage of interdisciplinary pain rehabilitation programs is unknown and scarcely studied. This study is the first to analyse dosage as primary aim. Although results are inconclusive, they also suggest that differences in dosage may not automatically lead to differences in effects. Further research is needed to analyse what dosage works for whom; to detect optimum effective and cost-effective dosage of pain rehabilitation programmes.

Background: Allergic contact dermatitis caused by p-phenylenediamine (PPD) is a health concern for hair dye users. Because of its lower sensitization potency, the PPD derivative 2-methoxymethyl-p-phenylenediamine (ME-PPD) has been developed as an alternative hair dye for primary prevention. However, cross-elicitation responses can occur in PPD-allergic subjects.Objectives: To compare cross-elicitation responses to ME-PPD in open use and diagnostic patch testing of PPD-allergic subjects with hair dye-related allergic contact dermatitis.Methods: Reactions to ME-PPD were investigated in 25 PPD-allergic subjects by performing (1) 45-minute open use testing with a hair dye containing 2.0% of either ME-PPD or PPD, and (2) patch testing with increasing ME-PPD concentrations (0.1%-2.0% pet.).Results: Of the 25 PPD-allergic subjects, 21 (84%) reacted to open use testing with a hair dye containing 2.0% PPD, and testing with 2.0% ME-PPD led to cross-elicitation in 12 (48%). When patch tested with increasing ME-PPD concentrations, 13 (52%) cross-reacted at 0.1% (lowest dose) and 21 (84%) at 2.0% (highest dose), indicating decreased reactivity as compared with published PPD dose-response data.Conclusion: In line with the decreased cross-reactivity of ME-PPD in hair dye open use testing, PPD-allergic subjects show an attenuated cross-elicitation dose response to ME-PPD in patch testing.

In phenylketonuria, treatment and subsequent lowering of phenylalanine levels usually occur within the first month of life. This study investigated whether different indicators of metabolic control during the neonatal period were associated with IQ during late childhood/early adolescence.Overall phenylalanine concentration during the first month of life (total "area under the curve"), proportion of phenylalanine concentrations above upper target level (360 μmol/L) and proportion below lower target level (120 μmol/L) during this period, diagnostic phenylalanine levels, number of days until phenylalanine levels were360 μmol/L, and lifetime and concurrent phenylalanine levels were correlated with IQ scores of 64 PKU patients (mean age 10.8 years, SD 2.9).Overall phenylalanine concentration and proportion of phenylalanine concentrations360 μmol/L during the first month of life negatively correlated with IQ in late childhood/early adolescence. Separately, phenylalanine concentrations during different periods within the first month of life (0-10 days, 11-20 days, 21-30 days) were negatively correlated with later IQ as well, but correlation strengths did not differ significantly. No further significant associations were found.In phenylketonuria, achievement of target-range phenylalanine levels during the neonatal period is important for cognition later in life, also when compared to other indicators of metabolic control.In phenylketonuria, it remains unclear during which age periods or developmental stages metabolic control is most important for later cognitive outcomes. Phenylalanine levels during the neonatal period were clearly and negatively related to later IQ, whereas no significant associations were observed for other indices of metabolic control. This emphasizes the relative importance of this period for cognitive development in phenylketonuria. No further distinctions were observed in strength of associations with later IQ between different indicators of metabolic control during the neonatal period. Thus, achievement of good metabolic control within 1 month after birth appears "safe" with respect to later cognitive outcomes.

Objectives To assess the complementary value of human epidermal growth factor receptor 2 (HER2)-related biological tumor markers to clinico-radiomic models in predicting complete response to neoadjuvant chemoradiotherapy (NCRT) in esophageal cancer patients. Methods Expression of HER2 was assessed by immunohistochemistry in pre-treatment tumor biopsies of 96 patients with locally advanced esophageal cancer. Five other potentially active HER2-related biological tumor markers in esophageal cancer were examined in a sub-analysis on 43 patients. Patients received at least four of the five cycles of chemotherapy and full radiotherapy regimen followed by esophagectomy. Three reference clinico-radiomic models based on 18F-FDG PET were constructed to predict pathologic response, which was categorized into complete versus incomplete (Mandard tumor regression grade 1 vs. 2–5). The complementary value of the biological tumor markers was evaluated by internal validation through bootstrapping. Results Pathologic examination revealed 21 (22%) complete and 75 (78%) incomplete responders. HER2 and cluster of differentiation 44 (CD44), analyzed in the sub-analysis, were univariably associated with pathologic response. Incorporation of HER2 and CD44 into the reference models improved the overall performance (R2s of 0.221, 0.270, and 0.225) and discrimination AUCs of 0.759, 0.857, and 0.816. All models exhibited moderate to good calibration. The remaining studied biological tumor markers did not yield model improvement. Conclusions Incorporation of HER2 and CD44 into clinico-radiomic prediction models improved NCRT response prediction in esophageal cancer. These biological tumor markers are promising in initial response evaluation. Key Points • A multimodality approach, integrating independent genomic and radiomic information, is promising to improve prediction of γpCR in patients with esophageal cancer. • HER2 and CD44 are potential biological tumor markers in the initial work-up of patients with esophageal cancer. • Prediction models combining 18F-FDG PET radiomic features with HER2 and CD44 may be useful in the decision to omit surgery after neoadjuvant chemoradiotherapy in patients with esophageal cancer.

Contains fulltext : 245660.pdf (Publisher’s version ) (Closed access) Background: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up. Methods: In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen [β-CTX]) and formation (N-propeptide of type I collagen [PINP] and osteocalcin). Results: First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range [IQR] 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers β-CTX and PINP remained stable. Conclusions: This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency. Trial Registration: This follow-up study was registered in The Netherlands Trial Register under no. NL3280 (www.trialregister.nl/trial/3280).

BackgroundTitration of the continuous distending pressure during a staircase incremental–decremental pressure lung volume optimization maneuver in children on high-frequency oscillatory ventilation is traditionally driven by oxygenation and hemodynamic responses, although validity of these metrics has not been confirmed.MethodsRespiratory inductance plethysmography values were used construct pressure–volume loops during the lung volume optimization maneuver. The maneuver outcome was evaluated by three independent investigators and labeled positive if there was an increase in respiratory inductance plethysmography values at the end of the incremental phase. Metrics for oxygenation (SpO2, FiO2), proximal pressure amplitude, tidal volume and transcutaneous measured pCO2(ptcCO2) obtained during the incremental phase were compared between outcome maneuvers labeled positive and negative to calculate sensitivity, specificity, and the area under the receiver operating characteristic curve. Ventilation efficacy was assessed during and after the maneuver by measuring arterial pH and PaCO2. Hemodynamic responses during and after the maneuver were quantified by analyzing heart rate, mean arterial blood pressure and arterial lactate.Results41/54 patients (75.9%) had a positive maneuver albeit that changes in respiratory inductance plethysmography values were very heterogeneous. During the incremental phase of the maneuver, metrics for oxygenation and tidal volume showed good sensitivity (> 80%) but poor sensitivity. The sensitivity of the SpO2/FiO2ratio increased to 92.7% one hour after the maneuver. The proximal pressure amplitude showed poor sensitivity during the maneuver, whereas tidal volume showed good sensitivity but poor specificity. PaCO2decreased and pH increased in patients with a positive and negative maneuver outcome. No new barotrauma or hemodynamic instability (increase in age-adjusted heart rate, decrease in age-adjusted mean arterial blood pressure or lactate > 2.0 mmol/L) occurred as a result of the maneuver.ConclusionsAbsence of improvements in oxygenation during a lung volume optimization maneuver did not indicate that there were no increases in lung volume quantified using respiratory inductance plethysmography. Increases in SpO2/FiO2one hour after the maneuver may suggest ongoing lung volume recruitment. Ventilation was not impaired and there was no new barotrauma or hemodynamic instability. The heterogeneous responses in lung volume changes underscore the need for monitoring tools during high-frequency oscillatory ventilation.

Donor brain death (BD) is initiated by an increase in intracranial pressure (ICP), which subsequently damages the donor lung. In this study, we investigated whether the speed of ICP increase affects quality of donor lungs, in a rat model for fastversusslow BD induction. Rats were assigned to 3 groups: 1) control, 2) fast BD induction (ICP increase over 1 min) or 3) slow BD induction (ICP increase over 30 min). BD was induced by epidural inflation of a balloon catheter. Brain-dead rats were sacrificed after 0.5 hours, 1 hour, 2 hours and 4 hours to study time-dependent changes. Hemodynamic stability, histological lung injury and inflammatory status were investigated. We found that fast BD induction compromised hemodynamic stability of rats more than slow BD induction, reflected by higher mean arterial pressures during the BD induction period and an increased need for hemodynamic support during the BD stabilization phase. Furthermore, fast BD induction increased histological lung injury scores and gene expression levels of TNF-α and MCP-1 at 0.5 hours after induction. Yet after donor stabilization, inflammatory status was comparable between the two BD models. This study demonstrates fast BD induction deteriorates quality of donor lungs more on a histological level than slow BD induction.

Background For years, paediatric critical care practitioners used the adult American European Consensus Conference (AECC) and revised Berlin Definition (BD) for acute respiratory distress syndrome (ARDS) to study the epidemiology of paediatric ARDS (PARDS). In 2015, the paediatric specific definition, Paediatric Acute Lung Injury Consensus Conference (PALICC) was developed. The use of non-invasive metrics of oxygenation to stratify disease severity were introduced in this definition, although this potentially may lead to a confounding effect of disease severity since it is more common to place indwelling arterial lines in sicker patients. We tested the hypothesis that PALICC outperforms AECC/BD in our high acuity PICU, which employs a liberal use of indwelling arterial lines and high-frequency oscillatory ventilation (HFOV). Methods We retrospectively collected data from children Results Data from 909 out of 2433 patients was eligible for analysis. AECC/BD identified 35 (1.4%) patients (mortality 25.7%), whereas PALICC identified 135 (5.5%) patients (mortality 14.1%). All but two patients meeting AECC/Berlin criteria were also identified by PALICC. Almost half of the cohort (45.2%) had mild, 33.3% moderate and 21.5% severe PALICC PARDS at onset. Highest mortality rates were seen in patients with AECC acute lung injury (ALI)/mild Berlin and severe PALICC PARDS. The AUC-ROC for Berlin was the highest 24 h (0.392 [0.124–0.659]) after onset. PALICC showed the highest AUC-ROC at the same moment however higher than Berlin (0.531 [0.345–0.716]). Mortality rates were significantly increased in patients with bilateral consolidations (9.3% unilateral vs 26.3% bilateral, p = 0.025). Conclusions PALICC identified more new cases PARDS than the AECC/Berlin definition. However, both PALICC and Berlin performed poorly in terms of mortality risk stratification. The presence of bilateral consolidations was associated with a higher mortality rate. Our findings may be considered in future modifications of the PALICC criteria.

Background: Pseudomonas aeruginosa (Pa) is the predominant pulmonary pathogen in patients with cystic fibrosis (CF). Tobramycin nebulization is used for the eradication of Pa infection. Nowadays, tobramycin dry powder inhalation (DPI) is available as well. This study reports the results of eradicating Pa with tobramycin DPI versus nebulization. Methods: Adult CF patients with a Pa isolation between September 2010 and September 2017 from the University Medical Centre Groningen (UMCG), the Netherlands, were included in this retrospective study. Results: In total 27 Pa isolations were recorded. In 13 of these, eradication was attempted with tobramycin, 7 with DPI and 6 with nebulization. DPI eradicated Pa successfully in six isolations (85.7%). Of these, one patient received additional oral ciprofloxacin and one received intravenous ceftazidime. Nebulization eradicated three Pa isolations (50.0%), in two of these, additional oral ciprofloxacin was given. Conclusion: Eradication rates of DPI tobramycin are comparable with those for nebulized tobramycin reported in the literature. This study suggests that DPI tobramycin is an alternative to nebulized tobramycin for eradication of Pa. Trial registration: The Medical Ethics Committee of the UMCG granted a waiver (METC2017-349), as they concluded that this study was not subject to the Medical Research Involving Human Subjects Act. The reviews of this paper are available via the supplemental material section.

Tyrosinemia type 1 (TT1) treatment with 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) and a phenylalanine-tyrosine restricted diet is associated with low phenylalanine concentrations. Phenylalanine supplementation is prescribed without comprehensive consideration about its effect on metabolic control. We investigated the effect of phenylalanine supplementation on bloodspot phenylalanine, tyrosine, NTBC and succinylacetone. Eleven TT1 patients received 0, 20 and 40 mg/kg/day phenylalanine supplementation with the phenylalanine-tyrosine free L-amino acid supplements. Bloodspots were collected before breakfast, midday and evening meal. Differences between study periods, sample times and days within a study period were studied using (generalized) linear mixed model analyses. Twenty and 40 mg/kg/day phenylalanine supplementation prevented daytime phenylalanine decreases (p = 0.05) and most low phenylalanine concentrations, while tyrosine concentrations increased (p &lt, 0.001). Furthermore, NTBC and succinylacetone concentrations did not differ between study periods. To conclude, 20 mg/kg/day phenylalanine supplementation can prevent most low phenylalanine concentrations without increasing tyrosine to concentrations above the target range or influencing NTBC and succinylacetone concentrations, while 40 mg/kg/day increased tyrosine concentrations to values above the targeted range. Additionally, this study showed that the effect of phenylalanine supplementation, and a possible phenylalanine deficiency, should be assessed using pre-midday meal blood samples that could be combined with an overnight fasted sample when in doubt.

Background. Perioperative acute kidney injury (AKI) is an important predictor of long-term all-cause mortality after coronary artery bypass (CABG). However, the effect of AKI on long-term mortality after cardiac valve operations is hitherto undocumented.Methods. Perioperative renal injury and long-term allcause mortality after valve operations were studied in a prospective cohort of patients undergoing solitary valve operations (n = 2,806) or valve operations combined with CABG (n = 1,260) with up to 18 years of follow-up. Postoperative serum creatinine increase was classified according to AKI staging 0 to 3. Patients undergoing solitary CABG (n = 4,938) with cardiopulmonary bypass served as reference.Results. In both valve and valve+CABG operations, postoperative renal injury of AKI stage 1 or higher was progressively associated with an increase in long-term mortality (hazard ratio [HR], 2.27, p Conclusions. An increase in serum creatinine by more than 10% during the first week after valve operation is associated with an increased risk for long-term mortality after cardiac valve operation. Thus, AKI classification clearly underestimates long-term mortality risk in patients undergoing valve operations. (C) 2018 by The Society of Thoracic Surgeons

Background: It has been suggested that antidepressant benefits are smaller for mild than severe depression. Because antidepressants are also used for anxiety disorders, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD), we examined the influence of severity for these disorders.Methods: We used individual patient data of eight trials (3,430 participants) for generalized anxiety disorder (GAD); four trials (1,195 participants) for social anxiety disorder (SAD); four trials (1,132 participants) for OCD; three trials (1,071 participants) for PTSD; and 10 trials (2,151 participants) for panic disorder (PD). Mixed-effects models were used to investigate an interaction between severity and treatment group.Results: For GAD and PD, severity moderated antidepressant efficacy. The antidepressant-placebo difference was 1.4 (95% CI: 0.4-2.5; SMD: 0.21) Hamilton Anxiety Rating Scale (HAM-A) points for participants with mild GAD (baseline HAM-A=10), increasing to 4.0 (3.4-4.6; SMD: 0.45) or greater for severely ill participants (HAM-A >= 30). For PD, the difference was 0.4 (0.3-0.6) panic attacks/2weeks for participants with 10 panic attacks/2weeks at baseline, increasing to 4.7 (3.0-6.4) for participants with 40. For SAD, OCD, and PTSD, no interaction was found. Across severity levels, the differences were 16.1 (12.9-19.3; SMD: 0.59) Liebowitz Social Anxiety Scale points, 3.4 (2.5-4.4, SMD: 0.39) Yale-Brown Obsessive-Compulsive Scale points, and 10.3 (6.9-13.6; SMD: 0.41) Clinician-Administered PTSD Scale points.Conclusions: Antidepressants are equally effective across severity levels for SAD, OCD, and PTSD. For GAD and PD, however, benefits are small at low severity, and the benefit-risk ratio may be unfavorable for these patients.

Introduction In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens. Methods All patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively. Results NTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only (p = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found (p = 0.289). Momentary NTBC concentrations were negatively correlated with SA (p

Purpose: To identify a surrogate marker for late xerostomia 12 months after radiation therapy(Xer12m), according to information obtained shortly after treatment.Methods and Materials: Differences in parotid gland (PG) were quantified in image biomarkers (ΔIBMs) before and 6 weeks after radiation therapy in 107 patients. By performing stepwise forward selection, ΔIBMs that were associated with Xer12m were selected. Subsequently other variables, such as PG dose and acute xerostomia scores, were added to improve the prediction performance. All models were internally validated.Results: Prediction of Xer12m based on PG surface reduction (ΔPG-surface) was good (area under the receiver operating characteristic curve, 0.82). Parotid gland dose was related to ΔPG-surface (PR2 = 0.27). The addition of acute xerostomia scores to the ΔPG-surface improved the prediction of Xer12m significantly, and vice versa. The final model including ΔPG-surface and acute xerostomia had outstanding performance in predicting Xer12m early after radiation therapy (area under the receiver operating characteristic curve, 0.90).Conclusions: Parotid gland surface reduction was associated with late xerostomia. The early posttreatment model with ΔPG-surface and acute xerostomia scores can be considered as a surrogate marker for late xerostomia.

Background Patients with curable esophageal cancer (EC) who proceed beyond the original Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) eligibility criteria are also treated with neoadjuvant chemoradiotherapy (nCRT). This study assessed the effect that extending the CROSS eligibility criteria for nCRT has on treatment-related toxicity and overall survival (OS) in EC. Methods The study enrolled 161 patients with locally advanced EC (T1N1-3/T2-4aN0-3/M0) treated with the CROSS schedule followed by esophagectomy. Group 1 consisted of 89 patients who met the CROSS criteria, and group 2 consisted of 72 patients who met the extended eligibility criteria, i.e. a tumor length greater than 8 cm (n = 24), more than 10% weight loss (n = 35), more than 2–4 cm extension in the stomach (n = 21), celiac lymph node metastasis (n = 13), and/or age over 75 years (n = 2). The study assessed the differences in nCRT-associated toxicity [National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3] and 90-day postoperative mortality. Moreover, the prognostic value for OS was assessed with multivariate Cox regression analysis. Results No difference was found in nCRT-associated toxicity (P = 0.117), postoperative complications (P = 0.783), and 90-day mortality (P = 0.492). The OS differed significantly (P = 0.004), with a median of 37.3 months [95% confidence interval (CI), 10.4–64.2 months] for group 1 and 17.2 months (95% CI 13.8–20.7 months) for group 2. Pathologic N stage (P = 0.023), pathologic T stage (P = 0.043), and group 2 (P = 0.008) were independent prognostic factors for OS. Conclusions Extension of the CROSS study eligibility criteria for nCRT did not affect nCRT-associated toxicity, postoperative complications, and postoperative mortality, but was prognostic for OS. Electronic supplementary material The online version of this article (doi:10.1245/s10434-017-5797-3) contains supplementary material, which is available to authorized users.

Aims The aim of the present study was to evaluate the impact of adverse drug events (ADEs) and treatment satisfaction on antihypertensive medication adherence. Methods A cross-sectional study was conducted in six public hospitals in Ethiopia. We included adult ambulatory patients on antihypertensive medication. Adherence was measured using the eight-point Morisky Medication Adherence Scale, which categorizes as low (0–5), medium (6–7) and high (8) adherence. Treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4, which included questions about ADEs. Data were analysed using generalized ordered logistic regression with 95% confidence intervals (CIs). Results We included 925 out of 968 patients. Overall, 42% of patients scored low, 37% medium and 21% high adherence. Satisfaction with treatment was low, with a mean (standard deviation) TSQM score for global satisfaction of 51 (14). A total of 193 (21%) patients experienced 421 ADEs – mainly dyspeptic symptoms (12%), headache (11%) and cough (11). Experiencing more ADEs reduced the odds of being adherent [low vs. medium/high: odds ratio (OR) OR1 0.77 (95% CI 0.67, 0.89), and low/medium vs. high: OR2 0.55 (05% CI 0.41, 0.73)]. Being more satisfied increased the odds of being adherent [low vs. medium/high: OR1 1.02 (95% CI 1.01, 1.03)]. Taking medication >1 year [OR1 = 2, 0.60 (95% CI 0.43, 0.83)] and taking calcium channel blockers [OR1 = 2 0.71 (95% CI 0.54, 0.92)] decreased the odds for both low vs. medium/high and low/medium vs. high adherence. Conclusions Only one in five patients reported perfect (high) adherence to their antihypertensive treatment regimen. Experiencing ADEs and being dissatisfied with treatment were associated with lower adherence. In addition to addressing treatment satisfaction and drug safety in first-world countries, these should also be addressed in resource-poor settings, within patient consultations, to enhance adherence.

Background Kidney transplantation is associated with harmful processes affecting the viability of the graft. One of these processes is associated with the phenomenon of ischaemia–reperfusion injury. Anaesthetic conditioning is a widely described strategy to attenuate ischaemia–reperfusion injury. We therefore conducted the Volatile Anaesthetic Protection of Renal Transplants-1 trial, a pilot project evaluating the influence of two anaesthetic regimens, propofol- vs sevoflurane-based anaesthesia, on biochemical and clinical outcomes in living donor kidney transplantation. Methods Sixty couples were randomly assigned to the following three groups: PROP (donor and recipient propofol), SEVO (donor and recipient sevoflurane), and PROSE (donor propofol and recipient sevoflurane). The primary outcome was renal injury reflected by urinary biomarkers. The follow-up period was 2 yr. Results Three couples were excluded, leaving 57 couples for analysis. Concentrations of kidney injury molecule-1 (KIM-1), N-acetyl-β-d-glucosaminidase (NAG), and heart-type fatty acid binding protein (H-FABP) in the first urine upon reperfusion showed no differences. On day 2, KIM-1 concentrations were higher in SEVO [952.8 (interquartile range 311.8–1893.0) pg mmol−1] compared with PROP [301.2 (202.0–504.7) pg mmol−1]. This was the same for NAG: SEVO, 1.835 (1.162–2.457) IU mmol−1vs PROP, 1.078 (0.819–1.713) IU mmol−1. Concentrations of H-FABP showed no differences. Measured glomerular filtration rate at 3, 6, and 12 months showed no difference. After 2 yr, there was a difference in the acute rejection rate (P=0.039). Post hoc testing revealed a difference between PROP (35%) and PROSE (5%; P=0.020). The difference between PROP and SEVO (11%) was not significant (P=0.110). Conclusions The SEVO group showed higher urinary KIM-1 and NAG concentrations in living donor kidney transplantation on the second day after transplantation. This was not reflected in inferior graft outcome. Clinical trial registration NCT01248871.

Purpose A relationship between mean heart dose (MHD) and acute coronary event (ACE) rate was reported in a study of patients with breast cancer (BC). The main objective of our cohort study was to validate this relationship and investigate if other dose-distribution parameters are better predictors for ACEs than MHD. Patients and Methods The cohort consisted of 910 consecutive female patients with BC treated with radiotherapy (RT) after breast-conserving surgery. The primary end point was cumulative incidence of ACEs within 9 years of follow-up. Both MHD and various dose-distribution parameters of the cardiac substructures were collected from three-dimensional computed tomography planning data. Results The median MHD was 2.37 Gy (range, 0.51 to 15.25 Gy). The median follow-up time was 7.6 years (range, 0.1 to 10.1 years), during which 30 patients experienced an ACE. The cumulative incidence of ACE increased by 16.5% per Gy (95% CI, 0.6 to 35.0; P = .042). Analysis showed that the volume of the left ventricle receiving 5 Gy (LV-V5) was the most important prognostic dose-volume parameter. The most optimal multivariable normal tissue complication probability model for ACEs consisted of LV-V5, age, and weighted ACE risk score per patient (c-statistic, 0.83; 95% CI, 0.75 to 0.91). Conclusion A significant dose-effect relationship was found for ACEs within 9 years after RT. Using MHD, the relative increase per Gy was similar to that reported in the previous study. In addition, LV-V5 seemed to be a better predictor for ACEs than MHD. This study confirms the importance of reducing exposure of the heart to radiation to avoid excess risk of ACEs after radiotherapy for BC.