Cholestasis and meconium ileus in infants with cystic fibrosis and their clinical outcomes

Objective To identify the incidence and outcomes of cholestasis and meconium ileus (MI) in infants with cystic fibrosis (CF). Design Retrospective cohort study. Setting Single-centre study. Patients From January 1986 to December 2011, 401 infants with CF (69 with MI) presented to our centre. Main outcome measurements (1) incidence of cholestasis, (2) identification of risk factors for cholestasis, (3) association between the presence of cholestasis and MI and the development of clinically significant CF-associated liver disease (CFLD) defined as multilobular cirrhosis with portal hypertension. Results Cholestasis occurred in 23 of 401 infants (5.7%). There was a significantly higher incidence of cholestasis in infants with MI (27.1%) compared to those without MI (1.2%) (p Conclusions Cholestasis is an uncommon condition in CF affecting only 5.7% of the screened newborn CF population. The greatest risk factor for developing cholestasis is the presence of MI. However, the presence of MI appears not to be associated with the development of CFLD. An effect of neonatal cholestasis on the development of CFLD cannot be excluded by this study

Risk factors of impaired neuropsychological outcome in school-aged survivors of neonatal critical illness

__Objective__ Until now, long-term outcome studies have focused on general cognitive functioning and its risk factors following neonatal extracorporeal membrane oxygenation (ECMO) and/or congenital diaphragmatic hernia (CDH). However, it is currently unknown which neuropsychological domains are most affected in these patients, and which clinical variables can be used to predict specific neuropsychological problems. This study aimed to identify affected neuropsychological domains and its clinical determinants in survivors of neonatal ECMO and/or CDH. __Design__ Prospective follow-up study. __Setting__ Tertiary university hospital. __Patients__ Sixty-five eight-year-old survivors of neonatal ECMO and/or CDH. __Interventions__ None. __Measurements and Main Results__ Intelligence, attention, memory, executive functioning and visuospatial processing were evaluated

Nationwide Evaluation of Congenital Hypothyroidism Screening during Neonatal Extracorporeal Membrane Oxygenation

Background: Thyroid hormone concentrations may deviate from normal values during critical illness. This condition is known as nonthyroidal illness syndrome (NTIS), and it can influence the results of screening for congenital hypothyroidism (CH) during neonatal extracorporeal membrane oxygenation (ECMO). Objectives: To determine the incidence of aberrant CH screening results in ECMO-treated neonates, to identify possible determinants, and to follow up patients with abnormal thyroid hormone concentrations. Methods: In this retrospective cohort study, we included 168 ECMO-treated neonates admitted from 2004 to 2014 and screened by protocol and divided them into the following 3 groups: group 1 (screened during ECMO, n = 107), group 2 (screened shortly before ECMO, n = 26), and group 3 (screened shortly after ECMO, n = 35). Results: CH screening results were aberrant in 67.3% (72/107) of the neonates screened during ECMO, in 73.1% (19/26) of the neonates screened before ECMO, and in 31.4% (11/35) of the neonates screened after ECMO (p < 0.001). Of the neonates with an aberrant screening result, all but 2 (i.e. 98%) had a low thyroxine concentration with a normal thyrotropin concentration at screening, as is seen in NTIS. None was diagnosed with CH. Mortality did not significantly differ between neonates with an aberrant screening result (32.4%) and neonates with a normal screening result (22.7%; p = 0.18). Screening before ECMO (OR 5.92; 95% CI 1.93-18.20), screening during ECMO (OR 4.49; 95% CI 1.98-10.19), and a higher Pediatric Logistic Organ Dysfunction-2 score (OR 1.31; 95% CI 1.04-1.66) were associated with an aberrant screening result. Conclusions: Aberrant CH screening results were found in most ECMO-treated neonates screened before or during ECMO, which is likely due to NTIS. Follow-up of thyroid hormone concentrations is best started after recovery from critical illness. Our results suggest that thyroxine therapy is not required during ECMO

Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation

Loss of neurons in neurodegenerative diseases is usually preceded by the accumulation of protein deposits that contain components of the ubiquitin/proteasome system. Affected neurons in Alzheimer's disease often accumulate UBB+1, a mutant ubiquitin carrying a 19–amino acid C-terminal extension generated by a transcriptional dinucleotide deletion. Here we show that UBB+1 is a potent inhibitor of ubiquitin-dependent proteolysis in neuronal cells, and that this inhibitory activity correlates with induction of cell cycle arrest. Surprisingly, UBB+1 is recognized as a ubiquitin fusion degradation (UFD) proteasome substrate and ubiquitinated at Lys29 and Lys48. Full blockade of proteolysis requires both ubiquitination sites. Moreover, the inhibitory effect was enhanced by the introduction of multiple UFD signals. Our findings suggest that the inhibitory activity of UBB+1 may be an important determinant of neurotoxicity and contribute to an environment that favors the accumulation of misfolded proteins

The development of a Self-Rated ICF-based questionnaire (HEAR-COMMAND Tool) to evaluate Hearing, Communication, and Conversation disability: Multinational experts’ and patients’ perspectives

ObjectiveAn instrument that facilitates the advancement of hearing healthcare delivery from a biomedical model to a biopsychosocial one that underpins the International Classification of Functioning, Disability, and Health framework (ICF) brief and comprehensive Core Sets for Hearing Loss (CSHL) is currently unavailable. The objective is to describe the process of developing and validating a new questionnaire named the HEAR-COMMAND Tool created by transferring the ICF CSHL into a theory-supported, practically manageable concept.DesignA team from Germany, the USA, the Netherlands, and Egypt collaborated on development. The following ICF domains were considered; “Body Functions” (BF), “Activities and Participation” (AP), and “Environmental Factors” (EF). The development yielded English, German, and Arabic versions. A pilot validation study with a total of 109 respondents across three countries, Germany, Egypt, and the USA was conducted to revise the item terminology according to the feedback provided by the respondents.ResultsThe questionnaire included a total of 120 items. Ninety items were designed to collect information on the functioning and 30 items inquiring about demographic information, hearing status, and Personal Factors. Except for the “Body Structures” (BS) domain, all the categories of the brief ICF CSHL were covered (a total of 85% of the categories). Moreover, the items covered 44% of the comprehensive ICF CSHL categories including 73% of BF, 55% of AP, and 27% of EF domains. Overall, the terminology of 24 ICF-based items was revised based on the qualitative analysis of the respondents' feedback to further clarify the items that were found tod be unclear or misleading. The tool highlighted the broad connection of HL with bodily health and contextual factors.ConclusionsThe HEAR-COMMAND Tool was developed based on the ICF CSHL and from multinational experts' and patients' perspectives with the aim to improve the execution of audiological services, treatment, and rehabilitation for adult patients with HL. Additional validation of the tool is ongoing. The next step would be to pair the tool with BS categories since it was excluded from the tool and determine its effectiveness in guiding hearing health care practitioners to holistically classify categories influencing hearing, communication, and conversation disability

The Risk of QTc-Interval Prolongation in Breast Cancer Patients Treated with Tamoxifen in Combination with Serotonin Reuptake Inhibitors

Purpose: Antidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval. Methods: Electrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI. Results: The mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8–23.1 ms; P = 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4–33.0 ms; P = 0.04), escitalopram (12.5 ms; 95%CI:4.4–20.6 ms; P 500 ms. Conclusions: Concomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred

Homocysteine levels and the risk of osteoporotic fracture

BACKGROUND: Very high plasma homocysteine levels are characteristic of homocystinuria, a rare autosomal recessive disease accompanied by the early onset of generalized osteoporosis. We therefore hypothesized that mildly elevated homocysteine levels might be related to age-related osteoporotic fractures. METHODS: We studied the association between circulating homocysteine levels and the risk of incident osteoporotic fracture in 2406 subjects, 55 years of age or older, who participated in two separate prospective, population-based studies. In the Rotterdam Study, there were two independent cohorts: 562 subjects in cohort 1, with a mean follow-up period of 8.1 years; and 553 subjects in cohort 2, with a mean follow-up period of 5.7 years. In the Longitudinal Aging Study Amsterdam, there was a single cohort of 1291 subjects, with a mean follow-up period of 2.7 years. Multivariate Cox proportional-hazards regression mode

Prevalence of neoplasia at colonoscopy among testicular cancer survivors treated with platinum-based chemotherapy

Testicular cancer survivors (TCS) treated with platinum-based chemotherapy have an increased risk of colorectal cancer (CRC). We determined the yield of colonoscopy in TCS to assess its potential in reducing CRC incidence and mortality. We conducted a colonoscopy screening study among TCS in four Dutch hospitals to assess the yield of colorectal neoplasia. Neoplasia was defined as adenomas, serrated polyps (SPs), advanced adenomas (AAs: ≥10 mm diameter, high-grade dysplasia or ≥25% villous component), advanced serrated polyps (ASPs: ≥10 mm diameter or dysplasia) or CRC. Advanced neoplasia (AN) was defined as AA, ASP or CRC. Colonoscopy yield was compared to average-risk American males who underwent screening colonoscopy (n = 24,193) using a propensity score matched analysis, adjusted for age, smoking status, alcohol consumption and body mass index. A total of 137 TCS underwent colonoscopy. Median age was 50 years among TCS (IQR 43–57) vs 55 years (IQR 51–62) among American controls. A total of 126 TCS were matched to 602 controls. The prevalence of AN was higher in TCS than in controls (8.7% vs 1.7%; P =.0002). Nonadvanced adenomas and SPs were detected in 45.2% of TCS vs 5.5% of controls (P &lt;.0001). No lesions were detected in 46.0% of TCS vs 92.9% of controls (P &lt;.0001). TCS treated with platinum-based chemotherapy have a higher prevalence of neoplasia and AN than matched controls. These results support our hypothesis that platinum-based chemotherapy increases the risk of colorectal neoplasia in TCS. Cost-effectiveness studies are warranted to ascertain the threshold of AN prevalence that justifies the recommendation of colonoscopy for TCS.</p

Diagnostic yield of colonoscopy surveillance in testicular cancer survivors treated with platinum-based chemotherapy: study protocol of a prospective cross-sectional cohort study

Background: Testicular cancer (TC) survivors have an increased risk of various second primary malignancies. A recent cohort study detected an increased risk of colorectal cancer (CRC) in TC survivors treated with platinum-based chemotherapy with a hazard ratio of 3.9. CRC risk increased with higher cisplatin-dose. We know that colonoscopy surveillance in high-risk populations results in reduced incidence and mortality of CRC. TC survivors treated with platinum-based chemotherapy can potentially benefit from colonoscopy surveillance; however, to which extent is unknown. Furthermore, the pathogenesis of these secondary CRCs is unknown, and better insights into the carcinogenesis may affect surveillance decisions. Methods: This prospective multicenter study will be performed in four Dutch hospitals. TC survivors are eligible if treated with ≥ 3 cycles of cisplatin before age 50. Colonoscopy will be performed ≥ 8 years after initial treatment (minimum and maximum ages at colonoscopy, 35 and 75 years, respectively). The primary aim of the study is the diagnostic yield of advanced neoplasia detected during colonoscopy. As secondary aim, we will evaluate the molecular profile of advanced colorectal neoplasia and will assess current platinum levels in blood and urine and correlate blood-platinum levels with prevalence of colorectal lesions. Furthermore, we will investigate effectiveness of fecal immunochemical testing (FIT) and burden of colonoscopy by two questionnaires. Demographic data, previous history, results of colonoscopy, hemoglobin level of FIT and results of molecular and platinum levels will be obtained. Yield of colonoscopy will be determined by detection rate of adenoma and serrated lesions, advanced adenoma detection rate and CRC detection rate. The MISCAN model will be used for cost-effectiveness analyses of CRC surveillance. With 234 participants undergoing colonoscopy, we can detect an absolute difference of 6% of advanced neoplasia with 80% power. Discussion: TC survivors treated with cisplatin-based chemotherapy can benefit from CRC surveillance. Evaluation of the diagnostic performance and patient acceptance of CRC surveillance is of importance to develop surveillance recommendations. Insight into the carcinogenesis of cisplatin-related advanced colorectal lesions will contribute to CRC prevention in the increasing number of TC survivors. The results may also be important for the many other cancer survivors treated with platinum-based chemotherapy. Trial registration: Clinical Trials: NCT04180033, November 27, 2019, https://clinicaltrials.gov/ct2/sh