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Prader-Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues, especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.

Phylogenetic networks represent evolutionary histories of sets of taxa where horizontal evolution or hybridization has occurred. Placing a Markov model of evolution on a phylogenetic network gives a model that is particularly amenable to algebraic study by representing it as an algebraic variety. In this paper, we give a formula for the dimension of the variety corresponding to a triangle-free level-1 phylogenetic network under a group-based evolutionary model. On our way to this, we give a dimension formula for codimension zero toric fiber products. We conclude by illustrating applications to identifiability., (© 2024. The Author(s).)

Introduction: Manufacturer-supported didactic teaching programmes offer effective automated insulin delivery (AID) systems onboarding in children and young people (CYP) with type 1 diabetes (T1D). However, this approach has limited flexibility to accommodate the needs of families requiring additional support., Research Design and Methods: Evaluate the efficacy of an inperson manufacturer-supported didactic teaching programme (Group A), in comparison to a flexible flipped learning approach delivered virtually or inperson (Group B). Retrospective analysis of CYP with T1D using continuous glucose monitoring (CGM), who were initiated on AID systems between 2021 and 2023. Compare CGM metrics from baseline to 90 days for both groups A and B. Additionally, compare the two groups for change in CGM metrics over the 90-day period (∆), patient demographics and onboarding time., Results: Group A consisted of 74 CYP (53% male) with median age of 13.9 years and Group B 91 CYP (54% male) with median age of 12.7 years. From baseline to 90 days, Group A lowered mean (±SD) time above range (TAR, >10.0 mmol/L) from 47.6% (±15.0) to 33.2% (±15.0) (p<0.001), increased time in range (TIR, 3.9-10.0 mmol/L) from 50.4% (±14.0) to 64.7% (±10.2) (p<0.001). From baseline to 90 days, Group B lowered TAR from 51.3% (±15.1) to 34.5% (±11.3) (p<0.001) and increased TIR from 46.5% (±14.5) to 63.7% (±11.0) (p<0.001). There was no difference from baseline to 90 days for time below range (TBR, <3.9 mmol/L) for Group A and Group B. ∆ TAR, TIR and TBR for both groups were comparable. Group B consisted of CYP with higher socioeconomic deprivation, greater ethnic diversity and lower carer education achievement (p<0.05). The majority of Group B (n=79, 87%) chose virtual flipped learning, halving diabetes educator time and increasing onboarding cadence by fivefold., Conclusions: A flexible virtual flipped learning programme increases onboarding cadence and capacity to offer equitable AID system onboarding., Competing Interests: Competing interests: JP: Advisory Board for ROHCE and speaker payments for Dexcom., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Quantifying differences in service provision for children and young people (CYP) living with Congenital Adrenal Hyperplasia (CAH) across the United Kingdom., Methods: A national service evaluation using online questionnaires circulated to patients and clinicians from secondary and tertiary UK centres managing CYP with CAH, and via the "Living with CAH" support group mailing list., Results: Total of 195 responses relating to patients aged 0-20 years attending 33 clinics (43 patients, 152 carers), as well as 34 clinicians from 18 trusts working across the 33 clinics. Only 12% of clinicians were 'completely satisfied' with the service provided, compared to 68% of carers and 76% of patients. Whilst 94% of clinicians reported providing formal training to families with CAH, over 80% of both patients and carers reported not attending what they considered formal training. Appetite for further training was higher in carers (86%) than patients (55%), although further 'unsure' responses suggested formal training sessions would likely be well attended. Access to psychological services was difficult for 44% of clinicians. Biochemical monitoring of treatment was broadly in keeping with international guidelines, with 67% of clinicians reporting regular use of dried blood spots, and 12% regular urinary steroid metabolites., Conclusion: While there is overall good satisfaction with care provision among patients and carers with CAH in the UK, extra resources addressing the psychological and educational needs about the disease and its management would benefit patients and carers. Improved access to allied health professionals and psychologists will help support families and improve patient outcomes., (S. Karger AG, Basel.)

Background: Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs) and anti-angiogenics, are first-line therapies for advanced and metastatic hepatocellular carcinoma. Although TKIs have a greater potential for off-target adverse effects compared with bevacizumab (anti-angiogenics), a direct comparison of the risk of cardiovascular adverse events between these two types of therapies has not been performed., Objective: To compare the incidence of and characterize cardiovascular adverse events in patients with hepatocellular carcinoma receiving TKIs versus bevacizumab., Methods: This cohort study included adult patients with hepatocellular carcinoma who received first-line TKIs (sorafenib or lenvatinib) or bevacizumab at two academic medical centers and one community cancer center from September 2018 to August 2021. The primary outcome was risk of cardiovascular adverse events. Major secondary outcomes included the incidence of individual types of cardiovascular adverse events and risk factors associated with major adverse cardiovascular events (MACE)., Results: The study included 221 patients (159 TKI patients; 62 bevacizumab patients). At a median follow-up of 5 months, the probability of cardiovascular adverse events was not significantly different between the two groups (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.58-1.24; p = 0.390). The cumulative incidence of cardiovascular events was highest in patients receiving lenvatinib (sub-distribution hazard ratio [SHR]: 1.53; 95% CI: 1.02-2.30) compared with those receiving sorafenib (reference) or bevacizumab (SHR: 1.05; 95% CI: 0.68-1.64) after adjustment for comorbidities, liver transplant status, and presence of portal vein thrombosis at baseline. Cardiovascular adverse events were observed in 151 (68%) patients, and MACE were observed in 27 (12%) patients. Risk factors associated with MACE were hypertension (SHR: 3.5; 95% CI: 0.9087-15.83; p = 0.086), prior history of MACE (SHR: 2.01; 95% CI: 0.83-4.87; p = 0.124), and tobacco use (SHR: 2.85; 95% CI: 0.90-8.97; p = 0.074)., Conclusions: Cardiovascular risk was not significantly different between TKIs and bevacizumab. Lenvatinib appears to have the highest risk of cardiovascular adverse events among these first-line VEGF inhibitors., (© 2023 Pharmacotherapy Publications, Inc.)

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) leads to impaired glucocorticoid and mineralocorticoid synthesis with excess production of androgens. Replication of the normal circadian cortisol secretion is challenging and supraphysiological doses of glucocorticoids are often required. Most patients experience transient episodes of hyper- and hypocortisolaemia during the day leading to adverse metabolic outcomes such as insulin resistance, visceral adiposity, and cardiovascular morbidity, including hypertension. These health problems are commonly diagnosed in adolescence and adulthood., Summary: Herein, we review the published data on the variation in blood pressure in CAH due to 21OHD and the interrelation with disease and treatment factors., Key Messages: Hypertension in childhood is a well-known risk factor for poor cardiovascular health in later life. Children with CAH have a higher prevalence of hypertension, which is more commonly transient. The prevalence is higher at younger ages, while relatively fewer patients remain hypertensive in adolescence, requiring antihypertensive treatment. Most studies suggest, transient hypertension in early childhood is associated with mineralocorticoid replacement; however, its direct association with adverse cardiovascular and metabolic outcome is not well established. There is insufficient evidence to support a relationship between hypertension and either glucocorticoid dose or salt supplementation in infancy. Androgen excess has been suggested as a possible reason for the absence of gender dimorphism in the incidence of hypertension and cardiovascular risks in CAH. There is no conclusive evidence for a direct association between hypertension and hyperandrogenism or insulin resistance. Increased carotid intima media thickness is commonly found in children with CAH and is thought to be driven by increased blood pressure., (© 2023 S. Karger AG, Basel.)

Sulfate assimilation is an essential pathway of plant primary metabolism, regulated by the demand for reduced sulfur (S). The S-containing tripeptide glutathione (GSH) is the key signal for such regulation in Arabidopsis, but little is known about the conservation of these regulatory mechanisms beyond this model species. Using two model monocot species, C3 rice (Oryza sativa) and C4Setaria viridis, and feeding of cysteine or GSH, we aimed to find out how conserved are the regulatory mechanisms described for Arabidopsis in these species. We showed that while in principle the regulation is similar, there are many species-specific differences. For example, thiols supplied by the roots are translocated to the shoots in rice but remain in the roots of Setaria. Cysteine and GSH concentrations are highly correlated in Setaria, but not in rice. In both rice and Setaria, GSH seems to be the signal for demand-driven regulation of sulfate assimilation. Unexpectedly, we observed cysteine oxidation to sulfate in both species, a reaction that does not occur in Arabidopsis. This reaction is dependent on sulfite oxidase, but the enzyme(s) releasing sulfite from cysteine still need to be identified. Altogether our data reveal a number of unique features in the regulation of S metabolism in the monocot species and indicate the need for using multiple taxonomically distinct models to better understand the control of nutrient homeostasis, which is important for generating low-input crop varieties., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Compare the clinical and cost-effectiveness of an established face to face (F2F) structured education program to a new remote (VIRTUAL) program teaching dynamic glucose management (DynamicGM) to children and young people with type 1 diabetes (CYPD) using continuous glucose monitoring (CGM). To ascertain the most effective DynamicGM strategies predicting time in range (TIR) (3.9-10.0 mmol/L) and incorporating these into a user-friendly teaching aid., Design and Methods: Effectiveness of the F2F and VIRTUAL programs were ascertained by comparing the mean change (Δ) from baseline to 6 months in HbA1c, TIR and severe hypoglycemia. Delivery cost for the two programs were evaluated. Factors predicting TIR in the combined cohort were determined and incorporated into a user-friendly infographic., Results: First 50 graduates per group were evaluated. The mean difference in Δ HbA1c, Δ TIR and Δ episodes of severe hypoglycemia between VIRTUAL and F2F groups were 1.16 (p = 0.47), 0.76 (p = 0.78) and -0.06 (p = 0.61) respectively. Delivery cost per 50 CYPD for VIRTUAL and F2F were $5752 and $7020, respectively. The strongest predictors of TIR (n = 100) were short bursts of exercise (10-40 min) to lower hyperglycemia (p < 0.001), using trend arrow adjustment tools (p < 0.001) and adjusting pre-meal bolus timing based on trend arrows (p < 0.01). These strategies were translated into a GAME (Stop highs), SET (Stay in target), MATCH (Prevent lows) mnemonic., Conclusion: Teaching DynamicGM VIRTUALLY is just as effective as F2F delivery and cost saving. Short bursts of exercise and using CGM trend arrows to adjust insulin dose and timing improves TIR., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: There is a growing body of evidence to support tears as a non-traditional biological fluid in clinical laboratory testing. In addition to the simplicity of tear fluid processing, the ability to access key cancer biomarkers in high concentrations quickly and inexpensively is significantly enhanced. Tear fluid is a dynamic environment rich in both proteomic and genomic information, making it an ideal medium for exploring the potential for biological testing modalities., Methods: All protocols involving human subjects were reviewed and approved by the University of Arkansas IRB committee (13-11-289) prior to sample collection. Study enrollment was open to women ages 18 and over from October 30, 2017-June 19, 2019 at The Breast Center, Fayetteville, AR and Bentonville, AR. Convenience sampling was used and samples were age/sex matched, with enrollment open to individuals at any point of the breast health continuum of care. Tear samples were collected using the Schirmer strip method from 847 women. Concentration of selected tear proteins were evaluated using standard sandwich ELISA techniques and the resulting data, combined with demographic and clinical covariates, was analyzed using logistic regression analysis to build a model for classification of samples., Results: Logistic regression analysis produced three models, which were then evaluated on cases and controls at two diagnostic thresholds and resulted in sensitivity ranging from 52 to 90% and specificity from 31 to 79%. Sensitivity and specificity variation is dependent on the model being evaluated as well as the selected diagnostic threshold providing avenues for assay optimization., Conclusions and Relevance: The work presented here builds on previous studies focused on biomarker identification in tear samples. Here we show successful early classification of samples using two proteins and minimal clinical covariates., (© 2022. The Author(s).)

Over the last years, the development of offshore renewable energy installations such as offshore wind farms led to an increasing number of man-made structures in marine environments. Since 2009, benthic impact monitoring programs were carried out in wind farms installed in the southern North Sea. We collated and analyzed data sets from three major monitoring programs. Our analysis considered a total of 2849 sampling points converted to a set of biodiversity response metrics. We analyzed biodiversity changes related to the implementation of offshore wind farms and generalized the correlation of these changes with spatial and temporal patterns. Our results demonstrate that depth, season and distance to structure (soft-bottom community) consistently determined diversity indicators and abundance parameters, whereas the age and the country affiliation were significantly related to some but not all indices. The water depth was the most important structuring factor for fouling communities while seasonal effects were driving most of the observed changes in soft-sediment communities. We demonstrate that a meta-analysis can provide an improved level of understanding of ecological patterns on large-scale effects of anthropogenic structures on marine biodiversity, which were not visible in single monitoring studies. We believe that meta-analyses should become an indispensable tool for management of offshore wind farm effects in the future, particularly in the view of the foreseen development of offshore renewable energies. This might lead to a better picture and more comprehensive view on potential alterations. However, this requires a modern open-source data policy and data management, across institutions and across national borders., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sphingosine-1-phosphate lyase (SGPL1) insufficiency syndrome (SPLIS) is an autosomal recessive multi-system disorder, which mainly incorporates steroid-resistant nephrotic syndrome and primary adrenal insufficiency. Other variable endocrine manifestations are described. In this study, we aimed to comprehensively annotate the endocrinopathies associated with pathogenic SGPL1 variants and assess for genotype-phenotype correlations by retrospectively reviewing the reports of endocrine disease within our patient cohort and all published cases in the wider literature up to February 2022. Glucocorticoid insufficiency in early childhood is the most common endocrine manifestation affecting 64% of the 50 patients reported with SPLIS, and a third of these individuals have additional mineralocorticoid deficiency. While most individuals also have nephrotic syndrome, SGPL1 variants also account for isolated adrenal insufficiency at presentation. Primary gonadal insufficiency, manifesting with microphallus and cryptorchidism, is reported in less than one-third of affected boys, all with concomitant adrenal disease. Mild primary hypothyroidism affects approximately a third of patients. There is paucity of data on the impact of SGPL1 deficiency on growth, and pubertal development, limited by the early and high mortality rate (approximately 50%). There is no clear genotype-phenotype correlation overall in the syndrome, with variable disease penetrance within individual kindreds. However, with regards to endocrine phenotype, the most prevalent disease variant p.R222Q (affecting 22%) is most consistently associated with isolated glucocorticoid deficiency. To conclude, SPLIS is associated with significant multiple endocrine disorders. While endocrinopathy in the syndrome generally presents in infancy, late-onset disease also occurs. Screening for these is therefore warranted both at diagnosis and through follow-up.

Climate change combined with anthropogenic stressors (e.g. overfishing, habitat destruction) may have particularly strong effects on threatened populations of coastal invertebrates. The collapse of the population of European lobster ( Homarus gammarus ) around Helgoland constitutes a good example and prompted a large-scale restocking program. The question arises if recruitment of remaining natural individuals and program-released specimens could be stunted by ongoing climate change. We examined the joint effect of ocean warming and acidification on survival, development, morphology, energy metabolism and enzymatic antioxidant activity of the larval stages of the European lobster. Larvae from four independent hatches were reared from stage I to III under a gradient of 10 seawater temperatures (13-24°C) combined with moderate (∼470 µatm) and elevated (∼1160 µatm) seawater p CO 2 treatments. Those treatments correspond to the shared socio-economic pathways (SSP), SSP1-2.6 and SSP5-8.5 (i.e. the low and the very high greenhouse gas emissions respectively) projected for 2100 by the Intergovernmental Panel on Climate Change. Larvae under the elevated p CO 2 treatment had not only lower survival rates, but also significantly smaller rostrum length. However, temperature was the main driver of energy demands with increased oxygen consumption rates and elemental C:N ratio towards warmer temperatures, with a reducing effect on development time. Using this large temperature gradient, we provide a more precise insight on the aerobic thermal window trade-offs of lobster larvae and whether exposure to the worst hypercapnia scenario may narrow it. This may have repercussions on the recruitment of the remaining natural and program-released specimens and thus, in the enhancement success of future lobster stocks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Leiva, Tremblay, Torres, Boersma, Krone and Giménez.)

Offshore human activities lead to increasing amounts of underwater noise in coastal and shelf environments, which may affect commercially-important benthic invertebrate groups like the re-stocked Helgoland European lobster (Homarus gammarus) in the German Bight (North Sea). It is crucial to understand the impact tonal low-frequency noises, like maritime transport and offshore energy operations, may have on substrate choice and lobsters' behavior to assess potential benefits or bottlenecks of new hard-substrate artificial offshore environments that become available. In this study, we investigated the full factorial effect of a tonal low-frequency noise and predator presence on young-of-year (YOY) European lobsters' in a diurnal and nocturnal experiment. Rocks and European oyster shells (Ostrea edulis) were offered as substrate to YOY lobsters for 3 h. Video recordings (n = 134) allowed the identification of lobsters' initial substrate choice, diel activity and key behaviors (peeking, shelter construction, exploration and hiding). To ensure independence, YOY lobsters in the intermolt stage were randomly selected and assigned to the experimental tanks and used only once. We provide the first evidence that stressors alone, and in combination, constrain YOY lobsters' initial substrate choice towards rocks. During nighttime, the joint effect of exposure to a constant low-frequency noise and predator presence decreased antipredator behavior (i.e., hiding) and increased exploration behavior. Noise may thus interfere with YOY lobsters' attention and decision-making processes. This outcome pinpoints that added tonal low-frequency noise in the environment have the potential to influence the behavior of early-life stages of European lobsters under predator pressure and highlights the importance of including key benthic invertebrates' community relationships in anthropogenic noise risk assessments. Among others, effects of noise must be taken into consideration in plans involving the multi-use of any offshore area for decapods' stock enhancement, aquaculture, and temporary no-take zones., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To determine trends in clinical practice for individuals with DSD requiring gonadectomy., Design: Retrospective cohort study., Methods: Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019., Results: Data regarding gonadectomy were available in 668 (88%) individuals from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), respectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries., Conclusions: The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.

Objectives: Create and evaluate the effectiveness of a structured education program in children and young people (CYP) with type 1 diabetes using continuous glucose monitoring (CGM)., Design and Methods: Step 1: CGM devices were evaluated for predetermined criteria using a composite score. Step 2: The education program was developed following review of international structured education guidance, dynamic glucose management (DynamicGM) literature, award-winning diabetes educators' websites, and CGM user feedback. Step 3: Program effectiveness was assessed at six months by change in time below range (TBR) (<3.9mmol/L), time in range (TIR) (3.9-10.0mmol/L), time above range level 2 (TAR2) (>13.9mmol/L), severe hypoglycemia and HbA1c using a paired T-test. A DynamicGM score was developed to assess proactive glucose management. Factors predicting TBR and TIR were assessed using regression analysis., Results: Dexcom G6 was chosen for integrated CGM (iCGM) status and highest composite score (29/30). Progressive DynamicGM strategies were taught through five sessions delivered over two months. Fifty CYP (23 male) with a mean (±SD) age and diabetes duration of 10.2 (±4.8) and 5.2 (±3.7) years respectively, who completed the education program were prospectively evaluated. Evaluation at six months showed a significant reduction in TBR (10.4% to 2.1%, p<.001), TAR2 (14.1% to 7.3%, p<.001), HbA1c [7.4 to 7.1% (57.7 to 53.8 mmol/mol), p<.001] and severe hypoglycemic episodes (10 to 1, p<.05); TIR increased (47.4% to 57.0%, p<.001). Number of Dexcom followers (p<.05) predicted reduction in TBR and DynamicGM score (p<.001) predicted increased TIR., Conclusion: Teaching DynamicGM strategies successfully improves TIR and reduces hypoglycemia., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear., Methods: Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC., Results: A total of 518 children-with a median of 11 children (range 1, 53) per center-had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P < 0.001), respectively, and the median AC per patient-year was 0 (0, 2.2) vs 0 (0, 3.0) (P = 0.43), respectively., Conclusions: The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency-related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In this article international trends in surgical practice in girls with congenital adrenal hyperplasia (CAH) are evaluated. All cases that had been classified in the I-CAH/I-DSD registry as 46,XX CAH and who were born prior to 2017 were identified. Centers were approached to obtain information on surgical decision making. Of the 330 included participants, 208 (63.0%) presented within the first month of life, and 326 (98.8%) cases were assigned female. Genital surgery had been performed in 250 (75.8%). A total of 64.3, 89.2, and 96.8% of cases residing in Europe, South America and Asia, respectively, had at least one surgery. In a logistic regression model for the probability of surgery before the second birthday (early surgery) over time an increase of probability for early vaginal surgery could be identified, but not for clitoral surgery or both surgeries combined. Genitoplasty in girls with CAH remains controversial. This large international study provides a snapshot of current practice and reveals geographical and temporal differences. Fewer surgeries were reported for Europe, and there seems to be a significant trend towards aiming for vaginal surgery within the first 2 years of life., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis., (Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Context: No consensus exists for optimization of mineralocorticoid therapy in patients with primary adrenal insufficiency., Objective: To explore the relationship between mineralocorticoid (MC) replacement dose, plasma renin concentration (PRC), and clinically important variables to determine which are most helpful in guiding MC dose titration in primary adrenal insufficiency., Design: Observational, retrospective, longitudinal analysis., Patients: A total of 280 patients (with 984 clinical visits and plasma renin measurements) with primary adrenal insufficiency were recruited from local databases and the international congenital adrenal hyperplasia (CAH) registry (www.i-cah.org). Thirty-seven patients were excluded from the final analysis due to incomplete assessment. Data from 204 patients with salt-wasting CAH (149 adults and 55 children) and 39 adult patients with Addison disease (AD) were analysed., Main Outcome Measures: PRC, electrolytes, blood pressure (BP), and anthropometric parameters were used to predict their utility in optimizing MC replacement dose., Results: PRC was low, normal, or high in 19%, 36%, and 44% of patients, respectively, with wide variability in MC dose and PRC. Univariate analysis demonstrated a direct positive relationship between MC dose and PRC in adults and children. There was no relationship between MC dose and BP in adults, while BP increased with increasing MC dose in children. Using multiple regression modeling, sodium was the only measurement that predicted PRC in adults. Longitudinally, the change in MC dose was able to predict potassium, but not BP or PRC., Conclusions: The relationship between MC dose and PRC is complex and this may reflect variability in sampling with respect to posture, timing of last MC dose, adherence, and concomitant medications. Our data suggest that MC titration should not primarily be based only on PRC normalization, but also on clinical parameters such as BP and electrolyte concentration., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Monitoring of hormonal control represents a key part of the management of congenital adrenal hyperplasia (CAH). Monitoring strategies remain suboptimal because they rely on frequent blood tests and are not specific for adrenal-derived hormones. Recent evidence suggests the crucial role of adrenal-specific 11-oxygenated-C19 androgens in the pathogenesis of CAH., Objective: To establish a correlation between plasma and salivary adrenal-specific androgens in CAH as a noninvasive monitoring strategy., Design: This prospective cross-sectional study recruited patients between 2015 and 2018., Setting: Multicenter study including 13 tertiary centers in the United Kingdom., Participants: Seventy-eight children with CAH and 62 matched healthy controls., Methods: Using liquid chromatography-tandem mass spectrometry, plasma and salivary concentrations of five steroids were measured: 17-hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11-hydroxyandrostenedione (11OHA4), and 11-ketotestosterone (11KT). The correlation between plasma and salivary steroids was analyzed to assess their use in clinical practice., Results: Strong correlations between plasma and salivary steroid concentrations in patients with CAH were detected: 17OHP (rs = 0.871; P < 0.001), A4 (rs = 0.931; P < 0.001), T (rs = 0.867; P < 0.001), 11OH4A (rs = 0.876; P < 0.001), and 11KT (rs = 0.944; P < 0.001). These results were consistent for patient subgroups based on sex and age. Analysis of patient subgroups based on 17OHP concentrations established clear correlations between plasma and salivary concentrations of the adrenal-specific androgen 11KT., Conclusions: The current study identified tight correlations between plasma and saliva for the adrenal-derived 11-oxygenated C19 androgen 11KT, as well as 17OHP and A4, which are widely used for monitoring treatment in CAH. This combination of steroid hormones will serve as an improved noninvasive salivary test for disease monitoring in patients with CAH., (Copyright © 2019 Endocrine Society.)

Background: Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines provide a class I recommendation for patients with type 2 diabetes mellitus and multivessel coronary artery disease (CAD) to be treated with coronary artery bypass graft surgery (CABG). However, these patients are heterogeneous in terms of the risks and benefits associated with CABG. We sought to develop a risk score to identify low-risk patients with diabetes and multivessel CAD in whom CABG can be safely deferred., Methods: Patients in the CABG strata randomized to intensive medical therapy (IMT) in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial who experienced death, myocardial infarction (MI), or stroke were compared with those who did not. We developed a risk score for death, MI, or stroke using a Cox proportional hazards model that included the following variables: age, history of heart failure, history of hypercholesterolemia, history of stroke, transient ischemic attack, serum creatinine, insulin use, myocardial jeopardy index, and HbA1c., Results: Among patients with a risk score less than the median, those randomized to IMT or prompt CABG experienced similar rates of event-free survival at 5 years (77.8% vs. 83.2%, logrank P  = 0.24). Among patients with a risk score greater than the median, those randomized to IMT experienced worse rates of event-free survival at 5 years than those randomized to prompt CABG (60.3% vs 73.2%, logrank P  = 0.01)., Conclusions: A novel risk score identifies low-risk patients with diabetes and stable, symptomatic multivessel CAD in whom CABG can be safely deferred., Competing Interests: The Human Research Protection Office at Washington University granted this study exemption from Institutional Review Board oversight. Patients enrolled in the original BARI 2D trial provided informed consent and the study received ethics approval at each of the enrolling sites.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Mixtures of group-based Markov models of evolution correspond to joins of toric varieties. In this paper, we establish a large number of cases for which these phylogenetic join varieties realize their expected dimension, meaning that they are nondefective. Nondefectiveness is not only interesting from a geometric point-of-view, but has been used to establish combinatorial identifiability for several classes of phylogenetic mixture models. Our focus is on group-based models where the equivalence classes of identified parameters are orbits of a subgroup of the automorphism group of the abelian group defining the model. In particular, we show that for these group-based models, the variety corresponding to the mixture of r trees with n leaves is nondefective when [Formula: see text]. We also give improved bounds for claw trees and give computational evidence that 2-tree and 3-tree mixtures are nondefective for small n.

Low-intensity, unfocused, ultrasound-induced diathermy can produce undesired temperature increases at the interface of adjacent tissues within the body; particularly, at the interface of soft tissue and bone. This study provides a computational framework for predicting an upper bound on the temperature profile within a multiphase system composed of gel pad (water), tissue and bone from an input of acoustic energy, at frequencies and power levels consistent with applications of therapeutic hyperthermia. The model consists of solving a (one-dimensional) spatially discretized bioheat transfer equation via finite-difference method and updating the solution in time with a forward-Euler scheme. Simulations are then compared to experimental data to determine the energy-to-heat conversion factors within each constituent material using thermocouple-embedded, tissue-mimicking phantom material, with and without bone. Viscous heating artifacts from the presence of the thermocouples in the experimental phantom tissue are accounted for via additional experimental methods similar to those described by Morris et al. (Phys Med Biol 53:4759, 2008). Finally, an example application of the model is presented via prediction of the maximum temperature at the tissue-bone interface, as well as the peak temperatures in the composite structure at the end of a prescribed 2-min sonication, of blood-perfused, human soft-tissue at 1, 2 and 3 MHz frequencies and a spatial peak temporally averaged intensity of [Formula: see text]. The results of this simulation are then related to comparable experimental studies in the literature.

Environmental exposure to organic endocrine disrupting chemicals, including dioxins, dibenzofurans, bisphenol A (BPA), and phthalates has been associated with neurodevelopmental disorders, including autism spectrum disorder (ASD). We conducted a pilot monitoring study of 30 ASD cases and 10 typically developing (TD) controls ages 2-8 years from communities along the Gulf of Mexico near Alabama, which houses 14 Superfund sites, to assess the concentrations of dioxins and dibenzofurans in serum, and BPA and phthalate ester metabolites in urine. Based on General Linear Models, the lipid- or creatinine-adjusted geometric mean concentrations of the aforementioned chemicals did not differ between the ASD case and TD control groups (all p ≥ 0.27). We compared our findings to the adjusted means as reported by the National Health and Nutrition Examination Survey, survey years 2011-2012, and found that TD controls in our study had lower BPA (59%) and MEHHP (26%) concentrations, higher MBP (50%) concentration, and comparable (<20% difference) MEP, MBZP, MEOHP, and MCPP concentrations. We also conducted a preliminary investigation of dietary exposures and found that the consumption of certain types of fish may be associated with higher OCDD concentrations, and the consumption of soft drinks and juices may be associated with lower BPA and MEOHP concentrations, respectively., Competing Interests: The authors declare no conflict of interest.

Much has been written about brainstorming and prototyping in medical devices. These 2 topics are the crucial ingredients to innovation; which, if well seeded by organized and structured forays into each, will net much higher quality and more valuable results. Structure and process, although slightly counterintuitive as applied to brainstorming and prototyping, can greatly improve the value proposition of the innovation itself., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Poor growth and delayed puberty in children with cerebral palsy is frequently felt to be related to malnutrition. Although growth hormone deficiency is commonly described in these children, multiple pituitary hormone deficiency (MPHD) has not been previously reported. We present a series of four children with cerebral palsy who were born before 29 weeks gestation who were referred to the regional endocrinology service, three for delayed puberty and one for short stature, in whom investigations identified MPHD. All patients had a height well below -2 standard deviation score (2nd centile) at presentation and three who had MRI scans had an ectopic posterior pituitary gland. We therefore recommend that the possibility of MPHD should be considered in all children with cerebral palsy and poor growth or delayed puberty. Early diagnosis and treatment is essential to maximise growth and prevent associated morbidity and mortality., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633&#95;1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism.

Within the next decades the construction of thousands of different types of large wind turbine foundations in the North Sea will substantially increase the amount of habitat available to reef fauna. To gain first insights which effect these substantial changes in habitat structure and diversity might have on faunal stocks settling on hard substrata, we compared the mobile demersal megafauna associated with the common types of wind turbine foundations ('jacket', 'tripod' and 'monopile with scour protections of natural rock') in the southern German Bight, North Sea. Monopiles with scour protection were mostly colonized by typical reef fauna. They were inhabited by an average of about 5000 edible crabs Cancer pagurus (per foundation), which is more than twice as much as found at the foundation types without scour protection. Strong evidence was found that all three foundation types not only function as aggregation sites, but also as nursery grounds for C. pagurus. Assuming equal shares of the three foundation types in future wind farms, we project that about 27% of the local stock of C. pagurus might be produced on site. When, for example, comparing the existing fauna at 1000 ship wrecks and on the autochthonous soft substrate with those which probably will establish at the foundations of 5000 hypothetically realized wind turbines, it becomes clear that the German Bight in the future will provide new artificial reef habitats for another 320% crabs (C. pagurus) and 50% wrasse (Ctenolabrus rupestris) representing substrata-limited mobile demersal hard bottom species. Further research is urgently required in order to evaluate this overspill as it would be an important ecological effect of the recent offshore wind power development., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

There is an increasing awareness and clinical interest in cardiac safety during cancer therapy as well as in optimally addressing cardiac issues in cancer survivors. Although there is an emerging expertise in this area, known as cardio-oncology, there is a lack of organization in the essential components of contemporary training. This proposal, an international consensus statement organized by the International Cardioncology Society and the Canadian Cardiac Oncology Network, attempts to marshal the important ongoing efforts for training the next generation of cardio-oncologists. The necessary elements are outlined, including the expectations for exposure necessary to develop adequate training. There should also be a commitment to local, regional, and international education and research in cardio-oncology as a requirement for advancement in the field., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The comparative analysis of marine litter in different marine compartments has rarely been attempted. In this study, long-term time series of marine litter abundance on the seafloor and on the coast, both from the southeastern North Sea, were analyzed for temporal trends and correlations. On four beach sections of 100 m length, mean abundances of total beach litter collected four times a year from 2002 to 2008 varied between 105 and 435 items. Mean densities of total inorganic litter on the seafloor amounted to 10.6 ± 9.7 kg km(-2) in the offshore region (2001-2010) and 13.7 ± 12.6 kg km(-2) in the Wadden Sea (1998-2007), respectively. In the offshore region, there was no significant long-term trend, while in the Wadden Sea, densities of marine litter declined significantly. Correlations between time series were weak, indicating different sources and transport processes responsible for compositions of beach litter and litter on the seafloor. Decreases in inputs from fisheries and substantial export due to resuspension are discussed as reasons for the decrease in litter on the seafloor in the Wadden Sea., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: Hospitalization for worsening heart failure (HF) is known to increase mortality and morbidity risk and has been frequently used as an endpoint in randomized clinical trials. Whether outpatient management of HF exacerbation carries similar prognostic and therapeutic information is less well known, but could be important for the design of trials that use HF hospitalization as an endpoint., Methods and Results: MADIT-CRT randomized patients with mild HF symptoms to resynchronization therapy vs. control with an average follow-up of 3.3 years and a total of 191 deaths. HF events were centrally adjudicated for receiving i.v. decongestive therapy in an outpatient setting, or an augmented HF regimen during a hospital stay. Patients were compared according to whether their first HF was an out- or inpatient event. The first primary event was non-fatal outpatient HF, non-fatal inpatient HF, and death in 52, 331, and 78 patients, respectively. Patients with inpatient HF tended to be older and more likely to have HF of ischaemic aetiology than subjects who developed outpatient HF events. The risk of death following either type of non-fatal HF events was extremely high [hazard ratio (HR) 12.4, 95% confidence interval (CI) 9.1-16.9 for inpatient HF; HR 10.7, 95% CI 6.1-18.7 for outpatient HF] compared with subjects without non-fatal HF events. Allocation to CRT-D was associated with significant reduction in both types of HF., Conclusion: Outpatient management of worsening HF portends a high risk of death, similar to inpatient HF events, and may be equally sensitive to the effects of therapy. These findings suggest that outpatient HF events should be considered in publicly reported outcomes measures and future HF clinical trials., Trial Registration: NCT01294449., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

We present a method of characterizing the nonlinear stress-strain behavior of thin films of extremely soft, water-based polymer gels using uniaxial tension testing of bilayer laminates, in conjunction with methods of membrane nonlinear elasticity. A custom tensile testing apparatus is used to conduct quasi-static, uniaxial extension tests of narrow strips of thin, laminated sheets of bonded hydrogel and silicone rubber, submerged in a saline bath. The tensile load is measured via sensitive load cell and the position of material markers, at a central test-section of the sample, is optically tracked via digital image tracking methods. Stress-strain relationships are calculated for the hydrogel component of the bilayer, considered hyperelastic, homogeneous, isotropic, and incompressible, using membrane theories of finite hyperelasticity. We present the stress response for strains up to about 35% for poly(ethylene glycol) (PEG)-based hydrogels (>90% water) with polymer concentrations by weight of 5% to 10%. Polynomial functions are fit to the data for each formulation, whereby the one-dimensional strain-energy function for each formulation is determined by taking the indefinite integral., (© 2013 Elsevier Ltd. All rights reserved.)

Coronary steal could develop in patients with chronic coronary artery disease (CAD) with collateral circulation, and adversely affect ventricular function and long-term clinical outcome. Poorly developed collaterals are more prone than well-developed collaterals to withdrawing their blood support to the collateralized myocardium due to higher collateral pathway resistance and lower vasodilatory reserve of the collateral bed. Even with well-developed coronary collaterals, coronary steal could still occur when perfusion pressure in the donor artery becomes low, or the recipient microvasculature is maximally dilated with exhaustion of vasodilatory reserve. The evaluation of distinctive coronary collateral function with or without steal provides important therapeutic and prognostic information in patients with chronic CAD. However, due to lack of reliable assessment methods, the detection and quantitative measurement of coronary steal remains a challenge. In this article, we present typical clinical scenarios to illustrate the major mechanisms underlying coronary steal in patients with chronic CAD and coronary collateral circulation, and review invasive and noninvasive methods currently available to assess coronary steal in myocardium supplied by coronary collaterals. We specifically focus on recent advances in the resting and stress echocardiography with speckle tracking techniques., (© 2013, Wiley Periodicals, Inc.)

Introduction: The increase in detected vitamin D deficiency appears to be multifactorial: an increasingly multicultural society, reduced exposure to sunlight due to concern about skin cancer and a more sedentary lifestyle and dietary changes within the population., Methods: This was a retrospective survey of children found to be vitamin D deficient after attending the emergency department from March 2009 until March 2010. These data were then subdivided according to their age, ethnic origin, presenting complaint and biochemical associated features., Results: We identified 89 patients with a low vitamin D level (total vitamin D levels less than 50 nmol/l), with 83% of those having very low vitamin D levels (less than 25 nmol/l). The most common presenting features were abdominal pain (19%), a seizure (17%) and limb pain (15%). The most common ethnic origins in our series were Pakistani (37%) followed by black African (11.2%)., Conclusions: Vitamin D deficiency should be considered in children with pigmented skin presenting with a range of symptoms. The detected vitamin D deficiency probably represents only a very small proportion of the vitamin D deficiency in children in Birmingham.

Objectives: The purpose of this study was to compare in-hospital outcomes of percutaneous coronary intervention (PCI) in extreme obesity (EO) (body mass index [BMI] ≥ 40 kg/m²) with those of normal-weight (NW) patients and to examine the influence of access site on outcomes., Background: Little is known about the outcomes of PCI in EO patients., Methods: We analyzed CathPCI Registry data from patients who underwent radial or femoral PCI and were discharged between July 2009 and June 2011 and compared in-hospital outcomes of EO (N = 83,861) with those of NW patients (BMI 20 to 25 kg/m²; N = 217,616). Outcomes included in-hospital mortality and procedural and bleeding complications. Multivariable logistic regression models were used to assess the independent association of EO with outcomes, using previously validated risk models derived from the CathPCI Registry. The role of access site was specifically examined., Results: Compared with NW patients, EO patients were younger (median age 60 vs. 69 years), more likely female (47% vs. 37%), and more likely African American (12% vs. 7%). EO patients had lower unadjusted mortality (1.2% vs. 2.0%); however, after multivariable adjustment, EO was independently associated with increased risk of in-hospital mortality (odds ratio: 1.22; 95% CI: 1.08 to 1.39) in those presenting with ST-segment elevation myocardial infarction (STEMI). Access site had no effect on bleeding or outcome., Conclusions: EO patients who underwent PCI were younger and had less bleeding compared with NW patients. After multivariable adjustment for risk, EO was independently associated with higher in-hospital mortality overall and particularly in the patients undergoing STEMI., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

An increasing number of academic senior physicians are approaching their potential retirement in good health with accumulated clinical and research experience that can be a valuable asset to an academic institution. Considering the need to let the next generation ascend to leadership roles, when and how should a medical career be brought to a close? We explore the roles for academic medical faculty as they move into their senior years and approach various retirement options. The individual and institutional considerations require a frank dialogue among the interested parties to optimize the benefits while minimizing the risks for both. In the United States there is no fixed age for retirement as there is in Europe, but European physicians are initiating changes. What is certain is that careful planning, innovative thinking, and the incorporation of new patterns of medical practice are all part of this complex transition and timing of senior academic physicians into retirement., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In the light of the introduction of thousands of large offshore wind power foundations into the North Sea within the next decades, this manuscript focuses on the biofouling processes and likely reef effects. The study explores the macrozoobenthos (biofouling) colonization at an offshore platform which is comparable to offshore wind turbine foundations. A total of 183 single samples were taken and the parameters water depth and time were considered comparing biofouling masses and communities. The blue mussel Mytilus edulis, Anthozoa and the Amphipoda Jassa spp. were the dominant species. The community from the 1 m zone and those from the 5 and 20-28 m zones can clearly be differentiated. The 10 m zone community represents the transition between the M. edulis dominated 1 m and 5 m zones and the Anthozoa dominated 20-28 m zone. In the future offshore wind farms, thousands of wind turbine foundations will provide habitat for a hard bottom fauna which is otherwise restricted to the sparse rocky habitats scattered within extensive sedimentary soft bottoms of the German Bight. However, offshore wind power foundations cannot be considered natural rock equivalents as they selectively increase certain natural hard bottom species. The surface of the construction (1280 m²) was covered by an average of 4300 kg biomass. This foundation concentrates on its footprint area (1024 m²) 35 times more macrozoobenthos biomass than the same area of soft bottom in the German exclusive economic zone (0.12 kg m(-2)), functioning as a biomass hotspot. Concerning the temporal biomass variation, we assume that at least 2700 kg biomass was exported on a yearly basis. 345 × 10(4) single mussel shells of different sizes were produced during the study period. It is anticipated that the M. edulis abundance will increase in the North Sea due to the expansion of the offshore wind farm development. This will result in the enhanced production of secondary hard substrate (mussel shells) and its associated fauna and will intensify filtration rates of the seawater. This predicted ecological system change is coined the 'Mytilusation' of the German Bight., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Recent studies suggest that cancer patients may be at increased risk for supraventricular tachyarrhythmias (SVTA). We have observed clinically significant SVTA in patients undergoing hematopoietic stem cell transplantation occurring at a median of 6 days post transplant, manifesting as atrial fibrillation/flutter or regular narrow-complex tachycardia and persisting for a median of 3 days (range, 0-8). All patients received aggressive medical therapy and/or electrical cardioversion to restore sinus rhythm and to re-establish hemodynamic stability. Non-Hodgkin's lymphoma (NHL) was the most common diagnosis (53%), and a case control analysis in those patients demonstrated that SVTA occurred in 12% of patients and was associated with older age and pre-existing cardiac conditions. In conclusion, patients undergoing HSCT are at moderate risk for developing SVTA, particularly older patients with a diagnosis of NHL. These arrhythmias are clinically significant, and are a marker for increased mortality and prolonged hospital stay. Additional studies are needed to identify high-risk patients who may benefit from prophylactic anti-arrhythmic therapy.

Objective: The objective of this study was to evaluate the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for exercise testing (EXT) after successful coronary revascularization (CR) using the Bypass Angioplasty Revascularization Investigation experience., Background: The ACC/AHA guidelines state that EXT within three years of successful CR is not useful., Methods: The 1,678 patients randomized to CR by either angioplasty or bypass surgery were required to take symptom-limited treadmill tests one, three and five years after revascularization., Results: Patients who took the test at each specified time had a much lower subsequent two-year mortality than those who did not (1.9% vs. 9.4%, 3.5% vs. 12.6% and 3.3% vs. 11.0% at one, three and five years, respectively, after CR [p < 0.0001 for each]). Exercise parameters at the one- and three-year test did not improve a multivariable model of survival after including clinical parameters. Exercising to Bruce stage 3 or generating a Duke score >-6 were independently predictive of two-year survival after the five-year test. ST depression on the one-year test was associated with more revascularizations (relative risk = 1.6; p < 0.001)., Conclusions: Patients with stable multivessel coronary disease who took a protocol-mandated exercise test at one, three and five years after revascularization were at low risk for mortality in the two years subsequent to each test. Exercise parameters did not improve prediction of mortality in the two years after the one- and three-year tests. The ACC/AHA guidelines on exercise testing after CR (no value for routine testing in stable patients for three years after revascularization) are supported by these results.

Objectives: This study was designed to determine the effect of coronary stents on in-hospital mortality., Background: Despite extensive use of stents for percutaneous coronary interventions (PCIs), their effect on serious in-hospital events, especially mortality, is not well defined., Methods: A cohort study was performed using 16,811 consecutive native-vessel PCI procedures performed on patients in the Society for Cardiac Angiography & Interventions Registry from July 1, 1996, through December 31, 1998. Patients undergoing balloon-only angioplasty were compared with those receiving a planned or unplanned stent. Procedures with other devices were excluded. Multivariable analyses adjusted for detailed clinical characteristics and for individual laboratory., Results: Stents were associated with a significant reduction in in-hospital mortality (0.3%) compared with balloon procedures (0.6%; multivariable odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34, 0.89; p = 0.014). The risk of emergency coronary bypass also was reduced by stenting (0.3% vs. 0.7%; multivariable OR 0.47; 95% CI: 0.29, 0.76; p = 0.002). Adjustment for the use of glycoprotein IIb/IIIa inhibitors did not change the results, and the effects of stenting relative to balloon procedures were similar in those procedures with and without glycoprotein IIb/IIIa blockade (p = 0.94)., Conclusions: This study suggests that coronary stenting, compared with balloon procedures, reduces in-hospital mortality, independent of the clinical setting.

There are few data comparing the relative frequency of new electrocardiographic (ECG) abnormalities after coronary artery bypass grafting (CABG) compared with percutaneous transluminal coronary angioplasty (PTCA) and their association with long-term cardiac mortality. The study population consisted of 3,373 patients who were either randomized or eligible to be randomized to CABG or PTCA in the BARI trial. The frequency of new postprocedural ECG abnormalities was significantly greater after a CABG procedure than after PTCA. The incidence of new postprocedural major Q waves, ST-segment elevation, and T-wave abnormalities were significantly more frequent after CABG. After PTCA (n = 1,869), the 5-year cardiac mortality rates associated with the new development of major Q waves, ST-segment elevation, ST-segment depression, T-wave abnormalities, or no abnormality was 18.1%, 8.5%, 8.9%, 6.0%, and 5.4%, respectively. After CABG (n = 1,427), 5-year cardiac mortality rates were 8.0%, 4.2%, 3.8%, 2.8%, and 3.7%, respectively. The adjusted relative risk of 5-year cardiac mortality for new Q-wave abnormalities was 2.6 after CABG (p <0.04) and 4.6 after PTCA (p <0.01). Thus, patients who undergo CABG have more postinitial procedural ECG abnormalities than patients who undergo PTCA. Cardiac mortality is significantly increased by the new development of postprocedural Minnesota code Q-wave abnormalities regardless of whether patients undergo CABG or PTCA.

Cigarette smoking is linked to increased cardiac morbidity and mortality, and has been shown to affect both lipid profiles and thrombotic factors in healthy subjects. However, the influence of smoking on the atherothrombotic environment has not been studied in a large population of patients after acute myocardial infarction (AMI). Blood samples and medical history, including smoking status, were obtained from 1,045 patients at a 2-month visit after AMI. Smokers were asked to refrain 24 hours before the visit, but not all complied. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein-B, apolipoprotein-A, triglycerides, factor VII, factor VIIa, von Willebrand factor, D-dimer, and plasminogen activator inhibitor. There were 247 current, 443 past, and 349 nonsmokers. After adjustment for clinical variables, current smokers had higher levels of total cholesterol and apolipoprotein-B than past and nonsmokers (p <0.01). High-density lipoprotein cholesterol and apolipoprotein-A levels were similar between groups. Fibrinogen was elevated in current (p = 0.001) and past (p = 0.029) smokers, compared with nonsmokers. Smokers who smoked within 24 hours of blood sampling had higher apolipoprotein-B (p = 0.005), total cholesterol (p = 0.001), and fibrinogen (p = 0.015) levels than those who refrained from smoking. In conclusion, postinfarction patients, who historically have higher levels of atherogenic lipids than healthy subjects, have increased levels of these lipids attributed to active smoking. After smoking cessation, lipid profiles approach nonsmoker levels, but fibrinogen remains elevated. Smoking within 24 hours of blood sampling was associated with further adverse prothrombotic and lipogenic effects.

Background: The Bypass Angioplasty Revascularization Investigation (BARI) included 4039 patients with multivessel coronary artery disease; 1829 consented to randomization, and 2010 did not but were followed up in a registry. Thus, we can evaluate the outcome of physician-guided versus random assignment of percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass graft surgery (CABG)., Methods and Results: We compared the baseline features and outcomes for PTCA and CABG in the overall registry and its predesignated subgroups. We assessed the impact of treatment by choice versus random assignment by comparing the results in the registry with those of the randomized trial. Statistical adjustments for differences in baseline characteristics were made. Within the registry, nearly twice as many patients were selected for PTCA (1189) as CABG (625); mortality at 7 years was similar for PTCA (13.9%) and CABG (14.2%) (P=0.66) before and after adjustment for baseline differences between patients selected for PTCA versus CABG (adjusted RR, 1.02; P=0.86). In contrast to the randomized trial, the 7-year mortality rate of treated diabetics in the registry was equally high (26%) with PTCA or CABG. Seven-year mortality was higher for patients undergoing PTCA in the randomized trial than in the registry (19.1% versus 13.9%, P<0.01) but not for those undergoing CABG (15.6% versus 14.2%, P=0.57). The adjusted relative mortality risk for PTCA in the randomized versus registry population was 1.17 (P=0.16)., Conclusions: BARI physicians were able to select PTCA rather than CABG for 65% of registry patients who underwent revascularization without compromising long-term survival either in the overall population or in treated diabetics.

In 1988, the American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures presented a classification of coronary lesions utilizing 26 lesion features to predict the success and complications of balloon angioplasty. Using data from the Registry of the Society for Cardiac Angiography and Interventions (SCAI) we evaluated the ability of this classification to predict success and complications. Lesion success, death in hospital, emergency cardiac bypass surgery, and major adverse events were evaluated in 41,071 patients who underwent single-vessel angioplasty from January 1993 to June 1996. Logistic models using the ACC/AHA lesion classification, vessel patency, or both, were compared. A new classification based on the interaction of the ACC/AHA classification plus lesion patency was compared with the existing ACC/AHA classification. Vessel patency, added to the ACC/AHA classification, improved prediction of lesion success (p

This report of the Registry for the Society for Cardiac Angiography and Interventions provides data on the trends in coronary interventional procedures from the time period June 1966 through December 1998. A total of 19,510 consecutive coronary interventional procedures were recorded. Over this time period, significant trends in coronary stent implantation were recorded along with a decreasing reliance on balloon angioplasty as sole therapy. Patients with acute myocardial infarction comprised an increased fraction of all procedures. Almost half of all interventions were performed in patients with multivessel disease. Finally, decreasing rates of in-hospital death and emergent bypass surgery compared to prior reports from the registry characterize the current practice of interventional cardiology. Cathet. Cardiovasc. Intervent. 49:19-22, 2000., (Copyright 2000 Wiley-Liss, Inc.)

Background: Thrombosis is a pivotal event in the pathogenesis of coronary disease. We hypothesized that the presence of blood factors that reflect enhanced thrombogenic activity would be associated with an increased risk of recurrent coronary events during long-term follow-up of patients who have recovered from myocardial infarction., Methods and Results: We prospectively enrolled 1045 patients 2 months after an index myocardial infarction. Baseline thrombogenic blood tests included 6 hemostatic variables (D-dimer, fibrinogen, factor VII, factor VIIa, von Willebrand factor, and plasminogen activator inhibitor-1), 7 lipid factors [cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, lipoprotein(a), apolipoprotein (apo)A-I, and apoB], and insulin. Patients were followed up for an average of 26 months, with the primary end point being coronary death or nonfatal myocardial infarction, whichever occurred first. The hemostatic, lipid, and insulin parameters were dichotomized into their top and the lower 3 risk quartiles and evaluated for entry into a Cox survivorship model. High levels of D-dimer (hazard ratio, 2.43; 95% CI, 1.49, 3.97) and apoB (hazard ratio, 1.82; 95% CI, 1.10, 3.00) and low levels of apoA-I (hazard ratio, 1.84; 95% CI, 1.10, 3.08) were independently associated with recurrent coronary events in the Cox model after adjustment for 6 relevant clinical covariates., Conclusions: Our findings indicate that a procoagulant state, as reflected in elevated levels of D-dimer, and disordered lipid transport, as indicated by low apoA-1 and high apoB levels, contribute independently to recurrent coronary events in postinfarction patients.

Background: Patients with treated diabetes in the randomized-trial segment of the Bypass Angioplasty Revascularization Investigation (BARI) who were randomized to initial revascularization with PTCA had significantly worse 5-year survival than patients assigned to CABG. This treatment difference was not seen among diabetic patients eligible for BARI who opted to select their mode of revascularization. We hypothesized that differences in patient characteristics, assessed and unmeasured, together with the treatment selection in the registry, at least partially account for this discrepancy., Methods and Results: Among diabetics taking insulin or oral hypoglycemic drugs at entry, angiographic and clinical presentations were comparable between randomized and registry patients. However, more registry patients were white, and registry diabetics tended to be more educated and more physically active and to report better quality of life. Procedural characteristics and in-hospital complications were comparable. The 5-year all-cause mortality rate was 34.5% in randomized diabetic patients assigned to PTCA versus 19.4% in CABG patients (P=0.0024; relative risk [RR]=1.87); corresponding cardiac mortality rates were 23.4% and 8.2%, respectively (P=0.0002; RR=3.10). The CABG benefit was more apparent among patients requiring insulin. In the registry, all-cause mortality was 14.4% for PTCA versus 14.9% for CABG (P=0.86, RR=1.10), with corresponding cardiac mortality rates of 7.5% and 6. 0%, respectively (P=0.73; RR=1.07). These RRs in the registry increased to 1.29 and 1.41, respectively, after adjustment for all known differences between treatment groups., Conclusions: BARI registry results are not inconsistent with the finding in the randomized trial that initial CABG is associated with better long-term survival than PTCA in treated diabetic patients with multivessel coronary disease suitable for either surgical or catheter-based revascularization.

Patients who were stable 1 to 6 months after a cardiac event underwent routine exercise testing with thallium scintigraphy. The prognosis of patients with good exercise capacity (Bruce stage 3) was similar whether or not ischemia was demonstrated and similar to patients with reduced exercise capacity and no ischemia, whereas the presence of both ischemia and a reduced exercise tolerance identified patients with a significantly poorer prognosis.