(Wiley) Heart failure and cancer are conditions with a number of shared characteristics. A new study published in the Journal of Internal Medicine found that in patients with heart failure, several known tumor markers can also be indicators of heart failure severity and progression.

Objectives: Radioactive iodine (¹³¹I) therapy may be used to treat thyroid cancer in end-stage renal disease patients who undergo hemodialysis. Because iodine predominantly utilizes renal clearance, treatment management in hemodialysis patients may be problematic, and no formal recommendations on hemodialysis currently exist. This work details our experience with treating thyroid cancer with iodine in chronic renal failure patients who require hemodialysis and details the therapeutic dosimetry results obtained during treatment to ensure that the dose to the bone marrow (BM) was acceptable. Methods: We treated 6 patients in the metabolic radiotherapy unit after thyroid stimulation. Two hemodialysis sessions in the metabolic radiotherapy unit were performed at 42 and 90 hours after radiopharmaceutical administration. BM toxicity was estimated with activity measurements from blood samples and with whole-body measurements that were regularly repeated during hospitalization and measured with a gamma counter. The patients underwent thyroid and hematologic monitoring to assess treatment efficacy and therapeutic toxicity in the short, medium and long term. Results: Whole-body activity was reduced on average by 66.7% [60.1-71.5] after the first dialysis session and by 53.3% [30.4-67.8] after the second. The mean estimated total absorbed dose to the BM was 0.992 Gy for all patients [0.431 – 2.323]. We did not observe any significant hematologic toxicity, and the clinical, biological and ultrasound test results confirmed the success of ablative treatment for the majority of patients. Conclusion: An approximately 30% reduction from the nominal dose in the amount of ¹³¹I activity for hemodialysis patients with thyroid cancer appears to strike an appropriate balance between the absence of BM toxicity and therapeutic efficacy. To avoid overirradiation, we recommend pretherapeutic dosimetry studies for metastatic patients to calculate the amount of activity to be administered as well as dosimetry monitoring during the hemodialysis sessions performed after therapeutic dose administration and under the same conditions.

Research Event

Event participants

Alan Doss, President, Kofi Annan Foundation
 

In type 2 diabetes, β-cells endure various forms of cellular stress, including oxidative stress and endoplasmic reticulum stress, secondary to increased demand for insulin production and extracellular perturbations, including hyperglycemia. Chronic exposure to stress causes impaired insulin secretion, apoptosis, and loss of cell identity, and a combination of these processes leads to β-cell failure and severe hyperglycemia. Therefore, a better understanding of the molecular mechanisms underlying stress responses in β-cells promises to reveal new therapeutic opportunities for type 2 diabetes. In this perspective, we discuss posttranscriptional control of gene expression as a critical, but underappreciated, layer of regulation with broad importance during stress responses. Specifically, regulation of mRNA translation occurs pervasively during stress to activate gene expression programs; however, the convenience of RNA sequencing has caused translational regulation to be overlooked compared with transcriptional controls. We highlight the role of RNA binding proteins in shaping selective translational regulation during stress and the mechanisms underlying this level of regulation. A growing body of evidence indicates that RNA binding proteins control an array of processes in β-cells, including the synthesis and secretion of insulin. Therefore, systematic evaluations of translational regulation and the upstream factors shaping this level of regulation are critical areas of investigation to expand our understanding of β-cell failure in type 2 diabetes.

6 November 2019 , Volume 95, Number 6

Active maintenance of β-cell identity through fine-tuned regulation of key transcription factors ensures β-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of human β-cell maturity and β-cell failure through activation of the BMP/SMAD signaling pathway when administered under mild metabolic stress conditions. Tacrolimus-induced phosphorylated SMAD1/5 acts in synergy with metabolic stress–activated FOXO1 through formation of a complex. This interaction is associated with reduced expression of the key β-cell transcription factor MAFA and abolished insulin secretion, both in vitro in primary human islets and in vivo in human islets transplanted into high-fat diet–fed mice. Pharmacological inhibition of BMP signaling protects human β-cells from tacrolimus-induced β-cell dysfunction in vitro. Furthermore, we confirm that BMP/SMAD signaling is activated in protocol pancreas allograft biopsies from recipients on tacrolimus. To conclude, we propose a novel mechanism underlying the diabetogenicity of tacrolimus in primary human β-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes.

Western Bureau: Some displaced Iberostar employees in Rose Hall, St James, are angry with their employer, charging that they have been unable to benefit from the Government’s COVID-19 relief programme because of the hotel’s failure to pay over...

Inflammation contributes to ventricular remodeling after myocardial ischemia, but its role in nonischemic heart failure is poorly understood. Local tissue inflammation is difficult to assess serially during pathogenesis. Although ¹⁸F-FDG accumulates in inflammatory leukocytes and thus may identify inflammation in the myocardial microenvironment, it remains unclear whether this imaging technique can isolate diffuse leukocytes in pressure-overload heart failure. We aimed to evaluate whether inflammation with ¹⁸F-FDG can be serially imaged in the early stages of pressure-overload–induced heart failure and to compare the time course with functional impairment assessed by cardiac MRI. Methods: C57Bl6/N mice underwent transverse aortic constriction (TAC) (n = 22), sham surgery (n = 12), or coronary ligation as an inflammation-positive control (n = 5). MRI assessed ventricular geometry and contractile function at 2 and 8 d after TAC. Immunostaining identified the extent of inflammatory leukocyte infiltration early in pressure overload. ¹⁸F-FDG PET scans were acquired at 3 and 7 d after TAC, under ketamine-xylazine anesthesia to suppress cardiomyocyte glucose uptake. Results: Pressure overload evoked rapid left ventricular dilation compared with sham (end-systolic volume, day 2: 40.6 ± 10.2 μL vs. 23.8 ± 1.7 μL, P < 0.001). Contractile function was similarly impaired (ejection fraction, day 2: 40.9% ± 9.7% vs. 59.2% ± 4.4%, P < 0.001). The severity of contractile impairment was proportional to histology-defined myocardial macrophage density on day 8 (r = –0.669, P = 0.010). PET imaging identified significantly higher left ventricular ¹⁸F-FDG accumulation in TAC mice than in sham mice on day 3 (10.5 ± 4.1 percentage injected dose [%ID]/g vs. 3.8 ± 0.9 %ID/g, P < 0.001) and on day 7 (7.8 ± 3.7 %ID/g vs. 3.0 ± 0.8 %ID/g, P = 0.006), though the efficiency of cardiomyocyte suppression was variable among TAC mice. The ¹⁸F-FDG signal correlated with ejection fraction (r = –0.75, P = 0.01) and ventricular volume (r = 0.75, P < 0.01). Western immunoblotting demonstrated a 60% elevation of myocardial glucose transporter 4 expression in the left ventricle at 8 d after TAC, indicating altered glucose metabolism. Conclusion: TAC induces rapid changes in left ventricular geometry and contractile function, with a parallel modest infiltration of inflammatory macrophages. Metabolic remodeling overshadows inflammatory leukocyte signal using ¹⁸F-FDG PET imaging. More selective inflammatory tracers are requisite to identify the diffuse local inflammation in pressure overload.

OBJECTIVE

To characterize the status of cardiometabolic risk factors after late relapse of type 2 diabetes mellitus (T2DM) and to identify factors predicting relapse after initial diabetes remission following bariatric surgery to construct prediction models for clinical practice.

Poverty and poor or non-existent health insurance coverage might worsen the effects of heart failure, the American Heart Association said Thursday.

OBJECTIVE

To determine the effects of dapagliflozin in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM) on left ventricular (LV) remodeling using cardiac MRI.

OBJECTIVE

Although blood pressure variability is increasingly appreciated as a risk factor for cardiovascular disease, its relationship with heart failure (HF) is less clear. We examined the relationship between blood pressure variability and risk of HF in two cohorts of type 2 diabetes participating in trials of glucose and/or other risk factor management.

[S.i.] : [publisher not identified]

Emilia Athayde, Assis Azevedo, Michelli Barros, Víctor Leiva.

Source: Brazilian Journal of Probability and Statistics, Volume 33, Number 2, 301--328.

Abstract:
The Birnbaum–Saunders (BS) distribution has been largely studied and applied. A random variable with BS distribution is a transformation of another random variable with standard normal distribution. Generalized BS distributions are obtained when the normally distributed random variable is replaced by another symmetrically distributed random variable. This allows us to obtain a wide class of positively skewed models with lighter and heavier tails than the BS model. Its failure rate admits several shapes, including the unimodal case, with its change-point being able to be used for different purposes. For example, to establish the reduction in a dose, and then in the cost of the medical treatment. We analyze the failure rates of generalized BS distributions obtained by the logistic, normal and Student-t distributions, considering their shape and change-point, estimating them, evaluating their robustness, assessing their performance by simulations, and applying the results to real data from different areas.

Hongbin Zhang, Lang Wu.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2140--2157.

Abstract:
For a time-to-event outcome with censored time-varying covariates, a joint Cox model with a linear mixed effects model is the standard modeling approach. In some applications such as AIDS studies, mechanistic nonlinear models are available for some covariate process such as viral load during anti-HIV treatments, derived from the underlying data-generation mechanisms and disease progression. Such a mechanistic nonlinear covariate model may provide better-predicted values when the covariates are left censored or mismeasured. When the focus is on the impact of the time-varying covariate process on the survival outcome, an accelerated failure time (AFT) model provides an excellent alternative to the Cox proportional hazard model since an AFT model is formulated to allow the influence of the outcome by the entire covariate process. In this article, we consider a nonlinear mixed effects model for the censored covariates in an AFT model, implemented using a Monte Carlo EM algorithm, under the framework of a joint model for simultaneous inference. We apply the joint model to an HIV/AIDS data to gain insights for assessing the association between viral load and immunological restoration during antiretroviral therapy. Simulation is conducted to compare model performance when the covariate model and the survival model are misspecified.

A Christian football coach experiences what he says is the best gift from God, something “so much more than winning”.

Mardi Gras in New Orleans has always had a gothic element. The voodoo culture dates from the African American diaspora, though it’s now mostly for tourists. But this year there was an authentically macabre dimension to Fat Tuesday.

Next week, Nicola Sturgeon is promising to outline her proposals for lifting the lockdown. Good luck with that. She is unlikely to open the schools because she can't rely on parents to send their children.

Although China has the largest birth population in the world and a number of multicenter studies of neonatal respiratory failure are reported, there is a paucity of data regarding outcome measurement of very premature neonates requiring respiratory care and surfactant therapy.

This study is the largest survey, to date, in a Chinese network of 55 NICUs that presents the incidence, morbidity, and mortality rates, with risk factors of neonatal respiratory failure, with special emphasis on surfactant-treated very immature infants. (Read the full article)

Neonatal hearing screening occasionally fails because of several perinatal and neonatal factors. However, the effect of mode of delivery on hearing screening has not yet been established.

We show significantly more failures on hearing screening in cesarean delivery infants. Hence, the timing of screening after cesarean delivery should preferably be postponed beyond 48 hours to improve success rate, minimize maternal anxiety, and decrease costs. (Read the full article)

Failure to thrive (FTT) is a common and vexing pediatric problem. Evaluation has historically involved large batteries of tests, multiple consultations, radiologic studies, and prolonged hospital admissions, resulting in significant costs and inconsistent results.

Scheduled failure to thrive (FTT) admissions on weekends result in increased lengths of stay and health care costs compared with weekday admissions of similar levels of complexity. Reduction in planned weekend admissions for FTT could significantly reduce health care costs. (Read the full article)

Children with acute liver failure due to a single-dose acetaminophen exposure have a characteristic liver biochemistry profile of low conjugated bilirubin and high alanine aminotransferase, which is associated with a favorable clinical outcome when treated with N-acetylcysteine.

Children with acute liver failure associated with chronic acetaminophen exposure also have a similar liver biochemistry profile, but for unknown reasons, they have a poorer clinical outcome than patients with single-dose acetaminophen exposure. (Read the full article)

Extreme prematurity is a well-established cause of cognitive and motor impairment. There is some evidence that late prematurity and modifiable maternal attributes may negatively influence scholastic achievement, including standardized test performance.

We found that preterm birth significantly increases risk of first-grade failure rate even when the birth is just a few weeks before term gestation. Low maternal education status compounds the effect of prematurity. (Read the full article)

The American Academy of Pediatrics recommends neonates born at <37 weeks’ gestation receive a predischarge Infant Car Seat Challenge, meaning up to 500 000 infants qualify annually. However, little is known about incidence and risk factors for failure in this group.

This is the largest study to date to examine incidence and risk factors for failure of the Infant Car Seat Challenge. We sought to identify infants most at risk for failure to narrow the scope of testing. (Read the full article)

Surviving infants with hypoxic ischemic encephalopathy (HIE) treated with hypothermia have decreased rates of CP in childhood. CP is associated with increased risk of slow growth.

Term children with HIE who develop moderate/severe CP are at high risk of progressive impaired growth, high rates of cognitive impairment, and rehospitalizations from infancy to school age. Gastrostomy tube placement to facilitate feeds is protective of slow growth. (Read the full article)

The period of transition from childhood to adulthood and the period immediately after transfer of care is a challenging time for young people with kidney failure.

Young patients with kidney failure cared for exclusively in adult-oriented facilities experience increased rates of avoidable hospitalizations during late adolescence and young adulthood. Avoidable hospitalizations increased among pediatric kidney failure patients during the years immediately after transfer to adult care. (Read the full article)

Ceftriaxone at therapeutic doses can lead to renal stone formation.

Renal stone formation with ceftriaxone therapy can result in postrenal acute renal failure in children. The condition can be treated effectively by timely pharmacotherapy or retrograde ureteral catheterization with good prognosis. (Read the full article)

Lung ultrasound outperforms conventional radiology in the emergency diagnosis of pneumothorax and pleural effusions. In the pediatric age, lung ultrasound has been also successfully applied to the fluid-to-air transition after birth and to rapid pneumonia diagnosis.

Nasal ventilation has dramatically decreased the need for invasive mechanical respiratory support. This study demonstrates that, after a short trial on nasal continuous positive airway pressure, lung ultrasonography reliably predicts the failure of noninvasive ventilation unlike the conventional chest radiogram. (Read the full article)

Postnatal growth failure is common for very low birth weight infants. Although many of the major morbidities experienced by these infants during their initial NICU stays have decreased in recent years, it is unclear whether growth has improved.

For infants weighing 501 to 1500 g, average growth velocity increased and postnatal growth failure decreased from 2000 to 2013. Still, in 2013, half were discharged with a weight below the 10th percentile for postmenstrual age. (Read the full article)

053 - UEFA Club Financial Control Body investigatory chamber takes measures

The app failed for the same reason that every tech rollout struggles: bugs, user training, and the known unknowns.

Termed "a successful failure", the spacecraft which had three astronauts- James Lovell Jr, Fred Haise Jr, and John Swigert Jr- on board managed to return to the Earth despite facing an explosion like situation after a blast in its oxygen tank.

Proof of concept exploit for Mac OS X versions 10.4.6 and below which are susceptible to a vulnerability in launchd's syslog() function. PPC version.

RSA BSAFE Crypto-J versions prior to 6.2.2 suffer from improper OCSP validation and PKCS#12 timing attack vulnerabilities.

The Aastra 6753i IP telephone uses 3DES encrypted payloads in ECB mode to pass configuration files, allowing for modification to the phone's set up.

Back in the 1980s and 1990s, the twin forces of privatization and deregulation of public infrastructure services ascended to a global paradigm of progress and development. Government management of services such as telecommunications, transportation, water, and energy was deemed inefficient, underperforming, and monopolistic. Private industry – accountable to the profits and losses of an open market and, thus, believed more efficient than government – was proclaimed the better way for consumer choice and a more efficient use of taxpayers’ expenses.

Back in the 1980s and 1990s, the twin forces of privatization and deregulation of public infrastructure services ascended to a global paradigm of progress and development. Government management of services such as telecommunications, transportation, water, and energy was deemed inefficient, underperforming, and monopolistic. Private industry – accountable to the profits and losses of an open market and, thus, believed more efficient than government – was proclaimed the better way for consumer choice and a more efficient use of taxpayers’ expenses.

Back in the 1980s and 1990s, the twin forces of privatization and deregulation of public infrastructure services ascended to a global paradigm of progress and development. Government management of services such as telecommunications, transportation, water, and energy was deemed inefficient, underperforming, and monopolistic. Private industry – accountable to the profits and losses of an open market and, thus, believed more efficient than government – was proclaimed the better way for consumer choice and a more efficient use of taxpayers’ expenses.

In late 2008, the Financial Services Authority (FSA) reviewed how firms had implemented key aspects of the Markets in Financial Instruments Directive (MiFID). It has now published the results of that review. Generally the FSA has been encouraged by ...

 Amy Sadro, Principal Associate in Eversheds Sutherland’s Environment, Health and Safety Team and Dr Chris Nelson, a Principal Consultant and specialist in noise and vibration at Finch Consulting give their views on recent HAVS prosecutio...

The security of personal information, including customer payment card data and related details, is integral to the functioning of retailers with an online offering, and there are serious consequences in the event of security breaches. Penalties...

Suez Fortune Investments Ltd and another v Talbot Underwriting Ltd [2016] EWHC 1085 (Comm) Introduction On the 15 January 2015, the English Commercial Court handed down a decision that highlights the importance of compliance with disclosure obligati...

Investors and lawmakers in Hong Kong are urging regulators to seek compensation for people who lose money when listed companies collapse shortly after their initial public offerings.Under the current system, when banks sponsoring IPOs are found to have fallen short in their due diligence duties, the proceeds of any fine imposed by the watchdog goes to the government, not investors. Those fines amount to almost HK$1 billion (US$130 million) over the last 20 years, according to calculations by…