Is urologist burnout different on the other side of the pond? A European perspective.

The rate of burnout among physicians appears to be on the rise and urologist are no exception. In fact, urology appears to be one of the specialties most affected, with European urologists reporting burnout rates of up to 54% and those working in the United States up to 68%.Herein, we review the relatively few studies looking at burnout in European urologists to estimate its prevalence and discuss what could be done to reverse the trend. A total of seven studies were identified assessing burnout in urologists in Europe and Turkey. While the rates vary (9.3-68%), they indicate that burnout is prevalent within urology, with data from other studies suggesting there is a rising trend. Although the topic has been studied for many years, with an increased focus in the last decade, little seems to have been done to improve the situation.

The eIF4A inhibitor silvestrol sensitizes T-47D ductal breast carcinoma cells to external-beam radiotherapy.

PURPOSE: eIF4A is an RNA helicase that forms part of the machinery of translation initiation.Proteomic analysis demonstrated eIF4A expression to be at least two-fold greater in a radioresistant derivative of T-47D breast cancer cells compared to parental cells.Inhibition of eIF4A has previously been shown to re-sensitize lymphomas to chemotherapeutic agents that cause DNA damage.The objective of this work is to investigate whether inhibition of eIF4A using silvestrol sensitizes breast cancer cells to radiotherapy in tissue culture, using T-47D as a model system. METHODS AND MATERIALS: T-47D cells were incubated in medium containing 0 nM to 1 nM silvestrol either for 24 h prior to irradiation at 0 Gy to 10 Gy, delivered by linear accelerator (LINAC) or continually for six days post irradiation. MTT viability and clonogenic assays were used to quantify response. RESULTS: Pre-treatment of T-47D cells with 1 nM silvestrol caused a 34% reduction (p = 0.014) in viability on irradiation at 2 Gy compared to treatment with a DMSO control, as assessed by MTT assay.Maintenance of cells in 1 nM silvestrol for six days following irradiation at 2 Gy caused a 58% reduction (p = <0.001) in tumor cell viability.Clonogenic assays performed on cells maintained in 1 nM silvestrol following irradiation showed a dose modifying factor (DMF) of 1.4 (p = <0.001, one-way ANOVA). CONCLUSIONS: Low concentrations of silvestrol sensitize T-47D breast cancer cells to radiation with minimal effects on unirradiated cells. This highlights the possible usefulness of eIF4A inhibition in potentiating radiation-induced damage at the tumor site without causing systemic toxicity.

Presenting features of COVID-19 in older people: relationships with frailty, inflammation and mortality.

PURPOSE: To describe the clinical features of COVID-19 in older adults, and relate these to outcomes. METHODS: A cohort study of 217 individuals (median age 80, IQR 74-85 years; 62% men) hospitalised with COVID-19, followed up for all-cause mortality, was conducted. Secondary outcomes included cognitive and physical function at discharge. C-reactive protein and neutrophil:lymphocyte ratio were used as measures of immune activity. RESULTS: Cardinal COVID-19 symptoms (fever, dyspnoea, cough) were common but not universal. Inflammation on hospitalisation was lower in frail older adults. Fever, dyspnoea, delirium and inflammation were associated with mortality. Delirium at presentation was an independent risk factor for cognitive decline at discharge. CONCLUSIONS: COVID-19 may present without cardinal symptoms as well as implicate a possible role for age-related changes in immunity in mediating the relationship between frailty and mortality.

Functional and cognitive outcomes after COVID-19 delirium.

PURPOSE: To ascertain delirium prevalence and outcomes in COVID-19. METHODS: We conducted a point-prevalence study in a cohort of COVID-19 inpatients at University College Hospital. Delirium was defined by DSM-IV criteria. The primary outcome was all-cause mortality at 4 weeks; secondary outcomes were physical and cognitive function. RESULTS: In 71 patients (mean age 61, 75% men), 31 (42%) had delirium, of which only 12 (39%) had been recognised by the clinical team. At 4 weeks, 20 (28%) had died, 26 (36%) were interviewed by telephone and 21 (30%) remained as inpatients. Physical function was substantially worse in people after delirium - 50 out of 166 points (95% CI - 83 to - 17, p = 0.01). Mean cognitive scores at follow-up were similar and delirium was not associated with mortality in this sample. CONCLUSIONS: Our findings indicate that delirium is common, yet under-recognised. Delirium is associated with functional impairments in the medium term.

Outcomes from COVID-19 across the range of frailty: excess mortality in fitter older people.

PURPOSE: Our aim was to quantify the mortality from COVID-19 and identify any interactions with frailty and other demographic factors. METHODS: Hospitalised patients aged ≥ 70 were included, comparing COVID-19 cases with non-COVID-19 controls admitted over the same period. Frailty was prospectively measured and mortality ascertained through linkage with national and local statutory reports. RESULTS: In 217 COVID-19 cases and 160 controls, older age and South Asian ethnicity, though not socioeconomic position, were associated with higher mortality. For frailty, differences in effect size were evident between cases (HR 1.02, 95% CI 0.93-1.12) and controls (HR 1.99, 95% CI 1.46-2.72), with an interaction term (HR 0.51, 95% CI 0.37-0.71) in multivariable models. CONCLUSIONS: Our findings suggest that (1) frailty is not a good discriminator of prognosis in COVID-19 and (2) pathways to mortality may differ in fitter compared with frailer older patients.

Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a ß-Lactamase-Activated Antibacterial Prodrug.

Expression of ß-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to ß-lactam antibiotics. In this article, we describe the development of an antibiotic prodrug that combines ciprofloxacin with a ß-lactamase-cleavable motif. The prodrug is only bactericidal after activation by ß-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically relevant E. coli isolates expressing diverse ß-lactamases; bactericidal activity was not observed in strains without ß-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target ß-lactamase-producing bacteria using our prodrug approach, without adversely affecting bacteria that do not produce ß-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.

Uninformed Reform: The Attempt to Abolish the Hospital Managers' Section 23 Discharge Power Under the Mental Health Act 1983.

Under section 23 of the Mental Health Act 1983 a person can be discharged by the managers of the hospital from compulsory care. The limited evidence indicates that the section 23 power is normally delegated to a specially appointed panel who hold a hearing. Unfortunately, notwithstanding the implications for the liberty, autonomy, and dignity of the compelled person, very little is known about how this process operates. Nonetheless, since 1996 there has been a sustained effort to abolish the power. In view of this, the proposal to reform the 1983 Act contained in the Queen's Speech January 2017, and the subsequent establishment of the Independent Review of the Mental Health Act in October 2017, I critique the claims made in the abolition debate, and establish the conceptual gaps therein. I argue that a much more developed understanding of the power is required before any change is made to the law in this area.

Trends in UK regional cancer mortality 1991-2007.

BACKGROUND: Until 1990, there was an upward trend in mortality from breast, lung, prostate, and colon cancers in the United Kingdom. With improvements in cancer treatment there has, in general, been a fall in mortality over the last 20 years. We evaluate regional cancer mortality trends in the United Kingdom between 1991 and 2007. METHODS: We analysed mortality trends for breast, lung, prostate, and colon cancers using data obtained from the EUREG cancer database. We have described changes in age-standardised rates (using European standard population) per 100,000 for cancer mortality and generated trends in mortality for the 11 regions using Joinpoint regression. RESULTS: Across all regions in the United Kingdom there was a downward trend in mortality for the four most common cancers in males and females. Overall, deaths from colon cancer decreased most rapidly and deaths from prostate cancer decreased at the slowest rate. Similar downward trends in mortality were observed across all regions of the United Kingdom with the data for lung cancer exhibiting the greatest variation. CONCLUSIONS: Mortality from the four most common cancers decreased across all regions of the United Kingdom; however, the rate of decline varied between cancer type and in some instances by region.

eIF4A inhibition allows translational regulation of mRNAs encoding proteins involved in Alzheimer's disease.

Alzheimer's disease (AD) is the main cause of dementia in our increasingly aging population. The debilitating cognitive and behavioral symptoms characteristic of AD make it an extremely distressing illness for patients and carers. Although drugs have been developed to treat AD symptoms and to slow disease progression, there is currently no cure. The incidence of AD is predicted to increase to over one hundred million by 2050, placing a heavy burden on communities and economies, and making the development of effective therapies an urgent priority. Two proteins are thought to have major contributory roles in AD: the microtubule associated protein tau, also known as MAPT; and the amyloid-beta peptide (A-beta), a cleavage product of amyloid precursor protein (APP). Oxidative stress is also implicated in AD pathology from an early stage. By targeting eIF4A, an RNA helicase involved in translation initiation, the synthesis of APP and tau, but not neuroprotective proteins, can be simultaneously and specifically reduced, representing a novel avenue for AD intervention. We also show that protection from oxidative stress is increased upon eIF4A inhibition. We demonstrate that the reduction of these proteins is not due to changes in mRNA levels or increased protein degradation, but is a consequence of translational repression conferred by inhibition of the helicase activity of eIF4A. Inhibition of eIF4A selectively and simultaneously modulates the synthesis of proteins involved in Alzheimer's disease: reducing A-beta and tau synthesis, while increasing proteins predicted to be neuroprotective.

Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study.

BACKGROUND: Human and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt-Jakob disease (vCJD). METHODS: We did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection. FINDINGS: The PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2.5 x 10(-17); best haplotypic association in vCJD p=1 x 10(-24)). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1.9 x 10(-7)). A similar association was found in a small sample of patients with iatrogenic CJD (p=0.030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5.6 x 10(-5)), kuru incubation time (p=0.017), and resistance to kuru (p=2.5 x 10(-4)), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease. INTERPRETATION: The polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease.

First report of Creutzfeldt-Jakob disease occurring in 2 siblings unexplained by PRNP mutation.

Sibling concurrence of pathologically confirmed prion disease has only been reported in association with pathogenic mutation of the prion protein gene (PRNP). Here, we report 2 siblings with classic neuropathologic features of sporadic Creutzfeldt-Jakob disease unexplained by PRNP mutation or known risk factors for iatrogenic transmission of prion infection. Possible explanations include coincidental occurrence, common exposure to an unidentified environmental source of prions, horizontal transmission of disease, or the presence of unknown shared genetic predisposition.

Inherited prion disease with six octapeptide repeat insertional mutation--molecular analysis of phenotypic heterogeneity.

By far the largest known kindred with an inherited prion disease caused by a prion protein (PrP) octapeptide repeat insertion mutation originates from southeast England. This extended family shows very marked phenotypic heterogeneity and provides a unique opportunity to characterize this diversity and examine possible modifying factors amongst a large number of individuals in whom prion disease has been initiated by the same defined genetic mutation. As the inherited prion diseases comprise a significant proportion of familial early-onset dementia, an appreciation of their wide range of clinical presentation is important for differential diagnosis. Genealogical and clinical record review, together with the characterization of the mutation-linked single nucleotide polymorphism and microsatellite haplotype, suggested a single founder for both this large kindred and a smaller family in the mid-18th century. Here we report the phenotype of 86 affected individuals; at least another 84 individuals are known to be at risk of inheriting the disease. Clinical onset, typically with cognitive impairment, can be strikingly early in this kindred when compared with other inherited or sporadic prion diseases. We have investigated the effect of PrP genotype, candidate genes and prion strain type on clinical, neuroradiological and neuropathological phenotype. The transmission characteristics of prions from affected individuals resembled those of classical sporadic Creutzfeldt-Jakob disease. One surprising finding was a strong inverse correlation between age of onset and disease duration. The PrP gene polymorphic codon 129 was found to confer 41% of the variance in age of onset but interestingly this polymorphism had no effect on disease duration suggesting different molecular mechanisms are involved in determining disease onset and rate of clinical progression.

Crisis of faith vs. spiritual cry of distress.

Traumatic events radiate shock waves that impact the totality of an individual: the physical, cognitive, emotional, behavioral and spiritual aspects of a person. Symptoms of distress appear horizontally in relationships with family, friends, and co-workers and vertically in relationship with God. People who have a faith relationship with God will often use religious language to express their anguish and despair regarding a traumatic event. The challenge of any crisis interventionist is to be able to hear accurately the cry of the distressed individual and respond so as to connect with and instill hope in the traumatized individual.