Impact of Addition of Metformin to Abiraterone in Metastatic Castration-Resistant Prostate Cancer Patients With Disease Progressing While Receiving Abiraterone Treatment (MetAb-Pro): Phase 2 Pilot Study

Background

There is evidence linking metformin to improved prostate cancer–related outcomes.

Screening for Candida auris in patients admitted to eight intensive care units in England, 2017 to 2018

Background Candida auris is an emerging multidrug-resistant fungal pathogen associated with bloodstream, wound and other infections, especially in critically ill patients. C. auris carriage is persistent and is difficult to eradicate from the hospital environment.AimWe aimed to pilot admission screening for C. auris in intensive care units (ICUs) in England to estimate prevalence in the ICU population and to inform public health guidance.MethodsBetween May 2017 and April 2018, we screened admissions to eight adult ICUs in hospitals with no previous cases of C. auris, in three major cities. Swabs were taken from the nose, throat, axilla, groin, perineum, rectum and catheter urine, then cultured and identified using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Patient records were linked to routine ICU data to describe and compare the demographic and health indicators of the screened cohort with a national cohort of ICU patients admitted between 2016 and 2017.ResultsAll C. auris screens for 921 adults from 998 admissions were negative. The upper confidence limit of the pooled prevalence across all sites was 0.4%. Comparison of the screened cohort with the national cohort showed it was broadly similar to the national cohort with respect to demographics and co-morbidities.ConclusionThese findings imply that C. auris colonisation among patients admitted to ICUs in England is currently rare. We would not currently recommend widespread screening for C. auris in ICUs in England. Hospitals should continue to screen high-risk individuals based on local risk assessment.     

EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer—2020 Update. Part 1: Screening,Diagnosis, and Local Treatment with Curative Intent

ObjectiveTo present a summary of the 2020 version of the European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Geriatric Oncology (SIOG) guidelines on screening, diagnosis, and local treatment of clinically localised prostate cancer (PCa).Evidence acquisitionThe panel performed a literature review of new data, covering the time frame between 2016 and 2020. The guidelines were updated and a strength rating for each recommendation was added based on a systematic review of the evidence.Evidence synthesisA risk-adapted strategy for identifying men who may develop PCa is advised, generally commencing at 50 yr of age and based on individualised life expectancy. Risk-adapted screening should be offered to men at increased risk from the age of 45 yr and to breast cancer susceptibility gene (BRCA) mutation carriers, who have been confirmed to be at risk of early and aggressive disease (mainly BRAC2), from around 40 yr of age. The use of multiparametric magnetic resonance imaging in order to avoid unnecessary biopsies is recommended. When a biopsy is performed, a combination of targeted and systematic biopsies must be offered. There is currently no place for the routine use of tissue-based biomarkers. Whilst prostate-specific membrane antigen positron emission tomography computed tomography is the most sensitive staging procedure, the lack of outcome benefit remains a major limitation. Active surveillance (AS) should always be discussed with low-risk patients, as well as with selected intermediate-risk patients with favourable International Society of Urological Pathology (ISUP) 2 lesions. Local therapies are addressed, as well as the AS journey and the management of persistent prostate-specific antigen after surgery. A strong recommendation to consider moderate hypofractionation in intermediate-risk patients is provided. Patients with cN1 PCa should be offered a local treatment combined with long-term hormonal treatment.ConclusionsThe evidence in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. The 2020 EAU-EANM-ESTRO-ESUR-SIOG guidelines on PCa summarise the most recent findings and advice for their use in clinical practice. These PCa guidelines reflect the multidisciplinary nature of PCa management.Patient summaryUpdated prostate cancer guidelines are presented, addressing screening, diagnosis, and local treatment with curative intent. These guidelines rely on the available scientific evidence, and new insights will need to be considered and included on a regular basis. In some cases, the supporting evidence for new treatment options is not yet strong enough to provide a recommendation, which is why continuous updating is important. Patients must be fully informed of all relevant options and, together with their treating physicians, decide on the most optimal management for them.     

Ethylmercury and Hg2+ induce the formation of neutrophil extracellular traps (NETs) by human neutrophil granulocytes

Humans are exposed to different mercurial compounds from various sources, most frequently from dental fillings, preservatives in vaccines, or consumption of fish. Among other toxic effects, these substances interact with the immune system. In high doses, mercurials are immunosuppressive. However, lower doses of some mercurials stimulate the immune system, inducing different forms of autoimmunity, autoantibodies, and glomerulonephritis in rodents. Furthermore, some studies suggest a connection between mercury exposure and the occurrence of autoantibodies against nuclear components and granulocyte cytoplasmic proteins in humans. Still, the underlying mechanisms need to be clarified. The present study investigates the formation of neutrophil extracellular traps (NETs) in response to thimerosal and its metabolites ethyl mercury (EtHg), thiosalicylic acid, and mercuric ions (Hg²⁺). Only EtHg and Hg²⁺ triggered NETosis. It was independent of PKC, ERK1/2, p38, and zinc signals and not affected by the NADPH oxidase inhibitor DPI. Instead, EtHg and Hg²⁺ triggered NADPH oxidase-independent production of ROS, which are likely to be involved in mercurial-induced NET formation. This finding might help understanding the autoimmune potential of mercurial compounds. Some diseases, to which a connection with mercurials has been shown, such as Wegener’s granulomatosis and systemic lupus erythematosus, are characterized by high prevalence of autoantibodies against neutrophil-specific auto-antigens. Externalization in the form of NETs may be a source for exposure to these self-antigens. In genetically susceptible individuals, this could be one step in the series of events leading to autoimmunity.     

Unique sleep‐stage transitions determined by obstructive sleep apnea severity,age and gender

In obstructive sleep apnea, patients’ sleep is fragmented leading to excessive daytime sleepiness and co‐morbidities like arterial hypertension. However, traditional metrics are not always directly correlated with daytime sleepiness, and the association between traditional sleep quality metrics like sleep duration and arterial hypertension is still ambiguous. In a development cohort, we analysed hypnograms from mild (n = 209), moderate (n = 222) and severe (n = 272) obstructive sleep apnea patients as well as healthy controls (n = 105) from the European Sleep Apnea Database. We assessed sleep by the analysis of two‐step transitions depending on obstructive sleep apnea severity and anthropometric factors. Two‐step transition patterns were examined for an association to arterial hypertension or daytime sleepiness. We also tested cumulative distributions of wake as well as sleep‐states for power‐laws (exponent α) and exponential distributions (decay time τ) in dependency on obstructive sleep apnea severity and potential confounders. Independent of obstructive sleep apnea severity and potential confounders, wake‐state durations followed a power‐law distribution, while sleep‐state durations were characterized by an exponential distribution. Sleep‐stage transitions are influenced by obstructive sleep apnea severity, age and gender. N2 → N3 → wake transitions were associated with high diastolic blood pressure. We observed higher frequencies of alternating (symmetric) patterns (e.g. N2 → N1 → N2, N2 → wake → N2) in sleepy patients both in the development cohort and in a validation cohort (n = 425). In conclusion, effects of obstructive sleep apnea severity and potential confounders on sleep architecture are small, but transition patterns still link sleep fragmentation directly to obstructive sleep apnea‐related clinical outcomes like arterial hypertension and daytime sleepiness.     

Developmental Neurotoxicity of Domoic Acid: Evidence for a Critical Window of Exposure

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Harmful algal blooms are a growing worldwide problem.1 Toxins produced by some of these algae, including the neurotoxin domoic acid (DomA), may reach humans through contaminated seafood consumption.2^,3 Because acute high-level exposure may cause amnesic shellfish poisoning,4 countries around the world limit DomA to 20μg/g of shellfish tissue.5^,6^,7 However, relatively little is known about the health effects of chronic low-level exposure such as that experienced by people who regularly eat shellfish.8^,9^,10 In a recent study11 in Environmental Health Perspectives investigators based at the Woods Hole Oceanographic Institution (WHOI) in Massachusetts analyzed the developmental neurotoxic effects of DomA in zebrafish to help fill this gap.Open in a separate windowDomoic acid is produced by algal species including members of the Pseudo-nitzschia genus (shown). It causes amnesic shellfish poisoning, a potentially fatal illness that can strike people who eat contaminated seafood, such as clams, mussels, and crab. The disease was only discovered in 1987.3 Image: Pseudo-nitzschia: Vera Trainer/NOAA; razor clams: © iStockphoto/jack looney.The researchers exposed zebrafish embryos and larvae to DomA doses that were 3- to 260-fold lower than exposures tested in earlier studies.12^,13 Even the lowest nominal dose of 0.09ng during a defined developmental window caused behavioral deficits in the larvae. The researchers causally linked these deficits to disrupted myelination processes and altered gene expression.Zebrafish have distinct advantages as a model organism. Embryos are transparent during early development, and their nervous system structures are similar to those of humans. However, in zebrafish these structures develop externally rather than hidden inside a uterus. Thus, real-time imaging can reveal changes in labeled cells of interest during very early stages of development.Instead of the usual method of adding the agent of interest to the fish tanks, the researchers used microinjection into a cardinal vein to deliver a single dose of 0.09–0.18ng of DomA to the embryos and larvae. They administered doses at specific developmental periods between 1 and 4 days postfertilization (dpf). “Microinjection ensured that the desired dose reached the embryo and let us precisely time exposures throughout development to home in on a critical window,” says first author Jennifer M. Panlilio, who performed the research as a doctoral student in a joint program between WHOI and Massachusetts Institute of Technology.Following the injection, fluorescence time-lapse microscopy was used to track the movement of specialized cells in the spinal cord and the formation of protective myelin sheaths around axons, the part of the neuron that transmits electrical signals. Larval RNA was sequenced at 3 and 7 dpf, and myelin structure was assessed at 5–7 dpf. At 7 dpf, the researchers measured the larvae’s startle behavior in response to acoustic/vibrational stimuli. Well-known neural circuits and cell types drive this behavior.14^,15Exposure to 0.09ng DomA at 2 dpf had effects that were not observed at 1 or 4 dpf. It reduced the expression of genes required for maintaining axon and myelin structure, it produced structural deficits in myelin sheaths, and it delayed and changed typical motion features of the larvae’s startle response. However, it had no appreciable effects on mortality or gross morphology.“Our novel finding is a narrow critical window of development when DomA exposure disrupts the initial myelination of axons,” says Panlilio. “This is a potential molecular basis for an observable behavior, which provides an important functional end point for future research.” Even if the end point is similar in other organisms, she adds, the critical window may be different. The myelination process in humans, for example, starts in utero and continues throughout adolescence.For Rebekah Petroff, who was not involved in the new study, the results are consistent with observations in rodents,16^,17^,18^,19 marine mammals,20^,21 and nonhuman primates.22^,23 Petroff, a postdoctoral fellow at the University of Michigan, has studied DomA neurotoxicity in adult crab-eating macaques after low-level exposure.“Disrupted myelination pathways are a plausible mechanism for developmental end points that have been observed consistently across species,” says Petroff. “However, it will be difficult to translate how important these effects are until we know more about human exposure levels.” For example, the DomA exposure of fetuses and infants whose mothers consume contaminated shellfish is currently unknown.Jennifer Freeman, an associate professor of toxicology at Purdue University, appreciates the study’s precise targeting of different developmental stages. “I think we need to do more of that in developmental toxicology,” says Freeman, who also was not involved in the project. “If you don’t capture the susceptible period, you may completely miss an adverse health outcome.”Freeman finds the alignment of multiple pieces of evidence for the critical window of 2 dpf—namely, structural imaging, gene expression analysis, and functional outcome—compelling and considers it critical for regulating other environmental chemicals.Although researchers have identified several algal genes that produce DomA,24 we have only a limited understanding of the environmental stressors that trigger production of the toxin.25 Rising sea surface temperatures are predicted to increase the frequency of harmful algal blooms, including those with DomA-producing Pseudo-nitzschia species.26 DomA may persist in shellfish tissue long after the blooms dissipate, although substantial between- and within-species variation complicates predictions.27 “It’s a complex problem that’s challenging but important to regulate,” concludes Petroff.     

Variations in the anatomy of the vertebral artery cervical loop segment - a potential predisposing factor for traumatic basal subarachnoid hemorrhage?

Fatal traumatic basal subarachnoid hemorrhage (TBSAH) is a characteristic forensic pathological entity, the investigation of which requires special techniques. In Liverpool, post-mortem room angiography is undertaken, followed by complete removal of the vertebral arteries and histological examination. It has been observed that the arterial anatomy can be highly variable, particularly the length and course of the loop segments located between the C2 vertebra and the dura. In a number of cases of TBSAH the loop segments of torn vessels have appeared relatively short. Having observed this phenomenon subjectively in our case work, a radiological study was undertaken with the aim of quantifying vertebral artery loop anatomy variation in a ‘normal’ population. Multiphase post-mortem computed tomography angiography (MPMCTA) scans of 98 subjects were reviewed and the lengths of the different portions of the loop segments (foramen magnum to the upper border of C1, between C1 and C2, and the bony foramina themselves) of each vertebral artery were measured using semi-automated vessel analysis software. The measurements obtained provide objective evidence of marked anatomical variation, with some loop segments more than twice the length of others. These results are important because a short vertebral artery loop segment might be a significant factor in predisposing an individual to TBSAH following a blow to the head or neck.     

Treatment of blepharospasm and Meige’s syndrome with abo- and onabotulinumtoxinA: long-term safety and efficacy in daily clinical practice

Journal of Neurology - Thirty years after their approval, botulinum toxin injections still are the first-line therapy for blepharospasm. The aim of our study was to analyze long-term data...