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Summary: Melanoma‐associated retinopathy (MAR) is a rare paraneoplastic autoimmune manifestation of cutaneous malignant melanoma. Patients classically present with acute onset night blindness, positive visual phenomena and visual field defects, and typically have significantly reduced quality of life as a result. Early recognition of MAR is of prognostic significance as it can precede the diagnosis of primary or metastatic malignant melanoma, and early treatment can lower the risk of irreversible immunological damage to the retinal cells with improved visual outcomes. The focus of our review article is therefore to raise awareness of MAR and present the latest evidence relating to the investigation and management of this condition. Click here for the corresponding questions to this CME article. [ABSTRACT FROM AUTHOR]

Synthetic cannabinoids, which began proliferating in the United States in 2009, have gone through numerous iterations of modification to their chemical structures. More recent generations of compounds have been associated with significant adverse outcomes following use, including cognitive and psychomotor impairment, seizures, psychosis, tissue injury and death. These effects increase the urgency for forensic and public health laboratories to develop methods for the detection and identification of novel substances, and apply these to the determination of their metabolism and disposition in biological samples. This comprehensive review describes the history of the appearance of the drugs in the United States, discusses the naming conventions emerging to designate new structures, and describes the most prominent new compounds linked to the adverse effects now associated with their use. We review in depth the metabolic pathways that have been elucidated for the major members of each of the prevalent synthetic cannabinoid drug subclasses, the enzyme systems responsible for their metabolism, and the use of in silico approaches to assist in predicting and identifying the metabolites of novel compounds and drug subclasses that will continue to appear. Finally, we review and critique analytical methods applied to the detection of the drugs and their metabolites, including immunoassay screening, and liquid chromatography mass spectrometry confirmatory techniques applied to urine, serum, whole blood, oral fl uid, hair, and tissues. [ABSTRACT FROM AUTHOR]

Sam P Gurney, 1 Sateesh Ramalingam, 2 Alan Thomas, 2 Alex J Sinclair, 3–5 Susan P Mollan 1 1Birmingham Neuro-Ophthalmology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2WB, UK; 2Neuroradiology Department, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2WB, UK; 3Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; 4Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, UK; 5Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham B15 2WB, UKCorrespondence: Susan P MollanBirmingham Neuro-Ophthalmology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2WB, UKTel +44 1213716912 Email susan.mollan@uhb.nhs.ukAbstract: Idiopathic Intracranial Hypertension (IIH) is a debilitating disorder characterised by raised intracranial pressure (ICP), papilloedema with the potential risk of permanent visual loss, and headaches that are profoundly disabling and reduce the quality of life. The first consensus guidelines have been published on investigation and management of adult IIH and one key area of uncertainty is the utility of dural venous sinus stenting for the management of headache and visual loss. There are an increasing number of series published and to help understand the successes and complications. During a patient physician priority setting, the understanding of the best type of intervention to treat IIH was assigned to the top 10 of most desired research questions for the disease. Ultimately randomised clinical trials (RCTs) in neurovascular stenting for IIH would be instructive, as the literature to date may suffer from publication bias. Due to the increasing incidence of IIH, there is no better time to systematically investigate interventions that may reverse the disease process and achieve remission. In this review we discuss the pathophysiology of IIH in relation to venous sinus stenosis, the role of venous sinus stenting with a review of the relevant literature, the advantages and disadvantages of stenting compared with other surgical interventions, and the future of stenting in the treatment of IIH.Keywords: pseudotumor cerebri, raised intracranial pressure, venous sinus stenosis, neurovascular stenting, headache, papilloedema

Synthetic cannabinoid drugs have become an established part of the recreational drug landscape in the United States and internationally. These drugs are manufactured in clandestine laboratories internationally and distributed in the United States in smoking mixtures, use of which produces effects very similar to use of marijuana. The adverse-effect profile of the drugs has not been studied in humans and infrequently in animal models, so much of the information about their toxicity comes from emergency department and treatment reports and forensic case studies. This review considers the discovery and characterization of the endocannabinoid system, approaches to receptor-binding studies of various synthetic cannabinoids from the first wave ofnaphthoylindoles (e.g., JWH-018) to the emerging adamantoylindole drugs (e.g., AKB-48), and their analogs, to evaluate the potential activity of drugs in this class. Currently employed approaches to assessing functional activity of the drugs using in vitro and in vivo models is also described, and comparisons made to the effects of THC. The physiological effects of activation of the endocannabinoid system in humans are reviewed, and the physiological effects of cannabinoid use are described. Case reports of adverse events including emergency department admissions, mental health admissions, and clinical and forensic case reports are presented in detail and discussed to summarize the current state of knowledge of adverse effects, both clinical and forensic in humans, including effects on driving ability, and tissue injury and death. The greatest weight is accorded to those reports that include toxicological confirmation of use. Finally, we discuss the current status of attempts to schedule and control the distribution of synthetic cannabinoids and the relevance of receptor binding and functional activity in this context. There is growing toxicological and pharmacological evidence of impairment, psychosis, tissue injury, and isolated deaths attributable to this emerging class of drugs. [ABSTRACT FROM AUTHOR]

The literature on HIV disease has largely centred on the virus' biological, psychological and social impact on the infected individual. There is, however, an increasing recognition of the impact of this virus and the extent to which it reaches beyond the infected person and affects partners, families, friends and carers. This focus, from a family systems perspective, on the impact of illness (Rolland, 1994) and death (Walsh & McGoldrick, 1991), attempts to give attention to both the immediate and long term effects on nuclear and extended family members, whilst the work of Bor, Miller & Goldman (1992) specifically offers a family systems approach to psychotherapy for people affected by HIV. The following case is an illustration of the complex and challenging issues encountered in working with an affected family member and the way in which 'a range of feelings depending on the unique meaning of the relationship and its loss for each member and the implications of the death for the family unit' is experienced (Walsh & McGoldrick, 1991). [ABSTRACT FROM AUTHOR]

The identification of somatic RB1 variation is crucial to confirm the heritability of retinoblastoma. We and others have previously shown that, when tumour DNA is unavailable, cell-free DNA (cfDNA) derived from aqueous humour (AH) can be used to identify somatic RB1 pathogenic variation. Here we report RB1 pathogenic variant detection, as well as cfDNA concentration in an extended cohort of 75 AH samples from 68 patients. We show cfDNA concentration is highly variable and significantly correlated with the collection point of the AH. Cell-free DNA concentrations above 5 pg/µL enabled the detection of 93% of known or expected RB1 pathogenic variants. In AH samples collected during intravitreal chemotherapy treatment (Tx), the yield of cfDNA above 5 pg/µL and subsequent variant detection was low (≤46%). However, AH collected by an anterior chamber tap after one to three cycles of primary chemotherapy (Dx1+) enabled the detection of 75% of expected pathogenic variants. Further limiting our analysis to Dx1+ samples taken after ≤2 cycles (Dx ≤ 2) provided measurable levels of cfDNA in all cases, and a subsequent variant detection rate of 95%. Early AH sampling is therefore likely to be important in maximising cfDNA concentration and the subsequent detection of somatic RB1 pathogenic variants in retinoblastoma patients undergoing conservative treatment.

Introduction: Those who work and recreate outdoors experience woodsmoke exposure during fire season. Exercise during woodsmoke exposure harms the cardiovascular system, but the acute physiologic and biochemical responses are understudied. The purpose of this pilot laboratory-based study was to examine the effect of exercise during woodsmoke exposure on acute indicators of cardiovascular function, including heart rate variability (HRV), pulse wave velocity (PWV), blood pressure (BP), augmentation index (AIx), and blood oxidative stress., Methods: Ten participants performed 2 moderate-intensity exercise (70% V˙O 2 max ) trials (clean air 0 μg·m -3 , woodsmoke 250 μg·m -3 ) in a crossover design. HRV, PWV, BP, AIx, and blood oxidative stress were measured before, after, and 90 min after exercise for each trial. Blood oxidative stress was quantified through lipid damage (LOOH, 8-ISO), protein damage (3-NT, PC), and antioxidant capacity (TEAC)., Results: A 45-min woodsmoke exposure combined with moderate-intensity exercise did not result in a statistically significant difference in HRV, PWV, BP, AIx, or oxidative stress (P>0.05)., Conclusions: Despite the known deleterious effects of smoke inhalation, moderate-intensity aerobic exercise while exposed to woodsmoke particulate matter (250 μg·m -3 ) did not result in a statistically significant difference in HRV, PWV, or blood oxidative stress in this methodologic context. Although findings do not negate the negative impact of woodsmoke inhalation, additional research approaches are needed to better understand the acute effects of smoke exposure on the cardiovascular system., (Copyright © 2021 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this retrospective analysis was to assess if serial lung ultrasound assessments in patients with COVID-19 pneumonia, including a novel simplified scoring system, correlate with PaO 2 :FiO 2 ratio, as a marker of disease severity, and patient outcomes. Methods : Patients treated for COVID-19 pneumonia in a tertiary intensive care unit who had a lung ultrasound assessment were included. Standardised assessments of anterior and lateral lung regions were prospectively recorded. A validated lung ultrasound score-of-aeration and a simplified scoring system based on the number of disease-free lung regions were correlated with: PaO 2 :FiO 2 ratio, successful weaning from mechanical ventilation, and status (alive or dead) at discharge. MedCalc© statistical software was used for statistical analysis. Results : 28 patients (109 assessments) were included. Correlation was seen between score-of-aeration and PaO 2 :FiO 2 ratio (r = -0.61, p<0.0001) and between the simplified scoring system and PaO 2 :FiO 2 ratio (r = 0.52 p<0.0001). Achieving a score-of-aeration of ≤9/24 or ≥2 disease-free regions was associated with successful weaning from mechanical ventilation and survival to ICU discharge (accuracy of 94% and 97% respectively). Conclusion : Retrospective analysis from this small cohort of patients demonstrates that scores-of-aeration and a simplified scoring system based on the number of disease-free antero-lateral regions from serial LUS assessments correlate with PaO 2 :FiO 2 ratio as a marker of disease severity in patients with COVID-19 pneumonia. In addition, lung ultrasound may help identify patients who will have favourable outcomes., Competing Interests: None to declare, (Copyright (c) 2021 Matthew Llewelyn Gibbins, Quentin Otto, Paul Adrian Clarke, Stefan Gurney.)

With the recent increase in research into ferroelectric, anti-ferroelectric and piezoelectric materials, studying the solid-state properties in situ under applied electric fields is vital in understanding the underlying processes. Where this behaviour is the result of atomic displacements, crystallographic insight has an important role. This work presents a sample environment designed to apply an electric field to single-crystal samples in situ on the small-molecule single-crystal diffraction beamline I19, Diamond Light Source (UK). The configuration and operation of the cell is described as well as its application to studies of a proton-transfer colour-change material., (© Lucy K. Saunders et al. 2021.)

Background: Optimal prophylactic and therapeutic management of thromboembolic disease in patients with COVID-19 remains a major challenge for clinicians. The aim of this study was to define the incidence of thrombotic and haemorrhagic complications in critically ill patients with COVID-19. In addition, we sought to characterise coagulation profiles using thromboelastography and explore possible biological differences between patients with and without thrombotic complications., Methods: We conducted a multicentre retrospective observational study evaluating all the COVID-19 patients received in four intensive care units (ICUs) of four tertiary hospitals in the UK between March 15, 2020, and May 05, 2020. Clinical characteristics, laboratory data, thromboelastography profiles and clinical outcome data were evaluated between patients with and without thrombotic complications., Results: A total of 187 patients were included. Their median (interquartile (IQR)) age was 57 (49-64) years and 124 (66.3%) patients were male. Eighty-one (43.3%) patients experienced one or more clinically relevant thrombotic complications, which were mainly pulmonary emboli (n = 42 (22.5%)). Arterial embolic complications were reported in 25 (13.3%) patients. ICU length of stay was longer in patients with thrombotic complications when compared with those without. Fifteen (8.0%) patients experienced haemorrhagic complications, of which nine (4.8%) were classified as major bleeding. Thromboelastography demonstrated a hypercoagulable profile in patients tested but lacked discriminatory value between those with and without thrombotic complications. Patients who experienced thrombotic complications had higher D-dimer, ferritin, troponin and white cell count levels at ICU admission compared with those that did not., Conclusion: Critically ill patients with COVID-19 experience high rates of venous and arterial thrombotic complications. The rates of bleeding may be higher than previously reported and re-iterate the need for randomised trials to better understand the risk-benefit ratio of different anticoagulation strategies.

Background: Leptospirosis is a potentially fatal zoonosis. It can cause a wide range of symptoms, including diffuse alveolar haemorrhage which occurs in a minority of cases but carries a mortality of over 70%. These patients may present with severe acute respiratory failure. The differential diagnosis for diffuse alveolar haemorrhage is broad whereas prompt diagnosis and treatment can be lifesaving., Case Presentation: A 20-year-old previously fit and well trout farm worker presented with a 3-day history of malaise, fevers, diarrhoea, vomiting and jaundice. He developed haemoptysis, severe headaches, neck stiffness and photophobia on the day of emergency admission. He was anaemic and thrombocytopenic. Anuric acute kidney injury (urea 32, creat 507) required immediate haemofiltration. In view of progressive respiratory failure with four-quadrant lung infiltrates on imaging, he was given broad spectrum antibiotics and pulsed methylprednisolone empirically, in case of a vasculitic pulmonary-renal presentation. He was intubated within 48 h of admission. Despite attempted protective ventilatory management, he remained hypoxaemic and developed pneumomediastinum. He was retrieved to a specialist cardiorespiratory intensive care unit on femoro-femoral mobile VV-ECMO. Three days from admission, results showed positive Leptospira IgM and real-time PCR. Serial bronchoscopies showed old and fresh clots, but not the classical progressive late red tinge of the returned lavage fluid. After eight days, VV-ECMO was weaned, he was extubated three days later, and made a full recovery. At 9 months follow-up, he was clinically better, with resolution of the CT scan findings and near normal lung function, albeit with low normal gas transfer., Conclusions: Leptospirosis is a rare but important differential to be considered in diffuse alveolar haemorrhage presenting to the ICU, especially in young males. A thorough history for occupational or recreational risk factors may offer the diagnostic clue. Most patients recover fully with antibiotics. However, resulting acute severe respiratory failure can ensue. In this situation, early consideration for respiratory ECMO support offers time for clearance of endobronchial clot, parenchymal recovery, and prevention of ventilator-induced lung injury. Steroids have no clear evidence but may be used to avoid delay in treating suspected vasculitic or autoimmune causes of diffuse alveolar haemorrhage., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

In this article, the specification and application of the new double-sided YAG laser-heating system built on beamline I15 at Diamond Light Source are presented. This system, combined with diamond anvil cell and X-ray diffraction techniques, allows in situ and ex situ characterization of material properties at extremes of pressure and temperature. In order to demonstrate the reliability and stability of this experimental setup over a wide range of pressure and temperature, a case study was performed and the phase diagram of lead was investigated up to 80 GPa and 3300 K. The obtained results agree with previously published experimental and theoretical data, underlining the quality and reliability of the installed setup., (open access.)

Benzodiazepines increase vulnerability to infection through α1 subunit dependent Υ-amino-butyric-type-A (GABAA) signalling. Immune cell expression of GABAA receptors and the effect of diazepam on influenza infection was investigated. In patients with pneumonia, α1 GABAA subunits were expressed on alveolar macrophages and blood monocytes. In mice, influenza induced dynamic changes in immune cell GABAA subunit expression: α1 subunits decreased on alveolar macrophage, but increased on monocytes, CD4+ and CD8+ T cells. Following influenza viral infection, diazepam delayed weight loss on day 3 but later increased weight loss. Viral load was unaffected but increased bacterial superinfection was noted on day 10., (Copyright © 2015. Published by Elsevier B.V.)

Tracheal rupture is an infrequent, severe complication of endotracheal intubation, which can be difficult to diagnose. Post-intubation tracheal rupture (PiTR) is distinct from non-iatrogenic causes of tracheobronchial trauma and often requires different treatment. The increasing adoption of pre-hospital emergency services increases the likelihood of such complications from emergency intubations. Effective management strategies for PiTR outside specialist cardiothoracic units are possible. Two cases of severe PiTR, successfully managed non-operatively on a general medical-surgical intensive care unit, illustrate a modified approach to current standards. The evidence base for PiTR is reviewed and a pragmatic management algorithm presented.

Background/Aims. Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). In women with Down syndrome, we examined the relation of polymorphisms in hydroxysteroid-17beta-dehydrogenase (HSD17B1) to age at onset and risk of AD. HSD17B1 encodes the enzyme 17β-hydroxysteroid dehydrogenase (HSD1), which catalyzes the conversion of estrone to estradiol. Methods. Two hundred and thirty-eight women with DS, nondemented at baseline, 31-78 years of age, were followed at 14-18-month intervals for 4.5 years. Women were genotyped for 5 haplotype-tagging single-nucleotide polymorphisms (SNPs) in the HSD17B1 gene region, and their association with incident AD was examined. Results. Age at onset was earlier, and risk of AD was elevated from two- to threefold among women homozygous for the minor allele at 3 SNPs in intron 4 (rs676387), exon 6 (rs605059), and exon 4 in COASY (rs598126). Carriers of the haplotype TCC, based on the risk alleles for these three SNPs, had an almost twofold increased risk of developing AD (hazard ratio = 1.8, 95% CI, 1.1-3.1). Conclusion. These findings support experimental and clinical studies of the neuroprotective role of estrogen.

Type II errors may be having a significant impact on drug discovery. This is of particular importance in the clinical neurosciences, where endpoints are often subjective scores of disability rather than unequivocal events such as survival. Here we examine a recently published study [Lang AE, Gill S, Patel NK, et al. Randomized controlled study of intraputamenal glial cell-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006;59:459-66] in an area of immense importance to neuroscience. This small study found no detectable clinical benefit from infused intraputamenal GDNF as a treatment for Parkinson disease. However the standard deviation of the accrued data turned out to be considerably higher than had been anticipated in the power analysis performed prior to the study. In order to determine what impact, if any, this had on the conclusions that could be drawn, the actual data were analyzed by means of both the t-test and the rank-based Somers'D. The study was found to be underpowered and thus incapable of ruling out a large effect of GDNF on Parkinson disease. It therefore does not contradict the large effects seen in previous open-label studies.

Unlabelled: Urinary tract infection (UTI) is a common condition in children and may lead to renal scarring with a risk of later hypertension and renal insufficiency. We made a cross-sectional study of the 99mTc-DMSA findings in 496 children referred for following symptomatic UTI to a Department of Nuclear Medicine and we categorized the results, to provide a framework for further study., Method: A standard 99mTc-DMSA protocol was used to study 496 children (157 males, 339 females) aged from birth to 14 yr. Findings were classified according to the image appearance and relative function of each kidney. These were related to age, sex, history and timing of UTI and the results on micturating cysto-urethrography (MCU)., Results: Images were normal, with function within limits (45%-50% in one kidney), in approximately half the boys and girls studied. The other images were classified as equivocal in 68 children, abnormal unilaterally in 105 and bilaterally in 76, and they were subdivided according to the image appearance. No image changes could be identified that were specifically associated with acute UTI. Diffuse change alone was uncommon. A high proportion of abnormal images was found in infant boys, older girls with recurrent UTI and those children with vesico-ureteric reflux (VUR). Of the bilateral abnormal images, 98% were seen in children with VUR., Conclusion: Our findings suggest that infective renal change may be superimposed on underlying congenital lesions (perhaps detectable antenatally) or may be acquired following UTI in the presence of reflux and are thus potentially preventable. This study also suggests that VUR is almost certain to have occurred in a child who has bilateral abnormal 99mTc-DMSA images following UTI and is also commonly present in those with definite unilateral defects.

Nymphal Ixodes scapularis Say, the vector of Lyme borreliosis, was most common in forested areas across Shelter Island, Suffolk County, New York, and least common in xeric habitats such as beach and grassland. At the scale of individual house yards, nymphs were most common at wooded edges of property and least common on lawns. The abundance of ticks at yard edges was positively correlated with numbers on lawns and in landscaping, suggesting that tick abundance in woods affects abundances in adjacent yards. Because 57% of all yard area is adjacent to woodlands on Shelter Island, public health efforts to reduce tick populations in wooded areas should supplement efforts by individual yard owners to decrease risk. Methods of tick control for woodlands should also be evaluated for their effect on tick populations in adjacent yard habitats.

Nymphal Ixodes scapularis Say deer ticks were collected at 22 parks or other natural areas on Long Island, New York, to examine the relationship between tick populations and geographic position, size of area, presence of white-tailed deer, Odocoileus virginianus (Zimmerman), and numbers of human Lyme disease cases in adjacent communities. Nymphal ticks were 93% less abundant when deer were absent and were also less common in smaller natural areas. Geographic position on Long Island was not important. Tick numbers were significantly correlated with human Lyme disease incidence in adjacent townships. A second survey of larval ticks from five areas where deer were absent and six where deer were present found larvae present at four of the five sites without deer, but at only 2% of the levels found where deer were present. These results suggest that populations of I. scapularis can occur and reproduce in the absence of white-tailed deer, so that eradication of all deer would greatly reduce, but not eliminate, all risk of Lyme disease.