Princess Royal University Hospital

This position document has been developed by the Dysphagia Working Group, a committee of members from the European Society for Swallowing Disorders and the European Union Geriatric Medicine Society, and invited experts. It consists of 12 sections that cover all aspects of clinical management of oropharyngeal dysphagia (OD) related to geriatric medicine and discusses prevalence, quality of life, and legal and ethical issues, as well as health economics and social burden. OD constitutes impaired or uncomfortable transit of food or liquids from the oral cavity to the esophagus, and it is included in the World Health Organization's classification of diseases. It can cause severe complications such as malnutrition, dehydration, respiratory infections, aspiration pneumonia, and increased readmissions, institutionalization, and morbimortality. OD is a prevalent and serious problem among all phenotypes of older patients as oropharyngeal swallow response is impaired in older people and can cause aspiration. Despite its prevalence and severity, OD is still underdiagnosed and untreated in many medical centers. There are several validated clinical and instrumental methods (videofluoroscopy and fiberoptic endoscopic evaluation of swallowing) to diagnose OD, and treatment is mainly based on compensatory measures, although new treatments to stimulate the oropharyngeal swallow response are under research. OD matches the definition of a geriatric syndrome as it is highly prevalent among older people, is caused by multiple factors, is associated with several comorbidities and poor prognosis, and needs a multidimensional approach to be treated. OD should be given more importance and attention and thus be included in all standard screening protocols, treated, and regularly monitored to prevent its main complications. More research is needed to develop and standardize new treatments and management protocols for older patients with OD, which is a challenging mission for our societies.

BACKGROUND: Patent foramen ovale (PFO) is prevalent in patients with migraine with aura. Observational studies show that PFO closure resulted in migraine cessation or improvement in approximately 80% of such patients. We investigated the effects of PFO closure for migraine in a randomized, double-blind, sham-controlled trial. METHODS AND RESULTS: Patients who suffered from migraine with aura, experienced frequent migraine attacks, had previously failed > or = 2 classes of prophylactic treatments, and had moderate or large right-to-left shunts consistent with the presence of a PFO were randomized to transcatheter PFO closure with the STARFlex implant or to a sham procedure. Patients were followed up for 6 months. The primary efficacy end point was cessation of migraine headache 91 to 180 days after the procedure. In total, 163 of 432 patients (38%) had right-to-left shunts consistent with a moderate or large PFO. One hundred forty-seven patients were randomized. No significant difference was observed in the primary end point of migraine headache cessation between implant and sham groups (3 of 74 versus 3 of 73, respectively; P=0.51). Secondary end points also were not achieved. On exploratory analysis, excluding 2 outliers, the implant group demonstrated a greater reduction in total migraine headache days (P=0.027). As expected, the implant arm experienced more procedural serious adverse events. All events were transient. CONCLUSIONS: This trial confirmed the high prevalence of right-to-left shunts in patients with migraine with aura. Although no significant effect was found for primary or secondary end points, the exploratory analysis supports further investigation. The robust design of this study has served as the model for larger trials that are currently underway in the United States and Europe.

Gout is a common disease both in primary care and hospital practice [1]. Although drug therapy for gout has become a paradigm for the effective management and prevention of an acute and potentially chronic rheumatic disease, many of the recommendations for treatment are based on expert consensus rather than research evidence and audits of practice suggest that treatment is very variable. Evidence-based guidelines are needed at the present time: The aim has been to develop concise, patient-focussed, evidence-based recommendations for the management of gout for doctors and allied heath professionals in primary care and hospital practice in the UK, which will also provide a useful resource for patients. to provide a framework for improving standards of care. to assess the potential of new therapies such as Coxibs [2], urate oxidases [3] and novel xanthine oxidase inhibitors [4] currently in clinical development; to provide recommendations for alcohol consumption, diet and lifestyle modification in response to frequently asked questions by patients (www.ukgoutsociety.org) in the light of recent epidemiological studies linking gout with alcohol consumption [5], dietary protein intake [6] and features of the metabolic syndrome, which are assuming epidemic proportions [7]; to define recommendations for treating secondary atypical gout, and small subgroups of patients with severe recurrent gout associated with renal insufficiency, organ transplantation, allopurinol hypersensitivity or primary purine overproduction. Recommendations for the diagnosis and investigation of gout [8] are not addressed. This is a short summary of the guideline. The full guideline can be accessed at Rheumatology Online (www.rheumatology.oxfordjournals.org). The management pathways proposed are summarized in the accompanying flowchart. The strength recommendations, based on levels of evidence, are graded A–C [9], and the recommendations are divided into three sections: Affected joints should be rested (C) and analgesic, anti-inflammatory drug therapy commenced immediately, and continued for 1–2 weeks (A). Fast-acting oral NSAIDs at maximum doses are the drugs of choice when there are no contraindications (A). In patients with increased risk of peptic ulcers, bleeds or perforations, co-prescription of gastro-protective agents should follow standard guidelines for the use of NSAIDs and Coxibs (A). Colchicine can be an effective alternative but is slower to work than NSAIDs (A). In order to diminish the risks of adverse effects (especially diarrhoea) it should be used in doses of 500 μg bd–qds (C). Allopurinol should not be commenced during an acute attack (B) but in patients already established on allopurinol, it should be continued and the acute attack should be treated conventionally (A). Opiate analgesics can be used as adjuncts (C). Intra-articular corticosteroids are highly effective in acute gouty monoarthritis (B) and i.a, oral, i.m or i.v corticosteroids can be effective in patients unable to tolerate NSAIDs, and in patients refractory to other treatments (A). If diuretc drugs are being used to treat hypertension, an alternative antihypertensive agent should be considered, but in patients with heart failure, diuretic therapy should not be discontinued (C). In overweight patients dietary modification to achieve ideal body weight should be attempted (B), but ‘crash dieting’ (B) and high protein/low carbohydrate (Atkins-type) diets (C) should be avoided. Inclusion of skimmed milk and/or low fat yoghurt, soy beans and vegetable sources of protein and cherries, in the diet should be encouraged (B). Intake of high purine foods and red meat should be restricted (B). Liver, kidneys, shellfish and yeast extracts should be avoided (B), and overall protein intake should be restricted (C). Patients with gout and a history of urolithiasis should be encouraged to drink >2 l of water daily (B) and avoid dehydration (C). Alkalinization of the urine with potassium citrate (60 mEq/day) should be considered in recurrent stone formers (B). Alcohol consumption should be restricted to <21 units/week (men) and 14 units/week (women) (B), and patients should be encouraged to have at least 3 alcohol-free days per week (C). Beer, stout, port and similar fortified wines are best avoided (C). Patients should be discouraged from undertaking trials of herbal remedies without medical consultation (C). Affected joints should be elevated and exposed in a cool environment (C). ‘Bed cages’ (C) and ice packs (B) can be effective adjuncts to therapy. Trauma to joints (B) and intense physical exercise (B) should be avoided but moderate physical exercise encouraged (B). The full guideline also contains recommendations for the use of uricolytic agents and combined therapy with allopurinol and uricosuric drugs; as well as for the management of special groups of patients with chronic gout. The plasma urate should be maintained below, 300 μmol/l (C). In uncomplicated gout uric acid lowering drug therapy should be started if a second attack, or further attacks occur within 1 yr (B). Uric acid lowering drug therapy should also be offered to patients with tophi (C), patients with renal insufficiency (B) patients with uric acid stones and gout (B) and to patients who need to continue treatment with diuretics (B). Commencement of uric acid-lowering drug therapy should be delayed until 1–2 weeks after inflammation has settled (C). Initial long-term treatment of recurrent uncomplicated gout normally should be with allopurinol starting in a dose of 50–100 mg/day and increasing by 50–100 mg increments every few weeks, adjusted if necessary for renal function, until the therapeutic target (SUA <300 μmol/l) is reached (maximum dose 900 mg) (B). Uricosuric agents can be used as second-line drugs in patients who are under-excretors of uric acid and in those resistant to, or intolerant of, allopurinol (B). The preferred drugs are sulphinpyrazone (200–800 mg/day) in patients with normal renal function or benzbromarone (50–200 mg/day) in patients with mild/moderate renal insufficiency (B). Colchicine 0.5 mg bd should be co-prescribed following initiation of treatment with allopurinol or uricosuric drugs, and continued for up to 6 months (A). In patients who cannot tolerate colchicine, an NSAID or Coxib can be substituted provided that there are no contraindications, but the duration of NSAID or Coxib cover should be limited to 6 weeks (C). Aspirin in low doses (75–150 mg/day) has insignificant effects on the plasma urate, and should be used as required for cardiovascular prophylaxis (B). However, aspirin in analgesic doses (600–2400 mg/day) interferes with uric acid excretion and should be avoided (B). The guideline has been developed as a National Guideline, acceptable for use throughout the NHS in the UK. If followed and implemented, these guidelines will provide an opportunity to improve the quality of care for patients with gout in both hospital and community settings. Assess the impact of the guideline on: The frequency and duration of gout flares. The achievement of target reduction in plasma urate levels. Lifestyle modification (weight reduction, alcohol intake and dietary adjustment). The assessment and treatment of co-morbid disorders (diabetes mellitus, hypertension, and cardiovascular risk factors). The time to accurate diagnosis and treatment of gout in primary and hospital care settings. Documentation of all of the above.

Post-stroke dysphagia (a difficulty in swallowing after a stroke) is a common and expensive complication of acute stroke and is associated with increased mortality, morbidity, and institutionalization due in part to aspiration, pneumonia, and malnutrition. Although most patients recover swallowing spontaneously, a significant minority still have dysphagia at six months. Although multiple advances have been made in the hyperacute treatment of stroke and secondary prevention, the management of dysphagia post-stroke remains a neglected area of research, and its optimal management, including diagnosis, investigation and treatment, have still to be defined.

Reinke's space is a critical laryngeal structure, and the eponym remains in current use in both clinical and research settings. However, little is known about the life of the German anatomist Friedrich Berthold Reinke. His name is missing from the otolaryngological histories, despite his work on the structure he described being responsible for a fundamental advance in our understanding of the larynx. Although brilliant, Reinke was described as impetuous and coarse by his colleagues, resulting in his academic career being cut short. Reinke's relative anonymity is thought to derive from the fact that he never defined himself as a laryngologist. Without question, Reinke's observations of the human vocal fold are substantive contributions, without which modern laryngology could not have evolved. This article aimed to summarise this brilliant yet troubled man's life and achievements, allowing appreciation for his singular genius and fundamental contribution to laryngology.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Pain is a key unmet need and a major aspect of non-motor symptoms of Parkinson's disease (PD). No specific validated scales exist to identify and grade the various types of pain in PD. We report an international, cross-sectional, open, multicenter, one-point-in-time evaluation with retest study of the first PD-specific pain scale, the King's PD Pain Scale. Its seven domains include 14 items, each item scored by severity (0-3) multiplied by frequency (0-4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. One hundred seventy-eight PD patients with otherwise unexplained pain (age [mean ± SD], 64.38 ± 11.38 y [range, 29-85]; 62.92% male; duration of disease, 5.40 ± 4.93 y) and 83 nonspousal non-PD controls, matched by age (64.25 ± 11.10 y) and sex (61.45% males) were studied. No missing data were noted, and floor effect was observed in all domains. The difference between mean and median King's PD Pain Scale total score was less than 10% of the maximum observed value. Skewness was marginally high (1.48 for patients). Factor analysis showed four factors in the King's PD Pain Scale, explaining 57% of the variance (Kaiser-Mayer-Olkin, 0.73; sphericity test). Cronbach's alpha was 0.78, item-total correlation mean value 0.40, and item homogeneity 0.22. Correlation coefficients of the King's PD Pain Scale domains and total score with other pain measures were high. Correlation with the Scale for Outcomes in PD-Motor, Non-Motor Symptoms Scale total score, and quality of life measures was high. The King's PD Pain Scale seems to be a reliable and valid scale for grade rating of various types of pain in PD.

Myopia is a common, complex trait with considerable economic and social impact and, in highly affected individuals, ocular morbidity. We performed a classic twin study of 506 unselected twin pairs and inferred the heritability of refractive error to be 0.89 (95% confidence interval 0.86-0.91). A genomewide scan of 221 dizygotic twin pairs, analyzed by use of optimal Haseman-Elston regression methods implemented by use of generalized linear modeling, showed significant linkage (LOD >3.2) to refractive error at four loci, with a maximum LOD score of 6.1 at 40 cM on chromome 11p13. Evidence of linkage at this locus, as well as at the other linkage peaks at chromosomes 3q26 (LOD 3.7), 8p23 (LOD 4.1), and 4q12 (LOD 3.3), remained the same or became stronger after model fit was checked and outliers were downweighted. Examination of potential candidate genes showed the PAX6 gene directly below the highest peak at the 11p13 locus. PAX6 is fundamental to identity and growth of the eye, but reported mutations usually result in catastrophic congenital phenotypes such as aniridia. Haplotype tagging of 17 single-nucleotide polymorphisms (SNPs), which covered the PAX6 gene and had common minor allele frequencies, identified 5 SNPs that explained 0.999 of the haplotype diversity. Linkage and association analysis of the tagging SNPs showed strong evidence of linkage for all markers with a minimum chi 21 of 7.5 (P=.006) but no association. This suggests that PAX6 may play a role in myopia development, possibly because of genetic variation in an upstream promoter or regulator, although no definite association between PAX6 common variants and myopia was demonstrated in this study.

We have read the BTS guidelines for the management of pleural infection1 and are concerned about the proposed antibiotic choices for the initial treatment of culture negative or pending pleural infection. Section 2.8 of the text and table 2 detail the antibiotic choices but, in our opinion, leave considerable gaps in antibacterial cover against the likely pathogens. In particular:

Bupropion has been used as an antidepressant for over 20 years, though its licence for such use varies and it is typically a third- or fourth-line agent. It has a unique pharmacology, inhibiting the reuptake of noradrenaline and dopamine, potentially providing pharmacological augmentation to more common antidepressants such as selective serotonergic reuptake inhibitors (SSRIs). This systematic review and meta-analysis identified 51 studies, dividing into four categories: bupropion as a sole antidepressant, bupropion coprescribed with another antidepressant, bupropion in 'other' populations (e.g. bipolar depression, elderly populations) and primary evaluation of side effects. Methodologically more robust trials support the superiority of bupropion over placebo, and most head-to-head antidepressant trials showed an equivalent effectiveness, though some of these are hindered by a lack of a placebo arm. Most work on the coprescribing of bupropion with another antidepressant supports an additional effect, though many are open-label trials. Several large multi-medication trials, most notably STAR*D, also support a therapeutic role for bupropion; in general, it demonstrated similar effectiveness to other medications, though this literature highlights the generally low response rates in refractory cohorts. Effectiveness has been shown in 'other' populations, though there is an overall dearth of research. Bupropion is generally well tolerated, it has very low rates of sexual dysfunction, and is more likely to cause weight loss than gain. Our findings support the use of bupropion as a sole or coprescribed antidepressant, particularly if weight gain or sexual dysfunction are, or are likely to be, significant problems. However there are notable gaps in the literature, including less information on treatment naïve and first presentation depression, particularly when one considers the ever-reducing rates of response in more refractory illness. There are some data to support bupropion targeting specific symptoms, but insufficient information to reliably inform such prescribing, and it remains uncertain whether bupropion pharmacodynamically truly augments other drugs.

BACKGROUND: Contrary to early case-control studies that suggested smoking protects against Alzheimer disease (AD), recent prospective studies have shown that elderly who smoke may be at increased risk for dementia. OBJECTIVE: To examine prospectively the effect of smoking on cognition in nondemented elderly. METHOD: In a multicenter cohort, the European Community Concerted Action Epidemiology of Dementia (EURODEM), including the Odense, Personnes Agées Quid (Paquid), Rotterdam, and Medical Research Council: Ageing in Liverpool Project-Health Aspects (MRC ALPHA) Studies, 17,610 persons aged 65 and over were screened and examined for dementia. After an average 2.3 years of follow-up, 11,003 nondemented participants were retested. Excluding incident dementia cases and those without baseline information on smoking gave an analytical sample of 9,209 persons. Average yearly decline in Mini-Mental State Examination (MMSE) score was compared among groups, adjusting for age, sex, baseline MMSE, education, type of residence, and history of myocardial infarction or stroke. RESULTS: MMSE score of persons who never smoked on average declined 0.03 point/year. The adjusted decline of former smokers was 0.03 point greater and of current smokers 0.13 point greater than never smokers (p < 0.001). Higher rates of decline by smoking were found in men and women, persons with and without family history of dementia, and in three of four participating studies. Higher cigarette pack-year exposure was correlated with a significantly higher rate of decline. CONCLUSION: Smoking may accelerate cognitive decline in nondemented elderly.

Urinary tract infections (UTIs) are the most common bacterial infection in pregnancy, increasing the risk of maternal and neonatal morbidity and mortality. Urinary tract infections may present as asymptomatic bacteriuria, acute cystitis or pyelonephritis. Escherichia coli is the most common pathogen associated with both symptomatic and asymptomatic bacteriuria. If asymptomatic bacteriuria is untreated, up to 30% of mothers develop acute pyelonephritis, with an increased risk of multiple maternal and neonatal complications, such as preeclampsia, preterm birth, intrauterine growth restriction and low birth weight. Urinary tract infection is a common, but preventable cause of pregnancy complications, thus urinary tests, such as urine culture or new technologies such as high-throughput DNA sequence-based analyses, should be used in order to improve antenatal screening of pregnant women.

There has been growing clinical, public, and media awareness and concern about the availability and potential harmfulness of so-called 'legal highs', which are more appropriately called new or novel psychoactive substances (NPS). A cat-and-mouse process has emerged wherein unknown chemists and laboratories are producing new, and as yet nonproscribed, compounds for human consumption; and as soon as they are banned, which they inevitably are, slightly modified analogues are produced to circumvent new laws. This rapidly changing environment, 81 new substances were identified in 2013 alone, has led to confusion for clinicians, psychopharmacologists, and the public at large. Our difficulties in keeping up with the process has had a two-fold negative effect: the danger of ignoring what is confusing; and the problem that some of the newer synthesized compounds appear ever more potent. This review aims to circumscribe a quick moving and growing field, and to categorize NPS into five major groups based upon their 'parent' compounds: stimulants similar to cocaine, amphetamines and ecstasy; cannabinoids; benzodiazepine based drugs; dissociatives similar to ketamine and phencyclidine (PCP); and those modelled after classic hallucinogens such as LSD and psilocybin. Pharmacodynamic actions, subjective and physical effects, harmfulness, risk of dependency and, where appropriate, putative clinical potentials are described for each class. Clinicians might encounter NPS in various ways: anecdotal reportage; acute intoxication; as part of a substance misuse profile; and as a precipitant or perpetuating factor for longer-term physical and psychological ill health. Current data are overall limited, and much of our knowledge and treatment strategies are based upon those of the 'parent' compound. There is a critical need for more research in this field, and for professionals to make themselves more aware of this growing issue and how it might affect those we see clinically and try to help: a brave new world of so-called 'psychonauts' consuming NPS will also need informed 'psychotherapeutonauts'. The paper should serve as a primer for clinicians and interested readers, as well as provide a framework into which to place the new substances that will inevitably be synthesized in the future.

Owing to their ability to efficiently deliver biological cargo and sense the intracellular milieu, vertical arrays of high aspect ratio nanostructures, known as nanoneedles, are being developed as minimally invasive tools for cell manipulation. However, little is known of the mechanisms of cargo transfer across the cell membrane-nanoneedle interface. In particular, the contributions of membrane piercing, modulation of membrane permeability and endocytosis to cargo transfer remain largely unexplored. Here, combining state-of-the-art electron and scanning ion conductance microscopy with molecular biology techniques, it is shown that porous silicon nanoneedle arrays concurrently stimulate independent endocytic pathways which contribute to enhanced biomolecule delivery into human mesenchymal stem cells. Electron microscopy of the cell membrane at nanoneedle sites shows an intact lipid bilayer, accompanied by an accumulation of clathrin-coated pits and caveolae. Nanoneedles enhance the internalization of biomolecular markers of endocytosis, highlighting the concurrent activation of caveolae- and clathrin-mediated endocytosis, alongside macropinocytosis. These events contribute to the nanoneedle-mediated delivery (nanoinjection) of nucleic acids into human stem cells, which distribute across the cytosol and the endolysosomal system. This data extends the understanding of how nanoneedles modulate biological processes to mediate interaction with the intracellular space, providing indications for the rational design of improved cell-manipulation technologies.

The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established. The anaesthetic and hallucinogenic drug ketamine has provoked much interest over the past decade or so as an extremely rapidly acting antidepressant that does not modify 'classical' monoaminergic receptors. Current evidence has shown several ways through which it might exert therapeutic antidepressant actions: blockade of glutamatergic NMDA receptors and relative upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes may alter cortical connectivity patterns; through intracellular changes in protein expression, including the proteins mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF); and alteration of intracellular signalling cascades. The clinical evidence demonstrates rapid improvements in mood and suicidal thinking in most participants, although study numbers have generally been small and many trials are unblinded and methodologically weak. There is a small body of work to suggest ketamine might also augment electroconvulsive therapy and potentially have a role as a surgical anaesthetic in depressed patients. A major problem is that the effects of ketamine appear temporary, disappearing after days to weeks (although longer benefits have been sustained in some), and attempts to circumvent this through pharmacological augmentation have been disappointing thus far. These exciting data are providing new insights into neurobiological models of depression, and potentially opening up a new class of antidepressants, but there are significant practical and ethical issues about any future mainstream clinical role it might have.

AIMS: This study describes the use of the Masquelet technique to treat segmental tibial bone loss in 12 patients. PATIENTS AND METHODS: This retrospective case series reviewed 12 patients treated between 2010 and 2015 to determine their clinical outcome. Patients were mostly male with a mean age of 36 years (16 to 62). The outcomes recorded included union, infection and amputation. The mean follow-up was 675 days (403 to 952). RESULTS: The mean tibial defect measured 5.8 cm (2 to 15) in length. Of the 12 patients, 11 had an open fracture. Eight underwent fixation with an intramedullary nail, three with plates and one with a Taylor Spatial Frame. The mean interval between stages was 57 days (35 to 89). Bony union was achieved in only five patients. Five patients experienced infective complications during treatment, with two requiring amputation because of severe infection. CONCLUSION: 2017;99-B:680-5.

UNLABELLED: Laparoscopic cholecystectomy is the treatment of choice for gall bladder stone disease. Difficult cholecystectomy is associated with serious complications and a high conversion rate. The aim of this study was to review the current strategies to manage difficult cholecystectomy. METHODS: A Medline search was conducted to review all published English literatures relevant to difficult cholecystectomy through 1993 to 2009. The search words were "laparoscopic cholecystectomy," "difficult cholecystectomy," "difficult laparoscopy," "subtotal laparoscopic cholecystectomy," "fundus first cholecystectomy," and "causes of conversion of laparoscopic cholecystectomy." RESULTS: Ninety-one studies, which included 324,553 patients, were selected for this review. Five major categories of difficulty were identified. Conversion rate and iatrogenic injuries during laparoscopic cholecystectomy are still high despite significant improvement over the last 10 years. Depending on the technique of cholecystectomy, the degree of gall bladder inflammation, patient comorbidities, and surgical experience, the conversion rate was reported between 0.18% and 30%, whereas the incidence of iatrogenic injuries was from 0% to 0.6%. Subtotal cholecystectomy, antegrade and fundus first techniques, and peroperative cholangiogram were associated with lower complications and conversion rate. Risk factors for difficulty were male sex, increased age, acute and thick wall chronic cholecystitis, wide and short cystic duct, cholecystodigestive fistula, previous upper abdominal surgery, obesity, liver cirrhosis, anatomic variation, cholangiocarcinoma, and low surgeon's caseload. CONCLUSIONS: No consensus is found among surgeons on how to manage difficult laparoscopic cholecystectomy. Iatrogenic injuries and conversion rate can be reduced depending on the surgeon's experience, special techniques, and intraoperative investigations. Subtotal cholecystectomy, antegrade or fundus first techniques, and peroperative cholangiogram significantly reduced the complications and conversion rate.

Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.

STUDY DESIGN: Retrospective study. OBJECTIVE: To evaluate the clinical and functional outcomes in patients with spinal cord injury (SCI) and preexisting ankylosing spondylitis (AS). SUMMARY OF BACKGROUND DATA: AS alters the strength and biomechanical properties of the spine that renders it susceptible to fracture with minimal trauma. Neurologic involvement is common and outcomes largely depend on the early recognition and appropriate management. METHODS: A 10-year review (1996-2005) was carried out to identify all patients admitted with SCI associated with AS. The cause of injury, prehospital and emergency management, definitive treatment of fracture, final neurology, and functional outcomes were ascertained. Reasons for neurologic deterioration were determined. RESULTS: Eighteen patients were identified. In 15 patients, the injury resulted from trauma (fall 14, road accident 1) and in 3 the SCI followed spinal surgical interventions. Twelve of the 15 patients with traumatic injuries were able to walk immediately after the fall but subsequently deteriorated for various reasons. Spinal epidural hematomas developed in 3 patients (2 traumatic, 1 spinal intervention). The fractures were managed surgically in 3 patients, halo jacket was used in 2, and the remainder were managed expectantly on traction. Four patients died before discharge, 4 were able to walk with an aid at discharge, and the others were wheel chair dependent. CONCLUSION: Neurologic deficits were often subtle on initial presentation, resulting in many injuries being missed because of a low index of suspicion and poor visualization of lower cervical fractures on conventional radiographs. Extension of the ankylosed kyphotic cervical spine during conventional immobilization or for radiologic procedures resulted in neurologic deficits. Patients with an ankylosed cervical spine are normally unable to see the ceiling lying supine because of cervicothoracic kyphosis and use pillows to support their head. Cervical spine alignment in a similar flexed position is essential during immobilization or imaging. Medical alert cards as for patients with diabetes would be a way forward in correctly identifying patients with AS so that appropriate precautions can be instituted by emergency services.

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19 + non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care.