Low-dose ketamine in painful orthopaedic surgery: a systematic review and meta-analysis.

BACKGROUND: Ketamine is a phencyclidine intravenous anaesthetic that blocks N-methyl-d-aspartate receptors and HCN channels in the CNS. Lately it has gained acceptance in a low-dose form, with studies showing an analgesic benefit in orthopaedic surgery. Our goal was to critically appraise and synthesise current evidence regarding use of low-dose ketamine in major, painful orthopaedic surgeries. METHODS: We conducted searches in Medline, Embase, Cochrane, and specialty journals for randomised controlled trials (RCTs) that compared low-dose ketamine to placebo. Primary outcomes included total opioid use, time to first opioid, and VAS pain scores. Meta-analyses were undertaken in RevMan software using a random effects model. We rated the quality of the evidence using the GRADE Working Group criteria. RESULTS: We included 20 studies across four subgroups for meta-analysis. The overall quality of the evidence was moderate. Ketamine significantly decreased total opioid use and pain scores (VAS) at 24 and 48 h (Opioid: standardised mean difference [SMD] -0.82 [-1.24, -0.40], p=0.0001, and -0.65 [-1.03,-0.27], p=0.0008; VAS: SMD -0.53 [-0.91, -0.15], p=0.006 and -0.60 [-1.05, -0.16], p=0.008), and delayed the time to first opioid dose (SMD 0.64 [0.01, 1.27], p=0.05). Results for nausea and hallucinations were equivocal, whereas results for chronic pain were inconclusive. The most prominent effects were seen in total joint operations. CONCLUSION: Low-dose ketamine is an effective adjuvant that decreases pain and opioid requirements in painful orthopaedic procedures, especially in the first 24 h after procedure. Future research should focus on arthroscopic procedures and the incidence of chronic pain.

Women's experiences of more than one termination of pregnancy within two years: a mixed-methods study.

OBJECTIVE: To examine the experiences of women seeking more than one termination of pregnancy (TOP) within 2 years. DESIGN: Mixed methods study. SETTING: Six TOP services across Scotland. SAMPLE: Women presenting for TOP between July and December 2015. METHODS: Descriptive and inferential analysis of quantitative survey data, thematic analysis of qualitative interview data and integrative analysis. In quantitative analysis, multinomial logistic regression was used to compare three groups: previous TOP within 2 years, previous TOP beyond 2 years and no previous TOP. MAIN OUTCOME MEASURES: Characteristics and experiences of women seeking TOP. RESULTS: Of 1662 questionnaire respondents, 14.6% (n = 242) and 19.8% (n = 329) reported previous TOP within and beyond 2 years, respectively. The previous TOP within 2 years group was significantly less likely to own their accommodation than the no previous TOP group (adjusted odds ratio [aOR] 0.34, 95% CI: 0.18-0.62) and previous TOP beyond 2 years group (aOR: 0.44, 95% CI: 0.23-0.85); and more likely to report inconsistent (aOR: 1.63, 95% CI: 1.04-2.57; aOR: 1.95, 95% CI: 1.16-3.28) and consistent (aOR: 2.13, 95% CI: 1.39-3.26; aOR: 1.71, 95% CI: 1.07-2.76) contraceptive use than the no previous TOP and previous TOP within 2 years groups, respectively. Twenty-three women from the previous TOP within 2 years group were interviewed. Qualitative and integrative analyses highlight issues relating to contraceptive challenges, intimate partner violence, life aspirations and socio-economic disadvantage. CONCLUSIONS: Women undergoing more than one TOP within 2 years may experience particular challenges and vulnerabilities. Service provision should recognise this and move away from stigmatising discourses of 'repeat abortion'. FUNDING: Scottish Government. TWEETABLE ABSTRACT: Women having two or more terminations of pregnancy in 2 years may face key challenges/vulnerabilities including intimate partner violence and socio-economic disadvantage.

The developing landscape of diagnostic and prognostic biomarkers for spinal cord injury in cerebrospinal fluid and blood.

STUDY DESIGN: Review study. OBJECTIVES: The identification of prognostic biomarkers of spinal cord injury (SCI) will help to assign SCI patients to the correct treatment and rehabilitation regimes. Further, the detection of biomarkers that predict permanent neurological outcome would aid in appropriate recruitment of patients into clinical trials. The objective of this review is to evaluate the current state-of-play in this developing field. SETTING: Studies from multiple countries were included. METHODS: We have completed a comprehensive review of studies that have investigated prognostic biomarkers in either the blood or cerebrospinal fluid (CSF) of animals and humans following SCI. RESULTS: Targeted and unbiased approaches have identified several prognostic biomarkers in CSF and blood. These proteins associate with cellular damage following SCI and include components from neurons, oligodendrocytes and reactive astrocytes, that is, neurofilament proteins, glial fibrillary acidic protein, Tau and S100 calcium-binding protein ß. Unbiased approaches have also identified microRNAs that are specific to SCI, as well as other cell damage-associated proteins. CONCLUSIONS: The discovery and validation of stable, specific, sensitive and reproducible biomarkers of SCI is a rapidly expanding field of research. So far, few studies have utilised unbiased approaches aimed at the discovery of biomarkers within the CSF or blood in this field; however, some targeted approaches have been successfully used. Several studies using various animal models and some with small human patient cohorts have begun to pinpoint biomarkers in the CSF and blood with putative prognostic value. An increased sample size will be required to validate these biomarkers in the heterogeneous clinical setting.

Preparedness for use of the rapid result HIV self-test by gay men and other men who have sex with men (MSM): a mixed methods exploratory study among MSM and those involved in HIV prevention and care.

OBJECTIVES: The aim of the study was to explore preparedness for the HIV self-test among men who have sex with men (MSM) and those involved in HIV prevention and care. METHODS: A mixed methods exploratory research design was employed, detailing awareness and willingness to use the self-test and the perceived barriers and facilitators to implementation. Quantitative and qualitative data collection and analysis were completed in parallel. Descriptive and inferential analysis of cross-sectional bar-based survey data collected from MSM through a self-completed questionnaire and oral fluid specimen collection (n = 999) was combined with qualitative, thematic, analysis of data collected through 12 expert focus groups (n = 55) consisting of gay men, National Health Service (NHS) staff, community organizations, entrepreneurs and activists. Findings were subsequently combined and assessed for synergies. RESULTS: Among MSM, self-test awareness was moderate (55%). Greater awareness was associated with increased educational attainment [adjusted odds ratio 1.51; 95% confidence interval (CI) 1.00-2.30; P = 0.05] and previous history of sexually transmitted infection (STI) testing (adjusted odds ratio 1.63; 95% CI 1.11-2.39; P = 0.01). Willingness to use the test was high (89%) and associated with meeting sexual partners online (unadjusted odds ratio 1.96; 95% CI 1.31-2.94; P < 0.001). Experts highlighted the overall acceptability of self-testing; it was understood as convenient, discreet, accessible, and with a low burden to services. However, some ambivalence towards self-testing was reported; it could reduce opportunities to engage with wider services, wider health issues and the determinants of risk. CONCLUSIONS: Self-testing represents an opportunity to reduce barriers to HIV testing and enhance prevention and access to care. Levels of awareness are moderate but willingness to use is high. Self-testing may amplify health inequalities.

Frequency of HIV testing among gay and bisexual men in the UK: implications for HIV prevention.

OBJECTIVES: The aim of the study was to explore HIV testing frequency among UK men who have sex with men (MSM) in order to direct intervention development. METHODS: Cross-sectional surveys were completed by 2409 MSM in Edinburgh, Glasgow and London in 2011 and a Scotland-wide online survey was carried out in 2012/13. The frequency of HIV testing in the last 2 years was measured. RESULTS: Overall, 21.2% of respondents reported at least four HIV tests and 33.7% reported two or three tests in the last 2 years, so we estimate that 54.9% test annually. Men reporting at least four HIV tests were younger and less likely to be surveyed in London. They were more likely to report higher numbers of sexual and anal intercourse partners, but not "higher risk" unprotected anal intercourse (UAI) with at least two partners, casual partners and/or unknown/discordant status partners in the previous 12 months. Only 26.7% (238 of 893) of men reporting higher risk UAI reported at least four tests. Among all testers (n = 2009), 56.7% tested as part of a regular sexual health check and 35.5% tested following a risk event. Differences were observed between surveys, and those testing in response to a risk event were more likely to report higher risk UAI. CONCLUSIONS: Guidelines recommend that all MSM test annually and those at "higher risk" test more frequently, but our findings suggest neither recommendation is being met. Additional efforts are required to increase testing frequency and harness the opportunities provided by biomedical HIV prevention. Regional, demographic and behavioural differences and variations in the risk profiles of testers suggest that it is unlikely that a "one size fits all" approach to increasing the frequency of testing will be successful.

Adult patients with respiratory syncytial virus infection: impact of solid organ and hematopoietic stem cell transplantation on outcomes.

BACKGROUND: Respiratory syncytial virus (RSV) is a common community-acquired pathogen responsible for a substantial disease burden in adults. We investigated the outcomes after RSV infection in hospitalized adults over a 3-year period. METHODS: This single-center, retrospective study identified 174 patients hospitalized with RSV upper or lower respiratory tract infection (LRTI) between January 1, 2009 and June 30, 2012. Clinical data were extracted from medical records. The primary outcome analyzed was all-cause mortality, defined as death during the index hospital admission. Subjects were divided into 3 groups for comparison: hematopoietic stem cell transplant (HSCT) patients, solid organ transplant (SOT) patients, and non-transplant patients. RESULTS: In our study, 41/174 (23.6%) were HSCT recipients and 28/174 (16.1%) were SOT recipients. Twelve of 174 (6.9%) died. Death occurred in 2/41 (4.9%) HSCT and 3/28 (10.7%) SOT recipients, compared to 7/106 (6.6%) non-transplant patients. When compared to the non-transplant cohort, HSCT and SOT were not found to be significant risk factors for mortality (P = 0.685 and 0.645, respectively). In multivariate logistic regression, age >60 was associated with mortality (P = 0.019), while lymphopenia on admission trended toward an association with death (P = 0.054). HSCT patients were less likely to be admitted to an intensive care unit (odds ratio [OR] 0.26, P = 0.04), but were significantly more likely to receive ribavirin therapy (OR 11.62, P < 0.0001). CONCLUSION: Adults hospitalized with RSV LRTI are at significant risk of mortality, and this risk may be increased in patients age >60 or with lymphopenia on admission. This study did not identify any significant increased mortality or morbidity associated with RSV infection in immune suppressed transplant recipients vs. patients who had not received a transplant.

Physiological responses of lichens to factorial fumigations with nitric acid and ozone.

This paper addresses the effects of gaseous nitric acid (HNO(3)) and ozone (O(3)), two important air pollutants, on six lichen species with different morphological, ecological, and biological characteristics. The treatment chambers were set up in a factorial design consisting of control chambers, chambers fumigated with HNO(3), with O(3), and with HNO(3) and O(3), together. Each species showed a different sensitivity to the fumigations, reflecting the physiological variation among species. Our results clearly indicate that HNO(3) is a strong phytotoxin to many lichens, and that O(3) alone has little effect on the measured parameters. The combined fumigation effects of HNO(3) and O(3) were not significantly different from HNO(3) alone.

Single dose dexamethasone for postoperative nausea and vomiting--a matched case-control study of postoperative infection risk.

Dexamethasone is an effective prophylaxis against postoperative nausea and vomiting but is immunosuppressive and may predispose patients to an increased postoperative infection risk. This matched case-control study examined the association between the administration of a single intraoperative anti-emetic dose of dexamethasone (4 to 8 mg) and postoperative infection in patients undergoing non-emergency surgery in a university trauma centre. Cases were defined as patients who developed infection between one day and one month following an operative procedure under general anaesthesia. Controls who did not develop infection were matched for procedure, age and gender Exclusion criteria included immunosuppressive medications, chronic glucocorticoid therapy, cardiac surgical and solid-organ transplantation procedures. Sixty-three cases and 172 controls were identified. Cases were more likely to have received dexamethasone intraoperatively (25.4 vs. 11%, P = 0.006), and less likely to have received perioperative antibiotic prophylaxis (60.3 vs. 84.3%, P = 0.001). Stepwise, multivariate conditional logistic regression confirmed these associations, with adjusted odds ratios of 3.03 (1.06 to 19.3, P = 0.035) and 0.12 (0.02 to 0.7, P = 0.004) respectively for the associations between dexamethasone and perioperative antibiotic prophylaxis, with postoperative infection. We conclude that intraoperative administration of dexamethasone for anti-emetic purposes may confer an increased risk of postoperative infection.

Mycobacterium chelonae necrotizing pneumonia after allogeneic hematopoietic stem cell transplant: report of clinical response to treatment with tigecycline.

We present a case of progressive Mycobacterium chelonae ssp. chelonae necrotizing pneumonia after hematopoietic stem cell transplantation (HSCT) in the presence of chronic graft-versus-host disease. The patient failed to respond to standard combination therapy with multiple agents and developed resistance to most drugs over the course of treatment. Tigecycline, a new glycylcycline antimicrobial agent with in vitro activity against M. chelonae, was then used with a clinical response to treatment. To our knowledge, this is the first reported case demonstrating tigecycline to have a degree of clinical effectiveness to treat refractory pulmonary infection with M. chelonae in an HSCT recipient.

P boutons in lamina IX of the rodent spinal cord express high levels of glutamic acid decarboxylase-65 and originate from cells in deep medial dorsal horn.

Presynaptic inhibition of primary muscle spindle (group Ia) afferent terminals in motor nuclei of the spinal cord plays an important role in regulating motor output and is produced by a population of GABAergic axon terminals known as P boutons. Despite extensive investigation, the cells that mediate this control have not yet been identified. In this work, we use immunocytochemistry with confocal microscopy and EM to demonstrate that P boutons can be distinguished from other GABAergic terminals in the ventral horn of rat and mouse spinal cord by their high level of the glutamic acid decarboxylase (GAD) 65 isoform of GAD. By carrying out retrograde labeling from lamina IX in mice that express green fluorescent protein under the control of the GAD65 promoter, we provide evidence that the cells of origin of the P boutons are located in the medial part of laminae V and VI. Our results suggest that P boutons represent the major output of these cells within the ventral horn and are consistent with the view that presynaptic inhibition of proprioceptive afferents is mediated by specific populations of interneurons. They also provide a means of identifying P boutons that will be important in studies of the organization of presynaptic control of Ia afferents.

Disseminated Scedosporium apiospermum infection in a previously healthy woman with HELLP syndrome.

A previously healthy 33-year-old female died of disseminated infection with Scedosporium apiospermum in association with Hemolysis, Elevated Liver enzymes, and Low Platelets (HELLP) syndrome following the delivery of twins. Her postpartum course was complicated by multisystem organ failure managed with extracorporeal membrane oxygenation (ECMO). She also developed bowel and left lower extremity ischemia requiring surgical resection. Blood cultures yielded S. apiospermum, and histologic findings revealed in vivo adventitious sporulation, an unusual occurrence with this pathogen. Autopsy showed extensive fungal infection of brain, lungs, thyroid, heart, and kidneys.

Lack of evidence for significant neuronal loss in laminae I-III of the spinal dorsal horn of the rat in the chronic constriction injury model.

Peripheral nerve injury leads to structural and functional changes in the spinal dorsal horn, and these are thought to be involved in the development of neuropathic pain. In the chronic constriction injury (CCI) model, abnormal 'dark' neurons and apoptotic nuclei have been observed in laminae I-III of the dorsal horn in the territory innervated by the injured sciatic nerve. These findings have been taken as evidence that there is significant neuronal death in this model, and it has been suggested that loss of inhibition resulting from death of GABAergic inhibitory interneurons contributes to the neuropathic pain. However, loss of neurons from the dorsal horn has not been directly demonstrated in neuropathic models, even though this issue is of considerable importance for our understanding of the mechanisms that underlie neuropathic pain. In this study, we have looked for evidence of neuronal death by using a stereological method (the optical disector) with NeuN-immunostaining, and examining spinal cords of naïve rats, and of rats that had undergone CCI or sham operations. All of the CCI animals showed clear signs of thermal hyperalgesia. However, the numbers of neurons in laminae I-III of the ipsilateral dorsal horn in these animals did not differ significantly from those on the contralateral side, nor from those of sham-operated or naïve animals. These results do not, therefore, support the suggestion that there is significant neuronal death in the dorsal horn in this model.

Selective loss of spinal GABAergic or glycinergic neurons is not necessary for development of thermal hyperalgesia in the chronic constriction injury model of neuropathic pain.

GABA and glycine are inhibitory neurotransmitters used by many neurons in the spinal dorsal horn, and intrathecal administration of GABA(A) and glycine receptor antagonists produces behavioural signs of allodynia, suggesting that these transmitters have an important role in spinal pain mechanisms. Several studies have described a substantial loss of GABA-immunoreactive neurons from the dorsal horn in nerve injury models, and it has been suggested that this may be associated with a loss of inhibition, which contributes to the behavioural signs of neuropathic pain. We have carried out a quantitative stereological analysis of the proportions of neurons in laminae I, II and III of the rat dorsal horn that show GABA- and/or glycine-immunoreactivity 2 weeks after nerve ligation in the chronic constriction injury (CCI) model, as well as in sham-operated and nai;ve animals. At this time, rats that had undergone CCI showed a significant reduction in the latency of withdrawal of the ipsilateral hindpaw to a radiant heat stimulus, suggesting that thermal hyperalgesia had developed. However, we did not observe any change in the proportion of neurons in laminae I-III of the ipsilateral dorsal horn that showed GABA- or glycine-immunoreactivity compared to the contralateral side in these animals, and these proportions did not differ significantly from those seen in sham-operated or nai;ve animals. In addition, we did not see any evidence for alterations of GABA- or glycine-immunostaining in the neuropil of laminae I-III in the animals that had undergone CCI. Our results suggest that significant loss of GABAergic or glycinergic neurons is not necessary for the development of thermal hyperalgesia in the CCI model of neuropathic pain.

Suspected angina pectoris: a rapid-access chest pain clinic.

We prospectively evaluated a rapid-access chest pain clinic in terms of clinical diagnoses, outcomes, morbidity and mortality at 3 months follow-up in patients, and cost-effectiveness. All patients seen at the clinic from February 1999 to December 2000 were assessed. Referring doctors indicated the management they would have provided had the clinic been unavailable, to allow a cost-effectiveness analysis. Overall, 709 patients were referred, 471 (66%) from General Practitioners, 212 (30%) from Accident and Emergency doctors and 26 (4%) from other sources. All had recent onset, or increasing frequency of ischaemic-type chest pain (excluding those with suspected myocardial infarction or rest chest pain angina). Fifty-one (7%) had acute coronary syndromes, 119 (17%) had stable ischaemic heart disease, 144 (20%) had possible ischaemic heart disease, and 395 (56%) were considered to have non-ischaemic symptoms. Some 70% of patients were seen within 24 h. Only 57 patients (8%) were admitted. Had the clinic been unavailable, 160 patients would have been admitted. Out-patient cardiology appointments were arranged for 116 patients (16%), and 429 patients (60%) were discharged directly. Follow-up data at 3 months were obtained from 565/567 eligible patients (99.6%). No major cardiac events (death/myocardial infarction) occurred in those with non-ischaemic chest pain. There were five deaths (including one due to cancer) and three patients had a myocardial infarction (event rate 1%). There were eleven readmissions for angina: six were in patients with acute coronary syndromes, and four of these six were awaiting revascularization. The estimated net saving was pound 58/patient. A rapid-access chest pain clinic offers a prompt, safe and cost-effective service in a challenging group of patients.

Oral fluoroquinolone therapy results in drug adsorption on ureteral stents and prevention of biofilm formation.

The oral administration of ciprofloxacin (250mg bid) and ofloxacin (300mg bid) in 40 patients with ureteral stents, led to drug levels on all the device surfaces that were higher than the minimum inhibitory concentration (MIC) of Escherichia coli (0.004--0.015 mg/l), the most common uropathogen. The drug levels in the film were higher than the MIC of other common pathogens, namely Pseudomonas aeruginosa (0.25--1.0 mg/l), Enterococcus faecalis (0.25--2.0 mg/l) and Staphylococcus aureus (0.12--0.5 mg/l) in a few cases (six, three and 14 cases out of 40, respectively). For both antibiotics, the concentrations were greater than the MIC of many uropathogens on the film surrounding the devices (0.89 vs 0.31 mg/l respectively, P=0.05), and on the devices themselves (0.22 vs. 0.12 mg/l, P=0.207). Adsorption of the antibiotics was higher to the film than to the stent (P<0.0001). Ciprofloxacin concentration on the film surrounding the stents was significantly higher than that of ofloxacin (P=0.05), while there was no statistical concentration difference between the two antibiotics adsorbed onto the actual devices (P=0.207). No bacteria were found in patients' urine and no biofilms were detected. This is the first report of an oral antibiotic being adsorbed onto medical devices. It potentially provides a new approach of preventing infection, and avoids the need to pre-coat devices with agents whose use will be restricted once bacteria develop resistance to them. If biomaterial properties can be enhanced to increase further the adsorptive concentration of drug, the risk of infections and recalcitrant biofilm formation could be significantly reduced in a highly susceptible patient population.

Beta-adrenoceptor modulation and heart rate variability--the value of scatterplot measures of compactness.

This article compares different methods of scatterplot analysis to assess the optimal methodology. The scatterplot (Poincaré plot) is a nonlinear heart rate variability method where a "return map" is constructed by plotting each current cycle against the previous beat (RR vs. RR(n-1)). Geometric analysis of the scatterplot allows short-term and long-term heart rate variability (HRV) to be assessed. A three-dimensional construct is also possible, where the third axis represents the density of values, at any given RR vs. RR(n-1) intersection. Topological methods of analysis can compute the density distribution function or compactness of a dataset. Scatterplots that otherwise appear very similar in the two-dimensional plot may be clearly differentiated using this approach. Correct characterization may improve the ability of scatterplot analysis to predict outcomes in cardiovascular disease. We have assessed two computational approaches that take account of scatterplot density, namely, the heart rate variability fraction and the compactness measure. Scatterplots were constructed from three double-blind and randomized placebo controlled studies conducted in a total of 49 healthy subjects. Single oral doses of antagonists (atenolol 50 mg [beta-1], propranolol 160 mg [beta-1 and beta-2], and ICI 118,551 25 mg [beta-2]) or agonists (xamoterol 200 mg [beta-1], salbutamol 8 mg [beta-2], prenalterol 50 mg [beta-1 and beta-2], and pindolol 10 mg [mainly beta-2] of the cardiac beta-adrenoceptor were studied. Salbutamol, pindolol, and xamoterol increased compactness and reduced HRV fraction significantly compared with placebo. However, when compared with the more conventional scatterplot parameters, these newer density methods were found to be less discriminating. An alternative approach to improve scatterplot discrimination, using the combination of several scatterplot features, is under investigation.

Serotoninergic and noradrenergic axonal contacts associated with premotor interneurons in spinal pathways from group II muscle afferents.

We investigated the possibility that monoaminergic axons make contacts with spinal interneurons which project to motor nuclei and are monosynaptically activated by group II muscle afferents. Interneurons in midlumbar spinal segments of adult cats were characterized electrophysiologically and intracellularly labelled with tetramethylrhodamine dextran. Serotoninergic and noradrenergic axons were identified with immunofluorescence in sections containing labelled cells. Contacts between monoaminergic axons and interneurons were investigated with three-colour confocal laser scanning microscopy and analysed with a computer reconstruction program. Cell bodies and dendritic trees of five cells were reconstructed and putative contacts were plotted. The average number of contacts formed by serotoninergic axons was 140 and the average number of noradrenergic contacts was 38. The majority (95%) of contacts were formed with dendrites; these were distributed over the entire dendritic tree, even on the most distal branches. These findings provide a morphological basis for the modulatory actions of monoamines on premotor spinal interneurons in pathways from group II muscle afferents.