Appropriateness of acute-care antibiotic prescriptions for community-acquired infections and surgical antibiotic prophylaxis in England: analysis of 2016 national point prevalence survey data.

BACKGROUND: Estimates of inappropriate prescribing can highlight key target areas for antimicrobial stewardship (AMS) and inform national targets. OBJECTIVES: To (1) define and (2) produce estimates of inappropriate antibiotic prescribing levels within acute hospital trusts in England. METHODS: The 2016 national Healthcare-Associated Infections (HAI), Antimicrobial Use (AMU) and AMS point prevalence survey (PPS) was used to derive estimates of inappropriate prescribing, focusing on the four most reported community-acquired antibiotic indications (CAIs) in the PPS and surgical prophylaxis. Definitions of appropriate antibiotic therapy for each indication were developed through the compilation of national treatment guidelines. A Likert-scale system of appropriateness coding was validated and refined through a two-stage expert review process. RESULTS: Antimicrobial usage prevalence data were collected for 25,741 individual antibiotic prescriptions, representing 17,884 patients and 213 hospitals in England. 30.4% of prescriptions for the four CAIs of interest were estimated to be inappropriate (2054 prescriptions). The highest percentage of inappropriate prescribing occurred in uncomplicated cystitis prescriptions (62.5%), followed by bronchitis (48%). For surgical prophylaxis, 30.8% of prescriptions were inappropriate in terms of dose number, and 21.3% in terms of excess prophylaxis duration. CONCLUSIONS: The 2016 prevalence of inappropriate antibiotic prescribing in hospitals in England was approximated to be 30.4%; this establishes a baseline prevalence and provided indication of where AMS interventions should be prioritized. Our definitions appraised antibiotic choice, treatment duration and dose number (surgical prophylaxis only); however, they did not consider other aspects of appropriateness, such as combination therapy - this is an important area for future work.

Development and implementation of a national antimicrobial stewardship surveillance system, with open access data sharing.

BACKGROUND: Public Health England (PHE) developed an antimicrobial stewardship (AMS) surveillance system and conducted a national pilot to test the feasibility of centrally collecting data from AMS audits performed by NHS hospital trusts. The system was simplified, focusing on requirements of the NHS AMR CQUIN (Commissioning for Quality and Innovation; a financial incentive quality improvement scheme). AIM: To present results and user feedback from the national pilot, and results from using the AMS surveillance system as part of the AMR CQUIN. METHODS: An AMS surveillance system was developed and a national pilot conducted in which 33 NHS trusts submitted data and feedback on system utilization. The system was refined based on feedback and deployed nationally to collect AMS data for the 2016-17 AMR CQUIN. FINDINGS: Most trusts participating in the pilot collected data on documentation of indication (90%). Fewer collected data on documenting review decisions at 48-72 h (36%). On average 83% of patients had an indication documented, whereas 71% had formal documentation of 48-72 h review. AMR CQUIN data were submitted by 88% of trusts for at least one quarter of 2016-17. Approximately 92% of prescriptions had an indication documented and 87.5% of prescriptions had evidence of review within 72 h; these increased by 7 and 10 percentage points respectively between the first and final quarters. CONCLUSION: The AMS surveillance system allowed AMS audit data from NHS trusts in England to be collected centrally. PHE publishes these data openly online, on PHE Fingertips portal, a national public health data portal. The reported data highlight improvement in the percentage of antibiotic prescriptions with evidence of a documented review within 72 h.

How are genetic test results being used by Australian life insurers?

In Australia, the USA and many Asian countries the life insurance industry is self-regulated. Individuals must disclose genetic test results known to them in applications for new or updated policies including cover for critical care, income protection and death. There is limited information regarding how underwriting decisions are made for policies with such disclosures. The Australian Financial Services Council (FSC) provided de-identified data collected on applications with genetic test result disclosure from its life insurance member companies 2010-2013 to enable repetition of an independent examination undertaken of applications 1999-2003: age; gender; genetic condition; testing result; decision-maker; and insurance cover. Data was classified as to test result alone or additional other factors relevant to risk and decision. Where necessary, the FSC facilitated clarification by insurers. 345/548 applications related to adult-onset conditions. The genetic test result solely influenced the decision in 165/345 applications: positive (n = 23), negative (n = 139) and pending (n = 3). Detailed analyses of the decisions in each of these result categories are presented with specific details of 11 test cases. Policies with standard decisions were provided for all negative test results with evidence of reassessment of previous non-standard decisions and 20/23 positive results with recognition of risk reduction strategies. Disclosure of positive results for breast/ovarian cancer, Lynch syndrome and hereditary spastic paraplegia, and three pending results, generated non-standard decisions. The examination demonstrates some progress in addressing concerns in regard to utilisation of genetic test information but the self-regulatory system in Australia only goes some way in meeting internationally recommended best practice.

The Prostate Health Index adds predictive value to multi-parametric MRI in detecting significant prostate cancers in a repeat biopsy population.

Both multi-parametric MRI (mpMRI) and the Prostate Health Index (PHI) have shown promise in predicting a positive biopsy in men with suspected prostate cancer. Here we investigated the value of combining both tests in men requiring a repeat biopsy. PHI scores were measured in men undergoing re-biopsy with an mpMRI image-guided transperineal approach (n = 279, 94 with negative mpMRIs). The PHI was assessed for ability to add value to mpMRI in predicting all or only significant cancers (Gleason ≥7). In this study adding PHI to mpMRI improved overall and significant cancer prediction (AUC 0.71 and 0.75) compared to mpMRI + PSA alone (AUC 0.64 and 0.69 respectively). At a threshold of ≥35, PHI + mpMRI demonstrated a NPV of 0.97 for excluding significant tumours. In mpMRI negative men, the PHI again improved prediction of significant cancers; AUC 0.76 vs 0.63 (mpMRI + PSA). Using a PHI≥35, only 1/21 significant cancers was missed and 31/73 (42%) men potentially spared a re-biopsy (NPV of 0.97, sensitivity 0.95). Decision curve analysis demonstrated clinically relevant utility of the PHI across threshold probabilities of 5-30%. In summary, the PHI adds predictive performance to image-guided detection of clinically significant cancers and has particular value in determining re-biopsy need in men with a negative mpMRI.

Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes. METHODS: We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle. RESULTS: The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life. CONCLUSIONS: In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Risk profiles of prostate cancers identified from UK primary care using national referral guidelines.

OBJECTIVE: Prostate cancer in the United Kingdom is mainly diagnosed from primary care referrals based on national guidelines published by the Department of Health. Here we investigated the characteristics of cancers detected through the use of these guidelines. METHODS: A prospective two-centre study was established to assess men referred from the primary care based on the UK national guidelines. RESULTS: The overall cancer detection rate was 43% (169 out of 397) with 15% (26 out of 169) of all cancers metastatic at presentation. Amongst 50-69-year-old men these rates were 34% (68 out of 200) and 15% (10 out of 68). Only 21% (25 out of 123) of men with local cancers had low-risk disease. In comparison to a historical cohort from 2001 (n=137) we found no overall differences in rates of metastatic disease, locally advanced tumours, or risk categories. Amongst 50-69-year-old men with local disease, however, we observed an increase in detection of low-risk cancers in a contemporary cohort (P=0.04). This was primarily because of the increased detection of low-stage organ-confined tumours in this group (P=0.02). CONCLUSION: Use of the UK prostate cancer guidelines detects a high proportion of clinically significant cancers. Use of the guidelines does not seem to have led to an overall change in the clinical characteristics of presenting cancers. There may, however, be a specific benefit in detecting more low-risk disease in younger men.

Autoimmune T cell responses to seminal plasma in chronic pelvic pain syndrome (CPPS).

The aetiology of chronic prostatitis is not understood. The aim of this study is to investigate an autoimmune hypothesis by looking for T cell proliferation in response to proteins of the seminal plasma. We studied peripheral blood mononuclear cell proliferation from 20 patients with chronic prostatitis and 20 aged-matched controls in response to serial dilutions of seminal plasma (SP) from themselves (autologous SP) and from a healthy individual without the disease (allo-SP). We found that the patients have a statistically greater lymphocyte proliferation to autologous SP at the 1/50 dilution on day 6 compared to controls (P = 0 x 01). They also have a greater proliferation to allo-SP on both day 5 (P = 0 x 001) and day 6 (P = 0 x 01) at the same dilution. Using a stimulation index (SI) of 9 to either autologous SP or allo-SP on day 6 at the 1/50 dilution as a definition of a proliferative response to SP, then 13/20 patients as compared to 3/20 controls showed a proliferative response to SP (P = 0 x 003, Fishers exact test). These data support an autoimmune hypothesis for chronic prostatitis.

Indeno[1,2-b]pyrazin-2,3-diones: a new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity.

Indeno¿1,2-bpyrazin-2,3-diones have been identified as a novel series of potent ligands on the glycine site of the NMDA receptor. To improve their in vivo activities, an acetic acid-type side chain was introduced to the 5-position, giving water-soluble compounds when formulated as the sodium salt (>10 mg/mL). Introduction of a chlorine atom in the 8-position led to a dramatic improvement of anticonvulsant activity and this was surprising since this change did not improve binding affinity. A plausible explanation is a reduced recognition by a Na(+),K(+)-ATPase active transport system responsible for the excretion of these compounds from the brain and kidney. This promising new chemical series led to the optically active isomer (-)-10i (RPR 118723), a glycine/NMDA antagonist with nanomolar binding affinity and in vivo activity in animal model of convulsions and electrophysiology at doses in the range of 2-3 mg/kg following iv administration.

Is the conservative management of ureteric calculi of > 4 mm safe?

OBJECTIVE: To determine the safety of the conservative management of ureteric calculi of > 4 mm in diameter, using mercapto-acetyltriglycine (MAG3) radioisotope renography to monitor renal parenchymal function. PATIENTS AND METHODS: Patients with symptomatic unilateral ureteric calculi were recruited prospectively. After confirming the position of the stone using contrast urography, a MAG3 radioisotope renogram was taken within 48 h of admission and again 1 month after the patients became stone-free. The indications for intervention were ipsilateral loss of function (>/= 5% loss), infection, pain or any combination of these factors. The recovery of function was determined by follow-up renography. RESULTS: In all, 54 patients were recruited; 18 were initially allocated to conservative treatment although four later required intervention for pain. The remainder required early intervention for pain (eight), diminished function only (15) or diminished function with infection (13). Of the 54 patients, 28% had 'silent' loss of renal function at presentation. No calculi of > 7 mm diameter passed without intervention. The mode of initial management was determined according to individual clinical need. The upper tracts of all patients were relieved of obstruction and all patients were rendered stone-free. Intervention for reduced function only (at

An evidence-based approach to the treatment of prostatitis: is it possible?

The classification of prostatitis has been re-evaluated, and the National Institutes of Health (NIH) has defined the separate groups more thoroughly. Furthermore, the development of the NIH chronic prostatitis symptom index (CPSI) has allowed the symptoms to be measured and the effect of interventions calculated. A search of the literature finds that the quality of treatment trials in prostatitis is poor and the level of evidence for many of the existing strategies is lacking; there is a total absence of any meta-analyses of randomized controlled trials (level 1a). The bulk of literature consists of small descriptive studies (level III) or opinions from respected authorities (level IV). The advent of the NIH-CPSI has provided the opportunity for well-designed trials to be performed where the symptom outcomes can be quantified. This opportunity will be of greatest value in type III prostatitis where symptom amelioration is the main target of therapy and a number of treatment options abound.

Animal models of amyotrophic lateral sclerosis.

Animal models of human disease are important in unravelling the pathophysiology of the condition, for exploring the natural history of disease and for evaluating potential therapies. The development of animal models of human neurodegenerative disease such as ALS is particularly challenging, given the paucity of knowledge of their aetiology and the organizational specificity of the human motor system. Nonetheless, a range of spontaneously occurring, experimentally produced, or genetically engineered models of ALS are now available. Although not always a perfect replica of the ALS disease, these models are shown to be of outstanding importance for investigations of the mechanisms of dysfunction/death of motor neurons in vivo. This is particularly true for the transgenic mouse models expressing superoxide dismutase or cytoskeletal proteins. This approach has provided an unparalleled opportunity for testing of potential pharmacological or gene therapies, and it can be expected that the results of these studies will be translated into the clinical advances of the next years.

Vesicouterine fistula: MRI diagnosis.

A case of vesicouterine fistula in a young woman following caesarean section is presented. The diagnosis was established successfully using heavily T2-weighted MRI which clearly demonstrated fluid within the fistula, obviating the need for conventional radiographic contrast examination.

Immunoassay for urothelial cancers that detects DNA replication protein Mcm5 in urine.

Cancer-screening tests for internal organs are severely constrained by low specificity or sensitivity, cost, and morbidity. We report a non-invasive immunofluorometric assay for detection of urothelial cancers based on ectopic expression of the DNA replication protein Mcm5.

Riluzole series. Synthesis and in vivo "antiglutamate" activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines.

Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotransmission, have been synthesized: monosubstituted 2-benzothiazolamines and 3-substituted derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent anticonvulsant activity against administration of glutamic acid in rats. The most active compounds displaying in vivo "antiglutamate" activity were the 6-OCF(3) (riluzole), 6-OCF(2)CF(3), 6-CF(3), and 6-CF(2)CF(3) substituted derivatives with ED(50) values between 2.5 and 3.2 mg/kg i.p. Among the second series of variously substituted benzothiazolines, compounds as active as riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a beta-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their corresponding sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and 2-imino-3-(2-methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED(50) = 1.0 and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the best benzothiazolines protected mice from mortality produced by hypobaric hypoxia.

The role of excitotoxicity in neurodegenerative disease: implications for therapy.

Glutamic acid is the principal excitatory neurotransmitter in the mammalian central nervous system. Glutamic acid binds to a variety of excitatory amino acid receptors, which are ligand-gated ion channels. It is activation of these receptors that leads to depolarisation and neuronal excitation. In normal synaptic functioning, activation of excitatory amino acid receptors is transitory. However, if, for any reason, receptor activation becomes excessive or prolonged, the target neurones become damaged and eventually die. This process of neuronal death is called excitotoxicity and appears to involve sustained elevations of intracellular calcium levels. Impairment of neuronal energy metabolism may sensitise neurones to excitotoxic cell death. The principle of excitotoxicity has been well-established experimentally, both in in vitro systems and in vivo, following administration of excitatory amino acids into the nervous system. A role for excitotoxicity in the aetiology or progression of several human neurodegenerative diseases has been proposed, which has stimulated much research recently. This has led to the hope that compounds that interfere with glutamatergic neurotransmission may be of clinical benefit in treating such diseases. However, except in the case of a few very rare conditions, direct evidence for a pathogenic role for excitotoxicity in neurological disease is missing. Much attention has been directed at obtaining evidence for a role for excitotoxicity in the neurological sequelae of stroke, and there now seems to be little doubt that such a process is indeed a determining factor in the extent of the lesions observed. Several clinical trials have evaluated the potential of antiglutamate drugs to improve outcome following acute ischaemic stroke, but to date, the results of these have been disappointing. In amyotrophic lateral sclerosis, neurolathyrism, and human immunodeficiency virus dementia complex, several lines of circumstantial evidence suggest that excitotoxicity may contribute to the pathogenic process. An antiglutamate drug, riluzole, recently has been shown to provide some therapeutic benefit in the treatment of amyotrophic lateral sclerosis. Parkinson's disease and Huntington's disease are examples of neurodegenerative diseases where mitochondrial dysfunction may sensitise specific populations of neurones to excitotoxicity from synaptic glutamic acid. The first clinical trials aimed at providing neuroprotection with antiglutamate drugs are currently in progress for these two diseases.

New insights into the mechanism of action of hypnotics.

Between 1987 and 1989, the different protein subunits that make up the receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) were identified. These make up the alpha, beta, gamma and delta families, for each of which exist several subtypes. This receptor is the molecular target of modern hypnotic drugs (i.e. benzodiazepines, zopiclone, zolpidem and zaleplon). In the 10 years that have followed this milestone, significant progress has been made in exploring the molecular mechanisms of hypnotic drug action. Receptor subtype specificity of hypnotics has been explained in terms of differential affinity for receptors containing different alpha subunits, which are expressed in different brain regions. Zolpidem and zaleplon bind preferentially to alpha1-containing receptors, whereas benzodiazepines and zopiclone are aspecific. Different sets of subunits are encoded in contiguous 'cassettes' on the genome, and the transcription of each set appears to be regulated coherently. The predominant GABA(A) receptor composition found in the brain is alpha1beta2gamma2, which are all encoded on human chromosome 5. Targeted gene disruption has provided clues to the physiological functions served by GABA(A) receptors containing different subunits. Receptors containing gamma2 appear to have a vital role in maintaining appropriate central inhibition, beta3-containing receptors may also be important determinants of excitability in certain brain regions, whereas a clear role for alpha5-, alpha6- and gamma3-containing receptors has not yet been established by these techniques. Site-directed mutagenesis has indicated that benzodiazepines bind to a cleft on the GABA(A) receptor surface at the interface between the alpha and gamma subunits. Other drugs (flumazenil, zopiclone, zolpidem) also bind to the a subunit, but interact with amino acids in different binding domains to the benzodiazepines. The molecular mechanism of hypnotic dependence has been explored, and seems to involve downregulation of transcription of the normally prevalent alpha1, beta2 and gamma2 subunits, and the reciprocal upregulation of the expression of rarer subunits. Chronic treatment with hypnotic drugs that may have less dependence potential, such as zopiclone and zolpidem, appears to produce more limited change in GABA(A) receptor subunit expression. These ideas will be important both for designing new hypnotic drugs with a better safety/efficacy profile, and for evaluating more appropriate ways of using the drugs available today.

Effects of depolarizing stimuli on calcium homeostasis in cultured rat motoneurones.

Intracellular calcium concentrations in individual rat motoneurones in enriched primary cultures were measured by Indo-1 fluorimetry. Motoneurones in the cultures were characterized morphometrically and by cholineacetyltransferase immunocytochemistry. Depolarization of the cells with glutamic acid or veratridine increased intracellular calcium levels, which returned to baseline only slowly after removal of the depolarizing agent. The use of selective agonists (N-methyl-D-aspartic acid, AMPA, kainic acid, quisqualic acid and 1R-3S-ACPD) and antagonists (MK 801 and CNQX) showed that the excitatory amino acid-evoked responses were mediated by AMPA/kainate receptors rather than by NMDA receptors. Depolarization-evoked calcium transients in motoneurones are blocked by the neuroprotective drug riluzole Calcium transients reflected entry of calcium from without the cell, and their blockade by nitrendipine and lanthanum chloride suggested that this entry took place primarily through voltage-dependent calcium channels. These findings may be relevant for understanding the selective vulnerability of motoneurones to excitotoxicity in amyotrophic lateral sclerosis, and the therapeutic activity of riluzole in the treatment of this disease.

Therapeutic advances in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive and rapidly fatal neurodegenerative disease in which both upper and lower motoneurones are involved. The recent discovery of mutations affecting the superoxide dismutase (SOD) gene has given impetus to research on the role of oxidative stress in the pathogenesis of familial ALS, while further evidence for a role of excitotoxicity in the disease process has arisen. In this review, Erik Louvel, Jacques Hugon and Adam Doble discuss these findings and, in addition, describe how a number of large, well-controlled clinical trials have taken place to test potential therapies suggested by different aetiological hypotheses, including immunosuppressive therapies, neurotrophic factors, antioxidants and anti-excitotoxic drugs. These trials have led to the first modest steps in the treatment of this devastating neurological disease.

Interaction of brain cannabinoid receptors with guanine nucleotide binding protein: a radioligand binding study.

The binding of a classical cannabinoid agonist, [3H]R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2 ,3-de]-1,4-benzoxazin-6-yl)(1-napthalenyl)methanone monomethanesulfonate ([3H] WIN55212-2), and a selective cannabinoid receptor (CB1) antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)1-(2,4-dichlorophenyl)-4-meth yl-1H-pyrazole-3-carboxamide hydrochloride ([3H]SR141716A), to rat cannabinoid receptors was evaluated using rat cerebellar membranes. Guanine nucleotides inhibited [3H]WIN55212-2 binding by approximately 50% at 10 microM and enhanced [3H]SR141716A binding very slightly. In the same tissue, the binding of guanosine 5'-O-[gamma-[35S]thio]triphosphate ([35S]GTP-gamma-S) was characterized and the influence of cannabinomimetics evaluated on this binding. Cannabinoid receptor agonists enhanced [35S]GTP-gamma-S binding, whereas SR141716A was devoid of action by itself but antagonized the action of cannabinoid receptor agonists. The good correlation obtained between the half maximum efficient concentration (EC50) values in [35S]GTP-gamma-S binding and the IC50 values [3H]WIN55212-2 binding shows that [35S]GTP-gamma-S binding could be a good functional assay for brain cannabinoid receptors.