A quasi-experimental evaluation of partnerships for success's impact on community-level ethanol and prescription drug poisoning rates.

The emerging dual threats of underaged drinking (UAD) and prescription drug misuse (PDM) require sustained prevention efforts across multiple levels of interventions. In response to the continuing proliferation of UAD and PDM among youth and young adults, the Substance Abuse and Mental Health Services Administration (SAMHSA) developed the Partnerships for Success (PFS) program. Across five cohorts funded from 2012 to 2016, PFS created linkages between health care providers, treatment and prevention services providers, government agencies, and nonprofit organizations for the delivery of multiple sets of services (e.g., prevention education, community activities, screening) targeted toward UAD and PDM. This paper reports on the impact of the PFS program on reductions in ethanol and prescription drug poisoning exposures as reported from data in the National Poisoning Data System (NPDS). Across 35 States, communities targeted by PFS interventions were compared to non-targeted communities using a non-equivalent comparison groups design and propensity score weighting. Using propensity-weighted, multilevel latent growth modeling, steeper reductions in ethanol and prescription drug poisoning exposure call rates were observed in States which had a higher proportion of communities participating in PFS. Grantee-level longitudinal analogs to Cohen's d effect sizes ranged from -0.24 to -0.97, whereas PFS' effects on individual communities (net of Statewide effects) were negligible. The study serves as a unique exemplar of using the NPDS to extract community-level intervention effects that might otherwise be "hidden" within epidemiological data while underscoring the cumulative effects of PFS' community-level efforts in stemming the tide on underaged drinking and prescription drug misuse.

Quantitative analysis of antimicrobial use on British dairy farms.

Antimicrobial resistance has been reported to represent a growing threat to both human and animal health, and concerns have been raised around levels of antimicrobial usage (AMU) within the livestock industry. To provide a benchmark for dairy cattle AMU and identify factors associated with high AMU, data from a convenience sample of 358 dairy farms were analysed using both mass-based and dose-based metrics following standard methodologies proposed by the European Surveillance of Veterinary Antimicrobial Consumption project. Metrics calculated were mass (mg) of antimicrobial active ingredient per population correction unit (mg/PCU), defined daily doses (DDDvet) and defined course doses (DCDvet). AMU on dairy farms ranged from 0.36 to 97.79 mg/PCU, with a median and mean of 15.97 and 20.62 mg/PCU, respectively. Dose-based analysis ranged from 0.05 to 20.29 DDDvet, with a median and mean of 4.03 and 4.60 DDDvet, respectively. Multivariable analysis highlighted that usage of antibiotics via oral and footbath routes increased the odds of a farm being in the top quartile (>27.9 mg/PCU) of antimicrobial users. While dairy cattle farm AMU appeared to be lower than UK livestock average, there were a selection of outlying farms with extremely high AMU, with the top 25 per cent of farms contributing greater than 50 per cent of AMU by mass. Identification of these high use farms may enable targeted AMU reduction strategies and facilitate a significant reduction in overall dairy cattle AMU.

How safe is preterm operative vaginal delivery and which is the instrument of choice?

OBJECTIVE: The objective of this study was to determine neonatal outcomes in preterm operative vaginal delivery given the current paucity of data available to guide clinicians. STUDY DESIGN: A retrospective review of 64 cases was conducted, and neonatal outcomes were compared to spontaneous vaginal deliveries in similar gestations. The primary outcomes studied were death and occurrence of intraventricular haemorrhage. Secondary outcomes included admission to NICU, Apgar < 3 at 5 min, ventilation requirement, jaundice requiring treatment, culture-proven sepsis and necrotising enterocolitis. The study was conducted in a stand-alone maternity unit of approximately 9000 deliveries per year. RESULTS AND CONCLUSIONS: We concluded that although vacuum delivery is avoided in preterm infants, outcomes were similar to forceps deliveries of similar gestations.

Methadone dosing and prescribed medication use in a prospective cohort of opioid-dependent pregnant women.

AIMS: This study aimed to (i) describe methadone dosing before, during and after pregnancy, (ii) to compare the incidence of neonatal abstinence syndrome (NAS) between those with dose decreases and those with steady or increasing doses and (iii) to describe prescribed medication use among opioid-dependent pregnant women. DESIGN: Prospective cohort study. SETTING: Two Irish tertiary care maternity hospitals. PARTICIPANTS: A total of 117 pregnant women on methadone maintenance treatment (MMT) recruited between July 2009 and July 2010. MEASUREMENTS: Electronic dispensing records from addiction clinics and the Primary Care Reimbursement Service were used to determine methadone doses and dispensed medications in the year preceding and the month following delivery. The Finnegan score was used to determine need for medical treatment of NAS. FINDINGS: Of the 117 participants, sufficient dosing data were available for 89 women treated with MMT throughout pregnancy; 36 (40.4%) had their dose decreased from a mean pre-pregnancy dose of 73.3 mg [standard deviation (SD) 25.5] to a third-trimester dose of 58.0 mg (SD 26.0). The corresponding figures for those with increased doses (n = 31, 34.8%) were 70.7 mg (SD 25.3) and 89.7 mg (SD 21.0), respectively. The incidence of medically treated NAS did not differ between dosage groups. Antidepressants were dispensed for 29 women (25.7%) during pregnancy, with the rate decreasing from pre-pregnancy to postpartum. Benzodiazepines were prescribed for 43 women (38.0%). CONCLUSION: In the Irish health service, opioid-dependent women frequently have their methadone dose decreased during pregnancy but this does not appear to affect the incidence of the neonatal abstinence syndrome in their babies.

Methadone and perinatal outcomes: a prospective cohort study.

AIMS: Methadone use in pregnancy has been associated with adverse perinatal outcomes and neonatal abstinence syndrome (NAS). This study aimed to examine perinatal outcomes and NAS in relation to (i) concomitant drug use and (ii) methadone dose. DESIGN: Prospective cohort study. SETTING: Two tertiary care maternity hospitals. PARTICIPANTS: A total of 117 pregnant women on methadone maintenance treatment recruited between July 2009 and July 2010. MEASUREMENTS: Information on concomitant drug use was recorded with the Addiction Severity Index. Perinatal outcomes included pre-term birth (<37 weeks' gestation), small-for-gestational-age (<10th centile) and neonatal unit admission. NAS outcomes included: incidence of medically treated NAS, peak Finnegan score, cumulative dose of NAS treatment and duration of hospitalization. FINDINGS: Of the 114 liveborn infants 11 (9.6%) were born pre-term, 49 (42.9%) were small-for-gestational-age, 56 (49.1%) had a neonatal unit admission and 29 (25.4%) were treated medically for NAS. Neonates exposed to methadone-only had a shorter hospitalization than those exposed to methadone and concomitant drugs (median 5.0 days versus 6.0 days, P = 0.03). Neonates exposed to methadone doses ≥80 mg required higher cumulative doses of morphine treatment for NAS (median 13.2 mg versus 19.3 mg, P = 0.03). The incidence and duration of NAS did not differ between the two dosage groups. CONCLUSIONS: The incidence and duration of the neonatal abstinence syndrome is not associated with maternal methadone dose, but maternal opiate, benzodiazepine or cocaine use is associated with longer neonatal hospitalization.

The value of neonatal autopsy.

BACKGROUND AND OBJECTIVE: Neonatal autopsy rates were in decline internationally at the end of the last century. Our objective was to assess the current value of neonatal autopsy in providing additional information to families and healthcare professionals. METHODS: We conducted a review of neonatal autopsies performed in a tertiary perinatal centre over an 11-year period. Primary outcomes measured were the annual neonatal autopsy rates and concordance rates between clinical and autopsy diagnoses of the primary cause of death. Secondary outcomes were the clinical, genetic and audit value of the examinations. Findings were used to inform the consent process, and the effect this had on institutional post-mortem rates was assessed over the subsequent 5-year period. RESULTS: There was a marked decline in the annual neonatal autopsy rate from 73% in 1994 to 48% in 2004. 164 cases met the inclusion criteria for review. Complete concordance for cause of death was reached in 91% of cases. Previously unsuspected or unconfirmed clinical conditions, other than the primary cause of death, were uncovered at autopsy in 85 cases. Detailed information on inheritable conditions was obtained in 45 cases. Findings with perceived 'audit value' for clinical practice were identified in 29 cases. The dissemination of this information to staff and families contributed to the stabilisation of the consent rate in the following 5-year period. CONCLUSION: Neonatal autopsy remains a valuable diagnostic tool as it provides critical clinical and audit information for healthcare professionals and families.

A critical reassessment of ambulance service airway management in prehospital care: Joint Royal Colleges Ambulance Liaison Committee Airway Working Group, June 2008.

Paramedic tracheal intubation has been practised in the UK for more than 20 years and is currently a core skill for paramedics. Growing evidence suggests that tracheal intubation is not the optimal method of airway management by paramedics and may be detrimental to patient outcomes. There is also evidence that the current initial training of 25 intubations performed in-hospital is inadequate, and that the lack of ongoing intubation practice may compound this further. Supraglottic airway devices (eg, laryngeal mask airway), which were not available when extended training and paramedic intubation was first introduced, are now in use in many ambulance services and are a suitable alternative prehospital airway device for paramedics.

Pseudomonas aeruginosa MurE amide ligase: enzyme kinetics and peptide inhibitor.

The enzyme kinetics of the amide ligase MurE, a cell wall biosynthesis enzyme, from Pseudomonas aeruginosa were determined using the synthesized nucleotide substrate UDP-MurNAc-Ala-Glu (uridine 5'-diphosphoryl N-acetylmuramoyl-L-alanyl-D-glutamate). When coupled to a competitive bio-panning technique using a M13 phage display library encoding approximately 2.7 x 10(9) random peptide permutations and the specific substrates meso-A2pm (meso-diaminopimelic acid) and ATP, a peptide inhibitor of MurE was identified. The MurEp1 dodecamer selected and synthesized inhibited MurE ATPase activity with an IC(50) value of 500 microM. The inhibition was shown to be time-dependent and was reversed by the addition of meso-A2pm or UDP-MurNAc-Ala-Glu during the pre-incubation step. Kinetic analysis defined MurEp1 as a mixed inhibitor against both substrates with K(i) values of 160 and 80 microM respectively. MurEp1 was found to interfere in meso-A2pm and UDP-MurNAc-Ala-Glu binding necessary for amide bond formation. Modelling of Ps. aeruginosa MurE and docking of MurEp1 on the Ps. aeruginosa MurE surface indicated that MurEp1 binds at the juxtaposition of both meso-A2pm- and UDP-MurNAc-Ala-Glu-binding sites in the closed conformational state of the enzyme. Identification of the MurEp1 residues involved in MurE binding and inhibition will allow the development of a novel class of inhibitors having a novel mode of action against MurE.

Phage display-derived inhibitor of the essential cell wall biosynthesis enzyme MurF.

BACKGROUND: To develop antibacterial agents having novel modes of action against bacterial cell wall biosynthesis, we targeted the essential MurF enzyme of the antibiotic resistant pathogen Pseudomonas aeruginosa. MurF catalyzes the formation of a peptide bond between D-Alanyl-D-Alanine (D-Ala-D-Ala) and the cell wall precursor uridine 5'-diphosphoryl N-acetylmuramoyl-L-alanyl-D-glutamyl-meso-diaminopimelic acid (UDP-MurNAc-Ala-Glu-meso-A2pm) with the concomitant hydrolysis of ATP to ADP and inorganic phosphate, yielding UDP-N-acetylmuramyl-pentapeptide. As MurF acts on a dipeptide, we exploited a phage display approach to identify peptide ligands having high binding affinities for the enzyme. RESULTS: Screening of a phage display 12-mer library using purified P. aeruginosa MurF yielded to the identification of the MurFp1 peptide. The MurF substrate UDP-MurNAc-Ala-Glumeso-A2pm was synthesized and used to develop a sensitive spectrophotometric assay to quantify MurF kinetics and inhibition. MurFp1 acted as a weak, time-dependent inhibitor of MurF activity but was a potent inhibitor when MurF was pre-incubated with UDP-MurNAc-Ala-Glu-meso-A2pm or ATP. In contrast, adding the substrate D-Ala-D-Ala during the pre-incubation nullified the inhibition. The IC50 value of MurFp1 was evaluated at 250 microM, and the Ki was established at 420 microM with respect to the mixed type of inhibition against D-Ala-D-Ala. CONCLUSION: MurFp1 exerts its inhibitory action by interfering with the utilization of D-Ala-D-Ala by the MurF amide ligase enzyme. We propose that MurFp1 exploits UDP-MurNAc-Ala-Glu-meso-A2pm-induced structural changes for better interaction with the enzyme. We present the first peptide inhibitor of MurF, an enzyme that should be exploited as a target for antimicrobial drug development.

Characterization of Shewanella oneidensis MtrC: a cell-surface decaheme cytochrome involved in respiratory electron transport to extracellular electron acceptors.

MtrC is a decaheme c-type cytochrome associated with the outer cell membrane of Fe(III)-respiring species of the Shewanella genus. It is proposed to play a role in anaerobic respiration by mediating electron transfer to extracellular mineral oxides that can serve as terminal electron acceptors. The present work presents the first spectropotentiometric and voltammetric characterization of MtrC, using protein purified from Shewanella oneidensis MR-1. Potentiometric titrations, monitored by UV-vis absorption and electron paramagnetic resonance (EPR) spectroscopy, reveal that the hemes within MtrC titrate over a broad potential range spanning between approximately +100 and approximately -500 mV (vs. the standard hydrogen electrode). Across this potential window the UV-vis absorption spectra are characteristic of low-spin c-type hemes and the EPR spectra reveal broad, complex features that suggest the presence of magnetically spin-coupled low-spin c-hemes. Non-catalytic protein film voltammetry of MtrC demonstrates reversible electrochemistry over a potential window similar to that disclosed spectroscopically. The voltammetry also allows definition of kinetic properties of MtrC in direct electron exchange with a solid electrode surface and during reduction of a model Fe(III) substrate. Taken together, the data provide quantitative information on the potential domain in which MtrC can operate.

Mesangiocapillary glomerulonephritis type 2 associated with familial partial lipodystrophy (Dunnigan-Kobberling syndrome).

The lipodystrophies are a heterogeneous group of disorders of adipose tissue associated with insulin resistance. The sporadic form of partial lipodystrophy, characterised by fat loss from the face and upper body, is associated with complement abnormalities and mesangiocapillary glomerulonephritis type 2 (MCGN II) and the conditions are thought to have a shared autoimmune aetiology. We present the first case of the rare familial form of partial lipodystrophy, caused by a mutation in the LMNA gene, associated with MCGN II. This suggests that partial lipodystrophy of both the sporadic and familial subtypes may predispose to this condition and that the observed renal and complement abnormalities may be secondary to other factors associated with lipodystrophy.