Prevention is a privilege: Implementing drug-free community coalitions in Black communities.

Community-based interventions for youth substance use prevention require high levels of capacity to organize and coordinate community resources to support youth development and create opportunities to prevent youth substance use. This project aimed to better understand what Black prevention practitioners perceive as the requirements for a successful drug-free community coalition. Black prevention practitioners, who were engaged in drug-free community funded coalitions, had discussions about coalitions as a strategy for youth substance use prevention in Black communities. These facilitated discussions resulted in consensus over a set of nine core principles regarding successful youth substance use prevention coalition building in these communities.

Structural Properties of Inverted Hexagonal Phase: A Hybrid Computational and Experimental Approach.

Inverted/reverse hexagonal (HII) phases are of special interest in several fields of research, including nanomedicine. We used molecular dynamics (MD) simulation to study HII systems composed of dioleoylphosphatidylethanolamine (DOPE) and palmitoyloleoylphosphatidylethanolamine (POPE) at several hydration levels and temperatures. The effect of the hydration level on several HII structural parameters, including deuterium order parameters, was investigated. We further used MD simulations to estimate the maximum hydrations of DOPE and POPE HII lattices at several given temperatures. Finally, the effect of acyl chain unsaturation degree on the HII structure was studied via comparing the DOPE with POPE HII systems. In addition to MD simulations, we used deuterium nuclear magnetic resonance (2H NMR) and small-angle X-ray scattering (SAXS) experiments to measure the DOPE acyl chain order parameters, lattice plane distances, and the water core radius in HII phase DOPE samples at several temperatures in the presence of excess water. Structural parameters calculated from MD simulations are in excellent agreement with the experimental data. Dehydration decreases the radius of the water core. An increase in hydration level slightly increased the deuterium order parameter of lipids acyl chains, whereas an increase in temperature decreased it. Lipid cylinders undulated along the cylinder axis as a function of hydration level. The maximum hydration levels of PE HII phases at different temperatures were successfully predicted by MD simulations based on a single experimental measurement for the lattice plane distance in the presence of excess water. An increase in temperature decreases the maximum hydration and consequently the radius of the water core and lattice plane distances. Finally, DOPE formed HII structures with a higher curvature compared to POPE, as expected. We propose a general protocol for constructing computational HII systems that correspond to the experimental systems. This protocol could be used to study HII systems composed of molecules other than the PE systems used here and to improve and validate force field parameters by using the target data in the HII phase.

Paediatric Day Case Tonsillectomy - Audit of a New Programme.

Aims The primary objective of this audit was to assess 30-day unplanned admission or readmission rates following day case tonsillectomy. Secondary objectives included assessing demographic characteristics of patients and surgical and anaesthetic techniques employed. Methods Retrospective chart review was performed. Results 34 tonsillectomies or adenotonsillectomies were performed for children aged between 5 and 17 years. A total of six patients (17.6%) were either admitted from the day ward or readmitted within 30 days. This was not statistically significantly greater than the maximum acceptable rate of 15% as recommended by ENT UK and the Royal College of Surgeons (95% confidence intervals 4.8% - 30.5%, p = 0.33). Of these admissions, one (2.9%) was due to nausea and inadequate oral intake, one (2.9%) was due to clinical concerns regarding sleep apnoea and four readmissions (11.8%) were due to bleeding. Anaesthesia techniques used varied considerably. Conclusion Further multidisciplinary co-operation and standardisation of care may help to improve this programme and reduce unplanned admission and readmission rates.

Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver.

BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. OBJECTIVE: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. METHODS: A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs-/- mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. RESULTS: The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. CONCLUSION: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti-inflammatory therapies should be considered in patients with recurrent AIP.

Conversations with French medical geneticists. A personal perspective on the origins and early years of medical genetics in France.

The history of the beginnings of medical genetics in France is discussed, based on the personal perspective provided by recorded interviews with 16 early French workers in the field. The weakness of French genetics overall up to the beginning of the Second World War meant that post-war medical genetics had to start from new, with its origins largely derived from the medical fields of child health and the prevention of genetic disorders, rather than from basic science. The key people responsible for initiating these developments were Robert Debré and Maurice Lamy at Hôpital Necker in Paris and those interviewed included a number of their colleagues and successors, including Jean Frézal, Pierre Maroteaux, Josué Feingold, André and Joelle Boué, and Jean-Claude Kaplan. A separate group of paediatricians, originally at Hôpital Trousseau under Raymond Turpin, including Jérôme Lejeune, Marthe Gautier and Roland Berger, was responsible for major advances in human cytogenetics. Outside Paris, workers were interviewed from Marseille, Strasbourg and Nancy, although not from Lyon, where Jacques-Michel Robert was an early pioneer, particularly of genetic counselling. Challenges in the development of medical genetics in France included the advent of prenatal diagnosis with its ethical issues, the emergence of medical genetics as a distinct specialty from paediatrics, and its spread from Paris across France. These and other aspects are described by those interviewed from their own experiences, given in Appendix S1, while the fully edited transcripts for most interviews are accessible on the Web: www.genmedhist.org/interviews.

In-line and cascaded DWDM transmission using a 15dB net-gain polarization-insensitive fiber optical parametric amplifier.

We demonstrate and characterize polarization-division multiplexed (PDM) DWDM data transmission for the first time in a range of systems incorporating a net-gain polarization-insensitive fiber optical parametric amplifier (PI-FOPA) for loss compensation. The PI-FOPA comprises a modified diversity-loop architecture to achieve 15dB net-gain, and up to 2.3THz (~18nm) bandwidth. Three representative systems are characterized using a 100Gb/s PDM-QPSK signal in conjunction with emulated DWDM neighbouring channels: (a) a 4x75km in-line fiber transmission system incorporating multiple EDFAs and a single PI-FOPA (b) N cascaded PI-FOPA amplification stages in an unlevelled Nx25km recirculating loop arrangement, with no EDFAs used within the loop signal path, and (c) M cascaded PI-FOPA amplification stages as part of an Mx75.6km gain-flattened recirculating loop system with the FOPA compensating for the transmission fiber loss, and EDFA compensation for loop switching and levelling loss. For the 4x75km in-line system (a), we transmit 45x50GHz-spaced signals ('equivalent' data-rate of 4.5Tb/s) with average OSNR penalty of 1.3dB over the band at 10-3 BER. For the unlevelled 'FOPA-only' 25.2km cascaded system (b), we report a maximum of eight recirculations for all 10x100GHz-spaced signals, and five recirculations for 20x50GHz-spaced signals. For the 75.6km levelled system

Noise and transmission performance improvement of broadband distributed Raman amplifier using bidirectional Raman pumping with dual order co-pumps.

We demonstrate a low noise bidirectional broadband distributed Raman pumping scheme combining dual order co-propagated pumps without increasing the signal RIN level. The noise performance improvement is compared experimentally and numerically with conventional counter-pumping only and bidirectional pumping with only a 2nd order co-pump for a 70nm bandwidth and 61.5km distributed Raman amplifier. The proposed broadband pumping scheme shows 1.2dB maximum noise figure improvement and extends the long-haul transmission reach up to 6150km with a Q-factor improvement of ~0.7dB compared with counter-pumping only scheme.

Metabolomic analysis of human plasma reveals that arginine is depleted in knee osteoarthritis patients.

OBJECTIVE: To identify novel biomarker(s) for knee osteoarthritis (OA) using a metabolomics approach. METHOD: We utilized a two-stage case-control study design. Plasma samples were collected from knee OA patients and healthy controls after 8-h fasting and metabolically profiled using a targeted metabolomics assay kit. Linear regression was used to identify novel metabolic markers for OA. Receiver operating characteristic (ROC) analysis was used to examine diagnostic values. Gene expression analysis was performed on human cartilage to explore the potential mechanism for the novel OA marker(s). RESULTS: Sixty-four knee OA patients and 45 controls were included in the discovery stage and 72 knee OA patients and 76 age and sex matched controls were included in the validation stage. We identified and confirmed six metabolites that were significantly associated with knee OA, of which arginine was the most significant metabolite (P < 3.5 × 10(-13)) with knee OA patients having on average 69 µM lower than that in controls. ROC analysis showed that arginine had the greatest diagnostic value with area under the curve (AUC) of 0.984. The optimal cutoff of arginine concentration was 57 µM with 98.3% sensitivity and 89% specificity. The depletion of arginine in OA patients was most likely due to the over activity of arginine to ornithine pathway, leading to imbalance between cartilage repair and degradation. CONCLUSION: Arginine is significantly depleted in refractory knee OA patients. Further studies within a longitudinal setting are required to examine whether arginine can predict early OA changes.

Transmission performance improvement using random DFB laser based Raman amplification and bidirectional second-order pumping.

We demonstrate that a distributed Raman amplification scheme based on random distributed feedback (DFB) fiber laser enables bidirectional second-order Raman pumping without increasing relative intensity noise (RIN) of the signal. This extends the reach of 10 × 116 Gb/s DP-QPSK WDM transmission up to 7915 km, compared with conventional Raman amplification schemes. Moreover, this scheme gives the longest maximum transmission distance among all the Raman amplification schemes presented in this paper, whilst maintaining relatively uniform and symmetric signal power distribution, and is also adjustable in order to be highly compatible with different nonlinearity compensation techniques, including mid-link optical phase conjugation (OPC) and nonlinear Fourier transform (NFT).

Improved WDM performance of a fibre optical parametric amplifier using Raman-assisted pumping.

We experimentally demonstrate a Raman-Assisted Fibre Optical Parametric Amplifier (RA-FOPA) with 20dB net gain using wavelength division multiplexed signals. We report amplification of 10x58Gb/s 100GHz-spaced QPSK signals and show that by appropriate tuning of the parametric pump power and frequency, gain improvement of up to 5dB can be achieved for the RA-FOPA compared with combined individual contributions from the parametric and Raman pumps. We compare the RA-FOPA with an equivalent-gain conventional FOPA and find that four-wave mixing crosstalk is substantially reduced by up to 5.8 ± 0.4dB using the RA-FOPA. Worst-case performance penalty of the RA-FOPA is found to be only 1.0 ± 0.2dB over all measured OSNRs, frequencies and input powers, making it an attractive proposal for future communications systems.

No socioeconomic inequalities in ovarian cancer survival within two randomised clinical trials.

BACKGROUND: Ovarian cancer is the leading cause of death among cancers of the female genital tract, with poor outcomes despite chemotherapy. There was a persistent socioeconomic gradient in 1-year survival in England and Wales for more than 3 decades (1971-2001). Inequalities in 5-year survival persisted for more than 20 years but have been smaller for women diagnosed around 2000. We explored one possible explanation. METHODS: We analysed data on 1406 women diagnosed with ovarian cancer during 1991-1998 and recruited to one of two randomised clinical trials. In the second International Collaborative Ovarian Neoplasm (ICON2) trial, women diagnosed between 1991 and 1996 were randomised to receive either the three-drug combination cyclophosphamide, doxorubicin and cisplatin (CAP) or single-agent carboplatin given at optimal dose. In the ICON3 trial, women diagnosed during 1995-1998 were randomised to receive either the same treatments as ICON2, or paclitaxel plus carboplatin.Relative survival at 1, 5 and 10 years was estimated for women in five categories of socioeconomic deprivation. The excess hazard of death over and above background mortality was estimated by fitting multivariable regression models with Poisson error structure and a dedicated link function in a generalised linear model framework, adjusting for the duration of follow-up and the confounding effects of age, Federation of Gynecology and Obstetrics (FIGO) stage and calendar period. RESULTS: Unlike women with ovarian cancer in the general population, no statistically significant socioeconomic gradient was seen for women with ovarian cancer treated in the two randomised controlled trials. The deprivation gap in 1-year relative survival in the general population was statistically significant at -6.7% (95% CI (-8.1, -5.3)), compared with -3.6% (95% CI (-10.4, +3.2)) in the trial population. CONCLUSIONS: Although ovarian cancer survival is significantly lower among poor women than rich women in England and Wales, there was no evidence of an association between socioeconomic deprivation and survival among women with ovarian cancer who were treated and followed up consistently in two well-conducted randomised controlled trials. We conclude that the persistent socioeconomic gradient in survival among women with ovarian cancer, at least for 1-year survival, may be due to differences in access to treatment and standards of care.

Unrepeatered DPSK transmission over 360 km SMF-28 fibre using URFL based amplification.

Unrepeatered 42.7 Gb/s per channel RZ-DPSK transmission over standard SMF-28 fibre with novel URFL based amplification using fibre Bragg gratings is investigated. OSNR and gain performance are studied experimentally and through simulations. Error free transmission for 16 channels across the full C-band with direct detection was experimentally demonstrated for 280 km span length, as well as 6-channel transmission at 340 km and single-channel transmission up to 360 km (75 dB) without employing ROPA or specialty fibres.

1.14 Tb/s DP-QPSK WDM polarization-diverse optical phase conjugation.

Optical phase conjugation (OPC) of a polarization-multiplexed comb of 10x114Gb/s DP-QPSK signals has been demonstrated for the first time, occupying a spectral bandwidth of >1 THz (~9 nm). The nonlinear element employed for the OPC was highly nonlinear fiber (HNLF) optimized for the suppression of stimulated Brillouin scattering (SBS) and configured in a bi-directional loop offering polarization diversity. Pump power (each way about the loop) and input signal power to the OPC subsystem were optimized at 29.7 dBm and + 3 dBm respectively producing a Q(2) penalty of ≤ 0.9 dB over all conjugate wavelengths, polarizations and output OSNR (up to 20 dB).

Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity.

BACKGROUND: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity. METHODS: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models. RESULTS: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3'-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38-6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 × 10⁻6, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively). CONCLUSION: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.

A multicenter, randomized trial of flat dosing versus intrapatient dose escalation of single-agent carboplatin as first-line chemotherapy for advanced ovarian cancer: an SGCTG (SCOTROC 4) and ANZGOG study on behalf of GCIG.

BACKGROUND: The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing. PATIENTS AND METHODS: Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS). RESULTS: Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had ≥1 cycle. The median AUCs (cycle 2-6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non-hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85-1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81-1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value. CONCLUSIONS: Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia.

Hybrid gain-flattened and reduced power excursion scheme for distributed Raman amplification.

We propose and evaluate through extensive numerical modelling a novel distributed hybrid amplification scheme combining first and second-order Raman pumping which gives reduced signal power excursion over a wide spatial-spectral range of 60 km × 80 nm in C + L-bands.

Stroke thrombolysis in patients taking dabigatran.

Stroke thrombolysis is becoming a common practice in Australian and New Zealand hospitals. There are no established guidelines for thrombolysis of patients who are taking dabigatran, and accurate medication reconciliation may not be possible. Patients with normal activated partial thromboplastin time are unlikely to have clinically significant dabigatran concentration in the blood. For safest outcomes, we suggest incorporating thrombin time assay for acute stroke patients suspected to be taking dabigatran.

Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease.

The molecular analysis of a specific CAG repeat sequence in the Huntington's disease gene in 440 Huntington's disease patients and 360 normal controls reveals a range of 30-70 repeats in affected individuals and 9-34 in normals. We find significant negative correlations between the number of repeats on the HD chromosome and age at onset, regardless of sex of the transmitting parent, and between the number of repeats on the normal paternal allele and age at onset in individuals with maternally transmitted disease. This effect of the normal paternal allele may account for the weaker age at onset correlation between affected sib pairs with disease of maternal as opposed to paternal origin and suggests that normal gene function varies because of the size of the repeat in the normal range and a sex-specific modifying effect.

The relationship between vitamin D and chemotherapy-induced toxicity - a pilot study.

BACKGROUND: There are anecdotal data that lower levels of vitamin D may be associated with increased levels of toxicity in individuals receiving chemotherapy; we therefore wished to investigate this further. METHODS: From a cohort of over 11 000 individuals, we included those who had vitamin D levels (serum 1,25(OH)(2)D3) measured before and during chemotherapy. They were analysed for side effects correlating Chemotherapy Toxicity Criteria with vitamin D levels, normalising data for general markers of patient health including C-reactive protein and albumin. RESULTS: A total of 241 (2% of the total cohort) individuals entered the toxicity analysis. We found no overall difference in toxicity effects experienced by patients depending on whether they were vitamin D depleted or had sufficient levels (P=0.78). CONCLUSION: This pilot study suggests routine vitamin D measurement during treatment does not appear to be necessary in the management of chemotherapy-induced toxicity.

Identification of an AluY-mediated deletion of exon 5 in the CPOX gene by MLPA analysis in patients with hereditary coproporphyria.

Hereditary coproporphyria (HCP) is an autosomal dominantly inherited hepatic porphyria, caused by a mutation in the coproporphyrinogen oxidase (CPOX) gene. The genetic defect leads to a partial defect of CPOX, the sixth enzyme involved in haem biosynthesis. Affected individuals can develop acute life-threatening attacks of neurovisceral symptoms and/or more rarely cutaneous symptoms such as skin fragility and blistering. The identification of the genetic defect in HCP families is of crucial importance to detect the carrier status which allows counselling to prevent possible triggering factors, e.g. certain drugs, alcohol, or fasting. In a total of nine Swedish HCP families, routine gene sequence analysis had identified a causative mutation in only five. In the present study, using an in-house developed synthetic probe set for multiplex ligation-dependent probe amplification (MLPA) analysis, we detected a deletion of the fifth exon in the CPOX gene in the remaining four families. The deletion is 3381 bp in size and has originated by an Alu-mediated mechanism. This finding emphasizes the usefulness of MLPA analysis as a complement to gene sequencing for comprehensive genetic diagnostics in HCP patients.