Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.

PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

Associations of pigmentary and naevus phenotype with melanoma risk in two populations with comparable ancestry but contrasting levels of ambient sun exposure.

BACKGROUND: People at high risk of developing melanoma are usually identified by pigmentary and naevus phenotypes. OBJECTIVE: We examined whether associations of these phenotypes with melanoma risk differed by ambient sun exposure or participant characteristics in two population-based, case-control studies with comparable ancestry but different ambient sun exposure. METHODS: Data were analysed from 616 cases and 496 controls from the Australian Melanoma Family Study and 2012 cases and 504 controls from the Leeds (UK) case-control study. Questionnaire, interview and dermatological skin examination data were collected using the same measurement protocols. Relative risks were estimated as odds ratios using unconditional logistic regression, adjusted for potential confounders. RESULTS: Hair and skin colour were the strongest pigmentary phenotype risk factors. All associations of pigmentary phenotype with melanoma risk were similar across countries. The median number of clinically assessed naevi was approximately three times higher in Australia than Leeds, but the relative risks for melanoma associated with each additional common or dysplastic naevus were higher for Leeds than Australia, especially for naevi on the upper and lower limbs. Higher naevus counts on the head and neck were associated with a stronger relative risk for melanoma for women than men. The two countries had similar relative risks for melanoma based on self-reported naevus density categories, but personal perceptions of naevus number differed by country. There was no consistent evidence of interactions between phenotypes on risk. CONCLUSIONS: Classifying people at high risk of melanoma based on their number of naevi should ideally take into account their country of residence, type of counts (clinical or self-reported), body site on which the naevus counts are measured and sex. The presence of naevi may be a stronger indicator of a genetic predisposition in the UK than in Australia based on less opportunity for sun exposure to influence naevus development.

Microwave plasmonic mixer in a transparent fibre-wireless link.

To cope with the high bandwidth requirements of wireless applications1, carrier frequencies are shifting towards the millimetre-wave and terahertz bands2-5. Conversely, data is normally transported to remote wireless antennas by optical fibres. Therefore, full transparency and flexibility to switch between optical and wireless domains would be desirable6,7. Here, we demonstrate for the first time a direct wireless-to-optical receiver in a transparent optical link. We successfully transmit 20 and 10 Gbit/s over wireless distances of 1 and 5 m at a carrier frequency of 60 GHz, respectively. Key to the breakthrough was a plasmonic mixer directly mapping the wireless information onto optical signals. The plasmonic scheme with its subwavelength feature and pronounced field confinement provides a built-in field enhancement of up to 90'000 over the incident field in an ultra-compact and CMOS compatible structure. The plasmonic mixer is not limited by electronic speed and thus compatible with future terahertz technologies.

Smoking in pregnancy is a key factor for sudden infant death among Maori.

AIM: To examine the sudden unexpected death in infancy (SUDI) disparity between Maori and non-Maori in New Zealand. METHODS: A nationwide prospective case-control study ran from March 2012 to February 2015. Exposure to established SUDI risk factors was analysed to investigate the disparity experienced by Maori. Infant ethnicity was based on mother's ethnicity. Maori ethnicity was prioritised. Non-Maori includes Pacific, Asian, NZ European and Other. RESULTS: There were 137 cases and 649 controls. The Maori SUDI rate was 1.41/1000 live births compared to 0.53/1000 for non-Maori. Parents/caregivers of 132 cases (96%) and 258 controls (40%) were interviewed. Smoking in pregnancy was associated with an equally increased SUDI risk for Maori (adjusted OR = 8.11, 95% CI = 2.64, 24.93) and non-Maori (aOR = 5.09, 95% CI = 1.79, 14.47), as was bed-sharing (aOR = 3.66, 95% CI = 1.49, 9.00 vs aOR = 11.20, 95% CI = 3.46, 36.29). Bed-sharing prevalence was similar; however, more Maori controls smoked during pregnancy (46.7%) than non-Maori (22.8%). The main contributor relating to increased SUDI risk for Maori/non-Maori infants is the combination of smoking in pregnancy and bed sharing. CONCLUSION: The association between known SUDI risk factors, including bed sharing and/or smoking in pregnancy and SUDI risk, is the same regardless of ethnicity. Maori infants are exposed more frequently to both behaviours because of the higher Maori smoking rate.

Weight loss surgery in adolescents corrects high-density lipoprotein subspecies and their function.

BACKGROUND/OBJECTIVE: Youth with obesity have an altered high-density lipoprotein (HDL) subspecies profile characterized by depletion of large apoE-rich HDL particles and an enrichment of small HDL particles. The goal of this study was to test the hypothesis that this atherogenic HDL profile is reversible and that HDL function would improve with metabolic surgery. METHODS: Serum samples from adolescent males with severe obesity mean±s.d. age of 17.4±1.6 years were studied at baseline and 1 year following vertical sleeve gastrectomy (VSG). HDL subspecies and HDL function were evaluated pre and post VSG using paired t-tests. A lean group of adolescents was included as a reference group. RESULTS: After VSG, body mass index decreased by 32% and insulin resistance as estimated by homeostatic model assessment of insulin resistance decreased by 75% (both P<0.01). Large apoE-rich HDL subspecies increased following VSG (P<0.01) and approached that of lean adolescents despite participants with considerable residual obesity. In addition, HDL function improved compared with baseline (cholesterol efflux capacity increased by 12%, HDL lipid peroxidation potential decreased by 30% and HDL anti-oxidative capacity improved by 25%, all P<0.01). CONCLUSIONS: Metabolic surgery results in a significant improvement in the quantity of large HDL subspecies and HDL function. Our data suggest metabolic surgery may improve cardiovascular risk in adolescents and young adults.

Nitrogen utilization, preweaning nutrient digestibility, and growth effects of Holstein dairy calves fed 2 amounts of a moderately high protein or conventional milk replacer.

Studies have shown that calves fed milk replacers (MR) with crude protein (CP) concentrations greater than 20%, as typically found in conventional MR, have higher dry matter intakes (DMI) and greater average daily gains (ADG) but consume less starter, which can lead to stress during weaning and reduced rumen development. The greater amount of CP being fed to preweaned calves may alter their nitrogen (N) balance, and excess N may be excreted in the urine. The objective of this study was to determine N utilization in preweaned calves fed diets varying in the amount of CP and MR fed. This study used 24 newborn dairy heifer calves blocked by birth and randomly assigned to 1 of 3 treatments: (1) 446g dry matter (DM) of a conventional MR (CON; 20% CP, 20% fat), (2) 669g DM of a moderately high protein MR (moderate; MOD; 26% CP, 18% fat), or (3) 892g DM of a moderately high protein MR (aggressive; AGG; 26% CP, 18% fat). All calves had ad libitum access to starter and water. Both MR and starter were medicated with decoquinate. During weaning (d 43-49), the morning MR feeding ceased. On d 50, all MR feedings ended; however, starter and water intakes were continuously recorded until d 56. At 5wk of age, urine was collected using urinary catheters for 3d and chromium oxide was administered by bolus at 2g/d for 7d to estimate N efficiency. Calves fed MOD and AGG had similar starter intakes, feed efficiencies, and ADG, with the combined treatments having reduced starter intakes (258 vs. 537g/d), greater ADG (674 vs. 422g/d), and improved feed efficiency (0.57 vs. 0.45 gain:feed) compared with CON calves preweaning. However, DMI and water intake were similar across all treatments. Results from the N utilization phase showed that MOD and AGG treatments had similar but lower N efficiency compared with CON calves (45.5 vs. 52.7%). This could be due to MOD- and AGG-fed calves having greater urine volume and thereby, greater combined urine N output compared with CON calves (17.6 vs. 12.1 g/d). In summary, feeding >0.66kg (DM) from a 26% CP MR increased ADG and improved feed efficiency during the preweaning period but reduced starter intake and lowered N efficiency.

Plasmonic modulator with >170 GHz bandwidth demonstrated at 100 GBd NRZ.

We demonstrate a plasmonic Mach-Zehnder (MZ) modulator with a flat frequency response exceeding 170 GHz. The modulator comprises two phase modulators exploiting the Pockels effect of an organic electro-optic material in plasmonic slot waveguides. We further show modulation at 100 GBd NRZ and 60 GBd PAM-4. The electrical drive signals were generated using a 100 GSa/s digital to analog converter (DAC). The high-speed and small-scale devices are relevant for next-generation optical interconnects.

Plasmonic phased array feeder enabling ultra-fast beam steering at millimeter waves.

In this paper, we demonstrate an integrated microwave phoneeded for beamtonics phased array antenna feeder at 60 GHz with a record-low footprint. Our design is based on ultra-compact plasmonic phase modulators (active area <2.5µm2) that not only provide small size but also ultra-fast tuning speed. In our design, the integrated circuit footprint is in fact only limited by the contact pads of the electrodes and by the optical feeding waveguides. Using the high speed of the plasmonic modulators, we demonstrate beam steering with less than 1 ns reconfiguration time, i.e. the beam direction is reconfigured in-between 1 GBd transmitted symbols.

Integrated optical frequency shifter in silicon-organic hybrid (SOH) technology.

We demonstrate for the first time a waveguide-based frequency shifter on the silicon photonic platform using single-sideband modulation. The device is based on silicon-organic hybrid (SOH) electro-optic modulators, which combine conventional silicon-on-insulator waveguides with highly efficient electro-optic cladding materials. Using small-signal modulation, we demonstrate frequency shifts of up to 10 GHz. We further show large-signal modulation with optimized waveforms, enabling a conversion efficiency of -5.8 dB while suppressing spurious side-modes by more than 23 dB. In contrast to conventional acousto-optic frequency shifters, our devices lend themselves to large-scale integration on silicon substrates, while enabling frequency shifts that are several orders of magnitude larger than those demonstrated with all-silicon serrodyne devices.

High speed plasmonic modulator array enabling dense optical interconnect solutions.

Plasmonic modulators might pave the way for a new generation of compact low-power high-speed optoelectronic devices. We introduce an extremely compact transmitter based on plasmonic Mach-Zehnder modulators offering a capacity of 4 × 36 Gbit/s on a footprint that is only limited by the size of the high-speed contact pads. The transmitter array is contacted through a multicore fiber with a channel spacing of 50 µm.

Plasmonic-organic hybrid (POH) modulators for OOK and BPSK signaling at 40 Gbit/s.

We report on high-speed plasmonic-organic hybrid Mach-Zehnder modulators comprising ultra-compact phase shifters with lengths as small as 19 µm. Choosing an optimum phase shifter length of 29 µm, we demonstrate 40 Gbit/s on-off keying (OOK) modulation with direct detection and a BER < 6 × 10(-4). Furthermore, we report on a 29 µm long binary-phase shift keying (BPSK) modulator and show that it operates error-free (BER < 1 × 10(-10)) at data rates up to 40 Gbit/s and with an energy consumption of 70 fJ/bit.

Can a first-order exponential decay model fit heart rate recovery after resistance exercise?

The time-constant of postexercise heart rate recovery (HRRτ ) obtained by fitting heart rate decay curve by a first-order exponential fitting has being used to assess cardiac autonomic recovery after endurance exercise. The feasibility of this model was not tested after resistance exercise (RE). The aim of this study was to test the goodness of fit of the first-order exponential decay model to fit heart rate recovery (HRR) after RE. Ten healthy subjects participated in the study. The experimental sessions occurred in two separated days and consisted of performance of 1 set of 10 repetitions at 50% or 80% of the load achieved on the one-repetition maximum test [low-intensity (LI) and high-intensity (HI) sessions, respectively]. Heart rate (HR) was continuously registered before and during exercise and also for 10 min of recovery. A monoexponential equation was used to fit the HRR curve during the postexercise period using different time windows (i.e. 30, 60, 90, … 600 s). For each time window, (i) HRRτ was calculated and (ii) variation of HR explained by the model (R(2) goodness of fit index) was assessed. The HRRτ showed stabilization from 360 and 420 s on LI and HI, respectively. Acceptable R(2) values were observed from the 360 s on LI (R(2) > 0.65) and at all tested time windows on HI (R(2) > 0.75). In conclusion, this study showed that using a minimum length of monitoring (~420 s) HRR after RE can be adequately modelled by a first-order exponential fitting.

Silicon-organic hybrid (SOH) frequency comb sources for terabit/s data transmission.

We demonstrate frequency comb sources based on silicon-organic hybrid (SOH) electro-optic modulators. Frequency combs with line spacings of 25 GHz and 40 GHz are generated, featuring flat-top spectra with less than 2 dB power variations over up to 7 lines. The combs are used for WDM data transmission at terabit/s data rates and distances of up to 300 km.

Low-power silicon-organic hybrid (SOH) modulators for advanced modulation formats.

We demonstrate silicon-organic hybrid (SOH) electro-optic modulators that enable quadrature phase-shift keying (QPSK) and 16-state quadrature amplitude modulation (16QAM) with high signal quality and record-low energy consumption. SOH integration combines highly efficient electro-optic organic materials with conventional silicon-on-insulator (SOI) slot waveguides, and allows to overcome the intrinsic limitations of silicon as an optical integration platform. We demonstrate QPSK and 16QAM signaling at symbol rates of 28 GBd with peak-to-peak drive voltages of 0.6 V(pp). For the 16QAM experiment at 112 Gbit/s, we measure a bit-error ratio of 5.1 × 10⁻5 and a record-low energy consumption of only 19 fJ/bit.

Nationwide outbreak of Salmonella Montevideo infections associated with contaminated imported black and red pepper: warehouse membership cards provide critical clues to identify the source.

In November 2009, we initiated a multistate investigation of Salmonella Montevideo infections with pulsed-field gel electrophoresis pattern JIXX01.0011. We identified 272 cases in 44 states with illness onset dates ranging from 1 July 2009 to 14 April 2010. To help generate hypotheses, warehouse store membership card information was collected to identify products consumed by cases. These records identified 19 ill persons who purchased company A salami products before onset of illness. A case-control study was conducted. Ready-to-eat salami consumption was significantly associated with illness (matched odds ratio 8·5, 95% confidence interval 2·1-75·9). The outbreak strain was isolated from company A salami products from an environmental sample from one manufacturing plant, and sealed containers of black and red pepper at the facility. This outbreak illustrates the importance of using membership card information to assist in identifying suspect vehicles, the potential for spices to contaminate ready-to-eat products, and preventing raw ingredient contamination of these products.

Cardioventilatory coupling and inter-breath variability in children referred for polysomnography.

Measures of respiratory variability including cardioventilatory coupling (CVC), were examined in 8 Down syndrome (DS), 4 Prader Willi syndrome (PWS) and 42 non-syndromic children (median age 7 years) referred for diagnostic polysomnography. Inspiratory onsets (I) and corresponding ECG R waves were determined, I-I, R-R and R-I intervals derived, and ventilatory frequency (f), standard deviation of f (SDf), coefficient of variation of f (CVf), median I-I and kurtosis and skewness I-I calculated. Proportional Shannon Entropy of the RI(-1) interval (SHα) was measured to quantitate CVC. SHα varied with age (p=0.02), oxygen saturation (p<0.05) and PWS diagnosis (p=0.001) in Stage 4 but not REM sleep. SDf and CVf varied with sleep state (p<0.00001) as did kurtosis I-I (p<0.0001) and skewness I-I (p=0.004). Ventilatory frequency decreased with age in REM sleep (p=0.03) and increased in obese children in REM (p=0.02) and Stage 4 sleep (p=0.004). Sleep state influences respiratory variability in children and CVC may confer a physiological advantage in children with PWS.

Is community-acquired pneumonia an independent risk factor for cardiovascular disease?

Community-acquired pneumonia (CAP) is the most frequent infectious cause of death in western countries. The high mortality rate in CAP is commonly related to comorbid conditions such as cardiovascular disease. Clinical studies in both primary and secondary care settings have identified an increase in short- and long-term risk of cardiovascular events and death from vascular events following acute respiratory infections. The mechanism remains to be fully established, but it has been suggested that the inflammatory state in patients affected by CAP acts to promote platelet activation and thrombosis, and to narrow coronary arteries through vasoconstriction. Acute infections destabilise vascular endothelium and create an imbalance between myocardial oxygen supply and demand, leading to an increased risk of cardiovascular events. Acute infections have been shown to have both systemic effects and local effects on coronary vessels. These effects are mediated through both the host response to infection and, in some cases, direct effects of bacterial infection or bacterial products. In this review, we discuss the link between CAP and increased risk of cardiovascular events, drawing on existing evidence from clinical and mechanistic studies. Further studies into and increased awareness of this association is warranted to promote novel ways of protecting high-risk patients.

Akt phosphorylation on Thr308 but not on Ser473 correlates with Akt protein kinase activity in human non-small cell lung cancer.

BACKGROUND: The activity of the protein kinase Akt is frequently dysregulated in cancer and is an important factor in the growth and survival of tumour cells. Akt activation involves the phosphorylation of two residues: threonine 308 (Thr308) in the activation loop and serine 473 (Ser473) in the C-terminal hydrophobic motif. Phosphorylation of Ser473 has been extensively studied in tumour samples as a correlate for Akt activity, yet the phosphorylation of Thr308 or of downstream Akt substrates is rarely assessed. METHODS: The phosphorylation status of Thr308 and Ser473 was compared with that of three separate Akt substrates - PRAS40, TSC2 and TBC1D4 - in fresh frozen samples of early-stage human non-small cell lung cancer (NSCLC). RESULTS: Akt Thr308 phosphorylation correlated with the phosphorylation of each Akt substrate tested, whereas Akt Ser473 phosphorylation did not correlate with the phosphorylation of any of the substrates examined. CONCLUSION: The phosphorylation of Thr308 is a more reliable biomarker for the protein kinase activity of Akt in tumour samples than Ser473. Any evaluation of the link between Akt phosphorylation or activity in tumour samples and the prediction or prognosis of disease should, therefore, focus on measuring the phosphorylation of Akt on Thr308 and/or at least one downstream Akt substrate, rather than Akt Ser473 phosphorylation alone.

Control and analysis of hydrazine, hydrazides and hydrazones--genotoxic impurities in active pharmaceutical ingredients (APIs) and drug products.

This is the latest of a series of reviews focused on the analysis of genotoxic impurities. This review summarises the analytical approaches reported in the literature relating to hydrazine, hydrazines, hydrazides and hydrazones. It is intended to provide guidance for analysts needing to develop procedures to control such impurities, particularly where this is due to concerns relating to their potential genotoxicity. Of particular note is the wide variety of techniques employed, both chromatographic and spectroscopic, with most involving derivatisation. Such a wide variety of options allow the analyst a real choice in terms of selecting the most appropriate technique specific to their requirements. Several generic methodologies, covering the three main analytical approaches; i.e. HPLC (high performance liquid chromatography), GC (gas chromatography) and IC (ion chromatography), are also described.