Demonstration of stable, long-term operation of a nanosecond pulsed DPSSL at 10 J, 100 Hz.

We report on stable, long-term operation of a diode-pumped solid-state laser (DPSSL) amplifying 15 ns pulses at 1029.5 nm wavelength to 10 J energy at 100 Hz pulse rate, corresponding to 1 kW average power, with 25.4% optical-to-optical efficiency. The laser was operated at this level for over 45 minutes (∼3 · 105 shots) in two separate runs with a rms energy stability of 1%. The laser was also operated at 7 J, 100 Hz for 4 hours (1.44 · 106 shots) with a rms long-term energy stability of 1% and no need for user intervention. To the best of our knowledge, this is the first time that long-term reliable amplification of a kW-class high energy nanosecond pulsed DPSSL at 100 Hz has been demonstrated.

An ELISA Using Synthetic Mycolic Acid-Based Antigens with DIVA Potential for Diagnosing Johne's Disease in Cattle.

THE PROBLEM: Ante-mortem diagnosis of Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is normally achieved through faecal culture, PCR, or serological tests, but agreement as to which samples are positive for Johne's disease is often poor and sensitivities are low, particularly in early-stage infections. The potential solution: Mycobacterial cells contain very complex characteristic mixtures of mycolic acid derivatives that elicit antibodies during infection; this has been used to detect infections in humans. Here, we explore its application in providing an assay differentiating infected from vaccinated animals (DIVA assay) for Johne's disease in cattle. METHOD: Antibody responses to different classes of mycolic acid derivatives were measured using ELISA for serum from cattle positive for MAP by both faecal PCR and commercial serum ELISA, or just by PCR, and from animals from herds with no history of Johne's disease, bovine tuberculosis reactors, BCG-vaccinated, BCG-vaccinated and M. bovis-infected, and Gudair-vaccinated animals. RESULTS: The best-performing antigens, ZAM295 and ST123-the latter a molecule present in the cells of MAP but not of Mycobacterium bovis-achieved a sensitivity of 75% and 62.5%, respectively, for serum from animals positive by both faecal PCR and a commercial MAP serum ELISA, at a specificity of 94% compared to 80 no-history negatives. Combining the results of separate assays with two antigens (ST123 and JRRR121) increased the sensitivity/specificity to 75/97.5%. At the same cut-offs, animals vaccinated with Gudair or BCG vaccines and bTB reactors showed a similar specificity. The specificity in BCG-vaccinated but M. bovis-infected animals dropped to 85%. Combining the results of two antigens gave a sensitivity/specificity of 37.5/97.5% for the full set of 80 PCR-positive samples, detecting 30 positives compared 16 for IDEXX. CONCLUSION: Serum ELISA using synthetic lipids distinguishes effectively between MAP-negative cattle samples and those positive by both PCR and a commercial MAP serodiagnostic, without interference by Gudair or BCG vaccination. It identified almost twice as many PCR positives as the commercial serodiagnostic, offering the possibility of earlier detection of infection.

Improved stability second harmonic conversion of a diode-pumped Yb:YAG laser at the 0.5 kW level.

We report on efficient and stable, type-I phase-matched second harmonic conversion of a nanosecond high-energy, diode-pumped, Yb:YAG laser. With a frequency-doubling crystal in an enclosed, temperature controller with optical windows, 0.5% energy stability was achieved for approximately half an hour. This resulted in 48.9 J pulses at 10 Hz (489 W) and a conversion efficiency of 73.8%. These results are particularly important for stable and reliable operation of high-energy, frequency-doubled lasers.

High energy, high pulse rate laser operation using crystalline adhesive-free bonded Yb:YAG slabs.

We report on the successful amplification of 10 ns pulses to 10 J energy at 10 Hz in a DiPOLE laser amplifier using crystalline Yb:YAG/Cr:YAG composite slabs manufactured using adhesive-free bonding (AFB) technology. We demonstrate that bonded slabs are suitable for operation in high energy cryogenic laser amplifiers. We also report on frequency doubling of the beam amplified in the bonded slabs. When the pulse energy of the output infrared beam is set to 5 J, a pulse energy of 3.9 J is achieved in the green (corresponding to 78% conversion efficiency). Results demonstrate that AFB technology is suitable for producing large-sized gain material slabs and can overcome current limitations in the manufacture of large-aperture gain material pieces. We believe this work will facilitate energy scaling of high energy lasers where aperture scaling of optical elements is not achievable via conventional manufacturing techniques.

Generation of Joule-level green bursts of nanosecond pulses from a DPSSL amplifier.

A new approach to generation of a burst of high-energy green pulses by placing a high-energy multi-slab Yb:YAG DPSSL amplifier and SHG crystal inside a regenerative cavity is presented. In a proof-of-concept test, stable generation of a burst of six green (515 nm) pulses, each 10 ns in duration and separated by 29.4 ns (34 MHz), with 2.0 J total energy has been demonstrated at 1 Hz from a non-optimized ring cavity design. A maximum individual green pulse energy of 580 mJ was produced from a 1.78 J circulating infrared (1030 nm) pulse (average fluence 0.9 J/cm2), corresponding to a SHG conversion efficiency of 32%. Experimental results have been compared with predicted performance from a simple model. Efficient generation of a burst of high energy green pulses offers an attractive pump source for Ti:Sa amplifiers, providing the potential to reduce the impact of amplified stimulated emission by reducing instantaneous transverse gain.

Evaluation of a novel ELISA test using synthetic mycolic acid antigens for serodiagnosis of non-tuberculous mycobacterial (NTM) infections.

The diagnosis of non-tuberculous mycobacteria (NTM) is a particular challenge in people with cystic fibrosis. Current standard diagnostic approaches rely on serial sputum culture, which is resource demanding, dependent on patient expectoration and may be compromised by excessive decontamination, conventional bacterial overgrowth and masking by concomitant oral and nebulised antibiotics. An alternative rapid, reliable and inexpensive diagnostic method is therefore urgently needed. Serum of patients with Mycobacterium abscessus infection and chronic suppurative lung disease without NTM infection was tested against an array of novel synthetic mycolic acids, identical or similar to natural components of mycobacterial cell walls, and glycopeptidolipid (GPL)-core antigen, which has previously been investigated in Mycobacterium avium pulmonary infection. Diagnostic accuracy of individual antigens and combination of various antigens were calculated. An ELISA using individual trehalose dimycolates and GPL-core antigen was able to effectively distinguish serum from infected and non-infected individuals with a specificity of 88% and a sensitivity of up to 88%, which increased to 88% sensitivity and 93% specificity by combining several antigens in the test. These results suggest synthetic mycolic acid antigens, used individually or in combination with GPL-core antigen could be successfully used to distinguish patients with M. abscessus infection from disease controls.

Statin therapy is not warranted for a person with high LDL-cholesterol on a low-carbohydrate diet.

PURPOSE OF REVIEW: Although there is an extensive literature on the efficacy of the low carbohydrate diet (LCD) for weight loss and in the management of type 2 diabetes, concerns have been raised that the LCD may increase cardiovascular disease (CVD) risk by increasing the level of low-density lipoprotein cholesterol (LDL-C). We have assessed the value of LDL-C as a CVD risk factor, as well as effects of the LCD on other CVD risk factors. We have also reviewed findings that provide guidance as to whether statin therapy would be beneficial for individuals with high LDL-C on an LCD. RECENT FINDINGS: Multiple longitudinal trials have demonstrated the safety and effectiveness of the LCD, while also providing evidence of improvements in the most reliable CVD risk factors. Recent findings have also confirmed how ineffective LDL-C is in predicting CVD risk. SUMMARY: Extensive research has demonstrated the efficacy of the LCD to improve the most robust CVD risk factors, such as hyperglycemia, hypertension, and atherogenic dyslipidemia. Our review of the literature indicates that statin therapy for both primary and secondary prevention of CVD is not warranted for individuals on an LCD with elevated LDL-C who have achieved a low triglyceride/HDL ratio.

A novel brain-penetrant oral UGT8 inhibitor decreases in vivo galactosphingolipid biosynthesis in murine Krabbe disease.

Krabbe disease is a rare, inherited neurodegenerative disease due to impaired lysosomal ß-galactosylceramidase (GALC) activity and formation of neurotoxic ß-galactosylsphingosine ('psychosine'). We investigated substrate reduction therapy with a novel brain-penetrant inhibitor of galactosylceramide biosynthesis, RA 5557, in twitcher mice that lack GALC activity and model Krabbe disease. This thienopyridine derivative selectively inhibits uridine diphosphate-galactose glycosyltransferase 8 (UGT8), the final step in the generation of galactosylceramides which are precursors of sulphatide and, in the pathological lysosome, the immediate source of psychosine. Administration of RA 5557, reduced pathologically elevated psychosine concentrations (72-86%) in the midbrain and cerebral cortex in twitcher mice: the inhibitor decreased galactosylceramides by about 70% in midbrain and cerebral cortex in mutant and wild type animals. Exposure to the inhibitor significantly decreased several characteristic inflammatory response markers without causing apparent toxicity to myelin-producing cells in wild type and mutant mice; transcript abundance of oligodendrocyte markers MBP (myelin basic protein) and murine UGT8 was unchanged. Administration of the inhibitor before conception and during several breeding cycles to mice did not impair fertility and gave rise to healthy offspring. Nevertheless, given the unchanged lifespan, it appears that GALC has critical functions in the nervous system beyond the hydrolysis of galactosylceramide and galactosylsphingosine. Our findings support further therapeutic exploration of orally active UGT8 inhibitors in Krabbe disease and related galactosphingolipid disorders. The potent thienopyridine derivative with effective target engagement here studied appears to have an acceptable safety profile in vivo; judicious dose optimization will be needed to ensure efficacious clinical translation.

Good citizens, perfect patients, and family reputation: Stigma and prolonged isolation in people with drug-resistant tuberculosis in Vietnam.

Stigma and isolation are common in people with tuberculosis (TB). Social isolation contributes to reduced health outcomes and TB treatment adherence. Stigma and the drivers of isolation in people with Drug-Resistant (DR)-TB may include modifiable advice and practices of family and Health Care Workers (HCW). This study aimed to understand the drivers of isolation and stigma from the perspective of people with DR-TB in Vietnam. A greater understanding of stigma and isolation is important to identify and balance patients' needs and disease transmission risk. In-depth interviews were conducted with 12 people with DR-TB and seven HCWs who care for people with DR-TB in two provinces in Vietnam. Interviews were audio-recorded, transcribed verbatim and translated to English. Data collection and analysis were conducted simultaneously. The data were then analysed using a thematic framework approach. Stigma and extended isolation were common experiences among people with DR-TB. To mitigate stigma, people with DR-TB used the local term 'lao luc' to describe their condition to others which is believed to be a less infectious and less stigmatising type of TB. This study identified that although HCW informed people with DR-TB of when they were no longer infectious and isolation was no longer required, their infection control advice was not always consistent. Despite knowing they were no longer infectious, most people with DR-TB continued to self-isolate to minimise the perceived repercussions of societal stigma, to protect their 'the dien' (honour, prestige, reputation), and eliminate all risk of transmitting DR-TB to their family. This study identified three interconnected drivers of self-isolation in Vietnam, including fear of infecting others, fear of stigmatization, and to protect family reputation. TB control programmes need to better understand the social aspects of DR-TB to enable them to better support patients. Educating HCW to provide evidence-based infection control advice is vital.

150 J DPSSL operating at 1.5 kW level.

We report on obtaining output energy of 146 J in 10 ns long pulses at 10 Hz repetition rate from Bivoj, a multi-Joule multi-slab cryogenic gas-cooled diode pumped solid state laser, by overcoming its damage threshold bottleneck. This is a 40% energy and power increase of the laser system in comparison to our previous publication and to the most powerful multi-Joule high power laser system.

Route of administration affects the efficacy of moxidectin against Ostertagiinae nematodes in farmed red deer (Cervus elaphus).

The influence of route of administration on the pharmacokinetics and efficacy of macrocyclic lactone anthelmintics has been a subject of interest due to its potential to influence the development of anthelmintic resistance. For most parasite species studied so far, oral administration results in the highest concentrations of drug in the parasites and the highest efficacy against resistant genotypes. However, a recent study in cattle measured the highest levels of ivermectin in the abomasal Ostertagia ostertagi following subcutaneous injection, but it was not possible to correlate these elevated levels with efficacy. Therefore, the current study was initiated to determine whether injectable delivery might be optimal for attaining high efficacy against this important group of parasites. Three on-farm trials were conducted to measure the efficacy of moxidectin administered by the oral, injectable, and pour-on routes against Ostertagiinae parasites in farmed red deer. Groups of rising 1-year old stags (red or red-wapiti crossbreds) in the 84-104 kg weight range were randomised on liveweight into treatment groups of 6 (1 farm) or 8 (2 farms). Animals were treated to individual liveweight with moxidectin oral (0.2 mg/kg), injectable (0.2 mg/kg), pour-on (0.5 mg/kg) or remained untreated. Twelve days later all animals were euthanised and abomasa recovered for worm count. Adult worms were counted in a 2% aliquot of abomasal washings, and adult and fourth stage larvae in a 10 % aliquot following mucosal incubation in physiological saline. In addition, blood was collected from the same 5 animals in each of the treatment groups on days 0, 1, 2, 3, 5, 7 and 12 after treatment and moxidectin levels in plasma were determined using a mass spectrometer. The number of Ostertagiinae surviving treatment was significantly different for each of the treatment groups with injectable administration being most effective, oral administration being the next most effective and pour-on administration the least effective. This applied to both adult worms and fourth stage larvae. A similar pattern was seen in the levels of moxidectin in plasma with both the peak value and area under the concentration curve being highest following injectable administration and lowest following pour-on treatment. Although undertaken in a different host species, the results support the proposition that injectable administration of macrocyclic lactone anthelmintics is likely to be optimal for efficacy against Ostertagiinae parasites and potentially useful in slowing the emergence of resistance in these parasites.

Second and third harmonic conversion of a kilowatt average power, 100-J-level diode pumped Yb:YAG laser in large aperture LBO.

We report on the successful demonstration of second and third harmonic conversion of a high pulse energy, high average power 1030 nm diode pumped Yb-doped yttrium aluminum garnet (Yb:YAG) nanosecond pulsed laser in a large aperture lithium triborate (LBO) crystal. We demonstrated generation of 59.7 J at 10 Hz (597 W) at 515 nm (second harmonic) and of 65.0 J at 1 Hz (65 W) at 343 nm (third harmonic), with efficiencies of 66% and 68%, respectively. These results, to the best of our knowledge, represent the highest energy and power reported for frequency conversion to green and UV-A wavelengths.

Modelling and measurement of thermal stress-induced depolarisation in high energy, high repetition rate diode-pumped Yb:YAG lasers.

In this paper, we present a model to predict thermal stress-induced birefringence in high energy, high repetition rate diode-pumped Yb:YAG lasers. The model calculates thermal depolarisation as a function of gain medium geometry, pump power, cooling parameters, and input polarisation state. We show that model predictions are in good agreement with experimental observations carried out on a DiPOLE 100 J, 10 Hz laser amplifier. We show that single-pass depolarisation strongly depends on input polarisation state and pumping parameters. In the absence of any depolarisation compensation scheme, depolarisation varies over a range between 5% and 40%. The strong dependence of thermal stress-induced depolarisation on input polarisation indicates that, in the case of multipass amplifiers, the use of waveplates after every pass can reduce depolarisation losses significantly. We expect that this study will assist in the design and optimisation of Yb:YAG lasers.

Responsible innovation: Its role in an era of technological and regulatory transformation.

In the development of innovative technology products, companies of all sizes are being encouraged to innovate responsibly and regulators are encouraged to adapt their regulatory systems to be smarter, more proportionate and adaptive to the needs of innovative technologies. The British Standards Institution Responsible Innovation (RI) Guide (Publicly Available Specification [PAS] 440) is an industry-wide standard relevant to both these policy trends. It supports companies by providing a framework to demonstrate the balance between the potential benefits and harms and, if necessary, to take action to maximise the benefits and/or minimise the harms. It includes guidance on engagement with stakeholders and will codify what stakeholders can expect from companies undertaking responsible innovation, paving the way to more harmonious relationships among stakeholders with differing interests and values. A cross-sectoral survey of innovative companies showed that 90% favoured the development of such a standard. PAS 440 was also trialled in two early-stage biotechnology companies and its expected benefits included contributing to coordinated responsible behaviour along a supply chain; better company and stakeholder understanding of the product properties; supporting decision-making on whether or not to start a company; considering the risks of not developing the product and avoiding reputational risks. Benefits were expected to be increasingly significant as the RI standard becomes widely adopted.

National TB program shortages as potential factor for poor-quality TB care cascade: healthcare workers' perspective from Beira, Mozambique

Background Mozambique is one of the countries with the deadly implementation gaps in the tuberculosis (TB) care and services delivery. In-hospital delays in TB diagnosis and treatment, transmission and mortality still persist, in part, due to poor-quality of TB care cascade. Objective We aimed to assess, from the healthcare workers' (HCW) perspective, factors associated with poor-quality TB care cascade and explore local sustainable suggestions to improve inhospital TB management. Methods In-depth interviews and focus group discussions were conducted with different categories of HCW. Audio-recording and written notes were taken, and content analysis was performed through atlas.ti7. Results Bottlenecks within hospital TB care cascade, lack of TB staff and task shifting, centralized and limited time of TB laboratory services, and fear of healthcare workers getting infected by TB were mentioned to be the main factors associated with implementation gaps. Interviewees believe that task shifting from nurses to hospital auxiliary workers, and from higher and well-trained to lower HCW are accepted and feasible. The expansion and use of molecular TB diagnostic tools are seen by the interviewees as a proper way to fight effectively against both sensitive and MDR TB. Ensuring provision of N95 respiratory masks is believed to be an essential requirement for effective engagement of the HCW on high-quality in-hospital TB care. For monitoring and evaluation, TB quality improvement teams in each health facility are considered to be an added value. Conclusion Shortage of resources within the national TB control programme is one of the potential factors for poor-quality of the TB care cascade. Task shifting of TB care and services delivery, decentralization of the molecular TB diagnostic tools, and regular provision of N95 respiratory masks should contribute not just to reduce the impact of resource scarceness, but also to ensure proper TB diagnosis and treatment to both sensitive and MDR TB.

Public trust and global biobank networks.

BACKGROUND: Biobanks provide an important foundation for genomic and personalised medicine. In order to enhance their scientific power and scope, they are increasingly becoming part of national or international networks. Public trust is essential in fostering public engagement, encouraging donation to, and facilitating public funding for biobanks. Globalisation and networking of biobanking may challenge this trust. METHODS: We report the results of an Australian study examining public attitudes to the networking and globalisation of biobanks. The study used quantitative and qualitative methods in conjunction with bioethical analysis in order to determine factors that may contribute to, and threaten, trust. RESULTS: Our results indicate a generally high level of trust in biobanks and in medical research more broadly. Key factors that can reduce perceived trustworthiness of biobanks are commercialisation and involvement in global networking. CONCLUSIONS: We conclude that robust ethical oversight and governance standards can both promote trust in global biobanking and ensure that this trust is warranted.

Stable high-energy, high-repetition-rate, frequency doubling in a large aperture temperature-controlled LBO at 515 nm.

We report on frequency doubling of high-energy, high-repetition-rate ns pulses from a cryogenically gas cooled, multi-slab Yb:YAG laser system, using a type-I phase-matched lithium triborate (LBO) crystal. Pulse energy of 4.3 J was extracted at 515 nm for a fundamental input of 5.4 J at 10 Hz (54 W), corresponding to a conversion efficiency of 77%. However, during long-term operation, a significant reduction of efficiency (more than 25%) was observed owing to the phase mismatch arising due to the temperature-dependent refractive index change in the crystal. This forced frequent angle tuning of the crystal to recover the second-harmonic generation (SHG) energy. More than a five-fold improvement in energy stability of SHG was observed when the LBO crystal was mounted in an oven, and its temperature was controlled at 27°C. Stable frequency doubling with 0.8% rms energy variation was achieved at a higher input power of 74 W when the LBO temperature was controlled at 50°C.

In situ S-isotope compositions of sulfate and sulfide from the 3.2 Ga Moodies Group, South Africa: A record of oxidative sulfur cycling.

Sulfate minerals are rare in the Archean rock record and largely restricted to the occurrence of barite (BaSO4 ). The origin of this barite remains controversially debated. The mass-independent fractionation of sulfur isotopes in these and other Archean sedimentary rocks suggests that photolysis of volcanic aerosols in an oxygen-poor atmosphere played an important role in their formation. Here, we report on the multiple sulfur isotopic composition of sedimentary anhydrite in the ca. 3.22 Ga Moodies Group of the Barberton Greenstone Belt, southern Africa. Anhydrite occurs, together with barite and pyrite, in regionally traceable beds that formed in fluvial settings. Variable abundances of barite versus anhydrite reflect changes in sulfate enrichment by evaporitic concentration across orders of magnitude in an arid, nearshore terrestrial environment, periodically replenished by influxes of seawater. The multiple S-isotope compositions of anhydrite and pyrite are consistent with microbial sulfate reduction. S-isotope signatures in barite suggest an additional oxidative sulfate source probably derived from continental weathering of sulfide possibly enhanced by microbial sulfur oxidation. Although depositional environments of Moodies sulfate minerals differ strongly from marine barite deposits, their sulfur isotopic composition is similar and most likely reflects a primary isotopic signature. The data indicate that a constant input of small portions of oxidized sulfur from the continents into the ocean may have contributed to the observed long-term increase in Δ33 Ssulfate values through the Paleoarchean.

Using hospital auxiliary worker and 24-h TB services as potential tools to overcome in-hospital TB delays: a quasi-experimental study.

BACKGROUND: In-hospital logistic management barriers (LMB) are considered to be important risk factors for delays in TB diagnosis and treatment initiation (TB-dt), which perpetuates TB transmission and the development of TB morbidity and mortality. We assessed the contribution of hospital auxiliary workers (HAWs) and 24-h TB laboratory services using Xpert (24h-Xpert) on the delays in TB-dt and TB mortality at Beira Central Hospital, Mozambique. METHODS: A quasi-experimental design was used. Implementation strategy-HAWs and laboratory technicians were selected and trained, accordingly. Interventions-having trained HAW and TB laboratory technicians as expediters of TB LMB issues and assurer of 24h-Xpert, respectively. Implementation outcomes-time from hospital admission to sputum examination results, time from hospital admission to treatment initiation, proportion of same-day TB cases diagnosed, initiated TB treatment, and TB patient with unfavorable outcome after hospitalization (hospital TB mortality). A nonparametric test was used to test the differences between groups and adjusted OR (95% CI) were computed using multivariate logistic regression. RESULTS: We recruited 522 TB patients. Median (IQR) age was 34 (16) years, and 52% were from intervention site, 58% males, 60% new case of TB, 12% MDR-TB, 72% TB/HIV co-infected, and 43% on HIV treatment at admission. In the intervention hospital, 93% of patients had same-day TB-dt in comparison with a median (IQR) time of 15 (2) days in the control hospital. TB mortality in the intervention hospital was lower than that in the control hospital (13% vs 49%). TB patients admitted to the intervention hospital were nine times more likely to obtain an early laboratory diagnosis of TB, six times more likely to reduce delays in TB treatment initiation, and eight times less likely to die, when compared to those who were admitted to the control hospital, adjusting for other factors. CONCLUSION: In-hospital delays in TB-dt and high TB mortality in Mozambique are common and probably due, in part, to LMB amenable to poor-quality TB care. Task shifting of TB logistic management services to HAWs and lower laboratory technicians, to ensure 24h-Xpert through "on-the-spot strategy," may contribute to timely TB detection, proper treatment, and reduction of TB mortality.