Synchronous mode-locking of solid-state lasers by difference frequency generation.

This Letter introduces a novel, to the best of our knowledge, method for achieving mode-locking and synchronization of mode-locked output pulses from two lasers. The proposed technique leverages parametric gain from difference frequency generation. Specifically, a Nd:YAG laser is mode-locked by single-pass mode-locked pulses from a mode-locked Ti:sapphire laser using an intracavity nonlinear crystal. When the continuous-wave laser is not actively pumped, the system functions as a synchronously pumped optical parametric oscillator. This novel approach has the potential to enable new devices, especially for pump-probe applications or for generation of mode-locked pulses in spectral regions where conventional mode-locked devices are typically not available.

A study protocol outlining the development and evaluation of a training program for frontline managers on leading well-being and the psychosocial work environment in Danish hospital settings - a cluster randomized waitlist controlled trial.

BACKGROUND: Hospital staff are often exposed to stressful psychosocial working conditions and report high levels of stress and burnout, which may negatively impact the safety of employees and patients. Managers hold unique knowledge of workplace conditions and needs of employees, but leadership interventions to improve the well-being of managers and employees in hospital settings are scarce. This study evaluates the effects of a leadership intervention based on a health-oriented leadership approach on the well-being and psychosocial work environment aspects of managers and employees. METHODS/DESIGN: The study is designed as a randomized, waitlist-controlled trial with two groups (intervention and waitlist control group) and measurements at baseline, 6- and 12-month follow-up. We aim to include 200 frontline managers in Danish hospital settings and their approximately 5,000 employees. The leadership training comprises five full day modules and four smaller group-training sessions over a period of 5 months. The main aim is to improve stress, burnout, self-care, and perceived level of staff-care among managers and employees. Sickness absence will also be assessed at both manager and employee level. In addition, several psychosocial factors will be assessed at the employee level. A quantitative and qualitative process evaluation will also be conducted. DISCUSSION: Action towards supporting the mental health of hospital employees is important to maintain a strong healthcare system. There is increasing recognition that best practice in workplace mental health requires an integrated approach that prevents harm and promotes positive mental health. There is also increasing understanding of the key role managers' play in maintaining well-being within the workplace, however they often report a lack of knowledge and skills to promote employee mental health. The current leadership training program has been developed for frontline managers working in a hospital setting. The aim is to increase managers' application of strategies to facilitate a healthy psychosocial work environment to benefit well-being and mental health among staff and managers themselves. TRIAL REGISTRATION: The study was retrospectively registered on November 21, 2022 in Clinical Trial.gov with identifier: NCT05623371.

In vivo fluorescence molecular tomography of induced haemarthrosis in haemophilic mice: link between bleeding characteristics and development of bone pathology.

BACKGROUND: Haemophilic arthropathy is a chronic and debilitating joint disease caused by recurrent spontaneous joint bleeds in patients with haemophilia. Understanding how characteristics of individual joint bleeds relate to the subsequent development of arthropathy could improve management and prevention of this joint disease. Here, we aimed to explore relations between joint bleed characteristics and development of bone pathology in a mouse model of haemophilic arthropathy by using novel in vivo imaging methodology. METHODS: We characterised induced knee bleeds in a murine model of haemophilic arthropathy by quantitative in vivo fluorescence molecular tomography (FMT) and by measurements of changes in the diameter of the injured knee. Wild-type mice and non-injured haemophilic mice acted as controls. Development of arthropathy was characterised by post mortem evaluation of bone pathology by micro-CT 14 days after bleed-induction. In an in vitro study, we assessed the effect of blood on the quantification of fluorescent signal with FMT. RESULTS: In most injured haemophilic mice, we observed significant loss of trabecular bone, and half of the mice developed pathological bone remodelling. Development of pathological bone remodelling was associated with significantly increased fluorescent signal and diameter of the injured knee just 1 day after induction of the bleed. Further, a correlation between the fluorescent signal 1 day after induction of the bleed and loss of trabecular bone reached borderline significance. In the in vitro study, we found that high concentrations of blood significantly decreased the fluorescent signal. CONCLUSION: Our results add novel insights on the pathogenesis of haemophilic arthropathy and underline the importance of the acute phase of joint bleeds for the subsequent development of arthropathy.

Determinants of trabecular bone score and prevalent vertebral fractures in women with fragility fractures: a cross-sectional sub-study of NoFRACT.

Determinants of trabecular bone score (TBS) and vertebral fractures assessed semiquantitatively (SQ1-SQ3) were studied in 496 women with fragility fractures. TBS was associated with age, parental hip fracture, alcohol intake and BMD, not SQ1-SQ3 fractures. SQ1-SQ3 fractures were associated with age, prior fractures, and lumbar spine BMD, but not TBS. INTRODUCTION: Trabecular bone score (TBS) and vertebral fractures assessed by semiquantitative method (SQ1-SQ3) seem to reflect different aspects of bone strength. We therefore sought to explore the determinants of and the associations between TBS and SQ1-SQ3 fractures. METHODS: This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative included 496 women aged ≥ 50 years with fragility fractures. All responded to a questionnaire about risk factors for fracture, had bone mineral density (BMD) of femoral neck and/or lumbar spine assessed, TBS calculated, and 423 had SQ1-SQ3 fracture assessed. RESULTS: Mean (SD) age was 65.6 years (8.6), mean TBS 1.27 (0.10), and 33.3% exhibited SQ1-SQ3 fractures. In multiple variable analysis, higher age (ßper SD = - 0.26, 95% CI: - 0.36,- 0.15), parental hip fracture (ß = - 0.29, 95% CI: - 0.54,- 0.05), and daily alcohol intake (ß = - 0.43, 95% CI - 0.79, - 0.08) were associated with lower TBS. Higher BMD of femoral neck (ßper SD = 0.34, 95% CI 0.25-0.43) and lumbar spine (ßper SD = 0.40, 95% CI 0.31-0.48) were associated with higher TBS. In multivariable logistic regression analyses, age (ORper SD = 1.94, 95% CI 1.51-2.46) and prior fragility fractures (OR = 1.71, 95% CI 1.09-2.71) were positively associated with SQ1-SQ3 fractures, while lumbar spine BMD (ORper SD = 0.75 95% CI 0.60-0.95) was negatively associated with SQ1-SQ3 fractures. No association between TBS and SQ1-SQ3 fractures was found. CONCLUSION: Since TBS and SQ1-SQ3 fractures were not associated, they may act as independent risk factors, justifying the use of both in post-fracture risk assessment.

Development of the equine gut microbiota.

Shortly after birth the mammalian gut is colonized, by a transient microbiota, highly susceptible to environment and diet, that eventually stabilizes and becomes the resident gut microbiota. In a window of opportunity during the colonization, oral tolerance is established towards resident bacteria. In this study, the development of the equine gut microbiota was investigated in ten foals from parturition until post weaning. We found great differences in the core species of the gut microbiota composition between time-matched samples on Day 7 and 20 post-partum. Between day 20 and Day 50 post-partum, we saw the gut microbiota became increasingly dominated by fiber fermenting species. After Day 50, no significant changes in species abundance were observed. Gene expression analysis of pro- and anti-inflammatory cytokines in the blood revealed no significant changes before and after weaning. In summary, relative stability of the gut microbiota was reached within 50 days post-partum and, weaning did not have a major impact on the microbial composition.

Expression of immune regulatory genes correlate with the abundance of specific Clostridiales and Verrucomicrobia species in the equine ileum and cecum.

Billions of bacteria inhabit the gastrointestinal tract. Immune-microbial cross talk is responsible for immunological homeostasis, and symbiotic microbial species induce regulatory immunity, which helps to control the inflammation levels. In this study we aimed to identify species within the equine intestinal microbiota with the potential to induce regulatory immunity. These could be future targets for preventing or treating low-grade chronic inflammation occurring as a result of intestinal microbial changes and disruption of the homeostasis. 16S rRNA gene amplicon sequencing was performed on samples of intestinal microbial content from ileum, cecum, and colon of 24 healthy horses obtained from an abattoir. Expression of genes coding for IL-6, IL-10, IL-12, IL-17, 18 s, TNFα, TGFß, and Foxp3 in the ileum and mesenteric lymph nodes was measured by qPCR. Intestinal microbiota composition was significantly different in the cecum and colon compared to the ileum, which contains large abundances of Proteobacteria. Especially members of the Clostridiales order correlated positively with the regulatory T-cell transcription factor Foxp3 and so did the phylum Verrucomicrobia. We conclude that Clostridiales and Verrucomicrobia have the potential to induce regulatory immunity and are possible targets for intestinal microbial interventions aiming at regulatory immunity improvement.

Coherent combining of high brightness tapered amplifiers for efficient non-linear conversion.

We report on a coherent beam combination of three high-brightness tapered amplifiers, which are seeded by a single-frequency laser at λ = 976 nm in a simple architecture with efficiently cooled emitters. The maximal combined power of 12.9 W is achieved at a combining efficiency of > 65%, which is limited by the amplifiers' intrinsic beam quality. The coherent combination cleans up the spatial profile, as the central lobe's power content increases by up to 86%. This high-brightness infrared beam is converted into the visible by second harmonic generation. This results in a high non-linear conversion efficiency of 4.5%/W and a maximum power over 2 W at 488 nm, which is limited by thermal effects in the periodically poled lithium niobate (PPLN).

High-fat feeding induces mobilization of vitamin C in obese prone rats.

In obesity and dyslipidemia, hydrolysis of triacylglycerol (TAG) into non-esterified fatty acids (NEFAs) may contribute to insulin resistance, and production of oxygenated, bioactive polyunsaturated fatty acids may increase oxidative stress. Here we show that after six weeks of high-fat feeding of obese prone rats (Crl:OP(CD), vitamin C was increased both in liver (P < 0.01) and plasma (P < 0.001), while both TAG (P < 0.01) and NEFA (P < 0.001) were lower than in low-fat fed control rats. Hepatic vitamin C biosynthesis was similar between groups, indicating that a new steady state level was established with a higher vitamin C level adequate for supplying the systemic needs. Glucose and insulin sensitivity were unaffected at this stage. Eventually, the mobilization of vitamin C may be seen as a mechanism to protect the host against insulin resistance.

Should Europe follow the US and declare obesity a disease?: a discussion of the so-called utilitarian argument.

In 2013, the American Medical Association (AMA) decided to recognize obesity as a disease. One of the main arguments presented in favor of this was broadly 'utilitarian': the disease label would, it was claimed, provide more benefits than harms and thereby serve the general good. Several individuals and groups have argued that this reasoning is just as powerful in the European context. Drawing mainly on a review of relevant social science research, we discuss the validity of this argument. Our conclusion is that in a Western European welfare state, defining obesity as a disease will not on balance serve the general good, and that it is therefore more appropriate to continue to treat obesity as a risk factor. The main reasons presented in favor of this conclusion are: It is debatable whether a disease label would lead to better access to care and preventive measures and provide better legal protection in Europe. Medicalization and overtreatment are possible negative effects of a disease label. There is no evidence to support the claim that declaring obesity a disease would reduce discrimination or stigmatization. In fact, the contrary is more likely, since a disease label would categorically define the obese body as deviant.

Efficacy of RNA interference knockdown using aerosolized short interfering RNAs bound to nanoparticles in three diverse aphid species.

RNA interference (RNAi) has emerged as a promising method for validating gene function; however, its utility in nonmodel insects has proven problematic, with delivery methods being one of the main obstacles. This study investigates a novel method of RNAi delivery in aphids, the aerosolization of short interfering RNA (siRNA)-nanoparticle complexes. By using nanoparticles as a siRNA carrier, the likelihood of cellular uptake is increased, when compared to methods previously used in insects. To determine the efficacy of this RNAi delivery system, siRNAs were aerosolized with and without nanoparticles in three aphid species: Acyrthosiphon pisum, Aphis glycines and Schizaphis graminum. The genes targeted for knockdown were carotene dehydrogenase (tor), which is important for pigmentation in Ac. pisum, and branched chain-amino acid transaminase (bcat), which is essential in the metabolism of branched-chain amino acids in all three aphid species. Overall, we observed modest gene knockdown of tor in Ac. pisum and moderate gene knockdown of bcat in Ap. glycines along with its associated phenotype. We also determined that the nanoparticle emulsion significantly increased the efficacy of gene knockdown. Overall, these results suggest that the aerosolized siRNA-nanoparticle delivery method is a promising new high-throughput and non-invasive RNAi delivery method in some aphid species.

Impact of NET on torture survivors in the MENA region.

INTRODUCTION: Narrative Exposure Therapy (NET) is a brief cognitive-behavioural intervention for individuals with posttraumatic stress disorder (PTSD) which has mostly been used to treat traumatised asylum seekers and refugees in highincome settings. Evidence is scarce on the effectiveness of NET with torture survivors, especially in the Middle East and North African (MENA) region where health systems are unable to meet the increasing needs of mental health disorders caused by war and displacement. METHODS: During the period 2013 to 2016 DIGNITY - Danish Institute Against Torture, in collaboration with partners, implemented a capacity-building training programme on NET among 44 Arabic health professionals from highly specialised torture rehabilitation centers in Jordan, Palestine, Egypt, Lebanon, Iraq, Tunisia, Libya, Sudan and Syria. A multi-centre study was carried out across all centres comprising of the collection of client data on socio-demographic variables, torture exposure, and psychosomatic health indicators. Clinical assessment of mental health symptoms among torture survivors was performed by the NET therapists pre- and post NET therapy and at four months' follow-up, and means were compared. RESULTS: Our findings show a statistically significant reduction in average psychological symptom load for PTSD (from 3.20 to 1.80), anxiety (2.78 - 1.61) and depression (2.75 - 1.96) with the largest effect on PTSD symptoms, and a larger effect for women than men. The results indicate improvements in selfreported health (3.85-2.82) and physical disabilities (2.90-1.76), as well as reduction in pain perceptions after therapy (4.44 -3.44). The duration of treatment was three months on average with a span from one to eight months. DISCUSSION: This study provides new evidence suggesting a strong positive effect of NET in an Arab cultural setting which remains under-represented in the NET evidence base. However, some important limitations of the study preclude drawing firm conclusions, namely the lack of a control group, a high number of dropouts in follow up data and a potential risk of information bias. Contexts familiar to the torture survivor and shared cultural norms and language between the client and the therapist might positively affect the effect of NET on PTSD symptoms. This capacity-building training programme established a community of Arab trauma mental health experts in the MENA-region, and their implementation of NET was associated in time with a reduction of the mental health symptom load of survivors of torture and war.

Visualization of haemophilic arthropathy in F8-/- rats by ultrasonography and micro-computed tomography.

INTRODUCTION: A major complication of haemophilia is haemophilic arthropathy (HA), a debilitating disorder with an incompletely defined pathobiology. High-resolution imaging may provide new knowledge about onset and progression of HA, and thereby support identification of new treatment opportunities. Recently, a F8-/- rat model of HA was developed. The size of the rat allows for convenient and high resolution imaging of the joints, which could enable in vivo studies of HA development. AIM: To determine whether HA in the F8-/- rat can be visualized using ultrasonography (US) and micro-computed tomography (µCT). METHODS: Sixty F8-/- and 20 wild-type rats were subjected to a single or two induced knee bleeds. F8-/- rats were treated with either recombinant human FVIII (rhFVIII) or vehicle before the induction of knee bleeds. Haemophilic arthropathy was visualized using in vivo US and ex vivo µCT, and the observations correlated with histological evaluation. RESULTS: US and µCT detected pathologies in the knee related to HA. There was a strong correlation between disease severity determined by µCT and histopathology. rhFVIII treatment reduced the pathology identified with both imaging techniques. CONCLUSION: US and µCT are suitable imaging techniques for detection of blood-induced joint disease in F8-/- rats and may be used for longitudinal studies of disease progression.

Efficient generation of 1.9 W yellow light by cascaded frequency doubling of a distributed Bragg reflector tapered diode.

Watt-level yellow emitting lasers are interesting for medical applications, due to their high hemoglobin absorption, and for efficient detection of certain fluorophores. In this paper, we demonstrate a compact and robust diode-based laser system in the yellow spectral range. The system generates 1.9 W of single-frequency light at 562.4 nm by cascaded single-pass frequency doubling of the 1124.8 nm emission from a distributed Bragg reflector (DBR) tapered laser diode. The absence of a free-space cavity makes the system stable over a base-plate temperature range of 30 K. At the same time, the use of a laser diode enables the modulation of the pump wavelength by controlling the drive current. This is utilized to achieve a power modulation depth above 90% for the second harmonic light, with a rise time below 40 µs.

Mesenchymal stromal cells from human umbilical cords display poor chondrogenic potential in scaffold-free three dimensional cultures.

Many researchers world over are currently investigating the suitability of stromal cells harvested from foetal tissues for allogeneic cell transplantation therapies or for tissue engineering purposes. In this study, we have investigated the chondrogenic potential of mesenchymal stromal cells (MSCs) isolated from whole sections of human umbilical cord or mixed cord (UCSCs-MC), and compared them with cells isolated from synovial membrane (SMSCs), Hoffa's fat pad (HFPSCs) and cartilage. All MSCs were positive for surface markers including CD73, CD90, CD105, CD44, CD146 and CD166, but negative for CD11b, CD19, CD34, CD45 and HLA-DR in addition to CD106 and CD271. Chondrogenic potential of all cell sources was studied using 3D pellet cultures incubated in the presence of different combinations of anabolic substances such as dexamethasone, IGF-1, TGF-ß1, TGF-ß3, BMP-2 and BMP-7. BMP-2 and dexamethasone in combination with TGF-ß1 or TGF-ß3 excelled at inducing chondrogenesis on SMSCs, HFPSCs and chondrocytes, as measured by glycosaminoglycans and collagen type II staining of pellets, quantitative glycosaminoglycan expression, quantitative PCR of cartilage signature genes and electron microscopy. In contrast, none of the tested growth factor combinations was sufficient to induce chondrogenesis on UCSCs-MC. Moreover, incubation of UCSCs-MC spheroids in the presence of cartilage pieces or synovial cells in co-cultures did not aid chondrogenic induction. In summary, we show that in comparison with MSCs harvested from adult joint tissues, UCSCs-MC display poor chondrogenic abilities. This observation should alert researchers at the time of considering UCSCs-MC as cartilage forming cells in tissue engineering or repair strategies.

The F8(-/-) rat as a model of hemophilic arthropathy.

UNLABELLED: Essentials Validating the F8 rat as a new intermediate-size animal model of hemophilic arthropathy. Factor VIII (FVIII) treated F8(-/-) rats suffered induced hemarthrosis analyzed by histopathology. F8 (-/-) animals develop hemophilic arthropathy upon hemarthrosis, preventable by FVIII treatment. The F8 (-/-) rat presents as a new pharmacologic model of hemophilic arthropathy. SUMMARY: Background Translational animal models of hemophilia are valuable for determining the pathobiology of the disease and its co-morbidities (e.g. hemophilic arthropathy, HA). The biologic mechanisms behind the development of HA, a painful and debilitating condition, are not completely understood. We recently characterized a F8(-/-) rat, which could be a new preclinical model of HA. Objectives To establish the F8(-/-) rat as a model of HA by determining if the F8(-/-) rat develops HA resembling human HA after an induced joint bleed and whether a second joint bleed causes further disease progression. Methods Wild-type and F8(-/-) rats were treated with vehicle or recombinant human factor VIII (rhFVIII) prior to a needle-induced joint bleed. Joint swelling was measured prior to injury, the following 7 days and upon euthanasia. Histologic sections of the joint were stained, and athropathic changes identified and scored with regard to synovitis, bone remodelling, cartilage degradation and hemosiderin deposition. Results Vehicle-treated F8(-/-) rats experienced marked joint swelling and developed chronic degenerative joint changes (i.e. fibrosis of the subsynovial membrane, chondrocyte loss and excessive bone remodeling). Treatment with rhFVIII reduced or prevented swelling and degenerative joint changes, returning the F8(-/-) animals to a wild-type phenotype. Conclusion The hemophilic phenotype of the F8(-/-) rat resulted in a persistent hemarthrosis following an induced joint bleed. This caused development of HA resembling human HA, which was prevented by rhFVIII treatment, confirming the potential of the F8(-/-) rat as a model of HA.

Concept for power scaling second harmonic generation using a cascade of nonlinear crystals.

Within the field of high-power second harmonic generation (SHG), power scaling is often hindered by adverse crystal effects such as thermal dephasing arising from the second harmonic (SH) light, which imposes limits on the power that can be generated in many crystals. Here we demonstrate a concept for efficient power scaling of single-pass SHG beyond such limits using a cascade of nonlinear crystals, in which the first crystal is chosen for high nonlinear efficiency and the subsequent crystal(s) are chosen for power handling ability. Using this highly efficient single-pass concept, we generate 3.7 W of continuous-wave diffraction-limited (M(2)=1.25) light at 532 nm from 9.5 W of non-diffraction-limited (M(2)=7.7) light from a tapered laser diode, while avoiding significant thermal effects. Besides constituting the highest SH power yet achieved using a laser diode, this demonstrates that the concept successfully combines the high efficiency of the first stage with the good power handling properties of the subsequent stages. The concept is generally applicable and can be expanded with more stages to obtain even higher efficiency, and extends also to other combinations of nonlinear media suitable for other wavelengths.

Coulomb crystallization of highly charged ions.

Control over the motional degrees of freedom of atoms, ions, and molecules in a field-free environment enables unrivalled measurement accuracies but has yet to be applied to highly charged ions (HCIs), which are of particular interest to future atomic clock designs and searches for physics beyond the Standard Model. Here, we report on the Coulomb crystallization of HCIs (specifically (40)Ar(13+)) produced in an electron beam ion trap and retrapped in a cryogenic linear radiofrequency trap by means of sympathetic motional cooling through Coulomb interaction with a directly laser-cooled ensemble of Be(+) ions. We also demonstrate cooling of a single Ar(13+) ion by a single Be(+) ion-the prerequisite for quantum logic spectroscopy with a potential 10(-19) accuracy level. Achieving a seven-orders-of-magnitude decrease in HCI temperature starting at megakelvin down to the millikelvin range removes the major obstacle for HCI investigation with high-precision laser spectroscopy.

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD mice.

Gut microbiota regulated imbalances in the host's immune profile seem to be an important factor in the etiology of type 1 diabetes (T1D), and identifying bacterial markers for T1D may therefore be useful in diagnosis and prevention of T1D. The aim of the present study was to investigate the link between the early gut microbiota and immune parameters of non-obese diabetic (NOD) mice in order to select alleged bacterial markers of T1D. Gut microbial composition in feces was analyzed with 454/FLX Titanium (Roche) pyro-sequencing and correlated with diabetes onset age and immune cell populations measured in diabetic and non-diabetic mice at 30 weeks of age. The early gut microbiota composition was found to be different between NOD mice that later in life were classified as diabetic or non-diabetic. Those differences were further associated with changes in FoxP3(+) regulatory T cells, CD11b(+) dendritic cells, and IFN-γ production. The model proposed in this work suggests that operational taxonomic units classified to S24-7, Prevotella, and an unknown Bacteriodales (all Bacteroidetes) act in favor of diabetes protection whereas members of Lachnospiraceae, Ruminococcus, and Oscillospira (all Firmicutes) promote pathogenesis.

TL1A regulates TCRγδ+ intraepithelial lymphocytes and gut microbial composition.

TL1A is a proinflammatory cytokine, which is prevalent in the gut. High TL1A concentrations are present in patients with inflammatory bowel disease (IBD) and in IBD mouse models. However, the role of TL1A during steady-state conditions is relatively unknown. Here, we used TL1A knockout (KO) mice to analyse the impact of TL1A on the intestinal immune system and gut microbiota. The TL1A KO mice showed reduced amounts of small intestinal intraepithelial TCRγδ(+) and CD8(+) T cells, and reduced expression of the activating receptor NKG2D. Moreover, the TL1A KO mice had significantly reduced body weight and visceral adipose tissue deposits, as well as lower levels of leptin and CXCL1, compared with wild-type mice. Analysis of the gut microbial composition of TL1A KO mice revealed a reduction of caecal Clostridial cluster IV, a change in the Firmicutes/Bacteroidetes ratio in caecum and less Lactobacillus spp. in the mucosal ileum. Our results show that TL1A deficiency impacts on the gut microbial composition and the mucosal immune system, especially the intraepithelial TCRγδ(+) T-cell subset, and that TL1A is involved in the establishment of adipose tissue. This research contributes to a broader understanding of TL1A inhibition, which is increasingly considered for treatment of IBD.