Photo-induced structural dynamics of o-nitrophenol by ultrafast electron diffraction.

The photo-induced dynamics of o-nitrophenol, particularly its photolysis, has garnered significant scientific interest as a potential source of nitrous acid in the atmosphere. Although the photolysis products and preceding photo-induced electronic structure dynamics have been investigated extensively, the nuclear dynamics accompanying the non-radiative relaxation of o-nitrophenol on the ultrafast timescale, which include an intramolecular proton transfer step, have not been experimentally resolved. Herein, we present a direct observation of the ultrafast nuclear motions mediating photo-relaxation using ultrafast electron diffraction. This work spatiotemporally resolves the loss of planarity which enables access to a conical intersection between the first excited state and the ground state after the proton transfer step, on the femtosecond timescale and with sub-Angstrom resolution. Our observations, supported by ab initio multiple spawning simulations, provide new insights into the proton transfer mediated relaxation mechanism in o-nitrophenol.

Preliminary study of a new online and equipment-free vision screening alternative for remote and isolated community.

INTRODUCTION: Vision screening has been initiated to detect potential vision problems, paving referral pathways towards a full eye examination. Time-cost-labour practicality challenges of equipment-based vision screening have lingered for decades. Going for the highest sensitivity and specificity or opting for a pragmatic and affordable vision screening program remains a dilemma in public eye health. We aimed to report the development of a new online and equipment-free vision screening called Eye: Questionnairebased Vision Screening (EyeQVS). We also analysed the visual profile of Orang Bateq resided in a remote locality, using findings from EyeQVS, single test vision screening and full eye examination. MATERIALS AND METHODS: Multi-perspective development strategies were employed in designing EyeQVS. The questionnaire items were constructed using the working backward technique, compiling common vision disorders from the literature and face validation using expert panels. Face validation and usability assessment were performed on EyeQVS. The vision screening was carried out using EyeQVS and single test visual acuity screening method. The full eye examination included visual acuity, refraction, binocular vision and ocular health assessment. The visual profile of indigenous people (Orang Bateq) at Kampung Bengoi and Kampung Atok, Jerantut, Pahang was analysed using EyeQVS, single test visual acuity screening method and full eye examination. RESULTS: The performance of EyeQVS was affirmative in both face validation and usability. About 95% of Orang Bateq failed full eye examination, while 55% failed EyeQVS screening. None of them failed single test vision screening. Binocular disorders and dry eye problems were commonly found in Orang Bateq. EyeQVS unearthed more various vision problems compared to the single test vision screening (visual acuity alone) as a screening tool in a remote location. CONCLUSION: EyeQVS can screen for binocular disorders and dry eyes problem commonly found among indigenous people, which might be missed using a single-test visual acuity screening approach. EyeQVS is a practical alternative for vision screening in places where financial or location hinders eye healthcare access.

Pilot investigation of an activity-based approach to building hardiness.

BACKGROUND: The purpose was to describe an activity-based psychological hardiness training programme delivered by an occupational therapist and examine its acceptability and effectiveness in improving hardiness. METHOD: Participants (N=28) completed the 6-hour programme, which included pre/post-programme completion of the Dispositional Resilience Scale-15 (DRS-15) and a Program Evaluation Form. Paired t-tests were used to determine differences between pre-training and post-training scores on the DRS-15. RESULTS: Results showed a significant increase (p<0.05) in total hardiness, commitment, and control scores on the DRS-15 from pre-training to post-training and good-excellent ratings for all categories on the Program Evaluation Form. CONCLUSIONS: This programme evaluation described an occupational therapist's role in providing an activity-based psychological hardiness training programme and provided preliminary support for the acceptability of an activity-based approach to training psychological hardiness for service members.

Clonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population.

RATIONALE & OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 12,004 individuals from 3 community-based cohorts in the TOPMed Consortium. EXPOSURE: CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood. OUTCOME: Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period. ANALYTICAL APPROACH: Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis. RESULTS: The median baseline eGFR was 84mL/min/1.73m2. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m2, of age above or below 60 years, or with or without diabetes. LIMITATIONS: Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants. CONCLUSIONS: We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease.

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-ß signalling molecules and spectrin ß. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Conformer-specific photochemistry imaged in real space and time.

Conformational isomers (conformers) of molecules play a decisive role in biology and organic chemistry. However, experimental methods for investigating chemical reaction dynamics are typically not conformer-sensitive. We report on a gas-phase megaelectronvolt ultrafast electron diffraction investigation of α-phellandrene undergoing an electrocyclic ring-opening reaction. We directly imaged the evolution of a specific set of α-phellandrene conformers into the product isomer predicted by the Woodward-Hoffmann rules in real space and time. Our experimental results are in quantitative agreement with nonadiabatic quantum molecular dynamics simulations, which provide considerable detail of how conformation influences the time scale and quantum efficiency of photoinduced ring-opening reactions.

Evaluation of the Water Sorption and Solubility Behavior of Different Polymeric Luting Materials.

Objective: The study evaluated the water sorption (WSP) and water solubility (WSL) characteristics of different luting agents over a 180-day water storage period. Materials and Methods: Nine luting materials, i.e., conventional resin cement: Panavia F (PF), Rely X ARC (RA), self-adhesive resin cement: Rely X Unicem (RU), Breez (BZ), Maxcem Elite (MX), BisCem (BC) and resin-modified glass ionomer cement: FujiCem (FC), FujiPlus (FP) Rely X luting plus (RL) were assessed and fifty-two-disc specimens of each material were fabricated. All specimens were desiccated until a constant weight (W0) was reached. Thirteen specimens for each luting material were then randomly assigned to one of the four water immersion periods (7, 30, 90, and 180 days). After each period, the specimens were removed from the water and weighed to get W1. The samples were again desiccated for a second time and W2 was measured. Both WSP and WSL were determined by the following equations: WSP (%) = (W1 - W2) × 100/W0 and WSL (%) = (W0 - W2) × 100/W0. Assessments were performed following ISO standards. ANOVA was used to assess the effect of luting agent and time period on water sorption and solubility. Pair-wise comparisons were adjusted using Tukey's multiple comparison procedure. A significance level of 0.05 was used for all statistical tests. Results: The highest mean WSP and WSL (WSP/WSL) were demonstrated by resin-modified glass-ionomers (RL 18.32/3.25, FC 17.08/4.83, and FP 14.14/1.99), while resin luting agents showed lower WSP and WSL results (PF 1.6/0.67 and RA 1.76/0.46), respectively. The self-adhesive agents exhibited a wide range of WSP and WSL values (RU 1.86/0.13, BZ 4.66/0.93, and MX 3.68/1.11). Self-adhesive cement showed lower WSP and WSL compared with the resin-modified glass-ionomers (p < 0.05). All the materials reached equilibrium after 90-days. Conclusions: Resin-based luting materials have the lowest sorption and solubility. Rely X Unicem self-adhesive luting materials were comparable to resin luting materials for WSL and WSP. Resin-modified glass-ionomer showed the highest water sorption and solubility compared with both resin and self-adhesive materials.

Cage Environment Regulates Gut Microbiota Independent of Toll-Like Receptors.

The gut microbiome orchestrates epithelial homeostasis and both local and remote immunological responses. Critical to these regulatory interactions are innate immune receptors termed Toll-like receptors (TLRs). Studies to date have implicated innate immunity and Toll-like receptors in shaping key features of the gut microbiome. However, a variety of biological and environmental variables are also implicated in determining gut microbiota composition. In this report, we hypothesized that cohousing and environment dominated the regulation of the gut microbiota in animal models independent of innate immunity. To determine the importance of these variables, innate immunity, or environment in shaping gut microbiota, we used a randomized cohousing strategy and transgenic TLR-deficient mice. We have found that mice cohoused together by genotype exhibited limited changes over time in the composition of the gut microbiota. However, for mice randomized to cage, we report extensive changes in the gut microbiota, independent of TLR function, whereby the fecal microbiota of TLR-deficient mice converges with that of wild-type mice. TLR5-deficient mice in these experiments exhibit greater susceptibility to comparative changes in the microbiota than other TLR-deficient mice and wild-type mice. Our work has broad implications for the study of innate immunity and host-microbiota interactions. Given the profound impact that gut dysbiosis may have on immunity, this report highlights the potential impact of cohousing on the gut microbiota and indices of inflammation as outcomes in biological models of infectious or inflammatory disease.

Rapid multi-generational acclimation of coralline algal reproductive structures to ocean acidification.

The future of coral reef ecosystems is under threat because vital reef-accreting species such as coralline algae are highly susceptible to ocean acidification. Although ocean acidification is known to reduce coralline algal growth rates, its direct effects on the development of coralline algal reproductive structures (conceptacles) is largely unknown. Furthermore, the long-term, multi-generational response of coralline algae to ocean acidification is extremely understudied. Here, we investigate how mean pH, pH variability and the pH regime experienced in their natural habitat affect coralline algal conceptacle abundance and size across six generations of exposure. We show that second-generation coralline algae exposed to ocean acidification treatments had conceptacle abundances 60% lower than those kept in present-day conditions, suggesting that conceptacle development is initially highly sensitive to ocean acidification. However, this negative effect of ocean acidification on conceptacle abundance disappears after three generations of exposure. Moreover, we show that this transgenerational acclimation of conceptacle development is not facilitated by a trade-off with reduced investment in growth, as higher conceptacle abundances are associated with crusts with faster growth rates. These results indicate that the potential reproductive output of coralline algae may be sustained under future ocean acidification.

Magneto-optical diagnosis of symptomatic malaria in Papua New Guinea.

Improved methods for malaria diagnosis are urgently needed. Here, we evaluate a novel method named rotating-crystal magneto-optical detection (RMOD) in 956 suspected malaria patients in Papua New Guinea. RMOD tests can be conducted within minutes and at low cost. We systematically evaluate the capability of RMOD to detect infections by directly comparing it with expert light microscopy, rapid diagnostic tests and polymerase chain reaction on capillary blood samples. We show that compared to light microscopy, RMOD exhibits 82% sensitivity and 84% specificity to detect any malaria infection and 87% sensitivity and 88% specificity to detect Plasmodium vivax. This indicates that RMOD could be useful in P. vivax dominated elimination settings. Parasite density correlates well with the quantitative magneto-optical signal. Importantly, residual hemozoin present in malaria-negative patients is also detectable by RMOD, indicating its ability to detect previous infections. This could be exploited to reveal transmission hotspots in low-transmission settings.

Implementing TB preventive treatment within differentiated HIV service delivery models in global programs.

Global HIV program stakeholders, including the US President's Emergency Plan for AIDS Relief (PEPFAR), are undertaking efforts to ensure that eligible people living with HIV (PLHIV) receiving antiretroviral treatment (ART) receive a course of TB preventive treatment (TPT). In PEPFAR programming, this effort may require providing TPT not only to newly diagnosed PLHIV as part of HIV care initiation, but also to treatment-experienced PLHIV stable on ART who may not have been previously offered TPT. TPT scale-up is occurring at the same time as a trend to provide more person-centered HIV care through differentiated service delivery (DSD). In DSD, PLHIV stable on ART may receive less frequent clinical follow-up or receive care outside the traditional clinic-based model. The misalignment between traditional delivery of TPT and care delivery in innovative DSD may require adaptations to TPT delivery practices for PLHIV. Adaptations include components of planning and operationalization of TPT in DSD, such as determination of TPT eligibility and TPT initiation, and clinical management of PLHIV while on TPT. A key adaptation is alignment of timing and location for TPT and ART prescribing, monitoring, and dispensing. Conceptual examples of TPT delivery in DSD may help program managers operationalize TPT in HIV care.

Les parties prenantes du programme mondial VIH, notamment le plan américain PEPFAR (US President's Emergency Plan for AIDS Relief), entreprennent des efforts afin de s'assurer que les personnes vivant avec le VIH (PLVIH), éligibles, recevant un traitement antirétroviral (TAR), reçoivent également un traitement préventif TB (TPT). Dans la programmation PEPFAR, cet effort pourrait nécessiter de fournir le TPT non seulement aux PLVIH nouvellement diagnostiquées dans le cadre de l'initiation de la prise en charge du VIH, mais également aux PLVIH stables déjà traités par TAR à qui on n'aurait pas encore offert le TPT. L'expansion du TPT survient au même moment comme une tendance à offrir une prise en charge du VIH davantage centrée sur la personne à travers une prestation de services différenciée (DSD). Dans la DSD, les PLVIH stables sous TAR bénéficient d'un suivi clinique moins fréquent ou sont soignés hors du modèle traditionnel en structures de santé. Le décalage entre la prestation traditionnelle du TPT et la prestation de soins dans des DSD innovantes peut nécessiter des adaptations aux pratiques de prestation du TPT pour les PLVIH. Ces adaptations incluent des éléments de planification et d'opérationnalisation du TPT dans la DSD, comme la détermination de l'éligibilité au TPT et sa mise en route et la prise en charge clinique des PLVIH sous TPT. Une adaptation majeure est l'alignement en termes de temps et de lieu pour la prescription, le suivi et la délivrance du TPT et du TAR. Des exemples conceptuels de délivrance du TPT dans la DSD aideraient les gestionnaires de programme à rendre opérationnel le TPT au sein de la prise en charge du VIH.

Los interesados directos del Programa Mundial del VIH, incluido el Plan de Emergencia del Presidente (de los Estados Unidos) para el Alivio del Sida (PEPFAR), emprenden ahora esfuerzos encaminados a garantizar que las personas con infección por el VIH (PLVIH), que siguen un tratamiento antirretrovírico (TAR) y que reúnen las condiciones, reciban un ciclo de tratamiento preventivo de la TB (TPT). En la programación del PEPFAR esta iniciativa puede necesitar la provisión de TPT no solo a las personas con un diagnóstico reciente de infección por el VIH, como parte del inicio de la atención del VIH, sino también a las PLVIH, con experiencia de tratamiento y que se encuentran estables recibiendo el TAR, a quienes tal vez no se haya propuesto antes el TPT. La ampliación del TPT ocurre de manera simultánea con la tendencia a ofrecer una atención del VIH más centrada en la persona mediante la prestación diferenciada de servicios (DSD). En la DSD, las PLVIH, estables con el TAR, pueden tener encuentros de seguimiento clínico menos frecuentes o recibir atención por fuera del modelo tradicional en los consultorios. La discordancia entre la provisión tradicional del TPT y la prestación de atención en el marco innovador de la DSD exige adaptaciones de las prácticas de prestación del TPT a las PLVIH. Las adaptaciones incluyen componentes de planeación y puesta en práctica del TPT en la DSD, como la determinación de los criterios para recibir el TPT, el inicio del mismo y el manejo clínico de las PLVIH mientras reciben el TPT. Una adaptación primordial es la coordinación del ritmo y el lugar de prescripción, supervisión y suministro del TPT y el TAR. La presentación de ejemplos teóricos de provisión del TPT en el marco de la DSD puede ayudar a los gerentes de programas a poner en práctica el TPT en la atención del VIH.

Fat Mass Is Negatively Associated with Muscle Strength and Jump Test Performance.

BACKGROUND: It is known that maintenance of muscle mass cannot prevent loss of muscle strength in older adults. Recent evidence suggests that fat mass can weaken the relationship between muscle mass and functional performance. No information exists if fat mass can independently affect muscle strength and jump test performance in middle-aged and older adults. OBJECTIVE: To assess the independent relationships between fat mass, leg muscle mass, lower extremity muscle strength, and jump test performance in adults, 55-75 years of age. DESIGN: Cross-sectional. SETTING: University laboratory. PARTICIPANTS: Fifty-nine older adults (men, n = 27, age = 64.8 ± 6.5 years; women, n = 32, age = 62.5 ± 5.1 years) participated in this study. MEASUREMENTS: Dual energy X-ray absorptiometry was used to measure fat mass and leg muscle mass. An average of 3 maximal countermovement jumps was used to calculate jump power and jump height. Two leg press and hip abduction strength were assessed by 1-repetition maximum testing. RESULTS: Stepwise sequential regression analysis of fat mass and leg muscle mass versus jump test performance and measures of muscle strength after adjusting for age, height, and physical activity revealed that fat mass was negatively associated with jump height (p = 0.047, rpartial = -0.410) in men. In women, fat mass was negatively associated with jump height (p = 0.003, rpartial = -0.538), leg press (p = 0.002, rpartial = -0.544), and hip abduction strength (p < 0.001, rpartial = -0.661). Leg muscle mass was positively associated with jump power in women (p = 0.047, rpartial = 0.372) only. CONCLUSIONS: Fat mass has an independent negative relationship with jump test performance in middle-aged and older men and women. This has clinical implications for rehabilitating neuromuscular performance in middle-aged and older adults.

A narrative review of the definition of 'flare' in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory condition that can have periodic worsening or flares. Measurement of flare is important because it can inform treatment efficacy; however, it is unclear how HS flare should be defined. OBJECTIVES: This study reviewed the literature for definitions of HS flare. METHODS: The PubMed MEDLINE online database was searched on 10 January 2018 and the search was repeated on 8 December 2018 for new publications. Titles and abstracts were screened for inclusion. Subsequently, full articles were screened for inclusion. Papers were included if the publication was a systematic review, clinical trial, cohort study, case report or series, or cross-sectional study. Studies were excluded if they were journalistic reviews, did not discuss clinical findings of HS or did not use the words 'flare', 'exacerbation', 'relapse' or 'recurrence'. RESULTS: Two hundred and seventy-four papers were identified and 154 fulfilled the study criteria. Of these, 27 (17.5%) included the term 'flare' and 16 (10.4%) included the term 'exacerbation'. Two of the 27 papers (7%) defined the term flare and both included patient report of changes in symptoms or signs. One of 16 papers (6%) defined exacerbation, which was taken as one new HS lesion. The terms 'recurrence' and 'relapse' were more apt to be defined: 13% (13 of 100) and 14% (six of 44), respectively. CONCLUSIONS: The lack of a specific and measurable definition of HS flare is a barrier to assessment of this important outcome. Once a specific and measurable definition is established, validated and reliable measures of HS flare can be incorporated into future studies. What's already known about this topic? Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory skin condition. The ability to assess flares is important to people who have HS; however, it is unclear how this is defined. HS flare is one of the core outcomes in the core outcome set for HS clinical trials; however, it is unclear how this should be assessed. What does this study add? This literature review reveals the paucity of measurable definitions associated with the use of the term 'flare' in the HS literature. It also highlights the variation and lack of a validated and reliable measure of HS flare.

Organotypic brain slice cultures to model neurodegenerative proteinopathies.

Organotypic slice cultures of brain or spinal cord have been a longstanding tool in neuroscience research but their utility for understanding Alzheimer's disease (AD) and other neurodegenerative proteinopathies has only recently begun to be evaluated. Organotypic brain slice cultures (BSCs) represent a physiologically relevant three-dimensional model of the brain. BSCs support all the central nervous system (CNS) cell types and can be produced from brain areas involved in neurodegenerative disease. BSCs can be used to better understand the induction and significance of proteinopathies underlying the development and progression of AD and other neurodegenerative disorders, and in the future may serve as bridging technologies between cell culture and in vivo experiments for the development and evaluation of novel therapeutic targets and strategies. We review the initial development and general use of BSCs in neuroscience research and highlight the advantages of these cultures as an ex vivo model. Subsequently we focus on i) BSC-based modeling of AD and other neurodegenerative proteinopathies ii) use of BSCs to understand mechanisms underlying these diseases and iii) how BSCs can serve as tools to screen for suitable therapeutics prior to in vivo investigations. Finally, we will examine i) open questions regarding the use of such cultures and ii) how emerging technologies such as recombinant adeno-associated viruses (rAAV) may be combined with these models to advance translational research relevant to neurodegenerative disorders.

Femtosecond gas-phase mega-electron-volt ultrafast electron diffraction.

The development of ultrafast gas electron diffraction with nonrelativistic electrons has enabled the determination of molecular structures with atomic spatial resolution. It has, however, been challenging to break the picosecond temporal resolution barrier and achieve the goal that has long been envisioned-making space- and-time resolved molecular movies of chemical reaction in the gas-phase. Recently, an ultrafast electron diffraction (UED) apparatus using mega-electron-volt (MeV) electrons was developed at the SLAC National Accelerator Laboratory for imaging ultrafast structural dynamics of molecules in the gas phase. The SLAC gas-phase MeV UED has achieved 65 fs root mean square temporal resolution, 0.63 Å spatial resolution, and 0.22 Å-1 reciprocal-space resolution. Such high spatial-temporal resolution has enabled the capturing of real-time molecular movies of fundamental photochemical mechanisms, such as chemical bond breaking, ring opening, and a nuclear wave packet crossing a conical intersection. In this paper, the design that enables the high spatial-temporal resolution of the SLAC gas phase MeV UED is presented. The compact design of the differential pump section of the SLAC gas phase MeV UED realized five orders-of-magnitude vacuum isolation between the electron source and gas sample chamber. The spatial resolution, temporal resolution, and long-term stability of the apparatus are systematically characterized.

Fibroblast growth factor-21 (FGF21) administration to early-lactating dairy cows. I. Effects on signaling and indices of insulin action.

Modern dairy cows rely on hormonally driven mechanisms to coordinate the metabolic adaptations needed to meet the energy and nutrient deficits of early lactation. In the case of glucose, dairy cows cope with its scarcity during early lactation via reduced plasma concentrations of insulin and the insulin sensitizing hormone adiponectin and increased insulin resistance. Reduced insulin action promotes diversion of available glucose to the mammary gland but increases susceptibility to diseases if excessive. In earlier work, we reported that the insulin sensitizing hormone fibroblast growth factor-21 (FGF21) is increased in periparturient dairy cows and identified liver and adipose tissue as possible targets. These observations raised the possibility that FGF21 acts directly on these tissues to limit the insulin resistance of early lactation. To test this hypothesis, dairy cows were randomly assigned on d 12.6 ± 2.2 (± standard error) of lactation to receive either excipient (n = 6) or recombinant human FGF21 (n = 7), first as an FGF21 bolus of 3 mg/kg of body weight, followed 2 d later by a constant i.v. infusion of FGF21 at the rate of 6.3 mg/kg of metabolic body weight for 9 consecutive days. Biopsies of liver and adipose tissue were collected during the bolus phase of the experiment and used to analyze FGF21 signaling by Western blotting and expression of its receptor components by quantitative PCR. Bolus FGF21 administration caused a 4-fold increase in p44/42 MAPK (ERK1/2) activation in adipose tissue but had no effect on AKT and signal transducer and activator of transcription-3 (STAT3) signaling. The liver expressed negligible levels of the preferred FGF21 receptor FGFR1c and failed to mount any FGF21 signaling response. The FGF21 administered as a bolus had no effect on plasma glucose or insulin and did not stimulate an acute release of adiponectin from adipose tissue. Similarly, FGF21 infusion had no effect on plasma levels of glucose or insulin measured over the 9-d infusion or on glucose disposal during an i.v. glucose tolerance test performed on d 8 of infusion. Finally, the chronic FGF21 infusion had no effect on indices of adiponectin production, including plasma adiponectin and adipose tissue mRNA abundance of adiponectin and the endoplasmic reticulum chaperones ERO1A and DSBA-L involved in the assembly of adiponectin into multimeric complexes. These data show that human FGF21 does not act as an insulin sensitizer during the energy and glucose deficit of early lactation but do not rule out such a role in other physiological states.

Antibody-mediated protection against MERS-CoV in the murine model.

Murine antisera with neutralising activity for the coronavirus causative of Middle East respiratory syndrome (MERS) were induced by immunisation of Balb/c mice with the receptor binding domain (RBD) of the viral Spike protein. The murine antisera induced were fully-neutralising in vitro for two separate clinical strains of the MERS coronavirus (MERS-CoV). To test the neutralising capacity of these antisera in vivo, susceptibility to MERS-CoV was induced in naive recipient Balb/c mice by the administration of an adenovirus vector expressing the human DPP4 receptor (Ad5-hDPP4) for MERS-CoV, prior to the passive transfer of the RBD-specific murine antisera to the transduced mice. Subsequent challenge of the recipient transduced mice by the intra-nasal route with a clinical isolate of the MERS-CoV resulted in a significantly reduced viral load in their lungs, compared with transduced mice receiving a negative control antibody. The murine antisera used were derived from mice which had been primed sub-cutaneously with a recombinant fusion of RBD with a human IgG Fc tag (RBD-Fc), adsorbed to calcium phosphate microcrystals and then boosted by the oral route with the same fusion protein in reverse micelles. The data gained indicate that this dual-route vaccination with novel formulations of the RBD-Fc, induced systemic and mucosal anti-viral immunity with demonstrated in vitro and in vivo neutralisation capacity for clinical strains of MERS-CoV.

Activation of the cannabinoid receptor 2 increases renal perfusion.

Acute kidney injury (AKI) is an increasing clinical problem that is associated with chronic kidney disease progression. Cannabinoid receptor 2 (CB2) activation has been shown to mitigate some of the deleterious tubular effects due to AKI, but its role on the renal vasculature has not been fully described. In this study, we investigated the effects of our novel CB2 receptor agonist, SMM-295, on renal vasculature by assessing cortical perfusion with laser Doppler flowmetry and changes in luminal diameter with isolated afferent arterioles. In this study, intravenously infused SMM-295 (6 mg/kg) significantly increased cortical renal perfusion (13.8 ± 0.6%; P < 0.0001; n = 7) compared with vehicle (0.1 ± 1.5%; n = 10) normalized to baseline values in anesthetized C57BL/6J mice. This effect was not dependent upon activation of the CB1 receptor (met-anandamide; 6 mg/kg iv) and was predominantly abolished in Cnr2 knockout mice with SMM-295 (6 mg/kg iv). Ablation of the renal afferent nerves with capsaicin blocked the SMM-295-dependent increase in renal cortical perfusion, and the increased renal blood flow was not dependent upon products synthesized by cyclooxygenase or nitric oxide synthase. The increased renal perfusion by CB2 receptor activation is also attributed to a direct vascular effect, since SMM-295 (5 µM) engendered a significant 37 ± 7% increase ( P < 0.0001; n = 4) in luminal diameters of norepinephrine-preconstricted afferent arterioles. These data provide new insight into the potential benefit of SMM-295 by activating vascular and nonvascular CB2 receptors to promote renal vasodilation, and provide a new therapeutic target to treat renal injuries that impact renal blood flow dynamics.

Occult contralateral inguinal hernias: what is their true incidence and should they be repaired?

BACKGROUND: The true incidence of occult contralateral inguinal hernia is unknown; however, when found, there exists controversy as to whether or not they should be repaired. The aim of our study is to identify the incidence of contralateral incidental inguinal hernias in our surgical population, compare our results to previous studies timelining occult hernia identification to repair need, and generate debate as to whether incidental contralateral hernias should be repaired at the index operation. METHODS: We reviewed the charts of 297 consecutive patients undergoing robotic inguinal hernia repair between October 2014 and April 2018 at a single facility. By comparing preoperative physical examination to intraoperative findings, we determined the number of occult contralateral inguinal hernias in our patient population. RESULTS: Of 297 patients, 158 (53.2%) presented with a right inguinal hernia, 90 (30.3%) presented with a left inguinal hernia, and 49 (16.5%) presented with bilateral inguinal hernias. Forty-seven of the 297 patients (15.8%) were found to have an incidental contralateral inguinal hernia. Excluding patients with known bilateral inguinal hernias, 20% of patients with a left inguinal hernia were found to have an occult right inguinal hernia and 18.4% of patients with a right inguinal hernia were found to have an occult left inguinal hernia. CONCLUSIONS: The true incidence of occult contralateral inguinal hernia may be higher than originally thought. When inguinal hernia repair is performed through a transabdominal approach, these occult hernias may be easily addressed during the same operation without additional skin incisions. This may ultimately prevent the morbidity of developing a metachronous hernia that requires repair.

Food for thought. Malnutrition risk associated with increased risk of healthcare-associated infection.

BACKGROUND: Infection and malnutrition are interconnected. UK and Irish guidelines recommend the Malnutrition Universal Screening Tool (MUST) for nutritional risk screening. Patients with a MUST score of ≥2 are considered at high risk of malnutrition and referral for nutritional assessment is recommended. AIM: To explore the association between healthcare-associated infection (HCAI) and the MUST score categories of patients. METHODS: This was a cross-sectional study in May 2017 on ten representative wards in our institution. Patient demographics, MUST score, presence of medical devices, HCAI and antimicrobial use were collected. FINDINGS: Of 240 patients, the HCAI prevalence was 10.4% (N = 25) and 26% (N = 63) were at high risk of malnutrition (MUST score ≥2). Patients with HCAI were more likely to have had surgery (odds ratio (OR): 5.5; confidence interval (CI): 2.1-14.3; P < 0.001), a central vascular catheter (OR: 10.0; CI: 3.6-27.2; P < 0.001), or a urinary catheter in situ (OR: 7.5; CI: 2.8-20.0; P < 0.001), and to have a high risk of malnutrition (OR: 4.3; CI: 1.7-11.2; P < 0.001). A higher MUST score remained a significant predictor of a patient having HCAI on multivariate regression analysis (CI: 0.2-0.6; P < 0.001). CONCLUSION: Patients at risk of malnutrition when assessed with the MUST were more likely to have HCAI. However, prospective studies are required to investigate the temporal association between MUST and HCAI and which interventions best address malnutrition risk and HCAI reduction in different settings.