Kinematic and perceptual responses in heavy lifting and pulling: Are there differences between males and females?

This study investigated kinematic and perceptual differences between the sexes in a heavy lifting and pulling task. A 20 kg box was lifted from floor to chest height, and a 70 kg mannequin pulled across 20m. The effect of height, mass and average grip strength on kinematics and perceived workload was examined in 42 (19 females, 23 males) healthy individuals. A univariate linear regression analysis found females lifted with greater lumbar extension compared to males (p < 0.001), and adopted more hip (p = 0.006) and knee flexion (p = 0.036) in the pulling task. Females reported a greater perceived workload in both tasks (p < 0.001). After the multivariable analysis, only grip strength remained significant for perceived workload in the lift (p = 0.04), and height for knee flexion in the pull (p = 0.009). This highlights that height and strength are important factors driving kinematics and perceived workload. Clinicians may consider these factors in heavy manual tasks, more so than sex.

A Turing Test for Molecular Generators.

Machine learning approaches promise to accelerate and improve success rates in medicinal chemistry programs by more effectively leveraging available data to guide a molecular design. A key step of an automated computational design algorithm is molecule generation, where the machine is required to design high-quality, drug-like molecules within the appropriate chemical space. Many algorithms have been proposed for molecular generation; however, a challenge is how to assess the validity of the resulting molecules. Here, we report three Turing-inspired tests designed to evaluate the performance of molecular generators. Profound differences were observed between the performance of molecule generators in these tests, highlighting the importance of selection of the appropriate design algorithms for specific circumstances. One molecule generator, based on match molecular pairs, performed excellently against all tests and thus provides a valuable component for machine-driven medicinal chemistry design workflows.

Sedation with alfentanil versus fentanyl in patients receiving extracorporeal membrane oxygenation: outcomes from a single-centre retrospective study.

INTRODUCTION: In November 2016, our institution switched from alfentanil to fentanyl for analgesia and sedation in adult patients receiving extracorporeal membrane oxygenation. There is no published evidence comparing the use of alfentanil with fentanyl for sedation in extracorporeal membrane oxygenation patients. We conducted a retrospective observational study to explore any significant differences in patient outcomes or in the prescribing of adjunct sedatives before and after the switch. METHODS: Patients were retrospectively identified from a prospectively recorded database of all patients who received extracorporeal membrane oxygenation at our institution between January 2016 and October 2017. Patients included those sedated with alfentanil or fentanyl. The total daily doses of intravenous opioids (alfentanil or fentanyl) were calculated for each patient, and the prescribing of adjunctive sedative or analgesic agents was recorded. Patient demographics, extracorporeal membrane oxygenation modality, clinical outcomes including mortality and length of intensive care and hospital stay were recorded. RESULTS: A total of 174 patients were identified, 69 on alfentanil and 95 on fentanyl. There was no difference found between groups for mode of extracorporeal membrane oxygenation, age, Acute Physiology and Chronic Health Evaluation 2 score (APACHE II) and Charlson score, except for body mass index (p = 0.002). No differences in patient outcomes was observed between groups, although patients in the alfentanil group received a significantly higher median total daily dose of adjuvant sedatives (quetiapine (p = 0.016) and midazolam (p = 0.009)). CONCLUSIONS: No differences in patient outcomes were found between extracorporeal membrane oxygenation patients sedated with alfentanil compared with fentanyl. There was a statistically significant reduction in some adjunctive sedatives in patients managed with a fentanyl-based regimen. Prospective studies are required to confirm these results.

How to measure a patient's temperature non-invasively.

RATIONALE AND KEY POINTS: Temperature is a vital sign that is included in all early warning scoring tools and as part of patient observations. This article outlines the main non-invasive methods that can be used to measure a patient's temperature. REFLECTIVE ACTIVITY: 'How to' articles can help to update your practice and ensure it remains evidence-based. Apply this article to your practice. Reflect on and write a short account of.

GSK2646264, a spleen tyrosine kinase inhibitor, attenuates the release of histamine in ex vivo human skin.

BACKGROUND AND PURPOSE: Chronic spontaneous urticaria presents as a heterogeneous syndrome characterised by wheals, angioedema, or both for greater than 6 weeks. Spleen tyrosine kinase mediates allergen-induced mast cell degranulation via the IgE signalling pathway, a central component of wheal formation and inflammation. In this study, we investigated the effects of perfused or topically administered GSK2646264 on IgE-mediated histamine release from mast cells in an ex vivo human skin model. EXPERIMENTAL APPROACH: Using a novel SkiP device, ex vivo human skin from mastectomy surgeries was challenged with anti-IgE, complement 5a (C5a), and buffer to induce histamine release from skin mast cells. Histamine was collected via microdialysis fibres and measured fluorometrically. GSK2646264 was delivered via perfusion either using microdialysis fibres or topically in a cream. Drug concentrations in the skin were measured by LC-MS, and a pharmacokinetic/ pharmacodynamic (PK/PD) relationship developed. KEY RESULTS: Perfused GSK2646264 significantly inhibited anti-IgE (but not C5a)-induced histamine release in a concentration-dependent manner. The 0.5, 1, and 3% cream delivered GSK2646264 to the dermis above the IC90 and dose-dependently attenuated anti-IgE-induced histamine release. CONCLUSIONS AND IMPLICATIONS: GSK2646264 administered topically or direct to the dermis blocked histamine release from in situ skin mast cells. A PK/PD relationship curve suggests that dermal concentrations above 6.8 µM should lead to approximately 90% inhibition of histamine release from skin mast cells following activation of the Fc fragment of IgE receptor 1a, implicating a potential use for the compound in skin mast cell diseases such as urticaria.

Ocean acidification has little effect on developmental thermal windows of echinoderms from Antarctica to the tropics.

As the ocean warms, thermal tolerance of developmental stages may be a key driver of changes in the geographical distributions and abundance of marine invertebrates. Additional stressors such as ocean acidification may influence developmental thermal windows and are therefore important considerations for predicting distributions of species under climate change scenarios. The effects of reduced seawater pH on the thermal windows of fertilization, embryology and larval morphology were examined using five echinoderm species: two polar (Sterechinus neumayeri and Odontaster validus), two temperate (Fellaster zelandiae and Patiriella regularis) and one tropical (Arachnoides placenta). Responses were examined across 12-13 temperatures ranging from -1.1 °C to 5.7 °C (S. neumayeri), -0.5 °C to 10.7 °C (O. validus), 5.8 °C to 27 °C (F. zelandiae), 6.0 °C to 27.1 °C (P. regularis) and 13.9 °C to 34.8 °C (A. placenta) under present-day and near-future (2100+) ocean acidification conditions (-0.3 pH units) and for three important early developmental stages 1) fertilization, 2) embryo (prehatching) and 3) larval development. Thermal windows for fertilization were broad and were not influenced by a pH decrease. Embryological development was less thermotolerant. For O. validus, P. regularis and A. placenta, low pH reduced normal development, albeit with no effect on thermal windows. Larval development in all five species was affected by both temperature and pH; however, thermal tolerance was not reduced by pH. Results of this study suggest that in terms of fertilization and development, temperature will remain as the most important factor influencing species' latitudinal distributions as the ocean continues to warm and decrease in pH, and that there is little evidence of a synergistic effect of temperature and ocean acidification on the thermal control of species ranges.

Interfacing a biosurveillance portal and an international network of institutional analysts to detect biological threats.

The Early Alerting and Reporting (EAR) project, launched in 2008, is aimed at improving global early alerting and risk assessment and evaluating the feasibility and opportunity of integrating the analysis of biological, chemical, radionuclear (CBRN), and pandemic influenza threats. At a time when no international collaborations existed in the field of event-based surveillance, EAR's innovative approach involved both epidemic intelligence experts and internet-based biosurveillance system providers in the framework of an international collaboration called the Global Health Security Initiative, which involved the ministries of health of the G7 countries and Mexico, the World Health Organization, and the European Commission. The EAR project pooled data from 7 major internet-based biosurveillance systems onto a common portal that was progressively optimized for biological threat detection under the guidance of epidemic intelligence experts from public health institutions in Canada, the European Centre for Disease Prevention and Control, France, Germany, Italy, Japan, the United Kingdom, and the United States. The group became the first end users of the EAR portal, constituting a network of analysts working with a common standard operating procedure and risk assessment tools on a rotation basis to constantly screen and assess public information on the web for events that could suggest an intentional release of biological agents. Following the first 2-year pilot phase, the EAR project was tested in its capacity to monitor biological threats, proving that its working model was feasible and demonstrating the high commitment of the countries and international institutions involved. During the testing period, analysts using the EAR platform did not miss intentional events of a biological nature and did not issue false alarms. Through the findings of this initial assessment, this article provides insights into how the field of epidemic intelligence can advance through an international network and, more specifically, how it was further developed in the EAR project.

Enantioselective catalytic desymmetrization of maleimides by temporary removal of an internal mirror plane and stereoablative over-reduction: synthesis of (R)-pyrrolam A.

A highly enantioselective (>95% ee) strategy to affect the desymmetrization of a maleimide has been performed by temporary attachment to an anthracene template followed by asymmetric reduction with an oxazaborolidine catalyst. A stereoablative over-reduction process was partially responsible for the high levels of enantioselectivity. Exemplification of the strategy by stereoselective functionalization and retro-Diels-Alder reaction provided the natural product pyrrolam A.

Configuration of a high-content imaging platform for hit identification and pharmacological assessment of JMJD3 demethylase enzyme inhibitors.

The biological complexity associated with the regulation of histone demethylases makes it desirable to configure a cellular mechanistic assay format that simultaneously encompasses as many of the relevant cellular processes as possible. In this report, the authors describe the configuration of a JMJD3 high-content cellular mechanistic imaging assay that uses single-cell multiparameter measurements to accurately assess cellular viability and the enzyme-dependent demethylation of the H3K27(Me)3 mark by exogenously expressed JMJD3. This approach couples robust statistical analyses with the spatial resolving power of cellular imaging. This enables segregation of expressing and nonexpressing cells into discrete subpopulations and consequently pharmacological quantification of compounds of interest in the expressing population at varying JMJD3 expression levels. Moreover, the authors demonstrate the utility of this hit identification strategy through the successful prosecution of a medium-throughput focused campaign of an 87 500-compound file, which has enabled the identification of JMJD3 cellular-active chemotypes. This study represents the first report of a demethylase high-content imaging assay with the ability to capture a repertoire of pharmacological tools, which are likely both to inform our mechanistic understanding of how JMJD3 is modulated and, more important, to contribute to the identification of novel therapeutic modalities for this demethylase enzyme.

Effect of season on the sensory quality of sea urchin (Evechinus chloroticus) roe.

The influence of season, gender, and reproductive maturity on the sensory properties (appearance, odor, taste, flavor, texture/mouth feel, and after taste) of roe from sea urchins (Evechinus chloroticus) was investigated. A trained sensory panel applied descriptive analysis, with a comprehensive sensory vocabulary of 35 descriptors to analyze sea urchin roe obtained from samples collected during the austral autumn, winter, summer, and spring, over a 2-y period. Sensory differences between genders were less pronounced in autumn (March to May) and winter (June to August) when more nutritive cells were present in the roe, and more pronounced over spring (September to November) and summer (December to February) months as the gametogenic cells matured. Roe from female sea urchins were commonly associated with sulfur odor, bitter taste, and metallic flavor, while roe from the male sea urchins were associated with sweet taste. During autumn, female roe were closest in sensory quality to male roe (least bitter and most sweet compared to other seasons), while there were little differences in sweetness and bitterness of male roe over the 4 seasons. Despite the relative size of the roe being lowest in autumn, it appeared to be the optimum season to harvest E. chloroticus sea urchins to obtain high-quality roe.

Expression of the DNA repair enzyme, photolyase, in developmental tissues and larvae, and in response to ambient UV-R in the Antarctic sea urchin Sterechinus neumayeri.

Gene expression of the DNA repair enzyme, photolyase (E.C. 4.1.99.3) was examined in the gonads, eggs, embryos and larval stages of the Antarctic sea urchin, Sterechinus neumayeri. Partial sequencing of the gene revealed two highly conserved regions, including a 300 bp region representing the binding site for the cofactor flavin adenine dinucleotide. The second 1200 bp region, likely representing a second light-harvesting cofactor binding site, was identified in a second sea urchin species, Strongylocentrotus frascicanus. Probes for photolyase were developed from the shorter sequence, and expression in sea urchin developmental tissue and stages, and in response to in situ exposure to ultraviolet radiation was quantified using PCR and RT-qPCR, with concentrations of photolyase normalized to actin concentrations. Photolyase was expressed in all tissues and developmental stages examined. In controlled field-based experiments in McMurdo Sound, Antarctica, we found evidence of both constitutive expression of photolyase and induction in response to in situ exposure of embryos to UV-R. Induction of photolyase was observed in response to greater ambient UV-R (such as shallower water depths or sea ice-free regions).

Kinetic resolution of racemic pyrrolidine-2,5-diones using chiral oxazaborolidine catalysts.

Kinetic resolution of racemic C-3 substituted pyrrolidine-2,5-diones has been achieved for the first time using highly efficient oxazaborolidine catalysts derived from cis-1-amino-indan-2-ol.

Carbon-carbon bond forming reactions with substrates absorbed non-covalently on a cellulose chromatography paper support.

Reactions and purifications, including carbon-carbon bond forming reactions, can be carried out on a cellulose support on which the substrates are non-covalently absorbed.

DNA photorepair in echinoid embryos: effects of temperature on repair rate in Antarctic and non-Antarctic species.

To determine if an Antarctic species repairs DNA at rates equivalent to warmer water equivalents, we examined repair of UV-damaged DNA in echinoid embryos and larvae. DNA repair by photoreactivation was compared in three species Sterechinus neumayeri (Antarctica), Evechinus chloroticus (New Zealand) and Diadema setosum (Tropical Australia) spanning a latitudinal gradient from polar (77.86 degrees S) to tropical (19.25 degrees S) environments. We compared rates of photoreactivation as a function of ambient and experimental temperature in all three species, and rates of photoreactivation as a function of embryonic developmental stage in Sterechinus. DNA damage was quantified from cyclobutane pyrimidine dimer (CPD) concentrations and rates of abnormal embryonic development. This study established that in the three species and in three developmental stages of Sterechinus, photoreactivation was the primary means of removing CPDs, was effective in repairing all CPDs in less than 24 h, and promoted significantly higher rates of normal development in UV-exposed embryos. CPD photorepair rate constant (k) in echinoid embryos ranged from 0.33 to 1.25 h(-1), equating to a time to 50% repair of between 0.6 and 2.1 h and time to 90%repair between 3.6 and 13.6 h. We observed that experimental temperature influenced photoreactivation rate. In Diadema plutei, the photoreactivation rate constant increased from k=0.58 h(-1) to 1.25 h(-1), with a Q(10)=2.15 between 22 degrees C and 32 degrees C. When compared among the three species across experimental temperatures (-1.9 to 32 degrees C), photoreactivation rates vary with a Q(10)=1.39. Photoreactivation rates were examined in three developmental stages of Sterechinus embryos, and while not significantly different, repair rates tended to be higher in the younger blastula and gastrula stages compared with later stage embryos. We concluded that photoreactivation is active in the Antarctic Sterechinus, but at a significantly slower (non-temperature compensated) rate. The low level of temperature compensation in photoreactivation may be one explanation for the relatively high sensitivity of Antarctic embryos to UV-R in comparison with non-Antarctic equivalents.

Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series.

The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.

Design and synthesis of new nonsteroidal glucocorticoid modulators through application of an "agreement docking" method.

Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a is a partial agonist while 9e and 15a are micromolar antagonists in a mouse mammary tumor virus transactivation assay.