Small molecule screening in zebrafish: an in vivo approach to identifying new chemical tools and drug leads

In the past two decades, zebrafish genetic screens have identified a wealth of mutations that have been essential to the understanding of development and disease biology. More recently, chemical screens in zebrafish have identified small molecules that can modulate specific developmental and behavioural processes. Zebrafish are a unique vertebrate system in which to study chemical genetic systems, identify drug leads, and explore new applications for known drugs. Here, we discuss some of the advantages of using zebrafish in chemical biology, and describe some important and creative examples of small molecule screening, drug discovery and target identification

The utility of whole body vibration exercise in haemodialysis patients: a pilot study

Background: Exercise improves physical capacity in patients with end-stage renal disease on haemodialysis (HD), but few patients engage in it. Whole-body vibration exercise (WBVE) is a novel protocol that has been shown to benefit frail elderly patients’ rehabilitation. We assessed the utility of WBVE before HD sessions and tested methods to inform the design of a randomized controlled trial (RCT). Methods: Physical condition and quality of life were assessed at enrolment and repeated 2 weeks later in a pilot study of 49 patients undergoing regular HD. All patients then undertook 8 weeks of WBVE, thrice weekly for 3 min, after which the assessments were repeated and results compared (paired t-tests). Further assessments were made after a 4-week layoff. Patients completed a post-study questionnaire about their experiences of using WBVE. The reproducibility of WBVE and effects on measures of functionality, muscle strength, indirect exercise capacity, nutritional status, bone health and quality of life were recorded to undertake a power calculation for an RCT. Results: Of 49 patients enrolled, 25 completed all assessments. The dropout rate was high at 49%, but overall, WBVE was an acceptable form of exercise. Functionality as assessed by the 60-s sit-to-stand test (STS-60) improved significantly by 11% (P = 0.002). Some quality of life domains also improved significantly. All improvements were maintained 4 weeks after discontinuing WBVE. Conclusions: WBVE was acceptable, safe, easily incorporated into the routine of HD and was associated with useful improvements in physical function sufficient to justify a RCT

Incidence and prevalence of post-stroke insomnia: a systematic review and meta-analysis

Problems with sleep are reported to be common after stroke but the incidence and prevalence of insomnia and insomnia symptoms following stroke is not yet established. The aim of this review was to conduct a systematic review and meta-analysis of the incidence and prevalence of insomnia and insomnia symptoms in individuals affected by stroke. We searched seven main electronic databases to identify studies until September 25, 2018. No studies examining incidence of post-stroke insomnia were identified. Twenty-two studies on prevalence of insomnia or insomnia symptoms including individuals with stroke were included with fourteen studies suitable for inclusion in the meta-analysis. Meta-analysis indicated pooled prevalence of 38.2% (CI 30.1–46.5) with significantly higher prevalence estimates for studies using non-diagnostic tools, 40.70% (CI 30.96–50.82) compared to studies using diagnostic assessment tools 32.21% (CI 18.5–47.64). Greater insomnia symptoms were indicated in those with comorbid depression and anxiety. The prevalence of both insomnia and insomnia symptoms are considerably higher in stroke survivors compared to the general population. Studies investigating the incidence, insomnia symptom profile and changes in insomnia prevalence over time are needed to inform clinical practice and to encourage tailored interventions that consider this symptomatology. PROSPERO registration number CRD42017065670

The MITRE trial protocol: a study to evaluate the microbiome as a biomarker of efficacy and toxicity in cancer patients receiving immune checkpoint inhibitor therapy.

BACKGROUND: The gut microbiome is implicated as a marker of response to  immune checkpoint inhibitors (ICI) based on preclinical mouse models and preliminary observations in limited patient series. Furthermore, early studies suggest faecal microbial transfer may have therapeutic potential, converting ICI non-responders into responders. So far, identification of specific responsible bacterial taxa has been inconsistent, which limits future application. The MITRE study will explore and validate a microbiome signature in a larger scale prospective study across several different cancer types. METHODS: Melanoma, renal cancer and non-small cell lung cancer patients who are planned to receive standard immune checkpoint inhibitors are being recruited to the MITRE study. Longitudinal stool samples are collected prior to treatment, then at 6 weeks, 3, 6 and 12 months during treatment, or at disease progression/recurrence (whichever is sooner), as well as after a severe (≥grade 3 CTCAE v5.0) immune-related adverse event. Additionally, whole blood, plasma, buffy coat, RNA and peripheral blood mononuclear cells (PBMCs) is collected at similar time points and will be used for exploratory analyses. Archival tumour tissue, tumour biopsies at progression/relapse, as well as any biopsies from body organs collected after a severe toxicity are collected. The primary outcome measure is the ability of the microbiome signature to predict 1 year progression-free survival (PFS) in patients with advanced disease. Secondary outcomes include microbiome correlations with toxicity and other efficacy end-points. Biosamples will be used to explore immunological and genomic correlates. A sub-study will evaluate both COVID-19 antigen and antibody associations with the microbiome. DISCUSSION: There is an urgent need to identify biomarkers that are predictive of treatment response, resistance and toxicity to immunotherapy. The data generated from this study will both help inform patient selection for these drugs and provide information that may allow therapeutic manipulation of the microbiome to improve future patient outcomes. TRIAL REGISTRATION: NCT04107168 , ClinicalTrials.gov, registered 09/27/2019. Protocol V3.2 (16/04/2021)

A case study of transport of tropical marine boundary layer and lower tropospheric air masses to the northern midlatitude upper troposphere

Low‐ozone (ppbv) air masses were observed in the upper troposphere in northern midlatitudes over the eastern United States and the North Atlantic Ocean on several occasions in October 1997 during the NASA Subsonic Assessment, Ozone and Nitrogen Oxide Experiment (SONEX) mission. Three cases of low‐ozone air masses were shown to have originated in the tropical Pacific marine boundary layer or lower troposphere and advected poleward along a warm conveyor belt during a synoptic‐scale disturbance. The tropopause was elevated in the region with the low‐ozone air mass. Stratospheric intrusions accompanied the disturbances. On the basis of storm track and stratospheric intrusion climatologies, such events appear to be more frequent from September through March than the rest of the year

Simplifying Consent for HIV Testing Is Associated with an Increase in HIV Testing and Case Detection in Highest Risk Groups, San Francisco January 2003–June 2007

Populations at highest risk for HIV infection face multiple barriers to HIV testing. To facilitate HIV testing procedures, the San Francisco General Hospital Medical Center eliminated required written patient consent for HIV testing in its medical settings in May 2006. To describe the change in HIV testing rates in different hospital settings and populations after the change in HIV testing policy in the SFDH medical center, we performed an observational study using interrupted time series analysis.Data from all patients aged 18 years and older seen from January 2003 through June 2007 at the San Francisco Department of Public Health (SFDPH) medical care system were included in the analysis. The monthly HIV testing rate per 1000 had patient-visits was calculated for the overall population and stratified by hospital setting, age, sex, race/ethnicity, homelessness status, insurance status and primary language.By June 2007, the average monthly rate of HIV tests per 1000 patient-visits increased 4.38 (CI, 2.17-6.60, p<0.001) over the number predicted if the policy change had not occurred (representing a 44% increase). The monthly average number of new positive HIV tests increased from 8.9 (CI, 6.3-11.5) to 14.9 (CI, 10.6-19.2, p<0.001), representing a 67% increase. Although increases in HIV testing were seen in all populations, populations at highest risk for HIV infection, particularly men, the homeless, and the uninsured experienced the highest increases in monthly HIV testing rates after the policy change.The elimination of the requirement for written consent in May 2006 was associated with a significant and sustained increase in HIV testing rates and HIV case detection in the SFDPH medical center. Populations facing the higher barriers to HIV testing had the highest increases in HIV testing rates and case detection in response to the policy change

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure