Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome

Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5(pasireotide, or SOM230) or D2(cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin-dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D2receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases

The Development of Functional Overreaching Is Associated with a Faster Heart Rate Recovery in Endurance Athletes

Purpose The aim of the study was to investigate whether heart rate recovery (HRR) may represent an effective marker of functional overreaching (f-OR) in endurance athletes. Methods and Results Thirty-one experienced male triathletes were tested (10 control and 21 overload subjects) before (Pre), and immediately after an overload training period (Mid) and after a 2-week taper (Post). Physiological responses were assessed during an incremental cycling protocol to exhaustion, including heart rate, catecholamine release and blood lactate concentration. Ten participants from the overload group developed signs of f-OR at Mid (i.e. -2.1 ± 0.8% change in performance associated with concomitant high perceived fatigue). Additionally, only the f-OR group demonstrated a 99% chance of increase in HRR during the overload period (+8 ± 5 bpm, large effect size). Concomitantly, this group also revealed a >80% chance of decreasing blood lactate (-11 ± 14%, large), plasma norepinephrine (-12 ± 37%, small) and plasma epinephrine peak concentrations (-51 ± 22%, moderate). These blood measures returned to baseline levels at Post. HRR change was negatively correlated to changes in performance, peak HR and peak blood metabolites concentrations. Conclusion These findings suggest that i) a faster HRR is not systematically associated with improved physical performance, ii) changes in HRR should be interpreted in the context of the specific training phase, the athletes perceived level of fatigue and the performance response; and, iii) the faster HRR associated with f-OR may be induced by a decreased central commandand by a lower chemoreflex activity

Patients with persistent medically unexplained symptoms in general practice: characteristics and quality of care

<p>Abstract</p> <p>Background</p> <p>Medically unexplained physical symptoms (MUPS) are common in general practice (GP), and are even more problematic as they become persistent. The present study examines the relationship between persistent MUPS in general practice on the one hand and quality of life, social conditions, and coping on the other hand. Additionally, it is examined how patients with persistent MUPS evaluate the quality of GP-care.</p> <p>Methods</p> <p>Data were used from a representative survey of morbidity in Dutch general practice, in which data from the electronic medical records were extracted. A random sample of patients participated in an extensive health interview and completed self-reported measures on social isolation, coping and the quality of GP-care. Patients with persistent MUPS (N = 192) were compared with general practice patients not meeting the criteria for persistent MUPS (N = 7.314), and with a group of patients that visited the GP in comparable rates for medical diagnoses (N = 2.265). Multiple logistic regression analyses were used to control for relevant socio-demographic variables and chronic diseases.</p> <p>Results</p> <p>After adjustment for demographics and chronic diseases, patients with persistent MUPS reported more psychological distress, more functional impairment, more social isolation, and they evaluated the quality of GP-care less positive than the other two patient groups. Although the majority of MUPS patients were positive about the quality of GP-care, they more often felt that they were not taken seriously or not involved in treatment decisions, and more often reported that the GP did not take sufficient time. The three groups did not differ with respect to the statement that the GP unnecessarily explains physical problems as psychological ones.</p> <p>Conclusion</p> <p>Strengthening MUPS patients' social network and encouraging social activities may be a meaningful intervention in which the GP may play a stimulating role. To further improve MUPS patients' satisfaction with GP-care, GPs may pay extra attention to taking sufficient time when treating MUPS patients, taking the problems seriously, and involving them in treatment decisions.</p

All-sky, all-frequency directional search for persistent gravitational waves from Advanced LIGO’s and Advanced Virgo’s first three observing runs

We present the first results from an all-sky all-frequency (ASAF) search for an anisotropic stochastic gravitational-wave background using the data from the first three observing runs of the Advanced LIGO and Advanced Virgo detectors. Upper limit maps on broadband anisotropies of a persistent stochastic background were published for all observing runs of the LIGO-Virgo detectors. However, a broadband analysis is likely to miss narrowband signals as the signal-to-noise ratio of a narrowband signal can be significantly reduced when combined with detector output from other frequencies. Data folding and the computationally efficient analysis pipeline, {\tt PyStoch}, enable us to perform the radiometer map-making at every frequency bin. We perform the search at 3072 {\tt{HEALPix}} equal area pixels uniformly tiling the sky and in every frequency bin of width $1/32$~Hz in the range $20-1726$~Hz, except for bins that are likely to contain instrumental artefacts and hence are notched. We do not find any statistically significant evidence for the existence of narrowband gravitational-wave signals in the analyzed frequency bins. Therefore, we place $95\%$ confidence upper limits on the gravitational-wave strain for each pixel-frequency pair, the limits are in the range $(0.030 - 9.6) \times10^{-24}$. In addition, we outline a method to identify candidate pixel-frequency pairs that could be followed up by a more sensitive (and potentially computationally expensive) search, e.g., a matched-filtering-based analysis, to look for fainter nearly monochromatic coherent signals. The ASAF analysis is inherently independent of models describing any spectral or spatial distribution of power. We demonstrate that the ASAF results can be appropriately combined over frequencies and sky directions to successfully recover the broadband directional and isotropic results

All-sky search for continuous gravitational waves from isolated neutron stars in the early O3 LIGO data

We report on an all-sky search for continuous gravitational waves in the frequency band 20-2000 Hz and with a frequency time derivative in the range of [-1.0,+0.1]×10-8 Hz/s. Such a signal could be produced by a nearby, spinning and slightly nonaxisymmetric isolated neutron star in our Galaxy. This search uses the LIGO data from the first six months of Advanced LIGO's and Advanced Virgo's third observational run, O3. No periodic gravitational wave signals are observed, and 95% confidence-level (C.L.) frequentist upper limits are placed on their strengths. The lowest upper limits on worst-case (linearly polarized) strain amplitude h0 are ∼1.7×10-25 near 200 Hz. For a circularly polarized source (most favorable orientation), the lowest upper limits are ∼6.3×10-26. These strict frequentist upper limits refer to all sky locations and the entire range of frequency derivative values. For a population-averaged ensemble of sky locations and stellar orientations, the lowest 95% C.L. upper limits on the strain amplitude are ∼1.4×10-25. These upper limits improve upon our previously published all-sky results, with the greatest improvement (factor of ∼2) seen at higher frequencies, in part because quantum squeezing has dramatically improved the detector noise level relative to the second observational run, O2. These limits are the most constraining to date over most of the parameter space searched

The role of health literacy in explaining the association between educational attainment and the use of out-of-hours primary care services in chronically ill people: a survey study

Abstract Background Low socioeconomic status (SES) is persistently associated with poor health and suboptimal use of healthcare services, and more unplanned healthcare use. Suboptimal use of emergency and acute healthcare services may increase health inequalities, due to late diagnosis or lack of continuity of care. Given that health literacy has been associated with healthcare utilisation and with education attainment, we sought to explore whether health literacy is related to the use of out-of-hours (OOH) Primary Care Services (PCSs). Additionally, we aimed to study whether and to what extent health literacy accounts for some of the association between education and OOH PSC use. Methods A survey including measures of education attainment, health literacy (assessed by means of the Dutch version of the nine-dimension Health Literacy Questionnaire) and use of PCS was conducted among a sample of adults diagnosed with (any) somatic chronic condition in the Netherlands (response 76.3%, n = 1811). We conducted linear and logistic regression analyses to examine associations between education level and PCS use in the past year. We performed mediation analyses to assess whether the association between education and PCS use was (partly) explained by different aspects of health literacy. We adjusted the models for patient characteristics such as age and morbidity. Results Higher education attainment was associated with higher scores on the health literacy aspects Appraisal of health information, and Navigating the healthcare system. Additionally, appraisal and navigating the healthcare system partially accounted for educational differences in PCS use. Finally, higher appraisal of health information scores were associated with higher PCS utilisation. Conclusion Several aspects of health literacy were demonstrated to relate to PCS use, and partly accounted for educational differences herein. Accordingly, developing health literacy within individuals or communities may help to reduce inappropriate PCS use among people with low education

Search for gravitational waves associated with gamma-ray bursts detected by Fermi and Swift during the LIGO–Virgo run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC–2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate