Dopaminergic Regulation of Circadian Food Anticipatory Activity Rhythms in the Rat

Circadian activity rhythms are jointly controlled by a master pacemaker in the hypothalamic suprachiasmatic nuclei (SCN) and by food-entrainable circadian oscillators (FEOs) located elsewhere. The SCN mediates synchrony to daily light-dark cycles, whereas FEOs generate activity rhythms synchronized with regular daily mealtimes. The location of FEOs generating food anticipation rhythms, and the pathways that entrain these FEOs, remain to be clarified. To gain insight into entrainment pathways, we developed a protocol for measuring phase shifts of anticipatory activity rhythms in response to pharmacological probes. We used this protocol to examine a role for dopamine signaling in the timing of circadian food anticipation. To generate a stable food anticipation rhythm, rats were fed 3h/day beginning 6-h after lights-on or in constant light for at least 3 weeks. Rats then received the D2 agonist quinpirole (1 mg/kg IP) alone or after pretreatment with the dopamine synthesis inhibitor α-methylparatyrosine (AMPT). By comparison with vehicle injections, quinpirole administered 1-h before lights-off (19h before mealtime) induced a phase delay of activity onset prior to the next meal. Delay shifts were larger in rats pretreated with AMPT, and smaller following quinpirole administered 4-h after lights-on. A significant shift was not observed in response to the D1 agonist SKF81297. These results provide evidence that signaling at D2 receptors is involved in phase control of FEOs responsible for circadian food anticipatory rhythms in rats

Sleep Timing and Duration in Indigenous Villages with and Without Electric Lighting on Tanna Island, Vanuatu

It has been hypothesized that sleep in the industrialized world is in chronic deficit, due in part to evening light exposure, which delays sleep onset and truncates sleep depending on morning work or school schedules. If so, societies without electricity may sleep longer. However, recent studies of hunter-gatherers and pastoralists living traditional lifestyles without electricity report short sleep compared to industrialized population norms. To further explore the impact of lifestyles and electrification on sleep, we measured sleep by actigraphy in indigenous Melanesians on Tanna Island, Vanuatu, who live traditional subsistence horticultural lifestyles, in villages either with or without access to electricity. Sleep duration was long and efficiency low in both groups, compared to averages from actigraphy studies of industrialized populations. In villages with electricity, light exposure after sunset was increased, sleep onset was delayed, and nocturnal sleep duration was reduced. These effects were driven primarily by breastfeeding mothers living with electric lighting. Relatively long sleep on Tanna may reflect advantages of an environment in which food access is reliable, climate benign, and predators and significant social conflict absent. Despite exposure to outdoor light throughout the day, an effect of artificial evening light was nonetheless detectable on sleep timing and duration

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

An introduction to InP-based generic integration technology

Photonic integrated circuits (PICs) are considered as the way to make photonic systems or subsystems cheap and ubiquitous. PICs still are several orders of magnitude more expensive than their microelectronic counterparts, which has restricted their application to a few niche markets. Recently, a novel approach in photonic integration is emerging which will reduce the R&D and prototyping costs and the throughput time of PICs by more than an order of magnitude. It will bring the application of PICs that integrate complex and advanced photonic functionality on a single chip within reach for a large number of small and larger companies and initiate a breakthrough in the application of Photonic ICs. The paper explains the concept of generic photonic integration technology using the technology developed by the COBRA research institute of TU Eindhoven as an example, and it describes the current status and prospects of generic InP-based integration technology

To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

BACKGROUND: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition-a finding that was not replicated in another recently published long-term study. METHODS/DESIGN: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years. DISCUSSION: The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse. TRIAL STATUS: Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026. TRIAL REGISTRATION: European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 J

Predictions for Ultra-Deep Radio Counts of Star-Forming Galaxies

We have worked out predictions for the radio counts of star-forming galaxies down to nJy levels, along with redshift distributions down to the detection limits of the phase 1 Square Kilometer Array MID telescope (SKA1-MID) and of its precursors. Such predictions were obtained by coupling epoch dependent star formation rate (SFR) functions with relations between SFR and radio (synchrotron and free-free) emission. The SFR functions were derived taking into account both the dust obscured and the unobscured star-formation, by combining far-infrared (FIR), ultra-violet (UV) and H_alpha luminosity functions up to high redshifts. We have also revisited the South Pole Telescope (SPT) counts of dusty galaxies at 95,GHz performing a detailed analysis of the Spectral Energy Distributions (SEDs). Our results show that the deepest SKA1-MID surveys will detect high-z galaxies with SFRs two orders of magnitude lower compared to Herschel surveys. The highest redshift tails of the distributions at the detection limits of planned SKA1-MID surveys comprise a substantial fraction of strongly lensed galaxies. We predict that a survey down to 0.25 microJy at 1.4 GHz will detect about 1200 strongly lensed galaxies per square degree, at redshifts of up to 10. For about 30% of them the SKA1-MID will detect at least 2 images. The SKA1-MID will thus provide a comprehensive view of the star formation history throughout the re-ionization epoch, unaffected by dust extinction. We have also provided specific predictions for the EMU/ASKAP and MIGHTEE/MeerKAT survey

Treatment Characteristics and Real-World Progression-Free Survival in Patients With Unresectable Stage III NSCLC Who Received Durvalumab After Chemoradiotherapy: Findings From the PACIFIC-R Study.

IntroductionThe phase 3 PACIFIC trial established consolidation therapy with durvalumab as standard of care for patients with unresectable, stage III NSCLC and no disease progression after definitive chemoradiotherapy (CRT). The observational PACIFIC-R study assesses the real-world effectiveness of durvalumab in patients from an early access program. Here, we report treatment characteristics and a preplanned analysis of real-world progression-free survival (rwPFS).MethodsPACIFIC-R (NCT03798535) is an ongoing, international, retrospective study of patients who started durvalumab (intravenously; 10 mg/kg every 2 wk) within an early access program between September 2017 and December 2018. The primary end points are investigator-assessed rwPFS and overall survival (analyzed by Kaplan-Meier method).ResultsAs of November 30, 2020, the full analysis set comprised 1399 patients from 11 countries (median follow-up duration, 23.5 mo). Patients received durvalumab for a median of 11.0 months. Median rwPFS was 21.7 months (95% confidence interval: 19.1-24.5). RwPFS was numerically longer among patients who received concurrent versus sequential CRT (median, 23.7 versus 19.3 mo) and among patients with programmed cell death-ligand 1 expression greater than or equal to 1% versus less than 1% (22.4 versus 15.6 mo). Overall, 16.5% of the patients had adverse events leading to treatment discontinuation; 9.5% of all patients discontinued because of pneumonitis or interstitial lung disease.ConclusionsConsolidation durvalumab after definitive CRT was well tolerated and effective in this large, real-world cohort study of patients with unresectable, stage III NSCLC. As expected, rwPFS was longer among patients who received concurrent versus sequential CRT and patients with higher programmed cell death-ligand 1 expression. Nevertheless, favorable rwPFS outcomes were observed regardless of these factors

HIV/HCV Co-infection: Pathogenesis, Clinical Complications, Treatment, and New Therapeutic Technologies

World-wide, hepatitis C virus (HCV) accounts for approximately 130 million chronic infections, with an overall 3% prevalence. Four to 5 million persons are co-infected with HIV. It is well established that HIV has a negative impact on the natural history of HCV, including a higher rate of viral persistence, increased viral load, and more rapid progression to fibrosis, end-stage liver disease, and death. Whether HCV has a negative impact on HIV disease progression continues to be debated. However, following the introduction of effective combination antiretroviral therapy, the survival of coinfected individuals has significantly improved and HCV-associated diseases have emerged as the most important co-morbidities. In this review, we summarize the newest studies regarding the pathogenesis of HIV/HCV coinfection, including effects of coinfection on HIV disease progression, HCV-associated liver disease, the immune system, kidney and cardiovascular disease, and neurologic status; and effectiveness of current anti-HIV and HCV therapies and proposed new treatment strategies

Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery

Virally suppressed HIV-positive individuals on combination antiretroviral therapy who do not achieve a CD4 count >200 cells/µL have substantially increased long-term mortality. The increased mortality was seen across different patient groups and for all causes of deat