New Determinations of the UV Luminosity Functions from z~9 to z~2 show a remarkable consistency with halo growth and a constant star formation efficiency

Here we provide the most comprehensive determinations of the rest-frame $UV$ LF available to date with HST at z~2, 3, 4, 5, 6, 7, 8, and 9. Essentially all of the non-cluster extragalactic legacy fields are utilized, including the Hubble Ultra Deep Field (HUDF), the Hubble Frontier Field parallel fields, and all five CANDELS fields, for a total survey area of 1136 arcmin^2. Our determinations include galaxies at z~2-3 leveraging the deep HDUV, UVUDF, and ERS WFC3/UVIS observations available over a ~150 arcmin^2 area in the GOODS North and GOODS South regions. All together, our collective samples include >24,000 sources, >2.3x larger than previous selections with HST. 5766, 6332, 7240, 3449, 1066, 601, 246, and 33 sources are identified at z~2, 3, 4, 5, 6, 7, 8, and 9, respectively. Combining our results with an earlier z~10 LF determination by Oesch+2018a, we quantify the evolution of the $UV$ LF. Our results indicate that there is (1) a smooth flattening of the faint-end slope alpha from alpha~-2.4 at z~10 to -1.5 at z~2, (2) minimal evolution in the characteristic luminosity M* at z>~2.5, and (3) a monotonic increase in the normalization log_10 phi* from z~10 to z~2, which can be well described by a simple second-order polynomial, consistent with an "accelerated" evolution scenario. We find that each of these trends (from z~10 to z~2.5 at least) can be readily explained on the basis of the evolution of the halo mass function and a simple constant star formation efficiency model.Comment: 18 pages, 10 figures, 5 tables, in submission to ApJ, figures 9 and 10 show the main resul

Anticholinergic medications in patients admitted with cognitive impairment or falls (AMiCI). The impact of hospital admission on anticholinergic cognitive medication burden. Results of a multicentre observational study

What is known and objectiveDrugs with anticholinergic properties increase the risk of falls, delirium, chronic cognitive impairment, and mortality and counteract procholinergic medications used in the treatment of dementia. Medication review and optimisation to reduce anticholinergic burden in patients at risk is recommended by specialist bodies. Little is known how effective this review is in patients who present acutely and how often drugs with anticholinergic properties are used temporarily during an admission. The aim of the study was to describe the changes in the anticholinergic cognitive burden (ACB) in patients admitted to hospital with a diagnosis of delirium, chronic cognitive impairment or falls and to look at the temporary use of anticholinergic medications during hospital stay. MethodsThis is a multi-centre observational study that was conducted in seven different hospitals in the UK, Finland, The Netherlands and Italy. Results and discussion21.1% of patients had their ACB score reduced by a mean of 1.7%, 19.7% had their ACB increased by a mean of 1.6%, 22.8% of DAP naive patients were discharged on anticholinergic medications. There was no change in the ACB scores in 59.2% of patients. 54.1% of patients on procholinergics were taking anticholinergics. Out of the 98 medications on the ACB scale, only 56 were seen. Medications with a low individual burden were accounting for 64.9% of the total burden. Anticholinergic drugs were used temporarily during the admission in 21.9% of all patients. A higher number of DAPs used temporarily during admission was associated with a higher risk of ACB score increase on discharge (OR=1.82, 95% CI for OR: 1.36-2.45, P What is new and conclusionThere was no reduction in anticholinergic cognitive burden during the acute admissions. This was the same for all diagnostic subgroups. The anticholinergic load was predominantly caused by medications with a low individual burden. More than 1 in 5 patients not taking anticholinergics on admission were discharged on them and similar numbers saw temporary use of these medications during their admission. More than half of patients on cholinesterase-inhibitors were taking anticholinergics at the same time on admission, potentially directly counteracting their effects.Peer reviewe

Enantioselective metabolism of primaquine by human CYP2D6

BACKGROUND: Primaquine, currently the only approved drug for the treatment and radical cure of Plasmodium vivax malaria, is still used as a racemic mixture. Clinical use of primaquine has been limited due to haemolytic toxicity in individuals with genetic deficiency in glucose-6-phosphate dehydrogenase. Earlier studies have linked its therapeutic effects to CYP2D6-generated metabolites. The aim of the current study was to investigate the differential generation of the CYP2D6 metabolites by racemic primaquine and its individual enantiomers. METHODS: Stable isotope (13)C-labelled primaquine and its two enantiomers were incubated with recombinant cytochrome-P450 supersomes containing CYP2D6 under optimized conditions. Metabolite identification and time-point quantitative analysis were performed using LC-MS/MS. UHPLC retention time, twin peaks with a mass difference of 6, MS-MS fragmentation pattern, and relative peak area with respect to parent compound were used for phenotyping and quantitative analysis of metabolites. RESULTS: The rate of metabolism of (+)-(S)-primaquine was significantly higher (50% depletion of 20 μM in 120 min) compared to (−)-(R)-primaquine (30% depletion) when incubated with CYP2D6. The estimated V(max) (μmol/min/mg) were 0.75, 0.98 and 0.42, with K(m) (μM) of 24.2, 33.1 and 21.6 for (±)-primaquine, (+)-primaquine and (−)-primaquine, respectively. Three stable mono-hydroxylated metabolites, namely, 2-, 3- and 4-hydroxyprimaquine (2-OH-PQ, 3-OH-PQ, and 4-OH-PQ), were identified and quantified. 2-OH-PQ was preferentially formed from (+)-primaquine in a ratio of 4:1 compared to (−)-primaquine. The racemic (±)-primaquine showed a pattern similar to the (−)-primaquine; 2-OH-PQ accounted for about 15–17% of total CYP2D6-mediated conversion of (+)-primaquine. In contrast, 4-OH-PQ was preferentially formed with (−)-primaquine (5:1), accounting for 22% of the total (−)-primaquine conversion. 3-OH-PQ was generated from both enantiomers and racemate. 5-hydroxyprimaquine was unstable. Its orthoquinone degradation product (twice as abundant in (+)-primaquine compared to (−)-primaquine) was identified and accounted for 18–20% of the CYP2D6-mediated conversion of (+)-primaquine. Other minor metabolites included dihydroxyprimaquine species, two quinone-imine products of dihydroxylated primaquine, and a primaquine terminal alcohol with variable generation from the individual enantiomers. CONCLUSION: The metabolism of primaquine by human CYP2D6 and the generation of its metabolites display enantio-selectivity regarding formation of hydroxylated product profiles. This may partly explain differential pharmacologic and toxicologic properties of primaquine enantiomers

Chaotic systems in complex phase space

This paper examines numerically the complex classical trajectories of the kicked rotor and the double pendulum. Both of these systems exhibit a transition to chaos, and this feature is studied in complex phase space. Additionally, it is shown that the short-time and long-time behaviors of these two PT-symmetric dynamical models in complex phase space exhibit strong qualitative similarities.Comment: 22 page, 16 figure

Differential kinetic profiles and metabolism of primaquine enantiomers by human hepatocytes

BACKGROUND: The clinical utility of primaquine (PQ), used as a racemic mixture of two enantiomers, is limited due to metabolism-linked hemolytic toxicity in individuals with genetic deficiency in glucose-6-phosphate dehydrogenase. The current study investigated differential metabolism of PQ enantiomers in light of the suggestions that toxicity and efficacy might be largely enantioselective. METHODS: Stable isotope (13)C-labelled primaquine and its two enantiomers (+)-PQ, (−)-PQ were separately incubated with cryopreserved human hepatocytes. Time-tracked substrate depletion and metabolite production were monitored via UHPLC–MS/MS. RESULTS: The initial half-life of 217 and 65 min; elimination rate constants (λ) of 0.19 and 0.64 h(−1); intrinsic clearance (Cl(int)) of 2.55 and 8.49 (µL/min)/million cells, which when up-scaled yielded Cl(int) of 6.49 and 21.6 (mL/min)/kg body mass was obtained respectively for (+)- and (−)-PQ. The extrapolation of in vitro intrinsic clearance to in vivo human hepatic blood clearance, performed using the well-stirred liver model, showed that the rate of hepatic clearance of (+)-PQ was only 45 % that of (−)-PQ. Two major primary routes of metabolism were observed—oxidative deamination of the terminal amine and hydroxylations on the quinoline moiety of PQ. The major deaminated metabolite, carboxyprimaquine (CPQ) was preferentially generated from the (−)-PQ. Other deaminated metabolites including PQ terminal alcohol (m/z 261), a cyclized side chain derivative from the aldehyde (m/z 241), cyclized carboxylic acid derivative (m/z 257), a quinone-imine product of hydroxylated CPQ (m/z 289), CPQ glucuronide (m/z 451) and the glucuronide of PQ alcohol (m/z 437) were all preferentially generated from the (−)-PQ. The major quinoline oxidation product (m/z 274) was preferentially generated from (+)-PQ. In addition to the products of the two metabolic pathways, two other major metabolites were observed: a prominent glycosylated conjugate of PQ on the terminal amine (m/z 422), peaking by 30 min and preferentially generated by (+)-PQ; and the carbamoyl glucuronide of PQ (m/z 480) exclusively generated from (+)-PQ. CONCLUSION: Metabolism of PQ showed enantioselectivity. These findings may provide important information in establishing clinical differences in PQ enantiomers

Physical Aspects of Pseudo-Hermitian and PTPT-Symmetric Quantum Mechanics

For a non-Hermitian Hamiltonian H possessing a real spectrum, we introduce a canonical orthonormal basis in which a previously introduced unitary mapping of H to a Hermitian Hamiltonian h takes a simple form. We use this basis to construct the observables O of the quantum mechanics based on H. In particular, we introduce pseudo-Hermitian position and momentum operators and a pseudo-Hermitian quantization scheme that relates the latter to the ordinary classical position and momentum observables. These allow us to address the problem of determining the conserved probability density and the underlying classical system for pseudo-Hermitian and in particular PT-symmetric quantum systems. As a concrete example we construct the Hermitian Hamiltonian h, the physical observables O, the localized states, and the conserved probability density for the non-Hermitian PT-symmetric square well. We achieve this by employing an appropriate perturbation scheme. For this system, we conduct a comprehensive study of both the kinematical and dynamical effects of the non-Hermiticity of the Hamiltonian on various physical quantities. In particular, we show that these effects are quantum mechanical in nature and diminish in the classical limit. Our results provide an objective assessment of the physical aspects of PT-symmetric quantum mechanics and clarify its relationship with both the conventional quantum mechanics and the classical mechanics.Comment: 45 pages, 13 figures, 2 table

The ALMA REBELS survey: obscured star formation in massive Lyman-break galaxies at z = 4-8 revealed by the IRX-β\beta and M⋆M_{\star} relations

We investigate the degree of dust obscured star formation in 49 massive (${\rm log}_{10}(M_{\star}/{\rm M}_{\odot})>9$) Lyman-break galaxies (LBGs) at $z = 6.5$-$8$ observed as part of the ALMA Reionization Era Bright Emission Line Survey (REBELS) large program. By creating deep stacks of the photometric data and the REBELS ALMA measurements we determine the average rest-frame UV, optical and far-infrared (FIR) properties which reveal a significant fraction ($f_{\rm obs} = 0.4$-$0.7$) of obscured star formation, consistent with previous studies. From measurements of the rest-frame UV slope, we find that the brightest LBGs at these redshifts show bluer ($\beta \simeq -2.2$) colours than expected from an extrapolation of the colour-magnitude relation found at fainter magnitudes. Assuming a modified blackbody spectral-energy distribution (SED) in the FIR (with dust temperature of $T_{\rm d} = 46\,{\rm K}$ and $\beta_{\rm d} = 2.0$), we find that the REBELS sources are in agreement with the local ''Calzetti-like'' starburst Infrared-excess (IRX)-$\beta$ relation. By reanalysing the data available for 108 galaxies at $z \simeq 4$-$6$ from the ALPINE ALMA large program using a consistent methodology and assumed FIR SED, we show that from $z \simeq 4$-$8$, massive galaxies selected in the rest-frame UV have no appreciable evolution in their derived IRX-$\beta$ relation. When comparing the IRX-$M_{\star}$ relation derived from the combined ALPINE and REBELS sample to relations established at $z < 4$, we find a deficit in the IRX, indicating that at $z > 4$ the proportion of obscured star formation is lower by a factor of $\gtrsim 3$ at a given a $M_{\star}$. Our IRX-$\beta$ results are in good agreement with the high-redshift predictions of simulations and semi-analytic models for $z \simeq 7$ galaxies with similar stellar masses and SFRs.Comment: 18 pages, 10 figures, 2 tables (plus 1 figure and 2 tables in the appendix). Updated to match MNRAS accepted version after minor correction

Reionization Era Bright Emission Line Survey: selection and characterization of luminous interstellar medium reservoirs in the z > 6.5 universe

The Reionization Era Bright Emission Line Survey (REBELS) is a cycle-7 ALMA Large Program (LP) that is identifying and performing a first characterization of many of the most luminous star-forming galaxies known in the z &gt; 6.5 universe. REBELS is providing this probe by systematically scanning 40 of the brightest UV-selected galaxies identified over a 7 deg2 area for bright [C ii]158 μm and [O iii]88 μm lines and dust-continuum emission. Selection of the 40 REBELS targets was done by combining our own and other photometric selections, each of which is subject to extensive vetting using three completely independent sets of photometry and template-fitting codes. Building on the observational strategy deployed in two pilot programs, we are increasing the number of massive interstellar medium (ISM) reservoirs known at z &gt; 6.5 by ∼4-5× to &gt;30. In this manuscript, we motivate the observational strategy deployed in the REBELS program and present initial results. Based on the first-year observations, 18 highly significant ≥ 7σ [C ii]158 μm lines have already been discovered, the bulk of which (13/18) also show ≥3.3σ dust-continuum emission. These newly discovered lines more than triple the number of bright ISM-cooling lines known in the z &gt; 6.5 universe, such that the number of ALMA-derived redshifts at z &gt; 6.5 rival Lyα discoveries. An analysis of the completeness of our search results versus star formation rate (SFR) suggests an ∼79% efficiency in scanning for [C ii]158 μm when the SFRUV+IR is &gt;28 M yr-1. These new LP results further demonstrate ALMA's efficiency as a "redshift machine,"particularly in the Epoch of Reionization

Normal, dust-obscured galaxies in the epoch of reionization

Two serendipitously detected dust-obscured galaxies are reported at z = 6.7 and 7.4, with estimates that such galaxies provide an additional 10-25% contribution to the total star formation rate density at z &gt; 6.Over the past decades, rest-frame ultraviolet (UV) observations have provided large samples of UV luminous galaxies at redshift (z) greater than 6 (refs. (1-3)), during the so-called epoch of reionization. While a few of these UV-identified galaxies revealed substantial dust reservoirs(4-7), very heavily dust-obscured sources at these early times have remained elusive. They are limited to a rare population of extreme starburst galaxies(8-12) and companions of rare quasars(13,14). These studies conclude that the contribution of dust-obscured galaxies to the cosmic star formation rate density at z &gt; 6 is sub-dominant. Recent ALMA and Spitzer observations have identified a more abundant, less extreme population of obscured galaxies at z = 3-6 (refs. (15,16)). However, this population has not been confirmed in the reionization epoch so far. Here, we report the discovery of two dust-obscured star-forming galaxies at z = 6.6813 +/- 0.0005 and z = 7.3521 +/- 0.0005. These objects are not detected in existing rest-frame UV data and were discovered only through their far-infrared [C ii] lines and dust continuum emission as companions to typical UV-luminous galaxies at the same redshift. The two galaxies exhibit lower infrared luminosities and star-formation rates than extreme starbursts, in line with typical star-forming galaxies at z approximate to 7. This population of heavily dust-obscured galaxies appears to contribute 10-25% to the z &gt; 6 cosmic star formation rate density