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We present 30 optical spectra and 49 photometric epochs sampling the first 517 days after discovery of supernova (SN) 1999em and derive its distance through the expanding photosphere method (EPM). SN 1999em is shown to be a Type II-plateau (II-P) event, with a photometric plateau lasting until about 100 days after explosion. We identify the dominant ions responsible for most of the absorption features seen in the optical portion of the spectrum during the plateau phase. Using the weakest unblended absorption features to estimate photospheric velocity, we find the distance to SN 1999em to be D = 8.2 ± 0.6 Mpc, with an explosion date of HJD 2,451,475.6 ± 1.4, or 5.3 ± 1.4 days before discovery. We show that this distance estimate is about 10% closer than the distance that results if the strong Fe II λλ4924, 5018, 5169 absorption features, which have often been used in previous EPM studies, are used to estimate photospheric velocity. We examine potential sources of systematic error in EPM-derived distances and find the most significant to result from uncertainty in the theoretical modeling of the flux distribution emitted by the SN photosphere (i.e., the "flux dilution factor"). We compare previously derived EPM distances to eight SNe II in galaxies (or members of the same group) for which a recently revised Cepheid distance exists from the Hubble Space Telescope Key Project and find DCepheids/DEPM = 0.87 ± 0.06 (statistical); eliminating the three SNe II distances for which a Cepheid distance exists only to a group member, and not the host galaxy itself, yields DCepheids/DEPM = 0.96 ± 0.09. Additional direct comparisons, especially to spectroscopically and photometrically normal SNe II-P, will certainly help to produce a more robust comparison. Finally, we investigate the possible use of SNe II-P as standard candles and find that for eight photometrically confirmed SNe II-P with previously derived EPM distances and SN 1999em, the mean plateau absolute brightness is M̄v(plateau) = -16.4 ± 0.6 mag, implying that distances good to ∼30% (1 σ) may be possible without the need for a complete EPM analysis. At M̄v(plateau) = -15.9 ± 0.2 mag, SN 1999em is somewhat fainter than the average SN II-P. The general consistency of absolute SNe II-P brightness during the plateau suggests that the standard candle assumption may allow SNe II-P to be viable cosmological beacons at Z > 2.

Fan Zhang,1 Tianmei Si,2,3 Chiun-Fang Chiou,4 Anthony WF Harris,5 Chang Yoon Kim,6 Padmashree Jahagirdar,7 Steve Ascher8 1Xian Janssen Pharmaceuticals, Beijing, People’s Republic of China; 2Department of Clinical Psychopharmacology, Peking University Institute of Mental Health, Beijing, People’s Republic of China; 3Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, People’s Republic of China; 4Janssen Asia-Pacific, Singapore; 5Discipline of Psychiatry, Sydney Medical School, University of Sydney, Australia and Brian Dynamics Center, Westmead Millennium Institute for Medical Research, Westmead, NSW, Australia; 6Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 7Theorem Clinical Research, Bangalore, India; 8Janssen Research and Development, LLC, Titusville, NJ, USA Objective: To evaluate the efficacy, safety, and impact on hospitalizations of long-acting injectable paliperidone palmitate (PP) treatment, in patients with recent-onset schizophrenia who had not responded satisfactorily to oral antipsychotics.Methods: In this 18-month, open-label, Phase-IIIb study from Asia-Pacific region, patients (18–50 years) with recent-onset (≤5 years) schizophrenia unsatisfactorily treated with previous oral antipsychotics were initiated on PP 150 mg eq on day 1, 100 mg eq on day 8, followed by flexible once monthly maintenance doses of 50–150 mg eq. The number and duration of hospitalizations were compared using a mirror analysis method between two periods: retrospective (12 months before PP initiation) and prospective (12 and 18 months after PP treatment) periods.Results: A total of 303 out of 521 (58%) patients (mean age, 28.7 years; 65.5% men, 92.5% Asian) completed the study. Positive and Negative Syndrome Scale (PANSS) total score improved significantly from baseline to month 18 (mean [standard deviation, SD] change: -11.3 [21.38], P

The traditional view of hematopoiesis is that myeloid cells derive from a common myeloid progenitor (CMP), whereas all lymphoid cell populations, including B, T, and natural killer (NK) cells and possibly plasmacytoid dendritic cells (pDCs), arise from a common lymphoid progenitor (CLP). In Max41 transgenic mice, nearly all B cells seem to be diverted into the granulocyte lineage. Here, we show that these mice have an excess of myeloid progenitors, but their CLP compartment is ablated, and they have few pDCs. Nevertheless, T cell and NK cell development proceeds relatively normally. These hematopoietic abnormalities result from aberrant expression of Gata6 due to serendipitous insertion of the transgene enhancer (Eμ) in its proximity. Gata6 mis-expression in Max41 transgenic progenitors promoted the gene-regulatory networks that drive myelopoiesis through increasing expression of key transcription factors, including PU.1 and C/EBPa. Thus, mis-expression of a single key regulator like GATA6 can dramatically re-program multiple aspects of hematopoiesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Prior studies of aortic valve replacement (AVR) in patients with normal-flow, low-gradient aortic stenosis (NF-LG AS) have demonstrated conflicting results regarding the survival benefit of AVR. Changes in quality of life (QoL) after transcatheter AVR (TAVR) have not been reported in this population., Objectives: The purpose of this study was to compare changes in QoL after TAVR for patients with NF-LG AS to patients with high-gradient aortic stenosis (HG-AS)., Methods: Patients who underwent TAVR for severe aortic stenosis (AS) were divided into 4 hemodynamic profiles of AS, including NF-LG AS. Changes in Kansas City Cardiomyopathy Questionnaire-12 score from baseline to 1 year were compared between AS groups. The primary composite outcome indicating clinical improvement consisted of survival to 1 year and improved Kansas City Cardiomyopathy Questionnaire overall summary score of ≥5 points while adjusting for relevant baseline factors., Results: Out of 860 patients who underwent TAVR, high gradient AS was present in 368 (42.8%) patients and NF-LG AS in 245 (28.5%). HG-AS and NF-LG AS groups had a similar proportion of patients who met the primary unadjusted outcome of clinical improvement (70.4% vs 63.9%, respectively; P = 0.189). One-year Kaplan-Meier mortality estimates were higher for NF-LG AS patients than HG-AS patients (12.9% vs 5.8%, P  < 0.001). In the primary adjusted analysis, there was no significant difference in the composite outcome between HG and NF-LG AS groups (adjusted OR: 0.72, 95% CI: 0.47-1.11)., Conclusions: Selected patients with NF-LG AS experienced similar improvement in QoL after TAVR compared with HG-AS. Further investigation of patients with NF-LG AS will help to inform optimal selection for treatment with TAVR., Competing Interests: Dr Fukuhara is a consultant for Terumo Aortic. Dr Chetcuti has received grant support and sponsorship from 10.13039/100006520Edwards Lifesciences, 10.13039/100008497Boston Scientific, and 10.13039/100004374Medtronic has received research sponsorship from St. Jude Medical; and has received proctoring fees from and served as a consultant for Medtronic. Dr Grossman has received grant support from 10.13039/100006520Edwards Lifesciences, 10.13039/100008497Boston Scientific, and 10.13039/100004374Medtronic; and has received proctoring fees from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Speculation exists as to whether lisdexamfetamine dimesylate (LDX) acts on the functional connectivity (FC) of brain networks that modulate appetite, reward, or inhibitory control in binge-eating disorder (BED). Better insights into its action may help guide the development of more targeted therapeutics and identify who will benefit most from this medication. Here, we use a comprehensive data-driven approach to investigate the brain FC changes that underlie the therapeutic action of LDX in patients with BED., Methods: Forty-six participants with moderate to severe BED received LDX titrated to 50 or 70 mg for an 8-week period. Twenty age-matched healthy control participants were also recruited. Resting-state functional magnetic resonance imaging was used to probe changes in brain FC pre- and post treatment and correlated with change in clinical measures., Results: Ninety-seven percent of trial completers ( n  = 31) experienced remission or a reduction to mild BED during the 8-week LDX trial. Widespread neural FC changes occurred, with changes in default mode to limbic, executive control to subcortical, and default mode to executive control networks associated with improvements in clinical outcomes. These connections were not distinct from control participants at pretreatment but were different from control participants following LDX treatment. Pretreatment connectivity did not predict treatment response., Conclusions: FC between networks associated with self-referential processing, executive function, and reward seem to underlie the therapeutic effect of LDX in BED. This suggests that LDX activates change via multiple systems, with most changes in compensatory networks rather than in those characterizing the BED diagnosis., (© 2023 The Authors.)

Proximal spinal muscular atrophy (SMA) is a leading genetic cause for infant death in the world and results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of SMN protein and small molecules that can increase SMN expression are of considerable interest as potential therapeutics. Previous studies have shown that both 4-phenylbutyrate (4PBA) and trichostatin A (TSA) increase SMN expression in dermal fibroblasts derived from SMA patients. AR42 is a 4PBA-tethered TSA derivative that is a very potent histone deacetylase inhibitor. SMA patient fibroblasts were treated with either AR42, AR19 (a related analogue), 4PBA, TSA or vehicle for 5 days and then immunostained for SMN localization. AR42 as well as 4PBA and TSA increased the number of SMN-positive nuclear gems in a dose-dependent manner while AR19 did not show marked changes in gem numbers. While gem number was increased in AR42-treated SMA fibroblasts, there were no significant changes in FL-SMN mRNA or SMN protein. The neuroprotective effect of this compound was then assessed in SMNΔ7 SMA (SMN2 +/+ ;SMNΔ7 +/+ ;mSmn -/- ) mice. Oral administration of AR42 prior to disease onset increased the average lifespan of SMNΔ7 SMA mice by ~ 27% (20.1 ± 1.6 days for AR42-treated mice vs. 15.8 ± 0.4 days for vehicle-treated mice). AR42 treatment also improved motor function in these mice. AR42 treatment inhibited histone deacetylase (HDAC) activity in treated spinal cord although it did not affect SMN protein expression in these mice. AKT and GSK3β phosphorylation were both significantly increased in SMNΔ7 SMA mouse spinal cords. In conclusion, presymptomatic administration of the HDAC inhibitor AR42 ameliorates the disease phenotype in SMNΔ7 SMA mice in a SMN-independent manner possibly by increasing AKT neuroprotective signaling., (© 2023. The Author(s).)

COVID-19 has significant case fatality. Glucocorticoids are the only treatment shown to improve survival, but only among patients requiring supplemental oxygen. WHO advises patients to seek medical care for "trouble breathing," but hypoxemic patients frequently have no respiratory symptoms. Our cohort study of hospitalized COVID-19 patients shows that respiratory symptoms are uncommon and not associated with mortality. By contrast, objective signs of respiratory compromise-oxygen saturation and respiratory rate-are associated with markedly elevated mortality. Our findings support expanding guidelines to include at-home assessment of oxygen saturation and respiratory rate in order to expedite life-saving treatments patients to high-risk COVID-19 patients., (© 2021 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

In this work we report the effect of incorporating conducting oligophenylenes and a cobaltocene-based redox mediator on photodriven electron transfer between thioglycolic acid (TGA) capped CdS nanorods (NR) and the native nitrogenase MoFe protein (MoFeP) by following the reduction of H + to H 2 . First, we demonstrate that the addition of benzidine-a conductive diphenylene- to TGA-CdS and MoFeP increased catalytic activity by up to 3-fold as compared to CdS-MoFeP alone. In addition, in comparing the use of oligophenylenes composed of one ( p -phenylenediamine), two (benzidine) or three (4,4''-diamino- p -terphenyl)phenylene groups, the largest gain in H 2 was observed with the addition of benzidine and the lowest with phenylenediamine. As a comparison to the conductive oligophenylenes, a cobaltocene-based redox mediator was also tested with the TGA-CdS NRs and MoFeP. However, adding either cobaltocene diacid or diamine caused negligible gains in H 2 production and at higher concentrations, caused a significant decrease. Agarose gel electrophoresis revealed little to no detectable interaction between benzidine and TGA-CdS but strong binding between cobaltocene and TGA-CdS. These results suggest that the tight binding of the cobaltocene mediator to CdS may hinder electron transfer between CdS and MoFe and cause the mediator to undergo continuous reduction/oxidation events at the surface of CdS., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: There is accumulating evidence that adjunctive treatment with N -acetylcysteine may be effective for schizophrenia. This study aimed to conduct a comprehensive meta-analysis examining the efficacy of randomised control trials investigating N -acetylcysteine as an adjunct treatment for schizophrenia and the first to investigate cognition as an outcome., Methods: We systematically reviewed Medline, EmCare, PsycINFO, Embase, CINAHL Complete, China Knowledge Resource Integrated Database and the Cochrane Clinical Trials online registry for randomised control trials of N -acetylcysteine for schizophrenia. We undertook pairwise meta-analyses of N -acetylcysteine vs placebo for psychosis symptoms and cognition., Results: Seven studies, including n = 220 receiving N -acetylcysteine and n = 220 receiving placebo, met inclusion criteria for the pairwise meta-analyses. Positive and Negative Syndrome Scale negative and total scores were significantly improved in the N -acetylcysteine group after 24 weeks of treatment. The cognitive domain of working memory improved with N -acetylcysteine supplementation., Conclusion: Evidence supports the notion that N -acetylcysteine may be a useful adjunct to standard treatment for the improvement of schizophrenia symptoms, as well as the cognitive domain of working memory. Treatment effects were observed at the later time point (⩾24 weeks), suggesting that longer interventions are required for the success of N -acetylcysteine treatment.

We illustrate how intermolecular interactions facilitate ATP-free electron transfer between either native or engineered MoFe protein (MoFeP) from nitrogenase and a CdS nanorod (NR) by following the reduction of H + to H 2 . First, by varying the charge on the surface of the NR, we show the role of electrostatic interactions on MoFeP binding to the particle surface and subsequent H + reduction. Next, the role of strong, semicovalent thiol-CdS interactions was tested using free cysteines on the MoFeP. By blocking free cysteines, we show that the presence of free thiols on the protein has little to no influence on CdS binding and resultant photocatalytic activity. We next studied methods to covalently bind the protein to CdS by modifying the free cysteines with dibenzocyclooctyne (DBCO) and reacting the CdS NRs capped with a mixture of negatively charged thioglycolic acid and thiol-PEG3-azide ligands. As compared to that of the unmodified proteins, a 32.2 ± 1.5% and 61.7 ± 2.1% increase in H 2 production was observed from MoFeP and C-MoFeP, respectively. At last, to test the effect of both charge and covalent tethering, positively charged cysteamine/azide CdS NRs were reacted with DBCO-modified C-MoFeP, which showed little improvement over native C-MoFeP alone under irradiation. These results show the importance of both electrostatic associations between the NR and protein and covalently tethering the protein to the semiconductor surface for enhanced electron transfer and photodriven activity.

Current guidelines for management of adults with aortic stenosis recommend aortic valve replacement for patients with clinical consequences due to hemodynamically severe valve obstruction. However, advances in surgical and transcatheter techniques, and improved valve design have led to decreased procedural risk and improved long-term outcomes. Transcatheter aortic valve replacement (TAVR) is recommended for patients with prohibitive surgical risk and is reasonable in intermediate and high-risk patients. Recent trials demonstrated favorable short-term outcomes in patients with low surgical risk undergoing TAVR compared with surgical AVR. We review the current Guidelines recommendations and highlight key controversies in management due to evidence gaps., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Major depressive disorder commonly co-occurs with one or more anxiety disorders or with clinically significant levels of anxiety symptoms. Although evidence suggests that anxious forms of depression are prognostic of poorer antidepressant outcomes, there is no clear definition of anxious depression, and inferences about clinical outcomes are thus limited. Our objective was to compare and evaluate definitions of anxious depression and anxiety-related scales according to clinical and antidepressant outcome criteria., Method: A total of 1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic, major depressive disorder were assessed at baseline on clinical features. Participants were then randomised to one of three antidepressants and reassessed at 8 weeks regarding remission and response of the 17-item Hamilton Rating Scale Depression (HRSD 17 ) and the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR 16 ). Anxious depression was defined as major depressive disorder with one or more anxiety disorders or major depressive disorder with a HRSD 17 anxiety/somatisation factor score ⩾7. Anxiety-related scales included the HRSD 17 anxiety/somatisation factor and the 42-item Depression Anxiety Stress Scales (DASS 42 ) anxiety and stress subscales., Results: Anxious depression definitions showed poor agreement (κ = 0.15) and the HRSD 17 anxiety/somatisation factor was weakly correlated with both DASS 42 anxiety ( r  = 0.24) and stress subscales ( r  = 0.20). Anxious depression definitions were also associated with few impairments on clinical features and did not predict poorer antidepressant treatment outcome. However, higher DASS 42 anxiety predicted poorer HRSD 17 and QIDS-SR 16 remission, and item-level analysis found higher scores on items 9 (situational anxiety) and 23 (somatic anxiety) of the DASS 42 predicted poorer treatment outcome, even after adjusting for covariates and multiple comparisons., Conclusion: Common definitions of anxious depression show poor agreement and do not predict poorer treatment outcome. Anxiety symptoms may be better characterised dimensionally using DASS 42 when predicting treatment outcome.

We present lists of asteroid photometry opportunities for objects reaching a favorable apparition and have no or poorly-defined lightcurve parameters. Additional data on these objects will help with shape and spin axis modeling via lightcurve inversion. We also include lists of objects that will or might be radar targets. Lightcurves for these objects can help constrain pole solutions and/or remove rotation period ambiguities that might not come from using radar data alone.

Achieving global sustainability will require balancing encroaching climate changes while maintaining existing quality of life. Using sunlight to purify wastewater while simultaneously generating usable fuels is an opportunity to approach both targets in a cost-efficient manner. In addition, converting biomass products to usable polymers is a sustainable approach for potentially replacing polystyrene or other petroleum derived polymers. Phenols from medical, manufacturing, and agricultural waste are commonly found in many water sources, and they are known to foul common reverse osmosis membranes. Here, we show oxidative polymerization of guaiacol, an aromatic compound derived from biomass, with concurrent hydrogen gas generation by using platinum-seeded cadmium sulfide nanorods (Pt@CdS) as photocatalysts. Rather than forming short oligomers as typically made by enzymes such as laccase and peroxidase, the resulting polymers show higher molecular weights that can more easily flocculate out of water. By comparing guaiacol conversion to molecular weight and dispersity, the guaiacol was found to polymerize via a chain-growth process. We also show that Pt@CdS can polymerize other phenols as well by testing the monomers phenol, 2,6-dihydroxybenzoic acid, gallic acid, and vanillin. Lastly, because the aqueous solubility of these aromatic polymers decreases dramatically with molecular weight, polymerization reactions were also tested in biphasic solutions to determine if chain growth could propagate in the oil phase. We show that the Pt@CdS nanoparticles can form stable Pickering emulsions in various biphasic combinations, and that both H 2 formation and polymer molecular weight correlated with the partition coefficient of guaiacol into the oil phase as well as the solubility of the growing polymer chains. These combined studies demonstrate the possibility of using nanoscale photocatalysts to oxidatively polymerize phenolic substrates via a chain-growth mechanism, thereby providing a path for pretreating water by flocculating out contaminants with concurrent generation of hydrogen.

The simultaneous delivery of multiple therapeutics to a single site has shown promise for cancer targeting and treatment. However, because of the inherent differences in charge and size between drugs and biomolecules, new approaches are required for colocalization of unlike components in one delivery vehicle. In this work, we demonstrate that triblock copolymers containing click nucleic acids (CNAs) can be used to simultaneously load a prodrug enzyme (cytosine deaminase, CodA) and a chemotherapy drug (doxorubicin, DOX) in a single polymer nanoparticle. CNAs are synthetic analogs of DNA comprised of a thiolene backbone and nucleotide bases that can hybridize to complementary strands of DNA. In this study, CodA was appended with complementary DNA sequences and fluorescent dyes to allow its encapsulation in PEG-CNA-PLGA nanoparticles. The DNA-modified CodA was found to retain its enzyme activity for converting prodrug 5-fluorocytosine (5-FC) to active 5-fluorouracil (5-FU) using a modified fluorescent assay. The DNA-conjugated CodA was then loaded into the PEG-CNA-PLGA nanoparticles and tested for cell cytotoxicity in the presence of the 5-FC prodrug. To study the effect of coloading DOX and CodA within a single nanoparticle, cell toxicity assays were run to compare dually loaded nanoparticles with nanoparticles loaded only with either DOX or CodA. We show that the highest level of cell death occurred when both DOX and CodA were simultaneously entrapped and delivered to cells in the presence of 5-FC.

We present lists of asteroid photometry opportunities for objects reaching a favorable apparition and have no or poorly-defined lightcurve parameters. Additional data on these objects will help with shape and spin axis modeling via lightcurve inversion. We also include lists of objects that will or might be radar targets. Lightcurves for these objects can help constrain pole solutions and/or remove rotation period ambiguities that might not come from using radar data alone.

In July 2015, a cluster of five suspect cases of clinically diagnosed Mycobacterium marinum (M. marinum) skin infections were reported to the Haliburton, Kawartha, Pine Ridge District Health Unit (HKPRDHU), Ontario, Canada, with two additional cases subsequently identified through case finding. All seven cases presented with cutaneous lesions located on the finger, hand and/or elbow regions typical of M. marinum infection. Specimens were collected by skin biopsy for two of the seven cases; both cases tested positive for M. marinum by molecular detection (hsp65 gene amplification and sequencing), and one was confirmed positive for M. marinum by culture. All seven cases reported handling raw shrimp from an aquaculture facility in the Health Unit's jurisdiction. M. marinum is not a reportable disease in Ontario, and there are no known previous reports of a cluster of M. marinum reported in Ontario, Canada. A cluster investigation working group was struck that included representation from various agencies including Public Health Ontario (PHO), Public Health Ontario Laboratories (PHOL), Ontario Ministry of Agriculture and Rural Affairs (OMAFRA) and the two health units involved in case investigations. Several public health and aquaculture farming recommendations were made to mitigate further risks associated with handling of raw shrimp from the facility. Several challenges were faced during the investigation process. The paper discusses these challenges and public health recommendations made in order to mitigate occupational and public health risks related to the hazard identified., (© 2018 Blackwell Verlag GmbH.)