New bounds on light millicharged particles from the tip of the red-giant branch

Stellar energy loss is a sensitive probe of light, weakly coupled dark sectors, including ones containing millicharged particles (MCPs). The emission of MCPs can affect stellar evolution, and therefore can alter the observed properties of stellar populations. In this work, we improve upon the accuracy of existing stellar limits on MCPs by self-consistently modelling (1) the MCP emission rate, accounting for all relevant in-medium effects and production channels, and (2) the evolution of stellar interiors (including backreactions from MCP emission) using the MESA stellar evolution code. We find MCP emission leads to significant brightening of the tip of the red-giant branch. Based on photometric observations of 15 globular clusters whose bolometric magnitudes are inferred using parallaxes from Gaia astrometry, we obtain robust bounds on the existence of MCPs with masses below 100 keV.Comment: 12 pages, 8 figure

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Gene Regulatory Networks modulated by LHX2 in the Ncp and Hcp.

(A, C) Venn diagrams depicting the number of genes occupied by LHX2 and dysregulated (blue: downregulated, red: upregulated) upon loss of Lhx2 in the Ncp (A) and Hcp (C) respectively to identify direct targets of LHX2 in the Ncp and Hcp. (B, D) Genes dysregulated upon loss of Lhx2 in the Ncp (B) and Hcp (D) respectively, categorized by “Direct” or (direct + indirect) = “All” targets, mapped to the cell-type specific gene enrichment profiles in [28]) to identify progenitor-enriched (grey) and neuron-enriched genes (black). (E) Venn diagram comparing the direct targets of LHX2 that are dysregulated upon loss of Lhx2 in the Ncp (112 downregulated; 118 upregulated) and Hcp (70 downregulated; 153 upregulated), and in both tissues (43 downregulated; 35 upregulated). (F) Comparison of LHX2 occupancy in the E10.5 dorsal telencephalon (dtel; blue circle) with that in the E12.5 Ncp (red) and Hcp (green) results in genes occupied in all these three tissues (716, yellow), in the E10.5 dtel and the E12.5 Ncp (286, red) or the E12.5 Hcp (1252, green). (G) Venn diagram comparing the genes in E (LHX2 direct targets) that are also occupied by LHX2 at E10.5. In the Ncp, there are 62 downregulated 59 upregulated genes. In the Hcp there are 33 downregulated upregulated 94 upregulated. 37 downregulated and 25 upregulated are common to both tissues. (H) Heatmaps displaying genes occupied by LHX2. Cluster 1: Occupancy at both E10.5 (dtel) and E12.5 (Ncp and Hcp). Cluster 2: Occupancy at only E10.5. (I-L) KEGG pathway analysis (GO: BP) of genes identified in (E, G) reveals 4 pathways dysregulated upon loss of Lhx2 in the Ncp (red bars) and Hcp (green bars). Individual fold changes are plotted from the RNA-seq data (black: genes occupied by LHX2 at E12.5 and E10.5; blue: occupied only at E12.5).</p

LHX2 occupancy in the E12.5 mouse neocortical and hippocampal primordia (Ncp and Hcp, respectively).

(A) Schematic representation of the E12.5 mouse brain. (B) Progenitor markers PAX6, LHX2, and TBR2 immunostaining/in situ hybridization (Lhx2) in the Ncp and Hcp. (C-G) LHX2 ChIP-seq data in the Ncp and Hcp. Plots of PePr peak-called regions in the Ncp and Hcp show TF LHX2 occupancy in each tissue. Only statistically significant peaks were used for further analysis (p-value 0.0001 and fold change over input: cut off >10 fold) (C); The number of LHX2 occupancy peaks and associated number of genes (D); common genes occupied by LHX2 between the Ncp and Hcp (E); Percentage of LHX2 occupancy peaks categorized by type of genomic region (F); LHX2-occupied genes enriched in different cortical cell types identified by gene enrichment profiles in [28](G). The scale bars in B are 100 μm.</p

Worksheet containing raw data of DARs identified in Fig 2B, a list of annotated DARs identified in Fig 2B, a comparative analysis of genes associated with DARs and gene expression in wtHcp vs wtNcp related to S1B Fig.

Worksheet containing raw data of DARs identified in Fig 2B, a list of annotated DARs identified in Fig 2B, a comparative analysis of genes associated with DARs and gene expression in wtHcp vs wtNcp related to S1B Fig.</p

Worksheets containing raw data of DARs identified in Fig 4B, a list of annotated DARs identified in Fig 4B, an intersection list of DAR-associated genes that are also occupied by LHX2 in the wtHcp (311 DAGs) identified in Fig 4E.

Worksheets containing raw data of DARs identified in Fig 4B, a list of annotated DARs identified in Fig 4B, an intersection list of DAR-associated genes that are also occupied by LHX2 in the wtHcp (311 DAGs) identified in Fig 4E.</p

S2 Fig -

(A, B) KEGG pathway analysis of Ncp and Hcp enriched genes related to Fig 1B. (C-D) Motif analysis shows known motifs from 70 DARs (Ncp) and 14804 DARs (Hcp) related to Fig 2B. (E) Expression of many of the transcription factors identified among the top 10 motifs is undetectable in the E11.5 Ncp or Hcp (as obtained from; Allen Mouse Brain Atlas, http://mouse.brain-map.org/). Links to images represented in E: Dlx1Dlx2Dlx5Lhx1Lhx3Isl1Nkx6.1En1Rfx2Rfx5Xbp1. (TIF)</p

S4 Fig -

(A-F) GO: BPs corresponding to both up-and down-regulated genes upon loss of Lhx2 in the Ncp (A-C) and Hcp (D-F). (A, D) show the GSEA analysis and (B, C, E, F) show the overrepresentation test analysis. (TIF)</p

Chromatin accessibility comparison of the E12.5 wild type Ncp and Hcp.

(A) A heatmap comparing open chromatin in the Ncp and Hcp. (B) Differential accessibility analysis shows 14804 loci (9508 genes) to be preferentially open in the Hcp and 70 loci (64 genes) to be more open in the Ncp. (C) Motif analysis of the differentially open loci identified in (B) reveals LHX2 among the top candidates. (D) Heat maps display greater active histone modifications on the 14804 loci identified as more open in the Hcp. (E) Genomic loci corresponding to the Lef1 and Wif1 loci demonstrating the correspondence between the open chromatin and activating histone marks in the Ncp (red) and Hcp (green). Black boxes mark regions enriched in open chromatin in the Hcp that align with one or more histone modifications. The numbers indicate the maximum peak height for each pair of (Hcp/Ncp) tracks.</p

Characterization of Lhx2 occupancy across genomic regions.

(A, B) Lhx2 occupancy profiles in the Ncp and Hcp using Ncp peaks as a reference (A; 2222 peaks); using Hcp peaks as a reference (B, 5166 peaks). (C) Bedtools intersect analysis reveals 688 Lhx2 peaks overlap by at least 1bp in the Lhx2 Ncp (total 2222 peaks) and Hcp (total 5166 peaks) ChIP-seq data.(D) Bar plots of the average gene expression of the Lhx2 occupied genes in the Ncp and Hcp compared with the respective library averages.(E, F) bar plots of the distances of LHX2 peaks from the TSS in the Hcp and Ncp.(G) LHX2 occupancy profiles on 14874 DARs (70 Ncp + 14804 Hcp) from Fig 2B shows multiple DARs occupied by LHX2 in both tissues. (H) IGV tracks showing LHX2 peaks in the Hcp and Ncp together with their respective input control tracks. Black boxes mark regions equally enriched for LHX2 occupancy in Ncp and Hcp; green boxes indicate regions with greater LHX2 occupancy in Hcp; blue boxes indicate regions with greater LHX2 occupancy in Ncp. The numbers on the tracks indicate the maximum peak height. (I) Summary findings of the 360 DARs that mapped to LHX2 occupied regions. (TIF)</p