BACKGROUND AND OBJECTIVE Hypothermia in young infants may be secondary to an invasive bacterial infection. No studies have explored culture time-to-positivity (TTP) in hypothermic infants. Our objective was to compare TTP of blood and cerebrospinal fluid (CSF) cultures between pathogenic and contaminant bacteria in hypothermic infants ≤90 days of age. METHODS Secondary analysis of a retrospective cohort of 9 children’s hospitals. Infants ≤90 days of age presenting to the emergency department or inpatient setting with hypothermia from September 1, 2017, to May 5, 2021, with positive blood or CSF cultures were included. Differences in continuous variables between pathogenic and contaminant organism groups were tested using a 2-sample t test and 95% confidence intervals for the mean differences reported. RESULTS Seventy-seven infants met inclusion criteria. Seventy-one blood cultures were positive, with 20 (28.2%) treated as pathogenic organisms. Five (50%) of 10 positive CSF cultures were treated as pathogenic. The median (interquartile range [IQR]) TTP for pathogenic blood cultures was 16.8 (IQR 12.7–19.2) hours compared with 26.11 (IQR 20.5–48.1) hours for contaminant organisms (P < .001). The median TTP for pathogenic organisms on CSF cultures was 34.3 (IQR 2.0–53.7) hours, compared with 58.1 (IQR 52–72) hours for contaminant CSF organisms (P < .186). CONCLUSIONS Our study is the first to compare the TTP of blood and CSF cultures between pathogenic and contaminant bacteria in hypothermic infants. All pathogenic bacteria in the blood grew within 36 hours. No difference in TTP of CSF cultures between pathogenic and contaminant bacteria was detected.
Background A diagnosis of prostate cancer (PC) may cause psychosocial distress not only in a man but also his intimate partner. However, long-term risks of depression, anxiety, or suicide in partners of men with PC are largely unknown. Methods A national cohort study was conducted of 121,530 partners of men diagnosed with PC during 1998-2017 and 1,093,304 population-based controls in Sweden. Major depression, anxiety disorder, and suicide death were ascertained through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors. Results Partners of men with high-risk PC had increased risks of major depression (adjusted HR, 1.34; 95% CI, 1.30-1.39) and anxiety disorder (1.25; 1.20-1.30), which remained elevated ≥10 years later. Suicide death was increased in partners of men with distant metastases (adjusted HR, 2.38; 95% CI, 1.08-5.22) but not other high-risk PC (1.14; 0.70-1.88). Among partners of men with high-risk PC, risks of major depression and anxiety disorder were highest among those aged ≥80 years (adjusted HR, 1.73; 95% CI, 1.53-1.96; and 1.70; 1.47-1.96, respectively), whereas suicide death was highest among those aged <60 years (7.55; 2.20-25.89). In contrast, partners of men with low- or intermediate-risk PC had modestly or no increased risks of these outcomes. Conclusions In this large cohort, partners of men with high-risk PC had increased risks of major depression and anxiety disorder, which persisted for ≥10 years. Suicide death was increased 2-fold in partners of men with distant metastases. Partners as well as men with PC need psychosocial support and close follow-up for psychosocial distress.
Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights—together with neuroscience, biology and data science—closer.
The success of all-solid-state batteries (ASSBs) depends on the solid-state electrolyte (SSE) exhibiting high interfacial stability and room-temperature ionic conductivity. However, the current SSEs, especially those with practical ionic conductivities (≥10−3 S/cm) at room temperature, often develop unstable interfaces at the metal anode, in some cases with even greater severity than with liquid organic electrolytes. Despite persistent efforts, achieving interfacial stability and sufficient ionic conductivity simultaneously represents one of the greatest challenges in ASSBs. The current approaches focus on stabilizing the interface by incorporating secondary interlayers or introducing coatings by surface engineering. The method is often material-specific, and the added interlayers often deteriorate during cycling. In this work, using phase analysis and explicit interface modeling, we demonstrate a strategy to kinetically stabilize the interface between the SSE and metal anode by incorporating selected monoanion clusters in the SSE; they can effectively lower or even halt the reduction kinetics at the interface by promoting on-site formation of interphases that are highly electron insulating. The study provides insight into the kinetic effects to achieve SSEs with superior properties in bulk and at the interface.
Background In the U.S., ~50% of those who meet criteria for alcohol use disorder (AUD) during their lifetimes do not remit. We previously reported that a polygenic score for AUD (PGS AUD ) was positively associated with AUD severity as measured by DSM‐5 lifetime criteria count, and AUD severity was negatively associated with remission, therefore, we hypothesized that PGS AUD would be negatively associated with remission. Methods Individuals of European (EA) and African ancestry (AA) from the Collaborative Study on the Genetics of Alcoholism (COGA) who met lifetime criteria for AUD, and two EA cohorts ascertained for studying liver diseases and substance use disorders, respectively, from Indiana Biobank, were included. In COGA, 12‐month remission was defined as any period of ≥12 consecutive months without AUD criteria except craving and was further categorized as abstinent and non‐abstinent . In Indiana Biobank, remission was defined based on ICD codes and could not be further distinguished as abstinent or non‐abstinent . Sex and age were included as covariates. COGA analyses included additional adjustment for AUD severity, family history of remission, and AUD treatment history. Results In COGA EA, PGS AUD was negatively associated with 12‐month and non‐abstinent remission (P≤0.013, betas between ‐0.15 and ‐0.10) after adjusting for all covariates. In contrast to COGA findings, PGS AUD was positively associated with remission (P=0.004, beta=0.28) in Indiana Biobank liver diseases cohort but not in Indiana Biobank substance use disorder cohort (P=0.17, beta=0.15). Conclusions PGS AUD was negatively associated with 12‐month and non‐abstinent remission in COGA EA, independent of behavioral measures of AUD severity and family history of remission. The discrepant results in COGA and Indiana Biobank might reflect different ascertainment strategies: Indiana Biobank participants were older and had higher rates of liver diseases, suggesting remission due to alcohol‐related health conditions that manifested in later life.
The ability of cells to move in a mechanically coupled, coordinated manner, referred to as collective cell migration, is central to many developmental, physiological, and pathophysiological processes. Limited understanding of how mechanical forces and biochemical regulation interact to affect coupling has been a major obstacle to unravelling the underlying mechanisms. Focusing on the linker protein vinculin, we use a suite of Förster resonance energy transfer-based biosensors to probe its mechanical functions and biochemical regulation, revealing a switch that toggles vinculin between loadable and unloadable states. Perturbation of the switch causes covarying changes in cell speed and coordination, suggesting alteration of the friction within the system. Molecular scale modelling reveals that increasing levels of loadable vinculin increases friction, due to engagement of self-stabilizing catch bonds. Together, this work reveals a regulatory switch for controlling cell coupling and describes a paradigm for relating biochemical regulation, altered mechanical properties, and changes in cell behaviors.
The coloring reconfiguration graph has as its vertex set all the proper ‐colorings of , and two vertices in are adjacent if their corresponding ‐colorings differ on a single vertex. Cereceda conjectured that if an ‐vertex graph is ‐degenerate and , then the diameter of is . Bousquet and Heinrich proved that if is planar and bipartite, then the diameter of is . (This proves Cereceda's Conjecture for every such graph with degeneracy 3.) They also highlighted the particular case of Cereceda's Conjecture when is planar and has no 3‐cycles. As a partial solution to this problem, we show that the diameter of is for every planar graph with no 3‐cycles and no 5‐cycles.
Currently, there are no clinically approved drugs that directly thwart mutant KRAS G12D, a major driver of human cancer. Here, we report on the discovery of a small molecule, KRB-456, that binds KRAS G12D and inhibits the growth of pancreatic cancer patient-derived tumors. Protein NMR studies revealed that KRB-456 binds the GDP-bound and GCP-bound conformation of KRAS G12D by forming interactions with a dynamic allosteric binding pocket within the switch-I/II region. Isothermal titration calorimetry demonstrated that KRB-456 binds potently to KRAS G12D with 1.5-, 2- and 6-fold higher affinity than to KRAS G12V, KRAS wild-type and KRAS G12C, respectively. KRB-456 potently inhibits the binding of KRAS G12D to the RAS-binding domain (RBD) of RAF1 as demonstrated by GST-RBD pull-down and AlphaScreen assays. Treatment of KRAS G12D-harboring human pancreatic cancer cells with KRB-456 suppresses the cellular levels of KRAS bound to GTP and inhibits the binding of KRAS to RAF1. Importantly, KRB-456 inhibits P-MEK, P-AKT and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from pancreatic cancer patients whose tumors harbor KRAS G12D and KRAS G12V and who relapsed after chemotherapy and radiation therapy. These results warrant further development of KRB-456 for pancreatic cancer.
In acute myeloid leukemia (AML), donor NK-cell killer immunoglobulin-like receptors (KIR) and recipient HLA interactions may contribute to the graft-versus-leukemia effect of allogeneic hematopoietic cell transplantation (HCT). Analyses of individual KIR/HLA interactions however have yielded conflicting findings, and their importance in the HLA-matched unrelated donor (MUD) setting remains controversial. We systematically studied outcomes of individual donor-KIR/recipient-HLA interactions for HCT outcomes and empirically evaluated prevalent KIR genotypes for clinical benefit. Adult AML patients (n=2025) transplanted in complete remission who received MUD grafts reported to the Center for International Blood and Marrow Transplantation were evaluated. Only the donor-2DL2present/recipient-HLA-C1present pair was associated with reduced relapse (hazard ratio 0.79 [95% confidence interval: 0.67, 0.93], p = 0.006) compared with donor-2DL2absent/recipient-HLA-C1present. However, no association were found when comparing HLA-C groups among KIR-2DL2present-graft recipients. We identified nine prevalent donor KIR genotypes in our cohort and screened them for association with relapse risk. Genotype (G)5 in all recipients and G3 in Bw4present recipients were associated with decreased relapse risk (HR 0.52 [0.35, 0.78], p = 0.002; 0.32 [0.14, 0.72], p = 0.006, respectively) and G2 (HR 1.63 [1.15, 2.29], p = 0.005) with increased relapse risk C1-homozygous recipients, compared to patients with the same ligand. However, we could not validate these findings in an external dataset of 796 AML transplants from the German transplantation registry. Neither a systematic evaluation of known HLA-KIR interactions nor an empiric assessment of prevalent KIR genotypes demonstrated clinically actionable associations, therefore not supporting these KIR-driven strategies for MUD selection in AML.
Current predictors of DNA-binding residues (DBRs) from protein sequences belong to two distinct groups, those trained on binding annotations extracted from structured protein-DNA complexes (structure-trained) vs. intrinsically disordered proteins (disorder-trained). We complete the first empirical analysis of predictive performance across the structure- and disorder-annotated proteins for a representative collection of ten predictors. Majority of the structure-trained tools perform well on the structure-annotated proteins while doing relatively poorly on the disorder-annotated proteins, and vice versa. Several methods make accurate predictions for the structure-annotated proteins or the disorder-annotated proteins, but none performs highly accurately for both annotation types. Moreover, most predictors make excessive cross-predictions for the disorder-annotated proteins, where residues that interact with non-DNA ligand types are predicted as DBRs. Motivated by these results, we design, validate and deploy an innovative meta-model, hybridDBRpred, that uses deep transformer network to combine predictions generated by three best current predictors. HybridDBRpred provides accurate predictions and low levels of cross-predictions across the two annotation types, and is statistically more accurate than each of the ten tools and baseline meta-predictors that rely on averaging and logistic regression. We deploy hybridDBRpred as a convenient web server at http://biomine.cs.vcu.edu/servers/hybridDBRpred/ and provide the corresponding source code at https://github.com/jianzhang-xynu/hybridDBRpred.
Revision anterior cruciate ligament reconstruction (ACLR) can be achieved in a single-stage or two-stage approach. Single-stage revisions have several advantages, including one less operation, decreased cost, and a quicker recovery for patients. Revision ACLR can be complicated by malpositioned or dilated bone tunnels, which makes a single-stage revision more challenging or sometimes necessitates a two-stage approach. The use of fast-setting bone graft substitutes (BGS) has been described in recent literature as a strategy to potentially help address this problem in the setting of single-stage revision ACLR. The aim of this study was to evaluate patient-reported clinical outcomes of patients who have undergone single-stage revision ACLR using fast-setting BGS to address prior malpositioned or dilated tunnels. A retrospective review was conducted of the first nine consecutive patients who had undergone single-stage revision ACLR using a fast-setting BGS by a single surgeon between May 2017 and February 2020 with a minimum of 2-year follow-up. Patient-reported clinical outcomes, including the International Knee Documentation Committee (IKDC) questionnaire, the Tegner Lysholm Knee Scoring Scale, patient satisfaction questions, and the need for additional surgery were evaluated for this group between 26 and 49 months postoperative. Of the nine patients eligible for inclusion, eight patients (88.9%) were evaluated, and one was lost to follow-up. At an average follow-up of 37.9 months (range: 27.8–55.7), the mean postoperative IKDC score was 75.0 ± 11.3, and the mean postoperative Tegner Lysholm Knee Score was 83.0 ± 17.6. None of the patients required additional revision surgery or experienced construct failure at the time of follow-up. Seven of eight respondents (87.5%) had their preoperative expectations met with the surgery, and 100% of patients stated they would have the surgery again. Single-stage revision ACLR using fast-setting BGS showed overall positive clinical outcomes for this pilot group of patients at a minimum 2-year follow-up. In select revision scenarios, these materials may be a valuable option to allow the filling of defects without compromising fixation or clinical outcomes.
The imaging evaluation of acute abdominal pain in children with suspected appendicitis has evolved to include rapid abdominopelvic MRI (rMRI) over recent years. Through a collaborative effort between the Magnetic Resonance Imaging (MRI) and Emergency and Trauma Imaging Committees of the Society for Pediatric Radiology (SPR), we conducted a survey on the utilization of rMRI to assess practice specifics and protocols. Subsequently, we present a proposed consensus rMRI protocol derived from the survey results, literature review, and discussion and consensus between committee members.
Purpose To analytically assess the heterogeneity effect of vaginal cylinders (VC) made of high‐density plastics on dose calculations, considering the prescription point (surface or 5 mm beyond the surface), and benchmark the accuracy of a commercial model‐based dose calculation (MBDC) algorithm using Monte Carlo (MC) simulations. Methods and materials The GEANT4 MC code was used to simulate a commercial ¹⁹² Ir HDR source and VC, with diameters ranging from 20 to 35 mm, inside a virtual water phantom. Standard plans were generated from a commercial treatment planning system [TPS—BrachyVision ACUROS (BV)] optimized for a treatment length of 5 cm through two dose calculation approaches: (1) assuming all the environment as water (i.e., D w,w‐MC & D w,w‐TG43 ) and (2) accounting for the heterogeneity of VC applicators (i.e., D w,w‐App‐MC & D w,w‐App‐MBDC ). The compared isodose lines, and dose & energy difference maps were extracted for analysis. In addition, the dose difference on the peripheral surface, along the applicator and at middle of treatment length, as well as apical tip was evaluated. Results The D w,w‐App‐MC results indicated that the VC heterogeneity can cause a dose reduction of (up to) % 6.8 on average (for all sizes) on the peripheral surface, translating to 1 mm shrinkage of the isodose lines compared to D w,w‐MC . In addition, the results denoted that BV overestimates the dose on the peripheral surface and apical tip of about 3.7% and 17.9%, respectively, (i.e., D w,w‐App‐MBDC vs D w,w‐App‐MC ) when prescribing to the surface. However, the difference between the two were negligible at the prescription point when prescribing to 5 mm beyond the surface. Conclusion The VCs’ heterogeneity could cause dose reduction when prescribing dose to the surface of the applicator, and hence increases the level of uncertainty. Thus, reviewing the TG43 results, in addition to ACUROS, becomes prudent, when evaluating the surface coverage at the apex.
Gallstone-related disease comprises a spectrum of conditions resulting from biliary stone formation, leading to obstruction and inflammatory complications. These can significantly impact patient quality of life and carry high morbidity if not accurately detected. Appropriate imaging is essential for evaluating the extent of gallstone disease and assuring appropriate clinical management. Magnetic Resonance Imaging (MRI) techniques (including Magnetic Resonance Cholangiopancreatography (MRCP) are increasingly used for diagnosis of gallstone disease and its complications and provide high contrast resolution and facilitate tissue-level assessment of gallstone disease processes. In this review we seek to delve deep into the spectrum of MR imaging in diagnose of gallstone-related disease within the gallbladder and complications related to migration of the gallstones to the gall bladder neck or cystic duct, common hepatic duct or bile duct (choledocholithiasis) and beyond, including gallstone pancreatitis, gallstone ileus, Bouveret syndrome, and dropped gallstones, by offering key examples from our practice. Furthermore, we will specifically highlight the crucial role of MRI and MRCP for enhancing diagnostic accuracy and improving patient outcomes in gallstone-related disease and showcase relevant surgical pathology specimens of various gallstone related complications. Graphical abstract
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