Abstract Childhood abuse is a serious problem that has been linked to harmful alcohol and drug use in non-offender samples. In a sample of 219 criminal offenders, we examined the associations between ...childhood physical and sexual abuse and three indices of harmful substance use. Results indicate that physical abuse was associated with symptoms of alcohol use disorder and sexual abuse was associated with symptoms of drug use disorder among offenders. Both forms of childhood abuse were associated with substance use consequences, even after taking into account substance type and frequency of use. No gender by childhood abuse interactions were found. Symptoms of depression and generalized anxiety partially mediated relationships between childhood abuse and substance use consequences. Findings underscore the importance of assessing childhood abuse and treating anxiety and depression among offenders who exhibit harmful substance use.
IMPORTANCE: Redirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care ...discussions merits understanding. OBJECTIVE: To examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks’ gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic). MAIN OUTCOMES AND MEASURES: The primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks’ gestation, death and neurodevelopmental impairment at 22 to 26 months’ corrected age. RESULTS: Of the 15 629 infants (mean SD gestational age, 26 2 weeks; 7961 51% male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 15%; White, 1320/8836 15%) or ethnicity (Hispanic, 291/2105 14%; non-Hispanic, 2020/13 408 15%). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio aOR, 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type. CONCLUSIONS AND RELEVANCE: For infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.
Multimodality therapy may prolong survival among resectable malignant pleural mesothelioma (MPM). However, the role of adjuvant radiation remains controversial. We explored a large nationwide ...database to determine whether adjuvant radiation is associated with improved survival.
The National Cancer Database (NCDB) was queried to identify patients with MPM who received cancer-directed surgery between 2004-2013. Adjuvant radiation included intensity modulated radiation therapy or conformal 3D radiation. Propensity matching was performed with a 150-day landmark to address survivorship bias. Cox regression was used with an interaction term between pathologic stage and radiation.
A total of 2,846 patients were identified as having undergone cancer-directed surgery for MPM; among whom 213 (7%) received adjuvant radiation. Adjuvant radiation was associated with improved survival among those who were stage I-II (P=0.024), but not stage III or IV (P=0.890 and P=0.183, respectively). After propensity matching, adjuvant radiation was associated with improved survival for those who were stage I-II hazard ratio (HR) 0.52, P=0.035, whereas no similar effect was observed for those who were stage III or IV (P=0.190 and P=0.562, respectively). Multivariable regression revealed that sarcomatoid histology (HR 1.80, P=0.018) and stage IV disease (HR 1.65, P=0.033) were also associated with worse survival.
Adjuvant radiation was associated with improved survival among those with pathologic stage I-II MPM. No survival advantage was observed for those with pathologic stage III or stage IV MPM, however. Our results justify the need for further prospective trials to investigate the utility of adjuvant radiotherapy among those with MPM.
ObjectiveAfter aneurysmal subarachnoid haemorrhage (aSAH), extracellular haemoglobin (Hb) in the subarachnoid space is bound by haptoglobin, neutralising Hb toxicity and helping its clearance. Two ...exons in the HP gene (encoding haptoglobin) exhibit copy number variation (CNV), giving rise to HP1 and HP2 alleles, which influence haptoglobin expression level and possibly haptoglobin function. We hypothesised that the HP CNV associates with long-term outcome beyond the first year after aSAH.MethodsThe HP CNV was typed using quantitative PCR in 1299 aSAH survivors in the Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study, a retrospective multicentre cohort study with a median follow-up of 18 months. To investigate mediation of the HP CNV effect by haptoglobin expression level, as opposed to functional differences, we used rs2000999, a single nucleotide polymorphism associated with haptoglobin expression independent of the HP CNV. Outcome was assessed using modified Rankin and Glasgow Outcome Scores. SAH volume was dichotomised on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 patients with aSAH and related to the HP CNV.ResultsThe HP2 allele associated with a favourable long-term outcome after high-volume but not low-volume aSAH (multivariable logistic regression). However rs2000999 did not predict outcome. The HP2 allele associated with lower CSF haemoglobin-haptoglobin complex levels. The CSF Hb concentration after high-volume and low-volume aSAH was, respectively, higher and lower than the Hb-binding capacity of CSF haptoglobin.ConclusionThe HP2 allele carries a favourable long-term prognosis after high-volume aSAH. Haptoglobin and the Hb clearance pathway are therapeutic targets after aSAH.
Ca2+ stores were studied in a preparation of freshly dissociated terminals from hypothalamic magnocellular neurons. Depolarization from a holding level of -80 mV in the absence of extracellular Ca2+ ...elicited Ca2+ release from intraterminal stores, a ryanodine-sensitive process designated as voltage-induced Ca2+ release (VICaR). The release took one of two forms: an increase in the frequency but not the quantal size of Ca2+ syntillas, which are brief, focal Ca2+ transients, or an increase in global Ca2+. The present study provides evidence that the sensors of membrane potential for VICaR are dihydropyridine receptors (DHPRs). First, over the range of -80 to -60 mV, in which there was no detectable voltage-gated inward Ca2+ current, syntilla frequency was increased e-fold per 8.4 mV of depolarization, a value consistent with the voltage sensitivity of DHPR-mediated VICaR in skeletal muscle. Second, VICaR was blocked by the dihydropyridine antagonist nifedipine, which immobilizes the gating charge of DHPRs but not by Cd2+ or FPL 64176 (methyl 2,5 dimethyl-42-(phenylmethyl)benzoyl-1H-pyrrole-3-carboxylate), a non-dihydropyridine agonist specific for L-type Ca2+ channels, having no effect on gating charge movement. At 0 mV, the IC50 for nifedipine blockade of VICaR in the form of syntillas was 214 nM in the absence of extracellular Ca2+. Third, type 1 ryanodine receptors, the type to which DHPRs are coupled in skeletal muscle, were detected immunohistochemically at the plasma membrane of the terminals. VICaR may constitute a new link between neuronal activity, as signaled by depolarization, and a rise in intraterminal Ca2+.
Mutations in the serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) have been implicated in mediating resistance to checkpoint blockade among patients with advanced lung adenocarcinoma. We ...sought to examine the associations between clinicopathologic characteristics, tumor LKB1 expression, features of the immune microenvironment, and postoperative prognosis among patients with early stage lung adenocarcinoma undergoing surgical therapy.
Formalin-fixed, paraffin-embedded specimens of patients undergoing resection of stage I to III, chemotherapy-naïve adenocarcinomas (1997 to 2008) were analyzed using tissue microarray sectioning. Sublobar resections were excluded. Intratumoral LKB1/STK11 expression was quantified as H-score. In a subset, tumor-associated immune cell populations were quantified using whole tumor sections in peritumoral and intratumoral compartments.
In all, 104 patients met inclusion criteria. Expression of LKB1/STK11 (median H-score 102.9) was higher in women (median 123.3) than in men (100, P = .004) and in never-smokers (median 145) than in former/current smokers (100, P = .002). Expression of LKB1/STK11 was positively correlated with intratumoral infiltration of cluster of differentiation (CD) 3+ (r = 0.351, P = .005), CD4+ (r = 0.436, P < .001), and CD8+ (r = 0.263, P = .049) cells. Patients with extrathoracic recurrence had lower tumor expression of LKB1/STK11 than did other patients with recurrent disease. On multivariate analysis, low LKB1/STK11 expression remained independently associated with poor disease-free survival and distant disease-free survival.
Low LKB1/STK11 expression is associated with specific patient characteristics and poor postoperative prognosis in chemotherapy-naïve lung adenocarcinoma. Further investigation is warranted to delineate its clinical significance in the context of evaluating novel therapeutic agents in patients with resectable disease.
The essays in this collection honor Professor Ellis Sandoz, Hermann Moyse Jr. Distinguished Professor of Political Science, Louisiana State University, and founding director of the Eric Voegelin ...Institute for American Renaissance Studies, an institute located at Louisiana State University and devoted to research and publication in the fields of political philosophy, constitutional law, and Voegelin studies. The essays, each written especially for this volume, are grouped into the disciplines of philosophy, literature, and politics and range widely across these subjects, exploring writers as diverse as Xenophon, S?seki Natsume, Freud, and George Santayana and topics ranging from the leadership style of François Mitterrand and the Velvet Revolution to the nature of the Law and of the Political. Philosophy, Literature, and Politics is a fitting tribute to a man whose life's work has been formed by commitment to the philosophical enterprise and by a conviction in Eric Voegelin's contribution to that enterprise. The seventeen essays in this collection will be of particular interest to scholars of politics, comparative government, Japanese studies, political philosophy, and literary criticism.
Antibody-drug conjugates (ADCs) are a class of targeted therapeutics that utilize the specificity of antibodies to selectively deliver highly potent cytotoxins to target cells. Although recent years ...have witnessed significant interest in ADCs, problems remain with the standard linkage chemistries used for cytotoxin-antibody bioconjugation. These typically (1) generate unstable constructs, which may lead to premature cytotoxin release, (2) often give a wide variance in drug-antibody ratios (DAR) and (3) have poor control of attachment location on the antibody, resulting in a variable pharmacokinetic profile. Herein, we report a novel divinylpyrimidine (DVP) linker platform for selective bioconjugation
via
covalent re-bridging of reduced disulfide bonds on native antibodies. Model studies using the non-engineered trastuzumab antibody validate the utility of this linker platform for the generic generation of highly plasma-stable and functional antibody constructs that incorporate variable biologically relevant payloads (including cytotoxins) in an efficient and site-selective manner with precise control over DAR. DVP linkers were also used to efficiently re-bridge both monomeric and dimeric protein systems, demonstrating their potential utility for general protein modification, protein stabilisation or the development of other protein-conjugate therapeutics.
Divinylpyrimidine (DVP) linkers enable access to highly stable and functional antibody-drug conjugates.
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