Depression frequently co-occurs with substance use disorders, which are a severe health and financial burden on our society (Office of National Drug Control Policy, 2011; Office of National Drug ...Control Policy, 2014). This study examined transtheoretical model of change (TTM) constructs in individuals with elevated depressive symptoms and a comorbid substance use disorder, looking to better understand how the depressive symptoms influenced the individuals’ changing substance use behavior.This study was conducted at the Substance Abuse Research Center in the University of Texas Mental Sciences Institute in Houston, Texas in 2006. Participants (N = 138) who met the DSM-IV criteria for cocaine use or dependence disorder were recruited. The sample was 72.2% Black, 19.4% White, and 8.3% Latino. Participants were in one of two treatment conditions for cocaine use disorder: 1) a TTM group intervention, modified for cocaine users, or 2) the control condition, an education and advice group. Data on substance use, TTM constructs, symptoms of behavioral health disorders, and other factors were collected at the beginning of the intervention, the end of the intervention, and three months post-intervention. Profile analysis and general linear model (GLM) analysis of variance (ANOVA) were used to examine the hypotheses that cocaine users with elevated depressive symptoms would endorse the TTM constructs differently than the nondepressed participants, especially the processes of change constructs, but would reduce their cocaine use the same amount as the nondepressed users.This study found that participants with elevated depressive symptoms were as successful as nondepressed participants in reducing their cocaine use after treatment. However, participants with elevated depressive symptoms engaged with the TTM variables differently compared to nondepressed participants, especially the processes of change and temptation variables. The behavioral processes of change were significantly lower before treatment and the experiential processes of change were significantly higher after treatment compared to nondepressed participants. Temptation was higher in participants with elevated depressive symptoms compared to nondepressed participants and lower temptation in participants with elevated depressive symptoms was linked to more successful reduction in cocaine use. These findings indicate that temptation and the processes of change are important variables to target in treatment of substance use disorders in adults with elevated depressive symptoms.
Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will ...facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.
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•The subdominant NVDP minor repeats of PfCSP are neutralizing epitopes•Potent mAbs with junctional and NANP cross-reactivity bind PfCSP in two steps•Cytotoxic PfCSP mAbs kill sporozoites in the liver•PfCSP mAbs prevent sporozoites from exiting liver sinusoids to infect hepatocytes
Wang et al. isolate a potent neutralizing human mAb, L9 that preferentially binds NVDP minor repeats of Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites with high affinity while cross-reacting with NANP major repeats. Their findings define the subdominant PfCSP minor repeats as neutralizing epitopes and demonstrate that the liver is an important site for antibodies to prevent malaria.
Summary
Based on promising results in older adults with acute myeloid leukaemia (AML), we treated patients with NPM1mut measurable residual disease (MRD) using off‐label venetoclax in combination ...with low‐dose cytarabine or azacitidine. Twelve consecutive patients were retrospectively identified, including five with molecular persistence and seven with molecular relapse/progression. All patients with molecular persistence achieved durable molecular complete remission (CRMRD‐) without transplantation. Six of seven patients with molecular relapse/progression achieved CRMRD‐ after 1–2 cycles of venetoclax. This paper highlights the promising efficacy of venetoclax‐based therapy to reduce the relapse risk in patients with persistent or rising NPM1mut MRD.
Postoperative delirium and postoperative cognitive dysfunction share risk factors and may co-occur, but their relationship is not well established. The primary goals of this study were to describe ...the prevalence of postoperative cognitive dysfunction and to investigate its association with in-hospital delirium. The authors hypothesized that delirium would be a significant risk factor for postoperative cognitive dysfunction during follow-up.
This study used data from an observational study of cognitive outcomes after major noncardiac surgery, the Successful Aging after Elective Surgery study. Postoperative delirium was evaluated each hospital day with confusion assessment method-based interviews supplemented by chart reviews. Postoperative cognitive dysfunction was determined using methods adapted from the International Study of Postoperative Cognitive Dysfunction. Associations between delirium and postoperative cognitive dysfunction were examined at 1, 2, and 6 months.
One hundred thirty-four of 560 participants (24%) developed delirium during hospitalization. Slightly fewer than half (47%, 256 of 548) met the International Study of Postoperative Cognitive Dysfunction-defined threshold for postoperative cognitive dysfunction at 1 month, but this proportion decreased at 2 months (23%, 123 of 536) and 6 months (16%, 85 of 528). At each follow-up, the level of agreement between delirium and postoperative cognitive dysfunction was poor (kappa less than .08) and correlations were small (r less than .16). The relative risk of postoperative cognitive dysfunction was significantly elevated for patients with a history of postoperative delirium at 1 month (relative risk = 1.34; 95% CI, 1.07-1.67), but not 2 months (relative risk = 1.08; 95% CI, 0.72-1.64), or 6 months (relative risk = 1.21; 95% CI, 0.71-2.09).
Delirium significantly increased the risk of postoperative cognitive dysfunction in the first postoperative month; this relationship did not hold in longer-term follow-up. At each evaluation, postoperative cognitive dysfunction was more common among patients without delirium. Postoperative delirium and postoperative cognitive dysfunction may be distinct manifestations of perioperative neurocognitive deficits.
A two-neuron model of ventral tegmental area (VTA) opioid function classically involves VTA GABA neuron regulation of VTA dopamine neurons via a mu-opioid receptor dependent inhibitory circuit. ...However, this model predates the discovery of a third major type of neuron in the VTA: glutamatergic neurons. We found that about one-quarter of VTA neurons expressing the mu-opioid receptor are glutamate neurons without molecular markers of GABA co-release. Glutamate-Mu opioid receptor neurons are largely distributed in the anterior VTA. The majority of remaining VTA mu-opioid receptor neurons are GABAergic neurons that are mostly within the posterior VTA and do not express molecular markers of glutamate co-release. Optogenetic stimulation of VTA glutamate neurons resulted in excitatory currents recorded from VTA dopamine neurons that were reduced by presynaptic activation of the mu-opioid receptor ex vivo, establishing a local mu-opioid receptor dependent excitatory circuit from VTA glutamate neurons to VTA dopamine neurons. This VTA glutamate to VTA dopamine pathway regulated dopamine release to the nucleus accumbens through mu-opioid receptor activity in vivo. Behaviorally, VTA glutamate calcium-related neuronal activity increased following oral oxycodone consumption during self-administration and response-contingent oxycodone-associated cues during abstinent reinstatement of drug-seeking behavior. Further, chemogenetic inhibition of VTA glutamate neurons reduced abstinent oral oxycodone-seeking behavior in male but not female mice. These results establish 1) a three-neuron model of VTA opioid function involving a mu-opioid receptor gated VTA glutamate neuron pathway to VTA dopamine neurons that controls dopamine release within the nucleus accumbens, and 2) that VTA glutamate neurons participate in opioid-seeking behavior.
ABSTRACT
Background
Our objective was to assess the performance of machine learning methods to predict post-operative delirium using a prospective clinical cohort.
Methods
We analyzed data from an ...observational cohort study of 560 older adults (≥ 70 years) without dementia undergoing major elective non-cardiac surgery. Post-operative delirium was determined by the Confusion Assessment Method supplemented by a medical chart review (
N
= 134, 24%). Five machine learning algorithms and a standard stepwise logistic regression model were developed in a training sample (80% of participants) and evaluated in the remaining hold-out testing sample. We evaluated three overlapping feature sets, restricted to variables that are readily available or minimally burdensome to collect in clinical settings, including interview and medical record data. A large feature set included 71 potential predictors. A smaller set of 18 features was selected by an expert panel using a consensus process, and this smaller feature set was considered with and without a measure of pre-operative mental status.
Results
The area under the receiver operating characteristic curve (AUC) was higher in the large feature set conditions (range of AUC, 0.62–0.71 across algorithms) versus the selected feature set conditions (AUC range, 0.53–0.57). The restricted feature set with mental status had intermediate AUC values (range, 0.53–0.68). In the full feature set condition, algorithms such as gradient boosting, cross-validated logistic regression, and neural network (AUC = 0.71, 95% CI 0.58–0.83) were comparable with a model developed using traditional stepwise logistic regression (AUC = 0.69, 95% CI 0.57–0.82). Calibration for all models and feature sets was poor.
Conclusions
We developed machine learning prediction models for post-operative delirium that performed better than chance and are comparable with traditional stepwise logistic regression. Delirium proved to be a phenotype that was difficult to predict with appreciable accuracy.
The goals of this study were to describe the clinical and anatomic features of infants undergoing Kasai portoenterostomy (KPE) for biliary atresia (BA) and to examine associations between these ...parameters and outcomes.
Infants enrolled in the prospective Childhood Liver Disease Research and Education Network, who underwent KPE were studied. Patients enrolled in a blinded, interventional trial were excluded from survival analysis. Primary endpoints were successful surgical drainage (total bilirubin less than 2 mg/dL within the first 3 months), transplant-free survival (Kaplan-Meier), and time to transplant/death (Cox regression).
KPE was performed in 244 infants (54% female; mean age: 65 ± 29 days). Transplant-free survival was 53.7% and 46.7% at 1 and 2 years post-KPE. The risk of transplant/death was significantly lower in the 45.6% of patients who achieved successful bile drainage within 3 months post-KPE (HR: 0.08, P < 0.001). The risk of transplant/death was increased in patients with porta hepatis atresia (Ohi type II and III vs type I; HR: 2.03, P = 0.030), nonpatent common bile duct (Ohi subtype: b, c, and d vs a; HR: 4.31, P = 0.022), BA splenic malformation syndrome (HR: 1.92, P = 0.025), ascites > 20 mL (HR: = 1.90, P = 0.0230), nodular liver appearance compared to firm (HR: = 1.61, P = 0.008), and age at KPE ≥ 75 days (HR: 1.73, P < 0.002). Outcome was not associated with gestational age, gender, race, ethnicity, or extent of porta hepatis dissection.
Anatomic pattern of BA, BASM, presence of ascites and nodular liver appearance at KPE, and early postoperative jaundice clearance are significant predictors of transplant-free survival.
Foraging is a universal behaviour that has co-evolved with predation pressure. We investigated the role of the bed nucleus of the stria terminalis (BNST) GABA neurons in robotic and live predator ...threat processing and their consequences in post-threat encounter foraging. Both robotic and live predator interactions increased BNST GABA neuron activity. Mice were trained to procure food in a laboratory-based foraging apparatus in which food pellets were placed at incrementally greater distances from a nest zone. After mice learned to forage, they were exposed to a robotic or live predator threat, while BNST GABA neurons were chemogenetically inhibited. Post-robotic threat encounter, mice spent more time in the nest zone, but other foraging parameters were unchanged compared with pre-encounter behaviour. Inhibition of BNST GABA neurons had no effect on foraging behaviour post-robotic threat encounter. Following live predator exposure, control mice spent significantly more time in the nest zone, increased their latency to successfully forage, and significantly altered their overall foraging performance. Inhibition of BNST GABA neurons during live predator exposure prevented changes in foraging behaviour from developing after a live predator threat. BNST GABA neuron inhibition did not alter foraging behaviour during robotic or live predator threats. We conclude that these results demonstrate that while both robotic and live predator encounters effectively intrude on foraging behaviour, the perceived risk and behavioural consequences of the threat are distinguishable. Additionally, BNST GABA neurons may play a role in the integration of prior innate predator threat experience that results in hypervigilance during post-encounter foraging behaviour.
This study aimed to characterize rates of maternal morbidity associated with early (<34 wk) preeclampsia with severe features and to determine factors associated with developing these morbidities.
...Retrospective cohort study of patients with early preeclampsia with severe features at a single institution from 2013 to 2019. Inclusion criteria were admission between 23 and 34 weeks and diagnosis of preeclampsia with severe features. Maternal morbidity defined as death, sepsis, intensive care unit (ICU) admission, acute renal insufficiency (acute kidney injury AKI), postpartum (PP) dilation and curettage, PP hysterectomy, venous thromboembolism (VTE), PP hemorrhage (PPH), PP wound infection, PP endometritis, pelvic abscess, PP pneumonia, readmission, and/or need for blood transfusion. Death, ICU admission, VTE, AKI, PP hysterectomy, sepsis, and/or transfusion of >2 units were considered severe maternal morbidity (SMM). Simple statistics used to compare characteristics among patients experiencing any morbidity and those not. Poisson regression used to assess relative risks.
Of 260 patients included, 77 (29.6%) experienced maternal morbidity and 16 (6.2%) experienced severe morbidity. PPH (
= 46, 17.7%) was the most common morbidity, although 15 (5.8%) patients were readmitted, 16 (6.2%) needed a blood transfusion, and 14 (5.4%) had AKI. Patients who experienced maternal morbidity were more likely to be advanced maternal age, have preexisting diabetes, have multiples, and deliver nonvaginally (all
s < 0.05). Diagnosis of preeclampsia < 28 weeks or longer latency from diagnosis to delivery were not associated with increased maternal morbidity. In regression models, the relative risk of maternal morbidity remained significant for twins (adjusted odds ration aOR: 2.57; 95% confidence interval CI: 1.67, 3.96) and preexisting diabetes (aOR: 1.64; 95% CI: 1.04, 2.58), whereas attempted vaginal delivery was protective (aOR: 0.53; 95% CI: 0.30, 0.92).
In this cohort, more than 1 in 4 patients diagnosed with early preeclampsia with severe features experienced maternal morbidity, whereas 1 in 16 patients experienced SMM. Twins and pregestational diabetes were associated with higher risk of morbidity, whereas attempted vaginal delivery was protective. These data may be helpful in promoting risk reduction and counseling patients diagnosed with early preeclampsia with severe features.
· One in four patients diagnosed with preeclampsia w/ severe features experienced maternal morbidity.. · One in 16 patients with preeclampsia w/ severe features experienced severe maternal morbidity.. · Factors most associated with morbidity/severe morbidity were twins and pregestational diabetes.. · Patients who attempted vaginal delivery appeared to have a lower rate of morbidity..
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