The impact of caregiving for children with chronic conditions on the HPA axis: A scoping review.

Caregiving has been robustly linked to caregiver health through the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in the context of caregiving for an adult with a chronic illness. However, little research examines the physiological impact of caregiving for a child with a chronic illness despite high burden and unique stressors. In this review, we explore the links of caregiving for a child with a congenital, chromosomal, or genetic disorder to the regulation or dysregulation of the HPA axis. A search was conducted in PubMed, Embase, and the Web of Science and 15 studies met inclusion criteria. Overall, there were inconsistent links of caregiving to HPA axis functioning, perhaps due to the heterogeneity across disease contexts, study designs, and biomarker measurement. Future research should standardize measurement and study designs, increase participant diversity, and examine moderators of the links of caregiving to the HPA axis.

Bayesian Kernel Machine Regression for Social Epidemiologic Research.

BACKGROUND: Little attention has been devoted to framing multiple continuous social variables as a "mixture" for social epidemiologic analysis. We propose using the Bayesian kernel machine regression analytic framework that yields univariate, bivariate, and overall exposure mixture effects. METHODS: Using data from the 2023 Survey of Racism and Public Health, we conducted a Bayesian kernel machine regression analysis to study several individual, social, and structural factors as an exposure mixture and their relationships with psychological distress among individuals with at least one police arrest. Factors included racial and economic polarization, neighborhood deprivation, perceived discrimination, police perception, subjective social status, and substance use. We complemented this analysis with a series of unadjusted and adjusted models for each exposure mixture variable. RESULTS: We found that more self-reported discrimination experiences in the past year (posterior inclusion probability = 1.00) and greater substance use (posterior inclusion probability = 1.00) correlated with higher psychological distress. These associations were consistent with the findings from the unadjusted and adjusted linear regression analyses: past year perceived discrimination (unadjusted b = 2.58, 95% CI: 1.86, 3.30; adjusted b = 2.20, 95% CI: 1.45, 2.94) and substance use (unadjusted b = 2.92, 95% CI: 2.21, 3.62; adjusted b = 2.59, 95% CI: 1.87, 3.31). CONCLUSIONS: With the rise of big data and the expansion of variables in long-standing cohort and census studies, novel applications of methods from adjacent disciplines are a step forward in identifying exposure mixture associations in social epidemiology and addressing the health needs of socially vulnerable populations.

A Clinical-Community Partnership to Address Food Insecurity and Reduce Emergency Department Utilization Among Medicaid-Insured Patients in North Carolina.

CONTEXT: Socioeconomic risk factors have the greatest impact on overall health trajectory. Patients with Medicaid insurance are more likely to experience food insecurity, in addition to poor health and increased health care utilization. Targeted food and produce prescription programs can reduce food insecurity, but sustainable implementation is challenging and evidence demonstrating the impact on clinical utilization outcomes is lacking. PROGRAM: In 2021, a cross-sector collaboration between Mecklenburg County Public Health, Reinvestment Partners, and Atrium Health initiated a food prescription program in urban North Carolina. A low-cost mass text message campaign was used to identify and enroll Medicaid-insured patients with a history of emergency department (ED) utilization. METHODS: A nonrandomized before/after evaluation design was used with a 12-month data collection window (6 months before/after program enrollment) for 711 patients enrolled between June 2021 and 2022. Changes in the odds of nonadmission ED utilization were modeled using logistic regression, adjusting for race/ethnicity, gender, age, comorbidity, and dose, along with interaction by comorbidity. RESULTS: A majority of the sample was non-Hispanic Black (61%; n = 436), female (90%; n = 643), with "none to mild" chronic disease comorbidity (81%; n = 573). The unadjusted and adjusted odds of nonadmission ED utilization significantly reduced between time periods, along with significant interaction by comorbidity. Among the subsamples, patients with "none to mild" comorbidity showed 34% reduction in odds of nonadmission ED utilization (OR = 0.64; 95% CI, 0.47-0.86). DISCUSSION: Food prescription programming targeting Medicaid-insured patients may reduce ED utilization, particularly among those without severe comorbidity. Retrospective data collection and sample homogeneity reduced the quality of evidence, but results offer a pragmatic example that can be replicated for further study. Additional research is needed to strengthen the body of evidence and support cross-sector investment in food and produce prescription programming.

Survival and Toxicities after Yttrium-90 Transarterial Radioembolization of Cholangiocarcinoma in the RESiN Registry.

PURPOSE: To report outcomes in patients with intrahepatic cholangiocarcinoma treated with yttrium-90 resin microspheres (transarterial radioembolization [TARE]) from a multicenter, prospective observational registry. MATERIALS AND METHODS: Ninety-five patients (median age, 67 years [interquartile range {IQR}, 59-74]; 50 men) were treated in 27 centers between July 2015 and August 2020. Baseline demographic characteristics included imaging findings, performance status, and previous systemic or locoregional treatments. Dosimetry method was tracked. Overall survival (OS) and progression-free survival were calculated using the Kaplan-Meier method. The best imaging response was calculated using the Response Evaluation Criteria in Solid Tumors v1.1. Grade ≥3 toxicities were assessed using Common Terminology Criteria for Adverse Events v5. Cox regression analysis was performed. RESULTS: Fifty-two of 86 (60%) patients had multifocal tumors, and 24/89 (27%) had extrahepatic tumors. The median index tumor diameter was 7.0 cm (IQR, 4.9-10 cm). The activity calculation method was reported in 59/95 (62%) patients, with body surface area being the most frequently used method (45/59, 76%). Median OS for the cohort was 14 months (95% confidence interval, 12-22). OS at 3, 6, 12, and 24 months was 94%, 80%, 63%, and 34%, respectively. Median OS was longer in patients without cirrhosis (19.1 vs 12.2 months, P = .05). Cirrhosis, previous chemotherapy (OS, 19.1 vs 10.6 months for treatment-naïve; P = .07), and imaging response at 6 months (OS, 16.4 vs 9.5 months for no response; P = .06) underwent regression analysis. Imaging response predicted OS at regression (hazard ratio, 0.39; P = .008). Grade 3-4 bilirubin toxicities were noted in 5 of 72 (7%) patients. Grade 3 albumin toxicity was noted in 1 of 72 (1.4%) patients. CONCLUSIONS: Objective response at 6 months predicted longer OS after TARE for intrahepatic cholangiocarcinoma. The incidence of liver function toxicity was <10%.

Preliminary findings of thermal safety in children's outdoor playhouses.

Children are less proficient at regulating internal body temperatures, especially during physical activity, increasing the potential for heat-related illnesses during periods of elevated outdoor temperatures. Recent studies suggest that playgrounds and bounce houses create microclimates with potentially dangerous conditions elevating the risk of heat-related illnesses. The present pilot study extends the inquiry to children's outdoor playhouses to determine if the same capability of creating microclimatic conditions of elevated thermal risk exists. Air temperature (°C) and relative humidity (%) measurements were collected from inside two playhouses and the outside ambient environment over a 6-h period on a clear, warm, summer day. Measurements were used to calculate the National Weather Service (NWS) heat index for both playhouses and the outside environment. Results from a Kruskal-Wallis test demonstrated significant differences (p < 0.001) and post hoc test procedures indicated that playhouse A and playhouse B had significantly higher heat index values than the outside environment. Little is known about the thermal risks created by children's outdoor play equipment. This study adds to the preliminary work in this field, but continued research is warranted to fully understand the thermal safety of children's outdoor play equipment.

Hepatocyte autophagy is linked to C/EBP-homologous protein, Bcl2-interacting mediator of cell death, and BH3-interacting domain death agonist gene expression.

BACKGROUND: Endoplasmic reticulum (ER) stress and autophagy each play important roles in hepatocyte cell injury. We hypothesized that gene expression of C/EBP-homologous protein (CHOP) and the BH3 proteins Bcl2-interacting mediator of cell death (BIM) and BH3-interacting domain death agonist (BID) are involved in a complex interplay that regulates ER stress-induced autophagy and cell death. MATERIALS AND METHODS: Hepatocytes were cultured from lean Zucker rats. Confluent hepatocytes were incubated with single or combined small interfering RNA for CHOP, BIM, and/or BID for 24 h providing gene inhibition. Incubation with tunicamycin (TM) for another 24 h stimulated ER stress. Quantitative real-time polymerase chain reaction determined the expression levels of CHOP, BIM, and BID. Immunostaining with microtubule-associated protein 1 light chain 3 measured autophagy activity. Trypan blue exclusion determined the cell viability. RESULTS: TM treatment increased the messenger RNA levels of CHOP and BIM but decreased the messenger RNA levels of BID. TM increased autophagy and decreased cell viability. Individual inhibition of CHOP, BIM, or BID protected against autophagy and cell death. However, simultaneous treatment with any combination of CHOP, BIM, and BID small interfering RNAs reduced autophagy activity but increased cell death independent of ER stress induction. CONCLUSIONS: Autophagy in hepatocytes results from acute ER stress and involves interplay, at the gene expression level, of CHOP, BIM, and BID. Inhibition of any one of these individual genes during acute ER stress is protective against cell death. Conversely, inhibition of any two of the three genes results in increased nonautophagic cell death independent of ER stress induction. This study suggests interplay between CHOP, BIM, and BID expression that can be leveraged for protection against ER stress-related cell death. However, disruption of the CHOP/BH3 gene expression homeostasis is detrimental to cell survival independent of other cellular stress.

Ameliorative effects of Bacopa monniera on lead-induced oxidative stress in different regions of rat brain.

Bacopa monniera is a rejuvenating herb for brain cells enhancing learning and cognitive ability. In the present investigation, the ameliorative effects of Bacopa monniera were examined against lead-induced oxidative stress in different regions of rat brain. Male rats were divided into five groups: control (1000 ppm sodium acetate) and exposed (1000 ppm lead acetate) for 4 weeks; DMSA (Meso-2,3-Dimercaptosuccinic acid)-treated (90 mg/kg body weight/day); Bacopa monniera-treated (BM) (10 mg/kg body weight/day) and a combination of BM + DMSA for seven consecutive days after 4 weeks of lead exposure. After treatment, the whole brain was isolated by sacrificing rats and four regions were separated namely cerebellum, hippocampus, frontal cortex and brain stem. Results indicated a significant (p < 0.05) increase in reactive oxygen species (ROS), lipid peroxidation products (LPP) and total protein carbonyl content (TPCC) in association with tissue metal content in all the four regions of brain for exposed group compared with their respective controls. However, the lead-induced ROS, LPP, TPCC and tissue metal content were lowered on treatment with Bacopa monniera, almost reaching the control group values in all the above brain regions compared to DMSA and a combination therapy. Results suggest that Bacopa monniera can mitigate the lead induced-oxidative stress tissue specifically by pharmacologic interventions which encompass both chelation as well as antioxidant functions.

In situ pulmonary mucus hydration assay using rotational and translational diffusion of gold nanorods with polarization-sensitive optical coherence tomography.

Significance: Assessing the nanostructure of polymer solutions and biofluids is broadly useful for understanding drug delivery and disease progression and for monitoring therapy. Aim: Our objective is to quantify bronchial mucus solids concentration (wt. %) during hypertonic saline (HTS) treatment in vitro via nanostructurally constrained diffusion of gold nanorods (GNRs) monitored by polarization-sensitive optical coherence tomography (PS-OCT). Approach: Using PS-OCT, we quantified GNR translational (DT) and rotational (DR) diffusion coefficients within polyethylene oxide solutions (0 to 3 wt. %) and human bronchial epithelial cell (hBEC) mucus (0 to 6.4 wt. %). Interpolation of DT and DR data is used to develop an assay to quantify mucus concentration. The assay is demonstrated on the mucus layer of an air-liquid interface hBEC culture during HTS treatment. Results: In polymer solutions and mucus, DT and DR monotonically decrease with increasing concentration. DR is more sensitive than DT to changes above 1.5 wt. % of mucus and exhibits less intrasample variability. Mucus on HTS-treated hBEC cultures exhibits dynamic mixing from cilia. A region of hard-packed mucus is revealed by DR measurements. Conclusions: The extended dynamic range afforded by simultaneous measurement of DT and DR of GNRs using PS-OCT enables resolving concentration of the bronchial mucus layer over a range from healthy to disease in depth and time during HTS treatment in vitro.

Effects of gene dosage and development on subcortical nuclei volumes in individuals with 22q11.2 copy number variations.

The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in a total of 385 scans from 22qDel (n = 96, scans = 191, 53.1% female), 22qDup (n = 37, scans = 64, 45.9% female), and TD controls (n = 80, scans = 130, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the linear effects of 22q11.2 gene dosage and non-linear effects of age were characterized with generalized additive mixed models (GAMMs). Positive gene dosage effects (volume increasing with copy number) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age-related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.

An Emerging Role for Sigma Receptor 1 in Personalized Treatment of Breast Cancer.

Despite the major progress in treating breast cancer, recurrence remains a problem and types such as triple-negative breast cancer still lack targeted medicine. The orphan Sigma receptor1 (SigmaR1) has emerged as a target in breast cancer, but its mechanism of action is unclear and hinders clinical utility. SigmaR1 is widely expressed in organ tissues and localized to various sub-cellular compartments, particularly the endoplasmic reticulum (ER), the mitochondrial-associated membranes (MAMs) and the nuclear envelope. As such, it involves diverse cellular functions, including protein quality control/ER stress, calcium signaling, cholesterol homeostasis, mitochondrial integrity and energy metabolism. Consequently, SigmaR1 has been implicated in a number of cancers and degenerative diseases and thus has been intensively pursued as a therapeutic target. Because SigmaR1 binds a number of structurally unrelated ligands, it presents an excellent context-dependent therapeutic target. Here, we review its role in breast cancer and the current therapies that have been considered based on its known functions. As SigmaR1 is not classified as an oncoprotein, we propose a model in which it serves as an oligomerization adaptor in key cellular pathways, which may help illuminate its association with variable diseases and pave the way for clinical utility in personalized medicine.

Spontaneous hemothorax in pregnant patient with pulmonary arteriovenous malformation.

We present a case of a 34-year-old pregnant patient at 26 weeks' gestation by in vitro fertilization with past medical history of hypertension and infertility who presented to the hospital with abdominal pain. The patient stated her pain was in her left upper quadrant. The morning before arriving to the hospital the patient stated she woke up at 0300 with increasingly severe pain in the same area. A computed tomography angiogram of the chest demonstrated a left-sided pulmonary arteriovenous malformation with adjacent complex left effusion on chest suspicious for a hemothorax. The hemothorax was thought to be brought about by rupture of the arteriovenous malformation with likely intermittent small volume hemorrhages into the pleural space. Thoracic Surgery and Interventional radiology (IR) were each consulted for management of the arteriovenous malformation. Due to the patient's stable hemodynamic status and concern that an invasive procedure might enable a larger rupture and more substantial hemorrhage, the decision was made for embolization of the arteriovenous malformation.

Stress, Coping, and Physical Health in Caregiving.

Informal caregivers experience a great deal of stress due to care-related duties and responsibilities. Caregiving stress has the ability to impact caregivers' physical health, but has been largely understudied in caregivers of children with a chronic illness. In this study, we examine the associations of stress to both caregiver self-rated health and biomarkers of the hypothalamic-pituitary-adrenal (HPA) axis and immune systems (arginine vasopressin, c-reactive protein, tumor necrosis factor alpha). We also examine whether coping style (proactive, avoidant, support coping) buffers the links of stress to health across two different stressor contexts: caregiving for a child with a rare or undiagnosed disease (n = 101) and caregiving for a typically developing child (n = 69). Results indicated perceived stress was linked to worse self-rated health, however, stress was only linked to biological markers of health for caregivers of typically developing children. Results also suggest that coping style may moderate some of the links of stress to health, as proactive coping was linked to lower arginine vasopressin. However, models also suggested the role of coping style may differ based on caregiving context, as support coping was linked to better health only for caregivers of typically developing children, and more proactive coping overall was observed in the rare disease context. Future research should continue to examine how stress and coping interact within different caregiving contexts to protect caregiver health and well-being.

Effects of Gene Dosage and Development on Subcortical Nuclei Volumes in Individuals with 22q11.2 Copy Number Variations.

The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in 22qDel (n=96, 53.1% female), 22qDup (n=37, 45.9% female), and TD controls (n=80, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the effect of 22q11.2 gene dosage was examined using linear mixed models. Age-related changes were characterized with general additive mixed models (GAMMs). Positive gene dosage effects (22qDel < TD < 22qDup) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age-related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.

A method for revision of a foreshortened transjugular intrahepatic portosystemic shunt (TIPS) stent using transhepatic trans-stent access.

The high technical success rate of transjugular intrahepatic portosystemic shunt (TIPS) placement makes the procedure a popular treatment option for symptomatic portal hypertension. Among the major drawbacks of the procedure - hepatic encephalopathy, acute hepatic failure, hemorrhage, biliary injury - TIPS dysfunction is one of the most prevalent, often requiring endovascular reintervention. Conventional techniques for shunt revision rely on transjugular access to the stent; but in technically difficult cases of abnormal angulation or severe stenosis, transhepatic access may also be required. The pull-through method utilizes both transjugular and transhepatic access to achieve stable through-and-through access in order to advance a sheath into the stent and recannulate the shunt. In the case of TIPS foreshortening, however, the distal end of the stent may abut the wall of the hepatic vein, jailing it off and obviating the advancement of a wire out of that end. We present here a case of a modified pull-through method for TIPS revision whereby a transhepatic wire is passed through the interstices of the stent at the distal end to enter into the hepatic vein and IVC. Subsequent snaring of the wire at the transjugular end establishes through-and-through access, and balloon dilation through the interstices allows for insertion of a transjugular sheath into the TIPS stent for recanalization. Our case highlights how the modified pull-through method, using trans-stent access, can be safely performed in patients with a foreshortened TIPS that abuts against the hepatic and portal vessel walls.

Electrochemically Desulfurized Molybdenum Disulfide (MoS2) and Reduced Graphene Oxide Aerogel Composites as Efficient Electrocatalysts for Hydrogen Evolution.

Recent developments in graphene related materials including molybdenum disulfide (MoS2) is gaining popularity as efficient and cost-effective nanoscale electrocatalyst essential for hydrogen production. These "clean" energy technologies require delicate control over geometric, morphological, chemical and electronic structure affecting physical and electrochemical catalytic properties. In this work, we prepared three-dimensional hierarchical mesoporous aerogels consisting of two-dimensional functionalized graphene and MoS2 nanosheets of varying ratio of components under hydrothermal-solvothermal conditions (P <20 bar, T <200 °C). We systematically characterized these hybrid aerogels in terms of surface morphology, microstructure, understand heterointerfaces interaction through electron microscopy, X-ray diffraction, optical absorption and emission and Raman spectroscopy, besides electrochemical properties prior to and post electrochemical desulfurization that induces finely controlled sulfur vacancies. They feature enhanced electrical conductivity by means of eliminating contact resistance and meso-/nanoporous structure facilitating faster ion diffusion (mass transport). We demonstrate that controlled defects density, edges plane sites (nanowalls), mesoscale porosity and topological interconnectedness (monolithic aerogel sheets) invoked can accelerate electrocatalytic hydrogen production. For instance, low over potential with Tafel slope ~77 mV·dec-1 for 60 wt.% MoS2, highcurrent density, and good stability was achieved with desulfurization. These results are compared with continuous multilayer MoS2 films highlighting the multiple role of tunable structure and electronic properties. The adjacent S-vacancy defectsinduced increase in density of states, dissociation and confinement of water molecules at the pore edge and planar S-vacancy sites calculated using density functional theory helped in establishing improved heterogeneous electrocatalytic rate. This is supported with combined measurements of diffusion coefficient and heterogeneous electron transfer rate via surface-sensitive scanning electrochemical microscopy (SECM) technique.

Clinical predictors of early death from sepsis.

PURPOSE: Patients with severe sepsis who experience rapid, early deterioration and death are of particular concern. Our objective was to identify predictors of early death in Emergency Department (ED) patients with severe sepsis. METHODS: Secondary analysis of two prospective studies of adult ED patients with severe sepsis. The primary outcome was early death, defined as death within 24h of triage. RESULTS: Out of 410 severe sepsis admissions, 20 patients experienced early death. These patients demonstrated significantly higher initial lactate (7.3 versus 3.3mmol/L, p<0.001) and modified SOFA (mSOFA) scores (10 vs 6, p<0.001), were less likely to normalize their lactate (p<0.001), had lower initial pH (p<0.001), and more frequently had early positive blood cultures (p=0.021). Multivariable logistic regression identified initial serum lactate level (OR 1.19, 95% CI 1.06-1.35) and mSOFA score (OR 1.17, 95% CI 1.00-1.36) as independent predictors of early death. A repeat lactate≥5mmol/L had a sensitivity of 55% and specificity of 89% for early death. There were no significant treatment differences between groups. CONCLUSION: Initial serum lactate and mSOFA score were independent predictors of mortality within 24h of ED admission in patients with severe sepsis.

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept.

Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HTExt) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HTExt beyond the SSRI effect enhances antidepressant efficacy, but previous such drug strategies had prohibitive limitations. In humans, adjunct treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) elevates 5-HTExt beyond the SSRI effect. Small pilot trials suggest that adjunct 5-HTP can confer antidepressant response in treatment-resistant depression (TRD). However, sustained, stable 5-HTExt elevation is required for antidepressant effect; therefore, the rapid absorption and elimination of standard 5-HTP immediate release (IR) likely curtail 5-HTP IR's antidepressant potential. Slow-release (SR) drug delivery can crucially improve efficacy and safety of rapidly absorbed and eliminated compounds. Here we tested in mice the hypothesis that SR delivery will substantially improve 5-HTP's drug properties, by minimizing adverse effects and securing sustained 5-HTExt elevation beyond the SSRI effect. We modeled 5-HTP SR with minipumps, 5-HTP IR with injections, and chronic SSRI with dietary fluoxetine. We tested adjunct 5-HTP SR in wild-type mice and in mice with low brain 5-HT owing to expression of a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2. In both lines of mice, adjunct 5-HTP SR synergized with SSRI to elevate 5-HTExt beyond the SSRI effect. We observed no adverse effect. Adjunct 5-HTP IR could not produce this therapy-like profile, producing transient 5-HTExt spikes and marked adverse effects. Integrated with a body of clinical data, our mouse data suggest that an adjunct 5-HTP SR drug could safely and effectively elevate 5-HTExt beyond the SSRI effect and represent a novel treatment for TRD.

The long-term burden of severe sepsis and septic shock: Sepsis recidivism and organ dysfunction.

BACKGROUND: Severe sepsis and septic shock mortality has improved; however, rates of persistent (28-90 days) and long-term (>90 day) organ dysfunction in sepsis survivors are unknown. METHODS: Secondary analysis of a prospective cohort of adult emergency department patients with severe sepsis. RESULTS: Of 110 sepsis admissions, we obtained follow-up on 51 of 78 survivors of whom 41% (21 of 51) had persistent organ dysfunction: pulmonary, 18% (9 of 51); renal, 22% (11 of 51); coagulopathy, 10% (5 of 51); cardiovascular, 6% (3 of 51); hepatic, 2% (1 of 51); and neurologic, 3% (3 of 51). We obtained follow-up on 40 of 73 survivors at more than 90 days of whom 38% (15 of 40) had long-term organ dysfunction: pulmonary, 13% (5 of 40); renal, 18% (7 of 40); coagulopathy, 3% (1 of 40); cardiovascular, 5% (2 of 40); hepatic, 0%; and neurologic, 5% (2 of 40). Readmission rate within 90 days was 32% (25 of 78), and recurrent sepsis was the cause of readmission in 52% (13 of 25). Baseline SOFA scores from the index sepsis admission were compared using Wilcoxon rank-sum test and were significantly different in participants with organ dysfunction versus those without organ dysfunction at less than 90 days (z, -2.51; p = 0.01). CONCLUSION: Readmission with recurrent sepsis and organ dysfunction occurs frequently in sepsis survivors. Baseline SOFA score may be predictive of sepsis recidivism and persistent or recurrent organ dysfunction. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level IV.

The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse.

RATIONALE: Escitalopram appears to be a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, there by curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and hence anti-depressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram's inhibition here of. OBJECTIVES: Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5-HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram. METHODS: Recombinant generation of hSERT transgenic mice; in vivo microdialysis; SERT binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying). RESULTS: We generated mice expressing either the wild-type human SERT (hSERT(WT)) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERT(ALI/VFL+SI/TT)). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. The hSERT mice showed normal basal 5-HTExt levels. Escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co-treatment and was unaffected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small and tended to be enhanced by R-citalopram co-administration. CONCLUSIONS: We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram.