Too sensitive or not sensitive enough? Sensitivity to context and justice-involved youths' response to violence exposure.

With high rates of violence exposure among justice-involved youth, it is critical to identify factors that might impact the likelihood of youth engaging in violence themselves. One such factor is sensitivity to context, which describes how sensitive youth are to experiences in their environment. Using an ethnically diverse sample of justice-involved male adolescents (47% Latino, 38% Black/African American, 15% White) aged 13-17 at the time of their first arrest, the results of this study indicate that exposure to violence was related to increased violent behavior six months later, and this effect was strongest among youth who were low in sensitivity to context. These findings may help practitioners identify which youth are at greatest risk for violence in a policy-relevant population.

Typologies of Family Dependency Treatment Court Participants: Parental Characteristics and Differential Child Placement Outcomes.

Background: Family Dependency Treatment Court (FDTC) is a problem-solving court for parents who have child welfare involvement and designed to address parental substance misuse by providing treatment and wrap-around services, with the goal of reunifying parents with their children. Objectives: This study aimed to identify different classes of FDTC parents and compare how child placement outcomes differ by class. Parental characteristics and permanent placement outcomes for 354 parents participating in a Central Florida FDTC were assessed using administrative data. An exploratory latent class analysis was conducted to classify parents. Results: Results revealed three distinct classes of FDTC participants: 1) co-occurring issues, 2) racial/ethnic minority participants, and 3) prescription opioid, meth, and heroin users. Regression analyses showed that parents with co-occurring issues were over two times more likely to achieve permanency (OR = 2.05, p < .05), and were two times less likely to terminate their parental rights (TPR) compared to the other two classes. Conclusions: Implications for tailoring FDTC procedures to parents' individual needs, combating racial/ethnic disparities in access to services and placement outcomes, and improved child welfare and placement outcomes are discussed.

The Association between Gut Microbiota and Osteoarthritis: Does the Disease Begin in the Gut?

Some say that all diseases begin in the gut. Interestingly, this concept is actually quite old, since it is attributed to the Ancient Greek physician Hippocrates, who proposed the hypothesis nearly 2500 years ago. The continuous breakthroughs in modern medicine have transformed our classic understanding of the gastrointestinal tract (GIT) and human health. Although the gut microbiota (GMB) has proven to be a core component of human health under standard metabolic conditions, there is now also a strong link connecting the composition and function of the GMB to the development of numerous diseases, especially the ones of musculoskeletal nature. The symbiotic microbes that reside in the gastrointestinal tract are very sensitive to biochemical stimuli and may respond in many different ways depending on the nature of these biological signals. Certain variables such as nutrition and physical modulation can either enhance or disrupt the equilibrium between the various species of gut microbes. In fact, fat-rich diets can cause dysbiosis, which decreases the number of protective bacteria and compromises the integrity of the epithelial barrier in the GIT. Overgrowth of pathogenic microbes then release higher quantities of toxic metabolites into the circulatory system, especially the pro-inflammatory cytokines detected in osteoarthritis (OA), thereby promoting inflammation and the initiation of many disease processes throughout the body. Although many studies link OA with GMB perturbations, further research is still needed.

On the Relationship between Safety and Decision Significance.

Risk analysts are often concerned with identifying key safety drivers, that is, the systems, structures, and components (SSCs) that matter the most to safety. SSCs importance is assessed both in the design phase (i.e., before a system is built) and in the implementation phase (i.e., when the system has been built) using the same importance measures. However, in a design phase, it would be necessary to appreciate whether the failure/success of a given SSC can cause the overall decision to change from accept to reject (decision significance). This work addresses the search for the conditions under which SSCs that are safety significant are also decision significant. To address this issue, the work proposes the notion of a θ-importance measure. We study in detail the relationships among risk importance measures to determine which properties guarantee that the ranking of SSCs does not change before and after the decision is made. An application to a probabilistic safety assessment model developed at NASA illustrates the risk management implications of our work.

Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2 : role of carotid body CO2.

We asked if the type of carotid body (CB) chemoreceptor stimulus influenced the ventilatory gain of the central chemoreceptors to CO2 . The effect of CB normoxic hypocapnia, normocapnia and hypercapnia (carotid body PCO2 ≈ 22, 41 and 68 mmHg, respectively) on the ventilatory CO2 sensitivity of central chemoreceptors was studied in seven awake dogs with vascularly-isolated and extracorporeally-perfused CBs. Chemosensitivity with one CB was similar to that in intact dogs. In four CB-denervated dogs, absence of hyper-/hypoventilatory responses to CB perfusion with PCO2 of 19-75 mmHg confirmed separation of the perfused CB circulation from the brain. The group mean central CO2 response slopes were increased 303% for minute ventilation (V̇I)(P ≤ 0.01) and 251% for mean inspiratory flow rate (VT /TI ) (P ≤ 0.05) when the CB was hypercapnic vs. hypocapnic; central CO2 response slopes for tidal volume (VT ), breathing frequency (fb ) and rate of rise of the diaphragm EMG increased in 6 of 7 animals but the group mean changes did not reach statistical significance. Group mean central CO2 response slopes were also increased 237% for V̇I(P ≤ 0.01) and 249% for VT /TI (P ≤ 0.05) when the CB was normocapnic vs. hypocapnic, but no significant differences in any of the central ventilatory response indices were found between CB normocapnia and hypercapnia. These hyperadditive effects of CB hyper-/hypocapnia agree with previous findings using CB hyper-/hypoxia.We propose that hyperaddition is the dominant form of chemoreceptor interaction in quiet wakefulness when the chemosensory control system is intact, response gains physiological, and carotid body chemoreceptors are driven by a wide range of O2 and/or CO2 .

Pathophysiology of human ventilatory control.

We review the substantial recent progress made in understanding the underlying mechanisms controlling breathing and the applicability of these findings to selected human diseases. Emphasis is placed on the sites of central respiratory rhythm and pattern generation as well as newly described functions of the carotid chemoreceptors, the integrative nature of the central chemoreceptors, and the interaction between peripheral and central chemoreception. Recent findings that support critical contributions from cortical central command and muscle afferent feedback to exercise hyperpnoea are also reviewed. These basic principles, and the evidence supporting chemoreceptor and ventilatory control system plasticity during and following constant and intermittent hypoxaemia and stagnant hypoxia, are applied to: 1) the pathogenesis, consequences and treatment of obstructive sleep apnoea; and 2) exercise hyperpnoea and its control and limitations with ageing, chronic obstructive pulmonary disease and congestive heart failure.

Tissue penetration and antimicrobial activity of standard- and high-dose trimethoprim/sulfamethoxazole and linezolid in patients with diabetic foot infection.

OBJECTIVES: The purpose of this study was to conduct a pharmacokinetic and pharmacodynamic evaluation of high (320/1600 mg) and standard (160/800 mg) doses of trimethoprim/sulfamethoxazole and linezolid in outpatients with mild diabetic foot infections (DFIs). METHODS: Both viable skin/soft tissue from the infection site and serum were obtained at various times after antibiotic administration from 18 patients (6 per study group) being treated with linezolid, standard doses of trimethoprim/sulfamethoxazole or high doses of trimethoprim/sulfamethoxazole during a follow-up clinic visit. These samples were assayed for drug concentrations by liquid chromatography in tandem with mass spectrometry. Patient sera were also utilized in time-kill assays against two strains of Staphylococcus aureus and three strains of ß-haemolytic streptococci. RESULTS: The mean tissue/serum ratio for linezolid was 0.46 (range, 0.18-0.71). The mean tissue/serum ratio for trimethoprim was 1.2 (range, 0.3-4.5) for both standard and high doses, and 0.23 (range, 0.1-0.46) and 0.36 (range, 0.14-1.28) for standard and high doses of sulfamethoxazole, respectively. Linezolid exhibited inhibitory activity in time-kill assays against strains of S. aureus (0.45 ± 0.5 log10 cfu/mL) and ß-haemolytic streptococci (2.2 ± 0.6 log10 cfu/mL), while trimethoprim/sulfamethoxazole exhibited bactericidal (>3 log kill) activity against all of these isolates. These findings were consistent for each sampling time and for high as well as standard doses of trimethoprim/sulfamethoxazole. CONCLUSIONS: This pharmacokinetic/pharmacodynamic study found that trimethoprim/sulfamethoxazole exhibits good skin/soft tissue penetration in patients with DFIs as well as bactericidal activity in serum against strains of S. aureus and ß-haemolytic streptococci.

Pharmacokinetics and monte carlo simulations of doripenem in patients with febrile neutropenia.

BACKGROUND: Doripenem is a group 2 carbapenem with enhanced in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. There is a paucity of pharmacokinetic/pharmacodynamic data on doripenem in patients with febrile neutropenia. OBJECTIVE: To conduct a pharmacokinetic evaluation of 2 doses of doripenem in patients with febrile neutropenia and provide probability estimates of attaining effective drug exposure against common gram-negative pathogens. METHODS: We obtained multiple blood samples from 12 adults with febrile neutropenia who were receiving either 500 mg or 1000 mg of intravenous doripenem over 4 hours every 8 hours. Following at least 2 doses, serum concentrations were measured in each subject at 1, 4, 6, and 8 hours after initiation of a dose by a validated high-performance liquid chromatography assay. The derived pharmacokinetic parameters from these serum levels were used to perform a 5000-patient Monte Carlo simulation against bacteria with minimal inhibitory concentrations (MICs) of 0.008-64 mg/L to determine probability estimates of the time in which unbound drug concentrations remain above the MIC (fT(>MIC)). RESULTS: The mean pharmacokinetic parameters in these patients were a volume of distribution of 43.9 L, an elimination rate constant of 0.37 h(-1), a total clearance of 14.4 L/h, and an area under the concentration-time curve of 57.6 mg•h/L. An optimal probability of target attainment (40% fT(>MIC)) of 90% was obtained against bacteria with MICs ≤2 mg/L and ≤4 mg/L with 500-mg and 1000-mg doses, respectively. Adverse events associated with doripenem were not observed. CONCLUSIONS: The findings from this analysis of doripenem suggest that higher doses, as well as prolonged infusions, may be necessary to optimally treat selected gram-negative bacteria (eg, P. aeruginosa) in patients with febrile neutropenia.

Role of central/peripheral chemoreceptors and their interdependence in the pathophysiology of sleep apnea.

Unstable periodic breathing with intermittent ventilatory overshoots and undershoots commonly occurs in chronic heart failure, in hypoxia, with chronic opioid use and in certain types of obstructive sleep apnea. Sleep promotes breathing instability because it unmasks a highly sensitive dependence of the respiratory control system on chemoreceptor input, because transient cortical arousals promote ventilatory overshoots and also because upper airway dilator muscle tonicity is reduced and airway collapsibility enhanced. We will present data in support of the premise that carotid chemoreceptors are essential in the pathogenesis of apnea and periodicity; however it is the hyperadditive influence of peripheral chemoreceptor sensory input on central chemosensitivity that accounts for apnea and periodic breathing. This chemoreceptor interdependence also provides a significant portion of the normal drive to breathe in normoxia (i.e. eupnea) and in acute hypoxia. Finally, we discuss the effects of preventing transient hypocapnia (via selective increases in FICO(2)) on centrally mediated types of periodic breathing and even some varieties of cyclical obstructive sleep apnea.

Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO(2).

We assessed the contribution of carotid body chemoreceptors to the ventilatory response to specific CNS hypercapnia in eight unanaesthetized, awake dogs. We denervated one carotid body (CB) and used extracorporeal blood perfusion of the reversibly isolated remaining CB to maintain normal CB blood gases (normoxic, normocapnic perfusate), to inhibit (hyperoxic, hypocapnic perfusate) or to stimulate (hypoxic, normocapnic perfusate) the CB chemoreflex, while the systemic circulation, and therefore the CNS and central chemoreceptors, were exposed consecutively to four progressive levels of systemic arterial hypercapnia via increased fractional inspired CO(2) for 7 min at each level. Neither unilateral CB denervation nor CB perfusion, per se, affected breathing. Relative to CB control conditions (normoxic, normocapnic perfusion), we found that CB chemoreflex inhibition decreased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 19% of control values (range 0-38%; n = 6), whereas CB chemoreflex stimulation increased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 223% of control values (range 204-235%; n = 4). We conclude that the gain of the CNS CO(2)/H(+) chemoreceptors in dogs is critically dependent on CB afferent activity and that CNS-CB interaction results in hyperadditive ventilatory responses to central hypercapnia.

A reanalysis of competing hypotheses for the spread of the California sea otter.

From 1938 to 1972, the range of California sea otters (Enhydra lutris nereis) expanded with the northern and southern fronts spreading at rates of approximately 1.4 km/yr and 3.1 km/yr, respectively. J. A. Lubina and S. A. Levin proposed the following three factors to explain the large disparity in spread rates: (1) regional differences in dispersal; (2) regional differences in population growth; and (3) advection due to the known presence of a southerly flowing offshore current. While Lubina and Levin used a reaction-diffusion framework to argue for large differences in dispersal, our approach uses a stage-structured integrodifference matrix model to show that relatively minor differences in survival provide a more parsimonious explanation for the disparity in spread rates; especially if the survival rates between the northern and southern groups differ in more than one life stage. The argument is made that many of the present estimates for otter survival rates span intervals wide enough to explain the different spread rates--even more so in the likely case that advection plays at least a minor role in otter movement.

Contribution of the carotid body chemoreceptors to eupneic ventilation in the intact, unanesthetized dog.

We used extracorporeal perfusion of the reversibly isolated carotid sinus region to determine the effects of specific carotid body (CB) chemoreceptor inhibition on eupneic ventilation (Vi) in the resting, awake, intact dog. Four female spayed dogs were studied during wakefulness when CB was perfused with 1) normoxic, normocapnic blood; and 2) hyperoxic (>500 mmHg), hypocapnic ( approximately 20 mmHg) blood to maximally inhibit the CB tonic activity. We found that CB perfusion per se (normoxic-normocapnic) had no effect on Vi. CB inhibition caused marked reductions in Vi (-60%, range 49-80%) and inspiratory flow rate (-58%, range 44-87%) 24-41 s following the onset of CB perfusion. Thereafter, a partial compensatory response was observed, and a steady state in Vi was reached after 50-76 s following the onset of CB perfusion. This steady-state tidal volume-mediated hypoventilation ( approximately 31%) coincided with a significant reduction in mean diaphragm electromyogram (-24%) and increase in mean arterial pressure (+12 mmHg), which persisted for 7-25 min until CB perfusion was stopped, despite a substantial increase in CO(2) retention (+9 Torr, arterial Pco(2)) and systemic respiratory acidosis. We interpret these data to mean that CB chemoreceptors contribute more than one-half to the total eupneic drive to breathe in the normoxic, intact, awake animal. We speculate that this CB contribution consists of both the normal tonic sensory input from the CB chemoreceptors to medullary respiratory controllers, as well as a strong modulatory effect on central chemoreceptor responsiveness to CO(2).

Carotid chemoreceptor modulation of regional blood flow distribution during exercise in health and chronic heart failure.

Previous work has shown sensitization of carotid chemoreceptor (CC) responsiveness during exercise as well as in chronic heart failure (CHF). Accordingly, we hypothesized that the CCs contribute to the sympathetic restraint of skeletal muscle blood flow during exercise and CHF. We examined the effect of transient CC inhibition on total (Con(T)) and hindlimb (Con(L)) conductance, and blood pressure at rest and during exercise (2.5 miles per hour, 5% grade) in chronically instrumented dogs. Via a carotid arterial catheter, CCs were inhibited using dopamine (5 to 10 microg/kg) or hyperoxic lactated Ringer's solution. Although vasodilation did not occur with CC inhibition in resting healthy dogs, CC inhibition during exercise caused an immediate vasodilatory response (increase in Con(T) and Con(L) and decrease in blood pressure). When comparing the peak Con(L) response from CC inhibition versus alpha-adrenergic blockade (phentolamine), we found that the CCs accounted for approximately one-third of the total sympathetic restraint during exercise. CHF was then induced by chronic rapid cardiac pacing and characterized by impaired cardiac function, enhanced chemosensitivity, and greater sympathetic restraint at rest and during exercise. In contrast to healthy dogs, CC inhibition in resting CHF dogs produced vasodilation, whereas a similar vasodilatory response was observed during exercise in CHF as compared with healthy dogs. The vasodilation following CC inhibition during exercise and in CHF was abolished with alpha-adrenergic blockade and was absent in healthy exercising animals after carotid body denervation. These results establish an important role for the CCs in cardiovascular control in the healthy animal during exercise and in the CHF animal both at rest and during exercise.

Outpatient weight loss surgery: initiating a gastric bypass and gastric banding ambulatory weight loss surgery center.

BACKGROUND: Ambulatory surgery or outpatient surgery is becoming increasingly common. In 2002, 63% of all operations performed in the United States were ambulatory procedures. Bariatric procedures performed in the United States have increased from 16,200 in 1992 to approximately 205,000 in 2007. In 2002, our center began offering laparoscopic Roux-en-Y gastric bypass (LRYGB) procedures on an outpatient basis for select candidates at an ambulatory surgery center (ASC). We subsequently added laparoscopic adjustable gastric band procedures (LAGB) in 2005. METHODS: Between 2002 and 2008, 248 LRYGB and LAGB patients were carefully selected for ASC surgery by the bariatric surgeon and medical director. Extensive preoperative education was mandatory for all surgical candidates. RESULTS: Since 2002, we have performed 248 bariatric cases at the ASC, including 38 LRYGB and 210 LAGB procedures. In this overall experience, 5 patients (2%) required readmission within 30 days of surgery, and 98.6% of LAGB patients were discharged the same day; 62% were discharged after a 4-hour to 6-hour stay in the ASC. All LRYGB patients remained in the ASC overnight and were discharge within 24 hours of their procedure. Weight loss results have been excellent. CONCLUSION: LAGB surgery can be safely performed in an ASC setting in most patients. LRYGB can be performed safely in the ASC setting with careful scrutiny and cautious selection of patient candidates.

Update on Chemoreception: Influence on Cardiorespiratory Regulation and Pathophysiology.

We examine recent findings that have revealed interdependence of function within the chemoreceptor pathway regulating breathing and sympathetic vasomotor activity and the hypersensitization of these reflexes in chronic disease states. Recommendations are made as to how these states of hyperreflexia in chemoreceptors and muscle afferents might be modified in treating sleep apnea, drug-resistant hypertension, chronic heart failure-induced sympathoexcitation, and the exertional dyspnea of chronic obstructive pulmonary disease.

The Relationship Between Mixed Race/Ethnicity, Developmental Assets, and Mental Health Among Youth.

This study assessed whether high school youth with mixed race/ethnicity are at greater risk for poor mental health conditions compared to their single race/ethnic counterparts and whether this mental health risk can be mitigated by youth developmental assets regardless of one's race/ethnicity. Methods involved secondary data analysis of the 2009-2013 Youth Risk Behavioral Survey-Anchorage, Alaska subsample. Difference in rates of mental health conditions and mean number of developmental assets (protective factors) were assessed among three racial/ethnic groups. Logistic regression models tested whether race/ethnicity has an independent association with mental health conditions and whether there is an interaction effect between race/ethnicity and protective factors. Results show that, compared to white students, mixed race/ethnic students have significantly higher rates of poor mental health condition and significantly fewer protective factors. A significant interaction effect between race/ethnicity and protective factors was also found, showing decreasing likelihood of poor mental health condition with increasing number of protective factors among all racial/ethnic groups. However, this effect was more pronounced among white students compared to both mixed and single race/ethnicity minority students. Study findings indicate that youth of mixed race/ethnicity are more likely to be at risk for poor mental health outcomes, yet less likely to mitigate this risk even with similar number of external developmental assets as their single race/ethnic counterparts. More research is needed to further understand the differential effect of certain developmental assets among different racial/ethnic groups.

Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients.

BACKGROUND: The pharmacokinetics, especially the volume of distribution (Vd), of ß-lactam antibiotics can be altered in critically ill patients. This can lead to decreased serum concentrations and a reduction in clinical cures. Ceftazidime/avibactam (CZA) is a new antimicrobial agent utilized in critically ill patients although its pharmacokinetics has not been well defined in these patients. PATIENTS AND METHODS: In this study, the serum concentrations of CZA from adult patients treated in an intensive care unit (ICU) with standard dosing regimens were measured and both pharmacokinetic and pharmacodynamic parameters were computed. The pharmacodynamic analyses included Monte Carlo simulations to determine the probability of target attainment (PTA: free ceftazidime concentrations exceed the minimum inhibitory concentration [MIC] for 50% of the dosing interval; free avibactam concentrations exceed 1 mg/L over the dosing interval) and serum time-kill curves against multi-drug-resistant Enterobacteriaceae susceptible to CZA. Serum concentrations were measured in 10 critically ill patients at two, four, six, and eight hours after multiple doses (infused over two hours) of CZA. RESULTS: A significant linear relation between creatinine clearance and total body clearance was identified for both ceftazidime (R = 0.91) and avibactam (R = 0.88). The mean clearance, volume of distribution, and half-life for ceftazidime were 6.1 ± 3.8 L/h, 35 ± 10.5 L, and 4.8 ± 2.15 h, respectively. For avibactam, these values were 11.1 ± 6.8 L/h, 50.8 ± 14.3 L, and 4.1 ± 2.1 h, respectively. Ceftazidime/avibactam achieved optimal PTA for bacteria with MICs of 16 mg/L or less. Furthermore, time-kill experiments revealed that serum concentrations of CZA, at each collection time, exhibited bactericidal (≥ 3 log10 CFU/mL reduction) activity against each of the study isolates. CONCLUSION: In conclusion, our study results suggest that the current dosing regimens of CZA can provide effective antimicrobial activity in ICU patients against CZA-susceptible (MIC ≤8 mg/L) isolates.

Seven cases of gastric perforation in Roux-en-Y gastric bypass patients: what lessons can we learn?

BACKGROUND: Patients undergoing Roux-en-Y gastric bypass for the resolution of morbid obesity have significant medical sequelae related to their weight. One of the most common comorbid conditions is joint pain requiring the use of non-steroidal anti-inflammatory medications (NSAIDs). In addition to NSAIDs, patients may engage in behaviors such as smoking and alcohol misuse that increase the risk of long-term postoperative complications to include gastric perforation. METHODS: Data on 1,690 patients undergoing gastric bypass surgery were collected prospectively and reviewed retrospectively. RESULTS: We identified seven patients who presented to an emergency room and subsequently required emergent surgical intervention for repair of gastric perforation. Six of the seven cases involved use or abuse of NSAIDs. CONCLUSION: Important characteristics were identified including the use of NSAIDs, alcohol use, and non-compliance with routine long-term postoperative follow-up. Identifying those patients at high risk may decrease the incidence of this potentially life-threatening complication.