Ethical and Clinical Considerations During the Coronavirus Era.

The practice of child and adolescent psychiatry is evolving during an unprecedented global health catastrophe, the coronavirus disease 2019 (COVID-19) pandemic. As child and adolescent psychiatrists grapple with COVID-19's enormous medical, educational, social, and economic toll, a mental health crisis is co-occurring. Pre-existing disparities are recognized as contributors to the disproportionate impact of the COVID-19 pandemic on racial and ethnic minorities.1 The magnitude of COVID-19's effects on child and family mental health has yet to be fully revealed. child and adolescent psychiatrists are in a unique position to address this mental health crisis. Child and adolescent psychiatrists must stay up-to-date regarding federal, state, local, and institutional mandates, regulations, and policies informed by the Centers for Disease Control and Prevention2 and other public health institutions, while also navigating the ethical dilemmas unique to child and adolescent psychiatry during the coronavirus era.

The Role of Parental Capacity for Medical Decision-Making in Medical Ethics and the Care of Psychiatrically Ill Youth: Case Report.

Introduction: Parents/legal guardians are medical decision-makers for their minor children. Lack of parental capacity to appreciate the implications of the diagnosis and consequences of refusing recommended treatment may impede pediatric patients from receiving adequate medical care. Child and adolescent psychiatrists (CAPs) need to appreciate the ethical considerations relevant to overriding parental medical decision-making when faced with concerns for medical neglect. Methods: Two de-identified cases illustrate the challenges inherent in clinical and ethical decision-making reflected in concerns for parental capacity for medical decision-making. Key ethical principles are reviewed. Case 1: Treatment of an adolescent with an eating disorder ethically complex due to the legal guardian's inability to adhere with treatment recommendations leading to the patient's recurrent abrupt weight loss. Case 2: Questions of parental decisional capacity amid treatment of an adolescent with schizoaffective disorder raised due to parental mistrust of diagnosis, disagreement with treatment recommendations, and lack of appreciation of the medical severity of the situation with repeated discharges against medical advice and medication nonadherence. Discussion: Decisions to question parental capacity for medical decision-making when risk of imminent harm is low but concern for medical neglect exists are controversial. Systematic review of cases concerning for medical neglect benefits from the assessment of parental decisional capacity, review of ethical standards and principles. Conclusion: Recognition of the importance of parental decision-making capacity as relates to parental autonomy and medical neglect and understanding key ethical principles will enhance the CAP's capacity in medical decision-making when stakes are high and absolute recommendations are lacking.

Proteasome limits plasticity-related signaling to the nucleus in the hippocampus.

Proteolysis by the ubiquitin-proteasome pathway has pleiotropic effects on both induction and maintenance of long-term synaptic plasticity. In this study, we examined the effect of proteasome inhibition on signaling to the nucleus during late-phase long-term potentiation. When a subthreshold L-LTP induction protocol was used, proteasome inhibition led to a significant increase in phosphorylated CREB (pCREB) in the nucleus. Inhibitors of cAMP-dependent protein kinase/protein kinase A, extracellular signal-regulated kinase and cGMP-dependent protein kinase/protein kinase G all blocked the proteasome-inhibition-mediated increase in nuclear pCREB after subthreshold stimulation. These results lay the groundwork for understanding a novel role for the proteasome in limiting signaling to the nucleus in the absence of adequate synaptic stimulation.

Age-dependent changes in brain hydration and synaptic plasticity.

Aging in humans and animals is associated with gradual and variable changes in some cognitive functions, but what causes them and explains individual variations remains unclear. Hydration decreases with aging but whether dehydration contributes to cognitive dysfunction is not known. The brain hydration of aging mice was determined by colloidosmotic-pressure titration. Dehydration increased with age from ∼76 mmHg at 6 weeks to ∼105 mmHg at 40 weeks, or a progressive ∼10 percent loss of brain water but seemed to level off afterward. When we adjusted dehydration in hippocampal slices of <8-week-old mice to the levels seen in mice 40 weeks and older, their basal synaptic responses were amplified at all stimulus voltages tested, but induction of late-phase long-term potentiation was impaired. Our results document progressive brain dehydration with age in inbred mice to levels at which in vitro synaptic plasticity appears dysregulated. They also suggest that dehydration contributes to some of the changes in synaptic plasticity observed with aging, possibly due to adjustments in neuronal excitation mechanisms.

Local fluid transfer regulation in heart extracellular matrix

The interstitial myocardial matrix is a complex and dynamic structure that adapts to local fluctuations in pressure and actively contributes to the heart's fluid exchange and hydration. However, classical physiologic models tend to treat it as a passive conduit for water and solute, perhaps because local interstitial regulatory mechanisms are not easily accessible to experiment in vivo. Here, we examined the interstitial contribution to the fluid-driving pressure ex vivo. Interstitial hydration potentials were determined from influx/efflux rates measured in explants from healthy and ischemia-reperfusion-injured pigs during colloid osmotic pressure titrations. Adaptive responses were further explored by isolating myocardial fibroblasts and measuring their contractile responses to water activity changes in vitro. Results show hydration potentials between 5 and 60 mmHg in healthy myocardia and shifts in excess of 200 mmHg in edematous myocardia after ischemia-reperfusion injury. Further, rates of fluid transfer were temperature-dependent, and in collagen gel contraction assays, myocardial fibroblasts tended to preserve the micro-environment's hydration volume by slowing fluid efflux rates at pressures above 40 mmHg. Our studies quantify components of the fluid-driving forces in the heart interstitium that the classical Starling's equation does not explicitly consider. Measured hydration potentials in healthy myocardia and shifts with edema are larger than predicted from the known values of hydrostatic and colloid osmotic interstitial fluid pressures. Together with fibroblast responses in vitro, they are consistent with regulatory mechanisms that add local biological controls to classic fluid-balance models (AU)

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Local fluid transfer regulation in heart extracellular matrix.

The interstitial myocardial matrix is a complex and dynamic structure that adapts to local fluctuations in pressure and actively contributes to the heart's fluid exchange and hydration. However, classical physiologic models tend to treat it as a passive conduit for water and solute, perhaps because local interstitial regulatory mechanisms are not easily accessible to experiment in vivo. Here, we examined the interstitial contribution to the fluid-driving pressure ex vivo. Interstitial hydration potentials were determined from influx/efflux rates measured in explants from healthy and ischemia-reperfusion-injured pigs during colloid osmotic pressure titrations. Adaptive responses were further explored by isolating myocardial fibroblasts and measuring their contractile responses to water activity changes in vitro. Results show hydration potentials between 5 and 60 mmHg in healthy myocardia and shifts in excess of 200 mmHg in edematous myocardia after ischemia-reperfusion injury. Further, rates of fluid transfer were temperature-dependent, and in collagen gel contraction assays, myocardial fibroblasts tended to preserve the micro-environment's hydration volume by slowing fluid efflux rates at pressures above 40 mmHg. Our studies quantify components of the fluid-driving forces in the heart interstitium that the classical Starling's equation does not explicitly consider. Measured hydration potentials in healthy myocardia and shifts with edema are larger than predicted from the known values of hydrostatic and colloid osmotic interstitial fluid pressures. Together with fibroblast responses in vitro, they are consistent with regulatory mechanisms that add local biological controls to classic fluid-balance models.

Ameliorating Spinal Cord Injury in an Animal Model With Mechanical Tissue Resuscitation.

BACKGROUND: Traumatic spinal cord injury (SCI) is a major worldwide cause of mortality and disability with limited treatment options. Previous research applying controlled negative pressure to traumatic brain injury in rat and swine models resulted in smaller injuries and more rapid recovery. OBJECTIVE: To examine the effects of the application of a controlled vacuum (mechanical tissue resuscitation [MTR]) to SCI in a rat model under several magnitudes of vacuum. METHODS: Controlled contusion SCIs were created in rats. Vacuums of -50 and -75 mm Hg were compared. Analysis included open-field locomotor performance, magnetic resonance imaging (in vivo T2, ex vivo diffusion tensor imaging and fiber tractography), and histological assessments. RESULTS: MTR treatment significantly improved the locomotor recovery from a Basso, Beattie, and Bresnahan score of 7.8 ± 1.9 to 11.4 ± 1.2 and 10.7 ± 1.9 at -50- and -75-mm Hg pressures, respectively, 4 weeks after injury. Both pressures also reduced fluid accumulations > 10% by T2-imaging in SCI sites. The mean fiber number and mean fiber length were greater across injured sites after MTR treatment, especially with treatment with -50 mm Hg. Myelin volume was increased significantly by 60% in the group treated with -50 mm Hg. CONCLUSION: MTR of SCI in a rat model is effective in reducing edema in the injured cord, preserving myelin survival, and improving the rate and quantity of functional recovery. ABBREVIATIONS: BBB, Basso, Beattie, and BresnahanDTI, diffusion tensor imagingFA, fractional anisotropyMTR, mechanical tissue resuscitationMTR50, mechanical tissue resuscitation with 50-mm Hg subatmospheric pressureMTR75, mechanical tissue resuscitation with 75-mm Hg subatmospheric pressureROI, region of interestSCI, spinal cord injury.

Mechanical tissue resuscitation (MTR): a nonpharmacological approach to treatment of acute myocardial infarction.

BACKGROUND AND AIM: Myocardial ischemia-reperfusion injury is known to trigger an inflammatory response involving edema, apoptosis, and neutrophil activation/accumulation. Recently, mechanical tissue resuscitation (MTR) was described as a potent cardioprotective strategy for reduction of myocardial ischemia-reperfusion injury. Here, we further describe the protective actions of MTR and begin to define its therapeutic window. METHODS: A left ventricular, free-wall ischemic area was created in anesthetized swine for 85 minutes and then reperfused for three hours. Animals were randomized to two groups: (1) untreated controls (Control) and (2) application of MTR that was delayed 90 minutes after the initiation of reperfusion (D90). Hemodynamics and regional myocardial blood flow were assessed at multiple time points. Infarct size and neutrophil accumulation were assessed following the reperfusion period. In separate cohorts, the effect of MTR on myocardial interstitial water (MRI imaging) and blood flow was examined. RESULTS: Both groups had similar areas at risk (AAR), hemodynamics, and arterial blood gas values. MTR, even when delayed 90 minutes into reperfusion (D90, 29.2 ± 5.0% of AAR), reduced infarct size significantly compared to Controls (51.9 ± 2.7%, p = 0.006). This protection was associated with a 33% decrease in neutrophil accumulation (p = 0.047). Improvements in blood flow and interstitial water were also observed. Moreover, we demonstrated that the therapeutic window for MTR lasts for at least 90 minutes following reperfusion. CONCLUSIONS: This study confirms our previous observations that MTR is an effective therapeutic approach to reducing reperfusion injury with a clinically useful treatment window.

Mechanical tissue resuscitation at the site of traumatic brain injuries reduces the volume of injury and hemorrhage in a swine model.

BACKGROUND: Traumatic brain injuries (TBIs) continue to be a devastating problem with limited treatment options. Previous research applying controlled vacuum to TBI in a rat model resulted in smaller injuries and more rapid recovery. OBJECTIVE: To examine the effects of the application of a controlled vacuum (mechanical tissue resuscitation) to TBI in a large-animal model. The magnitude of vacuum, length of application, and length of delay between injury and the application of mechanical tissue resuscitation were investigated. METHODS: Localized, controlled cortical injuries were created in swine. Vacuums of -50 and -100 mm Hg were compared. Mechanical tissue resuscitation for 3 or 5 days was compared. Delays of 0, 3, or 6 hours between the creation of the TBI and the initiation of mechanical tissue resuscitation were examined. Analysis included histological assessments, computed tomographic perfusion, and magnetic resonance imaging (T2, proton magnetic spectra). RESULTS: A -100 mm Hg vacuum resulted in significantly smaller mean contused brain and hemorrhage volumes compared with -50 mm Hg and controls. Magnetic resonance spectra of treated animals returned to near baseline values. All 10 animals with 5-day mechanical tissue resuscitation treatment survived. Three of 6 animals treated for 3 days died after the discontinuation of treatment. A 3-hour delay resulted in similar results as immediate treatment. A 6-hour delay produced significant, but lesser responses. CONCLUSION: Application of mechanical tissue resuscitation to TBI was efficacious in the large-animal model. Application of -100 mm Hg for 5 days resulted in significantly improved outcomes. Delays of up to 3 hours between injury and the initiation of treatment did not diminish the efficacy of the mechanical tissue resuscitation treatment.

Interstitial-matrix edema in burns: mechanistic insights from subatmospheric pressure treatment in vivo.

Thermal injury disrupts fluid homeostasis and hydration, affecting hemodynamics and local interstitial fluid-driving forces, leading rapidly to edema. This study explores local mechanisms in vivo, after deep partial-thickness burns in the dermal matrix. Heat-damaged skin was obtained from pig corpses, byproducts of unrelated burn treatment protocols approved by the Institutional Animal-Care-and-Use Committee. Hydration potential and flow rates were measured by osmotic stress techniques at 4 and 37 °C, and collagen folding/unfolding was examined by differential scanning calorimetry and diffusion tensor magnetic resonance imaging. Kinetic and equilibrium hydration parameters differed in heat-damaged and undamaged skin; the mean hydration potential and initial flow rates of damaged skin were negative at 37 but positive at 4 °C, in contrast to the positive mean at either temperature of explants taken from undamaged skin sites on the same animals. After subatmospheric pressure treatment (125 mmHg), parameters in damaged reversed to values similar to those of undamaged, whereas the proportion of folded collagen and unidirectional resistance to water diffusion increased. Together, results support interfacial rather than colloidosmotic fluid transfer mechanisms in burns and confirm in vivo the relevance of collagen folding/unfolding, further suggesting collagen structural transitions as potential therapeutic targets and models for engineered biomimetic materials.

Collagen unfolding accelerates water influx, determining hydration in the interstitial matrix.

In the interstitial matrix, collagen unfolding at physiologic temperatures is thought to facilitate interactions with enzymes and scaffold molecules during inflammation, tissue remodeling, and wound healing. We tested the hypothesis that it also plays a role in modulating flows and matrix hydration potential. After progressively unfolding dermal collagen in situ, we measured the hydration parameters by osmotic stress techniques and modeled them as linear functions of unfolded collagen, quantified by differential scanning calorimetry after timed heat treatment. Consistent with the hypothetical model, the thermodynamic and flow parameters obtained experimentally were related linearly to the unfolded collagen fraction. The increases in relative humidity and intensity of T(2) maps were also consistent with interfacial energy contributions to the hydration potential and the hydrophobic character of the newly formed protein/water interfaces. As a plausible explanation, we propose that increased tension at interfaces formed during collagen unfolding generate local gradients in the matrix that accelerate water transfer in the dermis. This mechanism adds a convective component to interstitial transfer of biological fluids that, unlike diffusion, can speed the dispersion of water and large solutes within the matrix.

The local pathology of interstitial edema: surface tension increases hydration potential in heat-damaged skin.

The local pathogenesis of interstitial edema in burns is incompletely understood. This ex vivo study investigates the forces mediating water-transfer in and out of heat-denatured interstitial matrix. Experimentally, full-thickness dermal samples are heated progressively to disrupt glycosaminoglycans, kill cells, and denature collagen under conditions that prevent water loss/gain; subsequently, a battery of complementary techniques including among others, high-resolution magnetic resonance imaging, equilibrium vapor pressure and osmotic stress are used to compare water-potential parameters of nonheated and heated dermis. The hydration potential (HP) determined by osmotic stress is a measure of the total water-potential defined empirically as the pressure at which no net water influx/efflux into/from the dermis is detected. Results show that after heat denaturation, the HP, the intensity of T2-weighed magnetic resonance images, and the vapor pressure increase indicating higher water activity and necessarily, smaller contributions from colloidosmotic forces to fluid influx in burned relative to healthy dermis. Concomitant increases in HP and in water activity implicate local changes in interfacial and metabolic energy as the source of excess fluid-transfer potential. These ex vivo findings also show that these additional forces contributing to abnormal fluid-transfer in burned skin develop independently of inflammatory and systemic hydrodynamic responses.

Diffusion and reaction in the cell glycocalyx and the extracellular matrix.

Many biologically important macromolecular reactions are assembled and catalyzed at the cell lipid-surface and thus, the extracellular matrix and the glycocalyx layer mediate transfer and exchange of reactants and products between the flowing blood and the catalytic lipid-surface. This paper presents a mathematical model of reaction-diffusion equations that simply describes the transfer process and explores its influence on surface reactivity for a prototypical pathway, the tissue factor (Tf) pathway of blood coagulation. The progressively increasing friction offered by the matrix and glycocalyx to reactants and to the product (coagulation factors X, VIIa and Xa) approaching the reactive surface is simulated and tested by solving the equations numerically with both, monotonically decreasing and constant diffusion profiles. Numerical results show that compared to isotropic transfer media, the anisotropic structure of the matrix and glycocalyx sharply decreases overall reaction rates and significantly increases the mean transit time of reactants; this implies that the anisotropy modifies the distribution of reactants. Results also show that the diffusional transfer, whether isotropic or anisotropic, influences reaction rates according to the order at which the reactants arrive at the boundary. Faster rates are observed when at least one of the reactants is homogeneously distributed before the other arrives at the boundary than when both reactants transfer simultaneously from the boundary.

Swelling and pressure-volume relationships in the dermis measured by osmotic-stress technique.

Water transfer across the extracellular matrix (ECM) involves interstitial osmotic forces in as yet unclear ways. In particular, the traditional values of Starling forces cannot adequately explain fluid transfer rates. Here, we reassess these forces by analyzing fluid transfer in live pig and human dermal explants. Pressure potentials were controlled with inert polymers adjusted by membrane osmometry (range = 3-219 mmHg), and fluid transfer in and out of the explants was followed by sequential precision weighing. Water motional freedom in the dermis was examined by NMR. In pigs, mean hydration pressure (HP; the pressure at which volume did not change) was 107 +/- 22 and 47 +/- 12 (SE) mmHg at 4 degrees C and 37 degrees C (P = 0.012, paired t-test, n = 7). Volume changes observed in response to pressure potential were reversible. The equation, Volume change = V(max)/[1+(time/T(1/2))(d)], where V(max) is maximal volume change; T(1/2), time at volume = 1/2 V(max); and d, a rate parameter, was fitted to experimental progression curves (r(2) > 0.9), yielding V(max) values linearly related to pressure, with mean slopes -3.5 +/- 0.28 and -2.6 +/- 0.21(SE) mul.g(-1).mmHg(-1) at 4 degrees C and 37 degrees C. NMR spin-spin relaxation times (T(2)) varied within 200- to 400-mum distances in directions perpendicular to the epidermis, with slopes reaching 0.03 ms/mum. Results support a mechanism in which fluid transport across the ECM is locally regulated at micrometer scales by cell- and fiber-gel-dependent osmomechanical forces. The large HP helps to explain the fast interstitial in/out flow rates observed clinically.

Osmotic stress regulates the anticoagulant efficiency of dermatan sulfate.

Glycosaminoglycans (GAGs) in pericellular and interstitial spaces help to maintain local water homeostasis and blood coagulation balance. This study explored whether dehydrating microenvironment conditions influence dermatan sulfate's (DS) anticoagulant activity. Water transfer during antithrombin activation by dermatan sulfate was measured using osmotic stress techniques. Anticoagulant activity was determined from the change in the rate of coagulation factor Xa (fXa) inhibition. Osmotic stress accelerated reaction rates, indicating water transfer from reactants to bulk. The net volume transferred, measured using osmotic probes similar in size to the reacting proteins, was approximately 2500 mol of water per mole of fXa inhibited. The reaction efficiency, V(sat)/K 1/2 (rate at saturation/concentration resulting in half-maximal rates), determined in titrations with monosulfated dermatan sulfate and disulfated dermatan sulfate (DDS), were 4x10(4) and 2x10(5) M-1 s-1 under osmotic stress and in the presence of calcium, corresponding to 34- and 81-fold increases over efficiency measured under standard conditions. These results indicate that dermatan sulfate can contribute significantly to antithrombin activation, and that in dehydrating environments and depending of ionic conditions, its anticoagulant efficiency can exceed that of heparan sulfate (HS).

Endoscopy-assisted wide-vertex craniectomy, barrel stave osteotomies, and postoperative helmet molding therapy in the management of sagittal suture craniosynostosis.

OBJECT: Endoscopic techniques were introduced 7 years ago for the surgical management of patients with sagittal synostosis. In this study of 139 patients with sagittal synostosis, the authors assessed the efficacy, safety, complications, and outcomes after performing endoscopy-assisted wide-vertex craniectomies with bitemporal and biparietal barrel stave osteotomies. METHODS: The sample population consisted of a total of 99 boys and 40 girls who ranged in age from 0.4 to 9.2 months (mean 3.6 months). Two small incisions were made near the lambda and vertex. Using endoscopic visualization, wide-vertex craniectomies with bilateral temporal and parietal barrel stave osteotomies were performed. Postoperative treatment included custom-made surlyn cranial orthotic devices for cranial reshaping and maintenance. The mean craniectomy width was 5.4 cm and the length was 10 cm. The overall blood transfusion rate was 9% (two intraoperative and 12 postoperative transfusions). The mean estimated blood loss was 29 ml (range 5-150 ml). The mean preoperative hematocrit was 32%, whereas the postoperative level was 27%. One hundred thirty-two patients were discharged the morning following surgery. The majority of patients did not experience facial swelling, and none suffered postoperative fevers. Anthropometric cephalic index measurements indicated that excellent results were obtained in 87% of the patients (cephalic index > 75); good results in 8.7% (cephalic index 70-75); and poor results in 4.3% (cephalic index > 70). There were no cases of intraoperative death, infection, hemorrhage, or venous sinus injury. CONCLUSIONS: Analysis of the results indicates that use of the aforedescribed procedure in the early treatment of infants with sagittal synostosis provides excellent outcomes and that the morbidity rate is lower than that associated with traditional cranial vault reconstruction. Detailed anthropometric and radiographic analyses demonstrated that with adequate helmet therapy in our patients normocephaly was achieved and maintained without the need for secondary operations.

Design and care of helmets in postoperative craniosynostosis patients: our personal approach.

Since 1997, the authors have instituted the use of custom-made helmets to correct craniofacial deformities associated with craniosynostosis following endoscopic-assisted craniectomies of the stenosed sutures in infants. This article presents their experience and results using helmet therapy in their patient population.

Chondroitin sulfate anticoagulant activity is linked to water transfer: relevance to proteoglycan structure in atherosclerosis.

OBJECTIVE: Changes in chondroitin sulfate (CS) proteoglycan (PG) during atherosclerosis are associated with chronic inflammatory changes and increased incidence of thrombosis. To explore how glycosaminoglycan changes could influence the thrombogenicity of atherosclerotic lesions, water-transfer reactions were examined during activation of antithrombin by CS. METHODS AND RESULTS: Advanced type IV atherosclerotic lesions prone to thrombosis contained CSPG (versican) with undersulfated CS relative to CS of the adjacent healthy aorta. Approximately 11% of the CS disaccharide in versican from healthy arteries was oversulfated, but this proportion decreased markedly to 3% in atherosclerotic lesions. Oversulfated CS functionally bound antithrombin with a dissociation constant of 3.3+/-1.9 micromol/L. Measured by osmotic stress (OS) techniques with an approximately 26-A probe, the reaction was linked to transfer of approximately 2500 mol water per mole of coagulation factor Xa inhibited. Under OS, the anticoagulant efficiency of CS was 1.3 (micromol/L)(-1) x s(-1), approximately 5- and 15-fold higher than heparan sulfate efficiency measured under OS and standard conditions, respectively. CONCLUSIONS: Decreased sulfation of high molecular weight CSPG in the advancing atherosclerotic lesions may predispose the lesions to thrombosis by disrupting osmotic regulation, limiting avidity for antithrombin and decreasing activation efficiency.