Successful Use Research Articles

Recent Advances in Studying the Regulation of Fruit Ripening in Tomato Using Genetic Engineering Approaches.

Tomato (Solanum lycopersicum L.) is one of the most commercially essential vegetable crops cultivated worldwide. In addition to the nutritional value, tomato is an excellent model for studying climacteric fruits' ripening processes. Despite this, the available natural pool of genes that allows expanding phenotypic diversity is limited, and the difficulties of crossing using classical selection methods when stacking traits increase proportionally with each additional feature. Modern methods of the genetic engineering of tomatoes have extensive potential applications, such as enhancing the expression of existing gene(s), integrating artificial and heterologous gene(s), pointing changes in target gene sequences while keeping allelic combinations characteristic of successful commercial varieties, and many others. However, it is necessary to understand the fundamental principles of the gene molecular regulation involved in tomato fruit ripening for its successful use in creating new varieties. Although the candidate genes mediate ripening have been identified, a complete picture of their relationship has yet to be formed. This review summarizes the latest (2017-2023) achievements related to studying the ripening processes of tomato fruits. This work attempts to systematize the results of various research articles and display the interaction pattern of genes regulating the process of tomato fruit ripening.

Micellar solution of [223Ra]RaCl2: Reaching renal excretion, potent efficacy in osteoblastic osteosarcoma in PDX model, biochemistry alterations and pharmacokinetics

Despite the successful use of the radiopharmaceutical radium-223 dichloride ([223Ra]RaCl2) for targeted alpha therapy of castration-resistant prostate cancer patients with bone metastases, some short-term side effects, such as diarrhea and vomiting, have been documented, causing patient discomfort. Hence, we prepared a nanosized micellar solution of [223Ra]RaCl2 and evaluated its biodistribution, pharmacokinetics, and induced biochemical changes in healthy mice up to 96 h after intraperitoneal administration as an alternative to overcome the previous limitations. In addition, we evaluated the bone specificity of micellar [223Ra]RaCl2 in patient-derived xenografts in the osteosarcoma model. The biodistribution studies revealed the high bone-targeting properties of the micellar [223Ra]RaCl2. Interestingly, the liver uptake remained significantly low (%ID/g = 0.1–0.02) from 24 to 96 h after administration. In addition, the micellar [223Ra]RaCl2 exhibited a significantly higher uptake in left (%ID/g = 0.85–0.23) and right (%ID/g = 0.76–0.24) kidneys than in small (%ID/g = 0.43–0.06) and large intestines (%ID/g = 0.24–0.09) over time, suggesting its excretion pathway is primarily through the kidneys into the urine, in contrast to the non-micellar [223Ra]RaCl2. The micellar [223Ra]RaCl2 also had low distribution volume (0.055 ± 0.003 L) and longer elimination half-life (28 ± 12 days). This nanosystem was unable to change the enzymatic activities of alanine aminotransferase, aspartate aminotransferase, gamma GT, glucose, and liquiform lipase in the treated mice. Finally, microscopic examination of the animals' osteosarcoma tumors treated with micellar [223Ra]RaCl2 indicated regression of the tumor, with large areas of necrosis. In contrast, in the control group, we observed tumor cellularity and cell anaplasia, mitotic figures and formation of neoplastic extracellular bone matrix, which are typical features of osteosarcoma. Therefore, our findings demonstrated the efficiency and safety of nanosized micellar formulations to minimize the gastrointestinal excretion pathway of the clinical radiopharmaceutical [223Ra]RaCl2, in addition to promoting regression of the osteosarcoma. Further studies must be performed to assess dose–response outcomes and organ/tissue dosimetry for clinical translation.

Domestic pigs are susceptible to experimental infection with non-human primate-derived Reston virus without the need for adaptation

Domestic pigs are a critical component of the food supply and one of the most commonly raised production animals. Pork consumption has driven the intensification of pig production expanding into environments conducive to increased emergence and spread of infectious diseases, including the spillover of pathogens into human populations. One of these emerging viruses, Reston virus (RESTV), is an enigma among the Orthoebolavirus genus in that its lack of human pathogenicity is in stark contrast to the high virulence associated with most other ebolaviruses. RESTV is, however, associated with outbreaks of highly lethal hemorrhagic disease in non-human primates (NHP), as well as poorly understood clinical manifestations of mixed virulence and lethality in naturally and experimentally infected domestic pigs. Our results show it is possible for RESTV derived from an NHP to infect domestic pigs resulting in a spectrum of disease, from asymptomatic to severe respiratory distress. Further, we report on the first experimental transmission of RESTV between infected pigs and a co-housed, naïve animal, as well as the first report of the successful use of group oral fluids for the detection of RESTV RNA and virus-specific IgA antibodies.

Tissue Contamination Challenges the Credibility of Machine Learning Models in Real World Digital Pathology

Machine learning (ML) models are poised to transform surgical pathology practice. The most successful use attention mechanisms to examine whole slides, identify which areas of tissue are diagnostic, and use them to guide diagnosis. Tissue contaminants, such as floaters, represent unexpected tissue. While human pathologists are extensively trained to consider and detect tissue contaminants, we examined their impact on ML models.We trained 4 whole slide models. Three operate in placenta for 1) detection of decidual arteriopathy (DA), 2) estimation of gestational age (GA), and 3) classification of macroscopic placental lesions. We also developed a model to detect prostate cancer in needle biopsies. We designed experiments wherein patches of contaminant tissue are randomly sampled from known slides and digitally added to patient slides and measured model performance. We measured the proportion of attention given to contaminants and examined the impact of contaminants in T-distributed Stochastic Neighbor Embedding (tSNE) feature space.Every model showed performance degradation in response to one or more tissue contaminants. DA detection balanced accuracy decreased from 0.74 to 0.69 +/- 0.01 with addition of 1 patch of prostate tissue for every 100 patches of placenta (1% contaminant). Bladder, added at 10% contaminant raised the mean absolute error in estimating gestation age from 1.626 weeks to 2.371 +/ 0.003 weeks. Blood, incorporated into placental sections, induced false negative diagnoses of intervillous thrombi. Addition of bladder to prostate cancer needle biopsies induced false positives, a selection of high-attention patches, representing 0.033mm2, resulted in a 97% false positive rate when added to needle biopsies. Contaminant patches received attention at or above the rate of the average patch of patient tissue.Tissue contaminants induce errors in modern ML models. The high level of attention given to contaminants indicates a failure to encode biological phenomena. Practitioners should move to quantify and ameliorate this problem.

Advances and Challenges in Closed Loop Therapeutics: From Signal Selection to Optogenetic Techniques

The main objective of this paper is to develop closed-loop therapeutic systems by reviewing various neurological disorders. We propose a system that incorporates a biosensor, controller, and infusion pump to provide closed-loop feedback management of medicine delivery. To address the specific therapeutic requirements of a medication called Dox, they made precise adjustments to the system's functioning. The device incorporates a biosensor capable of real-time assessment of medicine levels in the bloodstream. The method utilizes aptamer probes that have been labeled with an electrochemical tag. When these probes connect to the drug target, they undergo a reversible change in shape, leading to a modification in redox current. A little quantity of blood is consistently extracted from the animal's circulatory system inside a microfluidic device, which is used for this measurement. The paper examines the challenges of seizure detection and the use of advanced learning algorithms and classification methods to enhance real- time seizure detection in closed-loop systems. Following the successful use of optogenetic techniques in epilepsy models, the authors discuss the potential of these technologies for controlling brain activity.

The role of conventionality and design in children’s function judgments about malfunctioning artifacts

This study investigated the individual influences of conventionality and designer’s intent on function judgments of possibly malfunctioning artifacts. Children aged 4 and 5 years and 6 to 8 years were presented with stories about an artifact with two equally plausible functions, one labeled as either conventional or designed. Subsequently, a character attempted to use the artifact for the cued function, which resulted in either malfunction or successful use. The children’s task was to identify the real function of the artifact. When the use attempt succeeded, 4- and 5-year-olds preferred conventional functions to the alternative (but did not show a clear preference between design functions and the alternative), and 6- to 8-year-olds preferred conventional and designed functions to the alternative. In case of malfunction, children’s choices were at chance, where the effect of either conventional or design cues was less salient. This contrasts with a baseline condition where children avoided the malfunctioning alternatives. Presenting additional cues about an artifact’s function can affect function judgments in cases of malfunction.

Co-Design and Energy Management for Future Vessels

The maritime industry is undergoing a significant shift towards more sustainable and efficient forms of transportation. As a result, designing Power, Propulsion and Energy (PPE) Systems for future vessels presents new challenges that require a systematic approach that reduces the risk in development and implementation. This paper focuses on three aspects of such a systematic approach: Model-Based System Engineering (MBSE), Co-design, and Verification and Validation. The MBSE approach can be used to mitigate the risks associated with the transition by maintaining a clear traceability of user needs, functional requirements and physical realizations. A rigorous needs analysis and functional design reduces the optimisation design space that results in a significant reduction in the complexity of a design optimisation problem. Further, co-design is discussed as a methodology for a combined optimisation of the hardware and software design where the Modular Energy Management approach supports automated controller generation for the optimisation, a key challenge when optimising PPE systems. An important aspect of the MBSE approach is the use of models for the verification and validation of the developed designs. However, the successful use of models is contingent on their applicability. This paper proposes a way to categorise model confidence for verification and validation studies.

Successful Use of Easyhaler® Dry Powder Inhaler in Patients with Chronic Obstructive Pulmonary Disease; Analysis of Peak Inspiratory Flow from Three Clinical Trials.

There is increasing pressure to use environmentally friendly dry powder inhalers (DPI) instead of pressurized metered-dose inhalers (pMDI). However, correct inhalation technique is needed for effective inhaler therapy, and there is persistent concern whether patients with chronic obstructive pulmonary disease (COPD) can generate sufficient inspiratory effort to use DPIs successfully. The aims of this study were to find clinical predictors for peak inspiratory flow rate (PIF) and to assess whether patients with COPD had difficulties in generating sufficient PIF with a high resistance DPI. Pooled data of 246 patients with COPD from previous clinical trials was analyzed to find possible predictors of PIF via the DPI Easyhaler (PIFEH) and to assess the proportion of patients able to achieve an inhalation flow rate of 30 l/min, which is needed to use the Easyhaler successfully. The mean PIF was 56.9l/min and 99% (243/246) of the study patients achieved a PIF ≥ 30l/min. A low PIF was associated with female gender and lower forced expiratory volume in 1s (FEV1), but the association was weak and a statistical model including both only accounted for 18% of the variation seen in PIFEH. Based on our results, impaired expiratory lung function or patient characteristics do not predict patients' ability to use DPIs in COPD; 99% of the patients generated sufficient PIFEH for successful dose delivery. Considering the targets for sustainability in health care, this should be addressed as DPIs are a potential option for most patients when choosing the right inhaler for the patient. Two of three included trials were registered under numbers NCT04147572 and NCT01424137. Third trial preceded registration platforms and therefore, was not registered.

Using normalization process theory to evaluate the use of patient-centred outcome measures in specialist palliative home care—a qualitative interview study

BackgroundStandardised use of patient-centred outcome measures (PCOMs) improves aspects of quality of care. Normalization Process Theory (NPT) considers the social (inter-)actions of implementation processes operationalised through four constructs: coherence-building, cognitive participation, collective action and reflexive monitoring. The aim of the study was to identify barriers and enablers for the successful use of PCOMs in specialist palliative home care (SPHC) using NPT, to collect clinically meaningful and reliable data to improve patient outcomes.MethodsQualitative study using semi-structured interviews with palliative care professionals from German SPHC teams who participated in a study using PCOMs. Data were analysed using Framework analysis, and contextualised within NPT.ResultsSeventeen interviews across five teams were conducted. Some teams already had an understanding of what PCOMs are and how to use them, based on previous experience. In other teams, this understanding developed through the perception of the benefits (coherence). Participation and engagement depended on individuals and was decisive for coherence-building. The attitude of the management level also played a major role (cognitive participation). Integration of PCOMs into everyday clinical practice varied and depended on the manifestation of the first two constructs and other already established routines (collective action). In the context of appraisal, both positive (e.g. focus on patient) and negative aspects (e.g. additional work) of using PCOMs were mentioned (reflexive monitoring).ConclusionsAlthough benefits of using PCOMs were partly recognised, not all teams continued standardised use. Here, not only the social (inter-)actions, but also the influence of the context (working environment) were decisive. Future implementation strategies should consider integrating PCOMs in existing electronic patient records, education sessions supporting coherence-building, internal facilitators/local champions, and ensuring frequent data analyses as it is beneficial and increases the readiness of using PCOMs.

High surface area cobalt aluminium layered double hydroxide printed electrodes for flexible supercapacitor and on-chip electrochemical bacterial lysing

This article describes the successful use of high surface area cobalt aluminium layered double hydroxide as an effective electrode material for fabricating highly flexible printed supercapacitor and electrochemical bacterial lysing chips. The flexible supercapacitor showed a high areal capacitance of 4.16 mF cm−2 at 0.4 mA cm−2 current density with 1.30 μWh cm−2 areal energy density and 301.04 μWcm−2 areal power density. Most importantly, the developed supercapacitor exhibited 91.32% initial areal capacitance even after 5000 continuous charge-discharge cycles and excellent mechanical stability over different bending states. An electrochemical chip for bacterial lysing was fabricated using a PDMS reservoir and catalyst-coated screen-printed carbon electrode. On-chip lysing of Gram-negative and Gram-positive bacteria was completely achieved at an applied potential of 3.5 V in 2 minutes, which is 1 V lower than that required for the unmodified electrode. The electrochemical chip outperforms commercial chemical lysing kits in terms of lysing time, DNA yield, longer DNA strands, and cost.

Ultrasound-Assisted Neuraxial Anaesthesia and Intra-Operative Non-Invasive Ventilation for Emergency Caesarean Section in a Parturient with Profound Respiratory Failure: A Case Report

Here we describe the perioperative management of a patient with profound respiratory failure. A 32-year-old parturient presented with acute-on-chronic respiratory failure at 30 weeks’ gestation. Her deterioration was attributed to advancing gestation on a background of significant respiratory comorbidity and required emergency caesarean section. Anaesthesia for a safe operative delivery was predicted to be difficult, carrying significant risk for both patient and fetus. We describe the successful use of intra-operative non-invasive ventilation and ultrasound-assisted neuraxial anaesthesia in order to facilitate emergency caesarean section without general anaesthesia.

Tumor-tropic Trojan horses: Using mesenchymal stem cells as cellular nanotheranostics.

Various classes of nanotheranostics have been developed for enhanced tumor imaging and therapy. However, key limitations for a successful use of nanotheranostics include their targeting specificity with limited off-site tissue accumulation as well as their distribution and prolonged retention throughout the entire tumor. Due to their inherent tumor-tropic properties, the use of mesenchymal stem cells (MSCs) as a "Trojan horse" has recently been proposed to deliver nanotheranostics more effectively. This review discusses the current status of "cellular nanotheranostics" for combined (multimodal) imaging and therapy in preclinical cancer models. Emphasis is placed on the limited knowledge of the signaling pathways and molecular mechanisms of MSC tumor-tropism, and how such information may be exploited to engineer MSCs in order to further improve tumor homing and nanotheranostic delivery using image-guided procedures.

Terbium alginate encapsulated CsPbI3@Pb-MOF: a ratiometric fluorescent bead for detection and adsorption of Fe3.

Halide perovskite nanocrystals are innovative luminescent materials for fluorescent probes with high quantum yield and narrow emission bandwidth. However, the limited stability, single-signal response, and separation challenges obstruct their widespread use in water ion detection. Herein, a ratiometric fluorescence sensor based on terbium alginate gel beads (green fluorescent, namely Tb-AG) embedded with powdered CsPbI3@Pb-MOF (red fluorescent) was prepared for fluorescent determination and adsorption of Fe3+. Pb-MOF's protection notably enhances the water stability of CsPbI3, while the energy transfer between CsPbI3@Pb-MOF and Tb3+ elevates the optical performance of CsPbI3@Pb-MOF@Tb-AG. Significantly, Fe3+ markedly suppresses CsPbI3@Pb-MOF red fluorescence at 647 nm, while not noticeably affecting Tb-AG green emission at 528 nm. The sensor exhibited a strong linear response to Fe3+ concentrations ranging from 0 to 90 μM, with a detection limit of 0.44 μM and high selectivity. The CsPbI3@Pb-MOF@Tb-AG-based sensor has been effectively validated through its successful use in detecting Fe3+ in tap and river water samples. Furthermore, CsPbI3@Pb-MOF@Tb-AG demonstrates a notable adsorption capacity of 325.4 mg g-1 Fe3+. Finally, the mechanism of Fe3+ detection and adsorption was determined.

The biopotential of extremophilic microorganisms isolated from Kuzbass for protection and growth stimulation of oat (Avena sativa L.)

Biological plant protection products are extensively utilized in agriculture owing to their safety, efficacy, and environmental friendliness. The utilization of these funds in locales with challenging weather patterns is constrained. In order to ensure the successful use of biological plant protection products, it is rational to search for microorganisms adapted to the specific soil and climatic conditions of the territory. The objective of the investigation is to evaluate the antagonistic and growth-stimulating properties of the consortium of extremophilic microorganisms of Kuzbass, and to conduct laboratory testing on oats (Avena sativa L.). The work used microorganisms isolated at the initial stages of the research, such as Leclercia sp., Sphingomonas paucimobilis, and Lactobacillus plantarum. The findings revealed that these microorganisms are capable of producing gibberellic acid, dissolving phosphates, and retaining atmospheric nitrogen. Furthermore, the co-cultivation of microorganisms facilitates the enhancement of these indicators. The negative impact of phytopathogens (Alternaria alternata (F-525), Fusarium graminearum (F-877) PH-1, Fusarium graminearum (F-892) and Fusarium sporotrichioides (F-902)) on oats in laboratory conditions was reduced by a consortium based on these microorganisms. Therefore, the consortium has the potential to develop commercial drugs. Field experiments are planned in the future.

Possibilities of «therapeutic retargeting» of 3-hydroxypyridine and succinic acid derivatives due to their dopaminergic action

The review is devoted to a comparative analysis of the clinical efficacy of the original domestic derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) in comparison with the results of an experimental study of their dopaminergic action. The position that the dopaminomimetic activity of emoxipin, reamberin and mexidol largely determines their anti-ischemic, antihypoxic, insulin-potentiating neuroprotective, nootropic and antidepressant potential has been substantiated. A comparative analysis of the safety profile of emoxipine, reamberin and mexidol was carried out, taking into account potential and real side-effects caused by iatrogenic deviations from the eudopaminergic state. It has been shown that mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate), which is simultaneously a derivative of 3-hydroxypyridine and succinic acid, has the best balance of efficacy and safety. A generalized assessment of the available data on the successful use of off-label derivatives of 3-hydroxypyridine and succinic acid indicates the advisability of a significant expansion of indications for their clinical use. The authors resume that the «therapeutic retargeting» of emoxipin, reamberin and mexidol (i.e. their use for qualitatively new indications) will contribute to progress in the treatment of socially significant and most common diseases.

Clinical Application of Angulated Prosthetic Platform Implants: A Retrospective Study.

This retrospective study reports on the survival of two-piece angulated prosthetic platform (APP) implants consecutively placed at a specialist periodontics clinic with a mean follow-up of 28.2 ± 15.6 months (range: 4.0 to 71.0). For 183 returning patients who received 239 implants, the survival rates at follow-up (up to 71 months) were 99.2% and 91.1% at the patient and implant levels, respectively. A majority of patients were nonsmokers and did not have diabetes, with a quarter having a history of treated periodontitis. Eighty percent of patients received a single APP implant. Of the implants, 63% supported a single crown, 28% a fixed partial denture, and 9% a fixed complete denture. Nearly all implants were placed either at tooth extraction or after complete bone healing, in approximately equal numbers. Of the implant sites, approximately 75% received bone grafting, with approximately 25% receiving adjunct soft tissue grafting. For 210 surviving and restored implants with satisfactory intraoral radiographs taken at the last recall (mean follow-up: 28.4 ± 15.5 months; range: 4.0 to 71.0 months), the mean radiographic bone levels were -0.70 ± 0.87 mm (range: -3.60 to 2.15 mm). The results demonstrated clinically successful use of this unique geometry implant for multiple applications with acceptable short- to medium-term clinical outcomes.

Reticular chemistry guided precise construction of zirconium-pentacarboxylate frameworks with 5-connected Zr6 clusters.

Zirconium-based metal-organic frameworks (Zr-MOFs) have been extensively studied due to their very rich structural chemistry. The combination of nearly unlimited carboxylic acid-based linkers and Zr6 clusters with multiple connectivities has led to diverse structures and specific properties of resultant Zr-MOFs. Herein, we demonstrate the successful use of reticular chemistry to construct two novel Zr-MOFs, HIAM-4040 and HIAM-4040-OH, with zfu topology. Based on a thorough structural analysis of (4,4)-connected lvt-type Zr-tetracarboxylate frameworks and a judicious linker design, we have obtained the first example of a Zr-pentacarboxylate framework featuring unprecedented 5-connected organic linkers and 5-connected Zr6 clusters. Compared with HIAM-4040, a larger Stokes shift is achieved in HIAM-4040-OH via hydroxyl group induced excited-state intramolecular proton transfer (ESIPT). HIAM-4040-OH exhibits high chemical and thermal stability and is used for HClO detection in aqueous solution with excellent sensitivity and selectivity.

Glycan-specific molecularly imprinted polymers towards cancer diagnostics: merits, applications, and future perspectives.

Aberrant glycans are a hallmark of cancer states. Notably, emerging evidence has demonstrated that the diagnosis of cancers with tumour-specific glycan patterns holds great potential to address unmet medical needs, especially in improving diagnostic sensitivity and selectivity. However, despite vast glycans having been identified as potent markers, glycan-based diagnostic methods remain largely limited in clinical practice. There are several reasons that prevent them from reaching the market, and the lack of anti-glycan antibodies is one of the most challenging hurdles. With the increasing need for accelerating the translational process, numerous efforts have been made to find antibody alternatives, such as lectins, boronic acids and aptamers. However, issues concerning affinity, selectivity, stability and versatility are yet to be fully addressed. Molecularly imprinted polymers (MIPs), synthetic antibody mimics with tailored cavities for target molecules, hold the potential to revolutionize this dismal progress. MIPs can bind a wide range of glycan markers, even those without specific antibodies. This capacity effectively broadens the clinical applicability of glycan-based diagnostics. Additionally, glycoform-resolved diagnosis can also be achieved through customization of MIPs, allowing for more precise diagnostic applications. In this review, we intent to introduce the current status of glycans as potential biomarkers and critically evaluate the challenges that hinder the development of in vitro diagnostic assays, with a particular focus on glycan-specific recognition entities. Moreover, we highlight the key role of MIPs in this area and provide examples of their successful use. Finally, we conclude the review with the remaining challenges, future outlook, and emerging opportunities.

A solid-state Li-air battery: computational studies of interfaces and relevance to discharge mechanism.

There is much interest in developing new energy storage systems to replace currently available ones that mainly work based on Li-ion intercalations. One attractive area is the Li-air battery for which most of the research has involved liquid electrolytes. There have been few studies on the use of a solid electrolyte in a Li-air battery. Recently, we reported the successful use of a solid-state electrolyte in a Li-air battery resulting in a Li2O product and potentially much higher energy density than in a Li-air battery based on either a Li2O2 or LiO2 product (Science, 2023, 379, 499). In this paper we discuss how the discharge mechanism involved in this solid-state Li-air battery differs from that of a Li-air battery with a liquid electrolyte. The solid-state mechanism is further explored with density functional studies of various interfaces involving the discharge product. We discuss the relevance of the results to the discharge mechanism in the solid-state Li-air battery.

Managing Challenging Child Behaviour in Pediatric Dentistry Using Pharmacologic Approaches: A Vanishing Art

Amongst the skills and competency expected of the pediatric dental specialist is an enhanced ability to circumvent and obtund interfering and refractory behaviour of moderately to severely apprehensive and resistive children. Wide variation exists among this specialist with respect to individual talents to accomplish treatment on this population making use of both nonpharmacological as well as pharmacological approaches. While advanced training programs vary greatly in the extent to which their residents are exposed to various modalities, likely explanation to account for such lies in the diversity to which their faculty bring competent and diversified experience. Some bring extensive background to the use of a variety of agents and dosing; others conceivably offer limited exposure to residents by not having had extensive use during their own training programs. Expertise and a propensity to include a broad repertoire of agents and modalities by Program Directors is highly variable. External sources include administrative perspectives, safety records, formulary limitations, and biases of state and regulatory agencies as to what agents and regimens impose restrictions on this teaching experience. This editorial expresses observations of this author over the past 40 plus years concludes that the use of pediatric sedation has diminished to the extent that its safe and successful use is at risk of becoming a vanishing art. The end result is that an increasing number of children by virtue of a lack of skilled clinicians in its safe use will be subjected to excessive if not unnecessary use of unconscious techniques and/or physical restraint.