Implementation of Video Laryngoscope-Assisted Coaching Reduces Adverse Tracheal Intubation-Associated Events in the PICU.

OBJECTIVES: To evaluate implementation of a video laryngoscope (VL) as a coaching device to reduce adverse tracheal intubation associated events (TIAEs). DESIGN: Prospective multicenter interventional quality improvement study. SETTING: Ten PICUs in North America. PATIENTS: Patients undergoing tracheal intubation in the PICU. INTERVENTIONS: VLs were implemented as coaching devices with standardized coaching language between 2016 and 2020. Laryngoscopists were encouraged to perform direct laryngoscopy with video images only available in real-time for experienced supervising clinician-coaches. MEASUREMENTS AND MAIN RESULTS: The primary outcome was TIAEs. Secondary outcomes included severe TIAEs, severe hypoxemia (oxygen saturation < 80%), and first attempt success. Of 5,060 tracheal intubations, a VL was used in 3,580 (71%). VL use increased from baseline (29.7%) to implementation phase (89.4%; p < 0.001). VL use was associated with lower TIAEs (VL 336/3,580 [9.4%] vs standard laryngoscope [SL] 215/1,480 [14.5%]; absolute difference, 5.1%; 95% CI, 3.1-7.2%; p < 0.001). VL use was associated with lower severe TIAE rate (VL 3.9% vs SL 5.3%; p = 0.024), but not associated with a reduction in severe hypoxemia (VL 15.7% vs SL 16.4%; p = 0.58). VL use was associated with higher first attempt success (VL 71.8% vs SL 66.6%; p < 0.001). In the primary analysis after adjusting for site clustering, VL use was associated with lower adverse TIAEs (odds ratio [OR], 0.61; 95% CI, 0.46-0.81; p = 0.001). In secondary analyses, VL use was not significantly associated with severe TIAEs (OR, 0.72; 95% CI, 0.44-1.19; p = 0.20), severe hypoxemia (OR, 0.95; 95% CI, 0.73-1.25; p = 0.734), or first attempt success (OR, 1.28; 95% CI, 0.98-1.67; p = 0.073). After further controlling for patient and provider characteristics, VL use was independently associated with a lower TIAE rate (adjusted OR, 0.65; 95% CI, 0.49-0.86; p = 0.003). CONCLUSIONS: Implementation of VL-assisted coaching achieved a high level of adherence across the PICUs. VL use was associated with reduced adverse TIAEs.

Planning for Change: Co-Designing Implementation Strategies to Improve the Use of Sensory Approaches in an Acute Psychiatric Unit.

Implementing sensory approaches in psychiatric units has proven challenging. This multi-staged study involved qualitative interviews (n = 7) with mental health care staff in an acute psychiatric ward to identify the local factors influencing use of sensory approaches, and co-design implementation strategies with key stakeholders to improve their use. Using framework analysis, results revealed that the use of sensory approaches were hindered by: inadequate access to sensory resources/equipment; lack of time; lack of staff knowledge; and belief that sensory approaches are not effective or part of staff's role. To address identified barriers a systematic theory-informed method was used to co-design implementation strategies to improve the use of sensory approaches.

Using the Theoretical Domain Framework to understand what helps and hinders the use of different sensory approaches in Australian psychiatric units: A survey of mental health clinicians.

BACKGROUND/AIM: Although sensory approaches are recommended to relieve distress and agitation and reduce the use of seclusion and restraint, many Australian psychiatric units have struggled to sustain their practice. The aim of this study was to investigate the barriers and enablers influencing the use of different sensory approaches across one health region in Australia and to obtain recommendations for strategies to improve their use. METHOD: This cross-sectional survey was informed by the Theoretical Domain Framework. Likert scale questions considered barriers and enablers to the use of non-weighted sensory interventions, weighted modalities, sensory rooms, and sensory assessments/plans. Open-ended questions explored participant concerns and recommendations to improve the use of sensory approaches. RESULTS: Participants (n = 211) were from nursing, allied health, medical, and peer support staff across inpatient psychiatric units. Factors most frequently identified as enablers for using sensory approaches were beliefs of positive benefits to consumers (e.g. decreasing distress and agitation); belief it was within the staff's role; and knowledge of the approaches. Limited time was the most common identified barrier. Factors statistically associated with more frequent use were knowledge, skills, confidence, availability, and easy access to sensory tools/equipment. Only 30% of participants were concerned about potential risks of sensory approaches, with this risk mitigated through adequate supervision and thorough risk assessment. Recommendations to improve practice included improved access to, and maintenance of, equipment, more training, and increased staffing. CONCLUSION: This study revealed how barriers and enablers vary for different sensory approaches and how these factors impact their frequency of use in psychiatric units. It provides insights into staff recommendations to improve the use of sensory approaches in one health region in Australia. This knowledge will lead to the development of implementation strategies to address identified barriers and improve the use of sensory approaches in psychiatric units.

Sensory approaches in psychiatric units: Patterns and influences of use in one Australian health region.

BACKGROUND/AIM: Australian guidelines and policies recommend the use of sensory approaches in mental health care. Nevertheless, many Australian psychiatric units report difficulty sustaining these approaches. To inform efforts to close the gap between recommendations and practice, the aim of this study was to understand the patterns of use of sensory approaches and what demographic and clinical factors influence their use, across one health region in Queensland, Australia. METHODS: Using a cross-sectional survey design, a custom-designed questionnaire was distributed via email and in paper form to health professionals and peer support workers working in acute, secure, and community care psychiatric units across one health region. Information on demographics and the use of various sensory interventions was gathered utilising both open-ended and Likert scale questions. RESULTS: Useable questionnaires were collected from 183 participants from various disciplines (77% nursing). The majority reported using sensory approaches with a limited number of consumers, and almost 9% never used the approach. Activity-based sensory interventions and sensory equipment were most often used, whereas sensory assessments, sensory plans, and sensory groups were least used. Sensory interventions were mainly used to reduce consumer anxiety and agitation and to assist with emotional regulation. Factors positively correlated with frequency of use for all interventions were discipline (occupational therapy); working in an acute inpatient unit; and training in sensory approaches. Age was negatively correlated with frequency of use only for weighted modalities. CONCLUSIONS: This study revealed that sensory approaches were used by most staff though with a limited proportion of consumers in psychiatric units in one large metropolitan health service. It provides insights into the factors influencing frequency of use, highlighting the importance of training in sensory approaches and access to occupational therapists. With this knowledge, we can work towards closing the gap between recommendations and the practice of sensory approaches.

Degos disease: A radiological-pathological correlation of the neuroradiological aspects of the disease.

Malignant atrophic papulosis (Degos disease) is an unusual thrombotic microangiopathy of uncertain etiology. The disease characteristically involves the skin and internal organs, with nervous system involvement more common in children. We present a case with diverse neurological manifestations including cranial nerve palsies, gait instability, and urinary incontinence. The patient also developed white papular lesions on her lower extremities and back. Magnetic resonance imaging (MRI) demonstrated progressive intracranial and spinal abnormalities. Despite treatment with numerous biologic agents, the patient had persistent clinical deterioration and expired one month after admission. We highlight the extensive neurologic manifestations of Degos disease correlated with neuroradiological imaging and pathological features. Nervous system involvement in Degos disease requires careful neurologic and dermatologic exam with central nervous system (CNS) magnetic resonance imaging to distinguish it from non-organic etiologies of similar symptoms.

Downward Trend in Pediatric Resident Laryngoscopy Participation in PICUs.

OBJECTIVES: As of July 2013, pediatric resident trainee guidelines in the United States no longer require proficiency in nonneonatal tracheal intubation. We hypothesized that laryngoscopy by pediatric residents has decreased over time, with a more pronounced decrease after this guideline change. DESIGN: Prospective cohort study. SETTING: Twenty-five PICUs at various children's hospitals across the United States. PATIENTS: Tracheal intubations performed in PICUs from July 2010 to June 2016 in the multicenter tracheal intubation database (National Emergency Airway Registry for Children). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Prospective cohort study in which all primary tracheal intubations occurring in the United States from July 2010 to June 2016 in the multicenter tracheal intubation database (National Emergency Airway Registry for Children) were analyzed. Participating PICU leaders were also asked to describe their local airway management training for residents. Resident participation trends over time, stratified by presence of a Pediatric Critical Care Medicine fellowship and airway training curriculum for residents, were described. A total of 9,203 tracheal intubations from 25 PICUs were reported. Pediatric residents participated in 16% of tracheal intubations as first laryngoscopists: 14% in PICUs with a Pediatric Critical Care Medicine fellowship and 34% in PICUs without one (p < 0.001). Resident participation decreased significantly over time (3.4% per year; p < 0.001). The decrease was significant in ICUs with a Pediatric Critical Care Medicine fellowship (p < 0.001) but not in ICUs without one (p = 0.73). After adjusting for site-level clustering, patient characteristics, and Pediatric Critical Care Medicine fellowship presence, the Accreditation Council for Graduate Medical Education guideline change was not associated with lower participation by residents (odds ratio, 0.86; 95% CI, 0.59-1.24; p = 0.43). The downward trend of resident participation was similar regardless of the presence of an airway curriculum for residents. CONCLUSION: Laryngoscopy by pediatric residents has substantially decreased over time. This downward trend was not associated with the 2013 Accreditation Council for Graduate Medical Education change in residency requirements.

Effectiveness of vocabulary intervention for older children with (developmental) language disorder.

BACKGROUND: Children with developmental language disorder (DLD) frequently have difficulties with word learning and understanding vocabulary. For these children, this can significantly impact on social interactions, daily activities and academic progress. Although there is literature providing a rationale for targeting word learning in such children, there is little evidence for the effectiveness of specific interventions in this area for children with identified DLD. AIMS: To establish whether direct one-to-one intervention for children with DLD over 9 years of age leads to improved abilities to identify, comprehend, define, and use nouns and verbs targeted in intervention as compared with non-targeted control items and whether or not the participants' rating of their own knowledge of the words changes with intervention. METHODS & PROCEDURES: Twenty-five children and young people with language disorder (aged 9;4-16;1) participated in the study: 18 with DLD and seven with a language disorder associated with autism spectrum disorder (ASD). Two assessments of different levels were created: a higher ability (less frequent words) and a lower ability (more frequent words). Participants' speech and language therapists (SLTs) decided which level would be the most appropriate for each participant. Four tasks were carried out as part of the assessment and the scores were used to identify which words each participant worked on. Participants received one 30-min session per week one-to-one with their own SLT for 7 weeks, plus a 5-min revision session in between each main session. During each of the first five sessions, participants learned two new words; the two final sessions were spent revising the 10 words which had been targeted. OUTCOMES & RESULTS: Post-intervention assessment showed an increase in scores for both treated and control words. However, progress on treated words was significantly greater than on control words (d = 1.07), indicating effectiveness of intervention. The difference between progress on targeted and control words was found both for nouns (d = 1.29) and verbs (d = 0.64), but the effect size was larger for nouns. Whether or not the participants had an associated ASD did not affect the results. The children's self-rating of their knowledge of the targeted words was also significantly higher than for control words post-intervention. CONCLUSIONS & IMPLICATIONS: The intervention delivered one-to-one by the participants' usual SLT was effective in teaching new vocabulary to older children with language disorders. This shows that older children with language disorders can make progress with direct one-to-one intervention focused on vocabulary.

Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation.

BACKGROUND: Prolonged opioid administration leads to tolerance characterized by reduced analgesic potency. Pain management is additionally compromised by the hedonic effects of opioids, the cause of their misuse. The multifunctional protein ß-arrestin2 regulates the hedonic effects of morphine and participates in tolerance. These actions might reflect µ opioid receptor up-regulation through reduced endocytosis. ß-Arrestin2 also recruits kinases to µ receptors. We explored the role of Src kinase in morphine analgesic tolerance, locomotor stimulation, and reinforcement in C57BL/6 mice. METHODS: Analgesic (tail withdrawal latency; percentage of maximum possible effect, n = 8 to 16), locomotor (distance traveled, n = 7 to 8), and reinforcing (conditioned place preference, n = 7 to 8) effects of morphine were compared in wild-type, µ, µ, and ß-arrestin2 mice. The influence of c-Src inhibitors dasatinib (n = 8) and PP2 (n = 12) was examined. RESULTS: Analgesia in morphine-treated wild-type mice exhibited tolerance, declining by day 10 to a median of 62% maximum possible effect (interquartile range, 29 to 92%). Tolerance was absent from mice receiving dasatinib. Tolerance was enhanced in µ mice (34% maximum possible effect; interquartile range, 5 to 52% on day 5); dasatinib attenuated tolerance (100% maximum possible effect; interquartile range, 68 to 100%), as did PP2 (91% maximum possible effect; interquartile range, 78 to 100%). By contrast, c-Src inhibition affected neither morphine-evoked locomotor stimulation nor reinforcement. Remarkably, dasatinib not only attenuated tolerance but also reversed established tolerance in µ mice. CONCLUSIONS: The ability of c-Src inhibitors to inhibit tolerance, thereby restoring analgesia, without altering the hedonic effect of morphine, makes c-Src inhibitors promising candidates as adjuncts to opioid analgesics.

Effectiveness of 1:1 speech and language therapy for older children with (developmental) language disorder.

BACKGROUND: Evidence of the effectiveness of therapy for older children with (developmental) language disorder (DLD), and particularly those with receptive language impairments, is very limited. The few existing studies have focused on particular target areas, but none has looked at a whole area of a service. AIMS: To establish whether for students with (developmental) language disorder attending a specialist school, 1:1 intervention with an SLT during one school term improves performance on targeted areas, compared with untreated control areas. Also, to investigate whether gender, receptive language status, autism spectrum disorder (ASD) status, or educational Key Stage affected their response to this intervention. METHODS & PROCEDURES: Seventy-two students (aged 9-17 years, 88% of whom had receptive language impairments) and all speech and language therapists (SLTs) in our specialist school for children with Language Disorder, most of whom have DLD participated in this study over one school term. During this term, the SLTs devised pre- and post-therapy measures for every student for each target they planned to treat 1:1. In addition, for each target area, a control measure was devised. The targets covered a wide range of speech, language and communication areas, both receptive and expressive. Post-therapy tests were administered 'blind'. OUTCOMES & RESULTS: During the term, SLTs and students worked 1:1 on 120 targets, the majority in the areas of expressive and receptive language. Targets and controls did not differ pre-therapy. Significant progress was seen both on targets (d = 1.33) and controls (d = 0.36), but the targeted areas improved significantly more than the controls with a large and clinically significant effect size (d = 1.06). There was no effect of language area targeted (targets improved more than their controls for all areas). Participants with versus those without receptive language difficulties, co-occurring ASD diagnosis or participants in different educational Key Stages did not differ significantly in terms of the progress they made on target areas. CONCLUSIONS & IMPLICATIONS: Direct 1:1 intervention with an SLT can be effective for all areas of language for older children with (D)LD, regardless of their gender, receptive language or ASD status, or age. This adds to the relatively limited evidence base regarding the effectiveness of direct SLT intervention for school-aged children with (D)LD and for children with receptive language impairments. If direct 1:1 intervention can be effective with this hard-to-treat group, it may well also be effective with younger children with (D)LD. Thus, direct SLT services should be available for school-aged children with (D)LD, including older children and adolescents with pervasive difficulties.

Psychological trauma and functional somatic syndromes: a systematic review and meta-analysis.

OBJECTIVE: This meta-analysis systematically examined the association of reported psychological trauma and posttraumatic stress disorder (PTSD) with functional somatic syndromes including fibromyalgia, chronic widespread pain, chronic fatigue syndrome, temporomandibular disorder, and irritable bowel syndrome. Our goals were to determine the overall effect size of the association and to examine moderators of the relationship. METHODS: Literature searches identified 71 studies with a control or comparison group and examined the association of the syndromes with traumatic events including abuse of a psychological, emotional, sexual, or physical nature sustained during childhood or adulthood, combat exposure, or PTSD. A random-effects model was used to estimate the pooled odds ratio and 95% confidence interval. Planned subgroup analyses and meta-regression examined potential moderators. RESULTS: Individuals who reported exposure to trauma were 2.7 (95% confidence interval = 2.27-3.10) times more likely to have a functional somatic syndrome. This association was robust against both publication bias and the generally low quality of the literature. The magnitude of the association with PTSD was significantly larger than that with sexual or physical abuse. The association of reported trauma with chronic fatigue syndrome was larger than the association with either irritable bowel syndrome or fibromyalgia. Studies using nonvalidated questionnaires or self-report of trauma reported larger associations than did those using validated questionnaires. CONCLUSIONS: Findings are consistent with the hypothesis that traumatic events are associated with an increased prevalence of functional somatic syndromes. The analyses also highlight limitations of the existing literature and emphasize the importance of prospective studies, examining the potential similarities and differences of these conditions, and pursuing hypothesis-driven studies of the mechanisms underlying the link between trauma, PTSD, and functional somatic syndromes.

Specific pain complaints in Iraq and Afghanistan veterans screening positive for post-traumatic stress disorder.

BACKGROUND: Post-traumatic stress disorder (PTSD) and pain are highly comorbid. OBJECTIVE: The purpose of this study was to examine the association of PTSD with specific pain complaints in veterans of Operations Enduring and Iraqi Freedom (OEF/OIF). METHOD: A total of 381 primarily male (88.5%) veterans with a mean age of 30 years completed a battery of self-report questionnaires. A positive PTSD screen was defined as a score of ≥40 on the Davidson Trauma Scale. Logistic regression was used to examine the association of positive PTSD screen with specific pain complaints. RESULTS: There were no significant demographic or physical and mental health differences between veterans who screened positive for PTSD only and those with PTSD and at least one pain complaint, although differences on rates of combat injury and depression approached significance. Veterans who screened positive for PTSD were 2 to 3 times more likely to report abdominal pain, muscle aches or cramps, and joint aches, even after controlling for age, gender, combat injury, and depression. CONCLUSIONS: Similar to findings in other populations, there is a relationship between PTSD and pain complaints in OEF/OIF veterans. Future research should examine the mechanisms that link PTSD with specific pain complaints, especially abdominal pain.

Pain sensitivity in posttraumatic stress disorder and other anxiety disorders: a preliminary case control study.

BACKGROUND: Despite substantial research on the comorbidity of anxiety disorders including posttraumatic stress disorder (PTSD) and chronic pain, little is known about the mechanisms underlying these conditions that might be potentially similar. Evoked pain sensitivity is one factor that has been associated with several pain conditions which might also have relevance to anxiety disorders and PTSD. The aim of this preliminary study was to examine evoked pain sensitivity in PTSD compared to other anxiety disorders and in control participants. METHOD: The study used a cross-sectional case-control design in which participants completed a battery of questionnaires and structured interview and underwent cold pressor testing. RESULTS: Of 61 total participants, those in the PTSD (n =16) and other anxiety groups (n =12) endorsed significantly higher levels of psychological symptoms and poorer health functioning than control participants (n =33). The linear trend across baseline, threshold, and tolerance pain ratings from the cold pressor task significantly differed between participants with PTSD and the other anxiety and control groups suggesting lower pain sensitivity to a standardized stimulus of pain in individuals with PTSD. CONCLUSIONS: These findings are similar to some of the prior research and suggest that individuals with PTSD may exhibit lower cold pain sensitivity compared to those with other anxiety disorders. There is a need for future research to determine explanatory mechanisms.

Stress responses of adolescent male and female rats exposed repeatedly to cat odor stimuli, and long-term enhancement of adult defensive behaviors.

In order to characterize the short- and long-term effects of repeated stressor exposure during adolescence, and to compare the effects of using two sources of cat odor as stressor stimuli, male and female adolescent rats (postnatal day (PND) ∼ 38-46) were exposed on five occasions to either a control stimulus, a cloth stimulus containing cat hair/dander, or a section of cat collar previously worn by a cat. Relative to control stimulus exposure, activity was suppressed and defensive behavior enhanced during exposure to either cat odor stimulus (most pervasively in rats exposed to the collar). Only cloth-exposed rats showed elevated levels of corticosterone (CORT), and only after repeated stressor exposure, but interestingly, rats exposed to the collar stimulus during adolescence continued to show increased behavioral indices of anxiety in adulthood. In this group, the time an individual spent in physical contact with a cagemate during the final adolescent exposure was negatively related to stress-induced CORT output in adulthood, which suggests that greater use of social support during adolescent stress may facilitate adult behavioral coping, without necessitating increased CORT release. These findings demonstrate that adolescent male and female rats respond defensively to cat odor stimuli across repeated exposures and that exposure to such stressors during adolescence can augment adult anxiety-like behavior in similar stressful conditions. These findings also suggest a potential role for social behavior during adolescent stressor exposure in mediating long-term outcomes.

CLIC4 is a tumor suppressor for cutaneous squamous cell cancer.

Chloride intracellular channel (CLIC) 4 is a member of a redox-regulated, metamorphic multifunctional protein family, first characterized as intracellular chloride channels. Current knowledge indicates that CLICs participate in signaling, cytoskeleton integrity and differentiation functions of multiple tissues. In metabolically stressed skin keratinocytes, cytoplasmic CLIC4 is S-nitrosylated and translocates to the nucleus where it enhances transforming growth factor-ß (TGF-ß) signaling by protecting phospho-Smad 2 and 3 from dephosphorylation. CLIC4 expression is diminished in multiple human epithelial cancers, and the protein is excluded from the nucleus. We now show that CLIC4 expression is reduced in chemically induced mouse skin papillomas, mouse and human squamous carcinomas and squamous cancer cell lines, and the protein is excluded from the nucleus. The extent of reduction in CLIC4 coincides with progression of squamous tumors from benign to malignant. Inhibiting antioxidant defense in tumor cells increases S-nitrosylation and nuclear translocation of CLIC4. Adenoviral-mediated reconstitution of nuclear CLIC4 in squamous cancer cells enhances TGF-ß-dependent transcriptional activity and inhibits growth. Adenoviral targeting of CLIC4 to the nucleus of tumor cells in orthografts inhibits tumor growth, whereas elevation of CLIC4 in transgenic epidermis reduces de novo chemically induced skin tumor formation. In parallel, overexpression of exogenous CLIC4 in squamous tumor orthografts suppresses tumor growth and enhances TGF-ß signaling. These results indicate that CLIC4 suppresses the growth of squamous cancers, that reduced CLIC4 expression and nuclear residence detected in cancer cells is associated with the altered redox state of tumor cells and the absence of detectable nuclear CLIC4 in cancers contributes to TGF-ß resistance and enhances tumor development.

Hsp90 inhibitors and drugs from fragment and virtual screening.

We have previously reported the structure-based optimisation of a number of series of potent compounds progressed as clinical candidates for oncology through inhibition of the ATPase activity of the molecular chaperone, Hsp90. The starting point for these candidates was compounds discovered using a combination of structure-based hit identification methods. This chapter summarises the overall story of how these methods were applied. Virtual screening of commercially available compounds identified a number of classes of compounds. At the same time, an initial fragment screen identified 17 fragments of various classes that bound to the N-terminal domain of Hsp90 with weak (0.5-10 mM) affinity. A subsequent screen identified a total of 60 compounds. This collection of fragments and virtual screening hits were progressed in a number of ways. Although two fragments could be observed binding together in the active site, the synthetic effort required to link these fragments was judged too high. For the resorcinol class of fragments, limited library synthesis generated compounds in the 1-10 µM range. In addition, the resorcinol substructure was used to select commercially available compounds that were filtered using focussed docking in the Hsp90 active site to select further sets of compounds for assay. This identified structural motifs that were exploited during lead optimisation to generate AUY922, currently in Phase II clinical trials. In a separate campaign, features identified in the structures of fragments, evolved fragments and virtual screening hits bound to Hsp90 were combined to generate an oral series of compounds, progressed to preclinical candidates. The crystal structures were determined of many of the fragments bound to Hsp90 and provide examples of both maintenance and change of protein conformation on fragment binding. Finally, we analyse the extent to which our initial set of fragments recapitulates the key structural features of the Hsp90 inhibitors published to date.

Targeting conserved water molecules: design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization.

Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.

Enhanced stress responses in adolescent versus adult rats exposed to cues of predation threat, and peer interaction as a predictor of adult defensiveness.

Development of the hypothalamic-pituitary-adrenal (HPA) axis is influenced by external factors during early life in mammals, which optimizes adult function for predicted conditions. We have hypothesized that adolescence represents a sensitive period for the development of some aspects of adult stress response regulation. This was based on prior work showing that repeated exposure of rats to a stressor across an adolescent period increases fearfulness in a novel environment in adulthood and results in lower levels of dopamine receptor subtype-2 protein in prefrontal cortex. Here, we further our investigation of both acute and long-term effects of repeated adolescent stressor exposure on physiological (i.e., corticosterone) and behavioral (i.e., defensive behavior) measures of stress responding in male and female rats. Furthermore, we compared outcomes with those following identical manipulations administered in early adulthood and found that animals exposed to cues of predation threat during adolescence showed the most robust defensive responses to a homotypic stressor encountered in adulthood. Peer interaction during control manipulation in adolescence was identified as an important individual characteristic mediating development of adult defensive strategies.

The Montreal Cognitive Assessment (MoCA) in geriatric rehabilitation: psychometric properties and association with rehabilitation outcomes.

BACKGROUND: Cognitive status has been reported to be an important predictor of rehabilitation outcome. The Montreal Cognitive Assessment (MoCA) was designed to overcome some of the limitations of established cognitive screening tools such as the Mini-Mental State Examination (MMSE). The purpose of this study is to evaluate the psychometric characteristics of the MoCA as a screening tool in a geriatric rehabilitation program and its ability to predict rehabilitation outcome. METHODS: Forty-seven geriatric rehabilitation program patients participated in the study. Assessments of each patient's functional (Functional Independence Measure) and cognitive status (MMSE and MoCA) were performed. Information on discharge destinations were obtained and rehabilitation efficacy and efficiency scores were calculated. RESULTS: Significant correlations were found between the MoCA and other cognitive status measures. Cognitive status at admission and successful rehabilitation were also associated. Defining rehabilitation success on the basis of relative functional efficacy (an indicator that includes the patient's potential for improvement), the sensitivity and specificity of the MoCA were 80% and 30% respectively. The attention subscale of the MoCA was also uniquely predictive of rehabilitation success. The attention subscale (cutoff 5/6) of the MoCA had a sensitivity of 40% and specificity of 90%, as did the MMSE. CONCLUSIONS: As a cognitive screening tool, the MoCA appears to have acceptable psychometric properties. Results suggest that the MoCA can have a considerable advantage over the MMSE in sensitivity and equivalence in specificity using both total and attention scale scores. The MoCA may be a more useful measure for detecting cognitive impairment and predicting rehabilitation outcome in this population.

Hypophosphatasia: Current Literature for Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment.

Hypophosphatasia (HPP) is a rare inherited bone disorder identified by impaired bone mineralization. There are seven subtypes of HPP mainly characterized by their age of onset. These subtypes consist of perinatal (prenatal) benign, perinatal lethal, infantile, childhood, adult, odontohypophosphatasia, and pseudohypophosphatasia. Due to limited awareness of the condition, either misdiagnosis or delayed diagnosis is common. Furthermore, the condition is frequently treated with contraindicated drugs. This literature illustrates the most recent findings on the etiology, pathophysiology, clinical manifestations, diagnosing, and treatment for HPP and its subtypes. The etiology of the disease consists of loss-of-function mutations of the ALPL gene on chromosome one, which encodes for tissue nonspecific isoenzyme of alkaline phosphatase (TNAP). A decrease of TNAP reduces inorganic phosphate (Pi) for bone mineralization and allows for an increase in inorganic pyrophosphate (PPi) and phosphorylated osteopontin (p-OPN), which further reduces bone mineralization. The combination of these processes softens bone and mediates a clinical presentation similar to rickets/osteomalacia. HPP has an additional wide range of clinical features depending on its subtype. Although a concrete diagnostic guideline has not yet been established, many studies have supported a similar method of identifying HPP. Clinical features, radiological findings, and/or biomarker levels of the disorder should raise suspicion and encourage the inclusion of HPP as a differential diagnosis. Biomarkers, especially alkaline phosphatase (ALP), are major contributors to diagnosis. However, genetic testing is done for definitive diagnosis. The primary treatment for HPP is the reintroduction of TNAP as a recombinant enzyme called asfotase alfa. There are additional pharmaceutical treatments and in some cases, surgical intervention may be indicated. Pharmaceutical therapies such as bisphosphonates, denosumab, potent antiresorptive agents, and vitamin D are contraindicated in adults with HPP. We hope to raise awareness for HPP in order to prevent delayed diagnosis or misdiagnosis. We plan to encourage appropriate care and avoid treatments that may be contraindicating. We also encourage the development of a diagnostic guideline that will promote a consistently favorable patient prognosis.