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Background: Idiopathic toe walking (ITW) is an exclusionary diagnosis given when children toe walk without a medical reason. Treatment effectiveness studies rarely collect data other than ankle range of motion or presence of toe walking.Research Question: To develop a set of outcome measures identified by health professionals for use when providing treatment with children who have ITW, to understand if parents agreed with this set, and if parents believed they could perform these measures in clinician absence.Methods: Study 1 developed consensus and agreement on outcome measures for children receiving treatment for ITW through the modified Delphi technique with 10 expert health professionals. Parents of children who toe walked were invited to participate in an online survey for the second study, in which they were asked to rate the importance of these measures and if they believed they may be able to collect the data about their child without the health professional being present.Results: Ten health professionals developed nine questions and assessments through consensus and agreement over the three rounds. There were 34 parents providing information about satisfaction with toe walking assessments and treatments. Of these, 27 provide detailed responses about the outcome questions and assessments. The majority (91 % of 24 parents) in support of the outcome measures identified by experts. Parents expressed a willingness to self-complete questions or be taught assessments to monitor their child's progress.Significance: Use of these clinically based measures may enable consistent data collection regardless of the setting and provide the foundation for large data pooling in future treatment research. [ABSTRACT FROM AUTHOR]

Background: Idiopathic toe walking (ITW) is an exclusionary diagnosis resulting in a child walking on the balls of their feet. Preferred treatment options may be due to the severity of the toe or the health professional preference There are limited guidelines supporting consistent treatment recommendations for this condition. This research aimed to understand agreement between health professionals' knowledge of evidence for common treatment strategies for ITW and if health professionals supported these strategies being used in clinical practice. Methods: An international online survey was opened to registered health professionals who treat children with ITW between July 2017 and March 2018. The survey had two components: (a) demographic variables and variables relating to knowledge of evidence about ITW treatments and (b) support for common treatment strategies. Additional data on strategy use, referrals, and preference were collected. Kappa statistics described intra‐rater agreement between evidence knowledge and support. Multivariable regression analyses identified factors associated with the 10 most commonly preferred treatments. Results: There were 908 international responses. Kappa agreement for paired correct responses determined a fair agreement for evidence support knowledge for four strategies including watch and wait (Kappa = 0.24), stretching (Kappa = 0.30), sensory integration strategies (Kappa = 0.40), and motor control strategies (Kappa = 0.24) and moderate responses for 13 others. No strategies had greater than moderate agreement between correct knowledge of evidence and strategy support. Profession, location, number of children seen in practice, and not correctly identifying the evidence factored into many of the most commonly used strategies for ITW (p <.05). Conclusions: The results from this study, which confirm a variety of interventions, are utilized in the management of ITW around the world. Furthermore, there remains a disconnection between paediatric health professionals' understanding of the evidence of common treatment strategies of ITW and a consensus for the treatment of this condition. [ABSTRACT FROM AUTHOR]

Background: Atherosclerotic plaques demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine (8oxoG) lesions. 8oxoG is repaired by base excision repair enzymes; however, the mechanisms regulating 8oxoG accumulation in vascular smooth muscle cells (VSMCs) and its effects on their function and in atherosclerosis are unknown.Methods: We studied levels of 8oxoG and its regulatory enzymes in human atherosclerosis, the mechanisms regulating 8oxoG repair and the base excision repair enzyme 8oxoG DNA glycosylase I (OGG1) in VSMCs in vitro, and the effects of reducing 8oxoG in VSMCs in atherosclerosis in ApoE-/- mice.Results: Human plaque VSMCs showed defective nuclear 8oxoG repair, associated with reduced acetylation of OGG1. OGG1 was a key regulatory enzyme of 8oxoG repair in VSMCs, and its acetylation was crucial to its repair function through regulation of protein stability and expression. p300 and sirtuin 1 were identified as the OGG1 acetyltransferase and deacetylase regulators, respectively, and both proteins interacted with OGG1 and regulated OGG1 acetylation at endogenous levels. However, p300 levels were decreased in human plaque VSMCs and in response to oxidative stress, suggesting that reactive oxygen species-induced regulation of OGG1 acetylation could be caused by reactive oxygen species-induced decrease in p300 expression. We generated mice that express VSMC-restricted OGG1 or an acetylation defective version (SM22α-OGG1 and SM22α-OGG1K-R mice) and crossed them with ApoE-/- mice. We also studied ApoE-/- mice deficient in OGG1 (OGG1-/-). OGG1-/- mice showed increased 8oxoG in vivo and increased atherosclerosis, whereas mice expressing VSMC-specific OGG1 but not the acetylation mutant OGG1K-R showed markedly reduced intracellular 8oxoG and reduced atherosclerosis. VSMC OGG1 reduced telomere 8oxoG accumulation, DNA strand breaks, cell death and senescence after oxidant stress, and activation of proinflammatory pathways.Conclusions: We identify defective 8oxoG base excision repair in human atherosclerotic plaque VSMCs, OGG1 as a major 8oxoG repair enzyme in VSMCs, and p300/sirtuin 1 as major regulators of OGG1 through acetylation/deacetylation. Reducing oxidative damage by rescuing OGG1 activity reduces plaque development, indicating the detrimental effects of 8oxoG on VSMC function. [ABSTRACT FROM AUTHOR]

Background and Purpose: Several anti-angiogenic cancer drugs that inhibit VEGF receptor (VEGFR) signalling for efficacy are associated with a 15-60% incidence of hypertension. Tyrosine kinase inhibitors (TKIs) that have off-target activity at VEGFR-2 may also cause blood pressure elevation as an undesirable side effect. Therefore, the ability to translate VEGFR-2 off-target potency into blood pressure elevation would be useful in development of novel TKIs. Here, we have sought to quantify the relationship between VEGFR-2 inhibition and blood pressure elevation for a range of kinase inhibitors.Experimental Approach: Porcine aortic endothelial cells overexpressing VEGFR-2 (PAE) were used to determine IC50 for VEGFR-2 phosphorylation. These IC50 values were compared with published reports of exposure attained during clinical use and the corresponding incidence of all-grade hypertension. Unbound average plasma concentration (Cav,u ) was selected to be the most appropriate pharmacokinetic parameter. The pharmacokinetic-pharmacodynamic (PKPD) relationship for blood pressure elevation was investigated for selected kinase inhibitors, using data derived either from clinical papers or from rat telemetry experiments.Key Results: All-grade hypertension was predominantly observed when the Cav,u was >0.1-fold of the VEGFR-2 (PAE) IC50 . Furthermore, based on the PKPD analysis, an exposure-dependent blood pressure elevation >1 mmHg was observed only when the Cav,u was >0.1-fold of the VEGFR-2 (PAE) IC50 .Conclusions and Implications: Taken together, these data show that the risk of blood pressure elevation is proportional to the amount of VEGFR-2 inhibition, and a margin of >10-fold between VEGFR-2 IC50 and Cav,u appears to confer a minimal risk of hypertension. [ABSTRACT FROM AUTHOR]

DNA damage affecting both genomic and mitochondrial DNA is present in a variety of both inherited and acquired vascular diseases. Multiple cell types show persistent DNA damage and a range of lesions. In turn, DNA damage activates a variety of DNA repair mechanisms, many of which are activated in vascular disease. Such DNA repair mechanisms either stall the cell cycle to allow repair to occur or trigger apoptosis or cell senescence to prevent propagation of damaged DNA. Recent evidence has indicated that DNA damage occurs early, is progressive, and is sufficient to impair function of cells composing the vascular wall. The consequences of persistent genomic and mitochondrial DNA damage, including inflammation, cell senescence, and apoptosis, are present in vascular disease. DNA damage can thus directly cause vascular disease, opening up new possibilities for both prevention and treatment. We review the evidence for and the causes, types, and consequences of DNA damage in vascular disease. [ABSTRACT FROM AUTHOR]

We use issues that arose in the management of a 4-year old girl with a congenital myopathy to consider the tension between respecting the choices and decisions of the child's parents and applying clinical practice guidelines that emphasise minimising risk to the child. This case raises the issue of when it is reasonable to override parents' choice of management options. [ABSTRACT FROM AUTHOR]

Background: Congenital talipes equinovarus, or clubfoot, is a common pediatric orthopaedic condition of unknown origin. In many clubfoot clinical trials, interventions are assigned to a patient, but response to treatment is assessed separately in each foot. Trials commonly report x patients with y feet where y is greater than x (eg, 35 patients with 56 feet). However, common statistical tests assume that each data point is independent. Although data from unilateral cases of clubfoot are independent, it is unknown if each foot of patients with bilateral clubfeet are correlated. Questions/purposes: The purpose of this study was to assess the correlation in the feet of patients with bilateral clubfeet by (1) evaluating the degree of severity between lower limbs of each patient with bilateral clubfeet at baseline; (2) determining if right and left feet of each patient responded to intervention in the same way; (3) determining the proportion of bilateral relapse; and (4) determining the proportion of right and left feet which required the same intervention to correct bilateral relapse. Methods: We performed a chart review of the records of 33 patients with bilateral clubfeet (66 feet). Baseline severity was assessed using the Pirani score. The number of Ponseti serial casts to correct the deformity, the proportion of patients who underwent bilateral Achilles tenotomy, the proportion of bilateral relapse, and the treatment to correct bilateral relapse were examined. Results: The degree of severity between right (Pirani score mean, 5.2; SD, 0.8) and left (Pirani score mean, 5.2; SD, 0.5) feet for each patient at baseline was highly correlated (r = 0.76, p < 0.001). Response to intervention between lower limbs was highly correlated for the number of Ponseti casts required for initial correction (right mean, 5.2, SD, 1.1; left mean, 5.2, SD, 1.3) (r = 0.89, p < 0.001) and the proportion of patients who underwent bilateral Achilles tenotomy (right, 17/18; left, 16/18) (r = 0.94, p < 0.001). In the nine patients who experienced relapse, eight experienced bilateral involvement. In all cases of bilateral relapse, the right and left foot of each patient required the same intervention to correct the relapse. Conclusions: In patients with bilateral clubfeet, baseline severity, response to initial Ponseti treatment, Achilles tenotomy, and relapse outcomes were highly correlated in the right and left feet of each patient. Pooling clinical results of patients who present with bilateral clubfeet is statistically inappropriate, since results in two limbs of the same patient do not represent independent observations. These results support analogous work in other specialties suggesting that patients with bilateral presentations should not be analyzed as independent data points. Level of Evidence: Level IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Background: Tibialis anterior tendon transfer surgery forms a part of Ponseti management for children with congenital talipes equinovarus who, after initial correction, present with residual dynamic supination. Although retrospective studies support good outcomes, prospective longitudinal studies in this population are lacking. Questions/purposes: We assessed strength, plantar loading, ROM, foot alignment, function, satisfaction, and quality of life in patients with clubfoot that recurred after Ponseti casting who met indications for tibialis anterior tendon transfer surgery, and compared them with a group of patients with clubfoot treated with casting but whose deformity did not recur (therefore who were not indicated for tibialis anterior tendon transfer surgery). Methods: Twenty children with idiopathic congenital talipes equinovarus indicated for tibialis anterior tendon transfer surgery were recruited. Assessment at baseline (before surgery), and 3, 6, and 12 months (after surgery) included strength (hand-held dynamometry), plantar loading (capacitance transducer matrix platform), ROM (Dimeglio scale), foot alignment (Foot Posture Index), function and satisfaction (disease-specific instrument for clubfoot), and quality of life (Infant Toddler Quality of Life Questionnaire™). Outcomes were compared with those of 12 age-matched children with congenital talipes equinovarus not indicated for tibialis anterior tendon transfer surgery. Followup was 100% in the control group and 95% (19 of 20) in the tibialis anterior transfer group. Results: At baseline, the tibialis anterior tendon transfer group had a significantly worse eversion-to-inversion strength ratio, plantar loading, ROM, foot alignment, and function and satisfaction. At 3 months after surgery, eversion-to-inversion strength, plantar loading, and function and satisfaction were no longer different between groups. Improvements were maintained at 12 months after surgery (eversion-to-inversion strength mean difference, 8% body weight; 95% CI, −26% to 11%; p = 0.412; plantar loading, p > 0.251; function and satisfaction, p = 0.076). ROM remained less and foot alignment more supinated in the tibialis anterior tendon transfer group between baseline and followup (p < 0.001, p < 0.001). Conclusions: Tibialis anterior tendon transfer surgery was an effective procedure, which at 12-month followup restored the balance of eversion-to-inversion strength and resulted in plantar loading and function and satisfaction outcomes similar to those of age-matched children with congenital talipes equinovarus who after Ponseti casting were not indicated for tibialis anterior tendon transfer. Level of Evidence: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

We report the progress of an 8-year-old child with spinal muscular atrophy ( SMA) type 1. The parents elected in infancy that the child should be on long-term ventilation, but all attempts to establish this care at home have failed, so the child remains ventilated in the hospital. The leader of the long-term ventilation team reports on the child's progress and describes a week in the child's life. Two paediatricians argue that the benefits of long-term ventilation have not and do not compensate the child for the burdens imposed on her by this treatment and explain why they would not support the withdrawal of long-term ventilation now. They argue that long-term ventilation might have been avoided by applying to a court of law when the child was an infant. An ethicist discusses ethical aspects of decision-making in SMA type 1. [ABSTRACT FROM AUTHOR]

Congental talipes equinovarus, or clubfoot, remains one of the commonest congenital limb deformities. The genetics of this condition are not yet fully understood. It is increasingly being diagnosed on prenatal ultrasound with implications for prenatal counselling. With the widespread acceptance of the Ponseti method of clubfoot treatment major surgical interventions are needed much less frequently and long-term outcomes are improved. [ABSTRACT FROM AUTHOR]

Abstract: Atherosclerosis leading to cardiovascular disease is the leading cause of death among western populations. Atherosclerosis in characterised by the development of a fibrofatty lesion that consists of a diverse cell population, including inflammatory cells that create an intensely oxidising environment within the vessel. Coupled with normal replication, the local intracellular and extracellular environment causes damage to cellular DNA that is recognised and repaired by the DNA damage response (DDR) pathway. The role of DNA damage and the resulting deregulation of ‘normal’ cellular behaviour and subsequent loss of cell cycle control checkpoints have been widely studied in cancer. However, despite the extensive evidence for DNA damage in atherosclerosis, it is only over the past two decades that a causative link between DNA damage and atherosclerosis has been hypothesised. Whilst atherosclerosis is a feature of human disease characterised by defects in DNA damage, currently the role of DNA damage in the initiation and progression of atherosclerosis remains highly debated, as a ‘chicken and egg’ situation. This review will analyse the evidence for, the causes of, and consequences of DNA damage in atherosclerosis, detail the DNA damage response pathway that results in these consequences, and highlight therapeutic opportunities in this area. We also outline the evidence that DNA damage is a cause of both initiation and progression of atherosclerosis, and not just a consequence of disease. [Copyright &y& Elsevier]

Abstract: Brain-derived neurotrophic factor (BDNF) is secreted as either a mature furin-processed form or an unprocessed pro-form. Here, we characterise the extracellular processing of pro-BDNF by the serine protease plasmin. Using recombinant BDNF, maintained in the pro-form by site-directed mutagenesis or inhibition of furin, we demonstrate that plasmin (but not related proteases) is a specific and efficient activator of pro-BDNF. The proteolytic cleavage site is identified as Arg125-Val, within the consensus furin-cleavage motif (RVRR), generating an active form that stimulated neurite outgrowth on TrkB-transfected PC12 cells. Furthermore, we demonstrate that this processing can also occur in the pericellular environment by the action of cell-associated plasminogen activators. [Copyright &y& Elsevier]

A correction to the article "Bilateral Clubfeet Are Highly Correlated: A Cautionary Tale for Researchers" that was published in the 2014 issue is presented.

• Adults and children with CF had an improvement in lung function during the pandemic. • There was a reduction in pulmonary exacerbations following the onset of the pandemic. • Virtual consultations increased from 8% to 47% following pandemic onset in Australia. • Clinical reviews occurred more frequently, though fewer clinical measures were taken. The onset of the COVID-19 pandemic was associated with restricted community movement and limited access to healthcare facilities, resulting in changed clinical service delivery to people with cystic fibrosis (CF). This study aimed to determine clinical outcomes of Australian adults and children with CF in the 12-months following the onset of the COVID-19 pandemic. This longitudinal cohort study used national registry data. Primary outcomes were 12-month change in percent predicted forced expiratory volume in one second (FEV1 %pred), body mass index (BMI) in adults and BMI z-scores in children. A piecewise linear mixed-effects model was used to determine trends in outcomes before and after pandemic onset. Data were available for 3662 individuals (median age 19.6 years, range 0-82). When trends in outcomes before and after pandemic onset were compared; FEV1 %pred went from a mean annual decline of -0.13% (95%CI -0.36 to 0.11) to a mean improvement of 1.76% (95%CI 1.46-2.05). Annual trend in BMI improved from 0.03 kg/m2 (95%CI -0.02-0.08) to 0.30 kg/m2 (95%CI 0.25-0.45) and BMI z-scores improved from 0.05 (95%CI 0.03-0.07) to 0.12 (95%CI 0.09-0.14). Number of hospitalisations decreased from a total of 2656 to 1957 (p < 0.01). Virtual consultations increased from 8% to 47% and average number of consultations per patient increased from median (IQR) of 4(2-5) to 5(3-6) (p < 0.01). In the 12-months following the onset of the COVID-19 pandemic, there was an improvement in the clinical outcomes of people with CF when compared to the pre-pandemic period. [ABSTRACT FROM AUTHOR]

An abstract of the article "Biomechanical Assessment of Children Requiring Tibialis Anterior Surgical Tendon Transfer for Residual Congenital Talipes Equinovarus," by Kelly Gray, Paul Gibbons, David Little, and Joshua Burns is presented.

The article presents findings of a study conducted by Consultation and Partnerships team of Mercy Mental Health in Victoria on the gap on primary mental health care. It presents ideas on how to address the gap including the need for the community to have proper education regarding mental health or illness. It indicates that mental health needs of individuals could potentially be overlooked in the primary care setting and calls for a larger scale research to further investigate the issue.

Pulmonary arterial hypertension (PAH) is an unmet clinical need. The lack of models of human disease is a key obstacle to drug development. We present a biomimetic model of pulmonary arterial endothelial-smooth muscle cell interactions in PAH, combining natural and induced bone morphogenetic protein receptor 2 (BMPR2) dysfunction with hypoxia to induce smooth muscle activation and proliferation, which is responsive to drug treatment. BMPR2- and oxygenation-specific changes in endothelial and smooth muscle gene expression, consistent with observations made in genomic and biochemical studies of PAH, enable insights into underlying disease pathways and mechanisms of drug response. The model captures key changes in the pulmonary endothelial phenotype that are essential for the induction of SMC remodelling, including a BMPR2-SOX17-prostacyclin signalling axis and offers an easily accessible approach for researchers to study pulmonary vascular remodelling and advance drug development in PAH. A biomimetic inducible model of pulmonary arterial hypertension (PAH) is presented, combining natural and induced BMPR2 dysfunction with hypoxia in lung endothelial cells and blood-derived PAH cells to induce smooth muscle activation & proliferation. [ABSTRACT FROM AUTHOR]

Human cerebellum consists of high density and complexity of neurons. Thus, it is challenging to differentiate cerebellar-like organoids with similar cellular markers and function to the human brain. Our previous study showed that the combination of retinoic acid (RA), Wingless/integrated (Wnt) activator, and Sonic Hedgehog (SHH) activator promotes cerebellar differentiation from human induced pluripotent stem cells (hiPSCs). This study examined phenotypic, metabolic, and biogenesis in early cerebellar development. Cerebellum spheroids were differentiated from human iPSK3 cells. During day 7–14, RA and Wnt activator CHIR99021 were used and SHH activator purmorphamine (PMR) was added later to promote ventralization. Gene expression for early cerebellar layer markers, metabolism, and extracellular vesicle (EV) biogenesis were characterized. Zinc-induced neurotoxicity was investigated as a proof-of-concept of neurotoxicity study. Flow cytometry results showed that there was no significant difference in NEPH3, PTF1A, OLIG2, and MATH1 protein expression between RCP (RA-CHIR-PMR) versus the control condition. However, the expression of cerebellar genes for the molecular layer (BHLE22), the granule cell layer (GABRB2, PAX6, TMEM266, KCNIP4), the Bergmann glial cells (QK1, DAO), and the Purkinje cell layer (ARHGEF33, KIT, MX1, MYH10, PPP1R17, SCGN) was significantly higher in the RCP condition than the control. The shift in metabolic pathways toward glycolysis was observed for RCP condition. The EV biogenesis marker expression was retained. Mild zinc-induced neurotoxicity may exist when zinc exposure exceeds 1.0 µM. RCP treatment can promote specific cerebellar-like differentiation from hiPSCs indicated by gene expression of early cerebellar markers and regionally enriched genes. The higher cerebellar marker expression is accompanied by the elevated glycolysis with the retained EV biogenesis. This study should advance the understanding of biomarkers during early cerebellar development for cerebellum organoid engineering and neurotoxicity study. [ABSTRACT FROM AUTHOR]

Purpose: Currently, the optimal time to initiate treatment among preterm infants with clubfoot is unknown. The aim of this study was to describe treatment outcomes up to 1year post-correction following Ponseti management in infants who were born preterm but treated at term age. Methods: A retrospective chart audit was conducted at a major pediatric hospital on preterm infants with clubfoot who commenced Ponseti management at term age (≥37weeks of gestation). Data are expressed as mean values (±standard deviation) or 95% confidence intervals (95% CIs). Results: Twenty-six participants (40 feet) born at 32.6/40 (±3.1) weeks of gestation were identified. Thirteen (50%) were male, 14 (54%) presented bilaterally, and 7 (27%) presented with syndromic clubfoot. Ponseti management was initiated at 41.4/40 (±2.8) weeks gestation. Baseline Pirani scores were 5.2 (95%CI: 4.8–5.6) in the idiopathic group and 5.7 (95%CI: 5.0–6.4) in the syndromic group. The number of casts to correction was 5.9 (95% CI: 5.1–6.6) for those with idiopathic clubfoot and 6.1 (95%CI: 5.0–7.3) for those with syndromic clubfoot. Achilles tenotomies were required in 13 (21 feet) with idiopathic clubfoot and five (7 feet) with syndromic clubfoot. Recurrence occurred in four infants (5 feet): 4 feet required further casting and bracing, and 1 foot required additional surgery. Conclusion: Ponseti management at term age in preterm-born infants yields comparable 1-year outcomes to termborn infants. Further research is required to determine whether outcomes beyond 1 year of age align with growth and development demonstrated by term-born infants who are managed with the Ponseti method. Level of evidence: Level IV. [ABSTRACT FROM AUTHOR]

Background-Vascular smooth muscle cells (VSMCs) in human atherosclerosis manifest extensive DNA damage and activation of the DNA damage response, a pathway that coordinates cell cycle arrest and DNA repair, or can trigger apoptosis or cell senescence. Sirtuin 1 deacetylase (SIRT1) regulates cell ageing and energy metabolism and regulates the DNA damage response through multiple targets. However, the direct role of SIRT1 in atherosclerosis and how SIRT1 in VSMCs might regulate atherosclerosis are unknown. Methods and Results-SIRT1 expression was reduced in human atherosclerotic plaques and VSMCs both derived from plaques and undergoing replicative senescence. SIRT 1 inhibition reduced DNA repair and induced apoptosis, in part, through reduced activation of the repair protein Nijmegen Breakage Syndrome-i but not p53. Fat feeding reduced SIRT1 and induced DNA damage in VSMCs. VSMCs from mice expressing inactive truncated SIRT1 (Δex4) showed increased oxidized low-density lipoprotein-induced DNA damage and senescence. ApoE-/- mice expressing SIRT1Δex4 only in smooth muscle cells demonstrated increased DNA damage response activation and apoptosis, increased atherosclerosis, reduced relative fibrous cap thickness, and medial degeneration. Conclusions-SIRT1 is reduced in human atherosclerosis and is a critical regulator of the DNA damage response and survival in VSMCs. VSMC SIRT1 protects against DNA damage, medial degeneration, and atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: Earlier studies have shown that acetaldehyde, the primary intermediate in the biological degradation of ethanol, interacts with enzymes and zymogens of the common coagulation pathway, prolonging prothrombin time and activated partial thromboplastin time (APTT), and that acetaldehyde-glycosaminoglycans (GAGs) mixtures synergistically prolong clotting times (Brecher, A. S. (2005). In Comprehensive Handbook of Alcohol Related Pathology. Vol. 3(93), pp. 1223–1244). In this study, the effect of acetaldehyde and GAGs upon Factor IXa, an intrinsic pathway enzyme, has been investigated. Individually, acetaldehyde, heparins of various molecular weights, dermatan sulfate, and chondroitin sulfates A and C affect Factor IXa, prolonging clotting time as measured by APTT. Pre-incubation of Factor IXa with a mixture of 22.3mM acetaldehyde and heparin17k, heparin6k, dermatan sulfate, or chondroitin sulfate A additively prolongs clotting times, reflecting individual, unrelated molecular mechanistic effects. In contrast, a synergistic effect is observed at the 44.7mM acetaldehyde level with heparin17k, heparin3k, chondroitin sulfates A and C, and dermatan sulfate, suggesting that acetaldehyde may cross-link with the enzyme and the GAGs, forming tertiary complexes, further influencing coagulopathy. These observations upon Factor IXa present a deeper dimension to the anticoagulation effect of alcohol on the coagulation cascade. [Copyright &y& Elsevier]

Introduction: Biomarkers of disease severity in Charcot-Marie-Tooth disease (CMT) are required to evaluate early responses to treatment. In this study we used magnetic resonance imaging (MRI) to evaluate the relationship between muscle volume and intramuscular fat accumulation with weakness, disability, and impaired gait in affected children and adolescents.Methods: Fifty-five participants underwent MRI of the anterior compartment of the lower leg. Muscle and fat volumes were calculated. Strength was measured using hand-held dynamometry, disability using the CMT Pediatric Scale, and 3-dimensional gait analysis using an 8-camera Vicon Nexus motion capture system.Results: Lower muscle volume was significantly associated with reduced dorsiflexion strength, increased disability, impaired gait profile score, and foot drop. Intramuscular fat accumulation was associated with reduced dorsiflexion strength and impaired gait profile score.Discussion: The MRI protocol described was feasible, reliable, and sensitive to the magnitude of weakness, disability, and walking difficulties in children with CMT. Muscle Nerve 59:213-217, 2019. [ABSTRACT FROM AUTHOR]

Background: Although vascular smooth muscle cell (VSMC) proliferation is implicated in atherogenesis, VSMCs in advanced plaques and cultured from plaques show evidence of VSMC senescence and DNA damage. In particular, plaque VSMCs show shortening of telomeres, which can directly induce senescence. Senescence can have multiple effects on plaque development and morphology; however, the consequences of VSMC senescence or the mechanisms underlying VSMC senescence in atherosclerosis are mostly unknown.Methods and Results: We examined the expression of proteins that protect telomeres in VSMCs derived from human plaques and normal vessels. Plaque VSMCs showed reduced expression and telomere binding of telomeric repeat-binding factor-2 (TRF2), associated with increased DNA damage. TRF2 expression was regulated by p53-dependent degradation of the TRF2 protein. To examine the functional consequences of loss of TRF2, we expressed TRF2 or a TRF2 functional mutant (T188A) as either gain- or loss-of-function studies in vitro and in apolipoprotein E(-/-) mice. TRF2 overexpression bypassed senescence, reduced DNA damage, and accelerated DNA repair, whereas TRF2(188A) showed opposite effects. Transgenic mice expressing VSMC-specific TRF2(T188A) showed increased atherosclerosis and necrotic core formation in vivo, whereas VSMC-specific TRF2 increased the relative fibrous cap and decreased necrotic core areas. TRF2 protected against atherosclerosis independent of secretion of senescence-associated cytokines.Conclusions: We conclude that plaque VSMC senescence in atherosclerosis is associated with loss of TRF2. VSMC senes cence promotes both atherosclerosis and features of plaque vulnerability, identifying prevention of senescence as a potential target for intervention. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about a study on the compliance of patients to depot antipsychotics.

A multicenter surveillance study was performed to determine the rates of hand carriage of potential pathogens among healthcare personnel in four neonatal intensive care units. Staphylococcus aureus, enterococci, and gram-negative bacilli were recovered from 8%, 3%, and 2% of 1000 hand culture samples, respectively. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this study was to examine the intra-rater and inter-rater reliability of physiotherapists using the Pirani scoring system for clubfoot to score digital photographs of infants' feet. Methods: Twelve infant feet were photographed to reflect variations in the six clinical signs of clubfoot. Physiotherapists viewed the photographs and scored the feet using the Pirani scoring system on two separate occasions. Results: Intra-rater reliability was excellent when scoring photographs, while inter-rater reliability was found to be fair to good for most subscales. Experienced therapists demonstrated higher reliability than novice therapists but not significantly so. Reliability was equivalent between the Pirani scoring system and a modified five-point scoring system created for this study. Scoring the rigidity of equinus subscale was found to be more reliable than the other subscales (P<0.01), which did not differ significantly from each other. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this study was to examine the intra-rater and inter-rater reliability of physiotherapists using the Pirani scoring system for clubfoot to score digital photographs of infants' feet. Methods: Twelve infant feet were photographed to reflect variations in the six clinical signs of clubfoot. Physiotherapists viewed the photographs and scored the feet using the Pirani scoring system on two separate occasions. Results: Intra-rater reliability was excellent when scoring photographs, while inter-rater reliability was found to be fair to good for most subscales. Experienced therapists demonstrated higher reliability than novice therapists but not significantly so. Reliability was equivalent between the Pirani scoring system and a modified five-point scoring system created for this study. Scoring the rigidity of equinus subscale was found to be more reliable than the other subscales (P<0.01), which did not differ significantly from each other. [ABSTRACT FROM AUTHOR]

Objective: To reflect upon the implementation of sensory-based approaches within the environment of a psychiatric inpatient unit.Method: A literature review on sensory modulation within psychiatric inpatient care, including seclusion and restraint reduction initiatives, was conducted. A variety of sensory-based principles were planned, developed and implemented over a 3-year period. Preliminary data regarding sensory room use and acute arousal ratings within the high-dependency area were analysed.Results: Preliminary sensory room data showed a significant reduction in patient distress levels, as per consumer and clinician ratings, and that the majority of sensory room sessions were conducted by nursing staff. A significant reduction was also found for acute arousal ratings, pre to post, for the HDU engagement program. Several issues were uncovered throughout implementation of the sensory-based strategies.Conclusions: Findings indicate the importance of cultural change, compared with simply an environmental change, giving all staff and consumers the confidence to utilise a variety of sensory-based methods during times of need. Further Australian research is required to explore the positive contribution sensory modulation can potentially make across the spectrum of psychiatric settings. [ABSTRACT FROM AUTHOR]

Objective: The aim of this paper is to review research evidence and describe our experience of facilitated discharge from mental health services to primary care. Method: A literature review of facilitated discharge was conducted. In addition, the clinical characteristics of 21 discharged and 21 non-discharged patients from one shared care service were compared in a retrospective file review. Thirty-one patients in another facilitated discharge program were surveyed. Results: Discharged patients had a higher level of function. There was a trend towards discharged patients being female and employed with less chronic illness, involuntary treatment, behavioural symptoms, depot medication, triage contact, service contact with family, and more mood disorder. Of the 10 survey respondents, 60% reported feeling better compared with their last service contact, 70% felt not having contact was a good thing and most saw their doctors regularly and reported a good relationship. Conclusions: There was a trend towards more stable patients being discharged and it appeared that they responded positively to this, without a clear indication of which factors best determine suitability for discharge. Consequently, we elected to incorporate discharge planning processes as a core function of case management and increase shared care with the primary care sector. [ABSTRACT FROM AUTHOR]