Delayed and significant hypercalcaemia due to teriparatide therapy: a case report and review.

INTRODUCTION: Transient hypercalcaemia due to teriparatide occurs in up to 11% of patients though delayed hypercalcaemia (> 24 h post injection) is rare. We report the case of a female who developed significant delayed hypercalcaemia after teriparatide treatment for osteoporosis and review other cases in the literature to date. CASE REPORT: A 72-year-old female on teriparatide for the treatment of osteoporosis was found to have hypercalcaemia (3.30 mmol/l) on routine testing approximately 3 months after starting therapy. Serum calcium pretreatment was normal at 2.39 mmol/l. She was admitted to the hospital for investigations which identified a serum 25-hydroxyvitamin D of 94 nmol/l, a low parathyroid hormone of 6.0 pg/ml, and normal test results for 1,25 dihydroxyvitamin D (115 pmol/l), parathyroid hormone-related peptide (< 1.4 pmol/ml), serum electrophoresis and angiotensin-converting enzyme (39 IU/l). CT abdomen, pelvis, and thorax revealed no evidence of malignancy and an isotope bone scan ruled out skeletal metastases. Serum calcium normalised (2.34 mmol/l) several days after stopping teriparatide and calcium supplements and administering intravenous fluid. On restarting teriparatide, delayed hypercalcaemia reoccurred and treatment was switched to denosumab. DISCUSSION: Delayed moderate to severe hypercalcaemia (serum calcium > 3.0 mmol/l) due to teriparatide is rare but may lead to therapy withdrawal. The underlying predisposing risk factors remain unclear and highlight the importance of a routine serum calcium assessment on therapy.

The Lighter Touch: Less-Restriction in Sequentially Implemented Behavioral Sleep Interventions for Children with Rare Genetic Neurodevelopmental Conditions.

PURPOSE: The prevalence of sleep difficulties among children with rare genetic neurodevelopmental conditions (RGNC) is high. Behavioral interventions are commonly used in the treatment of sleep difficulties in children with neurodevelopmental conditions such as autism, however, research is scarce in children with RGNC. The range of co-occurring complexities within this population, means there is a need for research to not only determine the effectiveness of behavioral sleep interventions, but also which components might be the least restrictive (i.e., intensive/aversive) and minimally sufficient. METHODS: This study used a single-case multiple baseline design to investigate the effectiveness and acceptability of behavioral sleep interventions, indicated within a Functional Behavior formulation in eight children with RGNC (M = 7.3 years). Intervention components were sequentially administered across up to three phases, based on the principle of less restriction (from least to relatively more intensive) to determine what might be minimally sufficient. RESULTS: Results showed an improvement in sleep onset latency, night wakings, early morning waking and unwanted bed-sharing for 7/7, 6/7, 3/3 and 3/3 children respectively. Improvement was observed for most participants following the less restrictive phases of intervention (circadian modifications, antecedent modifications and positive reinforcement), however, more restrictive, albeit modified, extinction procedures were still implemented for five participants. Improvements were maintained at follow-up and interventions were deemed acceptable to parents. CONCLUSIONS: Less restrictive function-based behavioral strategies are an effective, and in some cases sufficient, contribution to a sequence of interventions for a range of sleep difficulties. They should be implemented first, before more restrictive strategies.

The Type, Severity, and Impact of Sleep Problems in Children With Angelman Syndrome and Parental Help-seeking Patterns.

Angelman syndrome (AS) is a rare genetic developmental disability that presents with high rates of co-occurring sleep difficulties. Most existing research has focused on the pathophysiology of sleep problems in people with AS, and suggests that sleep problems are the result of genetic and neurobiological factors. However, little is known about the role of the social environment and learning in sleep problems in children with AS. This descriptive study used survey data from 139 parents of children with AS to investigate: 1) the type, topography and severity of children's sleep problems; 2) the collateral child, parent and family impacts of the sleep problems; 3) treatment selection practices and the perceived effectiveness of these treatments; and 4) sources of support and treatment advice received. Parents reported that the majority of children experienced sleep problems, resulting in numerous deleterious effects on child and family functioning. They also reported high levels of concern about these sleep problems, but low levels of perceived support. Study findings highlight the need to establish a disability-specific profile of the type and impact of sleep problems experienced by children with AS, and have further implications for the delivery of clinical services and support provided to parents of children with AS.

A requirement for astrocyte IP3R2 signaling for whisker experience-dependent depression and homeostatic upregulation in the mouse barrel cortex.

Changes to sensory experience result in plasticity of synapses in the cortex. This experience-dependent plasticity (EDP) is a fundamental property of the brain. Yet, while much is known about neuronal roles in EDP, very little is known about the role of astrocytes. To address this issue, we used the well-described mouse whiskers-to-barrel cortex system, which expresses a number of forms of EDP. We found that all-whisker deprivation induced characteristic experience-dependent Hebbian depression (EDHD) followed by homeostatic upregulation in L2/3 barrel cortex of wild type mice. However, these changes were not seen in mutant animals (IP3R2-/-) that lack the astrocyte-expressed IP3 receptor subtype. A separate paradigm, the single-whisker experience, induced potentiation of whisker-induced response in both wild-type (WT) mice and IP3R2-/- mice. Recordings in ex vivo barrel cortex slices reflected the in vivo results so that long-term depression (LTD) could not be elicited in slices from IP3R2-/- mice, but long-term potentiation (LTP) could. Interestingly, 1 Hz stimulation inducing LTD in WT paradoxically resulted in NMDAR-dependent LTP in slices from IP3R2-/- animals. The LTD to LTP switch was mimicked by acute buffering astrocytic [Ca2+] i in WT slices. Both WT LTD and IP3R2-/- 1 Hz LTP were mediated by non-ionotropic NMDAR signaling, but only WT LTD was P38 MAPK dependent, indicating an underlying mechanistic switch. These results demonstrate a critical role for astrocytic [Ca2+] i in several EDP mechanisms in neocortex.

Non-canonical endogenous expression of voltage-gated sodium channel NaV 1.7 subtype by the TE671 rhabdomyosarcoma cell line.

The human TE671 cell line was originally used as a model of medulloblastoma but has since been reassigned as rhabdomyosarcoma. Despite the characterised endogenous expression of voltage-sensitive sodium currents in these cells, the specific voltage-gated sodium channel (VGSC) subtype underlying these currents remains unknown. To profile the VGSC subtype in undifferentiated TE671 cells, endpoint and quantitative reverse transcription-PCR (qRT-PCR), western blot and whole-cell patch clamp electrophysiology were performed. qRT-PCR profiling revealed that expression of the SCN9A gene was ∼215-fold greater than the SCN4A gene and over 400-fold greater than any of the other VGSC genes, while western blot confirmed that the dominant SCN9A RNA was translated to a protein with a molecular mass of ∼250 kDa. Elicited sodium currents had a mean amplitude of 2.6 ± 0.7 nA with activation and fast inactivation V50 values of -31.9 ± 1.1 and -69.6 ± 1.0 mV, respectively. The currents were completely and reversibly blocked by tetrodotoxin at concentrations greater than 100 nm (IC50  = 22.3 nm). They were also very susceptible to the NaV 1.7 specific blockers Huwentoxin-IV and Protoxin-II with IC50 values of 14.6 nm and 0.8 nm, respectively, characteristic of those previously determined for NaV 1.7. Combined, the results revealed the non-canonical and highly dominant expression of NaV 1.7 in the human TE671 rhabdomyosarcoma cell line. We show that the TE671 cell line is an easy to maintain and cost-effective model for the study of NaV 1.7, a major target for the development of analgesic drugs and more generally for the study of pain. KEY POINTS: Undifferentiated TE671 cells produce a voltage-sensitive sodium current when depolarised. The voltage-gated sodium channel isoform expressed in undifferentiated TE671 cells was previously unknown. Through qRT-PCR, western blot and toxin pharmacology, it is shown that undifferentiated TE671 cells dominantly (>99.5%) express the NaV 1.7 isoform that is strongly associated with pain. The TE671 cell line is, therefore, a very easy to maintain and cost-effective model to study NaV 1.7-targeting drugs.

The Influence of Choice of Surgical Procedure on Long-Term Survival After Cardiac Surgery.

BACKGROUND: There is some interest in long-term survival after various cardiac surgical strategies, including off-pump versus on-pump coronary artery surgery (CAG), mitral valve (MV) repair versus replacement, and aortic valve (AV) bioprosthetic versus mechanical replacement. METHODS: We studied patients older than 49 years of age, recording risk factors and surgical details at the time of surgery. We classified procedures as: MV surgery with or without concurrent grafts or valves; AV surgery with or without concurrent CAG; or isolated CAG. Follow-up was through the state death register and state-wide hospital attendance records. Risk-adjusted survival was estimated using Cox proportional hazards. Observed survival was compared to the expected age- and sex- matched population survival. RESULTS: During a median follow-up of 14.8 years 5,807 of 11,718 patients died. The difference between observed and expected survival varied between 3.4 years for AV surgery and 9.6 years for females undergoing MV surgery. The risk-adjusted mortality hazard rate after off-pump CAG was 0.93 (95% CI 0.8-1.0, p=0.84), MV repair 0.67 (95% CI 0.6-0.8, p<0.0001), MV bioprosthesis 0.82 (95% CI 0.81 (0.6-1.0, p=0.11) and bioprosthetic AV replacement 1.02 (95% CI 0.9-1.2, p=0.82). CONCLUSIONS: Compared to the general population, cardiac surgical patients have a shorter than expected life expectancy. We observed a survival benefit of mitral valve repair over replacement. We did not observe significant survival differences between off-pump and on-pump CAG, nor between bioprosthetic and mechanical replacement.

Collateral Child and Parent Effects of Function­Based Behavioral Interventions for Sleep Problems in Children and Adolescents with Autism.

This study follows McLay et al., Journal of Autism and Developmental Disorders, (2020) to investigate whether the function-based behavioral sleep interventions received by 41 children and adolescents with autism spectrum disorder (ASD) produced collateral improvements in ASD severity, internalizing and externalizing symptoms and parent relationship quality, ratings of depression, anxiety and stress, and personal sleep quality. Concomitant with reduced sleep problem severity, improvements were found in children's internalizing and externalizing behavior and ASD symptom severity. Small improvements were also found in maternal sleep quality and parental stress. There was little change in parental relationship quality post-treatment, possibly reflecting high baseline scores. Overall, collateral benefits were generally small but positive, consistent with the limited extant research, and underscore the importance of investigating collateral effects across a range of variables.

A cross-sectional overview of the second 4000 incidents reported to webAIRS, a de-identified web-based anaesthesia incident reporting system in Australia and New Zealand.

This cross-sectional overview of the second 4000 incidents reported to webAIRS has findings that are very similar to the previous overview of the first 4000 incidents. The distribution of patient age, body mass index and American Society of Anesthesiologists physical status was similar, as was anaesthetist gender, grade, location and time of day of incidents. About 35% of incidents occurred during non-elective procedures (vs. 33% in the first 4000 incidents). The proportion of incidents in the various main categories was also similar, with respiratory/airway being most common, followed by cardiovascular, medication-related and medical device or equipment-related incidents. Together these categories made up about 78% of all incidents in both overviews. The immediate outcome was comparable with reports of harm in about a quarter of incidents and a similar rate of deaths (4.7% vs. 4.2%). However, the proportion of patients who had received total intravenous anaesthesia was higher (17.6% vs. 7.7%) and the proportion of patients who received combined intravenous and inhalational anaesthesia was lower (52.3% vs. 58.4%), as was the proportion receiving local anaesthesia alone (1.6% vs. 6.7%). There was a small increase in the number of incidents resulting in unplanned admission to a high dependency or intensive care unit (18.1% vs. 13.5%). It is not clear whether these differences represent trends or random observations. About 48% of incidents were considered preventable by the reporters (vs. 52% in the first 4000). These findings support continued emphasis on human and system factors to promote and improve patient safety in anaesthesia care.

Sleep and stereotypy in children with autism: effectiveness of function-based behavioral treatment.

OBJECTIVES: Children with autism spectrum disorder (ASD) experience high rates of sleep problems, which exacerbate the core symptoms of ASD, including stereotypy (restricted and repetitive behaviors). Conversely, stereotypy can interfere with sleep by actively competing with sleep-facilitative behaviors (eg, lying down quietly). Behavioral interventions informed by functional behavioral assessment (FBA) significantly reduce sleep problems in children with ASD, however, their impact on sleep-interfering stereotypy is not clear. This study investigated the effectiveness of function-based behavioral treatments for sleep problems, including sleep-interfering stereotypy, in children with ASD, the maintenance of these effects, and parents' satisfaction with the treatment process. METHODS: A non-concurrent multiple baselines across participants design was used to evaluate the effectiveness of function-based, individualized treatments for sleep problems and sleep-interfering stereotypy in three children with ASD. For each participant, stereotypy was automatically maintained and interfered with the initiation and/or re-initiation of sleep. Parents implemented multi-component treatments that included a faded bedtime procedure. RESULTS: Treatment reduced sleep problems in 2/3 participants, and the duration of stereotypy was reduced in all participants. Treatment effects were largely maintained at follow-up, and parent-reported satisfaction was high. CONCLUSION: These results support prior research demonstrating the effectiveness of FBA-informed behavioral treatments for sleep problems in children with ASD. Further, this study shows that these treatments may be effective in reducing sleep-interfering stereotypy. Future research should more thoroughly investigate the bidirectional relationships between sleep and core symptoms of ASD, and address how these relationships are assessed and treated in the sleep context.

Endogenous melatonin and sleep in individuals with Rare Genetic Neurodevelopmental Disorders (RGND): A systematic review.

Individuals with Rare Genetic Neurodevelopmental Disorders (RGND) present with significant sleep problems and circadian rhythm abnormalities of uncertain aetiology. Abnormal melatonin secretion may play a role in sleep disturbance in individuals with higher incidence developmental disabilities, however, RGND research is limited. This review compared the melatonin profiles in a range of RGND with that of the general population and considered the impact of any differences on sleep. A systematic search identified 19 studies that met inclusion criteria. Each study was examined to extract data relating to the study design, participant characteristics, objectives, sleep measures and results, and melatonin measures and findings. Studies were evaluated using the BIOCROSS quality appraisal tool. Nine studies focussed on Smith-Magenis syndrome (SMS), the rest included individuals with Angelman (AS), Fragile-X (FXS), Prader-Willi (PWS), septo-optic dysplasia, PAX6/WAGR and Williams (WS) syndromes (N = 349). Individuals with RGND present with a range of sleep problems, particularly dyssomnias. The melatonin profile varied within and between RGND, with low nocturnal melatonin levels commonly reported. Understanding the relationship between specific sleep and melatonin parameters within RGND may help inform sleep intervention.

Sequential Implementation of Functional Behavior Assessment-Informed Treatment Components for Sleep Disturbance in Autism: A Case Study.

Background: Sleep disturbances are a significant problem for people with autism spectrum disorder (ASD). Existing research supports the use of parent-implemented, functional behavior assessment (FBA)-informed interventions for sleep problems in children with ASD. There is also emerging evidence for combined parent- and young person-implemented behavioral sleep interventions for older children and adolescents with ASD. However, the active treatment components of such interventions have not been identified in previous studies, as components have not been evaluated independently of one another.Methods: The current study sequentially implemented FBA-informed treatment components (in the order of least to most restrictive and time intensive) within a single-case AB design, to evaluate at which point treatment resulted in a statistically and clinically substantive reduction in target sleep variables. Combined parent- and young person-implemented intervention components consisted of: (a) white noise; (b) white noise and relaxation instruction; and (c) white noise, relaxation instruction, and stimulus control.Participant: The participant was a 9-year-old girl with autism and selective mutism.Results: The combined use of white noise, relaxation instruction, and stimulus control resolved the participant's sleep problems. Other more restrictive and/or time intensive interventions were unnecessary. Treatment effects were maintained at 10-week follow-up.Conclusions: The current study illustrates the feasibility of administering FBA-informed treatment components sequentially, to ensure application of minimally sufficient interventions.

Longitudinal Study of Infant Sleep Development: Early Predictors of Sleep Regulation Across the First Year.

BACKGROUND: An important developmental task for infants over their first few years of life is to learn to settle to sleep with a reasonably short latency, maintain sleep through the night and coordinate with family sleeping and waking schedules. A child who can reliably do this is exhibiting self-regulated sleep. Otherwise, children's sleep may have to be other (non-self) regulated to some degree and they may exhibit pediatric sleep disturbances (e.g., extended sleep latency, and/or frequent nightwaking); these are reported by 36-45% of parents of infants between ages four to 12 months. PURPOSE: To answer the question: Can infant and parent factors observed at 1 month of infant age predict which infants will have regulated sleep at 6- and 12-months of age? Prediction from 1 month has not previously been investigated. METHODS: In a prospective longitudinal study, the mothers of 52 typically developing infants completed 6-day sleep diaries at 1, 3, 6, 9 and 12 months from which a composite sleep score (CSS) was derived for each child at each month. Diary reliability was assessed once (for 54% of families) using all-night videosomnography. RESULTS: At 6 months, CSS scores were distributed bi-modally and thus differentiated into two groups by an empirically observed CSS cutoff score, with a majority (56%) of infants classified as self-sleep regulated (S-R) and the rest as non-self sleep-regulated (NS-R). At 12 months, 72% could similarly be classified as S-R, while 28% exhibited some continuing sleep disturbance. Discriminant function analysis investigated the predictors of S-R vs NS-R group membership at 6 and 12 months from parent and child variables recorded at 1 month. Parent presence at sleep onset and less total infant sleep time predicted group membership at 6 months with 94% classification accuracy, and parental presence at sleep onset and frequency of infant night wakings predicted group membership at 12 months with 85% accuracy. At 1 month, parents of infants later classified as NS-R at 6 and 12 months had higher frequencies of all settling activities than parents of those later classified as S-R. CONCLUSION: Variables measured at 1 month that predicted sleep status at 6 and 12 months were parental presence at sleep onset, frequency of infant night waking and total infant sleep time. The overall frequency of parent settling activities at 1 month also clearly differentiated the two sleep groups at the older ages. Parenting behaviours are modifiable factors and thus may have the potential for preventing pediatric sleep disturbances in children.

Diagnostic accuracy of viscoelastic point-of-care identification of hypofibrinogenaemia in cardiac surgical patients: A systematic review.

Hypofibrinogenaemia during cardiac surgery may increase blood loss and bleeding complications. Viscoelastic point-of-care tests provide more rapid diagnosis than laboratory measurement, allowing earlier treatment. However, their diagnostic test accuracy for hypofibrinogenaemia has never been reviewed systematically. We aimed to systematically review their diagnostic test accuracy for the identification of hypofibrinogenaemia during cardiac surgery. Two reviewers assessed relevant articles from seven electronic databases, extracted data from eligible articles and assessed quality. The primary outcomes were sensitivity, specificity and positive and negative predictive values. A total of 576 articles were screened and 81 full texts were assessed, most of which were clinical agreement or outcome studies. Only 10 diagnostic test accuracy studies were identified and only nine were eligible (ROTEMdelta 7; TEG5000 1; TEG6S 1, n = 1820 patients) (ROTEM, TEM International GmbH, Munich, Germany; TEG, Haemonetics, Braintree, MA, USA). None had a low risk of bias. Four ROTEM studies with a fibrinogen threshold less than 1.5-1.6 g/l and FIBTEM threshold A10 less than 7.5-8 mm had point estimates for sensitivity of 0.61-0.88; specificity 0.54-0.94; positive predictive value 0.42-0.70; and negative predictive value 0.74-0.98 (i.e. false positive rate 30%-58%; false negative rate 2%-26%). Two ROTEM studies with higher thresholds for both fibrinogen (<2 g/l) and FIBTEM A10 (<9.5 mm) had similar false positive rates (25%-46%), as did the two TEG studies (15%-48%). This review demonstrates that there have been few diagnostic test accuracy studies of viscoelastic point-of-care identification of hypofibrinogenaemia in cardiac surgical patients. The studies performed so far report false positive rates of up to 58%, but low false negative rates. Further diagnostic test accuracy studies of viscoelastic point-of-care identification of hypofibrinogenaemia are required to guide their better use during cardiac surgery.

Attributions, causal beliefs, and help-seeking behavior of parents of children with autism spectrum disorder and sleep problems.

LAY ABSTRACT: Sleep problems are commonly reported among parents of children with autism spectrum disorder (ASD). Without effective treatment, such problems are unlikely to resolve. To date, we know very little about how and why parents of children with ASD seek help for sleep disturbance. Via an online survey, we gathered information about how parents make sense of their children's sleep problems, beliefs about their causes, sources of information, and help-seeking behavior. The analysis of responses from 244 parents revealed that parents commonly view sleep problems (a) as a consequence of their child's ASD, and unlikely to change over time (stable), and (b) as located within the child (intrinsic), stable over time, and difficult to treat. Despite this, parents also rated sleep problems as being important to treat. Eighty-two percent of parents surveyed reported seeking some kind of help for their child's sleep disturbance, and the average parent had tried six different treatment strategies, most commonly medical approaches (e.g. melatonin). The alignment between parents' treatment choices and those strategies that are supported by research was poor, but belief in the effectiveness of treatments was closely related to how often the treatment was used. These findings have important implications for parental education and clinical practice in the treatment of sleep problems in children with ASD.

In Vitro Evaluation of the Effects of Commercial Prebiotic GOS and FOS Products on Human Colonic Caco-2 Cells.

Prebiotic oligosaccharides are widely used as human and animal feed additives for their beneficial effects on the gut microbiota. However, there are limited data to assess the direct effect of such functional foods on the transcriptome of intestinal epithelial cells. The purpose of this study is to describe the differential transcriptomes and cellular pathways of colonic cells directly exposed to galacto-oligosaccharides (GOS) and fructo-oligosaccharides (FOS). We have examined the differential gene expression of polarized Caco-2 cells treated with GOS or FOS products and their respective mock-treated cells using mRNA sequencing (RNA-seq). A total of 89 significant differentially expressed genes were identified between GOS and mock-treated groups. For FOS treatment, a reduced number of 12 significant genes were observed to be differentially expressed relative to the control group. KEGG and gene ontology functional analysis revealed that genes up-regulated in the presence of GOS were involved in digestion and absorption processes, fatty acids and steroids metabolism, potential antimicrobial proteins, energy-dependent and -independent transmembrane trafficking of solutes and amino acids. Using our data, we have established complementary non-prebiotic modes of action for these frequently used dietary fibers.

Galacto-Oligosaccharides Modulate the Juvenile Gut Microbiome and Innate Immunity To Improve Broiler Chicken Performance.

Improvements in growth performance and health are key goals in broiler chicken production. Inclusion of prebiotic galacto-oligosaccharides (GOS) in broiler feed enhanced the growth rate and feed conversion of chickens relative to those obtained with a calorie-matched control diet. Comparison of the cecal microbiota identified key differences in abundances of Lactobacillus spp. Increased levels of Lactobacillus johnsonii in GOS-fed juvenile birds at the expense of Lactobacillus crispatus were linked to improved performance (growth rate and market weight). Investigation of the innate immune responses highlighted increases of ileal and cecal interleukin-17A (IL-17A) gene expression counterposed to a decrease in IL-10. Quantification of the autochthonous Lactobacillus spp. revealed a correlation between bird performance and L. johnsonii abundance. Shifts in the cecal populations of key Lactobacillus spp. of juvenile birds primed intestinal innate immunity without harmful pathogen challenge.IMPORTANCE Improvements in the growth rate of broiler chickens can be achieved through dietary manipulation of the naturally occurring bacterial populations while mitigating the withdrawal of antibiotic growth promoters. Prebiotic galacto-oligosaccharides (GOS) are manufactured as a by-product of dairy cheese production and can be incorporated into the diets of juvenile chickens to improve their health and performance. This study investigated the key mechanisms behind this progression and pinpointed L. johnsonii as a key species that facilitates the enhancements in growth rate and gut health. The study identified the relationships between the GOS diet, L. johnsonii intestinal populations, and cytokine immune effectors to improve growth.