Uncertainty, responsibility, and reassurance in paediatric palliative care: A conversation analytic study of telephone conversations between parents and clinicians

Background: Families play a vital role in the day-to-day medical care of children with life-limiting conditions. Navigating their child’s symptoms, treatments, and the possibility of sudden deteriorations, presents myriad challenges and can be distressing for the family. Paediatric palliative care can provide crucial support for families who are typically responsible for many aspects of their child’s care. Aim: To understand how paediatric palliative care clinicians use reassurance to support families through the uncertainties associated with caring for their children. Methods: One hundred routine telephone conversations between parents and clinicians of a paediatric palliative care service were recorded and analysed using Conversation Analytic methods. Findings: When parents report uncertainty about a specific care task, imply a causal link between this care task and an adverse outcome for their child, and a moral responsibility for the outcome, clinicians respond with reassurance. Clinicians produce reassurance through refuting parents’ accounts and providing an explanation to reframe the potential adverse outcome as independent of parent actions. Parents often agree with the clinicians’ reframings and demonstrate being reassured. Discussion: Specialist paediatric palliative care clinicians routinely foreground support for family members through reassurance. Conclusions: This study demonstrates how family-centred care can be accomplished in clinical practice

Complex attosecond waveform synthesis at fel fermi

Free-electron lasers (FELs) can produce radiation in the short wavelength range extending from the extreme ultraviolet (XUV) to the X-rays with a few to a few tens of femtoseconds pulse duration. These facilities have enabled significant breakthroughs in the field of atomic, molecular, and optical physics, implementing different schemes based on two-color photoionization mechanisms. In this article, we present the generation of attosecond pulse trains (APTs) at the seeded FEL FERMI using the beating of multiple phase-locked harmonics. We demonstrate the complex attosecond waveform shaping of the generated APTs, exploiting the ability to manipulate independently the amplitudes and the phases of the harmonics. The described generalized attosecond waveform synthesis technique with an arbitrary number of phase-locked harmonics will allow the generation of sub-100 as pulses with programmable electric fields

Psychiatric and cognitive phenotype in children and adolescents with myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is the most frequent inherited neuromuscular disorder. The juvenile form has been associated with cognitive and psychiatric dysfunction, but the phenotype remains unclear. We reviewed the literature to examine the psychiatric phenotype of juvenile DM1 and performed an admixture analysis of the IQ distribution of our own patients, as we hypothesised a bimodal distribution. Two-thirds of the patients had at least one DSM-IV diagnosis, mainly attention deficit/ hyperactivity disorder and anxiety disorder. Two-thirds had learning disabilities comorbid with mental retardation on one hand, but also attention deficit, low cognitive speed and visual spatial impairment on the other. IQ showed a bi-modal distribution and was associated with parental transmission. The psychiatric phenotype in juvenile DM1 is complex. We distinguished two different phenotypic subtypes: one group characterised by mental retardation, severe developmental delay and maternal transmission; and another group characterised by borderline full scale IQ, subnormal development and paternal transmission

Consensus-based care recommendations for adults with myotonic dystrophy type 1

Purpose of review Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. Recent findings The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. Summary The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments. Described as “one of the more variable diseases found in medicine,” myotonic dystrophy type 1 (DM1) is an autosomal dominant, triplet-repeat expansion disorder that affects somewhere between 1:3,000 and 1:8,000 individuals worldwide.1 There is a modest association between increased repeat expansion and disease severity, as evidenced by the average age of onset and overall morbidity of the condition. An expansion of over 35 repeats typically indicates an unstable and expanding mutation. An expansion of 50 repeats or higher is consistent with a diagnosis of DM1. DM1 is a multisystem and heterogeneous disease characterized by distal weakness, atrophy, and myotonia, as well as symptoms in the heart, brain, gastrointestinal tract, endocrine, and respiratory systems. Symptoms may occur at any age. The severity of the condition varies widely among affected individuals, even among members of the same family. Comprehensive evidence-based guidelines do not currently exist to guide the treatment of DM1 patients. As a result, the international patient community reports varied levels of care and care quality, and difficulty accessing care adequate to manage their symptoms, unless they have access to multidisciplinary neuromuscular clinics. Consensus-based care recommendations can help standardize and improve the quality of care received by DM1 patients and assist clinicians who may not be familiar with the significant variability, range of symptoms, and severity of the disease. Care recommendations can also improve the landscape for clinical trial success by eliminating some of the inconsistencies in patient care to allow more accurate understanding of the benefit of potential therapies

Defining Natural History: Assessment of the Ability of College Students to Aid in Characterizing Clinical Progression of Niemann-Pick Disease, Type C

Niemann-Pick Disease, type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1:a multicentre, single-blind, randomised trial

Background: Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults and leads to severe fatigue, substantial physical functional impairment, and restricted social participation. In this study, we aimed to determine whether cognitive behavioural therapy optionally combined with graded exercise compared with standard care alone improved the health status of patients with myotonic dystrophy type 1. Methods: We did a multicentre, single-blind, randomised trial, at four neuromuscular referral centres with experience in treating patients with myotonic dystrophy type 1 located in Paris (France), Munich (Germany), Nijmegen (Netherlands), and Newcastle (UK). Eligible participants were patients aged 18 years and older with a confirmed genetic diagnosis of myotonic dystrophy type 1, who were severely fatigued (ie, a score of ≥35 on the checklist-individual strength, subscale fatigue). We randomly assigned participants (1:1) to either cognitive behavioural therapy plus standard care and optional graded exercise or standard care alone. Randomisation was done via a central web-based system, stratified by study site. Cognitive behavioural therapy focused on addressing reduced patient initiative, increasing physical activity, optimising social interaction, regulating sleep–wake patterns, coping with pain, and addressing beliefs about fatigue and myotonic dystrophy type 1. Cognitive behavioural therapy was delivered over a 10-month period in 10–14 sessions. A graded exercise module could be added to cognitive behavioural therapy in Nijmegen and Newcastle. The primary outcome was the 10-month change from baseline in scores on the DM1-Activ-c scale, a measure of capacity for activity and social participation (score range 0–100). Statistical analysis of the primary outcome included all participants for whom data were available, using mixed-effects linear regression models with baseline scores as a covariate. Safety data were presented as descriptives. This trial is registered with ClinicalTrials.gov, number NCT02118779. Findings: Between April 2, 2014, and May 29, 2015, we randomly assigned 255 patients to treatment: 128 to cognitive behavioural therapy plus standard care and 127 to standard care alone. 33 (26%) of 128 assigned to cognitive behavioural therapy also received the graded exercise module. Follow-up continued until Oct 17, 2016. The DM1-Activ-c score increased from a mean (SD) of 61·22 (17·35) points at baseline to 63·92 (17·41) at month 10 in the cognitive behavioural therapy group (adjusted mean difference 1·53, 95% CI −0·14 to 3·20), and decreased from 63·00 (17·35) to 60·79 (18·49) in the standard care group (−2·02, −4·02 to −0·01), with a mean difference between groups of 3·27 points (95% CI 0·93 to 5·62, p=0·007). 244 adverse events occurred in 65 (51%) patients in the cognitive behavioural therapy group and 155 in 63 (50%) patients in the standard care alone group, the most common of which were falls (155 events in 40 [31%] patients in the cognitive behavioural therapy group and 71 in 33 [26%] patients in the standard care alone group). 24 serious adverse events were recorded in 19 (15%) patients in the cognitive behavioural therapy group and 23 in 15 (12%) patients in the standard care alone group, the most common of which were gastrointestinal and cardiac. Interpretation: Cognitive behavioural therapy increased the capacity for activity and social participation in patients with myotonic dystrophy type 1 at 10 months. With no curative treatment and few symptomatic treatments, cognitive behavioural therapy could be considered for use in severely fatigued patients with myotonic dystrophy type 1. Funding: The European Union Seventh Framework Programme

The FMR1 Gene and Differential Susceptibility to HPA-axis and Immune Dysfunction: Examination of a Gene-Environment Interaction with Stress

There is strong evidence linking psychological stress, HPA-axis activity, and the immune system dysregulation with negative health outcomes. For example, chronic stress, HPA-axis and immune system dysfunction are all associated with greater risk of infection and diagnosis of chronic inflammatory disease, autoimmune disease, depression, and anxiety. Yet, some individuals do not develop significant health issues and instead demonstrate great resilience under these same stressful environments. The factors or mechanisms that contribute to this variability remain to be determined. Understanding these influences and how they relate to both psychological and physiological changes are especially important for current and forthcoming research on intervention, prevention and clinical application. The following dissertation contains two related studies that together are guided by a gene x environment interaction approach aimed at understanding important unanswered questions regarding the relative and collective contributions of fragile X mental retardation 1 (FMR1) genotype and psychological stress on two important physiological systems, the HPA-axis and immune system. In the first study (Chapter 2), we examined how the relationship between FMR1 genotype and immunological functioning is moderated by self-reported psychological stress. Much of the research and theory thus far has focused on FMR1 gene expression-related pathogenic mechanism (i.e. mRNA toxicity) as the cause of various negative health outcomes associated with FMR1 alleles in the premutation range. Moreover, previous work has disproportionately focused on mothers caring for a son/daughter with FXS who are known to be greatly affected by caregiving-associated chronic stress. Therefore, an important goal of this first study was to determine the extent to which the effect of self-reported stress differentially affects the association between FMR1 genotype and immune functioning by oversampling women with the premutation who are not caregivers of affected children. Another important feature of the first study was the focus on underlying biologically-based endophenotypes instead of diagnostic categories. Women with activation ratio-corrected CGG (AR-CGG) repeat lengths in the mid-premutation range (around 60-80 AR-CGG repeats) were more sensitive to the effects of psychological stress, such that women in this range with higher levels of stress display higher levels of IL-10 and lower levels of Th1-associated cytokines. In part, these findings differ from previous research demonstrating more broad suppression of cytokine production among women with FMR1 alleles in the premutation range. However, our results are consistent with previous findings of a Th1/Th2 shift in the immune system reported to be associated with stress. Specifically, higher levels of cortisol are thought to shift the balance toward more Th2-associated cytokines. This type of immunological imbalance is observed in fibromyalgia, atopic dermatitis, asthma, anxiety and depression. This may in part explain why women with the premutation are also more likely to experience some of these health issues. Our second study (Chapter 3) focuses on how psychological stress and FMR1 genotype interact and affect HPA-axis activity. This study was a natural extension of the first, namely by determining whether HPA-axis activity, which has been shown to be dysregulated in women with certain FMR1 alleles, mediates the association between FMR1 genotype and immune system dysregulation. We found that among women with AR-CGG lengths greater than 80 repeats, higher levels of self-reported stress were associated with elevated waking cortisol levels and flatter diurnal slopes. Additionally, we observed a curvilinear association between AR-CGG repeat size and waking cortisol which was moderated by stress. Women with FMR1 alleles in the 60-80 AR-CGG repeat range were more sensitive to the effect of negative life events displaying elevated waking cortisol. Our moderated-mediation analysis found no mediating effect of HPA-axis activity between stress and FMR1 genotype with immune system functioning. In sum, women with FMR1 alleles in the mid-premutation range were found to be more sensitive to the effects of stress on diurnal cortisol. These findings have implications for understanding the association between the FMR1 gene and the increased risk of developing depression, anxiety, and various inflammatory/autoimmune disorders among women with the premutation. In total, the goal of these two studies was to implement a gene-environment interaction approach in order to; (a) determine the extent to which the susceptibility of developing immune system dysregulation among certain FMR1 alleles is regulated at least in part by psychological stress and (b) determine whether diurnal HPA-axis dysregulation is a possible biological mechanism underlying this relationship. The results of these studies have the potential to impact society in a variety of ways. First, the findings from these two studies can advance our general understanding of basic biological processes underlying why and how the environment in which we live and develop gets “under the skin” affecting two important physiological systems and overall health. Second, these findings have the capacity to inform a substantial portion of the population (1 in 113-152 women are FMR1 premutation carriers), indicating that the FMR1 gene may be an important contributor to immune dysregulation in the general population. Finally, counseling and preventative research will benefit from a better understanding of when and how stress can affect individuals who might be more genetically vulnerable

Uncertainty, responsibility, and reassurance in paediatric palliative care: A conversation analytic study of telephone conversations between parents and clinicians

Background: Families play a vital role in the day-to-day medical care of children with life-limiting conditions. Navigating their child’s symptoms, treatments, and the possibility of sudden deteriorations, presents myriad challenges and can be distressing for the family. Paediatric palliative care can provide crucial support for families who are typically responsible for many aspects of their child’s care. Aim: To understand how paediatric palliative care clinicians use reassurance to support families through the uncertainties associated with caring for their children. Methods: One hundred routine telephone conversations between parents and clinicians of a paediatric palliative care service were recorded and analysed using Conversation Analytic methods. Findings: When parents report uncertainty about a specific care task, imply a causal link between this care task and an adverse outcome for their child, and a moral responsibility for the outcome, clinicians respond with reassurance. Clinicians produce reassurance through refuting parents’ accounts and providing an explanation to reframe the potential adverse outcome as independent of parent actions. Parents often agree with the clinicians’ reframings and demonstrate being reassured. Discussion: Specialist paediatric palliative care clinicians routinely foreground support for family members through reassurance. Conclusions: This study demonstrates how family-centred care can be accomplished in clinical practice