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Wild sheep and many primitive domesticated breeds have two coats: coarse hairs covering shorter, finer fibres. Both are shed annually. Exploitation of wool for apparel in the Bronze Age encouraged breeding for denser fleeces and continuously growing white fibres. The Merino is regarded as the culmination of this process. Archaeological discoveries, ancient images and parchment records portray this as an evolutionary progression, spanning millennia. However, examination of the fleeces from feral, two-coated and woolled sheep has revealed a ready facility of the follicle population to change from shedding to continuous growth and to revert from domesticated to primitive states. Modifications to coat structure, colour and composition have occurred in timeframes and to sheep population sizes that exclude the likelihood of variations arising from mutations and natural selection. The features are characteristic of the domestication phenotype: an assemblage of developmental, physiological, skeletal and hormonal modifications common to a wide variety of species under human control. The phenotypic similarities appeared to result from an accumulation of cryptic genetic changes early during vertebrate evolution. Because they did not affect fitness in the wild, the mutations were protected from adverse selection, becoming apparent only after exposure to a domestic environment. The neural crest, a transient embryonic cell population unique to vertebrates, has been implicated in the manifestations of the domesticated phenotype. This hypothesis is discussed with reference to the development of the wool follicle population and the particular roles of Notch pathway genes, culminating in the specific cell interactions that typify follicle initiation.
This rejoinder notes that several key points were discussed in response to the authors' review of brief psychosocial interventions for personality disorders. In particular, the commentary suggested that understanding key mechanisms of change and moderators of treatment outcome were especially important to make forward progress in streamlining treatments for personality disorders. Here the authors highlight several shared candidate mechanisms of change across brief treatments for personality disorders, including a focus on education regarding emotion regulation, interpersonal processes, and instilling hope and expectancies for change. They also discuss the possibility that moderators of treatment outcome should be examined across types of outcomes. Moreover, some outcomes may be more amenable to brief treatments than others. Recommendations for future research in this area are discussed.
The last several decades have witnessed the emergence of several efficacious treatments for personality disorders, yet many of these treatments are lengthy and resource-intensive. There is a pressing public health need to identify briefer treatment options for the treatment of personality disorders. The present contribution is a comprehensive review of brief (i.e., less than one-year) psychosocial interventions for personality disorders. The authors' search criteria yielded 66 articles, which they summarize in this chapter. Of note, only a minority of these studies were randomized controlled trials, and nearly half focused on borderline personality disorders. A few brief treatments appear to be efficacious for personality disorders, namely short-term dynamic psychotherapy for Cluster C personality disorders, as well as manual-assisted cognitive therapy, six-month dialectical behavior therapy, and emotion regulation group therapy for borderline personality disorder and/or self-injury. Recommendations for future research in this area are discussed.
Mindfulness meditation has been practiced in the Eastern world for more than 25 centuries but only recently it has become popular in the West. Today, therapeutic interventions such as ‘Mindfulness Based Stress Reduction’ are used within health services throughout Europe as a means of improving patient wellbeing. Whilst these interventions have proved successful in reducing stress and depression a limitation is that they tend to apply the practices of mindfulness in an ‘out of context’ manner. Meditation Based Awareness Training (MBAT), on the other hand, includes a composite array of ‘spiritual-based’ trainings, which are traditionally assumed to enhance the cultivation of a more sustainable quality of wellbeing within the meditator.
The purpose of this program is to design, implement, and evaluate MBAT as an approach to meditation and mindfulness that can be adapted to meet the needs of various populations. In the current phase, MBAT was developed in a general format for individuals from the general population who want to increase their levels of wellbeing. A controlled comparison trial has been run to evaluate this version of MBAT: Participants of the study undertook an 8-week MBAT program and comparisons were made with a control group on perceived psychological wellbeing (depression, anxiety, and anger management) and stress. In a second phase (not included in this presentation) MBAT will be adapted to populations with special needs, e.g., elderly people, trauma victims, and forensic inmates.
Findings from the trial will be reported and implications for further development of MBAT will be discussed.
The aim of iSPOT-D is to identify biological pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators.
The iSPOT-D study is a multi-center, international, randomized, prospective, open-label trial (1). It is enrolling 2016 MDD outpatients (ages 18–65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or washed-out with no protocol ADM contraindications. Baseline assessments include symptoms; distress; daily function; cognitive performance; electroencephalogram and event-related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self-reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm.
First enrolment was in December 2008, and enrollment of the first 50% (1008 MDD participants) was completed in Dec 2010. iSPOT-D evaluates clinical and biological predictors of treatment response in the largest known sample of MDD collected worldwide.
Initial findings reveal a remission rate of 45.4% and a response rate of 62.6% after 6–8 weeks of treatment. Initial findings will be discussed including factors for response prediction and MDD subtype differences.
Deutetrabenazine (Austedo) is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The objective of this study was to evaluate the long-term safety and tolerability of deutetrabenazine in patients with TD at 3 years.
Patients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used for calculating AE frequencies. This analysis reports results up to Week 158.
A total of 343 patients were enrolled (111 received placebo and 232 received deutetrabenazine in the parent studies). At the time of this analysis, 183 patients were still receiving treatment; 259 completed 1 year, 172 completed 2 years, and 41 completed 3 years. There were 623 patient-years of exposure. More than 40% of patients reached the maximum dose. EAIRs of AEs were comparable to or lower than those observed in the ARM-TD and AIM-TD short-term randomized trials of deutetrabenazine vs. placebo. The frequency of SAEs (EAIR 0.10) was similar to that observed with short-term placebo (0.33) and short-term deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.06), dose reduction (0.10), and dose suspension (0.05) were uncommon.
These results support the safety outcomes observed in the ARM-TD and AIM-TD parent studies and the safety of deutetrabenazine for long-term use in patients with TD.
Funding Acknowledgements: This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel
In the 12-week ARM-TD and AIM-TD studies evaluating deutetrabenazine for the treatment of tardive dyskinesia (TD), the percentage of patients achieving ≥50% response was higher in the deutetrabenazine-treated group than in the placebo group. These studies also showed low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The current open-label study evaluated the long-term efficacy and safety of deutetrabenazine in patients with TD.
Patients with TD who completed ARM-TD or AIM-TD could enroll in this open-label, single-arm extension study, titrating up over 6 weeks to a maximum total daily dose of deutetrabenazine 48 mg/day on the basis of dyskinesia control and tolerability. The proportion of Abnormal Involuntary Movement Scale (AIMS; items 1-7) responders was assessed based on response rates for achieving ≥50% improvement from baseline in the open-label extension study. AlMS score was assessed by local site raters for this analysis.
343 patients enrolled in the extension study. At Week 54 (n=249; total daily dose [mean ± standard error]: 38.6±0.66 mg), the mean percentage change from baseline in AIMS score was –40%; 48% of patients achieved a ≥50% response and 59% of those had already achieved a ≥50% response at Week 15. Further, 34% of those who had not achieved a ≥50% response at Week 15 achieved a ≥50% response at Week 54. At Week 106 (n=169; total daily dose: 39.6±0.77 mg), the mean percentage change from baseline in AIMS score was –45%; 55% of patients achieved a ≥50% response, 59% of those patients had already achieved a ≥50% response at Week 15, and 41% of those who had not achieved a ≥50% response at Week 15 but who reached Week 106 achieved a ≥50% response. At Week 132 (n=109; total daily dose: 39.7±0.97 mg), the mean percentage change from baseline in AIMS score was –61%; 55% of patients achieved a ≥50% response, 61% of those patients had already achieved a ≥50% response at Week 15, and 43% of those who had not achieved a ≥50% response at Week 15 but who reached Week 132 achieved a ≥50% response. Completer analysis suggests that long-term efficacy was not due to dose increases over time. Treatment with deutetrabenazine was generally well tolerated. There were 623 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) of adverse events of special interest were 0.01 for akathisia and restlessness, 0.07 for somnolence and sedation, 0.04 for parkinsonism, and 0.05 for depression.
Patients who received long-term treatment with deutetrabenazine achieved response rates that were indicative of clinically meaningful long-term benefit. Results from this open-label trial suggest the possibility of increasing benefit over time with individual dose titration of deutetrabenazine.
This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.
Reading and language abilities are critical for educational achievement and success in adulthood. Variation in these traits is highly heritable, but the underlying genetic architecture is largely undiscovered. Genetic studies of reading and language skills traditionally focus on children with developmental disorders; however, much larger unselected adult samples are available, increasing power to identify associations with specific genetic variants of small effect size. We introduce an Australian adult population cohort (41.7–73.2 years of age, N = 1505) in which we obtained data using validated measures of several aspects of reading and language abilities. We performed genetic association analysis for a reading and spelling composite score, nonword reading (assessing phonological processing: a core component in learning to read), phonetic spelling, self-reported reading impairment and nonword repetition (a marker of language ability). Given the limited power in a sample of this size (~80% power to find a minimum effect size of 0.005), we focused on analyzing candidate genes that have been associated with dyslexia and developmental speech and language disorders in prior studies. In gene-based tests, FOXP2, a gene implicated in speech/language disorders, was associated with nonword repetition (p < .001), phonetic spelling (p = .002) and the reading and spelling composite score (p < .001). Gene-set analyses of candidate dyslexia and speech/language disorder genes were not significant. These findings contribute to the assessment of genetic associations in reading and language disorders, crucial for understanding their etiology and informing intervention strategies, and validate the approach of using unselected adult samples for gene discovery in language and reading.
Fetal growth restriction (FGR) can be defined as the failure of the fetus to meet its genetically predetermined growth potential  and is associated with significant fetal and perinatal morbidity and mortality. In addition, there is evidence to suggest a longer-term impact of FGR on childhood neurodevelopmental outcomes  and cardiovascular and metabolic diseases that manifest in adulthood . However, predicting FGR is not straightforward and methods for screening and diagnosis are imprecise. In the UK and USA, ultrasound scans in the second half of pregnancy are not performed routinely but targeted at women considered to be at risk for FGR, where high risk is identified by maternal characteristics (including anthropometry and pre-existing disease), the development of complications, or clinical suspicion based on being ‘small for dates’ on physical examination. For practical purposes, FGR may be suspected if biometric measurements are below a given threshold of the distribution in the population, typically <10th, 5th or 3rd centile for gestational age, or if there is a reduction in growth velocity (‘crossing centiles’) from previous scans . The difficulty with using biometry alone is that it does not differentiate between the growth-restricted fetus affected by placental insufficiency, and the healthy, constitutionally small fetus. Therefore, additional measures may be employed to diagnose placental dysfunction, such as Doppler studies of the fetal and uteroplacental circulation, and analysis of maternal serum biomarkers. At present, the only treatment available for FGR is to expedite delivery, but at preterm gestations this can also can cause harm. However, new genomics-based research could help us better understand the etiology of growth restriction and identify more accurate diagnostic biomarkers or potential therapeutic targets. This chapter will focus on current practice in screening for and intervention in FGR and will also consider new developments and the future of the field.
Balloon Eustachian tuboplasty is a surgical management option for Eustachian tube dysfunction; it has shown promising results in studies worldwide, but has had limited uptake in the UK. This study reports long-term outcomes for patients offered balloon Eustachian tuboplasty for chronic dilatory and baro-challenge-induced Eustachian tube dysfunction, and describes practical experience gained from its implementation.
Balloon Eustachian tuboplasty was conducted in 25 patients (36 ears) with Eustachian tube dysfunction over three years. Information on presenting symptoms and signs, audiometric findings, tympanometry, and Eustachian Tube Dysfunction Questionnaire-7 scores were recorded pre- and post-operatively with a minimum follow up of one year.
Sixteen (64 per cent) of the 25 patients demonstrated symptom resolution after balloon Eustachian tuboplasty according to the Eustachian Tube Dysfunction Questionnaire-7. Fourteen (64 per cent) of the 22 patients with a type B or C tympanogram pre-operatively, had a type A trace post-operatively. Fifteen (75 per cent) of 20 patients with pre-operative conductive hearing loss showed improvement post-operatively, and 11 (50 per cent) of 22 patients with pre-operative middle-ear effusion or tympanic membrane retraction showed resolution.
Balloon Eustachian tuboplasty can improve subjective and objective measures of Eustachian tube dysfunction, and provide longer-term resolution.
Fully slatted concrete floors are labour-efficient, cost-effective and thus common in beef cattle housing. However, the welfare of cattle accommodated on them has been questioned. The objective of this study was to evaluate the effect of floor and diet on hoof health and lying behaviours of housed dairy-origin bulls, from a mean age of 8 months to slaughter at 15.5 months old. Forty-eight bulls, which had a mean initial live weight of 212 (SD = 23.7) kg, were allocated to one of four treatments, which consisted of two floors and two diets arranged in a 2 × 2 factorial design. The floors evaluated were a fully slatted concrete floor and a fully slatted concrete floor overlaid with rubber, while the diets offered were either a high concentrate diet or a grass-silage-based diet supplemented with concentrates. The mean total duration of the study was 216 days. Floor had no significant effect on claw measurements measured on day 62 or 139. However, bulls accommodated on slats overlaid with rubber had a tendency to have a higher front toe length measured pre-slaughter than those accommodated on concrete slats (P = 0.063). Floor had no significant effect on the net growth of toes or heels during the duration of the study. The number of bruises (P < 0.01) and the bruising score (P < 0.05) were significantly higher on day 62 in bulls accommodated on fully slatted concrete floors than on concrete slats overlaid with rubber, but there was no significant effect of floor on these parameters on day 139 or at the measurement taken pre-slaughter. There was a tendency for bulls accommodated on concrete slats to have a higher probability of having sole bruising at the end of the experiment than those accommodated on slats overlaid with rubber (P = 0.052). Diet had no significant effect on toe length or heel height, number of bruises, or overall bruising score at any time point of the study. There was little evidence in the current study to suggest that bulls lying on fully slatted concrete floors could not express lying postures similar to those on concrete slats overlaid with rubber.
Describe the lived experience of a grassroots, nongovernmental disaster medical team (DMT) through a research lens and share practical lessons learned based on the DMT’s experience to support and inform future response teams.
Forty-five days after Hurricane Maria, a nongovernmental DMT provided primary medical care by means of community-based pop-up clinics and home visitations in 5 different areas of Puerto Rico. Observational data, photo images, and debriefing notes were collected and documented in the response team’s daily activity log. Field notes were coded using a descriptive coding method and then categorized into 2 domains specific to public health and medical diagnosis.
Medical aid was provided to nearly 300 (N = 296) residents. Field note observations identified exhaustion related to living conditions and the exacerbation of underlying conditions, such as reactive airway diseases, diabetes, hypertension, and depression due to the compounding effects of multiple post-disaster triggers. During home visitations, feelings of sadness and helplessness were identified secondary to natural disaster trauma and current living conditions.
Our nongovernmental DMT displayed similar characteristics demonstrated by federal DMTs post-natural disaster. Several strategic lessons learned emerged from the public health intervention important to future nongovernmental DMTs.
On November 7, 1917 Max Weber offered his comments on “Science as a Vocation” before an assembly of students and faculty at the University of Munich, declaring that “disenchantment” was an “inescapable condition” and “the fate of our times.” But history tells us that nothing is truly inevitable. Although modern European intellectual history is replete with narratives of disenchantment and religious decline, the fact remains that religious speculation and formal discourses of theology survived well through the end of the twentieth century. For intellectuals who have shed the last remnants of personal faith, the endurance of theology in late modernity may seem perplexing, a symptom of what Nietzsche called Unzeitgemäßigkeit, or a decalibration in time. Already in 1882 Nietzsche’s madman declared that “God is dead. God remains dead. And we have killed him.” But even the madman recognized that he had come “too early.” What he called the “tremendous event” of God’s death was “still on its way”; it had “not yet reached the ears of men.” Critics who harken to the madman’s prophesy may likewise insist that European religious thought is a remnant of an earlier and more pious age.
In November, 1917, the German sociologist Max Weber delivered a now-famous lecture, “Science as a Vocation,” before an assembly of students and faculty at the University of Munich. “The fate of our times,” he declared, “is characterized by rationalization and intellectualization and, above all, by the ‘disenchantment of the world.’” Weber intended this remark as a global characterization of a modern society in which the natural sciences and bureaucratic rationality had conspired to undermine confidence in religious values and traditional sources of meaning. But we may also take his words as a more general verdict on the condition of modern European thought at the dawn of the twentieth century, when intellectuals from across the continent looked upon the wreckage of the First World War as a turning point in civilization, as a violent end to the nineteenth century and a grim foretaste of the world to come. Weber himself remained in a posture of ambivalence: He feared that the higher ideals of the Enlightenment were “irretrievably lost” and that only the imperative of “economic compulsion” would prevail.