Synthesis and biological studies of 2-aminothiophene derivatives as positive allosteric modulators of glucagon-like peptide 1 receptor.

As a step toward the development of novel small-molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes, obesity, and heart diseases, we discovered a novel 2-amino-thiophene (2-AT) based lead compound bearing an ethyl 3-carboxylate appendage. In this work, we report the syntheses and biological studies of more than forty 2-AT analogs, that have revealed a 2-aminothiophene-3-arylketone analogue 7 (MW 299) showing approximately a 2-fold increase in insulin secretion at 5 µM when combined with the GLP-1 peptide at 10 nM. In vivo studies using CD1 mice at a dose of 10 mg/kg, clearly demonstrated that the blood plasma glucose level was lowered by 50% after 60 min. Co-treatment of 7 with sitagliptin, an inhibitor of GLP-1 degrading enzyme Dipeptidyl Peptidase IV, further confirmed 7 to be an effective PAM of GLP-1R. The small molecular weight and demonstrated allosteric modulating properties of these compound series, show the potential of these scaffolds for future drug development.

Temperature measurement of babies born in the pre-hospital setting: analysis of ambulance service data and qualitative interviews with paramedics.

BACKGROUND: Birth before arrival at hospital (BBA) is associated with unfavourable perinatal outcomes and increased mortality. An important risk factor for mortality following BBA is hypothermia, and emergency medical services (EMS) providers are well placed to provide warming strategies. However, research from the UK suggests that EMS providers (paramedics) do not routinely record neonatal temperature following BBA. This study aimed to determine the proportion of cases in which neonatal temperature is documented by paramedics attending BBAs in the South West of England and to explore the barriers to temperature measurement by paramedics. METHODS: A two-phase multi-method study. Phase I involved an analysis of anonymised data from electronic patient care records between 1 February 2017 and 31 January 2020 in a single UK ambulance service, to determine 1) the frequency of BBAs attended and 2) the percentage of these births where a neonatal temperature was recorded, and what proportion of these were hypothermic. Phase II involved interviews with 20 operational paramedics from the same ambulance service, to explore their experiences of, and barriers and facilitators to, neonatal temperature measurement and management following BBA. RESULTS: There were 1582 'normal deliveries' attended by paramedics within the date range. Neonatal temperatures were recorded in 43/1582 (2.7%) instances, of which 72% were below 36.5°C. Data from interviews suggested several barriers and potential facilitators to paramedic measurement of neonatal temperature. Barriers included unavailable or unsuitable equipment, prioritisation of other care activities, lack of exposure to births, and uncertainty regarding responsibilities and roles. Possible facilitators included better equipment, physical prompts, and training and awareness-raising around the importance of temperature measurement. CONCLUSIONS: This study demonstrates a lack of neonatal temperature measurement by paramedics in the South West following BBA, and highlights barriers and facilitators that could serve as a basis for developing an intervention to improve neonatal temperature measurement.

Management of functional communication, swallowing, cough and related disorders: consensus recommendations for speech and language therapy.

Communication problems (eg, dysphonia, dysfluency and language and articulation disorders), swallowing disorders (dysphagia and globus), cough and upper airway symptoms, resulting from functional neurological disorder (FND), are commonly encountered by speech and language professionals. However, there are few descriptions in the literature of the most effective practical management approaches. This consensus document aims to provide recommendations for assessment and intervention that are relevant to both adults and young people. An international panel of speech and language professionals with expertise in FND were approached to take part. Participants responded individually by email to a set of key questions regarding best practice for assessment and interventions. Next, a video conference was held in which participants discussed and debated the answers to these key questions, aiming to achieve consensus on each issue. Drafts of the collated consensus recommendations were circulated until consensus was achieved. FND should be diagnosed on the basis of positive clinical features. Speech and language therapy for FND should address illness beliefs, self-directed attention and abnormal movement patterns through a process of education, symptomatic treatment and cognitive behavioural therapy within a supportive therapeutic environment. We provide specific examples of these strategies for different symptoms. Speech and language professionals have a key role in the management of people with communication and related symptoms of FND. It is intended that these expert recommendations serve as both a practical toolkit and a starting point for further research into evidence-based treatments.

Offspring polymorphism and bet hedging: a large-scale, phylogenetic analysis.

Offspring polymorphism is a reproductive strategy where individual organisms simultaneously produce offspring that differ in morphology and ecology. It occurs across the Tree of Life but is particularly common among plants, where it is termed seed (diaspore) heteromorphism. The prevalence of this strategy in unpredictably varying environments has resulted in the assumption that it serves as a bet-hedging mechanism. We found 101 examples of this strategy in southwestern North America. We provide phylogenetically informed evidence for the hypothesis that the occurrence of seed heteromorphism increases with increasing environmental variability, though this pattern was only significant for aridity, one of our two rainfall variability metrics. We provide a strong test of bet hedging for a large, taxonomically diverse set of seed heteromorphic species, lending support to the hypothesis that bet hedging is an important mechanistic driver for the evolution of seed heteromorphism.

Understanding foreign accent syndrome.

OBJECTIVE: Foreign accent syndrome (FAS) is widely understood as an unusual consequence of structural neurological damage, but may sometimes represent a functional neurological disorder. This observational study aimed to assess the prevalence and utility of positive features of functional FAS in a large group of individuals reporting FAS. METHODS: Participants self-reporting FAS recruited from informal unmoderated online support forums and via professional networks completed an online survey. Speech samples were analysed in a subgroup. RESULTS: Forty-nine respondents (24 UK, 23 North America, 2 Australia) reported FAS of mean duration 3 years (range 2 months to 18 years). Common triggers were: migraine/severe headache (15), stroke (12), surgery or injury to mouth or face (6) and seizure (5, including 3 non-epileptic). High levels of comorbidity included migraine (33), irritable bowel syndrome (17), functional neurological disorder (12) and chronic pain (12). Five reported structural lesions on imaging. Author consensus on aetiology divided into, 'probably functional (n=35.71%), 'possibly structural' (n=4.8%) and 'probably structural' (n=10.20%), but positive features of functional FAS were present in all groups. Blinded analysis of speech recordings supplied by 13 respondents correctly categorised 11 (85%) on the basis of probable aetiology (functional vs structural) in agreement with case history assignment. CONCLUSIONS: This largest case series to date details the experience of individuals with self-reported FAS. Although conclusions are limited by the recruitment methods, high levels of functional disorder comorbidity, symptom variability and additional linguistic and behavioural features suggest that chronic FAS may in some cases represent a functional neurological disorder, even when a structural lesion is present.

Drooling in Parkinson's Disease: Evidence of a Role for Divided Attention.

Drooling is a frequently reported symptom in Parkinson's Disease (PD) with significant psychosocial impact and negative health consequences including silent aspiration of saliva with the associated risk of respiratory infections. It is suggested that in PD drooling is associated with inefficient oropharyngeal swallowing which reduces the effective clearance of saliva rather than hyper-salivation. This is compounded by unintended mouth opening and flexed posture increasing anterior loss of saliva. It is reported to occur most frequently during cognitively distracting concurrent tasks suggesting an impact from divided attention in a dual-task situation. However, this supposition has not been systematically examined. This study assessed whether frequency of saliva swallows reduced, and drooling severity and frequency increased, when people with PD engaged in a cognitively distracting task. 18 patients with idiopathic PD reporting daytime drooling on the Unified Parkinson's Disease Rating Scale (UPDRS) were recruited. They completed the Radboud Oral Motor Inventory for PD saliva questionnaire and the Montreal Cognitive Assessment. UPDRS drooling score, disease stage, duration, gender, and age were recorded. Swallow frequency and drooling severity and frequency were measured at rest and during a distracting computer-based language task. There was no significant difference between drooling severity at rest and during distraction (Wilcoxon signed rank test z = - 1.724, p = 0.085). There was a significant difference between at rest and distraction conditions for both drooling frequency (Wilcoxon signed rank test z = - 2.041, p = 0.041) and swallow frequency (Wilcoxon signed rank test z = - 3.054, p = 0.002). Participants swallowed less frequently and drooled more often during the distraction task. The frequency of saliva swallows and drooling are affected by divided attention in a dual-task paradigm. Further studies are needed to explore the exact role of attention in saliva management and the clinical applications in assessment and treatment.

Acoustic changes in the speech of children with cerebral palsy following an intensive program of dysarthria therapy.

BACKGROUND: The speech intelligibility of children with dysarthria and cerebral palsy has been observed to increase following therapy focusing on respiration and phonation. AIMS: To determine if speech intelligibility change following intervention is associated with change in acoustic measures of voice. METHODS & PROCEDURES: We recorded 16 young people with cerebral palsy and dysarthria (nine girls; mean age 14 years, SD = 2; nine spastic type, two dyskinetic, four mixed; one Worster-Drought) producing speech in two conditions (single words, connected speech) twice before and twice after therapy focusing on respiration, phonation and rate. In both single-word and connected speech we measured vocal intensity (root mean square-RMS), period-to-period variability (Shimmer APQ, Jitter RAP and PPQ) and harmonics-to-noise ratio (HNR). In connected speech we also measured mean fundamental frequency, utterance duration in seconds and speech and articulation rate (syllables/s with and without pauses respectively). All acoustic measures were made using Praat. Intelligibility was calculated in previous research. OUTCOMES & RESULTS: In single words statistically significant but very small reductions were observed in period-to-period variability following therapy: Shimmer APQ -0.15 (95% CI = -0.21 to -0.09); Jitter RAP -0.08 (95% CI = -0.14 to -0.01); Jitter PPQ -0.08 (95% CI = -0.15 to -0.01). No changes in period-to-period perturbation across phrases in connected speech were detected. However, changes in connected speech were observed in phrase length, rate and intensity. Following therapy, mean utterance duration increased by 1.11 s (95% CI = 0.37-1.86) when measured with pauses and by 1.13 s (95% CI = 0.40-1.85) when measured without pauses. Articulation rate increased by 0.07 syllables/s (95% CI = 0.02-0.13); speech rate increased by 0.06 syllables/s (95% CI = < 0.01-0.12); and intensity increased by 0.03 Pascals (95% CI = 0.02-0.04). There was a gradual reduction in mean fundamental frequency across all time points (-11.85 Hz, 95% CI = -19.84 to -3.86). Only increases in the intensity of single words (0.37 Pascals, 95% CI = 0.10-0.65) and reductions in fundamental frequency (-0.11 Hz, 95% CI = -0.21 to -0.02) in connected speech were associated with gains in intelligibility. CONCLUSIONS & IMPLICATIONS: Mean reductions in impairment in vocal function following therapy observed were small and most are unlikely to be clinically significant. Changes in vocal control did not explain improved intelligibility.

Is there an order of loss of sounds in speakers with Parkinson's disease?

Influential reports on speech changes in people with Parkinson's disease (PD; Logemann et al., 1978, 1981) reported a posterior to anterior pattern of loss of speech sound accuracy. These claims have never been examined. In a partial replication of Logemann et al.'s work, we examined whether posterior lingual sounds are most affected in people with Parkinson's disease, followed by anterior lingual sounds and then labial sounds. Ninety-nine people with PD (age: mean 70.7, SD 8.46; time since diagnosis: mean 6.97, SD 6.2) with mild to severe overall motor symptoms (Hoehn and Yahr stages 1-5, median 2.5) completed a diagnostic intelligibility test. This was scored by 60 listeners unfamiliar with PD and dysarthric speech. We calculated the proportion of posterior versus anterior lingual versus labial sounds misrecognized by the listeners. We compared profiles of misperceived sounds within and across Hoehn and Yahr stages of severity and in relation to Unified Parkinson's Disease Rating Scale (UPDRS) and speech intelligibility scores. Speech accuracy declined significantly in relation to overall motor impairment for labial and anterior lingual sounds but not for velar sounds. Speech sound accuracy was strongly associated with intelligibility outcomes (p = < 0.01). Contrary to previous assertions, there was no evidence supporting the existence of a posterior to anterior order of 'loss' of oral speech sounds in people with PD, nor an interaction of anterior-posterior speech profile changes with Hoehn and Yahr stage. Findings support the notion that a common underlying impairment of movement downscaling affects all sounds similarly and simultaneously in PD from the start.

A survey of speech-language therapy provision for people with post-stroke dysarthria in the UK.

BACKGROUND: A large number of people who experience a stroke are affected by dysarthria. This may be in isolation or in association with aphasia and/or dysphagia. Despite evidence highlighting the psychological and social impact of having post-stroke dysarthria and a number of clinical guidelines that make recommendations for appropriate management, little is known currently about UK service delivery issues relating to speech and language therapy (SLT) assessment and treatment for this group. Such evidence is necessary in order to plan, develop and research services for people with post-stroke dysarthria. AIMS: To gain an overview of SLT practices in the management of people with dysarthria after stroke in the UK. METHODS & PROCEDURES: SLTs in the UK were asked to complete an online survey addressing referral patterns, caseload profiles, and their assessment and intervention methods for post-stroke dysarthria. In the absence of a national register of clinicians working with people with acquired dysarthria, a snowballing method was used to facilitate participant recruitment. Results were analysed using descriptive statistics. OUTCOMES & RESULTS: A total of 146 SLTs responded. The majority were employed by the National Health Service (NHS). Most patients were referred within 1 week post-stroke. Almost half the respondents did not regularly use formal assessments and the use of instrumentation was rare, including the use of video recording. The focus of therapy for mild, moderate and severe dysarthria did not differ significantly for clinicians. A little under half the respondents endorsed non-verbal oral exercises in rehabilitation. The survey demonstrated some appreciation of the centrality of regular intensive practice to effect change, but this was in a minority. CONCLUSIONS & IMPLICATIONS: Through this research it became clear that basic information regarding post-stroke dysarthria incidence, prevalence and core demographics is currently unavailable. More embedded NHS SLT reporting systems would make a significant contribution to this area. A more in-depth examination is required of the natural history of dysarthria over the months and years following stroke, of SLT practices in relation to post-stroke dysarthria, with investigations to understand more fully the choices SLTs make and how this relates to available evidence to support their clinical decision-making.

Communication changes in Parkinson's disease.

This review looks at the nature and impact of communication changes in Parkinson's disease, approaches to assessment and directions for intervention. This is especially important since medical and surgical interventions that help limb movement are largely ineffective, or even detrimental, for speech. Most people with Parkinson's disease notice changes to their communication. Voice alters early on-even in the prodromal stage. Later, articulation may impair intelligibility further. These changes impact on mood and social participation. However, a full characterisation of communication changes in Parkinson's must acknowledge that changes are far more pervasive and varied than a quiet voice. Communication is affected by marked dysprosody, cognitive-linguistic impairment, alterations to social interaction and pragmatics. Changes entail not just expressive elements but also receptive. A comprehensive evaluation of potential communication challenges faced by people with Parkinson's disease must cover all these aspects. Similarly, interventions that ignore the breadth and depth of changes will always remain incomplete.

Speech therapy for children with dysarthria acquired before three years of age.

BACKGROUND: Children with motor impairments often have the motor speech disorder dysarthria, a condition which effects the tone, strength and co-ordination of any or all of the muscles used for speech. Resulting speech difficulties can range from mild, with slightly slurred articulation and breathy voice, to profound, with an inability to produce any recognisable words. Children with dysarthria are often prescribed communication aids to supplement their natural forms of communication. However, there is variation in practice regarding the provision of therapy focusing on voice and speech production. Descriptive studies have suggested that therapy may improve speech, but its effectiveness has not been evaluated. OBJECTIVES: To assess whether any speech and language therapy intervention aimed at improving the speech of children with dysarthria is more effective in increasing children's speech intelligibility or communicative participation than no intervention at all , and to compare the efficacy of individual types of speech language therapy in improving the speech intelligibility or communicative participation of children with dysarthria. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015 , Issue 7 ), MEDLINE, EMBASE, CINAHL , LLBA, ERIC, PsychInfo, Web of Science, Scopus, UK National Research Register and Dissertation Abstracts up to July 2015, handsearched relevant journals published between 1980 and July 2015, and searched proceedings of relevant conferences between 1996 to 2015. We placed no restrictions on the language or setting of the studies. A previous version of this review considered studies published up to April 2009. In this update we searched for studies published from April 2009 to July 2015. SELECTION CRITERIA: We considered randomised controlled trials and studies using quasi-experimental designs in which children were allocated to groups using non-random methods. DATA COLLECTION AND ANALYSIS: One author (LP) conducted searches of all databases, journals and conference reports. All searches included a reliability check in which a second review author independently checked a random sample comprising 15% of all identified reports. We planned that two review authors would independently assess the quality and extract data from eligible studies. MAIN RESULTS: No randomised controlled trials or group studies were identified. AUTHORS' CONCLUSIONS: This review found no evidence from randomised trials of the effectiveness of speech and language therapy interventions to improve the speech of children with early acquired dysarthria. Rigorous, fully powered randomised controlled trials are needed to investigate if the positive changes in children's speech observed in phase I and phase II studies are generalisable to the population of children with early acquired dysarthria served by speech and language therapy services. Research should examine change in children's speech production and intelligibility. It must also investigate children's participation in social and educational activities, and their quality of life, as well as the cost and acceptability of interventions.

Entraining with another person's speech rhythm: Evidence from healthy speakers and individuals with Parkinson's disease.

This study examines entrainment of speech timing and rhythm with a model speaker in healthy persons and individuals with Parkinson's. We asked whether participants coordinate their speech initiation and rhythm with the model speaker, and whether the regularity of metrical structure of sentences influences this behaviour. Ten native German speakers with hypokinetic dysarthria following Parkinson's and 10 healthy controls heard a sentence ('prime') and subsequently read aloud another sentence ('target'). Speech material comprised 32 metrically regular and irregular sentences, respectively. Turn-taking delays and alignment of speech rhythm were measured using speech wave analyses. Results showed that healthy participants initiated speech more closely in rhythm with the model speaker than patients. Metrically regular prime sentences induced anticipatory responses relative to metrically irregular primes. Entrainment of speech rhythm was greater in metrically regular targets, especially in individuals with Parkinson's. We conclude that individuals with Parkinson's may exploit metrically regular cues in speech.

Is Language a Factor in the Perception of Foreign Accent Syndrome?

Neurogenic foreign accent syndrome (FAS) is diagnosed when listeners perceive speech associated with motor speech impairments as foreign rather than disordered. Speakers with foreign accent syndrome typically have aphasia. It remains unclear how far language changes might contribute to the perception of foreign accent syndrome independent of accent. Judges with and without training in language analysis rated orthographic transcriptions of speech from people with foreign accent syndrome, speech-language disorder and no foreign accent syndrome, foreign accent without neurological impairment and healthy controls on scales of foreignness, normalness and disorderedness. Control speakers were judged as significantly more normal, less disordered and less foreign than other groups. Foreign accent syndrome speakers' transcriptions consistently profiled most closely to those of foreign speakers and significantly different to speakers with speech-language disorder. On normalness and foreignness ratings there were no significant differences between foreign and foreign accent syndrome speakers. For disorderedness, foreign accent syndrome participants fell midway between foreign speakers and those with speech-language impairment only. Slower rate, more hesitations, pauses within and between utterances influenced judgments, delineating control scripts from others. Word-level syntactic and morphological deviations and reduced syntactic and semantic repertoire linked strongly with foreignness perceptions. Greater disordered ratings related to word fragments, poorly intelligible grammatical structures and inappropriate word selection. Language changes influence foreignness perception. Clinical and theoretical issues are addressed.

Lee Silverman Voice Treatment for people with Parkinson's: audit of outcomes in a routine clinic.

BACKGROUND: Speaking louder/more intensely represents a longstanding technique employed to manage voice and intelligibility changes in people with Parkinson's. This technique has been formalized into a treatment approach and marketed as the Lee Silverman Voice Treatment (LSVT®) programme. Evidence for its efficacy has been published. Studies to date are dominated by research facility reports from the original LSVT® group or closely associated groups. Evidence for the efficacy of LSVT® in routine clinical settings is lacking. METHODS & PROCEDURES: We conducted an audit of outcomes for consecutive people with Parkinson's who were offered and completed LSVT® in a routine hospital outpatient setting. In- and exclusion criteria, assessment and treatment protocols followed precisely the methods stipulated by LSVT® Global. Additionally, participants completed the Voice Handicap Index (VHI) and 23 carers completed a visual analogue scale (VAS) for items relating to functional outcomes. OUTCOMES & RESULTS: Group data (n = 33) revealed statistically significant increases in all objective and subjective measures at the end of treatment, though outcomes on the different measures revealed variable individual responses. Mean intensity increases on prolonged vowel were 9.3 dB post-treatment. Significant gains of mean 7.5 and 6.8 dB were maintained at 12 (n = 25) and 24 months (n = 15) respectively for those available for follow-up. Significant intensity gains occurred for reading post-therapy (mean = 8.5 dB), but changes reverted to statistically non-significant at 12 and 24 months. Intensity increase (mean = 8.5 dB) was significant for monologues post-therapy, but not at 12 and 24 months. Median VHI improvement was statistically significant post-therapy and at 12 months, but not at 24 months. Carer VAS ratings all improved significantly post-therapy; at 12 months only perceived loudness, strain, mumbling and intelligibility remained statistically significantly above baseline. No significant gains persisted to 24 months. CONCLUSIONS & IMPLICATIONS: LSVT® was successful for most individuals in this study. Not all patients attained significant changes by the end of treatment. Few patients who achieved significant gain at the end of treatment maintained this at 12 or 24 months. Implications for maintenance, interpretation of results in a degenerative condition and implications for further research are discussed.

Acute and longitudinal changes in motor cortex function following mild traumatic brain injury.

PRIMARY OBJECTIVE: To evaluate excitability and inhibition of the motor cortex acutely and longitudinally following mild traumatic brain injury (mTBI). RESEARCH DESIGN: A longitudinal paired case-control design was used to examine cortical excitability and inhibition in 15 adults who had sustained an mTBI (mean age = 20.8 ± 1.2 years) and 15 matched control participants (mean age = 21.1 ± 1.3 years). METHODS AND PROCEDURES: Participants visited the lab within 72 hours of injury and again at 1, 2, 4 and 8 weeks post-injury. During each visit, transcranial magnetic stimulation was used to examine resting motor threshold (RMT), motor evoked potential peak-to-peak amplitude (MEPamp) and cortical silent period (CSP) duration of the first dorsal interosseous muscle. MAIN OUTCOMES AND RESULTS: There were no differences between groups in RMT (p = 0.10) or MEPamp (p = 0.22) at 72 hours post-injury or across the 2-month testing period (p ≥ 0.68), indicating similar cortical excitability. However, the CSP duration was higher in individuals with mTBI, indicating greater intra-cortical inhibition compared with the control group at 72 hours post-injury (p = 0.03) and throughout the 2 months of recovery (p = 0.009). CONCLUSIONS: mTBI appeared to have little effect on cortical excitability, but an acute and long-lasting effect on intra-cortical inhibition.

Aphasia and swallowing problems in subjects with incident stroke in rural northern Tanzania: a case-control study.

OBJECTIVES: This study was carried out to quantify the degree of cognitive impairment and the extent of speech, language, and swallowing problems in a representative cohort of Swahili-speaking people with stroke in Tanzania. METHODS: A case-control design was used, comparing people with and without stroke on a screening test for aphasia (spoken comprehension and expression), a water swallow test, and the Community Screening Instrument for Dementia (CSI-D). RESULTS: Fifty-eight persons between 6 and 60 months (median 36) post stroke and 58 age- and gender-matched control subjects were assessed. Twenty-eight strokes were left hemisphere; 25, right; 2, posterior circulation; and 3, undetermined. Forty-nine of 58 (84%) control subjects scored 19 to 20 (maximum) on the language screen compared with 26 of 56 (46%) persons with stroke who completed the assessment. Higher age and lower educational attainment, but not gender or time since stroke, were associated with poorer performance on language and swallow assessments. Poorer CSI-D score was significantly correlated with all items. Greater disability (Barthel Index score) was significantly correlated with poorer performance in all items except rate of drinking water. Those with a left hemisphere stroke performed less well on understanding and expression items but better than other subjects with stroke on the water swallow task. CONCLUSIONS: This is the first attempt to describe aphasia incidence in a sub-Saharan African language. Further work on the psychometric properties of the screening instrument is warranted. Given that it delivers a relatively coarse indication of language disturbance, it is likely that incidence of aphasia in the current cohort is underestimated.

Lipid levels in dissociative disorders: effects of psychodynamic psychotherapy.

Although there are several data suggesting a link between lower lipids levels and the risk of suicide, there are few data concerning lower lipids levels in patients with dissociative disorders (DD). This is the first longitudinal study investigating the evolution of the lipids levels during a specific 8 weeks of psychodynamic psychotherapy (PP) for patients with DD. 32 patients diagnosed with DD (SCID for DSMIVR) were assessed with Dissociative Experiences Scale (DES), Clinical Global Impression and Improvement Scale and their lipids levels (total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein and very low density lipoprotein) were measured at inclusion and after 3 and 8 weeks of PP. 30 patients finished the study. There is a significant positive (p < 0.05) link between lower lipids levels (total cholesterol, LDL, triglycerids) and a higher level of dissociation (DES scores) at the beginning and at the end of the study. Interestingly, we found a significant (p = 0.018) positive link between the reduction of the dissociation (DES) and the increase of the triglycerides levels after 8 weeks of treatment. While lower lipids seems related to a higher level of dissociation before and after the treatment, an increasing triglycerides level was observed after 8 weeks of PP in patients with a better outcome. Further studies are needed with larger samples and control groups, in order to confirm these preliminary data. These findings could open the way for hypothesis about the role of lipids in the pathophysiology of DD and raise the question of the patients with DD receiving antilipidemiants agents.

Inequalities in birth before arrival at hospital in South West England: a multimethods study of neonatal hypothermia and emergency medical services call-handler advice.

OBJECTIVES: To examine inequalities in birth before arrival (BBA) at hospitals in South West England, understand which groups are most likely to experience BBA and how this relates to hypothermia and outcomes (phase A). To investigate opportunities to improve temperature management advice given by emergency medical services (EMS) call-handlers during emergency calls regarding BBA in the UK (phase B). DESIGN: A two-phase multimethod study. Phase A analysed anonymised data from hospital neonatal records between January 2018 and January 2021. Phase B analysed anonymised EMS call transcripts, followed by focus groups with National Health Service (NHS) staff and patients. SETTING: Six Hospital Trusts in South West England and two EMS providers (ambulance services) in South West and North East England. PARTICIPANTS: 18 multidisciplinary NHS staff and 22 members of the public who had experienced BBA in the UK. RESULTS: 35% (64/184) of babies conveyed to hospital were hypothermic on arrival. When compared with national data on all births in the South West, we found higher percentages of women with documented safeguarding concerns at booking, previous live births and 'late bookers' (booking their pregnancy >13 weeks gestation). These women may, therefore, be more likely to experience BBA. Preterm babies, babies to first-time mothers and babies born to mothers with disability or safeguarding concerns at booking were more likely to be hypothermic following BBA. Five main themes emerged from qualitative data on call-handler advice: (1) importance placed on neonatal temperature; (2) advice on where the baby should be placed following birth; (3) advice on how to keep the baby warm; (4) timing of temperature management advice and (5) clarity and priority of instructions. CONCLUSIONS: Findings identified factors associated with BBA and neonatal hypothermia following BBA. Improvements to EMS call-handler advice could reduce the number of babies arriving at hospital hypothermic.

Genome-wide association study reveals shared and distinct genetic architecture underlying fatty acid and bioactive oxylipin metabolites in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Bioactive fatty acid-derived oxylipin molecules play key roles in mediating inflammation and oxidative stress, which underlie many chronic diseases. Circulating levels of fatty acids and oxylipins are influenced by both environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biological pathways. Thus, we performed a genome wide association study (GWAS) of n=81 fatty acids and oxylipins in n=11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years, standard deviation = 13.8 years). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom joint tests. Heritability estimates ranged from 0% to 47.9%, and 48 of the 81oxylipins and fatty acids were significantly heritable. Moreover, 40 (49.4%) of the 81 oxylipins and fatty acids had at least one genome-wide significant (p< 6.94E-11) variant resulting in 19 independent genetic loci involved in fatty acid and oxylipin synthesis, as well as downstream pathways. Four loci (lead variant minor allele frequency [MAF] range: 0.08-0.50), including the desaturase-encoding FADS and the OATP1B1 transporter protein-encoding SLCO1B1, exhibited associations with four or more fatty acids and oxylipins. The majority of the 15 remaining loci (87.5%) (lead variant MAF range = 0.03-0.45, mean = 0.23) were only associated with one oxylipin or fatty acid, demonstrating evidence of distinct genetic effects. Finally, while most loci identified in two-degree-of-freedom tests were previously identified in our main effects analyses, we also identified an additional rare variant (MAF = 0.002) near CARS2, a locus previously implicated in inflammation. Our analyses revealed shared and distinct genetic architecture underlying fatty acids and oxylipins, providing insights into genetic factors and motivating future multi-omics work to characterize these compounds and elucidate their roles in disease pathways.

Intensive dysarthria therapy for younger children with cerebral palsy.

AIM: The aim of this study was to investigate if intervention targeting breath support, phonation, and speech rate increases speech intelligibility and participation in the conversational interactions of younger children with dysarthria and cerebral palsy (CP). METHOD: Fifteen children with dysarthria and CP (nine males, six females; age range 5-11 y, mean age 8 y, SD 2 y; CP type: eight spastic, four dyskinetic, one ataxia, two Worster Drought syndrome; Gross Motor Function Classification System levels II-IV, median level II) participated in this study. Children received three sessions of individual therapy per week for 6 weeks. Intelligibility of single words and connected speech was compared across five points: 1 and 6 weeks before therapy and 1, 6, and 12 weeks after therapy. Three familiar listeners and three unfamiliar listeners scored each recording. Participation in communicative interactions was measured using the Focus on the Outcomes of Communication Under Six (FOCUS) tool. Analyses of variance and paired t-tests were used to investigate change. RESULTS: Mean speech intelligibility increased after therapy to familiar listeners (single words 10.8%, 95% confidence interval [CI] 7.2-14.4; connected speech 9.4%, 95% CI 4.8-14.1) and unfamiliar listeners (single words 9.3%, 95% CI 6.8-11.8; connected speech 10.5%, 95% CI 7.3-13.8). FOCUS scores increased following therapy for parents (mean increase 30.3, 95% CI 10.2-50.4) and for teachers (28.25, 95% CI 14.4-42.1), but changes did not correlate with intelligibility. A wide variation was seen in individual responses to therapy. INTERPRETATION: Brief intensive therapy is associated with gains in intelligibility and communicative interactions for some younger children with dysarthria.