An investigation of mechanisms underpinning substance dependence and novel interventions

A number of theories have attempted to explicate mechanisms underpinning the transition from recreational drug use to substance dependence. A highly reliable correlate of dependence is the value ascribed to the drug. However, supernormal drug valuation may be insufficient to fully account for a subgroup of dependent individuals for whom the course of dependence is chronic and relapsing and who persist in drug use in the face of devastating costs. Three candidate secondary mechanisms for dependence are considered in this thesis: cue reactivity, cost discounting, and sensitivity to negative affect. Neither cue reactivity nor cost discounting were found to be significantly associated with severity of alcohol dependence in samples of young adult drinkers. By contrast, induced negative affect was found to be reliably associated with augmented alcohol motivation, and sensitivity to this effect was related to symptoms of depression and self-reported drinking to cope with negative affect: both risk factors for the development of dependence. These findings delineate a particular subset of dependent individuals for whom negative affect may represent a substantial trigger to continued drug use. There are a lack of brief interventions to abolish or limit negative affect driven drug motivation. This thesis trialled three potential interventions. A natural walk intervention in hazardous drinkers showed no evidence of limiting this effect in two experiments. Brief instruction in acceptance-based coping showed no evidence of limiting annoyance in response to an aversive noise induction procedure in an alcohol dependent population, and was therefore also eliminated as a potential intervention. However, engagement with pleasant environmental images, as a proxy for environmental enrichment, significantly reduced negative affect driven alcohol choice in student drinkers who reported a desire to visit the locations shown (high liking), compared to low-liking individuals and controls. This provides preliminary evidence for the efficacy of environmental enrichment type interventions, justifying further trials. In treatment of dependence more generally, interventions to increase access to healthy, non-drug sources of positive reinforcement may prove effective.ESR

Negative mood induction increases choice of heroin versus food pictures in opiate-dependent individuals: Correlation with self-medication coping motives and subjective reactivity

This is the final version. Available from Frontiers Media via the DOI in this record.Acute growth in negative affect is thought to play a major role in triggering relapse in opiate-dependent individuals. Consistent with this view, three lab studies have demonstrated that negative mood induction increases opiate craving in opiate-dependent individuals. The current study sought to confirm these effects with a behavioral measure of heroin seeking, and test whether the effect is associated with self-reported opiate use to cope with negative affect and subjective reactivity to mood induction. Participants were heroin-dependent individuals engaged with treatment services (n = 47) and control participants (n = 25). Heroin users completed a questionnaire assessing reasons for using heroin: negative affect, social pressure, and cued craving. Baseline heroin choice was measured by preference to enlarge heroin versus food thumbnail pictures in two-alternative forced-choice trials. Negative mood was then induced by depressive statements and music before heroin choice was tested again. Subjective reactivity was indexed by negative and positive mood reported at the pre-induction to post-test timepoints. Heroin users chose heroin images more frequently than controls overall (p = .001) and showed a negative mood-induced increase in heroin choice compared to control participants (interaction p < .05). Mood-induced heroin choice was associated with self-reported heroin use to cope with negative affect (p < .05), but not social pressure (p = .39) or cued craving (p = .52), and with subjective mood reactivity (p = .007). These data suggest that acute negative mood is a trigger for heroin seeking in heroin-dependent individuals, and this effect is pronounced in those who report using heroin to cope with negative affect, and those who show greater subjective reactivity to negative triggers. Interventions should seek to target negative coping motives to build resilience to affective triggers for relapse.Alcohol Research U

Interprofessional education in geriatric medicine: towards best practice. A controlled before-after study of medical and nursing students

Objectives. To investigate nursing and medical students’ readiness for interprofessional learning before and after implementing geriatric interprofessional education (IPE), based on problem-based learning (PBL) case scenarios. To define the optimal number of geriatric IPE sessions, the size and the ratio of participants from each profession in the learner groups, the outcomes related to the Kirkpatrick four-level typology of learning evaluation, students’ concerns about joint learning and impact of geriatric IPE on these concerns. The study looked at the perception of roles and expertise of the ‘other’ profession in interprofessional teams, and students’ choice of topics for future sessions. Students’ expectations, experience, learning points and the influence on the understanding of IP collaboration, as well as their readiness to participate in such education again were investigated. Design. A controlled before–after study (2014/2015, 2015/2016) with data collected immediately before and after the intervention period. Study includes additional comparison of the results from the intervention with a control group of students. Outcomes were determined with a validated ‘Readiness for Interprofessional Learning’ questionnaire, to which we added questions with free comments, combining quantitative and qualitative research methods. The teaching sessions were facilitated by experienced practitioners/educators, so each group had both, a clinician (either geratology consultant or registrar) and a senior nurse. Participants. 300 medical, 150 nursing students. Setting. Tertiary care university teaching hospital. Results. Analysis of the returned forms in the intervention group had shown that nursing students scored higher on teamwork and collaboration post-IPE (M=40.78, SD=4.05) than pre-IPE (M=34.59, SD=10.36)—statistically significant. On negative professional identity, they scored lower post-IPE (M=7.21, SD=4.2) than pre-IPE (M=8.46, SD=4.1)—statistically significant. The higher score on positive professional identity post-IPE (M=16.43, SD=2.76) than pre-IPE (M=14.32, SD=4.59) was also statistically significant. Likewise, the lower score on roles and responsibilities post-IPE (M=5.41, SD=1.63) than pre-IPE (M=6.84, SD=2.75). Medical students scored higher on teamwork and collaboration post-IPE (M=36.66, SD=5.1) than pre-IPE (M=32.68, SD=7.4)—statistically significant. Higher positive professional identity post-IPE (M=14.3, SD=3.2) than pre-IPE (M=13.1, SD=4.31)—statistically significant. The lower negative professional identity post-IPE (M=7.6, SD=3.17) than pre-IPE (M=8.36, SD=2.91) was not statistically significant. Nor was the post-IPE difference over roles and responsibilities (M=7.4, SD=1.85), pre-IPE (M=7.85, SD=2.1). In the control group, medical students scored higher for teamwork and collaboration post-IPE (M=36.07, SD=3.8) than pre-IPE (M=33.95, SD=3.37)—statistically significant, same for positive professional identity post-IPE (M=13.74, SD=2.64), pre-IPE (M=12.8, SD=2.29), while negative professional identity post-IPE (M=8.48, SD=2.52), pre-IPE (M=9, SD=2.07), and roles and responsibilities post-IPE (M=7.89, SD=1.69), pre-IPE (M=7.91, SD=1.51) shown no statistically significant differences. Student concerns, enhanced understanding of collaboration and readiness for future joint work were addressed, but not understanding of roles. Conclusions. Educators with nursing and medical backgrounds delivered geriatric IPE through case-based PBL. The optimal learner group size was determined. The equal numbers of participants from each profession for successful IPE are not necessary. The IPE delivered by clinicians and senior nurses had an overall positive impact on all participants, but more markedly on nursing students. Surprisingly, it had the same impact on medical students regardless if it was delivered to the mixed groups with nursing students, or to medical students alone. Teaching successfully addressed students’ concerns about joint learning and communication and ethics were most commonly suggested topics for the future

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission

Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth