Genetic and pharmacological investigation of α4-containing GABAA receptors in conditioned behaviours influenced by cocaine

α4-subunit containing GABAA receptors (α4-GABAARs) are often found co-assembled with δ-subunits in extrasynaptic locations on nucleus accumbens (NAc) medium spiny neurons (MSNs), were they mediate a tonic form of inhibition thought to control the excitability of the neuron. This thesis combines genetic and pharmacological techniques to explore the role of α4-GABAARs in locomotor and reward-conditioned behaviours. Activation of α4-GABAARs by systemic or intra-accumbal administration of THIP, a GABAAR agonist with a preference for δ-subunits, was able to reduce cocainepotentiated locomotor activity in wildtype but not GABAAR α4-subunit knockout mice. Similarly, the ability of repeated cocaine to induce behavioural sensitisation was unaffected in GABAAR α4-subunit knockout mice, but systemic THIP was able to reduce the sensitised increase in locomotor activity in wildtype but not knockout mice. α4-GABAARs are also able to modulate behavioural responses to reward-conditioned stimuli and their enhancement by cocaine. Deletion of GABAAR α4-subunits from dopamine D1-expressing neurons facilitated cocaine-CPP, and activation of α4- GABAARs on NAc D1-MSNs was able to attenuate cocaine-enhancement of cocaine CPP. Conversely, deletion of GABAAR α4-subunits from dopamine D2-expressing neurons increased CRf responding, and activation of α4-GABAARs on NAc D2-MSNs was able to attenuate cocaine-potentiation of CRf responding. These data also indicate that there is a dissociation in the NAc MSNs mediating cocaine-CPP and CRf responding. This may be explained by the different glutamatergic inputs needed to provide information about conditioned cues important for these behaviours. The data presented within this thesis indicate that α4-GABAAR-mediated inhibition of D1- and D2-expressing neurons plays an important physiological role in controlling behavioural responses to conditioned cues. Furthermore, NAc α4βδ GABAARs may provide a potential therapeutic target by which to limit the enhancement of locomotor and conditioned-behaviours by cocaine

Nucleus Accumbens Dopamine D1-Receptor-Expressing Neurons Control the Acquisition of Sign-Tracking to Conditioned Cues in Mice

Following repeated pairings, the reinforcing and motivational properties (incentive salience) of a reward can be transferred onto an environmental stimulus which can then elicit conditioned responses, including Pavlovian approach behavior to the stimulus (a sign-tracking response). In rodents, acquisition of sign-tracking in autoshaping paradigms is sensitive to lesions and dopamine D1 receptor antagonism of the nucleus accumbens (NAc) of the ventral striatum. However, currently, the possible roles of dorsal striatal subregions, as well as of the two major striatal neuron types, dopamine D1-/D2-expressing medium spiny neurons (MSNs), in controlling the development of conditioned responses is still unclear and warrants further study. Here, for the first time, we used a transgenic mouse line combined with striatal subregion-specific AAV virus injections to separately express tetanus toxin in D1-/D2- MSNs in the NAc, dorsomedial striatum, and dorsolateral striatum, to permanently block neurotransmission in these neurons during acquisition of an autoshaping task. Neurotransmission blocking of NAc D1-MSNs inhibited the acquisition of sign-tracking responses when the initial conditioned response for each conditioned stimulus presentation was examined, confirming our initial hypothesis. These findings suggest that activity in NAc D1-MSNs contributes to the attribution of incentive salience to conditioned stimuli

High prevalence of TB disease in contacts of adults with extrapulmonary TB

UK guidelines no longer recommend routine screening of household contacts of adult patients with extrapulmonary TB (EPTB). From 27 March 2012 to 28 June 2016, we investigated the prevalence of active TB disease in household contacts of 1023 EPTB index cases in North West England, and compared estimates with: published new entrant migrant screening programme prevalence (~147/100 000 person-years); London-based contact screening data (700/100 000 contacts screened); and National Institute for Health and Care Excellence (NICE) new entrant TB screening thresholds (TB prevalence >40/100 000 people). Active TB disease prevalence in EPTB contacts was 440/100 000 contacts screened, similar to UK new entrant screening programmes, London EPTB contact prevalence and >10 times NICE’s threshold for new entrant screening. The decision to no longer recommend routine screening of EPTB contacts should be re-evaluated and cost-effectiveness analyses of screening strategies for EPTB contacts should be performed

Real-time measurement of pelvis and trunk kinematics during treadmill locomotion using a low-cost depth-sensing camera: A concurrent validity study

There is currently no suitable kinematic system for a large-scale prospective trial assessing risk factors of musculoskeletal disorders. A practical kinematic system is described which involves the use of a single low-cost depth-sensing camera for the real-time measurement of 3-dimensional linear and angular pelvic and trunk range-of-movement (ROM). The method is based on the creation and processing of dynamic point clouds taken from the posterior surface of the pelvis and trunk. Nine healthy participants performed 3 trials of treadmill locomotion when walking at self-selected speed (3.6-5.6 km/h), running at 70% (10.9-14.0 km/h) and 90% of maximal speed (14.0-18.0 km/h). Stride-by-stride linear and angular ROM data were captured concurrently using the single depth-sensing camera running at 30Hz (KinectTM for Windows, Microsoft, USA) and a six-camera motion capture system at 100Hz (Vicon MX13, Vicon Motion Systems, United Kingdom). Within subject correlation coefficients between the practical and criterion method ranged from very large to nearly perfect (r = 0.87–1.00) for the linear ROM. Correlation coefficients for the angular ROM ranged from moderate to very large (r = 0.41–0.80). The limits of agreement between the two systems for linear movements was ≤ 9.9 mm at all velocities of gait and ≤ 4.6 degrees at all velocities of gait. The single camera system using depth-sensing technology is capable of capturing linear pelvic and trunk ROM during treadmill locomotion with reasonable precision when compared to the criterion method. Further improvements to the measurement of angles and validation across a wider population are recommended

Seeing with sound? Exploring different characteristics of a visual-to-auditory sensory substitution device

Sensory substitution devices convert live visual images into auditory signals, for example with a web camera (to record the images), a computer (to perform the conversion) and headphones (to listen to the sounds). In a series of three experiments, the performance of one such device (‘The vOICe’) was assessed under various conditions on blindfolded sighted participants. The main task that we used involved identifying and locating objects placed on a table by holding a webcam (like a flashlight) or wearing it on the head (like a miner’s light). Identifying objects on a table was easier with a hand-held device, but locating the objects was easier with a head-mounted device. Brightness converted into loudness was less effective than the reverse contrast (dark being loud), suggesting that performance under these conditions (natural indoor lighting, novice users) is related more to the properties of the auditory signal (ie the amount of noise in it) than the cross-modal association between loudness and brightness. Individual differences in musical memory (detecting pitch changes in two sequences of notes) was related to the time taken to identify or recognise objects, but individual differences in self-reported vividness of visual imagery did not reliably predict performance across the experiments. In general, the results suggest that the auditory characteristics of the device may be more important for initial learning than visual associations

Effect of sand on knee load during a single-leg jump task: Implications for injury prevention and rehabilitation programs

The purpose of the study was to determine potential differences in landing strategies and subsequent joint loads at the knee (knee abduction moment [KAM], anterior-posterior [AP] tibial translation, and total knee shear force) when jumping onto sand and firm ground from both a level surface and a 30-cm height. Firm ground would act as the control for the study. Seventeen subjects (age: 23.6 ± 3.7 years; body mass: 67.7 ± 10.3 kg; height: 168.5 ± 7.4 cm) performed 3 single-leg jumps on their dominant leg for each of the 4 conditions tested (ground level, sand level, ground height, and sand height). A repeated-measures design investigated the effect of sand on KAM, AP tibial translation, and total knee shear force. Data were analyzed using magnitude-based inferences and presented as percentage change with 90% confidence limits. Results indicated that sand had a clear beneficial effect on KAM, which was possibly moderate during a drop jump (30 cm) and possibly small from a level jump. Sand also had a possibly moderate beneficial effect on AP tibial translation from a level jump. The effect of sand on total knee shear force was unclear. These results suggest that sand may provide a safer alternative to firm ground when performing jump tasks commonly used in anterior cruciate ligament and patellofemoral joint injury prevention and rehabilitation programs. Sand may also allow for an accelerated rehabilitation program because jumping activities could potentially be implemented more safely at an earlier stage in the process

Quantifying exposure and intra-individual reliability of high-speed and sprint running during sided-games training in soccer players: a systematic review and meta-analysis:High-speed and sprint running exposure in soccer sided-games

BACKGROUND: Sided games (i.e., small sided, medium sided, large sided) involve tactical, technical, physical, and psychological elements and are commonly implemented in soccer training. Although soccer sided-games research is plentiful, a meta-analytical synthesis of external load exposure during sided games is lacking. OBJECTIVE: The objective of this systematic review and meta-analysis was to: (1) synthesize the evidence on high-speed and sprint running exposure induced by sided games in adult soccer players, (2) establish pooled estimates and intra-individual reliability for high-speed and sprint running exposure, and (3) explore the moderating effects of game format and playing constraints. METHODS: A literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Four databases (PubMed/MEDLINE, Scopus, SPORTDiscus, Web of Science Core Collection) were systematically searched up to 25 January, 2022. Eligibility criteria were adult soccer players (population); training programs incorporating sided games (intervention); game manipulations including number of players, pitch dimension, and game orientation (comparator); and high-speed, very high-speed, and sprint relative (m[Formula: see text] min(−1)) running distances and associated intra-individual reliability (outcome). Eligible study risk of bias was evaluated using RoBANS. Pooled estimates for high-speed and sprint running exposure, and their intra-individual reliability, along with the moderating effect of tracking device running velocity thresholds, pitch dimension (i.e., area per player), and game orientation (i.e. score or possession), were determined via a multi-level mixed-effects meta-analysis. Estimate uncertainty is presented as 95% compatibility intervals (CIs) with the likely range of relative distances in similar future studies determined via 95% prediction intervals. RESULTS: A total of 104 and 7 studies met our eligibility criteria for the main and reliability analyses, respectively. The range of relative distances covered across small-sided games, medium-sided games, and large-sided games was 14.8 m[Formula: see text] min(−1) (95% CI 12.3–17.4) to 17.2 m[Formula: see text] min(−1) (95% CI 13.5–20.8) for high-speed running, 2.7 m[Formula: see text] min(−1) (95% CI 1.8–3.5) to 3.6 m[Formula: see text] min(−1) (95% CI 2.3–4.8) for very high-speed running, and 0.2 m[Formula: see text] min(−1) (95% CI 0.1–0.4) to 0.7 m[Formula: see text] min(−1) (95% CI 0.5–0.9) for sprinting. Across different game formats, 95% prediction intervals showed future exposure for high-speed, very high-speed running, and sprinting to be 0–46.5 m[Formula: see text] min(−1), 0–14.2 m[Formula: see text] min(−1), and 0–2.6 m[Formula: see text] min(−1), respectively. High-speed, very high-speed running, and sprinting showed poor reliability with a pooled coefficient of variation of 22.8% with distances being moderated by device speed thresholds, pitch dimension, and game orientation. CONCLUSIONS: This review is the first to provide a detailed synthesis of exposure and intra-individual reliability of high-speed and sprint running during soccer sided games. Our estimates, along with the moderating influence of common programming variables such as velocity thresholds, area per player, and game orientation should be considered for informed planning of small-sided games, medium-sided games, and large-sided games soccer training. CLINICAL TRIAL REGISTRATION: Open Science Framework available through https://osf.io/a4xr2/

Quantifying the need for enhanced case management for TB patients as part of TB cohort audit in the North West of England: a descriptive study

Abstract Background Patients with TB have diverse and often challenging clinical and social needs that may hamper successful treatment outcomes. Understanding the need for additional support during treatment (enhanced case management, or ECM) is important for workforce capacity planning. North West England TB Cohort Audit (TBCA) has introduced a 4-level ECM classification system (ECM 0–3) to quantify the need for ECM in the region. This study describes the data from the first 2 years of ECM classification. Methods Data collected between April 2013 and July 2015 were used to analyse the proportions of patients allocated to each ECM level and the prevalence of social and clinical factors indicating need for ECM. Single variable and multivariable logistic regression models were constructed to examine the association between ECM level and treatment outcome. Results Of 1714 notified cases 99.8% were assigned an ECM level: 31% ECM1, 19% ECM2 and 14% ECM3. The most common factors indicating need for ECM were language barriers (20.3%) and clinical complexity (16.9%). 1342/1493 (89.9%) of drug-sensitive, non-CNS cases completed treatment within 12 months. Patients in ECM2 and 3 were less likely to complete treatment at 12 months than patients in ECM0 (adjusted OR 0.47 [95% CI 0.27–0.84] and 0.23 [0.13–0.41] respectively). Conclusions Use of TBCA to quantify different levels of need for ECM is feasible and has demonstrated that social and clinical complexity is common in the region. Results will inform regional workforce planning and assist development of innovative methods to improve treatment outcomes in these vulnerable groups