Time to commencement of effective treatment in patients with drug-resistant tuberculosis diagnosed in the Torres Strait-Papua New Guinea cross-border region.

INTRODUCTION: Delays between self-reported symptom onset and commencement of effective treatment contribute to ongoing tuberculosis (TB) transmission, which is a particular concern in patients with drug-resistant (DR)-TB. The study authors assessed improvements in time to commencement of effective treatment in patients diagnosed with DR-TB in the Torres Strait-Papua New Guinea cross-border region. METHODS: All laboratory-confirmed DR-TB cases diagnosed in the Torres Strait between 1 March 2000 and 31 March 2020 were reviewed. Total time from self-reported onset of symptoms to effective treatment commencement in different programmatic time periods was assessed. Pairwise analyses and time to event proportional hazard calculations were used to explore the association between delays in median time to effective treatment, and selected variables. Data were further analysed to examine predictors of excessive treatment delay. RESULTS: The median number of days from self-reported onset of symptoms to effective treatment commencement was 124 days (interquartile range 51-214) over two decades. Between 2006 and 2012, most (57%) cases exceeded this 'grand median' while the median 'time to treat' in the most recent time period (2016-2020) was significantly reduced to 29 days (p<0.001). Although there was a reduction in the median 'time to treat' with the introduction of Xpert MTB/RIF (135 days pre-Xpert v 67 days post-Xpert) this was not statistically significant (p=0.07). Establishment of the Torres and Cape TB Control Unit on Thursday Island (2016-2020) was significantly associated with reduced treatment delay, compared to the previous TB program period (2000-2005, p<0.04; 2006-2012, p<0.001). CONCLUSION: Minimising TB treatment delay in remote settings like the Torres Strait-Papua New Guinea cross-border region requires effective decentralised diagnosis and management structures. The results of this study suggest that the establishment of the Torres and Cape TB Control Unit on Thursday Island significantly improved time to commencement of effective TB treatment. Possible contributing factors include better TB education, cross-border communication and patient-centred care.

Induction of the integrated stress response in the rat cornea.

Keratoconus (KC), a progressive, degenerative corneal disease, represents the second leading indication for corneal transplantation globally. We have previously demonstrated that components of the Integrated Stress Response (ISR) are upregulated in human keratoconic donor tissue, and treatment of normal tissue with ISR agonists attenuates collagen production. With no consistently accepted animal models available for translational KC research, we sought to establish an in vivo model based on ISR activation to elucidate its role in the development of the KC phenotype. Four-week-old female SD rats were treated with topical SAL003 formulated as a nanosuspension or vehicle every 48 h for four doses. Animals were subject to monitoring for ocular inflammation and discomfort before being euthanized at 1, 14, or 28 days after treatment was withdrawn. Schirmer's tear test, intraocular pressure, and body weight measurements were obtained at baseline and prior to euthanasia. Globes were subject to routine histopathology, immunohistochemistry for ATF4, and qPCR for Col1a1 expression. ANOVAs and Student's t tests were used to assess statistical significance (α = 0.05). SAL003 treatment did not produce any adverse ocular or systemic phenotype but did result in decreased keratocyte density. Col1a1 transcripts were reduced, corresponding to nuclear ATF4 expression within the axial cornea. In vivo topical treatment with a gel-formulated ISR agonist recapitulates key features of the activated ISR including nuclear ATF4 expression and decreased extracellular matrix (ECM) production. Exogenous ISR agonists may present one approach to establishing a rodent model for keratoconus, a charge essential for future evaluations of pathogenesis and therapeutic interventions.

Phenotypic homogeneity of emetic Bacillus cereus isolates in China.

Emetic Bacillus cereus strains produce a potent cereulide cytotoxin, which can cause acute and fatal cases of food poisoning. We isolated 18 emetic B. cereus strains from a food poisoning event, and from clinical and non-random food surveillance in China and phenotypic characteristics of haemolysis, starch hydrolysis, salicin fermentation, gelatin liquefaction, cytotoxicity, and susceptibility to antibiotics were assessed. All isolates were positive for haemolysis and gelatin liquefaction, and negative for starch hydrolysis and salicin fermentation. Their haemolytic potentials were intermediate to Bacillus anthracis and B. cereus ATCC 14579 (a non-emetic strain). All isolates were cytotoxic to CHO, Hep-2, and Vero cells, and were sensitive to ampicillin. The homogeneous phenotypes of emetic isolates from China are similar to the corresponding traits of European and Japanese isolates that have been characterized, suggesting highly similar phenotypes of emetic B. cereus worldwide.

Tuberculosis in the Torres Strait: the lady doth test too much.

INTRODUCTION: Smear-positive pulmonary tuberculosis (PTB) requires rapid diagnosis and treatment to prevent ongoing transmission. Collection of two sputum specimens is considered the minimum requirement for the diagnosis of PTB but current guidelines in the Torres Strait Islands, Australia, recommend three sputum specimens; this frequently delays treatment initiation. METHODS: A retrospective study was performed to ascertain the diagnostic yield of sputum specimens collected in the Torres Strait Islands. The study assessed demographics and characteristics of all PTB cases diagnosed between 2000 and 2018, and assessed the diagnostic yield in 143 patients from whom at least three sputum specimens had been collected prior to treatment commencement. Incremental and cumulative yield was calculated for each sputum specimen. Data were further analysed using binary logistic regression to examine the association between selected characteristics and a smear-positive acid-fast bacilli (AFB) result. RESULTS: Overall, AFB was detected from the first or second sputum specimen in 97 of 101 PTB cases that were sputum smear positive. A smear-positive result was more common (odds ratio 2.84, 95% confidence interval 1.08-7.46) for Papua New Guinea nationals compared to Australian born patients. Of the 429 samples collected, 76 (18%) were of poor quality and the association between poor quality specimens and smear-negative results was significant (p<0.01). Among sputum smear-negative cases, 5/42 (12%) had three consecutive poor quality specimens. The most common collection modality in adults was voluntary expectoration; done in 391/429 (91%) of all specimens collected. Alternative specimen collection methods were mainly used in children; induced sputum 1/429 (0.2%), gastric aspirate 26/429 (6%) and nasopharyngeal aspirate 7/429 (1.6%). Errors with labelling, packaging and transportation occurred in 44 specimens from 15 patients. CONCLUSION: Two good quality specimens ensure adequate diagnostic yield for PTB and a third specimen should only be collected from patients with two negative specimens who have persistent symptoms. Ideally, decentralised Xpert Ultra® should be the frontline diagnostic test in remote settings, especially in settings like the Torres Strait Islands with high rates of drug-resistant TB.

An impenetrable barrier to ultrarelativistic electrons in the Van Allen radiation belts.

Early observations indicated that the Earth's Van Allen radiation belts could be separated into an inner zone dominated by high-energy protons and an outer zone dominated by high-energy electrons. Subsequent studies showed that electrons of moderate energy (less than about one megaelectronvolt) often populate both zones, with a deep 'slot' region largely devoid of particles between them. There is a region of dense cold plasma around the Earth known as the plasmasphere, the outer boundary of which is called the plasmapause. The two-belt radiation structure was explained as arising from strong electron interactions with plasmaspheric hiss just inside the plasmapause boundary, with the inner edge of the outer radiation zone corresponding to the minimum plasmapause location. Recent observations have revealed unexpected radiation belt morphology, especially at ultrarelativistic kinetic energies (more than five megaelectronvolts). Here we analyse an extended data set that reveals an exceedingly sharp inner boundary for the ultrarelativistic electrons. Additional, concurrently measured data reveal that this barrier to inward electron radial transport does not arise because of a physical boundary within the Earth's intrinsic magnetic field, and that inward radial diffusion is unlikely to be inhibited by scattering by electromagnetic transmitter wave fields. Rather, we suggest that exceptionally slow natural inward radial diffusion combined with weak, but persistent, wave-particle pitch angle scattering deep inside the Earth's plasmasphere can combine to create an almost impenetrable barrier through which the most energetic Van Allen belt electrons cannot migrate.

Glancing-angle-deposited silica films for ultraviolet wave plates.

Birefringent silica films are formed by glancing-angle deposition to fabricate quarter- and half-wave plates at a wavelength of 351 nm. A multilayer design is implemented to achieve low-loss transmittance with a high 351-nm laser-induced damage threshold.

Cross-Border Movement of Highly Drug-Resistant Mycobacterium tuberculosis from Papua New Guinea to Australia through Torres Strait Protected Zone, 2010-2015.

In this retrospective study, we used whole-genome sequencing (WGS) to delineate transmission dynamics, characterize drug-resistance markers, and identify risk factors of transmission among Papua New Guinea residents of the Torres Strait Protected Zone (TSPZ) who had tuberculosis diagnoses during 2010-2015. Of 117 isolates collected, we could acquire WGS data for 100; 79 were Beijing sublineage 2.2.1.1, which was associated with active transmission (odds ratio 6.190, 95% CI 2.221-18.077). Strains were distributed widely throughout the TSPZ. Clustering occurred more often within than between villages (p = 0.0013). Including 4 multidrug-resistant tuberculosis isolates from Australia citizens epidemiologically linked to the TSPZ into the transmission network analysis revealed 2 probable cross-border transmission events. All multidrug-resistant isolates (33/104) belonged to Beijing sublineage 2.2.1.1 and had high-level isoniazid and ethionamide co-resistance; 2 isolates were extensively drug resistant. Including WGS in regional surveillance could improve tuberculosis transmission tracking and control strategies within the TSPZ.

Genome-wide association studies of placebo and duloxetine response in major depressive disorder.

We investigated variants associated with treatment response in depressed patients treated with either the antidepressant duloxetine or placebo using a genome-wide approach. Our sample (N=391) included individuals aged 18-75 years, diagnosed with major depressive disorder and treated with either duloxetine or placebo for up to 8 weeks. We conducted genome-wide associations for treatment response as operationalized by percentage change in Montgomery-Åsberg Depression Rating Scale score from baseline, as well as mixed models analyses across five time points. In the placebo-treated subsample (N=205), we observed a genome-wide association with rs76767803 (ß=0.69, P=1.25 × 10-8) upstream of STAC1. STAC1 rs76767803 was also associated with response using mixed model analysis (χ2=3.95; P=0.001). In the duloxetine-treated subsample (N=186), we observed suggestive associations with ZNF385D (rs4261893; ß=-0.46, P=1.55 × 10-5), NCAM1 (rs2303377; ß=0.45, P=1.76 × 10-5) and MLL5 (rs117986340; ß=0.91, P=3.04 × 10-5). Our findings suggest that a variant upstream of STAC1 is associated with placebo response, which might have implications for treatment optimization, clinical trial design and drug development.

"Kiss myAsthma": Using a participatory design approach to develop a self-management app with young people with asthma.

Objective: Young people with asthma often lack engagement in self-management. Smartphone apps offer an attractive, immediate method for obtaining asthma information and self-management support. In this research we developed an evidence-based asthma app tailored to young peoples needs, created using a participatory design approach to optimize user engagement. This paper describes the participatory design process. Methods: This multi-phased research included concept generation and ideation of app design by young people with asthma, and development of asthma information by the research team. Clinical review was sought regarding safety and accuracy of app content. Participants suggestions for improvement and any problems with the app were logged throughout. Our young co-designers were invited back to test a high fidelity prototype app using a "think aloud" process and completed a usability questionnaire. Results: Twenty asthma patients aged 15-24 years contributed to the initial app design. Three respiratory specialists and two pharmacists suggested minor corrections to clinical terminology in the app which were all incorporated. Nine co-designers acted as expert reviewers of the prototype app, of whom eight completed a usability questionnaire. Median usability scores (maximum score 6) indicated high satisfaction with app content, usefulness and ease of use [median item score 5.3 (range 4.7-6.0)]. All feedback was incorporated to create an updated prototype app. Conclusions: A clinically sound asthma app has been developed which is considered highly acceptable to the young co-designers. A six-week test of the engagement, acceptability, and usefulness of the app in young people not involved in the participatory design will follow.

Closure of the perineal defect after abdominoperineal excision for rectal adenocarcinoma - ACPGBI Position Statement.

BACKGROUND: Perineal wound morbidity is common following abdominoperineal excision of the rectum (APE). There is no consensus on the optimum perineal reconstruction method after APE, and in particular 'extra-levator APE' (ELAPE). METHODS: A systematic review of the PubMed, Embase and Cochrane databases was performed. This position statement formulated clinical questions and graded the evidence to make recommendations. RESULTS: Perineal wound complications may be higher following ELAPE compared to 'conventional APE (cAPE)' however there is insufficient evidence to recommend cAPE over ELAPE with regards to the impact upon perineal wound healing. The majority of cAPE studies have used primary closure with varying complication rates reported. Where concerns regarding perineal wound healing exist, myocutaneous flap closure may be considered as an alternative method. There is minimal available evidence on perineal mesh reconstruction following cAPE. Primary closure, mesh use and myocutaneous flap reconstruction following ELAPE has been reported although variations in definitions and low-quality of available evidence limit comparison. There is insufficient evidence to recommend one particular method of perineal closure after ELAPE. Primary perineal closure is likely to have a higher risk of perineal herniation. Myocutaneous flaps and biological mesh have been effectively used in ELAPE closure. There is insufficient evidence to support one particular type of flap or mesh. Perineal wound complication rates are significantly increased when neo-adjuvant radiotherapy is delivered, regardless of surgical technique. There is no evidence that laparoscopy reduces APE perineal wound complications. CONCLUSION: This position statement updates clinicians on current evidence around perineal closure after APE surgery.

EAES classification of intraoperative adverse events in laparoscopic surgery.

BACKGROUND: Surgical outcomes are traditionally evaluated by post-operative data such as histopathology and morbidity. Although these outcomes are reported using accepted systems, their ability to influence operative performance is limited by their retrospective application. Interest in direct measurement of intraoperative events is growing but no available systems applicable to routine practice exist. We aimed to develop a structured, practical method to report intraoperative adverse events enacted during minimal access surgical procedures. METHODS: A structured mixed methodology approach was adopted. Current intraoperative adverse event reporting practices and desirable system characteristics were sought through a survey of the EAES executive. The observational clinical human reliability analysis method was applied to a series of laparoscopic total mesorectal excision (TME) case videos to identify intraoperative adverse events. In keeping with survey results, observed events were further categorised into non-consequential and consequential, which were further subdivided into four levels based upon the principle of therapy required to correct the event. A second survey phase explored usability, acceptability, face and content validity of the novel classification. RESULTS: 217 h of TME surgery were analysed to develop and continually refine the five-point hierarchical structure. 34 EAES expert surgeons (69%) responded. The lack of an accepted system was the main barrier to routine reporting. Simplicity, reproducibility and clinical utility were identified as essential requirements. The observed distribution of intraoperative adverse events was 60.1% grade I (non-consequential), 37.1% grade II (minor corrective action), 2.4% grade III (major correction or change in post-operative care) and 0.1% grade IV (life threatening). 84% agreed with the proposed classification (Likert scale 4.04) and 92% felt it was applicable to their practice and incorporated all desirable characteristics. CONCLUSION: A clinically applicable intraoperative adverse event classification, which is acceptable to expert surgeons, is reported and complements the objective assessment of minimal access surgical performance.

Health promotion through sport: international sport federations' priorities, actions and opportunities.

OBJECTIVE: To identify areas of priority and activity for international sportsfederations (IFs) with respect to athlete health and safety, and global health. Results serve to direct the work of the Association of Summer Olympic IF Medical and Scientific Consultative Group, the International Olympic Committee and to influence IFs' planning and priorities. METHODS: The 28 IFs participating in the Summer Olympic Games (2016) were asked to rank the relative importance of 11 health-related topics and to report their activities or research initiatives on 27 identified topics using an electronic survey. A comparison with a similar survey (2012) was made. RESULTS: The response rate was 100%. In general, the 'fight against doping' had the highest priority followed by 'image as a safe sport'. The topics with the lowest importance ratings were 'increasing the number of elite athletes', and 'health of the general population'. Despite ranking 'health of your athletes,' as a top priority, IFs are not addressing all aspects of athlete health. In comparison with 2012, there was a significant decrease in priority for IFs is 'health of the general population'. CONCLUSION: Despite the widespread knowledge of the importance of the promotion of physical activity (sport) on global health, the decreasing priority and programming of the IFs on physical activity promotion is concerning. Although IFs have prioritised the protection of the health of elite athletes, there are gaps in programming demonstrating that IFs are missing important areas of athlete health. Improving recreational athlete health programming could also benefit population health as well as improve IF fan base and sport participation.

Stent-based delivery of adeno-associated viral vectors with sustained vascular transduction and iNOS-mediated inhibition of in-stent restenosis.

In-stent restenosis remains an important clinical problem in the era of drug eluting stents. Development of clinical gene therapy protocols for the prevention and treatment of in-stent restenosis is hampered by the lack of adequate local delivery systems. Herein we describe a novel stent-based gene delivery platform capable of providing local arterial gene transfer with adeno-associated viral (AAV) vectors. This system exploits the natural affinity of protein G (PrG) to bind to the Fc region of mammalian IgG, making PrG a universal adaptor for surface immobilization of vector-capturing antibodies (Ab). Our results: 1) demonstrate the feasibility of reversible immobilization of AAV2 vectors using vector tethering by AAV2-specific Ab appended to the stent surface through covalently attached PrG, 2) show sustained release kinetics of PrG/Ab-immobilized AAV2 vector particles into simulated physiological medium in vitro and site-specific transduction of cultured cells, 3) provide evidence of long-term (12 weeks) arterial expression of luciferase with PrG/Ab-tethered AAV2Luc, and 4) show anti-proliferative activity and anti-restenotic efficacy of stent-immobilized AAV2iNOS in the rat carotid artery model of stent angioplasty.

Risk of acute myeloid leukemia and myelodysplastic syndrome among older women receiving anthracycline-based adjuvant chemotherapy for breast cancer on Modern Cooperative Group Trials (Alliance A151511).

PURPOSE: We examined acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) events among 9679 women treated for breast cancer on four adjuvant Alliance for Clinical Trials in Oncology trials with >90 months of follow-up in order to better characterize the risk for AML/MDS in older patients receiving anthracyclines. METHODS: We used multivariable Cox regression to examine factors associated with AML/MDS, adjusting for age (≥65 vs. <65 years; separately for ≥70 vs. <70 years), race/ethnicity, insurance, performance status, and anthracycline receipt. We also examined the effect of cyclophosphamide, the interaction of anthracycline and age, and outcomes for those developing AML/MDS. RESULTS: On Cancer and Leukemia Group B (CALGB) 40101, 49907, 9344, and 9741, 7290 received anthracyclines; 15% were in the age ≥65 and 7% were ≥70. Overall, 47 patients developed AML/MDS (30 AML [0.3%], 17 MDS [0.2%]); 83% of events occurred within 5 years of study registration. Among those age ≥65 and ≥70, 0.8 and 1.0% developed AML/MDS (vs. 0.4% for age <65), respectively. In adjusted analyses, older age and anthracycline receipt were significantly associated with AML/MDS (adjusted hazard ratio [HR] for age ≥65 [vs. <65] = 3.13, 95% confidence interval [CI] 1.18-8.33; HR for anthracycline receipt [vs. no anthracycline] = 5.16, 95% CI 1.47-18.19). There was no interaction between age and anthracycline use. Deaths occurred in 70% of those developing AML/MDS. CONCLUSIONS: We observed an increased risk for AML/MDS for older patients and those receiving anthracyclines, though these events were rare. Our results help inform discussions surrounding anticipated toxicities of adjuvant chemotherapy in older patients.

The relationship between adiposity, bone density and microarchitecture is maintained in young women irrespective of diabetes status.

BACKGROUND: The relationship between bone health and adiposity and how it may be affected in people with chronic metabolic conditions is complex. METHODS: Seventeen women with type 1 diabetes mellitus (T1DM) and nine age-matched healthy women with a median age of 22.6 years (range, 17.4, 23.8) were studied by 3T MRI and MR spectroscopy to assess abdominal adiposity, tibial bone microarchitecture and vertebral bone marrow adiposity (BMA). Additional measures included DXA-based assessments of total body (TB), femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) and fat mass (FM). RESULTS: Although women with T1DM had similar BMI and BMA to the controls, they had higher visceral and subcutaneous adiposity on MRI (P<.05) and total body FM by DXA (P=.03). Overall, in the whole cohort, a clear inverse association was evident between BMA and BMD at all sites (P<.05). These associations remained significant after adjusting for age, BMI, FM and abdominal adiposity. In addition, visceral adiposity, but not subcutaneous adiposity, showed a positive association with BMA (r, .4, P=.03), and a negative association with total body BMD (r, .5, P=.02). Apparent trabecular separation as assessed by MRI showed an inverse association to total body BMD by DXA (r, -.4, P=.04). CONCLUSION: Irrespective of the presence of an underlying metabolic condition, young women display a negative relationship between MRI-measured BMA and DXA-based assessment of BMD. Furthermore, an association between BMA and visceral adiposity supports the notion of a common origin of these two fat depots.

Counterpropagating Radiative Shock Experiments on the Orion Laser.

We present new experiments to study the formation of radiative shocks and the interaction between two counterpropagating radiative shocks. The experiments are performed at the Orion laser facility, which is used to drive shocks in xenon inside large aspect ratio gas cells. The collision between the two shocks and their respective radiative precursors, combined with the formation of inherently three-dimensional shocks, provides a novel platform particularly suited for the benchmarking of numerical codes. The dynamics of the shocks before and after the collision are investigated using point-projection x-ray backlighting while, simultaneously, the electron density in the radiative precursor was measured via optical laser interferometry. Modeling of the experiments using the 2D radiation hydrodynamic codes nym and petra shows very good agreement with the experimental results.

Objective assessment of minimally invasive total mesorectal excision performance: a systematic review.

INTRODUCTION: Laparoscopy is widely used in colorectal practice, but recent trial results have questioned its use in rectal cancer resections. Patient outcomes are directly linked to the quality of total mesorectal excision (TME) specimen. Objective assessment of intraoperative performance could help ensure competence and delivery of optimal outcomes. Objective tools may also contribute to TME intervention trials, but their nature, structure and utilisation is unknown. AIM: To systemically review the available literature to report on the available tools for the objective assessment of minimally invasive TME operative performance and their use within multicentre laparoscopic TME randomised controlled trials. METHODS: A systematic search of the PubMed and Cochrane databases was performed to identify tools used in the objective intraoperative assessment of minimally invasive TME performance in accordance with the PRISMA guidelines, independently by two authors. The identified tools were then evaluated within reported TME RCTs. RESULTS: A total of 8642 abstracts were screened of which 12 papers met the inclusion criteria; ten prospective observational studies, one randomised trial and one educational consensus. Eight assessment methods were described, which include formative and summative tools. The tools were mostly adaptations of colonic surgery tools based on either operative video review or post-operative trainer rating. All studies reported objective assessment of intraoperative performance was feasible, but only 126 (7%) of the 1762 included laparoscopic cases were TME. No multicentre laparoscopic TME trial reported using any objective surgical performance assessment tool. CONCLUSION: Objective intraoperative laparoscopic TME performance assessment is feasible, but most of the current tools are adaptation of colonic surgery. There is a need to develop dedicated assessment tools for minimal access rectal surgery. No multicentre minimally invasive TME RCT reported using any objective assessment tool.

A Mayan founder mutation is a common cause of deafness in Guatemala.

Over 5% of the world's population has varying degrees of hearing loss. Mutations in GJB2 are the most common cause of autosomal recessive non-syndromic hearing loss (ARNHL) in many populations. The frequency and type of mutations are influenced by ethnicity. Guatemala is a multi-ethnic country with four major populations: Maya, Ladino, Xinca, and Garifuna. To determine the mutation profile of GJB2 in a ARNHL population from Guatemala, we sequenced both exons of GJB2 in 133 unrelated families. A total of six pathogenic variants were detected. The most frequent pathogenic variant is c.131G>A (p.Trp44*) detected in 21 of 266 alleles. We show that c.131G>A is associated with a conserved haplotype in Guatemala suggesting a single founder. The majority of Mayan population lives in the west region of the country from where all c.131G>A carriers originated. Further analysis of genome-wide variation of individuals carrying the c.131G>A mutation compared with those of Native American, European, and African populations shows a close match with the Mayan population.

In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [(18)F]GE-180 and effect of docosahexaenoic acid.

PURPOSE: Traumatic spinal cord injury (SCI) is a devastating condition which affects millions of people worldwide causing major disability and substantial socioeconomic burden. There are currently no effective treatments. Modulating the neuroinflammatory (NI) response after SCI has evolved as a major therapeutic strategy. PET can be used to detect the upregulation of the 18-kDa translocator protein (TSPO), a hallmark of activated microglia in the CNS. We investigated whether PET imaging using the novel TSPO tracer [(18)F]GE-180 can be used as a clinically relevant biomarker for NI in a contusion SCI rat model, and we present data on the modulation of NI by the lipid docosahexaenoic acid (DHA). METHODS: A total of 22 adult male Wistar rats were subjected to controlled spinal cord contusion at the T10 spinal cord level. Six non-injured and ten T10 laminectomy only (LAM) animals were used as controls. A subset of six SCI animals were treated with a single intravenous dose of 250 nmol/kg DHA (SCI-DHA group) 30 min after injury; a saline-injected group of six animals was used as an injection control. PET and CT imaging was carried out 7 days after injury using the [(18)F]GE-180 radiotracer. After imaging, the animals were killed and the spinal cord dissected out for biodistribution and autoradiography studies. In vivo data were correlated with ex vivo immunohistochemistry for TSPO. RESULTS: In vivo dynamic PET imaging revealed an increase in tracer uptake in the spinal cord of the SCI animals compared with the non-injured and LAM animals from 35 min after injection (P < 0.0001; SCI vs. LAM vs. non-injured). Biodistribution and autoradiography studies confirmed the high affinity and specific [(18)F]GE-180 binding in the injured spinal cord compared with the binding in the control groups. Furthermore, they also showed decreased tracer uptake in the T10 SCI area in relation to the non-injured remainder of the spinal cord in the SCI-DHA group compared with the SCI-saline group (P < 0.05), supporting a NI modulatory effect of DHA. Immunohistochemistry showed a high level of TSPO expression (38 %) at the T10 injury site in SCI animals compared with that in the non-injured animals (6 %). CONCLUSION: [(18)F]GE-180 PET imaging can reveal areas of increased TSPO expression that can be visualized and quantified in vivo after SCI, offering a minimally invasive approach to the monitoring of NI in SCI models and providing a translatable clinical readout for the testing of new therapies.

Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity.

Autism is a heritable disorder, with over 250 associated genes identified to date, yet no single gene accounts for >1-2% of cases. The clinical presentation, behavioural symptoms, imaging and histopathology findings are strikingly heterogeneous. A more complete understanding of autism can be obtained by examining multiple genetic or behavioural mouse models of autism using magnetic resonance imaging (MRI)-based neuroanatomical phenotyping. Twenty-six different mouse models were examined and the consistently found abnormal brain regions across models were parieto-temporal lobe, cerebellar cortex, frontal lobe, hypothalamus and striatum. These models separated into three distinct clusters, two of which can be linked to the under and over-connectivity found in autism. These clusters also identified previously unknown connections between Nrxn1α, En2 and Fmr1; Nlgn3, BTBR and Slc6A4; and also between X monosomy and Mecp2. With no single treatment for autism found, clustering autism using neuroanatomy and identifying these strong connections may prove to be a crucial step in predicting treatment response.