Pandemic lockdowns: who feels coerced and why? - a study on perceived coercion, perceived pressures and procedural justice during the UK COVID-19 lockdowns.

BACKGROUND: This study examined perceptions of coercion, pressures and procedural injustice and how such perceptions influenced psychological well-being in those who experienced a UK COVID-19 lockdown, with a view to preparing for the possibility of future lockdowns. METHODS: 40 individuals categorised as perceiving the lockdown(s) as either highly or lowly coercive took part in one of six asynchronous virtual focus groups (AVFGs). RESULTS: Using thematic analysis, the following key themes were identified in participants' discussions: (1) Choice, control and freedom; (2) threats; (3) fairness; (4) circumstantial factors; and (5) psychological factors. CONCLUSIONS: As the first qualitative study to investigate the psychological construct of perceived coercion in relation to COVID-19 lockdowns, its findings suggest that the extent to which individuals perceived pandemic-related lockdowns as coercive may have been linked to their acceptance of restrictions. Preparing for future pandemics should include consideration of perceptions of coercion and efforts to combat this, particularly in relation to differences in equity, in addition to clarity of public health messaging and public engagement.

The Role of Noncoding Variants in Heritable Disease.

The genetic basis of disease has largely focused on coding regions. However, it has become clear that a large proportion of the noncoding genome is functional and harbors genetic variants that contribute to disease etiology. Here, we review recent examples of inherited noncoding alterations that are responsible for Mendelian disorders or act to influence complex traits. We explore both rare and common genetic variants and discuss the wide range of mechanisms by which they affect gene regulation to promote disease. We also debate the challenges and progress associated with identifying and interpreting the functional and clinical significance of genetic variation in the context of the noncoding regulatory landscape.

Chronic ethanol induces a pro-inflammatory switch in interleukin-1ß regulation of GABAergic signaling in the medial prefrontal cortex of male mice.

Neuroimmune pathways regulate brain function to influence complex behavior and play a role in several neuropsychiatric diseases, including alcohol use disorder (AUD). In particular, the interleukin-1 (IL-1) system has emerged as a key regulator of the brain's response to ethanol (alcohol). Here we investigated the mechanisms underlying ethanol-induced neuroadaptation of IL-1ß signaling at GABAergic synapses in the prelimbic region of the medial prefrontal cortex (mPFC), an area responsible for integrating contextual information to mediate conflicting motivational drives. We exposed C57BL/6J male mice to the chronic intermittent ethanol vapor-2 bottle choice paradigm (CIE-2BC) to induce ethanol dependence, and conducted ex vivo electrophysiology and molecular analyses. We found that the IL-1 system regulates basal mPFC function through its actions at inhibitory synapses on prelimbic layer 2/3 pyramidal neurons. IL-1ß can selectively recruit either neuroprotective (PI3K/Akt) or pro-inflammatory (MyD88/p38 MAPK) mechanisms to produce opposing synaptic effects. In ethanol naïve conditions, there was a strong PI3K/Akt bias leading to a disinhibition of pyramidal neurons. Ethanol dependence produced opposite IL-1 effects - enhanced local inhibition via a switch in IL-1ß signaling to the canonical pro-inflammatory MyD88 pathway. Ethanol dependence also increased cellular IL-1ß in the mPFC, while decreasing expression of downstream effectors (Akt, p38 MAPK). Thus, IL-1ß may represent a key neural substrate in ethanol-induced cortical dysfunction. As the IL-1 receptor antagonist (kineret) is already FDA-approved for other diseases, this work underscores the high therapeutic potential of IL-1 signaling/neuroimmune-based treatments for AUD.

The Hunter-8 Scale Prehospital Triage Workflow for Identification of Large Vessel Occlusion and Brain Haemorrhage.

OBJECTIVE: The Hunter-8 prehospital stroke scale predicts large vessel occlusion in hyperacute ischemic stroke patients (LVO) at hospital admission. We wished to test its performance in the hands of paramedics as part of a prehospital triage algorithm. We aimed to determine (a) the proportion of patients identified by the Hunter-8 algorithm, receiving reperfusion therapies, (b) whether a call to stroke team improved this, and (c) performance for LVO detection using an expanded LVO definition. METHODS: A prehospital workflow combining pre-morbid functional status, time from symptom onset, and the Hunter-8 scale was implemented from July 2019. A telephone call to the stroke team was prompted for potential treatment candidates. Classic LVO was defined as a proximal middle cerebral artery (MCA-M1), terminal internal carotid artery, or tandem occlusion. Extended LVO added proximal MCA-M2 and basilar occlusions. RESULTS: From July 2019 to April 2021, there were 363 Hunter-8 activations, 320 analyzed: 181 (56.6%) had confirmed ischemic strokes, 13 (4.1%) transient ischemic attack, 91 (28.5%) stroke mimics, and 35 (10.9%) intracranial hemorrhage. Fifty-two patients (16.3%) received reperfusion therapies, 35 with Hunter-8 ≥ 8. The stroke doctor changed the final destination for 76 patients (23.7%), and five received reperfusion therapies. The AUCs for classic and extended LVO were 0.73 (95% CI 0.66-0.79) and 0.72 (95% CI 0.65-0.77), respectively. CONCLUSION: The Hunter-8 workflow resulted in 28.7% of confirmed ischemic stroke patients receiving reperfusion therapies, with no secondary transfers to the comprehensive stroke center. The role of communication with stroke team needs to be further explored.

Weight and BMI Patterns in a Biologicals-Treated IBD Cohort.

BACKGROUND: Biologic therapies are effective at inducing and maintaining remission in people with inflammatory bowel disease (IBD). Previous studies have associated TNF-a inhibitors with weight gain, however, it is unclear if this is a class-specific effect or a manifestation of good disease control. To clarify this issue, a retrospective study was undertaken to examine weight changes over time during therapy with different biologic agents. METHODS: Adult patients with IBD who received any biological therapy for at least 12 months, between 2008 and 2020, were identified at two specialised IBD services. Demographic, disease, and therapy-related data were examined. Weight change and patterns thereof were examined for each specific therapy and relationships amongst weight outcomes and various predictive factors explored. RESULTS: Of 294 patients (156 females), 165 received Infliximab (IFX), 68 Adalimumab (ADA), 36 Vedolizumab (VDZ) and 25 Ustekinumab (UST). There was a statistically significant weight gain over time in the IFX and VDZ groups and more weight gain in the IFX vs ADA and VDZ vs ADA at most time points. Three weight trajectories were identified: around 95% of patients had small weight loss or a modest weight gain but 5% of patients, most of whom were on IFX had marked weight gain (24.3 kg). Having a baseline high BMI, being female, having an initiation CRP ≤ 5 or albumin > 35 reduced the odds of major weight gain. CONCLUSION: Weight gain in biologic treated IBD patients appears to be associated with clinical factors (male gender, high CRP, low albumin) and therapy-specific factors.

Type I interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression.

Interferons (IFNs) are key regulators of a number of inflammatory conditions in which neutrophils play an important role in pathology, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), where type I IFNs are implicated in disease pathology. However, IFNs are usually generated in vivo together with other cytokines that also have immunoregulatory functions, but such interactions are poorly defined experimentally. We measured the effects of type I (IFN-α) IFN, elevated in both RA and SLE, on the functions of healthy neutrophils incubated in vitro in the absence and presence of proinflammatory cytokines typically elevated in inflammatory diseases [tumour necrosis factor (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF)]. IFN-α alone had no effect on neutrophil apoptosis; however, it abrogated the anti-apoptotic effect of GM-CSF (18 h, P < 0·01). The enhanced stability of the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1) and delayed activation of caspase activation normally regulated by GM-CSF were blocked by IFN-α: this effect was mediated, in part, by activation of p38 mitogen-activated protein kinase (MAPK). IFN-α alone also primed reactive oxygen species (ROS) production and maintained the transient priming effect of TNF-α for up to 4 h: it also down-regulated GM-CSF- and TNF-α-activated expression of chemokine (C-X-C motif) ligand (CXCL)1, CXCL2, CXCL3, CXCL8, CCL3 and CCL4 but, in contrast, increased the expression of CXCL10. These novel data identify complex regulatory signalling networks in which type I IFNs profoundly alter the response of neutrophils to inflammatory cytokines. This is likely to have important consequences in vivo and may explain the complexity and heterogeneity of inflammatory diseases such as RA, in which multiple cytokine cascades have been activated.

Slack as a virtual undergraduate dermatology community: a pilot study.

BACKGROUND: Dermatology is under-represented in UK undergraduate curricula, and with a diagnostic and educational toolkit that is heavily centred on face-to-face (F2F) clinical examination, dermatology education has been disproportionately affected by the COVID-19 pandemic. Online channel-based messaging apps such as Slack offer an opportunity to engage students in remote, multimodal collaborative learning by reproducing a classroom environment in the virtual space. AIM: To determine the feasibility, acceptability and proof of concept for an online Slack community in undergraduate dermatology education. METHODS: Undergraduate medical students participated in an online classroom for a 6-week programme encompassing case-based discussions, seminars and journal clubs. The platform was facilitated by junior doctors (n = 10) and patient educators (n = 6). Students and faculty completed a post-course evaluation. Students additionally completed a pre- and post-intervention dermatology quiz. Mixed methods analyses included quantitative analyses to explore data trends and qualitative phenomenographic analyses to assimilate key underlying themes. RESULTS: Students (n = 65) were enrolled to join the platform. The evaluation was completed by students (n = 52) from UK universities (n = 27). The majority of students (n = 27) interacted with the platform as passive observers (≤ 5 active interactions with the channel), with a small group (n = 4) of 'super-users' (≥ 100 active interactions). The overall quality of the course was described as 'excellent' by 96% of participants and 100% of faculty. CONCLUSION: A community-based online classroom can act as an enjoyable, acceptable and collaborative means of delivering dermatology education to undergraduate medical students. Its ease of use and supportive nature may also facilitate patient involvement. Such advances may provide vital safeguards against the reduction in F2F learning that has accompanied the COVID-19 pandemic.

The effect of advanced recovery room care on postoperative outcomes in moderate-risk surgical patients: a multicentre feasibility study.

Postoperative complications are common and may be under-recognised. It has been suggested that enhanced postoperative care in the recovery room may reduce in-hospital complications in moderate- and high-risk surgical patients. We investigated the feasibility of providing advanced recovery room care for 12-18 h postoperatively in the post-anaesthesia care unit. The primary hypothesis was that a clinical trial of advanced recovery room care was feasible. The secondary hypothesis was that this model may have a sustained impact on postoperative in-hospital and post-discharge events. This was a multicentre, prospective, feasibility before-and-after trial of moderate-risk patients (predicted 30-day mortality of 1-4%) undergoing non-cardiac surgery and who were scheduled for postoperative ward care. Patients were managed using defined assessment checklists and goals of care in an advanced recovery room care setting in the immediate postoperative period. This utilised existing post-anaesthesia care unit infrastructure and staffing, but extended care until the morning of the first postoperative day. The advanced recovery room care trial was deemed feasible, as defined by the recruitment and per protocol management of > 120 patients. However, in a specialised cancer centre, recruitment was slow due to low rates of eligibility according to narrow inclusion criteria. At a rural site, advanced recovery room care could not be commenced due to logistical issues in establishing a new model of care. A definitive randomised controlled trial of advanced recovery room care appears feasible and, based on the indicative data on outcomes, we believe this is warranted.

A comparison of ultrasound guided bilateral single injection shot Erector Spinae Plane blocks versus wound infiltration for post-operative analgesia in laparoscopic assisted colonic surgery- a prospective randomised study.

BACKGROUND: Both wound infiltration (WI) with local anaesthetic and Erector Spinae Plane block (ESPB) have been described for post-operative analgesia after abdominal surgery. This study compared the efficacy of WI versus ESPB for post-operative analgesia after laparoscopic assisted colonic surgery. METHODS: Seventy-two patients between 18 and 85 years of age undergoing elective surgery were randomised to receive either WI or ESPB. In the WI group a 40 ml bolus of 0.5% Ropivacaine, infiltrated at the ports and minimally invasive wound at subcutaneous and fascia layers. In the ESPB group at T8 level, under ultrasound guidance, a 22-gauge nerve block needle was passed through the Erector Spinae muscle to reach its fascia. A dose up to 40 ml of 0.5% Ropivacaine, divided into two equal volumes, was injected at each side. Both groups had a multimodal analgesic regime, including regular Paracetamol, dexamethasone and patient-controlled analgesia (PCA) with Fentanyl. The primary end point was a post-operative pain score utilising a verbal Numerical Rating Score (NRS, 0-10) on rest and coughing in the post anaesthetic care unit (PACU) and in the first 24 h. Secondary outcomes measured were: opioid usage, length of stay and any clinical adverse events. RESULTS: There was no significant treatment difference in PACU NRS at rest and coughing (p-values 0. 382 and 0.595respectively). Similarly, there were no significant differences in first 24 h NRS at rest and coughing (p-values 0.285 and 0.431 respectively). There was no significant difference in Fentanyl use in PACU or in the first 24 h (p- values 0.900 and 0.783 respectively). Neither was there a significant difference found in mean total Fentanyl use between ESPB and WI groups (p-value 0.787). CONCLUSION: Our observations found both interventions had an overall similar efficacy. TRIAL REGISTRATION: The study was registered with the Australian New Zealand Clinical Trial Registry (ACTRN: 12619000113156 ).

2020 European guideline on the management of genital molluscum contagiosum.

Molluscum contagiosum is a benign viral epidermal infection associated with high risk of transmission. The guideline is focused on the sexually transmitted molluscum contagiosum. The diagnosis is clinical with characteristic individual lesions, termed 'mollusca', seen as dome-shaped, smooth-surfaced, pearly, firm, skin-coloured, pink, yellow or white papules, 2 - 5 mm in diameter with central umbilication. Dermoscopy may facilitate diagnosis. Therapeutic options are numerous, including physical treatments (cautery, curettage and cryotherapy), topical chemical treatments (e.g. podophyllotoxin and imiquimod) or waiting for spontaneous resolution in immunocompetent patients. In pregnancy, it is safe to use physical procedures (e.g. cryotherapy). Immunosuppressed patients develop severe and recalcitrant molluscum lesions that may require treatment with cidofovir, imiquimod or interferon. Patients with molluscum contagiosum infection should be offered to be screened for other sexually transmitted infections.

VA Home Based Primary Care Teams: Partnering with and Acting as Caregivers for Veterans.

The U.S. Department of Veterans Affairs' Home-Based Primary Care (HBPC) Interdisciplinary Team (IDT) provides in-home, primary care for medically complex Veterans. This study explores how HBPC and Veterans' caregivers partner to provide care. Interviews, focus groups, and field observations were conducted during eight HBPC site visits. Qualitative thematic analysis was performed. Caregivers/IDT member partnerships are important to care. Effective partnerships include: ease of communication; caregiver-centered support; and when no caregiver is present, IDTs providing more monitoring/services to Veterans and connection to community services. As this model expands, understanding dynamics between IDT members and caregivers will optimize the success of HBPC programs.

APPA (apocynin and paeonol) modulates pathological aspects of human neutrophil function, without supressing antimicrobial ability, and inhibits TNFα expression and signalling.

Neutrophils are key players in the pathophysiological process underlying inflammatory conditions not only by release of tissue-damaging cytotoxic enzymes, reactive oxygen species (ROS) but also by secretion of important immunomodulatory chemokines and cytokines. Here, we report the effects of the novel agent APPA, undergoing formal clinical development for treatment of osteoarthritis, and its constituent components, apocynin (AP) and paeonol (PA) on a number of neutrophil functions, including effects on TNFα- expression and signalling. Neutrophils were treated with APPA (10-1000 µg/mL) prior to the measurement of cell functions, including ROS production, chemotaxis, apoptosis and surface receptor expression. Expression levels of several key genes and proteins were measured after incubation with APPA and the chromatin re-modelling agent, R848. APPA did not significantly affect phagocytosis, bacterial killing or expression of surface receptors, while chemotactic migration was affected only at the highest concentrations. However, APPA down-regulated neutrophil degranulation and ROS levels, and decreased the formation of neutrophil extracellular traps. APPA also decreased cytokine-stimulated gene expression, inhibiting both TNFα- and GM-CSF-induced cell signalling. APPA was as effective as infliximab in down-regulating chemokine and IL-6 expression following incubation with R848. Whilst APPA does not interfere with neutrophil host defence against infections, it does inhibit neutrophil degranulation, and cytokine-driven signalling pathways (e.g. autocrine signalling and NF-κB activation), processes that are associated with inflammation. These observations may explain the mechanisms by which APPA exerts anti-inflammatory effects and suggests a potential therapeutic role in inflammatory diseases in which neutrophils and TNFα signalling are important in pathology, such as rheumatoid arthritis.

Bone marrow lesions in knee osteoarthritis: regional differences in tibial subchondral bone microstructure and their association with cartilage degeneration.

OBJECTIVE: The aim of this study was to investigate how bone microstructure within bone marrow lesions (BMLs) relates to the bone and cartilage across the whole human tibial plateau. DESIGN: Thirty-two tibial plateaus from patients with osteoarthritis (OA) at total knee arthroplasty and eleven age-matched non-OA controls, were scanned ex vivo by MRI to identify BMLs and by micro CT to quantitate the subchondral (plate and trabecular) bone microstructure. For cartilage evaluation, specimens were processed histologically. RESULTS: BMLs were detected in 75% of the OA samples (OA-BML), located predominantly in the anterior-medial (AM) region. In contrast to non-OA control and OA-no BML, in OA-BML differences in microstructure were significantly more evident between subregions. In OA-BML, the AM region contained the most prominent structural alterations. Between-group comparisons showed that the AM region of the OA-BML group had significantly higher histological degeneration (OARSI grade) (P < .0001, P < .05), thicker subchondral plate (P < .05, P < .05), trabeculae that are more anisotropic (P < .0001, P < .05), well connected (P < .05, P = n.s), and more plate-like (P < 0.05, P < 0.05), compared to controls and OA-no BML at this site. Compared to controls, OA-no BML had significantly higher OARSI grade (P < .0001), and lower trabecular number (P < .05). CONCLUSION: In established knee OA, both the extent of cartilage damage and microstructural degeneration of the subchondral bone were dependent on the presence of a BML. In OA-no BML, bone microstructural alterations are consistent with a bone attrition phase of the disease. Thus, the use of BMLs as MRI image-based biomarkers appear to inform on the degenerative state within the osteochondral unit.

Treatment with potassium bromide mitigates ataxia and reduces tremor in lambs with perennial ryegrass toxicosis.

Aims: To assess the use of potassium bromide (KBr) as a therapeutic intervention for perennial ryegrass toxicosis (PRGT) in lambs fed ryegrass seed containing lolitrem B. Methods: Male lambs aged 10-12 months (n = 43) were assigned to receive ryegrass seed containing lolitrem B, at a dose of 0.16 mg/kg/day (Groups 2, 3 and 4), or lucerne chaff and molasses (Groups 1 and 5). Lambs in Groups 2 and 3 were observed for clinical signs and gait changes until defined signs of PGRT were observed, when they were transferred, with lambs in Group 1, to the Testing phase of the trial. Lambs in Group 3 were then treated with a single oral dose of 300 mg/kg bromide. Lambs in Groups 4 and 5 received KBr daily from the start of the trial (540 mg/kg bromide over 3 days then 20 mg/kg daily) and were transferred to the Testing phase after 18 days. Clinical examination and gait assessment, and surface electromyography of the triceps muscle, measuring root-mean-square (RMS) voltages, were carried out on Days 0, 1 and 2 of the Testing phase followed by necropsy, histopathology, measurement of concentrations of bromide in serum and CSF and faecal cortisol metabolites (FCM). Results: In Group 3 lambs, mean composite gait scores decreased between Testing phase Day 0 and Days 1 and 2 (p < 0.001), but increased in lambs in Group 2 between Day 0 and Day 2 (p = 0.015). Scores for lambs in Group 3 on Day 2 were lower than for lambs in Group 2 (p < 0.001). Mean RMS voltages on Day 2 were higher in lambs in Group 2 than Group 3 (p = 0.045). Mean concentrations of bromide in serum were >800 µg/mL in lambs in Groups 3 and 4 on Day 2. Concentrations of FCM were higher in lambs from Group 2 than in Groups 1 or 5, but were similar in Groups 2, 3 and 4. Histopathological findings in the cerebellum of lambs from Groups 2, 3 and 4 were similar, showing pyknosis of neurons within the granular layer of the cerebellum and Purkinje neuron proximal axonal spheroid formation. Conclusions and clinical relevance: A single oral dose of 300 mg/kg bromide in lambs with neurological signs of PRGT resulted in reduced composite gait scores and reduced RMS voltages, indicating a significant improvement in clinical signs of ataxia, movement disorder and muscle tremor associated with the neurotoxic effects of lolitrem B.

The CDK inhibitor purvalanol A induces neutrophil apoptosis and increases the turnover rate of Mcl-1: potential role of p38-MAPK in regulation of Mcl-1 turnover.

Human neutrophils are terminally differentiated cells that do not replicate and yet express a number of enzymes, notably cell cycle-dependent kinases (CDKs), that are associated normally with control of DNA synthesis and cell cycle progression. In neutrophils, CDKs appear to function mainly to regulate apoptosis, although the mechanisms by which they regulate this process are largely unknown. Here we show that the CDK2 inhibitor, purvalanol A, induces a rapid decrease in myeloid cell leukaemia factor-1 (Mcl-1) levels in human neutrophils and peripheral blood mononuclear cells (PBMCs), but only induces apoptosis in neutrophils which are dependent upon expression on this protein for survival. This rapid decrease in cellular Mcl-1 protein levels was due to a purvalanol A-induced decrease in stability, with the half-life of the protein decreasing from approximately 2 h in control cells to just over 1 h after addition of the CDK2 inhibitor: it also blocked the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent stabilization of Mcl-1. Purvanalol A blocked GM-CSF-stimulated activation of extracellular-regulated kinase (Erk) and signal transducer and activator of transcription (STAT)-3, and stimulated an additive activation of protein kinase B (Akt) with GM-CSF. Purvalanol A alone stimulated a rapid and sustained activation of p38-mitogen-activated protein kinase (MAPK) and the pan p38-MAPK inhibitor, BIRB796, partly blocked the purvalanol A-induced apoptosis and Mcl-1 loss. These novel effects of purvalanol A may result, at least in part, from blocking GM-CSF-mediated Erk activation. In addition, we propose that purvalanol A-induced activation of p38-MAPK is, at least in part, responsible for its rapid effects on Mcl-1 turnover and acceleration of neutrophil apoptosis.

GSK2878175, a pan-genotypic non-nucleoside NS5B polymerase inhibitor, in healthy and treatment-naïve chronic hepatitis C subjects.

GSK2878175 is a potent, pan-genotypic, non-nucleoside, nonstructural protein 5B palm polymerase inhibitor being developed for the treatment of chronic hepatitis C (CHC). A first-in-human, randomized, placebo-controlled, dose escalation study, evaluated the safety and pharmacokinetics of GSK2878175 administered as single and repeat oral doses (once daily for 14 days) to healthy volunteers. A separate proof-of-concept, placebo-controlled, repeat dose (once daily for 2 days) study evaluated the safety, pharmacokinetics and antiviral activity of GSK2878175 monotherapy in treatment-naïve, noncirrhotic, subjects with hepatitis C virus (HCV) genotype 1 [1a and 1b], 2, or 3. No deaths or SAEs were reported in either study, and treatment was well-tolerated. Across all the HCV genotypes, GSK2878175 monotherapy at doses of 10, 30 or 60 mg once daily for 2 days produced a statistically significant multilog reduction (P<.001) in plasma HCV RNA log10 IU/mL from Baseline to 24, 48 and 72 hours after the first dose of GSK2878175 compared to placebo. The reduction in HCV RNA was sustained for a prolonged period across all of the active treatment groups, consistent with the long apparent half-life of GSK2878175 that was observed (mean t1/2 range: 60-63 hours in the CHC subjects). In summary, GSK2878175, when administered to healthy subjects and subjects with CHC, did not reveal any safety concerns that would limit or preclude further clinical development. GSK2878175 monotherapy across a wide dose range produced substantial reduction in HCV RNA, irrespective of HCV genotype. The results from these studies support further evaluation of GSK2878175-based regimens.

InP-based quantum cascade lasers monolithically integrated onto silicon.

Lasing is reported for ridge-waveguide devices processed from a 40-stage InP-based quantum cascade laser structure grown on a 6-inch silicon substrate with a metamorphic buffer. The structure used in the proof-of-concept experiment had a typical design, including an Al0.78In0.22As/In0.73Ga0.27As strain-balanced composition, with high strain both in quantum wells and barriers relative to InP, and an all-InP waveguide with a total thickness of 8 µm. Devices of size 3 mm x 40 µm, with a high-reflection back facet coating, emitted at 4.35 µm and had a threshold current of approximately 2.2 A at 78 K. Lasing was observed up to 170 K. Compared to earlier demonstrated InP-based quantum cascade lasers monolithically integrated onto GaAs, the same laser structure integrated on silicon had a lower yield and reliability. Surface morphology analysis suggests that both can be significantly improved by reducing strain for the active region layers relative to InP bulk waveguide layers surrounding the laser core.

Accuracy of genotype imputation in Labrador Retrievers.

The dog is a valuable model species for the genetic analysis of complex traits, and the use of genotype imputation in dogs will be an important tool for future studies. It is of particular interest to analyse the effect of factors like single nucleotide polymorphism (SNP) density of genotyping arrays and relatedness between dogs on imputation accuracy due to the acknowledged genetic and pedigree structure of dog breeds. In this study, we simulated different genotyping strategies based on data from 1179 Labrador Retriever dogs. The study involved 5826 SNPs on chromosome 1 representing the high density (HighD) array; the low-density (LowD) array was simulated by masking different proportions of SNPs on the HighD array. The correlations between true and imputed genotypes for a realistic masking level of 87.5% ranged from 0.92 to 0.97, depending on the scenario used. A correlation of 0.92 was found for a likely scenario (10% of dogs genotyped using HighD, 87.5% of HighD SNPs masked in the LowD array), which indicates that genotype imputation in Labrador Retrievers can be a valuable tool to reduce experimental costs while increasing sample size. Furthermore, we show that genotype imputation can be performed successfully even without pedigree information and with low relatedness between dogs in the reference and validation sets. Based on these results, the impact of genotype imputation was evaluated in a genome-wide association analysis and genomic prediction in Labrador Retrievers.

Development of a model for investigation of perennial ryegrass toxicosis in sheep.

AIMS To develop a clinical model of perennial ryegrass toxicosis (PRGT) based on feeding a known dose of lolitrem B and ergotamine, and to produce a consistent clinical presentation for assessment of disease pathophysiology, neurological changes and neurohistopathology. METHODS Male lambs, aged between 10-12 months, were randomly assigned to either Treatment (n=9) or Control (n=9) groups. Lambs in the Treatment group received feed containing a novel endophyte-infested perennial ryegrass seed, commencing on Day 0 of the Feeding phase with a low induction dose, then increasing after 3 days to provide 0.16 mg/kg live bodywight (LBW)/day of lolitrem B and 0.054 mg/kg LBW/day ergotamine. Lambs were examined daily and when defined signs of PRGT were observed they were transferred to the Testing phase. Neurological examinations, assessment of gait, surface electromyography (EMG) and mechanosensory nociceptive threshold testing were carried out and blood samples collected during both phases of the trial, with a full necropsy, histopathological examination and measurement of faecal cortisol metabolites (FCM) performed on Day 2 of the Testing phase. RESULTS Typical clinical signs of PRGT, including ataxia of vestibulocerebellar origin leading to stumbling, were observed in all Treatment lambs. The median interval from the start of the Feeding phase to entry into the Testing phase was 21 (min 18, max 34) days. Histopathological characterisation of neurological lesions included the presence of Purkinje cell vacuolation, pyknotic granular layer neurons and proximal axonal Purkinje cell spheroids. Lesions were most apparent within the vestibulocerebellum. Mean root-mean-square voltages from triceps EMG increased in Treatment lambs between Feeding phase Day 0 and Testing phase Day 2 (p<0.001). Daily water intake during the Testing phase for the Treatment group was less than in Control group lambs (p=0.002), and concentrations of FCM at necropsy were higher in Treatment compared to Control lambs (p=0.02). CONCLUSIONS AND CLINICAL RELEVANCE Lolitrem B and ergotamine dosing in feed on a live weight basis combined with neurological/gait assessment provides an effective model for investigation of PRGT and potential therapeutics. Assessment of gait changes using defined criteria and RMS voltages from EMG appear to be useful tools for the assessment of the severity of neurological changes.

Accuracy of self-report of HIV viral load among people with HIV on antiretroviral treatment.

OBJECTIVES: The aim of the study was to assess, among people living with HIV, knowledge of their latest HIV viral load (VL) and CD4 count. METHODS: Agreement between self-report and clinic record was assessed among 2771 HIV-diagnosed individuals on antiretroviral treatment (ART) in the UK Antiretrovirals, Sexual Transmission Risk and Attitudes Study (2011-2012). A confidential self-completed questionnaire collected information on demographic, socioeconomic, HIV-related and health-related factors. Participants were asked to self-report their latest VL [undetectable (≤ 50 copies/mL), detectable (> 50 copies/mL) or "don't know"] and CD4 count (< 200, 200-350, 351-500 or > 500 cells/µL, or "don't know"). Latest clinic-recorded VL and CD4 count were documented. RESULTS: Of 2678 participants on ART, 434 (16.2%) did not accurately report whether their VL was undetectable. Of 2334 participants with clinic-recorded VL ≤ 50 copies/mL, 2061 (88.3%) correctly reported undetectable VL; 49 (2.1%) reported detectable VL; 224 (9.6%) did not know their VL. Of 344 participants with clinic-recorded VL > 50 copies/mL, 183 (53.2%) correctly reported detectable VL; 76 (22.1%) reported undetectable VL; 85 (24.7%) did not know their VL. Of 2137 participants who reported undetectable VL, clinic-recorded VL was ≤ 50 copies/mL for 2061 (96.4%) and <1000 copies/mL for 2122 (99.3%). In analyses adjusted for gender/sexual orientation, ethnicity, age and time since starting ART, factors strongly associated with inaccurate self-report of VL (including "don't know") included socioeconomic disadvantage [prevalence ratio (95% CI) for "not" vs. "always" having enough money for basic needs: 2.4 (1.9, 3.1)], poor English fluency [3.5 (2.4, 5.1) vs. UK born], nondisclosure of HIV status [1.7 (1.3, 2.1)], ART nonadherence [2.1 (1.7, 2.7) for three or more missed doses vs. none in the past 2 weeks] and depressive symptoms (PHQ-9 score ≥ 10) [1.9 (1.6, 2.2)]. Overall, 612 (22.9%) of 2667 participants on ART did not accurately self-report whether or not their CD4 count was ≤ 350 cells/µL. CONCLUSIONS: There is a high level of accuracy of a self-report of undetectable VL in people on ART in the UK. Overall, accurate knowledge of personal VL level varied according to demographic, socioeconomic, HIV-related and health-related factors. Active identification of people who may benefit from increased levels of support and engagement in care is important.