Monthly engagement with EIP keyworkers was associated with a five-fold increase in the odds of engagement with psychosocial interventions.

BACKGROUND: Early intervention in psychosis (EIP) supports people who are experiencing their first episode of psychosis (FEP). A new Model of Care (MoC) for EIP services was launched in Ireland in 2019. Three EIP demonstration sites were chosen to test this MoC through a 'hub and spoke' approach. These services were a new way of organising care for people experiencing FEP, based upon a recovery model of care, and which sought to standardise care, improve access by clinically led multidisciplinary teams. This included newly created EIP keyworker roles whereby keyworkers assumed responsibilities regarding assessment, comprehensive individual care planning and coordination of care. METHODS: A mixed methods design utilising the UK Medical Research Council's process evaluation framework. Purposive sampling techniques were utilised. Descriptive analyses and logistic regression were performed to examine how increased keyworker engagement influenced the use of other psychosocial interventions within the EIP demonstration sites. Thematic analyses was used for qualitative data. RESULTS: There was a strong positive relationship between keyworker contacts and psychosocial interventions offered. Specifically, the odds of achieving at least monthly engagement with cognitive behavioural therapy for psychosis (CBTp; (5.76 (2.43-13.64), p < 0.001), and behavioural family therapy (BFT; (5.52(1.63-18.69, p < 0.006)) increased by fivefold with each additional monthly keyworker contact. For individual placement support (IPS) each additional monthly keyworker contact was associated with a three-fold increase in the odds of achieving monthly attendance with IPS (3.73 (1.64-8.48), p < 0.002). Qualitative results found that the EIP keyworker role as viewed by both service users and staff as a valuable nodal point, with a particular emphasis on care coordination and effective communication. CONCLUSIONS: This study advances the understanding of keyworker effects through qualitative evidence of keyworkers functioning as a "linchpin" to the service, while the positive response association between keyworker contacts and engagement with other services provides quantitative support for keyworkers reducing the organisational or structural barriers to service access. Given the importance of these positions, health systems should ensure that EIP programmes identify qualified and experienced staff to fill these roles, as well as allocate the appropriate funding and protected time to support keyworker engagement and impact.

Postoperative Radiologic Imaging in Secondary Alveolar Bone Grafting for Cleft Lip and Palate: A Systematic Review and Meta-Analysis.

INTRODUCTION: Radiographs (XRs), computed tomography (CT) scans, and cone-beam CT (CBCT) scans are utilized for assessment of secondary alveolar bone graft (SABG) in patients with cleft lip and palate (CLP). However, the optimal choice for imaging modality remains unclear. This study compares the image fidelity and safety profile for XR, CT, and CBCT in the assessment of patients with CLP who have undergone SABG. METHODS: Articles from MEDLINE and Elsevier Embase were screened. The primary outcome was graft success rate. Secondary outcomes were percent-by-volume of graft maintained and patient safety, defined by radiation exposure. A random effects model was used to calculate the pooled outcomes for each imaging modality. Chi-squared analysis was used to compare pooled outcomes between different imaging modalities. RESULTS: Of the 149 articles identified initially, 14 were included. Computed tomography exhibited a significantly higher image fidelity demonstrated by a lower graft success rate (62.0%) compared with both XR (72.6%, P<0.01) and CBCT (69.8%, P<0.01). Cone-beam CT had the lowest reported percent-by-volume of graft maintained (32.1%). Computed tomography had a higher mean radiation dosage (39.7 milligray) than what has been reported for both XR and CBCT. CONCLUSION: Computed tomography demonstrated lower graft success rates than both XR and CBCT, possibly indicating a higher image fidelity. However, compared with CBCT, CT may have a higher radiation exposure. Randomized trials and longitudinal studies are necessary to perform a direct comparison between CT and CBCT and to correlate the image fidelity of these modalities with clinical outcomes.

Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy.

BACKGROUND: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies. MATERIALS AND METHODS: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers. RESULTS: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an 'immune-desert' group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival. CONCLUSIONS: We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical 'termini a quo' (starting points) to support an improved precision immunotherapy treatment approach.

Barriers and facilitators to the implementation of an early intervention in psychosis service in three demonstration sites in Ireland.

BACKGROUND: Programmes for early intervention (EIP) in psychosis for people experiencing a first episode of psychosis (FEP) have been found to be both clinically and cost effective. Following the publication of a new EIP model of care (MoC) in Ireland, the aim of this research is to describe how people participated in and responded to the MoC including service users, family members, HSE clinical staff and HSE management. METHODS: Qualitative design using the UK Medical Research Council's process evaluation framework. Purposive sampling techniques were used. A total of N = 40 key informant semi-structured interviews were completed which included clinical staff (N = 22), health service managers and administrators (N = 9), service users (N = 8) and a family member (N = 1). Thematic analyses were conducted. RESULTS: Unique features of the EIP service (e.g., speed of referral/assessment, multidisciplinary approach, a range of evidence-based interventions and assertive MDT follow up) and enthusiasm for EIP were identified as two key factors that facilitated implementation. In contrast, obstacles to staff recruitment and budget challenges emerged as two primary barriers to implementation. CONCLUSIONS: The findings from this research provide real world insights into the complexity of implementing an innovative service within an existing health system. Clear and committed financial and human resource processes which allow new innovations to thrive and be protected during their initiation and early implementation phase are paramount. These elements should be considered in the planning and implementation of EIP services both nationally in Ireland and internationally.

Healthcare Workers Beliefs about COVID-19; a Longitudinal, Mixed Methods Analysis.

The psychological impact of COVID-19 on Health Care Workers (HCWs) has been widely reported. Few studies have sought to examine HCWs personal models of COVID-19 utilising an established theoretical framework. We undertook a mixed methods study of beliefs about COVID-19 held by HCWs in the Mid-West and South of Ireland during the first and third waves of COVID-19. Template analysis was undertaken on the free text responses of 408 HCWs about their perceptions of the Cause of COVID-19 as assessed by the Brief Illness Perception Questionnaire (B-IPQ). Responses were re-examined in the same cohort for stability at 3 months follow-up (n = 100). This analytic template was subsequently examined in a new cohort (n = 253) of HCWs in the third wave. Female HCWs perceived greater emotional impact of COVID-19 than men (t = -4.31, df405, p < 0.01). Differences between occupational groups were evident in relation to Timeline (F4,401 = 3.47, p < 0.01), Treatment Control (F4,401 = 5.64, p < 0.001) and Concerns about COVID-19 (F4,401 = 3.68, p < 0.01). Administration staff believed that treatment would be significantly more helpful and that COVID-19 would last a shorter amount of time than medical/nursing staff and HSCP. However, administration staff were significantly more concerned than HSCP about COVID-19. Template analysis on 1059 responses to the Cause items of the B-IPQ identified ten higher order categories of perceived Cause of COVID-19. The top two Causes identified at both Waves were 'individual behavioural factors' and 'overseas travel'. This study has progressed our understanding of the models HCWs hold about COVID-19 over time, and has highlighted the utility of the template analysis approach in analysing free-text questionnaire data. We suggest that group and individual occupational identities of HCWs may be of importance in shaping HCWs responses to working through COVID-19.

Is the Message Clear? Evaluation of Readability Levels for Cleft Lip, Cleft Palate, and Craniofacial Websites.

Web-based health information is the leading source of medical knowledge for patients and families. The American Medical Association (AMA) and US Department of Health and Human Services recommend reading material be at or below a sixth-grade reading level. This study aimed to evaluate and compare the readability of the most popularly searched cleft lip and/or palate (CL/P) and other craniofacial syndrome (CFS) websites.Google searches for "cleft lip," "cleft palate," and "craniofacial syndromes" were performed to identify the top 40 websites in an incognito window with the location set to the United States. Flesch Reading Ease Score (FRES) was used to determine ease of reading from 0 (most difficult) to 100 (greatest ease of reading) and Flesch-Kincaid Reading Grade (FKGL) for website content and compared between websites using an FRES of 80 to 90 and FKGL of 6.0 to 6.9 for a sixth-grade reading level.Readability was low for all sites with 6 CL/P websites and no CFS websites at or below a sixth-grade reading level. CL/P websites had FRES readability scores of 58.5 ± 12.3 and were at a 9.4 ± 2.3 grade level. CFS websites had readability scores on the FRES of 39.8 ± 13.1 and were at a 10.8 ± 1.8 grade level.Web-based information related to CL/P and CFS is on average several grade levels above the recommended sixth-grade reading level. Online information for CL/P and CFS may need to be revised to improve understanding for the public and families.

Knotted Transosseous-Equivalent Technique for Rotator Cuff Repair Shows Superior Biomechanical Properties Compared With a Knotless Technique: A Systematic Review and Meta-analysis.

PURPOSE: To compare the biomechanical properties of the knotted versus knotless transosseous-equivalent (TOE) techniques for rotator cuff repair (RCR). METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using PubMed, Embase, and the Cochrane Library to identify studies that compared the biomechanical properties of knotted and knotless TOE RCR techniques. The search phrase used was as follows: (Double Row) AND (rotator cuff) AND (repair) AND (biomechanical). Evaluated properties included ultimate load to failure, cyclic displacement, stiffness, footprint characteristics, and failure mode. RESULTS: Eight studies met the inclusion criteria, including a total of 67 specimens in each group. Of 6 studies reporting on ultimate load to failure, 4 found tendons repaired with the knotted TOE technique to experience significantly higher ultimate load to failure compared with knotless TOE repairs (knotted range, 323.5-549.0 N; knotless range, 166.0-416.8 N; P < .05). Of 6 studies reporting on failure stiffness, 2 found knotted TOE repairs to have significantly higher failure stiffness compared with knotless TOE repairs (knotted range, 30.0-241.8 N/mm; knotless range, 28.0-182.5 N/mm; P < .05), whereas 1 study found significantly higher failure stiffness in knotless TOE repairs compared with knotted TOE repairs (P = .039). Cyclic gap formation favored the knotted TOE group in 2 of 3 studies (knotted range, 0.6-5.2 mm; knotless range, 0.4-9.1 mm; P < .05). The most common mode of failure in both groups was suture tendon tear. CONCLUSIONS: On the basis of the included cadaveric studies, rotator cuff tendons repaired via the knotted TOE technique display superior time-zero biomechanical properties, including greater ultimate load to failure, compared with rotator cuffs repaired via the knotless TOE technique. Suture tearing through the tendon remains a common failure method for both techniques. CLINICAL RELEVANCE: The results of this systematic review provide helpful insight into the biomechanical differences between 2 popular techniques for RCR. Although these results should be carefully considered by surgeons who are using either of these techniques in the operating room, they should not be mistaken for direct clinical applicability because cadaveric studies may not directly correlate to clinical outcomes.

It Only Affects Me: Pharmaceutical Regulation and Harm to Others.

In her Pharmaceutical Freedom, Jessica Flanigan argues that antibiotics can be regulated consistent with her otherwise largely deregulatory view with respect to pharmaceuticals and recreational drugs. I contend in this essay that the reasons for justifying antibiotic regulation are reasons that can be offered to justify the regulation of many other drugs, both pharmaceutical and recreational. After laying out the specifics of Flanigan's view, I suggest that it is amenable to the regulation of drugs like varenicline. Though such drugs can legitimately improve the quality of a patient's life by helping them quit smoking, they could be permissibly regulated if they expose others to impermissible risks. I then argue that recreational drugs like alcohol could be regulated using the same reasoning. In the penultimate section of this essay, I anticipate objections that one might have to my extension of arguments favoring antibiotic regulation to drugs correlated with aggression. Flanigan might find my extrapolation of her view as entirely plausible and accept that her view is relatively friendly to these regulations, or she might reconsider her antibiotic caveat if these regulations are overly paternalistic on her understanding. I conclude by briefly considering the benefits and drawbacks of adopting each view.

Influence of innate immune activation on endocrine and metabolic pathways in infancy.

Prematurity is the leading cause of neonatal morbidity and mortality worldwide. Premature infants often require extended hospital stays, with increased risk of developing infection compared with term infants. A picture is emerging of wide-ranging deleterious consequences resulting from innate immune system activation in the newborn infant. Those who survive infection have been exposed to a stimulus that can impose long-lasting alterations into later life. In this review, we discuss sepsis-driven alterations in integrated neuroendocrine and metabolic pathways and highlight current knowledge gaps in respect of neonatal sepsis. We review established biomarkers for sepsis and extend the discussion to examine emerging findings from human and animal models of neonatal sepsis that propose novel biomarkers for early identification of sepsis. Future research in this area is required to establish a greater understanding of the distinct neonatal signature of early and late-stage infection, to improve diagnosis, curtail inappropriate antibiotic use, and promote precision medicine through a biomarker-guided empirical and adjunctive treatment approach for neonatal sepsis. There is an unmet clinical need to decrease sepsis-induced morbidity in neonates, to limit and prevent adverse consequences in later life and decrease mortality.

New hints towards a precision medicine strategy for IDH wild-type glioblastoma.

Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches.

Voltammetric Analysis of Redox Reactions and Ion Transfer in Water Microdroplets.

We report a set of voltammetric experiments for studying redox reactions and ion transfer in water microdroplets emulsified in 1,2-dichloroethane (DCE). The electrochemistry of microdroplets (rdrop ∼ 700 nm) loaded with either ferrocyanide ([Fe(CN)6]4-) or ferricyanide ([Fe(CN)6]3-), chosen due to their hydrophilic nature, was tracked using cyclic voltammetry. These heterogeneous reactions necessitated ion transfer at the droplet interface to maintain charge balance in the two liquid phases during oxidation or reduction, which was facilitated by the tetrabutylammonium perchlorate ([TBA][ClO4]) salt in the DCE phase. Experiments were performed with (1) a single macrodroplet (10-7 L) on a macroelectrode (r ∼ 1.5 mm), (2) millions of microdroplets (10-15 L) adsorbed on to a macroelectrode (r ∼ 1.5 mm), and (3) at the single microdroplet level via observing individual microdroplet collisions at an ultramicroelectrode (r ∼ 5 µm). We demonstrate that when millions of microdroplets are adsorbed onto a macroelectrode, there are two surprising observations: (1) the half-wave potential (E1/2) for the [Fe(CN)6]3-/4- redox couple shifts by +100 mV, which is shown to depend on the number of droplets on the electrode surface. (2) The reduction of [Fe(CN)6]3-, which is assisted by the transfer of TBA+ into the water droplet, displays two waves in the voltammogram. This dual-wave behavior can be explained by the formation of TBAxK3-xFe(CN)6, which is soluble in DCE. Additionally, we demonstrate that the adsorption of microdroplets onto an electrode surface offers significant amplification (×103) of the water/oil/electrode three-phase boundary when compared to the adsorption of larger macrodroplets, permitting a rigorous evaluation of heterogeneous chemistry at this distinct interface. In combination, these experiments provide new energetic and mechanistic insights for droplet systems, as well as reactivity differences between microscale and bulk multiphase systems.

Therapeutic Listening for Preterm Children with Sensory Dysregulation, Attention and Cognitive Problems.

Introduction Is Therapeutic Listening effective for children born preterm presenting with sensory dysregulation, attention and cognitive problems? Methods 22 children (BW<1500g) 3-4 years were enrolled in a single centre, prospective, assessor-blinded RTC. Outcome measures: Winnie-Dunn Sensory Profile; Peabody Developmental Motor Scales; Reynell Attention Scale; Preschool Language Scales - 3; RAPT; WPPSI - IV; Parent Review Questionnaires. Results The intervention group (n=9) showed better improvement in sensory processing, compared to controls (n=9) (6.4 fold improvement in sensation seeking; 5.0 in auditory processing; 4.0 in tactile processing). Six intervention children (67%) improved in vestibular processing. Attention levels improved for 9 (100%) children in the intervention group and for 7 (78%) in the control group. Higher level domains (Peabody motor skills, Auditory Comprehension, Expressive Communication, RAPT scale, and WPPSI scores) showed mixed results. Parents reported positive changes in their child's development. Conclusion Therapeutic Listening (TL) is a feasible intervention for preterm children to improve attention levels and sensory processing skills.

The Early Impact of COVID-19 on Urological Service Provision.

Aim COVID-19 has posed an unprecedented challenge to healthcare systems. We aimed to observe the impact on urological care delivery in an Irish university hospital. Methods Data on urological activity was prospectively collected for 3 months from March 2020. A retrospective review of the same period in 2019 was performed for control data. Results Over the 2020 study period, 356 urological admissions were recorded; a 23.1% decrease from the 2019 corresponding period(n=463). A 21.7% decrease in flexible cystoscopies was seen (162 versus 207). 125 theatre cases (36 off-site) were performed in the 2020 period, versus 151 in 2019. Emergency case load remained stable, with 69 cases in the 2020 period. The percentage of trainee-performed cases was preserved. COVID-era outpatient activity increased, to involve 559 clinic consultations compared to 439 the preceding year; a reflection of annual growth in service demand and facilitated by virtual clinic application (n=403). There were 490 instances of patients cancelling/failing to attend outpatient appointments, compared to 335 in 2019. Conclusion The Irish COVID-19 outbreak has created obstacles for urological care. Nonetheless, urgent/emergent urological cases persist. Our unit has managed this to-date with flexible adaptation of service delivery. The global challenge posed by COVID-19 will demand ongoing resourcefulness to minimise impact on patients with time-sensitive urological conditions.

Coupled Electron- and Phase-Transfer Reactions at a Three-Phase Interface.

Coupled electron- and phase-transfer reactions are fundamentally important in electrochemical energy conversion and storage, e.g., intercalation of Li+ in batteries and electrochemistry at the three-phase boundary in fuel cells. The mechanism, energetics, and kinetics of these complex reactions play an important role in device performance. Herein, we describe experimental methodology to quantitatively investigate coupled electron- and phase-transfer reactions at an individual, geometrically well-defined, three-phase interface. Specifically, a Pt-Ir wire electrode is placed across a H2O/1,2-dichloroethane (DCE) interface, creating a Pt-Ir/H2O/DCE boundary that is defined mathematically by a line around the surface of the wire. We investigated the oxidation of ferrocene (Fc), initially present in DCE (but essentially insoluble in water), at the three-phase boundary, and the transfer of its charged reaction product ferrocenium (Fc+) across the interface into the aqueous phase. In cyclic voltammetry, a reversible wave at E1/2 ∼ 0.58 V is observed for Fc oxidation in DCE on the first scan. The Fc+ produced near the H2O/DCE interface transfers into the aqueous phase. On the second and subsequent cycles, a second reversible wave at more negative potentials, E1/2 ∼ 0.33 V, is observed, corresponding to the reduction of Fc+ (and reoxidation back to Fc) in the aqueous phase. Finite-element simulations quantitatively capture the voltammetric response of coupled electron and phase transfer at the three-phase interface and indicate that the electrochemical response observed in the aqueous phase occurs within ∼200 µm of the Pt-Ir/H2O/DCE boundary. Finally, we demonstrate that the rate of transfer of Fc+ is strongly dependent on the concentration of supporting electrolyte, reaching a maximum at an intermediate electrolyte concentration, suggesting a critical role of the electric field distribution in determining the reaction rates at the three-phase interface.

Incubation periods of enteric illnesses in foodborne outbreaks, United States, 1998-2013.

Early in a foodborne disease outbreak investigation, illness incubation periods can help focus case interviews, case definitions, clinical and environmental evaluations and predict an aetiology. Data describing incubation periods are limited. We examined foodborne disease outbreaks from laboratory-confirmed, single aetiology, enteric bacterial and viral pathogens reported to United States foodborne disease outbreak surveillance from 1998-2013. We grouped pathogens by clinical presentation and analysed the reported median incubation period among all illnesses from the implicated pathogen for each outbreak as the outbreak incubation period. Outbreaks from preformed bacterial toxins (Staphylococcus aureus, Bacillus cereus and Clostridium perfringens) had the shortest outbreak incubation periods (4-10 h medians), distinct from that of Vibrio parahaemolyticus (17 h median). Norovirus, salmonella and shigella had longer but similar outbreak incubation periods (32-45 h medians); campylobacter and Shiga toxin-producing Escherichia coli had the longest among bacteria (62-87 h medians); hepatitis A had the longest overall (672 h median). Our results can help guide diagnostic and investigative strategies early in an outbreak investigation to suggest or rule out specific etiologies or, when the pathogen is known, the likely timeframe for exposure. They also point to possible differences in pathogenesis among pathogens causing broadly similar syndromes.

Does locally delivered small group continuing medical education (CME) meet the learning needs of rural general practitioners?

The World Health Organisation policy of improving retention of rural health care practitioners recommended that continuing medical education (CME) programmes addressing their needs should be accessible and delivered where they live and work. This cross-sectional study involved a self-administered anonymous questionnaire completed by GPs attending CME small groups (CME-SGL) in Ireland. All GPs attending CME-SGL in a one-month period were invited to complete the questionnaire which examined demographic details, distance to travel to educational meetings/nearest regional hospital, barriers to accessing continuing education, whether CME-SGL met their educational needs, morale and professional isolation. A total of 1,686 responses were collected, of which 332 (19.6%) were from rural GPs. Of these, 289 (87%) reported that their educational needs were fully or mostly met by attending CME-SGL. Compared to urban doctors, rural GPs had further to travel to CME-SGL meetings, were further from the nearest regional hospital, and reported increased barriers to accessing continuing education. Rural GPs reported lower morale and greater levels of professional isolation. Despite considerable barriers to accessing continuing education, rural GPs reported that CME-SGL meets their educational needs. Future research should focus on the potential positive impact this may have on professional isolation and morale.

In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence.

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [11C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1-4 days (n=14) or 24 days (n=1) after their last drink. Linear mixed modeling of partial-volume-corrected [11C]PBR28 data revealed a main effect of alcohol dependence (P=0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P<0.035). Peripheral immune response was assessed in a subset of subjects by measuring cytokine expression from monocytes cultured both in the presence and absence of lipopolysaccharide. Peripheral monocyte response to lipopolysaccharide stimulation was lower in alcohol-dependent subjects compared with controls for the proinflammatory cytokines interleukin-6 and interleukin-8. Thus, alcohol-dependent individuals exhibited less activated microglia in the brain and a blunted peripheral proinflammatory response compared with controls. These findings suggest a role for pharmaceuticals tuning the neuroimmune system as therapeutics for alcohol dependence.

IFNL3/4 genotype is associated with altered immune cell populations in peripheral blood in chronic hepatitis C infection.

Single-nucleotide polymorphisms near the interferon lambda 3 (IFNL3) gene predict outcomes to infection and anti-viral treatment in hepatitis C virus (HCV) infection. To identify IFNL3 genotype effects on peripheral blood, we collected phenotype data on 400 patients with genotype 1 chronic hepatitis C (CHC). The IFNL3 responder genotype predicted significantly lower white blood cells (WBCs), as well as lower absolute numbers of monocytes, neutrophils and lymphocytes for both rs8099917 and rs12979860. We sought to define the WBC subsets driving this association using flow cytometry of 67 untreated CHC individuals. Genotype-associated differences were seen in the ratio of CD4CD45RO+ to CD4CD45RO-; CD8CD45RO+ to CD8CD45RO-, NK CD56 dim to bright and monocyte numbers and percentages. Whole blood expression levels of IFNL3, IFNLR1 (interferon lambda receptor 1), IFNLR1-mem (a membrane-associated receptor), IFNLR1-sol (a truncated soluble receptor), MxA and T- and NK (natural killer) cell transcription factors TBX21, GATA3, RORC, FOXP3 and EOMES in two subjects were also determined. CHC patients demonstrated endogenous IFN activation with higher levels of MxA, IFNLR1, IFNLR1-mem and IFNLR1-sol, and IFNL3 genotype-associated differences in transcription factors. Taken together, these data provide evidence of an IFNL3 genotype association with differences in monocyte, T- and NK cell levels in the peripheral blood of patients with CHC. This could underpin genotype associations with spontaneous and treatment-induced HCV clearance and hepatic necroinflammation.

Matched pair analysis of laparoscopic versus open radical nephrectomy for the treatment of T3 renal cell carcinoma.

PURPOSE: The perioperative and oncological outcomes of laparoscopic radical nephrectomy (LRN) for T1-T2 renal cell carcinoma (RCC) are well established. We aim to determine whether LRN is a comparable alternative to open radical nephrectomy (ORN) in the treatment of T3 RCC using a matched pair analysis study design. METHODS: A review of a prospectively collected database at the Western General Hospital, Edinburgh, between 2000 and 2011 was conducted. Patient pairs were matched based on age at operation, gender, histological subgroup, maximal tumour diameter, TNM stage and grade. Patient demographics, operative and post-operative outcomes were compared. Overall, cancer-specific and progression-free survival [overall survival, cancer-specific survival (CSS) and progression-free survival (PFS)] were estimated using the Kaplan-Meier method. RESULTS: From 252 patients with T3 disease, 25 pairs were matched. Patients were of median age 66.2 years, 64 % male. Tumours were all clear cell RCC, were stage pT3a (32 %) or pT3b and had maximal tumour diameters of 8.7 cm for LRN and 10.0 cm for ORN. Estimated blood loss (100 ml LRN; 650 ml ORN, p < 0.001) and length of post-operative hospital stay (4 days LRN: 9 days ORN, p < 0.001) were lower in the LRN group. Operation time and post-operative complication rates were comparable. CSS and PFS were comparable with a mean CSS of 91.3 months for LRN and 88.7 months for ORN. CONCLUSION: This study reports the longest median follow-up in a T3 LRN cohort. In matched patients, LRN has been shown to have a superior perioperative profile to ORN for the treatment of pT3a/b RCC, with no adverse effect on midterm oncological outcomes.

Treatment outcomes in a cohort of patients with mucosal-predominant pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV) is a rare autoimmune blistering condition. Treatment typically combines corticosteroids with another immunosuppressive agent, such as azathioprine, mycophenolate mofetil (MMF) or rituximab. AIM: This study aims to compare these second agents for their clinical efficacy and steroid-sparing effect. METHODS: This was a single-centre, retrospective observational cohort study of 21 patients with oral PV over a 6-year period, 18 of whom were newly diagnosed. Of the latter, the first 13 were initially given azathioprine, progressing to MMF and then rituximab on treatment failure, while the next five patients started directly on MMF. RESULTS: Of the 13 newly diagnosed patients, 2/13 were intolerant of azathioprine, and only 1/11 was controlled, with a median time to treatment failure (MTTF) of 254 days. MMF was given to 17 patients, either de novo (5) or after azathioprine (12), and was significantly more effective, controlling activity in 4/17 patients, and for a significantly longer time (MTTF 395 days, P = 0.019). All 13 patients failing MMF received rituximab, seven required a second dose, and three, a third dose. All patients responded, with 11/13 able to cease steroids. Control was maintained for a similar time to MMF (MTTF 364 days, P = NS). Rituximab also had the best steroid-sparing effect followed by MMF, then azathioprine. Side-effects were common with azathioprine, while the other two agents were well tolerated. CONCLUSION: Rituximab was the most effective of the three immunosuppressives for PV, although repeat dosing was frequently required. These observations have significant implications for the choice of drugs for this condition.