Risk-mitigating behaviours in people with inflammatory skin and joint disease during the COVID-19 pandemic differ by treatment type: a cross-sectional patient survey.

BACKGROUND: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. OBJECTIVES: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. METHODS: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. RESULTS: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. CONCLUSIONS: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients: results from a randomised phase III study.

BACKGROUND: The impact of rituximab on health-related quality of life (HRQoL) in primary central nervous system lymphoma patients is not well known. We determined the impact of rituximab added to standard high-dose methotrexate-based treatment on HRQoL in patients in a large randomised trial. PATIENTS AND METHODS: Patients from a large phase III trial (HOVON 105/ALLG NHL 24), randomly assigned to receive standard chemotherapy with or without rituximab and followed by 30 Gy whole brain radiotherapy (WBRT) in patients ≤60 years, completed the EORTC QLQ-C30 and QLQ-BN20 questionnaires before and during treatment, and up to 24 months of follow-up or progression. Differences between treatment arms over time in global health status, role functioning, social functioning, fatigue, and motor dysfunction were assessed. Differences ≥10 points were deemed clinically relevant. The effect of WBRT on HRQoL was analysed in irradiated patients. RESULTS: A total of 160/175 patients eligible for the HRQoL study completed at least one questionnaire and were included. Over time, scores improved statistically significantly and were clinically relevant in both arms. Between arms, there were no differences on any scale (range: -3.8 to +4.0). Scores on all scales were improved to a clinically relevant extent at 12 and 24 months compared with baseline in both arms, except for fatigue and motor dysfunction at 12 months (-7.4 and -8.8, respectively). In irradiated patients (n = 59), scores in all preselected scales, except motor dysfunction, remained stable up to 24 months compared with shortly after WBRT, overall mean difference ranging between 0.02 and 4.570. CONCLUSION: Compared with baseline, treatment resulted in improved HRQoL scores. The addition of rituximab to standard chemotherapy did not impact HRQoL over time. WBRT did not result in deterioration of HRQoL in the first 2 years.

Crop production in the USA is frequently limited by a lack of pollinators.

Most of the world's crops depend on pollinators, so declines in both managed and wild bees raise concerns about food security. However, the degree to which insect pollination is actually limiting current crop production is poorly understood, as is the role of wild species (as opposed to managed honeybees) in pollinating crops, particularly in intensive production areas. We established a nationwide study to assess the extent of pollinator limitation in seven crops at 131 locations situated across major crop-producing areas of the USA. We found that five out of seven crops showed evidence of pollinator limitation. Wild bees and honeybees provided comparable amounts of pollination for most crops, even in agriculturally intensive regions. We estimated the nationwide annual production value of wild pollinators to the seven crops we studied at over $1.5 billion; the value of wild bee pollination of all pollinator-dependent crops would be much greater. Our findings show that pollinator declines could translate directly into decreased yields or production for most of the crops studied, and that wild species contribute substantially to pollination of most study crops in major crop-producing regions.

Frequency-Dependent Squeezing for Advanced LIGO.

The first detection of gravitational waves by the Laser Interferometer Gravitational-Wave Observatory (LIGO) in 2015 launched the era of gravitational-wave astronomy. The quest for gravitational-wave signals from objects that are fainter or farther away impels technological advances to realize ever more sensitive detectors. Since 2019, one advanced technique, the injection of squeezed states of light, is being used to improve the shot-noise limit to the sensitivity of the Advanced LIGO detectors, at frequencies above ∼50 Hz. Below this frequency, quantum backaction, in the form of radiation pressure induced motion of the mirrors, degrades the sensitivity. To simultaneously reduce shot noise at high frequencies and quantum radiation pressure noise at low frequencies requires a quantum noise filter cavity with low optical losses to rotate the squeezed quadrature as a function of frequency. We report on the observation of frequency-dependent squeezed quadrature rotation with rotation frequency of 30 Hz, using a 16-m-long filter cavity. A novel control scheme is developed for this frequency-dependent squeezed vacuum source, and the results presented here demonstrate that a low-loss filter cavity can achieve the squeezed quadrature rotation necessary for the next planned upgrade to Advanced LIGO, known as "A+."

Drug survival of adalimumab, ustekinumab and secukinumab in patients with psoriasis: a prospective cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

BACKGROUND: Real-world biologic drug survival is an important proxy measure for effectiveness. Predictors of drug survival may help patients with psoriasis choose between biologic therapies. OBJECTIVES: (i) To assess the relative drug survival of adalimumab, ustekinumab and secukinumab in patients with psoriasis. (ii) To investigate predictors of biologic drug survival. METHODS: A prospective cohort study was performed in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2019. We performed survival analysis and fitted a flexible parametric survival model for biologic discontinuation due to ineffectiveness. RESULTS: In total 9652 patients were included: 5543 starting on adalimumab (57·4%), 991 on secukinumab (10·3%) and 3118 on ustekinumab (32·3%). The overall drug survivals of adalimumab, secukinumab and ustekinumab in year 1 were 0·78 [95% confidence interval (CI) 0·77-0·79], 0·88 (95% CI 0·86-0·91) and 0·88 (95% CI 0·87-0·89), respectively. The adjusted hazard ratios (adjHRs) for discontinuation of adalimumab and secukinumab compared with ustekinumab were 2·11 (95% CI 1·76-2·54) and 0·67 (95% CI 0·40-1·11), respectively. The presence of psoriatic arthritis predicted for survival in the adalimumab and secukinumab cohorts (adjHR 0·67, 95% CI 0·51-0·88 and 0·70, 95% CI 0·40-1·24, respectively), but for discontinuation in the ustekinumab cohort (adjHR 1·42, 95% CI 1·12-1·81). Previous exposure to biologic therapies predicted for discontinuation in the ustekinumab and secukinumab cohorts (adjHR 1·54, 95% CI 1·26-1·89 and 1·49, 95% CI 0·91-2·45, respectively) and for survival in the adalimumab cohort (adjHR 0·71, 95% CI 0·55-0·92). CONCLUSIONS: Secukinumab and ustekinumab have similar sustained drug survival, while adalimumab has a lower drug survival in patients with psoriasis. Psoriatic arthritis and previous biologic experience were predictors with differential effects between the biologic therapies. What is already known about this topic? There is conflicting evidence over the real-world drug survival of secukinumab in patients with psoriasis. Data from registries to date suggest that secukinumab has a lower drug survival than that reported from clinical trials. What does this study add? This study found that secukinumab and ustekinumab had similar sustained drug survival in the real world, while the drug survival of adalimumab was lower, suggesting that the real-world drug survival of secukinumab is higher than previously reported. We found that psoriatic arthritis and previous biologic experience had differential effects on drug discontinuation in the three biologic cohorts. These predictors may help patients and clinicians choose the most appropriate biologic therapy.

An international multidisciplinary consensus statement on fasting before procedural sedation in adults and children.

The multidisciplinary International Committee for the Advancement of Procedural Sedation presents the first fasting and aspiration prevention recommendations specific to procedural sedation, based on an extensive review of the literature. These were developed using Delphi methodology and assessment of the robustness of the available evidence. The literature evidence is clear that fasting, as currently practiced, often substantially exceeds recommended time thresholds and has known adverse consequences, for example, irritability, dehydration and hypoglycaemia. Fasting does not guarantee an empty stomach, and there is no observed association between aspiration and compliance with common fasting guidelines. The probability of clinically important aspiration during procedural sedation is negligible. In the post-1984 literature there are no published reports of aspiration-associated mortality in children, no reports of death in healthy adults (ASA physical status 1 or 2) and just nine reported deaths in adults of ASA physical status 3 or above. Current concerns about aspiration are out of proportion to the actual risk. Given the lower observed frequency of aspiration and mortality than during general anaesthesia, and the theoretical basis for assuming a lesser risk, fasting strategies in procedural sedation can reasonably be less restrictive. We present a consensus-derived algorithm in which each patient is first risk-stratified during their pre-sedation assessment, using evidence-based factors relating to patient characteristics, comorbidities, the nature of the procedure and the nature of the anticipated sedation technique. Graded fasting precautions for liquids and solids are then recommended for elective procedures based upon this categorisation of negligible, mild or moderate aspiration risk. This consensus statement can serve as a resource to practitioners and policymakers who perform and oversee procedural sedation in patients of all ages, worldwide.

Phenotypic switch to eczema in patients receiving biologics for plaque psoriasis: a systematic review.

The use of biologic therapies for the treatment of chronic plaque psoriasis has been linked to the development of atopic eczema, amongst other cutaneous adverse events. This can cause diagnostic confusion and create difficulty in the management of patients with plaque psoriasis. The main objective of this systematic review was to review all cases of eczema, including atopic eczema, reported in patients treated with biologics for chronic plaque psoriasis. PubMed, Medline and Embase databases were used to identify studies reporting eczema in patients treated with biologic therapy for chronic plaque psoriasis. A total of 92 patients were identified from 24 studies, with patients treated with either: adalimumab; etanercept; infliximab; ixekizumab; secukinumab; or ustekinumab. Factors common to some reported cases include: a prior history of atopy; eosinophilia; raised serum immunoglobulin E. Twenty-three had documented treatment outcomes; 14 had biologic therapy discontinued or switched. Management strategies included topical or oral corticosteroids, and treatment with alternative systemic agents such as ciclosporin or apremilast. This adverse event occurred in 1.0-12.1% of patients within trial data and observational studies. This review demonstrates that there are consistent reports of a switch to an atopic eczema phenotype from psoriasis in patients taking biologics inhibiting tumour necrosis factor alpha and the interleukin (IL)-17/IL-23 axis. The majority stopped the implicated biologic, but conservative management was successful in some cases. Those with an atopic diathesis may be more at risk. Elucidation of mechanisms and risk factors would contribute to optimal therapy selection for individual patients.

Risk of major cardiovascular events in patients with psoriasis receiving biologic therapies: a prospective cohort study.

BACKGROUND: The cardiovascular safety profile of biologic therapies used for psoriasis is unclear. OBJECTIVES: To compare the risk of major cardiovascular events (CVEs; acute coronary syndrome, unstable angina, myocardial infarction and stroke) in patients with chronic plaque psoriasis treated with adalimumab, etanercept or ustekinumab in a large prospective cohort. METHODS: Prospective cohort study examining the comparative risk of major CVEs was conducted using the British Association of Dermatologists Biologics and Immunomodulators Register. The main analysis compared adults with chronic plaque psoriasis receiving ustekinumab with tumour necrosis-α inhibitors (TNFi: etanercept and adalimumab), whilst the secondary analyses compared ustekinumab, etanercept or methotrexate against adalimumab. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using overlap weights by propensity score to balance baseline covariates among comparison groups. RESULTS: We included 5468 biologic-naïve patients subsequently exposed (951 ustekinumab; 1313 etanercept; and 3204 adalimumab) in the main analysis. The secondary analyses also included 2189 patients receiving methotrexate. The median (p25-p75) follow-up times for patients using ustekinumab, TNFi, adalimumab, etanercept and methotrexate were as follows: 2.01 (1.16-3.21), 1.93 (1.05-3.34), 1.94 (1.09-3.32), 1.92 (0.93-3.45) and 1.43 (0.84-2.53) years, respectively. Ustekinumab, TNFi, adalimumab, etanercept and methotrexate groups had 7, 29, 23, 6 and 9 patients experiencing major CVEs, respectively. No differences in the risk of major CVEs were observed between biologic therapies [adjusted HR for ustekinumab vs. TNFi: 0.96 (95% CI 0.41-2.22); ustekinumab vs. adalimumab: 0.81 (0.30-2.17); etanercept vs. adalimumab: 0.81 (0.28-2.30)] and methotrexate against adalimumab [1.05 (0.34-3.28)]. CONCLUSIONS: In this large prospective cohort study, we found no significant differences in the risk of major CVEs between three different biologic therapies and methotrexate. Additional studies, with longer term follow-up, are needed to investigate the potential effects of biologic therapies on incidence of major CVEs.

Evaluating networked drug checking services in Toronto, Ontario: study protocol and rationale.

BACKGROUND: The increasing incidence of fatal opioid overdose is a public health crisis in Canada. Given growing consensus that this crisis is related to the presence of highly potent opioid adulterants (e.g., fentanyl) in the unregulated drug supply, drug checking services (DCS) have emerged as part of a comprehensive approach to overdose prevention. In Canada's largest city, Toronto, a network of DCS launched in 2019 to prevent overdose and overdose-related risk behaviors. This network employs mass spectrometry technologies, with intake sites co-located with supervised consumption services (SCS) at three frontline harm reduction agencies. The protocol and rationale for assessing the impact of this multi-site DCS network in Toronto is described herein. The aims of this study are to (1) evaluate the impact of DCS access on changes in and factors influencing overdose and related risk behaviors, (2) investigate the perceived capacity of DCS to prevent overdose, and (3) identify composition (qualitative and quantitative) trends in Toronto's unregulated drug supply. METHODS: We will use a parallel-mixed-methods design with complementary data sources (including data from chemical analysis of drug samples, quantitative intake and post-test surveys, SCS, coroners, paramedic services, and qualitative interviews), followed by a meta-inference process wherein results from analyses are synthesized. RESULTS: Whereas most DCS globally target "recreational drug users," in Toronto, this networked DCS will primarily target marginalized people who use drugs accessing frontline services, many of whom use drugs regularly and by injection. This evolution in the application of DCS poses important questions that have not yet been explored, including optimal service delivery models and technologies, as well as unique barriers for this population. Increasing information on the unregulated drug supply may modify the risk environment for this population of people who use drugs. CONCLUSIONS: This study addresses evidence gaps on the emerging continuum of overdose prevention responses and will generate critical evidence on a novel approach to reducing the ongoing high incidence of drug-related morbidity and mortality in Canada and elsewhere.

Identifying demographic, social and clinical predictors of biologic therapy effectiveness in psoriasis: a multicentre longitudinal cohort study.

BACKGROUND: Biologic therapies have revolutionized the treatment of moderate-to-severe psoriasis. However, for reasons largely unknown, many patients do not respond or lose response to these drugs. OBJECTIVES: To evaluate demographic, social and clinical factors that could be used to predict effectiveness and stratify response to biologic therapies in psoriasis. METHODS: Using a multicentre, observational, prospective pharmacovigilance study (BADBIR), we identified biologic-naive patients starting biologics with outcome data at 6 (n = 3079) and 12 (n = 3110) months. Associations between 31 putative predictors and outcomes were investigated in univariate and multivariable regression analyses. Potential stratifiers of treatment response were investigated with statistical interactions. RESULTS: Eight factors associated with reduced odds of achieving ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) at 6 months were identified (described as odds ratio and 95% confidence interval): demographic (female sex, 0·78, 0·66-0·93); social (unemployment, 0·67, 0·45-0·99); unemployment due to ill health (0·62, 0·48-0·82); ex- and current smoking (0·81, 0·66-0·99 and 0·79, 0·63-0·99, respectively); clinical factors (high weight, 0·99, 0·99-0·99); psoriasis of the palms and/or soles (0·75, 0·61-0·91); and presence of small plaques only compared with small and large plaques (0·78, 0·62-0·96). White ethnicity (1·48, 1·12-1·97) and higher baseline PASI (1·04, 1·03-1·04) were associated with increased odds of achieving PASI 90. The findings were largely consistent at 12 months. There was little evidence for predictors of differential treatment response. CONCLUSIONS: Psoriasis phenotype and potentially modifiable factors are associated with poor outcomes with biologics, underscoring the need for lifestyle management. Effect sizes suggest that these factors alone cannot inform treatment selection.

Development and validation of a multivariable risk prediction model for serious infection in patients with psoriasis receiving systemic therapy.

BACKGROUND: Patients with psoriasis are often concerned about the risk of serious infection associated with systemic psoriasis treatments. OBJECTIVES: To develop and externally validate a prediction model for serious infection in patients with psoriasis within 1 year of starting systemic therapies. METHODS: The risk prediction model was developed using the British Association of Dermatologists Biologic Interventions Register (BADBIR), and the German Psoriasis Registry PsoBest was used as the validation dataset. Model discrimination and calibration were assessed internally and externally using the C-statistic, the calibration slope and the calibration in the large. RESULTS: Overall 175 (1·7%) out of 10 033 participants from BADBIR and 41 (1·7%) out of 2423 participants from PsoBest developed a serious infection within 1 year of therapy initiation. Selected predictors in a multiple logistic regression model included nine baseline covariates, and starting infliximab was the strongest predictor. Evaluation of model performance showed a bootstrap optimism-corrected C-statistic of 0·64 [95% confidence interval (CI) 0·60-0·69], calibration in the large of 0·02 (95% CI -0·14 to 0·17) and a calibration slope of 0·88 (95% CI 0·70-1·07), while external validation performance was poor, with C-statistic 0·52 (95% CI 0·42-0·62), calibration in the large 0·06 (95% CI -0·25 to 0·37) and calibration slope 0·36 (95% CI -0·24 to 0·97). CONCLUSIONS: We present the first results of the development of a multivariable prediction model. This model may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision-making process.

A standardization approach to compare treatment safety and effectiveness outcomes between clinical trials and real-world populations in psoriasis.

BACKGROUND: Patients recruited in randomized controlled trials (RCTs) for biologic therapies in psoriasis are not fully representative of the real-world psoriasis population. OBJECTIVES: Firstly, to investigate whether patient characteristics are associated with being included in a psoriasis RCT. Secondly, to estimate the differences in the incidence of severe adverse events (SAEs) and the response rate between RCT and real-world populations of patients on biologic therapies for psoriasis using a standardization method. METHODS: Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) were appended to individual participant-level data from two RCTs assessing ustekinumab in patients with psoriasis. Baseline variables were assessed for association of being in an RCT using a multivariable logistic regression model. Propensity score weights were derived to reweigh the registry population so that variables had the distribution of the trial population. We measured the C-statistic of the model with trial status as the dependent variable, and the risk differences in the incidence rate of SAEs in the first year and Psoriasis Area and Severity Index (PASI) after 6 months in the BADBIR cohort before and after weighting. RESULTS: In total 6790 registry and 2021 RCT participants were included. The multivariable logistic regression model had a C-statistic of 0.82 [95% confidence interval (CI) 0.81-0.83]. The risk differences for the incidence rate of SAEs and the proportion of patients with PASI < 1.5 were 9.27 (95% CI -3.91-22.5) per 1000 person-years and 0.95 (95% CI -1.98-4.15), respectively. CONCLUSIONS: Our results suggest that RCTs of biologic therapies in patients with psoriasis are not fully representative of the real-world population, but this lack of external validity does not account for the efficacy-effectiveness gap. What's already known about this topic? Patients with psoriasis who would not be eligible for randomized controlled trials (RCTs) investigating biologic therapies have a greater risk of serious adverse events and lower treatment effectiveness than patients who would have been eligible. What does this study add? Baseline patient characteristics were shown to be predictive of whether a patient would have been eligible for enrolment in an RCT for psoriasis biologic therapy. We did not find any efficacy-effectiveness gap between the sample representative of the real-world population of patients with psoriasis and the sample representative of the RCT population. Factors outside of baseline patient characteristics, such as observer effect and higher adherence in RCTs, may be more influential in any efficacy-effectiveness gap between trial and real-world populations of patients with psoriasis.

Persistence and effectiveness of nonbiologic systemic therapies for moderate-to-severe psoriasis in adults: a systematic review.

BACKGROUND: The persistence and effectiveness of systemic therapies for moderate-to-severe psoriasis in current clinical practice are poorly characterized. OBJECTIVES: To systematically review observational studies investigating the persistence and effectiveness of acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate, involving at least 100 adult patients with moderate-to-severe psoriasis, exposed to therapy for ≥ 3 months. METHODS: MEDLINE, Embase, the Cochrane Library and PubMed were searched from 1 January 2007 to 1 November 2017 for observational studies reporting on persistence (therapy duration or the proportion of patients discontinuing therapy during follow-up) or effectiveness [improvements in Psoriasis Area and Severity Index (PASI) or Physician's Global Assessment (PGA)]. This review was registered with PROSPERO, number CRD42018099771. RESULTS: Of 411 identified studies, eight involving 4624 patients with psoriasis were included. Variations in the definitions and analyses of persistence and effectiveness outcomes prevented a meta-analysis from being conducted. One prospective multicentre study reported drug survival probabilities of 23% (ciclosporin), 42% (acitretin) and 50% (methotrexate) at 1 year. Effectiveness outcomes were not reported for either acitretin or ciclosporin. The persistence and effectiveness of FAE and methotrexate were better characterized, but mean discontinuation times ranged from 28 to 50 months for FAE and 7·7 to 22·3 months for methotrexate. At 12 months of follow-up, three studies reported that 76% (FAE), 53% (methotrexate) and 59% (methotrexate) of patients achieved ≥ 75% reduction in PASI, and one reported that 76% of FAE-exposed patients achieved a markedly improved or clear PGA. CONCLUSIONS: The comparative persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate in real-world clinical practice in the past decade cannot be well described due to the inconsistency of the methods used.

Incidence, characterization, and impact of newly detected donor-specific anti-HLA antibody in the first year after pediatric heart transplantation: A report from the CTOTC-04 study.

Data on the clinical importance of newly detected donor-specific anti-HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One-third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population. In the absence of preexisting DSAs, patients with ndDSAs had significantly more acute cellular rejection but not antibody-mediated rejection, and there was no impact on graft and patient survival in the first year posttransplantation. Risk factors for ndDSAs included common sensitizing events. Given the early detection of the antibody response, memory responses may be more important in the first year after pediatric heart transplantation and patients with a history of a sensitizing event may be at risk even with a negative pretransplantation antibody screen. The impact on late graft and patient outcomes of first-year ndDSAs is being assessed in an extended cohort of patients.

Pediatric heart transplantation across a positive crossmatch: First year results from the CTOTC-04 multi-institutional study.

Sensitization is common in pediatric heart transplant candidates and waitlist mortality is high. Transplantation across a positive crossmatch may reduce wait time, but is considered high risk. We prospectively recruited consecutive candidates at eight North American centers. At transplantation, subjects were categorized as nonsensitized or sensitized (presence of ≥1 HLA antibody with MFI ≥1000 using single antigen beads). Sensitized subjects were further classified as complement-dependent cytotoxicity crossmatch (CDC-crossmatch) positive or negative and as donor-specific antibodies (DSA) positive or negative. Immunosuppression was standardized. CDC-crossmatch-positive subjects also received perioperative antibody removal, maintenance corticosteroids, and intravenous immunoglobulin. The primary endpoint was the 1 year incidence rate of a composite of death, retransplantation, or rejection with hemodynamic compromise. 317 subjects were screened, 290 enrolled and 240 transplanted (51 with pretransplant DSA, 11 with positive CDC-crossmatch). The incidence rates of the primary endpoint did not differ statistically between groups; nonsensitized 6.7% (CI: 2.7%, 13.3%), sensitized crossmatch positive 18.2% (CI: 2.3%, 51.8%), sensitized crossmatch negative 10.7% (CI: 5.7%, 18.0%), P = .2354. The primary endpoint also did not differ by DSA status. Freedom from antibody-mediated and cellular rejection was lower in the crossmatch positive group and/or in the presence of DSA. Follow-up will determine if acceptable outcomes can be achieved long-term.

Risk of cancer in patients with psoriasis on biological therapies: a systematic review.

BACKGROUND: Biological therapies are highly effective in psoriasis, but have profound effects on innate and adaptive immune pathways that may negatively impact on cancer immunosurveillance mechanisms. OBJECTIVES: To investigate the risk of cancer in patients with psoriasis treated with biological therapy. METHODS: We searched MEDLINE, Embase, and the Cochrane Library (up to August 2016) for randomized controlled trials, prospective cohort studies and systematic reviews that reported cancer incidence in people exposed to biological therapy for psoriasis compared with a control population. RESULTS: Eight prospective cohort studies met our inclusion criteria. All the evidence reviewed related to tumour necrosis factor inhibitors (TNFi) with the exception of one study on ustekinumab. An increased risk of nonmelanoma skin cancer (NMSC), particularly squamous cell carcinoma, was reported with TNFi compared with both a general United States population and a rheumatoid arthritis population treated with TNFi. No evidence for increased risk of cancers (reported as all cancers, lymphoma, melanoma, prostate, colorectal and breast cancer) other than NMSC was identified. CONCLUSIONS: There were important limitations to the studies identified including choice of comparator arms, inadequate adjustment for confounding factors and failure to account for latency periods of cancer. There remains a need for ongoing pharmacovigilance in relation to cancer risk and biological therapy; the NMSC signal requires further investigation to determine the risk specifically attributable to biological therapy using prospectively collected data with adjustment for known NMSC risk factors.

Cumulative exposure to biological therapy and risk of cancer in patients with psoriasis: a meta-analysis of Psonet studies from Israel, Italy, Spain, the U.K. and Republic of Ireland.

BACKGROUND: Cancer risk following long-term exposure to systemic immunomodulatory therapies in patients with psoriasis is possible. OBJECTIVES: To assess a dose-response relationship between cumulative length of exposure to biological therapy and risk of cancer. METHODS: Four national studies (a healthcare database from Israel, and prospective cohorts form Italy, Spain and the U.K. and Republic of Ireland) collaborating through Psonet (European Registry of Psoriasis) participated in these nested case-control studies, including nearly 60 000 person-years of observation. 'Cases' were patients who developed an incident cancer. Patients with previous cancers and benign or in situ tumours were excluded. Four cancer-free controls were matched to each case on year of birth, sex, geographic area and registration year. Follow-up for controls was censored at the date of cancer diagnosis for the matched case. Conditional logistic regression was performed by each registry. Results were pooled using random-effects meta-analysis. RESULTS: A total of 728 cases and 2671 controls were identified. After matching, differences between cases and controls were present for the Charlson Comorbidity Index in all three registries, and in the prevalence of previous exposure to psoralen-ultraviolet A and smoking (the British Association of Dermatologists Biologic Interventions Register only). The risk of first cancers was not significantly associated with cumulative exposure to biologics (adjusted odds ratio per year of exposure 1·02, 95% confidence interval 0·92-1·13). Results were similar if squamous and basal cell carcinomas were included in the outcome. CONCLUSIONS: Cumulative length of exposure to biological therapies in patients with psoriasis in real-world clinical practice does not appear to be linked to a higher risk of cancer after several years of use.

Tracking and Reporting Outcomes Of Procedural Sedation (TROOPS): Standardized Quality Improvement and Research Tools from the International Committee for the Advancement of Procedural Sedation.

Many hospitals, and medical and dental clinics and offices, routinely monitor their procedural-sedation practices-tracking adverse events, outcomes, and efficacy in order to optimize the sedation delivery and practice. Currently, there exist substantial differences between settings in the content, collection, definition, and interpretation of such sedation outcomes, with resulting widespread reporting variation. With the objective of reducing such disparities, the International Committee for the Advancement of Procedural Sedation has herein developed a multidisciplinary, consensus-based, standardized tool intended to be applicable for all types of sedation providers in all locations worldwide. This tool is amenable for inclusion in either a paper or an electronic medical record. An additional, parallel research tool is presented to promote consistency and standardized data collection for procedural-sedation investigations.

Identification of factors that may influence the selection of first-line biological therapy for people with psoriasis: a prospective, multicentre cohort study.

BACKGROUND: The Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium has a collective aim to develop a prescribing algorithm to help stratify eligible patients with psoriasis to the most appropriate biological treatment. To facilitate the adoption of a stratified approach, it is necessary to first understand the factors driving the choice of first-line biological therapy. OBJECTIVES: To identify and quantify factors that influence the selection of the first-line biological therapy for people with psoriasis. METHODS: Multinomial logistic regression was used to determine the factors that influenced the probability of treatment selection, using data from the British Association of Dermatologists Biologic Interventions Register from January 2012 to December 2015. Sensitivity analyses were performed to assess the robustness of the findings to key assumptions. RESULTS: The main analysis was based on a dataset comprising 3040 people with psoriasis. The identified factors affecting first-line biological selection within the available therapies were: presence of psoriatic arthritis; patient weight; employment status; country of registration; and baseline disease severity. Importantly, the analysis showed a general shift in prescribing behaviour over time. These results were robust to sensitivity analysis. CONCLUSIONS: This study offers important insights into the factors influencing current prescribing practice for first-line biological therapies for people with psoriasis. It provides baseline data to inform the evaluation of future potential changes that may affect prescribing behaviour, such as stratified medicine.

Paediatric emergence delirium: a comprehensive review and interpretation of the literature.

There remain unanswered questions and implications related to emergence delirium in children. Although we know that there are some predisposing factors to emergence delirium, we still are unable to predict accurately those who are at greatest risk. Emergence delirium should be considered as a 'vital sign', which should be followed and documented in every child in the postanaesthesia recovery period. Standardized screening tools should be adopted for paediatric emergence delirium.