Acute Kidney Injury and Renal Replacement Therapy in COVID-19 Versus Other Respiratory Viruses: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute kidney injury (AKI) is a potentially fatal complication of Coronavirus Disease-2019 (COVID-19). Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, to its viral receptor, angiotensin converting enzyme 2 (ACE2), results in viral entry and may cause AKI. OBJECTIVES: We performed a systematic review and meta-analysis of the frequencies of AKI and renal replacement therapy (RRT) in critically ill COVID-19 patients and compared those frequencies with patients who were infected by respiratory viruses that bind or downregulate ACE2 (ACE2-associated viruses) and viruses that do not bind nor downregulate ACE2 (non-ACE2-associated viruses). DESIGN: Systematic review and meta-analysis. SETTING: Observational studies on COVID-19 and other respiratory viral infections reporting AKI and RRT were included. The exclusion criteria were non-English articles, non-peer-reviewed articles, review articles, studies that included patients under the age of 18, studies including fewer than 10 patients, and studies not reporting AKI and RRT rates. PATIENTS: Adult COVID-19, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and influenza patients. MEASUREMENTS: We extracted the following data from the included studies: author, year, study location, age, sex, race, diabetes mellitus, hypertension, chronic kidney disease, shock, vasopressor use, mortality, intensive care unit (ICU) admission, ICU mortality, AKI, and RRT. METHODS: We systematically searched PubMed and EMBASE for articles reporting AKI or RRT. AKI was defined by authors of included studies. Critical illness was defined by ICU admission. We performed a random effects meta-analysis to calculate pooled estimates for the AKI and RRT rate within each virus group using a random intercept logistic regression model. RESULTS: Of 23 655 hospitalized, critically ill COVID-19 patients, AKI frequencies were not significantly different between COVID-19 patients (51%, 95% confidence interval [CI]: 44%-57%) and critically ill patients infected with ACE2-associated (56%, 95% CI: 37%-74%, P = .610) or non-ACE2-associated viruses (63%, 95% CI: 43%-79%, P = .255). Pooled RRT rates were also not significantly different between critically ill, hospitalized patients with COVID-19 (20%, 95% CI: 16%-24%) and ACE2-associated viruses (18%, 95% CI: 8%-33%, P = .747). RRT rates for both COVID-19 and ACE2-associated viruses were significantly different (P < .001 for both) from non-ACE2-associated viruses (49%, 95% CI: 44%-54%). After adjusting for shock or vasopressor use, AKI and RRT rates were not significantly different between groups. LIMITATIONS: Limitations of this study include the heterogeneity of definitions of AKI that were used across different virus studies. We could not match severity of infection or do propensity matching across studies. Most of the included studies were conducted in retrospective fashion. Last, we did not include non-English publications. CONCLUSIONS: Our findings suggest that viral ACE2 association does not significantly alter the rates of AKI and RRT among critically ill patients admitted to the ICU. However, the rate of RRT is lower in patients with COVID-19 or ACE2-associated viruses when compared with patients infected with non-ACE2-binding viruses, which might partly be due to the lower frequencies of shock and use of vasopressors in these two virus groups. Prospective studies are necessary to demonstrate whether modulation of the ACE2 axis with Renin-Angiotensin System inhibitors impacts the rates of AKI and whether they are beneficial or harmful in COVID-19 patients.

MISE EN CONTEXTE: L'insuffisance rénale aiguë (IRA) est une complication potentiellement mortelle de la maladie à coronavirus-2019 (COVID-19). Obligatoire du Coronavirus 2 du Syndrome Respiratoire Aigu Sévère (SARS-CoV-2), le virus responsable du COVID-19, à son récepteur, l'enzyme de conversion de l'angiotensine 2 (ACE2), entraîne une entrée virale et peut provoquer une IRA. OBJECTIFS DE L'ÉTUDE: Nous avons effectué une revue systématique et une méta-analyse des fréquences de l'IRA et de la thérapie de remplacement renal (RRT) chez les patients COVID-19 gravement malades et a comparé ces fréquences avec les patients qui ont été infectés par des voies respiratoires virus qui lient ou régulent négativement l'ACE2 (virus associés à l'ACE2) et les virus qui ne régulent pas négativement ni ne lient l'ACE2 (virus non associés à l'ACE2). CADRE ET TYPE D'ÉTUDE: Revue systématique et méta-analyse. Des études d'observation sur le COVID-19 et d'autres infections virales respiratoires signalant une AKI et une RRT ont été incluses. Les critères d'exclusion étaient des articles non anglophones, des articles non évalués par des pairs, des articles de revue, des études incluant des patients moins de 18 ans, les études incluant moins de 10 patients et les études ne rapportant pas les taux d'IRA et de RRT. PATIENTS: Adultes COVID-19, syndrome respiratoire aigu sévère (SRAS), syndrome respiratoire du Moyen-Orient (MERS) et malades de la grippe. MESURES: Nous avons extrait les données suivantes des études incluses : auteur, année, lieu de l'étude, âge, sexe, race, diabète sucré, hypertension, maladie rénale chronique, état de choc, utilisation de vasopresseurs, mortalité, admission en unité de soins intensifs (USI), Mortalité en soins intensifs, AKI et RRT. MÉTHODOLOGIE: Nous avons systématiquement recherché dans PubMed et EMBASE les articles rapportant AKI ou RRT. AKI a été défini par les auteurs des études incluses. La maladie grave a été définie par l'admission aux soins intensifs. Nous avons effectué une méta-analyse à effets aléatoires pour calculer estimations regroupées pour le taux d'IRA et de RRT au sein de chaque groupe de virus à l'aide d'un modèle de régression logistique d'interception aléatoire. RÉSULTATS: Sur 23 655 patients hospitalisés et gravement malades COVID-19, les fréquences AKI n'étaient pas significativement différentes entre patients COVID-19 (51 %, intervalle de confiance à 95 % [IC] : 44 %-57 %) et patients gravement malades infectés par l'ACE2 associé (56 %, IC à 95 % : 37 % à 74 %, P = 0,610) ou des virus non associés à l'ACE2 (63 %, IC à 95 % : 43 % à 79 %, P = 0,255). Tarifs RRT groupés n'étaient pas non plus significativement différents entre les patients hospitalisés gravement malades atteints de COVID-19 (20 %, IC à 95 % : 16 % à 24 %) et virus associés à l'ACE2 (18 %, IC à 95 % : 8 % à 33 %, P = 0,747). Taux de RRT pour les virus associés au COVID-19 et à l'ACE2 étaient significativement différents (P < 0,001 pour les deux) des virus non associés à l'ACE2 (49 %, IC à 95 % : 44 % à 54 %). Après ajustement pour le choc ou l'utilisation de vasopresseurs, les taux d'IRA et de RRT n'étaient pas significativement différents entre les groupes. LIMITES DE L'ÉTUDE: Les limites de cette étude incluent l'hétérogénéité des définitions de l'IRA qui ont été utilisées pour différents virus études. Nous n'avons pas pu faire correspondre la gravité de l'infection ou faire une correspondance de propension entre les études. La plupart des études incluses ont été menées de manière rétrospective. Enfin, nous n'avons pas inclus les publications non anglophones. CONCLUSIONS: Nos résultats suggèrent que l'association virale ACE2 ne modifie pas de manière significative les taux d'IRA et de RRT parmi les patients gravement malades admis aux soins intensifs. Cependant, le taux de RRT est plus faible chez les patients atteints de COVID-19 ou associés à l'ACE2 virus par rapport aux patients infectés par des virus ne se liant pas à l'ACE2, ce qui pourrait être dû en partie à la plus faible fréquences de choc et utilisation de vasopresseurs dans ces deux groupes de virus. Des études prospectives sont nécessaires pour démontrer si la modulation de l'axe ACE2 avec les inhibiteurs du système rénine-angiotensine a un impact sur les taux d'IRA et si ells sont bénéfiques ou nocifs chez les patients COVID-19.

Examining the Role of Microbiota in Emotional Behavior: Antibiotic Treatment Exacerbates Anxiety in High Anxiety-Prone Male Rats.

Intestinal microbiota are essential for healthy gastrointestinal function and also broadly influence brain function and behavior, in part, through changes in immune function. Gastrointestinal disorders are highly comorbid with psychiatric disorders, although biological mechanisms linking these disorders are poorly understood. The present study utilized rats bred for distinct emotional behavior phenotypes to examine relationships between emotionality, the microbiome, and immune markers. Prior work showed that Low Novelty Responder (LR) rats exhibit high levels of anxiety- and depression-related behaviors as well as myriad neurobiological differences compared to High Novelty Responders (HRs). Here, we hypothesized that the divergent HR/LR phenotypes are accompanied by changes in fecal microbiome composition. We used next-generation sequencing to assess the HR/LR microbiomes and then treated adult HR/LR males with an antibiotic cocktail to test whether it altered behavior. Given known connections between the microbiome and immune system, we also analyzed circulating cytokines and metabolic factors to determine relationships between peripheral immune markers, gut microbiome components, and behavioral measures. There were no baseline HR/LR microbiome differences, and antibiotic treatment disrupted the microbiome in both HR and LR rats. Antibiotic treatment exacerbated aspects of HR/LR behavior, increasing LRs' already high levels of anxiety-like behavior while reducing passive stress coping in both strains. Our results highlight the importance of an individual's phenotype to their response to antibiotics, contributing to the understanding of the complex interplay between gut microbes, immune function, and an individual's emotional phenotype.

The impact of pre-eclampsia definitions on the identification of adverse outcome risk in hypertensive pregnancy - analyses from the CHIPS trial (Control of Hypertension in Pregnancy Study).

OBJECTIVE: To examine the association between pre-eclampsia definition and pregnancy outcome. DESIGN: Secondary analysis of Control of Hypertension in Pregnancy Study (CHIPS) trial data. SETTING: International multicentre randomised controlled trial (RCT). POPULATION: In all, 987 women with non-severe non-proteinuric pregnancy hypertension. METHODS: We evaluated the association between pre-eclampsia definitions and adverse pregnancy outcomes, stratified by hypertension type and blood pressure control. MAIN OUTCOME MEASURES: Main CHIPS trial outcomes: primary (perinatal loss or high-level neonatal care for >48 hours), secondary (serious maternal complications), birthweight <10th centile, severe maternal hypertension, delivery at <34 or <37 weeks, and maternal hospitalisation before birth. RESULTS: Of 979/987 women with informative data, 280 (28.6%) progressed to pre-eclampsia defined restrictively by new proteinuria, and 471 (48.1%) to pre-eclampsia defined broadly as proteinuria or one/more maternal symptoms, signs or abnormal laboratory tests. The broad (versus restrictive) definition had significantly higher sensitivities (range 62-79% versus 36-50%), lower specificities (range 53-65% versus 72-82%), and similar or higher diagnostic odds ratios and 'true-positive' to 'false-positive' ratios. Stratified analyses showed similar results. Addition of available fetoplacental manifestations (stillbirth or birthweight <10th centile) to the broad pre-eclampsia definition improved sensitivity (74-87%). CONCLUSIONS: A broad (versus restrictive) pre-eclampsia definition better identifies women who develop adverse pregnancy outcomes. These findings should be replicated in a prospective study within routine healthcare to ensure that the anticipated increase in surveillance and intervention in a larger number of women with pre-eclampsia is associated with improved outcomes, reasonable costs and congruence with women's values. TWEETABLE ABSTRACT: A broad (versus restrictive) pre-eclampsia definition better identifies the risk of adverse pregnancy outcomes.

Measuring vaccine effectiveness against persistent HPV infections: a comparison of different statistical approaches.

BACKGROUND: Persistent high-risk human papillomavirus (HPV) infection is endorsed by the World Health Organization as an intermediate endpoint for evaluating HPV vaccine effectiveness/efficacy. There are different approaches to estimate the vaccine effectiveness/efficacy against persistent HPV infections. METHODS: We performed a systematic literature search in Pubmed to identify statistical approaches that have been used to estimate the vaccine effectiveness/efficacy against persistent HPV infections. We applied these methods to data of a longitudinal observational study to assess their performance and compare the obtained vaccine effectiveness (VE) estimates. RESULTS: Our literature search identified four approaches: the conditional exact test for comparing two independent Poisson rates using a binomial distribution, Generalized Estimating Equations for Poisson regression, Prentice Williams and Peterson total time (PWP-TT) and Cox proportional hazards regression. These approaches differ regarding underlying assumptions and provide different effect measures. However, they provided similar effectiveness estimates against HPV16/18 and HPV31/33/45 persistent infections in a cohort of young women eligible for routine HPV vaccination (range VE 93.7-95.1% and 60.4-67.7%, respectively) and seemed robust to violations of underlying assumptions. CONCLUSIONS: As the rate of subsequent infections increased in our observational cohort, we recommend PWP-TT as the optimal approach to estimate the vaccine effectiveness against persistent HPV infections in young women. Confirmation of our findings should be undertaken by applying these methods after longer follow-up in our study, as well as in different populations.

Cardiorespiratory fitness and accelerometer-determined physical activity following one year of free-living high-intensity interval training and moderate-intensity continuous training: a randomized trial.

BACKGROUND: Free-living adherence to high-intensity interval training (HIIT) has not been adequately tested. This randomized trial examined changes in cardiorespiratory fitness (CRF) and accelerometer-measured purposeful physical activity over 12 months of free-living HIIT versus moderate-intensity continuous training (MICT). METHODS: Ninety-nine previously low-active participants with overweight/obesity were randomly assigned to HIIT (n = 47) or MICT (n = 52). Both interventions were combined with evidence-based behaviour change counselling consisting of 7 sessions over 2 weeks. Individuals in HIIT were prescribed 10 X 1-min interval-based exercise 3 times per week (totalling 75 min) whereas individuals in MICT were prescribed 150 min of steady-state exercise per week (50 mins 3 times per week). Using a maximal cycling test to exhaustion with expired gas analyses, CRF was assessed at baseline and after 6 and 12 months of free-living exercise. Moderate-to-vigorous physical activity of 10+ minutes (MVPA10+) was assessed by 7-day accelerometry at baseline, 3, 6, 9, and 12 months. Intention to treat analyses were conducted using linear mixed models. RESULTS: CRF was improved over the 12 months relative to baseline in both HIIT (+ 0.15 l/min, 95% CI 0.08 to 0.23) and MICT (+ 0.11 l/min, 95% CI 0.05 to 0.18). Both groups improved 12-month MVPA10+ above baseline (HIIT: + 36 min/week, 95% CI 17 to 54; MICT: + 69 min/week, 95% CI 49 to 89) with the increase being greater (by 33 min, 95% CI 6 to 60) in MICT (between group difference, P = 0.018). CONCLUSION: Despite being prescribed twice as many minutes of exercise and accumulating significantly more purposeful exercise, CRF improvements were similar across 12 months of free-living HIIT and MICT in previously low-active individuals with overweight/obesity.

Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study.

OBJECTIVE: Dolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada. DESIGN: The Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies. SETTING: Paediatric HIV clinics. POPULATION: Live-born infants born in Canada to WLWH between 2007 and 2017. METHODS: Data on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites. MAIN OUTCOME MEASURES: Congenital anomalies. RESULTS: Of the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%). CONCLUSION: Despite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies. TWEETABLE ABSTRACT: Five percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects.

Neomycin-polymyxin or gentamicin bladder instillations decrease symptomatic urinary tract infections in neurogenic bladder patients on clean intermittent catheterization.

INTRODUCTION: Recurrent urinary tract infections (UTIs) are common in patients with neurogenic bladder (NGB) performing clean intermittent catheterization (CIC) treated with or without oral antibiotic prophylaxis. OBJECTIVE: The authors aim to determine if daily neomycin-polymyxin or gentamicin bladder instillations reduce the rate of symptomatic UTIs, the need for oral antibiotic prophylaxis, emergency department (ED) visits for UTI, and inpatient hospitalizations for UTI in patients with NGB on CIC. The authors also aim to investigate resistance patterns in urine microorganisms in patients treated with antibiotic bladder instillations. STUDY DESIGN: The authors retrospectively reviewed the records of all-age patients cared for in the pediatric urology clinic with NGB on CIC having symptomatic UTIs and on daily intravesical instillations of neomycin-polymyxin or gentamicin between 2013 and 2017. Symptomatic UTIs were defined as a positive urine culture with greater than 10,000 colony forming units/mL associated with one or more of the following patient complaints: cloudy/foul-smelling urine, fevers, chills, increase in bladder spasms, pain, urinary leakage, or physician decision for antibiotic treatment. Multidrug-resistant organisms were resistant to two or more classes of antibiotics. RESULTS: Fifty-two patients with a median age of 14.5 years and 192 distinct urine cultures were identified. 90.4% and 9.6% of patients received neomycin-polymyxin and gentamicin instillations, respectively. After initiation of intravesical antibiotics, the rate of symptomatic UTIs was reduced by 58% (incidence rate ratio [IRR]: 0.42, 95% confidence interval [CI]: 0.31-0.56; P < 0.001), the rate of ED visits was reduced by 54% (IRR: 0.46, 95% CI: 0.30-0.71; P < 0.001), and the rate of inpatient hospitalizations for UTI was reduced by 39% (IRR: 0.61, 95% CI: 0.37-0.98; P = 0.043). Fewer patients received oral antibiotic prophylaxis after initiation of antibiotic instillations (odds ratio: 0.12, 95% CI: 0.02-0.067; P = 0.016). There was a trend toward a decrease in multidrug resistance and no change in gentamicin resistance in urine microorganisms. DISCUSSION: This study describes a feasible alternative treatment for patients with NGB on CIC who have persistent UTIs despite oral antibiotic prophylaxis, and for some patients, it may suggest a possibility of discontinuing oral prophylaxis. Limitations include a retrospective design with a small cohort of patients and varying dosages of neomycin-polymyxin. CONCLUSIONS: Antibiotic bladder instillations appear to decrease frequency of symptomatic UTIs, ED visits for UTI, inpatient hospitalizations for UTI, and the need for oral antibiotic prophylaxis in patients with NGB on CIC. There was no increase in multidrug resistance or gentamicin resistance in UTI organisms with use of intravesical antibiotic instillation.

Implementation of tailored interventions in a statewide programme to reduce central line-associated bloodstream infections.

BACKGROUND: There have been few studies exploring implementation strategies to central line-associated bloodstream infections (CLABSIs) in low- or middle-income countries. AIM: To implement tailored interventions to reduce CLABSI rates in adult intensive care units. METHODS: The implementation strategy of the State Health Department was performed in São Paulo State, Brazil, over two cycles. Cycle 1 (56 hospitals) was exploratory and cycle 2 (77 hospitals) was designed to confirm the hypothesis generated by the first cycle, with three phases each (pre-intervention, intervention, post-intervention). Cycles included: evaluation of healthcare workers' knowledge, observation of practices, and CLABSI rates monthly report. In cycle 1, a log-normal mixed model was used to select variables significantly associated with the reduction of CLABSI. In cycle 2, CLABSI rates were evaluated. FINDINGS: Healthcare workers' practices improved after intervention. In cycle 1, reduction of CLABSI rates was more pronounced in hospitals with initial CLABSI rates >7.4 per 1000 catheter-days (P < 0.001) and those that introduced the use of peripherally inserted central catheters (P = 0.01). For hospitals with high CLABSI initial rates, simulation demonstrated that the rates were expected to decrease by 36% (95% CI: 9-63), no matter the type of intervention. In cycle 2, there was an overall decrease in CLABSI rates during the intervention period; whereas the mean rate fell further post-intervention, rates at the 90th percentile increased. CONCLUSION: The implementation strategy may have had an effect on infection rates independently of the specific interventions implemented; however, the sustainability of reduction in the post-intervention period remains a challenge.

Preclinical In Vitro and In Vivo Evaluation of [18F]FE@SUPPY for Cancer PET Imaging: Limitations of a Xenograft Model for Colorectal Cancer.

Molecular imaging probes such as PET-tracers have the potential to improve the accuracy of tumor characterization by directly visualizing the biochemical situation. Thus, molecular changes can be detected early before morphological manifestation. The A3 adenosine receptor (A3AR) is described to be highly expressed in colon cancer cell lines and human colorectal cancer (CRC), suggesting this receptor as a tumor marker. The aim of this preclinical study was the evaluation of [18F]FE@SUPPY as a PET-tracer for CRC using in vitro imaging and in vivo PET imaging. First, affinity and selectivity of FE@SUPPY and its metabolites were determined, proving the favorable binding profile of FE@SUPPY. The human adenocarcinoma cell line HT-29 was characterized regarding its hA3AR expression and was subsequently chosen as tumor graft. Promising results regarding the potential of [18F]FE@SUPPY as a PET-tracer for CRC imaging were obtained by autoradiography as ≥2.3-fold higher accumulation of [18F]FE@SUPPY was found in CRC tissue compared to adjacent healthy colon tissue from the same patient. Nevertheless, first in vivo studies using HT-29 xenografts showed insufficient tumor uptake due to (1) poor conservation of target expression in xenografts and (2) unfavorable pharmacokinetics of [18F]FE@SUPPY in mice. We therefore conclude that HT-29 xenografts are not adequate to visualize hA3ARs using [18F]FE@SUPPY.

AllergoOncology: Opposite outcomes of immune tolerance in allergy and cancer.

While desired for the cure of allergy, regulatory immune cell subsets and nonclassical Th2-biased inflammatory mediators in the tumour microenvironment can contribute to immune suppression and escape of tumours from immunological detection and clearance. A key aim in the cancer field is therefore to design interventions that can break immunological tolerance and halt cancer progression, whereas on the contrary allergen immunotherapy exactly aims to induce tolerance. In this position paper, we review insights on immune tolerance derived from allergy and from cancer inflammation, focusing on what is known about the roles of key immune cells and mediators. We propose that research in the field of AllergoOncology that aims to delineate these immunological mechanisms with juxtaposed clinical consequences in allergy and cancer may point to novel avenues for therapeutic interventions that stand to benefit both disciplines.

HLA Mismatching Favoring Host-Versus-Graft NK Cell Activity Via KIR3DL1 Is Associated With Improved Outcomes Following Lung Transplantation.

Chronic lung allograft dysfunction (CLAD) is linked to rejection and limits survival following lung transplantation. HLA-Bw4 recipients of HLA-Bw6 grafts have enhanced host-versus-graft (HVG) natural killer (NK) cell activity mediated by killer cell immunoglobulin-like receptor (KIR)3DL1 ligand. Because NK cells may promote tolerance by depleting antigen-presenting cells, we hypothesized improved outcomes for HLA-Bw4 recipients of HLA-Bw6 grafts. We evaluated differences in acute cellular rejection and CLAD-free survival across 252 KIR3DL1+ recipients from University of California, San Francisco (UCSF). For validation, we assessed survival and freedom from bronchiolitis obliterans syndrome (BOS), retransplantation, or death in 12 845 non-KIR typed recipients from the United Network for Organ Sharing (UNOS) registry. Cox proportional hazards models were adjusted for age, gender, ethnicity, transplant type, and HLA mismatching. HVG-capable subjects in the UCSF cohort had a decreased risk of CLAD or death (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.36-0.88) and decreased early lymphocytic bronchitis. The HVG effect was not significant in subjects with genotypes predicting low KIR3DL1 expression. In the UNOS cohort, HVG-capable subjects had a decreased risk of BOS, retransplant, or death (HR 0.95, 95% CI 0.91-0.99). Survival improved with the higher-affinity Bw4-80I ligand and in Bw4 homozygotes. Improved outcomes in HVG-capable recipients are consistent with a protective NK cell role. Augmentation of NK activity could supplement current immunosuppression techniques.

AllergoOncology - the impact of allergy in oncology: EAACI position paper.

Th2 immunity and allergic immune surveillance play critical roles in host responses to pathogens, parasites and allergens. Numerous studies have reported significant links between Th2 responses and cancer, including insights into the functions of IgE antibodies and associated effector cells in both antitumour immune surveillance and therapy. The interdisciplinary field of AllergoOncology was given Task Force status by the European Academy of Allergy and Clinical Immunology in 2014. Affiliated expert groups focus on the interface between allergic responses and cancer, applied to immune surveillance, immunomodulation and the functions of IgE-mediated immune responses against cancer, to derive novel insights into more effective treatments. Coincident with rapid expansion in clinical application of cancer immunotherapies, here we review the current state-of-the-art and future translational opportunities, as well as challenges in this relatively new field. Recent developments include improved understanding of Th2 antibodies, intratumoral innate allergy effector cells and mediators, IgE-mediated tumour antigen cross-presentation by dendritic cells, as well as immunotherapeutic strategies such as vaccines and recombinant antibodies, and finally, the management of allergy in daily clinical oncology. Shedding light on the crosstalk between allergic response and cancer is paving the way for new avenues of treatment.

Exact inference for the risk ratio with an imperfect diagnostic test.

The risk ratio quantifies the risk of disease in a study population relative to a reference population. Standard methods of estimation and testing assume a perfect diagnostic test having sensitivity and specificity of 100%. However, this assumption typically does not hold, and this may invalidate naive estimation and testing for the risk ratio. We propose procedures that control for sensitivity and specificity of the diagnostic test, given the risks are measured by proportions, as it is in cross-sectional studies or studies with fixed follow-up times. These procedures provide an exact unconditional test and confidence interval for the true risk ratio. The methods also cover the case when sensitivity and specificity differ in the two groups (differential misclassification). The resulting test and confidence interval may be useful in epidemiological studies as well as in clinical and vaccine trials. We illustrate the method with real-life examples which demonstrate that ignoring sensitivity and specificity of the diagnostic test may lead to considerable bias in the estimated risk ratio.

Effect of Lung Transplantation on Health-Related Quality of Life in the Era of the Lung Allocation Score: A U.S. Prospective Cohort Study.

Under the U.S. Lung Allocation Score (LAS) system, older and sicker patients are prioritized for lung transplantation (LT). The impact of these changes on health-related quality of life (HRQL) after transplant has not been determined. In a single-center prospective cohort study from 2010 to 2016, we assessed HRQL before and repeatedly after LT for up to 3 years using the SF12-Physical and Mental Health, the respiratory-specific Airway Questionnaire 20-Revised, and the Euroqol 5D/Visual Analog Scale utility measures by multivariate linear mixed models jointly modeled with death. We also tested changes in LT-Valued Life Activities disability, BMI, allograft function, and 6-min walk test exercise capacity as predictors of HRQL change. Among 211 initial participants (92% of those eligible), LT improved HRQL by all 5 measures (p < 0.05) and all but SF12-Mental Health improved by threefold or greater than the minimally clinically important difference. Compared to younger participants, those aged ≥65 improved less in SF12-Physical and Mental Health (p < 0.01). Improvements in disability accounted for much of the HRQL improvement. In the LAS era, LT affords meaningful and durable HRQL improvements, mediated by amelioration of disability. Identifying factors limiting HRQL improvement in selected subgroups, especially those aged ≥65, are needed to maximize the net benefits of LT.

Efficacy and Effects of Parenteral Pethidine or Meptazinol and Regional Analgesia for Pain Relief during Delivery. A Comparative Observational Study.

Background: Peripartum anesthesia may consist of parenteral opioids and/or regional analgesia. There is only limited data in the literature comparing both methods in daily obstetric practice. This observational study investigated the opioids pethidine and meptazinol as well as regional analgesics with regard to their administration, efficacy, side effects and subjective maternal satisfaction with therapy. The rates of secondary regional analgesia administration after administration of the respective opioid served as a means of evaluating treatment. Methods: This study collected data on pain management during vaginal delivery in a German university hospital over a twelve month period. Severity of pain was measured intrapartum using a numerical rating scale. Maternal, neonatal and delivery-related data were obtained postpartum from the clinical records and from the mothers using a questionnaire. Results: The study is based on data obtained from 449 deliveries. Pain relief achieved by the administration of pethidine and meptazinol was similarly low; maternal satisfaction with the respective therapy was high. Meptazinol was usually administered intravenously (83 % vs. 6 %; p < 0.001), repeatedly (27 % vs. 6 %; p < 0.001) and closer to the birth (1.9 ± 2.7 h vs. 2.6 ± 2.8 h; p < 0.05) compared to pethidine. Secondary regional analgesia was more common after the administration of pethidine (16 % vs. 8 %; p < 0.05). Regional analgesia resulted in greater pain relief compared to opioid therapy (78 % vs. 24 % after 30 min; p < 0.001) and was associated with longer times to delivery (7.6 ± 2.5 h vs. 5.7 ± 2.5 h; p < 0.001) and higher levels of maternal satisfaction with therapy (6.1 ± 1.2 vs. 4.8 ± 1.6 on a 7-point scale; p < 0.001). Conclusion: In daily clinical practice, meptazinol can be adapted more readily to changes during birth and requires less secondary analgesia. Regional neuraxial analgesia was found to be an efficacious and safe way of managing labor pain.

Control of Hypertension In Pregnancy Study randomised controlled trial-are the results dependent on the choice of labetalol or methyldopa?

OBJECTIVE: To determine whether the difference in outcomes between 'less tight' (target diastolic blood pressure [dBP] of 100 mmHg) versus 'tight' control (target dBP of 85 mmHg) in the CHIPS Trial (ISRCTN 71416914, http://pre-empt.cfri.ca/;CHIPS) depended on the choice of labetalol or methyldopa, the two most commonly used antihypertensive agents in CHIPS. DESIGN: Secondary analysis of CHIPS Trial data. SETTING: International multicentre randomised controlled trial (94 sites, 15 countries). POPULATION OR SAMPLE: A total of 987 women with non-severe non-proteinuric pregnancy hypertension. METHODS: Logistic regression was used for comparisons of 'less tight' versus 'tight' control among women treated with labetalol (but not methydopa) versus methyldopa (but not labetalol). Analyses were adjusted for the influence of baseline factors, including use of any antihypertensive therapy at randomisation. MAIN OUTCOME MEASURES: Main CHIPS Trial outcomes: primary (perinatal loss or high-level neonatal care for > 48 hours), secondary (serious maternal complications), birthweight < 10th centile, severe maternal hypertension, pre-eclampsia, and delivery at < 34 or < 37 weeks. RESULTS: Of 987 women in CHIPS, antihypertensive therapy was taken by 566 women at randomisation (labetalol 111 ['less tight'] versus 127 ['tight'] or methyldopa 126 ['less tight'] versus 117 ['tight']) and 815 women after randomisation (labetalol 186 ['less tight'] versus 247 ['tight'] and methyldopa by 98 ['less tight'] versus 126 ['tight']). Following adjustment, odds ratios for outcomes in 'less tight' versus 'tight' control were similar between antihypertensive groups according to 'at randomisation' and 'after randomisation' therapy. CONCLUSION: Outcomes for 'less tight' versus 'tight' control were not dependent on use of methyldopa or labetalol. TWEETABLE ABSTRACT: In the CHIPS Trial, maternal and infant outcomes were not dependent on use of labetalol or methyldopa.

Do labetalol and methyldopa have different effects on pregnancy outcome? Analysis of data from the Control of Hypertension In Pregnancy Study (CHIPS) trial.

OBJECTIVE: To compare pregnancy outcomes, accounting for allocated group, between methyldopa-treated and labetalol-treated women in the CHIPS Trial (ISRCTN 71416914) of 'less tight' versus 'tight' control of pregnancy hypertension. DESIGN: Secondary analysis of CHIPS Trial cohort. SETTING: International randomised controlled trial (94 sites, 15 countries). POPULATION OR SAMPLE: Of 987 CHIPS recruits, 481/566 (85.0%) women treated with antihypertensive therapy at randomisation. Of 981 (99.4%) women followed to delivery, 656/745 (88.1%) treated postrandomisation. METHODS: Logistic regression to compare outcomes among women who took methyldopa or labetalol, adjusted for the influence of baseline factors. MAIN OUTCOME MEASURES: CHIPS primary (perinatal loss or high level neonatal care for >48 hours) and secondary (serious maternal complications) outcomes, birthweight <10th centile, severe maternal hypertension, pre-eclampsia and delivery at <34 or <37 weeks. RESULTS: Methyldopa and labetalol were used commonly at randomisation (243/987, 24.6% and 238/987, 24.6%, respectively) and post-randomisation (224/981, 22.8% and 433/981, 44.1%, respectively). Following adjusted analyses, methyldopa (versus labetalol) at randomisation was associated with fewer babies with birthweight <10th centile [adjusted odds ratio (aOR) 0.48; 95% CI 0.20-0.87]. Methyldopa (versus labetalol) postrandomisation was associated with fewer CHIPS primary outcomes (aOR 0.64; 95% CI 0.40-1.00), birthweight <10th centile (aOR 0.54; 95% CI 0.32-0.92), severe hypertension (aOR 0.51; 95% CI 0.31-0.83), pre-eclampsia (aOR 0.55; 95% CI 0.36-0.85), and delivery at <34 weeks (aOR 0.53; 95% CI 0.29-0.96) or <37 weeks (aOR 0.55; 95% CI 0.35-0.85). CONCLUSION: These nonrandomised comparisons are subject to residual confounding, but women treated with methyldopa (versus labetalol), particularly those with pre-existing hypertension, may have had better outcomes. TWEETABLE ABSTRACT: There was no evidence that women treated with methyldopa versus labetalol had worse outcomes.

Voriconazole Exposure and Risk of Cutaneous Squamous Cell Carcinoma, Aspergillus Colonization, Invasive Aspergillosis and Death in Lung Transplant Recipients.

Voriconazole is a triazole antifungal used to prevent and treat invasive fungal infections after lung transplantation, but it has been associated with an increased risk of developing cutaneous squamous cell carcinoma (SCC). Despite widespread use, there are no clear guidelines for optimal prophylactic regimens that balance the competing risks and benefits. We conducted a retrospective cohort study of all lung transplant recipients at the University of California, San Francisco, who were transplanted between October 1991 and December 2012 (n = 455) to investigate whether voriconazole exposure affected development of SCC, Aspergillus colonization, invasive aspergillosis and all-cause mortality. Voriconazole exposure was associated with a 73% increased risk of developing SCC (hazard ratio [HR] 1.73; 95% confidence interval [CI]: 1.04-2.88; p = 0.03), with each additional 30-day exposure at the standard dose increasing the risk by 3.0% (HR 1.03; 95% CI: 1.02-1.04; p < 0.001). Voriconazole exposure reduced risk of Aspergillus colonization by 50% (HR 0.50; 95% CI: 0.34-0.72; p < 0.001), but we were underpowered to detect risk reduction for invasive aspergillosis. Voriconazole exposure significantly reduced all-cause mortality among subjects who developed Aspergillus colonization (HR 0.34; 95% CI: 0.13-0.91; p = 0.03) but had no significant impact on those without colonization. Physicians should consider patient-specific factors that modify the potential risks and benefits of voriconazole for the care of lung transplant recipients.

Prolonged Barium-Impaction Ileus in Two Lung Transplant Recipients With Systemic Sclerosis: Case Report.

Lung transplantation can be a life-saving measure for people with end-stage lung disease from systemic sclerosis. However, outcomes of lung transplantation may be compromised by gastrointestinal manifestations of systemic sclerosis, which can involve any part of the gastrointestinal tract. Esophageal and gastric disease can be managed by enteral feeding with the use of a gastrojejunal feeding tube. In this report, we describe the clinical courses of 2 lung transplant recipients with systemic sclerosis who experienced severe and prolonged barium-impaction ileus after insertion of a percutaneous gastrojejunal feeding tube.