Transitional B cell cytokines predict renal allograft outcomes

Early immunological biomarkers that predict rejection and chronic allograft loss are needed to inform preemptive therapy and improve long-term outcomes. Here, we prospectively examined the ratio of interleukin-10 (IL-10) to tumor necrosis factor–α (TNFα) produced by transitional-1 B cells (T1B) 3 months after transplantation as a predictive biomarker for clinical and subclinical renal allograft rejection and subsequent clinical course. In both Training (n = 162) and Internal Validation (n = 82) Sets, the T1B IL-10/TNFα ratio 3 months after transplantation predicted both clinical and subclinical rejection anytime in the first year. The biomarker also predicted subsequent late rejection with a lead time averaging 8 months. Among biomarker high-risk patients, 60% had early rejection, of which 48% recurred later in the first posttransplant year. Among high-risk patients without early rejection, 74% developed rejection later in the first year. In contrast, only 5% of low-risk patients had early and 5% late rejection. The biomarker also predicted rejection in an External Validation Set (n = 95) and in key patient subgroups, confirming generalizability. Biomarker high-risk patients exhibited progressively worse renal function and decreased 5-year graft survival compared to low-risk patients. Treatment of B cells with anti-TNFα in vitro augmented the IL-10/TNFα ratio, restored regulatory activity, and inhibited plasmablast differentiation. To conclude, the T1B IL-10/TNFα ratio was validated as a strong predictive biomarker of renal allograft outcomes and provides a rationale for preemptive therapeutic intervention with TNF blockade

Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'.

Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required

Performance status score: do patients and their oncologists agree?

Oncologists traditionally assess their patients' ECOG performance status (PS), and few studies have evaluated the accuracy of these assessments. In this study, 101 patients attending a rapid access clinic at Papworth Hospital with a diagnosis of lung cancer were asked to assess their own ECOG PS score on a scale between 0 and 4. Patients' scores were compared to the PS assessment of them made by their oncologists. Of 98 patients with primary non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), weighted kappa statistics showed PS score agreement between patient and oncologist of 0.45. Both patient- and oncologist-assessed scores reflected survival duration (in NSCLC and SCLC) as well as disease stage (in NSCLC), with oncologist-assessed scores being only marginally more predictive of survival. There was no sex difference in patient assessment of PS scores, but oncologists scored female patients more pessimistically than males. This study showed that, with few exceptions, patients and oncologists assessed PS scores similarly. Although oncologists should continue to score PS objectively, it may benefit their clinical practice to involve their patients in these assessments

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought

Interventional radiology virtual simulator for liver biopsy

Purpose Training in Interventional Radiology currently uses the apprenticeship model, where clinical and technical skills of invasive procedures are learnt during practice in patients. This apprenticeship training method is increasingly limited by regulatory restrictions on working hours, concerns over patient risk through trainees’ inexperience and the variable exposure to case mix and emergencies during training. To address this, we have developed a computer-based simulation of visceral needle puncture procedures. Methods A real-time framework has been built that includes: segmentation, physically based modelling, haptics rendering, pseudo-ultrasound generation and the concept of a physical mannequin. It is the result of a close collaboration between different universities, involving computer scientists, clinicians, clinical engineers and occupational psychologists. Results The technical implementation of the framework is a robust and real-time simulation environment combining a physical platform and an immersive computerized virtual environment. The face, content and construct validation have been previously assessed, showing the reliability and effectiveness of this framework, as well as its potential for teaching visceral needle puncture. Conclusion A simulator for ultrasound-guided liver biopsy has been developed. It includes functionalities and metrics extracted from cognitive task analysis. This framework can be useful during training, particularly given the known difficulties in gaining significant practice of core skills in patients

Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer

The aim of this study was to investigate the worldwide evidence of the roles of adjuvant chemoradiation and adjuvant chemotherapy on survival in potentially curative resected pancreatic cancer. Five randomised controlled trials of adjuvant treatment in patients with histologically proven pancreatic ductal adenocarcinoma were identified, of which the four most recent trials provided individual patient data (875 patients). This meta-analysis includes previously unpublished follow-up data on 261 patients. The pooled estimate of the hazard ratio (HR) indicated a 25% significant reduction in the risk of death with chemotherapy (HR=0.75, 95% confidence interval (CI): 0.64, 0.90, P-valuesstratified (Pstrat)=0.001) with median survival estimated at 19.0 (95% CI: 16.4, 21.1) months with chemotherapy and 13.5 (95% CI: 12.2, 15.8) without. The 2- and 5-year survival rates were estimated at 38 and 19%, respectively, with chemotherapy and 28 and 12% without. The pooled estimate of the HR indicated no significant difference in the risk of death with chemoradiation (HR=1.09, 95% CI: 0.89, 1.32, Pstrat=0.43) with median survivals estimated at 15.8 (95% CI: 13.9, 18.1) months with chemoradiation and 15.2 (95% CI: 13.1, 18.2) without. The 2- and 5-year survival rates were estimated at 30 and 12%, respectively, with chemoradiation and 34 and 17% without. Subgroup analyses estimated that chemoradiation was more effective and chemotherapy less effective in patients with positive resection margins. These results show that chemotherapy is effective adjuvant treatment in pancreatic cancer but not chemoradiation. Further studies with chemoradiation are warranted in patients with positive resection margins, as chemotherapy appeared relatively ineffective in this patient subgroup

Improving the sensitivity of the hop index in patients with an ACL deficient knee by transforming the hop distance scores

BACKGROUND: The one leg hop for distance is one of the most commonly employed functional tests utilized in the evaluation of the ACL deficient and reconstructed patient. While the reliability of the hop test scores has been well established, validity studies have revealed low sensitivity rates in detecting functional limitations using the hop index (the ratio or percentage of limb performance). However, the impact of the inherent limitations associated with the hop index have not been investigated to date. One specific limitation relates to the impact of the differences in the underlying hop distance scores. Therefore, this pilot study set out to determine: 1) the impact that between limb differences in hop distance has on the sensitivity of the hop index in detecting functional limitations and; 2) whether a logarithmic transformation of the underlying hop distance scores improves the sensitivity of the hop index. METHODS: A cross sectional design involving the evaluation of one leg hop for distance performance in a consecutive sample of 10 ACL deficient males with an isolated ACL tear awaiting reconstructive surgery and nine gender, age-matched controls. RESULTS: In the ACL deficient, the hop index was associated with the distance hopped on the non-injured limb (r = -0.66, p = 0.04) but not on the injured limb. Transformation (logarithmic) of the hop distance scores and re-calculation of the hop index using the transformed scores increased the sensitivity of the hop index in the detection of functional limitations from 20 to 60% and 50 to 70% using the normal limb symmetry reference norms of ≥ 85% and 90% respectively. CONCLUSION: The distance hopped on the non-injured limb is a critical factor in detecting functional limitations using the hop index in patients with an ACL deficient knee. Logarithmic transformation of the hop distance scores minimizes the effect of the arithmetic differences between limbs however; the sensitivity of the hop index in detecting abnormal limb symmetry remains low

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Sexual life and dysfunction after maternal morbidity: A systematic review

© 2015 Andreucci et al. Background: Because there is a lack of knowledge on the long-term consequences of maternal morbidity/near miss episodes on women's sexual life and function we conducted a systematic review with the purpose of identifying the available evidence on any sexual impairment associated with complications from pregnancy and childbirth. Methods: Systematic review on aspects of women sexual life after any maternal morbidity and/or maternal near miss, during different time periods after delivery. The search was carried out until May 22nd, 2015 including studies published from 1995 to 2015. No language or study design restrictions were applied. Maternal morbidity as exposure was split into general or severe/near miss. Female sexual outcomes evaluated were dyspareunia, Female Sexual Function Index (FSFI) scores and time to resume sexual activity after childbirth. Qualitative syntheses for outcomes were provided whenever possible. Results: A total of 2,573 studies were initially identified, and 14 were included for analysis after standard selection procedures for systematic review. General morbidity was mainly related to major perineal injury (3rd or 4th degree laceration, 12 studies). A clear pattern for severity evaluation of maternal morbidity could not be distinguished, unless when a maternal near miss concept was used. Women experiencing maternal morbidity had more frequently dyspareunia and resumed sexual activity later, when compared to women without morbidity. There were no differences in FSFI scores between groups. Meta-analysis could not be performed, since included studies were too heterogeneous regarding study design, evaluation of exposure and/or outcome and time span. Conclusion: Investigation of long-term repercussions on women's sexual life aspects after maternal morbidity has been scarcely performed, however indicating worse outcomes for those experiencing morbidity. Further standardized evaluation of these conditions among maternal morbidity survivors may provide relevant information for clinical follow-up and reproductive planning for women

The impact of hypertension, hemorrhage, and other maternal morbidities on functioning in the postpartum period as assessed by the WHODAS 2.0 36-item tool

© 2018 World Health Organization; licensed by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics. Objective: To assess the scores of postpartum women using the WHO Disability Assessment Schedule 2.0 36-item tool (WHODAS-36), considering different morbidities. Methods: Secondary analysis of a retrospective cohort of women who delivered at a referral maternity in Brazil and were classified with and without severe maternal morbidity (SMM). WHODAS-36 was used to assess functioning in postpartum women. Percentile distribution of total WHODAS score was compared across three groups: Percentile (P)90. Cases of SMM were categorized and WHODAS-36 score was assessed according to hypertension, hemorrhage, or other conditions. Results: A total of 638 women were enrolled: 64 had mean scores below P90 (41.3). Of women scoring above P>90, those with morbidity had a higher mean score than those without (44.6% vs 36.8%, P=0.879). Women with higher WHODAS-36 scores presented more complications during pregnancy, especially hypertension (47.0% vs 37.5%, P=0.09). Mean scores among women with any complication were higher than those with no morbidity (19.0 vs 14.2, P=0.01). WHODAS-36 scores were higher among women with hypertensive complications (19.9 vs 16.0, P=0.004), but lower among those with hemorrhagic complications (13.8 vs 17.7, P=0.09). Conclusions: Complications during pregnancy, childbirth, and the puerperium increase long-term WHODAS-36 scores, demonstrating a persistent impact on functioning among women, up to 5 years postpartum