A Diaphragmic Traction Suture Increases Pleural Cavity Volume and Surgical Field Overview During Video-Assisted Thoracoscopic Surgery.

OBJECTIVES: An elevated hemidiaphragm may impair surgical field overview during video assisted thoracoscopic surgery (VATS) and may consequently jeopardize a safe surgical procedure or prolong the duration of surgery. The aim of this study was to evaluate if tension applied to a diaphragmatic suture improves the surgical field overview. METHODS: Following informed consent and at the surgeon's discretion during elective VATS procedures, a single stitch was placed at the posterior tendinous border of the diaphragm and retracted through the camera port. The surgical field overview was evaluated using a numeric rating scale (1-10) by the surgeon before and after applying tension during the procedure, and later by 9 VATS surgeons (> 10 years' experience) using video recordings. RESULTS: During a 4-month period, 43 patients scheduled for elective VATS by two surgeons gave informed consent to participate. The hemidiaphragm was elevated to such an extent in 27 patients that the surgeon placed a diaphragmatic stitch suture. When tension was applied to the suture, surgical field overview improved significantly (p < 0.001). CONCLUSION: A diaphragmatic traction suture improves surgical field overview in selected patients with elevation of the hemidiaphragm. This simple procedure may facilitate VATS in patients with impaired surgical field overview and consequently improve safety during VATS. CLINICAL TRIAL NUMBER: http://ClinicalTrials.gov (No. NCT04837950).

CT in planning transcatheter aortic valve implantation procedures and risk assessment.

For surgical aortic valve replacement, the Society of Thoracic Surgeons score (STSS) is the reference standard for the prediction of operative risk. In transcatheter aortic valve implantation (TAVI) though, where the procedure itself is minimally invasive, the traditional risk assessment is supplemented by CTA. Through a consistent approach to the acquisition of high-quality images and the standardised reporting of annular measurements and adverse root and vascular features, patients at risk of complications can be identified. In turn, this may allow for a personalised procedural approach and treatment strategies devised to potentially reduce or mitigate this risk. This article provides a systematic and standardised approach to pre-procedural work-up with computed tomography angiography (CTA) and explores the current state of evidence and future areas of development in this rapidly developing field.

Blockade of vascular endothelial growth factor receptor 2 inhibits intraplaque haemorrhage by normalization of plaque neovessels.

BACKGROUND: Plaque angiogenesis is associated with atherosclerotic lesion growth, plaque instability and negative clinical outcome. Plaque angiogenesis is a natural occurring process to fulfil the increasing demand of oxygen and nourishment of the vessel wall. However, inadequate formed, immature plaque neovessels are leaky and cause intraplaque haemorrhage. OBJECTIVE: Blockade of VEGFR2 normalizes the unbridled process of plaque neovessel formation and induces maturation of nascent vessels resulting in prevention of intraplaque haemorrhage and influx of inflammatory cells into the plaque and subsequently increases plaque stability. METHODS AND RESULTS: In human carotid and vein graft atherosclerotic lesions, leaky plaque neovessels and intraplaque haemorrhage co-localize with VEGF/VEGFR2 and angiopoietins. Using hypercholesterolaemic ApoE3*Leiden mice that received a donor caval vein interposition in the carotid artery, we demonstrate that atherosclerotic vein graft lesions at t28 are associated with hypoxia, Hif1α and Sdf1 up-regulation. Local VEGF administration results in increased plaque angiogenesis. VEGFR2 blockade in this model results in a significant 44% decrease in intraplaque haemorrhage and 80% less extravasated erythrocytes compared to controls. VEGFR2 blockade in vivo results in a 32% of reduction in vein graft size and more stable lesions with significantly reduced macrophage content (30%), and increased collagen (54%) and smooth muscle cell content (123%). Significant decreased VEGF, angiopoietin-2 and increased Connexin 40 expression levels demonstrate increased plaque neovessel maturation in the vein grafts. VEGFR2 blockade in an aortic ring assay showed increased pericyte coverage of the capillary sprouts. CONCLUSION: Inhibition of intraplaque haemorrhage by controlling neovessels maturation holds promise to improve plaque stability.

Th17 responses to pneumococcus in blood and adenoidal cells in children.

Pneumococcal infections cause a large global health burden, and the search for serotype-independent vaccines continues. Existing conjugate vaccines reduce nasopharyngeal colonization by target serotypes. Such mucosal effects of novel antigens may similarly be important. CD4+ Th17 cell-dependent, antibody-independent reductions in colonization and enhanced clearance have been described in mice. Here we describe the evaluation of T helper type 17 (Th17) cytokine responses to candidate pneumococcal protein vaccine antigens in human cell culture, using adenoidal and peripheral blood mononuclear cells. Optimal detection of interleukin (IL)-17A was at day 7, and of IL-22 at day 11, in these primary cell cultures. Removal of CD45RO+ memory T cells abolished these responses. Age-associated increases in magnitude of responses were evident for IL-17A, but not IL-22, in adenoidal cells. There was a strong correlation between individual IL-17A and IL-22 responses after pneumococcal antigen stimulation (P < 0·015). Intracellular cytokine staining following phorbol myristate acetate (PMA)/ionomycin stimulation demonstrated that  > 30% CD4+ T cells positive for IL-22 express the innate markers γδT cell receptor and/or CD56, with much lower proportions for IL-17A+ cells (P < 0·001). Responses to several vaccine candidate antigens were observed but were consistently absent, particularly in blood, to PhtD (P < 0·0001), an antigen recently shown not to impact colonization in a clinical trial of a PhtD-containing conjugate vaccine in infants. The data presented and approach discussed have the potential to assist in the identification of novel vaccine antigens aimed at reducing pneumococcal carriage and transmission, thus improving the design of empirical clinical trials.

Implementing a nursing systems framework in a developing country.

AIM: To test the effect on patient mortality of implementing a nursing systems framework across a national health system. BACKGROUND: There have been five previous observational studies that have tested the effect of a nursing systems framework on clinical outcomes for patients. Implementation of a nursing systems framework in the health system of a developing country has not been evaluated. DESIGN: Quasi-experimental (before and after) study. METHOD: A nursing systems framework consisting of six themes: (i) Professionalisation; (ii) Education; (iii) Structure; (iv) Quality of nursing care; (v) An academic health system; and (vi) Communication (Professional), was implemented across the national health system of Qatar in March 2015. Routine administrative data were extracted (March 2014-February 2016) for elective admissions. Our primary and secondary outcomes were, respectively, all cause mortality at discharge and readmission to hospital (within 28 days of discharge). We split the data into two time periods: before (March 2014-February 2015) and after (March 2015-February 2016) the implementation of the nursing systems framework. Multivariable regression modelling was used to examine the effect of the framework on patient mortality, after adjusting for key confounding variables (patient age, episode acuity, intensive care admission and length of stay). FINDINGS: Data were extracted for 318 548 patients (year 1 = 130 829; year 2 = 187 725). After adjusting for confounding, there was a significant association between the implementation of the nursing systems framework, mortality and readmission. CONCLUSION AND IMPLICATIONS FOR NURSING POLICY AND PRACTICE: Our observations suggest that the implementation of a nursing systems framework may be important in improving outcomes for patients in emerging health systems.

Development and operation of the defence COVID-19 lab as a SARS-CoV-2 diagnostic screening capability for UK military personnel.

BACKGROUND: In the face of the COVID-19 pandemic, the Defence Science and Technology Laboratory (Dstl) and Defence Pathology combined to form the Defence Clinical Lab (DCL), an accredited (ISO/IEC 17025:2017) high-throughput SARS-CoV-2 PCR screening capability for military personnel. LABORATORY STRUCTURE AND RESOURCE: The DCL was modular in organisation, with laboratory modules and supporting functions combining to provide the accredited SARS-CoV-2 (envelope (E)-gene) PCR assay. The DCL was resourced by Dstl scientists and military clinicians and biomedical scientists. LABORATORY RESULTS: Over 12 months of operation, the DCL was open on 289 days and tested over 72 000 samples. Six hundred military SARS-CoV-2-positive results were reported with a median E-gene quantitation cycle (Cq) value of 30.44. The lowest Cq value for a positive result observed was 11.20. Only 64 samples (0.09%) were voided due to assay inhibition after processing started. CONCLUSIONS: Through a sustained effort and despite various operational issues, the collaboration between Dstl scientific expertise and Defence Pathology clinical expertise provided the UK military with an accredited high-throughput SARS-CoV-2 PCR test capability at the height of the COVID-19 pandemic. The DCL helped facilitate military training and operational deployments contributing to the maintenance of UK military capability. In offering a bespoke capability, including features such as testing samples in unit batches and oversight by military consultant microbiologists, the DCL provided additional benefits to the UK Ministry of Defence that were potentially not available from other SARS-CoV-2 PCR laboratories. The links between Dstl and Defence Pathology have also been strengthened, benefitting future research activities and operational responses.

A nonlinear relationship between cerebral serotonin transporter and 5-HT(2A) receptor binding: an in vivo molecular imaging study in humans.

Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT(2A)) receptor and the presynaptic serotonin transporter (SERT) are sensitive to chronic changes in cerebral 5-HT levels. Additionally, experimental studies suggest that alterations in either the 5-HT(2A) receptor or SERT level can affect the protein level of the counterpart. The aim of this study was to explore the covariation between cerebral 5-HT(2A) receptor and SERT in vivo in the same healthy human subjects. Fifty-six healthy human subjects with a mean age of 36 +/- 19 years were investigated. The SERT binding was imaged with [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) and 5-HT(2A) receptor binding with [(18)F]altanserin using positron emission tomography. Within each individual, a regional intercorrelation for the various brain regions was seen with both markers, most notably for 5-HT(2A) receptor binding. An inverted U-shaped relationship between the 5-HT(2A) receptor and the SERT binding was identified. The observed regional intercorrelation for both the 5-HT(2A) receptor and the SERT cerebral binding suggests that, within the single individual, each marker has a set point adjusted through a common regulator. A quadratic relationship between the two markers is consistent with data from experimental studies of the effect on SERT and 5-HT(2A) receptor binding of chronic changes in 5-HT levels. That is, the observed association between the 5-HT(2A) receptor and SERT binding could be driven by the projection output from the raphe nuclei, but other explanations are also at hand.

The influence of a lost society, the Sadlermiut, on the environment in the Canadian Arctic.

High latitude freshwater ecosystems are sentinels of human activity and environmental change. The lakes and ponds that characterize Arctic landscapes have a low resilience to buffer variability in climate, especially with increasing global anthropogenic stressors in recent decades. Here, we show that a small freshwater pond in proximity of the archaeological site "Native Point" on Southampton Island (Nunavut, Arctic Canada) is a highly sensitive environmental recorder. The sediment analyses allowed for pinpointing the first arrival of Sadlermiut culture at Native Point to ~ 1250 CE, followed by a dietary shift likely in response to the onset of cooling in the region ~ 1400 CE. The influence of the Sadlermiut on the environment persisted long after the last of their population perished in 1903. Presently, the pond remains a distorted ecosystem that has experienced fundamental shifts in the benthic invertebrate assemblages and accumulated anthropogenic metals in the sediment. Our multi-proxy paleolimnological investigation using geochemical and biological indicators emphasizes that direct and indirect anthropogenic impacts have long-term environmental implications on high latitude ecosystems.

Fcgamma receptor-mediated phagocytosis in macrophages lacking the Src family tyrosine kinases Hck, Fgr, and Lyn.

Macrophage Fcgamma receptors (FcgammaRs) mediate the uptake and destruction of antibody-coated viruses, bacteria, and parasites. We examined FcgammaR signaling and phagocytic function in bone marrow-derived macrophages from mutant mice lacking the major Src family kinases expressed in these cells, Hck, Fgr, and Lyn. Many FcgammaR-induced functional responses and signaling events were diminished or delayed in these macrophages, including immunoglobulin (Ig)G-coated erythrocyte phagocytosis, respiratory burst, actin cup formation, and activation of Syk, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinases 1 and 2. Significant reduction of IgG-dependent phagocytosis was not seen in hck(-)(/)-fgr(-)(/)- or lyn(-)(/)- cells, although the single mutant lyn(-)(/)- macrophages did manifest signaling defects. Thus, Src family kinases clearly have roles in two events leading to FcgammaR-mediated phagocytosis, one involving initiation of actin polymerization and the second involving activation of Syk and subsequent internalization. Since FcgammaR-mediated phagocytosis did occur at modest levels in a delayed fashion in triple mutant macrophages, these Src family kinases are not absolutely required for uptake of IgG-opsonized particles.

Fentanyl buccal soluble film (FBSF) for breakthrough pain in patients with cancer: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Fentanyl buccal soluble film (FBSF) has been developed as a treatment of breakthrough pain in opioid-tolerant patients with cancer. The objective of this study was to evaluate the efficacy of FBSF at doses of 200-1200 microg in the management of breakthrough pain in patients with cancer receiving ongoing opioid therapy. PATIENTS AND METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, multiple-crossover study that included opioid-tolerant adult patients with chronic cancer pain who experienced one to four daily episodes of breakthrough pain. The primary efficacy assessment was the sum of pain intensity differences at 30 min (SPID30) postdose. RESULTS: The intent-to-treat population consisted of 80 patients with > or =1 post-baseline efficacy assessment. The least-squares mean (LSM +/- SEM) of the SPID30 was significantly greater for FBSF-treated episodes of breakthrough pain than for placebo-treated episodes (47.9 +/- 3.9 versus 38.1 +/- 4.3; P = 0.004). There was statistical separation from placebo starting at 15 min up through 60 min (last time point assessed). There were no unexpected adverse events (AEs) or clinically significant safety findings. CONCLUSIONS: FBSF is an effective option for control of breakthrough pain in patients receiving ongoing opioid therapy. In this study, FBSF was well tolerated in the oral cavity, with no reports of treatment-related oral AEs.

Sequential embryo scoring as a predictor of aneuploidy in poor-prognosis patients.

The delivery rates of 298 patients having preimplantation genetic diagnosis with aneuploidy screening (PGS) were compared with the delivery rates of 144 PGS patients that cancelled the plan for PGS with embryo transfer on day 2 or day 3. The goal of this study was to compare the impact of embryo de-selection with PGS to embryo selection using sequential embryo scoring (SES) on outcome in poor-prognosis patients. Embryos with good sequential scores were more likely to have a normal PGS result than embryos with poor SES scores (34% versus 12%; P<0.05). Patients proceeding with PGS had an overall delivery rate of 15% per oocyte retrieval. There was a significant difference in delivery rates between patients with less than six embryos and patients with greater than six embryos (6% versus 19%; P<0.005). The overall delivery rate for patients having transfers without PGS was 23% (P<0.05 compared with PGS patients) with no difference between low and good responders. It was concluded that PGS neither enhanced nor impaired delivery rates in high responding poor-prognosis patients yet SES may be more accurate than PGS as a means of selection for low-responding poor-prognosis patients.

The personality trait openness is related to cerebral 5-HTT levels.

Potentiation of serotonergic transmission increases cognitive flexibility, but can in other circumstances increase sensitivity to stressful environmental cues. The personality trait Openness to Experience reflects and is also associated with an increased risk for mood disorders. We hypothesized that the personality trait has an association with a biomarker of serotonergic transmission, the plasma membrane serotonin transporter (5-HTT). In 50 healthy volunteers, we tested for correlations between scores on the NEO-PI-R scale Openness to Experience and its subscales, and cerebral binding of the 5-HTT selective PET radioligand [11C]DASB. Subjects were genotyped for the 5-HTT long/short polymorphism, and for a single nucleotide polymorphism in the long allele, designated LA/LG. Midbrain [11C]DASB binding correlated negatively with scores for Openness to Experience and its two subscales, Openness to Actions and Openness to Values. The latter subscore was negatively correlated with [11C]DASB binding in all brain regions in which [11C]DASB binding was quantified. Genetic analysis showed that homozygote LA carriers had significantly higher [11C]DASB binding in the caudate nucleus, but no significant differences in openness scores. Thus, high scores in personality facets indicative of cognitive flexibility and openness to change are associated with lower [11C]DASB binding. Lower abundance of 5-HTT sites may result in potentiation of serotonergic signaling, which occurs during treatment with SSRIs. We speculate that the set-point of serotonergic signaling in an individual represents a trade-off between flexibility and vulnerability when exposed to environmental stress.

Sodium transport inhibition by amiloride reduces basolateral membrane potassium conductance in tight epithelia.

In toad and frog urinary bladder, electrophysiological data suggest that inhibition of transepithelial sodium transport by mucosal amiloride results in a decrease in basolateral membrane conductance. These results were confirmed by showing that amiloride addition caused a decrease in basolateral membrane potassium permeability.

Vascular remodeling after coronary stent implantation.

Drug eluting stents (DES) have significantly reduced restenosis when compared to BMS and are considered the standard of care in the treatment of symptomatic coronary artery disease. However, late stent thrombosis has emerged as a major concern with the use of first generation DES. Pathologic studies of patients dying from late DES thrombosis (first generation sirolimus-eluting stents and paclitaxel-eluting stents) showed that DES are associated with delayed healing characterized by poor endothelialization of stent struts and persistence of fibrin as compared to BMS. Additional risk factors for LST include long lesions, left main coronary artery, bifurcation stenting, ruptured plaques, and hypersensitivity reactions. Currently, the next generation DES are being developed to optimize the three major components of DES: the stent platform, the polymer coating and the drug. New technologies include biodegradable polymers and stents, polymer free drug delivery and prohealing approaches. Further preclinical testing and evaluation through large clinical trials are needed to determine the safety and efficacy of future DES in clinical practice.

For debate: health service support planning for large-scale defensive land operations (part 2).

This is the second of two articles that considers the medical planning implications of large-scale defensive military operations. This paper describes a unified approach to theatre level health services support planning based on four phases: collection, hospitalisation, evacuation and reception. It highlights the need for a modular and agile system of medical capability building blocks that can be grouped together for specific military medical challenges. It also reintroduces the concepts of mass casualty and the medical reserve. These two papers are designed to encourage debate around how we should be organised to face the new challenges of health services support in potential peer-on-peer military operations.

For debate: health service support planning for large-scale defensive land operations (part 1).

This is the first of two articles that considers the medical planning implications of large-scale defensive military operations. This paper considers the military context and planning factors that may require a medical plan that is different from that seen in recent counterinsurgency operations. The scale and complexity of the challenge is likely to require a greater level of decentralisation and a more sophisticated approach to medical planning at the strategic and operational levels.

Efficacy of pamidronate in children with chronic non-bacterial osteitis using whole body MRI as a marker of disease activity.

BACKGROUND: To study the response to pamidronate using whole body magnetic resonance imaging (WB-MRI) in children with chronic non-bacterial osteitis (CNO) in a tertiary health centre. METHODS: The medical records of children under the age of sixteen with a diagnosis of chronic non-bacterial osteitis between 2005 and 2018 were reviewed. All those who were treated with pamidronate were included and relevant data was collected. Response to therapy was determined based on the status of lesions on WB- MRI. RESULTS: Forty six patients were included in the study. Pre- and post-treatment WB-MRI was available in forty patients. Cumulative lesions pre-treatment were 150 and reduced to 45 (30%) post-treatment. Seventeen patients (42.5%) had a good response with complete resolution of all lesions and nine patients (22.5%) worsened during or following treatment with pamidronate. Vertebral disease had a good response and 82.3% of the lesions resolved completely. CONCLUSION: Our study describes the experience with pamidronate in a tertiary health centre using WB-MRI as a marker of disease activity. Pamidronate was well tolerated in our cohort and treatment response was fairly good. SIGNIFICANCE AND INNOVATION: 1. Bisphosphonates can be used in the treatment of CNO when response to NSAIDs is suboptimal. 2. In the presence of spinal or mandibular lesions bisphosphonates were used as first line. 3. Treatment was escalated to a TNF blocker when response to bisphosphonates was suboptimal.

Author Correction: Insights into Pasteurellaceae carriage dynamics in the nasal passages of healthy beef calves.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Insights into Pasteurellaceae carriage dynamics in the nasal passages of healthy beef calves.

We investigated three bovine respiratory pathobionts in healthy cattle using qPCR optimised and validated to quantify Histophilus somni, Mannheimia haemolytica and Pasteurella multocida over a wide dynamic range. A longitudinal study was conducted to investigate the carriage and density of these bacteria in the nasal passages of healthy beef calves (N = 60) housed over winter in an experimental farm setting. The three pathobiont species exhibited remarkably different carriage rates and density profiles. At housing, high carriage rates were observed for P. multocida (95%), and H. somni (75%), while fewer calves were positive for M. haemolytica (13%). Carriage rates for all three bacterial species declined over the 75-day study, but not all individuals became colonised despite sharing of environment and airspace. Colonisation patterns ranged from continuous to intermittent and were different among pathobiont species. Interval-censored exponential survival models estimated the median duration of H. somni and P. multocida carriage at 14.8 (CI95%: 10.6-20.9) and 55.5 (CI95%: 43.3-71.3) days respectively, and found higher density P. multocida carriage was associated with slower clearance (p = 0.036). This work offers insights into the dynamics of pathobiont carriage and provides a potential platform for further data collection and modelling studies.

Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal.

Morphine is unusual in its failure to promote robust desensitization and endocytosis of the mu opioid receptor (MOR), processes that for many receptors contribute directly to tolerance. This apparent paradox has led us to revise the idea that receptor desensitization and endocytosis are solely responsible for tolerance and withdrawal to morphine, and instead test the hypothesis that these side effects occur due to abnormally prolonged MOR signaling. We report here that MOR mutations that facilitate endocytosis reduce the development of cellular tolerance and cAMP superactivation, a cellular hallmark of withdrawal. Moreover, mutant receptors with reduced endocytosis produce exacerbated superactivation. These data demonstrate a critical role for receptor endocytosis in the development of adverse side effects associated with prolonged opiate use.