Advanced waveform analysis of diaphragm surface EMG allows for continuous non-invasive assessment of respiratory effort in critically ill patients at different PEEP levels.

BACKGROUND: Respiratory effort should be closely monitored in mechanically ventilated ICU patients to avoid both overassistance and underassistance. Surface electromyography of the diaphragm (sEMGdi) offers a continuous and non-invasive modality to assess respiratory effort based on neuromuscular coupling (NMCdi). The sEMGdi derived electrical activity of the diaphragm (sEAdi) is prone to distortion by crosstalk from other muscles including the heart, hindering its widespread use in clinical practice. We developed an advanced analysis as well as quality criteria for sEAdi waveforms and investigated the effects of clinically relevant levels of PEEP on non-invasive NMCdi. METHODS: NMCdi was derived by dividing end-expiratory occlusion pressure (Pocc) by sEAdi, based on three consecutive Pocc manoeuvres at four incremental (+ 2 cmH2O/step) PEEP levels in stable ICU patients on pressure support ventilation. Pocc and sEAdi quality was assessed by applying a novel, automated advanced signal analysis, based on tolerant and strict cut-off criteria, and excluding inadequate waveforms. The coefficient of variations (CoV) of NMCdi after basic manual and automated advanced quality assessment were evaluated, as well as the effect of an incremental PEEP trial on NMCdi. RESULTS: 593 manoeuvres were obtained from 42 PEEP trials in 17 ICU patients. Waveform exclusion was primarily based on low sEAdi signal-to-noise ratio (Ntolerant = 155, 37%, Nstrict = 241, 51% waveforms excluded), irregular or abrupt cessation of Pocc (Ntolerant = 145, 35%, Nstrict = 145, 31%), and high sEAdi area under the baseline (Ntolerant = 94, 23%, Nstrict = 79, 17%). Strict automated assessment allowed to reduce CoV of NMCdi to 15% from 37% for basic quality assessment. As PEEP was increased, NMCdi decreased significantly by 4.9 percentage point per cmH2O. CONCLUSION: Advanced signal analysis of both Pocc and sEAdi greatly facilitates automated and well-defined identification of high-quality waveforms. In the critically ill, this approach allowed to demonstrate a dynamic NMCdi (Pocc/sEAdi) decrease upon PEEP increments, emphasising that sEAdi-based assessment of respiratory effort should be related to PEEP dependent diaphragm function. This novel, non-invasive methodology forms an important methodological foundation for more robust, continuous, and comprehensive assessment of respiratory effort at the bedside.

Analysis and applications of respiratory surface EMG: report of a round table meeting.

Surface electromyography (sEMG) can be used to measure the electrical activity of the respiratory muscles. The possible applications of sEMG span from patients suffering from acute respiratory failure to patients receiving chronic home mechanical ventilation, to evaluate muscle function, titrate ventilatory support and guide treatment. However, sEMG is mainly used as a monitoring tool for research and its use in clinical practice is still limited-in part due to a lack of standardization and transparent reporting. During this round table meeting, recommendations on data acquisition, processing, interpretation, and potential clinical applications of respiratory sEMG were discussed. This paper informs the clinical researcher interested in respiratory muscle monitoring about the current state of the art on sEMG, knowledge gaps and potential future applications for patients with respiratory failure.

What to expect from a non-suspicious prostate MRI? A review.

BACKGROUND: Many guidelines now recommend multiparametric MRI (mpMRI) prior to an initial or repeat prostate biopsy. However, clinical decision making for men with a non-suspicious mpMRI (Likert or PIRADS score 1-2) varies. OBJECTIVES: To review the most recent literature to answer three questions. (1) Should we consider systematic biopsy if mpMRI is not suspicious? (2) Are there additional predictive factors that can help decide which patient should have a biopsy? (3) Can the low visibility of some cancers be explained and what are the implications? SOURCES: A narrative review was performed in Medline databases using two searches with the terms "MRI" and "prostate cancer" and ("diagnosis" or "biopsy") and ("non-suspicious" or "negative" or "invisible"); "prostate cancer MRI visible". References of the selected articles were screened for additional articles. STUDY SELECTION: Studies published in the last 5 years in English language were assessed for eligibility and selected if data was available to answer one of the three study questions. RESULTS: Considering clinically significant cancer as ISUP grade≥2, the negative predictive value (NPV) of mpMRI in various settings and populations ranges from 76% to 99%, depending on cancer prevalence and the type of confirmatory reference test used. NPV is higher among patients with prior negative biopsy (88-96%), and lower for active surveillance patients (85-90%). The PSA density (PSAd) with a threshold of PSAd<0.15ng/ml/ml was the most studied and relevant predictive factor used in combination with mpMRI to rule out clinically significant cancer. Finally, mpMRI-invisible tumours appear to differ from a histopathological and genetic point of view, conferring clinical advantage to invisibility. LIMITATIONS: Most published data come from expert centres and results may not be reproducible in all settings. CONCLUSION: mpMRI has high diagnostic accuracy and in cases of negative mpMRI, PSA density can be used to determine which patient should have a biopsy. Growing knowledge of the mechanisms and genetics underlying MRI visibility will help develop more accurate risk calculators and biomarkers.

Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection.

BACKGROUND: Rhinovirus (RV) infection in asthma induces varying degrees of airway inflammation (e.g. neutrophils), but the underlying mechanisms remain unclear. OBJECTIVE: The major goal was to determine the role of genetic variation [e.g. single nucleotide polymorphisms (SNPs)] of Toll-interacting protein (Tollip) in airway epithelial responses to RV in a type 2 cytokine milieu. METHODS: DNA from blood of asthmatic and normal subjects was genotyped for Tollip SNP rs5743899 AA, AG and GG genotypes. Human tracheobronchial epithelial (HTBE) cells from donors without lung disease were cultured to determine pro-inflammatory and antiviral responses to IL-13 and RV16. Tollip knockout and wild-type mice were challenged with house dust mite (HDM) and infected with RV1B to determine lung inflammation and antiviral response. RESULTS: Asthmatic subjects carrying the AG or GG genotype (AG/GG) compared with the AA genotype demonstrated greater airflow limitation. HTBE cells with AG/GG expressed less Tollip. Upon IL-13 and RV16 treatment, cells with AG/GG (vs. AA) produced more IL-8 and expressed less antiviral genes, which was coupled with increased NF-κB activity and decreased expression of LC3, a hallmark of the autophagic pathway. Tollip co-localized and interacted with LC3. Inhibition of autophagy decreased antiviral genes in IL-13- and RV16-treated cells. Upon HDM and RV1B, Tollip knockout (vs. wild-type) mice demonstrated higher levels of lung neutrophilic inflammation and viral load, but lower levels of antiviral gene expression. CONCLUSIONS AND CLINICAL RELEVANCE: Our data suggest that Tollip SNP rs5743899 may predict varying airway response to RV infection in asthma.

Intra-ureteric placement of a urinary catheter in the previously undiagnosed duplex ureter.

We report the inadvertent insertion of a urinary catheter into the upper moiety ureter of a duplex kidney, in a full-term pregnant woman prior to an emergency caesarean section. The patient complained of severe pain during inflation of the catheter balloon. All measures to deflate the balloon and remove the catheter failed. Retrograde ureteric contrast examination showed the placement of the catheter in the proximal part the right upper moiety ureter of a duplex ureter. The catheter was removed with ureteroscopic forceps. We concluded that congenital variation of the urinary tract can complicate a simple catheterisation.

Transcriptional responses of Trichodesmium to natural inverse gradients of Fe and P availability.

The filamentous diazotrophic cyanobacterium Trichodesmium is responsible for a significant fraction of marine di-nitrogen (N2) fixation. Growth and distribution of Trichodesmium and other diazotrophs in the vast oligotrophic subtropical gyres is influenced by iron (Fe) and phosphorus (P) availability, while reciprocally influencing the biogeochemistry of these nutrients. Here we use observations across natural inverse gradients in Fe and P in the North Atlantic subtropical gyre (NASG) to demonstrate how Trichodesmium acclimates in situ to resource availability. Transcriptomic analysis identified progressive upregulation of known iron-stress biomarker genes with decreasing Fe availability, and progressive upregulation of genes involved in the acquisition of diverse P sources with decreasing P availability, while genes involved in N2 fixation were upregulated at the intersection under moderate Fe and P availability. Enhanced N2 fixation within the Fe and P co-stressed transition region was also associated with a distinct, consistent metabolic profile, including the expression of alternative photosynthetic pathways that potentially facilitate ATP generation required for N2 fixation with reduced net oxygen production. The observed response of Trichodesmium to availability of both Fe and P supports suggestions that these biogeochemically significant organisms employ unique molecular, and thus physiological responses as adaptations to specifically exploit the Fe and P co-limited niche they construct.

Modulation of H+/H- exchange in iridium-hydride 2-hydroxypyridine complexes by remote Lewis acids.

A series of iridium hydride complexes featuring dihydrogen bonding are presented and shown to undergo rapid H+/H- exchange (1240 s-1 at 25 °C). We demonstrate that the H+/H- exchange rate can be modified by post-synthetic modification at a remote site using BH3, Zn(C6F5)2, and [Me3O][BF4]. This route provides a complementary strategy to traditional methods that rely on pre-metalation modifications to a metal's primary sphere.

ReIMAGINE: a prostate cancer research consortium with added value through its patient and public involvement and engagement.

BACKGROUND: ReIMAGINE aims to improve the current prostate specific antigen (PSA)/biopsy risk stratification for prostate cancer (PCa) and develop a new image-based method (with biomarkers) for diagnosing high/low risk PCa in men. ReIMAGINE's varied patient and public involvement (PPI) and engagement (PE) strategy maximises the impact of its scientific output by informing and shaping the different stages of research. AIMS: Through including the voice of patients and the public, the ReIMAGINE Consortium aims to translate these different perspectives into the design and implementation process. This will improve the overall quality of the research by: reflecting the needs and priorities of patients and the public, ensuring methods and procedures are feasible and appropriate ensuring information is relevant and accessible to those being recruited to the study identifying dissemination channels relevant to patients/the public and developing outputs that are accessible to a lay audience With support from our patient/user groups, the ReIMAGINE Consortium aims to improve our ability to derive prognostic information and allocate men to the most appropriate and effective therapies, using a novel image-based risk stratification with investigation of non-imaging biomarkers. FINDINGS: We have been working with patients and the public from initiation of the project to ensure that the research is relevant to men and their families. Our PPI Sub-Committee, led by a PCa patient, has been involved in our dissemination strategy, outreach activities, and study design recommendations. For example, the sub-committee have developed a variety of informative videos relevant and accessible to those being recruited, and organised multiple online research engagement events that are accessible to a lay audience. As quoted by one of the study participants, "the more we present the benefits and opportunities to patients and the public, the more research commitment we obtain, and the sooner critical clinical questions such as PCa diagnostics will be addressed".

One in eight men will be diagnosed with prostate cancer (PCa). Most will not die of it, but our ability to identify those men whose cancer poses the greatest threat to life has, thus far, been poor. Some men are diagnosed with small cancers which will never cause them a problem, some will have treatment which is unnecessary, others will have their cancers missed, and others will be misclassified as either having low risk cancer and will therefore miss out on the appropriate treatment, or told their cancer is high risk and have unnecessary treatment. Nowhere else in modern medicine are these errors of over-diagnosis, over-treatment, missed-diagnoses, and poor risk-stratification more common. The ReIMAGINE Consortium has been developed to undertake discoveries that will correct these four key errors in the PCa diagnostic pathway. We will investigate how to best identify which men have, or will develop, aggressive prostate cancer using imaging combined with advanced biomarker analyses of blood and urine (i.e., OMICs technologies such as whole genome sequencing, targeted sequencing (e.g.: = , methylation). We will achieve this by building on established partnerships between patients, advocacy organisations, clinicians, imaging experts, molecular biologists, methodologists, and a broad range of industrial partners.The Patient and Public Involvement (PPI) sub-committee is an integral part of the study workflow, contributing to study design and recruitment, results analysis, and dissemination. The committee, led by a funded PPI co-ordinator and a patient chair, have given invaluable insight into the study modifications due to COVID-19 restrictions.

Photodynamic therapy for focal ablation of the prostate.

Although in early stages of clinical development, photodynamic therapy (PDT) shows promise in delivering focal treatment of both primary and post-radiotherapy prostate cancer. This article will review the mechanism of action of PDT, previous research using PDT for treating prostate cancer including the development of newer vascular-acting photosensitizers, and the potential advantages and disadvantages of PDT in delivering focal therapy.

LHRH-Conjugated Drugs as Targeted Therapeutic Agents for the Specific Targeting and Localized Treatment of Triple Negative Breast Cancer.

Bulk chemotherapy and drug release strategies for cancer treatment have been associated with lack of specificity and high drug concentrations that often result in toxic side effects. This work presents the results of an experimental study of cancer drugs (prodigiosin or paclitaxel) conjugated to Luteinizing Hormone-Releasing Hormone (LHRH) for the specific targeting and treatment of triple negative breast cancer (TNBC). Injections of LHRH-conjugated drugs (LHRH-prodigiosin or LHRH-paclitaxel) into groups of 4-week-old athymic female nude mice (induced with subcutaneous triple negative xenograft breast tumors) were found to specifically target, eliminate or shrink tumors at early, mid and late stages without any apparent cytotoxicity, as revealed by in vivo toxicity and ex vivo histopathological tests. Our results show that overexpressed LHRH receptors serve as binding sites on the breast cancer cells/tumor and the LHRH-conjugated drugs inhibited the growth of breast cells/tumor in in vitro and in vivo experiments. The inhibitions are attributed to the respective adhesive interactions between LHRH molecular recognition units on the prodigiosin (PGS) and paclitaxel (PTX) drugs and overexpressed LHRH receptors on the breast cancer cells and tumors. The implications of the results are discussed for the development of ligand-conjugated drugs for the specific targeting and treatment of TNBC.

Elastin expression in very severe human COPD.

Alveolar elastic fibres are key targets of proteases during the pathogenesis of chronic obstructive pulmonary disease (COPD). In the current study, we hypothesised that a response to injury leads to enhanced alveolar elastin gene expression in very severe COPD. Lung samples obtained from 43 patients, including 11 with very severe COPD (stage 4), 10 donors, 10 with moderate/severe COPD (stage 2-3) and 12 non-COPD subjects, were analysed for elastin mRNA expression by real-time RT-PCR and in situ hybridisation. Alveolar elastic fibres were visualised using Hart's staining of sections of frozen inflated lungs obtained from 11 COPD stage 4 patients and three donor lungs. Compared with donors, non-COPD and stage 2-3 COPD, elastin mRNA expression was significantly increased in very severe COPD lungs (12-fold change), and localised in situ hybridisation induced elastin expression to alveolar walls. Compared with donors, alveolar elastic fibres also comprised a greater volume fraction of total lung tissue in very severe COPD lungs (p<0.01), but elastic fibre content was not increased per lung volume, and desmosine content was not increased. The present study demonstrates enhanced alveolar elastin expression in very severe COPD. The efficiency of this potential repair mechanism and its regulation remain to be demonstrated.

Double minute chromosomes can be produced from precursors derived from a chromosomal deletion.

Recent experiments have shown that gene amplification can be mediated by submicroscopic, autonomously replicating, circular extrachromosomal molecules. We refer to those molecules as episomes (S. Carroll, P. Gaudray, M. L. DeRose, J. F. Emery, J. L. Meinkoth, E. Nakkim, M. Subler, D. D. Von Hoff, and G. M. Wahl, Mol. Cell. Biol. 7:1740-1750, 1987). The experiments reported in this paper explore the way episomes are formed and their fate in the cell over time. The data reveal that in our system the episomes are initially 250 kilobases, but gradually enlarge until they become double minute chromosomes. In addition, we show that episomes or double minute chromosomes can integrate into chromosomes. Our results also suggest that episomes can be produced by deletion of the corresponding sequences from the chromosome.

When no treatment is the best treatment: Active surveillance strategies for low risk prostate cancers.

Although the incidence of prostate cancer is rising due to PSA screening and increased life expectancy, the metastatic potential of low-grade, organ-confined disease remains low. An increasing number of studies suggest that radical treatment in such cases confers little or no survival benefit at a significant cost to morbidity. Active surveillance is a promising management approach of such low-risk cancers: eligible patients are selected based on clinical and pathological findings at diagnosis and are regularly monitored with digital rectal examinations, PSA testing and biopsies. Treatment, however, is deferred until and unless there is evidence of disease progression. This is a key difference from watchful waiting, where treatment is avoided until and unless there are symptoms. The purpose of this work is to review the rationale and evidence behind active surveillance and to offer an overview of current active surveillance strategies and outcomes.

Iron limitation of microbial phosphorus acquisition in the tropical North Atlantic.

In certain regions of the predominantly nitrogen limited ocean, microbes can become co-limited by phosphorus. Within such regions, a proportion of the dissolved organic phosphorus pool can be accessed by microbes employing a variety of alkaline phosphatase (APase) enzymes. In contrast to the PhoA family of APases that utilize zinc as a cofactor, the recent discovery of iron as a cofactor in the more widespread PhoX and PhoD implies the potential for a biochemically dependant interplay between oceanic zinc, iron and phosphorus cycles. Here we demonstrate enhanced natural community APase activity following iron amendment within the low zinc and moderately low iron Western North Atlantic. In contrast we find no evidence for trace metal limitation of APase activity beneath the Saharan dust plume in the Eastern Atlantic. Such intermittent iron limitation of microbial phosphorus acquisition provides an additional facet in the argument for iron controlling the coupling between oceanic nitrogen and phosphorus cycles.

Desert Dust as a Source of Iron to the Globally Important Diazotroph Trichodesmium.

The marine cyanobacterium Trichodesmium sp. accounts for approximately half of the annual 'new' nitrogen introduced to the global ocean but its biogeography and activity is often limited by the availability of iron (Fe). A major source of Fe to the open ocean is Aeolian dust deposition in which Fe is largely comprised of particles with reduced bioavailability over soluble forms of Fe. We report that Trichodesmium erythraeum IMS101 has improved growth rate and photosynthetic physiology and down-regulates Fe-stress biomarker genes when cells are grown in the direct vicinity of, rather than physically separated from, Saharan dust particles as the sole source of Fe. These findings suggest that availability of non-soluble forms of dust-associated Fe may depend on cell contact. Transcriptomic analysis further reveals unique profiles of gene expression in all tested conditions, implying that Trichodesmium has distinct molecular signatures related to acquisition of Fe from different sources. Trichodesmium thus appears to be capable of employing specific mechanisms to access Fe from complex sources in oceanic systems, helping to explain its role as a key microbe in global biogeochemical cycles.

Trisomy of chromosome 18 in the baboon (Papio hamadryas anubis).

Trisomy 18 is usually a lethal chromosomal abnormality and is the second most common autosomal trisomy in humans, with an incidence of 1:8000 live births. It is commonly associated with abnormalities of the lower and upper extremities, having the frequency of 95% and 65%, respectively. A newborn female olive baboon (Papio hamadryas anubis) was diagnosed with intrauterine growth retardation and severe arthrogryposis-like congenital joint deformities. Cytogenetic analysis including G-banding and fluorescence in situ hybridization (FISH) revealed that the congenital abnormalities were associated with chromosomal mosaicism for trisomy 18. Genetic analysis with microsatellites from chromosome 18 confirmed the maternal origin of the extra chromosome 18. This is the first report of trisomy 18 in the baboon, which may be a promising animal model of human disease.

PSA nadir as a predictive factor for biochemical disease-free survival and overall survival following whole-gland salvage HIFU following radiotherapy failure.

BACKGROUND: Treatment options for radio-recurrent prostate cancer are either androgen-deprivation therapy or salvage prostatectomy. Whole-gland high-intensity focussed ultrasound (HIFU) might have a role in this setting. METHODS: An independent HIFU registry collated consecutive cases of HIFU. Between 2005 and 2012, we identified 50 men who underwent whole-gland HIFU following histological confirmation of localised disease following prior external beam radiotherapy (2005-2012). No upper threshold was applied for risk category, PSA or Gleason grade either at presentation or at the time of failure. Progression was defined as a composite with biochemical failure (Phoenix criteria (PSA>nadir+2 ng ml(-1))), start of systemic therapies or metastases. RESULTS: Median age (interquartile range (IQR)), pretreatment PSA (IQR) and Gleason score (range) were 68 years (64-72), 5.9 ng ml(-1) (2.2-11.3) and 7 (6-9), respectively. Median follow-up was 64 months (49-84). In all, 24/50 (48%) avoided androgen-deprivation therapies. Also, a total of 28/50 (56%) achieved a PSA nadir <0.5 ng ml(-1), 15/50 (30%) had a nadir ⩾0.5 ng ml(-1) and 7/50 (14%) did not nadir (PSA non-responders). Actuarial 1, 3 and 5-year progression-free survival (PFS) was 72, 40 and 31%, respectively. Actuarial 1, 3 and 5-year overall survival (OS) was 100, 94 and 87%, respectively. When comparing patients with PSA nadir <0.5 ng ml(-1), nadir ⩾0.5 and non-responders, a statistically significant difference in PFS was seen (P<0.0001). Three-year PFS in each group was 57, 20 and 0%, respectively. Five-year OS was 96, 100 and 38%, respectively. Early in the learning curve, between 2005 and 2007, 3/50 (6%) developed a fistula. Intervention for bladder outlet obstruction was needed in 27/50 (54%). Patient-reported outcome measure questionnaires showed incontinence (any pad-use) as 8/26 (31%). CONCLUSIONS: In our series of high-risk patients, in whom 30-50% may have micro-metastases, disease control rates were promising in PSA responders, however, with significant morbidity. Additionally, post-HIFU PSA nadir appears to be an important predictor for both progression and survival. Further research on focal salvage ablation in order to reduce toxicity while retaining disease control rates is required.

Factors affecting recognition and disjunction of chromosomes at distributive pairing in female Drosophila melanogaster. I. Total length vs. arm length.

The behavior of a compound metacentric fourth chromosome (see PDF) has been examined to determine whether arm length or total length is the basis for recognition in distributive pairing. Recognition was judged by the frequency with which the (see PDF) nondisjoined from a series of X duplications (Dp), ranging in size from 4 times the size of a single fourth chromosome. Dp, (see PDF) nondisjunction was measured in the absence and in the presence of a competitor, a compound metacentric X. In both situations, total length and not arm length, was found to confer the characteristic recognition property to the (see PDF). A comparison of Dp, (see PDF) nondisjunction curves for both the noncompetitive and competitive situations with analogous Dp, 4 curves previously obtained, show the Dp, (see PDF) curves to be similar in shape to those obtained earlier but displaced one unit to the right, corresponding precisely to the difference in size between the (see PDF) and the 4. Rules governing chromosome recognition for acrocentrics were found completely applicable to metacentrics; disjunctive behavior of metacentrics differed from that of acrocentrics in that two arms conferred on a chromosome the capacity to act as the intermediate of a trivalent when size no longer warranted this attribute. This capacity, itself, is size-dependent.

Factors affecting recognition and disjunction of chromosomes at distributive pairing in female Drosophila melanogaster. II. The effect of a second arm.

The behavior of heterozygously inverted X chromosomes that were members of the distributive pool at least 70% of the time was studied when the other pool members were either two free 4's or one compound 4. The X's were structurally modified by additions or deletions of heterochromatin, so that the two homologues differed in both size and configuration or in size alone. In the noncompetitive situation, with two free 4's, recognition between the X's remained high despite the modifications, and primary X nondisjunction was low. In the competitive situation, with the compound 4, distributive nondisjunction of the X's increased approximately two orders of magnitude, and trivalent formation was indicated. Disjunction from the trivalent varied with X size and configuration. When both X's were acrocentric, the smaller X directed the larger X and the very small (see PDF) to the same pole; when the larger X carried a second arm, it assumed the directing role; when the size ratio of the smaller, one-armed X to the larger, two-armed X became less than approximately 5/9, the smaller X again directed the other two.