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.</p

Patient Referral Patterns and the Spread of Hospital-Acquired Infections through National Health Care Networks

Rates of hospital-acquired infections, such as methicillin-resistant Staphylococcus aureus (MRSA), are increasingly used as quality indicators for hospital hygiene. Alternatively, these rates may vary between hospitals, because hospitals differ in admission and referral of potentially colonized patients. We assessed if different referral patterns between hospitals in health care networks can influence rates of hospital-acquired infections like MRSA. We used the Dutch medical registration of 2004 to measure the connectedness between hospitals. This allowed us to reconstruct the network of hospitals in the Netherlands. We used mathematical models to assess the effect of different patient referral patterns on the potential spread of hospital-acquired infections between hospitals, and between categories of hospitals (University medical centers, top clinical hospitals and general hospitals). University hospitals have a higher number of shared patients than teaching or general hospitals, and are therefore more likely to be among the first to receive colonized patients. Moreover, as the network is directional towards university hospitals, they have a higher prevalence, even when infection control measures are equally effective in all hospitals. Patient referral patterns have a profound effect on the spread of health care-associated infections like hospital-acquired MRSA. The MRSA prevalence therefore differs between hospitals with the position of each hospital within the health care network. Any comparison of MRSA rates between hospitals, as a benchmark for hospital hygiene, should therefore take the position of a hospital within the network into account

Differential miRNA expression profiles in cumulus and mural granulosa cells from human pre-ovulatory follicles

BACKGROUND: mural granulosa cells (MGCs) and cumulus cells (CCs) are two specialized cell types that differentiate from a common progenitor during folliculogenesis. Although these two cell types have specialized functions and gene expression profiles, little is known about their microRNA (miRNA) expression patterns.OBJECTIVE: to describe the miRNA profile of mural and cumulus granulosa cells from human pre-ovulatory follicles Methods: using small RNA sequencing, we definedinvestigated the miRNA expression profiles of human primary MGCs and CCs, isolated from healthy women undergoing ovum pick-up for in vitro fertilization (IVF).RESULTS: small RNA sequencing revealed expression of several hundreds of miRNAs in MGCsMGC and CCsCC with 53 miRNAs being significantly differentially expressed between MGCs and CCs. We validated differential expression for miR-146a-5p, miR-149-5p, miR-509-3p and miR-182-5p by RT-qPCR. Analysis of proven targets revealed 37 targets for miR-146a-5p, 43 for miR-182-5p, 2 for miR-509-3p and 9 for miR-149-5p. Gene ontology (GO) analysis for these 4 target gene sets revealed enrichment of 12 GO terms for miR-146a-5p and 10 for miR-182-5p. The GO term ubiquitin-like protein conjugation was enriched within both miRNA target gene sets.CONCLUSION: we generated miRNA expression profiles for MGCs and CCs and identified several differentially expressed miRNAs.</p

Systemic treatment of hormone receptor positive, human epidermal growth factor 2 negative metastatic breast cancer: retrospective analysis from Leeds Cancer Centre

Background Study aimed to characterise treatment and outcomes for patients with hormone receptor positive (HR+), human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (MBC) within a large regional cancer centre, as a benchmark for evaluating real-world impact of novel therapies. Methods Retrospective longitudinal cohort, using electronic patient records of adult females with a first diagnosis of HR+/HER2- MBC January 2012–March 2018. Results One hundred ninety-six women were identified with HR+/HER2- MBC. Median age was 67 years, 85.2% were post-menopausal and median time between primary diagnosis and metastasis was 5.4 years. Most (75.1%) patients received endocrine therapy as first line systemic treatment (1st LoT); use of 1st LoT chemotherapy halved between 2012 and 2017. Patients receiving 1st LoT chemotherapy were younger and more likely to have visceral metastasis (p < 0.01). Median OS was 29.5 months and significantly greater for patients with exclusively non-visceral metastasis (p < 0.01). The adjusted hazard ratio for death of patients with visceral (or CNS) metastasis was 1.91 relative to those with exclusively non-visceral metastasis. Conclusions Diverse endocrine therapies predominate as 1st LoT for patients with HR+/HER2- MBC, chemotherapy being associated with more aggressive disease in younger patients, emphasising the importance of using effective and tolerable therapies early

Not just a matter of size:a hospital-level risk factor analysis of MRSA bacteraemia in Scotland

Background: Worldwide, there is a wealth of literature examining patient-level risk 6 factors for methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. At the hospital-level it is generally accepted that MRSA bacteraemia is more common in larger hospitals. In Scotland, size does not fully explain all the observed variation among hospitals. The aim of this study was to identify risk factors for the presence and rate of MRSA bacteraemia cases in Scottish mainland hospitals. Specific hypotheses regarding hospital size, type and connectivity were examined. Methods: Data from 198 mainland Scottish hospitals (defined as having at least one inpatient per year) were analysed for financial year 2007-08 using logistic regression (Model 1: presence/absence of MRSA bacteraemia) and Poisson regression (Model 2: rate of MRSA bacteraemia). The significance of risk factors representing various measures of hospital size, type and connectivity were investigated. Results: In Scotland, size was not the only significant risk factor identified for the presence and rate of MRSA bacteraemia. The probability of a hospital having at least one case of MRSA bacteraemia increased with hospital size only if the hospital exceeded a certain level of connectivity. Higher levels of MRSA bacteraemia were associated with the large, highly connected teaching hospitals with high ratios of patients to domestic staff. Conclusions: A hospital’s level of connectedness within a network may be a better measure of a hospital’s risk of MRSA bacteraemia than size. This result could be used to identify high risk hospitals which would benefit from intensified infection control measures

Recruitment of trimeric eIF2 by phosphatase non-catalytic subunit PPP1R15B

Regulated protein phosphorylation controls most cellular processes. The protein phosphatase PP1 is the catalytic subunit of many holoenzymes that dephosphorylate serine/threonine residues. How these enzymes recruit their substrates is largely unknown. Here, we integrated diverse approaches to elucidate how the PP1 non-catalytic subunit PPP1R15B (R15B) captures its full trimeric eIF2 substrate. We found that the substrate-recruitment module of R15B is largely disordered with three short helical elements, H1, H2, and H3. H1 and H2 form a clamp that grasps the substrate in a region remote from the phosphorylated residue. A homozygous N423D variant, adjacent to H1, reducing substrate binding and dephosphorylation was discovered in a rare syndrome with microcephaly, developmental delay, and intellectual disability. These findings explain how R15B captures its 125 kDa substrate by binding the far end of the complex relative to the phosphosite to present it for dephosphorylation by PP1, a paradigm of broad relevance.</p

Low-frequency Raman study of the ferroelectric phase transition in a layered CuCl4-based organic-inorganic hybrid

The ferroelectric phase transition at TC = 340 K in (C6H5CH2CH2NH3)2CuCl4 is studied by means of temperature-dependent low-frequency Raman scattering, focusing on the coupling of a low-energy librational mode to the order parameter of the transition. Analysis of the symmetry and characteristics of this mode links the dipolar order to the tilt angle of the organic cations. The thermal evolution of the Raman spectrum demonstrates the displacive component of the phase transition in combinationwith order-disorder phenomena and the importance of the organic-inorganic interplay to the physical properties of the compound. The ferroelectric properties investigated here can be generalized to the family of layered organic-inorganic hybrids.

Cost-effectiveness of blended vs. face-to-face cognitive behavioural therapy for severe anxiety disorders: study protocol of a randomized controlled trial

Background: Anxiety disorders are among the most prevalent psychiatric conditions, and are associated with poor quality of life and substantial economic burden. Cognitive behavioural therapy is an effective treatment to reduce anxiety symptoms, but is also costly and labour intensive. Cost-effectiveness could possibly be improved by delivering cognitive behavioural therapy in a blended format, where face-to-face sessions are partially replaced by online sessions. The aim of this trial is to determine the cost-effectiveness of blended cognitive behavioural therapy for adults with anxiety disorders, i.e. panic disorder, social phobia or generalized anxiety disorder, in specialized mental health care settings compared to face-to-face cognitive behavioural therapy. In this paper, we present the study protocol. It is hypothesized that blended cognitive behavioural therapy for anxiety disorders is clinically as effective as face-to-face cognitive behavioural therapy, but that intervention costs may be reduced. We thus hypothesize that blended cognitive behavioural therapy is more cost-effective than face-to-face cognitive behavioural therapy. Methods/design: In a randomised controlled equivalence trial 156 patients will be included (n = 78 in blended cognitive behavioural therapy, n = 78 in face-to-face cognitive behavioural therapy) based on a power of 0.80, calculated by using a formula to estimate the power of a cost-effectiveness analysis: $n = \frac{2(z_\alpha + z_\beta)^2(sd^2 + (W^2sd^2) - (2Wpsd_csd_q))}{(WE-C)^2}$ Measurements will take place at baseline, midway treatment (7 weeks), immediately after treatment (15 weeks) and 12-month follow-up. At baseline a diagnostic interview will be administered. Primary clinical outcomes are changes in anxiety symptom severity as measured with the Beck Anxiety Inventory. An incremental cost-effectiveness ratio will be calculated to obtain the costs per quality-adjusted life years (QALYs) measured by the EQ-5D (5-level version). Health-economic outcomes will be explored from a societal and health care perspective. Discussion: This trial will be one of the first to provide information on the cost-effectiveness of blended cognitive behavioural therapy for anxiety disorders in routine specialized mental health care settings, both from a societal and a health care perspective