Separating ventricular activity in thoracic EIT using 4D image-based FEM simulations

One challenge in central hemodynamic monitoring based on electrical impedance tomography (EIT) is to robustly detect ventricular signal components and the corresponding EIT image region without external monitoring information. Current stimulation and voltage measurement of EIT were simulated with finite element porcine torso models in presence of a multitude ofthoracic blood volume shifts. The simulated measurement data was examined for linear dependence on changes in stroke volume. Based onthe results the EIT measurement information regardingstroke volume changesis sparse

Alopecia in a Viable Phospholipase C Delta 1 and Phospholipase C Delta 3 Double Mutant

BACKGROUND: Inositol 1,4,5trisphosphate (IP(3)) and diacylglycerol (DAG) are important intracellular signalling molecules in various tissues. They are generated by the phospholipase C family of enzymes, of which phospholipase C delta (PLCD) forms one class. Studies with functional inactivation of Plcd isozyme encoding genes in mice have revealed that loss of both Plcd1 and Plcd3 causes early embryonic death. Inactivation of Plcd1 alone causes loss of hair (alopecia), whereas inactivation of Plcd3 alone has no apparent phenotypic effect. To investigate a possible synergy of Plcd1 and Plcd3 in postnatal mice, novel mutations of these genes compatible with life after birth need to be found. METHODOLOGY/PRINCIPAL FINDINGS: We characterise a novel mouse mutant with a spontaneously arisen mutation in Plcd3 (Plcd3(mNab)) that resulted from the insertion of an intracisternal A particle (IAP) into intron 2 of the Plcd3 gene. This mutation leads to the predominant expression of a truncated PLCD3 protein lacking the N-terminal PH domain. C3H mice that carry one or two mutant Plcd3(mNab) alleles are phenotypically normal. However, the presence of one Plcd3(mNab) allele exacerbates the alopecia caused by the loss of functional Plcd1 in Del(9)olt1Pas mutant mice with respect to the number of hair follicles affected and the body region involved. Mice double homozygous for both the Del(9)olt1Pas and the Plcd3(mNab) mutations survive for several weeks and exhibit total alopecia associated with fragile hair shafts showing altered expression of some structural genes and shortened phases of proliferation in hair follicle matrix cells. CONCLUSIONS/SIGNIFICANCE: The Plcd3(mNab) mutation is a novel hypomorphic mutation of Plcd3. Our investigations suggest that Plcd1 and Plcd3 have synergistic effects on the murine hair follicle in specific regions of the body surface

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Expression of genes relevant to the developing hair follicle.

<p>Total RNA or mRNA was prepared from dorsal skin biopsies of postnatal day 8 of wild-type (<i>Del(9)olt1Pas</i> heterozygous and <i>Plcd3^mNab</i> heterozygous), <i>oltSH</i> and <i>oltNH</i> mice and gene-specific fragments were amplified by PCR from 1 µg of cDNA. The number of PCR cycles is given below the image. The primers are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039203#pone.0039203.s003" target="_blank">Table S2</a>. The first strand was synthesised from mRNA preparations for all RT-PCR experiments with <i>Krtap</i> genes and actin* in the Figure. The limitation of PCR cycles gives a semi-quantitative estimate that <i>Foxn1</i>, <i>Msx2</i>, <i>Hoxc13</i>, <i>Pdgfa</i>, <i>Pdgfb</i>, <i>Shh</i>, <i>Bmp2</i> and <i>Bmp4</i>, as well as the hair keratins Krt35 and Krt86, and the IRS keratin (<i>Krt71</i>) are expressed at comparable levels in wild-type, <i>oltSH</i> and <i>oltNH</i> mutants on postnatal day 8, when the hair shaft in the specimens is being formed (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039203#pone-0039203-g004" target="_blank">Figure 4C and 4I</a>). However, <i>Crisp1</i> and <i>Krtap12-1</i>, and possibly also <i>Krtap4-2</i> and <i>Krtap8-2</i> are expressed at lower levels in <i>oltNH</i> mice compared to wild-type and <i>oltSH</i> mutants.</p

Histology of the infundibular region and distorted hair shafts.

<p>Methacrylate (Technovit 7100) sections of representative areas in the dorsal skin on postnatal day 9, HE stain. The phenotype (Wt, <i>olt</i> (i.e. <i>Del(9)olt1Pas</i>), <i>oltSH</i> or <i>oltNH</i>, respectively) and genotype with respect to the <i>Plcd1</i> (<i>Plcd1*</i> “-” refers to the <i>Del(9)olt1Pas</i> mutation) and <i>Plcd3</i> (Plcd3** “-” refers to the <i>Plcd3</i>^mNab allele) gene is indicated for each image. At least 4 biopsies of each genotype have been investigated. In E, Bar  = 25 µm. These is no hair loss and are no distorted hair shafts neither in wild-type mice heterozygous for both mutant alleles (A), nor those heterozygous for the <i>Del(9)olt1Pas</i> mutation and homozygous for the <i>Plcd3</i>^mNab allele (B), nor others being wild-type for <i>Plcd1</i> and homozygous for the <i>Plcd3</i>^mNab mutant allele (C). Arrows indicate normal hair shafts. Arrowheads mark distorted hair shafts in <i>Del(9)olt1Pas</i> (<i>olt</i>), <i>oltSH</i> and <i>oltNH</i> mice. The alterations of the hair shafts appear histologically similar in all three mutant specimens.</p

Histological aspects of <i>oltSH</i> mutants on postnatal day 12.

<p>Methacrylate (Technovit 7100) sections of representative areas in the dorsal skin on postnatal day 12 <i>oltSH</i> mice, HE stain, bar  = 100 µm in A, bar  = 25 µm in B to D. Boxed areas in A are shown at higher magnification B, C, and D respectively. Four different animals were investigated. A. The overview shows hair follicles in anagen (box B) and catagen (box C) side by side. B. The hair follicle shows active melanogenesis as a hallmark of anagen (arrowhead). C. The hair follicle is in catagen and has excluded the dermal papilla (arrowhead). D. Accumulations of neutrophilic granulocytes (arrowhead) are seen in the vicinity of follicles in catagen.</p

Histomorphometric analysis of hair follicle length and hair bulb diameter.

<p>Measurements were taken from a sample of 150 hair follicles in three different biopsies using the Image J software. Statistical analysis using the paired t-Test was performed employing the GraphPad Prism4 software. Data are expressed as mean ± SEM. *** signifies p<0.001. White columns depict data from wild-type mice and chequered columns those from <i>oltNH</i> mice. The age of the mice is given on the X axis. Hair follicle length represents the distance from the infundibulum to the most distal part of the hair follicle. The widest diameter of the hair bulb or distal end of the hair follicle in catagen and telogen stages is shown as “hair bulb diameter”. Both parameters indicate that <i>oltNH</i> mice terminate their first postnatal anagen by day 14 and re-initiate a growth phase thereafter, which in turn ends by day 24. The second cyclic growth phase of <i>oltNH</i> hair follicles ends by day 37.</p

Proliferation in wild-type and <i>oltNH</i> hair follicles.

<p>Proliferation in the hair follicles of wild-type (A, B, C, D, E) and <i>oltNH</i> (<i>del(9)olt1Pas</i> −/−, <i>Plcd3^mNab</i> −/−) (F, G, H, I, J) dorsal skin on postnatal day 2 (A, F), day 6 (B, G), day 8 (C, H), day 11 (D, I), and day 12 (E, J) is visualised by PCNA immunoreactivity (red signal). DAPI was used as a nuclear counter stain (blue signal). Paraffin sections. Bar  = 50 µm for all images is given in A. White arrowheads mark the hair bulb. Three biopsies from different animals were used for each time point investigated. In wild-type mice, PCNA immunoreactivity is detected in the nuclei of the matrix cells of the hair bulb throughout the period examined (arrowheads in A to E). In the <i>oltNH</i> mutant, the PCNA immunoreactivity is prominent in the matrix on days 2 and 6 (arrowheads in F and G), while already on day 8 some hair bulbs show much fainter immunoreactivity (right arrowhead in H). In the trailing ends of the hair follicles on days 11 the immunoreactivity is very faint (arrowheads in I), and on day 12 undetectable (arrowhead in J). Note that there is no PCNA immunoreactivity in the cells of the dermal papilla.</p

Apoptosis in <i>oltNH</i> hair follicles.

<p>Apoptosis was investigated by performing the TUNEL assay on paraffin sections. Apoptosis is visualised by Cy3 fluorescence (red signal). DAPI was used as a nuclear counterstain (blue signal). Sections were taken from skin biopsies of <i>oltNH</i> mice (A to G) from postnatal day 2 to 25. A wild-type skin section on postnatal day 13 is shown as control (H). Three biopsies from different animals were used for each time point investigated. Arrows mark the hair bulb (B) or the trailing ends (T) of regressing hair follicles. Arrowheads point at TUNEL positive cells. There are numerous TUNEL positive cells in the matrix of <i>oltNH</i> hair follicles beginning on days 6 and 8 (arrow heads in B and C) and the regressing follicles on day 11 to 13. On day 25, the <i>oltNH</i> hair follicle re-enters anagen and shows no TUNEL positive cells (arrow in G). Throughout this period, there were no TUNEL positive cells in the hair bulbs of wild-type mice (not shown), only some cells in the inner root sheath exhibited a TUNEL positive signal (arrowheads in H), while the medulla showed unspecific autofluorescence. E, epidermis. Bar in E  = 50 µm for all images.</p