A protocol for a randomised clinical trial of the effect of providing feedback on inhaler technique and adherence from an electronic device in patients with poorly controlled severe asthma

ntroduction In clinical practice, it is difficult to distinguish between patients with refractory asthma from those with poorly controlled asthma, where symptoms persist due to poor adherence, inadequate inhaler technique or comorbid diseases. We designed an audio recording device which, when attached to an inhaler, objectively identifies the time and technique of inhaler use, thereby assessing both aspects of adherence. This study will test the hypothesis that feedback on these two aspects of adherence when passed on to patients improves adherence and helps clinicians distinguish refractory from difficult-to-control asthma. Methods This is a single, blind, prospective, randomised, clinical trial performed at 5 research centres. Patients with partially controlled or uncontrolled severe asthma who have also had at least one severe asthma exacerbation in the prior year are eligible to participate. The effect of two types of nurse-delivered education interventions to promote adherence and inhaler technique will be assessed. The active group will receive feedback on their inhaler technique and adherence from the new device over a 3-month period. The control group will also receive training in inhaler technique and strategies to promote adherence, but no feedback from the device. The primary outcome is the difference in actual adherence, a measure that incorporates time and technique of inhaler use between groups at the end of the third month. Secondary outcomes include the number of patients who remain refractory despite good adherence, and differences in the components of adherence after the intervention. Data will be analysed on an intention-to-treat and a per-protocol basis. The sample size is 220 subjects (110 in each group), and loss to follow-up is estimated at 10% which will allow results to show a 10% difference (0.8 power) in adherence between group means with a type I error probability of 0.05. Trial registration number NCT01529697; Pre-results

The effect of starting point placement technique on thoracic transverse process strength: an ex vivo biomechanical study

<p>Abstract</p> <p>Background</p> <p>The use of thoracic pedicle screws in spinal deformity, trauma, and tumor reconstruction is becoming more common. Unsuccessful screw placement may require salvage techniques utilizing transverse process hooks. The effect of different starting point placement techniques on the strength of the transverse process has not previously been reported. The purpose of this paper is to determine the biomechanical properties of the thoracic transverse process following various pedicle screw starting point placement techniques.</p> <p>Methods</p> <p>Forty-seven fresh-frozen human cadaveric thoracic vertebrae from T2 to T9 were disarticulated and matched by bone mineral density (BMD) and transverse process (TP) cross-sectional area. Specimens were randomized to one of four groups: A, control, and three others based on thoracic pedicle screw placement technique; B, straightforward; C, funnel; and D, in-out-in. Initial cortical bone removal for pedicle screw placement was made using a burr at the location on the transverse process or transverse process-laminar junction as published in the original description of each technique. The transverse process was tested measuring load-to-failure simulating a hook in compression mode. Analysis of covariance and Pearson correlation coefficients were used to examine the data.</p> <p>Results</p> <p>Technique was a significant predictor of load-to-failure (<it>P </it>= 0.0007). The least squares mean (LS mean) load-to-failure of group A (control) was 377 N, group B (straightforward) 355 N, group C (funnel) 229 N, and group D (in-out-in) 301 N. Significant differences were noted between groups A and C, A and D, B and C, and C and D. BMD (0.925 g/cm²[range, 0.624-1.301 g/cm²]) was also a significant predictor of load-to-failure, for all specimens grouped together (<it>P </it>< 0.0001) and for each technique (<it>P <</it>0.05). Level and side tested were not found to significantly correlate with load-to-failure.</p> <p>Conclusions</p> <p>The residual coronal plane compressive strength of the thoracic transverse process is dependent upon the screw starting point placement technique. The funnel technique significantly weakens transverse processes as compared to the straightforward technique, which does not significantly weaken the transverse process. It is also dependent upon bone mineral density, and low failure loads even in some control specimens suggest limited usefulness of the transverse process for axial compression loading in the osteoporotic thoracic spine.</p

ALDH Activity Selectively Defines an Enhanced Tumor-Initiating Cell Population Relative to CD133 Expression in Human Pancreatic Adenocarcinoma

Multiple studies in recent years have identified highly tumorigenic populations of cells that drive tumor formation. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit properties of normal stem cells and are associated with resistance to current therapies. As pancreatic adenocarcinoma is among the most resistant human cancers to chemo-radiation therapy, we sought to evaluate the presence of cell populations with tumor-initiating capacities in human pancreatic tumors. Understanding which pancreatic cancer cell populations possess tumor-initiating capabilities is critical to characterizing and understanding the biology of pancreatic CSCs towards therapeutic ends. cell populations were further examined for co-expression of CD44 and/or CD24. We demonstrate that unlike cell populations demonstrating low ALDH activity, as few as 100 cells enriched for high ALDH activity were capable of tumor formation, irrespective of CD133 expression. In direct xenograft tumors, the proportions of total tumor cells expressing ALDH and/or CD133 in xenograft tumors were unchanged through a minimum of two passages. We further demonstrate that ALDH expression among patients with pancreatic adenocarcinoma is heterogeneous, but the expression is constant in serial generations of individual direct xenograft tumors established from bulk human pancreatic tumors in NOD/SCID mice. phenotypes do not appear to significantly contribute to tumor formation at low numbers of inoculated tumor cells. ALDH expression broadly varies among patients with pancreatic adenocarcinoma and the apparent expression is recapitulated in serial generations of direct xenograft tumors in NOD/SCID. We have thus identified a distinct population of TICs that should lead to identification of novel targets for pancreatic cancer therapy

Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline. The aim is to assist clinicians caring for individuals with glomerulonephritis (GN), both adults and children. The scope includes various glomerular diseases, including IgA nephropathy and IgA vasculitis, membranous nephropathy, nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related GN, antineutrophil cytoplasmic antibody (ANCA) vasculitis, lupus nephritis, and anti-glomerular basement membrane antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations based on evidence syntheses, with useful infographics incorporating views from experts in the field. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad global audience of clinicians treating GN while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process whereby treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented

Towards disappearing user interfaces for ubiquitous computing: human enhancement from sixth sense to super senses

The enhancement of human senses electronically is possible when pervasive computers interact unnoticeably with humans in Ubiquitous Computing. The design of computer user interfaces towards “disappearing” forces the interaction with humans using a content rather than a menu driven approach, thus the emerging requirement for huge number of non-technical users interfacing intuitively with billions of computers in the Internet of Things is met. Learning to use particular applications in Ubiquitous Computing is either too slow or sometimes impossible so the design of user interfaces must be naturally enough to facilitate intuitive human behaviours. Although humans from different racial, cultural and ethnic backgrounds own the same physiological sensory system, the perception to the same stimuli outside the human bodies can be different. A novel taxonomy for Disappearing User Interfaces (DUIs) to stimulate human senses and to capture human responses is proposed. Furthermore, applications of DUIs are reviewed. DUIs with sensor and data fusion to simulate the Sixth Sense is explored. Enhancement of human senses through DUIs and Context Awareness is discussed as the groundwork enabling smarter wearable devices for interfacing with human emotional memories

Crystal Structure of Reovirus Attachment Protein σ1 in Complex with Sialylated Oligosaccharides

Many viruses attach to target cells by binding to cell-surface glycans. To gain a better understanding of strategies used by viruses to engage carbohydrate receptors, we determined the crystal structures of reovirus attachment protein σ1 in complex with α-2,3-sialyllactose, α-2,6-sialyllactose, and α-2,8-di-siallylactose. All three oligosaccharides terminate in sialic acid, which serves as a receptor for the reovirus serotype studied here. The overall structure of σ1 resembles an elongated, filamentous trimer. It contains a globular head featuring a compact β-barrel, and a fibrous extension formed by seven repeating units of a triple β-spiral that is interrupted near its midpoint by a short α -helical coiled coil. The carbohydrate-binding site is located between β-spiral repeats two and three, distal from the head. In all three complexes, the terminal sialic acid forms almost all of the contacts with σ1 in an identical manner, while the remaining components of the oligosaccharides make little or no contacts. We used this structural information to guide mutagenesis studies to identify residues in σ1 that functionally engage sialic acid by assessing hemagglutination capacity and growth in murine erythroleukemia cells, which require sialic acid binding for productive infection. Our studies using σ1 mutant viruses reveal that residues 198, 202, 203, 204, and 205 are required for functional binding to sialic acid by reovirus. These findings provide insight into mechanisms of reovirus attachment to cell-surface glycans and contribute to an understanding of carbohydrate binding by viruses. They also establish a filamentous, trimeric carbohydrate-binding module that could potentially be used to endow other trimeric proteins with carbohydrate-binding properties

Identification of Candidate Growth Promoting Genes in Ovarian Cancer through Integrated Copy Number and Expression Analysis

Ovarian cancer is a disease characterised by complex genomic rearrangements but the majority of the genes that are the target of these alterations remain unidentified. Cataloguing these target genes will provide useful insights into the disease etiology and may provide an opportunity to develop novel diagnostic and therapeutic interventions. High resolution genome wide copy number and matching expression data from 68 primary epithelial ovarian carcinomas of various histotypes was integrated to identify genes in regions of most frequent amplification with the strongest correlation with expression and copy number. Regions on chromosomes 3, 7, 8, and 20 were most frequently increased in copy number (>40% of samples). Within these regions, 703/1370 (51%) unique gene expression probesets were differentially expressed when samples with gain were compared to samples without gain. 30% of these differentially expressed probesets also showed a strong positive correlation (r≥0.6) between expression and copy number. We also identified 21 regions of high amplitude copy number gain, in which 32 known protein coding genes showed a strong positive correlation between expression and copy number. Overall, our data validates previously known ovarian cancer genes, such as ERBB2, and also identified novel potential drivers such as MYNN, PUF60 and TPX2

Between a Rock and a Hard Place: Habitat Selection in Female-Calf Humpback Whale (Megaptera novaeangliae) Pairs on the Hawaiian Breeding Grounds

The Au'au Channel between the islands of Maui and Lanai, Hawaii comprises critical breeding habitat for humpback whales (Megaptera novaeangliae) of the Central North Pacific stock. However, like many regions where marine mega-fauna gather, these waters are also the focus of a flourishing local eco-tourism and whale watching industry. Our aim was to establish current trends in habitat preference in female-calf humpback whale pairs within this region, focusing specifically on the busy, eastern portions of the channel. We used an equally-spaced zigzag transect survey design, compiled our results in a GIS model to identify spatial trends and calculated Neu's Indices to quantify levels of habitat use. Our study revealed that while mysticete female-calf pairs on breeding grounds typically favor shallow, inshore waters, female-calf pairs in the Au'au Channel avoided shallow waters (<20 m) and regions within 2 km of the shoreline. Preferred regions for female-calf pairs comprised water depths between 40–60 m, regions of rugged bottom topography and regions that lay between 4 and 6 km from a small boat harbor (Lahaina Harbor) that fell within the study area. In contrast to other humpback whale breeding grounds, there was only minimal evidence of typical patterns of stratification or segregation according to group composition. A review of habitat use by maternal females across Hawaiian waters indicates that maternal habitat choice varies between localities within the Hawaiian Islands, suggesting that maternal females alter their use of habitat according to locally varying pressures. This ability to respond to varying environments may be the key that allows wildlife species to persist in regions where human activity and critical habitat overlap

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Contribution of Microbe-Mediated Processes in Nitrogen Cycle to Attain Environmental Equilibrium

Nitrogen (N), the most important element, is required by all living organisms for the synthesis of complex organic molecules like amino acids, proteins, lipids etc. Nitrogen cycle is considered to be the most complex yet arguably important cycle next to carbon cycle. Nitrogen cycle includes oxic and anoxic reactions like organic N mineralization, ammonia assimilation, nitrification denitrification, anaerobic ammonium oxidation (anammox), dissimilatory nitrate reduction to ammonium (DNRA), comammox, codenitrification etc. Nitrogen cycling is one of the most crucial processes required for the recycling of essential chemical requirements on the planet. Soil microorganisms not only improve N-cycle balance but also pave the way for sustainable agricultural practices, leading to improved soil properties and crop productivity as most plants are opportunistic in the uptake of soluble or available forms of N from soil. Microbial N transformations are influenced by plants to improve their nutrition and vice versa. Diverse microorganisms, versatile metabolic activities, and varied biotic and abiotic conditions may result in the shift in the equilibrium state of different N-cycling processes. This chapter is an overview of the mechanisms and genes involved in the diverse microorganisms associated in the operation of nitrogen cycle and the roles of such microorganisms in different agroecosystems