title: Targeting Intrinsically Disordered Proteins through Dynamic Interactions

text: Intrinsically disordered proteins (IDPs) are over-represented in major disease pathways and have attracted significant interest in understanding if and how they may be targeted using small molecules for therapeutic purposes. While most existing studies have focused on extending the traditional structure-centric drug design strategies and emphasized exploring pre-existing structure features of IDPs for specific binding, several examples have also emerged to suggest that small molecules could achieve specificity in binding IDPs and affect their function through dynamic and transient interactions. These dynamic interactions can modulate the disordered conformational ensemble and often lead to modest compaction to shield functionally important interaction sites. Much work remains to be done on further elucidation of the molecular basis of the dynamic small molecule–IDP interaction and determining how it can be exploited for targeting IDPs in practice. These efforts will rely critically on an integrated experimental and computational framework for disordered protein ensemble characterization. In particular, exciting advances have been made in recent years in enhanced sampling techniques, Graphic Processing Unit (GPU)-computing, and protein force field optimization, which have now allowed rigorous physics-based atomistic simulations to generate reliable structure ensembles for nontrivial IDPs of modest sizes. Such de novo atomistic simulations will play crucial roles in exploring the exciting opportunity of targeting IDPs through dynamic interactions.


title: Serum Metabolomics Revealed the Differential Metabolic Pathway in Calves with Severe Clinical Diarrhea Symptoms

text: SIMPLE SUMMARY: The present study focuses on the metabolic changes in the diarrhea of calves, which are manifested with the following symptoms: a thin water-like stool, cold ears and nose, throbbing bowels, oliguria, a pale or yellowish complexion, a smooth mouth, and a slow pulse. The differential metabolic pathways in calves with diarrhea were screened by metabolomics. There were nine biomarkers in the serum of healthy calves and calves with diarrhea. On the basis of these biomarkers, their associated mineral absorption, protein digestion and absorption, and other metabolic pathways, the targeted regulation of the metabolic differences of calves with diarrhea may contribute to the diagnosis, treatment, and discussion of the mechanism of calf diarrhea. ABSTRACT: The complex etiology, higher morbidity and mortality, poor prognosis, and expensive cost of calf diarrhea have made it a catastrophic disease in the dairy industry. This study aims to assess the biomarkers in calves with diarrhea and to predict the biomarkers related to the pathway. As subjects, nine calves with diarrhea and nine healthy calves were enrolled, according to strict enrollment criteria. The serum metabolites were detected by a liquid chromatographic tandem mass spectrometry (LC-MS/MS), and then analyzed by online multivariate statistical analysis software to further screen the biomarkers. In addition, the biomarkers involved in the metabolic pathways of calves with diarrhea and healthy calves were analyzed. In the serum of calves with diarrhea, nine biomarkers were found to which several biomarkers exhibited a certain relation. Moreover, these biomarkers were involved in important metabolic pathways, including protein digestion and absorption, ABC transporters, aminoacyl-tRNA biosynthesis, mineral absorption, and fatty acid biosynthesis. All these findings suggested that the imbalance of these markers was closely related to the occurrence and development of calf diarrhea. The targeted regulation of metabolic pathways involved in these biomarkers may facilitate the diagnosis, treatment, and discussion of the mechanism of calf diarrhea.


title: Study of the Metabolomics of Equine Preovulatory Follicular Fluid: A Way to Improve Current In Vitro Maturation Media

text: SIMPLE SUMMARY: Commercial in vitro embryo production in horses by ICSI (intracytoplasmic sperm injection) is currently used to produce embryos clinically. However, the successful pregnancy and foaling rates obtained after ICSI are only 10% of the oocytes matured in vitro. Conditions used for oocyte in vitro maturation are not optimized for equine oocytes. Hence, in the present work, we aimed to elucidate the major metabolites present in equine preovulatory follicular fluid obtained from postmortem mares using proton nuclear magnetic resonance spectroscopy ((1)H-NMR). Twenty-two metabolites were identified; among these, nine of them are not included in the composition of in vitro maturation media. Hence, our data suggest that the currently used media for equine oocyte maturation can be further improved. ABSTRACT: Production of equine embryos in vitro is currently a commercial technique and a reliable way of obtaining offspring. In order to produce those embryos, immature oocytes are retrieved from postmortem ovaries or live mares by ovum pick-up (OPU), matured in vitro (IVM), fertilized by intracytoplasmic sperm injection (ICSI), and cultured until day 8–10 of development. However, at best, roughly 10% of the oocytes matured in vitro and followed by ICSI end up in successful pregnancy and foaling, and this could be due to suboptimal IVM conditions. Hence, in the present work, we aimed to elucidate the major metabolites present in equine preovulatory follicular fluid (FF) obtained from postmortem mares using proton nuclear magnetic resonance spectroscopy ((1)H-NMR). The results were contrasted against the composition of the most commonly used media for equine oocyte IVM: tissue culture medium 199 (TCM-199) and Dulbecco’s modified eagle medium/nutrient mixture F-12 Ham (DMEM/F-12). Twenty-two metabolites were identified in equine FF; among these, nine of them are not included in the composition of DMEM/F-12 or TCM-199 media, including (mean ± SEM): acetylcarnitine (0.37 ± 0.2 mM), carnitine (0.09 ± 0.01 mM), citrate (0.4 ± 0.04 mM), creatine (0.36 ± 0.14 mM), creatine phosphate (0.36 ± 0.05 mM), fumarate (0.05 ± 0.007 mM), glucose-1-phosphate (6.9 ± 0.4 mM), histamine (0.25 ± 0.01 mM), or lactate (27.3 ± 2.2 mM). Besides, the mean concentration of core metabolites such as glucose varied (4.3 mM in FF vs. 5.55 mM in TCM-199 vs. 17.5 mM in DMEM/F-12). Hence, our data suggest that the currently used media for equine oocyte IVM can be further improved.


title: Epidemiology of firearm injuries in a Scandinavian trauma center

text: BACKGROUND: There is a concern that civilian gunshot injuries in Europe are increasing but there is a lack of contemporary studies. The purpose of this study was to investigate the current epidemiology and outcome of firearm injuries. METHODS: Retrospective cohort study of all patients (n = 235) treated for firearm injuries admitted to a Scandinavian trauma center between 2005 and 2016. Local and national trauma registries were used for data collection. RESULTS: Mean age was 31.3 years (SD ± 12.9; range 16–88 years); 93.6% males; mean ISS was 14.3 (SD ± 15.9); 31.9% (75/235) had ISS > 15. There was a significant increase in penetrating trauma (P < 0.001) and firearm injuries (P < 0.001) over the years. The most common anatomical location of firearm injury was the lower extremity, (n = 138/235; 38%), followed by the abdomen (n = 69;19%), upper extremity (n = 53;15%), chest (n = 50; 14%), and head and neck (n = 50; 14%). Ninety patients (38.3%) had more than one anatomic injury location. There were in total 360 firearm injuries and 168 major surgical procedures were performed. 53% (n = 125) of patients underwent at least one surgical procedure. The most common procedures were fracture surgery 42% (n = 70/168), followed by laparotomy 30%% (n = 51), chest tube 17% (n = 29), and thoracotomy 11% (n = 18). Forty-one patients (17%) had at least one major vascular injury (n = 54). The most common vascular injury was lower extremity vessel injuries, 26/54 (48%), followed by vessels in chest and abdomen. There was a significant increase in vascular injuries during the study period (P < 0.006). The 30-day mortality was 12.8% (n = 30); 24 patients died within 24 h mainly due to injuries to the chest and the head and neck region. CONCLUSIONS: Firearm injuries cause significant morbidity and mortality and are an important medical and public health problem. In a Scandinavian trauma center there has been an increase of firearm injuries in recent years. The lower extremities followed by the abdomen are the dominating injured regions and there has been an increase in associated vascular injuries.


title: Antiedematogenic and Anti-Inflammatory Activity of the Monoterpene Isopulegol and Its β-Cyclodextrin (β-CD) Inclusion Complex in Animal Inflammation Models

text: Isopulegol (ISO) is an alcoholic monoterpene widely found in different plant species, such as Melissa officinalis, and has already been reported to have a number of pharmacological properties. Like other terpenes, ISO is a highly volatile compound that is slightly soluble in water, so its inclusion into cyclodextrins (CDs) is an interesting approach to increase its solubility and bioavailability. Thus, our aim was to evaluate the antiedematogenic and anti-inflammatory activity of isopulegol and a β-cyclodextrin–isopulegol inclusion complex (ISO/β-CD) in rodent models. For the anti-inflammatory activity evaluation, antiedematogenic plethysmometry and acute (peritonitis and pleurisy), as well as chronic (cotton pellet-induced granuloma) anti-inflammatory models, were used. The docking procedure is used to evaluate, analyze, and predict their binding mode of interaction with H1 and Cox-2 receptors. The animals (n = 6) were divided into groups: ISO and ISO/β-CD, negative control (saline), and positive control (indomethacin and promethazine). ISO and ISO/β-CD were able to reduce acute inflammatory activity by decreasing albumin extravasation, leukocyte migration, and MPO concentration, and reducing exudate levels of IL-1β and TNF-α. ISO and ISO/β-CD significantly inhibited edematogenic activity in carrageenan- and dextran-induced paw edema. Moreover, both significantly reduced chronic inflammatory processes, given the lower weight and protein concentration of granulomas in the foreign body granulomatous inflammation model. The results suggest that the inclusion of ISO in β-cyclodextrins improves its pharmacological properties, with the histamine and prostaglandin pathways as probable mechanisms of inhibition, and also reinforces the anti-inflammatory profile of this terpene.


title: EDEM1 Drives Misfolded Protein Degradation via ERAD and Exploits ER-Phagy as Back-Up Mechanism When ERAD Is Impaired

text: Endoplasmic reticulum (ER)-associated degradation (ERAD) is the main mechanism of targeting ER proteins for degradation to maintain homeostasis, and perturbations of ERAD lead to pathological conditions. ER-degradation enhancing α-mannosidase-like (EDEM1) was proposed to extract terminally misfolded proteins from the calnexin folding cycle and target them for degradation by ERAD. Here, using mass-spectrometry and biochemical methods, we show that EDEM1 is found in auto-regulatory complexes with ERAD components. Moreover, the N-terminal disordered region of EDEM1 mediates protein–protein interaction with misfolded proteins, whilst the absence of this domain significantly impairs their degradation. We also determined that overexpression of EDEM1 can induce degradation, even when proteasomal activity is severely impaired, by promoting the formation of aggregates, which can be further degraded by autophagy. Therefore, we propose that EDEM1 maintains ER homeostasis and mediates ERAD client degradation via autophagy when either dislocation or proteasomal degradation are impaired.


title: Ophthalmology of clinically normal alpacas (Vicugna pacos) in the United Kingdom: a cross-sectional study

text: BACKGROUND: Alpacas are being more frequently presented to veterinarians in the UK. It is important to validate whether published normal ocular parameters are consistent with the alpaca population in the UK. METHODS: Ophthalmic examinations were performed on healthy alpacas (Vicugna pacos) from three farms in East Anglia, UK. RESULTS: On direct ophthalmoscopy of 35 alpacas, there was a 50 per cent prevalence of opacities within the lens in alpacas older than two years old (n=8/16). There was a 36.8 per cent prevalence of persistent hyaloid arteries in alpacas under two years old (n=7/19). The mean Schirmer tear test-1 value was 20.0 ±6 mm/minute (n=40). The mean intraocular pressure measured by rebound tonometry was 17.2 ±5.5 mmHg (n=46), and applanation tonometry resulted in statistically similar values (P=0.30; n=25). There was a significant variation in intraocular pressure throughout a 24-hour period (n=8). Fluorescein dye was not detected at the nostrils of any of the alpacas which underwent a Jones test to assess nasolacrimal duct patency (n=8). CONCLUSION: The ophthalmic findings appear largely consistent with previously published values from North America and continental Europe. Variations include the large range of measurements obtained and evidence of diurnal variation in intraocular pressure.


title: Characterising keratometry in different dog breeds using an automatic handheld keratometer

text: BACKGROUND: Keratometry is clinically important and is routinely performed as part of human ophthalmic examination. In veterinary ophthalmology, little is known about keratometry in dogs, and its practical application has been limited. The present study aimed to describe keratometry in some dog breeds popular in Japan using a handheld keratometer. METHODS: Client-owned dogs of various signalment were enrolled prospectively in the keratometry examination. Interbreed variations in mean corneal curvatures (R1R2avg) and corneal astigmatism (Δ(R1−R2)) were evaluated statistically with respect to their bodyweight based on the data which fulfilled the predetermined inclusion criteria. P<0.05 was considered statistically significant. RESULTS: On examination of 237 dogs from 16 different breeds, R1R2avg (mean±sd) ranged from 7.54±0.30 mm in Pomeranians to 9.28±0.19 mm in golden retrievers. Δ(R1−R2) (mean±sd) ranged from 0.22±0.11 mm in miniature schnauzers to 0.57±0.30 mm in French bulldogs. CONCLUSION: The present study successfully described keratometry in 16 dog breeds. The study revealed considerable interbreed variations in both R1R2avg and Δ(R1−R2), which did not necessarily correlate with bodyweight. These results are useful both clinically in fitting contact lenses in the management of corneal diseases and non-clinically in optometric studies in dogs.


title: Identification of the MAPK Cascade and its Relationship with Nitrogen Metabolism in the Green Alga Chlamydomonas reinhardtii

text: The mitogen activated protein kinases (MAPKs) form part of a signaling cascade through phosphorylation reactions conserved in all eukaryotic organisms. The MAPK cascades are mainly composed by three proteins, MAPKKKs, MAPKKs and MAPKs. Some signals induce MAPKKK-mediated phosphorylation and activation of MAPKK that phosphorylate and activate MAPK. Afterward, MAPKs can act either in the cytoplasm or be imported into the nucleus to activate other proteins or transcription factors. In the green microalga Chlamydomonas reinhardtii the pathway for nitrogen (N) assimilation is well characterized, yet its regulation still has many unknown features. Nitric oxide (NO) is a fundamental signal molecule for N regulation, where nitrate reductase (NR) plays a central role in its synthesis. The MAPK cascades could be regulating N assimilation, since it has been described that the phosphorylation of NR by MAPK6 promotes NO production in Arabidopsis thaliana. We have identified the proteins involved in the MAPK cascades in Chlamydomonas reinhardtii, finding 17 MAPKs, 2 MAPKKs and 108 MAPKKKs (11 MEKK-, 94 RAF- and 3 ZIK-type) that have been structurally and phylogenetically characterized. The genetic expressions of MAPKs and the MAPKK were slightly regulated by N. However, the genetic expressions of MAPKKKs RAF14 and RAF79 showed a very strong repression by ammonium, which suggests that they may have a key role in the regulation of N assimilation, encouraging to further analyze in detail the role of MAPK cascades in the regulation of N metabolism.


title: The KOMPACT-P study: Knee Osteoarthritis Management with Physiotherapy informed by Acceptance and Commitment Therapy—Pilot study protocol

text: INTRODUCTION: Incidence of total knee arthroplasty (TKA) is projected to rise 276% in 2030, and psychological distress affects up to 42% of people with knee osteoarthritis undergoing TKA, with demonstrated detrimental effects on postoperative outcomes. Few studies have assessed psychological treatment in people awaiting TKA, and these have been psychologist-delivered treatments. No evidence exists regarding psychologically-informed interventions delivered by health professionals currently embedded in TKA clinical pathways. The primary aim of this pilot study is to explore the safety, acceptability and feasibility of the Knee Osteoarthritis Management with Physiotherapy informed by Acceptance and Commitment Therapy (KOMPACT) approach in people awaiting TKA. METHODS AND ANALYSIS: 51 community-dwelling adults scheduled for a primary TKA at two hospitals will be recruited to this pilot, mixed-methods, prospective randomised controlled trial with assessor blinding. Participants will be randomised in a 1:2 ratio to either usual care (education class) or usual care plus KOMPACT (2 hours 20 min of preoperative physiotherapy informed by Acceptance and Commitment Therapy). Our primary outcome measures are safety (length of stay, complications and psychological health after KOMPACT), acceptability (treatment credibility and qualitative data) and feasibility (recruitment, retention and intervention fidelity) of the KOMPACT approach. Secondary outcomes include health service outcomes, patient-reported physical and psychological outcomes, and physical performance measures. Quantitative data collection was conducted at baseline, 1–2 weeks before TKA, 6 weeks after TKA and 6 months after TKA. Qualitative data collection is 1–2 weeks before TKA. Data analysis will take a quantitative-led approach with triangulation after thematic analysis of the qualitative data. ETHICS AND DISSEMINATION: This study has full ethics approval (HREC/18/WMEAD/440). Results from this study will be published in peer-reviewed journals and presented at local and international conferences. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry (ACTRN12618001867280p).


title: Targeting the C-Terminal Domain Small Phosphatase 1

text: The human C-terminal domain small phosphatase 1 (CTDSP1/SCP1) is a protein phosphatase with a conserved catalytic site of DXDXT/V. CTDSP1’s major activity has been identified as dephosphorylation of the 5th Ser residue of the tandem heptad repeat of the RNA polymerase II C-terminal domain (RNAP II CTD). It is also implicated in various pivotal biological activities, such as acting as a driving factor in repressor element 1 (RE-1)-silencing transcription factor (REST) complex, which silences the neuronal genes in non-neuronal cells, G1/S phase transition, and osteoblast differentiation. Recent findings have denoted that negative regulation of CTDSP1 results in suppression of cancer invasion in neuroglioma cells. Several researchers have focused on the development of regulating materials of CTDSP1, due to the significant roles it has in various biological activities. In this review, we focused on this emerging target and explored the biological significance, challenges, and opportunities in targeting CTDSP1 from a drug designing perspective.


title: Development of a Portable SPR Sensor for Nucleic Acid Detection

text: Nucleic acid detection is of great significance in clinical diagnosis, environmental monitoring and food safety. Compared with the traditional nucleic acid amplification detection method, surface plasmon resonance (SPR) sensing technology has the advantages of being label-free, having simple operation, and providing real-time detection. However, the angle scanning system in many SPR angle modulation detection applications usually requires a high-resolution stepper motor and complex mechanical structure to adjust the angle. In this paper, a portable multi-angle scanning SPR sensor was designed. The sensor only uses one stepping motor to rotate a belt, and the belt pulls the mechanical linkages of incident light and reflected light to move in opposite directions for achieving the SPR angle scanning mode that keeps the incident angle and reflected angle equal. The sensor has an angle scanning accuracy of 0.002°, response sensitivity of 3.72 × 10(−6) RIU (refractive index unit), and an angle scanning range of 30°–74°. The overall size of the system is only 480 mm × 150 mm × 180 mm. The portable SPR sensor was used to detect nucleic acid hybridization on a gold film chip modified with bovine serum albumin (BSA). The result revealed that the sensor had high sensitivity and fast response, and could successfully accomplish the hybridization detection of target DNA solution of 0.01 μmol/mL.


title: Impact and Diagnostic Gaps of Comprehensive Genomic Profiling in Real-World Clinical Practice

text: Purpose: next-generation sequencing based comprehensive genomic profiling (CGP) is becoming common practice. Although numerous studies have shown its feasibility to identify actionable genomic alterations in most patients, its clinical impact as part of routine management across all cancers in the community remains unknown. Methods: we conducted a retrospective study of all patients that underwent CGP as part of routine cancer management from January 2013 to June 2017 at an academic community-based NCI-designated cancer center. CGP was done in addition to established first tier reflex molecular testing as per national guidelines (e.g., EGFR/ALK for non-small cell lung cancer (NSCLC) and extended-RAS for colorectal cancer). Results: 349 tests were sent for CGP from 333 patients and 95% had at least one actionable genomic alteration reported. According to the reported results, 23.2% had a Food and Drug Administration (FDA) approved therapy available, 61.3% had an off-label therapy available and 77.9% were potentially eligible for a clinical trial. Treatment recommendations were also reviewed within the OncoKB database and 47% of them were not clinically validated therapies. The CGP results led to treatment change in only 35 patients (10%), most commonly in NSCLC. Nineteen of these patients (54% of those treated and 5% of total) had documented clinical benefit with targeted therapy. Conclusion: we demonstrate that routine use of CGP in the community across all cancer types detects potentially actionable genomic alterations in a majority of patients, however has modest clinical impact enriched in the NSCLC subset.


title: mRNA stem-loops can pause the ribosome by hindering A-site tRNA binding

text: Although the elongating ribosome is an efficient helicase, certain mRNA stem-loop structures are known to impede ribosome movement along mRNA and stimulate programmed ribosome frameshifting via mechanisms that are not well understood. Using biochemical and single-molecule Förster resonance energy transfer (smFRET) experiments, we studied how frameshift-inducing stem-loops from E. coli dnaX mRNA and the gag-pol transcript of Human Immunodeficiency Virus (HIV) perturb translation elongation. We find that upon encountering the ribosome, the stem-loops strongly inhibit A-site tRNA binding and ribosome intersubunit rotation that accompanies translation elongation. Electron cryo-microscopy (cryo-EM) reveals that the HIV stem-loop docks into the A site of the ribosome. Our results suggest that mRNA stem-loops can transiently escape the ribosome helicase by binding to the A site. Thus, the stem-loops can modulate gene expression by sterically hindering tRNA binding and inhibiting translation elongation.


It’s not you versus us, it’s us versus the virus


The case for national standards for the development, management and delivery of interprofessional education


title: Mycobacterium bovis: From Genotyping to Genome Sequencing

text: Mycobacterium bovis is the main pathogen of bovine, zoonotic, and wildlife tuberculosis. Despite the existence of programs for bovine tuberculosis (bTB) control in many regions, the disease remains a challenge for the veterinary and public health sectors, especially in developing countries and in high-income nations with wildlife reservoirs. Current bTB control programs are mostly based on test-and-slaughter, movement restrictions, and post-mortem inspection measures. In certain settings, contact tracing and surveillance has benefited from M. bovis genotyping techniques. More recently, whole-genome sequencing (WGS) has become the preferential technique to inform outbreak response through contact tracing and source identification for many infectious diseases. As the cost per genome decreases, the application of WGS to bTB control programs is inevitable moving forward. However, there are technical challenges in data analyses and interpretation that hinder the implementation of M. bovis WGS as a molecular epidemiology tool. Therefore, the aim of this review is to describe M. bovis genotyping techniques and discuss current standards and challenges of the use of M. bovis WGS for transmission investigation, surveillance, and global lineages distribution. We compiled a series of associated research gaps to be explored with the ultimate goal of implementing M. bovis WGS in a standardized manner in bTB control programs.


Joint Statement of the Korean Society for Preventive Medicine and the Korean Society of Epidemiology on the response to the COVID-19 outbreak


Medical Education in Turkey in the Time of COVID-19.


Asymptomatic Patients with Novel Coronavirus Disease (COVID-19)


title: Ocrelizumab shorter infusion: Primary results from the ENSEMBLE PLUS substudy in patients with MS

text: OBJECTIVE: To assess the safety of ocrelizumab (OCR) shorter duration infusion in patients with MS. METHODS: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early stage relapsing-remitting MS received OCR 600 mg initially as two 300 mg IV infusions 2 weeks apart and subsequently as a single 3.5-hour 600 mg infusion every 24 weeks for 192 weeks. In ENSEMBLE PLUS, OCR 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration). The primary end point was the proportion of patients with infusion-related reactions (IRRs) after the first randomized dose (assessed during and up to 24 hours postinfusion). RESULTS: From November 1, 2018, to September 27, 2019, 580 patients were randomized 1:1 to the conventional or shorter infusion group. After the first randomized dose, 67 of 291 patients (23.1%) in the conventional and 71 of 289 patients (24.6%) in the shorter infusion group experienced IRRs. Most IRRs were mild or moderate in both groups; one patient in each group experienced a severe IRR, and in both groups, 98.6% (136 of 138) of all IRRs resolved without sequelae. No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuation occurred. During the first randomized dose, 14 of 291 (4.8%) and 25 of 289 (8.7%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. CONCLUSION: The frequency and severity of IRRs were similar between conventional and shorter OCR infusions. Shortening the infusion time to 2 hours reduces the total infusion site stay time and lessens the overall patient and site staff burden. CLASSIFICATION OF EVIDENCE: This interventional study provides Class I evidence that the frequency and severity of IRRs were similar at the first randomized dose using OCR (600 mg) infusions of conventional and shorter duration in patients with relapsing-remitting MS. CLINICAL TRIAL IDENTIFIER NUMBER: NCT03085810.


Easy and Accessible Protection against Aerosol Contagion during Airway Management


The “Uncurated Exposure” of Videoconferencing


Honoring the Hippocratic Oath: Medical Student Perspective Amidst the COVID-19 Pandemic


title: Thinking Outside the Box: A Low-cost and Pragmatic Alternative to Aerosol Boxes for Endotracheal Intubation of COVID-19 Patients

text: Supplemental Digital Content is available in the text.


Psychological Effects of COVID-19 on Children of Health Care Workers


title: Master manipulators: how herpesviruses alter immune responses to RSV

text: In this commentary on “A gammaherpesvirus licenses CD8 T cells to protect the host from pneumovirus-induced immunopathologies”, the authors highlight the growing literature suggesting that herpesvirus infections shape subsequent immune responses to other pathogens, especially by broadening CD8+T-cell responses. These observations have implications for vaccine development against other important pathogens, such as Respiratory Syncytial Virus.


title: Less invasive surfactant administration versus endotracheal surfactant instillation followed by limited peak pressure ventilation in preterm infants with respiratory distress syndrome in China: study protocol for a randomized controlled trial

text: BACKGROUND: Less invasive surfactant administration (LISA) is a way of giving surfactant without endotracheal intubation and has shown to be promising in reducing the incidence of bronchopulmonary dysplasia (BPD) in preterm infants. However, the mechanism underlying its beneficial effect and variations in the technique of administration may prevent its widespread use. This trial aims to evaluate the effects of two methods of surfactant administration, LISA or endotracheal surfactant administration followed by low peak pressure (LPPSA) ventilation, in preterm infants with respiratory distress syndrome (RDS). METHODS: The LISA Or Low Peak Pressure trial is to be conducted in 14 tertiary neonatal intensive care units in China. A total of 600 preterm infants born with gestational age between 25(0/7) and 31(6/7) weeks and with a primary diagnosis of RDS will be involved in the study. Infants will be randomized to the LISA or LPPSA group when surfactant therapy is indicated. Primary outcomes include mortality, severity of bronchopulmonary dysplasia at 36 weeks of postmenstrual age (PMA), and mechanical ventilation (MV) in the first 72 h of life. Secondary outcomes include the days of MV, duration of all sorts of non-invasive respiratory support, fraction of inspired oxygen, oxygen saturation before and after surfactant administration, and time required to perform the procedure for surfactant administration. The incidence of comorbidities, including retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), hemodynamically significant patent ductus arteriosus (hsPDA), pneumothorax, and massive pulmonary hemorrhage within 48 h of surfactant administration, and the failure rates of each technique will be determined. DISCUSSION: Data from recent systematic review and meta-analysis have suggested a possible improvement in outcomes of preterm infants with RDS by the LISA technique. However, robust evidence is lacking. Why LISA plays a potential role in reducing respiratory morbidity, mainly BPD in preterm infants, remains unclear. The possible explanations are the active and uninterrupted delivery of continuous positive airway pressure during the LISA procedure and the avoidance of complications caused by intubation and relatively high pressure/volume ventilation following surfactant administration. We hypothesized that LISA’s effectiveness lies mainly in avoiding relatively high-pressure positive ventilation immediately following surfactant administration. Thus, this multicenter randomized controlled trial will focus on issues of endotracheal intubation and the pressure/volume used during conventional surfactant administration. The effectiveness, safety and comorbidities of preterm infants following LISA or LPPSA will be evaluated. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR1900020970. Registered on 23 January 2019.


title: Procalcitonin and C-reactive protein perform better than the neutrophil/lymphocyte count ratio in evaluating hospital acquired pneumonia

text: BACKGROUND: The relationship between biomarkers and hospital-acquired pneumonia (HAP) is understudied, especially in severe cases admitted to the intensive care unit (ICU). Compared with community-acquired pneumonia (CAP), HAP might have different traits regarding biomarkers due to the previous history in hospitals. METHODS: A total of 593 adult patients were enrolled in this retrospective cohort study to determine the neutrophil/lymphocyte count ratio (NLCR), procalcitonin (PCT), C-reactive protein (CRP) and serum lactate level upon admission to the ICU. According to diagnosis, patients were divided into two groups: non-infection and HAP. Discriminant analysis was performed based on better outcomes of diagnostic performance and severity evaluation. The diagnostic performance of each individual biomarker was assessed by constructing receiver operating characteristic (ROC) curves and calculating the area under each ROC curve (AUROC). Multivariable analysis was also applied to determine the most appropriate prognostic factors. RESULTS: NLCR, PCT and CRP were markedly different between the non-infection and HAP groups. NLCR had a worse ability to discriminate severe infection (AUROC 0.626; 95% CI 0.581–0.671) than conventional markers such as CRP (0.685, 95% CI 0.641–0.730) and PCT (0.661, 95% CI 0.615–0.707). In addition, the AUROC of composite biomarkers, especially the combination of NLCR, CRP and WBC, was significantly greater than that of any single biomarker. CONCLUSIONS: NLCR was not comparable to conventional single biomarkers, such as CRP and PCT, for diagnosing or evaluating the severity of HAP. Composite biomarkers that have good accessibility, especially the combination of NLCR, CRP and WBC, could help with early diagnosis and severity evaluation.


title: Secretive and close? How sharing secrets may impact perceptions of distance

text: Having secrets is incredibly common. However, secrecy has only recently started to receive more attention in research. What has largely been neglected so far are the consequences of secret-sharing for the relationship between sharer and receiver. In this project, we aim to fill this gap. Previous research has shown that closeness can make secret-sharing more likely. Building on research from the self-disclosure and relationship literature, we experimentally investigate whether secret-sharing might in turn increase perceptions of closeness. In addition, we test the valence of the secrets shared as potential driver of the hypothesized effect, as negative secrets might signal a high level of trust, but might also present a burden to the receiver. To provide a holistic picture, we build on a variety of methods to investigate three perspectives: Study 1 focuses on the receiver and tests whether another person sharing secrets (vs. nonconfidential information) decreases distance in the eyes of the receiver. Study 2 investigates lay theories and tests how an observer perceives the relationship between two people who share secrets (vs. nonconfidential information). Study 3 tests whether these lay theories about sharing secrets are predictive of behavior, and how a sharer might choose secrets of negative or positive valence to decrease perceived distance on the receiver’s side. Our results will contribute to the understanding of how sharing secrets affects the way individuals think about each other, how close they feel to each other, and how they interact with each other.


title: The effectiveness of internal control and innovation performance: An intermediary effect based on corporate social responsibility

text: From the perspective of the effectiveness of internal control, this study analyzes the influence of internal control on innovation performance and internal control on corporate social responsibility (CSR), and then analyzes the intermediary effect of CSR between internal control and innovation performance. The results show that the improvement of the effectiveness of internal control has a significant promoting effect on innovation performance, and promotes enterprises to strengthen CSR performance. Meanwhile, CSR activities take a significant intermediary effect in the process of improving innovation performance through internal control. Finally, it is suggested that state-owned enterprises and non-state-owned enterprises should communicate and cooperate, strengthen the construction of internal control system, and improve innovation performance and CSR practices. Furthermore, the intermediary effect of CSR activities in the process of improving innovation performance through internal control should be brought into play, so as to return the expectations and demands of stakeholders.


title: Epigenetic inheritance of circadian period in clonal cells

text: Circadian oscillations are generated via transcriptional-translational negative feedback loops. However, individual cells from fibroblast cell lines have heterogeneous rhythms, oscillating independently and with different period lengths. Here we showed that heterogeneity in circadian period is heritable and used a multi-omics approach to investigate underlying mechanisms. By examining large-scale phenotype-associated gene expression profiles in hundreds of mouse clonal cell lines, we identified and validated multiple novel candidate genes involved in circadian period determination in the absence of significant genomic variants. We also discovered differentially co-expressed gene networks that were functionally associated with period length. We further demonstrated that global differential DNA methylation bidirectionally regulated these same gene networks. Interestingly, we found that depletion of DNMT1 and DNMT3A had opposite effects on circadian period, suggesting non-redundant roles in circadian gene regulation. Together, our findings identify novel gene candidates involved in periodicity, and reveal DNA methylation as an important regulator of circadian periodicity.


title: Identification of interferon-stimulated genes that attenuate Ebola virus infection

text: The West Africa Ebola outbreak was the largest outbreak ever recorded, with over 28,000 reported infections; this devastating epidemic emphasized the need to understand the mechanisms to counteract virus infection. Here, we screen a library of nearly 400 interferon-stimulated genes (ISGs) against a biologically contained Ebola virus and identify several ISGs not previously known to affect Ebola virus infection. Overexpression of the top ten ISGs attenuates virus titers by up to 1000-fold. Mechanistic studies demonstrate that three ISGs interfere with virus entry, six affect viral transcription/replication, and two inhibit virion formation and budding. A comprehensive study of one ISG (CCDC92) that shows anti-Ebola activity in our screen reveals that CCDC92 can inhibit viral transcription and the formation of complete virions via an interaction with the viral protein NP. Our findings provide insights into Ebola virus infection that could be exploited for the development of therapeutics against this virus.


title: Transcriptome Analysis of Gene Expression Profiles of Tomato Yellow Leaf Curl Virus-Infected Whiteflies over Different Viral Acquisition Access Periods

text: Tomato yellow leaf curl virus (TYLCV), which is transmitted by Bemisia tabaci in a persistent-circulative manner, threatens tomato production worldwide. Little is known about the complicated interaction during this process at the molecular level. In this study, viral AAPs at 0 h, 2 h, 6 h, 12 h and 48 h were investigated using a comparative transcriptome analysis to uncover the transcriptional responses of whiteflies to virus infection. Our results have shown that 755, 587, 1140 and 1347 differentially expressed genes (DEGs) were identified in the comparisons of the data of 0 h vs. 2 h, 0 h vs. 6 h, 0 h vs. 12 h and 0 h vs. 48 h, respectively. KEGG analysis showed that DEGs associated with metabolisms and signal transduction were down-regulated in virus-infected whiteflies. Additionally, 16 up-regulated putative transporter genes and 10 down-regulated genes associated with IL-17 signaling pathway were identified by time-associated gene cluster analysis. These data boost our comprehensions on whitefly-TYLCV interactions associated with different viral AAPs.


title: Drug Resistance Prediction Using Deep Learning Techniques on HIV-1 Sequence Data

text: The fast replication rate and lack of repair mechanisms of human immunodeficiency virus (HIV) contribute to its high mutation frequency, with some mutations resulting in the evolution of resistance to antiretroviral therapies (ART). As such, studying HIV drug resistance allows for real-time evaluation of evolutionary mechanisms. Characterizing the biological process of drug resistance is also critically important for sustained effectiveness of ART. Investigating the link between “black box” deep learning methods applied to this problem and evolutionary principles governing drug resistance has been overlooked to date. Here, we utilized publicly available HIV-1 sequence data and drug resistance assay results for 18 ART drugs to evaluate the performance of three architectures (multilayer perceptron, bidirectional recurrent neural network, and convolutional neural network) for drug resistance prediction, jointly with biological analysis. We identified convolutional neural networks as the best performing architecture and displayed a correspondence between the importance of biologically relevant features in the classifier and overall performance. Our results suggest that the high classification performance of deep learning models is indeed dependent on drug resistance mutations (DRMs). These models heavily weighted several features that are not known DRM locations, indicating the utility of model interpretability to address causal relationships in viral genotype-phenotype data.


Scope, quality, and inclusivity of clinical guidelines produced early in the covid-19 pandemic: rapid review


title: Innate Type 2 Responses to Respiratory Syncytial Virus Infection

text: Respiratory syncytial virus (RSV) is a common and contagious virus that results in acute respiratory tract infections in infants. In many cases, the symptoms of RSV remain mild, however, a subset of individuals develop severe RSV-associated bronchiolitis. As such, RSV is the chief cause of infant hospitalization within the United States. Typically, the immune response to RSV is a type 1 response that involves both the innate and adaptive immune systems. However, type 2 cytokines may also be produced as a result of infection of RSV and there is increasing evidence that children who develop severe RSV-associated bronchiolitis are at a greater risk of developing asthma later in life. This review summarizes the contribution of a newly described cell type, group 2 innate lymphoid cells (ILC2), and epithelial-derived alarmin proteins that activate ILC2, including IL-33, IL-25, thymic stromal lymphopoietin (TSLP), and high mobility group box 1 (HMGB1). ILC2 activation leads to the production of type 2 cytokines and the induction of a type 2 response during RSV infection. Intervening in this innate type 2 inflammatory pathway may have therapeutic implications for severe RSV-induced disease.


title: Evaluation of Viral RNA Recovery Methods in Vectors by Metagenomic Sequencing

text: Identification and characterization of viral genomes in vectors including ticks and mosquitoes positive for pathogens of great public health concern using metagenomic next generation sequencing (mNGS) has challenges. One such challenge is the ability to efficiently recover viral RNA which is typically dependent on sample processing. We evaluated the quantitative effect of six different extraction methods in recovering viral RNA in vectors using negative tick homogenates spiked with serial dilutions of tick-borne encephalitis virus (TBEV) and surrogate Langat virus (LGTV). Evaluation was performed using qPCR and mNGS. Sensitivity and proof of concept of optimal method was tested using naturally positive TBEV tick homogenates and positive dengue, chikungunya, and Zika virus mosquito homogenates. The amount of observed viral genome copies, percentage of mapped reads, and genome coverage varied among different extractions methods. The developed Method 5 gave a 120.8-, 46-, 2.5-, 22.4-, and 9.9-fold increase in the number of viral reads mapping to the expected pathogen in comparison to Method 1, 2, 3, 4, and 6, respectively. Our developed Method 5 termed ROVIV (Recovery of Viruses in Vectors) greatly improved viral RNA recovery and identification in vectors using mNGS. Therefore, it may be a more sensitive method for use in arbovirus surveillance.


The Obstacle Course of Reperfusion for ST-Segment–Elevation Myocardial Infarction in the COVID-19 Pandemic


docid: znvfhabk

title: Die Pandemiekatastrophe aus katastrophenrechtlicher und -medizinischer Sicht

text: The corona pandemic has caused a serious emergency also in the Federal Republic of Germany; shortages of medical capacities and failure of critical infrastructures may occur resulting in a pandemic catastrophe. German laws prescribe various mechanisms for disaster preparedness and disaster response. Nevertheless, both authorities and physicians will have to make difficult ethical and legal decisions. In the event of lack of resources (e. g. vaccines or ventilation capacity), conflict-laden selection decisions must be made. The regulations on pandemic preparedness need to be reviewed: preparing for the response to pandemics must be a clear and legally binding task and responsibility of all state and private agents involved. Here, among other things, planning, training, exercises and stockpiling are crucial elements of being prepared to deal with a pandemic.


title: Gesundheitskompetenz und die Corona-Krise

text: „Wir sind eine Demokratie. Wir leben nicht von Zwang, sondern von geteiltem Wissen und Mitwirkung“ Angela Merkel, TV-Ansprache an die Nation, 18.3.2020 Wenn es um Infektionskrankheiten geht, so waren unsere Gesundheitssysteme immer schon auf das aktive Mittun der Bevölkerung angewiesen. Die Menschen mussten sich auch früher schon angemessen verhalten, z. B. mit Hygienemaßnahmen im Alltag, um Infektionsketten zu unterbrechen, um Versorgungssysteme nicht zu überlasten oder anderweitig mithelfen, Schlimmeres zu verhindern.


title: HER2-LAMP vaccines effectively traffic to endolysosomal compartments and generate enhanced polyfunctional T cell responses that induce complete tumor regression

text: BACKGROUND: The advent of immune checkpoint blockade antibodies has demonstrated that effective mobilization of T cell responses can cause tumor regression of metastatic cancers, although these responses are heterogeneous and restricted to certain histologic types of cancer. To enhance these responses, there has been renewed emphasis in developing effective cancer-specific vaccines to stimulate and direct T cell immunity to important oncologic targets, such as the oncogene human epidermal growth factor receptor 2 (HER2), expressed in ~20% of breast cancers (BCs). METHODS: In our study, we explored the use of alternative antigen trafficking through use of a lysosome-associated membrane protein 1 (LAMP) domain to enhance vaccine efficacy against HER2 and other model antigens in both in vitro and in vivo studies. RESULTS: We found that inclusion of this domain in plasmid vaccines effectively trafficked antigens to endolysosomal compartments, resulting in enhanced major histocompatibility complex (MHC) class I and II presentation. Additionally, this augmented the expansion/activation of antigen-specific CD4+ and CD8+ T cells and also led to elevated levels of antigen-specific polyfunctional CD8+ T cells. Significantly, vaccination with HER2-LAMP produced tumor regression in ~30% of vaccinated mice with established tumors in an endogenous model of metastatic HER2+ BC, compared with 0% of HER2-WT vaccinated mice. This therapeutic benefit is associated with enhanced tumor infiltration of activated CD4+ and CD8+ T cells. CONCLUSIONS: These data demonstrate the potential of using LAMP-based endolysosomal trafficking as a means to augment the generation of polyfunctional, antigen-specific T cells in order to improve antitumor therapeutic responses using cancer antigen vaccines.


title: Being vulnerable

text: Early-career researchers feel discouraged from exposing vulnerability even during a global crisis.


title: Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells

text: Mechanical force is a determinant of Notch signalling but the mechanism of force detection and its coupling to Notch are unclear. We propose a role for Piezo1 channels, which are mechanically-activated non-selective cation channels. In cultured microvascular endothelial cells, Piezo1 channel activation by either shear stress or a chemical agonist Yoda1 activated a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a Ca(2+)-regulated transmembrane sheddase that mediates S2 Notch1 cleavage. Consistent with this observation, we found Piezo1-dependent increase in the abundance of Notch1 intracellular domain (NICD) that depended on ADAM10 and the downstream S3 cleavage enzyme, γ-secretase. Conditional endothelial-specific disruption of Piezo1 in adult mice suppressed the expression of multiple Notch1 target genes in hepatic vasculature, suggesting constitutive functional importance in vivo. The data suggest that Piezo1 is a mechanism conferring force sensitivity on ADAM10 and Notch1 with downstream consequences for sustained activation of Notch1 target genes and potentially other processes.


title: Abrogation of PRRSV infectivity by CRISPR-Cas13b-mediated viral RNA cleavage in mammalian cells

text: CRISPR/Cas9 enables dsDNA viral genome engineering. However, the lack of RNA targeting activities limits the ability of CRISPR/Cas9 to combat RNA viruses. The recently identified class II type VI CRISPR/Cas effectors (Cas13) are RNA-targeting CRISPR enzymes that enable RNA cleavage in mammalian and plant cells. We sought to knockdown the viral RNA of porcine reproductive and respiratory syndrome virus (PRRSV) directly by exploiting the CRISPR/Cas13b system. Effective mRNA cleavage by CRISPR/Cas13b-mediated CRISPR RNA (crRNA) targeting the ORF5 and ORF7 genes of PRRSV was observed. To address the need for uniform delivery of the Cas13b protein and crRNAs, an all-in-one system expressing Cas13b and duplexed crRNA cassettes was developed. Delivery of a single vector carrying double crRNAs enabled the simultaneous knockdown of two PRRSV genes. Transgenic MARC-145 cells stably expressing the Cas13b effector and crRNA mediated by lentiviral-based transduction showed a robust ability to splice the PRRSV genomic RNA and subgenomic RNAs; viral infection was almost completely abrogated by the combination of double crRNAs simultaneously targeting the ORF5 and ORF7 genes. Our study indicated that the CRISPR/Cas13b system can effectively knockdown the PRRSV genome in vitro and can potentially be used as a potent therapeutic antiviral strategy.


docid: cuawbowc

title: Time series analysis of temporal trends in hemorrhagic fever with renal syndrome morbidity rate in China from 2005 to 2019

text: Hemorrhagic fever with renal syndrome (HFRS) is seriously endemic in China with 70%~90% of the notified cases worldwide and showing an epidemic tendency of upturn in recent years. Early detection for its future epidemic trends plays a pivotal role in combating this threat. In this scenario, our study investigates the suitability for application in analyzing and forecasting the epidemic tendencies based on the monthly HFRS morbidity data from 2005 through 2019 using the nonlinear model-based self-exciting threshold autoregressive (SETAR) and logistic smooth transition autoregressive (LSTAR) methods. The experimental results manifested that the SETAR and LSTAR approaches presented smaller values among the performance measures in both two forecasting subsamples, when compared with the most extensively used seasonal autoregressive integrated moving average (SARIMA) method, and the former slightly outperformed the latter. Descriptive statistics showed an epidemic tendency of downturn with average annual percent change (AAPC) of −5.640% in overall HFRS, however, an upward trend with an AAPC = 1.213% was observed since 2016 and according to the forecasts using the SETAR, it would seemingly experience an outbreak of HFRS in China in December 2019. Remarkably, there were dual-peak patterns in HFRS incidence with a strong one occurring in November until January of the following year, additionally, a weak one in May and June annually. Therefore, the SETAR and LSTAR approaches may be a potential useful tool in analyzing the temporal behaviors of HFRS in China.


Antimicrobial resistance and over the counter use of drugs in Nepal


title: Effects of Sterilization With Hydrogen Peroxide and Chlorine Dioxide on the Filtration Efficiency of N95, KN95, and Surgical Face Masks

text: This quality improvement study examines the effects of sterilization with hydrogen peroxide and chlorine dioxide on the filtration efficiency of N95, KN95, and surgical face masks.


title: Integrative computational epigenomics to build data-driven gene regulation hypotheses

text: BACKGROUND: Diseases are complex phenotypes often arising as an emergent property of a non-linear network of genetic and epigenetic interactions. To translate this resulting state into a causal relationship with a subset of regulatory features, many experiments deploy an array of laboratory assays from multiple modalities. Often, each of these resulting datasets is large, heterogeneous, and noisy. Thus, it is non-trivial to unify these complex datasets into an interpretable phenotype. Although recent methods address this problem with varying degrees of success, they are constrained by their scopes or limitations. Therefore, an important gap in the field is the lack of a universal data harmonizer with the capability to arbitrarily integrate multi-modal datasets. RESULTS: In this review, we perform a critical analysis of methods with the explicit aim of harmonizing data, as opposed to case-specific integration. This revealed that matrix factorization, latent variable analysis, and deep learning are potent strategies. Finally, we describe the properties of an ideal universal data harmonization framework. CONCLUSIONS: A sufficiently advanced universal harmonizer has major medical implications, such as (i) identifying dysregulated biological pathways responsible for a disease is a powerful diagnostic tool; (2) investigating these pathways further allows the biological community to better understand a disease’s mechanisms; and (3) precision medicine also benefits from developments in this area, particularly in the context of the growing field of selective epigenome editing, which can suppress or induce a desired phenotype.


title: An automated pipeline for the discovery of conspiracy and conspiracy theory narrative frameworks: Bridgegate, Pizzagate and storytelling on the web

text: Although a great deal of attention has been paid to how conspiracy theories circulate on social media, and the deleterious effect that they, and their factual counterpart conspiracies, have on political institutions, there has been little computational work done on describing their narrative structures. Predicating our work on narrative theory, we present an automated pipeline for the discovery and description of the generative narrative frameworks of conspiracy theories that circulate on social media, and actual conspiracies reported in the news media. We base this work on two separate comprehensive repositories of blog posts and news articles describing the well-known conspiracy theory Pizzagate from 2016, and the New Jersey political conspiracy Bridgegate from 2013. Inspired by the qualitative narrative theory of Greimas, we formulate a graphical generative machine learning model where nodes represent actors/actants, and multi-edges and self-loops among nodes capture context-specific relationships. Posts and news items are viewed as samples of subgraphs of the hidden narrative framework network. The problem of reconstructing the underlying narrative structure is then posed as a latent model estimation problem. To derive the narrative frameworks in our target corpora, we automatically extract and aggregate the actants (people, places, objects) and their relationships from the posts and articles. We capture context specific actants and interactant relationships by developing a system of supernodes and subnodes. We use these to construct an actant-relationship network, which constitutes the underlying generative narrative framework for each of the corpora. We show how the Pizzagate framework relies on the conspiracy theorists’ interpretation of “hidden knowledge” to link otherwise unlinked domains of human interaction, and hypothesize that this multi-domain focus is an important feature of conspiracy theories. We contrast this to the single domain focus of an actual conspiracy. While Pizzagate relies on the alignment of multiple domains, Bridgegate remains firmly rooted in the single domain of New Jersey politics. We hypothesize that the narrative framework of a conspiracy theory might stabilize quickly in contrast to the narrative framework of an actual conspiracy, which might develop more slowly as revelations come to light. By highlighting the structural differences between the two narrative frameworks, our approach could be used by private and public analysts to help distinguish between conspiracy theories and conspiracies.


title: Health status of free-ranging ring-necked pheasant chicks (Phasianus colchicus) in North-Western Germany

text: Being a typical ground-breeding bird of the agricultural landscape in Germany, the pheasant has experienced a strong and persistent population decline with a hitherto unexplained cause. Contributing factors to the ongoing negative trend, such as the effects of pesticides, diseases, predation, increase in traffic and reduced fallow periods, are currently being controversially discussed. In the present study, 62 free-ranging pheasant chicks were caught within a two-year period in three federal states of Germany; Lower Saxony, North Rhine-Westphalia and Schleswig-Holstein. The pheasant chicks were divided into three age groups to detect differences in their development and physical constitution. In addition, pathomorphological, parasitological, virological, bacteriological and toxicological investigations were performed. The younger chicks were emaciated, while the older chicks were of moderate to good nutritional status. However, the latter age group was limited to a maximum of three chicks per hen, while the youngest age class comprised up to ten chicks. The majority of chicks suffered from dermatitis of the periocular and caudal region of the head (57–94%) of unknown origin. In addition, intestinal enteritis (100%), pneumonia (26%), hepatitis (24%), perineuritis (6%), tracheitis (24%), muscle degeneration (1%) and myositis (1%) were found. In 78% of the cases, various Mycoplasma spp. were isolated. Mycoplasma gallisepticum (MG) was not detected using an MG-specific PCR. Parasitic infections included Philopteridae (55%), Coccidia (48%), Heterakis/Ascaridia spp. (8%) and Syngamus trachea (13%). A total of 8% of the chicks were Avian metapneumovirus (AMPV) positive using RT-PCR, 16% positive for infectious bronchitis virus (IBV) using RT-PCR, and 2% positive for haemorrhagic enteritis virus (HEV) using PCR. All samples tested for avian encephalomyelitis virus (AEV), infectious bursal disease virus (IBDV) or infectious laryngotracheitis virus (ILTV) were negative. The pool samples of the ten chicks were negative for all acid, alkaline-free and derivative substances, while two out of three samples tested were positive for the herbicide glyphosate. Pheasant chick deaths may often have been triggered by poor nutritional status, probably in association with inflammatory changes in various tissues and organs as well as bacterial and parasitic pathogens. Theses impacts may have played a major role in the decline in pheasant populations.


FOMO in the time of coronavirus disease


An easy protective measure in ophthalmology against medical supply shortage


title: Cost–utility analysis of antibiotic treatment in patients with chronic low back pain and Modic changes: results from a randomised, placebo-controlled trial in Norway (the AIM study)

text: OBJECTIVE: To evaluate the cost–utility of 100 days of antibiotics in patients with chronic low back pain (LBP) and type I or II Modic changes included in the Antibiotic treatment In patients with chronic low back pain and Modic changes (AIM) study. DESIGN: A cost–utility analysis from a societal and healthcare perspective alongside a double-blinded, parallel group, placebo, multicentre trial. SETTING: Hospital outpatient clinics at six hospitals in Norway. The main results from the AIM study showed a small effect in back-related disability in favour of the antibiotics group, and slightly larger in those with type I Modic changes, but this effect was below the pre-defined threshold for clinically relevant effect. PARTICIPANTS: 180 patients with chronic LBP, previous disc herniation and Modic changes type I (n=118) or type II (n=62) were randomised to antibiotic treatment (n=89) or placebo-control (n=91). INTERVENTIONS: Oral treatment with either 750 mg amoxicillin or placebo three times daily for 100 days. MAIN OUTCOME MEASURES: Quality-adjusted life years (QALYs) by EuroQoL-5D over 12 months and costs for healthcare and productivity loss measured in Euro (€1=NOK 10), in the intention-to-treat population. Cost–utility was expressed in incremental cost-effectiveness ratio (ICER). RESULTS: Mean (SD) total cost was €21 046 (20 105) in the amoxicillin group and €19 076 (19 356) in the placebo group, mean difference €1970 (95% CI; −3835 to 7774). Cost per QALY gained was €24 625. In those with type I Modic changes, the amoxicillin group had higher healthcare consumption than the placebo group, resulting in €39 425 per QALY gained. Given these ICERs and a willingness-to-pay threshold of €27 500 (NOK 275 000), the probability of amoxicillin being cost-effective was 51%. Even when the willingness-to-pay threshold increased to €55 000, the probability of amoxicillin being cost-effective was never higher than 53%. CONCLUSIONS: Amoxicillin treatment showed no evidence of being cost-effective for people with chronic LBP and Modic changes during 1-year follow-up. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02323412.


title: General Anesthesia Recommendations for Electroconvulsive Therapy During the Coronavirus Disease 2019 Pandemic

text: Coronavirus disease 2019 is an infectious viral disease first identified in December 2019 in Wuhan, China, and very rapidly spread globally resulting in a pandemic. Common symptoms include fever, cough, and shortness of breath. Although the majority of patients recover, there are still a significant number of patients who progress to respiratory failure, multiorgan failure, and death. The virus is mainly spread during close contact and by small droplets produced by coughing, sneezing, or talking. Because of the highly contagious element and easy spread in a communal living arrangement that exists within an inpatient psychiatric hospitals, the following guidelines were established to improve patient and staff safety while still maintaining efficiency and capability to provide this needed treatment to a subgroup of patients. OBJECTIVE: The objective of this study was to devise a safe and efficient methodology to deliver potential lifesaving electroconvulsive therapy to inpatients during the coronavirus disease 2019 pandemic.


Conducting Clinical Trials in the Time of a Pandemic


docid: grhfdnkx

title: Global Pandemics and the Aspiring Plastic Surgery Applicant: Challenges and Potential Solutions


Pulchritudo in Brevitate (Beauty in Brevity): Introducing the Research Letter to Spine


In response to a Letter to the Editor of the American Journal of Physical Medicine & Rehabilitation, ID: AJPMR-D-20-00284


title: Genomic and phenotypic evolution of Escherichia coli in a novel citrate-only resource environment

text: Evolutionary innovations allow populations to colonize new ecological niches. We previously reported that aerobic growth on citrate (Cit(+)) evolved in an Escherichia coli population during adaptation to a minimal glucose medium containing citrate (DM25). Cit(+) variants can also grow in citrate-only medium (DM0), a novel environment for E. coli. To study adaptation to this niche, we founded two sets of Cit(+) populations and evolved them for 2500 generations in DM0 or DM25. The evolved lineages acquired numerous parallel mutations, many mediated by transposable elements. Several also evolved amplifications of regions containing the maeA gene. Unexpectedly, some evolved populations and clones show apparent declines in fitness. We also found evidence of substantial cell death in Cit(+) clones. Our results thus demonstrate rapid trait refinement and adaptation to the new citrate niche, while also suggesting a recalcitrant mismatch between E. coli physiology and growth on citrate.


title: Spider‐Web‐Inspired PM(0.3) Filters Based on Self‐Sustained Electrostatic Nanostructured Networks

text: Particulate matter (PM) pollution has become a serious public health issue, especially with outbreaks of emerging infectious diseases. However, most present filters are bulky, opaque, and show low‐efficiency PM(0.3)/pathogen interception and inevitable trade‐off between PM removal and air permeability. Here, a unique electrospraying–netting technique is used to create spider‐web‐inspired network generator (SWING) air filters. Manipulation of the dynamic of the Taylor cone and phase separation of its ejected droplets enable the generation of 2D self‐charging nanostructured networks on a large scale. The resultant SWING filters show exceptional long‐range electrostatic property driven by aeolian vibration, enabling self‐sustained PM adhesion. Combined with their Steiner‐tree‐structured pores (size 200–300 nm) consisting of nanowires (diameter 12 nm), the SWING filters exhibit high efficiency (>99.995% PM(0.3) removal), low air resistance (<0.09% atmosphere pressure), high transparency (>82%), and remarkable bioprotective activity for biohazard pathogens. This work may shed light on designing new fibrous materials for environmental and energy applications.


Beyond COVID‐19: How the ‘dismal science’ can prepare us for the future


In Response


Medical Ethics Versus Healthcare Workers’ Rights: Fight-or-Flee Response


Detection of Ciprofloxacin-Resistant, β-Lactamase–Producing Neisseria meningitidis Serogroup Y Isolates — United States, 2019–2020


title: Optimizing classical risk scores to predict complications in head and neck surgery: a new approach

text: PURPOSE: To validate tools to identify patients at risk for perioperative complications to implement prehabilitation programmes in head and neck surgery (H&N). METHODS: Retrospective cohort including 128 patients submitted to H&N, with postoperative Intermediate Care Unit admittance. The accuracy of the risk calculators ASA, P-POSSUM, ACS-NSQIP and ARISCAT to predict postoperative complications and mortality was assessed. A multivariable analysis was subsequently performed to create a new risk prediction model for serious postoperative complications in our institution. RESULTS: Our 30-day morbidity and mortality were 45.3% and 0.8%, respectively. The ACS-NSQIP failed to predict complications and had an acceptable discrimination ability for predicting death. The discrimination ability of ARISCAT for predicting respiratory complications was acceptable. ASA and P-POSSUM were poor predictors for mortality and morbidity. Our new prediction model included ACS-NSQIP and ARISCAT (area under the curve 0.750, 95% confidence intervals: 0.63–0.87). CONCLUSION: Despite the insufficient value of these risk calculators when analysed individually, we designed a risk tool combining them which better predicts the risk of serious complications. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00405-020-06133-1) contains supplementary material, which is available to authorized users.


title: Effect of Panax ginseng on preventing acute respiratory tract infection: A protocol for systematic review and meta-analysis

text: BACKGROUND: Acute respiratory tract infection (ARTI) should be deeply concerned all over the world. Panax ginseng (ginseng) as traditional Chinese medicine is widely used in the treatment and health care for respiratory diseases. However, only one similar systematic review based on common cold has been published in 2011. New studies have occurred and a new systematic evaluation which could describe ARTI is needed. METHODS AND ANALYSIS: We will search for randomized control trials of ginseng on preventing acute respiratory tract infection in the following 8 databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED (via OVID) and 4 Chinese databases (Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, and Wan fang Database). The time is limited from the construction of the library to April 2020. The selection of studies, data extraction and quality of assessment will be conducted independently by 2 reviewers. The morbidity of ARTI by assessing self-report, caregiver report or clinical confirmation will be considered as the primary outcome. ARTI-related death among children or adults, other adverse events, absenteeism, laboratory-confirmed infection will be regarded as secondary outcome. All reported side effects and adverse events will be included as safety outcomes. Standard meta-analysis will be performed using Rev Man software V5.3. RESULTS: This study will provide a better understanding of the association between P ginseng and ARTI. CONCLUSION: This systematic review may offer stronger evidences for the clinicians to prevent the patients from ARTI and update the former one based on basic diseases and the safety. PROSPERO REGISTRATION NUMBER: CRD42020181317.


Framing health stories: Highlights 2020 photography competition open for submissions


Multidisciplinary research priorities for the COVID-19 pandemic


Global governance for COVID-19 vaccines


ASGCT Meeting Showcases Fast-Paced Development of Gene and Cell Therapy Technologies


Response to ‘Evaluation of modelling study shows limits of COVID-19 importing risk simulations in sub-Saharan Africa’ (Epidemiology and Infection – HYG-LE-10513-May-20)


Is Teamwork Still Possible during a Global Pandemic?


title: Implementing sequence-based antigenic distance calculation into immunological shape space model

text: BACKGROUND: In 2009, a novel influenza vaccine was distributed worldwide to combat the H1N1 influenza “swine flu” pandemic. However, antibodies induced by the vaccine display differences in their specificity and cross-reactivity dependent on pre-existing immunity. Here, we present a computational model that can capture the effect of pre-existing immunity on influenza vaccine responses. The model predicts the region of the virus hemagglutinin (HA) protein targeted by antibodies after vaccination as well as the level of cross-reactivity induced by the vaccine. We tested our model by simulating a scenario similar to the 2009 pandemic vaccine and compared the results to antibody binding data obtained from human subjects vaccinated with the monovalent 2009 H1N1 influenza vaccine. RESULTS: We found that both specificity and cross-reactivity of the antibodies induced by the 2009 H1N1 influenza HA protein were affected by the viral strain the individual was originally exposed. Specifically, the level of antigenic relatedness between the original exposure HA antigen and the 2009 HA protein affected antigenic-site immunodominance. Moreover, antibody cross-reactivity was increased when the individual’s pre-existing immunity was specific to an HA protein antigenically distinct from the 2009 pandemic strain. Comparison of simulation data with antibody binding data from human serum samples demonstrated qualitative and quantitative similarities between the model and real-life immune responses to the 2009 vaccine. CONCLUSION: We provide a novel method to evaluate expected outcomes in antibody specificity and cross-reactivity after influenza vaccination in individuals with different influenza HA antigen exposure histories. The model produced similar outcomes as what has been previously reported in humans after receiving the 2009 influenza pandemic vaccine. Our results suggest that differences in cross-reactivity after influenza vaccination should be expected in individuals with different exposure histories.


title: Walk with a Doc—a Call to Action for Physician-Led Walking Programs

text: PURPOSE OF REVIEW: An abundance of data supports the health benefits of physical activity, social connectedness, and spending time outdoors. Yet, a majority of Americans are living lives that are sedentary, lonely, and not connected with nature. We have three primary goals in writing this paper. First, we will review the well-documented health challenges arising from a sedentary, isolated lifestyle. Second, we will discuss the benefits of walking as a primary means of increasing physical activity. Finally, we will shine a light on the exponential success of Walk with a Doc, a national non-profit organization. Walk with a Doc focuses on bringing physician-led enthusiasm into our communities by organizing regular doctor-led walks in the outdoors; as well as Walk with a Future Doc, which encourages medical students to start their own Walk with a Doc programs. RECENT FINDINGS: The Physical Activity Guidelines for Americans share that physical activity is an important action that people of all ages can take to improve their health. These guidelines recommend that adults partake in at least 150 min of moderate aerobic physical activity. Currently, only 23% of Americans are achieving this amount of aerobic activity. In addition, recent data suggest that 3 in 4 people are lonely, a significant social determinant of health. Finally, over half of all Americans spend fewer than 5 h outside each week. Walk with a Doc and Walk with a Future Doc are having an enormous impact on combating the negative effects of these health challenges. An evaluability assessment was completed in 2018 showing Walk with a Doc attendees felt the program increased their physical activity and their social connections, with a majority of Walk with a Doc gatherings occurring in nature. Physicians and other Walk with a Doc program leaders also reported high levels of satisfaction with their participation in Walk with a Doc. SUMMARY: As teammates in this healthcare fight, we are all painfully aware of the crisis on our hands. Of our patients, 70% are overweight or obese, nearly 80% of us are not getting enough physical activity, with all of this leading to billions of dollars in healthcare costs. Adding fuel to the fire, our doctors are burning out because of it. Today, we want to share what we have learned to be an extremely viable solution. The solution has the capacity to save 5 million lives and $68 billion dollars per year. Additionally, it is bolstering the job satisfaction and happiness of our providers. Personally, it turned my life around in 2005, and since then, it is now greater than 560 communities around the USA (and 34 other countries). We call it, simply, Walk with a Doc.


title: Performance and impact of a multiplex PCR in ICU patients with ventilator-associated pneumonia or ventilated hospital-acquired pneumonia

text: BACKGROUND: Early appropriate antibiotic therapy reduces morbidity and mortality of severe pneumonia. However, the emergence of bacterial resistance requires the earliest use of antibiotics with the narrowest possible spectrum. The Unyvero Hospitalized Pneumonia (HPN, Curetis) test is a multiplex PCR (M-PCR) system detecting 21 bacteria and 19 resistance genes on respiratory samples within 5 h. We assessed the performance and the potential impact of the M-PCR on the antibiotic therapy of ICU patients. METHODS: In this prospective study, we performed a M-PCR on bronchoalveolar lavage (BAL) or plugged telescoping catheter (PTC) samples of patients with ventilated HAP or VAP with Gram-negative bacilli or clustered Gram-positive cocci. This study was conducted in 3 ICUs in a French academic hospital: the medical and infectious diseases ICU, the surgical ICU, and the cardio-surgical ICU. A multidisciplinary expert panel simulated the antibiotic changes they would have made if the M-PCR results had been available. RESULTS: We analyzed 95 clinical samples of ventilated HAP or VAP (72 BAL and 23 PTC) from 85 patients (62 males, median age 64 years). The median turnaround time of the M-PCR was 4.6 h (IQR 4.4–5). A total of 90/112 bacteria were detected by the M-PCR system with a global sensitivity of 80% (95% CI, 73–88%) and specificity of 99% (95% CI 99–100). The sensitivity was better for Gram-negative bacteria (90%) than for Gram-positive cocci (62%) (p = 0.005). Moreover, 5/8 extended-spectrum beta-lactamases (CTX-M gene) and 4/4 carbapenemases genes (3 NDM, one oxa-48) were detected. The M-PCR could have led to the earlier initiation of an effective antibiotic in 20/95 patients (21%) and to early de-escalation in 37 patients (39%) but could also have led to one (1%) inadequate antimicrobial therapy. Among 17 empiric antibiotic treatments with carbapenems, 10 could have been de-escalated in the following hours according to the M-PCR results. The M-PCR also led to 2 unexpected diagnosis of severe legionellosis confirmed by culture methods. CONCLUSIONS: Our results suggest that the use of a M-PCR system for respiratory samples of patients with VAP and ventilated HAP could improve empirical antimicrobial therapy and reduce the use of broad-spectrum antibiotics.


title: A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy

text: All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.


title: Use of the prevented fraction for the population to determine deaths averted by existing prevalence of physical activity: a descriptive study

text: BACKGROUND: Disease and mortality burdens of unhealthy lifestyle behaviours are often reported. In contrast, the positive narrative around the burdens that an existing behaviour have averted is rarely acknowledged. We aimed to estimate the prevented fraction for the population (PFP) for premature mortality averted by physical activity on a global scale. METHODS: In this descriptive study, we obtained previously published data on physical activity prevalence (2001–16) and relative risks of all-cause mortality for 168 countries. We combined the data in Monte-Carlo simulations to estimate country-specific, mean PFP values, corresponding to percentage of mortality averted, and their 95% CIs. High prevented fractions indicated an increased proportion of deaths averted due to physical activity. Using mortality data for all people in a country aged 40–74 years, we estimated the number of premature deaths averted for all adults and by gender. We present the median and range of the prevented fractions globally, by WHO region, and by World Bank income classification. FINDINGS: The global median PFP was 15·0% (range 6·6–20·5), conservatively equating to 3·9 million (95% CI 2·5–5·6) premature deaths averted annually. The African region had the highest median prevented fraction (16·6% [range 12·1–20·5]) and the Americas had the lowest (13·1% [10·8–16·6]). Low-income countries tended to have higher prevented fractions (group median 17·9% [12·3–20·5]) than high-income countries (14·1% [6·6–17·8]). Globally, the median prevented fraction was higher for men (16·0% [7·8–20·7] than women (14·1% [5·0–20·4]). INTERPRETATION: Existing physical activity prevalence has contributed to averting premature mortality across all countries. PFP has utility as an advocacy tool to promote healthy lifestyle behaviours. By making the case of what has been achieved, the prevented fraction can show the value of current investment and services, which might be conducive to political support. FUNDING: UK Medical Research Council, British Heart Foundation, Cancer Research UK, Economic and Social Research Council, National Institute for Health Research, Wellcome Trust, Heart Foundation Australia.


Using indirect calorimetry in place of fixed energy prescription was feasible and energy targets were more closely met: do not forget an important limitation


title: Lissencephaly in Shih Tzu dogs

text: BACKGROUND: Lissencephaly is a brain malformation characterized by smooth and thickened cerebral surface, which may result in structural epilepsy. Lissencephaly is not common in veterinary medicine. Here, we characterize the first cases of lissencephaly in four Shih Tzu dogs, including clinical presentations and findings of magnetic resonance imaging of lissencephaly and several concomitant brain malformations. CASE PRESENTATION: Early-onset acute signs of forebrain abnormalities were observed in all dogs, which were mainly cluster seizures and behavioral alterations. Based on neurological examination, the findings were consistent with symmetrical and bilateral forebrain lesions. Metabolic disorders and inflammatory diseases were excluded. Magnetic resonance imaging for three dogs showed diffuse neocortical agyria and thickened gray matter while one dog had mixed agyria and pachygyria. Other features, such as internal hydrocephalus, supracollicular fluid accumulation, and corpus callosum hypoplasia, were detected concomitantly. Antiepileptic drugs effectively controlled cluster seizures, however, sporadic isolated seizures and signs of forebrain abnormalities, such as behavioral alterations, central blindness, and strabismus persisted. CONCLUSIONS: Lissencephaly should be considered an important differential diagnosis in Shih Tzu dogs presenting with early-onset signs of forebrain abnormalities, including cluster seizures and behavioral alterations. Magnetic resonance imaging was appropriate for ante-mortem diagnosis of lissencephaly and associated cerebral anomalies.


title: Choosing and Doing wisely: triage level I resuscitation a possible new field for starting palliative care and avoiding low-value care – a nationwide matched-pair retrospective cohort study in Taiwan

text: BACKGROUND: The association between palliative care and life-sustaining treatment following emergency department (ED) resuscitation is unclear. This study aims to analyze the usage of palliative care and life-sustaining treatments among ED triage level I resuscitation patients based on a nationally representative sample of patients in Taiwan. METHODS: A matched-pair retrospective cohort study was conducted to examine the association between palliative care and outcome variables using multivariate logistic regression and Kaplan–Meier survival analyses. Between 2009 and 2013, 336 ED triage level I resuscitation patients received palliative care services (palliative care group) under a universal health insurance scheme. Retrospective cohort matching was performed with those who received standard care at a ratio of 1:4 (usual care group). Outcome variables included the number of visits to emergency and outpatient departments, hospitalization duration, total medical expenses, utilization of life-sustaining treatments, and duration of survival following ED triage level I resuscitation. RESULTS: The mean survival duration following level I resuscitation was less than 1 year. Palliative care was administered to 15% of the resuscitation cohort. The palliative care group received significantly less life-sustaining treatment than did the usual care group. CONCLUSION: Among patients who underwent level I resuscitation, palliative care was inversely correlated with the scope of life-sustaining treatments. Furthermore, triage level I resuscitation status may present a possible new field for starting palliative care intervention and reducing low-value care.


title: Comparing clinical outcomes of piperacillin-tazobactam administration and dosage strategies in critically ill adult patients: a systematic review and meta-analysis

text: BACKGROUND: Recently, continuous administration of piperacillin-tazobactam has been proposed as a valuable alternative to traditional intermittent administration especially in critically ill patients. However, antibiotic dosing remains a challenge for clinicians as antibiotic dosing regimens are usually determined in non-critically ill hospitalized adult patients. The aim was to conduct a systematic review to identify and highlight studies comparing clinical outcomes of piperacillin tazobactam dosing regimens, continuous/prolonged infusion vs intermittent infusion in critically ill patients. Meta-analyses were performed to assess the overall effect of dosing regimen on clinical efficacy. METHODS: Studies were identified systematically through searches of PubMed and Science Direct, in compliance with PRISMA guidelines. Following the systematic literature review, meta-analyses were performed using Review Manager. RESULTS: Twenty-three studies were included in the analysis involving 3828 critically ill adult participants in total (continuous/prolonged infusion = 2197 and intermittent infusion = 1631) from geographically diverse regions. Continuous/prolonged resulted in significantly: higher clinical cure rates (Odds Ratio 1.56, 95% Confidence Interval 1.28–1.90, P = 0 .0001), lower mortality rates (Odds Ratio 0.68, 95% Confidence Interval 0.55–0.84, P = 0 .0003), higher microbiological success rates (Odds Ratio 1.52, 95% Confidence Interval 1.10–2.11, P = 0.01) and decreasing the length of hospital stay (Mean Difference − 1.27, 95% Confidence Interval − 2.45—0.08, P = 0.04) in critically ill patients. CONCLUSION: Results from this study show that there is a significant level of evidence that clinical outcome in critically ill patients is improved in patients receiving piperacillin-tazobactam via continuous/prolonged infusion. However, more rigorous scientific studies in critically ill patients are warranted to reach a sufficient level of evidence and promote further implementation of C/PI as a dosing strategy.


title: Pandemic flu: from the front lines

text: Researchers describe the scientific and public-health challenges they face in battling the H1N1 virus.


Wearable Technology for “Real-World Research”: Realistic or Not?


title: Protecting Participants in Genomic Research: Understanding the “Web of Protections” Afforded by Federal and State Law

text: Researchers now commonly collect biospecimens for genomic analysis together with information from mobile devices and electronic health records. This rich combination of data creates new opportunities for understanding and addressing important health issues, but also intensifies challenges to privacy and confidentiality. Here, we elucidate the “web” of legal protections for precision medicine research by integrating findings from qualitative interviews with structured legal research and applying them to realistic research scenarios involving various privacy threats.


title: People With Advanced Cancer: The Process of Living Well With Awareness of Dying

text: Literature suggests that it is possible to live well with advanced cancer but little is known about the process. In this article, we present a secondary analysis of experiences of living with advanced cancer (n = 22) that refines the theory of “Living Well with Chronic Illness” for a different context and population. The refined theory explains the experience of living well with advanced cancer illuminating a five-phase iterative process: struggling, accepting, living with advanced cancer, sharing the illness experience, and reconstructing life. These five phases revolve around the core concept of Awareness of Dying, which varied from awareness of the possibility of dying, to accepting the possibility of dying, to acceptance that “I am dying.” Awareness of Dying led to a focus on living well with advanced cancer and movement towards living a life rather than living an illness.


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title: UK consensus on pre-clinical vascular cognitive impairment functional outcomes assessment: Questionnaire and workshop proceedings

text: Assessment of outcome in preclinical studies of vascular cognitive impairment (VCI) is heterogenous. Through an ARUK Scottish Network supported questionnaire and workshop (mostly UK-based researchers), we aimed to determine underlying variability and what could be implemented to overcome identified challenges. Twelve UK VCI research centres were identified and invited to complete a questionnaire and attend a one-day workshop. Questionnaire responses demonstrated agreement that outcome assessments in VCI preclinical research vary by group and even those common across groups, may be performed differently. From the workshop, six themes were discussed: issues with preclinical models, reasons for choosing functional assessments, issues in interpretation of functional assessments, describing and reporting functional outcome assessments, sharing resources and expertise, and standardization of outcomes. Eight consensus points emerged demonstrating broadly that the chosen assessment should reflect the deficit being measured, and therefore that one assessment does not suit all models; guidance/standardisation on recording VCI outcome reporting is needed and that uniformity would be aided by a platform to share expertise, material, protocols and procedures thus reducing heterogeneity and so increasing potential for collaboration, comparison and replication. As a result of the workshop, UK wide consensus statements were agreed and future priorities for preclinical research identified.


title: A Critical Perspective on Mental Health News in Six European Countries: How Are “Mental Health/Illness” and “Mental Health Literacy” Rhetorically Constructed?

text: In this study, we aim to contribute to the field of critical health communication research by examining how notions of mental health and illness are discursively constructed in newspapers and magazines in six European countries and how these constructions relate to specific understandings of mental health literacy. Using the method of cluster-agon analysis, we identified four terminological clusters in our data, in which mental health/illness is conceptualized as “dangerous,” “a matter of lifestyle,” “a unique story and experience,” and “socially situated.” We furthermore found that we cannot unambiguously assume that biopsychiatric discourses or discourses aimed at empathy and understanding are either exclusively stigmatizing or exclusively empowering and normalizing. We consequently call for a critical conception of mental health literacy arguing that all mental health news socializes its audience in specific understandings of and attitudes toward mental health (knowledge) and that discourses on mental health/illness can work differently in varying contexts.


title: Optogenetic assessment of VIP, PV, SOM and NOS inhibitory neuron activity and cerebral blood flow regulation in mouse somato-sensory cortex

text: The impact of different neuronal populations on local cerebral blood flow (CBF) regulation is not well known and insight into these relationships could enhance the interpretation of brain function and dysfunction from brain imaging data. We investigated the role of sub-types of inhibitory neuron activity on the regulation of CBF using optogenetics, laser Doppler flowmetry and different transgenic mouse models (parvalbumin (PV), vasoactive intestinal peptide (VIP), somatostatin (SOM) and nitric oxide synthase (NOS)). Whisker stimulation was used to verify that typical CBF responses were obtained in all mice. Photo-stimulation of SOM-cre and NOS-cre mice produced significant increases in CBF that were similar to whisker responses. In NOS-cre mice, CBF responses scaled with the photo-stimulus pulse duration and frequency. In SOM-cre mice, CBF increases were followed by decreases. In VIP-cre mice, photo-stimulation did not consistently produce significant changes in CBF, while slower increases in CBF that peaked 14–18 s after stimulation onset were observed in PV-cre mice. Control experiments performed in non-expressing regions showed no changes in CBF. These findings suggest that dysfunction in NOS or SOM neurons can have a significant impact on vascular responses that are detected by brain imaging methods like functional magnetic resonance imaging (fMRI).


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title: Distinct Region- and Time-Dependent Functional Cortical Adaptations in C57BL/6J Mice after Short and Prolonged Alcohol Drinking

text: Alcohol (ethanol) use disorder is associated with changes in frontal cortical areas including the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) that contribute to cognitive deficits, uncontrolled drinking, and relapse. Acute ethanol exposure reduces intrinsic excitability of lateral OFC (lOFC) neurons, while chronic exposure and long-term drinking influence plasticity of intrinsic excitability and function of glutamatergic synapses. However, the time course that these adaptations occur across a history of ethanol drinking is unknown. The current study examined whether short-term and long-term voluntary ethanol consumption using an intermittent access paradigm would alter the biophysical properties of deep-layer pyramidal neurons in the ACC and lOFC. Neuronal spiking varied in the ACC with an initial increase in evoked firing after 1 d of drinking followed by a decrease in firing in mice that consumed ethanol for one week. No difference in lOFC spike number was observed between water controls and 1-d ethanol drinking mice, but mice that consumed ethanol for one week or more showed a significant increase in evoked firing. Voluntary ethanol drinking for 4 weeks also produced a total loss of ethanol inhibition of lOFC neurons. There was no effect of drinking on excitatory or inhibitory synaptic events in ACC or lOFC neurons across all time points in this model. Overall, these results demonstrate that voluntary drinking alters neuronal excitability in the ACC and lOFC in distinct ways and on a different time scale that may contribute to the impairment of prefrontal cortex-dependent behaviors observed in individuals with alcohol use disorder (AUD).


title: Detailed balance for diffusion in a potential with trapping and forward–backward symmetry of trapping time distributions

text: For particles diffusing in a potential, detailed balance guarantees the absence of net fluxes at equilibrium. Here, we show that the conventional detailed balance condition is a special case of a more general relation that works when the diffusion occurs in the presence of a distributed sink that eventually traps the particle. We use this relation to study the lifetime distribution of particles that start and are trapped at specified initial and final points. It turns out that when the sink strength at the initial point is nonzero, the initial and final points are interchangeable, i.e., the distribution is independent of which of the two points is initial and which is final. In other words, this conditional trapping time distribution possesses forward–backward symmetry.