Evolutionary history.

Few academic historians take an evolutionary perspective on the past, but this outcome was not inevitable. Leading eighteenth-century intellectuals often took evolutionary perspectives, but particularists largely discredited them in and after the 1780s. By the time Spencer and Darwin revived evolutionism in the 1850s, distinctive historical questions and methods were very well-established. Public intellectuals regularly called for Darwinian history, but almost no academics saw much to gain in it. Most twentieth-century social scientists became generalizers but not evolutionists, while most historians not only refused to engage in generalization of any kind but also criticized divisions of labor in which evolutionists would test theories against data generated by historians. Possibilities remain open for a properly evolutionary history, in which scholars trained as historians but asking evolutionary questions would work alongside those trained as evolutionists but analyzing historical data, but currently, this field's prospects depend too much on individual personalities and even luck.

nSeP: immune and metabolic biomarkers for early detection of neonatal sepsis-protocol for a prospective multicohort study.

INTRODUCTION: Diagnosing neonatal sepsis is heavily dependent on clinical phenotyping as culture-positive body fluid has poor sensitivity, and existing blood biomarkers have poor specificity.A combination of machine learning, statistical and deep pathway biology analyses led to the identification of a tripartite panel of biologically connected immune and metabolic markers that showed greater than 99% accuracy for detecting bacterial infection with 100% sensitivity. The cohort study described here is designed as a large-scale clinical validation of this previous work. METHODS AND ANALYSIS: This multicentre observational study will prospectively recruit a total of 1445 newborn infants (all gestations)-1084 with suspected early-or late-onset sepsis, and 361 controls-over 4 years. A small volume of whole blood will be collected from infants with suspected sepsis at the time of presentation. This sample will be used for integrated transcriptomic, lipidomic and targeted proteomics profiling. In addition, a subset of samples will be subjected to cellular phenotype and proteomic analyses. A second sample from the same patient will be collected at 24 hours, with an opportunistic sampling for stool culture. For control infants, only one set of blood and stool sample will be collected to coincide with clinical blood sampling. Along with detailed clinical information, blood and stool samples will be analysed and the information will be used to identify and validate the efficacy of immune-metabolic networks in the diagnosis of bacterial neonatal sepsis and to identify new host biomarkers for viral sepsis. ETHICS AND DISSEMINATION: The study has received research ethics committee approval from the Wales Research Ethics Committee 2 (reference 19/WA/0008) and operational approval from Health and Care Research Wales. Submission of study results for publication will involve making available all anonymised primary and processed data on public repository sites. TRIAL REGISTRATION NUMBER: NCT03777670.

The role of Trp53 in the mouse embryonic response to DNA damage.

Apoptosis occurs primarily in the blastocyst inner cell mass, cells of which go on to form the foetus. Apoptosis is likely to play a role in ensuring the genetic integrity of the foetus, yet little is known about its regulation. In this study, the role of the mouse gene, transformation-related protein 53 (Trp53) in the response of embryos to in vitro culture and environmentally induced DNA damage was investigated using embryos from a Trp53 knockout mouse model. In vivo-derived blastocysts were compared to control embryos X-irradiated at the two-cell stage and cultured to Day 5. An analysis of DNA by comet assay demonstrated that 1.5 Gy X-irradiation directly induced damage in cultured two-cell mouse embryos; this was correlated with retarded development to blastocyst stage and increased apoptosis at the blastocyst stage but not prior to this. Trp53 null embryos developed to blastocysts at a higher frequency and with higher cell numbers than wild-type embryos. Trp53 also mediates apoptosis in conditions of low levels of DNA damage, in vivo or in vitro in the absence of irradiation. However, following DNA damage induced by X-irradiation, apoptosis is induced by Trp53 independent as well as dependent mechanisms. These data suggest that Trp53 and apoptosis play important roles in normal mouse embryonic development both in vitro and in vivo and in response to DNA damage. Therefore, clinical ART practices that alter apoptosis in human embryos and/or select embryos for transfer, which potentially lack a functional Trp53 gene, need to be carefully considered.

Efficacy and safety of systemic hydrocortisone for the prevention of bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis.

Early lung inflammation has been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD). We aimed to establish the efficacy and safety of systemic hydrocortisone for the prevention of BPD. A systematic review and meta-analysis were undertaken, with a detailed electronic literature search. Trials involving preterm infants were included if they were randomised to receive systemic hydrocortisone or a placebo. The primary outcome was the composite of survival without BPD at 36-week postmenstrual age (PMA). Results are presented as relative risk (RR) or risk difference (RD) with 95% confidence intervals (CIs), along with numbers needed to treat (NNT) or harm (NNH). After filtering, 12 studies using early (within 1 week of birth) and two using late hydrocortisone were identified. Early systemic hydrocortisone significantly increased the chances of survival without BPD (RR 1.13, 95% CI [1.01, 1.26], NNT 18), and survival without moderate-to-severe neurodevelopmental impairment (1.13 [1.02, 1.26], NNT 14). Infants who received hydrocortisone had a higher risk of intestinal perforation (1.69 [1.07, 2.68], NNH 30), primarily with concurrent treatment for patent ductus arteriosus.Conclusion: Early systemic hydrocortisone is a modestly effective therapy for the prevention of BPD in preterm infants, although some safety concerns remain. No conclusions could be drawn for late hydrocortisone due to the paucity of studies. What is Known: • Preterm infants are at high risk of developing bronchopulmonary dysplasia (BPD) and early lung inflammation plays a significant role in its pathogenesis. • Both early and late systemic dexamethasone seems to reduce the incidence of BPD, but its use is associated with serious neurodevelopmental impairment at follow-up. What is New: • Early systemic hydrocortisone significantly improved survival without BPD at 36 weeks and survival without moderate to severe neurodevelopmental impairment on follow up. • Incidence of gastrointestinal perforation associated with concurrent treatment for PDA was significantly higher, although early systemic hydrocortisone reduced the need for treatment of PDAs.

Update of the risk assessment on 3-monochloropropane diol and its fatty acid esters.

The CONTAM Panel updated the assessment of the risks for human health related to the presence of 3-monochloropropane diol (3-MCPD) and its fatty acid esters in food published in 2016 in view of the scientific divergence identified in the establishment of the tolerable daily intake (TDI) in the Joint FAO/WHO Expert Committee on Food Additives and Contaminants (FAO/WHO) report published in 2017. In this update, dose-response analysis was performed following the recent EFSA Scientific Committee guidance on the use of benchmark dose (BMD) approach in risk assessment, and a review of available data on developmental and reproduction toxicity was included. The outcome of this review indicates that in rats short-term exposure to 3-MCPD above 1 mg/kg body weight (bw) per day can induce reduced sperm motility associated with reduced male fecundity. Decreased sperm count and histopathological changes in the testis and epididymis were observed following longer treatment periods at higher doses. Regarding increased incidence kidney tubular hyperplasia, BMD analysis using model averaging resulted in a BMDL 10 of 0.20 mg/kg bw per day in male rats, which was selected as the new Reference Point (RP) for renal effects. For the effects on male fertility, decreased sperm motility was selected as the most sensitive relevant endpoint and a BMDL 05 of 0.44 mg/kg bw per day was calculated. The RP for renal effects was considered to derive an updated group TDI of 2 µg/kg bw per day for 3-MCPD and its fatty acid esters and was considered protective also for effects on male fertility. The established TDI of 2 µg/kg bw per day is not exceeded in the adult population. A slight exceedance of the TDI was observed in the high consumers of the younger age groups and in particular for the scenarios on infants receiving formula only.

A deliberately restricted laryngeal view with the GlideScope® video laryngoscope is associated with faster and easier tracheal intubation when compared with a full glottic view: a randomized clinical trial.

INTRODUCTION: During video laryngoscopy (VL) with angulated or hyper-curved blades, it is sometimes difficult to complete tracheal intubation despite a full view of the larynx. When using indirect VL, it has been suggested that it may be preferable to obtain a deliberately restricted view of the larynx to facilitate passage of the endotracheal tube. We used the GlideScope® GVL video laryngoscope (GVL) to test whether deliberately obtaining a restricted view would result in faster and easier tracheal intubation than with a full view of the larynx. METHODS: We recruited 163 elective surgical patients and randomly allocated the participants to one of two groups: Group F, where a full view of the larynx was obtained and held during GVL-facilitated tracheal intubation, and Group R, with a restricted view of the larynx (< 50% of glottic opening visible). Study investigators experienced in indirect VL performed the intubations. The intubations were recorded and the video recordings were subsequently assessed for total time to intubation, ease of intubation using a visual analogue scale (VAS; where 0 = easy and 100 = difficult), first-attempt success rate, and oxygen saturation after intubation. Complications were also assessed. RESULTS: The median [interquartile range (IQR)] time to intubation was faster in Group R than in Group F (27 [22-36] sec vs 36 [27-48] sec, respectively; median difference, 9 sec; 95% confidence interval [CI], 5 to 13; P < 0.001). The median [IQR] VAS rating for ease of intubation was also better in Group R than in Group F (14 [6-42) mm vs 50 mm [17-65], respectively; median difference, 20 mm; 95% CI, 10 to 31; P < 0.001). There was no difference between groups regarding the first-attempt success rate, oxygen saturation immediately after intubation, or complications. CONCLUSIONS: Using the GVL with a deliberately restricted view of the larynx resulted in faster and easier tracheal intubation than with a full view and with no additional complications. Our study suggests that obtaining a full or Cormack-Lehane grade 1 view may not be desirable when using the GVL. This trial was registered at ClinicalTrials.gov: NCT02144207.

The incidence, success rate, and complications of awake tracheal intubation in 1,554 patients over 12 years: an historical cohort study.

PURPOSE: Awake tracheal intubation is one recommended option to address select situations in the management of a patient with an anticipated difficult airway. A scarcity of data exists on how often awake intubation is performed or whether its use is changing over time, particularly with the increasingly widespread availability of video laryngoscopy. This retrospective database review was undertaken to determine the incidence, success, and complications of awake intubation and the incidence of other tracheal intubation techniques in the operating room over a 12-yr period (2002-2013) at our institution. METHODS: The Anesthesia Information Management System in use at a Canadian tertiary care centre was searched for all awake intubations that occurred during the years 2002-2013. Records were also searched to identify airway methods other than direct laryngoscopy that may have been used after the induction of general anesthesia. Changes in both the incidence of awake intubation and in the use of video laryngoscopy over the 12 years were analyzed using linear regression modelling. RESULTS: Of 146,252 cases performed under general anesthesia with endotracheal intubation, 1,554 intubations (1.06%) were performed awake. There was no significant change in the rate of awake intubation over the studied years (slope -1.4(-4) incidence·year(-1); 95% confidence interval [CI]: -3.0(-4) to 3.0(-5); P = 0.102). The relatively steady rate of awake intubation occurred despite a significant increase in the use of video laryngoscopy over the same time (slope 0.080 incidence·year(-1); 95% CI: 0.076 to 0.083; P < 0.001), particularly from 2009 onwards. Attempted awake intubation failed in 31 (2%) of the cases. Self-reported complications occurred in 15.7% of successful procedures. In addition, in a convenience sample of three years (2011-2013), the rate at which each of 49 attending staff performed awake intubation varied widely from 0-3.4 awake intubations per 100 cases of general anesthesia with endotracheal intubation. CONCLUSIONS: At our tertiary care centre, we did not find a significant change in the use of awake tracheal intubation over the studied years 2002-2013 despite increasing availability and use of video laryngoscopy. It appears that awake tracheal intubation retains an important and consistent role in the management of the difficult airway.

Variation in treatment of acute childhood wheeze in emergency departments of the United Kingdom and Ireland: an international survey of clinician practice.

OBJECTIVE: National clinical guidelines for childhood wheeze exist, yet despite being one of the most common reasons for childhood emergency department (ED) attendance, significant variation in practice occurs in other settings. We, therefore, evaluated practice variations of ED clinicians in the UK and Ireland. DESIGN: Two-stage survey undertaken in March 2013. Stage one examined department practice and stage two assessed ED consultant practice in acute childhood wheeze. Questions interrogated pharmacological and other management strategies, including inhaled and intravenous therapies. SETTING AND PARTICIPANTS: Member departments of Paediatric Emergency Research in the United Kingdom and Ireland and ED consultants treating children with acute wheeze. RESULTS: 30 EDs and 183 (81%) clinicians responded. 29 (97%) EDs had wheeze guidelines and 12 (40%) had care pathways. Variation existed between clinicians in dose, timing and frequency of inhaled bronchodilators across severities. When escalating to intravenous bronchodilators, 99 (54%) preferred salbutamol first line, 52 (28%) magnesium sulfate (MgSO4) and 27 (15%) aminophylline. 87 (48%) administered intravenous bronchodilators sequentially and 30 (16%) concurrently, with others basing approach on case severity. 146 (80%) continued inhaled therapy after commencing intravenous bronchodilators. Of 170 who used intravenous salbutamol, 146 (86%) gave rapid boluses, 21 (12%) a longer loading dose and 164 (97%) an ongoing infusion, each with a range of doses and durations. Of 173 who used intravenous MgSO4, all used a bolus only. 41 (24%) used non-invasive ventilation. CONCLUSIONS: Significant variation in ED consultant management of childhood wheeze exists despite the presence of national guidance. This reflects the lack of evidence in key areas of childhood wheeze and emphasises the need for further robust multicentre research studies.

Increased affluence explains the emergence of ascetic wisdoms and moralizing religions.

BACKGROUND: Between roughly 500 BCE and 300 BCE, three distinct regions, the Yangtze and Yellow River Valleys, the Eastern Mediterranean, and the Ganges Valley, saw the emergence of highly similar religious traditions with an unprecedented emphasis on self-discipline and asceticism and with "otherworldly," often moralizing, doctrines, including Buddhism, Jainism, Brahmanism, Daoism, Second Temple Judaism, and Stoicism, with later offshoots, such as Christianity, Manichaeism, and Islam. This cultural convergence, often called the "Axial Age," presents a puzzle: why did this emerge at the same time as distinct moralizing religions, with highly similar features in different civilizations? The puzzle may be solved by quantitative historical evidence that demonstrates an exceptional uptake in energy capture (a proxy for general prosperity) just before the Axial Age in these three regions. RESULTS: Statistical modeling confirms that economic development, not political complexity or population size, accounts for the timing of the Axial Age. CONCLUSIONS: We discussed several possible causal pathways, including the development of literacy and urban life, and put forward the idea, inspired by life history theory, that absolute affluence would have impacted human motivation and reward systems, nudging people away from short-term strategies (resource acquisition and coercive interactions) and promoting long-term strategies (self-control techniques and cooperative interactions).

More than 50% of players sustained a time-loss injury (>1†day of lost training or playing time) during the 2012 Super Rugby Union Tournament: a prospective cohort study of 17,340 player-hours.

BACKGROUND: Professional Rugby Union is a contact sport with a high risk of injury. OBJECTIVE: To document the incidence and nature of time-loss injuries during the 2012 Super Rugby tournament. DESIGN: Prospective cohort study. SETTING: 2012 Super Rugby tournament (Australia, New Zealand, South Africa). PARTICIPANTS: 152 players from 5 South African teams. METHODS: Team physicians collected daily injury data through a secure, web-based electronic platform. Data included size of the squad, type of day, main player position, training or match injury, hours of play (training and matches), time of the match injury, mechanism of injury, main anatomical location of the injury, specific anatomical structure of the injury, the type of injury, the severity of the injury (days lost). RESULTS: The proportion (%) of players sustaining a time-loss injury during the tournament was 55%, and 25% of all players sustained >1 injury. The overall incidence rate (IR/1000 player-hours) of injuries was 9.2. The IR for matches (83.3) was significantly higher than for training (2.1) and the IR was similar for forwards and backs. Muscle/tendon (50%) and joint/ligament (32.7%) injuries accounted for >80% of injuries. Most injuries occurred in the lower (48.1%) and upper limb (25.6%). 42% of all injuries were moderate (27.5%) or severe (14.8%), and tackling (26.3%) and being tackled (23.1%) were the most common mechanisms of injury. The IR of injuries was unrelated to playing at home compared with away (locations ≥6 h time difference). CONCLUSIONS: 55% of all players were injured during the 4-month Super Rugby tournament (1.67 injuries/match). Most injuries occurred in the lower (knee, thigh) or upper limb (shoulder, clavicle). 42% of injuries were severe enough for players to not play for >1 week.

DAMP molecule S100A9 acts as a molecular pattern to enhance inflammation during influenza A virus infection: role of DDX21-TRIF-TLR4-MyD88 pathway.

Pathogen-associated molecular patterns (PAMPs) trigger host immune response by activating pattern recognition receptors like toll-like receptors (TLRs). However, the mechanism whereby several pathogens, including viruses, activate TLRs via a non-PAMP mechanism is unclear. Endogenous "inflammatory mediators" called damage-associated molecular patterns (DAMPs) have been implicated in regulating immune response and inflammation. However, the role of DAMPs in inflammation/immunity during virus infection has not been studied. We have identified a DAMP molecule, S100A9 (also known as Calgranulin B or MRP-14), as an endogenous non-PAMP activator of TLR signaling during influenza A virus (IAV) infection. S100A9 was released from undamaged IAV-infected cells and extracellular S100A9 acted as a critical host-derived molecular pattern to regulate inflammatory response outcome and disease during infection by exaggerating pro-inflammatory response, cell-death and virus pathogenesis. Genetic studies showed that the DDX21-TRIF signaling pathway is required for S100A9 gene expression/production during infection. Furthermore, the inflammatory activity of extracellular S100A9 was mediated by activation of the TLR4-MyD88 pathway. Our studies have thus, underscored the role of a DAMP molecule (i.e. extracellular S100A9) in regulating virus-associated inflammation and uncovered a previously unknown function of the DDX21-TRIF-S100A9-TLR4-MyD88 signaling network in regulating inflammation during infection.

The difficult airway with recommendations for management--part 2--the anticipated difficult airway.

BACKGROUND: Appropriate planning is crucial to avoid morbidity and mortality when difficulty is anticipated with airway management. Many guidelines developed by national societies have focused on management of difficulty encountered in the unconscious patient; however, little guidance appears in the literature on how best to approach the patient with an anticipated difficult airway. METHODS: To review this and other subjects, the Canadian Airway Focus Group (CAFG) was re-formed. With representation from anesthesiology, emergency medicine, and critical care, CAFG members were assigned topics for review. As literature reviews were completed, results were presented and discussed during teleconferences and two face-to-face meetings. When appropriate, evidence- or consensus-based recommendations were made, and levels of evidence were assigned. PRINCIPAL FINDINGS: Previously published predictors of difficult direct laryngoscopy are widely known. More recent studies report predictors of difficult face mask ventilation, video laryngoscopy, use of a supraglottic device, and cricothyrotomy. All are important facets of a complete airway evaluation and must be considered when difficulty is anticipated with airway management. Many studies now document the increasing patient morbidity that occurs with multiple attempts at tracheal intubation. Therefore, when difficulty is anticipated, tracheal intubation after induction of general anesthesia should be considered only when success with the chosen device(s) can be predicted in a maximum of three attempts. Concomitant predicted difficulty using oxygenation by face mask or supraglottic device ventilation as a fallback makes an awake approach advisable. Contextual issues, such as patient cooperation, availability of additional skilled help, and the clinician's experience, must also be considered in deciding the appropriate strategy. CONCLUSIONS: With an appropriate airway evaluation and consideration of relevant contextual issues, a rational decision can be made on whether an awake approach to tracheal intubation will maximize patient safety or if airway management can safely proceed after induction of general anesthesia. With predicted difficulty, close attention should be paid to details of implementing the chosen approach. This should include having a plan in case of the failure of tracheal intubation or patient oxygenation.

The difficult airway with recommendations for management--part 1--difficult tracheal intubation encountered in an unconscious/induced patient.

BACKGROUND: Previously active in the mid-1990s, the Canadian Airway Focus Group (CAFG) studied the unanticipated difficult airway and made recommendations on management in a 1998 publication. The CAFG has since reconvened to examine more recent scientific literature on airway management. The Focus Group's mandate for this article was to arrive at updated practice recommendations for management of the unconscious/induced patient in whom difficult or failed tracheal intubation is encountered. METHODS: Nineteen clinicians with backgrounds in anesthesia, emergency medicine, and intensive care joined this iteration of the CAFG. Each member was assigned topics and conducted reviews of Medline, EMBASE, and Cochrane databases. Results were presented and discussed during multiple teleconferences and two face-to-face meetings. When appropriate, evidence- or consensus-based recommendations were made together with assigned levels of evidence modelled after previously published criteria. CONCLUSIONS: The clinician must be aware of the potential for harm to the patient that can occur with multiple attempts at tracheal intubation. This likelihood can be minimized by moving early from an unsuccessful primary intubation technique to an alternative "Plan B" technique if oxygenation by face mask or ventilation using a supraglottic device is non-problematic. Irrespective of the technique(s) used, failure to achieve successful tracheal intubation in a maximum of three attempts defines failed tracheal intubation and signals the need to engage an exit strategy. Failure to oxygenate by face mask or supraglottic device ventilation occurring in conjunction with failed tracheal intubation defines a failed oxygenation, "cannot intubate, cannot oxygenate" situation. Cricothyrotomy must then be undertaken without delay, although if not already tried, an expedited and concurrent attempt can be made to place a supraglottic device.

The production of monokaryotic hyphae by Cryptococcus neoformans can be induced by high temperature arrest of the cell cycle and is independent of same-sex mating.

Cryptococcus neoformans is a heterothallic fungal pathogen of humans and animals. Although the fungus grows primarily as a yeast, hyphae are produced during the sexual phase and during a process called monokaryotic fruiting, which is also believed to involve sexual reproduction, but between cells of the same mating type. Here we report a novel monokaryotic fruiting mechanism that is dependent on the cell cycle and occurs in haploid cells in the absence of sexual reproduction. Cells grown at 37°C were found to rapidly produce hyphae (∼4 hrs) and at high frequency (∼40% of the population) after inoculation onto hyphae-inducing agar. Microscopic examination of the 37°C seed culture revealed a mixture of normal-sized and enlarged cells. Micromanipulation of single cells demonstrated that only enlarged cells were able to produce hyphae and genetic analysis confirmed that hyphae did not arise from α-α mating or endoduplication. Cell cycle analysis revealed that cells grown at 37°C had an increased population of cells in G2 arrest, with the proportion correlated with the frequency of monokaryotic fruiting. Cell sorting experiments demonstrated that enlarged cells were only found in the G2-arrested population and only this population contained cells able to produce hyphae. Treatment of cells at low temperature with the G2 cell cycle arrest agent, nocodazole, induced hyphal growth, confirming the role of the cell cycle in this process. Taken together, these results reveal a mating-independent mechanism for monokaryotic fruiting, which is dependent on the cell cycle for induction of hyphal competency.