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Charles William Hargett,1 Joseph P Doty,2 Jennifer N Hauck,3 Allison MB Webb,4 Steven H Cook,5 Nicholas E Tsipis,4 Julie A Neumann,6 Kathryn M Andolsek,7 Dean C Taylor6 1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, 2Feagin Leadership Program, 3Department of Anesthesiology, 4School of Medicine, 5Department of Neurosurgery, 6Department of Orthopaedic Surgery, 7Department of Community and Family Medicine, Duke University School of Medicine, Durham, NC, USA Purpose: Despite increasing awareness of the importance of leadership in healthcare, our understanding of the competencies of effective leadership remains limited. We used a concept mapping approach (a blend of qualitative and quantitative analysis of group processes to produce a visual composite of the group’s ideas) to identify stakeholders’ mental model of effective healthcare leadership, clarifying the underlying structure and importance of leadership competencies.Methods: Literature review, focus groups, and consensus meetings were used to derive a representative set of healthcare leadership competency statements. Study participants subsequently sorted and rank-ordered these statements based on their perceived importance in contributing to effective healthcare leadership in real-world settings. Hierarchical cluster analysis of individual sortings was used to develop a coherent model of effective leadership in healthcare.Results: A diverse group of 92 faculty and trainees individually rank-sorted 33 leadership competency statements. The highest rated statements were “Acting with Personal Integrity”, “Communicating Effectively”, “Acting with Professional Ethical Values”, “Pursuing Excellence”, “Building and Maintaining Relationships”, and “Thinking Critically”. Combining the results from hierarchical cluster analysis with our qualitative data led to a healthcare leadership model based on the core principle of Patient Centeredness and the core competencies of Integrity, Teamwork, Critical Thinking, Emotional Intelligence, and Selfless Service.Conclusion: Using a mixed qualitative-quantitative approach, we developed a graphical representation of a shared leadership model derived in the healthcare setting. This model may enhance learning, teaching, and patient care in this important area, as well as guide future research. Keywords: core competencies, healthcare leadership, medical education, mental models, mixed methods research

Abstract Background Little is known about how individuals who have a diagnosis of epilepsy have experienced healthcare services or their views about how they should best be organised to meet their ongoing needs. Methods Focus group interviews. Individuals with epilepsy were identified in 5 practices in Wales: 90 were invited, 40 confirmed attendance and 19 individuals attended interviews in 5 groups of size 6, 5, 4, 3 and 1 (Table 2). Inclusion criteria: individuals with a confirmed diagnosis of epilepsy, aged between 18–65. The exclusion criteria were learning disability or an inability to travel to interview locations. Results The individuals in these group interviews were not 'epilepsy activists' yet they remained critical in extended discussions about the services encountered during their patient careers, wanting more information and advice about how to adapt to problems, particularly after initial diagnosis, more involvement in decision making, rapid access to expertise, preferably local, and improved communication between clinicians. A central concern was the tendency for concerns to be silenced, either overtly, or covertly by perceived haste, so that they felt marginalised, despite their own claims to own expert personal knowledge. Conclusions Users of existing services for epilepsy are critical of current systems, especially the lack of attention given to providing information, psychosocial support and the wishes of patients to participate in decision making. Any reorganisation of services for individuals with epilepsy should take into account these perceived problems as well as try to reconcile the tension between the distant and difficult to access expertise of specialists and the local but unconfident support of generalists. The potential benefit of harnessing information technology to allow better liaison should be investigated.

The electronic excitation of key combustion species or flow tagging of chemical species requires a narrowband tunable UV source. In this work, a potassium titanyl phosphate (KTP) burst-mode optical parametric oscillator (OPO) pumped by a 532 nm laser is developed to generate a spectrally narrow signal and an idler output with 1.48 ± 0.19 cm -1 bandwidth without the need for injection seeding. The idler (1410-1550 nm range) is further mixed with 355 or 266 nm to generate 284 or 226 nm for OH or NO planar laser-induced fluorescence (PLIF), respectively, with up to 1.9% conversion efficiency from 1064 nm to the UV. MHz-rate burst profiles are reported, and OH and NO PLIF are demonstrated in a rotating detonation combustor at rates up to 200 kHz.

Simple and efficient total synthesis of homogeneous and chemically modified protein samples remains a significant challenge. Here, we report development of a convergent hybrid phase native chemical ligation (CHP-NCL) strategy for facile preparation of proteins. In this strategy, proteins are split into ~100-residue blocks, and each block is assembled on solid support from synthetically accessible peptide fragments before ligated together into full-length protein in solution. With the new method, we increase the yield of CENP-A synthesis by 2.5-fold compared to the previous hybrid phase ligation approach. We further extend the new strategy to the total chemical synthesis of 212-residue linker histone H1.2 in unmodified, phosphorylated, and citrullinated forms, each from eight peptide segments with only one single purification. We demonstrate that fully synthetic H1.2 replicates the binding interactions of linker histones to intact mononucleosomes, as a proxy for the essential function of linker histones in the formation and regulation of higher order chromatin structure., Competing Interests: Conflict of Interests The authors declare no competing interests.

Objective: Despite the absolute requirement of Delta/Notch signaling to activate lateral inhibition during early blood vessel development, many mechanisms remain unclear about how this system is regulated. Our objective was to determine the involvement of Epsin 15 Homology Domain Containing 2 (EHD2) in delta-like ligand 4 (Dll4) endocytosis during Notch activation., Approach and Results: Using both in vivo and in vitro models, we demonstrate that EHD2 is a novel modulator of Notch activation in endothelial cells through controlling endocytosis of Dll4. In vitro, EHD2 localized to plasma membrane-bound Dll4 and caveolae. Chemical disruption of caveolae complexes resulted in EHD2 failing to organize around Dll4 as well as loss of Dll4 internalization. Reduced Dll4 internalization blunted Notch activation in endothelial cells. In vivo, EHD2 is primarily expressed in the vasculature, colocalizing with junctional marker VE-cadherin and Dll4. Knockout of EHD2 in zebrafish produced a significant increase in dysmorphic sprouts in zebrafish intersomitic vessels during development and a reduction in downstream Notch signaling., Conclusions: Overall, we demonstrate that EHD2 is necessary for Dll4 transcytosis and downstream Notch activation., (© 2021 The Authors. Microcirculation published by John Wiley & Sons Ltd.)

Collagen type IV (Col IV) is a basement membrane protein associated with early blood vessel morphogenesis and is essential for blood vessel stability. Defects in vascular Col IV deposition are the basis of heritable disorders, such as small vessel disease, marked by cerebral hemorrhage and drastically shorten lifespan. To date, little is known about how endothelial cells regulate the intracellular transport and selective secretion of Col IV in response to angiogenic cues, leaving a void in our understanding of this critical process. Our aim was to identify trafficking pathways that regulate Col IV deposition during angiogenic blood vessel development. We have identified the GTPase Rab10 as a major regulator of Col IV vesicular trafficking during vascular development using both in vitro imaging and biochemistry as well as in vivo models. Knockdown of Rab10 reduced de novo Col IV secretion in vivo and in vitro. Mechanistically, we determined that Rab10 is an indirect mediator of Col IV secretion, partnering with atypical Rab25 to deliver the enzyme lysyl hydroxylase 3 (LH3) to Col IV-containing vesicles staged for secretion. Loss of Rab10 or Rab25 results in depletion of LH3 from Col IV-containing vesicles and rapid lysosomal degradation of Col IV. Furthermore, we demonstrate that Rab10 is Notch responsive, indicating a novel connection between permissive Notch-based vessel maturation programs and vesicle trafficking. Our results illustrate both a new trafficking-based component in the regulated secretion of Col IV and how this vesicle trafficking program interfaces with Notch signaling to fine-tune basement membrane secretion during blood vessel development., (© 2021. The Author(s).)

Megahertz-rate hydroxyl radical planar laser-induced fluorescence (OH-PLIF) was demonstrated in a hydrogen/air rotating detonation combustor for the first time, to the best of our knowledge. A custom injection-seeded optical parametric oscillator (OPO) pumped by the 355 nm output of a high-energy burst-mode laser produced narrowband pulses near 284 nm for OH excitation. The system generated sequences of more than 150 ultraviolet pulses with 400 µJ/pulse at 1 MHz and 150 µJ/pulse at 2 MHz. The order of magnitude improvement in the repetition rate over prior OH-PLIF measurements and in the number of pulses over previous megahertz burst-mode OPOs enables spatiotemporal analysis of complex detonation combustion dynamics.

In the presented case, the authors describe an obese middle-aged man that presented to the emergency department for persistent oedema, scleral icterus and fatigue. He was admitted to the hospital and diagnosed with liver cirrhosis via transjugular liver biopsy. He continued to bleed from the biopsy site for 5 days from accelerated intravascular coagulation and fibrinolysis (AICF) requiring multiple transfusions of packed red blood cells, fresh-frozen plasma and cryoprecipitate. The authors then used thromboelastography (TEG) to further characterise the patient's coagulopathy, which revealed platelet inhibition. The results of the TEG significantly changed future transfusion management. Finally, the authors conducted a literature review to summarise the current literature available for the use of TEG in the management of liver cirrhosis with AICF., Competing Interests: Conflicts of Interest: None declared., (2016 BMJ Publishing Group Ltd.)

Minimally invasive investigation of plant parts (root, stem, leaves, and flower) has good potential to elucidate the dynamics of plant growth, morphology, physiology, and root-rhizosphere interactions. Laboratory based absorption X-ray imaging and computed tomography (CT) systems are extensively used for in situ feasibility studies of plants grown in natural and artificial soil. These techniques have challenges such as low contrast between soil pore space and roots, long X-ray imaging time, and low spatial resolution. In this study, the use of synchrotron (SR) based phase contrast X-ray imaging (PCI) has been demonstrated as a minimally invasive technique for imaging plants. Above ground plant parts and roots of 10 day old canola and wheat seedlings grown in sandy clay loam soil were successfully scanned and reconstructed. Results confirmed that SR-PCI can deliver good quality images to study dynamic and real time processes such as cavitation and water-refilling in plants. The advantages of SR-PCI, effect of X-ray energy, and effective pixel size to study plant samples have been demonstrated. The use of contrast agents to monitor physiological processes in plants was also investigated and discussed.

Purpose: To characterize leadership curricula in undergraduate medical education as a first step toward understanding best practices in leadership education., Method: The authors systematically searched the PubMed, Education Resources Information Center, Academic Search Complete, and Education Full Text databases for peer-reviewed English-language articles published 1980-2014 describing curricula with interventions to teach medical students leadership skills. They characterized educational settings, curricular format, and learner and instructor types. They assessed effectiveness and quality of evidence using five-point scales adapted from Kirkpatrick's four-level training evaluation model (scale: 0-4) and a Best Evidence Medical Education guide (scale: 1-5), respectively. They classified leadership skills taught into the five Medical Leadership Competency Framework (MLCF) domains., Results: Twenty articles describing 24 curricula met inclusion criteria. The majority of curricula (17; 71%) were longitudinal, delivered over periods of one semester to four years. The most common setting was the classroom (12; 50%). Curricula were frequently provided to both preclinical and clinical students (11; 46%); many (9; 28%) employed clinical faculty as instructors. The majority (19; 79%) addressed at least three MLCF domains; most common were working with others (21; 88%) and managing services (18; 75%). The median effectiveness score was 1.5, and the median quality of evidence score was 2., Conclusions: Most studies did not demonstrate changes in student behavior or quantifiable results. Aligning leadership curricula with competency models, such as the MLCF, would create opportunities to standardize evaluation of outcomes, leading to better measurement of student competency and a better understanding of best practices.

Background: Recently developed methods for genome editing in bacteria take advantage of the introduction of double-strand breaks by I-SceI in a mutation cassette to select for cells in which homologous recombination has healed the break and introduced a desired mutation. This elegantly designed method did not work well in our hands for most genes., Results: We corrected a mutation in the gene encoding I-SceI that compromised the function of a previously used Red helper plasmid. Further, we found that transcription extending into the mutation cassette interferes with cleavage by I-SceI. Addition of two transcription terminators upstream of the cleavage site dramatically increases the efficiency of genome editing. We also developed an improved method for modification of essential genes. Inclusion of a segment of the essential gene consisting of synonymous codons restores an open reading frame when the mutation cassette is integrated into the genome and decreases the frequency of recombination events that fail to incorporate the desired mutation. The optimized protocol takes only 5 days and has been 100% successful for over 100 genomic modifications in our hands., Conclusions: The method we describe here is reliable and versatile, enabling various types of genome editing in Escherichia coli and Salmonella enterica by straightforward modifications of the mutation cassette. We provide detailed descriptions of the methods as well as designs for insertions, deletions, and introduction of point mutations.

Objectives: To identify the prevalence of Neisseria gonorrhoeae (NG) within a population screened for Chlamydia trachomatis (CT). To monitor confirmatory microscopy, culture, and partner findings following reactive Aptima Combo2 assay (AC2) gonorrhoea screening tests., Methods: Between June and December 2004, all gonorrhoea screening tests performed using AC2 for clients taking part in the Liverpool Chlamydia Screening Programme were monitored. Clients with AC2 NG reactive results were referred to a local genitourinary medicine (GUM) department for confirmatory microscopy, culture, treatment, and partner follow up., Results: 47 (1%) of 4680 women and eight (1.7%) of 473 men had AC2 reactive gonorrhoea screening tests. Of those clients who agreed to follow up and were tested before any treatment, supportive evidence for a gonorrhoea diagnosis was found in 37 (97%) of 38 women and all five men. In the population opportunistically screened for chlamydia, CT prevalence rates were 12% for women and 15.7% for men. Although both women and men showed a higher relative risk for NG if chlamydia positive, of the 47 women who were reactive for NG by AC2, 55% (26) were negative for chlamydia., Conclusions: Sexually transmitted infections are rising in England and reduction of gonorrhoea rates is an objective of the Department of Health Sexual Health and HIV Strategy. AC2 tests provide an acceptable and accurate means of testing for gonorrhoea in an asymptomatic population in the community. AC2 had a higher positive predictive value than might be suggested by previous clinical trials in this low prevalence population. Although antibiotic sensitivity must be monitored, AC2 testing may offer a more acceptable alternative to microscopy and culture for NG in some populations.

Bright-field, diffraction-contrast imaging in the transmission electron microscope has been applied to the determination of the diameter and height populations of a single layer of buried, pure, InAs/InP quantum dots (QDs). Plan-view diffraction contrast from the QDs was observed to increase significantly when the sample was tilted away from the [001] growth direction to near the [111] zone-axis orientation. This added contrast was a result of contributions to the displacement of atoms in a direction perpendicular to the electron beam arising from strain in the growth direction. Since the strain in the growth direction was about an order of magnitude larger than the strain perpendicular to the growth direction, as the sample is tilted away from the [001] zone-axis condition, the larger strain component increases the projected strain thereby increasing the QD contrast in the image. For the sample studied, both of the populations for the QD diameter and the image contrast were observed to be multimodal with the seven peaks in the contrast distribution correlating with seven distinct populations of QDs each differing in height by one monolayer (ML), from 3 to 9MLs. An analysis of the theoretically expected and experimentally observed standard deviations in the Gaussian fits to the QD diameter and height distributions provided an additional constraint in the selection of the optimal model for the multimodal distributions.

Objective: To determine if the documentation for intrauterine device (IUD) insertions was satisfactory and to agree minimum standards for practice., Method: A list was drawn up with minimum standards for documentation in the case notes. These were agreed at the clinical audit meeting. A retrospective analysis of case notes was done and a list completed for each IUD insertion., Setting and Participants: IUD fittings at all the Abacus clinics from 1 September 1999 to 31 October 1999., Results: Of the 232 IUD insertions, the gold standard for documentation was met in 20%, however documentation of essential criteria was met 93% and all criteria 83% of the time. Each doctor received individual, confidential, comparative feedback., Conclusion: We were able to agree a minimum standard for documentation to enhance adequate counselling, safe insertion, communication with colleagues and risk management.

Unlabelled: We studied the time course of clinical and pharmacokinetic effects after the rectal administration of diclofenac 100 mg in seven patients using patient-controlled morphine (PCA) on the first postoperative day after major spinal surgery. Plots of plasma diclofenac concentrations and pain intensity difference (PID) demonstrated counterclockwise hysteresis consistent with distribution to a central effect compartment such as the central nervous system. Mean +/- SEM (range) maximum PID and its timing were 62%+/-10% (32%-98%) and 309+/-20 (210-360) min after the administration of diclofenac, respectively. Minimal respiratory rates were significantly slower after the administration of diclofenac (P < 0.001), occurring at 197+/-51.9 (60-360) min; arterial desaturations occurred in two patients without oxygen therapy. Plasma morphine and morphine-6-glucuronide (M6G) concentrations interpolated to the average time of minimal respiratory rate indicated decreases of 23%+/-13% (0%-79%) and 1%+/-9% (0%-32%) from their respective starting values. Plasma M6G concentrations were significantly different from baseline only 420 and 480 min after the administration of diclofenac. The potential opioid-sparing effects of a nonsteroidal antiinflammatory drug added during PCA morphine use may not be manifest for several hours. During this lag, plasma concentrations of M6G may reach and remain at levels high enough to increase the risk of respiratory depression and other opioid side effects for hours., Implications: Plasma concentrations of morphine, morphine-6-glucuronide, and diclofenac were measured postoperatively after a single dose of rectal diclofenac 100 mg was added to morphine patient-controlled analgesia. Peak analgesia occurred 309 min and respiratory depression 197 min after diclofenac administration. Morphine consumption had decreased by 20%, but concentrations of the active metabolite morphine-6-glucuronide were unchanged. Vigilance is recommended in patients receiving patient-controlled analgesia opioids and nonsteroidal antiinflammatory drugs.

Although the Yuzpe regimen of emergency contraception is the one most commonly used, there are alternatives. Copper-containing intrauterine devices are very effective and can be inserted for at least 5 days after unprotected intercourse and sometimes longer. They may, however, transmit pre-existing infection into the upper genital tract and cause discomfort when being fitted. Progestogen-only emergency contraception appears, from WHO studies, to be a useful adjunct to current therapies. Mifepristone has been studied in various doses and has been shown to be very effective but is not yet commercially available. Health services should provide a full range of methods including emergency contraception by appropriately trained people in an acceptable environment.

There is a need to balance the provision of safe and effective contraception against the desire to avoid interventions which might unnecessarily restrict the availability of combined oral contraceptives (COCs). In March 1996, an international group of recognised authorities in their field met to review the available evidence concerning the effects of COCs and the value of various screening procedures in pre-menopausal women. Current scientific evidence suggests only two pre-requisites for the safe provision of COCs: a careful personal and family medical history with particular attention to cardiovascular risk factors, and an accurate blood pressure measurement. Further assessment is required only if a relevant personal or family history is disclosed or the blood pressure is elevated. Only a small minority of women will require this further assessment.

Objective: To compare the effectiveness and acceptability of three regimens of postcoital contraception., Design: Randomised group comparison of ethinyloestradiol 100 micrograms plus levonorgestrel 500 micrograms repeated after 12 hours (Yuzpe method); danazol 600 mg repeated after 12 hours; and mifepristone 600 mg single dose., Setting: Community family planning clinic., Subjects: 616 consecutive women with regular cycles aged 16 to 45 years., Main Outcome Measures: Number of pregnancies, incidence of side effects, and timing of next period., Results: The raw pregnancy rates (with 95% confidence intervals) for the Yuzpe, danazol, and mifepristone groups were 2.62% (0.86% to 6.00%), 4.66% (2.15% to 8.67%), and 0% (0% to 1.87%) respectively. Overall, these rates differed significantly (chi 2 = 8.988, df = 2; p = 0.011). The differences between the mifepristone and Yuzpe groups and between the mifepristone and danazol groups were also significant. Side effects were more common and more severe in the Yuzpe group (133 women (70%)) than in either the danazol group (58 (30%)) or the mifepristone group (72 (37%)). The Yuzpe regimen tended to induce bleeding early but mifepristone prolonged the cycle. Three women bled more than seven days late in the Yuzpe group compared with 49 in the mifepristone group., Conclusions: Mifepristone was effective in reducing expected pregnancy rates and the Yuzpe method also had a clinical effect. Danazol had little or no effect. A further multicentre trial is needed.

The study compares the effectiveness and acceptability of three regimes of postcoital contraception: 1) ethinylestradiol 100 micrograms/levonorgestrel 500 micrograms repeated after 12 hours (Yuzpe method); 2) danazol 600 mg repeated after 12 hours; and 3) RU486 600 mg single dose. Between 1 April 1990 and 15 October 1990, 215 women were selected and randomly allocated to the three treatment groups. One hundred and sixty eight were fully followed up, 35 ongoing and 8 lost to follow-up. All women had regular cycles and were aged 16-45 years. All treatments were given within 72 hours of unprotected intercourse and follow-up was until normal menstruation or diagnosis of pregnancy. beta-HCG was measured quantitatively where there was a suspicion of pregnancy. The data obtained show similar failure rates (Yuzpe 1/57, danazol 2/57, RU486 1/54) but more side-effects in the Yuzpe group (nausea 74.1%, vomiting 22.4%, breast tenderness 22.4%) than in the other two (danazol: nausea 31.6%, vomiting 3.5%, breast tenderness 19.3%) and (RU486: nausea 36.4%, vomiting 3.6%, breast tenderness 23.6%). There was one apparent allergic reaction in the danazol group. RU486 caused greater cycle disturbance, prolonging the cycle considerably. Initial results suggest that danazol and RU486 may be much more acceptable methods of postcoital contraception due to reduced side-effects and, in the latter case, single dose. Although numbers are small at present, the effectiveness of the newer methods appear similar to Yuzpe.

Glycosylated haemoglobin (GHb), glycosylated albumin (GAlb), and blood glucose were measured from 283 non-diabetic, 7 insulin-dependent diabetic, and 5 gestational diabetic mothers, and in the cord blood of their babies. Significant correlation was found between mother and baby for GHb (r = 0.31) and GAlb (r = 0.42). However, GHb, GAlb and glucose concentration were significantly higher in maternal blood compared to cord blood (p less than 0.001). Only GAlb showed any difference between a pregnant and a non-pregnant population (p less than 0.001). All three parameters were significantly higher in the diabetic mothers compared to the non-diabetic mothers (p less than 0.001). No difference was found between the levels of GHb and GAlb in babies from these two groups. There was no difference in the level of GHb between gestational and insulin-dependent mothers although the latter showed a significantly higher blood glucose (p less than 0.05).