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Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Few studies describe the frequency of antibiotic regimen modification behaviors in the acute care setting. We sought to ascertain patient and treatment characteristics, details of regimen modification, and clinical outcomes with antibiotic modifications. This retrospective study included patients admitted to Hoag Memorial Hospital from 1 January 2019–31 March 2021 with a complicated infection caused by a Gram-negative organism resistant to extended-spectrum cephalosporins or with the potential for resistance (AmpC producers). A total of 400 patients were included. The predominant sources were bloodstream (33%), urine (26%), and respiratory (24%), including patients with multiple sources. The most isolated organisms were Pseudomonas spp. and ESBL-producing organisms, 38% and 34%, respectively. A total of 72% of patients had antibiotic regimen modifications to their inpatient antibiotic regimens. In patients where modifications occurred, the number ranged from one to six modifications. The most common reasons for modifications included a lack of patient response (14%), additional history reviewed (9%), and decompensation (7%). No difference in clinical outcomes was observed based on antibiotic modifications. The numerous changes in therapy observed may reflect the limitations in identifying patients with resistant organisms early on in admission. This highlights the need for more novel antibiotics and the importance of identifying patients at risk for resistant organisms.

Summary: Background: Due to geographic isolation and border controls Aotearoa New Zealand (AoNZ) attained high levels of population coronavirus disease-19 (COVID-19) vaccination before widespread transmission of COVID-19. We describe outcomes of SARS-CoV-2 infection (Omicron variant) in people with inflammatory rheumatic diseases in this unique setting. Methods: This observational study included people with inflammatory rheumatic disease and SARS-CoV-2 infection in AoNZ between 1 February and 30 April 2022. Data were collected via the Global Rheumatology Alliance Registry including demographic and rheumatic disease characteristics, and COVID-19 vaccination status and outcomes. Multivariable logistic regression was used to explore associations of demographic and clinical factors with COVID-19 hospitalisation and death. Findings: Of the 1599 cases included, 96% were from three hospitals that systematically identified people with inflammatory rheumatic disease and COVID-19. At time of COVID-19, 1513 cases (94.6%) had received at least two COVID-19 vaccinations. Hospitalisation occurred for 104 (6.5%) cases and 10 (0.6%) patients died. Lower frequency of hospitalisation was seen in cases who had received at least two vaccinations (5.9%), compared to the unvaccinated (20.6%) or those with a single vaccine dose (10.7%). In multivariable adjusted models, people with gout or connective tissue diseases (CTD) had increased risk of the combined outcome of hospitalisation/death, compared to people with inflammatory arthritis. Glucocorticoid and rituximab use were associated with increased rates of hospitalisation/death. All patients who died had three or more co-morbidities or were over 60 years old. Interpretation: In this cohort with inflammatory rheumatic diseases and high vaccination rates, severe outcomes from SARS-CoV-2 Omicron variant were relatively infrequent. The outcome of Omicron variant infection among vaccinated but SARS-CoV-2 infection-naive people with inflammatory rheumatic disease without other known risk factors were favourable. Funding: Financial support from the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) included management of COVID-19 Global Rheumatology Alliance funds.

OBJECTIVES:. To analyze the temporal trend in enrollment rates in a COVID-19 platform trial during the first three waves of the pandemic in the United States. DESIGN:. Secondary analysis of data from the I-SPY COVID randomized controlled trial (RCT). SETTING:. Thirty-one hospitals throughout the United States. PATIENTS:. Patients who were approached, either directly or via a legally authorized representative, for consent and enrollment into the I-SPY COVID RCT. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Among 1,338 patients approached for the I-SPY COVID trial from July 30, 2020, to February 17, 2022, the number of patients who enrolled (n = 1,063) versus declined participation (n = 275) was used to calculate monthly enrollment rates. Overall, demographic and baseline clinical characteristics were similar between those who enrolled versus declined. Enrollment rates fluctuated over the course of the COVID-19 pandemic, but there were no significant trends over time (Mann-Kendall test, p = 0.21). Enrollment rates were also comparable between vaccinated and unvaccinated patients. In multivariable logistic regression analysis, age, sex, region of residence, COVID-19 severity of illness, and vaccination status were not significantly associated with the decision to decline consent. CONCLUSIONS:. In this secondary analysis of the I-SPY COVID clinical trial, there was no significant association between the enrollment rate and time period or vaccination status among all eligible patients approached for clinical trial participation. Additional studies are needed to better understand whether the COVID-19 pandemic has altered clinical trial participation and to develop strategies for encouraging participation in future COVID-19 and critical care clinical trials.

Summary: Background: An urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality. Methods: Using an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6 L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (

Objective To evaluate the impact of telemedicine use during the coronavirus disease 2019 (COVID‐19) pandemic on rheumatology trainees. Methods A voluntary, anonymous, web‐based survey was administered in English, Spanish, or French from August 19 to October 5, 2020. Adult and pediatric rheumatology trainees were invited to participate via social media and email. Using multiple‐choice questions and Likert scales, the survey assessed prior and current telemedicine use, impact on training, and supervision after COVID‐19 prompted rapid telemedicine implementation. Results Surveys were received from 302 trainees from 33 countries, with 83% in adult rheumatology training programs. Reported telemedicine use increased from 13% before the pandemic to 82% during the pandemic. United States trainees predominantly used video visits, whereas outside the United States telemedicine was predominantly audio only. Most (65%) evaluated new patients using telemedicine. More respondents were comfortable using telemedicine for follow‐up patients (69%) than for new patients (25%). Only 39% of respondents reported receiving telemedicine‐focused training, including instruction on software, clinical skills, and billing, whereas more than half of United States trainees (59%) had training. Postconsultation verbal discussion was the most frequent form of supervision; 24% reported no supervision. Trainees found that telemedicine negatively impacted supervision (50%) and the quality of clinical teaching received (70%), with only 9% reporting a positive impact. Conclusions Despite widespread uptake of telemedicine, a low proportion of trainees received telemedicine training, and many lacked comfort in evaluating patients, particularly new patients. Inadequate supervision and clinical teaching were areas of concern. If telemedicine remains in widespread use, ensuring appropriate trainee supervision and teaching should be prioritized.

Abstract Background Normally functioning airway cilia is essential for efficient mucociliary clearance to protect the airway from various insults. Impaired clearance may lead to increased risk of infections and progressive lung damage. Significant morbidity in the immediate post lung transplantation period is associated with airway infection, which we hypothesize may be caused by impaired cilia function. Methods Airway cilia beating pattern (CBP) and frequency (CBF) were studied on brushing samples taken from above and below the transplant anastomosis of adult lung transplant recipients (n = 20) during routine bronchoscopies at 6, 12, and 26 weeks posttransplant. Bronchoaveolar Lavage (BAL) samples were also collected at each time points. Results At 6 weeks posttransplant (n = 16), CBP from the donated lung showed reduced beating amplitude with the overall CBF 2.28 Hz slower than the patients' native upper airway cilia (median ± SIQR: 5.36 ± 0.93 Hz vs. 7.64 ± 0.92 Hz, p value

Objective To determine if methotrexate or folic acid prescription was associated with differential risk for COVID-19 diagnosis or mortality.Design Case–control analysis.Setting The population-based UK Biobank (UKBB) cohort.Participants Data from 380 380 UKBB participants with general practice prescription data for 2019–2021. Updated medical information was retrieved on 13 December 2021.Primary and secondary outcome measures The outcomes of COVID-19 diagnosis and COVID-19-related mortality were analysed by multivariable logistic regression. Exposures evaluated were prescription of folic acid and/or methotrexate. Criteria for COVID-19 diagnosis were (1) a positive SARS-CoV-2 test or (2) ICD-10 code for confirmed COVID-19 (U07.1) or probable COVID-19 (U07.2) in hospital records, or death records. By these criteria, 26 003 individuals were identified with COVID-19 of whom 820 were known to have died from COVID-19. Logistic regression statistical models were adjusted for age sex, ethnicity, Townsend deprivation index, body mass index, smoking status, presence of rheumatoid arthritis, sickle cell disease, use of anticonvulsants, statins and iron supplements.Results Compared with people prescribed neither folic acid nor methotrexate, people prescribed folic acid supplementation had increased risk of diagnosis of COVID-19 (OR 1.51 (1.42–1.61)). The prescription of methotrexate with or without folic acid was not associated with COVID-19 diagnosis (p≥0.18). People prescribed folic acid supplementation had positive association with death after a diagnosis of COVID-19 (OR 2.64 (2.15–3.24)) in a fully adjusted model. The prescription of methotrexate in combination with folic acid was not associated with an increased risk for COVID-19-related death (1.07 (0.57–1.98)).Conclusions We report an association of increased risk for COVID-19 diagnosis and COVID-19-related death in people prescribed folic acid supplementation. Our results also suggest that methotrexate might attenuate these associations.

Abstract BRAF and MEKis have revolutionized the management of BRAFV600‐mutated melanoma patients. Left ventricular ejection fraction decrease (LVEF‐D) related to these treatments has not been thoroughly evaluated to date. The main objective of this study was to describe characteristics of LVEF‐D in melanoma patients treated with BRAF and/or MEKis. Metastatic melanoma patients treated with BRAF and/or MEKis between March 1, 2012 and May 18, 2018 were included retrospectively (Lyon Sud University Hospital, Hospices Civils de Lyon). LVEF‐D was defined as a reduction in LVEF ≥10% from baseline to a value

Abstract Background Medical imaging can be used to assist with the diagnosis of plantar heel pain. The aim of this study was to synthesise medical imaging features associated with plantar heel pain. Methods This systematic review and meta‐analysis conducted searches in MEDLINE, CINAHL, SPORTDiscus, Embase and the Cochrane Library from inception to 12th February 2021. Peer‐reviewed articles of cross‐sectional observational studies written in English that compared medical imaging findings in adult participants with plantar heel pain to control participants without plantar heel pain were included. Study quality and risk of bias was assessed using the National Institutes of Health quality assessment tool for observational cohort and cross‐sectional studies. Sensitivity analyses were conducted where appropriate to account for studies that used unblinded assessors. Results Forty‐two studies (2928 participants) were identified and included in analyses. Only 21% of studies were rated ‘good’ on quality assessment. Imaging features associated with plantar heel pain included a thickened plantar fascia (on ultrasound and MRI), abnormalities of the plantar fascia (on ultrasound and MRI), abnormalities of adjacent tissue such as a thickened loaded plantar heel fat pad (on ultrasound), and a plantar calcaneal spur (on x‐ray). In addition, there is some evidence from more than one study that there is increased hyperaemia within the fascia (on power Doppler ultrasound) and abnormalities of bone in the calcaneus (increased uptake on technetium‐99 m bone scan and bone marrow oedema on MRI). Conclusions People with plantar heel pain are more likely to have a thickened plantar fascia, abnormal plantar fascia tissue, a thicker loaded plantar heel fat pad, and a plantar calcaneal spur. In addition, there is some evidence of hyperaemia within the plantar fascia and abnormalities of the calcaneus. Whilst these medical imaging features may aid with diagnosis, additional high‐quality studies investigating medical imaging findings for some of these imaging features would be worthwhile to improve the precision of these findings and determine their clinical relevance.

Background and objectives: Procedural simulation training for difficult airway management offers acquisition opportunities. The hypothesis was that 3 hours of procedural simulation training for difficult airway management improves: acquisition, behavior, and patient outcomes as reported 6 months later. Methods: This prospective comparative study took place in two medical universities. Second-year residents of anesthesiology and intensive care from one region participated in 3 h procedural simulation (intervention group). No intervention was scheduled for their peers from the other region (control). Prior to simulation and 6 months later, residents filled-out the same self-assessment form collecting experience with different devices. The control group filled-out the same forms simultaneously. The primary endpoint was the frequency of use of each difficult airway management device within groups at 6 months. Secondary endpoints included modifications of knowledge, skills, and patient outcomes with each device at 6 months. Intervention cost assessment was provided. Results: 44 residents were included in the intervention group and 16 in the control group. No significant difference was observed for the primary endpoint. In the intervention group, improvement of knowledge and skills was observed at 6 months for each device, and improvement of patient outcomes was observed with the use of malleable intubation stylet and Eschmann introducer. No such improvement was observed in the control group. Estimated intervention cost was 406€ per resident. Conclusions: A 3 h procedural simulation training for difficult airway management did not improve the frequency of use of devices at 6 months by residents. However, other positive effects suggest exploring the best ratio of time/acquisition efficiency with difficult airway management simulation. ClinicalTrials.gov Identifier: NCT02470195. Resumo: Justificativa e objetivos: O treinamento em simulação para o manejo de via aérea difícil oferece oportunidades de aprendizagem. A hipótese foi que um treinamento em simulação de procedimentos de três horas, para o manejo de via aérea difícil, melhoraria o aprendizado, o comportamento e os resultados dos pacientes, conforme relatado seis meses após o treinamento. Métodos: Este estudo comparativo prospectivo foi realizado em duas universidades médicas. Residentes do segundo ano de anestesiologia e terapia intensiva de uma região participaram de um curso de três horas em simulação de procedimentos (grupo intervenção). Nenhuma intervenção foi programada para seus pares da outra região (grupo controle). Antes da simulação e seis meses após, os residentes preencheram a mesma ficha de autoavaliação sobre sua experiência com diferentes dispositivos. O grupo controle preencheu os mesmos formulários simultaneamente. O desfecho primário foi a frequência de uso de cada dispositivo para o manejo de via aérea difícil dentro dos grupos aos seis meses. Os pontos de corte secundários incluíram modificações em relação ao conhecimento, às habilidades e aos resultados dos pacientes com cada dispositivo aos seis meses. A avaliação do custo da intervenção foi registrada. Resultados: Foram incluídos no grupo intervenção 44 residentes e 16 no grupo controle. Nenhuma diferença significativa foi observada para o ponto de corte primário. No grupo intervenção, a melhoria do conhecimento e das habilidades foi observada aos seis meses para cada dispositivo e a melhoria dos desfechos dos pacientes foi analisada com o uso de estilete maleável e do introdutor de Eschmann para intubação. Nenhuma melhoria foi observada no grupo controle. O custo da intervenção estimado foi de 406€ por residente. Conclusões: Um treinamento simulado de três horas para o manejo de via aérea difícil não melhorou a frequência do uso de dispositivos pelos residentes aos seis meses. No entanto, outros efeitos positivos sugerem a exploração da melhor relação tempo/eficiência de aquisição de conhecimento com a simulação do manejo de via aérea difícil. ClinicalTrials.gov Identifier: NCT02470195. Keywords: Airway management, Education, Learning acquisition, Procedural simulation, Palavras-chave: Manejo de vias aéreas, Educação, Aquisição de aprendizagem, Simulação processual

Abstract Background The contemporary diagnosis of bronchiectasis requires CT scanning to describe specific structural lung changes. Scoring systems have been designed and validated in some specific causes of bronchiectasis to allow investigators to correlate CT changes with other indices of disease severity, to describe changes over time, with exacerbation and in response to treatment. Several scoring systems have been developed for CF including the Bhalla Score, Brody score, and the Helbich score. These scoring systems have also been applied to other causes of bronchiectasis including Primary Ciliary Dyskinesia (PCD). This assumes that the nature of structural lung disease in these conditions, as well as the rate and nature of longitudinal changes are identical to, or at least very similar to, those found in CF. This assumption has not been tested. The underlying pathophysiology of PCD is not the same as CF and may cause bronchiectasis that is radiologically similar but not necessarily the same as CF or any other cause of bronchiectasis. The development of a disease specific scoring system for structural change in cases of non-CF bronchiectasis due to any cause, would require consideration of the full range of changes seen in that condition without reference to changes seen in other conditions. We present a summary of structural findings that have been described in PCD and highlight the radiological differences between PCD and other causes of bronchiectasis. We suggest that a PCD specific CT scoring system is required to properly describe changes seen in PCD.

Abstract Background Kidney transplantation following uncontrolled donation after circulatory death (uDCD) presents a high risk of delayed graft function due to prolonged warm ischemia time. In order to minimise the effects of ischemia/reperfusion injury during warm ischemia, normothermic recirculation recently replaced in situ perfusion prior to implantation in several institutions. The aim of this study was to compare these preservation methods on kidney graft outcomes. Methods The primary endpoint was the one-year measured graft filtration rate (mGFR). We collected retrospective data from 64 consecutive uDCD recipients transplanted over a seven-year period in a single centre. Results Thirty-two grafts were preserved by in situ perfusion and 32 by normothermic recirculation. The mean ± SD mGFR at 1 year post-transplantation was 43.0 ± 12.8 mL/min/1.73 m2 in the in situ perfusion group and 53.2 ± 12.8 mL/min/1.73 m2 in the normothermic recirculation group (p = 0.01). Estimated GFR levels were significantly higher in the normothermic recirculation group at 12 months (p = 0.01) and 24 months (p = 0.03) of follow-up. We did not find any difference between groups regarding patient and graft survival, delayed graft function, graft rejection, or interstitial fibrosis. Conclusions Function of grafts preserved by normothermic recirculation was better at 1 year and the results suggest that this persists at 2 years, although no difference was found in short-term outcomes. Despite the retrospective design, this study provides an additional argument in favour of normothermic recirculation.

Background Endoscopic mucosal resection (EMR) with snare is the recommended technique to resect non-invasive colorectal neoplastic lesions between 10 and 30 mm in diameter. The objective of EMR is to resect completely the neoplastic tissue en bloc and preferably with free margins (R0), avoiding recurrences. Anchoring the tip of the snare in the submucosa is a technical trick that allows snare sliding to be reduced and larger pieces to be caught. The aim of the present study was to evaluate the effectiveness and safety of anchoring-EMR (A-EMR). Methods This was a retrospective analysis of A-EMR procedures for lesions of diameter between 10 and 30 mm (endoscopic evaluation) performed consecutively in four French centers between May 2017 and January 2018. A-EMR was routinely performed for all EMR using Olympus conventional snares (10 or 25 mm). The primary outcome was evaluation of the proportion of R0 resections. Results A total of 141 A-EMR procedures were performed by 10 operators. Mean lesion size was 19.8 mm. Anchoring was feasible in 96.5 % of cases. There were 81.6 % en bloc resections and 70.2 % R0 resections, with the percentage of procedures decreasing with increasing lesion size (82.8 % 30 mm, P = 0.002). Complete perforations closed endoscopically occurred in 3/141 cases (2.1 %); none occurred in lesions

BackgroundIn atherosclerotic renal artery disease, the benefit of revascularization is controversial. A clinical decision-making process based on a multidisciplinary meeting was formalized in the Lyon university hospital.ObjectivesTo investigate whether this decisional process ensured a clinical benefit to patients assigned to renal revascularization.MethodsSingle-centre retrospective cohort study, including patients diagnosed from April 2013 to February 2015 with an atherosclerotic renal artery disease with a peak systolic velocity >180cm/s. For each patient, the decision taken in multidisciplinary meeting (medical treatment or revacularization) was compared to the one guided by international guidelines. Blood pressure values, number of antihypertensive medications, presence of an uncontrolled or resistant hypertension, and glomerular filtration rate at one-year follow-up were compared to baseline values. Safety data were collected.ResultsForty-nine patients were included: 26 (53%) were assigned to a medical treatment and 23 (47%) to a renal revascularization. Therapeutic decision was in accordance with the 2013 American Health Association guidelines and with the 2017 European Society of Cardiology guidelines for 78% and 22% of patients who underwent revascularization, respectively. Patients assigned to revascularization presented a significant decrease in systolic blood pressure (-23±34mmHg, p = 0.007), diastolic blood pressure (-12±18mmHg, p = 0.007), number of antihypertensive medications (-1.00±1.03, p = 0.001), and number of uncontrolled or resistant hypertension (p = 0.022 and 0.031) at one-year follow-up. Those parameters were not modified among patients assigned to medical treatment alone. There was no grade 3 adverse event.ConclusionBased on a multidisciplinary selection of revascularization indications, patients on whom a renal revascularization was performed exhibited a significant improvement of blood pressure control parameters with no severe adverse events.

Hip and groin pain often presents a diagnostic and therapeutic challenge. The differential diagnosis is extensive, comprising intra-articular and extra-articular pathology and referred pain from lumbar spine, knee and elsewhere in the pelvis. Various ultrasound-guided techniques have been described in the hip and groin region for diagnostic and therapeutic purposes. Ultrasound has many advantages over other imaging modalities, including portability, lack of ionising radiation and real-time visualisation of soft tissues and neurovascular structures. Many studies have demonstrated the safety, accuracy and efficacy of ultrasound-guided techniques, although there is lack of standardisation regarding the injectates used and long-term benefit remains uncertain.

Purpose. To prospectively evaluate regional referrals into a soft tissue sarcoma service from outside the tertiary centre with local hospital imaging. Materials and Methods. Consecutive referrals were prospectively assessed for: patient demographics, source, referral date, date received by Multidisciplinary Team (MDT), lesion size, local radiology, MDT radiology and final diagnoses. Radiology diagnosis was categorised benign, indeterminate or malignant by consensus. Delays were defined as >10 days. Results. 112 patients were included with high correlation between local and MDT radiology categrorisation and histology (P=0.54 and P=0.49, resp.). There was only a trend for MDT radiology diagnosis to downgrade local imaging diagnosis (n=15, P>0.05). 48 cases (43%) had ultrasound and MRI at referral and 20 (18%) ultrasound only. 85% of cases were benign (lipoma most common), 15% malignant (sarcoma most common). Delay occurred in 34% of cases. Discussion. In comparison to previous series these results show a reduction in benign lesions, increased biopsy and malignancy rate for lesions referred to a tertiary centre when imaging is performed and reviewed by local radiologists. Advances in Knowledge. Imaging triage of soft tissue masses can decrease benign referral rates and increase the proportion of indeterminate and malignant lesions referred to specialist centres.

Voltage-gated calcium channels (Ca(v)) exist as heteromultimers comprising a pore-forming α(1) with accessory β and α(2)δ subunits which modify channel trafficking and function. We previously showed that α(2)δ-1 (and likely the other mammalian α(2)δ isoforms--α(2)δ-2, 3 and 4) is required for targeting Ca(v)s to lipid rafts, although the mechanism remains unclear. Whilst originally understood to have a classical type I transmembrane (TM) topology, recent evidence suggests the α(2)δ subunit contains a glycosylphosphatidylinositol (GPI)-anchor that mediates its association with lipid rafts. To test this notion, we have used a strategy based on the expression of chimera, where the reported GPI-anchoring sequences in the gabapentinoid-sensitive α(2)δ-1 subunit have been substituted with those of a functionally inert Type I TM-spanning protein--PIN-G. Using imaging, electrophysiology and biochemistry, we find that lipid raft association of PIN-α(2)δ is unaffected by substitution of the GPI motif with the TM domain of PIN-G. Moreover, the presence of the GPI motif alone is not sufficient for raft localisation, suggesting that upstream residues are required. GPI-anchoring is susceptible to phosphatidylinositol-phospholipase C (PI-PLC) cleavage. However, whilst raft localisation of PIN-α(2)δ is disrupted by PI-PLC treatment, this is assay-dependent and non-specific effects of PI-PLC are observed on the distribution of the endogenous raft marker, caveolin, but not flotillin. Taken together, these data are most consistent with a model where α(2)δ-1 retains its type I transmembrane topology and its targeting to lipid rafts is governed by sequences upstream of the putative GPI anchor, that promote protein-protein, rather than lipid-lipid interactions.

The E6 oncoprotein produced by high-risk mucosal HPV stimulates ubiquitinylation and proteasome-dependent degradation of the tumour suppressor p53 via formation of a trimeric complex comprising E6, p53, and E6-AP. p53 is also degraded by its main cellular regulator MDM2. The main binding site of p53 to MDM2 is situated in the natively unfolded N-terminal region of p53. By contrast, the regions of p53 implicated in the degradation by viral E6 are not fully identified to date. Here we generated a series of mutations (Y103G, Y107G, T155A, T155V, T155D, L264A, L265A) targeting the central folded core domain of p53 within a region opposite to its DNA-binding site. We analysed by in vitro and in vivo assays the impact of these mutations on p53 degradation mediated by viral E6 oncoprotein. Whereas all mutants remained susceptible to MDM2-mediated degradation, several of them (Y103G, Y107G, T155D, L265A) became resistant to E6-mediated degradation, confirming previous works that pointed to the core domain as an essential region for the degradation of p53. In parallel, we systematically checked the impact of the mutations on the transactivation activity of p53 as well as on the conformation of p53, analysed by Nuclear Magnetic Resonance (NMR), circular dichroism (CD), and antibody probing. These measurements suggested that the conformational integrity of the core domain is an essential parameter for the degradation of p53 by E6, while it is not essential for the degradation of p53 by MDM2. Thus, the intracellular stability of a protein may or may not rely on its biophysical stability depending on the degradation pathway taken into consideration.

Abstract Background and objectives Procedural simulation training for difficult airway management offers acquisition opportunities. The hypothesis was that 3 hours of procedural simulation training for difficult airway management improves: acquisition, behavior, and patient outcomes as reported 6 months later. Methods This prospective comparative study took place in two medical universities. Second-year residents of anesthesiology and intensive care from one region participated in 3 h procedural simulation (intervention group). No intervention was scheduled for their peers from the other region (control). Prior to simulation and 6 months later, residents filled-out the same self-assessment form collecting experience with different devices. The control group filled-out the same forms simultaneously. The primary endpoint was the frequency of use of each difficult airway management device within groups at 6 months. Secondary endpoints included modifications of knowledge, skills, and patient outcomes with each device at 6 months. Intervention cost assessment was provided. Results 44 residents were included in the intervention group and 16 in the control group. No significant difference was observed for the primary endpoint. In the intervention group, improvement of knowledge and skills was observed at 6 months for each device, and improvement of patient outcomes was observed with the use of malleable intubation stylet and Eschmann introducer. No such improvement was observed in the control group. Estimated intervention cost was 406€ per resident. Conclusions A 3 h procedural simulation training for difficult airway management did not improve the frequency of use of devices at 6 months by residents. However, other positive effects suggest exploring the best ratio of time/acquisition efficiency with difficult airway management simulation. ClinicalTrials.gov Identifier NCT02470195.