International consensus for a dissection room quality system (DRQS): A Delphi panel study.

Dissection Rooms (DRs) are key facilities that allow teaching and research on human anatomy, where students and researchers work with human bodies to acquire, increase, or create new knowledge. Usually, DRs work with a Body Donation Program (BDP), where living donors bequeath their bodies for use in teaching and research after they expire. Despite DRs being part of universities worldwide, no common guidelines, regulations, or quality management systems (QMS) exist that could be applied to different countries. With that purpose in mind, we aimed to develop a QMS that could be applied to DRs globally, using a Delphi panel to achieve consensus about the items that should constitute the QMS. The panel was constituted by 20 anatomy professors from 20 different countries, and the 167 standards to create the rules or guidelines that constitute the QMS were divided in five categories: direction, body donation, students, instructors, and research. After two rounds of revisions, 150 standards were considered "essential" or "important" by more than 70% of the participants, thus being incorporated to the Dissection Room Quality System (DRQS). The results of this panel represent a minimum list of items of the DRQS for improving the functioning of DRs globally.

Timing of umbilical cord occlusion, delayed vs early, in preterm babies: A randomized controlled trial (CODE-P Trial).

INTRODUCTION: Our hypothesis was that delayed cord clamping (DCC) (not earlier than 30 s; at 30-60 s) in premature neonates (born between 26.0 and 32.6 weeks of gestation), as compared with the usual early cord clamping (ECC), significantly reduces the need for blood transfusions and incidence of intraventricular haemorrhage (IVH) without an increased rate of maternal postpartum haemorrhage. MATERIAL AND METHODS: A prospective, open-label, randomized, controlled trial was conducted at Vall d'Hebron Hospital from July 2014 to December 2018. All pregnant women at risk of impending preterm birth (≥26.0-<33.0 weeks of gestation) who were admitted to the obstetrics emergency department were evaluated for eligibility. If they met the eligibility criteria, they were invited to participate in the study and, if they agreed, they signed an informed consent. Patients were randomly assigned to one of two groups: ECC group and DCC group. RESULTS: Our study included a total of 57 patients: 30 in the ECC group and 27 in the DCC group. Due to a lack of funding and low recruitment rates, the study was discontinued in 2018. Maternal characteristics and obstetric outcomes were similar between both groups. The intention-to-treat analysis did not reveal any differences between groups for neonatal red blood cell transfusions, neonatal IVH or maternal postpartum haemorrhage. There were no differences for secondary outcomes. Similarly, no differences were observed in the as-treated analysis. CONCLUSION: The primary and secondary outcomes of our study were not achieved. Therefore, more meta-analysis and trials are needed to evaluate the appropriate timing of cord clamping in preterm birth.

Comparison of two different lingual flap advancement techniques and vascular structure identification: a human cadaver study.

BACKGROUND: One of the most frequent complications in guided bone regeneration (GBR) is wound dehiscence, which compromises treatment outcomes. Thus, primary tension-free suture is essential to avoid wound dehiscence. The purpose of this study was to compare the extension of 2 different mandibular flaps in human cadaveric specimens, and to measure the size of the supraperiosteal blood vessels. MATERIAL AND METHODS: Five freshly unfrozen human cadaveric specimens were used. Arteries and veins were marked and bilateral classical lingual flaps (extending from the second premolar to the retromolar area) were prepared. In one side, the mylohyoid muscle was detached to increase the coronal extension of the flap. An implant drill was used to measure the extension of the flap after exerting 30 g of traction, before and after detaching the mylohyoid muscle. The size of the largest vascular structures of the flap was measured using a periodontal probe. RESULTS: The classical flap extension was 5.99 mm (95% confidence interval (CI): 5.08 to 6.90), while the coronally advanced flap extension with mylohyoid muscle detachment was 14.96 mm (95%CI: 10.81 - 19.11). A statistically significant difference was found between the 2 groups (p= 0.0002), with a mean extension difference was 8.97 mm (95%CI: 5.02 to 12.91). The mean largest artery had 0.20 mm of diameter (95%CI: 0.15 - 0.26). CONCLUSIONS: The detachment of the mylohyoid muscle from the lingual flap allows to significantly increase its extension by 2.5 times. The superficial arteries found in the lingual flap have a small diameter (around 0.2mm).

All-in-one biofabrication and loading of recombinant vaults in human cells.

One of the most promising approaches in the drug delivery field is the use of naturally occurring self-assembling protein nanoparticles, such as virus-like particles, bacterial microcompartments or vault ribonucleoprotein particles as drug delivery systems (DDSs). Among them, eukaryotic vaults show a promising future due to their structural features,in vitrostability and non-immunogenicity. Recombinant vaults are routinely produced in insect cells and purified through several ultracentrifugations, both tedious and time-consuming processes. As an alternative, this work proposes a new approach and protocols for the production of recombinant vaults in human cells by transient gene expression of a His-tagged version of the major vault protein (MVP-H6), the development of new affinity-based purification processes for such recombinant vaults, and the all-in-one biofabrication and encapsulation of a cargo recombinant protein within such vaults by their co-expression in human cells. Protocols proposed here allow the easy and straightforward biofabrication and purification of engineered vaults loaded with virtually any INT-tagged cargo protein, in very short times, paving the way to faster and easier engineering and production of better and more efficient DDS.

Modelling diagnostics for Echinococcus granulosus surveillance in sheep using Latent Class Analysis: Argentina as a case study.

Echinococcus granulosus sensu lato is a globally prevalent zoonotic parasitic cestode leading to cystic echinococcosis (CE) in both humans and sheep with both medical and financial impacts, whose reduction requires the application of a One Health approach to its control. Regarding the animal health component of this approach, lack of accurate and practical diagnostics in livestock impedes the assessment of disease burden and the implementation and evaluation of control strategies. We use of a Bayesian Latent Class Analysis (LCA) model to estimate ovine CE prevalence in sheep samples from the Río Negro province of Argentina accounting for uncertainty in the diagnostics. We use model outputs to evaluate the performance of a novel recombinant B8/2 antigen B subunit (rEgAgB8/2) indirect enzyme-linked immunosorbent assay (ELISA) for detecting E. granulosus in sheep. Necropsy (as a partial gold standard), western blot (WB) and ELISA diagnostic data were collected from 79 sheep within two Río Negro slaughterhouses, and used to estimate individual infection status (assigned as a latent variable within the model). Using the model outputs, the performance of the novel ELISA at both individual and flock levels was evaluated, respectively, using a receiver operating characteristic (ROC) curve, and simulating a range of sample sizes and prevalence levels within hypothetical flocks. The estimated (mean) prevalence of ovine CE was 27.5% (95%Bayesian credible interval (95%BCI): 13.8%-58.9%) within the sample population. At the individual level, the ELISA had a mean sensitivity and specificity of 55% (95%BCI: 46%-68%) and 68% (95%BCI: 63%-92%), respectively, at an optimal optical density (OD) threshold of 0.378. At the flock level, the ELISA had an 80% probability of correctly classifying infection at an optimal cut-off threshold of 0.496. These results suggest that the novel ELISA could play a useful role as a flock-level diagnostic for CE surveillance in the region, supplementing surveillance activities in the human population and thus strengthening a One Health approach. Importantly, selection of ELISA cut-off threshold values must be tailored according to the epidemiological situation.

Características y resultados de pacientes COVID-19 tratados con ventilación mecánica invasiva en Hospital San Juan de Dios. Marzo-junio 2020

Background: The overall mortality of patients with COVID-19 admitted to intensive care units is approximately 40%. Aim: To describe the characteristics of a cohort of patients with COVID-19 who required invasive mechanical ventilation due to severe hypoxemic acute respiratory failure at a general hospital in Santiago, Chile. Material and Methods: Review of medical records and follow up for 28 days of patients with COVID-19 confirmed by polymerase chain reaction who required invasive mechanical ventilation and who were admitted to the intensive care unit from March 24 to June 7, 2020. Results: Data from 152 patients aged 58 (interquartile range (IQR) 47-65 years (66% men) was analyzed. As of July 5, 36 (24%) had died, 75 (49%) were discharged, 10 (7%) were still on invasive mechanical ventilation, 11 (7%) remained with tracheostomy but without invasive mechanical ventilation, and 20 (13%) were hospitalized in a basic unit. The median time on invasive mechanical ventilation among extubated patients was 14 days (IQR 10-21) and 121 (80%) were in the prone position. Patients who died were older, had a higher frequency of diabetes mellitus and a higher driving pressure at 7 days than those discharged alive from the intensive care unit. Conclusions: In this study mortality was lower than that reported in the first international studies, probably due to the selection of younger patients and greater knowledge of the disease.

Prematurity and ADHD in Childhood: An Observational Register-Based Study in Catalonia.

Objective: To evaluate the association between prematurity (by the gestational week [gw]) and ADHD during childhood. Method: Observational, matched cohort study using data from children born in a tertiary-level hospital (Hospital Universitari Vall d'Hebron, Catalonia, Spain) during 1995-2007 and data from the Information System for the Development of Research in Primary Health Care (SIDIAP database, Catalonia, Spain). Results: Prevalence of ADHD increases as gestational age decreases, 12.7% for those born ≤28 gw, compared to 3.2% for those born after the 37 gw. The risk of developing ADHD in the non-premature children tends to increase as the gw decreases (35-36 gw, hazard ratio [HR] = 1.70, 95% confidence interval [CI] [1.19, 2.44]; 33-34 gw, HR = 3.38, 95% CI [2.08, 5.50]; 29-32 gw, HR = 2.37, 95% CI [1.54, 3.63]; and ≤28 gw, HR = 5.57, 95% CI [2.49, 12.46]) Conclusion: Being born preterm is associated with a risk of developing ADHD, also in late preterm children (35-36 gw). Attention when taking care of these infants regarding their mental health must be made.

[Features and evolution of patients with COVID-19 who required mechanical ventilation]. / Características y resultados de pacientes COVID-19 tratados con ventilación mecánica invasiva en Hospital San Juan de Dios. Marzo-junio 2020.

BACKGROUND: The overall mortality of patients with COVID-19 admitted to intensive care units is approximately 40%. AIM: To describe the characteristics of a cohort of patients with COVID-19 who required invasive mechanical ventilation due to severe hypoxemic acute respiratory failure at a general hospital in Santiago, Chile. MATERIAL AND METHODS: Review of medical records and follow up for 28 days of patients with COVID-19 confirmed by polymerase chain reaction who required invasive mechanical ventilation and who were admitted to the intensive care unit from March 24 to June 7, 2020. RESULTS: Data from 152 patients aged 58 (interquartile range (IQR) 47-65 years (66% men) was analyzed. As of July 5, 36 (24%) had died, 75 (49%) were discharged, 10 (7%) were still on invasive mechanical ventilation, 11 (7%) remained with tracheostomy but without invasive mechanical ventilation, and 20 (13%) were hospitalized in a basic unit. The median time on invasive mechanical ventilation among extubated patients was 14 days (IQR 10-21) and 121 (80%) were in the prone position. Patients who died were older, had a higher frequency of diabetes mellitus and a higher driving pressure at 7 days than those discharged alive from the intensive care unit. CONCLUSIONS: In this study mortality was lower than that reported in the first international studies, probably due to the selection of younger patients and greater knowledge of the disease.

Application of an enhanced homogenization technique to the structural multiscale analysis of a femur bone.

Bone is a complex hierarchical material that can be characterized from the microscale to macroscale. This work demonstrates the application of an enhanced homogenization methodology to the multiscale structural analysis of a femoral bone. The use of this homogenization technique allows to remove subjectivity and reduce the computational cost associated with the iterative process of creating a heterogeneous mesh. Thus, it allows to create simpler homogenized meshes with its mechanical properties defined using information directly from the mesh source: the medical images. Therefore, this methodology is capable to accurately predict bone mechanical behavior in a fraction of the time required by classical approaches. The results show that using the homogenization technique, despite the differences between the used homogeneous and heterogeneous meshes, its mechanical behavior is similar. The proposed homogenization technique is useful for a multiscale modelling and it is computationally efficient.

Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors.

BACKGROUND: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). PATIENTS AND METHODS: We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. RESULTS: In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. CONCLUSIONS: We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.

Could land cover influence Aedes aegypti mosquito populations?

Aedes aegypti is mainly found in urban environments, where human activity guarantees the permanent availability of potential larval habitats. The present study aimed to test for a possible association between Ae. aegypti infestation and land cover classes. From 23 February to 22 May 2015, immature mosquitoes (except eggs) were sampled in artificial containers identified in dwellings in Córdoba city, Argentina. The proportion of each land cover class was determined by SPOT-5 (Satellites Pour 1'Observation de la Terre or Earth-observing Satellites) image classification. Generalized linear models were developed to assess a suite of predetermined hypotheses and identified cover class variables associated with Ae. aegypti infestation. Arboreal vegetation was identified as the land cover with the greatest relative importance, negatively associated with Ae. aegypti mosquitoes. More infestation was find in areas with less arboreal vegetation, which corresponds to more urbanized areas.

Successful pulp revascularization of an autotransplantated mature premolar with fragile fracture apicoectomy and plasma rich in growth factors: a 3-year follow-up.

AIM: This case report demonstrates a positive outcome of the adjuvant use of fragile fracture (FF), which is a technique used to harvest dental pulp stem cells (DPSCs), and platelet-rich plasma (PRP) in a mandibular premolar (tooth 44) with a completely formed root that was transplanted into a surgically created socket and which maintained pulp vitality and function. SUMMARY: After virtual surgical planning, a 3D tooth replica of tooth 44 was fabricated. A surgical socket was created in the position of tooth 14; then, tooth 44 was extracted and the root dentine was abraded using a turbine diamond bur 3 mm from the apex until a circular groove was prepared around the outer circumference of the root; and then, an FF was performed without damaging the pulp tissue. PRP was placed in the socket, after which the donor tooth was inserted in the recipient area. At 2 weeks post-treatment, orthodontic traction was applied. At 3-year follow-up, the tooth had adequate alignment and was asymptomatic. Response to pulp testing was positive, and the presence of pulp canal obliteration was observed as a sign of pulpal healing. KEY LEARNING POINTS: Autotransplantation is a good alternative for replacing missing teeth, with repair of tissues and pulp revascularization. Revascularization of an autotransplanted mature tooth using the fragile fracture technique and PRP scaffold is a feasible option and might have positive effects on the long-term outcome of the procedure. Including completely formed teeth as donors in autotransplantation, maintaining vitality and their functions is an option that warrants further study.

Antitumoral effect of maintained neutrophilia induced by rhG-CSF in a murine model of pancreatic cancer.

Although the protumoral functions of polymorphonuclear neutrophils are well known, some now-forgotten studies report antitumoral roles for these cells. The present work examines the antitumoral effect of maintained neutrophilia induced via the injection of recombinant human granulocyte colony stimulating factor (rhG-CSF, 100 µg/kg/day) in a Panc-1 subcutaneous xenograft murine model of pancreatic cancer. This treatment was compared with gemcitabine administration (120 mg/kg every two days) and a saline control (n = 6-7 mice per group). Compared to the controls, both the rhG-CSF- and gemcitabine-treated mice showed significantly suppressed tumor growth by day 4 (p < 0.001 and p = 0.013 respectively). From a mean starting volume of 106.9 ± 3.1 mm3 for all treatment groups, the final mean tumor volumes reached were 282.0 ± 30.7 mm3 for the rhG-CSF-treated mice, 202.6 ± 18.1 mm3 for the gemcitabine-treated mice and 519.4 ± 62.9 mm3 for the control mice (p < 0.004 and p < 0.01, respectively, vs. control). The rhG-CSF-treated tumors showed higher percentage necrosis than those treated with gemcitabine (37.4 ± 4.6 vs. 7.5 ± 3.0; p < 0.001). This is the first report of a clear anti-tumoral effect of rhG-CSF when used in monotherapy against pancreatic cancer. Since rhG-CSF administration is known to be associated with very few adverse events, it may offer an attractive alternative in the clinical treatment of pancreatic cancer.

In vivo efficiency of antimicrobial inorganic bone grafts in osteomyelitis treatments.

The purpose of the present work was to evaluate in vivo different antimicrobial therapies to eradicate osteomyelitis created in the femoral head of New Zealand rabbits. Five phosphate-based cements were evaluated: calcium phosphate cements (CPC) and calcium phosphate foams (CPF), both in their pristine form and loaded with doxycycline hyclate, and an intrinsic antimicrobial magnesium phosphate cement (MPC; not loaded with an antibiotic). The cements were implanted in a bone previously infected with Staphylococcus aureus to discern the effects of the type of antibiotic administration (systemic vs. local), porosity (microporosity, i.e. <5 µm vs. macroporosity, i.e. >5 µm) and type of antimicrobial mechanism (release of antibiotic vs. intrinsic antimicrobial activity) on the improvement of the health state of the infected animals. A new method was developed, with a more comprehensive composite score that integrates 5 parameters of bone infection, 4 parameters of bone structural integrity and 4 parameters of bone regeneration. This method was used to evaluate the health state of the infected animals, both before and after osteomyelitis treatment. The results showed that the composite score allows to discern statistically significant differences between treatments that individual evaluations were not able to identify. Despite none of the therapies completely eradicated the infection, it was observed that macroporous materials (CPF and CPFd, the latter loaded with doxycycline hyclate) and intrinsic antimicrobial MPC allowed a better containment of the osteomyelitis. This study provides novel insights to understand the effect of different antimicrobial therapies in vivo, and a promising comprehensive methodology to evaluate the health state of the animals was developed. We expect that the implementation of such methodology could improve the criteria to select a proper antimicrobial therapy.

El fill amagat. Un embaràs que dona llum a un fill anterior en l'ombra / No disponible

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Modelling the distribution of the vector Aedes aegypti in a central Argentine city.

Aedes aegypti (Diptera: Culicidae) is an urban mosquito involved in the transmission of numerous viruses, including dengue, chikungunya and Zika. In Argentina, Ae. aegypti is the main vector of dengue virus and has been involved in several outbreaks in regions ranging from northern to central Argentina since 2009. In order to evaluate areas of potential vector-borne disease transmission in the city of Córdoba, Argentina, the present study aimed to identify the environmental, socioeconomic and demographic factors driving the distribution of Ae. aegypti larvae through spatial analysis in the form of species distribution models (SDMs). These models elucidate relationships between known occurrences of a species and environmental data in order to identify areas with suitable habitats for that species and the consequent risk for disease transmission. The maximum entropy species distribution model was able to fit the training data well, with an average area under the receiver operating characteristic curve (AUC) of > 0.8, and produced models with fair extrapolation capacity (average test AUC: > 0.75). Human population density, distance to vegetation and water channels were the main variables predictive of the vector suitability of an area. The results of this work will be used to target surveillance and prevention measures, as well as in mosquito management.

Genetic screening and molecular characterization of MET alterations in non-small cell lung cancer

Purpose: Aberrant activation of MET as a result of exon 14-skipping (METex14) mutations or gene amplification is an oncogenic mechanism in non-small cell lung carcinoma (NSCLC) and a potential therapeutic target. The purpose of this study was to characterize MET alterations in a cohort of NSCLC patients treated with surgery. Methods and patients: 157 NSCLCs of various histopathologies, including pulmonary sarcomatoid carcinomas (PSC), were tested for MET alterations. METex14 mutations, MET copy number alterations and the levels of MET protein were determined by Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry, respectively. Concurrent alterations of other important cancer genes and immunostaining of the downstream effector, phopho-S6, were also determined. Results: METex14 mutations and MET amplification were detected in seven tumors. MET genetic alterations were found predominantly in the lung adenocarcinoma (ADC) and PSC histopathologies. High levels of MET protein were found in most MET-amplified tumors, but not in all METex14-mutated tumors. Strong phopho-S6 staining was observed in about half of the MET-activated tumors. One tumor with METex14 exhibited concurrent ERBB2 amplification. Conclusions: MET activation, by either METex14 mutations or amplification, is characteristic of a subset of early stage NSCLCs and may coexist with ERBB2 amplification. This may have potential therapeutic implications. The presence of METex14 mutations was associated with low levels of MET protein, which may limit the use of total MET immunostaining as a marker for preselecting patients for MET-targeted therapies

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Genetic screening and molecular characterization of MET alterations in non-small cell lung cancer.

PURPOSE: Aberrant activation of MET as a result of exon 14-skipping (METex14) mutations or gene amplification is an oncogenic mechanism in non-small cell lung carcinoma (NSCLC) and a potential therapeutic target. The purpose of this study was to characterize MET alterations in a cohort of NSCLC patients treated with surgery. METHODS AND PATIENTS: 157 NSCLCs of various histopathologies, including pulmonary sarcomatoid carcinomas (PSC), were tested for MET alterations. METex14 mutations, MET copy number alterations and the levels of MET protein were determined by Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry, respectively. Concurrent alterations of other important cancer genes and immunostaining of the downstream effector, phopho-S6, were also determined. RESULTS: METex14 mutations and MET amplification were detected in seven tumors. MET genetic alterations were found predominantly in the lung adenocarcinoma (ADC) and PSC histopathologies. High levels of MET protein were found in most MET-amplified tumors, but not in all METex14-mutated tumors. Strong phopho-S6 staining was observed in about half of the MET-activated tumors. One tumor with METex14 exhibited concurrent ERBB2 amplification. CONCLUSIONS: MET activation, by either METex14 mutations or amplification, is characteristic of a subset of early stage NSCLCs and may coexist with ERBB2 amplification. This may have potential therapeutic implications. The presence of METex14 mutations was associated with low levels of MET protein, which may limit the use of total MET immunostaining as a marker for preselecting patients for MET-targeted therapies.

The Graduating European Dentist: Contemporaneous Methods of Teaching, Learning and Assessment in Dental Undergraduate Education.

It is often the case that good teachers just "intuitively" know how to teach. Whilst that may be true, there is now a greater need to understand the various processes that underpin both the ways in which a curriculum is delivered, and the way in which the students engage with learning; curricula need to be designed to meet the changing needs of our new graduates, providing new, and robust learning opportunities, and be communicated effectively to both staff and students. The aim of this document is to draw together robust and contemporaneous methods of teaching, learning and assessment that help to overcome some of the more traditional barriers within dental undergraduate programmes. The methods have been chosen to map specifically to The Graduating European Dentist, and should be considered in parallel with the benchmarking process that educators and institutions employ locally.

The Graduating European Dentist-Domain II: Safe and Effective Clinical Practice.

This position paper outlines the areas of competence and learning outcomes of "The Graduating European Dentist" that specifically relate to Safe and Effective Clinical Practice. Dentists are required to ensure that they are capable of providing appropriate care for their patients, whilst also effectively managing and leading the wider clinical team. The care that is provided should align to a contemporaneous evidence base wherever possible, and the quality of care and the management systems that underpin it should be regularly audited and improved.