Experience of an NIHR Clinical Lectureship (medical/dental) and the determining factors for a clinical academic career post lectureship: a mixed-method evaluation.

OBJECTIVES: The objective of this study is to investigate early-to-late postdoctoral clinical academic progression and the experiences of NIHR Clinical Lectureship (CL) fellows, considering enablers and barriers to success, and identifying the factors associated with immediate progression to a clinical academic role following completion of the award. SETTING: Datasets of CL awardees across the UK. PARTICIPANTS: For semistructured interviews, n=40 CL awardees that had finished their award within the previous 5 years. For quantitative analysis, n=1226 completed or currently active CL awardees. OUTCOME MEASURES: The responses from the semistructured interviews to the defined questions on experiences during the award, postaward progression, and enablers and barriers to academic progression. Other primary outcome measures were quantitative data on first destinations postaward, demographic data, and whether an awardee had previously held an NIHR Academic Clinical Fellowship (ACF) or was a recipient of the Academy of Medical Sciences (AMS) Starter Grant. RESULTS: CL awardees identified numerous benefits to the award, with the majority achieving their aims. Most awardees progressed to a clinical academic role; however, some returned to a clinical only position, citing concerns around the time pressure associated with balancing clinical and academic responsibilities, and the competition to attain further postdoctoral awards. The region of the award partnership, year of award end and success in applying for an AMS Starter Grant were associated with progression to a clinical academic role. Gender, holding an ACF and having a craft or non-craft specialty had no independent statistical association with clinical academic progression. CONCLUSIONS: The CL is a valued element of the Integrated Academic Pathway. By addressing issues around later postdoctoral progression opportunities, responding to challenges experienced by CLs, and by understanding the factors identified in this study associated with clinical academic progression, it should be possible to increase the proportion of CLs that become fully independent clinical academic research leaders. PARTICIPANTS: 1226 NIHR CLs active or completed on the award between 2006 and 2020.

Venous thromboembolism: Exploring incidence and utility of screening in spinal cord injury.

OBJECTIVE: To assess the incidence and possible risk factors for venous thromboembolism (VTE) in patients admitted to a SCI rehabilitation center. DESIGN: Retrospective review. SETTING: Acute neurorehabilitation hospital specializing in SCI. METHODS: Records of 228 consecutive admissions were reviewed. All patients received screening four limb ultrasounds on admission. Charts were reviewed to determine whether VTE was diagnosed at the acute care hospital or in the rehabilitation center; either on admission screening or later in the rehabilitation stay. Charts were reviewed to identify potential risk factors for VTE as well as the incidence of bleeding complications in patients on full anticoagulation. RESULTS: In this cohort, 115 deep venous thromboses (DVTs) were identified in the following settings: 27% in acute care [n = 31], 70% on admission to rehabilitation [n = 80], and 24% during the rehabilitation stay [n = 28]. Of those on therapeutic anticoagulation due to admission diagnosis of VTE [n = 63], 12.7% developed recurrent DVT and 9.5% had bleeding complications. Of those who were initiated and continued on therapeutic anticoagulation, there was zero incidence of PE. Risk factors for the development of VTE included age, body mass index (BMI), rehabilitation length of stay, injury etiology, spinal cord-related surgery, and history of inferior vena cava filter. CONCLUSIONS: DVT was identified in 70% of this cohort with screening ultrasound on admission to rehabilitation and of those initiated and continued on therapeutic anticoagulation, none developed PE, while 9.5% had bleeding complications. Given the findings of this study, prospective research in noninvasive vascular ultrasound screening for VTE should be considered.

Venous Thromboembolism: Exploring Incidence and Utility of Screening in Individuals With Brain Injury.

OBJECTIVE: To determine the incidence of VTE in the population with brain injuries (BIs) using ultrasonography, and to assess the risk of pulmonary embolism (PE) development and/or bleeding complications related to anticoagulation. DESIGN: Retrospective study. SETTING: Acute rehabilitation hospital. PARTICIPANTS: 238 individuals with moderate to severe BI who were routinely screened for VTE with ultrasonography on admission to rehabilitation (N=238). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Retrospective chart review was performed to identify individuals who were diagnosed with VTE at the following 3 time points: in acute care prior to admission to rehabilitation, at the time of admission diagnosed via screening examination, and after admission to rehabilitation. Additionally, risk factors for VTE, PE, and incidence of bleeding complications related to therapeutic anticoagulation were assessed. RESULTS: 123 deep vein thromboses (DVTs) were identified with 38.2% in acute care (n=47), 69.1% on admission to rehabilitation (n=85), and 7.3% during the course of rehabilitation stay (n=9). Risk factors for development of VTE included age at injury, body mass index, injury etiology, history of neurosurgical procedure, and surgery during inpatient rehabilitation. Of those who were placed on therapeutic anticoagulation due to admission diagnosis of VTE (n=50), 2% developed recurrent DVT and 2% had bleeding complications. There was zero incidence of PE. CONCLUSION: We demonstrated a high prevalence of VTEs identified on screening ultrasonography on admission to inpatient rehabilitation among individuals with moderate to severe BIs, and low complications related to anticoagulation. Given the findings of this study, prospective research in ultrasonography screening for VTE in moderate to severe BI is needed.

What impact has the NIHR Academic Clinical Fellowship (ACF) scheme had on clinical academic careers in England over the last 10 years? A retrospective study.

OBJECTIVES: The Academic Clinical Fellowship (ACF) was introduced to support the early career clinical and research training of potential future clinical academics in England. The driver for the model was concern about falling numbers of clinical academic trainees. This study examines the impact of the ACF model, over its first 10 years, in developing clinical academic careers by tracking the progression of ACF trainees. DESIGN: Retrospective analysis of National Institute for Health Research (NIHR) ACF career progression. This was performed using mixed methods including routine data collections of career destination, analysis of application rates to doctoral level fellowships and supplemented by survey information that captured the perceived benefits and challenges from previous ACFs and their current career activities. PARTICIPANTS: 1239 NIHR ACFs who completed or left their posts between 2006 and March 2015. RESULTS: ACFs are perceived by the candidate population as attractive posts, with high numbers of applications leading to high fill rates. Balancing clinical and academic commitments is one of the reported challenges when completing an ACF. We have found that undertaking an ACF was shown to increase the likelihood of securing an externally funded doctoral training award and the vast majority of ACFs move into academic roles, with many completing PhDs. Previous ACFs continue to show positive career progression, predominantly in translational and clinical research. The knowledge acquired during the ACF continues to be useful in subsequent roles and trainees would recommend the scheme to others. CONCLUSIONS: The NIHR ACF scheme is successful as part of an integrated training pathway in developing careers in academic medicine and dentistry.

Increasing support for the next generation of clinical trials leaders.

The National Institute for Health Research (NIHR) has identified a gap in the number of people it funds who are on a pathway to become future leaders of clinical trials, compared to how much the NIHR invests in clinical trials. In order to support the clinical trials of tomorrow, it is vital that the right people are supported now to lead these trials. To address this issue, NIHR organised a workshop with key stakeholders to understand the barriers to embarking on a clinical trials career and explore initiatives to increase capacity and capability in clinical trials. The output from the workshop was a set of recommendations which NIHR is now considering to shape future support.

Angiosarcoma involving native abdominal aortic aneurysm sac after endograft repair.

Primary angiosarcoma of the aorta is a rare malignancy that is characterized by rapid proliferation and propensity for metastasis. It has been reported only 35 times in the surgical literature. This case report presents a 66-year-old man diagnosed with angiosarcoma of his native aorta 7 years after endograft repair of an abdominal aortic aneurysm. We then reviewed the world surgical literature for occurrence, tumorigenic studies, prognosis, and management of aortic angiosarcoma. Because native aortic tissue is retained after endovascular repair of an abdominal aortic aneurysm, the treating physician should have an awareness of this pathology and entertain the diagnosis as appropriate.

Minimally invasive aortic valve replacement surgery through lower half sternotomy.

Less invasive approaches to aortic valve surgery frequently rely upon the development of new technology and instrumentation. While not suitable for every patient requiring an aortic valve procedure, these less invasive operations can offer certain clinical benefits and are becoming an important part of the modern cardiothoracic surgeon's skillset. A lower partial sternotomy approach provides excellent visualization of the operative field, efficient execution of the operation and many of the benefits of minimally invasive surgery. Importantly, the lower partial sternotomy requires no new or unusual instruments and presents a familiar view to the surgeon. The technique, therefore, lends itself well to being adapted and utilized quickly with a potentially shorter "learning curve" for maximal surgical flexibility and patient benefit.

Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk.

To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.

Feeding jejunostomy tubes placed during esophagectomy: are they necessary?

BACKGROUND: Jejunostomy tubes (JT) are routinely placed at the time of esophagectomy and can be associated with low--but not insignificant--morbidity. Increased emphasis on evidence-based medicine prompted this critical review of JT use during esophagectomy and factors that predict the absolute need for JT. METHODS: All esophagectomies performed at one tertiary care institution from 1995 through 2009 were retrospectively reviewed. Statistical analyses were performed to determine preoperative variables that would assist in selecting patients who should receive a JT. RESULTS: A total of 143 JTs were placed in 151 patients undergoing esophagectomy for carcinoma (83.4%), high-grade dysplasia (13.2%), and perforation (2.6%). Of these, 110 patients (76.9%) had returned to oral intake before discharge (median, 7 days), whereas 33 patients (23.1%) still required tube feedings. Of 8 patients who did not undergo intraoperative JT placement, 6 had resumed oral intake at discharge. Two patients were discharged on total parenteral nutrition. Logistic regression analysis of preoperative variables showed a body mass index of less than 18.5 kg/m2 conferred a likelihood of requiring a JT at discharge (odds ratio, 7.56; p<0.05). Age, sex, albumin level, type of esophagectomy, histology, stage, preoperative neoadjuvant therapy, and type of cancer were not significant predictors of JT need at discharge. CONCLUSIONS: The only absolute indication for JT placement after esophagectomy was a body mass index of less than 18.5 kg/m2. Other patients may have selective JT placement based on the surgeon's judgment.

Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

BACKGROUND: A diagnosis of chronic lymphocytic leukemia (CLL) requires a count of over 5000 circulating CLL-phenotype cells per cubic millimeter. Asymptomatic persons with fewer CLL-phenotype cells have monoclonal B-cell lymphocytosis (MBL). The goal of this study was to investigate the relation between MBL and CLL. METHODS: We investigated 1520 subjects who were 62 to 80 years of age with a normal blood count and 2228 subjects with lymphocytosis (>4000 lymphocytes per cubic millimeter) for the presence of MBL, using flow cytometry. Monoclonal B cells were further characterized by means of cytogenetic and molecular analyses. A representative cohort of 185 subjects with CLL-phenotype MBL and lymphocytosis were monitored for a median of 6.7 years (range, 0.2 to 11.8). RESULTS: Monoclonal CLL-phenotype B cells were detected in 5.1% of subjects (78 of 1520) with a normal blood count and 13.9% (309 of 2228) with lymphocytosis. CLL-phenotype MBL had a frequency of 13q14 deletion and trisomy 12 similar to that of CLL and showed a skewed repertoire of the immunoglobulin heavy variable group (IGHV) genes. Among 185 subjects presenting with lymphocytosis, progressive lymphocytosis occurred in 51 (28%), progressive CLL developed in 28 (15%), and chemotherapy was required in 13 (7%). The absolute B-cell count was the only independent prognostic factor associated with progressive lymphocytosis. During follow-up over a median of 6.7 years, 34% of subjects (62 of 185) died, but only 4 of these deaths were due to CLL. Age above 68 years and hemoglobin level below 12.5 g per deciliter were the only independent prognostic factors for death. CONCLUSIONS: The CLL-phenotype cells found in the general population and in subjects with lymphocytosis have features in common with CLL cells. CLL requiring treatment develops in subjects with CLL-phenotype MBL and with lymphocytosis at the rate of 1.1% per year.

Potentially oncogenic B-cell activation-induced smaller isoforms of FOXP1 are highly expressed in the activated B cell-like subtype of DLBCL.

The FOXP1 forkhead transcription factor is targeted by recurrent chromosome translocations in several subtypes of B-cell non-Hodgkin lymphomas, where high-level FOXP1 protein expression has been linked to a poor prognosis. Western blotting studies of diffuse large B-cell lymphoma (DLBCL) cell lines unexpectedly identified the atypical high-level expression of 2 smaller, 60 to 65 kDa, FOXP1 isoforms in all 5 of those with the activated B cell (ABC)-like DLBCL subtype and in a subgroup of primary DLBCL. The anti-FOXP1 (JC12) monoclonal antibody cannot distinguish FOXP1 isoforms by immunohistochemistry, a finding that may be clinically relevant as high-level expression of the full-length FOXP1 protein was observed in some germinal center-derived DLBCLs. ABC-like DLBCL-derived cell lines were observed to express 2 novel, alternatively spliced FOXP1 mRNA isoforms, encoding N-terminally truncated proteins. These transcripts and the smaller protein isoforms were induced as a consequence of normal B-cell activation, which thus represents an additional mechanism for up-regulating FOXP1 expression in lymphomas. The expression of potentially oncogenic smaller FOXP1 isoforms may resolve the previously contradictory findings that FOXP1 represents a favorable prognostic marker in breast cancer and an adverse risk factor in B-cell lymphomas.

Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma.

The ability to rearrange the germ-line DNA to generate antibody diversity is an essential prerequisite for the production of a functional repertoire. While this is essential to prevent infections, it also represents the "Achilles heel" of the B-cell lineage, occasionally leading to malignant transformation of these cells by translocation of protooncogenes into the immunoglobulin (Ig) loci. However, in evolutionary terms this is a small price to pay for a functional immune system. The study of the configuration and rearrangements of the Ig gene loci has contributed extensively to our understanding of the natural history of development of myeloma. In addition to this, the analysis of Ig gene rearrangements in B-cell neoplasms provides information about the clonal origin of the disease, prognosis, as well as providing a clinical useful tool for clonality detection and minimal residual disease monitoring. Herein, we review the data currently available on both Ig gene rearrangements and protein patterns seen in myeloma with the aim of illustrating how this knowledge has contributed to our understanding of the pathobiology of myeloma.

Deregulated over expression of FOXP1 protein in diffuse large B-cell lymphoma does not occur as a result of gene rearrangement.

Strong uniform expression of FOXP1 protein occurs in a subgroup of non-germinal centre (GC) diffuse large B-cell lymphomas (DLBCL). We have investigated gene rearrangement as a potential mechanism for deregulated expression of FOXP1 however, using FISH FOXP1 translocations were not found in any case with over-expression of the protein.

Novel repair of venous aneurysms secondary to arteriovenous dialysis fistulae.

This report describes the surgical management of 12 hemodialysis patients with arteriovenous fistulae in whom non-infected, fusiform venous aneurysms developed that compromised access for dialysis. The venous aneurysmal changes were too extensive to permit excision and primary veno-venous anastomosis. To avoid the use of synthetic interpositional grafts, the venous aneurysms were left in situ and reduced in size to match the diameters of the veins entering and exiting the aneurysms. After decompression, the lumens of the venous aneurysms were reduced by firing staple lines along the longitudinal axes of the venous aneurysms and excision of the aneurysmal tissue anterior to the staple lines. Twenty-eight aneurysms were repaired by this method of reduction aneurysmoplasty, in 15 operations on 12 patients over the past 10 years. There were no wound infections or dehiscences and no bleeding or hematomas. After the operations, the arteriovenous fistulae were used continuously for hemodialysis until the patients died (7 patients for 36 months -/+ 28 SD), were lost to follow-up (1 patient at 30 days postoperatively), until the arteriovenous fistulae thrombosed following revision of the arteriovenous anastomosis (1 patient at 41 months postoperatively), or until the arteriovenous fistulae was ligated to relieve pain in the upper arm (1 patient at 6 months postoperatively). Two patients continue to use their arteriovenous fistulae until and including the time of this report at 10 and 11 months, respectively. Reduction aneurysmoplasty as described in this report offers an effective and low-risk option for the management of venous aneurysms secondary to arteriovenous fistulae in hemodialysis patients.

Immunoglobulin heavy chain sequence analysis in Waldenstrom's macroglobulinemia and immunoglobulin M monoclonal gammopathy of undetermined significance.

In this study, we used IGH sequence analysis to assess the maturational status of Waldenstrom's (WM) macroglobulinemia and its putative precursor immunoglobulin (Ig)-M monoclonal gammopathy of undetermined significance (MGUS). IGH sequence analysis was performed using standard methods in 23 cases (20 WM and 3 IgM MGUS as defined by consensus panel criteria). Waldenstrom's macroglobulinemia cases were characterized by heavily mutated IGH genes (median, 6.3%; range, 3.8%-13.9%) but without intraclonal variation (ICV). IgM MGUS was similarly characterized by somatic hypermutation (median, 7.5%; range, 7%-7.7%), but ICV was evident in 1 of the 3 cases. We would therefore conclude that WM is characterized by somatic hypermutation without ICV, which supports a derivation from postgerminal center/memory B cells. IgM MGUS is also characterized by somatic hypermutation but, in a manner similar to IgA/IgG MGUS, can be associated with ICV, although the significance of this remains unclear.

t(3;14)(p14;q32) results in aberrant expression of FOXP1 in a case of diffuse large B-cell lymphoma.

Strong expression of Forkhead box-P1 (FOXP1), a winged-helix transcription factor, has been identified as an independent prognostic factor in diffuse large B-cell lymphoma (DLBCL). However, possible mechanisms of deregulation of this gene, on 3p14.1, have yet to be elucidated. We have identified a breakpoint at the IGA1 gene in the immunoglobulin heavy chain (IGH) locus at 14q32 that was juxtaposed to the FOXP1 gene locus in a gastric DLBCL that showed strong expression of FOXP1. This may be one possible mechanism of deregulating FOXP1 expression by placing it under the control of IGH enhancers.

Complex biallelic IGH rearrangements in IgM-expressing Z-138 cell line: Involvement of downstream immunoglobulin class switch recombination.

Chromosomal translocations involving the immunoglobulin (Ig) receptor loci usually disrupt and silence these loci. On the basis of observations in follicular lymphoma (FL) with downstream Ig heavy chain (IGH) class switch recombination (CSR), we hypothesized that downstream CSR-mediated chromosomal translocations would leave the V(D)J-Cmu transcription unit intact, thereby still allowing IgM expression from the IGH allele involved in the translocation. To test this hypothesis, we analyzed biallelic IGH translocations in the IgM-expressing cell line Z-138 by interphase FISH, DNA fiber-FISH, long-distance vectorette PCR, and DNA sequencing. One IGH allele was involved in a t(11;14), showing a break in the JH region that juxtaposed the Emu enhancer and the 3' Calpha enhancers to the cyclin D1 gene. The other IGH allele contained a t(8;14) breakpoint involving the 3' end of a Sgamma region, whereas the reciprocal breakpoint at 8q24 was approximately 40 kb centromeric of MYC. Molecular analysis showed that this IGH allele harbored a normal V(D)J-Cmu complex, which is responsible for IgM expression. These data show that chromosomal breakpoints such as the t(8;14) can occur in downstream IGH constant regions and do not necessarily interfere with Ig expression.

A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma.

PURPOSE: Our purpose in this report was to define genes and pathways dysregulated as a consequence of the t(4;14) in myeloma, and to gain insight into the downstream functional effects that may explain the different prognosis of this subgroup. EXPERIMENTAL DESIGN: Fibroblast growth factor receptor 3 (FGFR3) overexpression, the presence of immunoglobulin heavy chain-multiple myeloma SET domain (IgH-MMSET) fusion products and the identification of t(4;14) breakpoints were determined in a series of myeloma cases. Differentially expressed genes were identified between cases with (n = 5) and without (n = 24) a t(4;14) by using global gene expression analysis. RESULTS: Cases with a t(4;14) have a distinct expression pattern compared with other cases of myeloma. A total of 127 genes were identified as being differentially expressed including MMSET and cyclin D2, which have been previously reported as being associated with this translocation. Other important functional classes of genes include cell signaling, apoptosis and related genes, oncogenes, chromatin structure, and DNA repair genes. Interestingly, 25% of myeloma cases lacking evidence of this translocation had up-regulation of the MMSET transcript to the same level as cases with a translocation. CONCLUSIONS: t(4;14) cases form a distinct subgroup of myeloma cases with a unique gene signature that may account for their poor prognosis. A number of non-t(4;14) cases also express MMSET consistent with this gene playing a role in myeloma pathogenesis.