Exploring recent patterns of migration of doctors to the United Kingdom: a mixed-methods study.

INTRODUCTION: A shortage of doctors is currently one of the biggest challenges faced by the healthcare workforce in the United Kingdom (UK). While plans are in place to increase the number of medical school places, in the short-term this gap will need to continue to be filled by the international recruitment of doctors. The aim of this study is to identify key factors that explain the patterns of migration of doctors to the UK, in order to aid the development of policies to recruit and retain a sustainable workforce. METHODS: We analysed General Medical Council (GMC) secondary data on the patterns of migration of internationally trained doctors (2009-2019). Qualitative interviews were conducted with 17 stakeholders by videoconferencing which were audio-recorded, transcribed and thematically analysed using NVivo. RESULTS: In 2019, 34.5% of UK doctors were trained internationally mainly in India, Pakistan, Italy, Nigeria, Greece, Romania and Egypt. Most new registrations by internationally trained doctors from 2009-2019 did not have a specialty at the time of initial registration (96.2% in 2019). Only a relatively small number of these doctors go on to gain specialist or GP registration (11.6% within 5 years and 27.2% within 10 years of registration). The stakeholder interviews highlighted training opportunities and career progression as the main drivers of migration. The barriers internationally trained doctors face regarding specialty training included differences between UK and destination health systems, systematic bias, bureaucracy and selection processes not being accessible. CONCLUSION: This study makes a contribution to the literature by identifying recent patterns in the migration of doctors to the UK. The UK's dependence on internationally trained doctors has important global implications as source countries are losing skilled health workers which is undermining their health systems. In keeping with the WHO Global Code on the International Recruitment of Healthcare Personnel, policymakers need to consider how to reduce the UK's reliance on internationally trained doctors, particularly from countries on the safeguard list whilst continuing the drive to increase medical school places. Additional support is required for internationally trained doctors, to ensure that they get on the training programmes they seek, enabling their career progression.

Drivers and barriers of international migration of doctors to and from the United Kingdom: a scoping review.

BACKGROUND: Many high-income countries are heavily dependent on internationally trained doctors to staff their healthcare workforce. Over one-third of doctors practising in the UK received their primary medical qualification abroad. Simultaneously, an average of around 2.1% of doctors leave the UK medical workforce annually to go overseas. The aim of this study was to identify the drivers and barriers of international migration of doctors to and from the UK. METHODS: A scoping review was conducted. We searched EMBASE, MEDLINE, CINAHL, ERIC and BEI in January 2020 (updated October 2021). Grey literature and citation searching were also carried out. Empirical studies reporting on the drivers and barriers to the international migration of doctors to and from the UK published in the English language from 2009 to present were included. The drivers and barriers were coded in NVivo 12 building on an existing framework. RESULTS: 40 studies were included. 62% were quantitative, 18% were qualitative, 15% were mixed-methods and 5% were literature reviews. Migration into and out of the UK is determined by a variety of macro- (global and national factors), meso- (profession led factors) and micro-level (personal factors). Interestingly, many of the key drivers of migration to the UK were also factors driving migration from the UK, including: poor working conditions, employment opportunities, better training and development opportunities, better quality of life, desire for a life change and financial reasons. The barriers included stricter immigration policies, the registration process and short-term job contracts. CONCLUSIONS: Our research contributes to the literature by providing a comprehensive up-to-date review of the drivers and barriers of migration to and from the UK. The decision for a doctor to migrate is multi-layered and is a complex balance between push/pull at macro-/meso-/micro-levels. To sustain the UK's supply of overseas doctors, it is vital that migration policies take account of the drivers of migration particularly working conditions and active recruitment while addressing any potential barriers. Immigration policies to address the impact of Brexit and the COVID-19 pandemic on the migration of doctors to and from the UK will be particularly important in the immediate future. Trial registration PROSPERO CRD42020165748.

The use of in situ perfusion of the rat mesentery as a model to investigate vascular injury directly induced by drugs.

Exposure of the vasculature to vasodilators, pharmaceuticals and industrial chemicals may lead to injury of the blood vessel wall in animals. Vascular injury may begin with changes in the permeability of vascular endothelial cell and vessels, resulting in possible hemorrhage and edema leading subsequently to immune cell infiltration. The present study was undertaken to determine if the direct exposure of the Sprague Dawley rat mesenteric vasculature through the perfusion of aminophylline, fenoldopam, compound 48/80, histamine or serotonin has any such effects on the blood vessels, and if the two vital dyes Monastral blue B and Evans blue can be used to enhance the visualization of the vascular damage. Microscopic visualization was enhanced by the use of dyes and a variety of alterations of the perfused mesenteric vessels were detected, including varying degrees of mast cell degranulation, microvascular vasodilatation and increased vascular permeability. Macroscopic evidence of vascular damage was minimal. This study demonstrates that in situ perfusion of the rat mesentery is a simple and useful method to eliminate the influence of a variety of physiologic influences or homeostatic responses and can be used to further investigate drug-induced vascular damage.

Cytochrome c: a non-invasive biomarker of drug-induced liver injury.

Limitations of existing biomarkers to detect liver injury in experimental animals highlight the need for additional tools to predict human toxicity. The utility of cytochrome c (cyt c) as a biomarker in serum and urine was evaluated in two rodent liver injury models. Adult Sprague-Dawley rats treated with acetaminophen or D-galactosamine (GalN) showed dose- and time-dependent histomorphological changes and TUNEL staining in liver consistent with hepatocellular necrosis, apoptosis and inflammation up to 72 h. Matching changes in serum alanine transaminase (ALT), aspartate transaminase (AST) and cyt c peaked at 24 h for either drug at the highest dose, cyt c falling rapidly at 48 hours with ALT and AST remained high. Intracellular transit of cyt c from mitochondria to the cytoplasm in damaged hepatocytes, and then to peripheral circulation, was observed by immunohistochemistry. Correlation coefficients between cyt c and serum diagnostic tests indicate the liver to be the primary source of cyt c. Urinary analysis for cyt c revealed time-dependent increase at 6 h, peaking at 24 h in GalN-treated rats in contrast with irregular patterns of urinary ALT and AST activity. Histological changes detected at 6 h preceded altered ALT, AST and cyt c at 12 and 18 h, respectively, in GalN-treated rats. These studies demonstrate cyt c to be a useful indicator of hepatic injury in rodents and support its utility as a non-invasive predictor of drug-induced hepatotoxicity, when utilized as a potential urinary biomarker.

The utility of the K6/ODC transgenic mouse as an alternative short term dermal model for carcinogenicity testing of pharmaceuticals.

The use of transgenic rodents may overcome many limitations of traditional cancer studies. Regulatory perspectives continue to evolve as new models are developed and validated. The transgenic mouse, K6/ODC, develops epidermal tumors when exposed to genotoxic carcinogens. In this study, K6/ODC mice were evaluated for model fitness and health robustness in a 36-week study to determine oncogenic risk of residual DNA in vaccines from neoplastic cell substrates. K6/ODC and C57BL/6 mice were treated with T24-H-ras expression plasmid, carrier vector DNA, or saline topically or by subcutaneous injection. One group of K6/ODC mice received 7,12-dimethylbenz-[a]anthracene [DMBA] dermally. Only DMBA-treated mice developed papillomas by six weeks, increasing in incidence to 25 weeks. By week 11, many K6/ODC mice showed severe dehydration and dermal eczema. By week 32, (6/8) surviving K6/ODC mice showed loss of mobility and balance. Microscopic evaluation of tissues revealed dermal/sebaceous gland hyperplasia, follicular dystrophy, splenic atrophy, and amyloid deposition/neutrophilic infiltration within liver, heart, and spleen, in all K6/ODC mice. Pathology was not detected in C57BL/6 mice. Progressive adverse health, decreased survival, and failure to develop papillomas to the H-ras plasmid suggest that K6/ODC mice may be an inappropriate alternative model for detection of oncogenic DNA and pharmaceutical carcinogenicity testing.

The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity.

PURPOSE: To compare the protective effect of dexrazoxane (DRZ) against cardiotoxicity induced by doxorubicin (DXR) and mitoxantrone (MTX). METHODS: Adult male spontaneously hypertensive rats (SHR) were treated with 1 mg/kg DXR (i.v.) or 0.5 mg/kg MTX (i.v.), either alone or 30 min after 25 mg/kg DRZ (i.p.) weekly for up to 12 weeks. Animals treated with DXR alone either died (n = 2) or were killed (n = 3) at a cumulative dose of 10 mg/kg. The severity of cardiac lesions (cytoplasmic vacuolization and myofibrillar loss) were graded semiquantitatively by light microscopy on a scale of 0 to 3. RESULTS: Cardiac lesions were observed in all SHR given DXR or MTX alone, and were attenuated in those given DRZ prior to either DXR (mean lesion scores 2.7 vs 1.5; P < 0.05) or MTX (mean lesion scores 2.0 vs 1.25; P < 0.05). Cardioprotection was also demonstrated by monitoring serum levels of cardiac troponin T (cTnT), which were elevated in all animals receiving DXR or MTX alone. These elevations were attenuated in SHR given the combination of DXR and DRZ (mean values 0.79 ng/ml vs 0.24 ng/ml; P < 0.05) and MTX and DRZ (mean values 0.19 ng/ml vs 0.04 ng/ ml; P < 0.05). Biochemical studies have shown that both DXR and MTX form potentially cardiotoxic complexes with iron. ADR-925 (the hydrolysis product of DRZ) and other chelators (EDTA, diethylenetriaminepentaacetic acid and desferrioxamine) removed Fe(III) from its complex with MTX or DXR. CONCLUSIONS: The present study showed that DRZ significantly attenuates the cardiotoxicity induced by DXR and MTX, and that this protective activity can be assessed by morphological evaluation of cardiac tissues and by monitoring the concentrations of cTnT in serum.

Influence of beta-adrenergic antagonists, H1-receptor blockers, analgesics, diuretics, and quinolone antibiotics on the cellular accumulation of the anticancer drug, daunorubicin: P-glycoprotein modulation.

BACKGROUND: Treatment of patients with several drugs simultaneously may result in modulation of the naturally expressed P-glycoprotein (Pgp) at different tissues. With this possibility in mind, we have assessed the ability of different classes of drugs to modulate Pgp function in vitro. Modulation of the Pgp function was studied at in vitro drug concentrations comparable to therapeutic blood levels of the drugs. MATERIALS AND METHODS: Human blood brain barrier endothelial cells and human colon adenocarcinoma cells were transduced or transfected with the multidrug resistance gene (MDR1) to express Pgp. The uptake of fluorescent substrates of Pgp, Rhodamine 123 and daunorubicin, into these cells and NIH3T3/MDR1 and MDCK/MDR1 cells was measured by flow cytometry and in monolayers in the presence and absence of the different drugs. RESULTS: From the tested six H1-receptor blockers, seven beta-adrenergic antagonists, four analgesics, ten diuretics and five quinolons, five drugs inhibited Pgp at therapeutic blood levels and two at somewhat higher concentrations. Significant synergism for blocking Pgp could be demonstrated for several drugs. CONCLUSION: We conclude that administration of several drugs which modulate the function of Pgp to patients may adversely affect the natural function of this efflux pump and may cause drug-drug interactions induced side effects.

Influence of antipsychotic, antiemetic, and Ca(2+) channel blocker drugs on the cellular accumulation of the anticancer drug daunorubicin: P-glycoprotein modulation.

We investigated the effect of antiemetic, antipsychotic, and Ca(2+) blocker drugs on the function of P-glycoprotein (Pgp) in vitro and compared inhibitory concentrations with therapeutic blood levels. Human colon adenocarcinoma (Caco-2) and human blood-brain barrier endothelial cells were transfected or transduced to express Pgp, and the uptake of rhodamine123, calcein AM, or daunorubicin was measured by flow cytometry in the presence of the drugs. NIH3T3/MDR1 cells were used for reference testing. Results of the flow cytometric studies were supported by cell proliferation and monolayer permeability studies. Thirty-five drugs are included in this study, of which 13 modulate the function of Pgp at the therapeutic blood concentration and 8 at a concentration 2 to 4 times higher. Two drugs, which block the function of Pgp only partially at therapeutic blood concentrations, blocked the function of Pgp completely if used concomitantly. Based on these in vitro experiments, we conclude that administration of several drugs that modulate the function of Pgp simultaneously may adversely affect the natural function of this efflux pump and may cause drug-induced side effects in patients.

Micronucleated erythrocyte frequency in peripheral blood of B6C3F(1) mice from short-term, prechronic, and chronic studies of the NTP carcinogenesis bioassay program.

The mouse peripheral blood micronucleus (MN) test was performed on samples collected from 20 short-term, 67 subchronic, and 5 chronic toxicity and carcinogenicity studies conducted by the National Toxicology Program (NTP). Data are presented for studies not previously published. Aspects of protocol that distinguish this test from conventional short-term bone marrow MN tests are duration of exposure, and absence of repeat tests and concurrent positive controls. Furthermore, in contrast to short-term bone marrow MN tests where scoring is limited to polychromatic erythrocytes (PCE), longer term studies using peripheral blood may evaluate MN in both, or either, the normochromatic (NCE) or PCE populations. The incidence of MN-PCE provides an index of damage induced within 72 hr of sampling, whereas the incidence of MN in the NCE population at steady state provides an index of average damage during the 30-day period preceding sampling. The mouse peripheral blood MN test has been proposed as a useful adjunct to rodent toxicity tests and has been effectively incorporated as a routine part of overall toxicity testing by the NTP. Data derived from peripheral blood MN analyses of dosed animals provide a useful indication of the in vivo potential for induced genetic damage and supply an important piece of evidence to be considered in the overall assessment of toxicity and health risk of a particular chemical. Although results indicate that the test has low sensitivity for prediction of carcinogenicity, a convincingly positive result in this assay appears to be highly predictive of rodent carcinogenicity.

The liver in transforming growth factor-Beta-1 (TGF-beta 1) null mutant mice.

Transforming growth factor-beta-1 (TGF-beta 1) null mutant mice have no gross developmental abnormalities at birth but succumb to multifocal inflammatory lesions that lead to organ failure and death about 20 days after birth. Treatment with anti-inflammatory and immune suppressive agents, such as rapamycin, reduces the severity and extent of inflammatory infiltrates in the liver and can prolong the life of knockout (KO) mice compared to untreated null mice. To determine whether there is an associated hepatic phenotype, livers of "young" (< 3 weeks), "old" (> 3 weeks), and age-matched wild-type (WT) mice were studied using light and electronmicroscopy. On light microscopy, old KO mice had foci of mononuclear cells in liver parenchyma in addition to scattered foci of megalocytosis. Intracytoplasmic vacuoles, some of which were juxtanuclear in location, were also seen but these were most prominent in the oldest (10 weeks) rapamycin-treated mouse. In the untreated young KO mice, there were only foci of mononuclear cells in the liver parenchyma and portal tracts and variable numbers of binucleated hepatocytes. Ultrastructurally, there was a significant increase in the number of mitochondria in livers of the old KO mice, when compared either to the age-matched wild-type or to the young KO mice (p > .001). Hepatocytes from all KO mice showed increased numbers of hypertrophied or enlarged Golgi complexes compared to age-matched wild-type mice. Intracytoplasmic canaliculi lined with microvilli were seen in livers of old KO mice, but were absent in the young KO and wild-type mice. Primary cultures of hepatocytes, derived from livers of both young and old KO mice, showed similar changes on phase contrast and electronmicroscopy. These included juxtanuclear vacuoles, intracytoplasmic canaliculi, enlarged Golgi vesicles, and increased numbers of autolysosomes. Phenotypic abnormalities of mitochondria were either minimal or absent in cultured KO hepatocytes. The findings demonstrate, for the first time, that targeted disruption of the TGF-beta 1 gene in mice results in an altered ultrastructural phenotype of hepatocytes. The data suggest that TGF-beta 1 may be required for normal development and regulation of subcellular organelles in hepatocytes and may be essential for physiological functions involving mitochondria and Golgi complex.

Hepatic silicosis, cirrhosis, and liver tumors in mice and hamsters: studies of transforming growth factor beta expression.

Hepatic silicosis, cirrhosis, liver cell adenoma, and carcinomas developed in nude mice (NCr-Nu) given quartz by the subcutaneous and intraperitoneal routes. Syrian golden hamsters (15:16 EHS:cr) given quartz by both routes developed extensive fibrosis and cirrhosis and had higher morbidity and mortality rates after 3 months. Crystalline silica (quartz) induces fibrosis, adenomas, and carcinomas in the lungs of Fisher 344 rats, but certain strains of mice and hamsters are resistant to quartz-induced pulmonary carcinogenesis. Pulmonary fibrosis, however, is minimal in mice and absent in hamsters who received quartz intratracheally. To determine whether species differences are due to organ-specific rather than species-specific factors, susceptibility of the liver to quartz toxicity was investigated in nude mice and hamsters. The present study shows that the differential manifestations of quartz toxicity by these rodent species are dependent on factors that are organ-specific rather than host-specific. At 3 months, hepatocytes in mice were immunostained with intracellular transforming growth factor (TGF) beta 1 (LC 1-30) but not with TGF-beta 1 latency-associated peptide (LAP) protein (266-278); at 12 months, hepatocytes were immunostained with TGF-beta 1 LAP (266-278) but not with TGF-beta 1 (LC1-30). The hepatocytes of hamsters at 3 months showed immunoreactivities to TGF-beta 1 LAP (266-278) and TGF-beta 1 (LC1-30); immunostaining to TGF-beta 1 (LC1-30) was detected in nonparenchymal cells. Extracellular TGF-beta 1 (CC1-30) was detected in the silicotic granulomas and fibrous tissue in livers of both species. Quartz-induced liver carcinoma did not express TGF-beta 1 LAP (266-278) and LC (1-30) proteins, but these were detected in the cells of the adenoma in the same liver. Control animals showed no hepatic lesions nor immunoreactivity to TGF-beta 1. The spatial and temporal patterns of expression of TGF-beta 1, TGF-beta 2, TGF-beta receptor type II messenger RNAs (mRNAs), and TGF-beta 1 proteins in the different hepatic lesions suggests that TGF-beta isoforms may play a role in the pathogenesis of quartz-induced fibrosis, cirrhosis, liver cell adenoma, and carcinoma.

Transforming growth factor beta expression and transformation of rat lung epithelial cells by crystalline silica (quartz).

Crystalline silica (quartz) induces silicosis and associated peripheral lung carcinomas in rats. The role and pattern of expression of transforming growth factor (TGF)-beta1/beta2 mRNA transcripts were investigated in the fetal rat lung epithelial cell line FRLE, its neoplastic transformants and derived tumors in athymic nude mice. FRLE cells, treated with 100 microgram/cm2 of quartz in serum-free medium, gave rise to phenotypically altered, tumorigenic cells. Quartz-treated, transformed and tumorigenic cells, subcultured directly (QTT-C1) or after growth in soft agar (QTT-C2), formed tumors in athymic nude mice (QTT-T1). Cells subcultured from the tumors (QTT-T1C) were also tumorigenic in nude mice (QTT-T2). QTT-T1 and QTT-T2 tumors were poorly differentiated carcinomas with variable amounts of extracellular matrix-associated TGF-beta1 and desmoplasia. For comparison, a tumorigenic cell line derived from FRLE cells transformed with a mutated K-ras plasmid (RT-C1) and cells subcultured from a corresponding nude mouse tumor (RT-T1) and designated RT-T1C were used. Whereas TGF-beta1 and TGF-beta2 inhibited the growth of QTT-T1C and FRLE cells in a dose-dependent fashion, RT-T1C cells, containing an activated ras gene, were relatively unaffected. TGF-beta1 and TGF-beta2 mRNAs were expressed at higher levels in QTT-T1C cells than in FRLE and TR-T1C cells, and there was an increase in TGF-beta type II receptor (TGR-betaR) mRNA expression in QTT-T1C and RT-T1C cells compared to FRLE cells. Carcinomas in nude mice derived from QTT and RT cells and silicosis-associated lung carcinomas induced in rats by intra-tracheal quartz did not express either active or latent forms of TGF-beta1 protein on immunohistochemistry. The disparity between TGF-beta1 mRNA and TGF-beta1 protein expression in QTT tumors may be due to post-transcriptional regulation of TGF-beta1.

Reaction of Cr(VI) with ascorbate and hydrogen peroxide generates hydroxyl radicals and causes DNA damage: role of a Cr(IV)-mediated Fenton-like reaction.

Incubation of Cr(VI) with ascorbate generated Cr(V), Cr(IV) and ascorbate-derived carbon-centered alkyl radicals, as well as formyl radicals. H2O2 caused generation of hydroxyl radicals (OH) and much higher levels of Cr(V), showing that .OH can be generated via a Cr(IV)-mediated Fenton-like reaction (Cr(IV) + H2O2-->Cr(V) + .OH + OH-). 1,10-Phenanthroline and deferoxamine inhibited the formation of both .OH and Cr(V) from the reaction of Cr(VI) with ascorbate in the presence of H2O2. Electrophoretic assays showed that ascorbate-derived free radicals caused DNA double-strand breaks. .OH radicals generated by Cr(V)- and Cr(IV)-mediated Fenton-like reactions also caused DNA double-strand breaks. HPLC measurements showed that .OH radicals generated by Cr(IV) and Cr(V) from H2O2 caused 2'-deoxyguanine hydroxylation to form 8-hydroxy-2'-deoxyguanine.