The NHS visitor and migrant cost recovery programme - a threat to health?

BACKGROUND: In April 2014 the UK government launched the 'NHS Visitor and Migrant Cost Recovery Programme Implementation Plan' which set out a series of policy changes to recoup costs from 'chargeable' (largely non-UK born) patients. In England, approximately 75% of tuberculosis (TB) cases occur in people born abroad. Delays in TB treatment increase risk of morbidity, mortality and transmission in the community. We investigated whether diagnostic delay has increased since the Cost Recovery Programme (CRP) was introduced. METHODS: There were 3342 adult TB cases notified on the London TB Register across Barts Health NHS Trust between 1st January 2011 and 31st December 2016. Cases with missing relevant information were excluded. The median time between symptom onset and treatment initiation before and after the CRP was calculated according to birthplace and compared using the Mann Whitney test. Delayed diagnosis was considered greater or equal to median time to treatment for all patients (79 days). Univariable logistic regression was used to manually select exposure variables for inclusion in a multivariable model to test the association between diagnostic delay and the implementation of the CRP. RESULTS: We included 2237 TB cases. Among non-UK born patients, median time-to-treatment increased from 69 days to 89 days following introduction of CRP (p < 0.001). Median time-to-treatment also increased for the UK-born population from 75.5 days to 89.5 days (p = 0.307). The multivariable logistic regression model showed non-UK born patients were more likely to have a delay in diagnosis after the CRP (adjOR 1.37, 95% CI 1.13-1.66, p value 0.001). CONCLUSION: Since the introduction of the CRP there has been a significant delay for TB treatment among non-UK born patients. Further research exploring the effect of policies restricting access to healthcare for migrants is urgently needed if we wish to eliminate TB nationally.

Support of vulnerable patients throughout TB treatment in the UK.

Despite well-established treatment regimens, tuberculosis (TB) remains a public health burden; it disproportionately affects poor and marginalized populations who may not have access to social support, including migrants, homeless people and those dependent on drugs or alcohol. There is a clearly demonstrated need for housing and other appropriate social support, as part of a package of integrated clinical and social care. However, TB prevention and control efforts in the UK often do not address the specific vulnerabilities of these groups and it can be a challenge to support the continued TB treatment of these underserved populations. This challenge is exacerbated by complex issues concerning funding, immigration and the law. In this paper, we have reviewed current UK guidance and legislation, discussed several case studies and highlighted examples of existing models of community support for TB patients. Finally, we lay out our recommendations for ensuring a co-ordinated, whole system approach to successful TB treatment.

A UK-based resource to support the monitoring and safe use of anti-TB drugs and second-line treatment of multidrug-resistant TB.

Using the best available evidence and expert consensus, this document provides guidance for adverse effect monitoring in multidrug-resistant TB (MDR-TB). It includes recommendations for baseline tests, routine drug and toxicity monitoring guides as well as individual drug monographs for all drugs currently available in the UK to treat TB. These recommendations provide a structure through which healthcare professionals can better manage the complex drug regimens required for the treatment of MDR-TB; minimising the risk of adverse incidents and helping to improve patients' tolerance, compliance and treatment completion.

An unusual presentation of miliary tuberculosis.

A young Bangladeshi woman presented to the emergency department with vaginal discharge on a history of fevers and rigours. Although initially treated for pelvic inflammatory disease, the patient rapidly developed respiratory failure with acute respiratory distress syndrome. An axillary biopsy and a high-resolution CT of the chest confirmed miliary tuberculosis (TB). She was initiated on anti-TB medication and made a rapid recovery.

Diet quality of Australian breast cancer survivors: a cross-sectional analysis from the Australian Longitudinal Study on Women's Health.

BACKGROUND: Evidence supports strong associations between healthful eating patterns and maintaining a healthy weight with favourable health outcomes for breast cancer survivors (BCS). The present study aimed to evaluate the diet quality of Australian BCS and to determine whether diet quality differed between BCS and age-matched healthy controls (HC) or by geographical location. METHODS: This cross-sectional study included 281 BCS and 4069 HC from the Australian Longitudinal Study on Women's Health mid-aged cohort completing Survey 3 in 2001. Data from the Dietary Questionnaire for Epidemiological Studies food frequency questionnaire were used to calculate the Australian Recommended Food Score (ARFS), a validated summary estimate of diet quality based on adherence to the Australian dietary guidelines. RESULTS: The mean (SD) ARFS of the BCS group was 33.2 (9.4) out of a maximum of 74. Mean (SD) total ARFS and component scores of BCS did not differ from the HC group [32.9 (8.7)] and no differences were found in ARFS between urban and rural BCS. CONCLUSIONS: This is the first study dedicated exclusively to describing the diet quality of Australian BCS. Although no difference was found when comparisons were made with a HC group, there is considerable room for improvement in the diet quality of Australian BCS. Given research suggesting higher risk of chronic conditions such as obesity amongst BCS, and the recognition of optimising diet quality as a key factor in health promotion for all population groups, data from the present study suggest the need for research targeting the feasibility and impact of improving diet quality of Australian BCS.

Prioritizing policy interventions to improve diets? Will it work, can it happen, will it do harm?

Policies from non-health sectors have considerable impacts on the food environment and in turn on population nutrition. Health impact assessment (HIA) methods have been developed to identify the potential health effects of non-health policies; however, they are underused both within and outside the health sector. HIA and other assessment methods and tools can be used more extensively in health promotion to assist with the identification of the best policy options to pursue to improve and protect health. A participatory process is presented in this paper which combines HIAs with feasibility and effectiveness assessments. The intention is to enable health promoters to more accurately identify which policy change options would be most likely to improve diets, considering both impact and likelihood of implementation. The process was successfully used in Fiji and Tonga and provided a more systematic way of understanding which policy interventions showed the most promise.

TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells.

Triggering receptor expressed on myeloid cells-2 (TREM-2) is an innate immune receptor that initiates cellular activation upon ligation. In this study, we examined the interaction of TREM-2 with Neisseria gonorrhoeae using murine TREM-2A, as it has been reported to recognize bacterial ligands. Using a whole-bacteria enzyme-linked immunosorbent assay (ELISA), TREM-2A bound to all six strains in variable degrees. Far-western blots of gonococcal outer membranes revealed TREM-2A binding to lipooligosaccharide (LOS) and opacity (Opa) protein, with predominant binding to LOS. Binding of TREM-2A to LOS was confirmed by ELISA and surface plasmon resonance. O-deacylation of the lipid A significantly reduced binding. Flow cytometry and reporter cell assays showed that gonococci bound to TREM-2A-transfected cells and induced transmembrane signaling. In humans, TREM-2 was constitutively expressed by genitourinary and fallopian tube epithelial cells, both of which are primary targets of gonococcal invasion. Ligation of TREM-2 by LOS induced interleukin-6 production in HeLa cervical carcinoma cells. To our knowledge, this is the first report of the expression of human TREM-2 by cells deriving from a non-myeloid lineage. We conclude that gonococci can interact with TREM-2 receptors through binding to LOS and Opa protein and initiate cell signaling and cytokine production.

PCR and DNA Hybridization Methods for Specific Detection of Bean-Infecting Begomoviruses in the Americas and Caribbean.

Begomoviruses are a major problem for common bean production in the tropics and subtropics of the Americas and the Caribbean. Multiplex polymerase chain reaction (PCR) primer pairs and nucleic acid hybridization probes have been developed to differentiate five bean-infecting begomoviruses and were used to assay reference and field-collected bean samples from Florida, Mexico, Central America, the Caribbean, and Brazil. Bean golden mosaic virus was found in Brazil, Bean calico mosaic virus in Mexico, and Bean golden yellow mosaic virus in Central America, the Caribbean, and Florida. Bean dwarf mosaic virus was not detected in any of the field samples. Tomato yellow leaf curl virus was found only in tomato samples from the Caribbean. These detection methods will provide tools to assist in the understanding of the epidemiology and diversity of geminiviruses as well as to facilitate resistance breeding, cultivar selection, and development of strategies for control.

First Report of Tomato yellow leaf curl virus Associated with Beans, Phaseolus vulgaris, in Cuba.

Beans with yellow mosaic and/or leaf crumple symptoms were collected in three fields in the southern area of the province of Havana, Cuba in December 2001 and February 2002. DNA was extracted from the fresh bean leaves of 25 samples (1). Dot blot hybridization was performed at high stringency with a specific probe for Tomato yellow leaf curl virus (TYLCV). The specific probe was prepared by alkaline phosphatase labeling of the polymerase chain reaction (PCR) fragment amplified with primer pair, PTYIRv21/PTYIRc287, containing the intergenic region (IR) of TYLCV, and chemiluminescent hybridization was completed as described by the manufacturer (AlkPhos Direct Labeling and Detection Systems, Amersham Pharmacia Biotech Inc., Piscataway, NJ). Four of the samples had positive hybridization signals. PCR was performed with overlapping primers for TYLCV (2) with the DNA extract from sample 01-44, which gave a positive hybridization signal with the TYLCV probe, and a 2.8-kb fragment was obtained. This fragment was cloned in pGem T-Easy (pBeTY44) and partially sequenced. Greater than 96% nt identity was obtained for the 591 nt of the IR and 504 nt of the N-terminus of the Rep gene with TYLCV (GenBank Accession No. AF260331). Also, PCR was completed on 11 of the 25 samples with the degenerate primer pair PAL1v1978/PAR1c715 for DNA-A (3). Eight samples gave fragment sizes of 1.4 kb and one sample gave a fragment of 1.3 kb. The 1.3-kb fragment from sample number 01-50 was cloned in pGem T-Easy (pBeBG50) and partially sequenced. Pairwise nucleotide comparisons with Bean golden yellow mosaic virus (BGYMV, GenBank Accession No. M91604) were 95% for 719 nt of the N-terminus of the Rep gene. These results are consistent with the association of both TYLCV and BGYMV in beans and have important implications for future disease management strategies. References: (1) G. P. Accotto et al. Eur. J. Plant. Pathol. 106:179, 2000. (2) M. K. Nakhla et al. Plant Dis. 78:926, 1994. (3) M. Rojas et al. Plant Dis. 77:340, 1993.

First Report and Characterization of Rhynchosia golden mosaic virus in Honduras.

Rhynchosia minima was suspected to be a weed host of Bean golden yellow mosaic virus (BGYMV, previously designated Bean golden mosaic virus type II). Leaf tissue that exhibited yellow mosaic foliar symptoms characteristic of a geminivirus infection was collected in the Comayagua Valley in Honduras in July 1999. Extraction of viral DNA from the symptomatic leaves was accomplished with the DNeasy Plant Mini Kit (Qiagen Inc., Valencia, CA). Subsequent viral DNA amplification was accomplished with degenerative primers for the cp gene (AV494/AC1048) (4). The 570-bp fragment was cloned into the pGEM T-Easy vector (Promega Corp., Madison, WI) producing the recombinant plasmid pRhyb5. The viral insert was sequenced, and from this sequence, specific primers (RHc549 and RHv29) were designed to amplify the remaining part of DNA-A. The 2.1-kb-amplified polymerase chain reaction (PCR) fragment was cloned into the pGEM T-Easy vector producing the recombinant plasmid (pRhya-sp), and the viral insert was sequenced. Nucleotide sequence comparison (GAP program, Wisconsin Package Version 10.0, Genetics Computer Group, Madison, WI) of the complete 2,624-bp DNA-A (GenBank accession no. AF239671) to geminiviruses representing the major phylogenetic clusters (1) showed nucleotide identities ranging from 63 to 82%. Sequence comparisons for the common region and rep, trap, ren, and cp genes with the most closely related geminivirus, Pepper hausteco virus (PHV, X70418), gave 76, 82, 79, 81, and 82% nucleotide identities, respectively. There is a direct repeat (TATCGGT) of 7 nt 5' (viral sense polarity) of the conserved TATA box, and this repeat is most analogous to that in PHV (1). Specific primers were designed in the complementary sense (RGBc2414, BGBc2553) from the common region DNA-A sequence and used with a degenerative viral sense primer for the DNA-B (PBC1v2039) (3) to amplify a 647-bp fragment. Sequence comparison for the common region (134 nt from the rep gene start codon toward the 3' end) from the DNA-B sequence had 88% nt identity to the DNA-A sequence, thus indicating that this geminivirus is bipartite. These sequence analyses indicated that this geminivirus isolated from R. minima is distinct from previously described geminiviruses, and we propose the name Rhynchosia golden mosaic virus (RGMV). From rep gene sequence alignments, RGMV has an apparent genome recombination between Old and New World geminiviruses (Tomato yellow leaf curl virus and Bean dwarf mosaic virus) as previously noted for PHV (2). Our results indicate that RGMV is a distinct geminivirus from BGYMV, and, thus, additional studies are needed to establish the importance of R. minima as a reservoir for vegetable-infecting geminiviruses. This study is the first report of another virus in the PHV phylogenetic cluster and is thus of importance in the understanding of recombinant viruses and their phylogenetic relationship to other characterized geminiviruses. References: (1) J. C. Faria et al. Phytopathology 84:321, 1994. (2) M. Padidam et al. Virology 265:218, 1999. (3) M. R. Rojas et al. Plant Dis. 77:340, 1993. (4) S. Wyatt and J. K. Brown. Phytopathology 86:1288, 1996.

Precursor processing of pro-ISG15/UCRP, an interferon-beta-induced ubiquitin-like protein.

Induction of the 17-kDa ubiquitin-like protein ISG15/UCRP and its subsequent conjugation to cellular targets is the earliest response to type I interferons. The polypeptide is synthesized as a precursor containing a carboxyl-terminal extension whose correct processing is required for subsequent ligation of the exposed mature carboxyl terminus. Recombinant pro-ISG15 is processed in extracts of human lung fibroblasts by a constitutive 100-kDa enzyme whose activity is unaffected by type I interferon stimulation. The processing enzyme has been purified to apparent homogeneity by a combination of ion exchange and hydrophobic chromatography and found to be stimulated 12-fold by micromolar concentrations of ubiquitin. Analysis of the products of pro-ISG15 processing enzyme demonstrates specific cleavage exclusively at the Gly(157)-Gly(158) peptide bond to generate a mature ISG15 carboxyl terminus. Irreversible inhibition of pro-ISG15 processing activity by thiol-specific alkylating agents and a pH rate dependence conforming to titration of a single group of pK(a) 8.1 indicate the 100-kDa enzyme is a thiol protease. Partial sequencing of a trypsin-derived peptide indicates the enzyme is either the human ortholog of yeast Ubp1 or a Ubp1-related protein. As yeast do not contain ISG15, these results suggest that a ubiquitin-specific enzyme was recruited for pro-ISG15/UCRP processing by adaptive divergence.

Radiocontrast interference in screening tests for genetic-metabolic diseases.

Screening tests for genetic metabolic diseases remain extremely useful due to their rapidity, ease of interpretation and substantial reduction of cost. However, interferences in these tests are still a source of concern in laboratory medicine. Cost considerations have so compressed the duration of the medical work-up that the administration of radiologic contrast may often antedate the collection of body fluids for genetic-metabolic testing. It has been found that under these circumstances, certain contrast media may interfere with the urinary studies of amino acids, organic acids, and tests involving ultraviolet absorption such as those concerned with purines, pyrimidines, and related compounds. The consequences of interference may be misdiagnosis, repeated testing, extensive and expensive work-ups, and unnecessary delay and anxiety for the family. As in all testing, it is prudent to avoid medications and atypical diets, if possible. In the case of contrast media, it is a simple matter to collect samples for analysis prior to the administration of radiocontrast so as to avoid the pitfalls and yet not delay the diagnostic work-up.

Tracing gluconeogenesis with deuterated water: measurement of low deuterium enrichments on carbons 6 and 2 of glucose.

The contribution of gluconeogenesis to glucose production in vivo can be measured by enriching body water with 0.5% 2H2O and measuring the glucose labeling ratio C6/C2 (Landau et al., J. Clin. Invest. 95, 172-178, 1995). We present further refinements of the measurements of the 2H enrichments on C6 and C2 of glucose. The transfer of 2H from C6 of glucose to hexamethylenetetramine (HMT) and extraction in preparation for gas chromatography-mass spectrometry can be done in a single test tube, without distillation of the intermediate formaldehyde. In addition, extraction of small amounts of HMT is greatly improved by making a HMT-iodine adduct. For C2, glucose is reduced to sorbitol, and 2H on C2 is transferred enzymatically to [U-13C3]pyruvate, forming [U-13C3,2-2H]lactate. The latter is assayed by negative chemical ionization gas chromatography-mass spectrometry of the pentafluorobenzyl derivative. The natural enrichment of the [U-13C3]lactyl ion is only 0.4%, allowing measurements of 2H enrichment down to 0.1%. These techniques were used in dogs infused with 2H2O and in isolated rat livers perfused with buffer containing 1 to 5% 2H2O. Our data reveal a difference in the rate of labeling of C6 and C2 of glucose in vivo. Lastly, in cows infused with [6,6-2H2]glucose, we show that the turnover of glucose can be economically measured by assaying low tracer enrichment (down to 0.1%) via hexamethylenetetramine.

Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin.

The biological effect of type 1 interferons is proposed to arise in part from the conjugation of ubiquitin cross-reactive protein (UCRP), the ISG15 gene product, to intracellular target proteins in a process analogous to that of its sequence homolog ubiquitin, a highly conserved 8.6-kDa polypeptide whose ligation marks proteins for degradation via the 26 S proteasome. Inclusion of CoCl2 during the purification of recombinant UCRP blocks the proteolytic inactivation of the polypeptide occurring by cleavage of the carboxyl-terminal glycine dipeptide required for activation and subsequent ligation. Intact UCRP supports a low rate of ubiquitin-activating enzyme (E1)-dependent ATP:PPi exchange but fails to form a stoichiometric E1-UCRP thiol ester or undergo transfer to ubiquitin carrier protein (E2). The binding affinity of E1 for UCRP is significantly diminished relative to that of ubiquitin. These results suggest that UCRP conjugation proceeds through an enzyme pathway distinct from that of ubiquitin, at least with respect to the step of activation. This was confirmed for an in vitro conjugation assay in which 125I-UCRP could be ligated in an ATP-dependent reaction to proteins present within an A549 human lung carcinoma cell extract and could be competitively inhibited by excess unlabeled UCRP but not ubiquitin. Other results demonstrate that 125I-UCRP conjugation is significantly increased in cell extracts after 24 h of incubation in the presence of interferon-beta, consistent with the late induction of UCRP conjugating activity. Thus, interferon-responsive cells contain a pathway for UCRP ligation that is parallel but distinct from that of ubiquitin.

Neonatal glycine encephalopathy: biochemical and neuropathologic findings.

A patient with neonatal glycine encephalopathy who had severe neurologic retardation, spasticity, and seizures died at 17 years of age. Glycine concentration was markedly elevated in brain tissue, especially in the cerebellum. Neuropathologic study revealed spongy myelinopathy throughout the central nervous system and calcium oxalate crystals in the cerebellum, which are probably derived from degradation of glycine. Myelinopathy appeared to be static compared to neonatal patients. The neurologic manifestations of neonatal glycine encephalopathy are probably due to neurotransmitter abnormalities, not to myelin damage.