Can ENGLAND'S National Health System Reforms Overcome the Neoliberal Legacy?

England's National Health Service (NHS) is in the process of major reform as old institutional structures based around an internal "market" are being replaced with integrated care systems. The changes represent a significant shift in ethos away from commercialisation to collaboration between health providers. But the way that these policies unfold will depend on the context within which they are implemented, and three decades of neoliberal reforms have left their mark on the structure of the health system. This paper shows how a powerful, politically-connected financialised private sector has evolved alongside a weakened public system, depleted further by the pandemic. While the share of overall public health spending reaching the private sector has not increased greatly over the past decade, private financial investors are strongly embedded in some segments of health delivery, particularly mental health services where shareholder returns are boosted by financial engineering. The boundaries between private and public are increasingly blurred with the NHS treating private patients and self-payment for health services is increasingly normalised. Rather than traditional privatisation, the health system is facing a more subtle and pernicious erosion of public services across different dimensions which seems likely to continue despite the new reforms.

Accurate RNA consensus sequencing for high-fidelity detection of transcriptional mutagenesis-induced epimutations.

Transcriptional mutagenesis (TM) due to misincorporation during RNA transcription can result in mutant RNAs, or epimutations, that generate proteins with altered properties. TM has long been hypothesized to play a role in aging, cancer, and viral and bacterial evolution. However, inadequate methodologies have limited progress in elucidating a causal association. We present a high-throughput, highly accurate RNA sequencing method to measure epimutations with single-molecule sensitivity. Accurate RNA consensus sequencing (ARC-seq) uniquely combines RNA barcoding and generation of multiple cDNA copies per RNA molecule to eliminate errors introduced during cDNA synthesis, PCR, and sequencing. The stringency of ARC-seq can be scaled to accommodate the quality of input RNAs. We apply ARC-seq to directly assess transcriptome-wide epimutations resulting from RNA polymerase mutants and oxidative stress.

Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency.

Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are human photosensitive diseases with mutations in the nucleotide excision repair (NER) pathway, which repairs DNA damage from UV exposure. CS is mutated in the transcription-coupled repair (TCR) branch of the NER pathway and exhibits developmental and neurological pathologies. The XP-C group of XP patients have mutations in the global genome repair (GGR) branch of the NER pathway and have a very high incidence of UV-induced skin cancer. Cultured cells from both diseases have similar sensitivity to UV-induced cytotoxicity, but CS patients have never been reported to develop cancer, although they often exhibit photosensitivity. Because cancers are associated with increased mutations, especially when initiated by DNA damage, we examined UV-induced mutagenesis in both XP-C and CS cells, using duplex sequencing for high-sensitivity mutation detection. Duplex sequencing detects rare mutagenic events, independent of selection and in multiple loci, enabling examination of all mutations rather than just those that confer major changes to a specific protein. We found telomerase-positive normal and CS-B cells had increased background mutation frequencies that decreased upon irradiation, purging the population of subclonal variants. Primary XP-C cells had increased UV-induced mutation frequencies compared with normal cells, consistent with their GGR deficiency. CS cells, in contrast, had normal levels of mutagenesis despite their TCR deficiency. The lack of elevated UV-induced mutagenesis in CS cells reveals that their TCR deficiency, although increasing cytotoxicity, is not mutagenic. Therefore the absence of cancer in CS patients results from the absence of UV-induced mutagenesis rather than from enhanced lethality.

Sequencing small genomic targets with high efficiency and extreme accuracy.

The detection of minority variants in mixed samples requires methods for enrichment and accurate sequencing of small genomic intervals. We describe an efficient approach based on sequential rounds of hybridization with biotinylated oligonucleotides that enables more than 1-million-fold enrichment of genomic regions of interest. In conjunction with error-correcting double-stranded molecular tags, our approach enables the quantification of mutations in individual DNA molecules.

Accuracy of Next Generation Sequencing Platforms.

Next-generation DNA sequencing has revolutionized genomic studies and is driving the implementation of precision diagnostics. The ability of these technologies to disentangle sequence heterogeneity, however, is limited by their relatively high error rates. A Several single molecule barcoding strategies have been propose to reduce the overall error frequency. A Duplex Sequencing additionally exploits the fact that DNA is double-strand, with one strand reciprocally encoding the sequence information of its complement, and can eliminate nearly all sequencing errors by comparing the sequence of individually tagged amplicons derived from one strand of DNA with that of its complementary strand. This method reduces errors to fewer than one per ten million nucleotides sequenced.

Randomised, double-blind, placebo-controlled trial to determine whether steroids reduce the incidence and severity of nephropathy in Henoch-Schonlein Purpura (HSP).

BACKGROUND: The long-term prognosis of Henoch-Schönlein Purpura (HSP) is predominantly determined by the extent of renal involvement. There is no consensus as to whether treatment with prednisolone at presentation can prevent or ameliorate the progression of nephropathy in HSP. METHODS: Children under 18 years of age with new-onset HSP were randomly assigned to receive prednisolone or placebo for 14 days. The primary outcomes were (a) the presence of proteinuria at 12 months (defined as urine protein : creatinine ratio (UP : UC) >20 mg/mmol) and (b) the need for additional treatment (defined as the presence of hypertension requiring treatment or renal biopsy anomalies or the need for treatment of renal disease) during the 12 month study period. RESULTS: 352 children were randomised. Of those patients with laboratory UP : UC results available at 12 months, 18/123 (15%) patients on prednisolone and 13/124 (10%) patients on placebo had UP : UC >20 mg/mmol. There was no significant difference in the proportion of patients with UP : UC >20 mg/mmol at 12 months between the treatment groups (OR (prednisolone/placebo)=1.46, 95% CI 0.68 to 3.14, n=247), even after adjusting for baseline proteinuria and medications known to affect proteinuria (adjusted OR=1.29, 95% CI 0.58 to 2.82, n=247). Similarly, there was no significant difference in the time needed for additional treatment between the two groups (hazard ratio (HR) (prednisolone/placebo)=0.53, 95% CI 0.18 to 1.59, n=323). CONCLUSIONS: This is the largest trial of the role of steroids in children with HSP. We found no evidence to suggest that early treatment with prednisolone reduces the prevalence of proteinuria 12 months after disease onset in children with HSP. TRIAL REGISTRATION NUMBER: ISRCTN71445600.

On-pump coronary surgery with and without cardioplegic arrest: comparison of inflammation, myocardial, cerebral and renal injury and early and late health outcome in a single-centre randomised controlled trial.

OBJECTIVE: To assess the safety and efficacy of on-pump beating heart coronary surgery on organ function, and early and late health outcome as compared with conventional technique. METHODS: A total of 81 patients were randomised to (1) coronary surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest (CA) (on-pump with CA, n=41) or to (2) CPB without CA (on-pump without CA, n=40). Primary outcomes included serial measurement of interleukins (IL-6, IL-8 and IL-10) for inflammation, troponin I for myocardial injury, protein S100 for cerebral injury and creatinine clearance (CrCl) and urinary N-acetyl-ß-d-glucosaminidase (NAG) for renal injury. In-hospital health outcome and 5-year event-free survival were secondary outcomes. RESULTS: Baseline and intra-operative characteristics were similar between groups. A marked release of ILs was observed in both groups, but no significant differences between the groups were found (IL-6 +9%, 95% confidence interval (CI) -15% to +39%, p=0.49; IL-8 +4%, 95% CI -34% to +63%, p=0.86; IL-10 -0.1%, 95% CI -19% to +21%, p=0.93). Troponin I rose in both groups and was on average 34% higher in the on-pump without CA group but this did not reach statistical significance (95% CI -0.4% to +87%, p=0.08). S100 protein was higher in the on-pump without CA group at 12h (p=0.04) but did not differ at other times (p=0.16). The level of CrCl was higher 1h in the on-pump without CA group (+23%, 95% CI +1% to +50%, p=0.04), but not thereafter. NAG release was similar in both groups (+1% 95% CI -23% to +33%, p=0.91). Early and 5-year health outcomes were similar. CONCLUSIONS: On-pump without CA coronary surgery does not provide any obvious advantage when compared with the conventional technique of on-pump with CA in elective patients. Both techniques provide a comparable degree of inflammatory activation, myocardial, cerebral and renal injury with similar 5-year event-free survival.

Prospective randomized comparison of CarboMedics and St. Jude Medical bileaflet mechanical heart valve prostheses: ten-year follow-up.

OBJECTIVE: This is the final report of a randomized controlled trial comparing the performance of CarboMedics (CarboMedics Inc., Austin, Tex) and St. Jude Medical (St. Jude Medical Inc, St Paul, Minn) bileaflet mechanical heart valve prostheses 10 years after surgery. METHODS: Between 1992 and 1996, 485 patients undergoing mechanical heart valve replacement were randomized to receive CarboMedics (n = 234) or St. Jude Medical (n = 251) prostheses for aortic (n = 288), mitral (n = 160), or double (n = 37) valve replacements. Patients were followed annually to the end of 2004. RESULTS: Demographic, preoperative, and operative characteristics were similar between the 2 groups. The median follow-up was 10 years in both groups (CarboMedics 99% complete, St. Jude Medical 98% complete; 3879 patient-years of follow-up). Overall, 165 patients died, 25 of valve-related causes. Ten-year survivals were 66.4% (95% confidence interval: 59.6%-72.3%) and 64.7% (95% confidence interval: 58.0%-70.6%) in the CarboMedics and St. Jude Medical groups, respectively (P = .94). Freedom at 10 years from valve-related mortality was 95.0% (95% confidence interval: 90.8%-97.3%) in the CarboMedics group and 93.0% (95% confidence interval: 88.3%-95.9%) in the St. Jude Medical group. During follow-up, 34 patients had a thromboembolic event, 79 patients had at least 1 bleeding event, and 14 patients required reoperation. There were no significant differences between the groups with respect to freedom from complications (P > or = .12); freedom from thromboembolism at 10 years (CarboMedics: 91.5%, 95% confidence interval: 86.5%-94.7%; St. Jude Medical: 92.2%, 95% confidence interval: 87.5%-95.2%); freedom from bleeding events (CarboMedics: 83.0%, 95% confidence interval: 76.6%-87.8%; St. Jude Medical: 77.5%, 95% confidence interval: 71.1%-82.7%); and freedom from death or valve-related complication (CarboMedics: 51.6%, 95% confidence interval: 44.7%-58.0%; St. Jude Medical: 46.2%, 95% confidence interval: 39.7%-52.4%). Linearized rates per patient-year were 1.1% in the CarboMedics group and 0.8% in the St. Jude Medical group for thromboembolism; 2.3% in the CarboMedics group and 3.2% in the St. Jude Medical group for bleeding events; and 0.72% in the CarboMedics group and 0.47% in the St. Jude Medical group for nonstructural valve dysfunction. International normalized ratio values were similar between the 2 groups throughout the study period. CONCLUSION: At 10 years, the clinical outcome was similar with respect to these 2 mechanical bileaflet prostheses.