Meningococcal vaccination in primary care amongst adolescents in North West England:an ecological study investigating associations with general practice characteristics

Background In 2015 the meningococcal ACWY (MenACWY) vaccination was introduced amongst adolescents in England following increased incidence and mortality associated with meningococcal group W. Methods MenACWY vaccination uptake data for 17-18 years old and students delivered in primary care were obtained for 20 National Health Service clinical commissioning groups (CCGs) via the ImmForm vaccination system. Data on general practice characteristics, encompassing demographics and patient satisfaction variables, were extracted from the National General Practice Profiles resource. Univariable analysis of the associations between practice characteristics and vaccination was performed, followed by multivariable negative binomial regression. Results Data were utilized from 587 general practices, accounting for similar to 8% of all general practices in England. MenACWY vaccination uptake varied from 20.8% to 46.8% across the CCGs evaluated. Upon multivariable regression, vaccination uptake increased with increasing percentage of patients from ethnic minorities, increasing percentage of patients aged 15-24 years, increasing percentage of patients that would recommend their practice and total Quality and Outcomes Framework achievement for the practice. Conversely, vaccination uptake decreased with increasing deprivation. Conclusions This study has identified several factors independently associated with MenACWY vaccination in primary care. These findings will enable a targeted approach to improve general practice-level vaccination uptake

Ostracoda from Lee Point on Shoal Bay, Northern Australia: part 3, podocopina (cytheracea)

The littoral environments present in Shoal Bay, Northern Territory (Australia) show a high diversity of ostracods cyther&aacute;ceos (51 genera and 97 species). Probably this diversity is due to three factors: (1) marine environments warm and well oxygenated leading to a high level of biological productivity, (2) shallow marine environments favorable for the accumulation of material conch&iacute;fero post mortem, and (3) a location central in the way of dispersal on the continental shelf between the regions of the Pacific and Southeast Asia. A particular feature of this fauna Cytherscea is that some genres, such as Alocopocythere, can be traced back to the Cretaceous when it first appeared in the shallow waters of the Tethys. In this overlay component of the ancient ostracods are the dominant fauna in partnerships of the modern Indo / Pacific, such as gender Keiji. While the Cytheracea ostracods are the dominant groups, especially the Cypridacea marine Bairdiacea and Plstycopina, are well represented and are quite different (fide Whatley et al., 1995, 1996). We describe here a new genre, Paraxestoleberis, and 15 new species: Dentiby&iacute;here multituberosa, Dampiercythere papillolineata, Neocy&iacute;heromorpha papilloporosa, Loxoconcha catas&iacute;eros, Semicyrherura gamma, Callistocy&iacute;here cookei, Loxocorniculum koolpionyahensis, Ke&uacute;ia interim, K. profundosculpia, K. parademissa, Quasibradleya leepoin&iacute;ensis, Actinocy&iacute;hereis gippsi, Henryhowella sinespinosa, Pon&iacute;icocy&iacute;hereis spatulospinosa and Paraxestoleberis posteroacuminata. Due to the limited material obtained, 16 species are kept in open nomenclature: Bythoceratina sp. Corallicy&iacute;here sp. Venericythere sp. Tanella sp. Loxocorniculum sp. 1 L. sp. 2, Gambiella sp. Javanella sp. Paradoxostoma sp. Neomonoceratina sp., Bradley (sl) sp. Echinocytbereis (sl) sp. Pla&iacute;ycy&iacute;hereis? sp. Alocopocy&iacute;here sp. Xestoleberis sp. and Paraxestoleberis sp. The remaining 66 species have been described previously in other areas.<br /

The mTOR regulated RNA-binding protein LARP1 requires PABPC1 for guided mRNA interaction.

The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth, integrating multiple signalling cues and pathways. Key among the downstream activities of mTOR is the control of the protein synthesis machinery. This is achieved, in part, via the co-ordinated regulation of mRNAs that contain a terminal oligopyrimidine tract (TOP) at their 5'ends, although the mechanisms by which this occurs downstream of mTOR signalling are still unclear. We used RNA-binding protein (RBP) capture to identify changes in the protein-RNA interaction landscape following mTOR inhibition. Upon mTOR inhibition, the binding of LARP1 to a number of mRNAs, including TOP-containing mRNAs, increased. Importantly, non-TOP-containing mRNAs bound by LARP1 are in a translationally-repressed state, even under control conditions. The mRNA interactome of the LARP1-associated protein PABPC1 was found to have a high degree of overlap with that of LARP1 and our data show that PABPC1 is required for the association of LARP1 with its specific mRNA targets. Finally, we demonstrate that mRNAs, including those encoding proteins critical for cell growth and survival, are translationally repressed when bound by both LARP1 and PABPC1

A Phase I/II trial of Oral SRA737 (a Chk1 Inhibitor) given in combination with low-dose gemcitabine in patients with advanced cancer

Purpose: This was a phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737. Patients and Methods: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16 and 17, and intravenous gemcitabine on days 1, 8 and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors. Results: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia and thrombocytopenia were grade ≥3 in 8.3% to 11.7% of patients treated at the RP2D. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer. Conclusions: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

From the European Medicines Agency to Project Orbis: new activities and challenges to facilitate UK oncology drug approval following Brexit.

The departure of the UK from the European Union (EU) and affiliated European regulatory bodies, including the European Medicines Agency, on Dec 31, 2020, has resulted in the Medicines and Healthcare products Regulatory Agency becoming an independent national regulator. This change has required a fundamental transformation of the UK drug regulatory landscape, creating both opportunities and challenges for future development of oncology drugs. New UK pharmaceutical policies have sought to make the UK an attractive market for drug development and regulatory review, by offering expedited review pathways coupled to strong collaborative relations with other leading international medicines regulators, outside of Europe. Oncology is a key global therapy area for both drug development and regulatory approval, and the UK Government has been keen to show regulatory innovation and international collaboration through approval of new cancer medicines. In this Policy Review, we examine the new UK regulatory frameworks, policies, and global collaborations affecting new oncology drug approvals after departure from the EU. We explore some of the challenges that might lie ahead as the UK creates new and independent regulatory review and approval processes for the next generation of cancer medicines