Effect of second timed appointments for non-attenders of breast cancer screening in England : a randomised controlled trial

BACKGROUND: In England, participation in breast cancer screening has been decreasing in the past 10 years, approaching the national minimum standard of 70%. Interventions aimed at improving participation need to be investigated and put into practice to stop this downward trend. We assessed the effect on participation of sending invitations for breast screening with a timed appointment to women who did not attend their first offered appointment within the NHS Breast Screening Programme (NHSBSP). METHODS: In this open, randomised controlled trial, women in six centres in the NHSBSP in England who were invited for routine breast cancer screening were randomly assigned (1:1) to receive an invitation to a second appointment with fixed date and time (intervention) or an invitation letter with a telephone number to call to book their new screening appointment (control) in the event of non-attendance at the first offered appointment. Randomisation was by SX number, a sequential unique identifier of each woman within the NHSBSP, and at the beginning of the study a coin toss decided whether women with odd or even SX numbers would be allocated to the intervention group. Women aged 50-70 years who did not attend their first offered appointment were eligible for the analysis. The primary endpoint was participation (ie, attendance at breast cancer screening) within 90 days of the date of the first offered appointment; we used Poisson regression to compare the proportion of women who participated in screening in the study groups. All analyses were by intention to treat. This trial is registered with Barts Health, number 009304QM. FINDINGS: We obtained 33 146 records of women invited for breast cancer screening at the six centres between June 2, 2014, and Sept 30, 2015, who did not attend their first offered appointment. 26 054 women were eligible for this analysis (12 807 in the intervention group and 13 247 in the control group). Participation within 90 days of the first offered appointment was significantly higher in the intervention group (2861 [22%] of 12 807) than in the control group (1632 [12%] of 13 247); relative risk of participation 1·81 (95% CI 1·70-1·93; p<0·0001). INTERPRETATION: These findings show that a policy of second appointments with fixed date and time for non-attenders of breast screening is effective in improving participation. This strategy can be easily implemented by the screening sites and, if combined with simple interventions, could further increase participation and ensure an upward shift in the participation trend nationally. Whether the policy should vary by time since last attended screen will have to be considered. FUNDING: National Health Service Cancer Screening Programmes and Department of Health Policy Research Programme

Clinical Practice Recommendations for the Management and Prevention of Cisplatin-Induced Hearing Loss Using Pharmacogenetic Markers

Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field, (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment, and management of cisplatin-induced hearing loss in children and adults, and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature, and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin-based chemotherapy

Conditional Gene Targeting in Mouse Pancreatic β-Cells: Analysis of Ectopic Cre Transgene Expression in the Brain

B. W. and M. B. Contributed equally to this manuscript Corresponding authors

Incidence of Isolated Biliary Atresia during the COVID Lockdown in Europe: Results from a Collaborative Project by RARE-Liver

Background: Biliary atresia (BA) is a rare cholangiopathy where one of the proposed aetiological mechanisms is an infectious viral trigger. Coronavirus disease-19 (COVID) lockdown restrictions were implemented to reduce the transmission of infections. Strictness of lockdown varied across European countries. This study aimed to investigate if there was an association between strictness of lockdown and change in isolated BA (IBA) incidence in Europe. Methods: We approached European centres involved in the European Reference Network RARE-LIVER. We included IBA patients born between 2015 and June 2020. We calculated the number of IBA patients born per centre per month. The Stringency Index (SI) was used as lockdown strictness indicator. The association between percentage change of mean number of IBA patients born per month and the SI was assessed. Results: We included 412 IBA patients from thirteen different centres. The median number of patients per month did not change: 6 (1–15) pre-lockdown and 7 (6–9) during lockdown (p = 0.34). There was an inverse association between SI and percentage change in IBA (B = -0.73, p = 0.03). Median age at Kasai portoenterostomy (days) did not differ between time periods (51 (9–179) vs. 53 (19–126), p = 0.73). Conclusion: In this European study, a stricter COVID-lockdown was seemingly accompanied by a simultaneous larger decrease in the number of IBA patients born per month in the lockdown. Results should be interpreted with caution due to the assumptions and limitations of the analysis

The CCG-domain-containing subunit SdhE of succinate:quinone oxidoreductase from Sulfolobus solfataricus P2 binds a [4Fe–4S] cluster

In type E succinate:quinone reductase (SQR), subunit SdhE (formerly SdhC) is thought to function as monotopic membrane anchor of the enzyme. SdhE contains two copies of a cysteine-rich sequence motif (CXnCCGXmCXXC), designated as the CCG domain in the Pfam database and conserved in many proteins. On the basis of the spectroscopic characterization of heterologously produced SdhE from Sulfolobus tokodaii, the protein was proposed in a previous study to contain a labile [2Fe–2S] cluster ligated by cysteine residues of the CCG domains. Using UV/vis, electron paramagnetic resonance (EPR), 57Fe electron–nuclear double resonance (ENDOR) and Mössbauer spectroscopies, we show that after an in vitro cluster reconstitution, SdhE from S. solfataricus P2 contains a [4Fe–4S] cluster in reduced (2+) and oxidized (3+) states. The reduced form of the [4Fe–4S]2+ cluster is diamagnetic. The individual iron sites of the reduced cluster are noticeably heterogeneous and show partial valence localization, which is particularly strong for one unique ferrous site. In contrast, the paramagnetic form of the cluster exhibits a characteristic rhombic EPR signal with gzyx = 2.015, 2.008, and 1.947. This EPR signal is reminiscent of a signal observed previously in intact SQR from S. tokodaii with gzyx = 2.016, 2.00, and 1.957. In addition, zinc K-edge X-ray absorption spectroscopy indicated the presence of an isolated zinc site with an S3(O/N)1 coordination in reconstituted SdhE. Since cysteine residues in SdhE are restricted to the two CCG domains, we conclude that these domains provide the ligands to both the iron–sulfur cluster and the zinc site

Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1-(3′,4′,5′-Trimethoxyphenyl)-2-Aryl-1H-Imidazole

A novel series of tubulin polymerization inhibitors, based on the 1-(3',4',5'-trimethoxyphenyl)-2-aryl-1H-imidazole scaffold and designed as cis-restricted combretastatin A-4 analogues, was synthesized with the goal of evaluating the effects of various patterns of substitution on the phenyl at the 2-position of the imidazole ring on biological activity. A chloro and ethoxy group at the meta- and para-positions, respectively, produced the most active compound in the series (4o), with IC50 values of 0.4-3.8 nM against a panel of seven cancer cell lines. Except in HL-60 cells, 4o had greater antiproliferative than CA-4, indicating that the 3'-chloro-4'-ethoxyphenyl moiety was a good surrogate for the CA-4 B-ring. Experiments carried out in a mouse syngenic model demonstrated high antitumor activity of 4o, which significantly reduced the tumor mass at a dose thirty times lower than that required for CA-4P, which was used as a reference compound. Altogether, our findings suggest that 4o is a promising anticancer drug candidate that warrants further preclinical evaluation

Integrated pest management of Tuta absoluta: practical implementations across different world regions

The South American tomato pinworm, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae), has invaded most Afro-Eurasian countries and is threatening worldwide tomato production. Various strategies have been developed and implemented to manage this pest. Here, we present a timely review on the up-to-date development and practical implementation of integrated pest management (IPM) programs for tomato crops across different world regions infested by T. absoluta. While insecticide resistance is a growing concern, biological control via releasing or conserving arthropod natural enemies and sex pheromone-based biotechnical control are the most successful management practices. Agronomic control-related research is an emerging area where the soil fertilization and/or irrigation, as well as breeding of resistant cultivars, has the potential to enhance IPM effectiveness. Grower survey responses in the native areas (i.e., South America), early-invaded areas (i.e., first report between 2006 and 2012) and newly invaded areas (i.e., first report after 2012) showed that the control programs evolved along with the areas and time since invasion. Growers in the early-invaded areas shifted more rapidly from chemical control to biological control compared to those from the native area. In all concerned regions, the pest control failure risk following chemical insecticide applications and the high cost associated with either biological or biotechnical control methods have been the greatest concerns for growers. The information gathered from the native and/or early-invaded areas may help achieve a more effective management in newly invaded areas. Lastly, researchers are expected to break the bottlenecks of some key issues that would enable lowering application cost of novel biorational alternative management options

A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors

A series of combretastatin derivatives were designed and synthesised by a two-step stereoselective synthesis by use of Wittig olefination followed by Suzuki cross-coupling. Interestingly, all new compounds (2a-2i) showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, 2a, 2b and 2e were the most active across three cancer cell lines. In addition, these compounds inhibited the polymerisation of tubulin in vitro more efficiently than CA-4. They caused cell cycle arrest in G2/M phase further confirming their ability to inhibit tubulin polymerisation