Analysis and Reporting of Randomized Trials in Cleft Palate Surgery: Learning from the Timing of Primary Surgery (TOPS) Trial

\ua9 2024, American Cleft Palate Craniofacial Association.The Timing of Primary Surgery (TOPS) trial was published August 2023 in the New England Journal of Medicine and is a milestone achievement for a study focused on cleft palate. Due to the complexity of outcome reporting in cleft and the rarity of such comparative trials, TOPS presents a useful opportunity to critically review the design, analysis and reporting strategies utilised. This perspective article focused on the inclusion of participants, the choice of the primary outcome measure and the analysis of ordinal data within the trial. Considerations for future comparative studies in cleft care are discussed

Dimerisation induced formation of the active site and the identification of three metal sites in EAL-phosphodiesterases

The bacterial second messenger cyclic di-3′,5′-guanosine monophosphate (c-di-GMP) is a key regulator of bacterial motility and virulence. As high levels of c-di-GMP are associated with the biofilm lifestyle, c-di-GMP hydrolysing phosphodiesterases (PDEs) have been identified as key targets to aid development of novel strategies to treat chronic infection by exploiting biofilm dispersal. We have studied the EAL signature motif-containing phosphodiesterase domains from the Pseudomonas aeruginosa proteins PA3825 (PA3825EAL) and PA1727 (MucREAL). Different dimerisation interfaces allow us to identify interface independent principles of enzyme regulation. Unlike previously characterised two-metal binding EAL-phosphodiesterases, PA3825EAL in complex with pGpG provides a model for a third metal site. The third metal is positioned to stabilise the negative charge of the 5′-phosphate, and thus three metals could be required for catalysis in analogy to other nucleases. This newly uncovered variation in metal coordination may provide a further level of bacterial PDE regulation

The cost-effectiveness of follow-up strategies after cancer treatment: a systematic literature review

Introduction: The cost of treatment and follow-up of cancer patients in the UK is substantial. In a budget-constrained system such as the NHS, it is necessary to consider the cost-effectiveness of the range of management strategies at different points on cancer patients' care pathways to ensure that they provide adequate value for money. Sources of data: We conducted a systematic literature review to explore the cost-effectiveness of follow-up strategies of patients previously treated for cancer with the aim of informing UK policy. All papers that were considered to be economic evaluations in the subject areas described above were extracted. Areas of agreement: The existing literature suggests that intensive follow-up of patients with colorectal disease is likely to be cost-effective, but the opposite holds for breast cancer. Areas of controversy: Interventions and strategies for follow-up in cancer patients were variable across type of cancer and setting. Drawing general conclusions about the cost-effectiveness of these interventions/strategies is difficult. Growing points: The search identified 2036 references but applying inclusion/exclusion criteria a total of 44 articles were included in the analysis. Breast cancer was the most common (n = 11) cancer type followed by colorectal (n = 10) cancer. In general, there were relatively few studies of cost-effectiveness of follow-up that could influence UK guidance. Where there was evidence, in the most part, NICE guidance broadly reflected this evidence. Areas timely to develop research: In terms of future research around the timing, frequency and composition of follow-ups, this is dependent on the type of cancer being considered. Nevertheless, across most cancers, the possibility of remote follow-up (or testing) by health professionals other than hospital consultants in other settings appears to warrant further work

Chemical Behavior and Reaction Kinetics of Sulfur and Nitrogen Half-Mustard and Iprit Carbonate Analogues

Sulfur and nitrogen mustards are very toxic, yet versatile organic molecules with numerous applications. Herein, we report on a synthesis of a new class of green compounds, i.e., half-mustard and iprit carbonates, that result in new, unexplored, and safe molecules. Their chemical behavior with several nucleophiles and their reaction kinetics have been investigated

Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project

We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor-binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor-binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome

Ampligen therapy, exercise capacity and immune function in patients with chronic fatigue syndrome

Chronic Fatigue Syndrome (CFS) is a debilitating illness that is characterized by pervasive fatigue, sleep disturbance, neurocognitive problems, joint and muscle pain and numerous other symptoms. Results from CFS treatment studies are equivocal. The purpose of this study was to examine the effects of Ampligen® therapy on immune function and functional capacity in a group of patients with CFS. Natural killer cell number and activity, the activity of the 2-SA pathway, and results of serial cardiopulmonary exercise tests were examined for a total of seven subjects (n=7). A key finding was the normalization of RNase L. Only one subject demonstrated both a normalization in RNase L and increase in exercise performance. Trends in NK cell activity were difficult to determine. Improvements in functional capacity as measured by peak V02were seen in five subjects, but these improvements were minor. The expected improvement in both the immune system as measured by RNase L and NK cell function, and improvement in functional capacity were not seen in this study. This confirms that CFS is a very complicated syndrome and that more research is needed. Ampligen® may have been responsible for the RNase L normalization observed in some patients but NK cells seemed unaffected. It could be that Ampligen® is helping the immune system fight viruses present in the CFS subjects. Improvements in peak V02 were small but deconditioning in subjects might be a possible explanation. The exact cause of CFS remains unknown but with continued research it may yet be possible to increase our understanding of CFS

Ampligen therapy, exercise capacity and immune function in patients with chronic fatigue syndrome

Chronic Fatigue Syndrome (CFS) is a debilitating illness that is characterized by pervasive fatigue, sleep disturbance, neurocognitive problems, joint and muscle pain and numerous other symptoms. Results from CFS treatment studies are equivocal. The purpose of this study was to examine the effects of Ampligen® therapy on immune function and functional capacity in a group of patients with CFS. Natural killer cell number and activity, the activity of the 2-SA pathway, and results of serial cardiopulmonary exercise tests were examined for a total of seven subjects (n=7). A key finding was the normalization of RNase L. Only one subject demonstrated both a normalization in RNase L and increase in exercise performance. Trends in NK cell activity were difficult to determine. Improvements in functional capacity as measured by peak V02were seen in five subjects, but these improvements were minor. The expected improvement in both the immune system as measured by RNase L and NK cell function, and improvement in functional capacity were not seen in this study. This confirms that CFS is a very complicated syndrome and that more research is needed. Ampligen® may have been responsible for the RNase L normalization observed in some patients but NK cells seemed unaffected. It could be that Ampligen® is helping the immune system fight viruses present in the CFS subjects. Improvements in peak V02 were small but deconditioning in subjects might be a possible explanation. The exact cause of CFS remains unknown but with continued research it may yet be possible to increase our understanding of CFS