Tricyclic sesquiterpenes from Eremophila georgei

The structures of three new tricyclic sesquiterpenes from Eremophila georgei are described. The absolute stereochemistry of these sesquiterpenes is shown to be antipodal to that of the zizane sesquiterpenes of vetiver oil.     

Genetic Characterisation of Malawian Pneumococci Prior to the Roll-Out of the PCV13 Vaccine Using a High-Throughput Whole Genome Sequencing Approach

Background

Malawi commenced the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) into the routine infant immunisation schedule in November 2011. Here we have tested the utility of high throughput whole genome sequencing to provide a high-resolution view of pre-vaccine pneumococcal epidemiology and population evolutionary trends to predict potential future change in population structure post introduction.

Methods

One hundred and twenty seven (127) archived pneumococcal isolates from randomly selected adults and children presenting to the Queen Elizabeth Central Hospital, Blantyre, Malawi underwent whole genome sequencing.

Results

The pneumococcal population was dominated by serotype 1 (20.5% of invasive isolates) prior to vaccine introduction. PCV13 is likely to protect against 62.9% of all circulating invasive pneumococci (78.3% in under-5-year-olds). Several Pneumococcal Molecular Epidemiology Network (PMEN) clones are now in circulation in Malawi which were previously undetected but the pandemic multidrug resistant PMEN1 lineage was not identified. Genome analysis identified a number of novel sequence types and serotype switching.

Conclusions

High throughput genome sequencing is now feasible and has the capacity to simultaneously elucidate serotype, sequence type and as well as detailed genetic information. It enables population level characterization, providing a detailed picture of population structure and genome evolution relevant to disease control. Post-vaccine introduction surveillance supported by genome sequencing is essential to providing a comprehensive picture of the impact of PCV13 on pneumococcal population structure and informing future public health interventions.     

Intravenous tyramine response in migraine before and during treatment with indoramin.

We studied the response of 31 migraine sufferers (20 women, 11 men) to intravenous tyramine (the tyraminedose)pressor response test). Patients were treated either with pacebo tablets or indoramin, and alpha-adrenergic blocking agent, in a double-blind crrossover trial. We found that patients with migraine required significantly less tyramine to increase their cystolic blod pressure by 30 mm Hg when compared with matched controls. Indoramin significantly increased the amount of tyramine needed to raise the systolic blood pressure among migraine suffers and reduced the incidence of posttyramine migraine for m 46% while patients were on placebo tablets to 8% when they were receiveing indoramin. There was no association between tyramine sensitivity and a history of premenstrual or dietary migraine, nor was there a significant difference in the indierenence in the incidence of post-tyramine migrain between men women. We conclude that the intravenous tyramine test may be valuable in assessing migraine suffers who will respond to an alpha-advenergic blocking agent such as indoramin.     

Optimising informed consent for participants in a randomised controlled trial in rural Uganda: a comparative prospective cohort mixed-methods study

Background

Poor participant understanding of research information can be a problem in community interventional studies with rural African women, whose levels of illiteracy are high. This study aimed to improve the informed consent process for women living in rural eastern Uganda. We assessed the impact of alternative consent models on participants’ understanding of clinical trial information and their contribution to the informed consent process in rural Uganda.

Methods

The study applied a parallel mixed-methods design for a prospective comparative cohort, nested within a pilot study on the community distribution of an alcohol-based hand rub to prevent neonatal sepsis (BabyGel pilot trial). Women of at least 34 weeks’ pregnancy, suitable for inclusion in the BabyGel pilot trial, were recruited into this study from their homes in 13 villages in Mbale District. As part of the informed consent process, information about the trial was presented using one of three consent methods: standard researcher-read information, a slide show using illustrated text on a flip chart or a video showing the patient information being read as if by a newsreader in either English or the local language. In addition, all women received the patient information sheet in their preferred language. Each information-giving method was used in recruitment for 1 week. Two days after recruitment, women’s understanding of the clinical trial was evaluated using the modified Quality of Informed Consent (QuIC) tool. They were also shown the other two methods and their preference assessed using a 5-point Likert scale. Semi-structured interviews were administered to each participant. The interviews were audio-recorded, transcribed and translated verbatim, and thematically analysed.

Results

A total of 30 pregnant women in their homes participated in this study. Their recall of the trial information within the planned 48 h was assessed for the majority (90%, 27/30). For all three consent models, women demonstrated a high understanding of the study. There was no statistically significant difference between the slide-show message (mean 4.7; standard deviation, SD 0.47; range 4–5), video message (mean 4.9; SD 0.33; range 4–5) and standard method (mean 4.5; SD 0.53; range 4–5; all one-way ANOVA, p =?0.190). The slide-show message resulted in the most objective understanding of question items with the highest average QuIC score of 100 points. For women who had been recruited using any of the three models, the slide show was the most popular method, with a mean score for all items of not less than 4.2 (mean 4.8; SD 0.6; range 4–5). Most women (63%, 19/30) preferred the slide-show message, compared with 17% (5/30) and 20% (6/30) for the standard and video messages, respectively. The reasons given included the benefits of having pictures to aid understanding and the logical progression of the information.

Conclusion

Our results from this small study suggest that slide-show messages may be an effective and popular alternative way of presenting trial information to women in rural Uganda, many of whom have little or no literacy.

Trial registration

ISRCTN, ISRCTN67852437. Registered on 18 March 2018.

     

The Low Fall as a Surrogate Marker of Frailty Predicts Long-Term Mortality in Older Trauma Patients

Background

Frailty is associated with adverse outcomes including disability, mortality and risk of falls. Trauma registries capture a broad range of injuries. However, frail patients who fall comprise a large proportion of the injuries occurring in ageing populations and are likely to have different outcomes compared to non-frail injured patients. The effect of frail fallers on mortality is under-explored but potentially significant. Currently, many trauma registries define low falls as less than three metres, a height that is likely to include non-frailty falls. We hypothesized that the low fall from less than 0.5 metres, including same-level falls, is a surrogate marker of frailty and predicts long-term mortality in older trauma patients.

Methods

Using data from the Singapore National Trauma Registry, 2011–2013, matched till September 2014 to the death registry, we analysed adults aged over 45 admitted via the emergency department in public hospitals sustaining blunt injuries with an injury severity score (ISS) of 9 or more, excluding isolated hip fractures from same-level falls in the over 65. Patients injured by a low fall were compared to patients injured by high fall and other blunt mechanisms. Logistic regression was used to analyze 12-month mortality, controlling for mechanism of injury, ISS, revised trauma score (RTS), co-morbidities, gender, age and age-gender interaction. Different low fall height definitions, adjusting for injury regions, and analyzing the entire adult cohort were used in sensitivity analyses and did not change our findings.

Results

Of the 8111 adults in our cohort, patients who suffered low falls were more likely to die of causes unrelated to their injuries (p<0.001), compared to other blunt trauma and higher fall heights. They were at higher risk of 12-month mortality (OR 1.75, 95% CI 1.18–2.58, p = 0.005), independent of ISS, RTS, age, gender, age-gender interaction and co-morbidities. Falls that were higher than 0.5m did not show this pattern. Males were at higher risk of mortality after low falls. The effect of age on mortality started at age 55 for males, and age 70 for females, and the difference was attributable to the additional mortality in male low-fallers.

Conclusions

The low fall mechanism can optimize prediction of long-term mortality after moderate and severe injury, and may be a surrogate marker of frailty, complementing broader-based studies on aging.     

Characterization of tumor reactivity of human V gamma 9V delta 2 gamma delta T cells in vitro and in SCID mice in vivo

Human Vgamma9Vdelta2 gammadelta T cells are selectively activated by bacterial phosphoantigens and aminobisphosphonates and exert potent cytotoxicity toward various tumor cells. In this study we have characterized the cytotoxic reactivity of gammadelta T cell lines established from healthy donors by stimulation with aminobisphosphonate alendronate toward melanoma MeWo and pancreatic adenocarcinomas Colo357 and PancTu1 lines in vitro and in vivo upon adoptive transfer into SCID mice. Lysis of all tumor cells was enhanced when gammadelta effector cells were preactivated with phosphoantigens. Recognition of MeWo was TCR dependent, as shown by anti-TCR Ab blockade, whereas only the phosphoantigen-mediated increased, but not the basal, lysis of Colo357 and PancTu1 was inhibited by anti-TCR Ab. Furthermore, lysis of Colo357, but not that of MeWo or PancTu1, was completely inhibited by the pan-caspase inhibitor zVAD, indicating different recognition and effector mechanisms involved in the gammadelta T cell/tumor cell interactions. Upon transfer into SCID mice, alendronate-activated gammadelta T cells given together with IL-2 and alendronate significantly prolonged the survival of SCID mice inoculated with human tumor cells. The best results were thus obtained when gammadelta T cells were repetitively given five times over a period of 30 days. With this protocol, human gammadelta T cells prolonged the mean survival of mice inoculated with MeWo melanoma from 28.5 to 87.3 days (p < 0.0001) and in the case of PancTu1 adenocarcinoma from 23.0 to 48.4 days (p < 0.0001). We conclude that an effective gammadelta T cell-based immunotherapy might require activation of endogenous gammadelta T cells with aminobisphosphonate (or phosphoantigen) and IL-2, followed by adoptive transfer of in vitro expanded gammadelta T cells.     

Application and investigation of a bound for outcome reporting bias

Self-care interventions are promoted as effective strategies for improving the quality of life and health outcomes for individuals with long-term health conditions. Outcome measures used in evaluations using Randomised Controlled Trials (RCTs) are not designed to consider patients' prior management strategies and experience of illness. Yet the experience of illness literature suggests that adjusting to living with chronic illness, together with broader contextual influences, are likely to be relevant to understanding responses to self-management initiatives. Using group and individual interview data we attempt to illuminate the transposition of IBS from a condition unsatisfactorily managed by medicine to one successfully managed within the life worlds of individuals. If routine embedding of complex interventions depends on the accomplishment of integration and workability in patients' everyday lives then the design and evaluation of such interventions should view participation as part of a process of continuity as well as change. Responses to formal self-management can be extended beyond psychological and other quantitatively measured outcomes. A useful addendum to trial outcomes for self-management education is an understanding of change as being inextricably linked to people's previous attempts to, and experience of, managing long-term conditions. We suggest that the benefits of understanding the prior experience of managing illness and contact with health services include the acceptability and workability of complex interventions in patients' everyday lives.