SMIM1 absence is associated with reduced energy expenditure and excess weight.

BACKGROUND: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments. METHODS: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan. FINDINGS: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure. CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them. FUNDING: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.

Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom.

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency.

Long-term effect of introducing an early warning score on respiratory rate charting on general wards.

The respiratory rate is an early indicator of disease, yet many clinicians underestimate its importance and hospitals report a poor level of respiratory rate recording. We studied the short- and long-term effects of introducing a new patient vital signs chart and the modified early warning score (MEWS), which incorporates respiratory rate on the prevalence of respiratory rate recording in six general wards of our hospital. Prior to the commencement of the study, the average percentage of occupied beds where at least one respiratory rate recording had been made in a single 24-h period was 29.5+/-13.5%. After the introduction of the new vital signs chart to all six wards, and the introduction of MEWS to three wards, this rose to 68.9+/-20.9%. When all six wards had been using both the new chart and the MEWS system for almost 1 year, the figure had reached 91.2+/-5.6%. During the pre-introduction period, there was no difference in the prevalence of respiratory rate recording between the specialties (orthopaedic, 26.9%; surgery, 32.9%; medicine, 29.8%; p=0.118). During the second two audit periods, the prevalence of respiratory rate monitoring was consistently higher on medical wards than on surgical and orthopaedic wards (p<0.001). The study confirms the long-term beneficial effect of introducing the MEWS system on respiratory rate recording into the general wards of our hospital. As respiratory rate abnormalities are early markers of disease, it is hoped that improved monitoring will have an impact on the nature and timeliness of the response to critical illness. This may have an impact on the future incidence of potentially avoidable cardiac arrest, deaths and unanticipated intensive care unit admission.