Introduction Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722–9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia. Methods We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants’ blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures. Results Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9–1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019). Conclusion In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass.

BACKGROUND:Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia.METHODS:We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial.RESULTS:Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone.CONCLUSION:These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

This chapter presents a critical review of the potential benefits of theophylline as a means to reduce the burden of post-acute inflammation in older age groups. A pro-inflammatory state often persists, or is extended, after sepsis, trauma and other acute illnesses in old age, particularly above the age of 80 years. The presence of inflammation at above-baseline amplitudes or excessive duration is associated with a higher likelihood of delirium, anorexia, unplanned weight loss, lethargy, depression, weakness and other markers of frailty. There is also an association with less favourable clinical outcomes and a higher risk of losing personal independence. Theophylline has been shown to have an anti-inflammatory effect, probably mediated through the induction of histone deacetylase-dependent gene switching in immune competent cells, that has been observed at cellular and whole organism levels. The main effects are a reduction in the production and release of TNF, IL-1 and IL-6, with a sequential fall in CRP and increase in IL-10, and a change of immune cells to their anti-inflammatory phenotypes. This happens when theophylline levels are between 5 and 10 mg/L, which is lower than the range for bronchodilators (10 to 15 mg/L) and presents a relatively low risk of toxicity. We hypothesize that low-dose theophylline treatment given to elderly subjects with acute inflammation, for example due to respiratory infection, septicaemia or trauma, will change the setting of their biochemical status from an inappropriately extended pro-inflammatory pattern toward a more normalized baseline pattern and consequently reduce the risk of adverse clinical outcomes.

BACKGROUND:Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study.METHODS:Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables.RESULTS:Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo.CONCLUSION:Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Abstract Background This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. Methods Placebo‐controlled, parallel group, double‐blind, randomized two‐by‐two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4 m walk) and/or low handgrip strength (women < 20 kg, men < 30 kg) plus low muscle mass (using sex and body mass index category‐specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomized to perindopril 4 mg or placebo, and to oral leucine powder 2.5 g or placebo thrice daily. The primary outcome was the between‐group difference in the short physical performance battery (SPPB) score over 12‐month follow‐up by repeated‐measures mixed models. Results were combined with existing systematic reviews using random‐effects meta‐analysis to derive summary estimates of treatment efficacy. Results We screened 320 people and randomized 145 participants compared with an original target of 440 participants. For perindopril [n = 73, mean age 79 (SD 6), female sex 39 (53%), mean SPPB 7.1 (SD 2.3)] versus no perindopril [n = 72, mean age 79 (SD 6), female sex 39 (54%), mean SPPB 6.9 (SD 2.4)], median adherence to perindopril was lower (76% vs. 96%; P < 0.001). Perindopril did not improve the primary outcome [adjusted treatment effect −0.1 points (95%CI −1.2 to 1.0), P = 0.89]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect −0.4 kg (95%CI −1.1 to 0.3), P = 0.27]. More adverse events occurred in the perindopril group (218 vs. 165), but falls rates were similar. For leucine [n = 72, mean age 78 (SD 6), female sex 38 (53%), mean SPPB 7.0 (SD 2.1)] versus no leucine [n = 72, mean age 79 (SD 6), female sex 40 (55%), mean SPPB 7.0 (SD 2.5)], median adherence was the same in both groups (76% vs. 76%; P = 0.99). Leucine did not improve the primary outcome [adjusted treatment effect 0.1 point (95%CI −1.0 to 1.1), P = 0.90]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect −0.3 kg (95%CI −1.0 to 0.4), P = 0.47]. Meta‐analysis of angiotensin converting enzyme inhibitor/angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB [between‐group difference −0.1 points (95%CI −0.4 to 0.2)]. Conclusions Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta‐analysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

Persisting systemic inflammation of low amplitude is frequently found in elderly people and is a contributary factor to several components of the frailty phenotype, particularly sarcopenia, low mood and higher levels of dependency on others for essential activities, as well as higher all-cause mortality. Older patients with such “inflammaging” have raised baseline concentrations of several pro-inflammatory cytokines in peripheral blood, such as tumor necrosis factor alpha and interleukin-1 beta, and chronically raised C-reactive protein. There is a clear need to identify interventions, including drugs, that can ameliorate such inflammation by helping to re-set the innate immune system to a less inflamed baseline. Several classes of drugs have such properties. The purpose of this chapter is to provide a summary of the background science of the relationship between ageing, inflammation and frailty, then described the established role of methyl-xanthines, particularly theophylline, as immune modulating drugs, then proceeding to propose a case for the use of 4-aminoquinolines, such as chloroquine, in a similar role. The probable mechanisms of anti-inflammatory action for those classes of drugs are compared, leading to a suggestion that formal clinical trials should be conducted of chloroquine as an adjunctive immune modulator for “inflammaging” and persisting post-acute inflammation in old age.

Hospital mortality rates have frequently been improved by identifying diagnostic groups with high mortality and targeting interventions to those specific groups. We found that high residual inpatient mortality persisted after targeted measures had achieved an initial reduction, and that the causes were spread across a wide range of diagnostic groups. Further interventions were put in place consisting of a structured electronic mortality form and systematised mortality scrutiny and reporting (primary intervention) accompanied by a number of quality improvement interventions arising from the mortality analysis (secondary interventions). We found that those interventions were associated with progressive improvements in mortality rates and average lengths of inpatient stay over the 5-year study period. Winter quarter mortality improvements reached a high level of statistical significance but could not be attributed to changes in any particular diagnostic groups. We conclude that progress with mortality improvements is probably best achieved by applying both code-targeted and general interventions simultaneously.

Background: The recently identified SARS-CoV-2 coronavirus has resulted in the Covid-19 pandemic with severe morbidity and high mortality, particularly in certain sections of the population. The co-morbidity patterns associated with adverse outcomes are multiple and complex and there is emerging epidemiological, nutritional and molecular biological evidence that an inadequate vitamin D status is a contributing factor. Objective: The aim was to review the role of vitamin D in immune function with particular reference to the mechanisms whereby it supports immune efficiency, host protection and immune modulation. The evidence for the possible benefit of vitamin D supplementation to ameliorate the severity of respiratory infection by SARS-CoV-2 and other pathogens was also reviewed with a view to making a recommendation. Methods: PubMed, MEDLINE and Google Scholar were searched using the terms: Covid-19, coronavirus, SARS-CoV-2, vitamin D, calcitriol, deficiency, adaptive immunity, innate immunity, ventilation, critical care, intensive care, acute respiratory distress syndrome, cytokine storm, respiratory viruses, respiratory tract infection, respiratory syncytial virus, influenza, supplementation. Papers for inclusion were selected on the basis of relevance and quality. Findings: Vitamin D insufficiency is widespread in many parts of the world. Vitamin D is needed for normal protective and surveillance immune function and there is evidence that deficiency increases the risk of some respiratory infections, probably including Covid-19. By binding with dedicated receptors on immune cells vitamin D influences several strands of immune function, including the production of anti-microbial peptides and several cytokines that promote an appropriate immune response. Vitamin D supplementation probably reduces the risk of respiratory infection, with persuasive biological, epidemiological and observational evidence for possible benefit against Covid-19. Conclusion: Despite the lack of direct evidence specific to Covid-19 a cogent theoretical case can be made for giving adults from selected groups, and arguably all adults, routine supplementation with vitamin D to improve immune efficiency and reduce the incidence and severity of respiratory infections. This could be particularly important in sections of the population with a high prevalence of vitamin D insufficiency. Targeted research is required to provide firm evidence to guide practice.

We performed a retrospective cohort comparison study to look at the processes for concentrating geriatric resources in the acute admissions area in a general hospital in the UK and compare key outcomes. The number of consultant geriatricians and other staff working at the 'front door' - acute medical unit (AMU) and short stay ward (SSW) - was increased. We compared 'front door' outcomes with whole department outcomes in 2013 and 2014, looking at the proportion of patients discharged within 3 and 5 days of admission, the proportion discharged from the 'front door', mean lengths of stay (LOS) and readmissions within 28 days of discharge. There were 1,147 and 1,381 discharge episodes in 2013 and 2014, respectively. 'Front door' discharges rose from 36% to 46% (p<0.001) between 2013 and 2014, and the proportion of 'front door' discharges occurring within 3 days rose from 56% (2013) to 68% (2014), compared with 35% and 33% for the department as a whole (p=0.006). The mean LOS at the 'front door' fell from 6.1 to 3.8 days (p=0.007). Readmissions from 'front door' discharges rose from 12% to 14% (p=0.004). The change in the configuration of the acute geriatric service was associated with more favourable discharge performance outcomes at the 'front door' but modest improvements in discharge performance for the geriatric service as a whole.