Randomised placebo-controlled trial of continuous sciatic or posterior tibial nerve blockade on pain after major lower limb amputation

Persistent pain after major lower limb amputation is common, with an incidence of up to 80%. 1 Once established, phantom limb pain is very difficult to treat and can have a significant adverse effect on quality of life and rehabilitation. 2 Several techniques including regional anaesthesia, nerve stimulation, ketamine, or nerve stump infiltration with local anaesthetic have been investigated for the prevention or alleviation of long-term pain after amputation, but the data are conflicting and most studies have been very small

Severity of cystoid macular oedema in preterm infants observed using hand-held spectral domain optical coherence tomography improves weekly with postmenstrual age

Objective: To investigate the relationship between cystoid macular oedema (CMO) measured in preterm infants using hand-held spectral domain optical coherence tomography (HH SD-OCT), with gestational age at birth (GA), birthweight (BW), diagnosis of retinopathy of prematurity (ROP) and the presence or absence of the external limiting membrane (ELM). Methods: We conducted a prospective mixed cross-sectional/longitudinal observational study of 112 participants (23 to 36 weeks GA; n = 25 with, and n = 87 without, CMO). Retinal images were acquired using 344 HH SD-OCT (n = 66 with and n = 278 without, CMO) between 31 to 44 weeks postmenstrual age (PMA). CMO type (‘fovea’ and ‘dome’) was measured using thickness, width, area and peak. Results: CMO was observed in 22.9% of preterm infants, and 19.2% of images. The mean values for thickness, width, area and peak of ‘dome’ CMO were 128.47 µm (SD +/- 34.23), 3624.45 µm (SD +/- 1323.03), 0.49 mm2 (SD +/- 0.28) and 279.81 µm (SD +/- 13.57) respectively. The mean values for thickness, width, area and peak of ‘fovea’ CMO were 64.37 µm (SD +/- 17.11), 2226.28 µm (SD +/- 1123.82), 0.16 mm2 (SD +/- 0.11) and 95.03 µm (SD +/- 26.99) respectively. Thickness, area width and peak were significantly greater for ‘dome CMO compared with ‘fovea’ CMO (P < 0.0001 for thickness, area and peak; P < 0.01 for width). Area and width significantly decreased with PMA for ‘dome’ and ‘fovea’ CMO (p = 0.0028; p < 0.001 respectively). No association was found between the presence of ROP and the detection of CMO or detection of CMO with absence of ELM. Conclusions: HH -OCT in preterm infants demonstrates that the severity of CMO appearance improves each week for both fovea and dome CMO

Does treatment modality affect measures of arterial stiffness in women with gestational diabetes?

Objective: To investigate whether arterial stiffness (AS) differs between healthy women and women with gestational diabetes mellitus (GDM) managed by different treatment modalities. Methods: This was a prospective longitudinal cohort study comparing AS in pregnancies complicated by GDM and low-risk controls. AS was assessed by recording aortic pulse-wave velocity (AoPWV), brachial augmentation index (BrAIx) and aortic augmentation index (AoAIx) using the Arteriograph® at four gestational-age windows: 24 + 0 to 27 + 6 weeks (W1); 28 + 0 to 31 + 6 weeks (W2); 32 + 0 to 35 + 6 weeks (W3) and ≥ 36 + 0 weeks (W4). Women with GDM were considered both as a single group and as subgroups stratified by treatment modality. Data were analyzed using a linear mixed model on each AS variable (log-transformed) with group, gestational-age window, maternal age, ethnicity, parity, body mass index, mean arterial pressure and heart rate as fixed effects and individual as a random effect. We compared the group means including relevant contrasts and adjusted the P-values using Bonferroni correction. Results: The study population comprised 155 low-risk controls and 127 women with GDM, of whom 59 were treated with dietary intervention, 47 were treated with metformin only and 21 were treated with metformin + insulin. The two-way interaction term of study group and gestational age was significant for BrAIx and AoAIx (P < 0.001), but there was no evidence that mean AoPWV was different between the study groups (P = 0.729). Women in the control group demonstrated significantly lower BrAIx and AoAIx compared with the combined GDM group at W1–W3, but not at W4. The mean difference in log-transformed BrAIx was –0.37 (95% CI, –0.52 to –0.22), –0.23 (95% CI, –0.35 to –0.12) and –0.29 (95% CI, –0.40 to –0.18) at W1, W2 and W3, respectively. The mean difference in log-transformed AoAIx was –0.49 (95% CI, –0.69 to –0.30), –0.32 (95% CI, –0.47 to –0.18) and –0.38 (95% CI –0.52 to –0.24) at W1, W2 and W3, respectively. Similarly, women in the control group also demonstrated significantly lower BrAIx and AoAIx compared with each of the GDM treatment subgroups (diet, metformin only and metformin + insulin) at W1–W3. The increase in mean BrAIx and AoAIx seen between W2 and W3 in women with GDM treated with dietary management was attenuated in the metformin-only and metformin + insulin groups. However, the mean differences in BrAIx and AoAIx between these treatment groups were not statistically significant at any gestational-age window. Conclusions: Pregnancies complicated by GDM demonstrate significantly higher AS compared with low-risk pregnancies regardless of treatment modality. Our data provide the basis for further investigation into the association of metformin therapy with changes in AS and risk of placenta-mediated diseases. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology

Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors

BACKGROUND: Although short-term trials have suggested that PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are safe and reduce risk of cardiovascular diseases, their long-term safety is unclear. Genetic variants associated with lower activity of a gene can act as proxies to identify potential long-term side effects of drugs as recently exemplified by association of LDL (low-density lipoprotein)-lowering variants in the HMGCR (target for statins) and PCSK9 genes with increased risk of type 2 diabetes mellitus (T2DM). However, analyses of the full spectrum of potential side effects of PCSK9 inhibition using a genetic approach have not been undertaken. METHODS: We examined the association of an LDL-lowering variant in the PCSK9 gene (T allele of rs1159147), as well as 2 LDL-lowering HGCMR variants (G allele of rs17238484 and T allele of rs12916) with 80 diseases and traits in up to 479 522 individuals in UK Biobank. RESULTS: The PCSK9 T allele was significantly (Bonferroni P<6.25×10-4) associated with risk of T2DM, increased body mass index, waist circumference, waist-hip ratio, diastolic blood pressure, type 1 diabetes mellitus, and insulin use. The HMGCR variants were also associated with risk of T2DM, although their previously reported associations with anthropometric traits were found to be confounded. Mediation analysis suggested that the association of the PCSK9 T allele with risk of T2DM but not diastolic blood pressure was largely independent of its association with body mass index and central obesity. Nominally significant associations of the PCSK9 T allele were also seen with peptic ulcer disease, depression, asthma, chronic kidney disease, and venous thromboembolism. CONCLUSIONS: Our findings support previous genetic analyses suggesting that long-term use of PCSK9 inhibitors, like statins, may be associated with increased risk of T2DM. Some other potential side effects need to be looked for in future studies of PCSK9 inhibitors, although we did not find signals that raise substantial concerns about their long-term safety

HHIPL1, a Gene at the 14q32 Coronary Artery Disease Locus, Positively Regulates Hedgehog Signaling and Promotes Atherosclerosis.

BACKGROUND: Genome-wide association studies have identified chromosome 14q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterised gene called Hedgehog Interacting Protein Like 1 (HHIPL1), which encodes a sequence homologue of an antagonist of hedgehog signaling. The function of HHIPL1 and its role in atherosclerosis is unknown. METHODS: HHIPL1 cellular localization, interaction with Sonic Hedgehog (SHH) and influence on hedgehog signaling were tested. HHIPL1 expression was measured in coronary artery disease relevant human cells and protein localization was assessed in wild-type and Apoe-/- mice. Human aortic smooth muscle cell phenotypes and hedgehog signaling were investigated following gene knockdown. Hhipl1-/- mice were generated and aortic smooth muscle cells collected for phenotypic analysis and assessment of hedgehog signaling activity. Hhipl1-/- mice were bred onto both the Apoe-/- and Ldlr-/- knockout strains and the extent of atherosclerosis was quantified following 12 weeks of high fat diet. Cellular composition and collagen content of aortic plaques was assessed by immunohistochemistry. RESULTS: In vitro analyses revealed that HHIPL1 is a secreted protein that interacts with SHH and increases hedgehog signaling activity. HHIPL1 expression was detected in human smooth muscle cells and in smooth muscle within atherosclerotic plaques of Apoe-/- mice. The expression of Hhipl1 increased with disease progression in aortic roots of Apoe-/- mice. Proliferation and migration was reduced in Hhipl1 knockout mouse and HHIPL1 knockdown aortic smooth muscle cells and hedgehog signaling was decreased in HHIPL1 deficient cells. Hhipl1 knockout caused a reduction of more than 50% in atherosclerosis burden on both Apoe-/- and Ldlr-/- knockout backgrounds and lesions were characterized by reduced smooth muscle cell content. CONCLUSIONS: HHIPL1 is a secreted proatherogenic protein that enhances hedgehog signaling and regulates smooth muscle cell proliferation and migration. Inhibition of HHIPL1 protein function might offer a novel therapeutic strategy for coronary artery disease

Predictors and determinants of albuminuria in people with prediabetes and diabetes based on smoking status: A cross-sectional study using the UK Biobank data

Background Smoking is attributed to both micro- and macrovascular complications at any stage of metabolic deregulation including prediabetes. Current global diabetes prevention programmes appear to be glucocentric, and do not fully acknowledge the ramifications of cardiorenal risk factors in smokers and ex-smokers. A more holistic approach is needed to prevent vascular complications in people with prediabetes and diabetes before and after quitting. Methods A cross-sectional study was carried out on participants who agreed to take part in the UK Biobank dataset at the time of their first attendances between March 01, 2006, and December 31, 2010. Those who had their urinary albumin concentration (UAC) data available were included, and those who did not have this data, were excluded. A logistic regression model was fitted to explore the relationship between cardiorenal risk factors and albuminuria in people with prediabetes and diabetes, based on smoking status. Findings A total of 502,490 participants were included in the UK Biobank dataset. Of them, 30.4% (n=152,896) had their UAC level recorded. Compared with non-smokers, the odds of albuminuria in smokers with prediabetes and diabetes were 1.21 (95% CI 1.05 – 1.39, p=0.009), and 1.26 (95% CI 1.10 – 1.44, p=0.001), respectively. The odds declined after quitting in both groups, but it was not statistically significant (p>0.05). Each unit increase in HbA1c was associated with equivalent increased odds of albuminuria in current and ex-smokers, OR 1.035 (95% CI 1.030 – 1.039, p Interpretation Male smokers are at a higher risk of albuminuria after smoking cessation. Monitoring waist circumference in quitters may identify those who are at a higher risk of albuminuria. Combining smoking cessation intervention in smokers with prediabetes in the current diabetes prevention programmes may offset post-cessation weight gain and reduce the risk of albuminuria.</p

Leg Ischaemia Management collaboration (LIMb): study protocol for a prospective cohort study at a single UK centre

Introduction Severe limb ischaemia (SLI) is the end-stage of peripheral arterial occlusive disease where the viability of the limb is threatened. Around 25% of patients with SLI will ultimately require a major lower limb amputation which has a substantial adverse impact on quality of life. A newly established rapid-access vascular limb salvage clinic and modern revascularisation techniques may reduce amputation rate. The aim of this study is to investigate the 12-month amputation rate in a contemporary cohort of patients and compare this to a historical cohort. Secondary aims are to investigate the use of frailty and cognitive assessments, and cardiac MRI in risk-stratifying patients with SLI undergoing intervention and establish a biobank for future biomarker analyses. Methods & analysis This single-centre prospective cohort study will recruit patients aged 18-110 years presenting with SLI. Those undergoing intervention will be eligible to undergo additional venepuncture (for biomarker analysis) and/or cardiac MRI. Those aged ≥65 years and undergoing intervention will also be eligible to undergo additional frailty and cognitive assessments. Follow-up will be at 12 and 24 months and subsequently via data-linkage with NHS digital to 10 years post-recruitment. Those undergoing cardiac MRI and/or frailty assessments will receive additional follow-up during the first 12 months to investigate for peri-operative myocardial infarction and frailty related outcomes, respectively. A sample size of 420 patients will be required to detect a 10% reduction in amputation rate in comparison to a similar sized historical cohort, with 90% power and 5% type-I error rate. Statistical analysis of this comparison will be by adjusted and unadjusted logistic regression analyses. Ethics & dissemination Ethical approval for this study has been granted by the UK National Research Ethics Service (19/LO/0132). Results will be disseminated to participants, via scientific meetings, peerreviewed medical journals and social media. Study registration ClinicalTrials.gov [NCT04027244

Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure

Background: Despite major advances in pharmacological treatment for patients with heart failure, residual mortality remains high. This suggests that important pathways are not yet targeted by current heart failure therapies. Objectives: We sought integration of genetic, transcriptomic, and proteomic data in a large cohort of patients with heart failure to detect major pathways related to progression of heart failure leading to death. Methods: We used machine learning methodology based on stacked generalization framework and gradient boosting algorithms, using 54 clinical phenotypes, 403 circulating plasma proteins, 36,046 transcript expression levels in whole blood, and 6 million genomic markers to model all-cause mortality in 2,516 patients with heart failure from the BIOSTAT-CHF (Systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Results were validated in an independent cohort of 1,738 patients. Results: The mean age of the patients was 70 years (Q1-Q3: 61-78 years), 27% were female, median N-terminal pro–B-type natriuretic peptide was 4,275 ng/L (Q1-Q3: 2,360-8,486 ng/L), and 7% had heart failure with preserved ejection fraction. During a median follow-up of 21 months, 657 (26%) of patients died. The 4 major pathways with a significant association to all-cause mortality were: 1) the PI3K/Akt pathway; 2) the MAPK pathway; 3) the Ras signaling pathway; and 4) epidermal growth factor receptor tyrosine kinase inhibitor resistance. Results were validated in an independent cohort of 1,738 patients. Conclusions: A systems biology approach integrating genomic, transcriptomic, and proteomic data identified 4 major pathways related to mortality. These pathways are related to decreased activation of the cardioprotective ERBB2 receptor, which can be modified by neuregulin