Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

Population differences in associations of serotonin transporter promoter polymorphism (5HTTLPR) di- and triallelic genotypes with blood pressure and hypertension prevalence.

Based on prior research finding the 5HTTLPR L allele associated with increased cardiovascular reactivity to laboratory stressors and increased risk of myocardial infarction, we hypothesized that the 5HTTLPR L allele will be associated with increased blood pressure (BP) and increased hypertension prevalence in 2 large nationally representative samples in the United States and Singapore. METHODS: Logistic regression and linear models tested associations between triallelic (L'S', based on rs25531) 5HTTLPR genotypes and hypertension severity and mean systolic and diastolic blood pressure (SBP and DBP) collected during the Wave IV survey of the National Longitudinal Study of Adolescent to Adult Health (Add Health, N=11,815) in 2008-09 and during 2004-07 in 4196 Singaporeans. RESULTS: In US Whites, L' allele carriers had higher SBP (0.9 mm Hg, 95% CI=0.26-1.56) and greater odds (OR=1.23, 95% CI=1.10-1.38) of more severe hypertension than those with S'S' genotypes. In African Americans, L' carriers had lower mean SBP (-1.27mm Hg, 95% CI=-2.53 to -0.01) and lower odds (OR = 0.78, 95% CI=0.65-0.94) of more severe hypertension than those with the S'S' genotype. In African Americans, those with L'L' genotypes had lower DBP (-1.13mm Hg, 95% CI=-2.09 to -0.16) than S' carriers. In Native Americans, L' carriers had lower SBP (-6.05mm Hg, 95% CI=-9.59 to -2.51) and lower odds of hypertension (OR = 0.34, 95% CI=0.13-0.89) than those with the S'S' genotype. In Asian/Pacific Islanders those carrying the L' allele had lower DBP (-1.77mm Hg, 95% CI=-3.16 to -0.38) and lower odds of hypertension (OR = 0.68, 95% CI=0.48-0.96) than those with S'S'. In the Singapore sample S' carriers had higher SBP (3.02mm Hg, 95% CI=0.54-5.51) and DBP (1.90mm Hg, 95% CI=0.49-3.31) than those with the L'L' genotype. CONCLUSIONS: These findings suggest that Whites carrying the L' allele, African Americans and Native Americans with the S'S' genotype, and Asians carrying the S' allele will be found to be at higher risk of developing cardiovascular disease and may benefit from preventive measures.

Photokeratitis in Outdoor Event Participants Exposed to UV Radiation Display.

Importance: While UV radiation displays may be used for recreational purposes at outdoor events, unprotected eyes have been reported to have symptoms consistent with photokeratitis. Such symptoms warrant documentation and evaluation in ophthalmic peer reviewed literature. Objective: To describe a case series of photokeratitis associated with a single ultraviolet radiation display at an outdoor event. Design, Setting, and Participants: This case series involved a retrospective record review of 8 patients who presented in public and private health sectors in November 2023 after developing photokeratitis following UV radiation exposure at an outdoor event in Hong Kong on the night of November 4, 2023. Main Outcomes and Measures: Clinical symptoms, signs, and clinical course of patients who were diagnosed acute photokeratitis following exposure to UV radiation. Results: The mean time of UV display exposure for the 8 patients (mean [SD] age, 33.12 [5.19] years; 4 [50%] female) was 3.00 (1.41) hours, and symptoms presented at a mean (SD) 8.88 (8.24) hours after the exposure. None of the patients were wearing spectacles during the exposed period. All patients were affected bilaterally. All patients experienced eye pain, 6 experienced red eye, and 5 experienced tearing and photophobia. Mean (SD) presenting visual acuity was logMAR 0.10 (0.14) (approximate Snellen equivalent, 20/25) for right eyes and 0.06 (0.89) (approximate Snellen equivalent, 20/25) for left eyes. On examination, there were findings of cornea and conjunctival involvement with punctate epithelial erosions and ciliary vasodilation, but none of the patients presented with anterior chamber reaction. Corticosteroids, lubricants, and antibiotics, all provided topically, were prescribed. Five patients were not scheduled for a review, and 3 had follow-up visits, with the length of follow-up ranging from 7 to 10 days. All patients had undergone a complete recovery. Conclusions and Relevance: These findings provide evidence of an association between UV radiation used for recreational purposes and photokeratitis, which may help guide evaluation and management of future cases.

Infiltration between the popliteal artery and the capsule of the knee (IPACK) block in knee surgery: a narrative review.

BACKGROUND: The infiltration between the popliteal artery and the capsule of the knee (IPACK) block has been described as an alternative analgesic strategy for knee pain. OBJECTIVE: Our aim was to perform a narrative review to examine the place and value that the IPACK block has in comparison to and in conjunction with other regional anesthesia modalities. EVIDENCE REVIEW: Following an extensive search of electronic databases, we included anatomical studies, letters, comparative observational studies, and non-randomized and randomized controlled trials that examined the IPACK block in relation to surgery on the knee under general or neuraxial anesthesia. FINDINGS: In all, 35 articles were included. Cadaveric studies demonstrated the potential for injected dye to spread to the nerves responsible for the innervation of the posterior as well as anteromedial and anterolateral aspects of the knee. Of the comparative observational studies (n=15) and non-randomized (n=1) and randomized controlled trials (n=13), 2 and 27 were conducted in the context of anterior cruciate ligament reconstruction and knee replacement surgery, respectively. The role of the IPACK block with each different permutation of regional anesthesia techniques was investigated by a small number of studies. Clinical studies, in the setting of knee replacement surgery, revealed variation in the manner in which the IPACK block was performed, and indicated the possible superiority of distal injection at the level of the femoral condyles for the management of posterior knee pain. Evidence suggested the following: the IPACK block in combination with single shot adductor canal block (ACB) may be beneficial for analgesic and functional outcomes; in conjunction with single shot or continuous ACB, the IPACK block might be superior to local infiltration analgesia (LIA); and functional outcomes may be improved with the supplementation of continuous ACB and LIA with the IPACK block. The IPACK block did not commonly result in the occurrence of foot drop. Relative to tibial nerve block (TNB), the IPACK block reduced the occurrence of foot drop and increased the proportion of patients who were able to be discharged on the third postoperative day. CONCLUSIONS: The IPACK block was potentially complementary to the ACB and might be preferable to the TNB as a motor-sparing regional anesthesia technique in knee surgery. Definitive recommendations were not reached in the presence of the heterogeneous and limited evidence base.

Mode of Anesthesia and Quality of Recovery After Breast Surgery: A Case Series of 100 Patients.

PURPOSE: Regional anesthesia techniques may improve patient recovery beyond treating postoperative pain alone and may facilitate patients in their return to functional, psychological as well as emotional baselines. We hypothesized that the quality of recovery (QoR) experienced by patients following breast surgery was associated with the type of anesthesia received as well as the use of a regional anesthesia technique during surgery. METHODS: We performed a single-center prospective, observational cohort study of patients undergoing elective breast procedures (both cancer and non-cancer surgery). RESULTS:  One hundred patients completed baseline QoR-15 questionnaires prior to surgery, of which 96 also completed QoR-15 questionnaires on postoperative day 1. The median (IQR) QoR-15 score at baseline was 133 (124-141), decreasing to 121 (106.75-136.25) on postoperative day 1. In multivariable linear regression analysis, paravertebral blocks (PVB) were associated with a 16.7 point higher overall QoR-15 score on postoperative day 1 compared to no block (95% Confidence Interval [CI]: 7.7-25.8, p<0.001); while the use of combination blocks was associated with a 21.8 point higher postoperative QoR-15 score compared to no block (95% CI: 12.8-30.8, p<0.001). PVB and combination blocks were further associated with better postoperative pain, physical comfort, physical independence and emotional state scores, compared with no block. The use of total intravenous anesthetic was not associated with differences in postoperative QoR-15 score versus volatile anesthetic, after covariate adjustment. CONCLUSION: Breast surgery patients receiving PVB or a combination of regional blocks during surgery have higher postoperative QoR-15 scores, after adjustment for other factors.

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

Caudal analgesia versus abdominal wall blocks for pediatric genitourinary surgery: systematic review and meta-analysis.

BACKGROUND: Caudal block is a well-established technique for providing perioperative analgesia in pediatric genitourinary surgery, but abdominal wall blocks such as ilioinguinal-iliohypogastric (II-IH) and transversus abdominis plane (TAP) block are increasingly being used. METHODS: Our protocol for this meta-analysis was registered on PROSPERO (CRD42020163497). Central, CINAHL, Embase, Global Health, LILACS, MEDLINE, Scopus and Web of Science were searched from inception to 11 December 2019 for randomized controlled trials that included pediatric patients having genitourinary surgery with II-IH or TAP block as the intervention and caudal analgesia as the comparator. For continuous and dichotomous outcomes, respectively, we calculated the mean difference using the inverse-variance method and the risk ratio with the Mantel-Haenzel method. RESULTS: In all, 23 trials with 1399 patients were included. II-IH and TAP block were similar to caudal analgesia in the coprimary outcomes of the postoperative pain score at 0-2 hours (high-quality evidence) and the need for in-hospital rescue analgesia (moderate-quality evidence consequent to downgrading by publication bias). No subgroup differences in regard to the type of abdominal wall block or the method of block localization were demonstrated for these primary outcomes. Relative to caudal analgesia, II-IH and TAP block reduced the incidence of postoperative motor blockade and the time to micturition. CONCLUSIONS: This meta-analysis was limited by unclear risk of selection and performance biases and significant heterogeneity. In summary, II-IH and TAP block are a non-invasive and reasonable alternative to caudal analgesia in pediatric genitourinary surgery.

The V227A polymorphism at the PPARA locus is associated with serum lipid concentrations and modulates the association between dietary polyunsaturated fatty acid intake and serum high density lipoprotein concentrations in Chinese women.

Peroxisome proliferators activated receptor alpha (PPARalpha) regulates the transcription of several proteins involved in human lipoprotein metabolism. We screened the PPARA locus for polymorphisms in 20 unrelated subjects from each of three ethnic groups (Chinese, Malays and Asian Indians). Only the V227A polymorphism was observed. We genotyped 4248 subjects (2899 Chinese, 761 Malay and 588 Asian Indians) and found allele frequencies for the A227 allele of 0.04 in Chinese, 0.006 in Malays and 0.003 in Asian Indians. We examined the associations between this polymorphism and serum lipid concentrations in Chinese. In women, but not in men, the presence of the A227 allele was associated with lower serum concentrations of total cholesterol [5.38mmol/l (95%CI: 5.22-5.54) versus 5.21mmol/l (95%CI: 4.99-5.43), p=0.047] and triglycerides [1.19mmol/l (95%CI: 1.10-1.28) versus 1.09mmol/l (95%CI: 0.98-1.21), p=0.048]. We also found that the V227A polymorphism modulates the association between dietary polyunsaturated fatty acid intake and serum high density lipoprotein concentration (p-value for interaction=0.049). Our findings implicate PPARalpha in the lipid lowering associated with diets high in PUFA and suggests that genetic variation at the PPARA locus may determine the lipid response to changes in PUFA intake.

Ethnic Differences in the Role of Adipocytokines Linking Abdominal Adiposity and Insulin Sensitivity Among Asians.

CONTEXT: Among Asian ethnic groups, Chinese or Malays are more insulin sensitive than South Asians, in particular in lean individuals. We have further reported that body fat partitioning did not explain this ethnic difference in insulin sensitivity. OBJECTIVE: We examined whether adipocytokines might explain the ethnic differences in the relationship between obesity and insulin resistance among the three major ethnic groups in Singapore. DESIGN AND PARTICIPANTS: This was a cross-sectional study of 101 Chinese, 82 Malays, and 81 South Asian men. Insulin sensitivity index (ISI) was measured using hyperinsulinemic euglycemic clamp. Visceral (VAT) and subcutaneous adipose tissue (SAT) volumes were quantified using magnetic resonance imaging. MAIN OUTCOME MEASURES: Plasma total and high-molecular-weight adiponectin, leptin, visfatin, apelin, IL-6, fibroblast growth factor 21 (FGF21), retinol binding protein-4 (RBP 4), and resistin were measured using enzyme-linked immunoassays. RESULTS: Principle component (PC) analysis on the adipocytokines identified three PCs, which explained 49.5% of the total variance. Adiponectin loaded negatively, and leptin and FGF21 loaded positively onto PC1. Visfatin, resistin, and apelin all loaded positively onto PC2. IL-6 loaded positively and RBP-4 negatively onto PC3. Only PC1 was negatively associated with ISI in all ethnic groups. In the path analysis, SAT and VAT were negatively associated with ISI in Chinese and Malays without significant mediatory role of PC1. In South Asians, the relationship between VAT and ISI was mediated partly through PC1, whereas the relationship between SAT and ISI was mediated mainly through PC1. CONCLUSIONS: The relationships between abdominal obesity, adipocytokines and insulin sensitivity differ between ethnic groups. Adiponectin, leptin, and FGF21 play a mediating role in the relationship between abdominal adiposity and insulin resistance in South Asians, but not in Malays or Chinese.

Identification of specific cell-surface markers of adipose-derived stem cells from subcutaneous and visceral fat depots.

Adipose-derived stem/stromal cells (ASCs) from the anatomically distinct subcutaneous and visceral depots of white adipose tissue (WAT) differ in their inherent properties. However, little is known about the molecular identity and definitive markers of ASCs from these depots. In this study, ASCs from subcutaneous fat (SC-ASCs) and visceral fat (VS-ASCs) of omental region were isolated and studied. High-content image screening of over 240 cell-surface markers identified several potential depot-specific markers of ASCs. Subsequent studies revealed consistent predominant expression of CD10 in SC-ASCs and CD200 in VS-ASCs across 12 human subjects and in mice. CD10-high-expressing cells sorted from SC-ASCs differentiated better than their CD10-low-expressing counterparts, whereas CD200-low VS-ASCs differentiated better than CD200-high VS-ASCs. The expression of CD10 and CD200 is thus depot-dependent and associates with adipogenic capacities. These markers will offer a valuable tool for tracking and screening of depot-specific stem cell populations.

Management of Parkinson's Disease medication in acutely admitted patients.

This project aimed to identify problems in the management of Parkinson's Disease (PD) medications in those acutely admitted to the medical ward. Errors in prescription of medications are due to difficulties in conversion of formulation of medications to suit different needs, lack of awareness of help available amongst junior doctors and lack of awareness of trust guidance. Drug charts were audited over two weeks on medical wards. Dosing, frequency, formulation, and any difficulties in the administration were noted. A survey of junior doctors regarding their knowledge of PD management was also undertaken. The effects of our interventions (creation of summary guidance made available on wards, advice regarding where to obtain prescription information, and teaching sessions) were evaluated using a survey and audit. There was improved accuracy in PD prescriptions, improved confidence in switching formulation, increased awareness of trust guidance and the consequences of missed doses of PD medications. However there was no improvement in knowledge about appropriate resources used to make correct prescriptions. Increased education and training is required to continue improvement in prescription accuracy and awareness of where to seek help, to improve patient safety.

Macro-thyrotropin: a case report and review of literature.

CONTEXT: Isolated elevation of TSH in the absence of thyroid symptoms can be very rarely caused by a macromolecule formed between TSH and Ig (macro-TSH), confounding the interpretation of thyroid function test results. OBJECTIVE: We described the use of several commonly available laboratory-based approaches to investigate an isolated TSH elevation [232 mIU/liter; free T(4), 10 pmol/liter (reference interval, 10.0-23.0 pmol/liter), Vitros platform] in a clinically euthyroid elderly gentleman, which led to the diagnosis of macro-TSH. METHODS AND RESULTS: TSH concentration of the patient was significantly lower (122 mIU/liter) when measured on the Advia Centaur platform. Serial dilution of the patient's sample showed a nonlinear increase in TSH recovery at increasing dilution (nonlinearity). Polyethylene glycol precipitation and mixing the patient's sample with a hypothyroid patient sample showed reduced TSH recovery, suggesting the presence of a high molecular weight interfering substance and excess TSH binding capacity, respectively. Heterophile blocking tube studies and rheumatoid factors were negative. Gel filtration chromatography demonstrated a TSH peak fraction that approximated the molecular size of IgG; together with the excess TSH binding capacity, this indicated the presence of TSH-IgG macro-TSH. A review of 12 macro-TSH case reports showed that samples with macro-TSH produce over-recovery with dilution, return negative results on anti-animal and anti-heterophile blocking studies, and commonly have recovery of less than 20% when subjected to polyethylene glycol precipitation. CONCLUSION: Macro-TSH is an underrecognized laboratory interference. Routine laboratory techniques described above can help diagnose this rare entity. A close dialogue between the physician and the laboratory is important in approaching such cases.

Relationships between cholesterol efflux and high-density lipoprotein particles in patients with type 2 diabetes mellitus.

BACKGROUND: High-density lipoprotein (HDL) encompasses a heterogeneous population of lipoproteins with differences in functionality. The impact of HDL heterogeneity on its ability to support HDL-mediated cholesterol efflux has not been previously studied in patients with type 2 diabetes mellitus (T2DM). OBJECTIVES: To examine the relationships between various HDL subtypes and cholesterol efflux from macrophages in patients with T2DM. METHODS: Lipoprotein molecular profiles of 44 patients were studied by NMR spectroscopy. Cholesterol efflux was expressed as percentage efflux of radioactivity from lipid-laden THP-1 macrophages preincubated with (3)H-cholesterol and then incubated with serum depleted of apolipoprotein B to provide an HDL-enriched acceptor medium. RESULTS: There was a predominance of small HDL particles (59%) and small putatively atherogenic low-density lipoprotein particles (56%). Neither HDL-C nor ApoA-I concentrations showed statistically significant correlations with percentage cholesterol efflux, but a significant positive relationship was found with the total HDL particle concentration (r = 0.41, P = .005) contributed to largely by medium HDL particles (r = 0.41, P = .006). The correlation between medium-sized HDL particle concentration remained significantly associated with cholesterol efflux when assessed with the use of a linear regression model that included all the HDL lipoprotein subclass concentrations as well as apolipoprotein A-I. Importantly, no statistically significant association was observed between the number of small HDL particles and cholesterol efflux. Hemoglobin A1c showed a significant inverse correlation with cholesterol efflux (r = -0.31, P = .04). CONCLUSION: In patients with moderately controlled type 2 diabetes mellitus, cholesterol efflux from macrophages incubated with apolipoprotein B-depleted plasmas correlated significantly and positively with the concentration of total and medium-sized HDL and not with that of the smallest particles.

Deviation from major codons in the Toll-like receptor genes is associated with low Toll-like receptor expression.

Microbial structures activate Toll-like receptors (TLRs) and TLR-mediated cell signalling elicits and regulates host immunity. Most TLRs are poorly expressed but the underlying expression mechanism is not clear. Examination TLR sequences revealed that most human TLR genes deviated from using major human codons. CD14 resembles TLRs in sequence but its gene preferentially uses major codons. Indeed, CD14 expression on monocytes was higher than expression of TLR1 and TLR2. The TLR9 gene is abundant in major codons and it also showed higher expression than TLR1, TLR2 and TLR7 in transfected 293T cells. Change of the 5'-end 302 base pairs of the TLR2 sequence into major human codons markedly increased TLR2 expression, which led to increased TLR2-mediated constitutive nuclear factor-kappaB activation. Change of the 5'-end 381 base pairs of the CD14 sequence into prevalent TLR codons markedly reduced CD14 expression. These results collectively show that the deviation of TLR sequences from using major codons dictates the low TLR expression and this may protect the host against excessive inflammation and tissue damages.