Review of Risk Assessment Tools to Predict Morbidity and Mortality in Elderly Surgical Patients Brief title: Review of surgical risk assessment tools

Background Informed surgical consent requires accurate estimation of risks and benefits. Multiple risk assessment tools are available; however, most are not widely used or are specific to certain interventions. Assessing surgical risk is especially challenging in elderly patients because of their range of comorbidities, level of frailty, or severity of illness and a number of available surgical interventions. Data sources We searched MEDLINE from January 2014 to July 2017 for studies that used risk assessment tools in studies on elderly surgical patients. We then sought the original articles describing each assessment tool and subsequent validation studies. Conclusions We identified risk assessment tools that can improve surgical risk assessment in elderly surgical patients. The majority of the identified tools are not commonly used for pre-operative risk assessment. NSQIP-PMP, mFI and SURPAS are promising tools. Age is commonly used to predict risk, but frailty may be a more appropriate measure

Impact of Polymorphisms in PTK2 on Intrinsic Muscle Strength

Abstract Title: Impact of Polymorphisms in PTK2 on Intrinsic Muscle Strength Primary Presenter Full Name: Zachary Zeller Co-presenter Full Name(s): Click here to enter text. Co-author Full Name(s): Mohamed Al-Amoodi, Whitney Jones, Danny Lee, Steven Mckenzie, Helen Miller, Seth Stubblefied, Susan Knoblach, Heather Gordish-Dressman, Dustin Hittel, Laura L. Tosi Abstract Text (should not exceed 400 words): Recent studies have begun to search for correlations between genetic variations and muscle strength. One such study by Stebbings et al.1 examined two single nucleotide polymorphisms (SNPs)—rs7843014 and rs7460—on the PTK2 gene. The study found that genetic variation in the PTK2 gene impacts muscle-specific force, which is the force generated per unit of cross-sectional area of muscle. Muscle-specific force ultimately represents the intrinsic strength of a muscle and is a key determinant of functional capacity and mobility. This study sought to expand on prior research by looking for associations between genetic variants of PTK2 and measures of grip strength, as well as general anthropomorphic measures, in a cohort of healthy young adults. Our study assessed phenotypes for height, weight, VO2 max, max grip strength, and body mass index (BMI) using the Assessing Inherited Markers of Metabolic Syndrome in the Young (AIMMY) University of Calgary subset of 190 healthy, primarily Caucasian, individuals between the ages of 18 and 35. DNA samples were genotyped using ThermoFisher Taqman SNP genotype assays, and underwent the Applied Biosystems 7900HT real-time polymerase chain reaction (PCR) process. Analysis of covariance (ANCOVA) models were used to perform statistical analysis to look for genotype-phenotype associations. Unlike the findings by Stebbings et al.1 an association between the PTK2 genotypes and grip strength was not found. This could be due to the lower statistical power in the grip strength test, thus potentially indicating that grip strength and muscle-specific force do not measure similar parameters of muscle strength. Genetic variation in PTK2 has also been previously associated with VO2 max, but no association was found in the current study. Positive associations were found between genetic variants rs7843014 and rs7460 in PTK2 and BMI, and between genetic variant rs7843014 and height. High levels of functioning PTK2 have been found to have increased strength due to increased costamere density, resulting in more muscle myofibrils, and therein larger, presumably heavier muscles. However, this finding was only observed in males, and could be attributed to differential acquisition and maintenance of muscle mass based on sex. We identified a potentially novel association between genetic variants in PTK2 and anthropomorphic phenotypes. However, we were unable to confirm the effects of genetic variants on measures of intrinsic muscle strength, namely max grip strength or VO2 max in terms of functional capacity. Further research is needed to confirm this newly identified role for PTK2

The association of polymorphism rs3736228 within the LRP5 gene with Bone Mineral Density in a Cohort of Caucasian Young Adults

INTRODUCTION: Osteoporosis is a significant burden for our aging population. Developing a better understanding of the genetic underpinnings of poor bone quality may assist in the future development of prevention strategies. Correa-Rodriguez et al. have identified a group of single nucleotide polymorphisms (SNPs) that were associated with bone mineral density (BMD) in a population of Spanish Caucasians. In particular, they found that SNP rs3736228 in the low-density lipoprotein receptor related protein 5 (LRP5) gene had an influence on BMD. While the role of LRP5 in the Wnt canonical pathway has been fairly well characterized, its association with phenotypic BMD and osteoporosis has only been explored in a limited fashion. The aim of this study is to expand on this, and to replicate the findings of previous studies in a cohort of healthy young adults. METHODS: Cohort: The University of Calgary cohort from the Assessing Inherited Metabolic Syndrome Markers in the Young (UC AIMMY) study. Participants included consist of 168 healthy, predominantly Caucasian young adults. Phenotypes: height, weight, BMI, and total BMD. Genotyping: Allelic discrimination was determined. Statistical Analysis: After being tested for Hardy-Weinberg equilibrium (HWE), the data was run through analysis of covariance (ANCOVA). RESULTS: Using a dominant model, we found that females with one or more copies of the risk T allele of SNP rs3736228 had a significant negative association with total BMD (p = 0.0347). However, a similar association was not seen in males in this cohort. We did not find a significant association for this polymorphism and height, weight, or BMI. DISCUSSION: Polymorphisms in rs3736228 alter the codon in position 1330, downregulating the LRP5 cell surface receptor function. The LRP5 gene has now been shown in multiple studies to be associated with bone quality measures like calcaneal Qualitative Ultrasound (QUS) and BMD. Our study suggests that SNP rs3736228 also influences BMD in healthy young females. This supports the work of Correa-Rodriguez et al that found that when stratifying by sex, females only showed a trend towards significance (p = 0.092) in QUS measures. SIGNIFICANCE: This study expands our understanding of the importance of LRP5 rs3736228 polymorphisms in BMD by extending its relationship to a cohort of predominantly Caucasian college students. While the development of BMD is polygenic, this work broadened the role of SNP rs3736228 across the age span, and the sexual dimorphism seen in musculoskeletal traits

Unilateral laminotomy with bilateral spinal canal decompression: systematic review of outcomes and complications

Abstract Background Unilateral laminotomy with bilateral spinal canal decompression has gained popularity recently. Aim To systematically review the literature of unilateral laminotomy with bilateral spinal canal decompression for lumbar spinal stenosis (LSS) aiming to assess outcomes and complications of the different techniques described in literature. Methods On August 7, 2022, Pubmed and EMBASE were searched by 2 reviewers independently, and all the relevant studies published up to date were considered based on predetermined inclusion and exclusion criteria. The subject headings “unilateral laminotomy”, “bilateral decompression” and their related key terms were used. The Preferred Reporting Item for Systematic Reviews and Meta-Analyses statement was used to screen the articles. Results A total of seven studies including 371 patients were included. The mean age of the patients was 69.0 years (range: 55–83 years). The follow up duration ranged from 1 to 3 years. Rate of postoperative pain and functional improvement was favorable based on VAS, JOA, JOABPEQ, RMDW, ODI and SF-36, for example improved from a range of 4.2–7.5 preoperatively on the VAS score to a range of 1.4–3.0 postoperatively at the final follow up. Insufficient decompression was noted in 3% of the reported cases. The overall complication rate was reported at 18–20%, with dural tear at 3.6–9% and hematoma at 0–4%. Conclusion Unilateral laminotomy with bilateral decompression has favorable short- and mid-term pain and functional outcomes with low recurrence and complication rates. This, however, needs to be further confirmed in larger, long-term follow-up, prospective, comparative studies between open, and minimally invasive techniques

PPARGC1A and IGF Polymorphisms Correlate with Greater Strength Performance in Healthy Young Adult Caucasian Cohorts

Background Recent studies show single nucleotide polymorphisms (SNPs) in PPARGC1A (coding for PGC-1 α) and Insulin-like Growth Factor 1 (IGF-1) genes correlate with greater power sport performance in professional athletes.1,2 In rs8192678 on the PPARGC1A gene, a substitution causes lower PGC-1α expression and reduced performance.1 For IGF-1 rs7136446 polymorphism, GG homozygosity correlates with greater expression of IGF-1 and increased maximal force.3 Objective The purpose of our study was to investigate whether rs8192678 or rs7136446 predict strength performance in young Caucasian adults who are not elite athletes. Methods Different measurements of strength were obtained from two cohorts of young adult Caucasian individuals, Functional Single Nucleotide Polymorphism Associated with Human Muscle Size and Strength (FAMuSS) and a sub-cohort of the Assessing Inherited Markers of Metabolic Syndrome in the Young (AIMMY) University of Calgary cohort.IGF-1 in PPARGC1A was not in Hardy Weinberg equilibrium, but the distribution of alleles was similar to a prior study of IGF1 gene variants4. Analysis of covariance (ANCOVA) models were utilized to analyze for genotype-phenotype associations. Results Ser/Ser genotype females had a greater percentage change in 1-RM strength in the dominant (D) arm, but no statistical significance was found regarding baseline strength, percentage change in the non-dominant (ND) arm, or percentage change of isometric strength. In male participants, the Gly/Gly genotype was more beneficial to baseline 1-RM strength. Our study found no significant associations for variants of rs8192678 with VO2 max. Discussion We found male G/G individuals had a greater percent change in isometric strength than heterozygous individuals. Females with at least one G allele had a greater baseline isometric strength and VO2 max. Our results support earlier findings of correlation with greater maximal force production3 and indicate a sexually dimorphic effect. Variation in rs8192678 and rs7136446 may help predict individual response to an exercise program, particularly in females. References: 1) Gineviciene V, Jakaitiene A, Aksenow MO, et al. Association analysis of ACE, ACTN3 and PPARGC1A gene polymorphisms in two cohorts of European strength and power athletes. Biol Sport 2016; 33(3):199-206. 2) Ben-Zaken S, Malach S, Meckel Y, et al. Frequency of the IGF A/G rs7136446 Polymorphism and Athletic Performance. Acta Kinesiologiae Universitatis Tartuensis 2016; 22: 36-46. 3) Huuskonen A, Lappalainen J, Oksala N, et al. Common Genetic Variation in the IGF1 Associates with Maximal Force Output. Medicine & Science in Sports & Exercise 2011; 43: 2368-2374. 4) Rzehak P, Grote V, Lattka E, et al. Associations of IGF-1 gene variants and milk protein intake with IGF-1 concentrations in infants at age 6 months- results from a randomized clinical trial. Growth Hormone & IGF Research 2013; 23: 149-158

Association of recently described RANK and OPG polymorphisms and measures of bone quality in young adults

Background: Increased fracture susceptibility is correlated with suboptimal bone quality measures, which are thought to be highly influenced by genetic factors. Previous studies have determined that specific receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) single nucleotide polymorphisms (SNPs) are associated with bone mineral density (BMD) and bone geometry parameters in older men. The RANK, RANKL, and OPG systems play a vital role in the regulation of osteoclasts and bone resorption. Further investigation into genetic variation within these genes is essential in order to identify those at risk for future fragility fractures. Objective: Our study sought to determine whether RANKL/RANK/OPG SNPs rs3018362, rs17665435, rs6567276, and rs10505348 influence bone quality measures in younger populations. Methods: The Assessing Inherited Markers of Metabolic Syndrome in the Young (AIMMY) study comprised healthy, young adults (18-35yrs) from the University of Calgary (UC) sub-cohort (n=209). The Bone Health study comprised healthy African-American children (5-9yrs, n=97). The Functional Single Nucleotide Polymorphism Associated with Human Muscle Size and Strength (FAMuSS) study comprised healthy, young adults (18-40yrs, n=891). The bone quality phenotypes analyzed included total body BMD in AIMMY and total BMD adjusted for height in the Bone Health study measured by dual energy x-ray absorptiometry (DEXA). Three SNPs for RANK (rs3018362, rs17665435, rs6567276) and one SNP for OPG (rs10505348) were genotyped in the AIMMY sub-cohort using ThermoFisher’s Applied Biosystems Taqman SNP genotyping assays. Alleles were determined through allelic discrimination assays using real-time PCR (qPCR). SNPs were genotyped in the FAMuSS cohort using Illumina Multi-Ethnic Genotyping Array (MEGA). Hardy-Weinberg equilibrium was tested for the allelic frequency of each SNP and analysis of covariance (ANCOVA) was used to test for associations. Results and Discussion: Our results did not support those of previous studies and suggest that the SNPs rs3018362, rs17665435, rs6567276, and rs10505348 are not associated with BMD or other bone quality measures in young adults. The only association that approached significance was rs3018362 and height-adjusted BMD in males of the Bone Health cohort (p=0.07). We suspect that the lack of association in our study indicates that these SNPs may not play a role in the development of peak bone mass despite being important in determining bone quality in seniors. To further characterize the effect of RANKL/RANK/OPG variations on the multifactorial regulation of bone quality phenotypes, future studies should evaluate the relationship between these variants and bone phenotypes in cohorts of varying ages and ethnicities

Effect of genetic variation in GSTP1 and AXIN1 on bone mineral density in children and young adults

Background: The Glutathione S-transferase P 1 (GSTP1) family of enzymes minimize oxidative cellular damage which adversely affect bone health. Studieshave shown that variation at rs1695 in GSTP1 negatively impacts BMD. Another determinant in bone quality is the canonical-Wnt pathway in which the AXIN1 protein functions as a negative regulator. Previous studies have associated the rs9921222 variant of AXIN1 with lower total BMD/osteoporosis. Objective: To expand our understanding of the influence of rs1695 and rs9921222 on BMD. Methods: DNA samples from the Bone Health (African-American) cohort and a Caucasian sub-cohort of the Assessing Inherited Markers of Metabolic Syndrome in the Young (AIMMY) were utilized to measure total BMD without head z-score (adjusted for height) and total BMD, respectively. Illumina Multi-Ethnic Genotyping Array (MEGA) chip and Applied Biosystems Taqman allelic discrimination assays/Real-Time PCR were utilized for the Bone Health and AIMMY cohorts, respectively. ANCOVA models where genotype was the dependent variable, appropriate phenotype the independent variable, and age (for Bone Health) or age and height (for AIMMY) as covariates were utilized. Results: A statistically significant association between total BMD and rs1695 was observed in males of the AIMMY Caucasian cohort (p=0.047). No significant association between the homozygous GG variant of rs1695 and total BMD was found. No statistically significant genotype-phenotype associations between rs9921222 or rs1695 and total BMD were present in the Bone Health cohort using an additive genetic model. There was no reported association between total BMD and the rs1695 GG homozygote variant. Discussion: Significant differences in the association of genetic variants of rs1695 and BMD in both the AIMMY and Bone Health cohorts could be influenced by race/ethnicity- both of which have been significantly associated with bone quality/fracture risk. The significant association present in Caucasian males of the AIMMY cohort (p=0.047) but not in females (p = 0.33) underscores the important role of sexual dimorphism in determining musculoskeletal phenotypes. The presence of the rs1695 G allele variant in GSTP1 could indicate appreciable build-up of ROS in males and subsequently result in lower quality of bone. Our work did not find a significant association with rs9921222 and total BMD or BMD z-score minus head. Conflicting results with previous studies could be attributed to the highly polygenic nature of BMD. It is plausible that rs9921222 may be inherited with other SNPs that are associated with lower BMD. The present study could not account for confounding SNPs that may have been inherited along with rs9921222

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used