MitoH3: Mitochondrial Haplogroup and Homoplasmic/Heteroplasmic Variant Calling Pipeline for Alzheimer's Disease Sequencing Project.

Background: Mitochondrial DNA (mtDNA) is a double-stranded circular DNA and has multiple copies in each cell. Excess heteroplasmy, the coexistence of distinct variants in copies of mtDNA within a cell, may lead to mitochondrial impairments. Accurate determination of heteroplasmy in whole-genome sequencing (WGS) data has posed a significant challenge because mitochondria carrying heteroplasmic variants cannot be distinguished during library preparation. Moreover, sequencing errors, contamination, and nuclear mtDNA segments can reduce the accuracy of heteroplasmic variant calling. Objective: To efficiently and accurately call mtDNA homoplasmic and heteroplasmic variants from the large-scale WGS data generated from the Alzheimer's Disease Sequencing Project (ADSP), and test their association with Alzheimer's disease (AD). Methods: In this study, we present MitoH3-a comprehensive computational pipeline for calling mtDNA homoplasmic and heteroplasmic variants and inferring haplogroups in the ADSP WGS data. We first applied MitoH3 to 45 technical replicates from 6 subjects to define a threshold for detecting heteroplasmic variants. Then using the threshold of 5% ≤variant allele fraction≤95%, we further applied MitoH3 to call heteroplasmic variants from a total of 16,113 DNA samples with 6,742 samples from cognitively normal controls and 6,183 from AD cases. Results: This pipeline is available through the Singularity container engine. For 4,311 heteroplasmic variants identified from 16,113 samples, no significant variant count difference was observed between AD cases and controls. Conclusions: Our streamlined pipeline, MitoH3, enables computationally efficient and accurate analysis of a large number of samples.

Relationship between Workload, Psychological State and Sleep in Female Soccer Athletes.

This study assessed the multifaceted relations between measures of workload, psychological state, and recovery throughout an entire soccer season. A prospective longitudinal study was utilized to measure workload (GPS training load, RPE), psychological state (mental stress, mental fatigue, and mood), and recovery (sleep duration, sleep quality, and soreness), across ninety observations. Separate linear-mixed effect models were used to assess outcomes of RPE, soreness, and sleep duration. A linear mixed-effects model explained 59% of the variance in RPE following each session. Specifically, each standard deviation increase in GPS load and mental stress in the morning prior to training increased RPE by 1.46(SE=0.08) and 0.29(SE= 0.07) respectively, following that day's training. Furthermore, a significant interaction was found between several predictor variables and chronological day in the season while predicting RPE. Specifically, for each standard deviation increase in GPS load, RPE went up by 0.055 per day across the season suggesting that load had a higher impact on RPE as the season progressed. In contrast, the interaction of day by mental stress, sleep duration, and soreness continued to be stronger as the season progressed. Each linear mixed-effect model predicted a larger amount of variance when accounting for individual variations in the random effects.

A comparative study of structural variant calling in WGS from Alzheimer's disease families.

Detecting structural variants (SVs) in whole-genome sequencing poses significant challenges. We present a protocol for variant calling, merging, genotyping, sensitivity analysis, and laboratory validation for generating a high-quality SV call set in whole-genome sequencing from the Alzheimer's Disease Sequencing Project comprising 578 individuals from 111 families. Employing two complementary pipelines, Scalpel and Parliament, for SV/indel calling, we assessed sensitivity through sample replicates (N = 9) with in silico variant spike-ins. We developed a novel metric, D-score, to evaluate caller specificity for deletions. The accuracy of deletions was evaluated by Sanger sequencing. We generated a high-quality call set of 152,301 deletions of diverse sizes. Sanger sequencing validated 114 of 146 detected deletions (78.1%). Scalpel excelled in accuracy for deletions ≤100 bp, whereas Parliament was optimal for deletions >900 bp. Overall, 83.0% and 72.5% of calls by Scalpel and Parliament were validated, respectively, including all 11 deletions called by both Parliament and Scalpel between 101 and 900 bp. Our flexible protocol successfully generated a high-quality deletion call set and a truth set of Sanger sequencing-validated deletions with precise breakpoints spanning 1-17,000 bp.

Intensity Distribution of Collegiate Cross-Country Competitions.

The primary purpose of the current investigation was to perform an intensity distribution analysis of a collegiate cross-country (CC) competition, with a secondary purpose to compare race times (RT) with modeled performance times (MPT). Participants completed an incremental treadmill test to determine gas exchange threshold (GET), while the three-minute all-out test was conducted on a 400 m outdoor track to determine critical velocity (CV) and D prime (D'). GET and CV were used as physiological markers for the intensity zones based on heart rate (HR) and running velocity (RV), while CV and D' were used to determine modeled performance times. Participants wore a Global Positioning System (GPS) watch and heart rate (HR) monitor during competition races. Statistically, less time was spent in HR Zone 1 (12.1% ± 13.7%) compared to Zones 2 (37.6% ± 30.2%) and 3 (50.3% ± 33.7%), while a statically greater amount of time was spent in RV Zone 2 (75.0% ± 20.7%) compared to Zones 1 (8.4% ± 14.0%) and 3 (16.7% ± 19.1%). RTs (1499.5 ± 248.5 seconds (s)) were statistically slower compared to MPTs (1359.6 ± 192.7 s). The observed differences in time spent in each zone are speculated to be related to the influence of environmental conditions on internal metrics and difference in the kinetics of HR and running velocity. Differences in RTs and MPTs are likely due to the MPT equation modeling all-out performance and not considering race strategies.

DNA from multiple viral species is associated with Alzheimer's disease risk.

INTRODUCTION: Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer's disease (AD) risk by independent lines of evidence. We explored this association by comparing the frequencies of viral species identified in a large sample of AD cases and controls. METHODS: DNA sequence reads that did not align to the human genome in sequences were mapped to viral reference sequences, quantified, and then were tested for association with AD in whole exome sequences (WES) and whole genome sequences (WGS) datasets. RESULTS: Several viruses were significant predictors of AD according to the machine learning classifiers. Subsequent regression analyses showed that herpes simplex type 1 (HSV-1) (odds ratio [OR] = 3.71, p = 8.03 × 10-4) and human papillomavirus 71 (HPV-71; OR = 3.56, p = 0.02), were significantly associated with AD after Bonferroni correction. The phylogenetic-related cluster of Herpesviridae was significantly associated with AD in several strata of the data (p < 0.01). DISCUSSION: Our results support the hypothesis that viral infection, especially HSV-1, is associated with AD risk.

Acute Oxygen Consumption Response to Fast Start High-Intensity Intermittent Exercise.

The current investigation compared the acute oxygen consumption (VO2) response of two high-intensity interval exercises (HIIE), fast start (FSHIIE), and steady power (SPHIIE), which matched w prime (W') depletion. Eight cyclists completed an incremental max test and a three-minute all-out test (3MT) to determine maximal oxygen consumption (VO2max), critical power (CP), and W'. HIIE sessions consisted of 3 X 4 min intervals interspersed by 3 min of active recovery, with W' depleted by 60% (W'target) within each working interval. SPHIIE depleted the W'target consistently throughout the 3 min intervals, while FSHIIE depleted the W'target by 50% within the first minute, with the remaining 50% depleted evenly across the remainder of the interval. The paired samples t-test revealed no differences in the percentage of training time spent above 90% of VO2max (PT ≥ 90% VO2max) between SPHIIE and FSHIIE with an average of 25.20% and 26.07%, respectively. Pairwise comparisons indicated a difference between minute 1 peak VO2, minute 2, and minute 3, while no differences were present between minutes 2 and 3. The results suggest that when HIIE formats are matched based on W' expenditure, there are no differences in PT ≥ 90% VO2max or peak VO2 during each interval.

Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects.

Structural variations (SVs) are important contributors to the genetics of human diseases. However, their role in Alzheimer's disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. We analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (N = 16,905) and identified 400,234 (168,223 high-quality) SVs. Laboratory validation yielded a sensitivity of 82% (85% for high-quality). We found a significant burden of deletions and duplications in AD cases, particularly for singletons and homozygous events. On AD genes, we observed the ultra-rare SVs associated with the disease, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1. Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, exemplified by a 5k deletion in complete LD with rs143080277 in NCK2. We also identified 16 SVs associated with AD and 13 SVs linked to AD-related pathological/cognitive endophenotypes. This study highlights the pivotal role of SVs in shaping our understanding of AD genetics.

Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project.

Alzheimer's Disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. Here, we investigated the association between AD and both common variants and aggregates of rare coding and noncoding variants in 13,371 individuals of diverse ancestry with whole genome sequence (WGS) data. Pooled-population analyses identified genetic variants in or near APOE, BIN1, and LINC00320 significantly associated with AD (p < 5×10-8). Population-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and noncoding variants in this region. Finally, we observed suggestive associations (p < 5×10-5) of aggregates of rare coding rare variants in ABCA7 among non-Hispanic Whites (p=5.4×10-6), and rare noncoding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p=7.2×10-8). Complementary pooled-population and population-specific analyses offered unique insights into the genetic architecture of AD.

Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects.

Structural variations (SVs) are important contributors to the genetics of numerous human diseases. However, their role in Alzheimer's disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. Here, we analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP, N=16,905 subjects) and identified 400,234 (168,223 high-quality) SVs. We found a significant burden of deletions and duplications in AD cases (OR=1.05, P=0.03), particularly for singletons (OR=1.12, P=0.0002) and homozygous events (OR=1.10, P<0.0004). On AD genes, the ultra-rare SVs, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1, were associated with AD (SKAT-O P=0.004). Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, e.g., a deletion (chr2:105731359-105736864) in complete LD (R2=0.99) with rs143080277 (chr2:105749599) in NCK2. We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Novel loci for Alzheimer's disease identified by a genome-wide association study in Ashkenazi Jews.

INTRODUCTION: Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA). METHODS: We applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome-wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n = 42,682), whole genome sequencing (WGS, n = 16,815), and whole exome sequencing (WES, n = 20,504) data sets. The association of AD was tested genome wide (GW) in the GWAS and WGS data sets and exome wide (EW) in all three data sets (EW). Gene-based analyses were performed using aggregated rare variants. RESULTS: In addition to apolipoprotein E (APOE), GW analyses (1355 cases and 1661 controls) revealed associations with TREM2 R47H (p = 9.66 × 10-9 ), rs541586606 near RAB3B (p = 5.01 × 10-8 ), and rs760573036 between SPOCK3 and ANXA10 (p = 6.32 × 10-8 ). In EW analyses (1504 cases and 2047 controls), study-wide significant association was observed with rs1003710 near SMAP2 (p = 1.91 × 10-7 ). A significant gene-based association was identified with GIPR (p = 7.34 × 10-7 ). DISCUSSION: Our results highlight the efficacy of founder populations for AD genetic studies.

Six-year experience of Australia's first dedicated cancer of unknown primary clinic.

BACKGROUND: Diagnosis and management of cancers of unknown primary (CUP) remain challenging. This study examines the referral patterns, management and outcomes of patients referred to Australia's first dedicated CUP clinic. METHODS: Retrospective medical record review was conducted for patients seen at the Peter MacCallum Cancer Centre CUP clinic between July 2014 and August 2020. Overall survival (OS) was analysed for patients with a CUP diagnosis where treatment information was available. RESULTS: Of 361 patients referred, fewer than half had completed diagnostic work-up at the time of referral. A diagnosis of CUP was established in 137 (38%), malignancy other than CUP in 177 (49%) and benign pathology in 36 (10%) patients. Genomic testing was successfully completed in 62% of patients with initial provisional CUP and impacted management in 32% by identifying a tissue of origin or actionable genomic alteration. The use of site-specific, targeted therapy or immunotherapy was independently associated with longer OS compared to empirical chemotherapy. CONCLUSION: Our specialised CUP clinic facilitated diagnostic work-up among patients with suspected malignancy and provided access to genomic testing and clinical trials for patients with a CUP diagnosis, all of which are important to improve outcomes in this patient population.

Influence of water-level variability on fish assemblage and natural reproduction following connectivity enhancement in a Typha-dominated coastal wetland, USA.

We evaluated a wetland habitat modification strategy to contrast fish assemblage structure and the production of young-of-the-year (YOY) fish between different engineered habitats (i.e., spawning pool complexes and connectivity channels) relative to unmodified lateral channels in a large drowned river mouth tributary of the St Lawrence River. Prior to habitat modifications, the coastal wetland was impaired by water level regulations and dominance of the invasive hybrid cattail, Typha × glauca, which collectively replaced or created barriers to seasonally flooded spawning habitats important to fish. Connectivity enhancements provided fish access along a wetland habitat gradient from sedge-meadows to the deeper water robust emergent main channel. Across an 8-year fish emigration dataset (2012, 2013, 2016-2021) more than 90% of all captured fish (Ntotal = 218,086 fish) were YOY and modified habitats outperformed the unmodified channels in total fish catch-per-unit-effort (CPUE) per year (both YOY and non-YOY). Spawning pool complexes had higher YOY species richness than unmodified channel habitats. Fish assemblage structure differed between the modified habitats, where connectivity channels and unmodified channels shared a more similar fish assemblage than spawning pool complexes. Modified habitats, however, supported warmer water and higher dissolved oxygen than the unmodified channels. Redundancy analysis and linear mixed-effect modelling with abiotic variables (hydrology, temperature and dissolved oxygen) showed significant effects on fish assemblage structure, species richness and CPUE of fish emigrating from the modified and unmodified habitats. Historic flooding in 2017 and 2019 was a primary driver of YOY fish production and fish assemblage structure, but also appeared to be associated with near anoxic conditions systemwide. YOY fish for several species was inversely affected by floods at spawning pool complexes, but CPUE of YOY fish for these species appeared unaffected at the connectivity channels despite low dissolved oxygen. Diversified habitat structure (i.e., connectivity channels and spawning pool complexes) offers a management option to enhance habitat for fish that allowed compensatory effects on the capture of YOY fish of several species during floods. This multifaceted outcome from the habitat modifications resulted in unique fish assemblages between the channelized and spawning pool habitat. A connectivity-based habitat enhancement strategy provides adaptability for an uncertain climatic and regulatory future for the Laurentian Great Lakes and St Lawrence River.

Use of Exercise Training to Enhance the Power-Duration Curve: A Systematic Review.

ABSTRACT: Hurd, KA, Surges, MP, and Farrell, JW. Use of exercise training to enhance the power-duration curve: a systematic review. J Strength Cond Res 37(3): 733-744, 2023-The power/velocity-duration curve consists of critical power (CP), the highest work rate at which a metabolic steady state can obtained, and W' (e.g., W prime), the finite amount of work that can be performed above CP. Significant associations between CP and performance during endurance sports have been reported resulting in CP becoming a primary outcome for enhancement following exercise training interventions. This review evaluated and summarized the effects of different exercise training methodologies for enhancing CP and respective analogs. A systematic review was conducted with the assistance of a university librarian and in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Ten studies met the criteria for inclusion and were reviewed. Four, 2, 2, 1, and 1 articles included swimming, cycling, resistance training, rowing, and running, respectively. Improvements in CP, and respective analogs, were reported in 3 swimming, 2 cycling, and 1 rowing intervention. In addition, only 2 cycling and 1 swimming intervention used CP, and respective analogs, as an index of intensity for prescribing exercise training, with one cycling and one swimming intervention reporting significant improvements in CP. Multiple exercise training modalities can be used to enhance the power/velocity-duration curve. Significant improvements in CP were often reported with no observed improvements in W' or with slight decreases. Training may need to be periodized in a manner that targets enhancements in either CP or W' but not simultaneously.

Transmission of Carbapenem-Resistant Klebsiella pneumoniae in US Hospitals.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKp) is the most prevalent carbapenem-resistant Enterobacterales in the United States. We evaluated CRKp clustering in patients in US hospitals. METHODS: From April 2016 to August 2017, 350 patients with clonal group 258 CRKp were enrolled in the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae, a prospective, multicenter, cohort study. A maximum likelihood tree was constructed using RAxML. Static clusters shared ≤21 single-nucleotide polymorphisms (SNP) and a most recent common ancestor. Dynamic clusters incorporated SNP distance, culture timing, and rates of SNP accumulation and transmission using the R program TransCluster. RESULTS: Most patients were admitted from home (n = 150, 43%) or long-term care facilities (n = 115, 33%). Urine (n = 149, 43%) was the most common isolation site. Overall, 55 static and 47 dynamics clusters were identified involving 210 of 350 (60%) and 194 of 350 (55%) patients, respectively. Approximately half of static clusters were identical to dynamic clusters. Static clusters consisted of 33 (60%) intrasystem and 22 (40%) intersystem clusters. Dynamic clusters consisted of 32 (68%) intrasystem and 15 (32%) intersystem clusters and had fewer SNP differences than static clusters (8 vs 9; P = .045; 95% confidence interval [CI]: -4 to 0). Dynamic intersystem clusters contained more patients than dynamic intrasystem clusters (median [interquartile range], 4 [2, 7] vs 2 [2, 2]; P = .007; 95% CI: -3 to 0). CONCLUSIONS: Widespread intrasystem and intersystem transmission of CRKp was identified in hospitalized US patients. Use of different methods for assessing genetic similarity resulted in only minor differences in interpretation.

Innovative approaches to service integration addressing the unmet needs of irritable bowel syndrome patients and new approaches for the needs of IBS patients.

Background: Irritable bowel syndrome (IBS) is a common multifactorial condition that affects the large intestine and is characterized by chronic and relapsing abdominal pain and altered bowel habit. IBS is due to a combination of genetic, environmental and dietary factors. It's usually a lifelong problem very frustrating to live with and can have a big impact on quality of life, as single-agent therapy ra. Objective: To analyze the approaches and solutions that address the social and health unmet needs of patients with IBS. Design: A quantitative-qualitative approach was adopted in the current study to identify and specify key digital solution and high impact user scenarios applied to IBS patients, through an adaptation of the "Blueprint on Digital Transformation in Health and Care in an Ageing Society" persona methodology. Settings: Digital health solutions bring the potential of supporting health interventions through mobile apps, wearable devices, telemedicine. Patients: A Survey was administered to a group of patients in an anonymous form, and no need for Medical Ethical Committee approval was identified. Interventions: The theoretical elaboration IBS personas was developed through an interdisciplinary Focus Group, which also mapped the pathway for the patient's management. Main outcome: Three main needs were identified to be met to improve IBS patient's lifestyle: access to psychological support, mHealth solutions supporting diet and adapted physical activity, and home-based digital health support. mHealth intervention has been identified for diet adherence, physical exercise and psychological well-being. The process has been mapped and adapted to integrate the new solutions into the care pathway. Limitation: Further research is needed to evaluate how mHealth services enable IBS patients to manage their conditions and improve their quality of life. Conclusion: The person-centered approach was implemented through a multidisciplinary Focus group that enabled the identification of the need for a mHealth intervention.

The impact of increasing levels of blood C-reactive protein on the inflammatory loci SPI1 and CD33 in Alzheimer's disease.

Apolipoprotein ε4 (APOE ε4) is the most significant genetic risk factor for late-onset Alzheimer's disease (AD). Elevated blood C-reactive protein (CRP) further increases the risk of AD for people carrying the APOE ε4 allele. We hypothesized that CRP, as a key inflammatory element, could modulate the impact of other genetic variants on AD risk. We selected ten single nucleotide polymorphisms (SNPs) in reported AD risk loci encoding proteins related to inflammation. We then tested the interaction effects between these SNPs and blood CRP levels on AD incidence using the Cox proportional hazards model in UK Biobank (n = 279,176 white participants with 803 incident AD cases). The five top SNPs were tested for their interaction with different CRP cutoffs for AD incidence in the Framingham Heart Study (FHS) Generation 2 cohort (n = 3009, incident AD = 156). We found that for higher concentrations of serum CRP, the AD risk increased for SNP genotypes in 3 AD-associated genes (SPI1, CD33, and CLU). Using the Cox model in stratified genotype analysis, the hazard ratios (HRs) for the association between a higher CRP level (≥10 vs. <10 mg/L) and the risk of incident AD were 1.94 (95% CI: 1.33-2.84, p < 0.001) for the SPI1 rs1057233-AA genotype, 1.75 (95% CI: 1.20-2.55, p = 0.004) for the CD33 rs3865444-CC genotype, and 1.76 (95% CI: 1.25-2.48, p = 0.001) for the CLU rs9331896-C genotype. In contrast, these associations were not observed in the other genotypes of these genes. Finally, two SNPs were validated in 321 Alzheimer's Disease Neuroimaging (ADNI) Mild Cognitive Impairment (MCI) patients. We observed that the SPI1 and CD33 genotype effects were enhanced by elevated CRP levels for the risk of MCI to AD conversion. Furthermore, the SPI1 genotype was associated with CSF AD biomarkers, including t-Tau and p-Tau, in the ADNI cohort when the blood CRP level was increased (p < 0.01). Our findings suggest that elevated blood CRP, as a peripheral inflammatory biomarker, is an important moderator of the genetic effects of SPI1 and CD33 in addition to APOE ε4 on AD risk. Monitoring peripheral CRP levels may be helpful for precise intervention and prevention of AD for these genotype carriers.

THE EFFECTS OF EXERCISE TRAINING ON UPPER EXTREMITY FUNCTION FOR PERSONS WITH MULTIPLE SCLEROSIS: A SYSTEMATIC REVIEW.

Objective: To evaluate the effects of exercise training on upper extremity physical function and physiological fitness outcomes in persons with multiple sclerosis (PwMS). Methods: A search of 3 electronic databases (EMBASE, CINAHL, and ovidMEDLINE) was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The included studies were randomized control trials that reported at least one outcome measure related to upper extremity function, contained a component of exercise training, and included PwMS. Results: Of the 1381 articles retrieved from the electronic databases, 8 articles met the specific inclusion criteria. All the included articles incorporated strength training exercises into the rehabilitation intervention. Reported outcomes included the 9 Hole Peg Test (9HPT), Action Research Arm Test (ARAT), and Fugl-Meyer Assessment, with 3, 3, and 0 reporting significant improvements, respectively. Only grip strength was included as a physiological fitness outcome, with 2 articles reporting significant improvements. Conclusion: The results of this review suggest that strength training may elicit improvements in functional and physiological upper extremity outcomes for PwMS. Several limitations of the current review must be noted, including a limited number of studies and the combination of strength training with other rehabilitative modalities.