A prospective evaluation of survivorship of asymptomatic degenerative rotator cuff tears

BACKGROUND: The purpose of this prospective study was to report the long-term risks of rotator cuff tear enlargement and symptom progression associated with degenerative asymptomatic tears. METHODS: Subjects with an asymptomatic rotator cuff tear in one shoulder and pain due to rotator cuff disease in the contralateral shoulder enrolled as part of a prospective longitudinal study. Two hundred and twenty-four subjects (118 initial full-thickness tears, fifty-six initial partial-thickness tears, and fifty controls) were followed for a median of 5.1 years. Validated functional shoulder scores were calculated (visual analog pain scale, American Shoulder and Elbow Surgeons [ASES], and simple shoulder test [SST] scores). Subjects were followed annually with shoulder ultrasonography and clinical evaluations. RESULTS: Tear enlargement was seen in 49% of the shoulders, and the median time to enlargement was 2.8 years. The occurrence of tear-enlargement events was influenced by the severity of the final tear type, with enlargement of 61% of the full-thickness tears, 44% of the partial-thickness tears, and 14% of the controls (p < 0.05). Subject age and sex were not related to tear enlargement. One hundred subjects (46%) developed new pain. The final tear type was associated with a greater risk of pain development, with the new pain developing in 28% of the controls, 46% of the shoulders with a partial-thickness tear, and 50% of those with a full-thickness tear (p < 0.05). The presence of tear enlargement was associated with the onset of new pain (p < 0.05). Progressive degenerative changes of the supraspinatus muscle were associated with tear enlargement, with supraspinatus muscle degeneration increasing in 4% of the shoulders with a stable tear compared with 30% of the shoulders with tear enlargement (p < 0.05). Nine percent of the shoulders with a stable tear showed increased infraspinatus muscle degeneration compared with 28% of those in which the tear had enlarged (p = 0.07). CONCLUSIONS: This study demonstrates the progressive nature of degenerative rotator cuff disease. The risk of tear enlargement and progression of muscle degeneration is greater for shoulders with a full-thickness tear, and tear enlargement is associated with a greater risk of pain development across all tear types. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

Tel1(ATM) kinase mechanisms in S. cerevisiae telomere length regulation and DNA damage response

In S. cerevisiae Tel1 and Mec1 are kinases that regulate both DNA damage response and telomere length. Mass spectrometry approaches have identified hundreds of putative Tel1/Mec1 substrates in response to DNA damage, yet the biological significance of these phosphorylation events remain largely unexamined. We examined the relationship between Tel1 and Mec1 with two known substrates: Rad53 and the MRX complex. Mutation of critical Tel1/Mec1 phosphorylation motifs in Rad53 shortened telomeres similar to rad53∆ and mec1∆. Further genetic analysis suggested that Rad53 is in the Mec1 telomere length pathway which is distinct from the Tel1 pathway. Mutation of Tel1/Mec1 phosphorylation motifs in the MRX complex reduced the DNA damage response, specifically in the non-homologous end joining pathway, but surprisingly, had no telomere length phenotype. Epistasis analysis with a Tel1 hypermorphic allele, TEL1-hy909 and MRX complex components demonstrated that the MRX complex is required to activate Tel1 for telomere elongation but it is not required downstream of Tel1. Together these data demonstrate that the pathways regulated by Tel1 and Mec1 in telomere length regulation are distinct from the DNA damage response. Tel1(ATM) and Mec1(ATR) kinases regulate parallel pathways in telomere length regulation and the DNA damage response. Tel1 and Mec1 share a phosphorylation motif, many substrates, and similar domain structures, and yet they execute distinct functions. Regions of Mec1 were replaced with regions of Tel1 in a series of domain swaps to better understand which regions in Tel1 are sufficient for its functions. Telomere length regulation was assayed by Southern blot analysis and DNA damage response function was assayed by MMS challenge. We demonstrated that the N-terminus of Tel1 is conveys partial Tel1 telomere length regulation to Mec1. Additional data suggests that the combined swap of the N-terminus with the C-terminal FAT-C-terminal (FATC) domain may convey additional Tel1 telomere length function. The Tel1/ATM N-terminal (TAN) was previously shown to be necessary for Tel1 functions. Experiments performed in the context of a hypermorphic Tel1 allele, TEL1-hy909, suggest that the TAN domain is necessary for Tel1 kinase activation. Together these data increase our understanding of how Tel1 functions in key cellular processes

Tel1(ATM) kinase mechanisms in S. cerevisiae telomere length regulation and DNA damage response

In S. cerevisiae Tel1 and Mec1 are kinases that regulate both DNA damage response and telomere length. Mass spectrometry approaches have identified hundreds of putative Tel1/Mec1 substrates in response to DNA damage, yet the biological significance of these phosphorylation events remain largely unexamined. We examined the relationship between Tel1 and Mec1 with two known substrates: Rad53 and the MRX complex. Mutation of critical Tel1/Mec1 phosphorylation motifs in Rad53 shortened telomeres similar to rad53∆ and mec1∆. Further genetic analysis suggested that Rad53 is in the Mec1 telomere length pathway which is distinct from the Tel1 pathway. Mutation of Tel1/Mec1 phosphorylation motifs in the MRX complex reduced the DNA damage response, specifically in the non-homologous end joining pathway, but surprisingly, had no telomere length phenotype. Epistasis analysis with a Tel1 hypermorphic allele, TEL1-hy909 and MRX complex components demonstrated that the MRX complex is required to activate Tel1 for telomere elongation but it is not required downstream of Tel1. Together these data demonstrate that the pathways regulated by Tel1 and Mec1 in telomere length regulation are distinct from the DNA damage response. Tel1(ATM) and Mec1(ATR) kinases regulate parallel pathways in telomere length regulation and the DNA damage response. Tel1 and Mec1 share a phosphorylation motif, many substrates, and similar domain structures, and yet they execute distinct functions. Regions of Mec1 were replaced with regions of Tel1 in a series of domain swaps to better understand which regions in Tel1 are sufficient for its functions. Telomere length regulation was assayed by Southern blot analysis and DNA damage response function was assayed by MMS challenge. We demonstrated that the N-terminus of Tel1 is conveys partial Tel1 telomere length regulation to Mec1. Additional data suggests that the combined swap of the N-terminus with the C-terminal FAT-C-terminal (FATC) domain may convey additional Tel1 telomere length function. The Tel1/ATM N-terminal (TAN) was previously shown to be necessary for Tel1 functions. Experiments performed in the context of a hypermorphic Tel1 allele, TEL1-hy909, suggest that the TAN domain is necessary for Tel1 kinase activation. Together these data increase our understanding of how Tel1 functions in key cellular processes

Tel1 Activation by the MRX Complex Is Sufficient for Telomere Length Regulation but Not for the DNA Damage Response in Saccharomyces cerevisiae

Previous models suggested that regulation of telomere length in Saccharomyces cerevisiae by Tel1(ATM) and Mec1(ATR) would parallel the established pathways regulating the DNA damage response. Here, we provide evidence that telomere length regulation differs from the DNA damage response in both the Tel1 and Mec1 pathways. We found that Rad53 mediates a Mec1 telomere length regulation pathway but is dispensable for Tel1 telomere length regulation, whereas in the DNA damage response, Rad53 is regulated by both Mec1 and Tel1 Using epistasis analysis with a Tel1 hypermorphic allele, Tel1-hy909, we found that the MRX complex is not required downstream of Tel1 for telomere elongation but is required downstream of Tel1 for the DNA damage response. Our data suggest that nucleolytic telomere end processing is not a required step for telomerase to elongate telomeres

Progression from Sustained BK Viruria to Sustained BK Viremia with Immunosuppression Reduction Is Not Associated with Changes in the Noncoding Control Region of the BK Virus Genome

Changes in the BK virus archetypal noncoding control region (NCCR) have been associated with BK-virus-associated nephropathy (BKVAN). Whether sustained viremia, a surrogate for BKVAN, is associated with significant changes in the BK-NCCR is unknown. We performed PCR amplification and sequencing of (1) stored urine and (2) plasma samples from the time of peak viremia from 11 patients with sustained viremia who participated in a 200-patient clinical trial. The antimetabolite was withdrawn for BK viremia and reduction of the calcineurin inhibitor for sustained BK viremia. DNA sequencing from the 11 patients with sustained viremia revealed 8 insertions, 16 transversions, 3 deletions, and 17 transitions. None were deemed significant. No patient developed clinically evident BKVAN. Our data support, at a genomic level, the effectiveness of reduction of immunosuppression for prevention of progression from viremia to BKVAN

COVID 19 Vaccine Hesitancy and Health Literacy among Southern States in the United States

Introduction: COVID-19 vaccination in the United States (U.S.) has stalled, with the lowest rates observed in the southern parts of the country. Vaccine hesitancy is a primary contributor to this trend, and health literacy (HL) has been identified as a potential determinant for hesitancy. This study aims to assess the association between HL and COVID-19 vaccine hesitancy in a population residing in 14 southern states of the U.S. Methods: We utilized a web-based survey conducted in U.S. southern states between February and June 2021 that yielded 417 total responses. The outcome was “vaccine hesitancy”. The main independent variable was HL, assessed by validated measures whose responses were aggregated to an HL index score and subsequently categorized as “low or moderate HL”, and “high HL”. Descriptive statistics were performed, and multivariable logistic regression analysis was conducted, controlling for sociodemographic and other variables. Results: Of the total respondents (n=247 after data cleaning), the overall rate of vaccine hesitancy was 22.3%. The rate of vaccine hesitancy was 10.9% and 89.1% for low/moderate and high levels of HL, respectively, but the association was not significant. However, personal perception of COVID-19 threat was significantly associated with lower odds of vaccine hesitancy versus those without perception of threat [adjusted odds ratio, AOR: 0.15; 95% CI: 0.03-0.73; p = 0.0186]. Similarly, obtaining information from public health sources was significantly associated with a lower likelihood of vaccine hesitancy [AOR:0.17; 95% CI: 0.05-0.61; p=0.0064]. Conclusion: HL was not a significant predictor of vaccine hesitancy in a population residing in southern states, suggesting that low rates of vaccination in the region may not be due to knowledge about COVID-19. Personal perception of COVID-19 threats and obtaining information from public health sources were associated with decreased vaccine hesitancy. This implies that we should strengthen public health communication infrastructure in the country. We also need to unpack the contextual factors that contribute to the disproportionately high rates of vaccine hesitancy in the region