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Cell cycle dependent methylation of Dam1 contributes to kinetochore integrity and faithful chromosome segregation.
Get PDFThe kinetochore, a megadalton structure composed of centromeric (CEN) DNA and protein complexes, is required for faithful chromosome segregation in eukaryotes. The evolutionarily conserved Dam1/DASH complex (Ska1 in metazoans) is one of the essential protein sub-complexes of the budding yeast kinetochore. Previous studies showed that methylation of lysine residue 233 in Dam1 by Set1 is important for haploid growth as mutation of lysine 233 to alanine results in lethality. In this study, we report that Set1-mediated cell cycle dependent Dam1 lysine methylation contributes to kinetochore assembly and chromosomal stability. Our results show that Dam1 methylation is cell cycle regulated with the highest levels of methylation in metaphase. Consistent with these results, co-immunoprecipitation experiments revealed an interaction between Dam1 with Set1 in metaphase cells. Set1 has been shown to colocalize with Jhd2, a histone lysine demethylase which demethylates Set1-methylated histones. Affinity purification-based mass spectroscopy of Jhd2 associated proteins identified seven of the ten subunits of the Dam1 complex; an association of Jhd2 with non-histone proteins, such as Dam1 has not been previously reported. We confirmed the interaction of Jhd2 with Dam1 and showed that cells overexpressing JHD2 exhibit reduced levels of methylated lysine in Dam1 in wild type and UBP8 deletion strains, growth defects in kinetochore mutants, reduced levels of kinetochore proteins at CEN chromatin, defects in kinetochore biorientation and chromosome missegregation. In summary, we have shown that cell cycle dependent methylation of Dam1 plays a crucial role in the maintenance of kinetochore assembly for faithful chromosome segregation
Tough talks COVID-19 (TT-C) digital health intervention: multistate randomized controlled trial
Get PDFDuring the COVID-19 pandemic, rapid changes in variant virulence, limited personal protective equipment availability, and diminished hospital capacity necessitated aggressive vaccine distribution. To promote COVID-19 vaccination to historically underserved populations, the National Institutes of Health funded a small group of clinical trials, including the Tough Talks for COVID-19 vaccine (TT-C) digital health intervention (DHI) randomized controlled trial (RCT). Black young adults, 18–29 years, who were unvaccinated or insufficiently vaccinated against COVID-19 were recruited via social media in Alabama, Georgia, and North Carolina and randomized to the intervention or standard of care control (N = 360). Self-report data and vaccine cards were collected at baseline, 1- and 3-months post-randomization. Post-intervention, 6.4% received a new COVID-19 vaccine (8.4% intervention; 4.7% control). Odds of new COVID-19 vaccination were 1.88 (CI: 0.76, 4.69, p = 0.174) times higher in intervention compared to control participants adjusting for state. At 3 months post-randomziation, vaccine hesitancy was lower among intervention than control participants (CI:-0.34,-0.03, p = 0.02), and vaccine confidence and vaccine knowledge were higher in intervention versus control participants (CI:0.00,0.32, p = 0.05, CI:0.21,0.79, p = 0.01 respectively). Under rapidly changing conditions, the TT-C DHI produced promising results on vaccine attitudes but not behaviors among Southern Black young adults. The intervention could be adapted to address vaccine uptake among other minority populations.Trial registration: NCT05490329, registered on 03082022. https://clinicaltrials.gov/study/NCT05490329
Corrigendum to “Urban heat island impacts on heat-related cardiovascular morbidity: A time series analysis of older adults in US metropolitan areas” [Environ. Int. 178 (2023) 108005]
Get PDFCorrigendum to “Urban heat island impacts on heat-related cardiovascular morbidity: A time series analysis of older adults in US metropolitan areas
Exploring healthcare experiences of transgender people in the Jabula Uzibone study, South Africa: a longitudinal implementation science study
Get PDFINTRODUCTION: The World Health Organization promotes a transgender-differentiated service delivery (TG-DSD) model to overcome barriers to HIV service engagement among transgender people (TGP). For TGP, an essential element of DSD includes gender-affirming care which is non-stigmatising, free from discrimination and celebrates their gender identity. The Jabula Uzibone Study, launched in November 2023, assesses the cost and effectiveness of TG-DSD on HIV outcomes. In this paper, we describe the baseline characteristics of TGP in our study and explore whether there are differences in healthcare experiences among those seeking care at TG-DSD clinics versus standard service delivery (SSD) clinics at baseline. METHODS: This observational, mixed-method, prospective implementation study compares models of care at four TG-DSD and four SSD facilities using standardised observation checklists, in-depth and key informant interviews. For this paper, we asked participants about healthcare experiences and experiences of stigma through a structured, interviewer-administered quantitative survey. We assessed the sections of the quantitative survey which ask about self-reported experiences of stigma. RESULTS: The study enrolled 422 TGP with HIV (217 TG-DSD and 205 SSD) and 248 TGP without HIV (128 TG-DSD and 120 SSD); 15% (102/670) gender non-conforming, 15% (91/670) TG men and 70% (477/670) TG women. Participants' median age was 29 years, interquartile range: 24-35 years. SSD participants at baseline were 46% more likely to experience stigma compared to their TG-DSD counterparts (aOR = 1.46, 95% CI: 1.06, 2.01). SSD participants were more likely to encounter a healthcare provider who is unwilling to provide care for them (aOR = 1.55, 95% CI: 1.09, 2.21) and to report that healthcare workers are unable to provide the same quality care to TGP as they do other people (aOR = 1.46, 95% CI: 1.00, 1.91) compared to their TG-DSD counterparts. CONCLUSIONS: TGP from TG-DSD facilities were less likely to report experiences of facility-based enacted stigma at baseline, compared to the TGP from SSD facilities. Our study highlights the importance of provider training in tailored transgender healthcare to provide gender-affirming healthcare services. Results from the Jabula Uzibone study will provide further evidence of the effectiveness of TG-DSD models in sub-Saharan Africa, and the role of stigma and discrimination in HIV outcomes among TGP
LGBT+ Inclusion and Human Rights in Taiwan: A Scoping Review of the Literature
Get PDFTaiwan is regarded as the vanguard of LGBT+ rights in Asia. We conducted a scoping review to map research on LGBT+ inclusion in Taiwan, identify knowledge gaps and propose future directions for research and policy. Results indicate a predominant focus on health, with the over-representation of gay men and exclusion of lesbian and bisexual women and transgender/gender diverse people. Despite being the first Asian jurisdiction to legalise same-sex marriage, insufficient policy protections were evidenced concerning family formation, adoption, and parenting, with family systems that largely exclude LGBT+ people. Findings reveal pervasive discrimination and exclusion in education, an economic system that restricts LGBT+ people’s employment opportunities and advancement, and a healthcare system that lacks competencies in serving LGBT+ people. Future research on LGBT+ inclusion in Taiwan should address understudied populations, provide disaggregated data on LGBT+ individuals, and advance evidence to support policy protections in education, economic, family, health, and political domains
Red cell physiologic stress result in lower quality transfusions: A randomized trial in adults with sickle cell disease.
Get PDFPeople with sickle cell disease (SCD) may be transfused with red cell units that are near the end of their storage life, exposing them to components of the red cell storage lesion. The current study evaluated the clinical impact of storage age and red cell distress markers on chronically transfused adults with SCD. This randomized prospective clinical trial recruited 26 chronically transfused adults (>16-years-old) with SCD; 13 subjects were randomized to each study arm, i.e. targeted to receive only ≥ 30 day or ≤ 10 day stored red cell units for 3 consecutive outpatient transfusion events. The red cell units were evaluated via quantification of surface exposure of phosphatidylserine (PS) and phosphatidylethanolamine (PE). Differences in key clinical variables were also evaluated. We show that subjects receiving units with higher surface-exposed PS and PE, regardless of storage age, had a reduced hemoglobin increment at 2 weeks (PS-PE high: 0.59g/dL; PS-PE-low: 1.04g/dL, p=0.04), increased pain crises (IRR= 7.44; 95%CI: 1.53-36.25), and had higher odds of reported illness (OR=1.94; 95%CI: 1.06-3.54). Further, post-transfusion serum iron predicted subsequent subjective symptoms of illness (ROC-AUC=0.76) and correlated with smaller increases in HbA% post-transfusion (r=-0.36, p=0.04). These data suggest that, in addition to chronological storage age, the physiological state of transfused red cells as defined by PS and PE and subject serum iron may deleteriously affect patient outcomes. Future studies focusing on identifying and then avoiding lower quality red cell units in high-risk patients with SCD could enhance patient safety (NCT03704922)
Food Insecurity Interventions to Improve Blood Pressure
Get PDFFood insecurity is associated with worse blood pressure control, but the optimal design for a food insecurity intervention to improve blood pressure is unknown. To inform food insecurity intervention design by comparing different intervention elements: type of food resources provided, whether to offer lifestyle counseling, and intervention duration. A 2 × 2 × 2 factorial comparative effectiveness randomized clinical trial was carried out including adults with hypertension and systolic blood pressure (SBP) of 130 mm Hg or higher, who spoke English or Spanish, and reported food insecurity in 2 clinical networks across 364 clinical sites in North Carolina. Food resources included healthy food subsidy redeemable at grocery stores vs biweekly healthy food box home delivery. The lifestyle intervention included either no intervention or offering telephone-based lifestyle counseling. The intervention duration included 6 months vs 12 months. The primary outcome was SBP. Secondary outcomes were diastolic blood pressure (DBP) and food security. The primary time point was 6 months from randomization. Twelve and 18 months were secondary time points. Overall, 458 individuals were randomized. The mean (SD) age was 49.7 (10.7) years and 345 (75.3%) were female individuals. Fewer than 11 participants identified as American Indian/Alaska Native; 11 (2.4%) identified as Asian, 237 (51.7%) identified as Black, 20 (4.4%) identified with multiple races, fewer than 11 participants identified as Native Hawaiian/Pacific Islander, 165 (36.0%) identified as White, and 22 (4.8%) did not report a racial identity. Twenty two participants (4.8%) identified as Hispanic ethnicity. Mean (SD) preintervention SBP and DBP were 138.2 (11.9) and 87.4 (9.1) mm Hg, respectively. The food subsidy, compared with the food box, led to moderately lower SBP at the 6-month primary time point (132.8 vs 135.3 mm Hg; difference −2.5 mm Hg; 95% CI −4.1 to −0.9; P = .003). DBP was also lower at 6 months (80.5 vs 82.1 mm Hg; difference −1.5 mm Hg; 95% CI, −2.5 to −0.6). The food subsidy group also had lower SBP and DBP at 18 months (SBP difference, −2.1 mm Hg; 95% CI, −4.2 to −0.05; DBP difference, −1.6 mm Hg; 95% CI −2.8 to −0.3). SBP and DBP differences at 12 months were in favor of the food subsidy, but not significantly different. Offering lifestyle counseling did not produce significantly lower SBP or DBP than not offering counseling at any time point. The 12-month duration did not produce significantly lower SBP or DBP than 6-month duration at any time point. 6-, 12-, and 18-month food security scores decreased from baseline in all groups, and did not differ significantly between groups. In this randomized comparative effectiveness trial, a food subsidy produced a moderate reduction in SBP and DBP compared with a delivered food box. Offering lifestyle counseling and a longer benefit duration did not produce better blood pressure outcomes. Food insecurity declined from baseline in all groups, but did not differ between groups. ClinicalTrials.gov Identifier: NCT0504883
Annealing-Driven Phase Control Enables Plasmonic Tunability in Alloy Nanoparticles
Get PDFA critical aspect of designing and realizing useful solid state materials is controlling phase and structure to tailor physical properties. While common for semiconductor and quantum materials, plasmonic materials have inhabited a narrow phase space typically comprising one or two elements, e.g., face-centered cubic metals. While this simplicity has enabled robust use and understanding of Au and Ag nanoparticles, it has also limited the design and manipulation of solid state properties. Here, we show that by tuning the phase and elemental composition of binary Au–Sn nanoparticles, the steady-state absorbance and ultrafast thermalization properties of plasmonic nanoparticles can be controlled. Solid state characterization suggests this is due to the dealloying of Sn and destabilization of the AuSn phase, leading to higher quality Au5Sn intermetallic phases alongside Au. Consequently, this work shows that phase control can profoundly influence the properties of plasmonic nanoparticles, providing important tunability for applications in catalysis, photothermal heating, and sensing
NTCP model guided whole brain radiation re-planning to reduce risk of acute xerostomia and dry eye.
Get PDFPrevious work has shown that whole brain radiation (WBRT) can lead to acute xerostomia and dry eye from dose delivered to the parotid and lacrimal glands, respectively. We performed a retrospective study to assess whether a previously developed normal tissue complication probability (NTCP) model could guide planning to reduce the risk of these complications. We also evaluate if the use of VMAT/IMRT instead of 3D planning can reduce the risk of side effects while maintaining dose to the brain.We identified 11 patients who had previously received WBRT to 30 Gy in 10 fractions using 3D-conformal radiation therapy without prospective delineation of the parotid or lacrimal glands. For each patient, these structures were contoured and new 3D and IMRT plans were created to limit the V20 to the parotid glands and the V15 to the lacrimal glands while maintaining the dose to the brain. A previously developed relative seriality (RS) NTCP model was used to assess the reduction in xerostomia and dry eye risk relative to the original plan that was achieved with the new plans.The 3D re-plans significantly (p < 0.001) reduced the estimated risk of xerostomia, by 12.2 ± 4.5%, but did not significantly (p > 0.025) reduce the risk of dry eye. The IMRT re-plans significantly (p < 0.001) reduced the risk of xerostomia, by 20.6 ± 7.2%, and dry eye by 11.0 ± 3.8%. Both re-plans maintained target coverage.By using parameter values obtained from NTCP models, we were able to create whole brain plans that lowered the estimated risk of xerostomia and dry eye while maintaining target coverage
Advanced stage classical Hodgkin lymphoma patients with a positive interim-PET (PET-2) Deauville score 5 after 2 ABVD cycles: a pooled analysis of three multicenter trials
Get PDFPET after 2 ABVD cycles (PET-2) is widely adopted to select patients with classical Hodgkin lymphoma (cHL), who might benefit from intensifying or de-escalating therapy. Prolonged progression-free survival (PFS) has been reported in PET-2 positive patients switched to escalated BEACOPP (eBEACOPP) or BEACOPP-14. Nevertheless, the subgroup of patients with a PET-2 scored 5 according to Deauville score (PET-2 DS5) are known to poorly benefit from treatment intensification. To elucidate PET-2 DS5 outcome along with possible predictive factors of response to intensification, a pooled analysis from three multicenter trials, GITIL/FIL HD0607, RATHL, and SWOG S0816, was conducted. PFS and overall survival (OS) were assessed after 41-month median follow-up, the prognostic value of clinical, laboratory, and PET parameters at diagnosis was evaluated. Among 2231 patients, 136 (6%) PET-2 DS5 patients were identified. Their 3-year PFS was 32% (95% CI, 25–42), while the 3-year OS was 82% (95% CI, 75–89). In multivariate analysis low lymphocyte (< 600/mm3) counts were adversely associated with PFS, whereas age ≥ 45 years and leukocytes cells count <15 × 103/μL were barely associated with short OS. The study confirms on a suitable cohort of PET-2 DS5 patients, that this high-risk cHL subgroup has an inadequate response to treatment intensification. Nevertheless, PET-2 DS5 patients may still have good outcome after subsequent salvage treatments with > 80% survival at 3 years, thus excluding a real disease refractoriness. Few distinct parameters may have specific prediction for PFS or OS