p53 directly represses human LINE1 transposons.

p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germline tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5'UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the removal of corresponding binding sites in LINE1s, prompted these retroelements to become hyperactive. Concurrently, p53 loss instigated chromosomal rearrangements linked to LINE sequences and also provoked inflammatory programs that were dependent on reverse transcriptase produced from LINE1s. Taken together, our observations establish that p53 continuously operates at the LINE1 promoter to restrict autonomous copies of these mobile elements in human cells. Our results further suggest that constitutive restriction of these retroelements may help to explain tumor suppression encoded by p53, since erupting LINE1s produced acute oncogenic threats when p53 was absent.

Ultra-low dose chest CT with silver filter and deep learning reconstruction significantly reduces radiation dose and retains quantitative information in the investigation and monitoring of lymphangioleiomyomatosis (LAM).

PURPOSE: Frequent CT scans to quantify lung involvement in cystic lung disease increases radiation exposure. Beam shaping energy filters can optimize imaging properties at lower radiation dosages. The aim of this study is to investigate whether use of SilverBeam filter and deep learning reconstruction algorithm allows for reduced radiation dose chest CT scanning in patients with lymphangioleiomyomatosis (LAM). MATERIAL AND METHODS: In a single-center prospective study, 60 consecutive patients with LAM underwent chest CT at standard and ultra-low radiation doses. Standard dose scan was performed with standard copper filter and ultra-low dose scan was performed with SilverBeam filter. Scans were reconstructed using a soft tissue kernel with deep learning reconstruction (AiCE) technique and using a soft tissue kernel with hybrid iterative reconstruction (AIDR3D). Cyst scores were quantified by semi-automated software. Signal-to-noise ratio (SNR) was calculated for each reconstruction. Data were analyzed by linear correlation, paired t-test, and Bland-Altman plots. RESULTS: Patients averaged 49.4 years and 100% were female with mean BMI 26.6 ± 6.1 kg/m2. Cyst score measured by AiCE reconstruction with SilverBeam filter correlated well with that of AIDR3D reconstruction with standard filter, with a 1.5% difference, and allowed for an 85.5% median radiation dosage reduction (0.33 mSv vs. 2.27 mSv, respectively, p < 0.001). Compared to standard filter with AIDR3D, SNR for SilverBeam AiCE images was slightly lower (3.2 vs. 3.1, respectively, p = 0.005). CONCLUSION: SilverBeam filter with deep learning reconstruction reduces radiation dosage of chest CT, while maintaining accuracy of cyst quantification as well as image quality in cystic lung disease. CLINICAL RELEVANCE STATEMENT: Radiation dosage from chest CT can be significantly reduced without sacrificing image quality by using silver filter in combination with a deep learning reconstructive algorithm. KEY POINTS: • Deep learning reconstruction in chest CT had no significant effect on cyst quantification when compared to conventional hybrid iterative reconstruction. • SilverBeam filter reduced radiation dosage by 85.5% compared to standard dose chest CT. • SilverBeam filter in coordination with deep learning reconstruction maintained image quality and diagnostic accuracy for cyst quantification when compared to standard dose CT with hybrid iterative reconstruction.

Moderators of Loneliness Trajectories in People with Systemic Sclerosis During the COVID-19 Pandemic: A SPIN COVID-19 Cohort Longitudinal Study.

BACKGROUND: Many individuals with systemic sclerosis (SSc) are at heightened risk for COVID-19 related morbidity and isolation due to interstitial lung disease, frailty, and immunosuppressant use. Minimal research has explored loneliness predictors in individuals with chronic illnesses during COVID-19. This study evaluated moderators of loneliness trajectories in individuals with SSc during COVID-19. METHODS: Longitudinal data were analyzed across 30 timepoints from April 2020 to May 2022 from 775 adults in the Scleroderma Patient-centered Intervention Network (SPIN) COVID-19 Cohort. Hierarchical linear modeling evaluated cross-level moderators of loneliness trajectories, including marital status, baseline number of household members, number of virtual or telephone one-on-one or virtual group conversations, number of hours spent enjoying in-person household conversations or activities, and satisfaction with quality of in-person household conversations (all in the past week). Level-1 moderation analyses assessed effects of conversation, activity, and satisfaction means and slopes over time. RESULTS: Baseline values were not statistically significant moderators of loneliness trajectories. Higher mean (averaged over time) virtual or telephone one-on-one and in-person household conversations, in-person household activity, and in-person household conversation satisfaction were associated with lower loneliness trajectories (ps < .05). The relationship between in-person household conversation satisfaction and loneliness trajectory was statistically significantly but minimally attenuated over time (p < .001). CONCLUSIONS: For people with SSc, higher mean conversation, activity, and satisfaction variables were associated with lower levels of loneliness during the pandemic, but changes in these social variables were generally not predictive of changes in loneliness.

p53 genes function to restrain mobile elements.

Throughout the animal kingdom, p53 genes govern stress response networks by specifying adaptive transcriptional responses. The human member of this gene family is mutated in most cancers, but precisely how p53 functions to mediate tumor suppression is not well understood. Using Drosophila and zebrafish models, we show that p53 restricts retrotransposon activity and genetically interacts with components of the piRNA (piwi-interacting RNA) pathway. Furthermore, transposon eruptions occurring in the p53(-) germline were incited by meiotic recombination, and transcripts produced from these mobile elements accumulated in the germ plasm. In gene complementation studies, normal human p53 alleles suppressed transposons, but mutant p53 alleles from cancer patients could not. Consistent with these observations, we also found patterns of unrestrained retrotransposons in p53-driven mouse and human cancers. Furthermore, p53 status correlated with repressive chromatin marks in the 5' sequence of a synthetic LINE-1 element. Together, these observations indicate that ancestral functions of p53 operate through conserved mechanisms to contain retrotransposons. Since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates oncogenic disease in part by restricting transposon mobility.

Healing and wellbeing outcomes of services for Aboriginal people based on cultural therapeutic ways: A systematic scoping review.

Aboriginal Australians experience disproportionately high rates of mental health problems as the result of European colonisation, and Western evidence-based treatment has been strikingly ineffective in improving the situation. Cultural Therapeutic Ways is a culturally specific healing and wellbeing practice framework developed by the Victorian Aboriginal Child and Community Agency that focuses on culturally based practices, trauma awareness, and self-determination. Despite wide recognition of the importance of these elements in Indigenous healing and wellbeing programs, its measurable empirical impact is currently unclear. This paper summarises findings from a systematic scoping review to ascertain the published knowledge base for Cultural Therapeutic Ways and the gaps in knowledge that can inform future evaluation. Forty-two studies of programs that applied Cultural Therapeutic Ways with Indigenous participants from Australia, Canada, New Zealand, and the United States of America were identified from the literature search. Services based on Cultural Therapeutic Ways contributed to healing and wellbeing because they create safety, strengthen cultural connections, develop empowerment and provide opportunities to release emotion, and increase social and spiritual support. As the review set out to determine the published evidence base for Cultural Therapeutic Ways, other effective approaches may have been overlooked. To develop the evidence base for Cultural Therapeutic Ways, service design must clearly describe target groups, whether the program is delivered by Aboriginal people, the processes of Cultural Therapeutic Ways utilised in service delivery, and how they are blended with Western approaches. Research efforts could also productively be focused on identifying or constructing culturally appropriate outcome measures.

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination.

Kinetic studies on the intramolecular hydroamination of protected variants of 2,2-diphenylpent-4-en-1-amine were carried out under a variety of conditions with cationic gold catalysts supported by phosphine ligands. The impact of ligand on gold, protecting group on nitrogen, and solvent and additive on reaction rates was determined. The most effective reactions utilized more Lewis basic ureas, and more electron-withdrawing phosphines. A DCM/alcohol cooperative effect was quantified, and a continuum of isotope effects was measured with low KIE's in the absence of deuterated alcoholic solvent, increasing to large solvent KIE's when comparing reactions in pure MeOH to those in pure MeOH-d4. The effects are interpreted both within the context of a classic gold π-activation/protodeauration mechanism and a general acid-catalyzed mechanism without intermediate gold alkyls.

Soluble Guanylyl Cyclase Activator BI 685509 Reduces Portal Hypertension and Portosystemic Shunting in a Rat Thioacetamide-Induced Cirrhosis Model.

Portal hypertension (PT) commonly occurs in cirrhosis. Nitric oxide (NO) imbalance contributes to PT via reduced soluble guanylyl cyclase (sGC) activation and cGMP production, resulting in vasoconstriction, endothelial cell dysfunction, and fibrosis. We assessed the effects of BI 685509, an NO-independent sGC activator, on fibrosis and extrahepatic complications in a thioacetamide (TAA)-induced cirrhosis and PT model. Male Sprague-Dawley rats received TAA twice-weekly for 15 weeks (300-150 mg/kg i.p.). BI 685509 was administered daily for the last 12 weeks (0.3, 1, and 3 mg/kg p.o.; n = 8-11 per group) or the final week only (Acute, 3 mg/kg p.o.; n = 6). Rats were anesthetized to measure portal venous pressure. Pharmacokinetics and hepatic cGMP (target engagement) were measured by mass spectrometry. Hepatic Sirius Red morphometry (SRM) and alpha-smooth muscle actin (αSMA) were measured by immunohistochemistry; portosystemic shunting was measured using colored microspheres. BI 685509 dose-dependently increased hepatic cGMP at 1 and 3 mg/kg (3.92 ± 0.34 and 5.14 ± 0.44 versus 2.50 ± 0.19 nM in TAA alone; P < 0.05). TAA increased hepatic SRM, αSMA, PT, and portosystemic shunting. Compared with TAA, 3 mg/kg BI 685509 reduced SRM by 38%, αSMA area by 55%, portal venous pressure by 26%, and portosystemic shunting by 10% (P < 0.05). Acute BI 685509 reduced SRM and PT by 45% and 21%, respectively (P < 0.05). BI 685509 improved hepatic and extrahepatic cirrhosis pathophysiology in TAA-induced cirrhosis. These data support the clinical investigation of BI 685509 for PT in patients with cirrhosis. SIGNIFICANCE STATEMENT: BI 685509 is an NO-independent sGC activator that was tested in a preclinical rat model of TAA-induced nodular, liver fibrosis, portal hypertension, and portal systemic shunting. BI 685509 reduced liver fibrosis, portal hypertension, and portal-systemic shunting in a dose-dependent manner, supporting its clinical assessment to treat portal hypertension in patients with cirrhosis.

COVID-19 Incidence and Mortality Among Unvaccinated and Vaccinated Persons Aged ≥12 Years by Receipt of Bivalent Booster Doses and Time Since Vaccination - 24 U.S. Jurisdictions, October 3, 2021-December 24, 2022.

On September 1, 2022, CDC recommended an updated (bivalent) COVID-19 vaccine booster to help restore waning protection conferred by previous vaccination and broaden protection against emerging variants for persons aged ≥12 years (subsequently extended to persons aged ≥6 months).* To assess the impact of original (monovalent) COVID-19 vaccines and bivalent boosters, case and mortality rate ratios (RRs) were estimated comparing unvaccinated and vaccinated persons aged ≥12 years by overall receipt of and by time since booster vaccination (monovalent or bivalent) during Delta variant and Omicron sublineage (BA.1, BA.2, early BA.4/BA.5, and late BA.4/BA.5) predominance.† During the late BA.4/BA.5 period, unvaccinated persons had higher COVID-19 mortality and infection rates than persons receiving bivalent doses (mortality RR = 14.1 and infection RR = 2.8) and to a lesser extent persons vaccinated with only monovalent doses (mortality RR = 5.4 and infection RR = 2.5). Among older adults, mortality rates among unvaccinated persons were significantly higher than among those who had received a bivalent booster (65-79 years; RR = 23.7 and ≥80 years; 10.3) or a monovalent booster (65-79 years; 8.3 and ≥80 years; 4.2). In a second analysis stratified by time since booster vaccination, there was a progressive decline from the Delta period (RR = 50.7) to the early BA.4/BA.5 period (7.4) in relative COVID-19 mortality rates among unvaccinated persons compared with persons receiving who had received a monovalent booster within 2 weeks-2 months. During the early BA.4/BA.5 period, declines in relative mortality rates were observed at 6-8 (RR = 4.6), 9-11 (4.5), and ≥12 (2.5) months after receiving a monovalent booster. In contrast, bivalent boosters received during the preceding 2 weeks-2 months improved protection against death (RR = 15.2) during the late BA.4/BA.5 period. In both analyses, when compared with unvaccinated persons, persons who had received bivalent boosters were provided additional protection against death over monovalent doses or monovalent boosters. Restored protection was highest in older adults. All persons should stay up to date with COVID-19 vaccination, including receipt of a bivalent booster by eligible persons, to reduce the risk for severe COVID-19.

The nature and extent of outdoor alcohol marketing in Wellington, New Zealand: a longitudinal audit and spatio-temporal analysis of outdoor alcohol marketing.

AIM: exposure to alcohol marketing is associated with increased consumption. We aimed to (i) measure the nature and extent of outdoor alcohol marketing within a high-density urban neighbourhood and (ii) examine temporal and spatial trends in alcohol marketing. METHODS: this study used a longitudinal design to monitor paid advertising in public spaces over two 10-week periods in Wellington, New Zealand (Nov-Jan 2020-2021, Nov-Jan 2021-2022). The data were collected on-foot following an established route once a week using a phone camera, which also recorded gps data of ad locations. Temporal and spatial trends in alcohol ad prevalence were assessed. RESULTS: over the study period, 13% (n = 1619) of all ads (n = 12,472) were for alcohol. Alcohol ads were predominately for spirits (29%), ready-to-drink (27%) and beer (23%). Almost half of all alcohol ads (49%) did not contain a responsible consumption message, while those with a message were de-emphasized relative to promotional features. A temporal trend was observed in 2020, whereby alcohol marketing decreased over the summer, but this trend was not reflected in 2021. Alcohol ads were more likely than non-alcohol ads to be placed in premium positions on roads of high pedestrian and motor vehicle traffic. CONCLUSION: alcohol marketing is common in urban centres. Local and central government policy could substantially reduce the levels of alcohol marketing exposure via outdoor marketing.

Food tax policies in Pacific Island Countries and Territories: systematic policy review.

OBJECTIVE: To systematically identify and review food taxation policy changes in Pacific Island Countries and Territories (PICTs). DESIGN: Food taxation polices, regarding excise taxes and tariffs applied from 2000 to 2020 in twenty-two PICTs, and their key characteristics were reviewed. The search was conducted using databases, government legal repositories and broad-based search engines. Identified documents for screening included legislation, reports, academic literature, news articles and grey literature. Key informants were contacted from each PICT to retrieve further data and confirm results. Results were analysed by narrative synthesis. SETTING: Noncommunicable diseases (NCD) are the leading cause of premature death in PICTs and in many jurisdictions globally. An NCD crisis has been declared in the Pacific, and food taxation policy has been recommended to address the dietary risk factors associated with. Progress is unclear. RESULTS: Of the twenty-two PICTs included in the study, fourteen had food taxation policies and five introduced excise taxes. Processed foods, sugar and salt were the main target of excise taxes. A total of eighty-four food taxation policy changes were identified across all food groups. There was a total of 279 taxes identified by food group, of which 85 % were tariffs and 15 % were excise taxes. Individual tax rates varied substantially. The predominant tax design was ad valorem, and this was followed by volumetric. CONCLUSIONS: A quarter of PICTs have introduced food excise taxes from 2000 to 2020. Further excise taxes, specifically tiered or nutrient-specific designs, could be introduced and more systematically applied to a broader range of unhealthy foods.

Predictors of Mother and Infant Emergency Department Attendance and Admission: A Prospective Observational Study.

OBJECTIVE: To explore the predictors of emergency department attendance and admission for mothers and their infants. METHODS: Self-reported emergency department (ED) attendance and admission, sociodemographic, mental health, and other measures were recorded at baseline and at 12 months at 4 sites in England between May 2017 and March 2020. RESULTS: Infants' gestational age (OR 0.73, 95% CI 0.61 to 0.88, p = 0.001), mothers' mental health (OR 2.40, 95% CI 1.30 to 4.41, p = 0.005) and mothers' attendance at ED (OR 2.34, 95% CI 1.13 to 4.84, p = 0.022) predicted infant ED attendance. Frequency of attendance was predicted by ED site (IRR 0.46, 95% CI 0.29 to 0.73, p = 0.001) and mothers' age (IRR 0.96, 95% CI 0.92 to 1.00, p = 0.028). Infant hospital admissions were predominantly for respiratory (40%) and other infectious diseases (21%) and were predicted by previous health problems (OR 3.25, 95% CI 1.76 to 6.01, p < 0.001). Mothers' ED attendance was predicted by mixed or multiple ethnic origin (OR 9.62, 95% CI 2.19 to 42.27, p = 0.003), having a male infant (OR 2.08, 95% CI 1.03 to 4.20, p = 0.042), and previous hospitalisation (OR 4.15, 95% CI 1.81 to 9.56, p = 0.001). Hospital admission was largely for reproductive health issues (61%) with frequency predicted by having attended the ED at least once (IRR 3.39, 95% CI 1.66 to 6.93, p = 0.001), and being anxious or depressed (IRR 3.10, 95% CI 1.14 to 8.45, p = 0.027). CONCLUSIONS FOR PRACTICE: Improving the reproductive and mental health of mothers may help to avoid poor maternal and infant health outcomes and reduce emergency service utilisation and hospitalisation.

Situating reproductive coercion in the sociocultural context: An ecological model to inform research, practice, and policy in the United States.

Reproductive coercion (RC) can be conceptualized as any behavior that limits one's ability to make decisions about their reproductive health. Here, we broaden this definition to consider the impact of systemic and sociocultural factors on RC using an ecological model. Specifically, we use Bronfenbrenner's model as a framework for organizing the multilevel factors that influence reproductive coercion (RC) and its impacts on individual health. This paper is intended to offer a primer to historical, sociocultural, community, interpersonal, and individual processes that may interact to shape reproductive decision-making and its effect on individual health outcomes. We emphasize the importance of conceptualizing RC within the broader sociocultural and community context, and the potential implications for reproductive and sexual health research, clinical care, and policy in the United States.

Tissue-specific responses that constrain glucose oxidation and increase lactate production with the severity of hypoxemia in fetal sheep.

Fetal hypoxemia decreases insulin and increases cortisol and norepinephrine concentrations and may restrict growth by decreasing glucose utilization and altering substrate oxidation. Specifically, we hypothesized that hypoxemia would decrease fetal glucose oxidation and increase lactate and pyruvate production. We tested this by measuring whole body glucose oxidation and lactate production, and molecular pathways in liver, muscle, adipose, and pancreas tissues of fetuses exposed to maternal hypoxemia for 9 days (HOX) compared with control fetal sheep (CON) in late gestation. Fetuses with more severe hypoxemia had lower whole body glucose oxidation rates, and HOX fetuses had increased lactate production from glucose. In muscle and adipose tissue, expression of the glucose transporter GLUT4 was decreased. In muscle, pyruvate kinase (PKM) and lactate dehydrogenase B (LDHB) expression was decreased. In adipose tissue, LDHA and lactate transporter (MCT1) expression was increased. In liver, there was decreased gene expression of PKLR and MPC2 and phosphorylation of PDH, and increased LDHA gene and LDH protein abundance. LDH activity, however, was decreased only in HOX skeletal muscle. There were no differences in basal insulin signaling across tissues, nor differences in pancreatic tissue insulin content, ß-cell area, or genes regulating ß-cell function. Collectively, these results demonstrate coordinated metabolic responses across tissues in the hypoxemic fetus that limit glucose oxidation and increase lactate and pyruvate production. These responses may be mediated by hypoxemia-induced endocrine responses including increased norepinephrine and cortisol, which inhibit pancreatic insulin secretion resulting in lower insulin concentrations and decreased stimulation of glucose utilization.NEW & NOTEWORTHY Hypoxemia lowered fetal glucose oxidation rates, based on severity of hypoxemia, and increased lactate production. This was supported by tissue-specific metabolic responses that may result from increased norepinephrine and cortisol concentrations, which decrease pancreatic insulin secretion and insulin concentrations and decrease glucose utilization. This highlights the vulnerability of metabolic pathways in the fetus and demonstrates that constrained glucose oxidation may represent an early event in response to sustained hypoxemia and fetal growth restriction.

Finding My Way-Advanced: can a web-based psychosocial intervention improve the mental quality of life for women with metastatic breast cancer vs attention-control? Study protocol of a randomised controlled trial.

BACKGROUND: Women living with metastatic breast cancer (MBC) are at risk of significantly impaired quality of life (QOL), symptom burden, distress and fear of progression, and unmet needs, yet they face barriers to accessing evidence-based psychosocial treatments. Our group therefore developed Finding My Way-Advanced (FMW-A), a web-based self-guided psychosocial program for women with MBC. This study aims to assess its efficacy in improving mental and other QOL domains, distress, fear of progression, unmet needs, and health service utilisation. METHODS: The multi-site randomised controlled trial (RCT) will enrol 370 Australian participants. Eligible participants are adult (18 years +) women diagnosed with MBC, with a life expectancy of 6 months or more, with sufficient English-language literacy to provide informed consent. Participants will be identified, screened and referred from one of 10 Australian sites, or via self-referral in response to advertisements. Participants complete four online questionnaires: prior to accessing their program ('baseline'), 6 weeks later ('post-intervention'), then 3 months and 6 months post-intervention. Consenting participants will be randomised to either FMW-A (intervention), or Breast Cancer Network Australia's (BCNA) online/app resource My Journey (minimal intervention attention-control). This is a single-blind study, with randomisation computer-generated and stratified by site. FMW-A is a 6-module program addressing some of the most common issues experienced by women with MBC, with BCNA control resources integrated within the 'resources' section. All modules are immediately accessible, with an additional booster module released 10 weeks later. The primary outcome is mental QOL; statistical criteria for superiority is defined as a 4-point difference between groups at post-treatment. Secondary outcomes include other QOL domains, distress, fear of progression, health service use, intervention adherence, and user satisfaction. DISCUSSION: This will be the first adequately powered RCT of a self-directed online intervention for women with MBC. If efficacious, FMW-A will help address two national key priorities for management of MBC - enhancing QOL and reducing symptom burden. FMW-A has the potential to address unmet needs and overcome access barriers for this overlooked population, while reducing health system burden. TRIAL REGISTRATION: The study was registered prospectively with the ANZCTR on 29/10/2021. Trial ID ACTRN12621001482853p.  https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382714&isReview=true.

Evidence for Implementation: Management of TB in HIV and Pregnancy.

PURPOSE OF REVIEW: Pregnant people living with HIV (PLWH) are at especially high risk for progression from latent tuberculosis infection (LTBI) to active tuberculosis (TB) disease. Among pregnant PLWH, concurrent TB increases the risk of complications such as preeclampsia, intrauterine fetal-growth restriction, low birth weight, preterm-delivery, perinatal transmission of HIV, and admission to the neonatal intensive care unit. The grave impact of superimposed TB disease on maternal morbidity and mortality among PLWH necessitates clear guidelines for concomitant therapy and an understanding of the pharmacokinetics (PK) and potential drug-drug interactions (DDIs) between antitubercular (anti-TB) agents and antiretroviral therapy (ART) in pregnancy. RECENT FINDINGS: This review discusses the currently available evidence on the use of anti-TB agents in pregnant PLWH on ART. Pharmacokinetic and safety studies of anti-TB agents during pregnancy and postpartum are limited, and available data on second-line and newer anti-TB agents used in pregnancy suggest that several research gaps exist. DDIs between ART and anti-TB agents can decrease plasma concentration of ART, with the potential for perinatal transmission of HIV. Current recommendations for the treatment of LTBI, drug-susceptible TB, and multidrug-resistant TB (MDR-TB) are derived from observational studies and case reports in pregnant PLWH. While the use of isoniazid, rifamycins, and ethambutol in pregnancy and their DDIs with various ARTs are well-characterized, there is limited data on the use of pyrazinamide and several new and second-line antitubercular drugs in pregnant PLWH. Further research into treatment outcomes, PK, and safety data for anti-TB agent use during pregnancy and postpartum is urgently needed.

COVID-19 Incidence and Death Rates Among Unvaccinated and Fully Vaccinated Adults with and Without Booster Doses During Periods of Delta and Omicron Variant Emergence - 25 U.S. Jurisdictions, April 4-December 25, 2021.

Previous reports of COVID-19 case, hospitalization, and death rates by vaccination status† indicate that vaccine protection against infection, as well as serious COVID-19 illness for some groups, declined with the emergence of the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, and waning of vaccine-induced immunity (1-4). During August-November 2021, CDC recommended§ additional primary COVID-19 vaccine doses among immunocompromised persons and booster doses among persons aged ≥18 years (5). The SARS-CoV-2 B.1.1.529 (Omicron) variant emerged in the United States during December 2021 (6) and by December 25 accounted for 72% of sequenced lineages (7). To assess the impact of full vaccination with additional and booster doses (booster doses),¶ case and death rates and incidence rate ratios (IRRs) were estimated among unvaccinated and fully vaccinated adults by receipt of booster doses during pre-Delta (April-May 2021), Delta emergence (June 2021), Delta predominance (July-November 2021), and Omicron emergence (December 2021) periods in the United States. During 2021, averaged weekly, age-standardized case IRRs among unvaccinated persons compared with fully vaccinated persons decreased from 13.9 pre-Delta to 8.7 as Delta emerged, and to 5.1 during the period of Delta predominance. During October-November, unvaccinated persons had 13.9 and 53.2 times the risks for infection and COVID-19-associated death, respectively, compared with fully vaccinated persons who received booster doses, and 4.0 and 12.7 times the risks compared with fully vaccinated persons without booster doses. When the Omicron variant emerged during December 2021, case IRRs decreased to 4.9 for fully vaccinated persons with booster doses and 2.8 for those without booster doses, relative to October-November 2021. The highest impact of booster doses against infection and death compared with full vaccination without booster doses was recorded among persons aged 50-64 and ≥65 years. Eligible persons should stay up to date with COVID-19 vaccinations.

A stable home for an equine pathogen: valid publication of the binomial Prescottella equi gen. nov., comb. nov., and reclassification of four rhodococcal species into the genus Prescottella.

Opinion 106 of the Judicial Commission has clarified the nomenclature of the taxon variously named Rhodococcus equi, 'Prescottella equi' and Rhodococcus hoagii. As a consequence, we present here the genus name Prescottella and that of its nomenclatural type species, Prescottella equi comb. nov., for valid publication and propose the reclassification of four rhodococcal species as novel combinations in the genus, namely Prescottella agglutinans Guo et al. 2015 comb. nov., Prescottella defluvii Kämpfer et al. 2014 comb. nov., Prescottella soli Li et al. 2015 comb. nov. and Prescottella subtropica Lee et al. 2019 comb. nov. In addition, we note that a clinical isolate, strain 86-07 (=W8901), likely represents an additional species within the genus Prescottella. Nearly a century after the original description of the type strain of the type species as Corynebacterium equi, we provide a stable home for Prescottella equi and its relatives.

Comparing health gains, costs and cost-effectiveness of 100s of interventions in Australia and New Zealand: an online interactive league table.

BACKGROUND: This study compares the health gains, costs, and cost-effectiveness of hundreds of Australian and New Zealand (NZ) health interventions conducted with comparable methods in an online interactive league table designed to inform policy. METHODS: A literature review was conducted to identify peer-reviewed evaluations (2010 to 2018) arising from the Australia Cost-Effectiveness research and NZ Burden of Disease Epidemiology, Equity and Cost-Effectiveness Programmes, or using similar methodology, with: health gains quantified as health-adjusted life years (HALYs); net health system costs and/or incremental cost-effectiveness ratio; time horizon of at least 10 years; and 3% to 5% discount rates. RESULTS: We identified 384 evaluations that met the inclusion criteria, covering 14 intervention domains: alcohol; cancer; cannabis; communicable disease; cardiovascular disease; diabetes; diet; injury; mental illness; other non-communicable diseases; overweight and obesity; physical inactivity; salt; and tobacco. There were large variations in health gain across evaluations: 33.9% gained less than 0.1 HALYs per 1000 people in the total population over the remainder of their lifespan, through to 13.0% gaining > 10 HALYs per 1000 people. Over a third (38.8%) of evaluations were cost-saving. CONCLUSIONS: League tables of comparably conducted evaluations illustrate the large health gain (and cost) variations per capita between interventions, in addition to cost-effectiveness. Further work can test the utility of this league table with policy-makers and researchers.

Severe and Fatal Cycling Crash Injury in Britain: Time to Make Urban Cycling Safer.

Pedal cycling is advocated for increasing physical activity and promoting health and wellbeing. However, whilst some countries have achieved zero cyclist deaths on their roads, this is not the case for Great Britain (GB). A retrospective cross-sectional analysis was conducted of STATS19 cyclist crash data, a dataset of all police-reported traffic crashes in GB. Information about crash location, casualty, driver and vehicles involved were included as predictors of casualty severity (fatal or severe vs. slight). Sixteen thousand one hundred seventy pedal cycle crashes were reported during 2018. Severe or fatal cyclist crash injury was associated with increasing age of the cyclist (35-39 years, OR 1.38, 95% CI 1.11 to 1.73; 55-59 years, OR 1.73, 95% CI 1.35 to 2.2; 70 years and over, OR 2.87, 95% CI 2.12 to 3.87), higher road speed limits (50 MPH OR 2.10, 95% CI 1.43 to 3.07; 70 MPH OR 4.12, 95% CI 2.12 to 8.03), the involvement of goods vehicles (OR 2.08, 95% CI 1.30 to 3.33) and the months of May and June (OR 1.34 to 1.36, 95% CI 1.06 to 1.73). Urban planning that includes physical separation of pedal cyclists from other road users, raising awareness around the risks from goods vehicles and reducing road speed should be the urgent focus of interventions to increase the benefits and safety of cycling.

HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα.

MutS protein homolog 2 (MSH2) is a key DNA mismatch repair protein. It forms the MSH2-MSH6 (MutSα) and MSH2-MSH3 (MutSß) heterodimers, which help to ensure genomic integrity. MutSα not only recognizes and repairs mismatched nucleotides but also recognizes DNA adducts induced by DNA-damaging agents, and triggers cell-cycle arrest and apoptosis. Loss or depletion of MutSα from cells leads to microsatellite instability (MSI) and resistance to DNA damage. Although the level of MutSα can be reduced by the ubiquitin-proteasome pathway, the detailed mechanisms of this regulation remain elusive. Here we report that histone deacetylase 6 (HDAC6) sequentially deacetylates and ubiquitinates MSH2, leading to MSH2 degradation. In addition, HDAC6 significantly reduces cellular sensitivity to DNA-damaging agents and decreases cellular DNA mismatch repair activities by downregulation of MSH2. Overall, these findings reveal a mechanism by which proper levels of MutSα are maintained.