Health and Well-being of Family ('Ohana) Caregivers of Native Hawaiian and Pacific Islander Adults Living with Alzheimer's Disease and Related Dementias.

INTRODUCTION: We aimed to describe the health and well-being of family caregivers of Native Hawaiian and Pacific Islander (NHPI) adults living with Alzheimer's disease and related dementias (ADRD), explore cultural values related to caregiving, and characterize barriers and facilitators to their health and well-being. METHODOLOGY: Caregivers of NHPIs living with ADRD were recruited from across the United States to complete a multimethod study including a survey followed by an interview about their health and well-being. RESULTS: Eleven participants completed surveys, six of whom completed an interview. Themes included caring as a community, lokahi (balance), and the importance of sleep, food, and physical activity. Cultural values included connection to cultural practices, kupuna (elders) as cultural knowledge holders, and the kuleana (responsibility) of caregiving. DISCUSSION: Caregiving for an NHPI adult living with ADRD occurs beyond the dyad, and is a matter of family and community. Culturally-based interventions offered through community and healthcare organizations may be critical to promoting caregiver health.

High pressure-derived nonsymmetrical [Cu2O]2+ core for room-temperature methane hydroxylation.

Nonsymmetrical oxygen-bridged binuclear copper centers have been proposed and modeled as intermediates and transition states in several C─H oxidation pathways, leading to the postulation that structural dissymmetry enhances the reactivity of the bridging oxygen. However, experimentally characterizing the structure and reactivity of these transient species is remarkably challenging. Here, we report the high-pressure synthesis of a metastable nonsymmetrical dicopper-µ-oxo compound with exceptional reactivity toward the mono-oxygenation of aliphatic C─H bonds. The nonequivalent coordination environment of copper stabilizes localized mixed valency and greatly enhances the hydrogen atom abstraction activity of the bridging oxygen, enabling room-temperature hydroxylation of methane under pressure. These findings highlight the role of dissymmetry in the reactivity of binuclear copper centers and demonstrate precise control of molecular structures by mechanical means.

Eight-year efficacy and safety of tenofovir alafenamide for treatment of chronic hepatitis B virus infection: Final results from two randomised phase 3 trials.

BACKGROUND: In two phase 3 studies, tenofovir alafenamide (TAF) showed non-inferior efficacy versus tenofovir disoproxil fumarate (TDF), with more favourable renal and bone safety in patients with chronic hepatitis B (CHB). AIMS: Here, we report the studies' final 8-year results. METHODS: CHB patients (hepatitis B e antigen [HBeAg]-negative and HBeAg-positive) were randomised (2:1) to double-blind TAF 25 mg/day or TDF 300 mg/day for up to 3 years, followed by open-label (OL) TAF through year 8. Virological, biochemical, serological and fibrosis responses, and safety, including bone and renal parameters, were evaluated. Resistance to TAF was assessed annually by deep sequencing of polymerase/reverse transcriptase and by phenotyping. RESULTS: Among 1298 patients randomised to double-blind TAF (n = 866) or double-blind TDF (n = 432), 775 in the TAF group and 382 in the TDF group received OL TAF, including 180 and 202 who switched from TDF to TAF at year 2 (TDF2y → TAF6y) or year 3 (TDF3y → TAF5y), respectively. At year 8, among patients in the TAF8y, TDF2y → TAF6y and TDF3y → TAF5y groups, 69%, 66% and 73% (missing-equals-failure analysis) and 95%, 94% and 97% (missing-equals-excluded) of patients, respectively, achieved HBV DNA <29 IU/mL. Estimated glomerular filtration rate (Cockcroft-Gault method; eGFRCG) and hip/spine bone mineral density (BMD) remained stable in patients receiving double-blind/OL TAF, with only small declines at year 8. Decreases in eGFRCG and hip/spine BMD observed during double-blind TDF improved after switching to OL TAF. No patients developed resistance to TAF. CONCLUSION: Long-term TAF treatment exhibited favourable safety and tolerability with high rates of viral suppression and no development of resistance. CLINICALTRIALS: gov numbers NCT01940341 and NCT01940471.

Medicaid Expansion and Mortality Among Persons Who Were Formerly Incarcerated.

Importance: Since 2014, Medicaid expansion has been implemented in many states across the US, increasing health care access among vulnerable populations, including formerly incarcerated people who experience higher mortality rates than the general population. Objective: To examine population-level association of Medicaid expansion with postrelease mortality from all causes, unintentional drug overdoses, opioid overdoses, polydrug overdoses, suicides, and homicides among formerly incarcerated people in Rhode Island (RI), which expanded Medicaid, compared with North Carolina (NC), which did not expand Medicaid during the study period. Design, Setting, and Participants: A cohort study was conducted using incarceration release data from January 1, 2009, to December 31, 2018, linked to death records from January 1, 2009, to December 31, 2019, on individuals released from incarceration in RI and NC. Data analysis was performed from August 20, 2022, to February 15, 2024. Participants included those aged 18 years or older who were released from incarceration. Individuals who were temporarily held during ongoing judicial proceedings, died during incarceration, or not released from incarceration during the study period were excluded. Exposure: Full Medicaid expansion in RI effective January 1, 2014. Main Outcomes and Measures: Mortality from all causes, unintentional drug overdoses, unintentional opioid and polydrug overdoses, suicides, and homicides. Results: Between 2009 and 2018, 17 824 individuals were released from RI prisons (mean [SD] age, 38.39 [10.85] years; 31 512 [89.1%] male) and 160 861 were released from NC prisons (mean [SD] age, 38.28 [10.84] years; 209 021 [87.5%] male). Compared with NC, people who were formerly incarcerated in RI experienced a sustained decrease of 72 per 100 000 person-years (95% CI, -108 to -36 per 100 000 person-years) in all-cause mortality per quarter after Medicaid expansion. Similar decreases were observed in RI in drug overdose deaths (-172 per 100 000 person-years per 6 months; 95% CI, -226 to -117 per 100 000 person-years), including opioid and polydrug overdoses, and homicide deaths (-23 per 100 000 person-years per year; 95% CI, -50 to 4 per 100 000 person-years) after Medicaid expansion. Suicide mortality did not change after Medicaid expansion. After Medicaid expansion in RI, non-Hispanic White individuals experienced 3 times greater sustained decreases in all-cause mortality than all racially minoritized individuals combined, while non-Hispanic Black individuals did not experience any substantial benefits. There was no modification by sex. Individuals aged 30 years or older experienced greater all-cause mortality reduction after Medicaid expansion than those younger than 30 years. Conclusions and Relevance: Medicaid expansion in RI was associated with a decrease in all-cause, overdose, and homicide mortality among formerly incarcerated people. However, these decreases were most observed among White individuals, while racially minoritized individuals received little to no benefits in the studied outcomes.

Chylothorax in a Young Woman With Crohn Disease.

Chylothorax, which accounts for 1% to 3% of pleural effusions, typically results from either surgery (traumatic) or underlying malignancy (nontraumatic). Less common causes of nontraumatic chylothorax are numerous and include congenital lymphatic abnormalities, connective tissue diseases, cirrhosis, and infection, among others.1 We describe what appears to be the first reported case of chylothorax caused by chylous ascites in Crohn disease. This case highlights the importance of using diagnostic evidence to link new symptoms to preexisting diseases whenever possible, as well as the systemic nature of Crohn disease.

Sequence-Dependent Acylation of Peptide Lysine Residues by DNAzymes.

Methods for modifying intact peptides are useful but can be unselective with regard to amino acid position and sequence context. In this work, we used in vitro selection to identify DNAzymes that acylate a Lys residue of a short peptide in sequence-dependent fashion. The DNAzymes do not acylate Lys when placed at other residues in the peptide, and the acylation activity depends on the Lys sequence context. A good acylation yield is observed on the preparative nanomole scale. These findings are promising for further development of DNAzymes for broader application to top-down Lys acylation of peptide and protein substrates.

Aldehydes alter TGF-ß signaling and induce obesity and cancer.

Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)-affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2-/- and Aldh2-/-Sptbn1+/- mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor ß (TGF-ß) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (ß2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2-/- and Aldh2-/-Sptbn1+/- mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.

Native Hawaiian and Pacific Islanders' Identity and Housing Status: The Impact on Historical Trauma and Perceived Stress.

Native Hawaiian and Pacific Islanders (NHPIs) are overrepresented in Hawai'i's houseless population. Indigenous populations, such as NHPIs, may encounter experiences of historical trauma that impact their well-being. This original research project examines how NHPI identity and houselessness compound to affect the perceived stress and historical trauma of transition-aged youth. Fifty-one participants aged 18 to 24 (M = 21.37, SD = 1.93) completed a survey that included the historical traumatic events scale, historical loss scale, perceived stress scale, and a demographic questionnaire. Over half (n = 26, 51.0%) of the participants identified as NHPI. A two-way ANOVA indicated a non-significant effect of NHPI identity and housing status on perceived stress. However, housed participants scored significantly higher than participants experiencing houselessness on the historical traumatic events scale (p = 0.006). Our findings elucidate the role of knowledge in the experience of historical trauma. Further results, limitations, and future directions are offered.

The convergence of mTOR signaling and ethanol teratogenesis.

Ethanol is one of the most common teratogens and causes of human developmental disabilities. Fetal alcohol spectrum disorders (FASD), which describes the wide range of deficits due to prenatal ethanol exposure, are estimated to affect between 1.1 % and 5.0 % of births in the United States. Ethanol dysregulates numerous cellular mechanisms such as programmed cell death (apoptosis), protein synthesis, autophagy, and various aspects of cell signaling, all of which contribute to FASD. The mechanistic target of rapamycin (mTOR) regulates these cellular mechanisms via sensing of nutrients like amino acids and glucose, DNA damage, and growth factor signaling. Despite an extensive literature on ethanol teratogenesis and mTOR signaling, there has been less attention paid to their interaction. Here, we discuss the impact of ethanol teratogenesis on mTORC1's ability to coordinate growth factor and amino acid sensing with protein synthesis, autophagy, and apoptosis. Notably, the effect of ethanol exposure on mTOR signaling depends on the timing and dose of ethanol as well as the system studied. Overall, the overlap between the functions of mTORC1 and the phenotypes observed in FASD suggest a mechanistic interaction. However, more work is required to fully understand the impact of ethanol teratogenesis on mTOR signaling.

Butyrate-producing bacteria as probiotic supplement: beneficial effects on metabolism and modulation of behaviour in an obesity mouse model.

Obesity is a risk factor for cardio-metabolic and neurological disease. The contribution of gut microbiota to derangements of the gut-brain axis in the context of obesity has been acknowledged, particularly through physiology modulation by short-chain fatty acids (SCFAs). Thus, probiotic interventions and administration of SCFAs have been employed with the purpose of alleviating symptoms in both metabolic and neurological disease. We investigated the effects of four butyrate-producing bacteria from the Lachnospiraceae family on the development of metabolic syndrome and behavioural alterations in a mouse model of diet-induced obesity. Male mice were fed either a high-fat diet (HFD) or an ingredient-matched control diet for 2 months, and bacteria cultures or culture medium were given by gavage to HFD-fed mice every second day. Mice were assessed through a battery of metabolic and behaviour tests, and fluxes through the gut barrier and blood-brain barrier were determined using Dextran-based tracers. One of the administered bacteria from the Coprococcus genus, which produces butyrate and formate, afforded some degree of protection against the development of obesity and its complications. Results from this study, however, are insufficient to support brain health benefits of the bacteria tested. None of the bacteria modulated permeability through the gut or blood-brain barriers. Our results suggest health benefits of a bacteria from Lachnospiraceae family, and encourage further exploration of its use as probiotic.

Epidemiology of postinjury multiple organ failure: a prospective multicenter observational study.

PURPOSE: Postinjury multiple organ failure (MOF) is the sequela to the disease of polytrauma. We aimed to describe the contemporary population-based epidemiology of MOF within a mature trauma system, to analyse the time taken for MOF to develop, and to evaluate the temporal patterns and contributions of the individual constituent organ failures. METHODS: Prospective observational study conducted across five Level-1 trauma centers in New South Wales, Australia. Trauma patients at-risk of MOF (Denver > 3 from 48 h post-admission), aged > 16 years, ISS > 15, and who stayed in ICU for ≥ 48 h were eligible for inclusion. RESULTS: From May 2018-February 2021, 600 at-risk polytrauma patients were prospectively enrolled (mean(SD)age = 49(21)years, males = 453/600(76%),median(IQR)ISS = 26(20,34)). MOF incidence was 136/600(23%) among at-risk patients, 142/6248(2%) among major trauma patients (ISS > 12 per Australian definition), and 0.8/100,000 in the general population. The mortality rate was 55/600(11%) in the overall study population, and 34/136(25%) in MOF patients. 82/136(60%) of MOF patients developed MOF on day-3. No patients developed MOF after day-13. Among MOF patients, 60/136(44%) had cardiac failures (mortality = 37%), 39/136(29%) had respiratory failures (mortality = 23%), 24/136(18%) had renal failures (mortality = 63%), and 12/136(9%) had hepatic failures (mortality = 50%). CONCLUSION: Although a rare syndrome in the general population, MOF occurred in 23% of the most severely injured polytrauma patients. When compared to previous risk-matched cohorts, MOF become more common, but not more lethal, despite a decade older cohort. The heart has superseded the lungs as the most common organ to fail. Cardiac and respiratory failures occurred earlier and were associated with lower mortality than renal and hepatic failures.

Exercise-induced Nrf2 activation increases antioxidant defenses in skeletal muscles.

Following the discovery that exercise increases the production of reactive oxygen species in contracting skeletal muscles, evidence quickly emerged that endurance exercise training increases the abundance of key antioxidant enzymes in the trained muscles. Since these early observations, knowledge about the impact that regular exercise has on skeletal muscle antioxidant capacity has increased significantly. Importantly, in recent years, our understanding of the cell signaling pathways responsible for this exercise-induced increase in antioxidant enzymes has expanded exponentially. Therefore, the goals of this review are: 1) summarize our knowledge about the influence that exercise training has on the abundance of key antioxidant enzymes in skeletal muscles; and 2) to provide a state-of-the-art review of the nuclear factor erythroid 2-related factor (Nrf2) signaling pathway that is responsible for many of the exercise-induced changes in muscle antioxidant capacity. We begin with a discussion of the sources of reactive oxygen species in contracting muscles and then examine the exercise-induced changes in the antioxidant enzymes that eliminate both superoxide radicals and hydrogen peroxide in muscle fibers. We conclude with a discussion of the advances in our understanding of the exercise-induced control of the Nrf2 signaling pathway that is responsible for the expression of numerous antioxidant proteins. In hopes of stimulating future research, we also identify gaps in our knowledge about the signaling pathways responsible for the exercise-induced increases in muscle antioxidant enzymes.

Understanding exercise (in)tolerance in sickle cell disease: impacts of hemolysis and exercise training on skeletal muscle oxygen delivery.

Sickle cell disease (SCD) is characterized by central (cardiac) and peripheral vascular dysfunctions, significantly diminishing exercise capacity and quality of life. Although central cardiopulmonary abnormalities in SCD are known to reduce exercise capacity and quality of life; the impact of hemolysis and subsequent cell-free hemoglobin (Hb)-mediated peripheral vascular abnormalities on those outcomes are not fully understood. Despite the recognized benefits of exercise training for cardiovascular health and clinical management in chronic diseases like heart failure, there remains substantial debate on the advisability of regular physical activity for patients with SCD. This is primarily due to concerns that prolonged and/or high-intensity exercise might trigger metabolic shifts leading to vaso-occlusive crises. As a result, exercise recommendations for patients with SCD are often vague or nonexistent, reflecting a gap in knowledge about the mechanisms of exercise intolerance and the impact of exercise training on SCD-related health issues. This mini-review sheds light on recent developments in understanding how SCD affects exercise tolerance, with a special focus on the roles of hemolysis and the release of cell-free hemoglobin in altering cardiovascular and skeletal muscle function. Also highlighted here is the emerging research on the therapeutic effects and safety of exercise training in patients with SCD. In addition, the review identifies future research opportunities to fill existing gaps in our understanding of exercise (in)tolerance in SCD.

Intestinal Parasitic Infections May Be Overlooked Drivers of the Tuberculosis Pandemic.

The burden of tuberculosis (TB) is disproportionate in tropical and subtropical regions, where parasitic coinfections are common. Given the significant geographical overlap between TB and intestinal parasitic infections, it is important to consider the implications of intestinal parasitic infections for the TB pandemic. Intestinal parasitic infections have been theorized to increase vulnerability to TB by altering the inflammatory milieu, inducing undernutrition that blunts the immune response, and affecting drug pharmacokinetics. In this perspective, we provide a background of the epidemiological and immunological evidence that links parasitic infections to increased risk of TB progression and worse treatment outcomes. We also identify gaps in our knowledge and call for increased research on TB-parasitic coinfections to ensure action on a potentially widespread TB comorbidity.

Ventilator-induced diaphragm dysfunction: phenomenology and mechanism(s) of pathogenesis.

Mechanical ventilation (MV) is used to support ventilation and pulmonary gas exchange in patients during critical illness and surgery. Although MV is a life-saving intervention for patients in respiratory failure, an unintended side-effect of MV is the rapid development of diaphragmatic atrophy and contractile dysfunction. This MV-induced diaphragmatic weakness is labelled as 'ventilator-induced diaphragm dysfunction' (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a risk factor for the failure to wean patients from MV. Indeed, the inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. The pathogenesis of VIDD has been extensively investigated, revealing that increased mitochondrial production of reactive oxygen species within diaphragm muscle fibres promotes a cascade of redox-regulated signalling events leading to both accelerated proteolysis and depressed protein synthesis. Together, these events promote the rapid development of diaphragmatic atrophy and contractile dysfunction. This review highlights the MV-induced changes in the structure/function of diaphragm muscle and discusses the cell-signalling mechanisms responsible for the pathogenesis of VIDD. This report concludes with a discussion of potential therapeutic opportunities to prevent VIDD and suggestions for future research in this exciting field.

Adult Familial Influences on Rural Native Hawaiian and Pacific Islander Youths' E-Cigarette Use.

Background: Over the past decade, youth e-cigarette use has grown into a national epidemic, with Native Hawaiian and Pacific Islander (NHPI) youths' rates among some of the highest in the nation. Family factors significantly contribute to NHPI youths' decisions to engage in or resist substance use, yet few studies have specifically examined familial influences on NHPI youths' substance use decision-making and behaviors. Objective: The objective of this study is to examine adult familial influences on rural NHPI youths' decisions to engage in e-cigarette use. Method: Seventeen gender-specific focus groups with NHPI youths (N = 69) from eight public schools on Hawai'i Island were conducted. Results: Two family-related themes emerged from the data: 1) parental substance use permissiveness, and 2) family normalization of e-cigarette use. Conclusions: Examining adult familial contributors to NHPI youths' e-cigarette use needs to be part of a comprehensive effort to address NHPI health and substance use disparities. Prevention interventions should be explicit in addressing the family and relational context of NHPI youths' substance use.

Association Between Female Sex and Better Survival in Gastroenteropancreatic Neuroendocrine Tumors.

INTRODUCTION: Studies conflict on whether sex influences survival in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). GEP-NETs express receptors and genes responsive to female hormones. We hypothesized that women would have improved survival and this difference would be greater in premenopausal age women compared to older women. MATERIALS AND METHODS: The National Cancer Database from 2004 to 2016 was queried for patients with GEP-NETs based on histologic code. Demographic, tumor, treatment, and socioeconomic characteristics were compared between men and women and age ≤45 or >65 y using Fisher's exact and Wilcoxon tests as appropriate. The primary endpoint was overall survival (OS), assessed by Kaplan-Meier survival analysis. RESULTS: Included in the study were 73,521 patients with small bowel neuroendocrine tumors (SBNETs), gastric neuroendocrine tumors (GNETs), or pancreas neuroendocrine tumors (36,197 female, 37,324 male). Women lived longer regardless of primary site, with the largest difference in GNETs (median OS 139 versus 85 mo) and smallest in SBNETs (121 versus 116, P < 0.001 for both). While male patients more often had high grade and metastatic disease, female sex remained independently associated with improved OS after adjusting for confounders (hazard ratio 0.84, P < 0.001). In GNETs and SBNETs, female sex had a larger beneficial effect on OS in premenopausal than postmenopausal patients. CONCLUSIONS: Women with GEP-NETs have improved survival over men, especially in the premenopausal age group. This may be due to a protective effect of female hormones; however, further studies are necessary to uncover the biologic basis of this difference.

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer.

The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.

Site-specific N-alkylation of DNA oligonucleotide nucleobases by DNAzyme-catalyzed reductive amination.

DNA and RNA nucleobase modifications are biologically relevant and valuable in fundamental biochemical and biophysical investigations of nucleic acids. However, directly introducing site-specific nucleobase modifications into long unprotected oligonucleotides is a substantial challenge. In this study, we used in vitro selection to identify DNAzymes that site-specifically N-alkylate the exocyclic nucleobase amines of particular cytidine, guanosine, and adenosine (C, G and A) nucleotides in DNA substrates, by reductive amination using a 5'-benzaldehyde oligonucleotide as the reaction partner. The new DNAzymes each require one or more of Mg2+, Mn2+, and Zn2+ as metal ion cofactors and have kobs from 0.04 to 0.3 h-1, with rate enhancement as high as ∼104 above the splinted background reaction. Several of the new DNAzymes are catalytically active when an RNA substrate is provided in place of DNA. Similarly, several new DNAzymes function when a small-molecule benzaldehyde compound replaces the 5'-benzaldehyde oligonucleotide. These findings expand the scope of DNAzyme catalysis to include nucleobase N-alkylation by reductive amination. Further development of this new class of DNAzymes is anticipated to facilitate practical covalent modification and labeling of DNA and RNA substrates.