Integrin α5ß1 contributes to cell fusion and inflammation mediated by SARS-CoV-2 spike via RGD-independent interaction.

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infects host cells by engaging its spike (S) protein with human ACE2 receptor. Recent studies suggest the involvement of integrins in SARS-CoV-2 infection through interaction with the S protein, but the underlying mechanism is not well understood. This study investigated the role of integrin α5ß1, which recognizes the Arg-Gly-Asp (RGD) motif in its physiological ligands, in S-mediated virus entry and cell-cell fusion. Our results showed that α5ß1 does not directly contribute to S-mediated cell entry, but it enhances S-mediated cell-cell fusion in collaboration with ACE2. This effect cannot be inhibited by the putative α5ß1 inhibitor ATN-161 or the high-affinity RGD-mimetic inhibitor MK-0429 but requires the participation of α5 cytoplasmic tail (CT). We detected a direct interaction between α5ß1 and the S protein, but this interaction does not rely on the RGD-containing receptor binding domain of the S1 subunit of the S protein. Instead, it involves the S2 subunit of the S protein and α5ß1 homo-oligomerization. Furthermore, we found that the S protein induces inflammatory responses in human endothelial cells, characterized by NF-κB activation, gasdermin D cleavage, and increased secretion of proinflammatory cytokines IL-6 and IL-1ß. These effects can be attenuated by the loss of α5 expression or inhibition of the α5 CT binding protein phosphodiesterase-4D (PDE4D), suggesting the involvement of α5 CT and PDE4D pathway. These findings provide molecular insights into the pathogenesis of SARS-CoV-2 mediated by a nonclassical RGD-independent ligand-binding and signaling function of integrin α5ß1 and suggest potential targets for antiviral treatment.

Inhibition of GPR39 restores defects in endothelial cell-mediated neovascularization under the duress of chronic hyperglycemia: Evidence for regulatory roles of the sonic hedgehog signaling axis.

Impaired endothelial cell (EC)-mediated angiogenesis contributes to critical limb ischemia in diabetic patients. The sonic hedgehog (SHH) pathway participates in angiogenesis but is repressed in hyperglycemia by obscure mechanisms. We investigated the orphan G protein-coupled receptor GPR39 on SHH pathway activation in ECs and ischemia-induced angiogenesis in animals with chronic hyperglycemia. Human aortic ECs from healthy and type 2 diabetic (T2D) donors were cultured in vitro. GPR39 mRNA expression was significantly elevated in T2D. The EC proliferation, migration, and tube formation were attenuated by adenovirus-mediated GPR39 overexpression (Ad-GPR39) or GPR39 agonist TC-G-1008 in vitro. The production of proangiogenic factors was reduced by Ad-GPR39. Conversely, human ECs transfected with GPR39 siRNA or the mouse aortic ECs isolated from GPR39 global knockout (GPR39KO) mice displayed enhanced migration and proliferation compared with their respective controls. GPR39 suppressed the basal and ligand-dependent activation of the SHH effector GLI1, leading to attenuated EC migration. Coimmunoprecipitation revealed that the GPR39 direct binding of the suppressor of fused (SUFU), the SHH pathway endogenous inhibitor, may achieve this. Furthermore, in ECs with GPR39 knockdown, the robust GLI1 activation and EC migration were abolished by SUFU overexpression. In a chronic diabetic model of diet-induced obesity (DIO) and low-dose streptozotocin (STZ)-induced hyperglycemia, the GPR39KO mice demonstrated a faster pace of revascularization from hind limb ischemia and lower incidence of tissue necrosis than GPR39 wild-type (GPR39WT) counterparts. These findings have provided a conceptual framework for developing therapeutic tools that ablate or inhibit GPR39 for ischemic tissue repair under metabolic stress.

TAK1-binding protein 2 (TAB2) and TAB3 are redundantly required for TLR-induced cytokine production in macrophages.

Transforming growth factor-ß-activated kinase 1 (TAK1) plays a pivotal role in innate and adaptive immunity. TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways downstream of diverse immune receptors, including toll-like receptors (TLRs). Upon stimulation with TLR ligands, TAK1 is activated via recruitment to the lysine 63-linked polyubiquitin chain through TAK1-binding protein 2 (TAB2) and TAB3. However, the physiological importance of TAB2 and TAB3 in macrophages is still controversial. A previous study has shown that mouse bone marrow-derived macrophages (BMDMs) isolated from mice double deficient for TAB2 and TAB3 produced tumor necrosis factor (TNF)-α and interleukin (IL)-6 to the similar levels as control wild-type BMDMs in response to TLR ligands such as lipopolysaccharide (LPS) or Pam3CSK4, indicating that TAB2 and TAB3 are dispensable for TLR signaling. In this study, we revisited the role of TAB2 and TAB3 using an improved mouse model. We observed a significant impairment in the production of pro-inflammatory cytokines and chemokine in LPS- or Pam3CSK4-treated BMDMs deficient for both TAB2 and TAB3. Double deficiency of TAB2 and TAB3 resulted in the decreased activation of NF-κB and MAPK pathways as well as the slight decrease in TAK1 activation in response to LPS or Pam3CSK4. Notably, the TLR-mediated expression of inhibitor of NF-κB (IκB)ζ was severely compromised at the protein and messenger RNA (mRNA) levels in the TAB2/TAB3 double-deficient BMDMs, thereby impeding IL-6 production. Our results suggest that TAB2 and TAB3 play a redundant and indispensable role in the TLR signaling pathway.

A Research Agenda to Improve Outcomes in Patients with Chronic Obstructive Pulmonary Disease and Cardiovascular Disease. An Official American Thoracic Society Research Statement.

BACKGROUND: Individuals with chronic obstructive pulmonary disease (COPD) are often at risk for or have comorbid cardiovascular disease and are likely to die of cardiovascular-related causes. OBJECTIVES: To prioritize a list of research topics related to diagnosis and management of patients with COPD and comorbid cardiovascular diseases (heart failure, atherosclerotic vascular disease and atrial fibrillation) by summarizing existing evidence and using consensus-based methods. METHODS: A literature search was performed. References were reviewed by committee co-chairs. An international, multidisciplinary committee, including a patient advocate, met virtually to review evidence and identify research topics. A modified Delphi approach was used to prioritize topics in real-time based on their potential for advancing the field. RESULTS: Gaps spanned the translational science spectrum from basic science to implementation: 1) disease mechanisms, 2) epidemiology, 3) subphenotyping, 4) diagnosis and management, 5) clinical trials, 6) care delivery, 7) medication access, adherence and side effects, 8) risk factor mitigation, 9) cardiac and pulmonary rehabilitation, and 10) health equity. Seventeen experts participated and quorum was achieved for all votes (>80%). Of 17 topics, ≥70% agreement was achieved for 12 topics after 2 rounds of voting. Range of summative Likert score was -15 to 25. Highest priority was "Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements." Health equity was identified as an important topic that should be embedded within all research. CONCLUSIONS: We propose a prioritized research agenda with the purpose of stimulating high-impact research that will hopefully improve outcomes among people with COPD and cardiovascular disease.

Reduced effectiveness of repeat influenza vaccination: distinguishing among within-season waning, recent clinical infection, and subclinical infection.

Studies have reported that prior-season influenza vaccination is associated with higher risk of clinical influenza infection among vaccinees. This effect might arise from incomplete consideration of within-season waning and recent infection. Using data from the US Flu Vaccine Effectiveness (VE) Network (2011-2012 to 2018-2019 seasons), we found that repeat vaccinees were vaccinated earlier in a season by one week. After accounting for waning VE, repeat vaccinees were still more likely to test positive for A(H3N2) (OR=1.11, 95%CI:1.02-1.21) but not for influenza B or A(H1N1). We found that clinical infection influenced individuals' decision to vaccinate in the following season while protecting against clinical infection of the same (sub)type. However, adjusting for recent clinical infections did not strongly influence the estimated effect of prior-season vaccination. In contrast, we found that adjusting for subclinical infection could theoretically attenuate this effect. Additional investigation is needed to determine the impact of subclinical infections on VE.

α- or ß-Adrenergic blockade does not affect transplanted islet cell responses to hypoglycemia in type 1 diabetes.

Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to posttransplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (ß-adrenergic blockage), or placebo infusion. Characteristics of participants (5 females/4 males) were as follows: median (range) age 53 (34-63) yr, diabetes duration 29 (18-56) yr, posttransplant 7.0 (1.9-8.4) yr, HbA1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate was lower with propranolol versus placebo (P < 0.05). There was no difference in the suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and although levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo (P < 0.05). Pancreatic polypeptide was greater with phentolamine versus placebo during the euglycemic phase (P < 0.05), and free fatty acids were lower and the glucose infusion rate was higher with propranolol versus placebo during the hypoglycemic phase (P < 0.05 for both). These results indicate that neither physiological α- nor ß-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic reinnervation of the islet graft is not necessary for posttransplant glucose counterregulation.NEW & NOTEWORTHY Whether adrenergic input to islets is necessary for glucose homeostasis in humans is debated. Here, the adrenergic contribution to intrahepatically transplanted islet cell responses to hypoglycemia in individuals with type 1 diabetes was investigated through α- or ß-adrenergic receptor blockade during hyperinsulinemic euglycemic-hypoglycemic clamps. Neither α- nor ß-adrenergic blockage affected the suppression of endogenous insulin or activation of glucagon secretion, suggesting that sympathetic reinnervation of islet grafts is not required for posttransplant defense against hypoglycemia.

Genome-wide in vivo CRISPR screen identifies TGFß3 as actionable biomarker of palbociclib resistance in triple negative breast cancer.

Triple negative breast cancer (TNBC) remains exceptionally challenging to treat. While CDK4/6 inhibitors have revolutionized HR + breast cancer therapy, there is limited understanding of their efficacy in TNBC and meaningful predictors of response and resistance to these drugs remain scarce. We conducted an in vivo genome-wide CRISPR screen using palbociclib as a selection pressure in TNBC. Hits were prioritized using microarray data from a large panel of breast cancer cell lines to identify top palbociclib sensitizers. Our study defines TGFß3 as an actionable determinant of palbociclib sensitivity that potentiates its anti-tumor effects. Mechanistically, we show that chronic palbociclib exposure depletes p21 levels, contributing to acquired resistance, and that TGFß3 treatment can overcome this. This study defines TGFß3 as an actionable biomarker that can be used to improve patient stratification for palbociclib treatment and exploits the synergistic interaction between CDK4/6 and TGFß3 to propose a new combinatorial treatment for TNBC.

SARS-CoV-2 incidence, seroprevalence, and antibody dynamics in a rural, population-based cohort: March 2020 - July 2022.

Studies of SARS-CoV-2 incidence are important for response to continued transmission and future pandemics. We followed a rural community cohort with broad age representation with active surveillance for SARS-CoV-2 identification from November 2020 through July 2022. Participants provided serum specimens at regular intervals and following SARS-CoV-2 infection or vaccination. We estimated the incidence of SARS-CoV-2 infection identified by study RT-PCR, electronic health record documentation or self-report of a positive test, or serology. We also estimated the seroprevalence of SARS-CoV-2 spike and nucleocapsid antibodies measured by ELISA. Overall, 65% of the cohort had ≥1 SARS-CoV-2 infection by July 2022, and 19% of those with primary infection were reinfected. Infection and vaccination contributed to high seroprevalence, 98% (95% CI: 95%, 99%) of participants were spike or nucleocapsid seropositive at the end of follow-up. Among those seropositive, 82% were vaccinated. Participants were more likely to be seropositive to spike than nucleocapsid following infection. Infection among seropositive individuals could be identified by increases in nucleocapsid, but not spike, ELISA optical density values. Nucleocapsid antibodies waned more quickly after infection than spike antibodies. High levels of SARS-CoV-2 population immunity, as found in this study, are leading to changing epidemiology necessitating ongoing surveillance and policy evaluation.

Association Between Coronary Artery Disease Testing in Patients with New-Onset Heart Failure and Heart Failure Readmission and Mortality.

BACKGROUND: In patients with new-onset heart failure (HF), coronary artery disease (CAD) testing remains underutilized. Whether widespread CAD testing in patients with new-onset HF leads to improved outcomes remains to be determined. OBJECTIVE: We sought to examine whether CAD testing, and its timing, among patients hospitalized with new-onset HF with reduced ejection fraction (HFrEF), is associated with improved outcomes. DESIGN: Retrospective cohort study. PARTICIPANTS: Adult (≥ 18 years) non-pregnant patients with new-onset HFrEF hospitalized within one of 15 Kaiser Permanente Southern California medical centers between 2016 and 2021. Key exclusion criteria included history of heart transplant, hospice, and a do-not-resuscitate order. MAIN MEASURES: Primary outcome was a composite of HF readmission or all-cause mortality through end of follow-up on 12/31/2022. KEY RESULTS: Among 2729 patients hospitalized with new-onset HFrEF, 1487 (54.5%) received CAD testing. The median age was 66 (56-76) years old, 1722 (63.1%) were male, and 1074 (39.4%) were White. After a median of 1.8 (0.6-3.4) years, the testing group had a reduced risk of HF readmission or all-cause mortality (aHR [95%CI], 0.71 [0.63-0.79]). These results were consistent across subgroups by history of atrial fibrillation, diabetes, renal disease, myocardial infarction, and elevated troponin during hospitalization. In a secondary analysis where CAD testing was further divided to early (received testing before discharge) and late testing (up to 90 days after discharge), there was no difference in late vs early testing (0.97 [0.81-1.16]). CONCLUSIONS: In a contemporary and diverse cohort of patients hospitalized with new-onset HFrEF, CAD testing within 90 days of hospitalization was associated with a lower risk of HF readmission or all-cause mortality. Testing within 90 days after discharge was not associated with worse outcomes.

SARS-CoV-2 Viral Shedding and Rapid Antigen Test Performance - Respiratory Virus Transmission Network, November 2022-May 2023.

As population immunity to SARS-CoV-2 evolves and new variants emerge, the role and accuracy of antigen tests remain active questions. To describe recent test performance, the detection of SARS-CoV-2 by antigen testing was compared with that by reverse transcription-polymerase chain reaction (RT-PCR) and viral culture testing during November 2022-May 2023. Participants who were enrolled in a household transmission study completed daily symptom diaries and collected two nasal swabs (tested for SARS-CoV-2 via RT-PCR, culture, and antigen tests) each day for 10 days after enrollment. Among participants with SARS-CoV-2 infection, the percentages of positive antigen, RT-PCR, and culture results were calculated each day from the onset of symptoms or, in asymptomatic persons, from the date of the first positive test result. Antigen test sensitivity was calculated using RT-PCR and viral culture as references. The peak percentage of positive antigen (59.0%) and RT-PCR (83.0%) results occurred 3 days after onset, and the peak percentage of positive culture results (52%) occurred 2 days after onset. The sensitivity of antigen tests was 47% (95% CI = 44%-50%) and 80% (95% CI = 76%-85%) using RT-PCR and culture, respectively, as references. Clinicians should be aware of the lower sensitivity of antigen testing compared with RT-PCR, which might lead to false-negative results. This finding has implications for timely initiation of SARS-CoV-2 antiviral treatment, when early diagnosis is essential; clinicians should consider RT-PCR for persons for whom antiviral treatment is recommended. Persons in the community who are at high risk for severe COVID-19 illness and eligible for antiviral treatment should seek testing from health care providers with the goal of obtaining a more sensitive diagnostic test than antigen tests (i.e., an RT-PCR test).

Outcome of Mechanical Thrombectomy for Acute Basilar Artery Occlusion in Patients with Intracranial Atherosclerotic Disease.

INTRODUCTION: Intracranial atherosclerotic disease (ICAD) has been identified as a major cause of acute basilar artery occlusion (BAO).This study compared the characteristics and treatment outcomes in acute BAO patients with and without ICAD. METHODS: A prospective cohort study was conducted at 115 People's Hospital, Ho Chi Minh city, Vietnam from August 2021 to June 2023. Patients with acute BAO who underwent endovascular treatment within 24 h from symptom onset were included (thrombectomy alone or bridging with intravenous alteplase). The baseline characteristics and outcomes were analyzed and compared between patients with and without ICAD. Good functional outcome was defined as mRS ≤3 at 90 days. RESULTS: Among the 208 patients enrolled, 112 (53.8%) patients were categorized in the ICAD group, and 96 (46.2%) in the non-ICAD group. Occlusion in the proximal segment of the basilar artery was more common in patients with ICAD (55.4% vs. 21.9%, p < 0.001), whereas the distal segment was the most common location in the non-ICAD group (58.3% vs. 10.7%, p < 0.001). Patients in the ICAD group were more likely to undergo treatment in the late window, with a higher mean onset-to-treatment time compared to the non-ICAD group (11.6 vs. 9.5 h, p = 0.01). In multivariable logistic regression analysis, distal segment BAO was negatively associated with ICAD (aOR 0.13, 95% CI: 0.05-0.32, p < 0.001), while dyslipidemia showed a positive association (aOR 2.44, 95% CI: 1.15-5.17, p = 0.02). There was a higher rate for rescue stenting in the ICAD compared to non-ICAD group (15.2% vs. 0%, p < 0.001). However, no significant differences were found between the two groups in terms of good outcome (45.5% vs. 44.8%, p = 0.91), symptomatic hemorrhage rates (4.5% vs. 8.3%, p = 0.25), and mortality (42% vs. 50%, p = 0.25). CONCLUSION: ICAD was a common etiology in patients with BAO. The location segment of BAO and dyslipidemia were associated with ICAD in patients with BAO. There was no difference in 90-day outcomes between BAO patients with and without ICAD undergoing endovascular therapy.

Strength together: examining risk and protective factors associated with dementia and cognitive impairment in Aboriginal and Torres Strait Islander peoples through harmonisation of landmark studies.

BACKGROUND: Rates of dementia for Aboriginal and Torres Strait Islander peoples are three to five times greater compared to non-Indigenous Australians, with earlier age of onset. However, the risk and protective factors that drive these higher rates vary across existing cohort studies, with minimal findings on the role of vascular risk factors beyond stroke. Harmonisation of data across studies may offer greater insights through enhanced diversity and strengthened statistical capabilities. This study aims to combine three landmark cohort studies of Aboriginal and Torres Strait Islander participants to better understand the determinants of cognitive health and dementia. METHODS/DESIGN: Three cohort studies - the Kimberley Healthy Adults Project (KHAP, N = 363), Koori Growing Old Well Study (KGOWS, N = 336) and Torres Strait Dementia Prevalence Study (TSDPS, N = 274) - share a similar research methodology with demographic, medical history, psychosocial factors, cognitive tests and consensus clinical diagnoses of cognitive impairment and dementia. Associations between risk and protective factors of interest and the presence of dementia and/or cognitive impairment diagnoses will be evaluated by univariable and multivariable logistic regression in a harmonised cross-sectional cohort of 898 participants. Factors associated with incident dementia and/or cognitive impairment will be assessed in a subset of KHAP (n = 189) and KGOWS participants (n = 165) who were available in longitudinal follow-up, after exclusion of those with baseline dementia or cognitive impairment. Analyses in relation to outcome measure of death or dementia will be conducted to account for the competing risk of death. Logistic regression will be used to evaluate the association between the individual components of the 16-component Kimberley Indigenous Cognitive Assessment (KICA) tool and the presence of dementia and cognitive impairment determined by independent consensus diagnoses. Multivariable binary logistic regression will be used to adjust for the effect of confounding variables. Results will be reported as odds ratios (OR) with 95% confidence intervals (95% CI). DISCUSSION: Greater understanding of risk and protective factors of dementia and cognitive impairment relevant to Aboriginal and Torres Strait Islander peoples may improve approaches across the life course to delay cognitive decline and reduce dementia risk.

A systematic study of solvation structure of asymmetric lithium salts in water.

Aqueous electrolytes are promising in large-scale energy storage applications due to intrinsic low toxicity, non-flammability, high ion conductivity, and low cost. However, pure water's narrow electrochemical stability window (ESW) limits the energy density of aqueous rechargeable batteries. Water-in-salt electrolytes (WiSE) proposal has expanded the ESW to over 3 V by changing electrolyte solvation structure. The limited solubility and WIS electrolyte crystallization have been persistent concerns for imide-based lithium salts. Asymmetric lithium salts compensate for the above flaws. However, studying the solvation structure of asymmetric salt aqueous electrolytes is rare. Here, we applied small-angle x-ray scattering (SAXS) and Raman spectroscope to reveal the solvation structure of imide-based asymmetric lithium salts. The SAXS spectra show the blue shifts of the lowerqpeak with decreased intensity as the increasing of concentration, indicating a decrease in the average distance between solvated anions. Significantly, an exponential decrease in the d-spacing as a function of concentration was observed. In addition, we also applied the Raman spectroscopy technique to study the evolutions of solvent-separated ion pairs (SSIPs), contacted ion pairs (CIPs), and aggregate ions (AGGs) in the solvation structure of asymmetric salt solutions.

Agonists, inverse agonists, and antagonists as therapeutic approaches to manipulate retinoic acid-related orphan receptors.

Retinoic acid-related orphan receptors (RORs) serve as transcription factors that play a pivotal role in a myriad of physiological processes within the body. Their involvement extends to critical biological processes that confer protective effects in the heart, immune system, and nervous system, as well as contributing to the mitigation of several aggressive cancer types. These protective functions are attributed to ROR's regulation of key proteins and the management of various cellular processes, including autophagy, mitophagy, inflammation, oxidative stress, and glucose metabolism, highlighting the emerging need for pharmacological approaches to modulate ROR expression. Thus, the modulation of RORs is a rapidly growing area of research aimed not only at comprehending these receptors, but also at manipulating them to attain the desired physiological response. Despite the presence of natural ROR ligands, the development of synthetic agonists with high selectivity for these receptors holds substantial therapeutic potential. The exploration and advancement of such compounds can effectively target diseases associated with ROR dysregulation, thereby providing avenues for therapeutic interventions. Herein, we provide a comprehensive examination of the multifaceted role of ROR in diverse physiological and pathophysiological conditions, accompanied by an in-depth exploration of a spectrum of ROR agonists, inverse agonists, and antagonists.

Inflammatory Markers and Fatigue in Individuals With Moderate to Severe Chronic Obstructive Pulmonary Disease.

BACKGROUND: Fatigue, a prevalent complex symptom among patients with chronic obstructive pulmonary disease (COPD), is considered an important clinical indicator of disease severity. However, the underlying mechanisms of COPD-related fatigue are not fully understood. OBJECTIVES: This analysis explored the relationships between peripheral inflammatory markers and COPD-related fatigue in people with moderate to severe COPD. METHODS: This is a secondary analysis of a longitudinal observational study of individuals with COPD examining the biological causes and functional consequences of depression. The data used in this study were collected at baseline. Systemic inflammation markers included C-reactive protein (CRP) and three pro-inflammatory cytokines consisting of interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α. COPD-related fatigue was self-reported using the Chronic Respiratory Questionnaire. Covariates included age; gender; smoking status; disease severity; symptoms of depression, anxiety, and pain; and social support. Multivariable linear regression analyses were conducted. RESULTS: The sample included 300 adults living with COPD; 80% were male, and the average age was 67.6 years. Modest correlations were found between two systemic inflammatory markers (CRP and IL-8) and COPD-related fatigue. CRP was the only inflammatory marker significantly associated with fatigue symptoms after adjusting for covariates in multivariable analyses. Depression, pain, and education level were also significant predictors of COPD-related fatigue. DISCUSSION: The findings suggest that altered immune response based on CRP may contribute to COPD-related fatigue. Management of depression and pain may work as an effective treatment strategy for COPD-related fatigue. Further longitudinal studies with a broader range of inflammatory markers and multidimensional measures of fatigue symptoms are warranted.

A national program to advance dementia research in Vietnam.

BACKGROUND: As Vietnam and other low- and middle-income countries (LMIC) experience a rapid increase in the number of people living with dementia, an acute need exists to strengthen research capacity to inform policy, improve care and support, and develop national dementia plans. We describe the development and early outcomes of an National Institutes of Health (NIH)/National Institute on Aging (NIA)-funded national dementia research capacity building program in Vietnam. METHODS: The research capacity building program commenced in 2019 and has three components: (1) Vietnam Alzheimer's and other dementias research Network (VAN), (2) a mentored pilot grant program, and (3) research training, networking, and dissemination activities. The pilot grant program funds Vietnamese researchers for one to two years to conduct research focusing on Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD). Grants are reviewed and scored using NIH criteria, and priority is given to pilot grants with policy relevance and potential for future funding. An international pool of high-income country (e.g., United States, Australia, and United Kingdom) mentors has been engaged and mentors paired with each funded project. Training and networking activities include workshops on AD/ADRD research topics and regular meetings in conjunction with Vietnam's annual national dementia/geriatric conferences. Dissemination is facilitated through targeted outreach and the creation of a national network of institutions. RESULTS: Over four years (2019-2023), we received 62 applications, reviewed 58 applications, and funded 21 projects (4-5 per year). Funded investigators were from diverse disciplines and institutions across Vietnam with projects on a range of topics, including biomarkers, prevention, diagnosis, neuropsychological assessment, family caregiver support, dementia education, and clinical trials. A network of 12 leading academic and research institutions nationwide has been created to facilitate dissemination. Six research training workshops have been organized and included presentations from international speakers. Grantees have published or presented their studies at both national and international levels. The mentoring program has helped grantees to build their research skills and expand their research network. CONCLUSION: This research capacity building program is the first of its kind in Vietnam and may serve as a useful model for other LMIC.

Effectiveness of a Smartphone-Based Stress Management Program for Depression in Hospital Nurses During COVID-19 in Vietnam and Thailand: 2-Arm Parallel-Group Randomized Controlled Trial.

BACKGROUND: During the COVID-19 pandemic, health care professionals experienced high levels of depression. However, extant research has not highlighted effective internet-based psychological interventions to improve the mental health in this population during the pandemic. It remains unclear whether self-guided, internet-based cognitive behavioral therapy (iCBT) programs are effective in improving the mental health of health care workers during the COVID-19 pandemic. OBJECTIVE: The aim of this study was to evaluate the effectiveness of a smartphone-based iCBT stress management program for reducing the depression experienced by nurses in Vietnam and Thailand. METHODS: From March to April 2022, a 2-arm, parallel-group randomized controlled trial was implemented. One arm offered a 7-week self-guided iCBT program, and the other offered treatment as usual as a control arm. Full-time nurses were recruited from 6 hospitals: 2 hospitals in Vietnam and 4 hospitals in Thailand. The primary outcome of this program was the severity of depression measured by the Depression Anxiety Stress Scale-21 items. Follow-up surveys were conducted to measure the change in depression severity at 3 months (July-August 2022) and at 6 months (October-November 2022) after baseline. Mixed modeling for repeated measures was used to test the effects of the intervention compared with the control for the follow-up. RESULTS: A total of 1203 nurses were included in this study: 602 in the intervention group and 601 in the control group. The follow-up rate at 3 and 6 months ranged from 85.7% (515/601) to 87.5% (527/602). The completion rate for the program was 68.1% (410/602). The group difference in depression was significant at the 3-month follow-up (coefficient=-0.92, 95% CI -1.66 to -0.18; P=.02) and nonsignificant at the 6-month follow-up (coefficient=-0.33, 95% CI -1.11 to 0.45; P=.41). The estimated effect sizes were -0.15 and -0.06 at the 3- and 6-month follow-ups, respectively. CONCLUSIONS: Our study shows that the smartphone-based iCBT program was effective in reducing depression at the 3-month follow-up among hospital nurses in Vietnam and Thailand during the COVID-19 pandemic. However, the effect size was small, and therefore, these results may not be clinically meaningful. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000044145; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000050128. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.20944/preprints202303.0450.v1.

Treatment non-adherence among methadone maintenance patients and associated factors: a multicenter, cross-sectional study in Vietnam.

OBJECTIVE: This multicenter, cross-sectional study was conducted to investigate the prevalence of treatment non-adherence and its associated factors among methadone maintenance patients in Vietnam. METHODS: This secondary data analysis was conducted using the data from a previous study. Six hundred patients were interviewed face-to-face to collect data on their demographic characteristics and social support. Information about the treatment characteristics and patients' non-adherence was gathered from medical records and books monitoring their treatment process. Treatment non-adherence was defined as missing at least one methadone dose in the last three months. RESULTS: The overall prevalence of non-adherence was 45.7%. The average social support score of patients who completely adhered to treatment was significantly higher than that of those who did not (p < 0.001). In the multivariate logistic regression model, for each one-unit increase in social support (one score), treatment time (a year), and patient's monthly income (one million Vietnam dongs), the odds of non-adherence decreased by 28% (aOR = 0.72, 95%CI 0.59-0.88, p = 0.002), 15% (aOR = 0.85, 95%CI 0.80-0.91, p < 0.001) and 9% (aOR = 0.91, 95%CI 0.85-0.97, p = 0.004), respectively. Patients living in Son La (a mountainous province) were 1.72 times (95%CI 1.09-2.71) more likely to be non-adherent as compared to those in other areas (p = 0.020). As per univariate analyses, other associated factors could be age, education level, family monthly income, occupation, and opioid relapse (p < 0.001). CONCLUSIONS: A high non-adherence rate was found among Vietnamese methadone maintenance patients. Interventions involving social support, occupation, income, and education are needed to improve their treatment adherence.

Risk, protective, and biomarkers of dementia in Indigenous peoples: A systematic review.

INTRODUCTION: Dementia is an emergent health priority for Indigenous peoples worldwide, yet little is known about disease drivers and protective factors. METHODS: Database searches were conducted in March 2022 to identify original publications on risk, protective, genetic, neuroradiological, and biological factors related to dementia and cognitive impairment involving Indigenous peoples. RESULTS: Modifiable risk factors featured across multiple studies include childhood adversity, hearing loss, low education attainment, unskilled work history, stroke, head injury, epilepsy, diabetes, hypertension, hyperlipidemia, depression, low BMI, poor mobility, and continence issues. Non-modifiable risk factors included increasing age, sex, and genetic polymorphisms. Education, ex-smoking, physical and social activity, and engagement with cultural or religious practices were highlighted as potential protective factors. There is a paucity of research on dementia biomarkers involving Indigenous peoples. DISCUSSION: Greater understanding of modifiable factors and biomarkers of dementia can assist in strength-based models to promote healthy ageing and cognition for Indigenous peoples.

A pre-post evaluation of a digital intervention to improve psychosocial outcomes of caregivers of people living with cancer in Vietnam.

OBJECTIVES: To evaluate a co-designed intervention using digital resources "Vietnam Cancer Caring Coping" (V-CCC) on the health literacy, depression, and quality of life of caregivers supporting a cancer patient in oncology hospitals in Vietnam. METHODS: A pre-post quantitative evaluation with adult cancer caregivers across regional Oncology hospitals in Vietnam (Ho Chi Minh City, Da Nang, Can Tho, and Hue). Participants completed baseline and follow-up measures of health literacy (HLS-SF12) depression (PHQ-9) and Health-related Quality of Life (5Q-5D-5L). Participants accessed and reviewed V-CCC for a 2-week period. RESULTS: Two hundred and thirty-four caregivers completed pre and post-tests. Most participants were female (n = 143, 61%), married (n = 165, 70%), aged 18-44 (n = 155, 66%), lived rurally (n = 157, 67%). All health literacy scores of participants in post-intervention were significantly higher than that in pre-intervention across all domain's healthcare, disease prevention, and health promotion as well as the total score (p < 0.001). A significant reduction in the proportion of caregivers reporting PHQ-9 moderately severe/severe depression post-intervention was demonstrated (10.2 vs. 6.1%, respectively (p ≤ 0.001). No significant differences were observed pre and post-intervention across four 5Q-5D-5L health dimensions: mobility, self-care, usual activities, and pain/discomfort. Regarding anxiety/depression as measured by 5Q-5D-5L the proportion of participants who reported having moderate, severe, and extreme problems in pre- and post-intervention was statistically significant (32 vs. 24%), respectively (p = 0.0028). CONCLUSION: Co-designed digital resources can reduce health literacy inequities and improve psychological outcomes for cancer caregivers.