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Genetic susceptibility to oral and atherosclerotic cardiovascular diseases based on Dental and Heart SCORE studies
No full textPeriodontal disease and dental caries are two oral conditions that have been associated with atherosclerotic cardiovascular disease (ASCVD). However, it is unclear if one of the key mechanisms involved in this association could be a shared genetic susceptibility. The goal of this study was to explore whether there is an intersection of genetic loci among individuals with comprehensive oral examinations and subclinical ASCVD screenings. We leveraged data from oral and medical examinations obtained from the Dental and Heart Strategies Concentrating on Risk Evaluation (Dental/Heart SCORE) projects. Genome-wide association studies (GWASs) were performed independently in 552 participants (aged 45-75 years). The decayed, missing, or filled teeth index (DMFT) and periodontal disease indices were used to reflect oral conditions; coronary artery calcium scores (CAC) and carotid intima media thickness (CIMT) were analyzed as subclinical ASCVD traits. Single nucleotide variant (SNV) associations with oral and ASCVD traits were found; however, there were only a few regions of suggestive genetic loci overlap between these conditions. The most robust associations found for each phenotype are as follows: DMFT with rs79198416 (near CDC73/KCNT2; p = 7.57E-07), periodontal disease with rs73870587 (DIPK2A, p = 7.38E-08); CIMT with rs113152669 (LRP1B p = 4.07E-07), and CAC with rs76676138 (CNTNAP2; p = 2.47E-19). Although genetic associations were identified for each of the phenotypes of interest in the GWASs, there were no regions of shared genetic loci that significantly intersected across phenotypes. Thus, our results suggest that incorporation of environmental, behavioral, microbiome-related factors, and larger sample sizes, are warranted in future studies between oral and cardiovascular health
NRF2 immunobiology in cancer: Implications for immunotherapy and therapeutic targeting
No full textNuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that acts as a key regulator in cellular defense mechanisms against oxidative stress and xenobiotics. NRF2 modulates the expression of over 200 genes involved in antioxidant response, drug metabolism, and cellular resilience. Constitutive activation of NRF2 is a common event in cancer and recent advances provide remarkable insights into the role of NRF2 in oncogenesis, immune evasion, and treatment resistance. This review aims to provide a comprehensive overview of the role of NRF2 in shaping the tumor immune microenvironment and the impact this has on clinical outcomes and treatment opportunities. Across multiple tumor subtypes, the activation of NRF2 is associated with impaired responses to anti-PD1 immunotherapy. Mechanistic insights from genetically engineered mouse models, in vitro studies, and clinical trial samples demonstrate how NRF2 activity supports cell resiliency, diminishes cytotoxic immune responses, and promotes metabolic reprogramming. This also provides a vulnerability which can be targeted through novel drug therapy and future directions will include development of optimal combination strategies to target tumor dependencies while minimizing toxicity and systemic off-target immune related effects
Phospholipid scramblase 1 (PLSCR1) regulates interferon-lambda receptor 1 (IFN-λR1) and IFN-λ signaling in influenza A virus (IAV) infection
No full textPhospholipid scramblase 1 (PLSCR1) is an interferon-stimulated gene (ISG) that has several known anti-influenza functions. However, the mechanisms in relation to its expression compartment and enzymatic activity have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. Our results showed that influenza A virus (IAV)-infecte
Effect of same-day HIV treatment initiation (SDI) on 1-year outcomes in low-and middle -income countries: Systematic review and meta-analysis of randomised trials
No full textINTRODUCTION: Same-day initiation (SDI) of antiretroviral therapy is recommended for people presenting with HIV who have no contraindications. We reviewed the evidence on SDI interventions in low- and middle-income countries (LMICs).
METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials of SDI in adults diagnosed with HIV in LMICs. We searched MEDLINE, Embase and the Cochrane Library up to December 2024. Primary outcomes were viral suppression and retention in care 6-12 months after enrolment. Based on a qualitative assessment of the complex trial interventions, we considered two subgroups: (1) interventions newly introducing SDI and (2) interventions improving SDI implementation in settings where it was already routinely available. We conducted random-effects meta-analysis, assessed risk of bias using the ROBUST instrument and used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of evidence.
RESULTS: We identified 12 eligible trials, 7 introducing and 5 improving SDI. The trial interventions introducing SDI were sufficiently similar for meta-analysis. Introducing SDI likely has an important benefit for viral suppression (relative risk (RR) 1.18, 95% CI 1.06 to 1.30, moderate certainty) and retention in care (RR 1.12, 95% CI 1.00 to 1.25, low certainty) at 6-12 months The five trials improving SDI were too heterogeneous for meaningful meta-analysis. Individually, they showed either low to very low certainty for an important effect or, when implementing SDI in patients with tuberculosis (TB) symptoms, moderate to high certainty for little to no effect on viral suppression and retention in care.
CONCLUSION: Newly introducing SDI likely improves viral suppression and retention in care. However, the impact of interventions to improve SDI where already available is less clear. Two studies provided evidence against the concern that SDI may have adverse effects in participants with TB symptoms.
PROSPERO REGISTRATION NUMBER: CRD42023482522
Intersectional stigma and resilience in the uptake of cervical cancer prevention services in Nigeria: A qualitative study
No full textBACKGROUND: Cervical cancer is one of the leading causes of death among women in Africa, but stigma often delays cervical cancer prevention. We explore the perceptions, enablers and nurturers through the lens of intersectional stigma in the uptake of cervical cancer prevention services in Nigeria.
METHOD: Indepth interviews and focus group discussions were conducted among women aged 30-65 years and girls aged 9-26 years in Lagos, Nigeria. Data were analysed thematically. Using the relationships and expectation domain of the PEN-3 cultural model, we identified perceptions, enablers and nurturers related to the uptake of primary and secondary cervical cancer prevention services in Nigeria. We also explored how social identities may intersect with health-related stigmas and affect the uptake of these services.
RESULT: We interviewed 31 women and 31 girls. 61% of the participants were Christians and 39% were Muslims and were from the three major ethnic groups in Nigeria: Igbo (34%), Hausa (38%) and Yoruba (28%). Themes emerging from the data: (1) positive perceptions (self-efficacy): many women understood the importance of protecting themselves and their daughters from cervical cancer and strongly believed that they could educate their partners/husbands and would not let other people\u27s experiences with the vaccine influence them negatively. (2) Negative perceptions (anticipated stigma): some women expressed that because the human papillomavirus that causes cervical cancer is mainly sexually transmitted, they were concerned that they may be perceived as being promiscuous if they decide to commence routine cervical cancer screening. (3) Enablers (social support): nearly all women wanted the support of their spouses before receiving cervical cancer screening. (4) Nurturers (resilience): many clearly understood the complex social and economic realities faced by Nigerians that negatively affect their access to healthcare.
CONCLUSION: These findings offer intersectional insights into advancing public health and culturally anchored interventions to preventing cervical cancer-related stigma in Nigeria
Conventional versus advanced imaging selection for endovascular treatment of basilar artery occlusion strokes
No full textINTRODUCTION: Endovascular thrombectomy (EVT) is an effective treatment for basilar artery occlusion (BAO) stroke in select patients. While there is a growing body of literature suggesting that advanced imaging modalities such as computed tomography perfusion (CTP) and magnetic resonance (MR) may not be necessary for selecting anterior circulation large vessel occlusion stroke patients for EVT, whether advanced imaging may be superior to conventional imaging (non-contrast CT and CT angiography) in identifying good treatment candidates among BAO patients is less clear.
PATIENTS AND METHODS: This was a multicenter retrospective cohort study of BAO EVT patients treated from 2013 to 2022 in the Stroke Thrombectomy and Aneurysm Registry. Patients selected for EVT by advanced imaging (CTP or MR) were matched with those selected by conventional imaging using propensity score matching (PSM) accounting for possible confounders. Primary outcome was functional independence at 90 days. Other outcomes include bedridden state or death at 90-days and symptomatic intracranial hemorrhage (sICH).
RESULTS: 268 patients were included. 150 patients were selected for BAO EVT by conventional imaging, 86 by CTP, and 32 by MR. Patients selected by advanced imaging were significantly older than those selected by conventional imaging (median age 71 vs 64 years,
CONCLUSIONS: Selecting patients for basilar EVT using conventional versus advanced imaging did not result in different clinical outcomes, regardless of treatment time windows. Conventional imaging appears sufficient as a first-line tool for selecting basilar EVT patients in routine clinical practice
Implementation of single-pill combination medication for hypertension treatment by nonphysician health care workers at primary healthcare facilities in Nigeria: An explanatory mixed methods study
No full textBACKGROUND: Single-pill combination (SPC) therapy improves hypertension control; however, its implementation in primary care settings remains limited. In Nigeria, there is insufficient evidence on factors influencing SPC uptake, particularly from the perspective of healthcare workers (HCWs). This study examined the implementation of SPC medications for hypertension treatment by nonphysician HCWs at primary healthcare facilities (PHCs) in Nigeria.
METHODS: An explanatory sequential mixed methods study was conducted, building on a cluster randomized controlled trial embedded within the Hypertension Treatment in Nigeria Program. The trial compared SPC medications with free-equivalent combination therapies across 60 PHCs (January-June 2021). A subsequent qualitative component (September-December 2021) included two focus group discussions from 30 PHCs assigned to the SPC arm of the trial and five key informant interviews. The Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework was used to assess implementation outcomes and identify facilitators and barriers. Integration of quantitative and qualitative findings was guided by the RE-AIM Qualitative Evaluation for Systematic Translation framework (QuEST).
RESULTS: All 30 PHCs assigned to dispense SPCs adopted the medications (Reach/Adoption). Effectiveness: Blood pressure control (\u3c 140/90 mm Hg) was 54% (95% CI: 0.52, 0.56) in the SPC arm and 48% (95% CI: 0.46, 0.50) in the free-equivalent arm (cluster-adjusted p = 0.29). Monthly SPC use ranged from 21-37% across sites (Implementation), and 49% of patients remained in care at six months (Maintenance). Facilitators included training on SPC protocols, simplicity of dispensing the regimen, and perceived improvements in patient adherence. Challenges included SPC stockouts and concerns regarding nonphysician HCW capacity to manage complex cases. Policymakers identified the potential role of a Drug Revolving Fund (DRF) to support sustained SPC supply.
CONCLUSIONS: The findings indicate favorable implementation outcomes associated with SPC use by nonphysician HCWs in PHCs. Addressing supply challenges, maintaining training, and providing supportive supervision may be important for sustaining SPC-based hypertension treatment
Electrophysiological characterization of sex-dependent hypnosis by an endogenous neuroactive steroid epipregnanolone
Full text linkNeuroactive steroids (NAS) have long been recognized for their hypnotic and anesthetic properties in both clinical and preclinical settings. While sex differences in NAS sensitivity are acknowledged, the underlying mechanisms remain poorly understood. Here, we examined sex-specific responses to an endogenous NAS epipregnanolone (EpiP) in wild-type mice using behavioral assessment of hypnosis (loss of righting reflex, LORR) and in vivo electrophysiological recordings. Specifically, local field potentials (LFPs) were recorded from the central medial thalamus (CMT) and electroencephalogram (EEG) signals were recorded from the barrel cortex. We found that EpiP-induced LORR exhibited clear sex differences, with females showing increased sensitivity. Spectral power analysis and thalamocortical (TC) and corticocortical (CC) phase synchronization further supported enhanced hypnotic susceptibility in female mice. Our findings reveal characteristic sex-dependent effects of EpiP on the synchronized electrical activity in both thalamus and cortex. These results support renewed exploration of endogenous NAS as clinically relevant anesthetic agents
A randomized, double-blind, placebo-controlled trial of IL-7 in critically ill patients with COVID-19
Full text linkBACKGROUND: Lymphopenia and failure of lymphocytes to mount an early IFN-γ response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients\u27 ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function.
METHODS: We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically ill, patients with lymphopenia who have COVID-19. The primary endpoint was to assess CYT107\u27s effect on lymphocyte recovery with secondary clinical endpoints including safety, ICU and hospital length-of-stay, incidence of secondary infections, and mortality.
RESULTS: CYT107 was well tolerated without precipitating a cytokine storm or worsening pulmonary function. Absolute lymphocyte counts increased in both groups without a significant difference between CYT107 and placebo. Patients with COVID-19 receiving CYT107 but not concomitant antiviral medications, known inducers of lymphopenia, had a final lymphocyte count that was 43% greater than placebo (P = 0.067). There were significantly fewer treatment-emergent adverse events in CYT107 versus placebo-treated patients (P \u3c 0.001), consistent with a beneficial drug effect. Importantly, CYT107-treated patients had 44% fewer hospital-acquired infections versus placebo-treated patients (P = 0.014).
CONCLUSION: Given that hospital-acquired infections are responsible for a large percentage of COVID-19 deaths, this effect of CYT107 to decrease nosocomial infections could substantially reduce late morbidity and mortality in this highly lethal disease. The strong safety profile of CYT107 and its excellent tolerability provide support for trials of CYT107 in other potential pandemic respiratory viral infections.
TRIAL REGISTRATION: NCT04379076, NCT04426201, NCT04442178, NCT04407689, NCT04927169.
FUNDING: Funding for the trial was provided by RevImmune and the Cancer Research Institute
Cryo-EM structures of a pentameric ligand-gated ion channel in liposomes
Full text linkDetergents and lipid nanodiscs affect the cryo-EM structures of pentameric ligand-gated ion channels (pLGICs) including ELIC. To determine the structure of a pLGIC in a membrane environment that supports ion channel function, we performed single particle cryo-EM of ELIC in liposomes. ELIC activation and desensitization were confirmed in liposomes with a stopped-flow thallium flux assay. Using WT ELIC and a non-desensitizing mutant (ELIC5), we captured resting, activated, and desensitized structures at high resolution. In the desensitized structure, the ion conduction pore has a constriction at the 9\u27 leucine of the pore-lining M2 helix, indicating that 9\u27 is the desensitization gate in ELIC. The agonist-bound structures of ELIC in liposomes are distinct from those in nanodiscs. In general, the transmembrane domain is more loosely packed in liposomes compared to nanodiscs. It has been suggested that large nanodiscs are superior for supporting membrane protein function. However, ELIC localizes to the rim of large circularized nanodiscs, and structures of ELIC in large nanodiscs deviate from the liposome structures more than those in small nanodiscs. Using liposomes for cryo-EM structure determination of a pLGIC increases our confidence that the structures are snapshots of functional states