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Background: Dementia with Lewy bodies (DLB) is the second most common age-related neurocognitive pathology after Alzheimer's disease. Animal models characterizing this disease are lacking and their development would ameliorate both the understanding of neuropathological mechanisms underlying DLB as well as the efficacy of pre-clinical studies tackling this disease., Methods: We performed extensive phenotypic characterization of a transgenic mouse model overexpressing, most prominently in the dorsal hippocampus (DH) and frontal cortex (FC), wild-type form of the human α-synuclein gene (mThy1-hSNCA, 12 to 14-month-old males). Moreover, we drew a comparison of our mouse model results to DH- and FC- dependent neuropsychological and neuropathological deficits observed in a cohort of patients including 34 healthy control subjects and 55 prodromal-DLB patients (males and females)., Results: Our study revealed an increase of pathological form of soluble α-synuclein, mainly in the FC and DH of the mThy1-hSNCA model. However, functional impairment as well as increase in transcripts of inflammatory markers and decrease in plasticity-relevant protein level were exclusive to the FC. Furthermore, we did not observe pathophysiological or Tyrosine Hydroxylase alterations in the striatum or substantia nigra, nor motor deficits in our model. Interestingly, the results stemming from the cohort of prodromal DLB patients also demonstrated functional deficits emanating from FC alterations, along with preservation of those usually related to DH dysfunctions., Conclusions: This study demonstrates that pathophysiological impairment of the FC with concomitant DH preservation is observed at an early stage of DLB, and that the mThy1-hSNCA mouse model parallels some markers of this pathology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: The emergence of antimalarial drug resistance poses a major threat to effective malaria treatment and control. This study aims to inform policymakers and vaccine developers on the potential of an effective malaria vaccine in reducing drug-resistant infections., Methods: A compartmental model estimating cases, drug-resistant cases, and deaths averted from 2021 to 2030 with a vaccine against Plasmodium falciparum infection administered yearly to 1-year-olds in 42 African countries. Three vaccine efficacy (VE) scenarios and one scenario of rapidly increasing drug resistance are modeled., Results: When VE is constant at 40% for 4 years and then drops to 0%, 235.7 (Uncertainty Interval [UI] 187.8-305.9) cases per 1000 children, 0.6 (UI 0.4-1.0) resistant cases per 1000, and 0.6 (UI 0.5-0.9) deaths per 1000 are averted. When VE begins at 80% and drops 20 percentage points each year, 313.9 (UI 249.8-406.6) cases per 1000, 0.9 (UI 0.6-1.3) resistant cases per 1000, and 0.9 (UI 0.6-1.2) deaths per 1000 are averted. When VE remains 40% for 10 years, 384.7 (UI 311.7-496.5) cases per 1000, 1.0 (0.7-1.6) resistant cases per 1000, and 1.1 (UI 0.8-1.5) deaths per 1000 are averted. Assuming an effective vaccine and an increase in current levels of drug resistance to 80% by 2030, 10.4 (UI 7.3-15.8) resistant cases per 1000 children are averted., Conclusions: Widespread deployment of a malaria vaccine could substantially reduce health burden in Africa. Maintaining VE longer may be more impactful than a higher initial VE that falls rapidly., (© 2023. Springer Nature Limited.)

In this work, we discuss the synthesis and characterization of a 2D coordination polymer composed of a dianionic perhydroxylated boron cluster, [B 12 (OH) 12 2- ], coordinated to Zn(II)-the first example of a transition metal-coordinated [B 12 (OH) 12 ] 2- compound. This material was synthesized via cation exchange from the starting cesium salt and then subjected to rigorous characterization prior to and after thermal activation. Numerous techniques, including XRD, FTIR, SEM, TGA, and solid-state NMR revealed a 2D coordination polymer composed of sheets of Zn(II) ions intercalated between planes of boron clusters. The as-synthesized material was then evacuated of solvent via thermal treatment, and atomic-level changes from this transformation were elucidated through a combination of 1D and 2D solid-state NMR analyses of 11 B and 1 H nuclei, suggesting the full removal of coordinated solvent molecules. Evidence also suggested that [B 12 (OH) 12 2- ] can adjust its coordination to Zn(II) in the solid-state through hemilability of its numerous -OH ligands.

Caffeine is the most widely consumed psychoactive substance in the world. Strikingly, the molecular pathways engaged by its regular consumption remain unclear. We herein addressed the mechanisms associated with habitual (chronic) caffeine consumption in the mouse hippocampus using untargeted orthogonal omics techniques. Our results revealed that chronic caffeine exerts concerted pleiotropic effects in the hippocampus at the epigenomic, proteomic, and metabolomic levels. Caffeine lowered metabolism-related processes (e.g., at the level of metabolomics and gene expression) in bulk tissue, while it induced neuron-specific epigenetic changes at synaptic transmission/plasticity-related genes and increased experience-driven transcriptional activity. Altogether, these findings suggest that regular caffeine intake improves the signal-to-noise ratio during information encoding, in part through fine-tuning of metabolic genes, while boosting the salience of information processing during learning in neuronal circuits.

Universal coverage of routine childhood vaccines remains a challenge in many low- and middle-income countries (LMICs). In India, vaccination campaigns have increased full immunization coverage among 12-23 month old children from an estimated 62% in 2015-2016 to 76% in 2019-2020. Long-term improvements in coverage will likely require systemic changes to both the supply and demand sides of immunization programs. However, the effect of health system inputs on child vaccination outcomes remains poorly quantified in India. We examined the association between the quality of public health facilities and child vaccination outcomes in rural India using data from the nationally representative Integrated Child Health and Immunization Survey (2015-2016) which covered 1,346 public primary health sub-centers and 44,571 households. We constructed two indices of sub-center quality using multiple correspondence analysis: one related to the general health infrastructure quality and the other measuring vaccine service delivery. Using probit regression, we analyzed the relationship between vaccination outcomes in children under 2 years of age and sub-center quality, controlling for household socioeconomic characteristics. Additionally, we conducted Fairlie decomposition analysis by wealth group - bottom wealth quintile relative to the top four wealth quintiles- to examine factors contributing to gaps in immunization between rich and poor households. Infrastructure quality index was positively associated with completion of seven vaccination outcomes: full immunization, DPT-1 (first dose of diphtheria, pertussis, and tetanus), DPT-2, DPT-3, Bacillus Calmette-Guérin (BCG), hepatitis B (birth dose), and on-time vaccination (OTV). Vaccine service delivery index was positively associated with completion of measles vaccination. The distribution of infrastructure quality contributed to increased gaps in full immunization and OTV between rich and poor households, while greater proximity to vaccination site for poorer households reduced these gaps. Improved quality of health facilities, particularly facilities used by low-income households, may improve vaccination outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

India's Universal Immunization Programme (UIP) is among the largest routine childhood vaccination programmes in the world. However, only an estimated 65% of Indian children under the age 2 years were fully vaccinated in 2019. We estimated the cost of raising childhood vaccination coverage to a minimum of 90% in each district in India. We obtained vaccine price data from India's comprehensive multi-year strategic plan for immunization. Cost of vaccine delivery by district was derived from a 2018 field study in 24 districts. We used propensity score matching methods to match the remaining Indian districts with these 24, based on indicators from the National Family Health Survey (2015-16). We assumed the same unit cost of vaccine delivery in matched pair districts and estimated the total and incremental cost of providing routine vaccines to 90% of the current cohort of children in each district. The estimated national cost of providing basic vaccinations-one dose each of Bacillus Calmette-Guerin (BCG) and measles vaccines, and three doses each of oral polio (OPV) and diphtheria, pertussis and tetanus vaccines-was $784.91 million (2020 US$). Considering all childhood vaccines included in UIP during 2018-22 (one dose each of BCG, hepatitis B and measles-rubella; four doses of OPV; two doses of inactivated polio; and three doses each of rotavirus, pneumococcal and pentavalent vaccines), the estimated national cost of vaccines and delivery to 90% of target children in each district was $1.73 billion. The 2018 UIP budget for vaccinating children, pregnant women and adults was $1.17 billion (2020 US$). In comparison, $1.73 billion would be needed to vaccinate 90% of children in all Indian districts with the recommended schedule of routine childhood vaccines. Additional costs for infrastructural investments and communication activities, not incorporated in this study, may also be necessary., (© The Author(s) 2021. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Vaccines can reduce antibiotic use and, consequently, antimicrobial resistance by averting vaccine-preventable and secondary infections. We estimated the associations between private vaccine and antibiotic consumption across Indian states during 2009-2017 using monthly and annual consumption data from IQVIA and employed fixed-effects regression and the Arellano-Bond Generalized Method of Moments (GMM) model for panel data regression, which controlled for income and public sector vaccine use indicators obtained from other sources. In the annual data fixed-effects model, a 1% increase in private vaccine consumption per 1000 under-5 children was associated with a 0.22% increase in antibiotic consumption per 1000 people (P < 0.001). In the annual data GMM model, a 1% increase in private vaccine consumption per 1000 under-5 children was associated with a 0.2% increase in private antibiotic consumption (P < 0.001). In the monthly data GMM model, private vaccine consumption was negatively associated with antibiotic consumption when 32, 34, 35, and 44-47 months had elapsed after vaccine consumption, with a positive association with lags of fewer than 18 months. These results indicate vaccine-induced longer-term reductions in antibiotic use in India, similar to findings of studies from other low- and middle-income countries., (© 2021 New York Academy of Sciences.)

Objectives: As of 13 January 2021, there have been 3 113 963 confirmed cases of SARS-CoV-2 and 74 619 deaths across the African continent. Despite relatively lower numbers of cases initially, many African countries are now experiencing an exponential increase in case numbers. Estimates of the progression of disease and potential impact of different interventions are needed to inform policymaking decisions. Herein, we model the possible trajectory of SARS-CoV-2 in 52 African countries under different intervention scenarios., Design: We developed a compartmental model of SARS-CoV-2 transmission to estimate the COVID-19 case burden for all African countries while considering four scenarios: no intervention, moderate lockdown, hard lockdown and hard lockdown with continued restrictions once lockdown is lifted. We further analysed the potential impact of COVID-19 on vulnerable populations affected by HIV/AIDS and tuberculosis (TB)., Results: In the absence of an intervention, the most populous countries had the highest peaks in active projected number of infections with Nigeria having an estimated 645 081 severe infections. The scenario with a hard lockdown and continued post-lockdown interventions to reduce transmission was the most efficacious strategy for delaying the time to the peak and reducing the number of cases. In South Africa, projected peak severe infections increase from 162 977 to 2 03 261, when vulnerable populations with HIV/AIDS and TB are included in the analysis., Conclusion: The COVID-19 pandemic is rapidly spreading across the African continent. Estimates of the potential impact of interventions and burden of disease are essential for policymakers to make evidence-based decisions on the distribution of limited resources and to balance the economic costs of interventions with the potential for saving lives., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Influenza, which peaks seasonally, is an important driver for antibiotic prescribing. Although influenza vaccination has been shown to reduce severe illness, evidence of the population-level effects of vaccination coverage on rates of antibiotic prescribing in the United States is lacking., Methods: We conducted a retrospective analysis of influenza vaccination coverage and antibiotic prescribing rates from 2010 to 2017 across states in the United States, controlling for differences in health infrastructure and yearly vaccine effectiveness. Using data from IQVIA's Xponent database and the US Centers for Disease Control and Prevention's FluVaxView, we employed fixed-effects regression analysis to analyze the relationship between influenza vaccine coverage rates and the number of antibiotic prescriptions per 1000 residents from January to March of each year., Results: We observed that, controlling for socioeconomic differences, access to health care, childcare centers, climate, vaccine effectiveness, and state-level differences, a 10-percentage point increase in the influenza vaccination rate was associated with a 6.5% decrease in antibiotic use, equivalent to 14.2 (95% CI, 6.0-22.4; P = .001) fewer antibiotic prescriptions per 1000 individuals. Increased vaccination coverage reduced prescribing rates the most in the pediatric population (0-18 years), by 15.2 (95% CI, 9.0-21.3; P < .001) or 6.0%, and the elderly (aged 65+), by 12.8 (95% CI, 6.5-19.2; P < .001) or 5.2%., Conclusions: Increased influenza vaccination uptake at the population level is associated with state-level reductions in antibiotic use. Expanding influenza vaccination could be an important intervention to reduce unnecessary antibiotic prescribing., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Room temperature photolysis of the bis(azide)cobaltate(II) complex [Na(THF) x ][( ket guan)Co(N 3 ) 2 ] ( ket guan = [( t Bu 2 CN)C(NDipp) 2 ] - , Dipp = 2,6-diisopropylphenyl) ( 3a ) in THF cleanly forms the binuclear cobalt nitride Na(THF) 4 {[( ket guan)Co(N 3 )] 2 (μ-N)} ( 1 ). Compound 1 represents the first example of an isolable, bimetallic cobalt nitride complex, and it has been fully characterized by spectroscopic, magnetic, and computational analyses. Density functional theory supports a Co III ═N═Co III canonical form with significant π-bonding between the cobalt centers and the nitride atom. Unlike other group 9 bridging nitride complexes, no radical character is detected at the bridging N atom of 1 . Indeed, 1 is unreactive toward weak C-H donors and even cocrystallizes with a molecule of cyclohexadiene (CHD) in its crystallographic unit cell to give 1 ·CHD as a room temperature stable product. Notably, addition of pyridine to 1 or photolyzed solutions of [( ket guan)Co(N 3 )(py)] 2 ( 4a ) leads to destabilization via activation of the nitride unit, resulting in the mixed-valent Co(II)/Co(III) bridged imido species [( ket guan)Co(py)][( ket guan)Co](μ-NH)(μ-N 3 ) ( 5 ) formed from intermolecular hydrogen atom abstraction (HAA) of strong C-H bonds (BDE ∼ 100 kcal/mol). Kinetic rate analysis of the formation of 5 in the presence of C 6 H 12 or C 6 D 12 gives a KIE = 2.5 ± 0.1, supportive of a HAA formation pathway. The reactivity of our system was further probed by photolyzing benzene/pyridine solutions of 4a under H 2 and D 2 atmospheres (150 psi), which leads to the exclusive formation of the bis(imido) complexes [( ket guan)Co(μ-NH)] 2 ( 6 ) and [( ket guan)Co(μ-ND)] 2 ( 6-D ), respectively, as a result of dihydrogen activation. These results provide unique insights into the chemistry and electronic structure of late 3d metal nitrides while providing entryway into C-H activation pathways.

Memory impairment is the main feature of Alzheimer's disease (AD). Initial impairments originate in the temporal lobe area and propagate throughout the brain in a sequential manner. Epigenetic mechanisms, especially histone acetylation, regulate plasticity and memory processes. These may be dismantled during the disease. The aim of this work was to establish changes in the acetylation-associated pathway in two key brain regions affected in AD: the hippocampus and the F2 area of frontal cortex in end-stage AD patients and age-matched controls. We found that the F2 area was more affected than the hippocampus. Indeed, CREB-Binding Protein (CBP), P300/CBP-associated protein (PCAF), Histone Deacetylase 1 (HDAC1) and HDAC2 (but not HDAC3) levels were strongly decreased in F2 area of AD compared to controls patients, whereas only HDAC1 was decreased and CBP showed a downward trend in the hippocampus. At the histone level, we detected a substantial increase in total (H3 and H2B) histone levels in the frontal cortex, but these were decreased in nuclear extracts, pointing to a dysregulation in histone trafficking/catabolism in this brain region. Histone H3 acetylation levels were increased in cell nuclei mainly in the frontal cortex. These findings provide evidence for acetylation dysfunctions at the level of associated enzymes and of histones in AD brains, which may underlie transcriptional dysregulations and AD-related cognitive impairments. They further point to stronger dysregulations in the F2 area of the frontal cortex than in the hippocampus at an end-stage of the disease, suggesting a differential vulnerability and/or compensatory mechanisms efficiency towards epigenetic alterations., Competing Interests: Conflict of interest All other authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

13-lined ground squirrels (Ictidomys tridecemlineatus) enter hibernation as a survival strategy during extreme environmental conditions. Typical ground squirrel hibernation is characterized by prolonged periods of torpor with significantly reduced heart rate, blood pressure, and blood flow, interrupted every few weeks by brief interbout arousals (IBA) during which blood flow fluctuates dramatically. These physiological conditions should increase the risk of stasis-induced blood clots and myocardial ischemia. However, ground squirrels have adapted to survive repeated bouts of torpor and IBA without forming lethal blood clots or sustaining lethal ischemic myocardial damage. The purpose of this study was to determine if ground squirrels are resistant to thrombosis and myocardial ischemia during hibernation. Blood markers of coagulation, fibrinolysis, thrombosis, and ischemia, as well as histological markers of myocardial ischemia were measured throughout the annual hibernation cycle. Hibernating ground squirrels were also treated with isoprenaline to induce myocardial ischemia. Thrombin-antithrombin complex levels were significantly reduced (p < 0.05) during hibernation, while D-dimer level remained unchanged throughout the annual cycle, both consistent with an antithrombotic state. During torpor, the ground squirrels were in a hyperfibrinolytic state with an elevated ratio of tissue plasminogen activator complexed with plasminogen activator inhibitor to total plasminogen activator inhibitor (p < 0.05). Histological markers of myocardial ischemia were reversibly elevated during hibernation with no increase in markers of myocardial cell death in the blood. These data suggest that ground squirrels do not form major blood clots during hibernation through suppression of coagulation and a hyperfibrinolytic state. These animals also demonstrate myocardial resistance to ischemia.