Antimicrobial resistance of Neisseria gonorrhoeae in Latin American countries: a systematic review.

BACKGROUND: Detailed information is needed on the dynamic pattern of antimicrobial resistance (AMR) in Neisseria gonorrhoeae in Latin America and the Caribbean (LAC). OBJECTIVES: To conduct a systematic review of AMR in N. gonorrhoeae in LAC. METHODS: Electronic searches without language restrictions were conducted in PubMed, Embase, Cochrane Library, EconLIT, Cumulative Index of Nursing and Allied Health Literature, Centre for Reviews and Dissemination, and Latin American and Caribbean Literature in Health Sciences. Studies were eligible if published between 1 January 2011 and 13 February 2021, conducted in any LAC country (regardless of age, sex and population) and measured frequency and/or patterns of AMR to any antimicrobial in N. gonorrhoeae. The WHO Global Gonococcal Antimicrobial Surveillance Programme (WHO-GASP) for LAC countries and Latin American AMR SurveillanceNetwork databases were searched. AMR study quality was evaluated according to WHO recommendations. RESULTS: AMR data for 38, 417 isolates collected in 1990-2018 were included from 31 publications, reporting data from Argentina, Brazil, Colombia, Peru, Uruguay, Venezuela and WHO-GASP. Resistance to extended-spectrum cephalosporins was infrequent (0.09%-8.5%). Resistance to azithromycin was up to 32% in the published studies and up to 61% in WHO-GASP. Resistance to penicillin, tetracycline and ciprofloxacin was high (17.6%-98%, 20.7%-90% and 5.9%-89%, respectively). Resistance to gentamicin was not reported, and resistance to spectinomycin was reported in one study. CONCLUSIONS: This review provides data on resistance to azithromycin, potentially important given its use as first-line empirical treatment, and indicates the need for improved surveillance of gonococcal AMR in LAC. Trial registration: Registered in PROSPERO, CRD42021253342.

Cocaine Selectively Reorganizes Excitatory Inputs to Substantia Nigra Pars Compacta Dopamine Neurons.

Substantia nigra pars compacta (SNc) dopamine neurons and their targets are involved in addiction and cue-induced relapse. However, afferents onto SNc dopamine neurons themselves appear insensitive to drugs of abuse, such as cocaine, when afferents are collectively stimulated electrically. This contrasts with ventral tegmental area (VTA) dopamine neurons, whose glutamate afferents react robustly to cocaine. We used an optogenetic strategy to isolate identified SNc inputs and determine whether cocaine sensitivity in the mouse SNc circuit is conferred at the level of three glutamate afferents: dorsal raphé nucleus (DR), pedunculopontine nucleus (PPN), and subthalamic nucleus (STN). We found that excitatory afferents to SNc dopamine neurons are sensitive to cocaine in an afferent-specific manner. A single exposure to cocaine in vivo led to PPN-innervated synapses reducing the AMPA-to-NMDA receptor-mediated current ratio. In contrast to work in the VTA, this was due to increased NMDA receptor function with no change in AMPA receptor function. STN synapses showed a decrease in calcium-permeable AMPA receptors after cocaine, but no change in the AMPA-to-NMDA ratio. Cocaine also increased the release probability at DR-innervated and STN-innervated synapses, quantified by decreases in paired-pulse ratios. However, release probability at PPN-innervated synapses remained unaffected. By examining identified inputs, our results demonstrate a functional distribution among excitatory SNc afferent nuclei in response to cocaine, and suggest a compelling architecture for differentiation and separate parsing of inputs within the nigrostriatal system.SIGNIFICANCE STATEMENT Prior studies have established that substantia nigra pars compacta (SNc) dopamine neurons are a key node in the circuitry that drives addiction and relapse, yet cocaine apparently has no effect on electrically stimulated excitatory inputs. Our study is the first to demonstrate the functional impact of a drug of abuse on synaptic mechanisms of identified afferents to the SNc. Optogenetic dissection of inputs originating from dorsal raphé, pedunculopontine, and subthalamic nuclei were tested for synaptic modifications following in vivo cocaine exposure. Our results demonstrate that cocaine differentially induces modifications to SNc synapses depending on input origin. This presents implications for understanding dopamine processing of motivated behavior; most critically, it indicates that dopamine neurons selectively modulate signal reception processed by afferent nuclei.

Carbamylated vimentin represents a relevant autoantigen in Latin American (Cuban) rheumatoid arthritis patients.

Smoking produces substances that activate proinflammatory, prothrombotic and vasoconstrictive mediators via posttranslational carbamylation of proteins. As a new consequence of carbamylation, induction of anti-carbamylated autoantibodies were observed in rheumatoid arthritis (RA) patients, sometimes prior to onset of the disease. The overall aim of this study was to characterize the reactivity of different isotypes of autoantibodies against carbamylated antigens of vimentin in relation to established rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) and markers of disease activity in a so far largely uncharacterized population of Latin American (Cuban) patients with RA. Antigenic properties of carbamylated vimentin as well as vimentin peptides were analyzed in 101 patients with RA, 50 disease controls and 51 healthy controls. The diagnostic performance was compared with established commercial ELISA rheumatoid factor, anti-cyclic citrullinated peptide antibodies of second generation (anti-CCP2) and anti-mutated citrullinated vimentin (anti-MCV) antibodies. Prevalence of anti-MCV IgG (86 %), anti-carbamylated vimentin (carbVIM) IgG (77 %) and anti-carbamylated MCV (carbMCV) IgG antibodies (65 %) was higher than the classical RF IgM (60 %) and anti-CCP2 IgG (52 %) in this RA cohort. Of note, smoking status was associated with positive IgG antibody reactivity against CCP2 in 75.0 % and against MCV in 90 % of patients. Furthermore, IgM antibody response against carbMCV and carbVIM was observed in 80 and 90.0 % of smokers, respectively. Due to a high sensitivity of the IgM antibody isotype of anti-carbVIM of 85.2 %, the combination of ACPA with anti-carbVIM IgM provided the best diagnostic performance so far achieved in a RA cohort of this ethnic origin. We demonstrate a high prevalence of anti-carbVIM antibodies and correlation with smoking in Latin American (Cuban) RA patients. Anti-carbVIM IgM represents an useful marker in ACPA-negative patients and, in combination with ACPA IgG assays, optimizes the strategy for autoantibody testing.

Health economic evaluation of 2-dose and 3-dose rotavirus vaccines in children below 5 years of age in Morocco.

Following the introduction of rotavirus vaccination into the Moroccan National Immunization Program, the prevalence of the disease has decreased by nearly 50%. However, evidence on the economic value of rotavirus vaccinations in Morocco is limited. This health economic analysis evaluated, from both country payer and societal perspectives, the costs and the cost-effectiveness of three rotavirus vaccines using a static, deterministic, population model in children aged < 5 years in Morocco. Included vaccines were HRV (2-dose schedule), HBRV (3-dose schedule) and BRV-PV 1-dose vial (3-dose schedule). One-way and probabilistic sensitivity analyses were conducted to assess the impact of uncertainty in model inputs. The model predicted that vaccination with HRV was estimated to result in fewer rotavirus gastroenteritis events (-194 homecare events, -57 medical visits, -8 hospitalizations) versus the 3-dose vaccines, translating into 7 discounted quality-adjusted life years gained over the model time horizon. HRV was associated with lower costs versus HBRV from both the country payer (-$1.8 M) and societal (-$4.1 M) perspectives, and versus BRV-PV 1-dose vial from the societal perspective (-$187,000), dominating those options in the cost-effectiveness analysis. However, costs of BRV-PV 1-dose vial were lower than HRV from the payer perspective, resulting in an ICER of approximately $328,376 per QALY, above the assumed cost effectiveness threshold of $3,500. Vaccination with a 2-dose schedule of HRV may be a cost-saving option and could lead to better health outcomes for children in Morocco versus 3-dose schedule rotavirus vaccines.

Modelling the Public Health Burden of Herpes Zoster and the Impact of Adjuvanted Recombinant Zoster Vaccine in Five Selected Countries in Southeast Asia.

INTRODUCTION: Herpes zoster (HZ) can cause substantial patient morbidity and lead to large healthcare costs. However, the disease burden of HZ in Southeast Asia may be underestimated. This study aimed to estimate the public health burden of HZ and the impact of vaccinating adults aged ≥ 50 years old in five Southeast Asian countries (Indonesia, Malaysia, Philippines, Thailand, and Vietnam), with adjuvanted recombinant zoster vaccine (RZV) compared with no vaccination. METHODS: For each country, we adapted a static multicohort Markov model developed with a 1-year cycle length and lifetime horizon. Demographics were obtained from the World Health Organization, HZ incidence from a worldwide meta-regression reporting Asian-specific values, proportions of postherpetic neuralgia (PHN) and non-PHN complications from local/regional studies, and vaccine efficacy from a long-term follow-up trial. First-dose coverage and second-dose compliance were assumed to be 30% and 70%, respectively. A one-way deterministic sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA) were performed to assess the robustness and uncertainty of inputs for each country. RESULTS: Without RZV, it was estimated that there would be a total of approximately 10 million HZ cases, 2.1 million PHN cases, and 1.4 million non-PHN complications in individuals aged ≥ 50 years included in the model. Introducing RZV under 30% coverage could avoid approximately 2.2 million (22%) HZ cases, almost 500,000 (21%) PHN cases, and around 300,000 (22%) non-PHN complications. OWSA showed that first-dose coverage and initial HZ incidence had the largest impact on the estimated number of HZ cases avoided. The number needed to vaccinate ranged from 15 to 21 to prevent one case of HZ and from 68 to 104 to prevent one case of PHN across each country. CONCLUSIONS: This study demonstrated that there is substantial HZ disease burden in older adults for the five selected countries in Southeast Asia, negatively impacting national healthcare systems. Introducing RZV could potentially reduce this burden. A graphical abstract is available with this article.

Economic Evaluation of Rotavirus Vaccination in Children Aged Under Five Years in South Africa.

BACKGROUND AND OBJECTIVE: Evidence on the economic value of rotavirus vaccines in middle-income countries is limited. We aimed to model the implementation of three vaccines (human rotavirus, live, attenuated, oral vaccine [HRV, 2 doses]; rotavirus vaccine, live, oral, pentavalent [HBRV, 3 doses] and rotavirus vaccine, live attenuated oral, freeze-dried [BRV-PV, 3 doses] presented in 1-dose and 2-dose vials) into the South African National Immunisation Programme. METHODS: Cost and cost-effectiveness analyses were conducted to compare three rotavirus vaccines using a static, deterministic, population model in children aged <5 years in South Africa from country payer and societal perspectives. Deterministic and probabilistic sensitivity analyses were conducted to assess the impact of uncertainty in model inputs. RESULTS: The human rotavirus, live, attenuated, oral vaccine (HRV) was associated with cost savings versus HBRV from both perspectives, and versus BRV-PV 1-dose vial from the societal perspective. In the cost-effectiveness analysis, HRV was estimated to avoid 1,107 home care rotavirus gastroenteritis (RVGE) events, 247 medical visits, 35 hospitalisations, and 4 RVGE-related deaths versus HBRV and BRV-PV. This translated to 73 quality-adjusted life years gained. HRV was associated with lower costs versus HBRV from both payer (-$3.9M) and societal (-$11.5M) perspectives and versus BRV-PV 1-dose vial from the societal perspective (-$3.8M), dominating those options. HRV was associated with higher costs versus BRV-PV 1-dose vial from the payer perspective and versus BRV-PV 2­dose vial from both payer and societal perspectives (ICERs: $51,834, $121,171, and $16,717, respectively), exceeding the assumed cost-effectiveness threshold of 0.5 GDP per capita. CONCLUSION: Vaccination with a 2-dose schedule of HRV may lead to better health outcomes for children in South Africa compared with the 3-dose schedule rotavirus vaccines.

Rotavirus Vaccine Impact since Its Introduction in the National Immunization Program of Argentina.

INTRODUCTION: Rotavirus (RV) is the most common cause of childhood diarrhea. Argentina introduced RV vaccination in the National Immunization Program in January 2015. This study evaluates the impact of RV vaccine implementation on the burden of acute diarrheal disease (ADD) and RV positive cases, and hospitalizations among children in Argentina. METHODS: A counterfactual time-series analysis was performed. Data on ADD (2013-2018) and RV diarrhea (2012-2018) cases in children aged < 5 years were collected from the National Healthcare Surveillance System (clinical and laboratory data). Data on hospital discharges following ADD and RV diarrhea (2011-2017) were retrieved from the Health Statistics and Information Office. All data were classified by the age groups < 1 year, < 2 years, 2-5 years. Vaccine impact was defined as the difference between the predicted time trend (simulated using 2012-2014 data) and the actual post-vaccination data (2015-2018). RESULTS: A significant reduction of 22.1% of notified ADD cases and 15.4% of hospital discharges following ADD among children < 2 years was observed in the 3 years after RV vaccine implementation. Data also showed a significant decline of 54.0% and 59.4% of notified RV cases in children < 2 and < 1 years, respectively, and a reduction of 39.3% and 40.8% in RV hospital discharges for the same age groups. CONCLUSION: This study shows a significant reduction in notified ADD cases and RV cases and hospital discharges following ADD and RV cases in children < 2 years after RV vaccine introduction in Argentina in 2015.

Assessing the Underestimation of Adult Pertussis Disease in Five Latin American Countries.

INTRODUCTION: Pertussis, a contagious respiratory disease, is underreported in adults. The study objective was to quantify underestimation of pertussis cases in adults aged ≥ 50 years in five Latin American countries (Argentina, Brazil, Chile, Mexico, Peru). METHODS: A previously published probabilistic model was adapted to adjust the number of pertussis cases reported to national surveillance systems by successive multiplication steps (proportion of pertussis cases seeking healthcare; proportion with a specimen collected; proportion sent for confirmatory testing; proportion positive for pertussis; proportion reported to passive surveillance). The proportions at each step were added in a random effects model to produce a pooled overall proportion, and a final multiplier was calculated as the simple inverse of this proportion. This multiplier was applied to the number of cases reported to surveillance to estimate the number of pertussis cases. Monte Carlo simulation with 10,000 iterations estimated median as well as upper and lower 90% values. Input data were obtained from surveillance systems and published sources. RESULTS: The estimated median underestimation factor for pertussis cases in adults ranged from 104 (90% limits 40, 451) in Chile to 114 (90% limits 39, 419) in Argentina. In all five countries, the largest estimated number of cases was in the group aged 50-59 years. The highest number per 100,000 population was in the group aged ≥ 90 years in most countries. The estimated median underestimation factor for pertussis hospitalizations was 2.3 (90% limits 1.8, 3.3) in Brazil and 2.4 (90% limits 1.8, 3.2) in Chile (data not available for other countries). CONCLUSION: This analysis indicates that the number of pertussis cases in adults aged ≥ 50 years in five Latin American countries is approximately 100 times higher than the number captured in surveillance data. These results could support decision-making in the diagnosis, management, and prevention of pertussis disease in adults.

How large could the public health impact of introducing recombinant zoster vaccination for people aged ≥50 years in five Latin American countries be?

This study aimed to: (1) estimate the disease burden of herpes zoster (HZ) and (2) assess the potential public health impact of introducing adjuvanted recombinant zoster vaccine (RZV) compared with no vaccination in adults aged ≥50 years in Argentina, Brazil, Mexico, Chile, and Colombia using the ZOster ecoNomic Analysis (ZONA) static multicohort Markov model. The model followed individuals aged ≥50 years from administration of RZV over their remaining lifetime. Inputs were based, most often, on local data. First dose coverage was assumed to be 35%, with 75% second dose compliance. It was predicted that without RZV, there would be 23,558,675 HZ cases, 6,115,981 post-herpetic neuralgia (PHN) cases, and 7,058,779 non-PHN complications in the five countries, but introducing RZV under assumed coverage could avoid 4,583,787 (19%) HZ cases, 1,130,751 (18%) PHN cases, and 1,373,419 (19%) non-PHN complications. Also, 10427,504 (20%) doctor's office visits and 1,630,201 (19%) days of hospitalization could be averted in the three countries (Argentina, Brazil, and Mexico) with available input data. The numbers needed to be vaccinated to avoid one case of HZ were 9-10 across countries, and to avoid one case of PHN, 35-40. One-way sensitivity analyses showed that the input parameters with the largest impact on the estimated number of HZ cases avoided were first dose coverage, initial HZ incidence, and vaccine efficacy waning. In conclusion, the introduction of RZV for older adults in Latin America could greatly reduce the public health burden of HZ and reduce the related doctor visits and hospitalization days.

Why was the study done?Herpes zoster (HZ), commonly known as shingles or "culebrilla," typically causes a painful, itchy rash on the trunk in older adults, and can result in long-term complications. It is difficult to study the lifetime burden of HZ due to follow-up time constraints. We therefore wanted to predict how many people could develop HZ as they age and how many cases of HZ could be avoided by introducing adjuvanted recombinant zoster vaccine (RZV) in people aged 50 years and older in five Latin American countries (Argentina, Brazil, Mexico, Chile, and Colombia).What did the researchers do and find?Using a mathematical model, we predicted that nearly 5 million of an estimated 24 million cases of HZ could be avoided by vaccinating 35% of older adults with RZV in the five countries. This vaccination approach would also avert various complications of HZ, including post-herpetic neuralgia (long-lasting pain at the rash site) and save doctor's office visits and hospitalizations for HZ.What do the results mean?Introducing RZV for older adults in Latin America ­ as is already the case in various other countries ­ could prevent a substantial proportion of HZ cases, leading to improved public health and less health care resource utilization.What is the objective influence on the wider field?In the absence of real-world data on the potential impact of RZV on HZ in Latin America, these predictions could help policymakers to assess the potential value of introducing RZV for older adults in Latin America.

Meningococcal burden of disease in Argentina: 10 years epidemiologic review.

Invasive meningococcal disease (IMD) is an uncommon but serious and potentially fatal condition, mainly affecting infants. In 2017, Argentina introduced a vaccination program against serogroups A, C, W and Y (MenACWY) for infants aged 3, 5 and 15 months and adolescents aged 11 years. The objective of this study was to review the burden of IMD in Argentina in 2010-2019. Data were obtained from national surveillance databases, and the study estimated IMD incidence, mortality, case-fatality rates, and serogroup distributions across age groups. A total of 1,972 IMD cases were reported in the study period, with the highest incidence in infants aged < 1 year. Incidence peaked in 2013 and subsequently declined. Mortality rates were 18 times higher in infants than in other age groups, reflecting the high impact of IMD in this age group. The case-fatality rate was 8.5% on average and increased with age. The proportion of notified cases with serogroup identification increased over the period, reaching 91% in 2019. The most common serogroups over the study period were serogroup B (48%) and serogroup W (42%), with an increase in B relative to W since 2015. In infants aged < 1 year, the proportion of serogroup B increased in recent years, reaching around 70% of characterized cases in 2018-2019. These results show the dynamism of IMD and indicate the importance of vaccination at an early age and offering protection against predominant serogroups. These data are valuable to support evidence-based decision-making in healthcare.

Choline Regulates SOX4 through miR-129-5p and Modifies H3K27me3 in the Developing Cortex.

Choline availability regulates neural progenitor cell proliferation and differentiation in the developing cerebral cortex. Here, we investigated the molecular mechanism underlying this process and demonstrated that choline regulates the transcription factor SOX4 in neural progenitor cells. Specifically, we found that low choline intake during neurogenesis reduces SOX4 protein levels, causing the downregulation of EZH2, a histone methyltransferase. Importantly, we demonstrate that low choline is not involved in SOX4 protein degradation rate and established that protein reduction is caused by aberrant expression of a microRNA (miR-129-5p). To confirm the role of miR-129-5p, we conducted gain-of-function and loss-of-function assays in neural progenitor cells and demonstrated that directly altering miR-129-5p levels could affect SOX4 protein levels. We also observed that the reduction in SOX4 and EZH2 led to decreased global levels of H3K27me3 in the developing cortex, contributing to reduced proliferation and precocious differentiation. For the first time, to our knowledge, we demonstrate that a nutrient, choline, regulates a master transcription factor and its downstream targets, providing a novel insight into the role of choline in brain development.

A cost-effectiveness analysis of PHiD-CV compared to PCV13 in a national immunization program setting in Tunisia.

BACKGROUND: In response to the substantial clinical and economic burden of diseases caused by Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) in Tunisia, the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) was recently introduced into the national immunization program. However, there has yet to be a full-scale health economic analysis comparing currently available pneumococcal conjugate vaccines (PCVs) in Tunisia. METHODS: A Markov model that simulated the disease processes of invasive pneumococcal disease (IPD), pneumonia, and acute otitis media (AOM) over a newborn cohort lifetime was used to evaluate the cost-effectiveness/utility of PHiD-CV and the 13-valent pneumococcal conjugate vaccine (PCV13) from payer's perspective, using 3% discounting. Vaccine effects were considered for up to 9 years of age. RESULTS: Vaccination with PHiD-CV or PCV13 was estimated to avert approximately 700 cases of IPD (200 meningitis, 500 bacteremia), and around 5,000 cases of all-cause pneumonia. However, PHiD-CV vaccination was estimated to avert around 4,000 additional AOM cases (18,000) versus PCV13 (14,000). Both PCVs were demonstrated to be cost-effective interventions, but PHiD-CV was estimated to generate additional cost savings of almost $1 million US dollars (USD) with similar levels of clinical benefits. An additional scenario which incorporated serotype-specific vaccine efficacy found no significant change in overall results. CONCLUSION: PCVs are a cost-effective strategy to relieve the burden associated with diseases caused by S. pneumoniae and NTHi in Tunisia. PHiD-CV is more cost-effective than PCV13, generating similar health benefits, at a reduced net cost of almost $1 million USD per vaccinated cohort.

Faster Serotonin Clearance in CA3 Region of Hippocampus and Antidepressant-like Effect of Decynium-22 in Juvenile Mice Are Putatively Linked to Increased Plasma Membrane Monoamine Transporter Function: Implications for Efficacy of Antidepressants in Juveniles.

Selective serotonin reuptake inhibitors (SSRIs) are less efficacious in treating depression in children than in adults. SSRIs block serotonin uptake via the high-affinity, low-capacity serotonin transporter. However, the low-affinity, high-capacity organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) are emerging as important players in serotonin uptake. We hypothesized that OCT3 and/or PMAT are functionally upregulated in juveniles, thereby buffering SSRIs' ability to enhance serotonergic neurotransmission. Unlike in adult mice, we found the OCT/PMAT blocker, decynium-22, to have standalone antidepressant-like effects in juveniles. Using in vivo high-speed chronoamperometry, we found that juveniles clear serotonin from the CA3 region of the hippocampus ~2-fold faster than adult mice. Cell density did not differ between ages, suggesting that faster serotonin clearance in juveniles is unrelated to faster diffusion through the extracellular matrix. Western blot and immunohistochemistry showed that juvenile mice have modestly greater expression of PMAT than adults, whereas OCT3 expression in the CA3 region of the hippocampus was similar between ages. Together, these data suggest that faster serotonin clearance and antidepressant-like effects of decynium-22 in juvenile mice may be due to functionally upregulated PMAT. Faster serotonin clearance via PMAT in juveniles may contribute to reduced therapeutic efficacy of SSRIs in children relative to adults.

Constrained Optimization for Pneumococcal Vaccination in Brazil.

OBJECTIVES: To identify the most cost-efficient combination of pneumococcal vaccines in infants and aging adults for a 10-year period in Brazil. METHODS: Constrained optimization (CO) prioritized 9 pneumococcal vaccine regimens according to their gain in quality-adjusted life-years (QALYs) and their related costs over a prespecified time horizon with defined constraints for 2 age groups, infants and aging adults. The analysis starts from the current universal infant vaccination of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV), 2 primary and 1 booster dose at 2, 4, and 12 months, respectively. Key constraints are the fixed annual vaccine budget increase and the relative return on investment (ROIR) per regimen, which must be > 1, the reference intervention being the current vaccination strategy in infants and the most cost-efficient one in aging adults. RESULTS: The CO analysis including all the constraints indicates that over 10 years the maximum extra health gain is 126 194 QALYs for an extra budget of $974 million Brazilian reals (ROIR = 1.15). Results could be improved with a higher proportion of the at-risk population in aging adults, less herd effect, and better QALY scores. CONCLUSION: The study shows that with 4 constraints on budget, time horizon, vaccine coverage, and cost efficiency, a CO analysis could identify the most cost-efficient overall pneumococcal vaccination strategy for Brazil, allowing for limited vaccine budget increase while obtaining appropriate health gain.

Modeling the public health impact of different meningococcal vaccination strategies with 4CMenB and MenACWY versus the current toddler MenACWY National Immunization Program in Chile.

Invasive meningococcal disease (IMD) is an uncommon yet unpredictable, severe, and life-threatening disease with the highest burden in young children. In Chile, most IMD is caused by meningococcal serogroup B (MenB) and W (MenW) infection. In response to a MenW outbreak in 2012, a toddler vaccination program was implemented using quadrivalent meningococcal conjugate vaccine against serogroups A, C, W and Y (MenACWY). The vaccine program, however, does not protect infants or other unvaccinated age groups and does not protect against MenB IMD. Since 2017, MenB IMD cases are becoming increasingly prevalent. Using a dynamic transmission model adapted for Chile, this analysis assessed the public health impact (reduction in IMD cases, long-term sequelae, deaths, and quality-adjusted life-years) of six alternative vaccination strategies using MenACWY and/or the four-component MenB (4CMenB) vaccine in infants, toddlers, and/or adolescents compared to the National Immunization Program (NIP) implemented in 2014. Strategies that added infant 4CMenB to MenACWY in toddlers or adolescents would prevent more IMD than the current NIP, observed within the first 5 years of the program. Replacing the NIP by an adolescent MenACWY strategy would prevent more IMD in the longer term, once herd immunity is established to protect unvaccinated infants or older age groups. The strategy that maximized reduction of IMD cases and associated sequelae in all age groups with immediate plus long-term benefits included infant 4CMenB and MenACWY in both toddlers and adolescents. This analysis can help policymakers determine the best strategy to control IMD in Chile and improve public health. A set of audio slides linked to this manuscript can be found at https://doi.org/10.6084/m9.figshare.16837543.

Plain Language Summary (PLS)What is the context?Invasive meningococcal disease (IMD) is a severe, sometimes fatal, unpredictable disease with highest rates in infants, young children, and adolescents. It is caused by different serogroups of Neisseria meningitidis bacteria. Most cases in Chile are due to meningococcal serogroups B (MenB) and W (MenW). Following a MenW IMD outbreak in 2012, vaccination was introduced, leading to the current National Immunization Program (NIP) in toddlers with quadrivalent meningococcal conjugate vaccine (MenACWY) (protecting against IMD caused by MenA, C, W, and Y).What is new?A disease model to predict the impact of vaccination strategies in the Chilean population compared six alternative strategies, using the multi-component MenB (4CMenB) vaccine for infants (protecting against MenB, with potential cross-protection against MenW and Y IMD) and/or the MenACWY vaccine for toddlers and/or adolescents.What is the impact?Results, compared to the NIP, show that: Strategy 1 (a program targeting only infants with 4CMenB) would reduce more MenB cases but fewer MenA, C, W and Y cases resulting in a lower reduction of total IMD cases in the long term; Strategy 3 (a program targeting only adolescents with MenACWY) would have a similar effect to the NIP in the short term but a far greater IMD reduction in the long term (as vaccinating this age group eventually reduces transmission to other age groups, reducing their risk of disease); all the other strategies targeted more than one age group, further reducing numbers of IMD cases compared with the NIP. The greatest benefits were seen with infant 4CMenB vaccination combined with toddler and adolescent MenACWY vaccination. Results can help policymakers determine the best IMD strategy to maximize the benefits of available meningococcal vaccines.

Liver Cancer: Therapeutic Challenges and the Importance of Experimental Models.

Liver cancer is one of the main causes of death related to cancer worldwide; its etiology is related with infections by C or B hepatitis virus, alcohol consumption, smoking, obesity, nonalcoholic fatty liver disease, diabetes, and iron overload, among other causes. Several kinds of primary liver cancer occur, but we will focus on hepatocellular carcinoma (HCC). Numerous cellular signaling pathways are implicated in hepatocarcinogenesis, including YAP-HIPPO, Wnt-ß-catenin, and nuclear factor-κB (NF-κB); these in turn are considered novel therapeutic targets. In this review, the role of lipid metabolism regulated by peroxisome proliferator-activated receptor gamma (PPARγ) in the development of HCC will also be discussed. Moreover, recent evidence has been obtained regarding the participation of epigenetic changes such as acetylation and methylation of histones and DNA methylation in the development of HCC. In this review, we provide detailed and current information about these topics. Experimental models represent useful tools for studying the different stages of liver cancer and help to develop new pharmacologic treatments. Each model in vivo and in vitro has several characteristics and advantages to offer for the study of this disease. Finally, the main therapies approved for the treatment of HCC patients, first- and second-line therapies, are described in this review. We also describe a novel option, pirfenidone, which due to its pharmacological properties could be considered in the future as a therapeutic option for HCC treatment.

Response to article by Matthew Wasserman et al. (2018): "Modeling the sustained use of the 13-valent pneumococcal conjugate vaccine compared to switching to the 10-valent vaccine in Mexico".

In a recent article, Wasserman et al. estimated and forecasted the health and economic impact of switching from the 13-valent (PCV-13) to the 10-valent (PHiD-CV) pneumococcal conjugate vaccine in Mexico's national immunization program. In this response letter, we highlight various methodological inconsistencies and model input considerations that potentially bias the results and further recommendations made by the authors.

Estimated Annual Health and Cost Impact of PHiD-CV Immunization Program in Brazil.

BACKGROUND: Streptococcus pneumoniae causes invasive pneumococcal disease (IPD), community-acquired pneumonia (CAP) and acute otitis media (AOM). Two higher-valent pneumococcal conjugate vaccines (PCV) are available, pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) and 13-valent PCV (PCV-13). This study estimated the economic and health impact of PHiD-CV vaccination on pneumococcal disease burden in children <5 years of age in Brazil. METHODS: The disease burden prior to the PHiD-CV vaccination program was estimated from literature and databases. The effect of PHiD-CV was estimated as a reduction of 70% for IPD, 26% for CAP and 40% for AOM, based on published studies. Residual IPD cases attributable to serotype 19A were estimated using surveillance data. PCV-13 effectiveness against 19A-IPD was set at 30%-70% higher than PHiD-CV. Vaccine prices were US$12.85/dose for PHiD-CV and US$14.50/dose for PCV-13. RESULTS: PHiD-CV vaccination reduced IPD by 6359, CAP by 315,016 and AOM by 669,943 cases, with estimated cost savings of >US$84 million annually and US$211-22,232 per case averted depending on the outcome. Switching from PHiD-CV to PCV-13 would avoid only a few additional IPD cases at additional costs exceeding US$18 million per year (US$125,192-386,230 per IPD case averted). CONCLUSIONS: The PHiD-CV vaccination program in Brazil has resulted in important reductions of pneumococcal disease and substantial cost savings. Instead of switching PCVs, expanding vaccine coverage or investing in other health care interventions would be a more efficient use of resources to improve the health of the population in Brazil.

Synthesis and Characterization of Clay Polymer Nanocomposites of P(4VP-co-AAm) and Their Application for the Removal of Atrazine.

Atrazine (ATZ) is an herbicide which is applied to the soil, and its mechanism of action involves the inhibition of photosynthesis. One of its main functions is to control the appearance of weeds in crops, primarily in corn, sorghum, sugar cane, and wheat; however, it is very toxic for numerous species, including humans. Therefore, this work deals with the adsorption of ATZ from aqueous solutions using nanocomposite materials, synthesized with two different types of organo-modified clays. Those were obtained by the free radical polymerization of 4-vinylpyridine (4VP) and acrylamide (AAm) in different stoichiometric ratios, using tetrabutylphosphonium persulfate (TBPPS) as a radical initiator and N,N'-methylenebisacrylamide (BIS) as cross-linking agent. The structural, morphological, and textural characteristics of clays, copolymers, and nanocomposites were determined through different analytical and instrumental techniques, i.e., X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). Adsorption kinetics experiments of ATZ were determined with the modified and synthesized materials, and the effect of the ratio between 4VP and AAm moieties on the removal capacities of the obtained nanocomposites was evaluated. Finally, from these sets of experiments, it was demonstrated that the synthesized nanocomposites with higher molar fractions of 4VP obtained the highest removal percentages of ATZ.

Dorsal Raphe Dual Serotonin-Glutamate Neurons Drive Reward by Establishing Excitatory Synapses on VTA Mesoaccumbens Dopamine Neurons.

Dorsal raphe (DR) serotonin neurons provide a major input to the ventral tegmental area (VTA). Here, we show that DR serotonin transporter (SERT) neurons establish both asymmetric and symmetric synapses on VTA dopamine neurons, but most of these synapses are asymmetric. Moreover, the DR-SERT terminals making asymmetric synapses on VTA dopamine neurons coexpress vesicular glutamate transporter 3 (VGluT3; transporter for accumulation of glutamate for its synaptic release), suggesting the excitatory nature of these synapses. VTA photoactivation of DR-SERT fibers promotes conditioned place preference, elicits excitatory currents on mesoaccumbens dopamine neurons, increases their firing, and evokes dopamine release in nucleus accumbens. These effects are blocked by VTA inactivation of glutamate and serotonin receptors, supporting the idea of glutamate release in VTA from dual DR SERT-VGluT3 inputs. Our findings suggest a path-specific input from DR serotonergic neurons to VTA that promotes reward by the release of glutamate and activation of mesoaccumbens dopamine neurons.