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This systematic review describes herpes zoster (HZ) economic burden in terms of healthcare resource use and cost outcomes in the Latin America and Caribbean (LAC) region. We searched online databases from 1 January 2000 to 20 February 2020 to identify eligible publications. We identified 23 publications that reported direct costs, indirect costs, and resources associated with HZ and its complications. The primary direct medical resources reported in the different studies were visits to doctors, transportation, days in the hospital, nursing, medication schedules, and physical therapy. Direct total costs per patient ranged from $99.99 to $4177.91. The highest cost was found in Brazil. Direct costs are, in average, 81.39% higher than indirect costs. The cost per patient that includes postherpetic neuralgia treatment is 115% higher on average for the directs and 73% for the indirect costs. Brazil reported a higher total cost per patient than Argentina and Mexico, while for indirect costs per patient, Brazil and Argentina had higher costs than Mexico, respectively. A meta-analysis on the number of days due to HZ hospitalization, performed on non-immunosuppressed patients over 65 years of age from three studies, resulted in a cumulative measure of 4.5 days of hospitalization. In the LAC region, the economic burden of HZ and associated complications is high, particularly among high-risk populations and older age groups. Preventative strategies such as vaccination could help avoid or reduce the HZ-associated disease economic burden in the LAC region.
Knockdown of the insulator factor CCCTC binding factor (CTCF), which binds XL9, an intergenic element located between HLA-DRB1 and HLA-DQA1, was found to diminish expression of these genes. The mechanism involved interactions between CTCF and class II transactivator (CIITA), the master regulator of major histocompatibility complex class II (MHC-II) gene expression, and the formation of long-distance chromatin loops between XL9 and the proximal promoter regions of these MHC-II genes. The interactions were inducible and dependent on the activity of CIITA, regulatory factor X, and CTCF. RNA fluorescence in situ hybridizations show that both genes can be expressed simultaneously from the same chromosome. Collectively, the results suggest a model whereby both HLA-DRB1 and HLA-DQA1 loci can interact simultaneously with XL9, and describe a new regulatory mechanism for these MHC-II genes involving the alteration of the general chromatin conformation of the region and their regulation by CTCF.
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.
The epidemiology and burden of Herpes Zoster (HZ) are largely unknown, and there are no recent reviews summarizing the available evidence from the Latin America and Caribbean (LAC) region. We conducted a systematic review and meta-analysis to characterize the epidemiology and burden of HZ in LAC. Bibliographic databases and grey literature sources were consulted to find studies published (January 2000 -February 2020) with epidemiological endpoints: cumulative incidence and incidence density (HZ cases per 100,000 person-years), prevalence, case-fatality rates, HZ mortality, hospitalization rates, and rates of each HZ complication. Twenty-six studies were included with most studies coming from Brazil. No studies reported the incidence of HZ in the general population. In population at higher risk, the cumulative incidence ranged from 318-3,423 cases of HZ per 100,000 persons per year of follow-up. The incidence density was 6.4-36.5 cases per 1,000 person-years. Age was identified as a major risk factor towards HZ incidence which increase significantly in people >50 years of age. Hospitalization rates ranged from 3%-35.7%. The in-hospital HZ mortality rate ranged from 0%-36%. Overall, HZ mortality rates were found to be higher in females across all age groups and countries. The incidence of HZ complications (such as post-herpetic neuralgia, ophthalmic herpes zoster, and Ramsay Hunt syndrome) was higher in the immunosuppressed compared to the immunocompetent population. Acyclovir was the most frequently used therapy. Epidemiological data from Ministry of Health databases (Argentina, Brazil, Colombia, Chile y Mexico) and Institute for Health Metrics and Evaluation's Global Burden of Disease project reported stable rates of hospitalizations and deaths over the last 10 years. High-risk groups for HZ impose a considerable burden in LAC. They could benefit from directed healthcare initiatives, including adult immunization, to prevent HZ occurrence and its complications.
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.
: The progressive death of dopamine producing neurons in the substantia nigra pars compacta is the principal cause of symptoms of Parkinson's disease (PD). Stem cells have potential therapeutic use in replacing these cells and restoring function. To facilitate development of this approach, we sought to establish a preclinical model based on a large nonhuman primate for testing the efficacy and safety of stem cell-based transplantation. To this end, we differentiated baboon fibroblast-derived induced pluripotent stem cells (biPSCs) into dopaminergic neurons with the application of specific morphogens and growth factors. We confirmed that biPSC-derived dopaminergic neurons resemble those found in the human midbrain based on cell type-specific expression of dopamine markers TH and GIRK2. Using the reverse transcriptase quantitative polymerase chain reaction, we also showed that biPSC-derived dopaminergic neurons express PAX6, FOXA2, LMX1A, NURR1, and TH genes characteristic of this cell type in vivo. We used perforated patch-clamp electrophysiology to demonstrate that biPSC-derived dopaminergic neurons fired spontaneous rhythmic action potentials and high-frequency action potentials with spike frequency adaption upon injection of depolarizing current. Finally, we showed that biPSC-derived neurons released catecholamines in response to electrical stimulation. These results demonstrate the utility of the baboon model for testing and optimizing the efficacy and safety of stem cell-based therapeutic approaches for the treatment of PD.
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.
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.
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.
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