Epidemiological profile of gestational syphilis and congenital syphilis in a reference center in Northeast Brazil: risk factors and trend from 2019 to 2021 / Perfil epidemiológico de sífilis gestacional e sífilis congênita em centro de referência no Nordeste do Brasil: fatores de risco e tendência de 2019 a 2021

Introduction: Syphilis is an infectious systemic disease caused by the bacterium Treponema pallidum. The Amaury de Medeiros Integrated University Health Center in Recife is a reference maternity hospital for high-risk pregnancies and the management of the most common Sexually Transmitted Infections during prenatal care, including Gestational Syphilis and Congenital Syphilis. Objective: To determine the epidemiological profile of the population exposed to these conditions, the rate of Gestational Syphilis detection, the incidence of Congenital Syphilis, and the associated unfavorable outcomes in Amaury de Medeiros Integrated University Health Center between January 2019 and December 2021. Methods: This retrospective cohort study included pregnant women and neonates diagnosed with syphilis at Amaury de Medeiros Integrated University Health Center. Data were collected from the Notification/Investigation Forms for Gestational Syphilis and Congenital Syphilis, between January 2019 and December 2021. Results: At Amaury de Medeiros Integrated University Health Center, 463 cases of Gestational Syphilis and 296 of Congenital Syphilis were reported. During the three-year study, 4444, 4360, and 4265 live births were recorded, confirming the Gestational Syphilis detection rates ­ 33.30, 36.92, and 36.10 per 1000 live births, with the incidence of Congenital Syphilis being 26.1, 21.33, and 20.39 per 1000 live births. Pregnant women in their third trimester who were brown, had incomplete primary education, and lived in an urban area were the main sociodemographic variables. In total, 217 (73.3%) patients were diagnosed with Gestational Syphilis during or after delivery, indicating a low prenatal coverage (70.6%). In terms of the progression of Congenital Syphilis, unfavorable outcomes was found in 40 (13.5%) patients, including 16 (40%) abortions, 10 (25%) stillbirths, nine (22.5%) deaths from Congenital Syphilis, and 5 (12.5%) deaths from other causes. Conclusion: Gestational Syphilis detection rates and Congenital Syphilis incidence remain alarming, with abortions and stillbirths being the most common unfavorable outcomes. To change the dramatic situation of Congenital Syphilis in Brazil, the associated factors point to a poor quality of prenatal care and an urgent need to change public policies for pregnant women and newborns, in conjunction with socioeconomic assistance

Demonstrating Value for Biosimilars: A Conceptual Framework.

BACKGROUND: The value proposition for biosimilars can be characterized as a concept that moves beyond the argument of cost reduction relative to the innovator biologic drug and into a framework that incorporates the diverse needs of key healthcare stakeholders during the transition from clinical development to commercialization in the marketplace. OBJECTIVES: To identify factors that facilitate and inhibit the development, commercialization, and adoption of biosimilars, and to recommend modifications in program design that are likely to support the demonstration of the value of biosimilars for payers, providers, and patients. METHODS: The primary data sources for this article include surveys conducted by Boston Healthcare Associates with payers and clinicians in the United States and the European Union 5 markets and blinded international protocol feasibility assessments completed by Worldwide Clinical Trials. Survey methodology used either convenience or purposeful sampling as appropriate, with participants extracted from diverse audiences, representative of those who generate or evaluate clinical data shaping the economic exchange and preferential status influencing physician adoption and patient access to biosimilars. Patient characteristics and psychosocial issues influencing patients' perception of small-molecule generics were extracted from the available literature to inform exploratory hypotheses, given the relative absence of such information for biosimilars. DISCUSSION: This article reviews the current evidence and summarizes results of surveys conducted with payers, providers, and drug investigation sites in the United States. Based on a review of published literature, as well as these survey results, conflicting and convergent demands exist for gathering data related to biosimilars. The motivations and data needs for these new agents are diverse, requiring adjudication of regulatory, economic, and clinical incentives beginning at program inception and extending through commercialization of the final biosimilar agent. CONCLUSIONS: The development and commercialization of biosimilars represent an international activity that can encounter unanticipated challenges, as well as opportunities to achieve clinical and commercial success. Evolving regulatory guidance mapped in relation to payer, physician, and patient sentiments may inform the biosimilar development program designs, implementation, and positioning of the new drug.

Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP.

We identified four PDZ domain-containing proteins, syntenin, PICK1, GRIP, and PSD95, as interactors with the kainate receptor (KAR) subunits GluR5(2b,) GluR5(2c), and GluR6. Of these, we show that both GRIP and PICK1 interactions are required to maintain KAR-mediated synaptic function at mossy fiber-CA3 synapses. In addition, PKC alpha can phosphorylate ct-GluR5(2b) at residues S880 and S886, and PKC activity is required to maintain KAR-mediated synaptic responses. We propose that PICK1 targets PKC alpha to phosphorylate KARs, causing their stabilization at the synapse by an interaction with GRIP. Importantly, this mechanism is not involved in the constitutive recycling of AMPA receptors since blockade of PDZ interactions can simultaneously increase AMPAR- and decrease KAR-mediated synaptic transmission at the same population of synapses.

Presynaptic cross-talk of beta-adrenoreceptor and 5-hydroxytryptamine receptor signalling in the modulation of glutamate release from cerebrocortical nerve terminals.

1. The presynaptic interactions between facilitatory beta-adrenoreceptors and inhibitory 5-hydroxytryptamine (5-HT) receptors modulating glutamate release from cerebrocortical nerve terminals were examined. 2. 4-aminopyridine (4-AP, 1 mM)-evoked glutamate release was facilitated by the membrane permeant cyclic-3',5'-adenosine monophosphate (cAMP) analogue, 8-bromo-cAMP (8-Br-cAMP), used to directly activate cAMP-dependent protein kinase (PKA). 3. The beta-adrenoreceptor agonist, isoprenaline (ISO), effected a concentration-dependent potentiation of 4-AP-evoked glutamate release which was abolished by the beta-adrenoreceptor antagonist, propranolol, and the PKA inhibitor, Rp-cyclic-3',5'-adenosine-monophosphothioate (Rp-cAMPS). 4. 5-HT receptor activation by 100 microM 5-HT produced an inhibition of 4-AP-evoked glutamate release in nerve terminals. The inhibitory effect of 5-HT could be mimicked by the selective 5-HT(1A) receptor agonist, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and antagonized by 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)piperazine (NAN-190). 5. When 5-HT (or 8-OH-DPAT) was used in conjunction with ISO or 8-Br-cAMP, the beta-adrenoreceptor- and PKA-mediated potentiation of glutamate release was abrogated. 6. The inhibitory crosstalk of 5-HT(1A) receptors to beta-adrenoceptor-mediated facilitation of glutamate release was abolished in the presence of NAN-190. 7. Examination of voltage-dependent Ca(2+) influx revealed that, while ISO and 5-HT alone caused a respective potentiation and diminution of the 4-AP-evoked increase in [Ca(2+)](c), the co-presence of 5-HT abolished the ISO mediated potentiation of Ca(2+) influx. 8. Together, these results suggest that beta-adrenoreceptors and 5-HT(1A) receptors coexist on the cerebrocortical nerve terminals and that the cross-talk between the two receptor signalling pathways occurs at a locus downstream from cAMP production, possibly at the level of voltage-dependent Ca(2+) influx.

Metabotropic glutamate receptors: electrical and chemical signaling properties.

Over the last two decades, glutamate has been established as the main excitatory neurotransmitter in the mammalian brain. Glutamate released from synapses activates ion channel-forming receptors at postsynaptic cells and consequently mediates fast postsynaptic potentials. These receptors are termed ionotropic glutamate receptors (iGluRs). The subsequent discovery of metabotropic glutamate receptors (mGluRs) revealed that glutamate can also mediate slow synaptic potentials, modulate ion channels, and directly couple to GTP binding proteins. In contrast to the iGluRs, the mGluRs possess seven transmembrane domains and a large intracellular C-terminus that involves interactions with a variety of other intracellular signaling systems. Eight functionally distinct mGluR subtypes are known to be localized to specific neuron types at presynaptic and/or postsynaptic membranes. Their physiological functions involve the generation of slow excitatory and inhibitory synaptic potentials, modulation of synaptic transmission, synaptic integration, and plasticity. The classical role of glutamate as a fast excitatory synaptic transmitter was largely extended by mGluRs acting as a neuromodulator and even as an activator of inhibitory mechanisms at certain synapses.