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Background: Pharmaceutical formularies play a crucial role in guiding medication use by balancing clinical effectiveness and cost efficiency. Although formulary implementation has been increasing in Japan, comprehensive evaluations of its impact on both clinical and economic outcomes are limited. This study aimed to assess the effect of introducing an antimicrobial formulary at Yokohama City University Hospital on antibiotic usage and treatment outcomes in intra-abdominal infections. Methods: We conducted a segmented time-series analysis to evaluate changes in carbapenem usage, including doripenem, before and after formulary implementation in October 2018. Monthly antibiotic consumption was measured by antibiotic use density (AUD). The primary outcomes were changes in doripenem use and treatment efficacy for intra-abdominal infections. To assess treatment efficacy, we used non-inferiority analysis with propensity score matching based on age, sex, body mass index, cancer status, and baseline blood test results. The treatment outcomes were evaluated using predefined clinical indicators. Results: Following the formulary intervention, doripenem use significantly decreased from 10.8 to 4.9%, meropenem use slightly increased, and imipenem/cilastatin usage remained stable. Overall, carbapenem use significantly decreased during the study period. Treatment effectiveness for intra-abdominal infections remained non-inferior, with a higher proportion of patients classified as having an "effective" response post-intervention (86.6% vs. 79.4% pre-intervention). The confidence interval confirmed the non-inferiority margin, indicating no clinically significant reduction in treatment effectiveness following the formulary introduction. Conclusions: The introduction of an antibiotic formulary at Yokohama City University Hospital effectively reduced the use of doripenem without compromising the effectiveness of treatment of intra-abdominal infections. These findings suggest that formulary management can be a valuable strategy for optimizing antibiotic use while maintaining clinical outcomes and contributing to improved antimicrobial stewardship in healthcare settings. Further research is warranted to explore the broader implications of formulary implementation in Japanese healthcare practices. [ABSTRACT FROM AUTHOR]

Background: Sleep on the first night in a sleep laboratory is characterized by a lower sleep quality and frequency of rhythmic masticatory muscle activity (RMMA) than that on the second night in moderate to severe sleep bruxism (SB) patients. Objective: The aims of this study was to clarify the physiological factors contributing to the first night effect on oromotor activity during sleep and investigate whether physiological factors involved in the first night effect differed between rhythmic and non‐rhythmic oromotor activities. Methods: Polysomnographic data collected on two consecutive nights from 15 moderate to severe SB subjects (F 7: M 8; age: 23.2 ± 1.3 [mean ± SD] years) were retrospectively analysed. Sleep variables, RMMA and non‐specific masticatory muscle activity (NSMA) were scored in relation to episode types (i.e. phasic or tonic and cluster or isolated), sleep architecture and transient arousals. The relationships between nightly differences in oromotor and sleep variables were assessed. The distribution of oromotor events, arousals, cortical electroencephalographic power, RR intervals and heart rate variability were examined in relation to sleep cycle changes. These variables were compared between the first and second nights and between RMMA and NSMA. Results: Sleep variables showed a lower sleep quality on Night 1 than on Night 2. In comparisons with Night 1, the RMMA index increased by 18.8% (p <.001, the Wilcoxon signed‐rank test) on Night 2, while the NSMA index decreased by 17.9% (p =.041). Changes in the RMMA index did not correlate with those in sleep variables, while changes in the NSMA index correlated with those in arousal‐related variables (p <.001, Spearman's rank correlation). An increase in the RMMA index on Night 2 was found for the cluster type and stage N1 related to sleep cyclic fluctuations in cortical and cardiac activities. In contrast, the decrease in the NSMA index was associated with increases in the isolated type and the occurrence of stage N2 and wakefulness regardless of the sleep cycle. Conclusion: Discrepancies in first night effect on the occurrence of RMMA and NSMA represent unique sleep‐related processes in the genesis of oromotor phenotypes in SB subjects. [ABSTRACT FROM AUTHOR]

Background: Sleep bruxism (SB), an oral behaviour in otherwise healthy individuals, is characterised by frequent rhythmic masticatory muscle activity (RMMA) during sleep. RMMA/SB episodes occur over various sleep stages (N1‐N3 and rapid eye movement (REM)), sleep cycles (non‐REM to REM), and frequently with microarousals. It currently remains unclear whether these characteristics of sleep architecture are phenotype candidates for the genesis of RMMA/SB. Objectives: This narrative review investigated the relationship between sleep architecture and the occurrence of RMMA as a SB phenotype candidate. Methods: PubMed research was performed using keywords related to RMMA/SB and sleep architecture. Results: In non‐SB and SB healthy individuals, RMMA episodes were most frequent in the light non‐REM sleep stages N1 and N2, particularly during the ascending phase of sleep cycles. The onset of RMMA/SB episodes in healthy individuals was preceded by a physiological arousal sequence of autonomic cardiovascular to cortical activation. It was not possible to extract a consistent sleep architecture pattern in the presence of sleep comorbidities. The lack of standardisation and variability between subject complexified the search for specific sleep architecture phenotype(s). Conclusion: In otherwise healthy individuals, the genesis of RMMA/SB episodes is largely affected by oscillations in the sleep stage and cycle as well as the occurrence of microarousal. Furthermore, a specific sleep architecture pattern cannot be confirmed in the presence of sleep comorbidity. Further studies are needed to delineate sleep architecture phenotype candidate(s) that contribute to the more accurate diagnosis of SB and treatment approaches using standardised and innovative methodologies. [ABSTRACT FROM AUTHOR]

Abstract Background In the orofacial region, limited information is available concerning pathological tongue pain, such as inflammatory pain or neuropathic pain occurring in the tongue. Here, we tried for the first time to establish a novel animal model of inflammatory tongue pain in rats and to investigate the roles of metabotropic glutamate receptor 5 (mGluR5)-extracellular signal-regulated kinase (ERK) signaling in this process. Methods Complete Freund’s adjuvant (CFA) was submucosally injected into the tongue to induce the inflammatory pain phenotype that was confirmed by behavioral testing. Expression of phosphorylated ERK (pERK) and mGluR5 in the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) were detected with immunohistochemical staining and Western blotting. pERK inhibitor, a selective mGluR5 antagonist or agonist was continuously administered for 7 days via an intrathecal (i.t.) route. Local inflammatory responses were verified by tongue histology. Results Submucosal injection of CFA into the tongue produced a long-lasting mechanical allodynia and heat hyperalgesia at the inflamed site, concomitant with an increase in the pERK immunoreactivity in the Vc and C1-C2. The distribution of pERK-IR cells was laminar specific, ipsilaterally dominant, somatotopically relevant, and rostrocaudally restricted. Western blot analysis also showed an enhanced activation of ERK in the Vc and C1-C2 following CFA injection. Continuous i.t. administration of the pERK inhibitor and a selective mGluR5 antagonist significantly depressed the mechanical allodynia and heat hyperalgesia in the CFA-injected tongue. In addition, the number of pERK-IR cells in ipsilateral Vc and C1-C2 was also decreased by both drugs. Moreover, continuous i.t. administration of a selective mGluR5 agonist induced mechanical allodynia in naive rats. Conclusions The present study constructed a new animal model of inflammatory tongue pain in rodents, and demonstrated pivotal roles of the mGluR5-pERK signaling in the development of mechanical and heat hypersensitivity that evolved in the inflamed tongue. This tongue-inflamed model might be useful for future studies to further elucidate molecular and cellular mechanisms of pathological tongue pain such as burning mouth syndrome.

Abstract Background It has been reported that the P2Y12 receptor (P2Y12R) is involved in satellite glial cells (SGCs) activation, indicating that P2Y12R expressed in SGCs may play functional roles in orofacial neuropathic pain mechanisms. However, the involvement of P2Y12R in orofacial neuropathic pain mechanisms is still unknown. We therefore studied the reflex to noxious mechanical or heat stimulation of the tongue, P2Y12R and glial fibrillary acidic protein (GFAP) immunohistochemistries in the trigeminal ganglion (TG) in a rat model of unilateral lingual nerve crush (LNC) to evaluate role of P2Y12R in SGC in lingual neuropathic pain. Results The head-withdrawal reflex thresholds to mechanical and heat stimulation of the lateral tongue were significantly decreased in LNC-rats compared to sham-rats. These nocifensive effects were apparent on day 1 after LNC and lasted for 17 days. On days 3, 9, 15 and 21 after LNC, the mean relative number of TG neurons encircled with GFAP-immunoreactive (IR) cells significantly increased in the ophthalmic, maxillary and mandibular branch regions of TG. On day 3 after LNC, P2Y12R expression occurred in GFAP-IR cells but not neuronal nuclei (NeuN)-IR cells (i.e. neurons) in TG. After 3 days of successive administration of the P2Y12R antagonist MRS2395 into TG in LNC-rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly decreased coincident with a significant reversal of the lowered head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue compared to vehicle-injected rats. Furthermore, after 3 days of successive administration of the P2YR agonist 2-MeSADP into the TG in naïve rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly increased and head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue were significantly decreased in a dose-dependent manner compared to vehicle-injected rats. Conclusions The present findings provide the first evidence that the activation of P2Y12R in SGCs of TG following lingual nerve injury is involved in the enhancement of TG neuron activity and nocifensive reflex behavior, resulting in neuropathic pain in the tongue.

Abstract Background The purpose of the present study was to elucidate the mechanisms that may underlie the sensitization of trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) neurons to heat or cold stimulation of the orofacial region following glutamate (Glu) injection. Results Glu application to the tongue or whisker pad skin caused an enhancement of head-withdrawal reflex and extracellular signal-regulated kinase (ERK) phosphorylation in Vc-C2 neurons. Head-withdrawal reflex and ERK phosphorylation were also enhanced following cold stimulation of the tongue but not whisker pad skin in Glu-injected rats, and the head-withdrawal reflex and ERK phosphorylation were enhanced following heat stimulation of the tongue or whisker pad skin. The enhanced head-withdrawal reflex and ERK phosphorylation after heat stimulation of the tongue or whisker pad skin, and those following cold stimulation of the tongue but not whisker pad skin were suppressed following ionotropic glutamate receptor antagonists administration into the tongue or whisker pad skin. Furthermore, intrathecal administration of MEK1/2 inhibitor PD98059 caused significant suppression of enhanced head-withdrawal reflex in Glu-injected rats, heat head-withdrawal reflex in the rats with Glu injection into the tongue or whisker pad skin and cold head-withdrawal reflex in the rats with Glu injection into the tongue. Conclusions The present findings suggest that peripheral Glu receptor mechanisms may contribute to cold hyperalgesia in the tongue but not in the facial skin, and also contribute to heat hyperalgesia in the tongue and facial skin, and that the mitogen-activated protein kinase cascade in Vc-C2 neurons may be involved in these Glu-evoked hyperalgesic effects.

Neuropathic pain is characterized by sensory abnormalities, such as mechanical allodynia and heat hyperalgesia, associated with alteration in the peripheral and central nervous systems. After trigeminal nerve injury, phenotypic changes that involve the expression of calcitonin gene-related peptide occur in large- and medium-sized myelinated neurons; primary afferent neurons exhibit hyperexcitability because of neuron-glia interactions in the trigeminal ganglion. Increased nociceptive inputs from C- and Aδ-fiber and innocuous inputs from Aβ-fiber into the trigeminal spinal subnucleus caudalis (Vc) contribute to the phenotypic changes; further, they potentiate noxious information transmission in the ascending nociceptive pathways to the thalamus and parabrachial nucleus (PBN). It is noteworthy that C-fiber mediated nociceptive inputs can activate both the Vc-ventral posteromedial thalamic nucleus and Vc-PBN pathways, while mechanoreceptive fiber inputs specifically activate the Vc-PBN pathway. The Vc-PBN pathways project to the central nucleus of the amygdala (CeA) where affective behaviors are modulated. In addition, the PBN interacts with wakefulness-regulating neurons and hunger-sensitive neurons in the hypothalamus, suggesting that the Vc-PBN pathway can modulate sleep and appetite. Therefore, phenotypic changes in primary neurons and stimulus modality-specific activation of ascending nociceptive pathways to the PBN may exacerbate affective aspects of trigeminal neuropathic pain, including behavioral problems, such as sleep disturbance and anorexia, via the PBN-CeA-hypothalamus circuits. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury can induce neuroplastic changes in the central nervous system and result in neuropathic pain. This study investigated functional involvement in dorsal paratrigeminal nucleus (dPa5) and nucleus tractus solitarii (NTS) neurons projecting to the parabrachial nucleus (PBN) after trigeminal nerve injury. Anatomical quantification was performed based on phosphorylated extracellular signal-regulated kinase (pERK) expression underlying orofacial neuropathic pain associated with infraorbital nerve chronic constriction injury (ION-CCI) in rats. ION-CCI rats exhibited heat and mechanical hypersensitivity in the ipsilateral upper lip. After injection of retrograde tracer fluorogold (FG) into the contralateral PBN, ION-CCI rats received capsaicin or noxious mechanical stimulation to the upper lip. The total number of FG-labeled neurons in dPa5 and NTS did not change after ION-CCI, and pERK expression in dPa5 did not differ between sham and ION-CCI rats. In the NTS contralateral to ION-CCI, the number of pERK-immunoreactive neurons and percentage of pERK-immunoreactive FG-labeled PBN projection neurons were increased after capsaicin stimulation in ION-CCI rats. The present findings suggest that enhanced noxious inputs from the NTS to the PBN after trigeminal nerve injury modulates PBN neuron activity, which accompanies the affective components of orofacial neuropathic pain. [ABSTRACT FROM AUTHOR]