Forecasting Hospital Room and Ward Occupancy Using Static and Dynamic Information Concurrently: Retrospective Single-Center Cohort Study.

BACKGROUND: Predicting the bed occupancy rate (BOR) is essential for efficient hospital resource management, long-term budget planning, and patient care planning. Although macro-level BOR prediction for the entire hospital is crucial, predicting occupancy at a detailed level, such as specific wards and rooms, is more practical and useful for hospital scheduling. OBJECTIVE: The aim of this study was to develop a web-based support tool that allows hospital administrators to grasp the BOR for each ward and room according to different time periods. METHODS: We trained time-series models based on long short-term memory (LSTM) using individual bed data aggregated hourly each day to predict the BOR for each ward and room in the hospital. Ward training involved 2 models with 7- and 30-day time windows, and room training involved models with 3- and 7-day time windows for shorter-term planning. To further improve prediction performance, we added 2 models trained by concatenating dynamic data with static data representing room-specific details. RESULTS: We confirmed the results of a total of 12 models using bidirectional long short-term memory (Bi-LSTM) and LSTM, and the model based on Bi-LSTM showed better performance. The ward-level prediction model had a mean absolute error (MAE) of 0.067, mean square error (MSE) of 0.009, root mean square error (RMSE) of 0.094, and R2 score of 0.544. Among the room-level prediction models, the model that combined static data exhibited superior performance, with a MAE of 0.129, MSE of 0.050, RMSE of 0.227, and R2 score of 0.600. Model results can be displayed on an electronic dashboard for easy access via the web. CONCLUSIONS: We have proposed predictive BOR models for individual wards and rooms that demonstrate high performance. The results can be visualized through a web-based dashboard, aiding hospital administrators in bed operation planning. This contributes to resource optimization and the reduction of hospital resource use.

Peptide Lv augments L-type voltage-gated calcium channels through vascular endothelial growth factor receptor 2 (VEGFR2) signaling.

We previously identified peptide Lv, a novel bioactive peptide that enhances the activity of L-type voltage-gated calcium channels (L-VGCCs) in cone photoreceptors. In this study, we verified that peptide Lv was able to augment L-VGCC currents in cardiomyocytes, as well as promote proliferation of endothelial cells. We used a proteomics approach to determine the specific receptors and binding partners of peptide Lv and found that vascular endothelial growth factor receptor 2 (VEGFR2) interacted with peptide Lv. Peptide Lv treatment in embryonic cardiomyocytes stimulated tyrosine autophosphorylation of VEGFR2 and activated its downstream signaling. Peptide Lv activity was blocked by DMH4, a VEGFR2 specific blocker, but not by SCH202676, an allosteric inhibitor of G protein-coupled receptors, suggesting that the activity of peptide Lv was mediated through VEGFR2 signaling. Inhibition of VEGFR tyrosine kinase or its downstream signaling molecules abolished the augmentation of L-VGCCs elicited by peptide Lv in cardiomyocytes. In addition, peptide Lv promoted cell proliferation of cultured human endothelial cells. Calcium entry through L-VGCCs is essential for excitation-contraction coupling in cardiomyocytes. Since peptide Lv was able to augment L-VGCCs through activation of VEGF signaling in cardiomyocytes and promote proliferation of endothelial cells, peptide Lv may play an important role in regulating the cardiovascular system.

Inflammasome activation by altered proteostasis.

The association between altered proteostasis and inflammatory disorders has been increasingly recognized, but the underlying mechanisms are not well understood. In this study, we show that deficiency of either autophagy or sequestosome 1 (p62 or SQSTM) led to inflammasome hyperactivation in response to LPS and ATP in primary macrophages and in mice in vivo. Importantly, induction of protein misfolding by puromycin, thapsigargin, or geldanamycin resulted in inflammasome activation that was more pronounced in autophagy- or p62-deficient macrophages. Accumulation of misfolded proteins caused inflammasome activation by inducing generation of nonmitochondrial reactive oxygen species and lysosomal damage, leading to release of cathepsin B. Our results suggest that altered proteostasis results in inflammasome activation and thus provide mechanisms for the association of altered proteostasis with inflammatory disorders.

Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress.

Failure to maintain protein homeostasis (proteostasis) leads to accumulation of unfolded proteins and contributes to the pathogenesis of many human diseases. Accumulation of unfolded proteins in the endoplasmic reticulum (ER) elicits unfolded protein response (UPR) that serves to attenuate protein translation, and increase protein refolding or degradation. In contrast to UPR in the ER, the regulatory molecules operative in cytosolic responses and their potential relation to ER stress are not well elucidated. Aggresome-like induced structures (ALIS) have been described as transient aggregation of ubiquitinated proteins in the cytosol. In this study, we show that cells respond to inflammation, infection or ER stress by cytosolic formation of ALIS, indicating that ALIS formation represents an early event in cellular adjustment to altered proteostasis that occurs under these conditions. This response was aided by rapid transcriptional up-regulation of polyubiqutin-binding protein p62. NF-κB and mTOR activation were also required for ALIS formation. Importantly, we show a cross talk between UPR in the ER and cytosolic ALIS. Down-regulation of ER UPR in XBP1 deficient cells increases cyotosolic ALIS formation. Furthermore, lysosomal activity but not macroautophagy is responsible for ALIS clearance. This study reveals the underlying regulatory mechanisms of ALIS formation and clearance, and provides a previously unrecognized common adaptive mechanism for cellular responses against inflammation and ER stress.

Comparison of volume-controlled and pressure-controlled ventilation using a laryngeal mask airway during gynecological laparoscopy.

BACKGROUND: Several publications have reported the successful, safe use of Laryngeal Mask Airway (LMA)-Classic devices in patients undergoing laparoscopic surgery. However, there have been no studies that have examined the application of volume-controlled ventilation (VCV) or pressure-controlled ventilation (PCV) using a LMA during gynecological laparoscopy. The aim of this study is to compare how the VCV and PCV modes and using a LMA affect the pulmonary mechanics, the gas exchange and the cardiovascular responses in patients who are undergoing gynecological laparoscopy. METHODS: Sixty female patients were randomly allocated to one of two groups, (the VCV or PCV groups). In the VCV group, baseline ventilation of the lung was performed with volume-controlled ventilation and a tidal volume of 10 ml/kg ideal body weight (IBW). In the PCV group, baseline ventilation of the lung using pressure-controlled ventilation was initiated with a peak airway pressure that provided a tidal volume of 10 ml/kg IBW and an upper limit of 35 cmH(2)O. The end-tidal CO(2), the peak airway pressures (P(peak)), the compliance, the airway resistance and the arterial oxygen saturation were recorded at T1: 5 minutes after insertion of the laryngeal airway, and at T2 and T3: 5 and 15 minutes, respectively, after CO(2) insufflation. RESULTS: The P(peak) at 5 minutes and 15 minutes after CO(2) insufflation were significantly increased compared to the baseline values in both groups. Also, at 5 minutes and 15 minutes after CO(2) insufflation, there were significant differences of the P(peak) between the two groups. The compliance decreased in both groups after creating the pneumopertoneim (P < 0.05). CONCLUSIONS: Our results demonstrate that PCV may be an effective method of ventilation during gynecological laparoscopy, and it ensures oxygenation while minimizing the increases of the peak airway pressure after CO(2) insufflation.

Lysine methylation and functional modulation of androgen receptor by Set9 methyltransferase.

Lysine methyltransferases modulate activities of transcription factors and transcription coregulators by methylating specific lysine residue(s). We report that the androgen receptor (AR) is methylated at lysine-630 by Set9, which was originally identified as a histone H3K4 monomethyltransferase. Alanine substitution of lysine-630 prevented AR methylation in vitro and in vivo. Set9 methylated the nuclear and cytoplasmic AR utilizing the cofactor S-adenosyl-methionine. A pan-methyllysine antibody recognized endogenous AR, and Set9 coimmunoprecipitated with nuclear and cytoplasmic AR. Set9 overexpression potentiated AR-mediated transactivation of the probasin promoter, whereas Set9 depletion inhibited AR activity and target gene expression. Similar to AR, chromatin occupancy of Set9 at androgen response elements (AREs) was androgen dependent, and associated with methylated histone H3K4 chromatin activation marks and p300/CBP associated factor acetyltransferase recruitment. Set9 depletion increased the histone H3K9-dimethyl repressive mark at AREs and reduced histone activation marks and occupancy of p300/CBP associated factor. K630A mutation reduced amino- and carboxy-terminal (N-C) interaction in Set9-intact cells, whereas N-C interaction for wild-type AR was reduced upon Set9 depletion. The K630A mutant was resistant to loss of activity from Set9 silencing and to increase of activity from Set9 overexpression. The K630 dependence of Set9-regulated N-C interaction and AR activity suggests that Set9 directly acts on AR at the amino acid level. Chromatin recruitment of Set9 to AREs is suggestive of its additional role as a transcriptional coactivator. Because the cellular metabolic state determines the level of S-adenosylmethionine and consequently the activity of Set9, the enhanced activity of methylated AR may have special significance in certain metabolic contexts.

Loss of androgen receptor in aging and oxidative stress through Myb protooncoprotein-regulated reciprocal chromatin dynamics of p53 and poly(ADP-ribose) polymerase PARP-1.

Poly(ADP-ribosyl)ation of transcription factors and coregulators, mediated by the poly(ADP-ribose) polymerase PARP-1, has been emerging as an important epigenetic mechanism that controls transcriptional dynamics in response to diverse intra- and extracellular signals. PARP-1 activity is also implicated in the regulation of mammalian lifespan. Herein we show that transcriptional down-regulation of androgen receptor (AR) in the aging rat liver and in oxidatively stressed hepatoma cells involves exchange of a PARP-1-associated, p/CAF-containing coactivator assembly for a p53-interacting, Groucho/TLE1-, and mSin3A-included corepressor complex at an age- and oxidant-responsive DNA element (age-dependent factor (ADF) element) in the AR promoter. The coregulator switch is mediated by B-Myb and c-Myb, which bind to the ADF element and physically associate with PARP-1 and the tumor suppressor p53. Heterogeneous nuclear ribonucleoprotein K, residing at the ADF element in association with PARP-1, may serve a platform role in stabilizing the activating complex. PARP-1 coactivated B-Myb- and c-Myb-mediated transactivation of the AR promoter, and p53 antagonized the B-Myb/c-Myb-induced AR promoter activation. PARP-1, heterogeneous nuclear ribonucleoprotein K, B-Myb, and c-Myb each serves as a positive regulator of cellular AR content, whereas p53 negatively regulates AR expression. Our results identify a shared, PARP-1-regulated sensing mechanism that coordinates transcriptional repression of AR during aging and in response to oxidative stress. This study may provide insights as to how advancing age and intracellular redox balance might influence androgen-regulated physiology.

Interplay of nuclear factor-kappaB and B-myb in the negative regulation of androgen receptor expression by tumor necrosis factor alpha.

Increased androgen receptor (AR) levels are associated with prostate cancer progression to androgen independence and therapy resistance. Evidence has suggested that chronic inflammation is closely linked to various cancers including prostate cancer. Herein we show that the proinflammatory cytokine TNFalpha negatively regulates AR mRNA and protein expression and reduces androgen sensitivity in androgen-dependent LNCaP human prostate cancer cells. Decreased AR expression results from transcription repression involving essential in cis interaction of nuclear factor-kappaB (NF-kappaB) with the B-myb transcription factor at a composite genomic element in the 5'-untranslated region of AR. The negative regulation was abrogated when NF-kappaB activity was inhibited by a superrepressor of the inhibitory kappaB protein. In contrast, androgen-independent C4-2 (LNCaP-derived) cells fail to show AR down-regulation by TNFalpha, despite expression of B-myb and TNFalpha-induced NF-kappaB activity similar to that in LNCaP cells. The negatively regulated AR gene chromatin region showed TNFalpha-dependent enrichment of B-myb and the NF-kappaB proteins p65 and p50. In parallel, the histone deacetylase 1, corepressor silencing mediator of retinoid and thyroid hormone receptor and the corepressor-associated scaffold protein mSin3A were recruited to the inhibitory site. In C4-2 cells, neither NF-kappaB and B-myb, nor any of the corepressor components, were detected at the negative site in response to TNFalpha. Apoptosis was induced in TNFalpha-treated LNCaP cells, likely in part due to the down-regulation of AR. The androgen-independent, AR-expressing C4-2 and C4-2B (derived from C4-2) cells were resistant to TNFalpha-induced apoptosis. The results linking androgen dependence to the NF-kappaB and AR pathways may be insightful in identifying novel treatment targets for prostate cancer.