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Background: Delirium is common in critically ill patients. Haloperidol has long been used for the treatment of delirium. Dexmedetomidine has recently been used to treat delirium among intubated critically ill patients. However, the efficacy of dexmedetomidine for delirium in non-intubated critically ill patients remains unknown. We hypothesize that dexmedetomidine is superior to haloperidol for sedation of patients with hyperactive delirium, and would reduce the prevalence of delirium among non-intubated patients after administration. We will conduct a randomized controlled trial to compare dexmedetomidine and haloperidol for the treatment of nocturnal hyperactive delirium in non-intubated patients in high dependency units (HDUs). Methods: This is an open-label, parallel-group, randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for nocturnal hyperactive delirium in non-intubated patients at two HDUs of a tertiary hospital. We will recruit consecutive non-intubated patients who are admitted to the HDU from the emergency room, and allocate them in a 1:1 ratio to the dexmedetomidine or haloperidol group in advance. The allocated investigational drug will be administered only when participants develop hyperactive delirium (Richmond Agitation-Sedation Scale [RASS] score ≥1 and a positive score on the Confusion Assessment Method for the ICU between 19:00 and 6:00 the next day) during the night at an HDU. Dexmedetomidine is administered continuously, while haloperidol is administered intermittently. The primary outcome is the proportion of participants who achieve the targeted sedation level (RASS score of between -3 and 0) 2h after the administration of the investigational drug. Secondary outcomes include the sedation level and prevalence of delirium on the day following the administration of the investigational drugs, and safety. We plan to enroll 100 participants who develop nocturnal hyperactive delirium and receive one of the two investigational drugs. Discussion: This is the first randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for sedation of non-intubated critically ill patients with hyperactive delirium in HDUs. The results of this study may confirm whether dexmedetomidine could be another option to sedate patients with hyperactive delirium. Trial registration: Japan Registry of Clinical Trials, jRCT1051220015, registered on 21 April 2022. [ABSTRACT FROM AUTHOR]

Summary: Recently an association between blood glucose dysregulation and sleep disruption was suggested. The association between sleep disordered breathing, most of which is due to obstructive sleep apnea (OSA) in the general population, and diabetic severity, as well as the impact of antidiabetic treatment, remains unclear. This study aimed to investigate these associations as well as age and sex differences. This cross‐sectional study evaluated 7,680 community participants as the main cohort (population‐based cohort). OSA was assessed by the 3% oxygen desaturation index from pulse oximetry, which was corrected for sleep duration obtained by wrist actigraphy. For arguing the limitations for using pulse oximetry, 597 hospitalised patients, who were assessed by the apnea–hypopnea index from attended polysomnography, were also evaluated as the validation cohort (hospital‐based cohort). Moderate‐to‐severe OSA was more prevalent as haemoglobin A1c (HbA1c) levels increased (<5.6%/5.6%–<6.5%/6.5%–<7.5%/≥7.5%, respectively) in both cohorts (p < 0.001), but only in those without antidiabetic treatment. The HbA1c level was an independent factor for moderate‐to‐severe OSA (population‐based cohort, odds ratio [OR] 1.26, 95% confidence interval [CI] 1.10–1.45; hospital‐based cohort, OR 1.69, 95% CI 1.22–2.33, per 1% increase). These associations were more prominent in the middle‐aged (aged <60 years) than in the elderly (aged ≥60 years) and in women than in men in both cohorts. The prevalence of moderate‐to‐severe OSA in patients with antidiabetic treatment in the hospital‐based cohort was ≥75% regardless of HbA1c levels. In conclusion, an association between the prevalence of OSA and HbA1c level even within or over the normal range was found only in patients without antidiabetic treatment and was more prominent in the middle‐aged and in women. [ABSTRACT FROM AUTHOR]

Rationale: Obstructive sleep apnea (OSA) can affect not only sleep quality but also sleep duration. Determining the therapeutic effects of continuous positive airway pressure (CPAP) on habitual sleep profiles may shed light on the impact of OSA on sleep duration.Objectives: To determine whether and how CPAP affects habitual sleep duration in patients with OSA.Methods: Assessments of sleep duration and sleep quality were performed on 57 newly diagnosed study subjects with OSA (46 men; median age, 63 yr; apnea-hypopnea index, >20 h-1) at baseline and 3 months after initiation of CPAP therapy. Measurements included in-laboratory sleep tests (polysomnography), assessments of habitual sleep (actigraphy with sleep diary for 7 d), and questionnaires on subjective symptoms (Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Hospital Anxiety and Depression Scale).Results: Actigraphic night sleep time did not change after CPAP (from 354.0 ± 64.5 min to 353.0 ± 57.0 min; P = 0.87) in the entire group, despite improvements in sleep efficiency and sleep fragmentation. Changes in habitual night sleep duration varied among the participants; habitual night sleep duration increased by 33 minutes (interquartile range, 14-45 min) in 28 participants (sleep time restorers) and decreased by 23 minutes (interquartile range, -48 to -11 min) in 29 participants (sleep time nonrestorers). Subgroup analyses revealed that sleep time restorers were characterized at baseline as having shorter and more fragmented sleep with frequent daytime napping. Nonrestorers were characterized by frequent use of hypnotic drugs and comorbid insomnia, despite longer habitual sleep duration. Actigraphic sleep fragmentation, sleep efficiency, daytime sleepiness, and the frequency of daytime napping were improved after CPAP only in the sleep time restorers, whereas subjective sleep quality was improved in the nonrestorers. Multivariate linear regression showed that shorter baseline night sleep time, baseline daytime napping, and percentage of sleep time under CPAP were positive predictors of the restoration of actigraphic night sleep time, whereas hypnotic use was a negative predictor.Conclusions: Short-term CPAP did not affect habitual night sleep duration in the group as a whole but induced intraindividual changes in relation to phenotypic features of OSA. Clinical trial registered with www.umin.ac.jp (UMIN000012639). [ABSTRACT FROM AUTHOR]

Rationale: Disrupted energy homeostasis in obstructive sleep apnea (OSA) may lead to weight gain. Paradoxically, treating OSA with continuous positive airway pressure (CPAP) may also promote weight gain, although the underlying mechanism remains unclear.Objectives: To explore the underlying mechanism by which patients with OSA gain weight after CPAP.Methods: A comprehensive assessment of energy metabolism was performed in 63 newly diagnosed OSA study participants (51 men; 60.8 ± 10.1 yr; apnea-hypopnea index >20 h(-1)) at baseline, CPAP initiation, and at a 3-month follow-up. Measurements included polysomnography, body weight, body composition, basal metabolic rate (BMR), hormones (norepinephrine, cortisol, leptin, ghrelin, insulin-like growth factor-1), dietary intake, eating behavior, and physical activity.Measurements and Main Results: BMR significantly decreased after CPAP (1,584 kcal/d at baseline, 1,561 kcal/d at CPAP initiation, and 1,508 kcal/d at follow-up; P < 0.001), whereas physical activity and total caloric intake did not significantly change. In multivariate regression, baseline apnea-hypopnea index, Δurine norepinephrine, and CPAP adherence were significant predictors of ΔBMR. The weight gainers had higher leptin levels, lower ghrelin levels, and higher eating behavior scores than the non-weight gainers, indicating a positive energy balance and disordered eating behavior among the weight gainers. Among the parameters related to energy metabolism, increased caloric intake was a particularly significant predictor of weight gain.Conclusions: Although a reduction in BMR after CPAP predisposes to a positive energy balance, dietary intake and eating behavior had greater impacts on weight change. These findings highlight the importance of lifestyle modifications combined with CPAP. Clinical trial registered with http://www.umin.ac.jp/english/ (UMIN000012639). [ABSTRACT FROM AUTHOR]

Rationale: Incretin hormones, namely glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP), and dipeptidyl peptidase-4 (DPP-4) activity are important factors in glucose metabolism and have not been investigated in patients with obstructive sleep apnea (OSA).Objectives: The objective of this study was to investigate the association between OSA and incretin and DPP-4 activity.Methods: This study included 96 consecutive patients without diabetes who were suspected of having OSA. We investigated the fasting and post-prandial incremental area under the curve (IAUC) of GLP-1, GIP serum levels, and serum DPP-4 activity levels, as well as their association with OSA. Changes in clinical variables were evaluated in the 43 patients who continued continuous positive airway pressure therapy for 3 months.Measurements and Main Results: Apnea-hypopnea index was an independent determining factor for fasting GLP-1 (β = 0.31; P = 0.0019) and IAUC GIP (β = -0.21; P = 0.037) after adjusting for known confounding factors. In those with very severe OSA (apnea-hypopnea index ≥50), the IAUCs for GLP-1 and GIP were significantly decreased, while fasting GLP-1 and fasting GIP were significantly increased. DPP-4 activity had no relation to OSA parameters or severity, while body mass index was significantly higher in those with severe OSA. Although significant changes in incretin secretion were not seen for 3 months after onset of continuous positive airway pressure therapy, the fasting GLP-1 level in the treated patients with severe OSA decreased to the same level as in untreated patients with normal to moderately severe OSA.Conclusions: OSA is associated with elevated serum levels of the incretin hormones GLP-1 (fasting) and GIP (post-prandial) in patients without diabetes. A significant association between body mass index and DPP-4, which is said to exist in healthy persons, was not found in the patients with OSA. Fasting GLP-1 in patients without diabetes with OSA may influence fasting glucose levels. [ABSTRACT FROM AUTHOR]

Rationale: Microalbuminuria is said to reflect systemic vascular damage and endothelial dysfunction and is an established indicator of cardiovascular morbidity and mortality. Patients with obstructive sleep apnea (OSA)-chronic obstructive pulmonary disease (COPD) overlap syndrome have worse survival than those with OSA or COPD alone.Objectives: This study evaluated the association between overlap syndrome and microalbuminuria.Methods: Data on patients in whom OSA was suspected and who underwent polysomnography between January 2010 and December 2012 were reviewed. Microalbuminuria was defined as an albumin-creatinine ratio between 20 and 299 mg/g in men and between 30 and 299 mg/g in women.Measurements and Main Results: Of 740 consecutive patients, 344 were analyzed. Sixty-four were control participants, 248 had OSA only, 4 had COPD only, and 28 had OSA-COPD overlap syndrome. Prevalence of microalbuminuria significantly increased in the order of control, OSA, and overlap syndrome groups (3.1, 12.9, and 32.1%, respectively; P = 0.0006). After adjusting for age and sex, multivariate logistic regression analysis demonstrated a significant association of overlap syndrome with microalbuminuria compared with OSA (odds ratio, 2.61; 95% confidence interval, 1.02-6.38; P = 0.047), but after adjusting for other confounding factors, the difference in the association did not reach significance (odds ratio, 2.54; 95% confidence interval, 0.93-6.72; P = 0.070). Of 63 patients reevaluated after 3 months of continuous positive airway pressure therapy, the logarithm of the albumin-creatinine ratio in 36 patients with good compliance significantly decreased, but there was no difference in patients with poor compliance.Conclusions: OSA-COPD overlap syndrome was more prevalent than OSA alone in patients with microalbuminuria, but the difference might be mediated by conventional risk factors rather than the addition of COPD itself. [ABSTRACT FROM AUTHOR]

Background: This study aimed to examine the preventive effect of amino acids on postoperative acute kidney injury (AKI). Methods: This was single-center, patient- and assessor-blinded, randomized controlled trial. Patients who underwent aortic surgery with cardiopulmonary bypass were included. The intervention group received 60 g/day of amino acids for up to 3 days. The control group received standard care. The primary outcome was the incidence of AKI. We assessed the effect of amino acids on AKI using a Cox proportional hazards regression model. Results: Sixty-six patients were randomly assigned to the control or intervention group. One patient in the control group withdrew consent after randomization. The incidence of AKI was 10 patients (30.3%) in the intervention group versus 18 patients (56.2%) in the control group (adjusted hazard ratio, 0.44; 95% confidence interval, 0.20–0.95; P = 0.04). Conclusions: This trial demonstrated a significant reduction in AKI incidence with amino acid supplementation. Trial registration: jRCT, jRCTs051210154. Registered 31 December 2021, https://jrct.niph.go.jp/re/reports/detail/69916 [ABSTRACT FROM AUTHOR]

Non-enzymatic proteins including antibodies function as biomarkers and are used as biopharmaceuticals in several diseases. Protein-responsive soft materials capable of the controlled release of drugs and proteins have potential for use in next-generation diagnosis and therapies. Here, we describe a supramolecular/agarose hydrogel composite that can release a protein in response to a non-enzymatic protein. A non-enzymatic protein-responsive system is developed by hybridization of an enzyme-sensitive supramolecular hydrogel with a protein-triggered enzyme activation set. In situ imaging shows that the supramolecular/agarose hydrogel composite consists of orthogonal domains of supramolecular fibers and agarose, which play distinct roles in protein entrapment and mechanical stiffness, respectively. Integrating the enzyme activation set with the composite allows for controlled release of the embedded RNase in response to an antibody. Such composite hydrogels would be promising as a matrix embedded in a body, which can autonomously release biopharmaceuticals by sensing biomarker proteins. Responsive hydrogels are of interest for diagnostic and controlled drug release applications. Here, the authors report on the design of a hydrogel with protein triggered release of an embedded protein through recovery of enzyme activity and subsequent degradation of supramolecular fibers. [ABSTRACT FROM AUTHOR]

For crystallographic analysis, Leu was substituted for Orn in Gramicidin S (LGS) to suppress interactions with hydrophilic solvent molecules, which increased the flexibility of the Orn side chains, leading to disorder within the crystals. The asymmetric unit (C62H94N10O10·1.296C3H8O·1.403H2O) contains three LGS molecules (A, B and C) forming β‐turn and intramolecular β‐sheet structures. With the exception of one motif in molecule C, d‐Phe‐Pro turn motifs (Phe is phenylalanine and Pro is proline) were classed as type II′ β‐turns. The peptide backbones twist slightly to the right along the long axis of the molecule. The puckering of Pro is in a Cγ‐endo or twisted Cγ‐endo–Cβ‐exo form. Flanking molecules are arranged such that the angles (A...B = 104°, B...C = 139° and C...A = 117°) form helical β‐sheets. Solvent molecules interact with the peptide backbones supporting the β‐sheets. The forms of the replacement Leu side chains are consistent with the e‐form of the Orn side chain in GS analogues. No hydrophilic region composed of solvent molecules, such as that observed in Gramicidin S hydrochloride (GS·HCl) crystals, was found. The perturbation of αH chemical shifts and coupling constants of CONH showed that the structural properties of GS·HCl and LGS are similar to each other in solution. CD spectra also supported the structural similarity. With the sequence cyclo(–Val–Leu–Leu–d‐Phe–Pro–)2 (Val is valine and Leu is leucine), LGS lacks the amphiphilicity and antimicrobial activity of parental Gramicidin S (GS). However, the structure of LGS reflects the structural characteristics of GS and no disordering inconvenient for structural analysis was found. Thus, LGS could be a novel scaffold useful for studying β‐turn and sheet structures. [ABSTRACT FROM AUTHOR]