Central Sleep Apnea in Patients With Coronary Heart Disease Taking P2Y12 Inhibitors.

ABSTRACT: Central sleep apnea (CSA) is common in patients with heart failure. Recent studies link ticagrelor use with CSA. We aimed to evaluate CSA prevalence in patients with coronary heart disease (CHD) and whether ticagrelor use is associated with CSA. We reviewed consecutive patients with CHD who underwent a polysomnography (PSG) test over a 5-year period from 3 sleep centers. We sampled patients who were on ticagrelor or clopidogrel during a PSG test at a 1:4 ticagrelor:clopidogrel ratio. Patients with an active opioid prescription during PSG test were excluded. Age, left ventricle (LV) dysfunction, and P2Y12 inhibitor use were included in a multivariate logistic regression. A total of 135 patients were included with 26 on ticagrelor and 109 on clopidogrel (age 64.1 ± 11.4, 32% male). High CSA burden (12%) and strict CSA (4.4%) were more common in patients on ticagrelor than in those on clopidogrel (27% vs. 8.3% and 10.0% vs. 1.8%). Ticagrelor use (vs. clopidogrel) was associated with high CSA burden (OR 3.53, 95% CI 1.04-12.9, P = 0.039) and trended toward significance for strict CSA (OR 6.32, 95% CI 1.03-51.4, P = 0.052) when adjusting for age and LV dysfunction. In an additional analysis also adjusting for history of atrial fibrillation, ticagrelor use and strict CSA became significantly associated (OR 10.0, 95% CI 1.32-117, P = 0.035). CSA was uncommon in patients with CHD undergoing sleep studies. Ticagrelor use (vs. clopidogrel) was associated with high CSA burden and trended toward significance for strict CSA.

The Impact of a Recently Approved Automated Insulin Delivery System on Glycemic, Sleep, and Psychosocial Outcomes in Older Adults With Type 1 Diabetes: A Pilot Study.

BACKGROUND: Older adults with type 1 diabetes (≥65 years) are often under-represented in clinical trials of automated insulin delivery (AID) systems. We sought to test the efficacy of a recently FDA-approved AID system in this population. METHODS: Participants with type 1 diabetes used sensor-augmented pump (SAP) therapy for four weeks and then used an AID system (Control-IQ) for four weeks. In addition to glucose control variables, patient-reported outcomes (PRO) were assessed with questionnaires and sleep parameters were assessed by actigraphy. RESULTS: Fifteen older adults (mean age 68.7 ± 3.3, HbA1c of 7.0 ± 0.8) completed the pilot trial. Glycemic outcomes improved during AID compared to SAP. During AID use, mean glucose was 146.0 mg/dL; mean percent time in range (TIR, 70-180 mg/dL) was 79.6%; median time below 70 mg/dL was 1.1%. The AID system was in use 92.6% ± 7.0% of the time. Compared to SAP, while participants were on AID the TIR increased significantly (+10%, P = .002) accompanied by a reduction in both time above 180 mg/dL (-6.9%, P = .005) and below 70 mg/dl (-0.4%, P = .053). Diabetes-related distress decreased significantly while using AID (P = .028), but sleep parameters remained unchanged. CONCLUSIONS: Use of this AID system in older adults improved glycemic control with high scores in ease of use, trust, and usability. Participants reported an improvement in diabetes distress with AID use. There were no significant changes in sleep.

Elucidation of obstructive sleep apnoea related blood pressure surge using a novel continuous beat-to-beat blood pressure monitoring system.

BACKGROUND: Obstructive sleep apnoea (OSA) episode related blood pressure (BP) surge may mediate the association of OSA with cardiovascular disease. However, BP is not measured during a clinical sleep study. METHOD: We tested the feasibility of incorporating the Caretaker physiological monitor, which utilizes a novel continuous beat-to-beat (b-b) BP monitoring technology, into polysomnography (PSG) and aimed to characterize BP surges related to obstructive respiratory events. B-b BP was concurrently collected and merged with PSG data on a posthoc basis. We compared BP surge between mean respiratory (apnoea, hypopnea and desaturation-alone events) and nonrespiratory events (spontaneous or leg movement-related arousals). We examined the association of the degree of oxygen desaturation with BP surge in a given respiratory event combining all events. A total of 17 consecutive patients (12 men, mean 52 years old, nine diagnostic and eight split-night PSGs) undergoing clinically indicated PSG were included after excluding one patient with poor signal quality due to excessive movement. RESULTS: Caretaker was well tolerated. Mean respiratory BP surge ranged from 5 to 19 mmHg [Median (IQR) = 13.9 (9.5--16.2)]. Mean BP surge between the respiratory and nonrespiratory events was similar [13.8 (4.5) vs. 14.9 (5.3) mmHg, P = 0.13]. Accounting for the count distribution of desaturation/BP surge data pair events, there was a linear correlation between the degree of oxygen desaturation and BP surge (R = 0.57, P < 0.001). In eight patients undergoing split-night sleep studies, the number of BP surge events (≥10 mmHg/h) decreased during continuous positive airway pressure in all but one patient. CONCLUSION: We demonstrated highly variable OSA-related BP surge patterns using the Caretaker's b-b BP monitoring technology that has the potential to be integrated into sleep studies.

Sleep and diabetes-specific psycho-behavioral outcomes of a new automated insulin delivery system in young children with type 1 diabetes and their parents.

BACKGROUND: Data on the use of Control-IQ, the latest FDA-approved automated insulin delivery (AID) system for people with T1D 6 years of age or older is still scarce, particularly regarding nonglycemic outcomes. Children with T1D and their parents are at higher risk for sleep disturbances. This study assesses sleep, psycho-behavioral and glycemic outcomes of AID compared to sensor-augmented pump therapy (SAP) therapy in young children with T1D and their parents. METHODS: Thirteen parents and their young children (ages 7-10) on insulin pump therapy were enrolled. Children completed an initial 4-week study with SAP using their own pump and a study CGM followed by a 4-week phase of AID. Sleep outcomes for parents and children were evaluated through actigraphy watches. Several questionnaires were administered at baseline and at the end of each study phase. CGM data were used to assess glycemic outcomes. RESULTS: Actigraphy data did not show any significant change from SAP to AID, except a reduction of number of parental awakenings during the night (p = 0.036). Parents reported statistically significant improvements in Pittsburgh Sleep Quality Index total score (p = 0.009), Hypoglycemia Fear Survey total score (p = 0.011), diabetes-related distress (p = 0.032), and depression (p = 0.023). While on AID, time in range (70-180 mg/dL) significantly increased compared to SAP (p < 0.001), accompanied by a reduction in hyperglycemia (p = 0.001). CONCLUSIONS: These results suggest that use of AID has a positive impact on glycemic outcomes in young children as well as sleep and diabetes-specific quality of life outcomes in their parents.

Influence of Sleep Stage on LH Pulse Initiation in the Normal Late Follicular Phase and in Polycystic Ovary Syndrome.

OBJECTIVE: During the early follicular phase, sleep-related luteinizing hormone (LH) pulse initiation is positively associated with brief awakenings but negatively associated with rapid eye movement (REM) sleep. The relationship between sleep architecture and LH pulse initiation has not been assessed in other cycle stages or in women with polycystic ovary syndrome (PCOS). DESIGN AND METHODS: We performed concomitant frequent blood sampling (LH pulse analysis) and polysomnography on 8 normal women (cycle day 7-11) and 7 women with PCOS (at least cycle day 7). RESULTS: In the normal women, the 5 min preceding LH pulses contained more wake epochs and fewer REM epochs than the 5 min preceding randomly determined time points (wake: 22.3 vs. 9.1%, p = 0.0111; REM: 4.4 vs. 18.8%, p = 0.0162). However, LH pulse initiation was not related to wake or REM epochs in PCOS; instead, the 5 min preceding LH pulses contained more slow-wave sleep (SWS) than the 5 min before random time points (20.9 vs. 6.7%, p = 0.0089). Compared to the normal subjects, the women with PCOS exhibited a higher REM-associated LH pulse frequency (p = 0.0443) and a lower proportion of wake epochs 0-5 min before LH pulses (p = 0.0205). CONCLUSIONS: Sleep-related inhibition of LH pulse generation during the later follicular phase is normally weakened by brief awakenings and strengthened by REM sleep. In women with PCOS, LH pulse initiation is not appropriately discouraged by REM sleep and may be encouraged by SWS; these abnormalities may contribute to a high sleep-related LH pulse frequency in PCOS.

Safety assessment of cre recombinase.

Cre recombinase, when used as a tool in agricultural biotechnology, can precisely excise DNA sequences that may be useful in the introduction of a new trait but are not needed in the commercial product. Although the cre genetic material would not be present in the final product, the present studies were performed to assess the safety of Cre recombinase to provide confirmatory evidence of the safe use of Cre-lox technology in agricultural biotechnology. Cre recombinase shares no relevant sequence similarity to known allergens or toxins. When Cre recombinase was exposed to a pH 1.2 solution of simulated gastric fluid lacking pepsin, CD spectroscopy showed that there was a loss of secondary structure and that the protein was no longer active in a functional assay. Cre recombinase was degraded rapidly when exposed to pepsin in a standardized gastric digestion model; therefore, Cre recombinase would not survive the harsh gastric environment. When orally administered to mice as an acute dosage of 53 mg/kg of body weight, no treatment-related adverse findings were observed. These data support the conclusion that human and animal dietary exposure to Cre recombinase pose no known safety concerns; consistent with the fact that bacteriophage P1, the source of the cre gene and expressed protein, is commonly encountered in the environment and in normal enteric bacteria without reports of adverse consequences.

A role for the RabA4b effector protein PI-4Kbeta1 in polarized expansion of root hair cells in Arabidopsis thaliana.

The RabA4b GTPase labels a novel, trans-Golgi network compartment displaying a developmentally regulated polar distribution in growing Arabidopsis thaliana root hair cells. GTP bound RabA4b selectively recruits the plant phosphatidylinositol 4-OH kinase, PI-4Kbeta1, but not members of other PI-4K families. PI-4Kbeta1 colocalizes with RabA4b on tip-localized membranes in growing root hairs, and mutant plants in which both the PI-4Kbeta1 and -4Kbeta2 genes are disrupted display aberrant root hair morphologies. PI-4Kbeta1 interacts with RabA4b through a novel homology domain, specific to eukaryotic type IIIbeta PI-4Ks, and PI-4Kbeta1 also interacts with a Ca2+ sensor, AtCBL1, through its NH2 terminus. We propose that RabA4b recruitment of PI-4Kbeta1 results in Ca2+-dependent generation of PI-4P on this compartment, providing a link between Ca2+ and PI-4,5P2-dependent signals during the polarized secretion of cell wall components in tip-growing root hair cells.

Structure of the nucleotide complex of PyrR, the pyr attenuation protein from Bacillus caldolyticus, suggests dual regulation by pyrimidine and purine nucleotides.

PyrR is a protein that regulates the expression of genes and operons of pyrimidine nucleotide biosynthesis (pyr genes) in many bacteria. PyrR acts by binding to specific sequences on pyr mRNA and causing transcriptional attenuation when intracellular levels of uridine nucleotides are elevated. PyrR from Bacillus subtilis has been purified and extensively studied. In this work, we describe the purification to homogeneity and characterization of recombinant PyrR from the thermophile Bacillus caldolyticus and the crystal structures of unliganded PyrR and a PyrR-nucleotide complex. The B. caldolyticus pyrR gene was previously shown to restore normal regulation of the B. subtilis pyr operon in a pyrR deletion mutant. Like B. subtilis PyrR, B. caldolyticus PyrR catalyzes the uracil phosphoribosyltransferase reaction but with maximal activity at 60 degrees C. Crystal structures of B. caldolyticus PyrR reveal a dimer similar to the B. subtilis PyrR dimer and, for the first time, binding sites for nucleotides. UMP and GMP, accompanied by Mg2+, bind specifically to PyrR active sites. Nucleotide binding to PyrR is similar to other phosphoribosyltransferases, but Mg2+ binding differs. GMP binding was unexpected. The protein bound specific sequences of pyr RNA 100 to 1,000 times more tightly than B. subtilis PyrR, depending on the RNA tested and the assay method; uridine nucleotides enhanced RNA binding, but guanosine nucleotides antagonized it. The new findings of specific GMP binding and its antagonism of RNA binding suggest cross-regulation of the pyr operon by purines.

Regional pharmacokinetics of amifostine in anesthetized dogs: role of the liver, gastrointestinal tract, lungs, and kidneys.

Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. In this study, we characterized the sites and extent of organ-specific activation by the liver, gastrointestinal tract, lungs, and kidneys after systemic administrations of amifostine. A total of 10 dogs were infused via the cephalic vein using sequential dose rates of drug at 0.125, 0.500, and 1.00 micro mol/min/kg. Infusion of each dose rate lasted 2 h, at which time steady-state plasma concentrations were obtained (i.e., portal vein, carotid artery, hepatic vein, pulmonary artery, and renal vein). The hepatic arterial, portal venous, and renal arterial blood flows, and cardiac output, were measured. The hepatic and splanchnic extraction of amifostine remained high at 90%, whereas gastrointestinal extraction decreased from 43 to 12 to 15% with increasing dose. Pulmonary extraction of amifostine was low at 7%, whereas renal extraction was intermediate at 57%. Because blood flow measurements were relatively constant during the drug infusions, clearance parameters paralleled that of organ extraction. As a result, saturability was observed in the gastrointestinal blood clearance (i.e., from 9.8 to 2.8-3.3 ml/min/kg) and total body plasma clearance of amifostine (i.e., from 52.6 to about 37.3 ml/min/kg), as the doses increased. Due to the drug's high activation in liver, these findings suggest that amifostine may offer good protection of this organ against the toxicities of chemotherapy and radiation.

A pilot study of topical intrarectal application of amifostine for prevention of late radiation rectal injury.

PURPOSE: Clinical symptomatic late injury to the rectal wall occurs in about one-third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of the prostate to the anterior rectal wall. On the basis of our previous observations in an animal model that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall, a Phase I dose-escalation clinical trial was undertaken. METHODS AND MATERIALS: Twenty-nine patients with localized prostate cancer were accrued. Eligibility criteria included histologically confirmed adenocarcinoma, Karnofsky performance status >or=70, and no pelvic lymphadenopathy or distant metastases. The total dose to the prostate was 70.2 Gy in 20 patients and 73.8 Gy in 9 patients. Therapy was delivered using a 4-field technique with three-dimensional conformal planning. Amifostine was administered intrarectally as an aqueous solution 30 min before irradiation on the first 15 days of therapy. Amifostine was escalated in cohorts from 500 to 2500 mg. Proctoscopy was performed before therapy and at 9 months after completion. Most patients underwent repeat proctoscopy at 18 months. On Days 1 and 10 of radiotherapy, serum samples were collected for pharmacokinetic studies. The clinical symptoms (Radiation Therapy Oncology Group scale) and a proctoscopy score were assessed during follow-up. RESULTS: All patients completed therapy with no amifostine-related toxicity at any dose level. The application was feasible and well tolerated. No substantial systemic absorption occurred. With a median follow-up of 26 months, 9 patients (33%) developed rectal bleeding (8 Grade 1, 1 Grade 2). At 9 months, 16 and 3 patients developed Grade 1 and Grade 2 telangiectasia, respectively. This was mostly confined to the anterior rectal wall. No visible mucosal edema, ulcerations, or strictures were noted. No significant differences were found between the proctoscopy findings at 9 and 18 months. Four patients (14%) developed symptoms suggestive of radiation damage that, on sigmoidoscopy, proved to be secondary to unrelated processes. These included preexisting nonspecific proctitis (n = 1), diverticular disease of the sigmoid colon (n = 1), rectal polyp (n = 1), and ulcerative colitis (n = 1). Symptoms developed significantly more often in patients receiving 500-1000 mg than in patients receiving 1500-2500 mg amifostine (7 [50%] of 14 vs. 2 [15%] of 13, p = 0.0325, one-sided chi-square test). CONCLUSION: Intrarectal application of amifostine is feasible and well tolerated. Systemic absorption of amifostine and its metabolites is negligible, and close monitoring of patients is not required with rectal administration. Proctoscopy is superior to symptom score as a method of assessing radiation damage of the rectal wall. The preliminary efficacy data are encouraging, and further clinical studies are warranted.