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Chronic opioid therapy for pain management has increased dramatically without adequate study of potential deleterious effects on breathing during sleep. A retrospective cohort study comparing 60 patients taking chronic opioids matched for age, sex, and body mass index with 60 patients not taking opioids was conducted to determine the effect of morphine dose equivalent on breathing patterns during sleep. The apnea-hypopnea index was greater in the opioid group (43.5/h vs 30.2/h, p < .05) due to increased central apneas (12.8/h vs 2.1/h; p < .001). Arterial oxygen saturation (SpO2) in the opioid group was significantly lower during both wakefulness (difference 2.1%, p < .001) and non-rapid eye movement (NREM) sleep (difference 2.2%, p < .001) but not during rapid eye movement (REM) sleep (difference 1.2%) than in the nonopioid group. Within the opioid group, and after controlling for body mass index, age, and sex, there was a dose-response relationship between morphine dose equivalent and apnea-hypopnea (p < .001), obstructive apnea (p < .001), hypopnea (p < .001), and central apnea indexes (p < .001). Body mass index was inversely related to apnea-hypopnea index severity in the opioid group. Ataxic or irregular breathing during NREM sleep was also more prevalent in patients who chronically used opioids (70% vs 5.0%, p < .001) and more frequent (92%) at a morphine dose equivalent of 200 mg or higher (odds ratio = 15.4, p = .017). There is a dose-dependent relationship between chronic opioid use and the development of a peculiar pattern of respiration consisting of central sleep apneas and ataxic breathing. Although potentially significant, the clinical relevance of these observations remains to be established.

Background Osteoarthritis (OA) is a major cause of chronic pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are analgesics commonly used for musculoskeletal pain; however, NSAIDs can increase the risk of certain adverse events, such as gastrointestinal bleeding, edema, heart failure, and hypertension. Objective The objective of this study was to characterize existing comorbidities among patients with OA. For patients with OA with and without a coexisting medical condition of interest (CMCOI), we estimated the prevalence of prescribing and dispensing NSAIDs pre-OA and post-OA diagnosis. Methods Data from three large administrative claims databases were used to construct an OA retrospective cohort. Databases leveraged were IBM MarketScan Medicare Supplemental Database (MDCR), IBM MarketScan Commercial Database (CCAE), and Optum’s de-identified Clinformatics ® Data Mart Database (Optum CDM). The OA study population was defined to be those patients who had an OA diagnosis from an inpatient or outpatient visit with at least 365 days of prior observation time in the database during January 2000 through May 2021. Asthma, cardiovascular disorders, renal impairment, and gastrointestinal bleeding risks were the CMCOI of interest. Patients with OA were then classified as having or not having evidence of a CMCOI. For both groups, NSAID dispensing patterns pre-OA and post-OA diagnosis were identified. Descriptive analysis was performed within the Observational Health Data Sciences and Informatics framework. Results In each database, the proportion of the OA population with at least one CMCOI was nearly 50% or more (48.0% CCAE; 74.4% MDCR; 68.6% Optum CDM). Cardiovascular disease was the most commonly observed CMCOI in each database, and in two databases, nearly one in four patients with OA had two or more CMCOI (23.2% MDCR; 22.6% Optum CDM). Among the OA population with CMCOI, NSAID utilization post-OA diagnosis ranged from 33.0 to 46.2%. Following diagnosis of OA, an increase in the prescribing and dispensing of NSAIDs was observed in all databases, regardless of patient CMCOI presence. Conclusions This study provides real-world evidence of the pattern of prescribing and dispensing of NSAIDs among patients with OA with and without CMCOI, which indicates that at least half of patients with OA in the USA have a coexisting condition. These conditions may increase the risk of side effects commonly associated with NSAIDs. Yet, at least 32% of these patients were prescribed and dispensed NSAIDs. These data support the importance of shared decision making between healthcare professionals and patients when considering NSAIDs for the treatment of OA in patients with NSAID-relevant coexisting medical conditions.

Amyloid-β peptide (Aβ) is the toxic agent in Alzheimer's disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive Aβ binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD. We demonstrated that HD triggers the release of oxidants (e.g., H₂O₂) from mitochondria due to the loss of complex IV, which contains heme-a. Now we add more evidence that Aβ binding to regulatory heme in vivo is the mechanism by which Aβ causes HD. Heme binds to Aβ, thus preventing Aβ aggregation by forming an Aβ-heme complex in a cell-free system. We suggest that this complex depletes regulatory heme, which would explain the increase in heme synthesis and iron uptake we observe in human neuroblastoma cells. The Aβ-heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H₂O₂. Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of Aβ to heme supports a unifying mechanism by which excessive Aβ induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive Aβ for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.

Protein–protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic potential in the development of small molecules that modulate these interactions; however, rational design of small molecule enhancers of PPIs remains elusive. Herein, we report the prospective identification and rational design of potent small molecules that enhance the interaction between an oncogenic transcription factor, β-Catenin, and its cognate E3 ligase, SCF β-TrCP . These enhancers potentiate the ubiquitylation of mutant β-Catenin by β-TrCP in vitro and induce the degradation of an engineered mutant β-Catenin in a cellular system. Distinct from PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, with contacts optimized for both the substrate and ligase within the same small molecule entity. The prospective discovery of ‘molecular glue’ presented here provides a paradigm for the development of small molecule degraders targeting hard-to-drug proteins. Directed protein degradation to target hard-to-drug proteins is a promising therapeutic approach. Here, the authors report the prospective discovery of small molecule “molecular glue” that inserts into a naturally occurring E3 ligase-substrate interface leading to degradation of substrate protein.

Coexisting medical conditions and concomitant medications contribute to treatment challenges primary-care professionals (PCPs) face daily. The current study assessed the extent and distribution of nonaspirin NSAID-relevant coexisting medical conditions of interest (CMCOI) in patients visiting PCPs. This retrospective database review analyzed data from three large health-care claim databases to identify the frequency of nonaspirin NSAID-relevant CMCOI among adults aged ≥18 years with a PCP visit in 2013. Claim databases employed were the Truven Health MarketScan Commercial Claims and Encounters database, representative of the privately insured (PI) population; Truven Health MarketScan Multi-State Medicaid, representative of the Medicaid population (Medicaid); and Truven MarketScan Medicare Supplemental, representative of the Medicare population with employer-based supplemental Medicare insurance (Medicare-Supplement). Nonaspirin NSAID-relevant CMCOI, asthma, cardiovascular risk factors, gastrointestinal bleeding risk factors, and renal insufficiency were chosen based on US NSAID over-the-counter Drug Facts label warnings. Frequency of CMCOI was determined for those without and with a musculoskeletal diagnosis. In each database, ≥19% (19.0% PI, 29.9% Medicaid, 33.6% Medicare-Supplement) had a musculoskeletal diagnosis. A greater proportion of individuals with a musculoskeletal diagnosis had one or more CMCOI compared with those without a musculoskeletal diagnosis (61.3% vs 50.4% PI, 78.1% vs 66.8% Medicaid, 87.1% vs 82.3% Medicare-Supplement). The frequency of one or more CMCOI increased with age in each database. Across databases among CMCOI, cardiovascular risk factors were most common, followed by gastrointestinal bleeding risk factors, and proportions were higher among those with a musculoskeletal diagnosis. These data confirm the high frequency of nonaspirin NSAID-relevant CMCOI among patients presenting to PCPs for musculoskeletal diagnosis, as well as among older patients. These analyses reinforce the critical role health-care professionals can play in identifying patients with nonaspirin NSAID-relevant CMCOI, providing those patients with ongoing guidance on appropriate choice and use of over-the-counter analgesics, and educating patients about the impact aging, health status, concomitant conditions, and medicines have on selection of all medicines, including analgesics.

The mechanisms by which the extreme desmoplasia observed in pancreatic tumors develops remain unknown and its role in pancreatic cancer progression is unsettled. Chemokines have a key role in the recruitment of a wide variety of cell types in health and disease. Transcript and protein profile analyses of human and murine cell lines and human tissue specimens revealed a consistent elevation in the receptors CCR10 and CXCR6, as well as their respective ligands CCL28 and CXCL16. Elevated ligand expression was restricted to tumor cells, whereas receptors were in both epithelial and stromal cells. Consistent with its regulation by inflammatory cytokines, CCL28 and CCR10, but not CXCL16 or CXCR6, were upregulated in human pancreatitis tissues. Cytokine stimulation of pancreatic cancer cells increased CCL28 secretion in epithelial tumor cells but not an immortalized activated human pancreatic stellate cell line (HPSC). Stellate cells exhibited dose- and receptor-dependent chemotaxis in response to CCL28. This functional response was not linked to changes in activation status as CCL28 had little impact on alpha smooth muscle actin levels or extracellular matrix deposition or alignment. Co-culture assays revealed CCL28-dependent chemotaxis of HPSC toward cancer but not normal pancreatic epithelial cells, consistent with stromal cells being a functional target for the epithelial-derived chemokine. These data together implicate the chemokine CCL28 in the inflammation-mediated recruitment of cancer-associated stellate cells into the pancreatic cancer parenchyma.

Background: Adaptive servoventilation (ASV) can be effective therapy for specific types of central apnea such as Cheyne-Stokes respiration (CSR). Patients treated chronically with opioids develop central apneas and ataxic breathing patterns (Biot’s respiration), but therapy with CPAP is usually unsuccessful. There are no published studies of ASV in patients with sleep apnea complicated by chronic opioid therapy. Methods: Retrospective analysis of 22 consecutive patients referred for evaluation and treatment of sleep apnea who had been using opioid medications for at least 6 months, had an apnea-hypopnea index (AHI) >20/h, and had been tested with ASV. Baseline polysomnography was compared with CPAP and ASV. Outcome variables: AHI, central apnea index (CAI), obstructive apnea index (OAI), hypopnea index (HI), desaturation index, mean SpO 2 , lowest SpO 2 , time SpO 2 <90%, and degree of Biot’s respiration. Results: Mean (SD) AHI measured 66.6/h (37.3) at baseline, 70.1/h (32.6) on CPAP, and 54.2/h (33.0) on ASV. With ASV, the mean OAI was significantly decreased to 2.4/h (p < 0.0001), and the mean HI increased significantly to 35.7/h (p < 0.0001). The decrease of CAI from 26.4/h to 15.6/h was not significant (p = 0.127). Biot’s breathing persisted, and oxygenation parameters were unimproved with ASV. Conclusions: Due to residual respiratory events and hypoxemia, ASV was considered insufficient therapy in these patients. Persistence of obstructive events could be due to suboptimal pressure settings (end expiratory and/or maximal inspiratory). Residual central events could be related to fundamental differences in the pathophysiology of CSR compared to opioid induced breathing disturbances. Citation: Farney RJ; Walker JM; Boyle KM; Cloward TV; Shilling KC. Adaptive servoventilation (ASV) in patients with sleep disordered breathing associated with chronic opioid medications for non-malignant pain. J Clin Sleep Med 2008 ;4(4):311-319.

In this study, the authors propose and test a model of professional identity development among early career student affairs professionals. Using survey data from 173 new professionals (0–5 years of experience), factor analysis revealed 3 dimensions of professional identity: commitment, values congruence, and intellectual investment. Multivariate analyses found significant associations of age, master’s program characteristics, and influential people and experiences (e.g., interactions with professional colleagues and associations) with the dimensions of professional identity. Findings indicated key socialization experiences during and after graduate school were associated with the development of professional identity. The authors conclude with recommendations for practice and research.

Professional identity is one outcome of successful socialization. The purpose of this study was to understand how socialization in graduate programs contributes to the development of professional identity for new professionals in student affairs. Via survey, we found significant relationships between program qualities, standards, activities, and experiences and measures of professional identity. Out-of-class experiences were perceived to have a stronger influence than in-class experiences. Implications for graduate preparation programs and supervisors are discussed.

Women with pulmonary arterial hypertension (PAH) experience multiple symptoms, including dyspnea, fatigue, and sleep disturbance, that impair their health‐related quality of life (HRQOL). However, we know little about phenotypic subgroups of patients with PAH with similar, concurrent, multiple symptoms. The objectives of this study were to define the “symptome” by symptom cluster phenotypes and compare characteristics such as biomarkers, cardiac structure and function (echocardiography), functional capacity (6‐min walk distance), and HRQOL between the groups. This cross‐sectional study included 60 women with PAH. Subjects completed an assessment battery: Pulmonary Arterial Hypertension Symptom Scale, Pittsburgh Sleep Quality Index, Multidimensional Dyspnea Profile, Patient‐Reported Outcomes Measurement Information System (PROMIS®) Physical Function, PROMIS® Sleep‐Related Impairment, and the emPHasis‐10. Subjects also underwent transthoracic echocardiography, phlebotomy, 6‐min walk distance, and actigraphy. The three symptoms of dyspnea, fatigue, and sleep disturbance were used to define the symptom clusters. Other PAH symptoms, plasma and serum biomarkers, cardiac structure and function (echocardiography), exercise capacity (6‐min walk distance), sleep (actigraphy), and HRQOL were compared across phenotypes. The mean age was 50 ± 18 years, 51% were non‐Hispanic white, 32% were non‐Hispanic Black and 40% had idiopathic PAH. Cluster analysis identified Mild (n = 28, 47%), Moderate (n = 20, 33%), and Severe Symptom Cluster Phenotypes (n = 12, 20%). There were no differences for age, race, or PAH etiology between the phenotypes. WHO functional class (p < 0.001), norepinephrine levels (p = 0.029), right atrial pressure (p = 0.001), physical function (p < 0.001), sleep onset latency (p = 0.040), and HRQOL (p < 0.001) all differed significantly across phenotypes. We identified three distinctive symptom cluster phenotypes (Mild, Moderate, and Severe) for women with PAH that also differed by PAH‐related symptoms, physical function, right atrial pressure, norepinephrine levels, and HRQOL. These phenotypes could suggest targeted interventions to improve symptoms and HRQOL in those most severely affected.