Associated comorbidities, healthcare utilization & mortality in hospitalized patients with haemophilia in the United States: Contemporary nationally representative estimates.

INTRODUCTION: Current in-hospital burden and healthcare utilization patterns for persons with haemophilia (PWH) A and B, including both children (ages < 18 years) and adults (ages ≥ 18 years), in the United States (US) are lacking. AIM: To evaluate healthcare utilization, the prevalence of comorbidities, and mortality in hospitalized paediatric and adult PWH using a contemporary nationally representative cohort. METHODS: Hospitalizations of PWH either as the primary reason for admission (principal diagnosis) or one of all listed diagnoses were identified using ICD-10 codes from the 2017 Nationwide Inpatient Sample (NIS), the largest publicly available all-payer inpatient discharge database in the US. Sampling weights were applied to generate nationally representative estimates. RESULTS: The contemporary cohort included 10,555 hospitalizations (paediatrics, 18.3%; adults, 81.7%) among PWH as one-of-all listed diagnoses (n = 1465 as principal diagnosis). Median age (interquartile range) was 46 (24-66) years overall; adults, 54 (35-70) years and paediatric, 4 (1-11). The most common comorbidities in adults were hypertension (33.4%), hyperlipidaemia (23.6%), and diabetes (21.1%). In children, hemarthrosis (11.4%), contusions (9.6%), and central line infections (9.3%) were the most common. The overall mortality rate was 2.3%. Median hospital charges per haemophilia admission were $52,616 ($24,303-$135,814) compared to $26,841 ($12,969-$54,568) for all-cause admissions in NIS. CONCLUSION: Bleeding and catheter-related infections are the significant reasons for paediatric haemophilia admissions. Adult haemophilia admissions tend to be associated with age-related comorbidities. Costs for haemophilia-related hospitalizations are higher than the national average for all-cause hospitalizations.

Identifying novel members of the Wntless interactome through genetic and candidate gene approaches.

Wnt signaling is an important pathway that regulates several aspects of embryogenesis, stem cell maintenance, and neural connectivity. We have recently determined that opioids decrease Wnt secretion, presumably by inhibiting the recycling of the Wnt trafficking protein Wntless (Wls). This effect appears to be mediated by protein-protein interaction between Wls and the mu-opioid receptor (MOR), the primary cellular target of opioid drugs. The goal of this study was to identify novel protein interactors of Wls that are expressed in the brain and may also play a role in reward or addiction. Using genetic and candidate gene approaches, we show that among a variety of protein, Wls interacts with the dopamine transporter (target of cocaine), cannabinoid receptors (target of THC), Adenosine A2A receptor (target of caffeine), and SGIP1 (endocytic regulator of cannabinoid receptors). Our study shows that aside from opioid receptors, Wntless interacts with additional proteins involved in reward and/or addiction. Future studies will determine whether Wntless and WNT signaling play a more universal role in these processes.

MOR is not enough: identification of novel mu-opioid receptor interacting proteins using traditional and modified membrane yeast two-hybrid screens.

The mu-opioid receptor (MOR) is the G-protein coupled receptor primarily responsible for mediating the analgesic and rewarding properties of opioid agonist drugs such as morphine, fentanyl, and heroin. We have utilized a combination of traditional and modified membrane yeast two-hybrid screening methods to identify a cohort of novel MOR interacting proteins (MORIPs). The interaction between the MOR and a subset of MORIPs was validated in pulldown, co-immunoprecipitation, and co-localization studies using HEK293 cells stably expressing the MOR as well as rodent brain. Additionally, a subset of MORIPs was found capable of interaction with the delta and kappa opioid receptors, suggesting that they may represent general opioid receptor interacting proteins (ORIPS). Expression of several MORIPs was altered in specific mouse brain regions after chronic treatment with morphine, suggesting that these proteins may play a role in response to opioid agonist drugs. Based on the known function of these newly identified MORIPs, the interactions forming the MOR signalplex are hypothesized to be important for MOR signaling and intracellular trafficking. Understanding the molecular complexity of MOR/MORIP interactions provides a conceptual framework for defining the cellular mechanisms of MOR signaling in brain and may be critical for determining the physiological basis of opioid tolerance and addiction.