Therapeutic Potential of Treprostinil Inhalation Powder for Patients with Pulmonary Arterial Hypertension: Evidence to Date.

Pulmonary arterial hypertension (PAH) is a complex and incurable disease for which pulmonary vasodilators remain the core therapy. Of the three primary pathways that vasodilators target, the prostacyclin pathway was the earliest to be used and currently has the largest number of modalities for drug delivery. Inhaled treprostinil has been introduced as a treatment option in PAH and, more recently, pulmonary hypertension (PH) due to interstitial lung disease (PH-ILD), and the earlier nebulized form has been joined by a dry powder form allowing for more convenient use. In this review, we discuss inhaled treprostinil, focusing on the dry powder inhalation (DPI) formulation, and explore its dosing, applications, and evidence to support patient tolerance and acceptance. Recent trials underpinning the evidence for use of inhaled treprostinil and the most recent developments concerning the drug are discussed. Finally, the review looks briefly into premarket formulations of inhaled treprostinil and relevant early studies suggesting efficacy in PAH treatment.

Diagnosis and management of chronic thromboembolic pulmonary hypertension (CTEPH) in sickle cell disease: A review.

Pulmonary hypertension in sickle cell disease (SCD) is a complex phenomenon resulting from multiple overlapping etiologies, including pulmonary vasoconstriction in the setting of chronic hemolytic anemia, diastolic dysfunction, and chronic thromboembolic disease. The presence of pulmonary hypertension of any cause in SCD confers a significant increase in mortality risk. Evidence to guide the management of patients with sickle cell disease and chronic thromboembolic pulmonary hypertension (CTEPH) is scant and largely the realm of case reports and small case series. Centered on a discussion of a complex young patient with hemoglobin hemoglobin SC who ultimately underwent treatment with pulmonary thromboendarterectomy, we review the available literature to guide management and discuss and overview of treatment of CTEPH in SCD, considering the unique considerations and challenges facing patients suffering from this multisystem disease.

Severity of illness and risk of mortality in Mayo Clinic's virtual hybrid advanced care at home program: a retrospective cohort study.

BACKGROUND: In July 2020, Mayo Clinic launched Advanced Care at Home (ACH), a high-acuity virtual hybrid hospital-at-home model (HaH) of care at Mayo Clinic Florida and Northwest Wisconsin, an urban destination medical center and a rural community practice respectively. This study aims to describe demographic characteristics of ACH patients as well as their acuity of illness using severity of illness (SOI) and risk of mortality (ROM), to illustrate the complexity of patients in the program, taking into account the different diagnostic related groups. METHODS: Mayo Clinic uses All Patient Refined-Diagnosis Related Groups (APR-DRG) to calculate SOI and ROM on hospitalized patients. APR-DRG data, including SOI and ROM, were gathered from individual chart reviews from July 6, 2020, to March 31, 2022. RESULTS:  Out of 923 patients discharged from ACH, the average APR-DRG SOI was 2.89 (SD 0.81) and ROM was 2.73. (SD 0.92). Mean age was 70.88 (SD 14.46) years, 54.6% were male patients and the average length of stay was 4.10 days. The most frequent diagnosis was COVID-19 infection with 162 patients (17.6%), followed by heart failure exacerbation (12.7%) and septicemia (10.9%). The 30-day readmission rate after discharge from ACH was 11.2% (n = 103) and the 30-day mortality rate was 1.8% (n = 17). There were no in-program patient deaths. CONCLUSIONS: SOI and ROM from patients at the ACH program have been shown to be in the range of "moderate/major" according to the APR-DRG classification. The ACH program is capable of accepting and managing highly complex patients that require advanced therapeutic means. Furthermore, the ACH program has an in-program mortality rate of 0 to date. Therefore, ACH is rising as a capable alternative to the brick-and-mortar hospital.

Implementation of a virtual and in-person hybrid hospital-at-home model in two geographically separate regions utilizing a single command center: a descriptive cohort study.

BACKGROUND: As providers look to scale high-acuity care in the patient home setting, hospital-at-home is becoming more prevalent. The traditional model of hospital-at-home usually relies on care delivery by in-home providers, caring for patients in urban communities through academic medical centers. Our objective is to describe the process and outcomes of Mayo Clinic's Advanced Care at Home (ACH) program, a hybrid virtual and in-person hospital-at-home model combining a single, virtual provider-staffed command center with a vendor-mediated in-person medical supply chain to simultaneously deliver care to patients living near an urban hospital-at-home command center and patients living in a rural region in a different US state and time zone. METHODS: A descriptive, retrospective medical records review of all patients admitted to ACH between July 6, 2020, and December 31, 2021. Patients were admitted to ACH from an urban academic medical center in Florida and a rural community hospital in Wisconsin. We collected patient volumes, age, sex, race, ethnicity, insurance type, primary hospital diagnosis, 30-day mortality rate, in-program mortality, 30-day readmission rate, rate of return to hospital during acute phase, All Patient Refined-Diagnosis Related Groups (APR-DRG) Severity of Illness (SOI), and length of stay (LOS) in both the inpatient-equivalent acute phase and post-acute equivalent restorative phase. RESULTS: Six hundred and eighty-six patients were admitted to the ACH program, 408 in Florida and 278 in Wisconsin. The most common diagnosis seen were infectious pneumonia (27.0%), septicemia / bacteremia (11.5%), congestive heart failure exacerbation (11.5%), and skin and soft tissue infections (6.3%). Median LOS in the acute phase was 3 days (IQR 2-5) and median stay in the restorative phase was 22 days (IQR 11-26). In-program mortality rate was 0% and 30-day mortality was 0.6%. The mean APR-DRG SOI was 2.9 (SD 0.79) and the 30-day readmission rate was 9.7%. CONCLUSIONS: The ACH hospital-at-home model was able to provide both high-acuity inpatient-level care and post-acute care to patients in their homes through a single command center to patients in urban and rural settings in two different geographical locations with favorable outcomes of low mortality and hospital readmissions.

Impact of an Acquisition Advanced Practice Provider on Home Hospital Patient Volumes and Length of Stay.

In July 2020, Mayo Clinic introduced a hospital-at-home program, known as Advanced Care at Home (ACH) as an alternate option for clinically stable medical patients requiring hospital-level care. This retrospective cohort study evaluates the impact of the addition of a dedicated ACH patient acquisition Advanced Practice Provider (APP) on average length of stay (ALOS) and the number of patients admitted into the program between in Florida and Wisconsin between 6 July 2020 and 31 January 2022. Patient volumes and ALOS of 755 patients were analyzed between the two sites both before and after a dedicated acquisition APP was added to the Florida site on 1 June 2021. The addition of a dedicated acquisition APP did not affect the length of time a patient was in the emergency department or hospital ward prior to ACH transition (2.91 days [Florida] vs. 2.59 days [Wisconsin], p = 0.22), the transition time between initiation of the ACH consult to patient transfer home (0.85 days [Florida] vs. 1.16 days [Wisconsin], p = 0.28), or the total ALOS (6.63 days [Florida] vs. 6.34 days [Wisconsin], p = 0.47). The average number of patients acquired monthly was significantly increased in Florida (38.3 patients per month) compared with Wisconsin (21.6 patients per month) (p < 0.01). The addition of a dedicated patient acquisition APP resulted in significantly higher patient volumes but did not affect transition time or ALOS. Other hospital-at-home programs may consider the addition of an acquisition APP to maximize patient volumes.

Treatment of a high healthcare utilizer with sepsis in a virtual hybrid hospital-at-home program.

High healthcare utilizers are often chronically ill patients who require aggressive hospital and outpatient care. We describe a patient with septic shock who was stabilized in the intensive care unit, then transitioned to a virtual hybrid hospital-at-home to complete both inpatient care as well as outpatient wound and rehabilitation therapy.

A Virtual Hybrid Care Hotel Model Supports the Recovery of Post-procedural Patients with Mild to Severe Systemic Diseases.

BACKGROUND: Patients with mild to severe chronic systemic disease undergoing low-risk procedures are often hospitalized for observation. The Care Hotel is a novel virtual medicine hybrid model of care that offers patients a comfortable, out of hospital environment where they can receive both in-person and virtual care after a surgery or procedure. This study aimed to analyze if virtual hybrid post-procedure care in a hotel could be both conducted on and accepted by patients, even those with moderate to severe chronic diseases. METHODS: This retrospective cohort study was conducted between July 23, 2020 and June 4, 2021 at Mayo Clinic in Florida, a 306-bed community academic hospital. We collected the sex, age, race, ethnicity, acceptance rate, ASA score, and primary procedure of patients using the Care Hotel. RESULTS: Out of 392 patients, 272 (69.4%) opted for care in the program. Median patient age was 61.5 years, 59.56% were males, and 86.40% were white. We found that 50.37% had an ASA score of 2 and 43.4% had an ASA score of 3. Ten different surgical specialties were able to utilize the Care Hotel for care in 47 different procedure types. Urology had the most patients (n=70, 25.7%). Post-electrophysiologic procedures were the most common procedures (n=39, 14.3%). CONCLUSION: Our virtual hybrid Care Hotel program was widely accepted by patients and could care for a multitude of post-operative procedures. Additionally, this novel program can care for patients with both mild and severe systemic diseases.

The ASA Classification System as a Predictive Factor to Stay at the Virtual Hybrid Care Hotel.

INTRODUCTION: The Care Hotel is a virtual hybrid care model for postoperative patients after low-risk procedures which allow recovery in an outpatient environment. This study aimed to analyze if the American Society of Anesthesiologists Physical Status (ASA PS) Classification System can be used as a predictive factor for staying at Mayo Clinic's Care Hotel. METHODS: This retrospective cohort study was conducted between July 23, 2020, and June 4, 2021, at Mayo Clinic in Florida, a 306-bed community academic hospital. ASA PS Class and post-procedure care setting (Care Hotel vs inpatient ward) were collected. Patients were classified into two ASA PS groups (ASA PS Classes 1-2 and 3-4). Pearson's Chi-square test was used to determine if the ASA PS Class and having stayed or not at the Care Hotel were independent and an Odds Ratio (OR) calculated. RESULTS: Out of 392 surgical and procedural patients, 272 (69.39%) chose the Care Hotel and 120 (30.61%) chose the inpatient ward. There was a statistically significant association between ASA PS Class and staying at the Care Hotel, P < .01. The OR of preferring to stay at the Care Hotel in patients with ASA PS Class 1-2 vs ASA PC Class 3-4 was 1.91 (P = .0041, 95% CI: 1.229-2.982). CONCLUSION: Patients with ASA PS Classes 1-2 are almost twice as likely to elect to stay at the Care Hotel compared to those with ASA PS Classes 3-4. This finding may help care teams focus their Care hotel recruitment efforts.

Nanopore Sensing of DNA-Histone Complexes on Nucleosome Arrays.

The location of nucleosomes in DNA and their structural stability are critical in regulating DNA compaction, site accessibility, and epigenetic gene regulation. Here, we combine the nanopore platform-based fast and label-free single-molecule detection technique with a voltage-dependent force rupture assay to detect distinct structures on nucleosomal arrays and then to induce breakdown of individual nucleosome complexes. Specifically, we demonstrate direct measurement of distinct nucleosome structures present on individual 12-mer arrays. A detailed event analysis showed that nucleosomes are present as a combination of complete and partial structures, during translocation through the pore. By comparing with the voltage-dependent translocation of the mononucleosomes, we find that the partial nucleosomes result from voltage-dependent structural disintegration of nucleosomes. High signal-to-noise detection of heterogeneous levels in translocation of 12-mer array molecules quantifies the heterogeneity and nucleosomal substructure sizes on the arrays. These results facilitate the understanding of electrostatic interactions responsible for the integrity of the nucleosome structure and possible mechanisms of its unraveling by chromatin remodeling enzymes. This study also has potential applications in chromatin profiling.

Hypertriglyceridemia induced acute pancreatitis: 4 years' experience from a tertiary care institute and quick literature review.

Hypertriglyceridemia (HTG) is infrequent but an established etiology that can trigger recurrent episodes of acute pancreatitis. The risk of acute pancreatitis is significant when serum triglycerides levels surpass >1000 mg/dL. Although the severity of HTG-induced acute pancreatitis (HTG-AP) may be correlated to higher HTG levels in the early stages, the overall clinical outcomes are similar to other aetiologies. The initial management also differs from the routine recommendations with additional diagnostic and therapeutic challenges. This retrospective case series includes a 4-year experience with HTG-AP at our facility and a brief literature review.

Temperature dependent in vitro binding and release of target DNA by Cas9 enzyme.

The CRISPR-associated protein 9 (Cas9) system has proven to be a powerful technology for genome editing in a wide variety of in vivo and in vitro applications. CRISPR-Cas9, when loaded with the guide RNA, cleaves the DNA at the target position as recognized by the guide RNA sequence. For successful application of this technology, it is important to study the biophysical parameters affecting its function. Temperature dependence of the Cas9 binding as well as energetics of product release after cleavage has not been well reported in the literature. In this work, we study the binding properties of Cas9 enzyme to the sequence specific target DNA at a range of temperatures and, surprisingly, find that the Cas9 enzyme, in our study, can find and bind its target DNA with 90 ± 20% efficiency at temperatures as low as 4 °C. Further, we show that the cleaved DNA products remain bound to the Cas9 enzyme strongly and is released from the enzyme only at higher temperatures. Using the gel shift assays, we quantify the rate of Cas9 binding to target DNA to be 0.8 ± 0.2 min-1 at 37 °C. We also tested denaturant (SDS) dependent release of cleaved product which showed a similar release pattern with a dissociation constant of 0.23 ± 0.04 mM. Our results of heat and denaturant dependence on Cas9-DNA binding and release mechanics will provide valuable insights for developing temperature dependent applications of the CRISPR-Cas9 technology.

BREEZE: Open-label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI™ in patients with pulmonary arterial hypertension.

Inhaled treprostinil is an approved therapy for pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease in the United States. Studies have confirmed the robust benefits and safety of nebulized inhaled treprostinil, but it requires a time investment for nebulizer preparation, maintenance, and treatment. A small, portable treprostinil dry powder inhaler has been developed for the treatment of PAH. The primary objective of this study was to evaluate the safety and tolerability of treprostinil inhalation powder (TreT) in patients currently treated with treprostinil inhalation solution. Fifty-one patients on a stable dose of treprostinil inhalation solution enrolled and transitioned to TreT at a corresponding dose. Six-minute walk distance (6MWD), device preference and satisfaction (Preference Questionnaire for Inhaled Treprostinil Devices [PQ-ITD]), PAH Symptoms and Impact (PAH-SYMPACT®) questionnaire, and systemic exposure and pharmacokinetics for up to 5 h were assessed at baseline for treprostinil inhalation solution and at Week 3 for TreT. Adverse events (AEs) were consistent with studies of inhaled treprostinil in patients with PAH, and there were no study drug-related serious AEs. Statistically significant improvements occurred in 6MWD, PQ-ITD, and PAH-SYMPACT. Forty-nine patients completed the 3-week treatment phase and all elected to participate in an optional extension phase. These results demonstrate that, in patients with PAH, transition from treprostinil inhalation solution to TreT is safe, well-tolerated, and accompanied by statistically significant improvements in key clinical assessments and patient-reported outcomes with comparable systemic exposure between the two formulations at evaluated doses (trial registration: clinicaltrials.gov identifier: NCT03950739).

Provider Evaluation of a Novel Virtual Hybrid Hospital at Home Model.

BACKGROUND: Healthcare provider's experience with new models of care is crucial for long-term success. In July 2020, Mayo Clinic implemented a novel virtual hybrid hospital at home program called Advanced Care at Home (ACH). This model allows virtual providers in a command center to care for high-acuity patients in the home setting through collaboration with a vendor-mediated supply chain. This study aims to describe the outcomes obtained from a survey applied to the ACH providers to determine their acceptance of the quality and safety of the virtual hybrid care model, their perception towards the decision-making and teamwork between the command center and supplier network, and determine if the overall experience with ACH was rewarding. METHODS: A 15-question anonymous survey was distributed via email quarterly to all the physicians and nurse practitioners registered in ACH program at Mayo Clinic. The survey encompassed questions related to the overall experience in ACH concerning work environment, quality of care, service reliability, teamwork, decision-making, and satisfaction. All the questions were Likert-like scale choice, and a descriptive analysis using frequency distribution and percentages of the data was performed. RESULTS: Between September 1, 2020 and April 30, 2021, three quarterly surveys were sent to a total of 21 physicians and nurse practitioners caring for patients virtually in ACH. The response rate reported was 72%, 33%, and 66%, respectively, at the first, second, and third quarters. Eighty percent or more of providers consistently gave positive scores to all three areas analyzed throughout the 8-month study. CONCLUSION: Providers found the ACH virtual hybrid model of home hospital care very rewarding. They were able to deliver high-quality and safe care to their patients through positive teamwork with a vendor-mediated supply chain. This novel model of hospital at home has the potential to be a great provider satisfier moving forward.

Improving Patient Selection and Prioritization for Hospital at Home Through Predictive Modeling.

Hospital at home is designed to offer patients hospital level care in the comfort of their own home. The process by which clinicians select eligible patients that are clinically and socially appropriate for this model of care requires labor-intensive manual chart reviews. We addressed this problem by providing a predictive model, web application, and data pipeline that produces an eligibility score based on a set of clinical and social factors that influence patients' success in the program. Providers used this predictive model to prioritize the order in which they perform chart reviews and patient screenings. Training performance area under the curve (AUC) was 0.77. Testing 'in production' had an AUC of 0.75. Admission criteria in training rapidly changed over the course of the study due to the novelty of the clinical model. The current algorithm successfully identified many inconsistencies in enrollment and has streamlined the process of patient identification.

Case Report: An Atypical Case of Carney Complex.

BACKGROUND Intracardiac tumors are a rare entity, with myxomas being the most common among them (approximately 50% of intracardiac tumors). Up to 80% of myxomas originate within the left atrium and while most are incidental or isolated findings in asymptomatic patients, others may result in clinical manifestations of heart failure or emboli. Moreover, in some cases, myxomas can be part of a genetically inherited syndrome known as Carney complex (CNC), and present with varied phenotypes, including skin, endocrine, and neuroendocrine tumors. CASE REPORT We present a case of a 54-year-old male patient who presented with a several-month history of non-specific cough, dyspnea on exertion, and palpitations along with several skin tags, nevi, and nodules. He was found to have a retrocardiac density on chest X-ray, which was revealed to be a large left atrial myxoma on echocardiography. The myxoma was surgically excised and genetic testing for a mutation of the PRKAR1A gene (the most common mutation underlying CNC) was negative. However, 2 major clinical criteria for diagnosis of CNC were fulfilled based on cardiac myxoma and spotty skin pigmentation. In this report, we focus on the clinical manifestations of CNC, including guidance on tumor surveillance and genetic variants of CNC. CONCLUSIONS While CNC is most commonly associated with an inactivating mutation of the PRKAR1A gene, it can be diagnosed clinically in the absence of an identifiable genetic mutation. In patients presenting with atypical cardiac tumors, the early recognition of cutaneous manifestations can raise the index of suspicion for CNC, which can facilitate early diagnosis, treatment, and initiation of surveillance for neoplasia development.

Description of Stenotrophomonas sepilia sp. nov., isolated from blood culture of a hospitalized patient as a new member of Stenotrophomonas maltophilia complex.

Stenotrophomonas sepilia strain SM16975 (= JCM 32102; = KCTC 62052) is a new species isolated from the blood culture of a hospitalized patient. The biochemical characterization, phenotypic criteria, phylogenomic reconstruction, and genomic analysis were carried out to differentiate it from its phylogenetic neighbours, establishing novel species status in the genus Stenotrophomonas and within Stenotrophomonas maltophilia complex (Smc).

A rare etiology of persistent jaundice in type 1 autoimmune hepatitis.

A 24-year-old male without previously known comorbidities presented with progressive jaundice and hepatomegaly. Autoimmune serology and liver biopsy revealed features of autoimmune hepatitis. A treatment by oral prednisolone and azathioprine was initiated, after which he achieved remission. However, hyperbilirubinemia persisted, with a predominantly unconjugated fraction. Hemolytic causes of unconjugated hyperbilirubinemia were ruled out, and the diagnosis of Gilbert syndrome was established.

Three-tier stratification for CNS COVID-19 to help decide which patients should undergo lumbar puncture with CSF analysis: a case report and literature review.

The COVID-19 pandemic continues to overwhelm global healthcare systems. While the disease primarily causes pulmonary complications, reports of central nervous system (CNS) involvement have recently emerged ranging from encephalopathy to stroke. This raises a practical dilemma for clinicians as to when to pursue neuroimaging and lumbar tap with cerebrospinal fluid (CSF) analysis in COVID-19 patients with neurological symptoms. We present a case of an encephalopathic patient infected with SARS-CoV-2 with no pulmonary symptoms. We propose a three-tier risk stratification for CNS COVID-19 aiming to help clinicians to decide which patients should undergo CSF analysis. The neurological examination remains an integral component of screening and evaluating patients for COVID-19 considering the range of emerging CNS complications.