Comparative adherence of macitentan versus ambrisentan and bosentan in Australian patients with pulmonary arterial hypertension: a retrospective real-world database study.

AIM: Bosentan, ambrisentan, and macitentan are endothelin receptor antagonists (ERAs), currently available in Australia for treatment of pulmonary arterial hypertension (PAH). This study assessed the comparative adherence of these ERAs for PAH in Australian patients. METHODS: This retrospective, observational study used data for adults with PAH from the Services Australia 10% Pharmaceuticals Benefits Scheme (PBS) dataset (01/2006-10/2020). The primary outcome was treatment adherence (i.e. receiving ≥80% of ERA doses over 12 months). Secondary outcomes were time to treatment change (add-on or switch) and overall survival. RESULTS: The study included 436 patients who took bosentan (n = 200), ambrisentan (n = 69), or macitentan (n = 167). Treatment adherence was significantly greater in patients who received macitentan (65.3%) versus ambrisentan (56.5%) and bosentan (58.0%), with odds ratios (ORs; 95% CI) of 0.51 (0.30-0.88; p = 0.016) for bosentan versus macitentan and 0.48 (0.24-0.96; p = 0.037) for ambrisentan versus macitentan. The median time to treatment change was 47.2 and 43.4 months for bosentan and ambrisentan, respectively (not calculated for macitentan because of insufficient duration of data). LIMITATIONS AND CONCLUSIONS: Real-world data for Australian patients with PAH showed that treatment adherence for ERAs was suboptimal. Adherence was higher for macitentan compared with ambrisentan and bosentan.

Impact of Left Heart Disease Risk Factors on Outcomes in Pulmonary Arterial Hypertension Therapy.

BACKGROUND: Current guidelines recommend initial monotherapy for pulmonary arterial hypertension (PAH) with cardiopulmonary comorbidities, despite limited available evidence to guide management. RESEARCH QUESTION: Do left heart disease (LHD) risk factors have an impact on treatment response and influence applicability of risk assessment in a real-world cohort of patients with PAH? STUDY DESIGN AND METHODS: The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial criteria was used to define the phenotype of patients with PAH with risk factors for LHD. Treatment strategy, functional outcome, long-term survival, and risk discrimination were compared with a reference PAH cohort using the Pulmonary Hypertension Society of Australia and New Zealand Registry. RESULTS: A total of 487 incident patients with PAH diagnosed between 2011 and 2020 were included. Of these, 103 (21.1%) fulfilled the definition of PAH with LHD risk factors, with 384 (78.9%) remaining as the reference group. Patients in the PAH with LHD risk factors group were older (66 ± 13 vs 58 ± 19 years; P < .001), had lower pulmonary vascular resistance (393 ± 266 vs 708 ± 391 dyn.s/cm5; P = .031), and had worse 6-min walk distance (286 ± 130 vs 327 ± 136 m; P = .005) at diagnosis. The PAH with LHD risk factors group was less likely to receive initial combination therapy (27% vs 44%; P = .02). Changes in 6-min walk distance at 12 months were similar in both groups (43 ± 77 m in the PAH with LHD risk factors group and 50 ± 90 m in the reference group; P = .50), including when stratified by initial treatment strategy (PAH with LHD risk factors group vs reference PAH group: monotherapy: 40 ± 81 vs 38 ± 95 m, P = .87; combination therapy: 53 ± 78 vs 64 ± 106 m, P = .511). Functional class improvements were also similar in both groups. REVEAL Registry 2.0 risk score effectively discriminated risk in both populations (C statistic = 0.756 for the PAH with LHD risk factors group and C statistic = 0.750 for the reference PAH group). There was no difference in survival between the two groups (log-rank test, P = .29). INTERPRETATION: In a real-world cohort, patients with PAH with LHD risk factors were less likely to be exposed to initial combination therapy. Nevertheless, selected patients with PAH with LHD risk factors who were treated with initial combination therapy derived similar functional response compared with the reference group. Further studies are needed to phenotype patients with PAH with cardiopulmonary comorbidities who may benefit from initial combination therapy.

What Are the Mortality, Infection, and Nonunion Rates After Periprosthetic Femoral Fractures in the United States?

BACKGROUND: Periprosthetic femoral fractures are a serious complication that put a high burden on patients. However, comprehensive analyses of their incidence, mortality, and complication rates based on large-registry data are scarce. QUESTIONS/PURPOSES: In this large-database study, we asked: (1) What is the incidence of periprosthetic femoral fractures in patients 65 years and older in the United States? (2) What are the rates of mortality, infection, and nonunion, and what factors are associated with these outcomes? METHODS: In this retrospective, comparative, large-database study, periprosthetic femoral fractures occurring between January 1, 2010, and December 31, 2019, were identified from Medicare physician service records encompassing services rendered in medical offices, clinics, hospitals, emergency departments, skilled nursing facilities, and other healthcare institutions from approximately 2.5 million enrollees. These were grouped into proximal, distal, and shaft fractures after TKA and THA. We calculated the incidence of periprosthetic femur fractures by year. Incidence rate ratios (IRR) were calculated by dividing the incidence in 2019 by the incidence in 2010. The Kaplan-Meier method with Fine and Gray subdistribution adaptation was used to calculate the cumulative incidence rates of mortality, infection, and nonunion. Semiparametric Cox regression was applied with 23 measures as covariates to determine factors associated with these outcomes. RESULTS: From 2010 to 2019, the incidence of periprosthetic femoral fractures increased steeply (TKA for distal fractures: IRR 3.3 [95% CI 1 to 9]; p = 0.02; THA for proximal fractures: IRR 2.3 [95% CI 1 to 4]; p = 0.01). One-year mortality rates were 23% (95% CI 18% to 28%) for distal fractures treated with THA, 21% (95% CI 19% to 24%) for proximal fractures treated with THA, 22% (95% CI 19% to 26%) for shaft fractures treated with THA, 21% (95% CI 18% to 25%) for distal fractures treated with TKA , 22% (95% CI 17% to 28%) for proximal fractures treated with TKA, and 24% (95% CI 19% to 29%) for shaft fractures treated with TKA. The 5-year mortality rate was 63% (95% CI 54% to 70%) for distal fractures treated with THA, 57% (95% CI 54% to 62%) for proximal fractures treated with THA, 58% (95% CI 52% to 63%) for shaft fractures treated with THA, 57% (95% CI 52% to 62%) for distal fractures treated with TKA , 57% (95% CI 49% to 65%) for proximal fractures treated with TKA, and 57% (95% CI 49% to 64%) for shaft fractures treated with TKA. Age older than 75 years, male sex, chronic obstructive pulmonary disease (HR 1.48 [95% CI 1.32 to 1.67] after THA and HR 1.45 [95% CI 1.20 to 1.74] after TKA), cerebrovascular disease after THA, chronic kidney disease (HR 1.28 [95% CI 1.12 to 1.46] after THA and HR 1.50 [95% CI 1.24 to 1.82] after TKA), diabetes mellitus, morbid obesity, osteoporosis, and rheumatoid arthritis were clinical risk factors for an increased risk of mortality. Within the first 2 years, fracture-related infections occurred in 5% (95% CI 4% to 7%) of patients who had distal fractures treated with THA, 5% [95% CI 5% to 6%]) of patients who had proximal fractures treated with THA, 6% (95% CI 5% to 7%) of patients who had shaft fractures treated with THA, 6% (95% CI 5% to 7%) of patients who had distal fractures treated with TKA , 7% (95% CI 5% to 9%) of patients who had proximal fractures treated with TKA, and 6% (95% CI 4% to 8%) of patients who had shaft fractures treated with TKA. Nonunion or malunion occurred in 3% (95% CI 2% to 4%) of patients with distal fractures treated with THA, 1% (95% CI 1% to 2%) of patients who had proximal fractures treated with THA, 2% (95% CI 1% to 3%) of patients who had shaft fractures treated with THA, 4% (95% CI 3% to 5%) of those who had distal fractures treated with TKA, , 2% (95% CI 1% to 4%) of those who had proximal fractures treated with TKA, and 3% (95% CI 2% to 4%) of those who had shaft fractures treated with TKA. CONCLUSION: An increasing number of periprosthetic fractures were observed during the investigated period. At 1 and 5 years after periprosthetic femur fracture, there was a substantial death rate in patients with Medicare. Conditions including cerebrovascular illness, chronic kidney disease, diabetes mellitus, morbid obesity, osteoporosis, and rheumatoid arthritis are among the risk factors for increased mortality. After the surgical care of periprosthetic femur fractures, the rates of fracture-related infection and nonunion were high, resulting in a serious risk to affected patients. Patient well-being can be enhanced by an interdisciplinary team in geriatric traumatology and should be improved to lower the risk of postoperative death. Additionally, it is important to ensure that surgical measures to prevent fracture-related infections are followed diligently. Furthermore, there is a need to continue improving implants and surgical techniques to avoid often-fatal complications such as fracture-associated infections and nonunion, which should be addressed in further studies. LEVEL OF EVIDENCE: Level III, therapeutic study.

Strikingly High Rates of Periprosthetic Joint Infection Following Revision Surgery for Periprosthetic Fractures Regardless of Surgery Timing.

BACKGROUND: Periprosthetic fractures following total hip arthroplasty (THA) often occur in the early postoperative period. Recent data has indicated that early revisions are associated with higher complication rates, particularly periprosthetic joint infection (PJI). The purpose of this study was to assess the effect of timing of periprosthetic fracture surgery on complication rates. We hypothesized that complication rates would be significantly higher in revision surgeries performed within 3 months of the index THA. METHODS: The Medicare Part A claims database was queried from 2010 to 2017 to identify patients who underwent surgery for a periprosthetic fracture following primary THA. Patients were divided based on time between index and revision surgeries: <1, 1 to 2, 2 to 3, 3 to 6, 6 to 9, 9 to 12, and >12 months. Complication rates were compared between groups using multivariate analyses to adjust for demographics, comorbidities, and types of revision surgery. RESULTS: Of 492,340 THAs identified, 4,368 (0.9%) had a subsequent periprosthetic fracture requiring surgery: 1,725 (39.4%) at <1 month, 693 (15.9%) at 1 to 2 months, 202 (4.6%) at 2 to 3 months, 250 (5.7%) at 3 to 6 months, 134 (3.1%) at 6 to 9 months, 85 (19.4%) at 9 to12 months, and 1,279 (29.3%) at >12 months. The risk of PJI was 11.0% in the <1 month group, 11.1% at 1 to 2 months, 7.9% at 2 to 3 months, 6.8% at 3 to 6 months, 8.2% at 6 to 9 months, 9.4% at 9 to 12 months, and 8.5% at >12 months (P = .12). Adjusting for confounding factors, risk of PJI following periprosthetic fracture surgery was similar regardless of timing (P > .05). Rates of subsequent dislocation and aseptic loosening were also similar regardless of timing. CONCLUSIONS: The risk of PJI following repeat surgery for a periprosthetic fracture was strikingly high regardless of timing (6.8 to 11.1%), underscoring the high-risk of complications.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.

Impact of cystic fibrosis multidisciplinary virtual clinics on patient experience, time commitments and costs.

BACKGROUND AND AIMS: The experience of outpatient care may differ for select patient groups. This prospective study evaluates the adult patient experience of multidisciplinary outpatient cystic fibrosis (CF) care with videoconferencing through telehealth compared with face-to-face care the year prior. METHODS: People with CF without a lung transplant were recruited. Patient-reported outcomes were obtained at commencement and 12 months into the study, reflecting both their face-to-face and telehealth through videoconferencing experience, respectively. Three patient cohorts were analysed: (i) participants with a regional residence, (ii) participants with a nonregional including metropolitan residence and (iii) participants with colonised multiresistant microbiota. RESULTS: Seventy-four patients were enrolled in the study (mean age, 37 ± 11 years; 50% male; mean forced expiratory volume in the first second of expiration, 60% [standard deviation, 23]) between February 2020 and May 2021. No differences between models were observed in the participants' rating of the health care team, general and mental health rating, and their confidence in handling treatment plans at home. No between-group differences in the Cystic Fibrosis Questionnaire - Revised (CFQ-R) were observed. Travel duration and the cost of attending a clinic was significantly reduced, particularly for the regional group (4 h, AU$108 per clinic; P < 0.05). A total of 93% respondents preferred to continue with a hybrid approach. CONCLUSION: In this pilot study, participants' experience of care and quality of life were no different with face-to-face and virtual care between the groups. Time and cost-savings, particularly for patients living in regional areas, were observed. Most participants preferred to continue with a hybrid model for outpatient care.

Complications and associated risk factors after surgical management of proximal femoral fractures.

Aims: This work aimed at answering the following research questions: 1) What is the rate of mechanical complications, nonunion and infection for head/neck femoral fractures, intertrochanteric fractures, and subtrochanteric fractures in the elderly USA population? and 2) Which factors influence adverse outcomes? Methods: Proximal femoral fractures occurred between 1 January 2009 and 31 December 2019 were identified from the Medicare Physician Service Records Data Base. The Kaplan-Meier method with Fine and Gray sub-distribution adaptation was used to determine rates for nonunion, infection, and mechanical complications. Semiparametric Cox regression model was applied incorporating 23 measures as covariates to identify risk factors. Results: Union failure occured in 0.89% (95% confidence interval (CI) 0.83 to 0.95) after head/neck fracturs, in 0.92% (95% CI 0.84 to 1.01) after intertrochanteric fracture and in 1.99% (95% CI 1.69 to 2.33) after subtrochanteric fractures within 24 months. A fracture-related infection was more likely to occur after subtrochanteric fractures than after head/neck fractures (1.64% vs 1.59%, hazard ratio (HR) 1.01 (95% CI 0.87 to 1.17); p < 0.001) as well as after intertrochanteric fractures (1.64% vs 1.13%, HR 1.31 (95% CI 1.12 to 1.52); p < 0.001). Anticoagulant use, cerebrovascular disease, a concomitant fracture, diabetes mellitus, hypertension, obesity, open fracture, and rheumatoid disease was identified as risk factors. Mechanical complications after 24 months were most common after head/neck fractures with 3.52% (95% CI 3.41 to 3.64; currently at risk: 48,282). Conclusion: The determination of complication rates for each fracture type can be useful for informed patient-clinician communication. Risk factors for complications could be identified for distinct proximal femur fractures in elderly patients, which are accessible for therapeutical treatment in the management.

Epidemiology and treatment of proximal femoral fractures in the elderly U.S. population.

Proximal femoral fractures are a serious complication, especially for elderly patients. Detailed epidemiological analyzes provide a valuable resource for stakeholders in the health care system in order to foresee future development possibly influenceable by adaption of therapeutic procedures and prevention strategies. This work aimed at answering the following research questions: (1) What are the incidence rates of proximal femoral fractures in the elderly U.S. population? (2) What is the preferred treatment procedure for these fractures? Proximal femoral fractures occurred between January 1, 2009 and December 31, 2019 in patients ≥ 65 years were identified from the Medicare Physician Service Records Data Base. The 5% sample of Medicare beneficiaries, equivalent to the records from approximately 2.5 million enrollees formed the basis of this study. Fractures were grouped into head/neck, intertrochanteric, and subtrochanteric fractures. The overall incidence rate, age and sex specific incidence rates as well as incidence rate ratios were calculated. Common Procedural Terminology (CPT) codes were used to identify procedures and operations. In 2019, a total number of 7982 femoral head/neck fractures was recorded. In comparison to 9588 cases in 2009, the incidence substantially decreased by 26.6% from 666.7/100,000 inhabitants to 489.3/100,000 inhabitants (z = - 5.197, p < 0.001). Also, in intertrochanteric fractures, a significant decline in the incidence by 17.3% was evident over the years from 367.7/100,000 inhabitants in 2009 to 304.0 cases per 100,000 inhabitants in 2019 (z = - 2.454, p = 0.014). A similar picture was observable for subtrochanteric fractures, which decreased by 29.6% (51.0 cases per 100,000 to 35.9 cases per 100,000) over the time period (z = - 1.612, p = 0.107). Head/neck fractures were mainly treated with an arthroplasty (n = 36,301, 40.0%). The majority of intertrochanteric fractures and subtrochanteric fractures received treatment with an intramedullary device (n = 34,630, 65.5% and n = 5870, 77.1%, respectively). The analysis indicated that the incidence of all types of proximal femoral neck fractures decreased for the population of elderly patients in the U.S. within the last decade. Treatment of head and neck fractures was mainly conducted through arthroplasty, while intertrochanteric and subtrochanteric fractures predominantly received an intramedullary nailing.

Factors associated with mortality after proximal femoral fracture.

Proximal femoral fractures are a serious complication, especially for elderly patients. Therefore, we have aimed to answer the following research question: What is the postfracture mortality rate in the elderly population and what are associated risk factors? For this, proximal femoral fractures that occurred between 1 January 2009 and 31 December 2019 were identified from the Medicare Physician Service Records database. The Kaplan-Meier (KM) method with the Fine and Gray subdistribution adaptation was used to determine rates of mortality. A semiparametric Cox regression model was applied, incorporating 23 measures as covariates to identify risk factors. The estimated 1 year mortality rate was 26.8% after head/neck fracture, 28.2% after intertrochanteric fracture, and 24.2% after subtrochanteric fracture. Male sex, age over 70 years, chronic obstructive pulmonary disease (COPD), cerebrovascular disease, chronic kidney disease, a concomitant fracture, congestive heart failure, diabetes mellitus, hypertension, insulin use, ischemic heart disease, morbid obesity, osteoporosis, tobacco dependence, and median household income were determined as risk factors for increased mortality. An early assessment of individual risk factors accessible for therapeutic treatment is crucial in the management of proximal femur fractures to aid in attempts at reducing the high mortality apparent in the elderly US population.

Proximal Humerus Fractures in the Elderly U.S. Population: A Cross-Sectional Study of Treatment Trends and Comparison of Complication Rates after Joint Replacement, Open Reduction and Internal Fixation, and Non-Surgical Management.

Proximal humerus fracture (PHF) treatment remains challenging. Multiple therapy options exist, and the optimal choice of management has been increasingly discussed in the literature. The aim of this study was to (1) analyze trends in the propensity of proximal humerus fracture treatments and (2) compare complication rates after joint replacement, surgical repair, and non-surgical treatment in terms of mechanical complications, union failure, and infection rates. In this cross-sectional study, patients aged 65 years or older with proximal humerus fractures occurring between 1 January 2009 and 31 December 2019 were identified from Medicare physician service claims records. The Kaplan-Meier method with the Fine and Gray adjustment was used to calculate the cumulative incidence rates for malunion/nonunion, infection, and mechanical complications for the following treatment categories: shoulder arthroplasty, open reduction and internal fixation (ORIF), and non-surgical treatment, respectively. Semiparametric Cox regression was performed incorporating 23 demographic, clinical, and socioeconomic covariates to determine risk factors. Between 2009 through 2019, conservative procedures decreased by 0.9%. ORIF procedures decreased from 9.51% (95% CI: 8.7-10.4) to 6.95% (95% CI: 6.2-7.7), whereas shoulder arthroplasties rose from 1.99% (95% CI: 1.6-2.4), to 5.45% (95% CI: 4.8-6.2). PHFs managed through ORIF were associated with higher union failure rates compared to conservatively treated fractures (HR = 1.31, 95% CI: 1.15-1.5, p < 0.001). The risk of developing an infection was increased after joint replacement compared to ORIF (2.66% vs. 1.09%, HR = 2.09, 95% CI: 1.46-2.98, p < 0.001). Mechanical complications were more common after joint replacement (6.37% vs. 4.85%, HR = 1.66, 95% CI: 1.32-2.09, p < 0.001). Complication rates differed significantly across treatment modalities. This should be considered when choosing a management procedure. Vulnerable elderly patient cohorts could be identified, and the optimization of modifiable risk factors might lead to a decrease of complication rates in both surgically and non-surgically treated patients.

Femoral shaft fractures in eldery patients - An epidemiological risk analysis of incidence, mortality and complications.

OBJECTIVES: This work aimed at answering the following research questions: (1) What is the incidence of femoral shaft fractures in the geriatric population in the U.S.? (2) What is the rate of mortality, mechanical complications, nonunion and infection, and what are the associated risk factors? STUDY DESIGN AND SETTING: In this cross-sectional study, femoral shaft fractures occurred between January 1, 2009, and December 31, 2019, were identified from Medicare records. Rates of mortality, nonunion, infection, and mechanical complications were calculated with the Kaplan-Meier method with Fine and Gray sub-distribution adaptation. Semiparametric Cox regression was applied with twenty-three covariates to determine risk factors. RESULTS: Between 2009 through 2019 the incidence of femoral shaft fractures decreased by 12.07% to 40.8/100,000 inhabitants (p = 0.549). The 5-year mortality risk was 58.5%. Male sex, age over 75 years, chronic obstructive pulmonary disease, cerebrovascular disease, chronic kidney disease, congestive heart failure, diabetes mellitus, osteoporosis, tobacco dependence, and lower median household income were significant risk factors. The infection rate was 2.22% [95%CI: 1.90-2.58] and the union failure rate 2.52% [95%CI: 2.17-2.92] after 24 months. CONCLUSION: An early assessment of individual patient risk factors may be beneficial in the care and treatment of patients with these fractures.

Characteristic changes to pulsatile and steady-state load according to pulmonary hypertension classification.

It is of increasing importance to understand and predict changes to the systemic and pulmonary circulations in pulmonary hypertension (PH). To do so, it is necessary to describe the circulation in complete quantitative terms. Characteristic impedance (Zc) expresses opposition of the circulation to pulsatile blood flow. Evaluation of systemic and pulmonary Zc relationships according to PH classification has not previously been described. Prospective study of 40 clinically indicated patients referred for CMR and RHC (56 ± 18 years; 70% females, eight mPAP ≤ 25 mmHg, 16 pre-capillary [Pre-cPH], eight combined pre- and post-capillary [Cpc-PH] and eight isolated left-heart disease [Ipc-PH]). CMR provided assessment of ascending aortic (Ao) and pulmonary arterial (PA) flow, and RHC, central Ao and PA pressure. Systemic and pulmonary Zc were expressed as the relationship of pressure to flow in the frequency domain. Baseline demographic characteristics were well-matched across PH subclasses. In those with a mPAP ≤25mHg, systemic Zc and SVR were >2 times higher than pulmonary Zc and PVR. Only Pre-cPH was associated with inverse pulsatile (systemic Zc 58 [45-69] vs pulmonary Zc 70 [58-85]), but not steady-state (SVR 1101 [986-1752] vs. PVR 483 [409-557]) relationships. Patients with CpcPH and IpcPH had concordant pulsatile and steady-state relationships (Graphical Abstract). Measurement of, and the relationship between, systemic and pulmonary Zc in patients according to PH sub-classification has not previously been described. Systemic Zc was routinely higher than pulmonary Zc, except in patients with newly diagnosed Pre-cPH, where inverse pulsatile but not steady-state relationships were observed.

Prognostic role of pulmonary impedance estimation to predict right ventricular dysfunction in pulmonary hypertension.

BACKGROUND: The effect of pulmonary hypertension (PH) on right ventricular (RV) afterload is commonly defined by elevation of pulmonary artery (PA) pressure or pulmonary vascular resistance (PVR). In humans however, one-third to half of the hydraulic power in the PA is contained in pulsatile components of flow. Pulmonary impedance (Zc) expresses opposition of the PA to pulsatile blood flow. We evaluate pulmonary Zc relationships according to PH classification using a cardiac magnetic resonance (CMR)/right heart catheterization (RHC) method. METHODS: Prospective study of 70 clinically indicated patients referred for same-day CMR and RHC [60 ± 16 years; 77% females, 16 mPAP <25 mmHg (PVR <240 dynes.s.cm-5 /mPCWP <15 mmHg), 24 pre-capillary (PrecPH), 15 isolated post-capillary (IpcPH), 15 combined pre-capillary/post-capillary (CpcPH)]. CMR provided assessment of PA flow, and RHC, central PA pressure. Pulmonary Zc was expressed as the relationship of PA pressure to flow in the frequency domain (dynes.s.cm-5 ). RESULTS: Baseline demographic characteristics were well matched. There was a significant difference in mPAP (P < 0.001), PVR (P = 0.001), and pulmonary Zc between mPAP<25 mmHg patients and those with PH (mPAP <25 mmHg: 47 ± 19 dynes.s.cm-5 ; PrecPH 86 ± 20 dynes.s.cm-5 ; IpcPH 66 ± 30 dynes.s.cm-5 ; CpcPH 86 ± 39 dynes.s.cm-5 ; P = 0.05). For all patients with PH, elevated mPAP was found to be associated with raised PVR (P < 0.001) but not with pulmonary Zc (P = 0.87), except for those with PrecPH (P < 0.001). Elevated pulmonary Zc was associated with reduced RVSWI, RVEF, and CO (all P < 0.05), whereas PVR and mPAP were not. CONCLUSIONS: Raised pulmonary Zc was independent of elevated mPAP in patients with PH and more strongly predictive of maladaptive RV remodelling than PVR and mPAP. Use of this straightforward method to determine pulmonary Zc may help to better characterize pulsatile components of RV afterload in patients with PH than mPAP or PVR alone.

ß3 adrenergic agonism: A novel pathway which improves right ventricular-pulmonary arterial hemodynamics in pulmonary arterial hypertension.

Efficacy of therapies that target the downstream nitric oxide (NO) pathway in pulmonary arterial hypertension (PAH) depends on the bioavailability of NO. Reduced NO level in PAH is secondary to "uncoupling" of endothelial nitric oxide synthase (eNOS). Stimulation of ß3 adrenergic receptors (ß3 ARs) may lead to the recoupling of NOS and therefore be beneficial in PAH. We aimed to examine the efficacy of ß3 AR agonism as a novel pathway in experimental PAH. In hypoxia (5 weeks) and Sugen hypoxia (hypoxia for 5 weeks + SU5416 injection) models of PAH, we examined the effects of the selective ß3 AR agonist CL316243. We measured echocardiographic indices and invasive right ventricular (RV)-pulmonary arterial (PA) hemodynamics and compared CL316243 with riociguat and sildenafil. We assessed treatment effects on RV-PA remodeling, oxidative stress, and eNOS glutathionylation, an oxidative modification that uncouples eNOS. Compared with normoxic mice, RV systolic pressure was increased in the control hypoxic mice (p < 0.0001) and Sugen hypoxic mice (p < 0.0001). CL316243 reduced RV systolic pressure, to a similar degree to riociguat and sildenafil, in both hypoxia (p < 0.0001) and Sugen hypoxia models (p < 0.03). CL316243 reversed pulmonary vascular remodeling, decreased RV afterload, improved RV-PA coupling efficiency and reduced RV stiffness, hypertrophy, and fibrosis. Although all treatments decreased oxidative stress, CL316243 significantly reduced eNOS glutathionylation. ß3 AR stimulation improved RV hemodynamics and led to beneficial RV-PA remodeling in experimental models of PAH. ß3 AR agonists may be effective therapies in PAH.

Proximal humerus fractures - epidemiology, comparison of mortality rates after surgical versus non-surgical treatment, and analysis of risk factors based on Medicare registry data.

AIMS: The optimal choice of management for proximal humerus fractures (PHFs) has been increasingly discussed in the literature, and this work aimed to answer the following questions: 1) what are the incidence rates of PHF in the geriatric population in the USA; 2) what is the mortality rate after PHF in the elderly population, specifically for distinct treatment procedures; and 3) what factors influence the mortality rate? METHODS: PHFs occurring between 1 January 2009 and 31 December 2019 were identified from the Medicare physician service records. Incidence rates were determined, mortality rates were calculated, and semiparametric Cox regression was applied, incorporating 23 demographic, clinical, and socioeconomic covariates, to compare the mortality risk between treatments. RESULTS: From 2009 to 2019, the incidence decreased by 11.85% from 300.4 cases/100,000 enrollees to 266.3 cases/100,000 enrollees, although this was not statistically significant (z = -1.47, p = 0.142). In comparison to matched Medicare patients without a PHF, but of the same five-year age group and sex, a mean survival difference of -17.3% was observed. The one-year mortality rate was higher after nonoperative treatment with 16.4% compared to surgical treatment with 9.3% (hazard ratio (HR) = 1.29, 95% confidence interval (CI) 1.23 to 1.36; p < 0.001) and to shoulder arthroplasty with 7.4% (HR = 1.45, 95% CI 1.33 to 1.58; p < 0.001). Statistically significant mortality risk factors after operative treatment included age older than 75 years, male sex, chronic obstructive pulmonary disease (COPD), cerebrovascular disease, chronic kidney disease, a concomitant fracture, congestive heart failure, and osteoporotic fracture. CONCLUSION: Mortality risk factors for distinct treatment modes after PHF in elderly patients could be identified, which may guide clinical decision-making.Cite this article: Bone Joint Res 2023;12(2):103-112.

Acute Vasoreactivity Testing and Outcomes in Pulmonary Arterial Hypertension: A Call for Increased Testing.

BACKGROUND: Pulmonary arterial hypertension (PAH) has a progressive, unremitting clinical course. Vasoreactivity testing (VdT) during right heart catheterisation (RHC) identifies a subgroup with excellent long-term response to calcium channel blockade (CCB). Reporting on these patients is limited. Established in 2011, the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry offers the opportunity to assess the frequency of VdT during RHC, treatment and follow up of PAH patients. METHODS: Registry data from 3,972 PAH patients with index RHC revealed 1,194 VdT appropriate patients. Data was analysed in three groups: 1) VdT+CCB+: VdT positive, CCB treated; 2) VdT+CCB-: VdT positive, no CCB prescribed, 3) VdT-/noVdT: VdT negative, or VdT not tested. Data was reviewed for adherence to guidelines, clinical response (World Health Organization functional class [WHO FC], 6-minute-walk-distance [6MWD], RHC), and outcomes (survival or lung transplantation). RESULTS: Patients included had idiopathic (IPAH=1,087), heritable (HPAH=67) and drug or toxin-induced PAH (DPAH=40). A VdT was performed in 22% (268/1,194), with incomplete data in 26% (70/268); 28% (55/198) were VdT+. Analysis group allocation was: VdT+CCB+ (33/55), VdT+CCB- (22/55), VdT- (143)/noVdT (996). From patients with 1-year data VdT+CCB+ and VdT-/noVdT patients improved WHO FC, 6MWD and cardiac index (CI); VdT+CCB- data remained similar. Within the VdT+CCB+ group, 30% (10/33) were long-term CCB responders with a 100% 5-year survival; non-responders had a 61% survival at 5.4 years. Long-term responders were younger at diagnosis (40 yrs vs 54 yrs). CONCLUSION: Use of VdT testing and documentation is poor in this contemporary patient cohort. Nonetheless, survival in VdT+CCB+ patients from the PHSANZ registry is excellent, supporting guidelines promoting VdT testing. Strategies to promote the use of VdT are warranted.