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Rationale: Iron deficiency, in the absence of anemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin concentrations. The safety and benefit of parenteral iron replacement in this patient population is unclear. Objectives: To evaluate the safety and efficacy of parenteral iron replacement in PAH. Methods: In two randomized, double-blind, placebo-controlled 12-week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject) (1,000 mg or 15 mg/kg if weight

Biodynamic agriculture as a form of alternative agriculture dates to a series of lectures delivered by philosopher Rudolf Steiner in 1924 at Schloss Koberwitz (then in Germany now Kobierzyce in Poland). In 2019 biodynamic agriculture occupies some 190,000ha in 55 countries, though nearly half remains concentrated in Germany. This paper explores the introduction of biodynamic agriculture principles and practices to New Zealand in the 1920s and 1930s.

Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. We identified 155 patients—71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I–III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Case series Patient: Female, 29 • Female, 69 • Female, 52 • Female, 71 • Male, 62 • Female, 67 Final Diagnosis: Neuroendocrine carcinoma Symptoms: Abdominal pain Medication: — Clinical Procedure: — Specialty: Oncology Objective: Unusual clinical course Background: Neuroendocrine tumors (NETs) encompass a diverse group of varying clinicopathological entities arising from cells of the endocrine and nervous systems. The presentation of these unique tumors can range from occult disease discovered incidentally to hyperactive, metastatic secretory tumors. NETs most commonly originate in the gastrointestinal and respiratory tract, although they may occur at any site in the body due to the wide distribution of neuroendocrine cells. Their classification system is complex and continues to evolve, and the current system uses histological grade in defining these subtypes. Neuroendocrine carcinomas (NECs), or high-grade, poorly-differentiated NETs, are the most aggressive subtype. Surgical resection remains the primary treatment modality and may be curative, thus early diagnosis is paramount. Management of advanced NETs remains both a diagnostic and therapeutic challenge; however, advances in our understanding of these unique neoplasms as well as an evolving classification system has led to the development of adjunctive therapeutic approaches aimed to minimize morbidity and improve patient outcomes. Case Report: We present 6 cases of unusual sites of high-grade neuroendocrine carcinomas involving the cervix, gallbladder, oesophagus, ovary, prostate, and urinary bladder. Conclusions: Our case series highlights the heterogenous and aggressive nature of this subtype of NETs as well as their diagnostic and therapeutic difficulties. We also review the evolution of the NET classification system and its impact on the management of these malignancies.

Young women with breast cancer (YWBC) represent 7–12% of breast cancer diagnoses and ostensibly have more biologically aggressive subtypes with higher relapse and mortality rates. We studied the clinical and pathological characteristics in YWBC and examined how outcomes and treatment have evolved. YWBC were identified from pathology databases at two tertiary centers. Patients were divided into two cohorts: those diagnosed from 2000 to 2005 (C1) and from 2006 to 2015 (C2). Data were retrieved from clinical, radiology, and histology databases. Statistical analysis was performed using R® (V3.2.0). We identified 345 patients. Median age was 36 years (23–39 years). Mastectomy was performed in 232 patients (67.2%) and axillary lymph node clearance (ALNC) in 207 patients (60% [C1 82.7 vs. C2: 49.4%, p

BackgroundT cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor expressed on T cells, including regulatory T cells (Tregs) and natural killer (NK) cells. In the tumor microenvironment, TIGIT is often overexpressed and directly inhibits both T cell and NK cell effector function and proliferation. TIGIT is also involved in regulating Treg function. Therefore, inhibiting the TIGIT-related immunosuppressive pathway may result in antitumor activity. M6223 is an intravenously (IV) administered, human, antagonistic, immunoglobulin G1 (IgG1) anti-TIGIT antibody with an Fc mediated effector region. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (a TGFβ ”trap”) fused to a human IgG1 monoclonal antibody blocking programed death ligand 1 (PD-L1). As TIGIT and programed death receptor 1 (PD-1) are co-expressed on T cells, dual inhibition of both immune checkpoints may enhance antitumor activity. This phase Ia study (NCT04457778) aims to determine the safety, tolerability, maximum tolerated dose and recommended dose for expansion of M6223 monotherapy and M6223 (both the once every 2 weeks [Q2W] and once every 3 weeks [Q3W] regimens) in combination with bintrafusp alfa. Secondary objectives include the evaluation of pharmacokinetics and clinical activity of M6223 with and without bintrafusp alfa.MethodsEligible patients include those aged ≥18 years with: an Eastern Cooperative Oncology Group performance status ≤1; adequate baseline hematological, renal and hepatic function; and histologically or cytologically proven locally advanced or advanced solid tumors, for which no effective standard therapy is available. Patients previously treated with a TIGIT targeting agent or bintrafusp alfa are excluded. Patients with brain metastases are also excluded, except those without neurological symptoms ≥4 weeks before start of treatment and those receiving either a stable or decreasing dose of steroids AcknowledgementsThe authors would like to thank Daniel Holland of the healthcare business of Merck KGaA, Darmstadt, Germany for his involvement and contribution to the design and conduct of this study. Medical writing assistance was provided by David Lester of Bioscript Stirling Ltd, Macclesfield, UK, and funded by the healthcare business of Merck KGaA, Darmstadt, Germany [CrossRef Funder ID: 10.13039/100009945].Funding: The healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).Trial RegistrationNCT04457778Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site. All patients provided written informed consent before any study procedures were performed.

Major growth in rail traffic in many parts of the world in recent years has brought railway networks close to capacity and restricted the time available for track access to carry out maintenance work without costly temporary route closures. There are, therefore, significant benefits in designing or modifying ballasted track systems to reduce maintenance and associated access requirements. Under sleeper pads (USPs) offer the potential to extend ballasted track system life and to extend the intervals between routine maintenance. This paper presents and evaluates field measurements, made using geophones and high speed filming with digital image correlation (DIC), of the performance of a renewed section of track incorporating two switches and crossings (S&C) over a period of two years. One S&C was fitted with two types of USP (categorised as medium and soft), while the other had no USPs and acted as a control. Measurements demonstrate that the bearers with USPs fitted showed less variability in movement than bearers without USPs fitted. The provision of soft USPs caused large increases (>40%) in vertical bearer movements relative to bearers without USPs, although the medium USPs showed little difference. Increased movements of elongated bearers supporting both tracks fitted with soft USPs led to increased bearer rotations towards the loaded track. This effect was aided by the rigid steel collar fixing in the middle of the bearer used in this design of S&C, and raises questions concerning the desirability of this feature. DIC measurements showed that the at rest position of the elongated bearers rotated towards the track on which a train had most recently passed.

Applying machine learning of complex motion phenotypes obtained from cardiac MR images allows more accurate prediction of patient outcomes in pulmonary hypertension., Purpose To determine if patient survival and mechanisms of right ventricular failure in pulmonary hypertension could be predicted by using supervised machine learning of three-dimensional patterns of systolic cardiac motion. Materials and Methods The study was approved by a research ethics committee, and participants gave written informed consent. Two hundred fifty-six patients (143 women; mean age ± standard deviation, 63 years ± 17) with newly diagnosed pulmonary hypertension underwent cardiac magnetic resonance (MR) imaging, right-sided heart catheterization, and 6-minute walk testing with a median follow-up of 4.0 years. Semiautomated segmentation of short-axis cine images was used to create a three-dimensional model of right ventricular motion. Supervised principal components analysis was used to identify patterns of systolic motion that were most strongly predictive of survival. Survival prediction was assessed by using difference in median survival time and area under the curve with time-dependent receiver operating characteristic analysis for 1-year survival. Results At the end of follow-up, 36% of patients (93 of 256) died, and one underwent lung transplantation. Poor outcome was predicted by a loss of effective contraction in the septum and free wall, coupled with reduced basal longitudinal motion. When added to conventional imaging and hemodynamic, functional, and clinical markers, three-dimensional cardiac motion improved survival prediction (area under the receiver operating characteristic curve, 0.73 vs 0.60, respectively; P < .001) and provided greater differentiation according to difference in median survival time between high- and low-risk groups (13.8 vs 10.7 years, respectively; P < .001). Conclusion A machine-learning survival model that uses three-dimensional cardiac motion predicts outcome independent of conventional risk factors in patients with newly diagnosed pulmonary hypertension. Online supplemental material is available for this article.

Background: Iron deficiency in the absence of anaemia is common in patients with idiopathic pulmonary arterial hypertension (IPAH). It has been associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis and correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Methods: Iron-deficient patients (defined as ferritin 28.1nmol/L) were randomised to receive a single infusion of ferric carboxymaltose (FCM) 15 mg/kg up to 1000mg or saline placebo with cross-over after 12 weeks of treatment. The primary outcome was change in endurance time on cardio-pulmonary exercise testing (CPET) at 12 weeks. Secondary measures included resting haemodynamics, incremental CPET, iron indices, 6 minute walk distance, WHO functional class, quality of life score, NT-proBNP and cardiac anatomy and function from MRI. Results: 40 patients enrolled and 39 provided data for analysis. FCM improved iron indices, with a significant increase in ferritin (P=0.0003) and reduction in soluble transferrin receptor levels (P Conclusion: Iron repletion through a single infusion of FCM improves iron indices and is well tolerated but does not improve exercise capacity in PAH.

This study compares the theoretical information content of single- and multi-compartment models of diffusion-weighted signal attenuation in prostate tissue. Diffusion-weighted imaging (DWI) was performed at 9.4 T with multiple diffusion times and an extended range of b values in four whole formalin-fixed prostates. Ten models, including different combinations of isotropic, anisotropic and restricted components, were tested. Models were ranked using the Akaike information criterion. In all four prostates, two-component models, comprising an anisotropic Gaussian component and an isotropic restricted component, ranked highest in the majority of voxels. Single-component models, whether isotropic (apparent diffusion coefficient, ADC) or anisotropic (diffusion tensor imaging, DTI), consistently ranked lower than multi-component models. Model ranking trends were independent of voxel size and maximum b value in the range tested (1.6-16 mm(3) and 3000-10,000 s/mm(2)). This study characterizes the two major water components previously identified by biexponential models and shows that models incorporating both anisotropic and restricted components provide more information-rich descriptions of DWI signals in prostate tissue than single- or multi-component anisotropic models and models that do not account for restricted diffusion.

Introduction: Significant obesity is an increasing co-morbidity in pulmonary hypertension (PH). We note many patients with echo features of pre-capillary PH (PrePH) who were being classified as post-capillary PH (PostPH), due to elevated pulmonary wedge pressure (PWP). We wished to assess the impact of intrathoracic pressure (ITP) measurements on haemodynamics during artificial alterations of ITP in obese patients and on classification. Methods: Obese individuals underwent invasive cardiac cath and intra-oesophageal pressure (IOP) measurements. Haemodynamics were measured during end-expiration, Valsalva and external compression of the abdomen. Fluid challenge was administered in selected patients. Results: 17 patients underwent investigation between Jan ‘13 and Dec ’16. There was a direct 1:1 linear relationship between ITP, as assessed by IOP, and wedge pressure (PWP) (Fig 1A). There was a tight relationship between IOB and PWP during manoeuvres (Valsalva, 1B; external compression, 1C). Following fluid, PWP rose by 4 mmHg. 14/17 patients were classified as PostPH, but following correction for expected ITP (4mmHg), only 3/17 were classified as PostPH (1D). Conclusions: ITP has a 1:1 relationship on PWP. We show that this may frequently result in misclassification of patients as PostPH who have echo features of PrePH and whose PWP does not change significant with fluid challenge.

Introduction: Lung cancer is a leading cause of morbidity and mortality worldwide. Patients with lung cancer may experience a plethora of symptoms, which can be debilitating and affect their quality of life. Palliative care input to manage their physical and psychological well-being is a crucial component of their oncological care. The benefit of early palliative care input has been shown in patients with non-small cell lung cancer; however, data pertaining to patients with small-cell lung cancer are scarce. Nevertheless, early palliative care input is recommended by several national and international guidelines. Thus, we aimed to assess the time to palliative care referrals in patients diagnosed with small-cell lung cancer in an Irish tertiary hospital and to determine what impact this had on overall survival. Methods: We performed a retrospective, single-center audit of all patients diagnosed with extensive stage small-cell lung cancer over a 6-year period in an Irish tertiary hospital. Results: Overall, 91 patients were identified. Median age at diagnosis was 66 years (range: 38-83 years). The median Eastern Cooperative Oncology Group Performance Status at diagnosis was 1 (range: 0-3); 24 (26%) patients had multiple sites of distant metastasis at diagnosis; 45 (49.5%) patients were alive at 6 months, and 15 (16.5%) patients were alive at 12 months. One hundred percent of patients received palliative care input in our center over the course of their care. In the patients alive at 6 months after diagnosis, there was no survival advantage in those receiving palliative care within 1 month ( P = .002, odd ratio: 0.23, 95% confidence interval: 0.09-0.59). Conclusion: Palliative care treatment is a critical aspect in the oncological treatment of all patients diagnosed with advanced cancer, and this study highlights good compliance with existing national guidelines. Further research focusing on quality-of-life issues with the use of questionnaires to assess physical and psychological symptoms should be performed to further understand the impact of palliative care in these patients.

Purpose To investigate diffusion anisotropy in whole human prostate specimens Methods Seven whole radical prostatectomy specimens were obtained with informed patient consent and institutional ethics approval. Diffusion tensor imaging was performed at 9.4 Tesla. Diffusion tensors were calculated from the native acquired data and after progressive downsampling Results Fractional anisotropy (FA) decreased as voxel volume increased, and differed widely between prostates. Fixation decreased mean FA by ∼0.05–0.08 at all voxel volumes but did not alter principle eigenvector orientation. In unfixed tissue high FA (> 0.6) was found only in voxels of volume 0.25. FA decreased at longer diffusion times (Δ = 60 or 80 ms compared with 20 ms), but only by ∼0.02 at typical clinical voxel volume. Peripheral zone FA was significantly lower than transition zone FA in five of the seven prostates Conclusion FA varies widely between prostates. The very small proportion of clinical size voxels with high FA suggests that in clinical DWI studies ADC based on three-direction measurements will be minimally affected by anisotropy. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Non-Gaussian diffusion dynamics was investigated in the two distinct water populations identified by a biexponential model of diffusion in prostate tissue. Diffusion-weighted MRI (DWI) signal attenuation was measured ex vivo in two formalin-fixed prostates at 9.4 T with diffusion times Δ = 10, 20 and 40 ms, and b values in the range 0.017–8.2 ms/µm2. A conventional biexponential model was compared with models in which either the lower diffusivity component or both of the components of the biexponential were stretched. Models were compared using Akaike's Information Criterion (AIC) and a leave-one-out (LOO) test of model prediction accuracy. The doubly stretched (SS) model had the highest LOO prediction accuracy and lowest AIC (highest information content) in the majority of voxels at Δ = 10 and 20 ms. The lower diffusivity stretching factor (α2) of the SS model was consistently lower (range ~0.3–0.9) than the higher diffusivity stretching factor (α1, range ~0.7–1.1), indicating a high degree of diffusion heterogeneity in the lower diffusivity environment, and nearly Gaussian diffusion in the higher diffusivity environment. Stretched biexponential models demonstrate that, in prostate tissue, the two distinct water populations identified by the simple biexponential model individually exhibit non-Gaussian diffusion dynamics. Copyright © 2015 John Wiley & Sons, Ltd.

BackgroundIn contrast to systemic hypertension, the significance of arterial waves in pulmonary hypertension (PH) is not well understood. We hypothesized that arterial wave energy and wave reflection are augmented inPHand that wave behavior differs between patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).Methods and ResultsRight heart catheterization was performed using a pressure and Doppler flow sensor–tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery. Wave intensity analysis was subsequently applied to the acquired data. Ten control participants, 11 patients withPAH, and 10 patients withCTEPHwere studied. Wave speed and wave power were significantly greater inPHpatients compared with controls, indicating increased arterial stiffness and right ventricular work, respectively. The ratio of wave power to mean right ventricular power was lower inPAHpatients thanCTEPHpatients and controls. Wave reflection index inPHpatients (PAH: ≈25%;CTEPH: ≈30%) was significantly greater compared with controls (≈4%), indicating downstream vascular impedance mismatch. Although wave speed was significantly correlated to disease severity, wave reflection indexes of patients with mildly and severely elevated pulmonary pressures were similar.ConclusionsWave reflection in the pulmonary artery increased in PH and was unrelated to severity, suggesting that vascular impedance mismatch occurs early in the development of pulmonary vascular disease. The lower wave power fraction inPAHcompared withCTEPHindicates differences in the intrinsic and/or extrinsic ventricular load between the 2 diseases.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.

Visual Abstract, Highlights • The effects of apelin on pulmonary hemodynamics in patients with PAH are unknown. • Systemic infusion caused a significant reduction in pulmonary vascular resistance and increase in cardiac output without a change in heart rate or systemic vascular resistance. • This effect was most prominent in the subgroup of patients receiving concomitant PDE5 inhibition. • Apelin agonism is a novel potential therapeutic target for PAH., Summary Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr1)apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr1)apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170)

Background: Identifying the optimal starting point for intramedullary fixation of tibia and femur fractures is well described in the literature using a retrograde or anterograde technique. This technique has not been applied to the fifth metatarsal, where screw trajectory can cause iatrogenic malreduction. The generally accepted starting point for the fifth metatarsal is “high and inside” to accommodate the fifth metatarsal’s dorsal apex and medial curvature. We used a retrograde technique to identify the optimal starting position for intramedullary fixation of fifth metatarsal fractures. Methods: Five matched cadaveric lower extremity pairs were dissected to the fifth metatarsal neck. An osteotomy was made to access the intramedullary canal. A retrograde reamer was passed to the base of the fifth metatarsal to ascertain the ideal entry point. Distances from each major structure on the lateral aspect of the foot were measured. Computed tomography scans helped assess base edge measurements. Results: In 6 of 10 specimens, the retrograde reamer hit the cuboid with a cuboid invasion averaging 0.7 mm. The peroneus brevis and longus were closest to the starting position with an average distance of 5.1 mm and 5.7 mm, respectively. Distances from the entry point to the dorsal, plantar, medial, and lateral edges of the metatarsal base were 8.3 mm, 6.9 mm, 9.7 mm, and 9.7 mm, respectively. Conclusion: Optimal starting position was found to be essentially at the center of the base of the fifth metatarsal at the lateral margin of the cartilage. Osteoplasty of the cuboid or forefoot adduction may be required to gain access to this site. Clinical Relevance: This study evaluated the ideal starting position for screw placement of zone II base of the fifth metatarsal fractures, which should be considered when performing internal fixation for these fractures.

Purpose: To investigate the microscopic diffusion properties of formalin-fixed breast tissue.

To describe the imaging and histopathological findings and provide an overview of a recently described and rare cause of bone sclerosis. Five cases of intra-osseous hibernoma of bone that presented over the last year. The imaging and histopathology is reviewed. All cases were identified in asymptomatic middle-aged to elderly adults as incidental findings with bone sclerosis in the axial skeleton. MRI showed lesions that were T1 hypointense to subcutaneous fat and hyperintense to skeletal muscle and one showed contrast enhancement. Glucose avidity was demonstrated on FDGPET in both cases tested and isotope bone scan performed in three cases showed strong positivity in two, but uptake was inconspicuous in one case. Intra-osseous hibernoma is a rare cause of sclerotic bone lesions, predominating in the axial skeleton of middle-aged and elderly adults. They have a non-aggressive appearance on CT and on MRI are T1 hypointense to subcutaneous fat and hyperintense to skeletal muscle. They are usually T2 hyperintense and may show peripheral contrast enhancement. They may show increased glucose avidity on FDGPET and may or may not be positive on isotope bone scans. We suspect that with ever-increasing use of a variety of imaging techniques, particularly in a setting of staging for malignant disease, more such cases will come to light. This diagnosis should be added to the differential diagnosis of sclerotic bone lesions.

Purpose To compare the theoretical information content of four popular models of diffusion-weighted signal attenuation. Method Four whole prostates were imaged fresh unfixed and fixed at 9.4T. Biexponential, kurtosis, stretched exponential, and monoexponential models were ranked using Akaike's Information Criterion (AIC) with validation by a leave-one-out test of model prediction error. Results For unfixed tissue measurements (b-value range: 17–2104 s/mm2) the biexponential and kurtosis models had similar information content to each other and this was distinctly higher than for the stretched and monoexponential models. In fixed-tissue measurements (b-value range: 17–8252 s/mm2), the biexponential model had much higher information content than the three other models. Conclusion AIC-based model ranking is consistent with an independent prediction accuracy test. Biexponential and kurtosis models consistently perform better than stretched and monoexponential models. The biexponential model has increasing superiority over all three other models as maximum b-value increases above ∼2000 s/mm2. Magn Reson Med 72:1418–1426, 2014. © 2013 Wiley Periodicals, Inc.

During the last decade, it emerged that cyclic guanosine monophosphate (cGMP) is a novel drug target for the treatment of pulmonary arterial hypertension (PAH). cGMP regulates many cellular functions, ranging from contractility to growth, of relevance to the disease. Generated from guanylyl cyclases in response to natriuretic peptides or nitric oxide (NO), cGMP transduces its effects through a number of cGMP effectors, including cGMP-regulated phosphodiesterases and protein kinases. Furthermore, the cGMP concentration is modulated by cGMP-degrading phosphodiesterases. Data to date demonstrate that increasing intracellular cGMP through stimulation of GCs, inhibition of PDEs, or both is a valid therapeutic strategy in drug development for PAH. New advances in understanding of cGMP are unravelled, as well as the pathobiology of PAH. cGMP remains an attractive future PAH drug target. This review makes a more detailed examination of cGMP signalling with particular reference to PAH.

Introduction: Simulated learning environments (SLEs) are used worldwide in health professional education, including physiotherapy, to train certain attributes and skills. To date, no randomized controlled trial (RCT) has evaluated whether education in SLEs can partly replace time in the clinical environment for physiotherapy cardiorespiratory practice. Methods: Two independent single-blind multi-institutional RCTs were conducted in parallel using a noninferiority design. Participants were volunteer physiotherapy students (RCT 1, n = 176; RCT 2, n = 173) entering acute care cardiorespiratory physiotherapy clinical placements. Two SLE models were investigated as follows: RCT 1, 1 week in SLE before 3 weeks of clinical immersion; RCT 2, 2 weeks of interspersed SLE/clinical immersion (equivalent to 1 SLE week) within the 4-week clinical placement. Students in each RCT were stratified on academic grade and randomly allocated to an SLE plus clinical immersion or clinical immersion control group. The primary outcome was competency to practice measured in 2 clinical examinations using the Assessment of Physiotherapy Practice. Secondary outcomes were student perception of experience and clinical educator and patient rating of student performance. Results: There were no significant differences in student competency between the SLE and control groups in either RCT, although students in the interspersed group (RCT 2) achieved a higher score in 5 of 7 Assessment of Physiotherapy Practice standards (all P < 0.05). Students rated the SLE experience positively. Clinical educators and patients reported comparability between groups. Conclusions: An SLE can replace clinical time in cardiorespiratory physiotherapy practice. Part education in the SLE satisfied clinical competency requirements, and all stakeholders were satisfied.

Background: Arthrodesis is a standard operative treatment for symptomatic arthritis of the first metatarsophalangeal (MTP) joint. Patients with degenerative joint disease (DJD), severe hallux valgus, and metatarsus primus varus may also require fusion of the first MTP joint. An important question in the latter group of patients is whether a proximal first metatarsal osteotomy is required, in addition to the first MTP joint fusion. Our hypothesis was that patients with severe hallux valgus and metatarsus primus varus, treated with first MTP joint arthrodesis alone, would have correction of the first-to-second intermetatarsal angle (1-2 IMA) and hallux valgus angle (HVA) to near population norms, without the addition of a proximal first metatarsal osteotomy. Methods: Preoperative and postoperative radiographs of 19 feet, in 17 patients, with preoperative IMA greater than 15 were analyzed. Weight-bearing radiographs were divided into pre- and postoperative cohorts. Three independent reviewers measured these radiographs and mean 1-2 IMA and HVA were calculated. Mean follow-up was 10 months. Results: The mean preoperative 1-2 IMA was 19.2 degrees (15.6-24.3). The mean preoperative HVA was 48.5 (36-56.6). The mean postoperative values for 1-2 IMA and HVA were 10.8 and 12.3 degrees, respectively. The mean change in IMA was 8.3 degrees and in the hallux valgus angle was 36.4 degrees. The differences between pre- and postoperative measurement for both angles were statistically significant ( P < .001). Seven of 19 (37%) feet were corrected to an IMA of less than 9 degrees (normal), whereas in 15/19 feet the postoperative IMA was 12.3 degrees or less. The postoperative HVA was less than 15 degrees in 15/19 (79%) feet. Conclusion: This pre- and postoperative radiographic analysis of patients with severe bunion deformity demonstrated that HVA and 1-2 IMA were acceptably corrected without the addition of a proximal first metatarsal osteotomy. Level of Evidence: Level III, retrospective comparative series.