Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms. Results: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years. Conclusion: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH

Riociguat treatment in patients with pulmonary arterial hypertension. Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3–6 months) and collated via case report forms. Results: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years. Conclusion: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol.

INTRODUCTION: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. METHODS AND ANALYSIS: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. ETHICS AND DISSEMINATION: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. TRIAL REGISTRATION NUMBER: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18–32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children’s Abilities-Revised questionnaire. Ethics and dissemination The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200

The Delphi and GRADE methodology used in the PSOGI 2018 consensus statement on Pseudomyxoma Peritonei and Peritoneal Mesothelioma.

Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are currently under debate. To aid physicians involved in the treatment of these patients in clinical decision making, the PSOGI executive committee proposed to create a consensus statement on PMP and PM. This manuscript describes the methodology of the consensus process. The Delphi technique is a reliable method for attaining consensus on a topic that lacks scientific evidence through multiple voting rounds which feeds back responses to the participants in between rounds. The GRADE system provides a structured framework for presenting and grading the available evidence. Separate questionnaires were created for PMP and PM and sent during two voting rounds to 80 and 38 experts, respectively. A consensus threshold of 51.0% was chosen. After the second round, consensus was reached on 92.9%-100.0% of the questions. The results were presented and discussed in the plenary session at the PSOGI 2018 international meeting in Paris. A third round for the remaining issues is currently in progress. In conclusion, using the Delphi technique and GRADE methodology, consensus was reached in many issues regarding the treatment of PM and PMP amongst an international panel of experts. The main results will be published in the near future

The ORthopaedic Trauma Hospital Outcomes - Patient Operative Delays (ORTHOPOD) study

Aims: This is a multicentre, prospective assessment of a proportion of the overall orthopaedic trauma caseload of the UK. It investigates theatre capacity, cancellations, and time to surgery in a group of hospitals that is representative of the wider population. It identifies barriers to effective practice and will inform system improvements. Methods: Data capture was by collaborative approach. Patients undergoing procedures from 22 August 2022 and operated on before 31 October 2022 were included. Arm one captured weekly caseload and theatre capacity. Arm two concerned patient and injury demographics, and time to surgery for specific injury groups. Results: Data was available from 90 hospitals across 86 data access groups (70 in England, two in Wales, ten in Scotland, and four in Northern Ireland). After exclusions, 709 weeks' of data on theatre capacity and 23,138 operations were analyzed. The average number of cases per operating session was 1.73. Only 5.8% of all theatre sessions were dedicated day surgery sessions, despite 29% of general trauma patients being eligible for such pathways. In addition, 12.3% of patients experienced at least one cancellation. Delays to surgery were longest in Northern Ireland and shortest in England and Scotland. There was marked variance across all fracture types. Open fractures and fragility hip fractures, influenced by guidelines and performance renumeration, had short waits, and varied least. In all, nine hospitals had 40 or more patients waiting for surgery every week, while seven had less than five. Conclusion: There is great variability in operative demand and list provision seen in this study of 90 UK hospitals. There is marked variation in nearly all injuries apart from those associated with performance monitoring. There is no evidence of local network level coordination of care for orthopaedic trauma patients. Day case operating and pathways of care are underused and are an important area for service improvement. Cite this article: Bone Jt Open 2023;4(6):463–471

May Measurement Month 2017: screening for hypertension in Nigeria-Sub-Saharan Africa.

Hypertension and its complications are now responsible for about a quarter of emergency medical admissions in urban hospitals in Nigeria. It is the commonest risk factor for stroke, heart failure, chronic kidney disease, and dementia. Furthermore, high blood pressure is the commonest cause of sudden unexpected natural death in the country. Regrettably, the rate of awareness, treatment, and control is abysmally low in the country and in many parts of the world. May Measurement Month (MMM) is a global initiative of the International Society of Hypertension aimed at raising awareness of high blood pressure (BP) and to act as a temporary solution to the lack of screening programs worldwide. An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2017. Blood pressure measurement, the definition of hypertension and statistical analysis followed the standard MMM protocol. A total of 19 904 individuals with a mean age of 40.9 years, were screened during MMM17. After multiple imputation, 6709 (36.2%) had hypertension. Of individuals not receiving anti-hypertensive medication, 4140 (25.9%) were found to have hypertension. Of individuals receiving anti-hypertensive medication, 1449 (58.8%) had uncontrolled BP. MMM17 was one of the largest BP screening campaigns undertaken in Nigeria. A significant number of the participants were identified with hypertension (but not on any treatment) and uncontrolled BP despite being treated. These results suggest that opportunistic screening can identify significant numbers with raised BP

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry.

OBJECTIVE: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. METHODS: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. RESULTS: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]). CONCLUSION: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified