Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial.

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

Cardiac implantable electronic devices in pregnancy: A position statement.

The aim of this document is to provide guidance for the management of women and birthing people with a permanent pacemaker (PPM) or implantable cardioverter defibrillator (ICD). Cardiac devices are becoming more common in obstetric practice and a reference document for contemporary evidence-based practice is required. Where evidence is limited, expert consensus has established recommendations. The purpose is to improve safety and reduce the risk of adverse events relating to implanted cardiac devices during pregnancy, birth and the postnatal period.

Technique and Outcomes of Concomitant Aortic and Caval Resection and Reconstruction for Retroperitoneal Tumors.

BACKGROUND: Major vascular involvement is often considered a contraindication to resection of malignant tumors, but in highly selected patients, it can be performed safely, with results that are highly dependent upon the tumor biology. Resection of both the aorta and inferior vena cava (IVC) is a rare undertaking, requiring both favorable tumor biology and a patient fit for a substantial surgical insult; nevertheless, it provides the possibility of a cure. METHODS: Patients requiring resection and reconstruction of both the aorta and IVC from 2009 through 2019 at 2 university medical centers were included. Patient characteristics, operative technique, and outcomes were retrospectively collected. RESULTS: We identified 9 patients, all with infrarenal reconstruction or repair of the aorta and IVC. All cases were performed with systemic heparinization and required simultaneous aortic and caval cross-clamping for tumor resection. No temporary venous or arterial bypass was used. Since arterial reperfusion with the IVC clamped was poorly tolerated in 1 patient, venous reconstruction was typically completed first. Primary repair was performed in 1 patient, while 8 required replacements. In 2 patients, aortic homograft was used for replacement of both the aortoiliac and iliocaval segments in contaminated surgical fields. In the remaining 6, Dacron was used for arterial replacement; either Dacron (n = 2) or polytetrafluoroethylene (n = 4) were used for venous replacement. Patients were discharged after a median stay of 8 days (range: 5-16). At median follow-up of 17 months (range 3-79 months), 2 patients with paraganglioma and 1 patient with Leydig cell carcinoma had cancer recurrences. Venous reconstructions occluded in 3 patients (38%), although symptoms were minimal. One patient presented acutely with a thrombosed iliac artery limb and bilateral common iliac artery anastomotic stenoses, treated successfully with thrombolysis and stenting. CONCLUSIONS: Patients with tumor involving both the aorta and IVC can be successfully treated with resection and reconstruction. En bloc tumor resection, restoration of venous return before arterial reconstruction, and most importantly, careful patient selection, all contribute to positive outcomes in this otherwise incurable population.

Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics.

BACKGROUND AND AIMS: To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. METHODS AND RESULTS: A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. CONCLUSION: In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04860011.

A review of radiation doses and associated parameters in Western Australian mining operations (2020-23).

Government policies have stimulated the Western Australian (WA) mining industry to position itself as a significant global supplier of critical minerals, including lithium and rare earths. In WA the lithology that supports these minerals is often associated with elevated concentrations of naturally occurring radioactive materials (NORMs) and the increase in the number of mining operations pursuing the minerals has witnessed a commensurate increase in the number of workers potentially exposed to the radiation emitted from the NORMs. The regulatory framework for radiation protection in WA mining operations underwent significant change with the implementation of the Work Health and Safety Act 2020 and Work Health and Safety (Mines) Regulations 2022 which both came into effect on the 31 of March 2022. Under the new framework mining operations identified as having workers who were likely to receive annual effective doses (EDs) from NORMS above one mSvy-1are referenced asrelevant mines (RM). RMs are required to submit an annual report of the estimates of EDs)received by their workforce to the mining regulatory authority (WorkSafe WA: Mines Safety). This research provides an overview of the new legislative framework and updates the information in Ralph and Cattani (2022J. Radiol. Prot.42012501) to include data derived from annual occupational EDs submitted by RMs in the three-year period spanning 2020-21, 2021-22 and 2022-23. In 2022-23, 38 mining operations were identified as RMs, an increase of ten from 2021-22 which in turn had increased by six from the 2020-21 reporting period. The mean annual ED reported for the three-year period was 1.0 mSv, the level at which regulatory intervention should be considered. The maximum ED was 4.9 mSv, just below the threshold of 5 mSv above which exposed workers are considered Designated Workers and are subject to focused monitoring. The collective effective annual dose of the mine worker population reached an historical maximum of 2339 man mSv in 2022-23. Analysis of the three main exposure pathways confirms that inhalation of long-lived alpha emitting radionuclides in dust remains the most significant contributor to worker EDs. Inhalation of radon-222 and radon-220 and their short-lived progeny, once considered as a negligible contributor to worker annual EDs is the second most significant exposure pathway. A declining trend in the number of samples collected per worker is highlighted as requiring remediation to provide confidence in the reported annual EDs. The transition to the new legislative framework for radiation protection in mines has been supported by the publication of guidance materials which have been widely endorsed by the industry.

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. METHODS: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 µg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. FINDINGS: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8-3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference -7·00% [95% CI -12·69 to -1·32]; p=0·016). INTERPRETATION: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. FUNDING: British Heart Foundation and Pharmacosmos.

Conduction system pacing, a European survey: insights from clinical practice.

AIMS: The field of conduction system pacing (CSP) is evolving, and our aim was to obtain a contemporary picture of European CSP practice. METHODS AND RESULTS: A survey was devised by a European CSP Expert Group and sent electronically to cardiologists utilizing CSP. A total of 284 physicians were invited to contribute of which 171 physicians (60.2%; 85% electrophysiologists) responded. Most (77%) had experience with both His-bundle pacing (HBP) and left bundle branch area pacing (LBBAP). Pacing indications ranked highest for CSP were atrioventricular block (irrespective of left ventricular ejection fraction) and when coronary sinus lead implantation failed. For patients with left bundle branch block (LBBB) and heart failure (HF), conventional biventricular pacing remained first-line treatment. For most indications, operators preferred LBBAP over HBP as a first-line approach. When HBP was attempted as an initial approach, reasons reported for transitioning to utilizing LBBAP were: (i) high threshold (reported as >2 V at 1 ms), (ii) failure to reverse bundle branch block, or (iii) > 30 min attempting to implant at His-bundle sites. Backup right ventricular lead use for HBP was low (median 20%) and predominated in pace-and-ablate scenarios. Twelve-lead electrocardiogram assessment was deemed highly important during follow-up. This, coupled with limitations from current capture management algorithms, limits remote monitoring for CSP patients. CONCLUSIONS: This survey provides a snapshot of CSP implementation in Europe. Currently, CSP is predominantly used for bradycardia indications. For HF patients with LBBB, most operators reserve CSP for biventricular implant failures. Left bundle branch area pacing ostensibly has practical advantages over HBP and is therefore preferred by many operators. Practical limitations remain, and large randomized clinical trial data are currently lacking.

A brief history of brain iron accumulation in Parkinson disease and related disorders.

Iron has a long and storied history in Parkinson disease and related disorders. This essential micronutrient is critical for normal brain function, but abnormal brain iron accumulation has been associated with extrapyramidal disease for a century. Precisely why, how, and when iron is implicated in neuronal death remains the subject of investigation. In this article, we review the history of iron in movement disorders, from the first observations in the early twentieth century to recent efforts that view extrapyramidal iron as a novel therapeutic target and diagnostic indicator.

The Hyperattenuating Crescent Sign Is Not Necessarily a Sign of Impending Aortic Aneurysm Rupture.

BACKGROUND: The "crescent sign" is a hyperattenuating crescent-shaped region on CT within the mural thrombus or wall of an aortic aneurysm. Although it has previously been associated with aneurysm instability or impending rupture, the literature is largely based on retrospective analyses of urgently repaired aneurysms. We strove to more rigorously assess the association between an isolated "crescent sign" and risk of impending aortic rupture. METHODS: Patients were identified by querying a single health system PACS database for radiology reports noting a crescent sign. Adult patients with a CT demonstrating a descending thoracic, thoracoabdominal, or abdominal aortic aneurysm and "crescent sign" between 2004 and 2019 were included, with exclusion of those showing definitive signs of aortic rupture on imaging. RESULTS: A total of 82 patients were identified. Aneurysm size was 7.1 ± 2.0 cm. Thirty patients had emergent or urgent repairs during their index admission (37%), 19 had elective repairs at a later date (23%), and 33 patients had no intervention due to either patient choice or prohibitive medical comorbidities (40%). Patients without intervention had a median follow up of 275 days before death or loss to follow up. In patients undergoing elective intervention, 6,968 patient-days elapsed between presentation and repair, with zero episodes of acute rupture (median 105 days). Patients undergoing elective repair had smaller aneurysms compared to those who underwent emergent/urgent repair (6.2 ± 1.3 vs. 7.7 ± 2.1 cm, P = 0.008). No surgical candidate with an aneurysm smaller than 8 cm ruptured. There were 31 patients with previous axial imaging within 2 years prior to presentation with a "crescent sign," with mean aneurysm growth rate of 0.85 ± 0.62 cm per 6 months [median 0.65, range 0-2.6]. Those with aneurysms sized below 5.5 cm displayed decreased aneurysm growth compared to patients with aneurysm's sized 5.5-6.5 cm or patients with aneurysms greater than 6.5 cm (0.12 vs. 0.64 vs. 1.16 cm per 6 months, P= 0.002). CONCLUSIONS: The finding of an isolated radiographic "crescent sign" without other signs of definitive aortic rupture (i.e., hemothorax, aortic wall disruption, retroperitoneal bleeding) is not necessarily an indicator of impending aortic rupture, but may be found in the setting of rapid aneurysm growth. Many factors, including other associated radiographic findings, aneurysm size and growth rate, and patient symptomatology, should guide aneurysm management in these patients. We found that patients with minimal symptoms, aneurysm sizes below 6.5 cm, and no further imaging findings of aneurysm instability, such as periaortic fat stranding, can be successfully managed with elective intervention after optimization of comorbid factors with no evidence of adverse outcomes.

The origins and early history of neurochemistry and its societies.

At the 2017 joint meeting of the International Society for Neurochemistry (ISN) and the European Society for Neurochemistry, 150 years of neurochemistry - the 50th anniversary of ISN, 40 years of European Society for Neurochemistry, and 60 years of the Journal of Neurochemistry (JNC) - was celebrated with a historical symposium that explored the foundations of neurochemical societies, key international figures in the discipline of neurochemistry, and the pre-eminent role of the JNC. The foundations of neurochemistry were laid in Europe, notably France and Germany, in the late 18th and early 19th centuries. Neurochemists in the United Kingdom made globally relevant contributions before and after the Second World War, and Swedish contributions were especially prominent in the 1950s and 1960s. As neurochemistry is a truly international branch of neuroscience, the important contributions of neurochemists in the Americas and the Asia-Pacific were also recognized, as were the seminal roles of the American, Asia-Pacific, and Japanese Societies of Neurochemistry. Although ISN was only formed in 1967, earlier international meetings in Europe and the Americas reflected the growing recognition of the importance of chemistry and biochemistry for understanding and responding to the pathophysiology of clinical conditions and diseases of the central and peripheral nervous systems. JNC was first published in 1956, but the ISN only assumed complete ownership of the journal under tempestuous circumstances in 1970. The ISN-JNC interface and the sterling work of the JNC Editors has meant that the income generated by the journal has allowed the ISN Council to implement diverse programs for supporting neurochemistry internationally, including sustaining regional neurochemical societies, and supporting neurochemists in the developing world and schools of neurochemistry.