Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies.

ABSTRACT: There is significant ongoing debate regarding type 1 von Willebrand disease (VWD) defintion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with significant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained <30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (>50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age (ß = 0.00; 95% confidence interval, -0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our findings demonstrate that low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classification criteria.

How I treat bleeding disorder of unknown cause.

Recent studies have demonstrated that only 30% of patients referred for assessment of a possible bleeding tendency will eventually be diagnosed with a mild bleeding disorder (MBD) such as von Willebrand disease (VWD) or platelet function defect (PFD). Rather, most of these patients will be diagnosed with bleeding disorder of unknown cause (BDUC). There remains an important unmet need to define consensus regarding the clinical and laboratory criteria necessary for a formal BDUC diagnosis. Accumulating recent data suggest that BDUC is being diagnosed with increasing frequency. Objective assessment of bleeding phenotype using a standardized bleeding assessment tool (BAT) therefore represents a fundamental first step in the diagnosis of BDUC. Because BDUC is a diagnosis by exclusion, accurate quantification of bleeding phenotype is critical because this will be the primary determinant on which a diagnosis of BDUC is reached. Importantly, BAT scores suggest that patients with BDUC display bleeding phenotypes comparable to those seen in patients with VWD or PFD. Despite the prevalence of BDUC, diagnosis and management of these patients commonly pose significant clinical dilemmas. We consider these challenges in the context of a number of typical case studies, discuss the available evidence, and outline our approach to the management of these patients.

A Multicenter Trial of Vena Cava Filters in Severely Injured Patients.

BACKGROUND: Whether early placement of an inferior vena cava filter reduces the risk of pulmonary embolism or death in severely injured patients who have a contraindication to prophylactic anticoagulation is not known. METHODS: In this multicenter, randomized, controlled trial, we assigned 240 severely injured patients (Injury Severity Score >15 [scores range from 0 to 75, with higher scores indicating more severe injury]) who had a contraindication to anticoagulant agents to have a vena cava filter placed within the first 72 hours after admission for the injury or to have no filter placed. The primary end point was a composite of symptomatic pulmonary embolism or death from any cause at 90 days after enrollment; a secondary end point was symptomatic pulmonary embolism between day 8 and day 90 in the subgroup of patients who survived at least 7 days and did not receive prophylactic anticoagulation within 7 days after injury. All patients underwent ultrasonography of the legs at 2 weeks; patients also underwent mandatory computed tomographic pulmonary angiography when prespecified criteria were met. RESULTS: The median age of the patients was 39 years, and the median Injury Severity Score was 27. Early placement of a vena cava filter did not result in a significantly lower incidence of symptomatic pulmonary embolism or death than no placement of a filter (13.9% in the vena cava filter group and 14.4% in the control group; hazard ratio, 0.99; 95% confidence interval [CI], 0.51 to 1.94; P = 0.98). Among the 46 patients in the vena cava filter group and the 34 patients in the control group who did not receive prophylactic anticoagulation within 7 days after injury, pulmonary embolism developed in none of those in the vena cava filter group and in 5 (14.7%) in the control group, including 1 patient who died (relative risk of pulmonary embolism, 0; 95% CI, 0.00 to 0.55). An entrapped thrombus was found in the filter in 6 patients. CONCLUSIONS: Early prophylactic placement of a vena cava filter after major trauma did not result in a lower incidence of symptomatic pulmonary embolism or death at 90 days than no placement of a filter. (Funded by the Medical Research Foundation of Royal Perth Hospital and others; Australian New Zealand Clinical Trials Registry number, ACTRN12614000963628.).

Thermoreversible Reverse-Phase-Shift Foam for Treatment of Noncompressible Torso Hemorrhage.

BACKGROUND: Noncompressible torso hemorrhage (NCTH) is a leading cause of traumatic exsanguination, requiring emergent damage control surgery performed by a highly trained surgeon in a sterile operating environment. A self-expanding, intraabdominally deployed, thermoreversible foam is one proposed method to potentially task shift temporizing hemostasis to earlier providers and additional settings. The purpose of this study was to assess the feasibility of using Fast Onset Abdominal Management (FOAM) in a lethal swine model of NCTH. METHODS: This was a proof-of-concept study comparing FOAM intervention in large Yorkshire swine to historical control animals in the established Ross-Burns model of NCTH. After animal preparation, a Grade IV liver laceration was surgically induced, followed by a free bleed period of 10 min. FOAM was then deployed to a goal intraabdominal pressure of 60 mm Hg for 5 min, followed by a total 60-min observation period following injury. RESULTS: At the end of the experiment, the FOAM agent was found to be distributed throughout the peritoneal cavity in all animals, without signs of iatrogenic injury. The FOAM group demonstrated a significantly higher mean arterial pressure compared with historical controls and a trend toward improved survival: 82% (9/11) compared with 50% for controls (7/14; P = 0.082). CONCLUSIONS: This is the first study to describe the use of a thermoresponsive foam to manage NCTH and successfully demonstrated proof-of-concept feasibility of FOAM deployment. These results provide strong support for future, higher-powered studies to confirm improved survival with this novel intervention.

Non-Melanoma Skin Cancers in the Older Patient.

PURPOSE OF REVIEW: The incidence of non-melanomatous skin cancer (NMSC) increases with age and there are specific considerations regarding management of NMSC for the older patient population. Here we will review current data regarding treatment considerations and options for older patients with NMSC. RECENT FINDINGS: Hypofractionated regimens and high-dose brachytherapy may be non-surgical treatment options for older patients with NMSC. Other less aggressive strategies such as active surveillance can also be considered in some settings. Management of NMSC in the older patient population requires a thorough assessment of comorbidities, frailty, and life expectancy. Additionally, discussions regarding goals of care and quality of life (QOL) issues are especially important in this population. Older patients with NMSC in particular may benefit from a tailored treatment plan based on current available data rather than a broad application of general treatment guidelines for NMSC.

The platelet Fc receptor, FcγRIIa.

Human platelets express FcγRIIa, the low-affinity receptor for the constant fragment (Fc) of immunoglobulin (Ig) G that is also found on neutrophils, monocytes, and macrophages. Engagement of this receptor on platelets by immune complexes triggers intracellular signaling events that lead to platelet activation and aggregation. Importantly these events occur in vivo, particularly in response to pathological immune complexes, and engagement of this receptor on platelets has been causally linked to disease pathology. In this review, we will highlight some of the key features of this receptor in the context of the platelet surface, and examine the functions of platelet FcγRIIa in normal hemostasis and in response to injury and infection. This review will also highlight pathological consequences of engagement of this receptor in platelet-based autoimmune disorders. Finally, we present some new data investigating whether levels of the extracellular ligand-binding region of platelet glycoprotein VI which is rapidly shed upon engagement of platelet FcγRIIa by autoantibodies, can report on the presence of pathological anti-heparin/platelet factor 4 immune complexes and thus identify patients with pathological autoantibodies who are at the greatest risk of developing life-threatening thrombosis in the setting of heparin-induced thrombocytopenia.

Influence of co-morbid fibromyalgia on disease activity measures and response to tumour necrosis factor inhibitors in axial spondyloarthritis: results from a UK national register.

Objective: To quantify the extent to which co-morbid FM is associated with higher disease activity, worse quality of life (QoL) and poorer response to TNF inhibitors (TNFis) in patients with axial SpA. Methods: A prospective study recruiting across 83 centres in the UK. Clinical information and patient-reported measures were available, including 2011 criteria for FM. Multivariable linear regression was used to model the effect of meeting the FM criteria on disease activity, QoL and response to TNFis. Results: A total of 1757 participants were eligible for analyses, of whom 22.1% met criteria for FM. Those with co-morbid FM criteria had higher disease activity [BASDAI average difference FM+ - FM- 1.04 (95% CI 0.75, 1.33)] and worse QoL [Ankylosing Spondylitis Quality of Life score difference 1.42 (95% CI 0.88, 1.96)] after adjusting for demographic, clinical and lifestyle factors. Among 291 participants who commenced biologic therapy, BASDAI scores in those with co-morbid FM were 2.0 higher at baseline but decreased to 1.1 higher at 12 months. There was no significant difference in the likelihood of meeting Assessment of SpondyloArthritis international Society 20 criteria at 12 months. Less improvement in disease activity and QoL over 3 months of TNFi therapy was most strongly related to high scores on the FM criteria symptom severity scale component. Conclusion: Fulfilling criteria for FM has a modest impact on the assessment of axial SpA disease activity and QoL and does not significantly influence response to biologic therapy. Those with a high symptom severity scale on FM assessment may benefit from additional specific management for FM.

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A.

Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927.

Construction of a Bivalent Thrombin Binding Aptamer and Its Antidote with Improved Properties.

Aptamers are short synthetic DNA or RNA oligonucleotides that adopt secondary and tertiary conformations based on Watson-Crick base-pairing interactions and can be used to target a range of different molecules. Two aptamers, HD1 and HD22, that bind to exosites I and II of the human thrombin molecule, respectively, have been extensively studied due to their anticoagulant potentials. However, a fundamental issue preventing the clinical translation of many aptamers is degradation by nucleases and reduced pharmacokinetic properties requiring higher dosing regimens more often. In this study, we have chemically modified the design of previously described thrombin binding aptamers targeting exosites I, HD1, and exosite II, HD22. The individual aptamers were first modified with an inverted deoxythymidine nucleotide, and then constructed bivalent aptamers by connecting the HD1 and HD22 aptamers either through a triethylene glycol (TEG) linkage or four consecutive deoxythymidines together with an inverted deoxythymidine nucleotide at the 3'-end. The anticoagulation potential, the reversal of coagulation with different antidote sequences, and the nuclease stability of the aptamers were then investigated. The results showed that a bivalent aptamer RNV220 containing an inverted deoxythymidine and a TEG linkage chemistry significantly enhanced the anticoagulation properties in blood plasma and nuclease stability compared to the existing aptamer designs. Furthermore, a bivalent antidote sequence RNV220AD efficiently reversed the anticoagulation effect of RNV220 in blood plasma. Based on our results, we believe that RNV220 could be developed as a potential anticoagulant therapeutic molecule.

Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B.

BACKGROUND: Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was developed to reduce the frequency of injections required. METHODS: We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. RESULTS: As compared with recombinant factor IX, rFIXFc exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving rFIXFc; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia. CONCLUSIONS: Prophylactic rFIXFc, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B. (Funded by Biogen Idec; ClinicalTrials.gov number, NCT01027364.).

Salivary Cortisol and Cortisone do not Appear to be Useful Biomarkers for Monitoring Hydrocortisone Replacement in Addison's Disease.

Salivary cortisol has been used to monitor hydrocortisone replacement in patients with Addison's disease (AD). Since salivary cortisol is metabolised to salivary cortisone, it may be an adjunctive analyte to assess adequacy of hydrocortisone replacement in patients with AD. We aimed to characterise the exposure of salivary cortisol and cortisone in patients and healthy controls. We measured salivary cortisol and cortisone by liquid chromatography-tandem mass spectrometry and constructed a day curve (08:00 until 24:00 h) with 16 time points in 25 AD patients taking their usual hydrocortisone dose and in 26 healthy controls. The median (interquartile range) area under the curve (AUC) for cortisol was not different for patients, compared with controls [55.63 (32.91-151.07) nmol*min*l-1 vs. 37.49 (27.41-52.00) nmol*min*l-1; p=0.098, respectively], whereas the peak cortisol Cmax was higher in patients [32.61 (5.75-146.19) nmol/l vs. 8.96 (6.96-12.23) nmol/l; p=0.013], compared with controls. The AUC for cortisone [23.65 (6.10-54.76) nmol*min*l-1 vs. 227.73 (200.10-280.52) nmol*min*l-1; p≤ 0.001, respectively], and peak cortisone Cmax was lower in patients than in controls [11.11 (2.91-35.85) nmol/l vs. 33.12 (25.97-39.95) nmol/l; p=0.002]. The AUC for salivary cortisol and salivary cortisone were not correlated with any measures of hydrocortisone dose. The time-course and AUC of salivary cortisol were similar between Addison's patients and healthy controls. Patients had substantially lower salivary cortisone AUC, compared to healthy controls. Salivary cortisol AUC and pharmacokinetics were not related to hydrocortisone dose and thus are not likely useful markers for the adequacy of hydrocortisone replacement.

Current state and novel approaches of antiplatelet therapy.

An unresolved problem with clinical use of antiplatelet therapy is that a significant number of individuals either still get thrombosis or run the risk of life-threatening bleeding. Antiplatelet drugs are widely used clinically, either chronically for people at risk of athero/thrombotic disease or to prevent thrombus formation during surgery. However, a subpopulation may be resistant to standard doses, while the platelet targets of these drugs are also critical for the normal hemostatic function of platelets. In this review, we will briefly examine current antiplatelet therapy and existing targets while focusing on new potential approaches for antiplatelet therapy and improved monitoring of effects on platelet reactivity in individuals, ultimately to improve antithrombosis with minimal bleeding. Primary platelet adhesion-signaling receptors, glycoprotein (GP)Ib-IX-V and GPVI, that bind von Willebrand factor/collagen and other prothrombotic factors are not targeted by drugs in clinical use, but they are of particular interest because of their key role in thrombus formation at pathological shear.

Nanoparticle Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy.

More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.

HLA similarities indicate shared genetic risk in 21-hydroxylase autoantibody positive South African and United States Addison's disease.

Genetic similarities between patients from the United States and South African (SA) Addison's Disease (AD) strengthen evidence for genetic association. SA-AD (n = 73), SA healthy controls (N = 78), and US-AD patients (N = 83) were genotyped for DQA1, DQB1, DRB1, and HLA-B alleles. Serum was tested for the quantity of 21OH-AA and IFNα-AA at the Barbara Davis Center. Although not as profound as in US-AD, in SA-AD 21OH-AA + subjects the predominantly associated risk haplotypes were DRB1*0301-DQB1*0201 (DR3), DRB1*04xx-DQB1*0302 (DR4), and the combined DR3/4 genotype. DQB1*0302 associated DRB1*04xx haplotypes conferred higher risk than those DRB1*04xx haplotypes associated with other DQB1 alleles. We found negative association in 21OH-AA + SA-AD for DQA1*0201-DQB1*0202 and DQA1*0101-DQB1*0501 vs SA controls, and positive association for DQA1*0401-DQB1*0402 vs US-AD. Apart from the class II DR3 haplotype, HLA-B8 did not have an independent effect; however together DR3 and HLA-B8 conferred the highest risk vs 21OH-AA negative SA-AD and SA-controls. HLA-B7 (often with DR4) conferred novel risk in 21OH-AA + SA-AD vs controls. This study represents the first comparison between South African and United States AD populations utilizing genotyping and serology performed at the same center. SA-AD and US-AD 21OH-AA + patients share common HLA risk haplotypes including DR4 (with HLA-B7) and DR3 (with HLA-B8), strengthening previously described HLA associations and implicating similar genetic etiology.

Male and female hypogonadism are highly prevalent in South Africans with Addison's disease.

Hypogonadism may complicate Addison's disease (primary hypoadrenalism), but prevalence and metabolic sequelae of hypogonadism in Addison's disease are poorly described. We recruited patients from the South African Addison's disease national registry who received stable replacement doses of hydrocortisone and had no acute illness. Male biochemical testosterone deficiency was defined as an early morning basal testosterone<9.9 nmol/l and premature ovarian failure (POF) when menopause occurred before 40 years of age. Cardiometabolic risk variables were measured in males only. Male hypogonadism prevalence was 33% (14/42), and 10 patients had newly diagnosed hypogonadism. Two untreated patients had elevated FSH or LH (>10 or 12 IU/l). Testosterone deficiency did not correlate with age, disease duration or hydrocortisone dose. Untreated male hypogonadal subjects had a higher (mean ± standard deviation) BMI compared to eugonadal subjects 29.2 ± 4.9 kg/m(2) vs. 24.7 ± 3.4 kg/m(2) (p=0.01) and a higher median (interquartile range) high-sensitive-CRP 6.4 (2.5-14.0) mg/l vs. 1.45 (0.6-2.8) mg/l (p=0.002). There were no differences between the 2 groups in lipids, lipoproteins and fasting glucose. The median (interquartile range) DHEAS was lower in the hypogonadal 0.31 (0.27-0.37) µmol/l, compared with the eugonadal group 0.75 (0.50-1.51) µmol/l (p=0.005). POF was documented in 11% of female patients. Male testosterone deficiency was highly prevalent in this cohort and was primarily due to secondary hypogonadism. Only BMI and hs-CRP were increased in untreated male hypogonadal subjects. Male and female hypogonadism appears to be a common complication of Addison's disease and may contribute to its morbidity.

Single-stranded DNA-binding protein hSSB1 is critical for genomic stability.

Single-strand DNA (ssDNA)-binding proteins (SSBs) are ubiquitous and essential for a wide variety of DNA metabolic processes, including DNA replication, recombination, DNA damage detection and repair. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating nucleases, helicases and strand-exchange proteins, activating transcription and mediating protein-protein interactions. In eukaryotes, the major SSB, replication protein A (RPA), is a heterotrimer. Here we describe a second human SSB (hSSB1), with a domain organization closer to the archaeal SSB than to RPA. Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1. Upon induction of DNA damage, hSSB1 accumulates in the nucleus and forms distinct foci independent of cell-cycle phase. These foci co-localize with other known repair proteins. In contrast to RPA, hSSB1 does not localize to replication foci in S-phase cells and hSSB1 deficiency does not influence S-phase progression. Depletion of hSSB1 abrogates the cellular response to DSBs, including activation of ATM and phosphorylation of ATM targets after ionizing radiation. Cells deficient in hSSB1 exhibit increased radiosensitivity, defective checkpoint activation and enhanced genomic instability coupled with a diminished capacity for DNA repair. These findings establish that hSSB1 influences diverse endpoints in the cellular DNA damage response.

EXAMINING VARIABILITY IN THE DIAGNOSIS AND MANAGEMENT OF PEOPLE WITH BLEEDING DISORDERS OF UNKNOWN CAUSE: COMMUNICATION FROM THE ISTH SSC SUBCOMMITTEE ON VON WILLEBRAND FACTOR.

BACKGROUND: Bleeding disorder of unknown cause (BDUC) is characterised by a bleeding phenotype in the setting of normal haemostatic testing. No standardised diagnostic criteria or treatment algorithms exist for people with BDUC. To address the unmet need, the International Society on Thrombosis and Haemostasis von Willebrand Factor Scientific Subcommittee (ISTH VWF SCC) performed a real-world survey, aimed at addressing knowledge gaps, developing consensus pathways and ultimately improving care. OBJECTIVES AND METHODS: We sought to determine current international clinical practices in the investigation, registration, and treatment of people with BDUC through an online structured survey of health care providers (HCPs) who managed patient with bleeding disorders. RESULTS: Two hundred and sixteen respondents from 39 countries were included in the final analysis. The clinical assessment of those with a possible bleeding disorder varied, with only 55% excluding hypermobility but high levels (80%) of bleeding assessment tools (BAT) usage. In haemostatic testing only the prothrombin time (PT) and activated partial thromboplastin time (APTT) tests gained universal support. Tranexamic acid (TXA) was favoured for prophylaxis for minor (71%)/major (59%) surgeries and pregnancy (58%) but advice on the treatment advised if bleeding occurred was heterogeneous. The management of heavy menstrual bleeding (HMB) in women despite combined oral contraceptive pill (COCP) use also proved challenging with HCPs selecting multiple alternative strategies. CONCLUSION: Significant variation exists in the recognition, registration and management of people with BDUC worldwide. This survey emphasises the need for consensus pathways to diagnose and treat BDUC to standardise and improve care for patients internationally.

Balancing Expectations: Navigating Medically Necessary Torso Procedures with Cosmetic Components in the Military Healthcare System.

Background: Surgeons performing federal insurance-financed procedures involving medically necessary and cosmetic components must navigate patient expectations to avoid postoperative disappointment. This challenge is amplified in military healthcare, where different surgical specialties concurrently address the same diagnosis, while the Department of Defense policy on cosmetic fees and TRICARE's definition of excluded services adds further complexity. With the increasing prevalence of elevated body mass index, focus is directed toward diagnoses involving the torso, specifically gynecomastia in male individuals, and diastasis of the rectus abdominis muscles (DRAM) in female individuals. Methods: The study involves a team of experienced board-certified surgeons conducting a narrative review of surgical procedures addressing gynecomastia and DRAM. Relevant literature from 2000 to 2023 is reviewed, focusing on patient satisfaction regarding outcome of medically necessary and cosmetic aspects. Results: For gynecomastia, distinguishing between true and pseudogynecomastia is critical. A protocol is presented based on the Simon classification, offering evidence-based guidelines for surgical interventions. Similarly, for DRAM, a minimally invasive approach balances deployment readiness and surgical recovery. The presence of a symptomatic panniculus, however, requires more invasive intervention. The downstream ramification of limited Current Procedural Terminology codes for these interventions is discussed. Conclusions: In medically necessary procedures funded through federal health plans such as TRICARE, the primary goal is functional improvement, not the final torso contour. Clear communication and preoperative counseling are crucial to managing patient expectations. Providers in military healthcare must navigate the complex landscape of patient expectations, policy guidelines, and duty readiness while maintaining the standard of care.