Net Clinical Benefit of Oral Anticoagulation Among Frail Patients With Atrial Fibrillation: Nationwide Cohort Study.

BACKGROUND: Frail people with atrial fibrillation are often undertreated with oral anticoagulants (OACs), and evidence for the net clinical benefit (NCB) of OAC is sparse. We, therefore, examined the risk of thromboembolic events, major bleeding, and NCB of anticoagulation treatment. METHODS: This was a nationwide cohort study including frail patients aged with incident atrial fibrillation between 2013 and 2018. Patients were categorized according to OAC treatment exposure. One-year risks of thromboembolic events and major bleeding were ascertained where death was treated as a competing risk. The NCB of anticoagulation was assessed by a bivariate trade-off between thromboembolism and bleeding. RESULTS: We identified 36 223 frail patients with atrial fibrillation (median age, 79 years; 50.5% female), of whom 61.8% started OAC therapy, while 38.2% were untreated despite indication for stroke prevention. At 1 year, the risk of thromboembolic events was 2.1% (95% CI, 1.8%-2.3%) among patients not receiving OAC versus 1.5% (95% CI, 1.4%-1.7%) in patients with OAC. The bleeding risk was 3.2% (95% CI, 2.9%-3.5%) among patients without OAC versus 3.5% (95% CI, 3.2%-3.8%) among anticoagulated patients. The NCB was 0.70% (95% CI, 0.32%-1.08%), suggesting a benefit of OAC treatment; however, the NCB declined with age and increasing frailty and was lowest among patients >75 years of age or with high frailty level. CONCLUSIONS: Frail patients with atrial fibrillation are often untreated with OAC in routine clinical care despite an indication for stroke prevention. The NCB balancing thromboembolic events and major bleeding was in favor of anticoagulation but decreased with advancing age and increasing frailty.

Adherence and Persistence to Antiplatelet Therapy in Lower Extremity Peripheral Arterial Disease: A Danish Population Based Cohort Study.

OBJECTIVE: Adherence to antiplatelet therapy is recommended but unexplored in patients with symptomatic lower extremity peripheral arterial disease (PAD). Therefore, this study aimed to determine adherence and persistence to antiplatelet therapy in patients with PAD, defined as intermittent claudication and chronic limb threatening ischaemia. DESIGN: Population based nationwide cohort study. METHODS: This study included all Danish citizens aged ≥ 40 years with a first inpatient or outpatient diagnosis of symptomatic PAD between 2010 - 2017, and who had at least one prescription claim for aspirin and/or clopidogrel within 90 days after diagnosis. Adherence was determined by the proportion of days covered (PDC) during the first year after diagnosis. Persistence was defined as no treatment gap ≥ 30 days between prescription renewals over three year follow up. RESULTS: A total of 39 687 patients were eligible for inclusion, of whom 23 279 (58.7%) claimed a prescription for aspirin and/or clopidogrel within 90 days of diagnosis. Among these, 12 898 (55.4%) were prevalent users, while the remainder comprised new users who initiated the therapy after the index PAD diagnosis. The mean PDC was 74.5% (SD 35.0%) for prevalent users and 60.5% (SD 30.5%) for new users. Adherence increased with age and number of concomitant drugs. The overall one year cumulative incidence treatment discontinuation was 13.0% (95% CI 12.5 - 13.4%) overall, 17.2% (CI 16.6 - 17.9%) for prevalent users, and 7.9% (CI 7.4 - 8.4%) for new users. At three year follow up, the cumulative incidence of discontinuation was 31.5% (CI 30.9 - 32.2%) overall, 44.6% (CI 43.7 - 45.4%) for prevalent users, and 14.6% (CI 13.9 - 15.3) for new users. CONCLUSION: Less than 60% of patients with newly diagnosed symptomatic PAD claimed a prescription for antiplatelet therapy within 90 days of diagnosis, and both adherence and persistence were moderate during the first year after diagnosis. These findings underscore the importance of efforts to improve the initiation and continuation of antiplatelet therapy in patients with PAD.

Coronavirus Disease 2019 and Airborne Transmission: Science Rejected, Lives Lost. Can Society Do Better?

This is an account that should be heard of an important struggle: the struggle of a large group of experts who came together at the beginning of the COVID-19 pandemic to warn the world about the risk of airborne transmission and the consequences of ignoring it. We alerted the World Health Organization about the potential significance of the airborne transmission of SARS-CoV-2 and the urgent need to control it, but our concerns were dismissed. Here we describe how this happened and the consequences. We hope that by reporting this story we can raise awareness of the importance of interdisciplinary collaboration and the need to be open to new evidence, and to prevent it from happening again. Acknowledgement of an issue, and the emergence of new evidence related to it, is the first necessary step towards finding effective mitigation solutions.

Epidemiological Trends and Projections of Incidence, Prevalence, and Disease Related Mortality Associated With Peripheral Arterial Disease: Observations Using Nationwide Danish Data.

OBJECTIVE: Peripheral arterial disease (PAD) trends remain unclear because contemporary data are sparse and conflicting. This nationwide cohort study quantified changes in PAD incidence, prevalence, and all cause mortality, and projected prevalence development through to 2040. METHODS: Population based registries covering the entire Danish population aged ≥ 40 years from 2000 to 2018 were linked to assess trends in PAD incidence, prevalence, and all cause mortality, overall and by sex and age groups. Based on observed trends in incidence and mortality, and estimated future annual age distribution and population mortality, the PAD prevalence through to 2040 was projected. RESULTS: The Danish population aged 40 - 99 years in 2000 - 2018 included 4 811 281 individuals, among whom 145 870 incident PAD diagnoses were identified. The age and sex standardised PAD incidence decreased from 2.26 per 1 000 person years in 2000 to 1.65 in 2018 (incidence RR 0.74, 95% CI 0.72 - 0.77). The incidence was approximately 20% higher in men than women but declined similarly over time. Concurrently, PAD prevalence in the Danish adult population increased from 1.3% to 1.6% (prevalence ratio 1.28, 95% CI 1.26 - 1.30). Among patients aged ≥ 80 years, the prevalence reached 5.7% in women and 7.9% in men. The age and sex standardised annual mortality among patients with PAD decreased from 9.8% in 2000 to 7.2% in 2018 (mortality ratio 0.75, 95% CI 0.72 - 0.78). Projections of PAD prevalence demonstrated that the rising PAD prevalence will continue until around 2030, followed by a decline towards 2040. Among individuals aged ≥ 80 years, the prevalence was projected to plateau at 8.9% for men and 6.2% for women before declining. CONCLUSION: Within an unselected nationwide population, the incidence and all cause mortality of PAD have declined over the last two decades. Concurrently, prevalence increased and is projected to increase further over the coming decade, emphasising the growing burden of this common atherosclerotic disease in ageing populations.

Structural Investigations of Human A2M Identify a Hollow Native Conformation That Underlies Its Distinctive Protease-Trapping Mechanism.

Human α2-macroglobulin (A2M) is the most characterized protease inhibitor in the alpha-macroglobulin (αM) superfamily, but the structure of its native conformation has not been determined. Here, we combined negative stain electron microscopy (EM), small-angle X-ray scattering (SAXS), and cross-linking-mass spectrometry (XL-MS) to investigate native A2M and its collapsed conformations that are obtained through aminolysis of its thiol ester by methylamine or cleavage of its bait region by trypsin. The combined interpretation of these data resulted in a model of the native A2M tetramer and its conformational changes. Native A2M consists of two crescent-shaped disulfide-bridged subunit dimers, which face toward each other and surround a central hollow space. In native A2M, interactions across the disulfide-bridged dimers are minimal, with a single major interface between the linker (LNK) regions of oppositely positioned subunits. Bait region cleavage induces both intrasubunit domain repositioning and an altered configuration of the disulfide-bridged dimer. These changes collapse the tetramer into a more compact conformation, which encloses an interior protease-trapping cavity. A recombinant A2M with a modified bait region was used to map the bait region's position in native A2M by XL-MS. A second recombinant A2M introduced an intersubunit disulfide into the LNK region, demonstrating the predicted interactions between these regions in native A2M. Altogether, our native A2M model provides a structural foundation for understanding A2M's protease-trapping mechanism, its conformation-dependent receptor interactions, and the dissociation of native A2M into dimers due to inflammatory oxidative stress.

Incidence of venous thromboembolism following head and neck surgery.

PURPOSE: Venous thromboembolism (VTE) is associated with significant morbidity and mortality in patients undergoing surgery, but conflicting data exist on VTE risk in patients undergoing head and neck surgery for malignant and non-malignant conditions. Our aim was to examine the risk of VTE among patients with and without cancer undergoing head and neck surgery. METHODS: We conducted a nationwide cohort study to examine the risk of VTE among patients with an otolaryngological diagnosis using data from the Danish National Patient Register between 2010 and 2018. Analyses were stratified by cancer and anatomical areas of the surgical procedure. RESULTS: In total, 116,953 patients were included of whom 10% (n = 12,083) had active cancer. After 3 months, 1.2% of the patients with cancer and 0.3% of the patients without cancer experienced VTE, respectively. For patients undergoing mouth/throat surgery, 0.8% with cancer and 0.2% without cancer had VTE, respectively. After nose/sinuses surgery 0.7% and 0.2%, respectively. No patients experienced VTE after ear surgery; and after endoscopies the numbers were 1.3% and 0.6% respectively. CONCLUSIONS: While the minority of patients undergoing head and neck surgery develop VTE postoperatively, the risk increases among those with cancer. To support clinical decision making on anticoagulation, risk stratification tools could be further developed to recognize this hazard in patients with cancer undergoing head and neck surgery.

Links between the timing of life-history transitions and dietary and morphological variation during early life history in the sand goby, Pomatoschistus minutus.

Bipartite life histories involve a suite of morphological changes that support the pelagic to demersal transition and an expanded range of prey options and microhabitats. Pelagic individuals are thought to shift (settle) to their preferred benthic habitat at the earliest opportunity once they have attained a minimum level of morphological competency to access their new environment. In theory, early changes in larval morphology (collectively termed 'metamorphosis'), habitat and diet-a measure of habitat-use-ought to be synchronous. Yet relationships may be decoupled by factors linked to behaviour, prey availability or morphological complexity, and few descriptions exist to allow such synchrony to be assessed. The sand goby, Pomatoschistus minutus, is a common coastal fish across north-western Europe, with a size at larval metamorphosis and settlement of around 10 and 16-18 mm standard length (SL), respectively. We sampled shoreline larval and juvenile populations to examine relationships between morphology, diet and life stage. Prey diversity increased with body length; however, dietary change was clearest at 16-18 mm SL, with a reduction in calanoid copepods and shift to larger prey such as Nereis polychaetes and mysid and amphipod crustacea. Early growth in five prey capture and processing morphologies was rapid. Four of these showed a subsequent marked shift to slower growth, but none of these changes were aligned with size at metamorphosis and only that of mouth width coincided with body size at settlement. Early life history in P. minutus appears geared towards a protracted morphological reorganization prior to demersal life and an alternative suite of prey resources. Larval metamorphosis seems to be of limited consequence in this regard. Comparable studies of other Baltic Sea fishes would confirm whether these dynamics relate to shared environmental pressures or to factors intrinsic to P. minutus biology.

Development of selective protease inhibitors via engineering of the bait region of human α2-macroglobulin.

Human α2-macroglobulin (A2M) is an abundant protease inhibitor in plasma, which regulates many proteolytic processes and is involved in innate immunity. A2M's unique protease-trapping mechanism of inhibition is initiated when a protease cleaves within the exposed and highly susceptible "bait region." As the wild-type bait region is permissive to cleavage by most human proteases, A2M is accordingly a broad-spectrum protease inhibitor. In this study, we extensively modified the bait region in order to identify any potential functionally important elements in the bait region sequence and to engineer A2M proteins with restrictive bait regions, which more selectively inhibit a target protease. A2M in which the bait region was entirely replaced by glycine-serine repeats remained fully functional and was not cleaved by any tested protease. Therefore, this bait region was designated as the "tabula rasa" bait region and used as the starting point for further bait region engineering. Cleavage of the tabula rasa bait region by specific proteases was conveyed by the insertion of appropriate substrate sequences, e.g., basic residues for trypsin. Screening and optimization of tabula rasa bait regions incorporating matrix metalloprotease 2 (MMP2) substrate sequences produced an A2M that was specifically cleaved by MMPs and inhibited MMP2 cleavage activity as efficiently as wild-type A2M. We propose that this approach can be used to develop A2M-based protease inhibitors, which selectively inhibit target proteases, which might be applied toward the clinical inhibition of dysregulated proteolysis as occurs in arthritis and many types of cancer.

Temporal Changes in Secondary Prevention and Cardiovascular Outcomes After Revascularization for Peripheral Arterial Disease in Denmark: A Nationwide Cohort Study.

BACKGROUND: Patients with peripheral arterial disease (PAD) are at increased risk of cardiovascular morbidity and mortality. Medical prevention with antithrombotic and statin therapies is a mainstay of treatment to prevent adverse outcomes; nevertheless, patients with PAD are often undertreated. This study describes the temporal changes in medical prevention and adverse outcomes in a national cohort of patients with symptomatic PAD after revascularization. METHODS: We identified all patients with a first open surgical or endovascular revascularization procedure in the lower extremities or abdomen in Denmark, from 2000 to 2016. We examined temporal changes in the use of aspirin, clopidogrel, and statins and 1-year cause-specific hazard ratios for adverse clinical outcomes, after adjusting for procedure type, treatment indication, age, sex, and cardiovascular risk factors. The analyses were performed overall and within strata of index procedure (endovascular versus surgical), treatment indication, age, sex, and high-risk comorbidities. RESULTS: Between 2000 and 2016, we identified 32 911 patients who underwent revascularization for symptomatic PAD. The mean age was 69 years and increased over time, as did the burden of comorbidity. The cumulative incidence of medication use increased between 2000 to 2004 and 2013 to 2016, respectively, from 57.3% to 64.3% for aspirin, 3.6% to 24.8% for clopidogrel, and 36.2% to 77.1% for statins. Concurrently, the 1-year outcome rates declined. Compared with 2000 to 2004, the adjusted hazard ratios in 2013 to 2016 were 0.73 (95% CI, 0.62-0.84) for major adverse cardiovascular events, 0.92 (95% CI, 0.85-1.00) for major adverse limb events, 0.60 (95% CI, 0.48-0.74) for myocardial infarction, 0.94 (95% CI, 0.75-1.18) for ischemic stroke, 0.92 (95% CI, 0.75-1.12) for major bleeding, 0.54 (95% CI, 0.39-0.76) for cardiovascular death, and 0.80 (95% CI, 0.72-0.88) for all-cause death. These improvements in prognosis were most prominent from 2000 to 2004 to 2005 to 2008 and occurred in all strata of index procedure, treatment indication, sex, age, and comorbidity. In contrast, the adjusted hazard ratio for major amputations was 1.00 (95% CI, 0.90-1.11) when comparing 2013 to 2016 to 2000 to 2004. CONCLUSIONS: Medical prevention of adverse events has increased considerably over time in patients who underwent revascularization for symptomatic PAD. This increase was accompanied by reductions in all adverse outcomes, except major amputations.

Risk of Cerebrovascular Events in Intracerebral Hemorrhage Survivors With Atrial Fibrillation: A Nationwide Cohort Study.

BACKGROUND: In patients with intracerebral hemorrhage (ICH) and prevalent atrial fibrillation (AF), the optimal stroke prevention strategy is unclear. We sought to estimate the risk of cerebrovascular events among ICH survivors with AF. METHODS: We used the Danish Stroke Registry to identify patients with incident ICH and prevalent AF between 2003 and 2018. Key inclusion/exclusion criteria of the PRESTIGE-AF (Prevention of Stroke in Intracerebral hemorrhage Survivors With Atrial Fibrillation) trial were applied. Cumulative incidence of recurrent ICH, cerebrovascular ischemic event, and all-cause death were investigated after one year. RESULTS: A total of 1885 patients (median age 80.0 years; 47.6% females) were included in the study. We observed 191 cerebrovascular events and 650 all-cause deaths, and more cerebrovascular ischemic events (N=63) than recurrent ICH events (N=40). Risks of recurrent ICH, cerebrovascular ischemic event, and all-cause death were 1.5%, 3.2%, and 30.3%, respectively, among patients not exposed to OAC during follow-up. The cumulative incidences were 2.8% for recurrent ICH, 3.2% for cerebrovascular ischemic events, and 22.0% for all-cause death among patients initiating/resuming OAC during follow-up. CONCLUSIONS: We observed a high risk of cerebrovascular ischemic events and a very high risk of all-cause death at one year after the incident ICH. The results of ongoing clinical trials are warranted to determine optimal stroke prevention treatment among ICH survivors with concomitant AF.

Continuous signaling of CD79b and CD19 is required for the fitness of Burkitt lymphoma B cells.

Expression of the B-cell antigen receptor (BCR) is essential not only for the development but also for the maintenance of mature B cells. Similarly, many B-cell lymphomas, including Burkitt lymphoma (BL), require continuous BCR signaling for their tumor growth. This growth is driven by immunoreceptor tyrosine-based activation motif (ITAM) and PI3 kinase (PI3K) signaling. Here, we employ CRISPR/Cas9 to delete BCR and B-cell co-receptor genes in the human BL cell line Ramos. We find that Ramos B cells require the expression of the BCR signaling component Igß (CD79b), and the co-receptor CD19, for their fitness and competitive growth in culture. Furthermore, we show that in the absence of any other BCR component, Igß can be expressed on the B-cell surface, where it is found in close proximity to CD19 and signals in an ITAM-dependent manner. These data suggest that Igß and CD19 are part of an alternative B-cell signaling module that use continuous ITAM/PI3K signaling to promote the survival of B lymphoma and normal B cells.

Oral anti-coagulant treatment patterns in atrial fibrillation patients diagnosed with cancer: A Danish nationwide cohort study.

Data on the use of oral anti-coagulants (OAC) for stroke prevention in cancer patients with atrial fibrillation (AF) are sparse. Nationwide cohort study of patients with AF (2012-2018) and an indication for OAC who were diagnosed with cancer at least one year later (N = 12 756). We identified treatment with OAC at cancer diagnosis and the following year and described the incidence of discontinuing or switching between warfarin and direct oral anti-coagulants (DOACs). We also described baseline characteristics associated with OAC non-persistence. One third of the cancer patients received no OAC therapy, whereas 42% received warfarin and 24% received DOAC treatment. Switching incidence between OACs was higher for those receiving warfarin treatment (8.6%) than DOAC treatment (1.7%) within one year. Treatment discontinuation was 61% for warfarin and 26% for DOAC. Females were less likely to discontinue DOAC than males (ratio 0.77, 95% confidence interval: 0.66, 0.90). Increasing cancer stage was associated with discontinuation of DOAC, but not warfarin. OAC for stroke prevention in AF was used by two thirds of patients with newly diagnosed cancer. Switching between OACs and discontinuation was more common for warfarin than DOAC, and females had higher persistence with DOACs.

Translocation of non-lytic antimicrobial peptides and bacteria penetrating peptides across the inner membrane of the bacterial envelope.

The increase in multidrug-resistant pathogenic bacteria has become a problem worldwide. Currently there is a strong focus on the development of novel antimicrobials, including antimicrobial peptides (AMP) and antimicrobial antisense agents. While the majority of AMP have membrane activity and kill bacteria through membrane disruption, non-lytic AMP are non-membrane active, internalize and have intracellular targets. Antimicrobial antisense agents such as peptide nucleic acids (PNA) and phosphorodiamidate morpholino oligomers (PMO), show great promise as novel antibacterial agents, killing bacteria by inhibiting translation of essential target gene transcripts. However, naked PNA and PMO are unable to translocate across the cell envelope of bacteria, to reach their target in the cytosol, and are conjugated to bacteria penetrating peptides (BPP) for cytosolic delivery. Here, we discuss how non-lytic AMP and BPP-PMO/PNA conjugates translocate across the cytoplasmic membrane via receptor-mediated transport, such as the cytoplasmic membrane transporters SbmA, MdtM/YjiL, and/or YgdD, or via a less well described autonomous process.

Optimal reperfusion strategy in acute high-risk pulmonary embolism requiring extracorporeal membrane oxygenation support: a systematic review and meta-analysis.

BACKGROUND: The optimal pulmonary revascularisation strategy in high-risk pulmonary embolism (PE) requiring implantation of extracorporeal membrane oxygenation (ECMO) remains controversial. METHODS: We conducted a systematic review and meta-analysis of evidence comparing mechanical embolectomy and other strategies, including systemic thrombolysis, catheter-directed thrombolysis or ECMO as stand-alone therapy, with regard to mortality and bleeding outcomes. RESULTS: We identified 835 studies, 17 of which were included, comprising 327 PE patients. Overall, 32.4% were treated with mechanical pulmonary reperfusion (of whom 85.9% had surgical embolectomy), while 67.6% received other strategies. The mortality rate was 22.6% in the mechanical reperfusion group and 42.8% in the "other strategies" group. The pooled odds ratio for mortality with mechanical reperfusion was 0.439 (95% CI 0.237-0.816) (p=0.009; I2=35.2%) versus other reperfusion strategies and 0.368 (95% CI 0.185-0.733) (p=0.004; I2=32.9%) for surgical embolectomy versus thrombolysis. The rate of bleeding in patients under ECMO was 22.2% in the mechanical reperfusion group and 19.1% in the "other strategies" group (OR 1.27, 95% CI 0.54-2.96; I2=7.7%). The meta-regression model did not identify any relationship between the covariates "more than one pulmonary reperfusion therapy", "ECMO implantation before pulmonary reperfusion therapy", "clinical presentation of PE" or "cancer-associated PE" and the associated outcomes. CONCLUSIONS: The results of the present meta-analysis and meta-regression suggest that mechanical reperfusion, notably by surgical embolectomy, may yield favourable results regardless of the timing of ECMO implantation in the reperfusion timeline, independent of thrombolysis administration or cardiac arrest presentation.

Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel.

Allergies to nickel (Ni(2+)) are the most frequent cause of contact hypersensitivity (CHS) in industrialized countries. The efficient development of CHS requires both a T lymphocyte-specific signal and a proinflammatory signal. Here we show that Ni(2+) triggered an inflammatory response by directly activating human Toll-like receptor 4 (TLR4). Ni(2+)-induced TLR4 activation was species-specific, as mouse TLR4 could not generate this response. Studies with mutant TLR4 proteins revealed that the non-conserved histidines 456 and 458 of human TLR4 are required for activation by Ni(2+) but not by the natural ligand lipopolysaccharide. Accordingly, transgenic expression of human TLR4 in TLR4-deficient mice allowed efficient sensitization to Ni(2+) and elicitation of CHS. Our data implicate site-specific human TLR4 inhibition as a potential strategy for therapeutic intervention in CHS that would not affect vital immune responses.

Disparities in oral anticoagulation initiation in patients with schizophrenia and atrial fibrillation: A nationwide cohort study.

AIMS: Schizophrenia is associated with poor anticoagulation control and clinical prognosis in patients with atrial fibrillation (AF). Little is known about initiation of oral anticoagulation therapy (OAC) in this patient population. METHODS: In the nationwide Danish health registries, we identified all patients with incident AF and schizophrenia with indication for OAC treatment. Patients with schizophrenia (n = 673) were matched 1:5 on sex, age, stroke risk score, and calendar-period to incident AF patients without schizophrenia. We calculated absolute risk and risk difference (RD) of OAC initiation, adjusting for stroke and bleeding risk factors. Analyses were stratified by calendar period (2000-2011 and 2012-2018) to account for changes after the introduction of non-vitamin K OACs (NOAC). RESULTS: Among patients with schizophrenia (mean age 69.5 years, 50.3% females), 33.7% initiated OAC within the first year after AF diagnosis, compared with 54.4% of patients without schizophrenia, corresponding to an adjusted RD of -20.7 (95% confidence interval [CI]: -24.7 to -16.7). OAC initiation increased over time regardless of schizophrenia status. During 2000-2011, 18.3% of patients with schizophrenia and 42.9% without schizophrenia initiated OAC (adjusted RD -23.6%, 95% CI -28.8 to -18.6). During 2012-2018, this was 48.5% and 65.7%, respectively (adjusted RD -14.4%, 95% CI -20.4 to -8.4). CONCLUSION: Initiation of OAC was substantially lower among patients with AF and schizophrenia compared with matched AF peers. These findings accentuate the importance of close attention to disparities in initiation of OAC treatment, and potential missed opportunities for prevention of disabling strokes in AF patients with schizophrenia.

Revascularisation for Symptomatic Peripheral Artery Disease: External Applicability of the VOYAGER PAD Trial.

OBJECTIVE: In the VOYAGER PAD trial, rivaroxaban 2.5 mg plus aspirin significantly reduced the primary composite efficacy outcome of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death compared with aspirin alone. However, patients enrolled in the trial may not reflect patients encountered in daily clinical practice. This study described the proportion of patients eligible for VOYAGER PAD within the nationwide Danish Vascular Registry (DVR), reasons for ineligibility, and outcomes according to eligibility. METHODS: In total, 32 911 patients who underwent lower extremity revascularisation for symptomatic peripheral arterial disease (PAD) in the DVR (2000-2016) were identified. Trial inclusion and exclusion criteria were applied, and the three year cumulative incidence of primary and secondary trial outcomes was estimated. RESULTS: Altogether, 27.1% of patients with PAD in the DVR were "VOYAGER eligible". Of those not included, 30.7% had at least one exclusion criterion ("VOYAGER excluded"), and an additional 42.3% did not fulfil the inclusion criteria ("VOYAGER not included"). The main reasons for exclusion were atrial fibrillation (32.3%), poorly regulated hypertension (20.6%), requirement for long term dual antiplatelet therapy (10.9%), cytochrome P450 inhibitors or inducers (9.7%), and renal failure (9.3%). The three year rate of the primary efficacy outcome was 10.08 per 100 person years among the "VOYAGER eligible", 16.32 among "VOYAGER excluded", and 6.98 among the "VOYAGER not included". For the primary safety outcome of thrombolysis in myocardial infarction (TIMI) major bleeding, rates were 2.24, 3.76, and 1.17, respectively. Rates of secondary endpoints were also consistently lower for patients who did not meet the inclusion criteria (predominantly due to central aorto-iliac procedures) and highest for "VOYAGER excluded" patients. "VOYAGER eligible" patients experienced a higher cumulative incidence of most endpoints than patients enrolled in the control arm of the VOYAGER PAD trial. CONCLUSION: Among patients in routine clinical practice, 27.1% were eligible for the VOYAGER PAD trial. These patients were older, had more severe vascular symptoms, higher bleeding risk, and worse prognosis than trial participants.

Comparative Analyses of Unsupervised PCA K-Means Change Detection Algorithm from the Viewpoint of Follow-Up Plan.

In this study, principal component analysis and k-means clustering (PCAKM) methods for synthetic aperture radar (SAR) data are analyzed to reduce the sensitivity caused by changes in the parameters and input images of the algorithm, increase the accuracy, and make an improvement in the computation time, which are advantageous for scoring in the follow-up plan. Although there are many supervised methods described in the literature, unsupervised methods may be more appropriate in terms of computing time, data scarcity, and explainability in order to supply a trustworthy system. We consider the PCAKM algorithm, which is used as a benchmark method in many studies when making comparisons. Error metrics, computing times, and utility functions are calculated for 22 modified PCAKM regarding difference images and filtering methods. Various images with different characteristics affect the results of the configurations. However, it is evident that the PCAKM becomes less sensitive and more accurate for both the overall results and image results. Scoring by utilizing these results and other map information is a gap and innovation. Obtaining a change map in a fast, explainable, more robust and less sensitive way is one of the aims of our studies on scoring points in the follow-up plan.

A modified Delphi approach to determine current treatment advances for the development of a resuscitation program for maternal cardiac arrest.

OBJECTIVE: Maternal cardiac arrest is a rare and complex process requiring pregnancy-specific responses and techniques. The goals of this study were to (1) identify, evaluate, and determine the most current best practices to treat this patient population and (2) establish a standardized set of guidelines to serve as a foundation for a future educational simulation-based curriculum. STUDY DESIGN: We used a three-step modified Delphi process to achieve consensus. Twenty-two healthcare experts from across North America agreed to participate in the expert panel. In round 1, 12 pregnancy-specific best practice statements were distributed to the expert panel. Panelists anonymously ranked these using a 7-point Likert scale and provided feedback. Round 2 consisted of a face-to-face consensus meeting where statements that had not already achieved consensus were discussed and then subsequently voted upon by the panelists. RESULTS: Through two rounds, we achieved consensus on nine evidence-based pregnancy-specific techniques to optimize response to maternal cardiac arrest. Round one resulted in one of the 12 best practice statements achieving consensus. Round two resulted in six of the remaining 12 gaining consensus. Best practice techniques involved use of point-of care ultrasound, resuscitative cesarean delivery, cardiopulmonary resuscitation techniques, and the use of extracorporeal cardiopulmonary resuscitation. CONCLUSION: The results of this study provide the foundation to develop an optimal, long-term strategy to treat cardiac arrest in pregnancy. We propose these nine priorities for standard practice, curricula, and guidelines to treat maternal cardiac arrest and hope they serve as a foundation for a future educational curriculum.