| 1. |
- Aldrin-Kirk, Patrick, et al.
(author)
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A novel two-factor monosynaptic TRIO tracing method for assessment of circuit integration of hESC-derived dopamine transplants
- 2022
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In: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 17:1, s. 159-172
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Journal article (peer-reviewed)abstract
- Transplantation in Parkinson's disease using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons is a promising future treatment option. However, many of the mechanisms that govern their differentiation, maturation, and integration into the host circuitry remain elusive. Here, we engrafted hESCs differentiated toward a ventral midbrain DA phenotype into the midbrain of a preclinical rodent model of Parkinson's disease. We then injected a novel DA-neurotropic retrograde MNM008 adeno-associated virus vector capsid, into specific DA target regions to generate starter cells based on their axonal projections. Using monosynaptic rabies-based tracing, we demonstrated for the first time that grafted hESC-derived DA neurons receive distinctly different afferent inputs depending on their projections. The similarities to the host DA system suggest a previously unknown directed circuit integration. By evaluating the differential host-to-graft connectivity based on projection patterns, this novel approach offers a tool to answer outstanding questions regarding the integration of grafted hESC-derived DA neurons.
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| 2. |
- Baranowska, Julia, et al.
(author)
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Associations between medical therapy after surgical aortic valve replacement for aortic stenosis and long-term mortality: a report from the SWEDEHEART registry.
- 2022
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In: European heart journal. Cardiovascular pharmacotherapy. - : Oxford University Press (OUP). - 2055-6837 .- 2055-6845. ; 8:8, s. 837-846
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Journal article (peer-reviewed)abstract
- The association between use of statins, renin-angiotensin system (RAS) inhibitors and/or β-blockers and long-term mortality in patients with aortic stenosis who underwent surgical aortic valve replacement (SAVR) is unknown.All patients with aortic stenosis who underwent isolated first time SAVR in Sweden from 2006 to 2017 and survived six months after discharge were included. Individual patient data from four mandatory nationwide registries were merged. Cox proportional hazards models, with time-updated data on medication status and adjusted for age, sex, comorbidities, type of prosthesis, and year of surgery, were used to investigate associations between dispensed statins, RAS inhibitors, and β-blockers, and all-cause mortality. In total, 9553 patients were included, and median follow-up time was 4.9 years (range 0-11); 1738 patients (18.2%) died during follow-up. Statins were dispensed to 49.1% and 49.0% of the patients within six months of discharge from hospital and after ten years, respectively. Corresponding figures were 51.4% and 53.9% for RAS inhibitors, and 79.3% and 60.7% for β-blockers. Ongoing treatment was associated with lower mortality risk for statins [adjusted hazard ratio (aHR) 0.67 (95% confidence interval 0.60-0.74), p<0.001] and RAS inhibitors [aHR 0.84 (0.76-0.93), p<0.001] but not for β-blockers [aHR 1.17 (1.05-1.30), p=0.004]. The associations were robust in subgroups based on age, sex, and comorbidities (p for interactions>0.05).The results of this large population-based real-world study support the use of statins and RAS inhibitors for patients who underwent SAVR due to aortic stenosis.
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| 3. |
- Björklund, Andreas, et al.
(author)
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The fine-grained complexity of computing the tutte polynomial of a linear matroid
- 2021
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In: ACM-SIAM Symposium on Discrete Algorithms, SODA 2021. - 9781611976465 ; , s. 2333-2345
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Conference paper (peer-reviewed)abstract
- We show that computing the Tutte polynomial of a linear matroid of dimension k on kO(1) points over a field of kO(1) elements requires kΩ(k) time unless the #ETH-a counting extension of the Exponential Time Hypothesis of Impagliazzo and Paturi [CCC 1999] due to Dell et al. [ACM TALG 2014]-is false. This holds also for linear matroids that admit a representation where every point is associated to a vector with at most two nonzero coordinates. Moreover, we also show that the same is true for computing the Tutte polynomial of a binary matroid of dimension k on kO(1) points with at most three nonzero coordinates in each point's vector. These two results stand in sharp contrast to computing the Tutte polynomial of a k-vertex graph (that is, the Tutte polynomial of a graphic matroid of dimension k-which is representable in dimension k over the binary field so that every vector has exactly two nonzero coordinates), which is known to be computable in 2kkO(1) time [Björklund et al., FOCS 2008]. Our lower-bound proofs proceed in three steps: 1. a classic connection due to Crapo and Rota [1970] between the number of tuples of codewords of full support and the Tutte polynomial of the matroid associated with the code; 2. an earlier-established #ETH-hardness of counting the solutions to a bipartite (d, 2)-CSP on n vertices in do(n) time; and 3. new embeddings of such CSP instances as questions about codewords of full support in a linear code. Geometrically, our hardness results also establish that it is #ETH-hard to compute the volume of proper hyperplane chambers in time ko(k) for a given arrangement of hyperplanes through the origin of a finite k-dimensional vector space over a kO(1)-element field. We complement these lower bounds with two algorithm designs to form essentially a complexity dichotomy under #ETH. The first design computes the Tutte polynomial of a linear matroid of dimension k on kO(1) points in kO(k) arithmetic operations in the base field. The second design generalizes the Björklund et al. algorithm from the graphic case and runs in qk+1kO(1) time for linear matroids of dimension k defined over the q-element field by kO(1) points with at most two nonzero coordinates each.
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| 4. |
- Björklund, Andreas, et al.
(author)
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The shortest even cycle problem is tractable
- 2022
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In: STOC 2022 - Proceedings of the 54th Annual ACM SIGACT Symposium on Theory of Computing. - New York, NY, USA : ACM. - 0737-8017. - 9781450392648 ; , s. 117-130
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Conference paper (peer-reviewed)abstract
- Given a directed graph as input, we show how to efficiently find a shortest (directed, simple) cycle on an even number of vertices. As far as we know, no polynomial-time algorithm was previously known for this problem. In fact, finding any even cycle in a directed graph in polynomial time was open for more than two decades until Robertson, Seymour, and Thomas (Ann. of Math. (2) 1999) and, independently, McCuaig (Electron. J. Combin. 2004; announced jointly at STOC 1997) gave an efficiently testable structural characterisation of even-cycle-free directed graphs. Methodologically, our algorithm relies on the standard framework of algebraic fingerprinting and randomized polynomial identity testing over a finite field, and in fact relies on a generating polynomial implicit in a paper of Vazirani and Yannakakis (Discrete Appl. Math. 1989) that enumerates weighted cycle covers by the parity of their number of cycles as a difference of a permanent and a determinant polynomial. The need to work with the permanent-known to be #P-hard apart from a very restricted choice of coefficient rings (Valiant, Theoret. Comput. Sci. 1979)-is where our main technical contribution occurs. We design a family of finite commutative rings of characteristic 4 that simultaneously (i) give a nondegenerate representation for the generating polynomial identity via the permanent and the determinant, (ii) support efficient permanent computations by extension of Valiant's techniques, and (iii) enable emulation of finite-field arithmetic in characteristic 2. Here our work is foreshadowed by that of Björklund and Husfeldt (SIAM J. Comput. 2019), who used a considerably less efficient commutative ring design-in particular, one lacking finite-field emulation-to obtain a polynomial-time algorithm for the shortest two disjoint paths problem in undirected graphs. Building on work of Gilbert and Tarjan (Numer. Math. 1978) as well as Alon and Yuster (J. ACM 2013), we also show how ideas from the nested dissection technique for solving linear equation systems-introduced by George (SIAM J. Numer. Anal. 1973) for symmetric positive definite real matrices-leads to faster algorithm designs in our present finite-ring randomized context when we have control on the separator structure of the input graph; for example, this happens when the input has bounded genus.
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| 5. |
- Björklund, Erik, et al.
(author)
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Comparison of Midterm Outcomes Associated With Aspirin and Ticagrelor vs Aspirin Monotherapy After Coronary Artery Bypass Grafting for Acute Coronary Syndrome.
- 2021
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In: JAMA network open. - : American Medical Association (AMA). - 2574-3805. ; 4:8
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Journal article (peer-reviewed)abstract
- Guidelines recommend dual antiplatelet therapy after coronary artery bypass grafting (CABG) for patients with acute coronary syndrome (ACS). However, the evidence for these recommendations is weak.To compare midterm outcomes after CABG in patients with ACS treated postoperatively with acetylsalicylic acid (ASA) and ticagrelor or with ASA monotherapy.This cohort study used merged data from several national registries of Swedish patients who were diagnosed with ACS and subsequently underwent CABG. All included patients underwent isolated CABG in Sweden between 2012 and 2017 with an ACS diagnosis less than 6 weeks before the procedure, survived 14 days after discharge from hospital, and were treated postoperatively with ASA plus ticagrelor or ASA monotherapy. A multivariable Cox regression model was used for the main analysis, and propensity score-matched models were performed as sensitivity analysis. Data were analyzed between May and September 2020.Postoperative antiplatelet treatment, defined as filled prescriptions, with either ASA and ticagrelor or ASA only.Major adverse cardiovascular events (MACE), defined as all-cause mortality, myocardial infarction, and stroke, and major bleeding, at 12 months and at the end of follow-up.A total of 6558 patients (5281 [80.5%] men; mean [SD] age at surgery, 67.6 [9.3] years) were included; 1813 (27.6%) were treated with ASA plus ticagrelor and 4745 (72.4%) were treated with ASA monotherapy. Crude MACE rate was 3.0 per 100 person years (95% CI, 2.5-3.6 per 100 person years) in the ASA plus ticagrelor group and 3.8 per 100 person years (95% CI, 3.5-4.1 per 100 person years) in the ASA group. After adjustment, there was no significant difference in MACE risk between ASA plus ticagrelor vs ASA only, neither during the first 12 months (adjusted hazard ratio [aHR], 0.84; 95% CI, 0.58-1.21; P=.34) or during total follow-up (aHR, 0.89; 95% CI, 0.71-1.11; P=.29). The use of ASA plus ticagrelor was associated with a significantly increased risk for major bleeding during the first 12 months (aHR, 1.90; 95% CI, 1.16-3.13; P=.011). Sensitivity analyses confirmed the results.In patients with ACS who survived 2 weeks after CABG, no significant difference in the risk of death or ischemic events could be demonstrated between ASA plus ticagrelor and patients treated with ASA only, while the risk for major bleeding was higher in patients treated with ASA plus ticagrelor. Sufficiently powered prospective randomized trials comparing different antiplatelet therapy strategies after CABG are warranted.
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| 6. |
- Björklund, Erik, et al.
(author)
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Postdischarge major bleeding, myocardial infarction, and mortality risk after coronary artery bypass grafting
- 2023
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In: HEART. - 1355-6037 .- 1468-201X.
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Journal article (peer-reviewed)abstract
- Objective To investigate the incidence and mortality risk associated with postdischarge major bleeding after coronary artery bypass grafting (CABG), and relate this to the incidence of, and mortality risk from, postdischarge myocardial infarction.Methods All patients undergoing first-time isolated CABG in Sweden in 2006-2017 and surviving 14 days after hospital discharge were included in a cohort study. Individual patient data from the SWEDEHEART Registry and five other mandatory nationwide registries were merged. Piecewise Cox proportional hazards models were used to investigate associations between major bleeding, defined as hospitalisation for bleeding, with subsequent mortality risk. Similar Cox proportional hazards models were used to investigate the association between postdischarge myocardial infarction and mortality risk.Results Among 36 633 patients, 2429 (6.6%) had a major bleeding event and 2231 (6.1%) had a myocardial infarction. Median follow-up was 6.0 (range 0-11) years. Major bleeding was associated with higher mortality risk <30 days (adjusted HR (aHR)=20.2 (95% CI 17.3 to 23.5)), 30-365 days (aHR=3.8 (95% CI 3.4 to 4.3)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)) after the event. Myocardial infarction was associated with higher mortality risk <30 days (aHR=20.0 (95% CI 16.7 to 23.8)), 30-365 days (aHR=4.1 (95% CI 3.6 to 4.8)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)) after the event.Conclusions The increase in mortality risk associated with a postdischarge major bleeding after CABG is substantial and is similar to the mortality risk associated with a postdischarge myocardial infarction.
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| 7. |
- Björklund, Filip, et al.
(author)
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Breathlessness and exercise performance to predict mortality in long-term oxygen therapy : The population-based DISCOVERY study
- 2023
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In: Respiratory Medicine. - : Elsevier. - 0954-6111 .- 1532-3064. ; 216
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Journal article (peer-reviewed)abstract
- BACKGROUND: Patients with chronic respiratory failure treated with long-term oxygen therapy (LTOT) often have severe breathlessness, impaired exercise performance, and high but variable mortality that is difficult to predict. We aimed to evaluate breathlessness and exercise performance upon starting LTOT as predictors of overall and short-term mortality.METHODS: This was a longitudinal, population-based study of patients who initiated LTOT between 2015 and 2018 in Sweden. Breathlessness was measured using the Dyspnea Exertion Scale, and exercise performance using the 30s-Sit-To-Stand test. Associations with overall and three-month mortality were analyzed using Cox-regression. Subgroup analyses were performed for patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) respectively. The predictive capacity of models was assessed using a C-statistic.RESULTS: A total of 441 patients (57.6% female, aged 75.4 ± 8.3 years) were analyzed, of whom 141 (32%) died during a median follow-up of 260 (IQR 75-460) days. Both breathlessness and exercise performance were independently associated with overall mortality in the crude models, but only exercise performance remained independently associated with overall mortality when models were adjusted for other predictors, when short-term mortality was analyzed, or when breathlessness and exercise capacity were analyzed concurrently. The multivariable model including exercise performance but not breathlessness provided a relatively high predictive capacity for overall mortality, C-statistic 0.756 (95% CI 0.702-0.810). Similar results were seen in the COPD and ILD subgroups.CONCLUSION: Exercise performance as measured by the 30s-STS may be useful to identify patients with higher mortality on LTOT for optimized management and follow-up.
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| 8. |
- Björklund, Filip, et al.
(author)
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Breathlessness and exercise performance to predict mortality in long-term oxygen therapy
- 2023
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In: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 62:Suppl. 67
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Journal article (other academic/artistic)abstract
- Background: Patients with chronic respiratory failure treated with long-term oxygen therapy (LTOT) often have severe breathlessness, impaired exercise performance, and high but variable mortality that is difficult to predict. We aimed to evaluate breathlessness and exercise performance upon starting LTOT as predictors of overall and short-term mortality.Methods: This was a longitudinal, population-based study of patients who initiated LTOT between 2015-2018 in Sweden. Breathlessness was measured using the Dyspnea Exertion Scale, and exercise performance using the 30s-Sit-To-Stand test. Associations with overall and three-month mortality were analyzed using Cox-regression. Subgroup analyses were performed for patients with COPD and ILD respectively. The predictive capacity of models was assessed using a C-statistic.Results: A total of 441 patients (57.6% female, aged 75.4±8.3 years) were analyzed. Both breathlessness and exercise performance were independently associated with overall mortality in the crude models, but only exercise performance remained independently associated with overall mortality when models were adjusted for other predictors, when three-month mortality was analyzed, or when breathlessness and exercise capacity were analyzed concurrently. The multivariable model including exercise performance but not breathlessness provided a relatively high predictive capacity for overall mortality, C-statistic 0.756 (95% CI 0.702-0.810). Similar results were seen in the COPD and ILD subgroups.Conclusion: Exercise performance as measured by the 30s-STS may be useful to identify patients with higher mortality on LTOT for optimized management and follow-up.
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| 9. |
- Björklund Hultman, Martin, 1994, et al.
(author)
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I see what you’re watching on your streaming service: Fast identification of dash encrypted network traces
- 2023
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In: Proceedings - IEEE Consumer Communications and Networking Conference, CCNC. - 2331-9860. ; 2023-January, s. 1116-1122
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Conference paper (peer-reviewed)abstract
- In recent years, concerns about the privacy of users data have raised as testified by the wide adoption of the HTTPS protocol over its unencrypted predecessor. This work demonstrates, however, that the encryption used in HTTPS does not guarantee that the user’s data is hidden when streaming videos using the DASH protocol. We show that the encryption can be bypassed by exploiting recognizable and predictable patterns produced by DASH in side-channels. To demonstrate our attack, we have collected 100k fingerprints from the SVT Play streaming platform, and have shown that encrypted videos can reliably and quickly be identified by capturing streamed HTTPS traffic and comparing it against the fingerprint database. Compared with previous work, our evaluation demonstrates the superior accuracy in our approach as well as its capacity of swiftly identify videos that are playing from an arbitrary timestamp. Our prototype is, to the best of our knowledge, the fastest and most accurate video streaming recognizer to date, only requiring as little as 12 seconds of network traffic to infer a video title with more than 98% accuracy among a catalogue of 20k videos. Our results call for future updates in the DASH protocol designed to circumvent the privacy leak we have shown. An open- source implementation of our prototype is publicly available at https://github.com/embeage/streaming-identification.
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| 10. |
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