Poor long-term prognosis in patients admitted with strong suspicion of acute myocardial infarction but discharged with another diagnosis.

BACKGROUND: Characteristics and prognosis of patients admitted with strong suspicion of myocardial infarction (MI) but discharged without an MI diagnosis are not well-described. OBJECTIVES: To compare background characteristics and cardiovascular outcomes in patients discharged with or without MI diagnosis. METHODS: The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial compared 6629 patients with strong suspicion of MI randomized to oxygen or ambient air. The main composite end-point of this subgroup analysis was the incidence of all-cause death, rehospitalization with MI, heart failure (HF) or stroke during a follow-up of 2.1 years (median; range: 1-3.7 years) irrespective of randomized treatment. RESULTS: 1619 (24%) received a non-MI discharge diagnosis, and 5010 patients (76%) were diagnosed with MI. Groups were similar in age, but non-MI patients were more commonly female and had more comorbidities. At thirty days, the incidence of the composite end-point was 2.8% (45 of 1619) in non-MI patients, compared to 5.0% (250 of 5010) in MI patients with lower incidences in all individual end-points. However, for the long-term follow-up, the incidence of the composite end-point increased in the non-MI patients to 17.7% (286 of 1619) as compared to 16.0% (804 of 5010) in MI patients, mainly driven by a higher incidence of all-cause death, stroke and HF. CONCLUSIONS: Patients admitted with a strong suspicion of MI but discharged with another diagnosis had more favourable outcomes in the short-term perspective, but from one year onwards, cardiovascular outcomes and death deteriorated to a worse long-term prognosis.

The association of mode of location activity and mobility with acute coronary syndrome: a nationwide ecological study.

BACKGROUND: We aimed to study the effect of social containment mandates on ACS presentation during COVID-19 pandemic using location activity and mobility data from mobile phone map services. METHODS: We conducted a cross-sectional study using data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) including all ACS presentations during the pandemic until 7 May 2020. Using a count regression model, we adjusted for day of the week, daily weather and incidence of COVID-19. RESULTS: A 10% increase in activity around areas of residence was associated with 38% lower rates of ACS hospitalizations, whereas increased activity relating to retail and recreation, grocery stores and pharmacies, workplaces and mode of mobility was associated with 10-20% higher rates of ACS hospitalizations. CONCLUSION: Government policy regarding social containment mandates has important public health implications for medical emergencies such as ACS and may explain the decline in ACS presentations observed during COVID-19 pandemic.

Long term outcome after treatment of de novo coronary artery lesions using three different drug coated balloons.

OBJECTIVE: To evaluate the long-term efficacy of three currently available drug coated balloons (DCB) for the treatment of de-novo coronary lesions. METHODS: This was a retrospective analysis of prospectively collected data from the Swedish Coronary Angiography and Angioplasty Registry. Between 2009 and 2017, three currently available DCB brands used in the treatment of de novo lesions were included. Outcomes were clinically driven restenosis and target lesion thrombosis (TLT) (per device) and major adverse cardiac events (MACE) including death, myocardial infarction or target vessel revascularization (per patient) at 4 years. Multivariable Cox regression models were used to adjust for differences. RESULTS: We included 6715 lesions treated with DCBs, 4483 SeQuent® Please (S-DCB), 1071 IN.PACT Falcon (I-DCB) and 1161 Pantera® Lux (P-DCB), in 5670 patients. The mean DCB diameter was 2.4 mm. Bailout stenting occurred in 6.7% of lesions. Angiographic success was 98.5%. The overall cumulative rate of restenosis was 5.5% (299 events). The risk for reported restenosis did not significantly differ between I-DCB vs S-DCB, adjusted hazard ratio (aHR) 0.96; 95% confidence interval (CI) 0.69-1.34, P-DCB vs S-DCB aHR 0.88; 95% CI 0.63-1.23 and I-DCB vs P-DCB aHR 1.10; 95% CI 0.72-1.68. The cumulative risk for TLT was 0.8% in all three DCBs. The risk for MACE or individual components of MACE did not differ between the three patient-groups. CONCLUSION: In de novo coronary lesions, we found comparable long-term efficacy with three currently available DCB brands. DCB angioplasty was feasible with low risk for long-term restenosis and TLT.

Activated platelet aggregation is transiently impaired also by a reduced dose of protamine.

Objectives: Protamine reduces platelet aggregation after cardiopulmonary bypass (CPB). We studied the inhibitory effect of a reduced protamine dose, the duration of impaired platelet function and the possible correlation to postoperative bleeding. Design: Platelet function was assessed by impedance aggregometry in 30 patients undergoing cardiac surgery with CPB at baseline, before protamine administration, after 70% and 100% of the calculated protamine dose, after 20 minutes and at arrival to the intensive care unit. Adenosine diphosphate (ADP), thrombin receptor activating peptide-6 (TRAP), arachidonic acid (AA) and collagen (COL) were used as activators. Blood loss was measured during operation and three hours after surgery. Results are presented as median (25th-75th percentile). Results: Platelet aggregation decreased markedly after the initial dose of protamine (70%) with all activators; ADP 89 (71-110) to 54 (35-78), TRAP 143 (116-167) to 109 (77-136), both p < .01; AA 25 (16-49) to 17 (12-24) and COL 92 (47-103) to 60 (38-81) U, both p < .05. No further decrease was seen after 100% protamine. The effect was transient and after twenty minutes platelet aggregation had started to recover; ADP 76 (54-106), TRAP 138 (95-158), AA 20 (10-35), COL 70 (51-93) U. Blood loss during operation correlated to aggregometry measured at baseline and after protaminization. Conclusions: Protamine after CPB induces a marked decrease in platelet aggregation already at a protamine-heparin ratio of 0.7:1. The impairment seems to be transient and recovery had started after 20 minutes.

Sex-related response to bivalirudin and unfractionated heparin in patients with acute myocardial infarction undergoing percutaneous coronary intervention: A subgroup analysis of the VALIDATE-SWEDEHEART trial.

AIMS: Our aim was to study the impact of sex on anticoagulant treatment outcomes during percutaneous coronary intervention in acute myocardial infarction patients. METHODS: This study was a prespecified analysis of the Bivalirudin versus Heparin in ST-Segment and Non ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated according to Recommended Therapies Registry Trial (VALIDATE-SWEDEHEART) trial, in which patients with myocardial infarction were randomised to bivalirudin or unfractionated heparin during percutaneous coronary intervention. The primary outcome was the composite of death, myocardial infarction or major bleeding at 180 days. RESULTS: There was a lower risk of the primary outcome in women assigned to bivalirudin than to unfractionated heparin (13.6% vs 17.1%, hazard ratio 0.78, 95% confidence interval (0.60-1.00)) with no significant difference in men (11.8% vs 11.2%, hazard ratio 1.06 (0.89-1.26), p for interaction 0.05). The observed difference was primarily due to lower risk of major bleeding (Bleeding Academic Research Consortium definition 2, 3 or 5) associated with bivalirudin in women (8.9% vs 11.8%, hazard ratio 0.74 (0.54-1.01)) but not in men (8.5% vs 7.3%, hazard ratio 1.16 (0.94-1.43) in men, p for interaction 0.02). Conversely, no significant difference in the risk of Bleeding Academic Research Consortium 3 or 5 bleeding, associated with bivalirudin, was found in women 4.5% vs 5.4% (hazard ratio 0.84 (0.54-1.31)) or men 2.9% vs 2.1% (hazard ratio 1.36 (0.93-1.99)). Bleeding Academic Research Consortium 2 bleeding occurred significantly less often in women assigned to bivalirudin than to unfractionated heparin. The risk of death or myocardial infarction did not significantly differ between randomised treatments in men or women. CONCLUSION: In women, bivalirudin was associated with a lower risk of adverse outcomes, compared to unfractionated heparin, primarily due to a significant reduction in Bleeding Academic Research Consortium 2 bleeds.

Supplemental oxygen therapy does not affect the systemic inflammatory response to acute myocardial infarction.

BACKGROUND: Oxygen therapy has been used routinely in normoxemic patients with suspected acute myocardial infarction (AMI) despite limited evidence supporting a beneficial effect. AMI is associated with a systemic inflammation. Here, we hypothesized that the inflammatory response to AMI is potentiated by oxygen therapy. METHODS: The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) multicentre trial randomized patients with suspected AMI to receive oxygen at 6 L min-1 for 6-12 h or ambient air. For this prespecified subgroup analysis, we recruited patients with confirmed AMI from two sites for evaluation of inflammatory biomarkers at randomization and 5-7 h later. Ninety-two inflammatory biomarkers were analysed using proximity extension assay technology, to evaluate the effect of oxygen on the systemic inflammatory response to AMI. RESULTS: Plasma from 144 AMI patients was analysed whereof 76 (53%) were randomized to oxygen and 68 (47%) to air. Eight biomarkers showed a significant increase, whereas 13 were decreased 5-7 h after randomization. The inflammatory response did not differ between the two treatment groups neither did plasma troponin T levels. After adjustment for increase in troponin T over time, age and sex, the release of inflammation-related biomarkers was still similar in the groups. CONCLUSIONS: In a randomized controlled setting of normoxemic patients with AMI, the use of supplemental oxygen did not have any significant impact on the early release of systemic inflammatory markers.

Structured skills training for adults with ADHD in an outpatient psychiatric context: an open feasibility trial.

The aim of the current study was to evaluate the feasibility, acceptability, and effectiveness of Dialectical Behavioral Therapy-based skills training groups for adults with ADHD in an outpatient psychiatric context. Furthermore, the purpose was to analyze the impact of clinical characteristics on the effect and attrition. Ninety-eight adults (out of 102) with ADHD were allocated to the treatment. Self-rating scales were administered as baseline before the first session (T1), post-treatment (T2), and at 3-month follow-up (T3). Approximately 80 % (74 individuals) attended at least two-thirds of the sessions. Treatment satisfaction was good. ADHD symptoms and ADHD-related functional impairment in every-day life were reduced. Well-being, ability to be mindful, acceptance of emotions and quality of life were increased. The results were stable at 3-month follow-up. None of the predictors, i.e., age, comorbidity, ADHD medication status, IQ-level, treatment credibility, or functional impairment at the beginning of treatment, significantly predicted treatment outcome (change in ADHD symptoms from T1 to T2). Likewise, none of the predictors, i.e., irritability/aggression, comorbidity, and functional impairment, were significantly associated with attrition. Due to the difficulties in predicting treatment outcome, as well as attrition, based on clinical characteristics, broad inclusion criteria should be applied.

APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells.

Two main causes of platinum resistance are mutation in the tumor suppressor gene TP53 and drug-induced increase in intracellular glutathione concentration. Mutations in TP53 occur in about 50% of human tumors. APR-246 (PRIMA-1(MET)) is the first clinical-stage compound that reactivates mutant p53 and induces apoptosis. APR-246 is a prodrug that is converted to the active compound methylene quinuclidinone (MQ), a Michael acceptor that binds to cysteine residues in mutant p53 and restores its wild-type conformation. Here, we show that MQ also binds to cysteine in glutathione, thus decreasing intracellular free glutathione concentration. We also show that treatment with APR-246 completely restores the cisplatin and doxorubicin sensitivity to p53-mutant drug-resistant ovarian cancer cells. We propose that this unique ability of APR-246/MQ to bind to cysteines in both mutant p53 and glutathione has a key role in the resensitization as well as in the outstanding synergistic effects observed with APR-246 in combination with platinum compounds in ovarian cancer cell lines and primary cancer cells. However, MQ binding to cysteines in other targets, for example, thioredoxin reductase, may contribute as well. Strong synergy was also observed with the DNA-damaging drugs doxorubicin and gemcitabine, while additive effects were found with the taxane docetaxel. Our results provide a strong rationale for the ongoing clinical study with APR-246 in combination with platinum-based therapy in patients with p53-mutant recurrent high-grade serous (HGS) ovarian cancer. More than 96% of these patients carry TP53 mutations. Combined treatment with APR-246 and platinum or other DNA-damaging drugs could allow dramatically improved therapy of a wide range of therapy refractory p53 mutant tumors.

Evaluating the relationship between leaf chlorophyll concentration and SPAD-502 chlorophyll meter readings.

Relationships between chlorophyll concentration ([chl]) and SPAD values were determined for birch, wheat, and potato. For all three species, the relationships were non-linear with an increasing slope with increasing SPAD. The relationships for birch and wheat were strong (r (2) approximately 0.9), while the potato relationship was comparatively weak (r (2) approximately 0.5). Birch and wheat had very similar relationships when the chlorophyll concentration was expressed per unit leaf area, but diverged when it was expressed per unit fresh weight. Furthermore, wheat showed similar SPAD-[chl] relationships for two different cultivars and during two different growing seasons. The curvilinear shape of the SPAD-[chl] relationships agreed well with the simulated effects of non-uniform chlorophyll distribution across the leaf surface and multiple scattering, causing deviations from linearity in the high and low SPAD range, respectively. The effect of non-uniformly distributed chlorophyll is likely to be more important in explaining the non-linearity in the empirical relationships, since the effect of scattering was predicted to be comparatively weak. The simulations were based on the algorithm for the calculation of SPAD-502 output values. We suggest that SPAD calibration curves should generally be parameterised as non-linear equations, and we hope that the relationships between [chl] and SPAD and the simulations of the present study can facilitate the interpretation of chlorophyll meter calibrations in relation to optical properties of leaves in future studies.

IgE-receptor activation of mast cells regulates phosphorylation and expression of forkhead and Bcl-2 family members.

Activation of the high-affinity IgE-receptor, FcepsilonRI, expressed on mast cells can result in either enhanced survival or apoptosis depending on the circumstances. In this study, we have analysed signalling pathways involved in the regulation of mast cell survival and apoptosis. FcepsilonRI cross-linking induces phosphorylation of Akt and its downstream target forkhead transcription factors. In addition, Bad, GSK-3beta and IkappaB-alpha also become phosphorylated. A1, a prosurvival Bcl-2 homologue transcriptionally controlled by NFkappaB transcription factors, is upregulated upon FcepsilonRI activation. These events have prosurvival effects on the mast cells. Moreover, FcepsilonRI activation upregulates the levels of the proapoptotic protein Bim and induces a rapid, but transient, phosphorylation of Bim. Thus, FcepsilonRI activation of mast cells leads to both prosurvival and proapoptotic signalling events where the outcome most likely depends on the balance between these signals.

Proapoptotic Bcl-2 family member Bim is involved in the control of mast cell survival and is induced together with Bcl-XL upon IgE-receptor activation.

Mast cells play critical roles in the regulation of acute and chronic inflammations. Apoptosis is one of the mechanisms that limit and resolve inflammatory responses. Mast cell survival can be controlled by growth factors and activation of the IgE-receptor FcvarepsilonRI. Members of the Bcl-2 protein family are critical regulators of apoptosis and our study provides evidence that the proapoptotic BH3-only family member Bim is essential for growth factor deprivation-induced mast cell apoptosis and that Bim levels increase upon FcvarepsilonRI activation. Bim deficiency or Bcl-2 overexpression delayed or even prevented cytokine withdrawal-induced mast cell apoptosis in culture. The prosurvival protein Bcl-XL and the proapoptotic Bim were both induced upon FcvarepsilonRI activation. These results suggest that Bim and possibly also other BH3-only proteins control growth factor withdrawal-induced mast cell apoptosis and that the fate of mast cells upon FcvarepsilonRI activation depends on the relative levels of pro- and antiapoptotic Bcl-2 family members.

Stem cell factor-induced migration of mast cells requires p38 mitogen-activated protein kinase activity.

Stem cell factor (SCF) can be considered a cardinal cytokine in mast cell biology as it affects mast cell differentiation, survival, and migration. The objective of this study was to investigate the role of two mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK) and p38, in SCF-induced cell migration. This was examined in mouse mast cells by using PD 098059 and SB203580, which are specific inhibitors of mitogen-induced extracellular kinase (MEK) and p38 MAP kinase, respectively. SCF induced a rapid and transient activation of ERK and p38 in a dose-dependent manner. Inhibition of p38 activity by SB203580 was paralleled with a marked reduction of migration toward SCF, whereas the effect of the MEK inhibitor was less pronounced. This is the first report of a physiological function of SCF-dependent activation of p38. Whether p38-mediated mast cell migration is a possible target for suppression of mast cell hyperplasia remains to be determined.

A polymorphic region in the human transcription factor AP-2beta gene is associated with specific personality traits.

Transcription factor AP-2beta is implicated in playing an important role during embryonic development of different parts of the brain, eg, midbrain, hindbrain, spinal cord, dorsal and cranial root ganglia.1,2 The gene encoding AP-2beta contains a polymorphic region which includes a tetranucleotide repeat of [CAAA] four or five times, located in intron 2 between nucleotides 12593 and 12612.3 Since the midbrain contains structures important for variables such as mood and personality, we have investigated if the AP-2beta genotype is associated with personality traits estimated by the Karolinska Scales of Personality (KSP). Identification of transcription factor genes as candidate genes in psychiatric disorders is a novel approach to further elucidate the genetic factors that, together with environmental factors, are involved in the expression of specific psychiatric phenotypes. The AP-2beta genotype and KSP scores were determined for 137 Caucasian volunteers (73 females and 64 males). The personality traits muscular tension, guilt, somatic anxiety, psychastenia and indirect aggression were significantly associated with the specific AP-2beta genotype, albeit with significant difference between genders. Based on this result the human AP-2beta gene seems to be an important candidate gene for personality disorders. Moreover, the present results suggest that the structure of the intron 2 region of the AP-2beta gene is one factor that contributes to development of the constitutional component of specific personality traits.

Incidence of spontaneous abortion following artificial insemination by donor.

This study examines the frequency of spontaneous abortions in pregnancies achieved by artificial inseminations with donor semen (AID), with special respect to the use of cryopreserved semen and ovulation induction with clomiphene citrate. The abortion rate was found to be similar in AID series using frozen semen to those using fresh semen, nor was the rate increased in composite AID series (both fresh and frozen semen) when compared with the rate of spontaneous abortions in the general population. When clomiphene was used, the abortion rate was increased only in groups of anovulatory and irregularly ovulating women. Those AID series where all women treated are given clomiphene show no increase in abortion rates. The discussion is focused on factors that influence the abortion rate and on possible etiological factors.

Success of donor insemination and male diagnosis.

Of 72 women receiving artificial donor insemination with frozen semen, 49 (68%) conceived. The success rate was significantly better in patients whose husbands were azoospermic (79.5%) than in women whose mates were oligospermic (54.5%). This result may be explained on the assumption that the most fertile women in the latter (male oligospermic) group have disappeared through previous natural conception. It may be concluded that the diagnosis of male infertility is a factor influencing the probability of conception following artificial insemination with donor semen.

Monocytosis and monocytic infiltration of decidua in early pregnancy.

This study showed a marked increase of blood monocytes in the 7th-20th week of pregnancy. The highest monocyte values were observed in the very first weeks whereas neutrophil counts were increasing throughout the observation period. No significant pregnancy associated changes were found in T-cell subpopulations or in HLA-DR expression by monocytes. First trimester decidual tissue contained many HLA-DR, Leu-M3 positive cells. Their distribution was patchy and mainly confined to areas of prominent decidual reaction. In contrast normal secretory phase endometrium showed only occasional Leu-M3, HLA-DR positive cells but a few clusters of glandular epithelial cells expressed HLA-DR. Culture supernatants from both decidual and secretory endometrial tissues contained PGE2 in concentrations known to suppress PHA lymphocyte responses in vitro. We postulate that monocytes infiltrating the decidual tissue may, possibly through PGE2 mediated immunosuppression, help to prevent rejection of the fetal allograft early in pregnancy.

Artificial insemination with frozen semen. Sex ratio at birth.

The purpose of this study was to find out if cryostorage of human semen affects the sex ratio of births resulting from artificial insemination (AI). A survey of the available literature over the last 10-15 years was undertaken. The sex ratio of 3950 births after AI with frozen semen was compared to that of 3086 births resulting from AI with fresh semen and to the total number of births in Iceland during the 10 year period 1972 to 1981, 44.623 births. The normal predominance slightly decreased in births resulting from AI, both with fresh and frozen semen, 50.4% for AI with fresh semen and 49.8% with frozen semen. The difference between the two types of AI in sex ratio is not significant statistically but the two types of AI combined give a probably significant reduction of the sex ratio (P less than 0.05), compared to the general population. It is concluded that cryostorage of semen has not been found to affect the sex ratio at birth but the practice of AI during the last decade might in some way cause a slight reduction of the secondary sex ratio.