Trends in infant mortality: an evaluation of forensic autopsied infants in Eastern Denmark over 39 years.

BACKGROUND: SIDS is a diagnosis of exclusion applied to the death of an infant < 1 year of age after an extensive post-mortem investigation. From 1980 to 2018, a total of 870 infants have been autopsied at the Section of Forensic Pathology, Department of Forensic Medicine, UCPH, covering East Denmark. In the same period, Danish national guidelines for infant care have been revised to avoid infants dying of SIDS. OBJECTIVE: This study aimed to describe trends in infant autopsies regarding cause and manner of death, gender, age, month of death, sleeping position, and bed-sharing. The trends were compared to the change in national SIDS guidelines during the period of this study. DESIGN: Information from autopsy reports from 1980 to 2018 were collected into 55 categories designed specifically for this study. Data from 7 of these categories were chosen and processed in Excel for basic epidemiological comparison. RESULTS: The trends show that most infants in the study die of natural manner and most predominant causes of death are SIDS, infection, and congenital malformations. A change in national guidelines in 1991 recommending supine- or side sleeping position coincided with a reduction in the overall infant mortality and cases of SIDS. The peak age in the cohort is 90 days, but stratification in decades shows the infants dying younger each decade. Through the study period, the number of infants found dead sleeping in the prone position has declined. Relatively more infants in this cohort have been found dead while bed-sharing, even though the prevalence of these cases has remained largely the same for four decades.

Bystander Efforts and 1-Year Outcomes in Out-of-Hospital Cardiac Arrest.

BACKGROUND: The effect of bystander interventions on long-term functional outcomes among survivors of out-of-hospital cardiac arrest has not been extensively studied. METHODS: We linked nationwide data on out-of-hospital cardiac arrests in Denmark to functional outcome data and reported the 1-year risks of anoxic brain damage or nursing home admission and of death from any cause among patients who survived to day 30 after an out-of-hospital cardiac arrest. We analyzed risks according to whether bystander cardiopulmonary resuscitation (CPR) or defibrillation was performed and evaluated temporal changes in bystander interventions and outcomes. RESULTS: Among the 2855 patients who were 30-day survivors of an out-of-hospital cardiac arrest during the period from 2001 through 2012, a total of 10.5% had brain damage or were admitted to a nursing home and 9.7% died during the 1-year follow-up period. During the study period, among the 2084 patients who had cardiac arrests that were not witnessed by emergency medical services (EMS) personnel, the rate of bystander CPR increased from 66.7% to 80.6% (P<0.001), the rate of bystander defibrillation increased from 2.1% to 16.8% (P<0.001), the rate of brain damage or nursing home admission decreased from 10.0% to 7.6% (P<0.001), and all-cause mortality decreased from 18.0% to 7.9% (P=0.002). In adjusted analyses, bystander CPR was associated with a risk of brain damage or nursing home admission that was significantly lower than that associated with no bystander resuscitation (hazard ratio, 0.62; 95% confidence interval [CI], 0.47 to 0.82), as well as a lower risk of death from any cause (hazard ratio, 0.70; 95% CI, 0.50 to 0.99) and a lower risk of the composite end point of brain damage, nursing home admission, or death (hazard ratio, 0.67; 95% CI, 0.53 to 0.84). The risks of these outcomes were even lower among patients who received bystander defibrillation as compared with no bystander resuscitation. CONCLUSIONS: In our study, we found that bystander CPR and defibrillation were associated with risks of brain damage or nursing home admission and of death from any cause that were significantly lower than those associated with no bystander resuscitation. (Funded by TrygFonden and the Danish Heart Foundation.).

Increased risk of sudden death in untreated primary carnitine deficiency.

Primary carnitine deficiency (PCD) affects fatty acid oxidation and is associated with cardiomyopathy and cardiac arrhythmia, but the risk of sudden death in PCD is unknown. The Faroe Islands have a high prevalence of PCD, 1:300. This study systematically investigated a possible association between untreated PCD and sudden death in young Faroese subjects. We investigated all medico-legal cases of sudden death between 1979 and 2012 among subjects below the age of 45. Stored biomaterial was examined with molecular genetic analysis to reveal PCD. We compared the prevalence of PCD among sudden death cases with that of the background population (0.23%) to calculate the odds ratio (OR) for sudden death with PCD. Biomaterial was available and genetically analyzed from 53 of 65 sudden death cases (82%) in the Faroe Islands. Six (one male and five females) of the 53 cases were homozygous for the PCD related c.95A>G mutation-a prevalence of 11.3% (95% CI 5%-23%) and an OR of 54.3 (95% CI 21-138, P < .0001) for the association between sudden death and untreated PCD. Only 11 of the 53 sudden death cases were women-of whom five were homozygous for the c.95A>G mutation (45.5%) yielding an OR of 348.8 (95% CI 94-1287, P < .0001) for the association between sudden death and untreated PCD in females. This study showed a strong association between sudden death and untreated PCD, especially in females.

Functionalized Trigonal Lanthanide Complexes: A New Family of 4f Single-Ion Magnets.

We report the synthesis, characterization, and magnetic properties of eight neutral functionalized trigonal lanthanide coordination complexes LnL with Ln = Gd (1), Tb (2), Dy (3), Ho (4), Er (5), Tm (6), Yb (7), Lu (8). These were prepared through a one-pot synthesis where, first, the ligand H3L was synthesized in situ through a Schiff base reaction of tris(2-aminoethyl)amine with 2,6-diformyl-p-cresol. Following addition of Ln(OTf)3·xH2O and base, LnL was obtained. Powder X-ray diffraction confirms that all complexes are isostructural. LnL contain pendant, noncoordinating carbonyl functions that are reactive and represent direct anchoring points to appropriately functionalized surfaces. Furthermore, these reactive carbonyl functions can be used to postfunctionalize LnL: for example, with aromatic π systems. We present herein the Schiff base condensation of 7 with benzylamine to yield 9 as well as the characterization and magnetic properties of 9. Our study establishes LnL as a truly versatile module for the surface deposition of Ln-based single-ion magnets.

Lead one ratio in left bundle branch block predicts poor cardiac resynchronization therapy response.

BACKGROUND: A low electrocardiogram (ECG) lead one ratio (LOR) of the maximum positive/negative QRS amplitudes is associated with lower left ventricular ejection fraction (LVEF) and worse outcomes in left bundle branch block (LBBB); however, the impact of LOR on cardiac resynchronization therapy (CRT) outcomes is unknown. We compared clinical outcomes and echocardiographic changes after CRT implantation by LOR. METHODS: Consecutive CRT-defibrillator recipients with LBBB implanted between 2006 and 2015 at Duke University Medical Center were included (N = 496). Time to heart transplant, left ventricular assist device (LVAD) implantation, or death was compared among patients with LOR <12 vs ≥12 using Cox-proportional hazard models. Changes in LVEF and LV volumes after CRT were compared by LOR. RESULTS: Baseline ECG LOR <12 was associated with an adjusted hazard ratio (HR) of 1.69 (95% CI: 1.12-2.40, P = .01) for heart transplant, LVAD, or death. Patients with LOR <12 had less reduction of LV end diastolic volume (ΔLVEDV -4 ± 21 vs -13 ± 23%, P = .04) and LV end systolic volume (ΔLVESV -9 ± 27 vs -22 ± 26%, P = .03) after CRT. In patients with QRS duration (QRSd) ≥150 ms, LOR <12 was associated with an adjusted HR of 2.01 (95% CI 1.21-3.35, P = .008) for heart transplant, LVAD, or death, compared with LOR ≥12. CONCLUSIONS: Baseline ECG LOR <12 portends worse outcomes after CRT implantation in patients with LBBB, specifically among those with QRSd ≥150 ms. This ECG ratio may identify patients with a class I indication for CRT implantation at high risk for poor postimplantation outcomes.

Concomitant changes in ventricular depolarization and repolarization and long-term outcomes of biventricular pacing.

BACKGROUND: Biventricular (BiV) pacing increases transmural repolarization heterogeneity due to epicardial to endocardial conduction from the left ventricular (LV) lead. However, limited evidence is available on concomitant changes in ventricular depolarization and repolarization and long-term outcomes of BiV pacing. Therefore, we investigated associations of BiV pacing-induced concomitant changes in ventricular depolarization and repolarization with mortality (i.e., LV assist device, heart transplantation, or all-cause mortality) and sustained ventricular arrhythmia endpoints. METHODS: Consecutive BiV-defibrillator recipients with digital preimplantation and postimplantation electrocardiograms recorded between 2006 and 2015 at Duke University Medical Center were included. We calculated changes in QRS duration and corrected JT (JTc) interval and split them by median values. For simplicity, these variables were named QRSdecreased (≤ -12 ms), QRSincreased (> -12 ms), JTcdecreased (≤22 ms), and JTcincreased (> 22 ms) and subsequently used to construct four mutually exclusive groups. RESULTS: We included 528 patients (median age, 68 years; male, 69%). No correlation between changes in QRS duration and JTc interval was observed (P = .295). Compared to QRSdecreased /JTcincreased , increased risk of the composite mortality endpoint was associated with QRSdecreased /JTcdecreased (hazard ratio [HR] = 1.62; 95% confidence interval [CI] = 1.09-2.43), QRSincreased /JTcdecreased (HR = 1.86; 95% CI = 1.27-2.71), and QRSincreased /JTcincreased (HR = 2.25; 95% CI = 1.52-3.35). No QRS/JTc group was associated with excess sustained ventricular arrhythmia risk (P = .400). CONCLUSION: Among BiV-defibrillator recipients, QRSdecreased /JTcincreased was associated with the most favorable long-term survival free of LV assist device, heart transplantation, and sustained ventricular arrhythmias. Our findings suggest that improved electrical resynchronization may be achieved by assessing concomitant changes in ventricular depolarization and repolarization.

Outcomes for Hemodialysis Patients Given Cardiopulmonary Resuscitation for Cardiac Arrest at Outpatient Dialysis Clinics.

BACKGROUND: Out-of-hospital cardiac arrest, the leading cause of death among patients on hemodialysis, occurs frequently within outpatient dialysis centers. Practice guidelines recommend resuscitation training for all dialysis clinic staff and on-site defibrillator availability, but the extent of staff involvement in cardiopulmonary resuscitation (CPR) efforts and its association with outcomes is unknown. METHODS: We used data from the Cardiac Arrest Registry to Enhance Survival and the Centers for Medicare & Medicaid Services dialysis facility database to identify patients who had cardiac arrest within outpatient dialysis clinics between 2010 and 2016 in the southeastern United States. We compared outcomes of patients who received dialysis staff-initiated CPR with those who did not until the arrival of emergency medical services (EMS). RESULTS: Among 398 OHCA events in dialysis clinics, 66% of all patients presented with a nonshockable initial rhythm. Dialysis staff initiated CPR in 81.4% of events and applied defibrillators before EMS arrival in 52.3%. Staff were more likely to initiate CPR among men and witness cardiac arrests, and were more likely to provide CPR within larger dialysis clinics. Staff-initiated CPR was associated with a three-fold increase in the odds of hospital discharge and favorable neurologic status on discharge. There was no overall association between staff-initiated defibrillator use and outcomes, but there was a nonsignificant trend toward improved survival to hospital discharge in the subgroup with shockable initial cardiac arrest rhythms. CONCLUSIONS: Dialysis staff-initiated CPR was associated with a large increase in survival but was only performed in 81% of cardiac arrest events. Further investigations should focus on understanding the potential facilitators and barriers to CPR in the dialysis setting.

Bystander cardiopulmonary resuscitation and long-term outcomes in out-of-hospital cardiac arrest according to location of arrest.

Aims: Bystander cardiopulmonary resuscitation (CPR) has increased in several countries following nationwide initiatives to facilitate bystander resuscitative efforts in out-of-hospital cardiac arrest (OHCA). We examined the importance of public or residential location of arrest on temporal changes in bystander CPR and outcomes. Methods and results: From the nationwide Danish Cardiac Arrest Registry, all OHCAs from 2001 to 2014 of presumed cardiac cause and between 18 and 100 years of age were identified. Arrests witnessed by emergency medical services personnel were excluded. Of 25 505 OHCAs, 26.4% (n = 6738) and 73.6% (n = 18 767) were in public and residential locations, respectively. Bystander CPR increased during 2001-2014 in both locations: from 36.4% [95% confidence interval (CI) 30.6-42.6%] to 83.1% (95% CI 80.0-85.8%) in public (P < 0.001) and from 16.0% (95% CI 13.2-19.3%) to 61.0% (95% CI 58.7-63.2%) in residential locations (P < 0.001). Concurrently, 30-day survival increased in public from 6.4% (95% CI 4.0-10.0%) to 25.2% (95% CI 22.1-28.7%) (P < 0.001), and in residential from 2.9% (95% CI 1.8-4.5%) to 10.0% (95% CI 8.7-11.4%) (P < 0.001). Among 2281 30-day survivors, 1-year risk of anoxic brain damage/nursing home admission during 2001-2014 decreased from 18.8% (95% CI 6.6-43.0%) to 6.8% (95% CI 3.9-11.8%) in public (P < 0.001), whereas the corresponding change was insignificant in residential locations from 11.8% (95% CI 3.3-34.3) to 17.6% (95% CI 12.7-23.9%) (P = 0.52). Conclusion: During 2001-2014, bystander CPR and 30-day survival more than doubled in both public and residential OHCA locations. A significant decrease in anoxic brain damage/nursing home admission was observed among 30-day survivors in public, but not among survivors from residential OHCAs.

Non-invasively quantified changes in left ventricular activation predict outcomes in patients undergoing cardiac resynchronization therapy.

BACKGROUND: Changes in left ventricular (LV) activation after cardiac resynchronization therapy (CRT) influence survival but are difficult to quantify noninvasively. METHODS AND RESULTS: We studied 527 CRT patients to assess whether noninvasive quantification of changes in LV activation, defined by change (Δ) in QRS area (QRSA), can predict outcomes after CRT. The study outcome was time until LV assist device(LVAD), cardiac transplant, or death. The three-dimensional QRSA was measured from clinical 12 lead ECGs which were transformed into vectorcardiograms using the Kors method. QRSA was calculated as (QRSx2 + QRSy2 + QRSz2 )1/2 ; ΔQRSA was calculated as post-QRSA minus pre-QRSA, where a negative value represents a reduction in LV activation delay. Kaplan-Meier plots and multivariable Cox proportional hazards models were used to relate ΔQRSA area with outcomes after stratifying the population into quartiles of ΔQRSA. The median baseline QRSA of 93.6 µVs decreased to 59.7 µVs after CRT. Progressive reductions in QRSA with CRT were associated with a lower rate of LVAD, transplant, or death across patient quartiles (P < .001). In Cox regression analyses, ΔQRSA was associated with outcomes independent of QRS morphology and other clinical variables (Q1[greatest decrease] vs Q4[smallest change=reference], HR 0.45, CI, 0.30-0.70, P < .001). There was no interaction between ΔQRSA and QRS morphology. CONCLUSIONS: CRT induced ΔQRSA was associated with clinically meaningful changes in event-free survival. ΔQRSA may be a novel target to guide lead implantation and device optimization.

Plasma creatinine medians from patients partitioned by gender and age used as a tool for assessment of analytical stability at different concentrations.

Background Monthly medians of patient results are useful in assessment of analytical quality in medical laboratories. Separate medians by gender makes it possible to generate two independent estimates of contemporaneous errors. However, for plasma creatinine, reference intervals (RIs) are different by gender and also higher over 70 years of age. Methods Daily, weekly and monthly patient medians were calculated from the raw data of plasma creatinine concentrations for males between 18 and 70 years, males >70 years, females between 18 and 70 years and females >70 years. Results The medians of the four groups were all closely associated, with similar patterns. The mean of percentage bias from each group defined the best estimate of bias. The maximum half-range (%) of the bias evaluations provided an estimate of the uncertainty comparable to the analytical performance specifications: thus, bias estimates could be classified as optimum, desirable or minimum quality. Conclusions Medians by gender and age are useful in assessment of analytical stability for plasma creatinine concentration ranging from 60 to 90 µmol/L. The daily medians are valuable in rapid detection of large systematic errors, the weekly medians in detecting minor systematic errors and monthly medians in assessment of long-term analytical stability.

PR Prolongation predicts inadequate resynchronization with biventricular pacing in left bundle branch block.

BACKGROUND: PR interval prolongation is associated with poor outcome after cardiac resynchronization therapy (CRT) among patients with left bundle branch block (LBBB) but the mechanisms are unknown. We investigated clinical outcomes, electrocardiogram (ECG), and echocardiogram changes after CRT by PR interval. METHODS: This is a retrospective study of CRT recipients with a baseline ejection fraction ≤35% and ECG showing sinus rhythm and LBBB. Patients were stratified by baseline PR interval quartile and the primary combined endpoint was time to heart transplantation, left ventricular assist device (LVAD) implantation, or death. ECG, echocardiogram, and clinical variables were compared to identify mechanisms for observed differences in outcomes. RESULTS: Of 291 eligible patients, the mean age was 65 years, 60% were male, and 19% had prior atrial fibrillation. Patients with PR prolongation (quartile 4, PR > 200 ms) more frequently had a history of atrial fibrillation, coronary artery bypass graft surgery, prior implantable cardioverter defibrillator implantation, and use of amiodarone than patients in PR quartiles 1-3. A PR > 200ms was associated with an adjusted hazard ratio of 1.7 (95% CI: 1.1-2.5) for the primary endpoint. Patients with PR > 200 ms had less reduction in QRS duration and QRS area after CRT while having more increase in QT and QTc intervals than patients with PR ≤ 200 ms. No major differences were observed in echocardiography by baseline PR interval quartiles. CONCLUSIONS: PR prolongation predicts shorter survival free of heart transplantation or LVAD implantation in patients with LBBB. This may be due to inadequate ventricular resynchronization.

Opioid-Induced Reductions in Gait Variability in Healthy Volunteers and Individuals with Knee Osteoarthritis.

OBJECTIVE: To investigate differences in gait variability induced by two different single-dose opioid formulations and an inert placebo in healthy volunteers and knee osteoarthritis patients. DESIGN: Experimental, randomized, double-blinded, crossover study of inert placebo (calcium tablets), 50 mg of tapentadol, and 100 mg of tramadol. SETTING: Laboratory setting. SUBJECTS: Healthy volunteers and knee osteoarthritis patients. METHODS: At three visits, separated by seven days, one tablet was administered per visit according to the randomization code. At each visit, a baseline measurement was done before tablet administration, after which hourly measurements were performed for six hours, yielding a total of seven measurements per visit. Gait variability was measured by three-dimensional gait analysis, recorded during six minutes of continuous treadmill walking at self-selected speed. One hundred seventy gait cycles were identified from detection of clear events of the knee joint angle trajectories. Gait variability was assessed as average standard deviations over a gait cycle of the sacrum displacements and accelerations; sagittal plane ankle, knee, and hip joint angles; step widths; and stride times. RESULTS: Twenty-four opioid-naïve and neurologically intact participants (12 healthy volunteers and 12 knee osteoarthritis patients) were included and completed the experiment. Tapentadol reduced the variability of sacrum displacements and accelerations compared with placebo and tramadol. There were no differences between experimental conditions regarding the variability in lower-extremity joint angle variability, step widths, or stride times. CONCLUSIONS: In opioid-naïve and neurologically intact individuals, tapentadol seems to reduce movement variability during treadmill walking, compared with placebo and tramadol. This can be interpreted as a loss of adaptability that might increase the risk of falling if the system is perturbed.

The Association of a classical left bundle Branch Block Contraction Pattern by vendor-independent strain echocardiography and outcome after cardiac resynchronization therapy.

BACKGROUND: The association of a Classical left bundle branch block (LBBB) contraction pattern and better outcome after cardiac resynchronization therapy (CRT) has only been studied using vendor-specific software for echocardiographic speckle-tracked longitudinal strain analysis. The purpose of this study was to assess whether a Classical LBBB contraction pattern on longitudinal strain analysis using vendor-independent software is associated with clinical outcome in CRT recipients with LBBB. METHODS: This was a retrospective cohort study including CRT recipients with LBBB, heart failure, and left ventricular (LV) ejection fraction ≤35%. Speckle-tracked echocardiographic longitudinal strain analysis was performed retrospectively on echocardiograms using vendor-independent software. The presence of a Classical LBBB contraction pattern was determined by consensus of two readers. The primary end point was a composite of time to death, heart transplantation or LV assist device implantation. Secondary outcome was ≥15% reduction in LV end-systolic volume. Intra- and inter-reader agreement of the longitudinal strain contraction pattern was assessed by calculating Cohen's κ. RESULTS: Of 283 included patients, 113 (40%) were women, mean age was 66 ± 11 years, and 136 (48%) had ischemic heart disease. A Classical LBBB contraction pattern was present in 196 (69%). The unadjusted hazard ratio for reaching the primary end point was 1.93 (95% confidence interval, 1.36-2.76, p < 0.001) when comparing patients without to patients with a Classical LBBB contraction pattern. Adjusted for ischemic heart disease and QRS duration < 150 milliseconds the hazard ratio was 1.65 (95% confidence interval, 1.12-2.43, p = 0.01). Of the 123 (43%) patients with a follow-up echocardiogram, 64 of 85 (75%) of patients with a Classical LBBB contraction pattern compared to 13 of 38 (34%) without, had ≥15% reduction in LV end-systolic volume (p < 0.001). Cohen's κ were 0.86 (95% confidence interval, 0.71-1.00) and 0.42 (95% confidence interval, 0.30-0.54) for intra- and inter-reader agreement, respectively. CONCLUSION: Using vendor-independent strain software, a Classical LBBB contraction pattern is associated with better outcome in CRT recipients with LBBB, but inter-reader agreement for the classification of contraction pattern is only moderate.

The effect of early-life and adult socioeconomic position on development of lifestyle-related diseases.

BACKGROUND: Early-life socioeconomic position (SEP) is associated with lifestyle-related diseases in adulthood. However, evidence is lacking on the extent to which adult SEP mediates this association. METHODS: Time to either chronic obstructive pulmonary disease (COPD), cardiovascular disease or diabetes were assessed in the Danish population born between 1961 and 1971 (n = 793 674) from age 30 until 2015. Early-life position was assessed in 1981 (by parental) and again at age 30 (own) by four markers; income, occupation, education-divided into high, middle, low-and a combined score for all markers. Using a counterfactual approach, we estimated the total effect of early-life position on disease onset and the degree to which adult position mediated this effect. RESULTS: Results of the time-to-event analysis showed a gradient of all early-life markers on the risk of developing all lifestyle-related diseases. Notably, comparing those in the lowest to the highest educational position, the hazard of COPD was 130% higher for women [hazard ratio = 2.30(95% confidence interval = 2.20-2.41)] and 114% higher for men [2.14 (2.05-2.25)]. About 67%(63-70%) of the effect of educational position was mediated through adult position for COPD, 55% for cardiovascular disease and 50% for diabetes. For the combined score 44, 29 and 33%, respectively, was mediated. CONCLUSION: About one-tenth to two-thirds of the effect of early-life position is mediated by the position attained in adulthood. The degree mediated depend on the outcome investigated, gender and the social position marker used indicating that alternative pathways may play a key role in developing effective policies targeting early-life behaviours.

Association between T-wave discordance and the development of heart failure in left bundle branch block patients: Results from the Copenhagen ECG study.

BACKGROUND: In left bundle branch block (LBBB), discrepancies between depolarization and repolarization of the heart can be assessed by similar direction (concordant) or opposite direction (discordant) of the lateral T-waves compared to the direction of the QRS complex and by the QRS-T angle. We examined the association between discordant T-waves and high QRS-T angles for heart failure development in primary care LBBB patients. METHODS: Between 2001 and 2011, we identified 2540 patients from primary care with LBBB without overt heart failure. We examined the development of heart failure in relation to two ECG measures: (1) LBBB as either discordant (two or three monophasic T-waves in the opposite direction of the QRS complex in leads I, V5 or V6) or concordant, and (2) the frontal plane QRS-T angle in quartile groups. RESULTS: In total, 244 of 913 patients (26.7%) with discordant LBBB developed heart failure compared to 302 of 1627 patients (16.7%) with concordant LBBB. Multivariable Cox regression comparing discordant with concordant LBBB showed a hazard ratio (HR) of 2.58 (95% Confidence interval [CI] 1.71-3.89) for heart failure development within 30 days of follow-up and a HR of 1.45 (95%CI 1.19-1.77) after 30 days. For QRS-T angle, comparing the highest quartile (160°-180°) with the lowest quartile (0°-110°) we found a HR of 2.25 (95%CI 1.26-4.02) within 30 days and a HR of 1.67 (95%CI 1.25-2.23) after 30 days. CONCLUSION: T-wave discordance in lateral ECG leads and a high QRS-T angle are associated with heart failure development in primary care LBBB patients.

The relationship between serum potassium concentrations and electrocardiographic characteristics in 163,547 individuals from primary care.

AIMS: Potassium disturbances are common and associated with increased morbidity and mortality, even in patients without prior cardiovascular disease. We examined six electrocardiographic (ECG) measures and their association to serum potassium levels. METHODS AND RESULTS: From the Copenhagen General Practitioners' Laboratory, we identified 163,547 individuals aged ≥16 years with a first available ECG and a concomitant serum potassium measurement during 2001-2011. Restricted cubic splines curves showed a non-linear relationship between potassium and the Fridericia corrected QT (QTcF) interval, T-wave amplitude, morphology combination score (MCS), PR interval, P-wave amplitude and duration. Therefore, potassium was stratified in two intervals K: 2.0-4.1 mmol/L and 4.2-6.0 mmol/L for further analyses. Within the low potassium range, we observed: QTcF was 12.8 ms longer for each mmol/L decrease in potassium (p < 0.0001); T-wave amplitude was 43.1 µV lower for each mmol/L decrease in potassium (p < 0.0001); and MCS was 0.13 higher per mmol/L decrease in potassium (p < 0.001). Moreover, P-wave duration and PR interval were prolonged by 2.7 and 4.6 ms for each mmol/L decrease in potassium (p < 0.0001), respectively. Within the lowest potassium range (2.0-4.1 mmol/L) P-wave amplitude was 3.5 µV higher for each mmol/L decrease in potassium (p < 0.0001). Within the high potassium range associations with the above-mentioned ECG parameters were much weaker.

Cumulative anthracycline exposure and risk of cardiotoxicity; a Danish nationwide cohort study of 2440 lymphoma patients treated with or without anthracyclines.

Cardiotoxicity is a known risk of anthracycline treatment. However, the relative contribution of anthracyclines to the development of congestive heart failure (CHF), when included in a poly-chemotherapy regimen, is unclear. We examined cardiotoxicity in adult patients with diffuse large B-cell lymphoma and follicular lymphoma undergoing first-line immunochemotherapy from 2000-2012. In total, 2440 patients without previous heart disease were identified from the Danish Lymphoma Registry, of which 1994 (81·7%) were treated with anthracycline-containing chemotherapy [R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOEP (R-CHOP + etoposide)] and 446 (18·3%) were treated without anthracyclines (reference group). Compared to the reference group, the adjusted hazard ratio of CHF after 3-5 cycles of R-CHOP/CHOEP was 5·0 [95% confidence interval (CI) 1·4; 18·5], 6 cycles 6·8 (95% CI 2·0; 23·3) and >6 cycles 13·4 (95% CI 4·0; 45·0). The cumulative 5-year risk of CHF with all-cause mortality as competing risk was 4·6% after 3-5 cycles of R-CHOP/CHOEP, 4·5% after 6 and 7·9% after more than 6 cycles. Cumulative 5-year risk for patients treated without anthracyclines was 0·8%. Using anthracyclines in first-line lymphoma treatment increases risk of CHF in patients without previous history of heart disease. In particular, treatment with >6 cycles of R-CHOP/CHOEP is associated with a significant increase in CHF rate.

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma.

BACKGROUND & AIMS: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects children and young adults with no underlying liver disease. A somatic, 400 Kb deletion on chromosome 19 that fuses part of the DnaJ heat shock protein family (Hsp40) member B1 gene (DNAJB1) to the protein kinase cAMP-activated catalytic subunit alpha gene (PRKACA) has been repeatedly identified in patients with FL-HCC. However, the DNAJB1-PRKACA gene fusion has not been shown to induce liver tumorigenesis. We used the CRISPR/Cas9 technique to delete in mice the syntenic region on chromosome 8 to create a Dnajb1-Prkaca fusion and monitored the mice for liver tumor development. METHODS: We delivered CRISPR/Cas9 vectors designed to juxtapose exon 1 of Dnajb1 with exon 2 of Prkaca to create the Dnajb1-Prkaca gene fusion associated with FL-HCC, or control Cas9 vector, via hydrodynamic tail vein injection to livers of 8-week-old female FVB/N mice. These mice did not have any other engineered genetic alterations and were not exposed to liver toxins or carcinogens. Liver tissues were collected 14 months after delivery; genomic DNA was analyzed by PCR to detect the Dnajb1-Prkaca fusion, and tissues were characterized by histology, immunohistochemistry, RNA sequencing, and whole-exome sequencing. RESULTS: Livers from 12 of the 15 mice given the vectors to induce the Dnajb1-Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms. The tumors contained the Dnajb1-Prkaca gene fusion and had histologic and cytologic features of human FL-HCCs: large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes. In comparing expression levels of genes between the mouse tumor and non-tumor liver cells, we identified changes similar to those detected in human FL-HCC, which included genes that affect cell cycle and mitosis regulation. Genomic analysis of mouse neoplasms induced by the Dnajb1-Prkaca fusion revealed a lack of mutations in genes commonly associated with liver cancers, as observed in human FL-HCC. CONCLUSIONS: Using CRISPR/Cas9 technology, we found generation of the Dnajb1-Prkaca fusion gene in wild-type mice to be sufficient to initiate formation of tumors that have many features of human FL-HCC. Strategies to block DNAJB1-PRKACA might be developed as therapeutics for this form of liver cancer.

DLSanalysis.org: a web interface for analysis of dynamic light scattering data.

A web interface ( www.DLSanalysis.org ) for indirect Laplace transformation of dynamic light scattering data is presented. When experimental data are uploaded to the server they are processed in a few seconds, and the result is displayed on the screen in the form of a size distribution together with the experimental data and the fit to the data. No other user input than the experimental data is necessary, but various options for the analysis may be selected. No local installation of software or registration is necessary. The result of the analysis can be downloaded.

Association between socioeconomic factors and ICD implantation in a publicly financed health care system: a Danish nationwide study.

Aims: For patients surviving out-of-hospital cardiac arrest (OHCA) with a shockable rhythm, implantable cardioverter defibrillator (ICD) is recommended for non-reversible causes of arrest. We aimed to determine factors associated with implantation of ICD and survival in patients surviving non-AMI OHCA in a nationwide register covering all OHCAs in Denmark. Methods and results: We identified 36 950 OHCAs between 2001 and 2012, 1700 of whom were ICD naïve, ≥18 years, of non-AMI cardiac aetiology and surviving until discharge. Six hundred fifty eight patients had ICD implanted during index admission. Association to ICD implantation during index admission was analysed in logistic regression, survival was assessed using Cox regression. Implantable cardioverter defibrillator implantation increased during the study period [odds ratio (OR) 1-year increase: 1.04, 95% confidence intervals (95% CI): 1.00-1.08, P = 0.03]. Non-shockable rhythm and age ≥70 years were associated with lower odds of ICD implantation (ORnon-shockable: 0.27, 95% CI: 0.19-0.37, P < 0.001, OR70-79 years: 0.71, 95% CI: 0.52-0.98, P = 0.04, OR≥80 years: 0.13, 95% CI: 0.07-0.22, P < 0.001). Non-AMI ischaemic heart disease, highest income tertile and chronic heart failure were associated with higher odds (ORIHD: 2.51, 95% CI: 1.77-3.60, P < 0.001, ORhighest income tertile: 1.58, 95% CI: 1.06-2.23, P = 0.02, ORHF: 1.77, 95% CI: 1.35-2.32, P < 0.001). Implantable cardioverter defibrillator implantation was associated with a lower risk of mortality (HR: 0.70, 95% CI: 0.53-0.92, P = 0.01). Conclusion: Implantable cardioverter defibrillator implantation rates increased over the study period. CHF, previous IHD and high income were associated with ICD implantation, while older age and non-shockable rhythm was associated with lower odds of ICD implantation. Implantable cardioverter defibrillator implantation was associated with higher survival rates.