Contemporary guideline-directed medical therapy in de novo, chronic, and worsening heart failure patients: First data from the TITRATE-HF study.

AIMS: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. METHODS AND RESULTS: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. CONCLUSION: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.

Serially measured high-sensitivity cardiac troponin T, N-terminal-pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 for risk assessment after acute coronary syndrome: the BIOMArCS cohort.

AIMS: Evidence regarding the role of serial measurements of biomarkers for risk assessment in post-acute coronary syndrome (ACS) patients is limited. The aim was to explore the prognostic value of four, serially measured biomarkers in a large, real-world cohort of post-ACS patients. METHODS AND RESULTS: BIOMArCS is a prospective, multi-centre, observational study in 844 post-ACS patients in whom 12 218 blood samples (median 17 per patient) were obtained during 1-year follow-up. The longitudinal patterns of high-sensitivity cardiac troponin T (hs-cTnT), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and growth differentiation factor 15 (GDF-15) were analysed in relation to the primary endpoint (PE) of cardiovascular mortality and recurrent ACS using multivariable joint models. Median age was 63 years, 78% were men and the PE was reached by 45 patients. The average biomarker levels were systematically higher in PE compared with PE-free patients. After adjustment for 6-month post-discharge Global Registry of Acute Coronary Events score, 1 standard deviation increase in log[hs-cTnT] was associated with a 61% increased risk of the PE [hazard ratio (HR) 1.61, 95% confidence interval (CI) 1.02-2.44, P = 0.045], while for log[GDF-15] this was 81% (HR 1.81, 95% CI 1.28-2.70, P = 0.001). These associations remained significant after multivariable adjustment, while NT-proBNP and hs-CRP were not. Furthermore, GDF-15 level showed an increasing trend prior to the PE (Structured Graphical Abstract). CONCLUSION: Longitudinally measured hs-cTnT and GDF-15 concentrations provide prognostic value in the risk assessment of clinically stabilized patients post-ACS. CLINICAL TRIAL REGISTRATION: The Netherlands Trial Register. Currently available at URL https://trialsearch.who.int/; Unique Identifiers: NTR1698 and NTR1106.

[Sonographic localization of non-palpable implanon hormone implants]. / Sonografische Lokalisation nicht tastbarer Implanon(R)-Hormonimplantate.

PURPOSE: Implanon is a rod-shaped hormone implant which leads to reliable contraception. The rod is implanted in the subcutis of the upper arm and is usually removed easily after its effective period. In the scenario where the rod is not palpable, the removal of the rod can be difficult or impossible. The purpose of this study was to evaluate the reliability of US in locating non-palpable Implanon implants and to investigate the optimal technical parameters for determining the location. MATERIALS AND METHODS: In a prospective study we evaluated 21 women between June 2004 and June 2008. In 14 patients previous examinations with US, radiography, CT and/or MRI were non-diagnostic. The US evaluation followed a standardized protocol in transverse and longitudinal sections. The technical parameters US frequency, position and number of focal zones and compound imaging were varied to define the optimal parameters for the visualization of the Implanon implant. RESULTS: The Implanon implant was detected in all 21 patients. Reasons for negative palpability were mainly an intramuscular or subfascial location as well as a significant migration of the Implanon implant in 2 patients. The use of a high US frequency, the position of the focal zones in the near field and the deactivation of compound imaging all facilitate visualization of the characteristic US morphology of the plastic rod. CONCLUSION: High resolution US is the method of choice for determining the location of non-palpable Implanon implants. Knowledge of US morphology and optimal technical settings as well as the use of high-resolution scan heads are essential for determining the correct location.

Influence of rotational inertia on turning performance of theropod dinosaurs: clues from humans with increased rotational inertia.

The turning agility of theropod dinosaurs may have been severely limited by the large rotational inertia of their horizontal trunks and tails. Bodies with mass distributed far from the axis of rotation have much greater rotational inertia than bodies with the same mass distributed close to the axis of rotation. In this study, we increased the rotational inertia about the vertical axis of human subjects 9.2-fold, to match our estimate for theropods the size of humans, and measured the ability of the subjects to turn. To determine the effect of the increased rotational inertia on maximum turning capability, five subjects jumped vertically while attempting to rotate as far as possible about their vertical axis. This test resulted in a decrease in the average angle turned to 20 % of the control value. We also tested the ability of nine subjects to run as rapidly as possible through a tight slalom course of six 90 degrees turns. When the subjects ran with the 9.2-fold greater rotational inertia, the average velocity through the course decreased to 77% of the control velocity. When the subjects ran the same course but were constrained as to where they placed their feet, the average velocity through the course decreased to 65 % of the control velocity. These results are consistent with the hypothesis that rotational inertia may have limited the turning performance of theropods. They also indicate that the effect of rotational inertia on turning performance is dependent on the type of turning behavior. Characters such as retroverted pubes, reduced tail length, decreased body size, pneumatic vertebrae and the absence of teeth reduced rotational inertia in derived theropods and probably, therefore, improved their turning agility. To reduce rotational inertia, theropods may have run with an arched back and tail, an S-curved neck and forelimbs held backwards against the body.

Influence of increased rotational inertia on the turning performance of humans.

The rotational inertia of an animal can be expected to influence directly its ability to execute rapid turning maneuvers. We hypothesized that a ninefold increase in rotational inertia would reduce maximum turning performance to one-ninth of control values. To test this prediction, we increased rotational inertia about the vertical axis of six human subjects and measured their ability to turn during maximum-effort jump turns. We measured the free moment about a vertical (i.e. yaw) axis as the subjects performed maximum-effort jump turns under three conditions: (i) unencumbered, (ii) wearing a backpack with a control weight and (iii) wearing a backpack of the same mass that increased the rotational inertia of the subject to 9.2 times that with the control weight. Rotational inertia measurements allowed us to estimate the angle turned during the take-off period (i.e. from jump initiation until the feet leave the ground) and the angular power and work of the maximum-effort turns. Surprisingly, the angle turned during take-off in the increased inertia trials was 44.7 % of that of the control trials, rather than the 10.9 % (9.2-fold reduction) expected on the basis of the increase in rotational inertia. When the subjects turned with increased rotational inertia, the maximum and mean torques exerted were, on average, 142 % and 190 %, respectively, of the values recorded during the control trials. Maximum torques during increased rotational inertia trials actually approached isometric maxima. In the increased rotational inertia trials, the angular impulse was 252 % of that of the control trials and the take-off period was 130 % of that of the control trials. By exerting larger torques over longer take-off periods, the subjects were able partially to compensate for the excess rotational inertia. In contrast to the observed changes in torque, maximum and mean angular power were highest in the unencumbered trials and lowest in the increased inertia trials. On the basis of a decreased ability to generate vertical force when turning and of our estimates of angular power, we speculate that the greater than expected turning performance was due (i) to adjustments in the pattern of muscle recruitment and (ii) to a reduction in the velocity of muscle shortening that resulted in increased muscle forces.

Adolescent growth and maturation in zinc-deprived rhesus monkeys [see comment].

Growth retardation has been associated with zinc deficiency in adolescent human populations, but animal models were not available previously to explore this syndrome. Moderate dietary zinc deprivation (2 micrograms Zn/g diet) was introduced in female rhesus monkeys (Macaca mulatta; n = 10) from the beginning of puberty through menarche. Subgroups of animals (n = 4) continued to be fed the zinc-deficient diet through 45 mo of age (sexual maturity). Reduced weight gain and linear growth and lower plasma zinc concentrations (11.8 +/- 0.6 and 9.2 +/- 0.8 mumol/L in control and zinc-deficient monkeys, respectively) were evident during the premenarcheal growth spurt. Slower skeletal growth, maturation, and mineralization were recorded in the postmenarcheal period and some indicators of sexual maturation were delayed. Food intake was slightly higher in the zinc-deficient group than in controls. These data confirm that adolescent growth and maturation are vulnerable to disruption by moderate dietary zinc deprivation in nonhuman primates.

[Rate of thrombosis after cava filter implantation. Long-term results]. / Thromboserate nach Kavafilterimplantation. Langzeitergebnisse.

Thrombosis of the access site and occlusion of the inferior vena cava after placement of an inferior vena caval filter are known complications of caval interruption. 30 patients were evaluated with colour-coded Doppler sonography 4 to 66 months (average 2.5 years) after percutaneous placement of either a Günther filter, a Bird's Nest filter or a Simon-Nitinol filter. One right internal jugular vein had post-thrombotic alterations. One inferior vena cava was found to be occluded 15 months after Simon-Nitinol filter placement. The long-term occlusion rates of access site and inferior vena cava after percutaneous filter introduction are low. These two factors need not be considered if implantation of a caval filter is contemplated.

Copper deficiency affects selenoglutathione peroxidase and selenodeiodinase activities and antioxidant defense in weanling rats.

Copper deficiency has been postulated result in low selenoglutathione peroxidase (Se-GSHPx) activity, secondary to alterations in the antioxidant defense system. Type I iodothyronine 5'-deiodinase contains selenium; because it is not part of the antioxidant defense system its measurement provides a way to evaluate the influence of copper on selenoenzymes independent of the antioxidant system. Weanling rats were fed the control diet (125.9 nmol Cu/g diet), copper-deficient diet (7.9 nmol Cu/g diet), or the control diet restricted to the intake of the deficient rats (restrict-fed), for 21 d. Rats fed the copper-deficient diet had cardiomegaly, low hematocrit values, and low tissue copper concentrations, but normal liver selenium concentrations. Liver and plasma Se-GSHPx activities were lowest in the deficient rats. Non-Se-GSHPx activity was similar between control and copper-deficient groups. Liver selenodeiodinase activity was lowest in the copper-deficient rats; this reduction was functionally significant as evidenced by low plasma 3,3',5-triiodothyronine and high plasma 3,3',5'-triiodothyronine concentrations.

Long-term intermittent intravenous insulin therapy and type 1 diabetes mellitus.

An important defect in insulin-dependent diabetes mellitus (IDDM) is that the liver does not meet its full fuel-processing function, because many of the enzymes involved depend on high insulin concentrations in the portal vein. We tried to reactivate the liver by long-term treatment of IDDM patients with intravenous insulin in pulses, with the aim of achieving high portal-vein concentrations during and after a glucose meal. We studied 20 IDDM patients with brittle disease; despite use of a four-injection regimen with manipulation of insulin doses, diet, and physical activity, and frequent clinic visits for at least a year, these patients still had wide swings in blood glucose and frequent hypoglycaemic reactions. The intermittent therapy consisted of 7-10 pulses of intravenous insulin, infused while the patient was ingesting carbohydrate, primarily glucose, during the first hour of a 3 h treatment; three treatments were given in a day. After 2 consecutive days' treatment, patients were treated for 1 day per week. No patient was withdrawn from the study. At the time of this analysis the duration of intermittent treatment ranged from 7 to 71 months (mean 41 [SE 5] months). Haemoglobin A1C concentrations declined from 8.5 (0.4)% at the end of the stabilisation phase to 7.0 (0.2)% at the analysis point (p = 0.0003). During the same time the frequencies of major and minor hypoglycaemic events also fell significantly (major 3.0 [1.1] to 0.1 [0], minor 13.0 [2.6] to 2.4 [0.8] per month; both p < 0.0001). Because the use of saline rather than insulin pulses would have led to unacceptable hyperglycaemia we opted for a historical control design. The absence of a true control group limits the interpretation of these preliminary results, but we believe further studies of hepatic and muscle metabolism before and after long-term intermittent intravenous insulin therapy would be worth while.

Duplex Doppler sonography of celiac trunk and superior mesenteric artery: comparison with intra-arterial angiography.

DDS was compared to intra-arterial angiography for the diagnosis of significant (> 50%) stenoses of the celiac trunk and the SMA in 38 consecutive patients referred for angiographic evaluation of peripheral arterial occlusive disease. Celiac trunk occlusion was correctly identified by DDS in three of three patients. In patients with significant celiac trunk stenoses, mean peak systolic velocity was 246 (+/- 154) cm/sec and differed significantly (P < 0.05) from the peak systolic velocity (101 +/- 22 cm/sec) of 22 patients with no angiographic evidence of significant stenosis. Five false-negative DDS examinations in patients with > 50% celiac trunk stenoses were noted. Using a peak systolic velocity of > 160 cm/sec (mean value in normal vessels plus 3 standard deviations) to diagnose > 50% celiac trunk stenosis, sensitivity of DDS was 57% and specificity was 100%. However, considering celiac trunk stenoses and occlusions as a single group, the sensitivity rate of DDS in diagnosing significant stenosis and occlusion of celiac trunk was 70%.

[Bile duct injuries in laparoscopic cholecystectomy]. / Gallengangsverletzungen bei laparoskopischer Cholezystektomie.

We report on three patients with iatrogenic lesions of the common bile duct after laparoscopic cholecystectomy. In one patient, an additional occlusion of the hepatic artery was found. The leading postoperative signs were jaundice and cholangitis. Endoscopic and radiologic intervention failed to correct the common bile duct stenosis in all three patients. Surgical correction by hepaticojejunostomy was successful, although the postoperative follow-up is still short.

[Value of ultrasound in follow-up of biliary metal stents--initial results]. / Wertigkeit der Sonographie in der Kontrolle biliärer Metallstents--Erste Ergebnisse.

Self-expandable metallic biliary endoprostheses (= "stents") are an accepted therapeutic alternative in the palliative treatment of malignant biliary obstruction. The physiological direction of bile flow is re-established for a varying period of time. Sonography is an acutely available modality for the evaluation of symptomatic patients who are carriers of such endoprostheses. The cause of recurrent obstructive jaundice can be diagnosed quickly and a new intervention can be planned carefully.

Renal biopsy: in vitro and in vivo comparison of a new automatic biopsy device and conventional biopsy systems. Work in progress.

A nondisposable full-cut biopsy gun with a disposable needle (system 1, prototype of system 2) and a disposable gun-needle combination (system 2) were compared with conventional needles and Tru-Cut-type biopsy systems in renal parenchymal biopsy procedures. In cadaveric kidneys, more glomeruli were harvested with system 1 than with four other biopsy systems. In native kidneys, more glomeruli were harvested and core quality was better with system 2 than with a Tru-Cut-type biopsy gun.

65zinc metabolism is altered during diabetic pregnancy in rats.

To assess further diabetes-induced alterations in gestational Zn metabolism we examined the uptake/retention and distribution of 65Zn during pregnancy. Control and streptozotocin-induced diabetic rats, with and without insulin treatment, were gavaged with 65Zn on gestational d 12 or 18. Six hours post-intubation, untreated diabetic dams at d 12 of gestation had a lower percentage of retained 65Zn in bone, plasma, erythrocytes, pancreas and spleen than did controls. Retention of 65Zn in amniotic fluid and sacs and in embryos was similar among groups. Untreated diabetic dams at d 18 of gestation had a higher percentage of retained 65Zn in liver, intestine and urine, and most notably a lower percentage in amniotic fluid, placenta, fetus and fetal liver. Lower percentages of 65Zn were found in bone, muscle, plasma, erythrocytes, lung, spleen, heart, pancreas and uterus of diabetic dams compared with controls. HPLC fractionation of samples from maternal livers showed a higher percentage of Zn, Cu and 65Zn associated with the metallothionein peak in samples from untreated diabetic dams compared with other groups, whereas the percentages of Zn, Cu and 65Zn per fraction in fetal liver were similar. The marked decrease in retained 65Zn in products of conception at d 18 suggests either decreased placental transport or altered maternal and/or fetal Zn-binding ligands. Insulin treatment significantly reversed the streptozotocin diabetes-induced derangements in maternal and fetal Zn metabolism.

Coaxial transthoracic fine-needle biopsy in patients with a history of malignant lymphoma.

Efficacy and safety of coaxial transthoracic fine-needle biopsy were evaluated in 54 patients with a history of malignant lymphoma and new chest lesions. Twenty-one patients had recurrent lymphoma. Correct diagnosis was made in 17 of the 21 patients (81%) after one biopsy. The sensitivity increased to 95% with repeat needle biopsy in three patients. Immunophenotyping (determining phenotype by means of immunologic examination) was essential for a definitive diagnosis of lymphoma in three patients. Non-lymphomatous malignancies were correctly diagnosed in 14 patients. An infectious organism was identified in 11 of 19 patients (58%) with benign lesions. Pneumothorax occurred in eight patients (15%), necessitating placement of a chest tube in two (4%). Mild hemoptysis was observed in four patients (7%). The authors conclude that coaxial transthoracic fine-needle biopsy in patients with a history of lymphoma is safe and accurate. The use of large cutting needles or surgical biopsy can be restricted to patients with false-negative findings at percutaneous biopsy and to patients in whom histologic transformation of lymphoma is suspected.

Copper, zinc, manganese, and magnesium status and complications of diabetes mellitus.

OBJECTIVE: To evaluate copper, zinc, manganese, magnesium, and other indices of peroxidative status in diabetic and nondiabetic human subjects. RESEARCH DESIGN AND METHODS: Convenience sample of 57 insulin-dependent or non-insulin-dependent diabetic subjects recruited from the diabetes clinic of the University of California, Davis, Medical Center and 28 nondiabetic subjects recruited from the staffs of the Departments of Internal Medicine and Nutrition. Individuals conducting laboratory analyses were blind to subject group. A fasting blood sample was collected from all subjects and appropriately processed for future analyses. A 24-h urine collection was obtained in a subset of subjects. RESULTS: Hyperzincuria and hypermagnesuria were evident in diabetic subjects compared with control subjects. There were no differences in plasma magnesium or whole-blood manganese between groups. Plasma copper was higher and plasma zinc was lower in diabetic than in control subjects. When data were viewed with respect to specific diabetes-associated complications, diabetic subjects with retinopathy, hypertension, or microvascular disease had higher plasma copper concentrations compared with both diabetic subjects without complications and with control subjects. There were no significant differences between control and diabetic subjects in erythrocyte copper-zinc superoxide dismutase activity or whole-blood glutathione peroxidase or glutathione reductase activities. Plasma peroxide concentrations were higher in diabetic than control subjects. CONCLUSIONS: Diabetes can alter copper, zinc, magnesium, and lipid peroxidation status. Perturbations in mineral metabolism are more pronounced in diabetic populations with specific complications. It is not known whether differences in trace element status are a consequence of diabetes, or alternatively, whether they contribute to the expression of the disease.

[The percutaneous ultrasonic-guided fluoroscopy-controlled drainage of pericardial fluids]. / Perkutane ultraschallgezielte und durchleuchtungskontrollierte Drainage perikardialer Flüssigkeiten.

The results of 25 ultrasonographically guided percutaneous pericardial drainage procedures and of one pericardiocentesis performed in 25 patients with pericardial fluid collections are reported. After initial puncture of the pericardial cavity under sonographic guidance, dilatation and placement of 5F to 8.3F catheters in Seldinger technique was controlled fluoroscopically in 22 procedures. Clinical indications were emergency treatment of tamponade (n = 6) or urgent treatment of large (n = 14) pericardial effusions. The remaining 6 procedures were performed to establish specific diagnoses of small effusions. Puncture sites were subxiphoid in 23 and left parasternal in 3 cases. The volume of aspirated fluid ranged from 20 to 1710 ml (median: 615 ml). Median duration of pericardial drainage was 3 days (range less than 1 day to 21 days). A specific diagnosis was obtained in 48% of patients. 4 patients had subsequent elective surgical intervention for recurrent effusion or for pericardial biopsy. Three minor complications included one vasovagal reaction and two asymptomatic pneumothoraces. Percutaneous ultrasonically guided and fluoroscopically controlled placement of a pericardial catheter is safe and effective for treatment and diagnosis of pericardial effusions.

Prolactin responses in dexamethasone suppression test in patients with anorexia nervosa.

In anorexia nervosa (AN), abnormalities are present in the hypothalamic-pituitary-adrenal axis, but the prolactin (PRL) response to dexamethasone suppression test (DST) has not yet been studied. In order to study the interrelationships between the various endocrine abnormalities, we investigated the responses of PRL and cortisol to DST (1 mg of dexamethasone at 2300) in AN patients. The subjects were 12 female inpatients with AN and 8 age- and sex-matched healthy controls. The percentage suppression and absolute change in PRL levels before and after dexamethasone administration were significantly different in the 2 groups. In the control group PRL levels suppressed to 36.5 +/- 3.7% of basal, while AN levels declined to 79.4 +/- 8.9% of basal. When the percentage suppression of PRL was compared between patients with and without cortisol suppression, the mean PRL level was 68.9 +/- 7.8% of the basal level for the cortisol-suppressed patients and 100.4 +/- 19.1% for the nonsuppressed patients. Hence in both groups, the percentage PRL suppression was significantly reduced compared with the control group, and indeed nonexistent in cortisol-nonsuppressed patients. The finding that there was less PRL suppression in the cortisol-suppressed patients than in the controls suggests that, in AN, there may be an abnormality in PRL secretion not related to the hypothalamic-pituitary-adrenal axis. Further work is needed to distinguish between the PRL response to stress and potential hypothalamic abnormality.

Hypoglycemia: still a risk in the elderly.

Hypoglycemia is an underappreciated and potentially fatal complication of insulin and sulfonylurea treatment of diabetes mellitus in the elderly. After several years of diabetes, patients typically lose glucagon and epinephrine responses to hypoglycemia, resulting in loss of adrenergic warning symptoms, as well as prolongation of hypoglycemic episodes. Also of pertinence to the elderly, renal disease, liver disease, congestive heart failure, hypothyroidism, hypoadrenalism, medications, and inadequate monitoring may also contribute to hypoglycemia. The benefits of tight control can be observed only if it is applied to appropriately selected patients.