Dupilumab Drug Survival and Associated Predictors in Patients With Moderate to Severe Atopic Dermatitis: Long-term Results From the Daily Practice BioDay Registry.

Importance: Long-term data on dupilumab drug survival in patients with atopic dermatitis (AD) are scarce. Furthermore, little is known about the factors associated with drug survival of dupilumab in AD. Objective: To describe the drug survival of dupilumab in patients with AD and to identify associated predictors. Design, Setting, and Participants: This cohort study was based on data from the multicenter prospective daily practice BioDay registry, in which 4 university and 10 nonuniversity hospitals in the Netherlands participated. Analysis included patients (age ≥18 years) participating in the BioDay registry with a follow-up of at least 4 weeks. The first patient treated with dupilumab was recorded in the BioDay registry in October 2017; data lock took place in December 2020, and data analysis was performed from October 2017 to December 2020. Main Outcomes and Measures: Drug survival was analyzed by Kaplan-Meier survival curves and associated characteristics by using univariate and multivariate Cox regression analysis. Results: A total of 715 adult patients with AD (mean [SD] age, 41.8 [16.0] years; 418 [58.5%] were male) were included with a 1-year, 2-year, and 3-year overall dupilumab drug survival of 90.3%, 85.9%, and 78.6%, respectively. Characteristics associated with shorter drug survival owing to ineffectiveness were the use of immunosuppressant drugs at baseline (hazard ratio [HR], 2.64; 95% CI, 1.10-6.37) and being a nonresponder at 4 weeks (HR, 8.68; 95% CI, 2.97-25.35). Characteristics associated with shorter drug survival owing to adverse effects were the use of immunosuppressant drugs at baseline (HR, 2.69; 95% CI, 1.32-5.48), age 65 years or older (HR, 2.94; 95% CI, 1.10-7.87), and Investigator Global Assessment score of very severe AD (HR, 3.51; 95% CI, 1.20-10.28). Conclusions and Relevance: This cohort study demonstrated a good overall 1-year, 2-year, and 3-year dupilumab drug survival. Patients using immunosuppressive therapy at baseline and those with an absence of treatment effect at week 4 tended to discontinue treatment owing to ineffectiveness more frequently. Using immunosuppressant drugs at baseline, older age, and Investigator Global Assessment score of very severe AD were characteristics associated with an increased risk for discontinuation owing to adverse effects. These data provide more insight and new perspectives regarding dupilumab treatment in AD and can contribute to the optimization of patient outcomes.

Modelling frequency- and voltage-dependent effects of a class I antiarrhythmic drug (nicainoprol) on Vmax of the cardiac action potential from guinea-pig papillary muscle.

Frequency- and voltage-dependent effects of a class I antiarrhythmic agent (nicainoprol) on the maximal upstroke velocity (Vmax) of the action potential of guinea-pig papillary muscle are compared with the effects predicted by a kinetic model of frequency- and voltage-dependent block of fast sodium channels. The model is based on the guarded-receptor hypothesis, which assumes a constant affinity binding site with the drug access to and egress from the binding site being controlled by the channel conformational state. At normal resting membrane potential (RMP approximately -86 mV) nicainoprol (3.3 x 10(-6) mol/l and 10(-5) mol/l) causes no Vmax-reduction after a resting period (i.e. no resting block) but a frequency-dependent decrease of Vmax (frequency-dependent block), which saturates at above 2.0 Hz. Both, resting and frequency-dependent block strongly depend on the RMP in a way that the frequency-dependent block decreases with depolarizing RMP while the resting block increases. Development of and recovery from frequency-dependent block is faster at depolarized RMP. These results can be interpreted in terms of the guarded-receptor hypothesis with nicainoprol preferentially binding to inactivated sodium channels. All its effects on Vmax can be fully described by only three model parameters: a binding rate coefficient (kB = 8.49 x 10(3) mol-1.1.s-1), an unbinding rate coefficient (k-B = 6.24 x 10(-2).S-1), and a parameter with the meaning of an electrical location of the binding site (about 35% on the way through the membrane field from the extracellular surface).

Electrophysiological profile of the antiarrhythmic compound asocainol studied on perfused guinea-pig hearts and on isolated cardiac preparations.

The studies deal with electrophysiological effects of asocainol [(+/-)-6,7,8,9-tetrahydro-2,12-dimethoxy-7-methyl-6-phenetyl-5 H-dibenz(d,f)azonine-1-ol] on isolated perfused guinea-pig hearts (Langendorff-preparation), on right ventricular papillary muscles, on Purkinje fibres from the guinea pig, and on isolated sinus nodes from the rabbit. In the perfused heart (n = 5) the lowest effective concentration of asocainol is about 0.2 mumol/l. At a concentration of 2 mumol/l the cardiac electrogram shows in spontaneously beating hearts a mean decrease in frequency of 15%, in electrically driven hearts (150/min at 32 degrees C) prolongation of PQ (+31%), of QRS (+24%) and of QT (+5%). In papillary muscles (32 degrees C; K+e 5.9 mmol/l; stimulation rate 0.5 Hz) asocainol (3-30 mumol/l) exerts the following effects: no change of the resting potential, concentration-dependent reduction of the maximum rate of rise (Vmax) of the action potential (AP) (-16 to -67%) as well as of the AP-amplitude (-4 to -16%), and shortening of the AP-duration at 50% repolarisation (-18 to -43%). The steady-state dependence of Vmax on the resting potential (RP) determined by variation of K+e (5.9-15 mmol/l) is shifted by asocainol to more negative potentials. The percentage deviation from controls of the Vmax-RP relationship is more pronounced at lower membrane potentials. The influence of asocainol on the recovery from inactivation of Vmax shows marked time-dependence. Slow response (Ca2+-mediated) APs elicited by strong stimuli in a K+e-rich solution (K+e 20-24 mmol/l) respond to asocainol (3-10 mumol/l) with a marked reduction in amplitude, Vmax and duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a new antiarrhythmic compound [2-benzal-1-(2' diisopropyl-amino-ethoxy-imino)-cycloheptane hydrogen fumarate] on the electrophysiological properties of mammalian cardiac cells.

Intracellular microelectrodes were used to study the effects of Th 494 [2-benzal-1-(2' diisopropyl-amino-ethoxy-imino)-cycloheptane hydrogen fumarate; 1-100 mumol/1) on transmembrane electrical activity of sinus node and Purkinje fibres of the rabbit as well as on atrial trabeculae and papillary muscles of the guinea pig. In the atrial and in the ventricular myocardium (32 degrees C; driving rate 0.3-0.5 Hz) Th 494 exerted the following electrophysiological actions: no change of the resting potential nor of the amplitude of the action potential; concentration- dependent reduction of the maximum rate of rise (dV/dt)max of the action potential; slight increase of the action potential duration at lower concentrations (1-20 mumol/l), loss of the plateau at higher concentrations (above 20 mumol/l). The isometric force of contraction was moderately reduced by Th 494 (about 20% reduction by 2 mumol/l). The h infinity-curve relating (dV/dt)max of the action potential to the membrane potential was depressed by Th 494 without being shifted along the voltage axis. The reduction of (dV/dt)max was considerably more pronounced at higher driving frequencies. After interruption of stimulation for various periods, (dV/dt) max of the first action potential attained a steady-state value in a two-exponential fashion, suggesting use-dependence as well as a change in the recovery kinetics of the fast Na+ channel by Th 494. In Purkinje fibres (37 degrees C) Th 494 reduced (dV/dt) max in a similar manner. The duration of the action potential was considerably decreased at the level of the plateau. In the primary pacemaker region of the sinus node (37 degrees C) Th 494 moderately reduced the rate of diastolic depolarization and diminished at higher concentrations the amplitude of the action potential. All effects of Th 494 were only slowly reversible by drug-free perfusion. In view of its effect on (dV/dt) max, Th 494 resembles quinidine in its potential-dependence, whereas its time-dependence bears greater similarity with lidocaine.

Postoperative astigmatism and relative strength of tunnel incisions: a prospective clinical trial.

PURPOSE: To investigate the influence of incision depth and site on wound strength and postoperative astigmatism. SETTING: Virchow Memorial Hospital Eye Clinic, Berlin, Germany. METHODS: In this prospective, randomized study, 180 patients with a 7.0 mm tunnel incision depth of 300 and 500 microns; limbal incision and scleral incision; temporal scleral incision and scleral incision at the 12 o'clock position; temporal limbal incision and limbal incision at the 12 o'clock position. Postoperative astigmatism was measured by keratometry and videokeratoscopy 1 day, 1 and 4 weeks, and 8 months postoperatively. Wound strength was measured with an ophthalmodynamometer on the first postoperative day and after 1 week at the site with the least mechanical stability adjacent and posterior to the primary incision. RESULTS: The temporal incision, which was performed 1.0 mm behind the surgical limbus, led to induced astigmatism of 0.65 diopters (D) +/- 0.23 (SD) after 8 months. When incision was at the 12 o'clock position, the induced astigmatism was 0.97 +/- 0.41 D. Induced astigmatism was highest following a limbal incision in the 12 o'clock position (1.33 +/- 0.63 D). This effect was less pronounced with a temporal incision. Incision depth did not significantly influence induced astigmatism. An incision depth of 500 microns led to induced astigmatism of 0.94 +/- 0.50 D; a depth of 300 microns led to induced astigmatism of 0.78 +/- 0.64 D. After 1 week, wound strength was highest with temporal scleral incisions (38.6 +/- 2.1 kPa by ophthalmodynamometer) and lowest with limbal incisions in the 12 o'clock position (30.8 +/- 7.7 kPa). CONCLUSIONS: Incisions site significantly influenced mechanical wound strength and induced astigmatism; incision depth influenced neither. In general, incisions in the 12 o'clock position induced more astigmatism than temporal incisions.

[Cataract surgery in narrow pupil and postoperative fibrin reaction, especially after sphincterectomy]. / Kataraktchirurgie bei enger Pupille und postoperative Fibrinreaktion, insbesondere nach Sphinkterektomie.

BACKGROUND: Since increased intraoperative iris irritation can lead to increased postoperative inflammation, we are interested in postoperative reactions to several varied surgical procedures. We performed pupil stretching, iridotomy with iris suture, and partial sphincterectomy. MATERIALS AND METHODS: From January 1995 to January 1996, 100 patients (103 eyes) with narrow pupils underwent cataract surgery. In 13 eyes a iridotomy and iris suture were performed, in 28 eyes a partial sphincterectomy. In 62 eyes there was no surgical intervention after pupil stretching. Postoperative examinations were carried out in the early postoperative phase (up to 5 days postoperative) as well as 4 weeks after surgery. Fibrin reaction was classified according to 3 grades, (1) faint fibrinous threads, (II) fibrinous net, and (III) membranous fibrin exsudation. RESULTS: In the group without additional surgery there was a fibrinous reaction of grade I and II in 11 eyes. This complication occurred after iridotomy and iris suture in four cases and after sphincterectomy in four cases. While the intensity of fibrinous reaction was comparable in the first two groups, the fibrinous reaction after sphincterectomy was more intensive in one eye (grade III). However, response to intensive local antiphlogistic therapy was good. Frequency of fibrinous reaction in the three groups was statistically not significant. It should be pointed out that there was a partial restoration of pupil movements through sphincterectomy: mean pupil diameter was 4 mm, and 2.5 mm under exposure to light. Three patients had no pupillary reaction at all. CONCLUSIONS: Partial sphincterectomy facilities intraoperative manipulations of cataract surgery. Postoperative inflammatory reaction is rare and was very responsive to medical treatment. The reconstruction of pupillary movement is part of full visual function and, last but not least a round pupil is aesthetically more desirable.

[3 1/2 years experiences with ECCE with tunnel incision]. / Dreieinhalb Jahre Erfahrung bei ECCE mit Tunnelschnitt.

Since January 1992 planned extracapsular cataract extraction (ECCE) is performed routinely with the no-stitch technique at our clinic. To minimize surgically induced astigmatism further, modified wound constructions for planned ECCE with on 1.1-mm tunnel width were evaluated. The follow-up time was up to 3 years postoperatively. For 250 eyes wound closure was performed prospectively either sutureless (n = 70), with a single perpendicular suture (n = 100) or cross sutures (n = 40) at the 12 o'clock position or sutureless in the temporal position (n = 40). The complication rate was 4% (filtering bleb, iris prolapse or transient hypotonia). There were no wound ruptures, but once endophthalmitis was observed. Late mean astigmatism after up to 3 years follow-up for vertical incision was 2.05 +/- 1.16 D (1.01 +/- 0.96 D preoperatively) for sutureless wound closure, 1.63 +/- 1.08 D (0.86 +/- 0.95 D) for perpendicular and 1.76 +/- 0.88 D (0.73 +/- 0.55 D) for cross-sutures. A temporal incision resulted in 0.78 +/- 0.52 D (1.0 +/- 0.69 D) of astigmatism and was only performed on eyes with against the rule astigmatism preoperatively. Surgically induced astigmatism was stabilized early. For with the rule astigmatism preoperatively, a 12 o'clock incision with a perpendicular single suture is recommended and for against the rule astigmatism, a temporal incision.

Assessment of selected B cells populations in the workers of X-ray departments.

OBJECTIVES: Workers of X-ray departments are occupationally exposed to long-term low levels of ionizing radiation (LLIR), which may affect their humoral immunity. The aim of the study was to assess the influence of LLIR on the number and proportion of B cells (CD19+), B1 cells (CD5+CD19+) and memory B cells (CD27+CD19+) in peripheral blood of such workers. MATERIALS AND METHODS: In the study group of 47 X-ray departments workers and the control group consisting of 38 persons, the number and percentage of CD19+, CD5+CD19+, CD27+CD19+ cells as well as CD5+CD19+/CD19+ and CD27+CD19+/CD19+ cell ratios were assessed using flow cytometry. Additionally, the study group was divided into 2 groups by the length of employment below and over 15 years and analysis adjusted for age and smoking habit was performed. RESULTS: The total number of CD19+ cells showed significant increase in the group of workers in comparison with the persons from the control group, whereas the percentage of CD5+CD19+ cells as well as CD27+CD19+/CD19+ and CD5+CD19+/CD19+ cell ratios were lower. Percentage, number of CD5+CD19+ cells and CD5+CD19+/CD19+ cell ratio were significantly lower in the workers with length of employment longer than 15 years in comparison with those employed below 15 years. Moreover, we found positive associations between the number of CD19+ cells and employment as well as smoking habit, whereas the number of CD5+CD19+ cells was positively associated with cigarette smoking alone. Percentage of CD5+CD19+ cells as well as CD5+CD19+/CD19+ and CD27+CD19+/CD19+ cell ratios were negatively correlated with employment. CONCLUSIONS: The study suggests association between the suppressive influence of low level ionizing radiation on circulating in peripheral blood, especially of B1 cells as well as of memory B cells, in workers of X-ray units, which is adverse in relation to microbiological threat.

Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand?

AIM: Since the introduction of chemotherapy, survival in localised high-grade osteosarcoma has improved considerably. However, there is still no worldwide consensus on a standard chemotherapy approach. In this systematic review evidence for effectiveness of each single drug and the role of response guided salvage treatment of adjuvant chemotherapy are addressed, whereas in a meta-analysis the number of drugs in current protocols is considered. METHODS: A systematic literature search for clinical studies in localised high-grade osteosarcoma was undertaken, including both randomised and non-randomised trials. Historical clinical studies from the pre-chemotherapy era were included for comparison purposes. RESULTS: Nine historical studies showed a long-term survival of 16% after only local treatment. Fifty single agent phase II studies showed high response rates for adriamycin (A, 43%), ifosfamide (Ifo, 33%), methotrexate (M, 32%), cisplatin (P, 26%) but only 4% for etposide (E). In 19 neo-adjuvant studies the mean 5-year event free survival (EFS) was 48% for 2-drug regimens and 58% for ⩾3 drug regimens, with a 5-year overall survival (OAS) of 62% and 70%, respectively. Meta-analysis showed that ⩾3 drug regimens including methotrexate plus adriamycin plus cisplatin (plus ifosfamide) (MAP(Ifo)) had significant better outcome (EFS: HR=0.701 (95% confidence interval [95% CI]: 0.615-0.799); OAS: HR=0.792 (95% CI: 0.677-0.926) than 2-drug regimens, but there was no significant difference between MAP and MAPIfo (or plus etoposide). Salvage of poor responders by changing drugs, or intensifying treatment postoperatively has not proven to be useful in this analysis. CONCLUSION: Meta-analysis in patients with localised high-grade osteosarcoma shows that 3-drug regimens, for example MAP are the most efficacious drug regimens.

Radiofrequency ablation of spinal osteoid osteoma: clinical outcome.

STUDY DESIGN: A prospective study on 24 patients with spinal osteoid osteoma treated with radiofrequency ablation (RFA). OBJECTIVE: To determine if and when computed tomography (CT)-guided RFA is a safe and effective treatment for spinal osteoid osteomas. SUMMARY OF BACKGROUND DATA: Surgery has been considered the standard treatment for spinal osteoid osteomas. Surgery may cause spinal instability, infection, and nervous injury. We evaluated CT-guided RFA as an alternative treatment. METHODS: A total of 28 RFA procedures in 24 patients with spinal osteoid osteoma were performed, using a 5-mm noncooled electrode. Clinical symptoms and spinal deformity were evaluated before and after the procedure. Unsuccessful treatment was defined as the presence of residual or recurrent symptoms. The mean follow-up was 72 months (range: 9-142 months). RESULTS: Nineteen (79%) patients were successfully treated after 1 RFA, and all except one after repeat RFA. One patient with nerve root compression needed further surgery. No complications were observed. Spinal deformity persisted in 3 of 7 patients after successful RFA. CONCLUSION: CT-guided RFA is a safe and effective treatment for spinal osteoid osteoma. Surgery should be reserved for lesions causing nerve root compression.

The healing pattern of osteoid osteomas on computed tomography and magnetic resonance imaging after thermocoagulation.

OBJECTIVE: To compare the healing pattern of osteoid osteomas on computed tomography (CT) and magnetic resonance imaging (MRI) after successful and unsuccessful thermocoagulation. MATERIALS AND METHODS: Eighty-six patients were examined by CT and 18 patients by dynamic gadolinium-enhanced MRI before and after thermocoagulation for osteoid osteoma. Thermocoagulation was successful in 73% (63/86) and unsuccessful in 27% (23/86) of patients followed by CT. Thermocoagulation was successful in 72% (13/18) of patients followed by MRI. After treatment, the healing of the nidus on CT was evaluated using different healing patterns (complete ossification, minimal nidus rest, decreased size, unchanged size or thermonecrosis). On MRI the presence of reactive changes (joint effusion, "oedema-like" changes of bone marrow and soft tissue oedema) and the delay time (between arterial and nidus enhancement) were assessed and compared before and after thermocoagulation. RESULTS: Complete ossification or a minimal nidus rest was observed on CT in 58% (16/28) of treatment successes (with > 12 months follow-up), but not in treatment failures. "Oedema-like" changes of bone marrow and/or soft tissue oedema were seen on MR in all patients before thermocoagulation and in all treatment failures. However, residual "oedema-like" changes of bone marrow were also found in 69% (9/13) of treatment successes. An increased delay time was observed in 62% (8/13) of treatment successes and in 1/5 of treatment failures. CONCLUSION: Complete, or almost complete, ossification of the treated nidus on CT correlated with successful treatment. Absence of this ossification pattern, however, did not correlate with treatment failure. CT could not be used to identify the activity of the nidus following treatment. The value of MR parameters to assess residual activity of the nidus was limited in this study.

[Pathophysiology of cardiac arrhythmias]. / Pathophysiologie der Herzrhythmusstörungen.

Cardiac arrhythmias are ambiguous symptoms. Intracardiac as well as extracardiac alterations may be responsible. There is little direct information from the ECG concerning their pathophysiological mechanism. Bradycardic as well as tachycardic arrhythmias can be the result of two different fundamental disturbances: alterations of impulse formation (automaticity) or alterations of impulse conduction. Either one of these, or both of them acting together, may be responsible for the arrhythmia. Tachycardias due to disturbances of impulse formation may be brought about by enhanced firing of regular pacemakers (sino-atrial node, av-node, ventricular conduction system), by abnormal automaticity occurring in ordinary atrial or ventricular myocardium, or by triggered activity due to early or delayed afterdepolarizations. Bradycardic disturbances of impulse formation are primarily concerned with sino-atrial nodal function. Bradycardic conduction disturbances mainly impair sinoatrial or atrioventricular propagation causing partial or total conduction block. Tachyarrhythmias due to disturbances of conduction are generated by re-entry of excitatory waves either along anatomically preformed pathways or around functional obstacles (refractory zones) with excitable gaps being more or less pronounced. On the cellular level, altered activities of ionic channels or transport systems play a significant part. Such changes are caused by: alterations of electrolyte composition (potassium, sodium, calcium), acidosis or alkalosis, autonomic and hormonal influences, membrane active metabolites (long-chain acylcarnitine, lysophosphatidylcholine), drugs (class I and III antiarrhythmics, cardiac glycosides) and poisons. In disturbances of conduction other aspects like geometry of pathways or cable properties (anisotropic conduction, coupling resistances between cells) are of particular significance.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pathophysiology of cardiac arrhythmias involving autonomic transmitters]. / Pathophysiologie kardialer Arrhythmien unter Beteiligung autonomer Transmitter.

In general cardiac arrhythmias of different types and origins may be attributed to only a few basic electrophysiological effects. These are: changes in impulse formation, in impulse conduction, and/or in refractoriness. Autonomic transmitters are able to exert these effects on the heart and may therefore also induce or support cardiac arrhythmias. The stimulation of sympathetic nerves to the heart (transmitter noradrenaline) enhances via adrenergic beta-receptors the formation of impulses in nomotopic and heterotopic pacemakers by increasing the slope of their slow diastolic depolarizations. In principle identical effects are exerted by noradrenaline on abnormal ectopic pacemakers. Moreover, so-called triggered activity resulting from early or delayed after-depolarizations may be induced by sympathetic activation. In the normal atrial or ventricular myocardium as well as in the specialized ventricular conducting system the sympathetic transmitters are without direct influence on the conduction velocity. However, in the AV node, conduction velocity is markedly increased by noradrenaline. In the depolarized myocardium noradrenaline favours the generation of slowly propagated responses and may thus help to induce arrhythmias due to reentry. The refractory period is shortened by noradrenaline in the working myocardium and in the specialized conducting system. The described effects of noradrenaline are attributed to an increase of the slow inward current (Isi) carried by Ca2+ and Na+ ions. Moreover, a shift of the activation kinetics of the pacemaker current (If) to more positive potentials is discussed. Under the influence of beta receptor blockers, certain effects of noradrenaline may be unmasked which are mediated by adrenergic alpha receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Elementary events in excitation-contraction coupling of the mammalian myocardium.

Excitation-contraction coupling of the mammalian myocardium is widely assumed to comprise the following chain of events: (1) Influx of Ca++ into the cell during the plateau phase of the action potential as well as Ca++ release from the subsarcolemmal cisternae of sarcoplasmic reticulum. (2) Activation of the contractile proteins by interaction of Ca++ with the troponin-tropomyosin system. (3) Relaxation due to reuptake of Ca++ by the sarcotubular system as well as by pumping of Ca++ out of the cell through the surface membrane and the transverse tubular system. (4) Movement of Ca++ in the longitudinal tubules back to the subsarcolemmal cisternae. A short comment is included about the effects of hypertrophy on the excitatory processes as well as on cellular structural constituents directly involved in excitation-contraction coupling.

Disturbances of transmembrane ionic fluxes and their role in the pathogenesis of cardiac dysrhythmias.

Abnormalities of cardiac rhythm are due either to disorders of impulse propagation (delay or block of conduction, re-entry, circus movement, etc.), or to disturbances of impulse formation (dysfunction of ordinary pacemakers and induction of focal activity). In most instances certain disturbances of transmembrane movements of Na or K ions may be considered to be involved basically in the genesis of dysrhythmic cardiac activity. By means of intracellular recordings as well as of voltage clamp measurements and of analogical computations it is demonstrated that characteristic changes of the membrane potential might result from entirely different ionic mechanisms. Furthermore, an attempt is made to present a detailed analysis of permeability changes underlying normal pacemaker activity in Purkinje fibers as compared with the sinus node or with focal activity induced in myocardial fibers by different influences (aconitine, barium ions, stretch, and strong currents).