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BackgroundVariants in KCNH2, encoding the hERG channel which is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to Long QT Syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C>T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making.MethodsA genotype-phenotype overview of the patients and relatives was created. The biophysiological effects were assessed by manual whole-cell patch-clamp using HEK293a cells expressing: (I) wild type (WT) KCNH2, (II) KCNH2-p.S906L alone (homozygous, Hm) or (III) KCNH2-p.S906L in combination with WT (1:1) (heterozygous, Hz). A calibrated automated patch-clamp assay using Flp-In HEK293 was used to follow up on the functional data.ResultsIncomplete penetrance of LQTS2 in KCNH2:p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2, or AKAP9. The phenotype of carriers of KCNH2:p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch-clamp showed a reduced current density by 69.8%, and 60.4% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2-p.S906L-Hm compared to KCNH2-WT. Assessment of KCNH2-p.S906L-Hz, by calibrated automatic patch-clamp showed a reduction in current density by 35.6%.ConclusionThe reduced current density in the KCNH2-p.S906L-Hz indicates a moderate loss of function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2:p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.

White the difficulty of a motor task can act as a stimulus for learning in younger adults, it is unknown how task difficulty interacts with age-related reductions in motor performance and altered brain activation. We examined the effects of task difficulty on motor performance and used electroencephalography (EEG) to probe task-related brain activation after acquisition and 24-h retention of a mirror star-tracing skill in healthy older adults (N = 36, 65-86 years). The results showed that the difficulty of the motor skill affected both the magnitude of motor skill learning and the underlying neural mechanisms. Behavioral data revealed that practicing a motor task at a high difficulty level hindered motor skill consolidation. The EEG data indicated that task difficulty modulated changes in brain activation after practice. Specifically, a decrease in task-related alpha power in frontal and parietal electrodes was only present after practice of the skill at the low and medium, but not the high difficulty level. Taken together, our findings show that a failure to engage neural plasticity through practice of a highdifficulty task is accompanied by reduced motor skill retention in older adults. The data help us better understand how older adults learn new motor skills and might have implications for prescribing motor skill practice according to its difficulty in rehabilitation settings. (c) 2020 The Author(s). Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Dutch Research Council (NWO Talent Scheme) Background Variants in KCNH2, the gene encoding the hERG channel and responsible for the cardiac rapid delayed rectifier K+ current (IKr), have been linked to Long QT Syndrome type 2 (LQTS2). The KCNH2-p.S906L variant has been found in eight, small unrelated families with variable clinical pictures and incomplete penetrance of LQTS2. Purpose Due to the small size of the families, co-segregation analysis is limited. Functional studies were performed to evaluate the effect of the variant on channel functionality. Thereby assessing if KCNH2-p.S906L leads to functional changes explanatory for the phenotype. Methods Clinical data of the patients and family members were collected thereby, creating an overview of the phenotype. The biophysiological properties of the hERG channel were assessed by manual whole-cell patch-clamp, using HEK293a cells expressing (i) the wild type (WT) KCNH2, (ii) KCNH2-p.S906L alone (homozygous, hm) or KCNH2-p.S906L in combination with WT (heterozygous, Hz). Results Assessment of the clinical data of the patients and family members shows an incomplete and low penetrance of the LQTS2. All carriers were heterozygous for the variant. In carriers of the KCNH2-p.S906L variant, LQTS2 severity was very variable, ranging from asymptomatic, to life-threatening arrhythmic events. The KCNH2-p.S906L variant reduced current density in a dosage-dependent manner compared to KCNH2-WT. The current density was reduced by 63, and 54% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. Changes in gating properties were absent, except for activation kinetics in KCNH2-p.S906L-Hm. In these cells, an increase in the time constant, and a positive shift in voltage dependency of activation were observed. Conclusions Both the reduced current density and changes in activation kinetics suggest the variant to result in a moderate loss-of-function of the hERG channel, fitting with the observed LQTS2. These observed functional changes in hERG combined with the reduced penetrance in the affected individuals suggest that this variant in KCNH2 is a risk factor for LQTS2.

For many decades, the clinical unmet needs of primary Sjögren's Syndrome (pSS) have been left unresolved due to the rareness of the disease and the complexity of the underlying pathogenic mechanisms, including the pSS-associated lymphomagenesis process. Here, we present the HarmonicSS cloud-computing exemplar which offers beyond the state-of-the-art data analytics services to address the pSS clinical unmet needs, including the development of lymphoma classification models and the identification of biomarkers for lymphomagenesis. The users of the platform have been able to successfully interlink, curate, and harmonize 21 regional, national, and international European cohorts of 7,551 pSS patients with respect to the ethical and legal issues for data sharing. Federated AI algorithms were trained across the harmonized databases, with reduced execution time complexity, yielding robust lymphoma classification models with 85% accuracy, 81.25% sensitivity, 85.4% specificity along with 5 biomarkers for lymphoma development. To our knowledge, this is the first GDPR compliant platform that provides federated AI services to address the pSS clinical unmet needs. © 2022 The Author(s)

Although a general age-related decline in neural plasticity is evident, the effects of age on neural plasticity after motor practice are inconclusive. Inconsistencies in the literature may be related to between-study differences in task difficulty. Therefore, we aimed to determine the effects of age and task difficulty on motor learning and associated brain activity. We used task-related electroencephalography (EEG) power in the alpha (8–12 Hz) and beta (13–30 Hz) frequency bands to assess neural plasticity before, immediately after, and 24-h after practice of a mirror star tracing task at one of three difficulty levels in healthy younger (19–24 yr) and older (65–86 yr) adults. Results showed an age-related deterioration in motor performance that was more pronounced with increasing task difficulty and was accompanied by a more bilateral activity pattern for older vs. younger adults. Task difficulty affected motor skill retention and neural plasticity specifically in older adults. Older adults that practiced at the low or medium, but not the high, difficulty levels were able to maintain improvements in accuracy at retention and showed modulation of alpha TR-Power after practice. Together, these data indicate that both age and task difficulty affect motor learning, as well as the associated neural plasticity.

Mitochondrial cytopathies include a heterogeneous group of diseases that are characterized by impaired oxidative phosphorylation, leading to multi-organ involvement and progressive clinical deterioration. Most mitochondrial cytopathies that cause kidney symptoms are characterized by tubular defects, but glomerular, tubulointerstitial, and cystic diseases have also been described. Mitochondrial cytopathies can result from mitochondrial or nuclear DNA mutations. Early recognition of defects in the coenzyme Q10 (CoQ10) biosynthesis is important, as patients with primary CoQ10 deficiency may be responsive to treatment with oral CoQ10 supplementation, in contrast to most mitochondrial diseases. A literature search was conducted to investigate kidney involvement in genetic mitochondrial cytopathies and to identify mitochondrial and nuclear DNA mutations involved in mitochondrial kidney disease. Furthermore, we identified all reported cases to date with a CoQ10 deficiency with glomerular involvement, including 3 patients with variable renal phenotypes in our clinic. To date, 144 patients from 95 families with a primary CoQ10 deficiency and glomerular involvement have been described based on mutations in PDSS1, PDSS2, COQ2, COQ6, and COQ8B/ADCK4. This review provides an overview of kidney involvement in genetic mitochondrial cytopathies with a special focus on CoQ10 deficiency.

Introduction Task difficulty affects the amount of interpretable information from a task, which is thought to interfere with motor learning. However, it is unclear whether task difficulty in itself is a stimulus for motor learning because the experimental evidence is mixed in support of the optimal challenge point framework that predicts one specific level of task difficulty to produce the greatest magnitude of motor learning.Purpose We determined the effects of functional task difficulty on motor skill acquisition, retention, and transfer.Methods Healthy young participants (N = 36) learned a mirror star-tracing task at a low, medium, or hard difficulty level defined by the bandwidth of the star. We measured skill acquisition, retention, and transfer to untrained difficulty levels, as well as the perceived mental workload during the task.Results Task difficulty affected motor performance, but did not affect motor learning and transfer. For the groups that practiced the task at the medium and hard but not at the low difficulty level, initial skill level correlated with the magnitude of learning.Conclusions The optimal challenge point framework does not capture the complex relationship between task difficulty and motor learning. Previously reported effects of task difficulty on the magnitude of motor learning are probably mediated by perceived mental workload. Task difficulty did not affect the magnitude of visuomotor skill learning but it affected how learning occurred. The data have implications on how athletes learn new motor skills and patients relearn injury-impaired motor skills during rehabilitation.

Geriatricians have been increasingly involved in the pre-operative process in frail elderly patients with a hip fracture which can benefit re-hospitalization, post-operative functional performance, and mortality. The objective of this study was to compare the number of older patients with hip fractures who opted for non-surgical management after the addition of pre-operative comprehensive geriatric assessment (CGA) with shared decision making by a geriatrician to usual care. Secondary objectives were: reasons for non-surgical management, duration of life, and location of death. A single-center, with a level 2 trauma center, retrospective study comparing care before and after introducing pre-operative CGA with shared decision making in September 2014. Patients ≥ 70 years with a hip fracture, admitted from January 2014 to September 2015, were included. The percentages of patients elected for non-surgical management and palliative care without or with CGA were compared. Differences in secondary objectives (age, sex, medical history, medication use, functional, and social status) were compared descriptively and qualitatively. With pre-operative CGA significantly more patients (or representatives) elected the non-surgical management option after hip fracture (respectively, 9.1% vs 2.7%, p = 0.008). Patient characteristics were comparable. Reported reasons not to undergo surgery include aversion to be more dependent on others, and severe dementia. The geriatrician can have an important role in decisions for non-surgical management by shared decision making in the pre-operative period in patients ≥ 70 years with a hip fracture in the emergency room.

Although many older patients use analgesics from time to time, little is known about the safety and efficacy of these medicines in older people. The balance between effectiveness and side effects may be totally different from what is expected. Physiological and pathophysiological changes can cause the pharmacokinetics and pharmacodynamics of medicines to change. Drug-drug interactions can enhance or decrease the effects of medicines. In frail older people with multimorbidity and polypharmacy in particular, these changes may lead to a higher risk of side effects and a decline in the analgesic effect. The vulnerability of many older people means that even when pain is adequately controlled, concomitant side effects of medicines can have a big negative impact on their general functioning. Pharmacological pain management in older people requires specific competences and knowledge. In this article we present 10 tips for pain management in older people from a pharmacological perspective.

The original version of this article unfortunately contained a mistake. The presentation of Figure 1 was incorrect. The correct version of Figure 1 is given in the following page.

Pulmonary embolism (PE) is a potentially severe diagnosis with high short-term mortality. Recently, age-adjusted cut-off values (age × 10 μg/l) of D-dimer were introduced to improve the diagnostic workup in older patients. In clinical practice, PE is considered 'ruled out' in patients with a non-high clinical probability and a normal D-dimer. However, all diagnostic tests have a small false-negative rate. This small probability of misdiagnosis might be easily overlooked by clinicians when using simplified dichotomized flow charts. This case illustrates a normal D-dimer (age-adjusted) but with a PE. We recommend clinicians using the D-dimer test-either conventional or age-adjusted in a rule-out strategy to be aware of the-albeit small probability of a false-negative result.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a heart muscle disorder of unknown course that is characterised pathologically by fatty or fibrofatty replacement of the right ventricular myocardium and electrical instability. Clinical manifestations include structural and functional malformations of the right ventricle, electrocardiographic abnormalities, and presentation of ventricular tachycardias with left bundle branch pattern or sudden death. The disease is often familial with an autosomal inheritance. In addition to right ventricular dilatation, right ventricular aneurysms are typical deformities of ARVD/C and they are distributed in the so-called 'triangle of dysplasia', i.e. the right ventricular outflow tract, apex and infundibulum. Ventricular aneurysms at these sites can be considered highly suggestive for ARVD/C. Another typical hallmark of ARVD/C is fatty or fibrofatty infiltration of the right ventricular free wall with potential extension to the left ventricle. These functional and morphological characteristics are relevant to clinical imaging investigations such as contrast angiography, echocardiography, radionuclide angiography, ultrafast-computed tomography and magnetic resonance (MR) imaging. Among these techniques, MR imaging allows the most comprehensive assessment of the heart, in particular because it provides functional and flow-dynamic information in addition to anatomic images. Furthermore, MR imaging offers the specific advantage of visualising adipose infiltration as a bright signal of the right ventricular myocardium. Non-pharmacological treatment by radio-frequency ablation and implantable defibrillators will play an increasing role in the treatment of patients with ARVD/C, especially in case of drug ineffectivity. Despite new diagnostic and therapeutic approaches in ARVD/C, there remain many unanswered issues since the current guidelines present criteria that are highly specific but lack sensitivity. Therefore, optimal assessment of diagnostic criteria would require a prospective evaluation from a large population obtained by an international registry.

The goal of this study was to evaluate 1) the presence of psychosocial problems in both ICD patients and their partners, and 2) the relation between psychosocial problems and various clinical variables.Questionnaires were sent to 219 ICD patients and their partners.Sixty-eight percent of the ICD patients, 122 (81%) male, aged 59±12 years, and 62% of their partners, 28 (21%) male, aged 58±11 years, returned the questionnaires. Anxiety, depression or nervousness was reported by 49%, 30% and 52% respectively of the patients and by 36%, 24% and 66% of the partners. In patients, mental health problems were associated with a lower left ventricular ejection fraction (p=0.006), younger age (p=0.029), employment (p=0.011), unpleasant experiences from ICD discharges (p=0.032), prior myocardial infarction (p=0.019) and a higher NYHA functional class (p=0.05). Nervousness was more often reported by partners of ICD patients with prior myocardial infarction (p=0.049). Sixty percent of the partners had a need for counselling or support groups.Psychosocial problems are present in ICD patients and their partners and are associated with a number of clinical variables. A specific ICD rehabilitation programme should therefore not only be offered to ICD patients but to their partners as well.

The Si(111)-Pb interface is a prototypical metal-semiconductor interface and has been the subject of a number of experimental studies. The Schottky barrier height is known to depend on the initial reconstruction formed by the first monolayer of Pb atoms and we have previously shown that there are structural differences between the buried interfaces. We present surface X-ray diffraction measurements of the interface grown from the incommensurate [Formula: see text] reconstruction and show that, in contrast to the starting surface, the interface comprises the junction between unreconstructed, bulk-like Si(111) and disordered, bulk-like Pb(111). This interface is contrasted with the interface formed by growth on the Si(111)-(7 × 7)-Pb reconstruction at which the starting reconstruction is preserved.

The formation of the buried, 7 × 7-reconstructed Si(111)—Pb interface has been studied by X-ray diffraction. Oscillations in the reflected intensity confirm that, at 100 K, the Pb grows layer-by-layer beyond a critical coverage of 6 ml. Measurements of the specular reflectivity show that, at a coverage of 8.4 ml, the film is simply well-ordered Pb(111) with an under occupied first layer consistent with the preservation of the 7 × 7 reconstruction at the buried interface. At low coverages, growth oscillations and specular reflectivity data reveal significant disorder.

Item does not contain fulltext Background: Renin angiotensin system inhibitors (RASIs) are frequently involved in serious adverse events. These events principally occur in high-risk patients and often arise within the first days after treatment initiation; therefore, guidelines recommend biochemical monitoring within 3 weeks after the start of therapy with RASIs. Objective: The purpose of this study was to examine the level of biochemical monitoring directly after treatment initiation with RASIs in patients with different risk profiles and to study the attitudes of the physicians involved towards biochemical monitoring. Methods: We carried out a retrospective analysis of 202 patients who started RASI therapy in 2006 in Groesbeek, the Netherlands. We determined the rate of serum creatinine and potassium monitoring within 3 weeks after the start of therapy. In addition, we studied the intentions and attitudes towards biochemical monitoring during RASI therapy among 68 general practitioners and medical specialists by way of a brief questionnaire. Results: Serum creatinine and potassium monitoring after treatment initiation was performed in 34% and 28% of patients, respectively. Of all the patients, 29% had two or more additional risk factors for renal function deterioration. In these high-risk patients, creatinine was significantly less often monitored compared with low-risk patients (22% vs 39%). In contrast to these findings, the prescribing physicians claimed to check serum creatinine within 2 weeks after treatment initiation in 85% of their patients. Most of the prescribing physicians (88%) rated this monitoring as (very) important. Conclusions: We demonstrated that, despite positive intentions of physicians, the biochemical monitoring recommendation in patients treated with RASIs is poorly met. In addition, serum creatinine monitoring was significantly less often performed in high-risk patients compared with low-risk patients.

The colonization dynamics of antibiotic-resistant pathogens in hospital settings are complex, with multiple and continuously interacting variables (e.g., introduction of resistance, infection-control practices, antibiotic use). Quantification of these variables is indispensable in the evaluation of intervention studies, because these variables represent potential confounders. In this article, the complexity of colonization dynamics is described. Through a systematic review, we identified studies that evaluated the modification of antibiotic prescription to reduce antibiotic resistance in intensive care units (n=19), and the extent of confounding-control was determined. Most studies evaluated antimicrobial restriction/substitution (n=12) or antibiotic rotation (n=4). Sixteen studies had a prospective cohort design (before-after), of which 12 were without a control group. Introduction of antibiotic resistance was determined in 10 studies. The relative importance of colonization routes and adherence to infection-control measures were not determined in any study. Therefore, it remains uncertain whether observed changes in the prevalence of antibiotic resistance after intervention were causally related to the intervention. Appropriate choices of study design, primary end point (colonization rates rather than infection rates) and statistical tests, determination of colonization routes, and control of potential confounders are needed to increase validity of intervention studies.

Analysis of long-term results with radiofrequency catheter ablation (RF ablation) in children.Retrospective.Data were analysed from all 118 paediatric patientsor =18 years old who underwent RF ablation at the Leiden University Medical Centre (LUMC), the Netherlands, during the period 1 December 1992-31 May 2004.The group consisted of 6o boys and 58 girls with a mean age of 12.7 years (SD: 4.6). They underwent 140 RF ablation procedures for 122 disorders. Indications for RF ablation were: failure or side-effects of antiarrhythmic medication (45%), patient/parent choice (45%), cardiomyopathy or life-threatening arrhythmia (8%), and impending surgery for a congenital heart defect (2%). The mean follow-up interval was 4 years (SD: 3.2; range: 1.2 months-11.3 years). The final total success rate for RF was 93% (n = 110). 19 patients (16%) underwent a total of 22 repeat procedures. Recurrences occurred after a mean period of 2.3 months (SD: 2.5) following successful RF ablation. Major complications (2nd degree AV block) occurred in 2 patients. During follow-up, no evidence was found of new arrhythmias or of coronary artery lesion development as the result ofRF ablation. There was no difference between the10 years of age group and theor = 10 years of age group in terms of final success rate (93% vs. 93%; p = 0.914) and complication rate (3% vs. 7%, p = 0.680).The long-term outcome of paediatric patients who underwent RF ablation was good. RF ablation in young children (10 years) was found to be safe and effective. These results demonstrate that it is also possible to curatively treat this group of patients with RF ablation in specialized centres.

A 16-year-old boy suddenly fell off his stool, a 26-year-old man had persistent palpitations and a 29-year-old man was reanimated without an incriminating anamnesis. The diagnosis 'Wolff-Parkinson-White(WPW)-syndrome' was made in all three cases. The boy died as a result of postanoxic neurological injury; in the two men, further cardiac rhythm disturbances were prevented by interrupting the accessory atrioventricular connection via radiofrequency catheter ablation. In ECG databases, a WPW-pattern is encountered in 1-3 of 1000 electrocardiograms. Atrial fibrillation with 1:1 conduction via the accessory pathway, leading to ventricular fibrillation, is the most common cause of sudden death in WPW-patients. In some cases, atrial fibrillation with a rapid ventricular response is the first sign of the syndrome. The risk of sudden death in these patients is estimated to be 0.0-0.6% per patient per year and cannot be predicted easily. Curative treatment is possible in the form of radiofrequency catheter ablation.

A sinus of Valsalva aneurysm is an uncommon congenital defect, which requires appropriate diagnosis with either echocardiography, magnetic resonance imaging or contrast angiography. Treatment consists of aortic valve repair. We describe a young woman with an aneurysm of the non-coronary sinus of Valsalva, an atrial septal defect and pulmonary insufficiency. The different imaging techniques and possibilities of surgical correction are described.

The low-temperature Si(111)7 x 7-Pb interface has been investigated using surface X-ray diffraction. The Schottky barrier height of the Pb/Si diode is known to depend on the atomic reconstruction of the interface. We have studied the structure of the evolving interface using X-ray growth oscillations and by interrupting the growth and measuring the specular reflectivity. Both techniques reveal that the film is initially highly disordered with irregular oscillations in the reflected intensity during growth. At a critical coverage of approximately five Pb layers, the whole overlayer crystallizes to a well-ordered Pb(111) structure with subsequent growth being layer-by-layer. Detailed models of the mature interface are consistent with the preservation, after burial, of the Si(111)7 x 7-Pb reconstruction originally formed during growth of the first monolayer. (C) 1999 Elsevier Science B.V. All rights reserved.

According to the Rosenblueth-Simeone model, the heart rate (HR) is proportional to the sympathovagal balance. The individual proportionality constant is the intrinsic HR, which can be determined only invasively. The percentage low-frequency spectral HR variability power, relative to the low- plus high-frequency spectral power (%LF) has been raised as a noninvasive alternative. We previously studied young healthy male subjects, in whom gradual autonomic changes were induced by incremental head-up tilt (0-10-20-30-40-45-50-55-60-65-70-75-80 degrees). At each tilt angle we computed HR and %LF. Linear regressions of %LF on HR, characterizing individual autonomic dynamics, confirmed that, within a subject, changes in %LF were proportional to changes in HR. For the current study, we made repeated measurements in 19 subjects after 1 to 8 months. In six subjects, the session 1 and session 2 regression lines differed significantly (t-test, p0.05), demonstrating the time dependence of the autonomic dynamics. In such cases, similar HR values on different days are to be associated with different %LF values. We also determined the reproducibility of the supine HR and %LF values. For all 19 subjects, the coefficients of variation were 7 and 22%, respectively: HR reproduces better than %LF. Hence, time-dependent autonomic dynamics contribute systematically to the inferior reproducibility of %LF.

We investigated the morphological and structural changes that occur during the growth of Cu on Si(111)(7 × 7) at different substrate temperatures using reflection high energy electron diffraction (RHEED). For temperatures up to 100°C Cu grows in a layer-by-layer like fashion as indicated by the observation of RHEED intensity oscillations. The interface is intermixed, but only for growth above −50°C we found evidence for the formation of η-Cu3Si. Above 150°C the oscillations disappear and the growth proceeds in the Stranski-Krastanov mode producing a very rough surface.

The Schottky-barrier height for Si(111)-Pb diodes is known to depend on the initial reconstruction at monolayer coverages. While other studies have concentrated on the details of the initial stages of growth, we present evidence of structural differences at the buried interface which correlate with previously reported differences in the Schottky-barrier heights. X-ray diffraction measurements show that for growth on the Si(111)7\ifmmode\times\else\texttimes\fi{}7-Pb phase the reconstruction is essentially unchanged by burying whereas the Si(111)\ensuremath{\surd}3 \ifmmode\times\else\texttimes\fi{} \ensuremath{\surd}3 R30\ifmmode^\circ\else\textdegree\fi{}-Pb reconstruction is destroyed.

The absence of interdiffusion and chemical reaction at the Si(111)-Pb interface makes it an attractive prototypical system for studying metal-semiconductor interface formation. Of particular interest is the fact that the surface reconstruction in the early stages of growth influences the Schottky barrier height of Si(111)-Pb diodes. In this paper we present surface X-ray diffraction studies of the buried interfaces which reveal structural differences which correlate with the known electronic properties. In situ studies of the early stages of growth at 85 K are also presented.

Investigating whether and how the prescribing behaviour of general practitioners (GPs) can be changed by the pharmacist's feedback.Randomised, prospective.Residential home 'Bernlef', Groningen, the Netherlands.In the period 2 February-18 March 1993 the effect of different ways of sending prescriptions by the pharmacist on medication use was investigated. The 43 GPs of the inhabitants were randomly divided in 3 groups. Group A formed the control group and was requested to send their prescriptions as before, group B moreover received a list with the medication used by their patients, group C also got a list with the actual medication of their patients as well as recommendations by the pharmacist. Effects on medication use were determined after 4 weeks.The 196 inhabitants used an average of 6.5 drugs (range 0-19). No difference was found between group A and group B, but there was a difference with group C. In all three groups the number of added drugs increased by 5%, but the number of deleted drugs was 7% in group C, as against only 3% in groups A and B (p0.05). The feedback of the pharmacist that for 44% of GPs contained new information resulted 9 times in the ending of medication and 4 times in decreasing of the dose.Pharmacist's feedback by means of remarks on prescribed medication positively influences prescription behaviour of the GP.

Pronounced RHEED specular beam intensity oscillations have been observed during the growth of several metals on a Si(111)(7×7) substrate at low temperature (100 K), showing that the metals grow in a layer-by-layer fashion. For all metals studied three regimes can be distinguished. Up to one or two monolayers the variation of the reflected intensity is due to changes in the surface structure rather than surface morphology. Next, a limited number ofoscillations with an ill-defined period appears. Most surprisingly, however, in most cases a sudden revival of the oscillations with a much more regular period is observed. It is suggested that this phenomenon is caused by a transition from a lattice-matched to a relaxed layer-by-layer growth mechanism.