A value-based healthcare model for initiating and switching psoriasis therapies-Results from the prospective multicentre IMPROVE study.

BACKGROUND: Little is known about the therapeutic benefits of a value-based healthcare model compared to a traditional activity-based incentive model in psoriasis (PsO). OBJECTIVES: This prospective non-interventional study evaluated an outcome-based, patient-centred management model for patients with PsO. METHODS: In total, 49 patients with a Psoriasis Area and Severity Index (PASI) ≥3 who were starting or switching between treatments were included. Patients were assessed at baseline, 3 and 9 months. The patient benefit index (PBI) was calculated using predefined questionnaires. An expected PBI was calculated and adjusted for risk factors known to complicate treatment, that is overweight and smoking. The model remunerated the department on whether the observed PBI exceeded the expected PBI to incentivize over-performance. RESULTS: In total, 40 patients (80%) completed all three visits; 32.7% were smokers and 73.5% were overweight. Mean PASI at baseline was 11.5 (SD 9.1); PASI improved significantly from baseline through 3 months: mean reduction, 8.0 (SD 9.2), p < 0.001 and was maintained until 9 months: mean further reduction, 0.1 (SD 3.3), p = 0.893. The mean PBI was 2.5 (SD 1.3) and 2.8 (SD 1.1) at 3 and 9 months, respectively. A PBI ≥1 was achieved by 87.8% at 3 and 95.1% at 9 months. Overall, the department was remunerated a mean 2721.1 DKK (SD 4472.8) per patient. In subgroup analysis, the department was remunerated a mean of, respectively, 2428.6 (SD 5089.5), 2636.6 (SD 4471.3) and 3196.5 (SD 4497.1) DKK for patients with none, 1 or 2 risk factors, that is smoking or/and overweight. CONCLUSIONS: The model evaluated herein is the first value-based model to calculate remuneration from patient reported outcomes and showed to successfully predict the expected PBI and remunerate treatment based on whether the expected treatment goal was met or exceeded. This can be utilized in the patient-centred management of PsO.

Impact of microwave thermolysis energy levels on patient-reported outcomes for axillary hyperhidrosis and osmidrosis.

OBJECTIVE: Microwave thermolysis (MWT) is an emerging treatment for axillary hyperhidrosis reducing both sweat and odor. No prior studies have investigated and compared the different available energy settings of the MWT device. This study evaluated patient-reported outcome measures (PROMs) for axillary hyperhidrosis and osmidrosis following MWT treatment with two different energy levels. METHODS: Twenty adults with axillary hyperhidrosis and osmidrosis reported sweat on Hyperhidrosis Disease Severity scale (HDSS: 1-4) and odor on Odor scale (OS: 1-10), respectively, supplemented by overall Dermatology Life Quality Index (DLQI: 0-30). This was a prospective, randomized, patient-blinded and intraindividually controlled study with 3 months follow-up (FU). Randomization comprised MWT treatment of one axilla with a standard medium energy setting (energy level 3) and the contralateral axilla with a standard high energy setting (energy level 5). RESULTS: At baseline, patients reported substantial sweat and odor, negatively affecting their quality of life. At 3 months FU, PROMs showed improved quality of life with significantly reduced odor and sweat. Overall DLQI was reduced from a median of 10 to 4, with a median 6.5-point reduction (p = 0.0002). HDSS was reduced from a median of 4 to 2 on both sides, with a median reduction of 1 for medium energy level and 2 points for high energy level (p = 0.014). OS was reduced from a median of 8 to 3 for both energy levels, with a median reduction of 3.5 and 4.5 points for the medium and high energy level, respectively (p = 0.017). Local skin reactions were mild and transient, but slightly more pronounced following treatment with the high energy level. CONCLUSION: MWT effectively improved patients' quality of life, axillary sweat, and odor 3 months after on baseline treatment. Treatment with the high energy level presented a subtle but significant increase of efficacy based on PROMs for both sweat and odor. Patients were willing to accept a higher amount of temporary local skin reactions from a higher energy setting when experiencing greater odor and sweat reduction.

Prevalence and characterization of treatment-refractory psoriasis and super-responders to biologic treatment: a nationwide study.

INTRODUCTION: Treatment with biologics often leads to clearance of psoriasis. However, some patients do repeatedly fail to respond and/or lose an achieved response (treatment refractory) to the biologic, whereas other patients achieve excellent response to one biologic and remain clear of psoriasis for several years (super-responders). OBJECTIVE: To identify and characterize patients with treatment refractory psoriasis and patients who are super-responders to biologic treatment. MATERIAL AND METHODS: Patients registered in DERMBIO between January 2007 and November 2019 were included. Patients were categorized as being treatment refractory if they had had treatment failure to ≥3 biologics targeting ≥2 different pathways. Super-responders were patients treated with their first biologic for minimum 5 years without an absolute psoriasis area and severity index (PASI) > 3 between 6 months and 5 years of treatment. All remaining patients from DERMBIO served as comparators. RESULTS: In total, 3280 patients were included with a mean age of 45.0 years. 1221 (37%) of the patients were females. Of the included patients, 214 (6.5%) were categorized as treatment refractory and 207 (6.3%) were categorized as super-responders. Treatment refractory patients had higher mean body weight (100.6 kg vs. 90.6 kg, P < 0.0001) and higher mean BMI (32.2 vs. 29.4, P < 0.0001) compared with the rest of patients in DERMBIO. Super-responders had higher socioeconomic status and fewer comorbidities compared with the comparator group (P < 0.0001). CONCLUSION: A small proportion of patients with psoriasis treated with biologics are either super-responders or treatment refractory. Treatment refractory patients have higher body weight, whereas super-responders have fewer comorbidities and higher socioeconomic status.

Author Correction: Post-stroke insomnia in community-dwelling patients with chronic motor stroke: Physiological evidence and implications for stroke care.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Post-stroke insomnia in community-dwelling patients with chronic motor stroke: Physiological evidence and implications for stroke care.

Questionnaire studies suggest that stroke patients experience sustained problems with sleep and daytime sleepiness, but physiological sleep studies focussing specifically on the chronic phase of stroke are lacking. Here we report for the first time physiological data of sleep and daytime sleepiness obtained through the two gold-standard methods, nocturnal polysomnography and the Multiple Sleep Latency Test. Data from community-dwelling patients with chronic right-hemispheric stroke (>12 months) were compared to sex- and age-matched controls. Behavioural and physiological measures suggested that stroke patients had poorer sleep with longer sleep latencies and lower sleep efficiency. Patients further spent more time awake during the night, and showed greater high-frequency power during nonREM sleep than controls. At the same time the Multiple Sleep Latency Test revealed greater wake efficiency in patients than controls. Importantly these findings were not due to group differences in sleep disordered breathing or periodic limb movements. Post-stroke insomnia is presently not adequately addressed within the care pathway for stroke. A holistic approach to rehabilitation and care provision, that includes targeted sleep interventions, is likely to enhance long-term outcome and quality of live in those living with chronic deficits after stroke.

European guideline for the diagnosis and treatment of insomnia

This European guideline for the diagnosis and treatment of insomnia was developed by a task force of the European Sleep Research Society, with the aim of providing clinical recommendations for the management of adult patients with insomnia. The guideline is based on a systematic review of relevant meta-analyses published till June 2016. The target audience for this guideline includes all clinicians involved in the management of insomnia, and the target patient population includes adults with chronic insomnia disorder. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to grade the evidence and guide recommendations. The diagnostic procedure for insomnia, and its co-morbidities, should include a clinical interview consisting of a sleep history (sleep habits, sleep environment, work schedules, circadian factors), the use of sleep questionnaires and sleep diaries, questions about somatic and mental health, a physical examination and additional measures if indicated (i.e. blood tests, electrocardiogram, electroencephalogram; strong recommendation, moderate- to high-quality evidence). Polysomnography can be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders), in treatment-resistant insomnia, for professional at-risk populations and when substantial sleep state misperception is suspected (strong recommendation, high-quality evidence). Cognitive behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence). A pharmacological intervention can be offered if cognitive behavioural therapy for insomnia is not sufficiently effective or not available. Benzodiazepines, benzodiazepine receptor agonists and some antidepressants are effective in the short-term treatment of insomnia (≤4 weeks; weak recommendation, moderate-quality evidence). Antihistamines, antipsychotics, melatonin and phytotherapeutics are not recommended for insomnia treatment (strong to weak recommendations, low- to very-low-quality evidence). Light therapy and exercise need to be further evaluated to judge their usefulness in the treatment of insomnia (weak recommendation, low-quality evidence). Complementary and alternative treatments (e.g. homeopathy, acupuncture) are not recommended for insomnia treatment (weak recommendation, very-low-quality evidence).

Empathy training in medical students - a randomized controlled trial.

AIM: Empathy is a core element in the doctor-patient relationship. This study examined whether empathy in medical students can be improved by specific training. METHODS: 158 medical students were randomized into two groups. The intervention group participated in an empathy skills training with simulated patients (SPs). The control group participated in a history course. After the intervention, empathy was assessed by blinded SPs and experts in an Objective Structured Clinical Examination (OSCE). Students also filled out a self-assessment concerning their attitude on empathy (Jefferson Scale of Physician Empathy Student Version, JSPE-S-S). RESULTS AND CONCLUSIONS: Participants of the intervention group showed significantly higher levels of empathy when rated by SPs and experts than the control group. In contrast to that, no significant group differences were observed in self-rated empathy. The results underpin the value of empathy skills trainings in medical school study programs.

Increased protoporphyrin IX accumulation does not improve the effect of photodynamic therapy for actinic keratosis: a randomized controlled trial.

BACKGROUND: Photodynamic therapy (PDT) with methyl aminolaevulinate (MAL) is highly effective for treating actinic keratosis (AK) on the face/scalp, but less effective on the extremities. Insufficient accumulation of protoporphyrin IX (PpIX) may cause these inferior efficacy rates. However, it is possible to increase PpIX accumulation by extending the MAL application time and/or pretreating the skin with curettage. OBJECTIVES: To investigate whether increased PpIX accumulation improves the effect of MAL-PDT for AKs in a randomized intra-individual study. METHODS: Twenty-two patients with 533 AKs on both hands were treated with MAL-PDT. To obtain different concentrations of PpIX, four symmetrical areas on each patient were randomly allocated to different regimens: (i) 3-h MAL application without prior curettage (3hC-); (ii) 3 h with curettage (3hC+); (iii) 21 h without curettage (21hC-); and (iv) 21 h with curettage (21hC+). Treatment efficacy was evaluated after 3 months, whereas PpIX fluorescence, pain and erythema were assessed during and after PDT. RESULTS: Extended MAL application with and without curettage increased PpIX accumulation significantly compared with the standard 3hC+ regimen (P = 0·001 and P = 0·002, respectively). However, the median total clearance rates did not improve accordingly: 3hC+ (55·0%), 21hC- (55·0%) and 21hC+ (53·6%). Conversely, insufficient PpIX accumulation in the 3hC- regimen led to a significantly lower clearance rate (33·3%) than the other regimens (P < 0·045). Furthermore, pain and erythema were correlated to PpIX accumulation. CONCLUSIONS: Increased PpIX accumulation does not improve the effect of MAL-PDT for AKs on the hands, but leads to worse adverse events. Different strategies are needed to improve PDT on the extremities.

Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

Protoporphyrin IX formation after topical application of methyl aminolaevulinate and BF-200 aminolaevulinic acid declines with age.

BACKGROUND: Topical photodynamic therapy (PDT) is a popular treatment modality in dermatology. The effect of PDT in epidermal cells depends on formation of protoporphyrin IX (PpIX) from 5-aminolevulinic acid (ALA). A variety of physiological changes in epidermal function occur with increasing age, but no studies have investigated whether PpIX formation is age-related. OBJECTIVES: To investigate a possible relationship between age and PpIX formation. METHODS: Methyl aminolaevulinate cream (MAL) and 5-ALA gel (BF-200 ALA) were applied to two identical fields on the forearm of 30 healthy volunteers for 24 h. The volunteers were divided into two age groups: a young group under 55 years (range 18-54) and an older group over 55 years (range 65-85). PpIX formation was measured noninvasively every hour from 1-5 h, and after 18, 21 and 24 h. Skin phototype, stratum corneum hydration and ultraviolet (UV) damage were also assessed. Treatment efficacy in relation to age was evaluated in 100 basal cell carcinomas (BCCs) treated with MAL-PDT. RESULTS: Both photosensitizers induced significantly more PpIX formation in the younger group. Linear regression revealed a significant age-related decline in PpIX formation after the standard application time of 3 h (P < 0.001 for both treatments). Skin phototype, stratum corneum hydration and UV damage were not associated with PpIX formation. The treatment efficacy of BCCs 3 months after MAL-PDT was higher in young patients (P = 0.012). CONCLUSIONS: PpIX formation in human skin declines with age. No explanation could be attributed to skin phototype, stratum corneum hydration or UV damage. The consequence might be reduced efficacy of PDT in the elderly.

[Sleep, learning and memory: relevance for psychiatry and psychotherapy]. / Schlaf, Lernen und Gedächtnis: Relevanz für Psychiatrie und Psychotherapie.

BACKGROUND: Sleep has been identified as a state that optimizes the consolidation of newly acquired information in the memory. Sleep disturbances might essentially contribute to memory impairment in relevant psychiatric disorders, such as major depression and schizophrenia. METHODS: This article provides a brief review of the latest research results on sleep and its association with memory consolidation. RESULTS AND CONCLUSION: Specific disturbances of sleep structure are associated with particular memory deficits in psychiatric patients. Effective treatment of sleep disorders should not only improve signs of sleep but should also heal associated memory impairments.

[Hypnotics--state of the science]. / Hypnotika--Stand der Forschung.

This article provides an overview of the indications and effects of sleep-inducing drugs. Pharmacological treatment should only be considered in cases of insufficient response to non-pharmacological interventions. Benzodiazepines and benzodiazepine receptor agonists are indicated for the short-term treatment of acute insomnia. Due to the risk of tolerance and dependency, sedative antihistamines and antidepressants are widely used as long-term hypnotics. Other substances, including herbal compounds and melatonin have few side effects; however, the therapeutic efficacy is very limited. Currently, long-term data on the efficacy and tolerability of sleep-inducing substances are lacking. Specifically in cases of non-response to first line treatment, extended psychiatric and somatic evaluation and treatment of associated disorders are recommended.

REM sleep instability--a new pathway for insomnia?

Chronic insomnia afflicts approximately 10% of the adult population and is associated with daytime impairments and an elevated risk for developing somatic and mental disorders. Current pathophysiological models propose a persistent hyperarousal on the cognitive, emotional and physiological levels. However, the marked discrepancy between minor objective alterations in standard parameters of sleep continuity and the profound subjective impairment in patients with insomnia is unresolved. We propose that "instability" of REM sleep contributes to the experience of disrupted and non-restorative sleep and to the explanation of this discrepancy. This concept is based on evidence showing increased micro- and macro-arousals during REM sleep in insomnia patients. As REM sleep represents the most highly aroused brain state during sleep it seems particularly prone to fragmentation in individuals with persistent hyperarousal. The continuity hypothesis of dream production suggests that pre-sleep concerns of patients with insomnia, i. e., worries about poor sleep and its consequences, dominate their dream content. Enhanced arousal during REM sleep may render these wake-like cognitions more accessible to conscious perception, memory storage and morning recall, resulting in the experience of disrupted and non-restorative sleep. Furthermore, chronic fragmentation of REM sleep might lead to dysfunction in a ventral emotional neural network, including limbic and paralimbic areas that are specifically activated during REM sleep. This dysfunction, along with attenuated functioning in a dorsal executive neural network, including frontal and prefrontal areas, might contribute to emotional and cognitive alterations and an elevated risk of developing depression.

α-Adrenergic receptor function, arousal and sleep: mechanisms and therapeutic implications.

Noradrenergic (NE) neurotransmission and particularly α-adrenergic receptor function has been identified as a critical component of the sleep/wake regulation in animals and humans. This work (i) provides an update on the impact of NE neurotransmission on the sleep/wake regulation, (ii) summarizes the effects of α-receptor agonists and antagonists on arousal and sleep in animals and healthy humans, and (iii) reviews the current body of evidence for the effectiveness and safety of these compounds in the treatment of clinical conditions characterized by alterations of arousal or sleep, including attention deficit and hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), borderline personality disorder and primary sleep disorders. This systematic evaluation of the potential and limitations of the effects of α-adrenergic compounds might promote novel inroads for the treatment of these highly prevalent clinical conditions.

Scenario realism and welfare estimates in choice experiments--a non-market valuation study on the European water framework directive.

Using choice experiment data for economic valuation we analyse how disbelief in survey information could affect the retrieved welfare estimates. We distinguish between two types of survey information to the respondents. The first type of information concerns the current environmental status of a water body. This information is provided prior to the valuation questions and the corresponding beliefs in the provided information are also elicited before valuation. The second type of information concerns the proposed improvements in the environmental status of the water body. We find that average welfare measures differ considerably according to whether respondents who disagree with the status quo levels and find proposed scenarios unlikely are included or not.

[Substance-induced sleep disorders and abuse of hypnotics]. / Substanzinduzierte Schlafstörungen und Schlafmittelmissbrauch.

The intake of a large variety of substances has a negative impact on sleep. Widely used, readily available substances like alcohol, nicotine, or caffeine need to be mentioned here. Illicit drugs (e.g., heroin or ecstasy) have different mechanisms of action with a high sleep-disrupting potential. Prescription drugs, i.e., corticosteroids or ß-blockers, may also negatively affect sleep. An important question is whether the intake of hypnotics, especially benzodiazepines, may have a negative long-term effect on sleep. Classical benzodiazepines (BZ) initially lead to a reduction of nocturnal wake time and prolong total sleep time as a desired effect. Regarding the microstructure of sleep, BZ lead to a reduction of slow frequencies and an increase of fast frequencies in the EEG. With many BZ, tolerance may occur, thus, leading to unwanted dose increases. Further problems include rebound effects that occur upon discontinuation of BZ, including a drastic deterioration of sleep upon drug withdrawal. This phenomenon may pave the way for the development of drug dependency. Further unwanted side-effects (e.g., nocturnal falls) and the question of BZ abuse and dependency will be discussed.

Intracellular Fas ligand is elevated in T lymphocytes in severe aplastic anaemia.

Increased expression of Fas receptor by haemopoietic progenitors in aplastic anaemia (AA) suggests that excessive apoptosis contributes to multilineage bone marrow (BM) failure. To investigate the role of Fas ligand (FasL) in triggering progenitor cell death, we examined FasL levels in T lymphocytes of patients with severe untreated AA (n = 8). Expression of FasL on the surface of CD3+ cells was not detectable. However, flow cytometric analysis of saponin-permeabilized cells demonstrated higher levels of intracellular FasL in AA than in normal T cells (P < 0.005), both prior to and following activation with phytohaemagglutinin. Confocal microscopy revealed that FasL-specific signals overlapped with cathepsin D staining, indicating that intracellular FasL is stored in lysosomal granules. Levels of intracellular FasL in patients examined 1 month after immunosuppression with antilymphocyte globulin and cyclosporin A were lower than prior to treatment. The caspase inhibitors, DEVD and zVAD, enhanced colony formation and prolonged survival of AA BM cells in liquid cultures by about 10-fold (P < 0.05). Taken together, these data provide further evidence that apoptosis by the Fas/FasL system plays a role in the depletion of stem cells in AA.

Delta sleep ratio as a predictor of sleep deprivation response in major depression.

The fast but short-lasting improvement of depressive symptoms by sleep deprivation (SD) in about 60% of patients with a major depressive disorder is well established, but the mechanisms of action are still not clear. Recent studies suggest that changes in non rapid eye movement (NREM) sleep, especially in slow wave activity (SWA), could be associated with the therapeutic outcome of SD. In the current study, spectral analysis of NREM sleep EEG directly prior to SD was performed to determine if automatically derived sleep parameters predict SD response. Sixteen pair matched and drug free patients with a major depressive disorder, 8 SD responders and 8 non-responders (response criterion: 50% reduction on the 6-item HAMD score), were included. Average EEG spectral power was calculated for the whole night before SD and for single NREM episodes. While whole-night averages of spectral power did not differ significantly between subgroups, SD responders showed a steady decrease of SWA across successive NREM episodes, whereas in non-responders an increase from the first to the second episode was observed. The different distribution of SWA was significantly expressed in the delta sleep ratio (quotient of SWA in the first to the second NREM episode). In conclusion, a high delta sleep ratio is a positive predictor for SD response. Referred to psycho- and pharmacotherapeutic results it is hypothesized that low and high values of the delta sleep ratio characterize subgroups of depressed patients with different neurobiological alterations, which could be relevant for further scientific and therapeutic approaches.