Clozapine re-challenge and initiation following neutropenia: a review and case series of 14 patients in a high-secure forensic hospital.

OBJECTIVE: Clozapine remains the most effective intervention for treatment resistant schizophrenia; however, its use is prohibited following neutropenias. We review neutrophil biology as applied to clozapine and describe the strategies to initiate clozapine following neutropenia used in a case series of 14 consecutive patients rechallenged in a United Kingdom (UK) high-secure psychiatric hospital. We examine outcomes including the use of seclusion and transfer. METHODS: A case series of 14 male patients with treatment resistant schizophrenia treated with clozapine despite previous episodes of neutropenia between 2006 and 2015 is presented. Data were collected during 2015 and 2019. Using this routinely collected clinical data, we describe the patient characteristics, causes of neutropenia, the strategies used for rechallenging with clozapine and clinical outcomes. RESULTS: Previous neutropenias were the result of benign ethnic neutropenia, clozapine, other medications and autoimmune-related. Our risk mitigation strategies included: granulocyte-colony stimulating factor (G-CSF), lithium and watch-and-wait. There were no serious adverse events; at follow up half of the patient's had improved sufficiently to transfer them to conditions of lesser security. There were dramatic reductions in the use of seclusion. CONCLUSION: Even in this extreme group, clozapine can be safely and effectively re/initiated following neutropenias, resulting in marked benefits for patients. This requires careful planning based on an understanding of neutrophil biology and the aetiology of the specific episode of neutropenia.

The HCR-20 and violence risk assessment - will a peak of inflated expectations turn to a trough of disillusionment?

SUMMARY: The HCR-20 has taken on a life of its own. In forensic services it has been elevated from helpful aide-mémoire into a prophetic tool worthy of Nostradamus himself. Almost every outcome is interpreted through it. Despite the evidence of its limited utility, the difficulties of predicting rare events, the narrative fallacies and other heuristic biases it creates, and the massive opportunity costs it entails, commissioners and services alike mandate its use. Yet in routine practice the problems are not acknowledged, multiple conflicts of interest lie unobserved and other opportunities are neglected.

Characterization of Clozapine-Responsive Human T Cells.

Use of the atypical antipsychotic clozapine is associated with life-threatening agranulocytosis. The delayed onset and the association with HLA variants are characteristic of an immunological mechanism. The objective of this study was to generate clozapine-specific T cell clones (TCC) and characterize pathways of T cell activation and cross-reactivity with clozapine metabolites and olanzapine. TCC were established and characterized by culturing PBMCs from healthy donors and patients with a history of clozapine-induced agranulocytosis. Modeling was used to explore the drug-HLA binding interaction. Global TCC protein changes were profiled by mass spectrometry. Six well-growing clozapine-responsive CD4+ and CD8+ TCC were used for experiments; activation of TCC required APC, with clozapine interacting directly at therapeutic concentrations with several HLA-DR molecules. TCC were also activated with N-desmethylclozapine and olanzapine at supratherapeutic concentrations. Marked changes in TCC protein expression profiles were observed when clozapine treatment was compared with olanzapine and the medium control. Docking of the compounds into the HLA-DRB1*15:01 and HLA-DRB1*04:01 binding clefts revealed that clozapine and olanzapine bind in a similar conformation to the P4-P6 peptide binding pockets, whereas clozapine N-oxide, which did not activate the TCC, bound in a different conformation. TCC secreted Th1, Th2, and Th22 cytokines and effector molecules and expressed TCR Vß 5.1, 16, 20, and 22 as well as chemokine receptors CXCR3, CCR6, CCR4, and CCR9. Collectively, these data show that clozapine interacts at therapeutic concentrations with HLA-DR molecules and activates human CD4+ T cells. Olanzapine only activates TCC at supratherapeutic concentrations.

Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide.

Clozapine remains the only drug treatment likely to benefit patients with treatment resistant schizophrenia. Its use is complicated by an increased risk of neutropenia and so there are stringent monitoring requirements and restrictions in those with previous neutropenia from any cause or from clozapine in particular. Despite these difficulties clozapine may yet be used following neutropenia, albeit with caution. Having had involvement with 14 cases of clozapine use in these circumstances we set out our approach to the assessment of risks and benefits, risk mitigation and monitoring with a practical guide.

Evaluation of the effectiveness and acceptability of intramuscular clozapine injection: illustrative case series.

AIMS AND METHOD: A series of eleven patients prescribed intramuscular clozapine at five UK sites is presented. Using routinely collected clinical data, we describe the use, efficacy and safety of this treatment modality. RESULTS: We administered 188 doses of intramuscular clozapine to eight patients. The remaining three patients accepted oral medication. With the exception of minor injection site pain and nodules, side-effects were as expected with oral clozapine, and there were no serious untoward events. Nine patients were successfully established on oral clozapine with significant improvement in their clinical presentations. CLINICAL IMPLICATIONS: Although a novel formulation in the UK, we have shown that intramuscular clozapine can be used safely and effectively when the oral route is initially refused.

The assertive approach to clozapine: nasogastric administration.

Aims and methodAn 'assertive approach' to clozapine, where nasogastric administration is approved, is assessed through a case-load analysis to provide the first systematic description of its use and outcomes worldwide. RESULTS: Five of the most extremely ill patients with treatment-resistant schizophrenia were established and/or maintained on clozapine, resulting in improvements to their mental state; incidents were reduced, segregation was terminated and progression to less restrictive environments was achieved.Clinical implicationsDespite being underutilised and rarely enforced, in extreme circumstances, an assertive approach to clozapine can be justified. Nasogastric clozapine can be safely delivered and the approach itself, rather than actual nasogastric administration, may be enough to help establish and maintain patients with treatment-resistant schizophrenia on the most effective treatment.Declaration of interestE.S. has received speaker fees from Jansen Pharmaceuticals and Novartis.

The effects of circadian phase, time awake, and imposed sleep restriction on performing complex visual tasks: evidence from comparative visual search.

Cognitive performance not only differs between individuals, but also varies within them, influenced by factors that include sleep-wakefulness and biological time of day (circadian phase). Previous studies have shown that both factors influence accuracy rather than the speed of performing a visual search task, which can be hazardous in safety-critical tasks such as air-traffic control or baggage screening. However, prior investigations used simple, brief search tasks requiring little use of working memory. In order to study the effects of circadian phase, time awake, and chronic sleep restriction on the more realistic scenario of longer tasks requiring the sustained interaction of visual working memory and attentional control, the present study employed two comparative visual search tasks. In these tasks, participants had to detect a mismatch between two otherwise identical object distributions, with one of the tasks (mirror task) requiring an additional mental image transformation. Time awake and circadian phase both had significant influences on the speed, but not the accuracy of task performance. Over the course of three weeks of chronic sleep restriction, speed but not accuracy of task performance was impacted. The results suggest measures for safer performance of important tasks and point out the importance of minimizing the impact of circadian phase and sleep-wake history in laboratory vision experiments.

Amplitude reduction and phase shifts of melatonin, cortisol and other circadian rhythms after a gradual advance of sleep and light exposure in humans.

BACKGROUND: The phase and amplitude of rhythms in physiology and behavior are generated by circadian oscillators and entrained to the 24-h day by exposure to the light-dark cycle and feedback from the sleep-wake cycle. The extent to which the phase and amplitude of multiple rhythms are similarly affected during altered timing of light exposure and the sleep-wake cycle has not been fully characterized. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the phase and amplitude of the rhythms of melatonin, core body temperature, cortisol, alertness, performance and sleep after a perturbation of entrainment by a gradual advance of the sleep-wake schedule (10 h in 5 days) and associated light-dark cycle in 14 healthy men. The light-dark cycle consisted either of moderate intensity 'room' light (∼90-150 lux) or moderate light supplemented with bright light (∼10,000 lux) for 5 to 8 hours following sleep. After the advance of the sleep-wake schedule in moderate light, no significant advance of the melatonin rhythm was observed whereas, after bright light supplementation the phase advance was 8.1 h (SEM 0.7 h). Individual differences in phase shifts correlated across variables. The amplitude of the melatonin rhythm assessed under constant conditions was reduced after moderate light by 54% (17-94%) and after bright light by 52% (range 12-84%), as compared to the amplitude at baseline in the presence of a sleep-wake cycle. Individual differences in amplitude reduction of the melatonin rhythm correlated with the amplitude of body temperature, cortisol and alertness. CONCLUSIONS/SIGNIFICANCE: Alterations in the timing of the sleep-wake cycle and associated bright or moderate light exposure can lead to changes in phase and reduction of circadian amplitude which are consistent across multiple variables but differ between individuals. These data have implications for our understanding of circadian organization and the negative health outcomes associated with shift-work, jet-lag and exposure to artificial light.

Amoebic liver abscess production by Entamoeba dispar.

Although Entamoeba dispar displays a similar morphology to Entamoeba histolytica, cellular and molecular studies have revealed significant differences between these two amoebae, including the former being characterized as non-pathogenic and the later as pathogenic. However, recent in vivo and in vitro experiments have shown that E. dispar strains of different origin are capable of causing liver damage and destroying cell culture lines in the presence of common intestinal bacteria. These results suggested that E. dispar may present pathogenic behavior according to the specific E. dispar strain, culture and environmental conditions. To investigate this possibility, we carried out in vivo and in vitro studies using a xenic strain E. dispar (ICB-ADO) isolated from a symptomatic non-dysenteric Brazilian patient. This strain was able to induce liver necrosis in a hamster model that was more severe than that produced by E. histolytica. The ICB-ADO isolate also caused significantly more destruction of cultured MDCK cells and increased loss of transepithelial resistance than did the E. histolytica. Xenic E. dispar exhibited high proteolytic activity, which was partially inhibited by the addition of cysteine-protease inhibitors. Based on our biochemical and molecular characterization of E. dispar (ICB-ADO) xenic culture and its ability to produce liver abscesses, we conclude that this specific strain can indeed produce tissue damage, distinct from the frequently used non- pathogenic E. dispar SAW 760 strain.

Steinstrasse predictive factors and outcomes after extracorporeal shockwave lithotripsy.

PURPOSE: Urinary stone disease is a common medical problem. Extracorporeal shockwave lithotripsy (SWL) has been applied with high success and low complication rates. Steinstrasse (SS) is a possible complication after SWL. The aim of the present study was to prospectively evaluate the factors and outcomes associated with SS after SWL. MATERIALS AND METHODS: We have prospectively evaluated 265 SWL sessions (2005-2009). Two lithotriptors were used randomly: Siemens Lithostar and Dornier Compact S. All patients had imaging exams after 30 and 90 days or according to symptoms. RESULTS: SS was observed in 14 (5.3%) out of 265 SWL procedures (n = 175 patients, 51.5% women/48.5% men, mean ± SD age = 46.3 ± 15.5 years). SS was more common after SWL for pelviureteral calculi rather than caliceal stones (p = 0.036). There was a trend toward more occurrences of SS after SWL for larger stone area (> 200 mm², p = 0.072). Preoperative ureteral stent didn't prevent SS. SWL machine, intensity, number of pulses and frequency were not associated with SS formation. Post-SWL pain, fever and gravel elimination were factors associated with SS (p = 0.021; p = 0.011; p = 0.078). When SS occurred, treatment modalities included Medical Expulsive Therapy (MET), ureteroscopy and SWL. CONCLUSIONS: Steinstrasse is an uncommon event after SWL and seems to occur more frequently with larger pelviureteral stones. Impaction of stones is more frequent in the middle ureter. All patients should be followed after SWL, but SS should be specially suspected if there is macroscopic gravel elimination, flank pain and/or fever. When SS occurs, treatment should be promptly introduced, including medical expulsive therapy, surgical approach or SWL in selected cases. Further prospective studies are awaited to evaluated preventive measures for SS occurrence.

Giardia duodenalis: genotypic comparison between a human and a canine isolates.

INTRODUCTION: Evidence suggests that giardiasis is a zoonotic disease. The present work aimed to evaluate the genetic identity of Giardia duodenalis isolated from human and dog fecal samples from Belo Horizonte. METHODS: Human and dog fecal samples were cultured for isolation of G. duodenalis. To determine the genotype of the isolates, primers that amplify a specific region in rRNA of the protozoan were used. RESULTS: Two G. duodenalis isolates were obtained, which belong to the subgroup A genotype. CONCLUSIONS: These findings suggest that the transmission of giardiasis follows a zoonotic pattern.

Steinstrasse predictive factors and outcomes after extracorporeal shockwave lithotripsy

PURPOSE: Urinary stone disease is a common medical problem. Extracorporeal shockwave lithotripsy (SWL) has been applied with high success and low complication rates. Steinstrasse (SS) is a possible complication after SWL. The aim of the present study was to prospectively evaluate the factors and outcomes associated with SS after SWL. MATERIALS AND METHODS: We have prospectively evaluated 265 SWL sessions (2005-2009). Two lithotriptors were used randomly: Siemens Lithostar and Dornier Compact S. All patients had imaging exams after 30 and 90 days or according to symptoms. RESULTS: SS was observed in 14 (5.3 percent) out of 265 SWL procedures (n = 175 patients, 51.5 percent women/48.5 percent men, mean ± SD age = 46.3 ± 15.5 years). SS was more common after SWL for pelviureteral calculi rather than caliceal stones (p = 0.036). There was a trend toward more occurrences of SS after SWL for larger stone area (> 200 mm², p = 0.072). Preoperative ureteral stent didn't prevent SS. SWL machine, intensity, number of pulses and frequency were not associated with SS formation. Post-SWL pain, fever and gravel elimination were factors associated with SS (p = 0.021; p = 0.011; p = 0.078). When SS occurred, treatment modalities included Medical Expulsive Therapy (MET), ureteroscopy and SWL. CONCLUSIONS: Steinstrasse is an uncommon event after SWL and seems to occur more frequently with larger pelviureteral stones. Impaction of stones is more frequent in the middle ureter. All patients should be followed after SWL, but SS should be specially suspected if there is macroscopic gravel elimination, flank pain and/or fever. When SS occurs, treatment should be promptly introduced, including medical expulsive therapy, surgical approach or SWL in selected cases. Further prospective studies are awaited to evaluated preventive measures for SS occurrence.

Giardia duodenalis: genotypic comparison between a human and a canine isolates / Giardia duodenalis: comparação genotípica entre isolados humano e canino

INTRODUCTION: Evidence suggests that giardiasis is a zoonotic disease. The present work aimed to evaluate the genetic identity of Giardia duodenalis isolated from human and dog fecal samples from Belo Horizonte. METHODS: Human and dog fecal samples were cultured for isolation of G. duodenalis. To determine the genotype of the isolates, primers that amplify a specific region in rRNA of the protozoan were used. RESULTS: Two G. duodenalis isolates were obtained, which belong to the subgroup A genotype. CONCLUSIONS: These findings suggest that the transmission of giardiasis follows a zoonotic pattern.

INTRODUÇÃO: Evidências sugerem que a giardíase é uma doença zoonótica. O presente trabalho tem como objetivo avaliar a identidade genética da Giardia duodenalis isolada de fezes humanas e de cães de Belo Horizonte. MÉTODOS: Amostras de fezes humanas e de cães foram cultivadas para isolamento de G. duodenalis. Para determinação do genótipo dos isolados, foram usados oligonuclotídeos que amplificam regiões específicas do gene para rRNA. RESULTADOS: Dois isolados de G. duodenalis foram obtidos, os quais apresentaram o genótipo do sub-grupo A. CONCLUSÕES: Estes dados sugerem que a transmissão da giardíase segue um padrão zoonótico.

One night of sleep deprivation affects reaction time, but not interference or facilitation in a Stroop task.

The Stroop color-naming task is one of the most widely studied tasks involving the inhibition of a prepotent response, regarded as an executive function. Several studies have examined performance on versions of the Stroop task under conditions of acute sleep deprivation. Though these studies revealed effects on Stroop performance, the results often do not differentiate between general effects of sleep deprivation on performance and effects specifically on interference in the Stroop task. To examine the effect of prolonged wakefulness on performance on the Stroop task, we studied participants in a 40-h "constant routine" protocol during which they remained awake in constant conditions and performed a Stroop color-naming task every two hours. We found that reaction time was slowest when the color and word did not match (incongruent), fastest when the color and word did match (congruent), and intermediate when participants named the color of the non-word stimulus (neutral). Performance on all three trial types degraded significantly as a function of time awake. Extended wakefulness did not significantly change the additional time needed to respond when the color and word did not match (Stroop interference), nor did it change the amount of facilitation when color and word matched. These results indicate that one night of sleep deprivation influences performance on the Stroop task by an overall increase in response time, but does not appear to impact the underlying processes of interference or facilitation. The results suggest that the degree to which an "executive function" is affected by sleep deprivation may depend on the particular executive function studied and the degree to which it is subserved by the prefrontal cortex.

Periodic limb movements in sleep exhibit a circadian rhythm that is maximal in the late evening/early night.

OBJECTIVE: Periodic limb movements in sleep (PLMS) show a time-of-night pattern, with most movements at the beginning of the night. Our study aimed to determine whether this pattern is due to an endogenous circadian rhythm, like that in the related movement disorder Restless Legs Syndrome (RLS). METHODS: Four healthy older adults with a screening PLMI>20 were studied in an inpatient forced desynchrony protocol with an imposed sleep-wake cycle of 20 h for 12 "nights," allowing separation of circadian and sleep homeostatic influences on leg movements. We recorded sleep polysomnographically throughout each scheduled episode, including left and right anterior tibialis EMG. RESULTS: PLMS in Stage 2 showed both a significant time-within-sleep pattern and a significant circadian rhythm. The circadian rhythm in PLMS peaked at the circadian phases when usual sleep onset occurs, preceding the evening rise in melatonin secretion. CONCLUSIONS: In our subjects, the circadian pattern of PLMs expression was very similar to that previously reported in patients with RLS. This evidence for a circadian rhythm in PLMS has implications for treatment and provides direction for future studies of the pathophysiology of this movement disorder.

Circadian and wake-dependent influences on subjective sleepiness, cognitive throughput, and reaction time performance in older and young adults.

STUDY OBJECTIVES: To assess circadian and homeostatic influences on subjective sleepiness and cognitive performance in older adults when sleep and waking are scheduled at different times of day; to assess changes in subjective sleepiness and cognitive performance across several weeks of an inpatient study; and to compare these findings with results from younger adults. DESIGN: Three 24-h baseline days consisting of 16 h of wakefulness and an 8-h sleep opportunity followed by 3-beat cycles of a 20-h forced desynchrony (FD) condition; 18 20-h "days," each consisting of 13.33 h of scheduled wakefulness and 6.67 h of scheduled sleep opportunity. SETTING: Intensive Physiological Monitoring Unit of the Brigham and Women's Hospital General Clinical Research Center. PARTICIPANTS: 10 healthy older adults (age 64.00 +/- 5.98 y, 5 females) and 10 healthy younger adults (age 24.50 +/- 3.54 y, 5 females). INTERVENTIONS: Wake episodes during FD scheduled to begin 4 h earlier each day allowing for data collection at a full range of circadian phases. MEASUREMENTS AND RESULTS: Subjective sleepiness, cognitive throughput, and psychomotor vigilance assessed every 2 h throughout the study. Core body temperature (CBT) data collected throughout to assess circadian phase. Older subjects were less sleepy and performed significantly better on reaction time (RT) measures than younger subjects. Decrements among younger subjects increased in magnitude further into the experiment, while the performance of older subjects remained stable. CONCLUSIONS: Our findings demonstrate that the waking performance and alertness of healthy older subjects are less impacted by the cumulative effects of repeated exposure to adverse circadian phase than that of young adults. This suggests that there are age-related changes in the circadian promotion of alertness, in the wake-dependent decline of alertness, and/or in how these 2 regulatory systems interact in healthy aging.

EEG sleep spectra in older adults across all circadian phases during NREM sleep.

STUDY OBJECTIVES: Healthy aging is associated with changes in sleep-wake regulation, and those changes often lead to problems sleeping, both during the night and during daytime. We aimed to examine the electroencephalographic (EEG) sleep spectra during non-rapid eye movement (NREM) sleep when sleep was scheduled at all times of day. DESIGN/INTERVENTIONS: After three 24-h baseline (BL) days, participants were scheduled to live on 20-hour "days" consisting of 6.7 hours of bed rest and 13.3 hours of wakefulness for 12 consecutive days (forced desynchrony, FD). The EEG was recorded from a central derivation during all scheduled sleep episodes, with subsequent visual scoring and spectral analysis. SETTING: Intensive Physiological Monitoring Unit of the Brigham & Women's Hospital General Clinical Research Center. PARTICIPANTS: Twenty-four healthy older subjects (64.2 +/- 6.3 yr; 13 women, 11 men) MEASUREMENTS AND RESULTS: Compared with BL nights, EEG activity in the slow wave (0.5 to 5.25 Hz), theta (6 to 6.25 and 7 Hz), alpha (10 to 11.25 Hz), and high spindle range (14.5 to 15.5 Hz) was significantly greater during FD, when subjects slept across many times of day and night. During FD, there was a significant interaction between homeostatic and circadian factors, such that EEG delta activity (0.5 to 1.5 Hz) was higher in the biological morning/early afternoon than at other times. EEG activity was significantly increased in almost all frequency ranges (0.5 to 21 Hz) during the biological day, as compared with the biological night, except for the lower EEG spindle range (12.25 to 14 Hz). Overall, EEG beta activity was positively correlated with wakefulness and negatively correlated with total sleep time. CONCLUSION: Our findings provide some new evidence for the underlying mechanisms that contribute to age-related difficulties in sleep consolidation, especially when sleep occurs during the daytime.

Comparison of subjective and objective assessments of sleep in healthy older subjects without sleep complaints.

Older adults have reduced sleep quality compared with younger adults when sleeping at habitual times and greater sleep disruption when their sleep is at adverse times. The purpose of this analysis was to investigate how subjective measures of sleep relate to objectively recorded sleep in older subjects scheduled to sleep at all times of day. We analyzed data from 24 healthy older (55-74 years) subjects who took part in a 32-day inpatient study where polysomnography was recorded each night and subjective sleep was assessed after each scheduled wake time. The study included baseline nights and a forced desynchrony (FD) protocol when the subjects lived on a 20-h rest activity schedule. Our postsleep questionnaire both included quantitative and qualitative questions about the prior sleep. Under baseline and FD conditions, objective and subjective sleep latency were correlated, subjective sleep duration was related to slow-wave sleep and wake after sleep onset, subjective sleep quality was related to stage 1 and 2 sleep, and sleepiness and refreshment at wake time were related to duration of premature awakening. During FD, most measures of objective and subjective sleep varied with circadian phase and many additional correlations between objective and subjective sleep were present. Our findings show that when sleeping at habitual times, these healthy older subjects did not perceive their generally poor sleep quality, but under FD conditions where sleep quality changed from day-to-day their subjective sleep ratings were more associated with their objective sleep.

Neurobehavioral performance in young adults living on a 28-h day for 6 weeks.

OBJECTIVES: Performance on many cognitive tasks varies with time awake and with circadian phase, and the forced desynchrony (FD) protocol can be used to separate these influences on performance. Some performance tasks show practice effects, whereas the Psychomotor Vigilance Task (PVT) has been reported not to show such effects. We aimed to compare performance on the PVT and on an addition test (ADD) across a 6-week FD study, to determine whether practice effects were present and to analyze the circadian and wake-dependent modulation of the 2 measures. DESIGN AND SETTING: A 47-day FD study conducted at the Brigham and Women's Hospital General Clinical Research Center. PARTICIPANTS: Eleven healthy adults (mean age: 24.4 years, 2 women). MEASUREMENTS AND RESULTS: For 2 baseline days and across 6 weeks of FD, we gave a test battery (ADD, PVT, self-rating of effort and performance) every 2 hours. During FD, there was a significant (P < 0.0001) improvement in ADD performance (more correct calculations completed), whereas PVT performance (mean reaction time, fastest 10% reaction times, lapses) significantly (P < 0.0001) declined week by week. Subjective ratings of PVT performance indicated that subjects felt their performance improved across the study (P < 0.0001), but their rating of whether they could have performed better with greater effort did not change across the study (P > 0.05). CONCLUSIONS: The decline in PVT performance suggests a cumulative effect of sleep loss across the 6-week study. Subjects did not accurately detect their declining PVT performance, and a motivational factor could not explain this decline.