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Targeted drug development efforts in patients with CHD are needed to standardise care, improve outcomes, and limit adverse events in the post-operative period. To identify major gaps in knowledge that can be addressed by drug development efforts and provide a rationale for current clinical practice, this review evaluates the evidence behind the most common medication classes used in the post-operative care of children with CHD undergoing cardiac surgery with cardiopulmonary bypass.
We systematically searched PubMed and EMBASE from 2000 to 2019 using a controlled vocabulary and keywords related to diuretics, vasoactives, sedatives, analgesics, pulmonary vasodilators, coagulation system medications, antiarrhythmics, steroids, and other endocrine drugs. We included studies of drugs given post-operatively to children with CHD undergoing repair or palliation with cardiopulmonary bypass.
We identified a total of 127 studies with 51,573 total children across medication classes. Most studies were retrospective cohorts at single centres. There is significant age- and disease-related variability in drug disposition, efficacy, and safety.
In this study, we discovered major gaps in knowledge for each medication class and identified areas for future research. Advances in data collection through electronic health records, novel trial methods, and collaboration can aid drug development efforts in standardising care, improving outcomes, and limiting adverse events in the post-operative period.
Antisaccade tasks can be used to index cognitive control processes, e.g. attention, behavioral inhibition, working memory, and goal maintenance in people with brain disorders. Though diagnoses of schizophrenia (SZ), schizoaffective (SAD), and bipolar I with psychosis (BDP) are typically considered to be distinct entities, previous work shows patterns of cognitive deficits differing in degree, rather than in kind, across these syndromes.
Large samples of individuals with psychotic disorders were recruited through the Bipolar-Schizophrenia Network on Intermediate Phenotypes 2 (B-SNIP2) study. Anti- and pro-saccade task performances were evaluated in 189 people with SZ, 185 people with SAD, 96 people with BDP, and 279 healthy comparison participants. Logistic functions were fitted to each group's antisaccade speed-performance tradeoff patterns.
Psychosis groups had higher antisaccade error rates than the healthy group, with SZ and SAD participants committing 2 times as many errors, and BDP participants committing 1.5 times as many errors. Latencies on correctly performed antisaccade trials in SZ and SAD were longer than in healthy participants, although error trial latencies were preserved. Parameters of speed-performance tradeoff functions indicated that compared to the healthy group, SZ and SAD groups had optimal performance characterized by more errors, as well as less benefit from prolonged response latencies. Prosaccade metrics did not differ between groups.
With basic prosaccade mechanisms intact, the higher speed-performance tradeoff cost for antisaccade performance in psychosis cases indicates a deficit that is specific to the higher-order cognitive aspects of saccade generation.
During the Randomized Assessment of Rapid Endovascular Treatment (EVT) of Ischemic Stroke (ESCAPE) trial, patient-level micro-costing data were collected. We report a cost-effectiveness analysis of EVT, using ESCAPE trial data and Markov simulation, from a universal, single-payer system using a societal perspective over a patient’s lifetime.
Primary data collection alongside the ESCAPE trial provided a 3-month trial-specific, non-model, based cost per quality-adjusted life year (QALY). A Markov model utilizing ongoing lifetime costs and life expectancy from the literature was built to simulate the cost per QALY adopting a lifetime horizon. Health states were defined using the modified Rankin Scale (mRS) scores. Uncertainty was explored using scenario analysis and probabilistic sensitivity analysis.
The 3-month trial-based analysis resulted in a cost per QALY of $201,243 of EVT compared to the best standard of care. In the model-based analysis, using a societal perspective and a lifetime horizon, EVT dominated the standard of care; EVT was both more effective and less costly than the standard of care (−$91). When the time horizon was shortened to 1 year, EVT remains cost savings compared to standard of care (∼$15,376 per QALY gained with EVT). However, if the estimate of clinical effectiveness is 4% less than that demonstrated in ESCAPE, EVT is no longer cost savings compared to standard of care.
Results support the adoption of EVT as a treatment option for acute ischemic stroke, as the increase in costs associated with caring for EVT patients was recouped within the first year of stroke, and continued to provide cost savings over a patient’s lifetime.
Infants with moderate-to-severe CHD frequently undergo cardiopulmonary bypass surgery in childhood. Morbidity and mortality are highest in those who develop post-operative low cardiac output syndrome. Vasoactive and inotropic medications are mainstays of treatment for these children, despite limited evidence supporting their use.
To help inform clinical practice, as well as the conduct of future trials, we performed a systematic review of existing literature on inotropes and vasoactives in children after cardiac surgery using the PubMed and EMBASE databases. We included studies from 2000 to 2020, and the patient population was defined as birth – 18 years of age. Two reviewers independently reviewed studies to determine final eligibility.
The final analysis included 37 papers. Collectively, selected studies reported on 12 different vasoactive and inotropic medications in 2856 children. Overall evidence supporting the use of these drugs in children after cardiopulmonary bypass was limited. The majority of studies were small with 30/37 (81%) enrolling less than 100 patients, 29/37 (78%) were not randomised, and safety and efficacy endpoints differed widely, limiting the ability to combine data for meta-analyses.
Vasoactive and inotropic support remain critical parts of post-operative care for children after cardiopulmonary bypass surgery. There is a paucity of data for the selection and dosing of vasoactives and inotropes for these patients. Despite the knowledge gaps that remain, numerous recent innovations create opportunities to rethink the conduct of clinical trials in this high-risk population.
Prospective longitudinal studies of idiopathic autism spectrum disorder (ASD) have provided insights into early symptoms and predictors of ASD during infancy, well before ASD can be diagnosed at age 2–3 years. However, research on the emergence of ASD in disorders with a known genetic etiology, contextualized in a developmental framework, is currently lacking. Using a biobehavioral multimethod approach, we (a) determined the rate of ASD in N = 51 preschoolers with fragile X syndrome (FXS) using a clinical best estimate (CBE) procedure with differential diagnoses of comorbid psychiatric disorders and (b) investigated trajectories of ASD symptoms and physiological arousal across infancy as predictors of ASD in preschoolers with FXS. ASD was not diagnosed if intellectual ability or psychiatric disorders better accounted for the symptoms. Our results determined that 60.7% of preschoolers with FXS met the Diagnostic and Statistical Manual of Mental Disorders (fifth edition) (DSM-5) criteria for ASD using the CBE procedure. In addition, 92% of these preschoolers presented with developmental delay and 45.4% also met criteria for psychiatric disorders, either anxiety, ADHD, or both. ASD diagnoses in preschoolers with FXS were predicted by elevated scores on traditional ASD screeners in addition to elevated autonomic arousal and avoidant eye contact from infancy.
Cold winter temperatures significantly affect the biological control effort against water hyacinth, Pontederia ( = Eichhornia) crassipes Mart. (Pontederiaceae), in more temperate regions around the world. The population dynamics of the planthopper Megamelus scutellaris Berg. (Hemiptera: Delphacidae), a newly released biological control agent of water hyacinth, were recorded on the Kubusi River in the Eastern Cape Province (South Africa) over 15 months to determine the population recovery post-winter. Megamelus scutellaris incurred a severe population decline at the onset of winter when the water hyacinth plants became frost damaged. The combined effect of a population bottleneck and low minimum winter temperatures (6.12°C) below the agent's lower developmental threshold (11.46°C) caused a post-winter lag in agent density increase. Subsequently, the maximum agent population density was only reached at the end of the following summer growing season which allowed the water hyacinth population to recover in the absence of any significant biological control immediately post-winter. Supplementary releases of agents from mass-reared cultures at the beginning of the growing season (spring) is suggested as a potential method of reducing the lag-period in field populations in colder areas where natural population recovery of agents is slower.
While medical nutrition therapy is an essential part of the care for critically ill patients, uncertainty exists about the right form, dosage, timing and route in relation to the phases of critical illness. As enteral nutrition (EN) is often withheld or interrupted during the intensive care unit (ICU) stay, combined EN and parenteral nutrition (PN) may represent an effective and safe option to achieve energy and protein goals as recommended by international guidelines. We hypothesise that critically ill patients at high nutritional risk may benefit from such a combined approach during their stay on the ICU. Therefore, we aim to test if an early combination of EN and high-protein PN (EN+PN) is effective in reaching energy and protein goals in patients at high nutritional risk, while avoiding overfeeding. This approach will be tested in the here-presented EFFORTcombo trial. Nutritionally high-risk ICU patients will be randomised to either high (≥2·2 g/kg per d) or low protein (≤1·2 g/kg per d). In the high protein group, the patients will receive EN+PN; in the low protein group, patients will be given EN alone. EN will be started in accordance with international guidelines in both groups. Efforts will be made to reach nutrition goals within 48–96 h. The efficacy of the proposed nutritional strategy will be tested as an innovative approach by functional outcomes at ICU and hospital discharge, as well as at a 6-month follow-up.
Registry-based trials have emerged as a potentially cost-saving study methodology. Early estimates of cost savings, however, conflated the benefits associated with registry utilisation and those associated with other aspects of pragmatic trial designs, which might not all be as broadly applicable. In this study, we sought to build a practical tool that investigators could use across disciplines to estimate the ranges of potential cost differences associated with implementing registry-based trials versus standard clinical trials.
We built simulation Markov models to compare unique costs associated with data acquisition, cleaning, and linkage under a registry-based trial design versus a standard clinical trial. We conducted one-way, two-way, and probabilistic sensitivity analyses, varying study characteristics over broad ranges, to determine thresholds at which investigators might optimally select each trial design.
Registry-based trials were more cost effective than standard clinical trials 98.6% of the time. Data-related cost savings ranged from $4300 to $600,000 with variation in study characteristics. Cost differences were most reactive to the number of patients in a study, the number of data elements per patient available in a registry, and the speed with which research coordinators could manually abstract data. Registry incorporation resulted in cost savings when as few as 3768 independent data elements were available and when manual data abstraction took as little as 3.4 seconds per data field.
Registries offer important resources for investigators. When available, their broad incorporation may help the scientific community reduce the costs of clinical investigation. We offer here a practical tool for investigators to assess potential costs savings.
There is limited knowledge of how individuals reflect on their involuntary admission.
To investigate, at one year after an involuntary admission,
(i) peoples perception of the necessity of their involuntary admission
(ii) the enduring impact on the relationship with their family, consultant psychiatrist and employment prospects
(iii) readmission rates to hospital and risk factors for readmission.
People that were admitted involuntarily over a 15 month period were re-interviewed at one year following discharge.
Sixty eight people were re-interviewed at one year and this resulted in a follow-up rate of 84%. Prior to discharge, 72% of people reported that their involuntary admission had been necessary however this reduced to 60% after one year. Over one third of people changed their views and the majority of these patients reflected negatively towards their involuntary admission.
One quarter of people continued to experience a negative impact on the relationship with a family member and their consultant psychiatrist one year after an involuntary admission, while 13% reported a positive impact. A similar proportion perceived that it had negative consequences in their employment.
Within one year, 43% of all patients involuntarily admitted in the study period were readmitted to hospital and half of these admissions were involuntary. Involuntary readmission was associated with a sealing over recovery style.
Peoples’ perception of the necessity of their involuntary admissions changes significantly over time. Involuntary admissions can have a lasting negative impact on the relationship with family members and treating consultant psychiatrist.
The use of physical coercion and involuntary admission is one of the most controversial practices in medicine, it is now understood that perceived coercion is multidimensional and is associated with procedural justice and perceived pressures, and not simply related to the legal status of the patient.
We sought to determine the rate of physical coercion used and the perceived pressures and procedural justice experienced by the person at the time of involuntary admission and whether this influenced future engagement with the mental health services.
Over a 15 month period, people admitted involuntarily were interviewed prior to discharge and at one year follow-up.
81 people participated in the study and 81% were interviewed at one year follow-up. At the time of involuntary admission, over half of people experienced at least one form of physical coercion and it was found that the level of procedural justice experienced was unrelated to the use of physical coercive measures. A total of 20% of participants intended not to voluntarily engage with the mental health services upon discharge and they were more likely to have experienced lower levels of procedural justice at the time of admission. At one year following discharge, 65% of participants were adherent with outpatient appointments and 18% had been readmitted involuntarily. The level of procedural justice experienced at admission did not predict future engagement with services.
This study demonstrates that the use of physical coercive measures is a separate entity from procedural justice and perceived pressures.
Despite the scientific evidence, most families of people with schizophrenia in Europe never receive a carer education programme. We evaluated whether a carer education course delivered by telepsychiatry was as effective as a carer education course delivered in situ.
We delivered the carer education course for schizophrenia simultaneously to a carers group in rural north west Ireland (remote) via three ISDN lines and live to a carers group in a city (host). We compared knowledge gains using the Knowledge Questionnaire before and after each course.
Fifty-six carers of people with schizophrenia participated in the trial. At baseline, participants at the remote and host centers did not differ in terms of knowledge about schizophrenia. After the course, carers at both centers improved significantly and the knowledge gains between groups were equivalent at 6 weeks.
Telepsychiatry can deliver effective carer education programmes about schizophrenia and may provide one solution to bridging the chasm between scientific evidence and clinical reality.
We sought to determine the level of procedural justice experienced by individuals at the time of involuntary admission and whether this influenced future engagement with the mental health services.
Over a 15-month period, individuals admitted involuntarily were interviewed prior to discharge and at one-year follow-up.
Eighty-one people participated in the study and 81% were interviewed at one-year follow-up. At the time of involuntary admission, over half of individuals experienced at least one form of physical coercion and it was found that the level of procedural justice experienced was unrelated to the use of physical coercive measures. A total of 20% of participants intended not to voluntarily engage with the mental health services upon discharge and they were more likely to have experienced lower levels of procedural justice at the time of admission. At one year following discharge, 65% of participants were adherent with outpatient appointments and 18% had been readmitted involuntarily. Insight was associated with future engagement with the mental health services; however, the level of procedural justice experienced at admission did not influence engagement.
This study demonstrates that the use of physical coercive measures is a separate entity from procedural justice and perceived pressures.
We sought to establish if a brief psychoeducational intervention for relatives is effective in improving relatives’ knowledge about schizophrenia and reducing rehospitalization. We evaluated 101 relatives of 55 patients with schizophrenia before and after an 8-week psychoeducational group using a self-report method. We also conducted a matched case-control study of the effects on rehospitalisation for 28 of these patients. We calculated the number of hospital days for each index case and control in the 1 and 2 years before and after the intervention.
Relatives made significant gains in their knowledge about schizophrenia, particularly about medication. Patients whose relatives attended the group had significantly fewer days in hospital and days per admission compared to controls in the year after the programme but the effect waned in the second year after the intervention. Controls were almost four times more likely to be readmitted at 2 years than cases. Median time to readmission was significantly longer in cases compared to controls. We conclude that a psychoeducational group, which is valued by carers, is effective in increasing their knowledge about schizophrenia as well as reducing and forestalling the rehospitalization of their affected relatives. Such programmes deliver what carers frequently request in a cost-effective manner.
There is evidence that psycho-education courses for caregivers of individuals with schizophrenia improve the short-term outcome of the condition. However, most of the outcome studies are limited to two-year follow-up.
Materials and methods
This study is a five-year retrospective case-control follow-up of an original cohort of 63 patients and their 101 caregivers who completed a six-week Caregiver Psycho-education Programme (CPP) for schizophrenia and psychosis between 2002 and 2005, and 60 controls, matched for age, gender and severity of their psychotic illness.
Patients whose caregivers learned more from the six-week psycho-education course had a significantly longer time to relapse (P = 0.04) and a significantly shorter length of stay during their first relapse (P < 0.05). Patients whose caregivers attended the six-week psycho-education course (regardless of how much the caregivers learned) had a significantly better outcome than controls. This included a significantly smaller number of relapses (P < 0.01), longer time to relapse (P < 0.01), shorter length of stay during their first relapse (P < 0.01) and smaller number of bed days over five years (P < 0.01). The odds ratio of controls relapsing, although insignificant at one year, was 4.13 (1.85–9.21) at five years. Outcome was not affected by either the numbers of caregivers attending for each patient, or caregiver gender.
Discussion and conclusions
This study, which is among the first to examine outcome over five years, supports the efficacy of psycho-education for caregivers in improving outcome for patients. Caregivers should be encouraged to take up psycho-education where it is available.
In a RCT of family psychoeducation, 47 carers of 34 patients were allocated to one of three groups; Multifamily Group Psychoeducation, Solution Focussed Group Therapy or Treatment as Usual. Carers in both the MFGP intervention and the SFGP arm demonstrated greater knowledge and reduction in burden than those in the TAU arm.
Impaired insight is commonly seen in psychosis and some studies have proposed that is a biologically based deficit. Support for this view comes from the excess of neurological soft signs (NSS) observed in patients with psychoses and their neural correlates which demonstrate a degree of overlap with the regions of interest implicated in neuroimaging studies of insight. The aim was to examine the relationship between NSS and insight in a sample of 241 first-episode psychosis patients.
Total scores and subscale scores from three insight measures and two NSS scales were correlated in addition to factors representing overall insight and NSS which we created using principal component analysis.
There were only four significant associations when we controlled for symptoms. “Softer” Condensed Neurological Evaluation (CNE) signs were associated with our overall insight factor (r = 0.19, P = 0.02), with total Birchwood (r = −0.24, P<0.01), and the Birchwood subscales; recognition of mental illness (r = −0.24, P<0.01) and need for treatment (r = −0.18, P = 0.02). Total Neurological Evaluation Scale (NES) and recognition of the achieved effects of medication were also weakly correlated (r = 0.14, P = 0.04).
This study does not support a direct link between neurological dysfunction and insight in psychosis. Our understanding of insight as a concept remains in its infancy.
Covert brain infarcts (CBIs) are five times more prevalent than symptomatic brain infarcts. CBIs are associated with cognitive impairment and therefore may be a target for preventing cognitive decline and dementia. This review focuses on strategies for preventing CBI-related cognitive impairment, either by preventing incident or recurrent CBI or by enhancing cognitive reserve. CBIs begin to become prevalent during midlife and are highly prevalent in later life. The distribution of vascular pathologies of CBI differs from those that cause symptomatic stroke; therefore, preventive treatments may need to differ as well. Only a few randomized clinical trials have provided data on CBI prevention, without conclusive results. Limited data suggest that higher early-life education, hypothesized to enhance cognitive reserve, can protect the brain from effects of CBI.
The development of laser performance models having real-time prediction capability for the OMEGA EP laser system has been essential in meeting requests from its user community for increasingly complex pulse shapes that span a wide range of energies. The laser operations model PSOPS provides rapid and accurate predictions of OMEGA EP laser-system performance in both forward and backward directions, a user-friendly interface and rapid optimization capability between shots. We describe the model’s features and show how PSOPS has allowed real-time optimization of the laser-system configuration in order to satisfy the demands of rapidly evolving experimental campaign needs. We also discuss several enhancements to laser-system performance accuracy and flexibility enabled by PSOPS.