Three-year longitudinal cognitive functioning in patients recently diagnosed with bipolar disorder.

OBJECTIVE: The longitudinal course of neuropsychological functioning after the first manic episode in bipolar disorder is unknown. The present study evaluated cognitive change in bipolar disorder in the first 3 years after the initial manic episode. METHODS: Ninety-one newly diagnosed patients with bipolar disorder and 61 demographically similar healthy participants received a neuropsychological evaluation assessing multiple cognitive domains at baseline, 1-year, and 3-year time points. Patients also received clinical assessments including mood ratings at all time points. RESULTS: Patients showed deficits in all domains at baseline, but similar longitudinal trajectories across time relative to healthy participants in most cognitive domains. For processing speed, patients showed more gains than controls from baseline to 1 year, but these gains stabilized thereafter. Patients with alcohol/substance abuse showed an initial delay but subsequent recovery in executive functioning. Patients who discontinued antipsychotic treatment showed better cognitive outcomes in verbal memory. CONCLUSION: Appropriately treated patients with bipolar disorder showed favorable cognitive outcome in the first 3 years after experiencing an initial manic episode, arguing against cognitive neuroprogression at this stage of the illness. Discontinuation of antipsychotic treatment may be associated with better cognitive outcomes, but clarification of the role of antipsychotics on cognitive functioning requires further investigation.

Soft X-Ray Second Harmonic Generation as an Interfacial Probe.

Nonlinear optical processes at soft x-ray wavelengths have remained largely unexplored due to the lack of available light sources with the requisite intensity and coherence. Here we report the observation of soft x-ray second harmonic generation near the carbon K edge (∼284 eV) in graphite thin films generated by high intensity, coherent soft x-ray pulses at the FERMI free electron laser. Our experimental results and accompanying first-principles theoretical analysis highlight the effect of resonant enhancement above the carbon K edge and show the technique to be interfacially sensitive in a centrosymmetric sample with second harmonic intensity arising primarily from the first atomic layer at the open surface. This technique and the associated theoretical framework demonstrate the ability to selectively probe interfaces, including those that are buried, with elemental specificity, providing a new tool for a range of scientific problems.

Quality of life in bipolar disorder: towards a dynamic understanding.

BACKGROUND: Although quality of life (QoL) is receiving increasing attention in bipolar disorder (BD) research and practice, little is known about its naturalistic trajectory. The dual aims of this study were to prospectively investigate: (a) the trajectory of QoL under guideline-driven treatment and (b) the dynamic relationship between mood symptoms and QoL. METHODS: In total, 362 patients with BD receiving guideline-driven treatment were prospectively followed at 3-month intervals for up to 5 years. Mental (Mental Component Score - MCS) and physical (Physical Component Score - PCS) QoL were measured using the self-report SF-36. Clinician-rated symptom data were recorded for mania and depression. Multilevel modelling was used to analyse MCS and PCS over time, QoL trajectories predicted by time-lagged symptoms, and symptom trajectories predicted by time-lagged QoL. RESULTS: MCS exhibited a positive trajectory, while PCS worsened over time. Investigation of temporal relationships between QoL and symptoms suggested bidirectional effects: earlier depressive symptoms were negatively associated with mental QoL, and earlier manic symptoms were negatively associated with physical QoL. Importantly, earlier MCS and PCS were both negatively associated with downstream symptoms of mania and depression. CONCLUSIONS: The present investigation illustrates real-world outcomes for QoL under guideline-driven BD treatment: improvements in mental QoL and decrements in physical QoL were observed. The data permitted investigation of dynamic interactions between QoL and symptoms, generating novel evidence for bidirectional effects and encouraging further research into this important interplay. Investigation of relevant time-varying covariates (e.g. medications) was beyond scope. Future research should investigate possible determinants of QoL and the interplay between symptoms and wellbeing/satisfaction-centric measures of QoL.

Hyperbaric oxygen therapy: its use in medical emergencies and its development in Hong Kong.

Hyperbaric oxygen therapy is widely accepted as life-saving treatment for decompression illness. Yet its use in acute carbon monoxide poisoning has remained controversial because of inconsistent findings in clinical trials. Hyperbaric oxygen therapy has an adjunctive role in managing gas gangrene, necrotising soft-tissue infection, and crush injury, as supported by case series. Several cases have been reported in the literature detailing the use of hyperbaric oxygen therapy in patients with severe anaemia in whom blood transfusion is not possible. Today, use of hyperbaric oxygen therapy in Hong Kong is limited by low awareness among physicians and patients, a lack of service access, and inadequate hospital and critical care support for the existing non-hospital facility. The recent introduction of a hospital-based facility is expected to benefit more patients for whom hyperbaric oxygen therapy is appropriate. This article reviews the mechanistic basis of and emerging scientific evidence to support the use of hyperbaric oxygen therapy in a number of acute medical emergencies, as well as the past and future development of hyperbaric oxygen therapy in Hong Kong.

Cross-sectional study on emergency department management of sepsis.

INTRODUCTION: Emergency departments (EDs) play an important role in the early identification and management of sepsis. Little is known about local EDs' processes of care for sepsis, adoption of international recommendations, and the impact of the new Sepsis-3 definitions. METHODS: Structured telephone interviews based on the United Kingdom Sepsis Trust 'Exemplar Standards for the Emergency Management of Sepsis' were conducted from January to August 2017 with nominated representatives of all responding public hospital EDs in Hong Kong, followed by a review of hospital/departmental sepsis guidelines by the investigators. RESULTS: Sixteen of the 18 public EDs in Hong Kong participated in the study. Among various time-critical medical emergencies such as major trauma, sepsis was perceived by the interviewees to be the leading cause of in-hospital mortality and the second most important preventable cause of death. However, only seven EDs reported having departmental guidelines on sepsis care, with four adopting the Quick Sequential Organ Failure Assessment score or its modified versions. All responding EDs reported that antibiotics were stocked within their departments, and all EDs with sepsis guidelines mandated early intravenous antibiotic administration within 1 to 2 hours of detection. Reported major barriers to optimal sepsis care included lack of knowledge and experience, nursing human resources shortages, and difficulty identifying patients with sepsis in the ED setting. CONCLUSION: There are considerable variations in sepsis care among EDs in Hong Kong. More training, resources, and research efforts should be directed to early ED sepsis care, to improve patient outcomes.

Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Lower cognitive functioning as a predictor of weight gain in bipolar disorder: a 12-month study.

OBJECTIVE: In cross-sectional studies, elevated body mass index (BMI) is associated with cognitive impairment in bipolar disorder (BD). We investigated the direction of this association by prospectively examining changes in BMI and cognition. METHOD: We measured BMI and performance in six cognitive domains over 12 months in 80 adolescent and young adult BD patients and 46 healthy comparison subjects (HS). Ninety-three percent of patients received pharmacotherapy and 84% were euthymic. We used repeated-measures ancova and longitudinal mixed models to investigate whether (i) higher BMI and increasing BMI over time predicted lower subsequent cognitive functioning, and (ii) lower cognitive functioning and changes in cognition predicted increasing BMI. RESULTS: Neither baseline BMI nor BMI change predicted lower cognitive functioning. Lower baseline scores in attention, verbal memory, working memory, and a composite measure of global cognition predicted increasing BMI in patients and HS. In patients, lower cognitive functioning remained associated with increasing BMI when clinical and treatment variables were adjusted for. Improvement in working memory predicted a smaller subsequent BMI increase in patients. CONCLUSION: Lower cognitive functioning in specific domains predicts increasing BMI in patients with BD and healthy young adults. Targeting cognition may be important for minimizing weight gain in BD.

Clinical management of sepsis.

Sepsis is a common cause of hospital admission worldwide and contributes significantly to morbidity and mortality. The definition of sepsis has evolved from the 1991 American College of Chest Physicians/Society of Critical Care Medicine definition based on the criteria of systemic inflammatory response syndrome, to the 2016 Sepsis-3 definition that incorporates the Sequential Organ Failure Assessment score. The landmark trial on protocolised early goal-directed therapy was published in 2001, but three subsequent multicentre randomised controlled trials (ProCESS, ARISE, and ProMISe) in 2014-2015 did not confirm a survival benefit with protocolised care. Over the years, there has been considerable improvement in sepsis outcome and management that hinges on early detection; timely source control; prompt, appropriate, and correctly dosed antibiotics; aggressive fluid resuscitation; and shock reversal. These are all directed by repeated bedside assessment. This article summarises recent developments and landmark trials that should guide current sepsis management.

Identifying the differences in mechanisms of mycophenolic acid controlling fucose content of glycoproteins expressed in different CHO cell lines.

In the biopharmaceutical industry, glycosylation is a critical quality attribute that can modulate the efficacy of a therapeutic glycoprotein. Obtaining a consistent glycoform profile is desired because molecular function can be defined by its carbohydrate structures. Specifically, the fucose content of oligosaccharides in glycoproteins is one of the most important attributes that can significantly affect antibody-dependent cellular cytotoxicity (ADCC) activity. It is therefore important to understand the fucosylation pathway and be able to control fucosylation at the desired level to match predecessor materials in late stage and biosimilar programs. Several strategies were explored in this study and mycophenolic acid (MPA) was able to finely modulate the fucose content with the least undesired side effects. However, the response was significantly different between CHO cell lines of different lineages. Further experiments were then performed for a deeper understanding of the mechanism of fucosylation in different CHO cell lines. Results indicated that changes in the intracellular nucleotide involved in fucosylation pathway after MPA treatment are the main cause of the differences in fucosylation level response in different CHO cell lines. Differences in MPA metabolism in the various CHO cell lines directly resulted in different levels of afucosylation measured in antibodies produced by the CHO cell lines. Biotechnol. Bioeng. 2016;113: 2367-2376. © 2016 Wiley Periodicals, Inc.

A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes.

BACKGROUND: There is growing interest in glutamatergic agents in depression, particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. We aimed to assess the efficacy of ketamine in major depressive episodes. METHOD: We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January 2014 to identify double-blind, randomized controlled trials with allocation concealment evaluating ketamine in major depressive episodes. Clinical remission, response and depressive symptoms were extracted by two independent raters. The primary outcome measure was clinical remission at 24 h, 3 days and 7 days post-treatment. Analyses employed a random-effects model. RESULTS: Data were synthesized from seven RCTs employing an intravenous infusion and one RCT employing intranasal ketamine, representing 73 subjects in parallel arms and 110 subjects in cross-over designs [n = 34 with bipolar disorder (BD), n = 149 with major depressive disorder (MDD)]. Ketamine was associated with higher rates of clinical remission relative to comparator (saline or midazolam) at 24 h [OR 7.06, number needed to treat (NNT) = 5], 3 days (OR 3.86, NNT = 6), and 7 days (OR 4.00, NNT = 6), as well as higher rates of clinical response at 24 h (OR 9.10, NNT = 3), 3 days (OR 6.77, NNT = 3), and 7 days (OR 4.87, NNT = 4). A standardized mean difference of 0.90 in favor of ketamine was observed at 24 h based on depression rating scale scores, with group comparisons revealing greater efficacy in unipolar depression compared to bipolar depression (1.07 v. 0.68). Ketamine was associated with transient psychotomimetic effects, but no persistent psychosis or affective switches. CONCLUSION: Our meta-analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression. Additional research is required to determine optimal dosing schedules, route, treatment schedules, and the potential efficacy of other glutamatergic agents.

Rescue effects: irradiated cells helped by unirradiated bystander cells.

The rescue effect describes the phenomenon where irradiated cells or organisms derive benefits from the feedback signals sent from the bystander unirradiated cells or organisms. An example of the benefit is the mitigation of radiation-induced DNA damages in the irradiated cells. The rescue effect can compromise the efficacy of radioimmunotherapy (RIT) (and actually all radiotherapy). In this paper, the discovery and subsequent confirmation studies on the rescue effect were reviewed. The mechanisms and the chemical messengers responsible for the rescue effect studied to date were summarized. The rescue effect between irradiated and bystander unirradiated zebrafish embryos in vivo sharing the same medium was also described. In the discussion section, the mechanism proposed for the rescue effect involving activation of the nuclear factor κB (NF-κB) pathway was scrutinized. This mechanism could explain the promotion of cellular survival and correct repair of DNA damage, dependence on cyclic adenosine monophosphate (cAMP) and modulation of intracellular reactive oxygen species (ROS) level in irradiated cells. Exploitation of the NF-κB pathway to improve the effectiveness of RIT was proposed. Finally, the possibility of using zebrafish embryos as the model to study the efficacy of RIT in treating solid tumors was also discussed.

Radiation-induced non-targeted response in vivo: role of the TGFß-TGFBR1-COX-2 signalling pathway.

BACKGROUND: Previous studies from our group and others have shown that cyclooxygenase-2 (COX-2) has an essential role in radiation-induced non-targeted responses and genomic instability in vivo. However, the signalling pathways involved in such effects remain unclear. METHODS: A 1 cm(2) area (1 cm × 1 cm) in the lower abdominal region of gpt delta transgenic mice was irradiated with 5 Gy of 300 keV X-rays. Nimesulide, a selective COX-2 inhibitor, was given to mice for five consecutive days before irradiation. Changes in transforming growth factor-beta (TGF-ß) and TGF-ß receptor type-1 (TGFBR1) mediated signalling pathways, in the out of radiation field lung and liver tissues were examined. RESULTS: While the plasma level of cytokines remained unchanged, the expression of TGF-ß and its receptors was elevated in non-targeted lung tissues after partial body irradiation. In contrast to the predominant expression of TGF-ß in stromal and alveolar cells, but not in bronchial epithelial cells, TGF-ß receptors, especially TGFBR1 were significantly elevated in non-targeted bronchial epithelial cells, which is consistent with the induction of COX-2. The different expression levels of TGFBR1 between liver and lung resulted in a tissue specific induction of COX-2 in these two non-targeted tissues. Multiple TGF-ß induced signalling pathways were activated in the non-targeted lung tissues. CONCLUSION: The TGFß-TGFBR1-COX-2 Signalling Pathway has a critical role in radiation-induced non-targeted response in vivo.

Relationship between cognitive functioning and 6-month clinical and functional outcome in patients with first manic episode bipolar I disorder.

BACKGROUND: Although cognitive deficits in bipolar disorder have been associated with diminished functional outcome, this relationship has been studied primarily through cross-sectional designs, and has not been studied in patients early in the course of illness. The purpose of this study was to evaluate the impact of cognitive functioning on longitudinal 6-month functional and clinical outcome in recently diagnosed clinically stable patients with bipolar disorder. METHOD: A total of 53 recently diagnosed patients with DSM-IV bipolar disorder type I were assessed within 3 months of their first manic episode using a neuropsychological battery measuring verbal/pre-morbid intellectual functioning, learning/memory, spatial/non-verbal reasoning, attention/processing speed and executive function. Functional outcome was assessed at baseline and 6 months using the Multidimensional Scale of Independent Functioning (MSIF) and DSM-IV Global Assessment of Functioning Scale (GAF). Clinical outcome was assessed with symptom ratings and by monitoring onset of new mood episodes. RESULTS: Memory, particularly verbal learning/memory, was robustly associated with 6-month functional outcome on the MSIF, even after partialling out the influence of mood symptoms and substance abuse co-morbidity. Depression ratings at 6 months, but not cognitive variables, were associated with 6-month GAF scores. Cognitive functioning was not associated with 6-month clinical outcome. CONCLUSIONS: Memory was associated with 6-month longitudinal functional but not clinical outcome in recently diagnosed patients with bipolar disorder. These data further support the distinction between clinical and functional outcome, and emphasize the need for identification of, and development of treatments for, cognitive impairments early in the course of bipolar disorder.

Measurement of the reliability of pharmacy staff and simulated patient reports of non-prescription medicine requests in community pharmacies.

BACKGROUND: The use of simulated patients (SPs) in pharmacy practice research has become an established method to observe practice. The reliability of data reported using this method in comparison to pharmacy staff self-reported behaviour has yet to be ascertained. OBJECTIVE: To compare the inter-rater agreement of pharmacy staff and SP-reported data to researcher-reported data from audio recordings of SP encounters. METHODS: A dataset of 352 audio-recorded SP encounters was generated in March-October 2015 by 61 undergraduate pharmacy students completing SP visits to 36 community pharmacies in Sydney, Australia. Post-visit scores were recorded on data collection forms by SPs. Staff completed self-assessments on identical forms immediately after the encounter. Two-hundred-and-seventy visits were randomly selected as the sample for this study, where the researcher independently scored encounters via audio recordings. Inter-rater agreement was calculated through intra-class correlation (ICC) and weighted kappa analyses. RESULTS: Analysis of staff scores returned ICC values of 0.48 (95% CI:0.38-0.56; p < 0.001) for information gathering and 0.63 (95% CI:0.55-0.70; p < 0.001) for total score. Weighted kappa for information rating was 0.30 (95% CI:0.21-0.38; p < 0.001) and 0.43 (95% CI:0.34-0.51; p < 0.001) for overall outcome. ICC values for SPs were 0.91 (95% CI:0.88-0.93; p < 0.001) and 0.90 (95% CI:0.87-0.92; p < 0.001) for information gathering and total scores respectively. Weighted kappa values were 0.44 (95% CI:0.37-0.52; p < 0.001) for information rating and 0.63 (95% CI:0.55-0.70; p < 0.001) for overall outcome. CONCLUSION: Pharmacy staff self-reported their behaviour with a poor degree of reliability. Conversely, SPs had a high level of agreement with the researcher scoring from audio recordings. Disagreement for both groups of raters was most apparent in rating the information provided and overall appropriateness of outcome. Future research should investigate this discrepancy between staff-reported behaviour and actual behaviour and consider the implications of this discrepancy in the interpretation of self-reported data.

Single crystals of linear polyethylene crystallized from the glass.

Isolated single crystals of polyethylene have been crystallized from the glassy state by annealing uniformly thick films of amorphous linear polyethylene just above their glass transition temperature. In agreement with previous results for polycarbonate, substantial molecular mobility at the glass transition temperature is.