Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals.

BACKGROUND: Clozapine remains the only medication licensed for treating refractory schizophrenia. However, it remains underutilized in part due to concerns regarding adverse events. SOURCES OF DATA: Published literature. AREAS OF AGREEMENT: Common adverse events during clozapine treatment include sedation, hypersalivation, postural hypotension, dysphagia, gastrointestinal hypomotility, weight gain, diabetes mellitus and dyslipidaemia. Rare but serious events include agranulocytosis, cardiomyopathy, myocarditis, pneumonia, paralytic ileus and seizure. AREAS OF CONTROVERSY: It remains unclear how best to minimize clozapine-induced morbidity/mortality (i) during dose titration, (ii) from hypersalivation and (iii) from gastrointestinal hypomotility. It is also unclear how clozapine pharmacokinetics are affected by (i) gastrointestinal hypomotility, (ii) systemic infection and (iii) passive exposure to cigarette smoke. Whether monthly haematological monitoring needs to continue after 12 months of uninterrupted therapy is also a subject of debate. GROWING POINTS: There is a need for better management of serious clozapine-related adverse events in addition to agranulocytosis. There is also a need for better education of patients and carers, general practitioners, A&E and ITU staff and others of the problems posed in using clozapine safely. AREAS TIMELY FOR DEVELOPING RESEARCH: There is a need for more research on assessing clozapine dosage (i) as patients get older, (ii) with respect to exposure to cigarette smoke and (iii) optimizing response if adverse events or other factors limit dosage.

Vaginal progesterone is associated with decreased group B streptococcus colonisation at term: a retrospective cohort study.

OBJECTIVE: To investigate whether women using intravaginal progesterone suppositories for preterm birth prevention during pregnancy will have lower rates of group B streptococcus (GBS) colonisation at term, compared with women receiving intramuscular 17-alpha-hydroxyprogesterone caproate. DESIGN: This was a retrospective observational cohort study of women who were prescribed a progestogen during their pregnancy for preterm birth prevention, and who delivered at term. SETTING: A tertiary referral hospital in central Ohio. POPULATION: Patients who were prescribed a progestogen during their pregnancy for preterm birth prevention between 2004 and 2017 were included in the study. Patients who delivered at <37 weeks of pregnancy, switched progestogen type during the pregnancy, or had a pessary or cerclage placed were excluded. METHODS: Baseline characteristics were compared using Mann-Whitney U-test or Chi-square test as appropriate. The association between type of progestogen and GBS colonisation was assessed using bivariate and multivariable analyses. MAIN OUTCOME MEASURES: The primary outcome was GBS colonisation. RESULTS: In all, 565 patients were included in the study, of whom 173 received intravaginal progesterone, and 392 17-alpha-hydroxyprogesterone caproate. Patients receiving intravaginal progesterone were less likely to be colonised with GBS (19.7 versus 28.1%). After adjustments for potential confounders were made in a multivariable logistic regression analysis, receiving intravaginal progesterone suppositories (adjusted odds ratio [OR] 0.61, 95% CI 0.39-0.95) was associated with reduced GBS colonisation. CONCLUSIONS: Intravaginal progesterone is associated with a decreased prevalence of rectovaginal GBS colonisation at term. TWEETABLE ABSTRACT: Vaginal progesterone is associated with a lower incidence of rectovaginal GBS colonisation, compared with 17α-hydroxyprogesterone caproate.

Phenological sequences: how early-season events define those that follow.

PREMISE OF THE STUDY: Plant phenology is a critical trait, as the timings of phenophases such as budburst, leafout, flowering, and fruiting, are important to plant fitness. Despite much study about when individual phenophases occur and how they may shift with climate change, little is known about how multiple phenophases relate to one another across an entire growing season. We test the extent to which early phenological stages constrain later ones, throughout a growing season, across 25 angiosperm tree species. METHODS: We observed phenology (budburst, leafout, flowering, fruiting, and senescence) of 118 individual trees across 25 species, from April through December 2015. KEY RESULTS: We found that early phenological events weakly constrain most later events, with the strongest constraints seen between consecutive stages. In contrast, interphase duration was a much stronger predictor of phenology, especially for reproductive events, suggesting that the development time of flowers and fruits may constrain the phenology of these events. CONCLUSIONS: Much of the variation in later phenological events can be explained by the timing of earlier events and by interphase durations. This highlights that a shift in one phenophase may often have cascading effects on later phases. Accurate forecasts of climate change impacts should therefore include multiple phenophases within and across years.

A point-process response model for spike trains from single neurons in neural circuits under optogenetic stimulation.

Optogenetics is a new tool to study neuronal circuits that have been genetically modified to allow stimulation by flashes of light. We study recordings from single neurons within neural circuits under optogenetic stimulation. The data from these experiments present a statistical challenge of modeling a high-frequency point process (neuronal spikes) while the input is another high-frequency point process (light flashes). We further develop a generalized linear model approach to model the relationships between two point processes, employing additive point-process response functions. The resulting model, point-process responses for optogenetics (PRO), provides explicit nonlinear transformations to link the input point process with the output one. Such response functions may provide important and interpretable scientific insights into the properties of the biophysical process that governs neural spiking in response to optogenetic stimulation. We validate and compare the PRO model using a real dataset and simulations, and our model yields a superior area-under-the-curve value as high as 93% for predicting every future spike. For our experiment on the recurrent layer V circuit in the prefrontal cortex, the PRO model provides evidence that neurons integrate their inputs in a sophisticated manner. Another use of the model is that it enables understanding how neural circuits are altered under various disease conditions and/or experimental conditions by comparing the PRO parameters.

Variations in Neisseria meningitidis carriage by socioeconomic status: a cross-sectional study.

BACKGROUND: Deprivation is associated with an increased risk of invasive Neisseria meningitidis disease, but little is known about the relationship between deprivation and asymptomatic carriage of N. meningitidis. This analysis was conducted to examine the relationship between meningococcal carriage and deprivation. METHODS: As part of a rapid meningococcal carriage prevalence study conducted in West Cumbria to investigate an apparent cluster of invasive meningococcal disease, data were collected on lifestyle and social factors, including area-level indicators of socioeconomic status, to identify factors associated with meningococcal carriage. RESULTS: In a multivariable log binomial regression model adjusted for age, lower socioeconomic status was significantly associated with higher prevalence of meningococcal carriage. A 1-unit increase in Index of Multiple Deprivation (2010) score was associated with a 1.7% increase in meningococcal carriage prevalence (95% confidence interval 0.3-3.0%). Age was the only significant predictor of carriage of Neisseria lactamica. CONCLUSIONS: Living in a deprived area is associated with increased carriage of Group B meningococcus. Deprivation is an important factor to consider in the evaluation of the effectiveness and cost-effectiveness of the introduction of new meningococcal B vaccines and the development and implementation of immunization policies. Further work is required to understand whether deprivation has an effect on meningococcal carriage through other factors such as smoking.

Performance of three cognitive screening tools in a sample of older New Zealanders.

BACKGROUND: With the ubiquitous Mini-Mental State Exam now under copyright, attention is turning to alternative cognitive screening tests. The aim of the present study was to investigate three common cognitive screening tools: the Montreal Cognitive Assessment (MoCA), the Rowland Universal Dementia Assessment Scale (RUDAS), and the recently revised Addenbrooke's Cognitive Assessment Version III (ACE-III). METHODS: The ACE-III, MoCA and RUDAS were administered in random order to a sample of 37 participants with diagnosed mild dementia and 47 comparison participants without dementia. The diagnostic accuracy of the three tests was assessed. RESULTS: All the tests showed good overall accuracy as assessed by area under the ROC Curve, 0.89 (95% CI = 0.80-0.95) for the ACE-III, 0.84 (0.75-0.91) for the MoCA, and 0.86 (0.77-0.93) for RUDAS. The three tests were strongly correlated: r(84) = 0.85 (0.78-0.90) between the ACE-III and MoCA, 0.70 (0.57-0.80) between the ACE-III and RUDAS; and 0.65 (0.50-0.76) between the MoCA and RUDAS. The data derived optimal cut-off points for were lower than the published recommendations for the ACE-III (optimal cut-point ≤76, sensitivity = 81.1%, specificity = 85.1%) and the MoCA (≤20, sensitivity = 78.4%, specificity = 83.0%), but similar for the RUDAS (≤22, sensitivity = 78.4%, specificity = 85.1%). CONCLUSIONS: All three tools discriminated well overall between cases of mild dementia and controls. To inform interpretation of these tests in clinical settings, it would be useful for future research to address more inclusive and potentially age-stratified local norms.

Practitioner attitudes to clozapine initiation.

OBJECTIVE: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia. It is recommended as third-line treatment for schizophrenia in national and local guidelines. Despite this, it is underutilised. This survey aimed to clarify barriers to prescribing and elucidate factors that may improve patient access to clozapine. METHOD: A questionnaire was made available to all staff members at South London and Maudsley NHS Foundation Trust. RESULTS: In total, 144 clinical staff completed the questionnaire. The majority (81%) of respondents were 'fairly' or 'very' familiar with clozapine prescribing guidelines. Barriers to prescribing most commonly stated as being 'very frequently' a problem were patient concerns about tolerability of clozapine or patient refusal to adhere to blood test monitoring. Staff members also felt medical complications frequently prevented clozapine prescription. Dedicated staff or day hospital placements devoted to clozapine initiation were identified as factors most likely to increase prescribing of clozapine. CONCLUSION: Professionals identified the dominant barriers to prescribing as being patient focussed - refusal of blood test monitoring or concerns about tolerability. Clinician fears about compliance or medical complications were also important. The development of out-patient services specifically tasked with initiating clozapine may help to increase the frequency of prescribing of clozapine earlier in treatment than is currently seen.

Identifying immune signatures of sepsis to increase diagnostic accuracy in very preterm babies.

Bacterial infections are a major cause of mortality in preterm babies, yet our understanding of early-life disease-associated immune dysregulation remains limited. Here, we combine multi-parameter flow cytometry, single-cell RNA sequencing and plasma analysis to longitudinally profile blood from very preterm babies (<32 weeks gestation) across episodes of invasive bacterial infection (sepsis). We identify a dynamically changing blood immune signature of sepsis, including lymphopenia, reduced dendritic cell frequencies and myeloid cell HLA-DR expression, which characterizes sepsis even when the common clinical marker of inflammation, C-reactive protein, is not elevated. Furthermore, single-cell RNA sequencing identifies upregulation of amphiregulin in leukocyte populations during sepsis, which we validate as a plasma analyte that correlates with clinical signs of disease, even when C-reactive protein is normal. This study provides insights into immune pathways associated with early-life sepsis and identifies immune analytes as potential diagnostic adjuncts to standard tests to guide targeted antibiotic prescribing.

Development of optimized AAV3 serotype vectors: mechanism of high-efficiency transduction of human liver cancer cells.

Our recent studies have revealed that among the 10 different commonly used adeno-associated virus (AAV) serotypes, AAV3 vectors transduce human liver cancer cells extremely efficiently because these cells express high levels of human hepatocyte growth factor receptor (hHGFR), and AAV3 utilizes hHGFR as a cellular co-receptor for viral entry. In this report, we provide further evidence that both extracellular as well as intracellular kinase domains of hHGFR are involved in AAV3 vector entry and AAV3-mediated transgene expression. We also document that AAV3 vectors are targeted for degradation by the host cell proteasome machinery, and that site-directed mutagenesis of surface-exposed tyrosine (Y) to phenylalanine (F) residues on AAV3 capsids significantly improves the transduction efficiency of Y701F, Y705F and Y731F mutant AAV3 vectors. The transduction efficiency of the Y705+731F double-mutant vector is significantly higher than each of the single mutants in liver cancer cells in vitro. In immunodeficient mouse xenograft models, direct intratumoral injection of AAV3 vectors also led to high-efficiency transduction of human liver tumor cells in vivo. We also document here that the optimized tyrosine-mutant AAV3 vectors lead to increased transduction efficiency following both intratumoral and tail-vein injections in vivo. The optimized tyrosine-mutant AAV3 serotype vectors containing proapoptotic genes should prove useful for the potential gene therapy of human liver cancers.

Augmentation of clozapine with a second antipsychotic - a meta-analysis.

OBJECTIVE: To examine using meta-analysis the effect of adding a second antipsychotic to established clozapine monotherapy. METHOD: A literature search was conducted in April 2011, and randomised placebo-controlled double-blind studies were identified. We performed a meta-analysis of efficacy (as standardised mean difference) and tolerability (withdrawals from trials) and a regression analysis of duration of study versus effect size. We also examined publication bias using funnel-plot analysis. RESULTS: Overall, 14 studies were included (734 subjects). Individual study numbers ranged from 10 to 207 (mean 52.6, median 40). Augmentation of clozapine with a second antipsychotic conferred a small benefit over placebo (effect size -0.239 (95% CI: -0.452, -0.026); P = 0.028). Meta-regression of the effect of length of treatment on effect size showed no relationship (P = 0.254). The risk of discontinuing antipsychotic augmentation was no greater than the risk of discontinuing placebo (RR = 1.20, 95% CI 0.80-1.82). There was no evidence of publication bias. CONCLUSION: Augmentation with a second antipsychotic is modestly beneficial in patients not responding fully to clozapine. Tolerability seems not to be adversely affected, at least in the short term. Longer studies do not appear to increase the probability of showing positive effects for augmentation.

A systematic review of the association between fatigue and cognition in chronic noncommunicable diseases.

OBJECTIVES: Fatigue is one of the most common symptoms associated with chronic noncommunicable diseases, and it may also increase cognitive impairment. However, associations between fatigue and cognitive impairment in chronic illnesses remain unclear. Therefore, the purpose of this systematic review was to examine research that investigated associations between level of fatigue and cognitive status. METHODS: PubMed/Medline, PsycINFO, CINAHL, and Cochrane Database were searched for articles published between 2012 and 2018 using search terms fatigue, cognition, and various iterations of these terms. Study quality was assessed by the Joanna Briggs Institute Critical Appraisal Checklist tool. RESULTS: Of 1799 citations, 10 studies in samples of individuals with cancer, multiple sclerosis, neurosarcoidosis, and chronic fatigue syndrome met the inclusion criteria. Fatigue was found to be significantly correlated with cognitive impairment in one cancer-related study (r = -.480, p < .001), one multiple sclerosis study (ß= -0.52, p < .0001), and two chronic fatigue syndrome studies (r = 0.397, p < .001; r = 0.388, p < .001). DISCUSSION: There is insufficient evidence examining the relationship between fatigue and cognitive impairment in patients with chronic illnesses. As a result, more studies are needed that examine potential relationships between these two symptoms in order to develop effective treatments for individuals living with a chronic noncommunicable disease.

COVID-19: Seroprevalence and Vaccine Responses in UK Dental Care Professionals.

Dental care professionals (DCPs) are thought to be at enhanced risk of occupational exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, robust data to support this from large-scale seroepidemiological studies are lacking. We report a longitudinal seroprevalence analysis of antibodies to SARS-CoV-2 spike glycoprotein, with baseline sampling prior to large-scale practice reopening in July 2020 and follow-up postimplementation of new public health guidance on infection prevention control (IPC) and enhanced personal protective equipment (PPE). In total, 1,507 West Midlands DCPs were recruited into this study in June 2020. Baseline seroprevalence was determined using a combined IgGAM enzyme-linked immunosorbent assay and the cohort followed longitudinally for 6 mo until January/February 2021 through the second wave of the coronavirus disease 2019 pandemic in the United Kingdom and vaccination commencement. Baseline seroprevalence was 16.3%, compared to estimates in the regional population of 6% to 7%. Seropositivity was retained in over 70% of participants at 3- and 6-mo follow-up and conferred a 75% reduced risk of infection. Nonwhite ethnicity and living in areas of greater deprivation were associated with increased baseline seroprevalence. During follow-up, no polymerase chain reaction-proven infections occurred in individuals with a baseline anti-SARS-CoV-2 IgG level greater than 147.6 IU/ml with respect to the World Health Organization international standard 20-136. After vaccination, antibody responses were more rapid and of higher magnitude in those individuals who were seropositive at baseline. Natural infection with SARS-CoV-2 prior to enhanced PPE was significantly higher in DCPs than the regional population. Natural infection leads to a serological response that remains detectable in over 70% of individuals 6 mo after initial sampling and 9 mo from the peak of the first wave of the pandemic. This response is associated with protection from future infection. Even if serological responses wane, a single dose of the Pfizer-BioNTech 162b vaccine is associated with an antibody response indicative of immunological memory.

Spatio-temporal epidemiology of Campylobacter jejuni enteritis, in an area of Northwest England, 2000-2002.

A total of 969 isolates of Campylobacter jejuni originating in the Preston, Lancashire postcode district over a 3-year period were characterized using multi-locus sequence typing. Recently developed statistical methods and a genetic model were used to investigate temporal, spatial, spatio-temporal and genetic variation in human C. jejuni infections. The analysis of the data showed statistically significant seasonal variation, spatial clustering, small-scale spatio-temporal clustering and spatio-temporal interaction in the overall pattern of incidence, and spatial segregation in cases classified according to their most likely species-of-origin.

Spotlight on measles 2010: measles outbreak in Ireland 2009-2010.

Measles cases are increasing in Ireland, with 320 cases notified since August 2009. Nearly two-thirds of these cases (n=206) were unvaccinated. In the early stages of the outbreak a substantial number of cases were linked to the Traveller community with some cases also reported among the Roma community, other citizens from eastern Europe and children whose parents objected to vaccination. By February 2010, there had been considerable spread to the general population.

Assessment of dioxin-like soil contamination in Mexico by enzyme-linked immunosorbent assay.

In this work, we describe the results of a preliminary soil assessment program for the detection of dioxins at different sites in Mexico performed by immunoassay. We studied five different sectors considered relevant sources of dioxins: Anaversa and Tekchem industrial areas where organochlorine pesticides were manufactured and released by accidental explosions, secondary smelters, brick kilns, and rural dwellings. In the context of the Agency for Toxic Substances and Disease Registry (ATSDR) guidelines, only the brick kilns sites can be considered as low-risk areas. The dioxin concentrations detected in the vicinity of the Anaversa and Tekchem chemical plants and secondary smelters exceed the screening level of 0.05 ppb set by the ATSDR, and therefore further site-specific studies are needed. The dioxin levels found in all soot samples from indigenous dwellings where wood is used for indoor cooking were above the evaluation level. Considering that the studied areas are representative examples of dioxin sources in less developed countries, our work demonstrates the useful application of dioxin immunoassays as a tool for dioxin screening for environmental assessment programs in developing countries.

Symptom Experiences in Colorectal Cancer Survivors After Cancer Treatments: A Systematic Review and Meta-analysis.

BACKGROUND: With improved survivorship rates for colorectal cancer (CRC), more CRC survivors are living with long-term disease and treatment side effects. Little research exists on CRC symptoms or symptom management guidelines to support these individuals after cancer treatments. OBJECTIVES: The aims of this study were to systematically review symptom experiences, risk factors, and the impact of symptoms and to examine the pooled frequency and severity of symptoms via meta-analyses in CRC survivors after cancer treatments. METHODS: Relevant studies were systematically searched in 7 databases from 2009 to 2019. Meta-analysis was conducted for pooled estimates of symptom frequency and severity. RESULTS: Thirty-five studies met the inclusion criteria. Six studies assessed multiple CRC symptoms, whereas 29 focused on a single symptom, including peripheral neuropathy, psychological distress, fatigue, body image distress, cognitive impairment, and insomnia. The pooled mean frequency was highest for body image distress (78.5%). On a scale of 0 to 100, the pooled mean severity was highest for fatigue (50.1). Gastrointestinal and psychological symptoms, peripheral neuropathy, and insomnia were also major problems in CRC survivors. Multiple factors contributed to adverse symptoms, such as younger age, female gender, and lack of family/social support. Symptoms negatively impacted quality of life, social and sexual functioning, financial status, and caregivers' physical and mental conditions. CONCLUSIONS: Colorectal cancer survivors experienced multiple adverse symptoms related to distinct risk factors. These symptoms negatively impacted patients and caregivers' well-being. IMPLICATIONS FOR PRACTICE: Healthcare providers can use study findings to better assess and monitor patient symptoms after cancer treatments. More research is needed on CRC-specific symptoms and their effective management.

High-throughput method for ranking the affinity of peptide ligands selected from phage display libraries.

The use of phage display peptide libraries allows rapid isolation of peptide ligands for any target selector molecule. However, due to differences in peptide expression and the heterogeneity of the phage preparations, there is no easy way to compare the binding properties of the selected clones, which operates as a major "bottleneck" of the technology. Here, we present the development of a new type of library that allows rapid comparison of the relative affinity of the selected peptides in a high-throughput screening format. As a model system, a phage display peptide library constructed on a phagemid vector that contains the bacterial alkaline phosphatase gene (BAP) was selected with an antiherbicide antibody. Due to the intrinsic switching capacity of the library, the selected peptides were transferred "en masse" from the phage coat protein to BAP. This was coupled to an optimized affinity ELISA where normalized amounts of the peptide-BAP fusion allow direct comparison of the binding properties of hundreds of peptide ligands. The system was validated by plasmon surface resonance experiments using synthetic peptides, showing that the method discriminates among the affinities of the peptides within 3 orders of magnitude. In addition, the peptide-BAP protein can find direct application as a tracer reagent.

Deposition of pyrethrins and piperonyl butoxide following aerial ultra-low volume applications in the Coachella Valley, California.

Data on adulticide deposition were collected during studies optimizing aerial ultra-low volume applications and droplet size in the desert environment of the Coachella Valley, Riverside County, California. Pyrenone 25-5 and BVA Spray 13 oil were applied by a single-engine, fixed wing aircraft equipped with 2 Micronair AU5000 atomizers. Data recorded by a portable weather station documented that weather conditions were suitable for application. Adulticide residue was collected using 24-cm-diameter filter papers positioned along 2-3 transects, with 3 positive controls held outside of the treated zone. The trace amounts of 2 major insecticidal components (pyrethrin I and II) and the synergist piperonyl butoxide (PBO) were detected from samples near the center of the spray zone by high-performance liquid chromatography (HPLC); pyrethrin deposition was highest at the center, 156 microg/m2, and it was not detectable 60 m beyond the center of the transect, whereas PBO deposition was 5,000 microg/m2 at the center but was not detectable beyond 150 m. Droplet diameters on spinning Teflon slides were larger than expected for the rated output of the atomizers. For these single swath trials, the lack of swath overlap due to drift resulted in low mortality in sentinel mosquitoes. Detection of residues was limited to the centroid of droplet densities on spinning glass slides and with mortality among sentinel mosquitoes, indicating HPLC may be useful in detecting postspray residues.