A proposal for reducing maximum target doses of drugs for psychosis: Reviewing dose-response literature.

BACKGROUND: Presently, there is limited guidance on the maximal dosing of psychosis drugs that is based on effectiveness rather than safety or toxicity. Current maximum dosing recommendations may far exceed the necessary degree of dopamine D2 receptor blockade required to treat psychosis. This may lead to excess harm through cognitive impairment and side effects. AIMS: This analysis aimed to establish guidance for prescribers by optimally dosing drugs for psychosis based on efficacy and benefit. METHODS: We used data from two dose-response meta-analyses and reviewed seven of the most prescribed drugs for psychosis in the UK. Where data were not available, we used appropriate comparison techniques based on D2 receptor occupancy to extrapolate our recommendations. RESULTS: We found that the likely threshold dose for achieving remission of psychotic symptoms was often significantly below the currently licensed dose for these drugs. We therefore recommend that clinicians are cautious about exceeding our recommended doses. Individual factors, however, should be accounted for. We outline potentially relevant factors including age, ethnicity, sex, smoking status and pharmacogenetics. Additionally, we recommend therapeutic drug monitoring as a tool to determine individual pharmacokinetic variation. CONCLUSIONS: In summary, we propose a new set of maximum target doses for psychosis drugs based on efficacy. Further research through randomised controlled trials should be undertaken to evaluate the effect of reducing doses from current licensing maximums or from doses that are above our recommendations. However, dose reductions should be implemented in a manner that accounts for and reduces the effects of drug withdrawal.

Real-time millimeter wave holography with an arrayed detector.

Millimeter and terahertz wave imaging has emerged as a powerful tool for applications such as security screening, biomedical imaging, and material analysis. However, intensity images alone are often insufficient for detecting variations in the dielectric constant of a sample, and extraction of material properties without additional phase information requires extensive prior knowledge of the sample. Digital holography provides a means for intensity-only detectors to reconstruct both amplitude and phase images. Here we utilize a commercially available source and detector array, both operating at room temperature, to perform digital holography in real-time for the first time in the mm-wave band (at 290 GHz). We compare the off-axis and phase-shifting approaches to digital holography and discuss their trade-offs and practical challenges in this regime. Owing to the low pixel count, we find phase-shifting holography to be the most practical and high fidelity approach for such commercial mm-wave cameras even under real-time operational requirements.

Generation of PVP Membranes Using Extracts/Phenolic Fraction of Dysphania ambrosioides, Opuntia ficus-indica, and Tradescantia pallida.

In the present work, electrospun membranes of polyvinylpyrrolidone (PVP) nanofibers were manufactured using extracts and phenolic fractions of Dysphania ambrosioides (epazote), Opuntia ficus-indica (nopal), and Tradescantia pallida (chicken grass). The characterization of the membranes was carried out by scanning electron microscopy and Fourier transform infrared spectroscopy. The membranes synthesized through the use of the extracts generally showed a slight decrease in the diameter of the fibers but an increase in the size of the pores due to the presence of nanoparticles (rosaries) on the surface of the fibers, while the membranes synthesized using the phenolic fraction demonstrated an inversely proportional relationship between the compounds of this family with the diameter of the fibers and the size of the pore, allowing to elucidate part of the polymerization mechanisms of PVP nanofibers, in addition to proposing a reaction mechanism in the interaction between PVP and phenolic compounds for surface functionalization. Likewise, we demonstrate that the generation of reaction seeds through functionalization allows the addition of other compounds to the fibers in the membranes synthesized using the complete extract.

Ethics Inside the Black Box: Integrating Science and Technology Studies into Engineering and Public Policy Curricula.

There is growing need for hybrid curricula that integrate constructivist methods from Science and Technology Studies (STS) into both engineering and policy courses at the undergraduate and graduate levels. However, institutional and disciplinary barriers have made implementing such curricula difficult at many institutions. While several programs have recently been launched that mix technical training with consideration of "societal" or "ethical issues," these programs often lack a constructivist element, leaving newly-minted practitioners entering practical fields ill-equipped to unpack the politics of knowledge and technology or engage with skeptical publics. This paper presents a novel format for designing interdisciplinary coursework that combines conceptual content from STS with training in engineering and policy. Courses following this format would ideally be team taught by instructors with advanced training in diverse fields, and hence co-learning between instructors and disciplines is a key element of the format. Several instruments for facilitating both student and instructor collaborative learning are introduced. The format is also designed for versatility: in addition to being adaptable to both technical and policy training environments, topics are modularized around a conceptual core so that issues ranging from biotech to nuclear security can be incorporated to fit programmatic needs and resources.

Compressed gas diving fatalities in Australian waters 2014 to 2018.

INTRODUCTION: This study aimed to investigate compressed gas diving deaths in Australia from 2014-2018 and make comparison to those from 2001-2013 to identify ongoing problems and assess countermeasures. METHODS: Media reports and the National Coronial Information System were searched to identify scuba diving deaths for 2014-2018, inclusive. Data were extracted from the witness and police reports, medical histories, and autopsies. An Excel® database was created and a chain of events analysis conducted. Comparisons were made with the earlier report. RESULTS: Forty-two fatalities were identified, 38 using scuba and four using surface-supplied breathing apparatus involving 30 males and 12 females. The mean age of victims was 49.7 years, six years higher than the previous cohort. Fifty-four percent were obese. Six victims were unqualified, three were under instruction and at least 28 were experienced divers, significantly more than in the previous cohort. Health-related predisposing factors, predominantly obesity and cardiac-related, were identified as likely contributory to 26 incidents, and planning shortcomings to at least 22 deaths. One-third of the disabling conditions were primary drowning and one-quarter were cardiac. Three divers died subsequent to carbon monoxide poisoning and three likely from immersion pulmonary oedema. CONCLUSIONS: Advancing age, obesity and the associated cardiac disease have become increasingly prevalent in diving fatalities and the need for appropriate assessment of fitness to dive is evident.

Multi-resonant tessellated anchor-based metasurfaces.

In this work, a multi-resonant metasurface that can be tailored to absorb microwaves at one or more frequencies is explored. Surface shapes based on an 'anchor' motif, incorporating hexagonal, square and triangular-shaped resonant elements, are shown to be readily tailorable to provide a targeted range of microwave responses. A metasurface consisting of an etched copper layer, spaced above a ground plane by a thin (< 1/10th of a wavelength) low-loss dielectric is experimentally characterised. The fundamental resonances of each shaped element are exhibited at 4.1 GHz (triangular), 6.1 GHz (square) and 10.1 GHz (hexagonal), providing the potential for single- and multi-frequency absorption across a range that is of interest to the food industry. Reflectivity measurements of the metasurface demonstrate that the three fundamental absorption modes are largely independent of incident polarization as well as both azimuthal and elevation angles.

Championing inclusive terminology in ecology and evolution.

Amid a growing disciplinary commitment to inclusion in ecology and evolutionary biology (EEB), it is critical to consider how the use of scientific language can harm members of our research community. Here, we outline a path for identifying and revising harmful terminology to foster inclusion in EEB.

Antibody-mediated Rejection Without Detectable Donor-specific Antibody Releases Donor-derived Cell-free DNA: Results From the Trifecta Study.

BACKGROUND: Trifecta (ClinicalTrials.gov #NCT04239703) is a prospective trial defining relationships between donor-derived cell-free DNA (dd-cfDNA), donor-specific antibody (DSA), and molecular findings in kidney transplant biopsies. Previous analyses of double results showed dd-cfDNA was strongly associated with rejection-associated molecules in the biopsy. The present study analyzed the triple results in 280 biopsies, focusing on the question of dd-cfDNA levels in DSA-negative antibody-mediated rejection (AMR). METHODS: Molecular Microscope Diagnostic System biopsy testing was performed at Alberta Transplant Applied Genomics Centre, dd-cfDNA testing at Natera, Inc, and central HLA antibody testing at One Lambda Inc. Local DSA and histologic diagnoses were assigned per center standard-of-care. RESULTS: DSA was frequently negative in both molecular (56%) and histologic (51%) AMR. DSA-negative AMR had slightly less molecular AMR activity and histologic peritubular capillaritis than DSA-positive AMR. However, all AMRs-DSA-positive or -negative-showed elevated %dd-cfDNA. There was no association between dd-cfDNA and DSA in biopsies without rejection. In AMR, %dd-cfDNA ≥1.0 was more frequent (75%) than DSA positivity (44%). In logistic regression, dd-cfDNA percent (area under the curve [AUC] 0.85) or quantity (AUC 0.86) predicted molecular AMR better than DSA (AUC 0.66). However, the best predictions incorporated both dd-cfDNA and DSA, plus time posttransplant (AUC 0.88). CONCLUSIONS: DSA-negative AMR has moderately decreased mean molecular and histologic AMR-associated features compared with DSA-positive AMR, though similarly elevated dd-cfDNA levels. In predicting AMR at the time of indication biopsies in this population, dd-cfDNA is superior to DSA, reflecting the prevalence of DSA-negative AMR, but the optimal predictions incorporated both dd-cfDNA and DSA.

US payer budget impact of a microarray assay with machine learning to evaluate kidney transplant rejection in for-cause biopsies.

AIM: This study evaluates the economic impact to US commercial payers of MMDx-Kidney used in conjunction with histologic evaluation of for-cause kidney transplant biopsies. MATERIALS AND METHODS: An Excel-based model was developed to assess the cost impact of histology plus MMDx-Kidney versus histology alone for the evaluation of potential rejection in kidney transplant patients who receive a for-cause biopsy. Different model time periods were assessed, ranging from 1 to 5 years post-biopsy. A targeted literature review was used to identify parameter estimates, validated by two external clinicians with expertise in managing kidney transplant rejection. A sensitivity analysis was conducted to evaluate the relative impact of key clinical and cost parameters. In particular, the model identified the magnitude of MMDx-Kidney's impact on graft failure from rejection that would be required for MMDx-Kidney to be cost-neutral. RESULTS: By more accurately characterizing rejection, MMDx-Kidney is estimated to increase antirejection treatment costs by $1,126 per test. Nevertheless, a break-even analysis shows that the costs of MMDx-Kidney and anti-rejection medication, as well as the costs associated with an increase in the number of patients with functioning transplants, may be offset by reductions in costs associated with graft failure (i.e. costs of hospitalizations, dialysis, and repeat transplants) over 5 years, assuming MMDx-Kidney reduces annual graft failure from rejection by at least 5%. For the base case, with a 25% relative reduction in annual rate of graft failures from rejection, MMDx-Kidney increases overall costs incurred in the first year of the model but starts generating savings by the second year of the model. CONCLUSIONS: Compared with histologic evaluation of for-cause kidney transplant biopsies alone, the use of MMDx-Kidney in conjunction with histologic evaluation improves the diagnoses of graft dysfunction and may have the potential to generate overall savings from reductions in rejection-related graft failure.

Ethical allocation of COVID-19 vaccine in the United States: an evaluation of competing frameworks for the current pandemic and future events.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, created the need for an effective vaccine. Questions arose about allocating the initial limited supplies in the United States. We present four allocation models and compare their characteristics for ethically meeting the health needs of the population. The literature shares broad agreement on guiding ethical principles with those of the four proposed models for vaccine allocation, featuring the concepts of utilitarianism, prioritarianism, equity, and reciprocity. We conclude that the "Interim Framework for COVID-19 Vaccine Allocation and Distribution in the United States" from the Johns Hopkins Bloomberg School of Public Health is the most comprehensive and ethically sound. We recommend government officials and policymakers at all levels consider the principles and objectives in this model as US COVID-19 vaccination distribution efforts continue. This model may serve as an effective framework for initial vaccine distribution efforts during future epidemic and pandemic events.

Scuba diving-related fatalities in New Zealand, 2007 to 2016.

INTRODUCTION: New Zealand (NZ) diving-related fatalities have been reported since the 1960s. The aim is to identify contributing risk factors, including medical, and to inform appropriate preventative strategies. METHODS: NZ scuba diving fatalities from 2007 to 2016 were searched from multiple sources - the National Coronial Information System (NCIS); the NZ Chief Coroner's office; Water Safety NZ Drownbase™ and the NZ Police National Dive Squad records. For inclusion, a victim must have been wearing a scuba set (which may include a rebreather). A key word search of the NCIS was made and the results matched to the other databases. An Excel® database was created and a chain of events analysis (CEA) conducted. RESULTS: Forty-eight scuba diving fatalities were identified, 40 men and eight women, average age 47 years (range 17-68), 20 of Maori ethnicity. Thirty-five were classified as overweight (14) or obese (21). Pre-existing medical risk factors were identified, either pre dive or at autopsy, in 37 divers, the commonest being ischaemic heart disease (IHD, 20), left ventricular hypertrophy (LVH, 18) and hypertension (seven). IHD, LVH and obesity were variously associated with each other. The likely commonest disabling conditions, identified in 32 cases, were asphyxia (15), cardiac (nine) and pulmonary barotrauma/cerebral arterial gas embolism (five). Multiple environmental and diving practice breaches and poor planning were identified in the CEA, similar to those seen in other studies. Thirty-eight divers had not released their weight belt. Information on resuscitation was limited. CONCLUSIONS: Obesity and cardiovascular disease were common and Maori appear to be over-represented, both as previously reported.

LYSMD3: A mammalian pattern recognition receptor for chitin.

Chitin, a major component of fungal cell walls, has been associated with allergic disorders such as asthma. However, it is unclear how mammals recognize chitin and the principal receptor(s) on epithelial cells that sense chitin remain to be determined. In this study, we show that LYSMD3 is expressed on the surface of human airway epithelial cells and demonstrate that LYSMD3 is able to bind chitin, as well as ß-glucan, on the cell walls of fungi. Knockdown or knockout of LYSMD3 also sharply blunts the production of inflammatory cytokines by epithelial cells in response to chitin and fungal spores. Competitive inhibition of the LYSMD3 ectodomain by soluble LYSMD3 protein, multiple ligands, or antibody against LYSMD3 also blocks chitin signaling. Our study reveals LYSMD3 as a mammalian pattern recognition receptor (PRR) for chitin and establishes its role in epithelial cell inflammatory responses to chitin and fungi.

Alternative cause for hypoglycaemia in insulin-treated diabetes mellitus.

We present a case of a 73-year-old woman who developed recurrent hypoglycaemia during a prolonged hospital stay following a mechanical fall. She had a complex history of insulin-treated diabetes mellitus, hypothyroidism, diffuse systemic cutaneous sclerosis, Raynaud's disease, previous breast cancer, Barrett's oesophagus and previous partial gastrectomy for a benign mass. Hypoglycaemia persisted despite weaning of insulin. She had no clinical features of adrenal or pituitary insufficiency with an acceptable cortisol on stopping prednisolone and had an optimal thyroid replacement. A 72-hour fast elicited hypoglycaemia with corresponding low insulin level. Although the C-peptide was detectable, there were no clinical, biochemical or radiological features suggestive of insulinoma. Reactive hypoglycaemia post partial gastrectomy was ruled out based on limited relation of the hypoglycaemia to meals and the low insulin levels. Hydroxychloroquine (HCQ)-induced hypoglycaemia was considered based on previous case reports and the recent literature, with a successful resolution of hypoglycaemia on discontinuation of HCQ.

Endocarditis and the impact of intravenous drug use: a cohort study.

OBJECTIVES: This cohort study is a comparison of infective endocarditis in intravenous drug users (IDUs) and non-IDUs within a single tertiary centre. We aim to quantify and describe the factors that influence prognosis and microbiological characteristics. METHOD: All consecutive admissions to a tertiary referral hospital in the north of England with a diagnosis of endocarditis from April 2013 to January 2020 were identified. Outcomes were all-cause mortality at 30 days, 12 months and 3 years, length of stay and progression to surgery. RESULTS: A total of 303 cases were identified via clinical coding of which 287 cases of endocarditis were confirmed. First episode endocarditis was then confirmed in 263 episodes, 44 in IDUs and 219 in non-IDUs. Methicillin sensitive Staphylococcus aureus (MSSA) was the most common organism seen overall, significantly more so in IDU than non-IDU cases (29/44 [65.9%] vs. 51/219 [23.3%], p < .001). Overall progression to valve surgery was similar between the two groups (92/219 [42.0%] vs. 19/44[43.2%], p = .886). In IDUs 30-d survival was 93% (80-98) and 3-year survival 47% (30-63%). In non-IDU 30-d survival was 88% (83-92%) and 60% (53-67%) at 3 years. Of the 19 IDUs who underwent valve surgery 7 (37%) survived to study completion without reinfection and 8 (42%) died following recurrent endocarditis. CONCLUSIONS: We demonstrate that prognosis in IDUs is worse than previously described, particularly in those undergoing valve surgery. This is despite comparable receipt of inpatient treatment to non-IDUs as demonstrated by equal length of stay and rates of surgery. Clinicians should consider the role of addictions services on discharge to break the cycle of reinfection.

Absorption modes of Möbius strip resonators.

In this work, the electromagnetic response of a mathematically interesting shape-a Möbius strip-is presented, along with a ring resonator for comparison. Both resonators consist of a central lossy dielectric layer bounded by perfectly conducting layers. For the case of the Möbius strips, the computational results show that there are a family of half-integer wavelength modes within the dielectric layer. These additional modes result in increased absorption, and a corresponding reduction in the radar cross section. Interestingly, rotational scans show that these modes can be excited over a large angular range. This investigation gives an understanding of the electromagnetic response of these structures, paving the way for future experiments on Möbius strip resonators.

Robert M. Young's Mind, Brain and Adaptation revisited.

Robert Maxwell Young's first book Mind, Brain and Adaptation in the Nineteenth Century (1970), written from 1960 to 1965, still merits reading as a study of the naturalization of mind and its relation to social thought in Victorian Britain. I examine the book from two perspectives that give the volume its unique character: first, Young's interest in psychology, which he considered should be used to inform humane professional practices and be the basis of social reform; second, new approaches to the history of scientific ideas. I trace Young's intellectual interests to the Yale Philosophy Department, the Cambridge Department of Experimental Psychology and a new history and philosophy of science community. Although Young changed his political outlook and historiography radically after 1965, he always remained faithful to ideas about thought and practice described in Mind, Brain.

Reproductive compatibility among populations and host-associated lineages of the common bed bug (Cimex lectularius L.).

As populations differentiate across geographic or host-association barriers, interpopulation fertility is often a measure of the extent of incipient speciation. The bed bug, Cimex lectularius L., was recently found to form two host-associated lineages within Europe: one found with humans (human-associated, HA) and the other found with bats (bat-associated, BA). No unequivocal evidence of contemporary gene flow between these lineages has been found; however, it is unclear whether this is due to an inability to produce viable "hybrid" offspring. To address this question and determine the extent of compatibility between host-associated lineages, we set up mating crosses among populations of bed bugs based on both their host association (human-HA vs. bat-BA) and geographic origin (North America vs. Europe). Within-population fecundity was significantly higher for all HA populations (>1.7 eggs/day) than for BA populations (<1 egg/day). However, all within-population crosses, regardless of host association, had >92% egg hatch rates. Contrary to previous reports, in all interlineage crosses, successful matings occurred, fertile eggs were oviposited, and the F1 "hybrid" generation was found to be reproductively viable. In addition, we evaluated interpopulation genetic variation in Wolbachia among host-associated lineages. We did not find any clear patterns related to host association, nor did we observe a homogenization of Wolbachia lineages across populations that might explain a breakdown of reproductive incompatibility. These results indicate that while the HA and BA populations of C. lectularius represent genetically differentiated host-associated lineages, possibly undergoing sympatric speciation, this is in its incipient stage as they remain reproductively compatible. Other behavioral, physiological, and/or ecological factors likely maintain host-associated differentiation.