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ImportanceBlood donor selection policies should be evidence-based. Individual risk assessment allows potential donors to be evaluated based on their own behaviors.ObjectiveThe Assessing Donor Variability and New Concepts in Eligibility (ADVANCE) study examined behavioral and biomarkers of HIV risk in sexually active men who have sex with men (MSM) to estimate the proportion of the study population who would not be deferred for higher risk HIV sexual behaviors and might be eligible to donate.DesignA cross-sectional assessment of sexually active MSM interested in blood donation. Setting: An 8-city study of MSM aged 18 – 39 years assigned male sex at birth.Interventions or ExposuresParticipants completed surveys during 2 study visits to define eligibility, self-reported sexual and HIV prevention behaviors. Blood was drawn at study visit 1 and tested for HIV and the presence of tenofovir, 1 of the drugs in oral HIV pre-exposure prophylaxis (PrEP).Main Outcomes and MeasuresAssociations between HIV infection status or HIV PrEP use and self-reported HIV risk behaviors, including number of male sex partners, new partners, and anal sex.ResultsAmong 1788 screened MSM, 1593 were eligible and 1566 completed the visit 1 HIV risk questionnaire and blood draw. A median of 22 days later, 1197 completed the visit 2 follow-up questionnaire. Four individuals tested HIV positive (0.25%). Among HIV-negative participants, 789 (50.4%) reported no PrEP use in the past 3 months. The number of sex partners in the past 3 months was significantly higher among PrEP users versus non-users, as was the number reporting a new male sex partner in the same period. Among HIV-negative, non-PrEP using participants, 66.2% reported only 1 sexual partner or no anal sex and 69% reported no new sexual partners or no anal sex with a new partner in the past 3 months.Conclusion and RelevanceAmong sexually active MSM, there are subgroups who self-report no new sexual partners and only 1 sexual partner within the past 3 months. These individuals are likely at lower risk of HIV infection than other MSM and would meet proposed individual risk assessment criteria for blood donation in the U.S.Key PointsQuestionCan a set of blood donor screening questions based on individual behaviors identify a population of lower HIV risk men who have sex with men (MSM) who wish to donate blood?FindingsIn this cross-sectional study of 1566 enrolled MSM, among 1562 persons without HIV, 789 (50.4%) were not taking pre-exposure prophylaxis (PrEP). Of those not taking PrEP, 66.2% reported only 1 sexual partner or no anal sex and 69% reported no new sexual partners or no anal sex with a new partner in the past 3 months.MeaningPotential blood donor history questions were able to identify sexually active MSM with lower-risk sexual behaviors who may be eligible to donate blood.

Supplementary Data from Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy

As of April 2021, there are five commercially available chimeric antigen receptor (CAR) T cell therapies for hematologic malignancies. With the current transition of CAR T cell manufacturing from academia to industry, there is a shift toward Good Manufacturing Practice (GMP)–compliant closed and automated systems to ensure reproducibility and to meet the increased demand for patients with cancer. In this review, we describe current CAR T cell clinical manufacturing models and discuss emerging technologic advances that embrace scaling and production optimization. We summarize measures being used to shorten CAR T cell manufacturing times and highlight regulatory challenges to scaling production for clinical use.Significance:As the demand for CAR T cell cancer therapy increases, several closed and automated production platforms are being deployed, and others are in development. This review provides a critical appraisal of these technologies, which can be leveraged to scale and optimize the production of next-generation CAR T cells.See related video:https://aacrjournals.org/content/webinar-car-t-cell-manufacturing

We assess to what extent a (co)evolutionary macro level approach enhances our understanding of learning in governance processes. We ask the question: in what ways do actors learn to improve their chances of long-term survival in complex governance processes? We deploy a model of collective decision making moulded upon fitness landscapes to analyze a longitudinal case study of collective (political and administrative) decision making, namely the process of developing and acquiring the F35 Lightning II fighter jet. The study demonstrates that actors learn how to ensure survival over time but create a failing megaproject in the process.

This article presents a tool to disclose public values as emergent properties of needs on a systemic basis applied to a city district in Rotterdam. A tool which enables the public manager to identify public values in any territory based on how people think and feel about society. To accomplish this, it uses Group Model Building (GMB) principles to elicit the mental models that individuals use to make sense of their environment. The results show how the tool enhances a manager’s situational awareness and could assists him with information-driven service delivery.

BackgroundAntigen lateral flow devices (LFDs) have been widely used to control SARS-CoV-2. Changes in LFD sensitivity and detection of infectious individuals during the pandemic with successive variants, vaccination, and changes in LFD use are incompletely understood.MethodsPaired LFD and PCR tests were collected from asymptomatic and symptomatic participants, across multiple settings in the UK between 04-November-2020 and 21-March-2022. Multivariable logistic regression was used to analyse LFD sensitivity and specificity, adjusting for viral load, LFD manufacturer, setting, age, sex, assistance, symptoms, vaccination, and variant. National contact tracing data were used to estimate the proportion of transmitting index cases (with ≥1 PCR/LFD-positive contact) potentially detectable by LFDs over time, accounting for viral load, variant, and symptom status.Findings4131/75,382 (5.5%) participants were PCR-positive. Sensitivity vs. PCR was 63.2% (95%CI 61.7-64.6%) and specificity 99.71% (99.66-99.74%). Increased viral load was independently associated with being LFD-positive. There was no evidence LFD sensitivity differed between Delta vs. Alpha/pre-Alpha infections, but Omicron infections were more likely to be LFD positive. Sensitivity was higher in symptomatic participants, 68.7% (66.9-70.4%) than in asymptomatic participants, 52.8% (50.1-55.4%). 79.4% (68.6-81.3%) of index cases resulting in probable onward transmission with were estimated to have been detectable using LFDs, this proportion was relatively stable over time/variants, but lower in asymptomatic vs. symptomatic cases.InterpretationLFDs remained able to detect most SARS-CoV-2 infections throughout vaccine roll-out and different variants. LFDs can potentially detect most infections that transmit to others and reduce risks. However, performance is lower in asymptomatic compared to symptomatic individuals.FundingUK Government.Research in contextEvidence before this studyLateral flow devices (LFDs; i.e. rapid antigen detection devices) have been widely used for SARS-CoV-2 testing. However, due to their imperfect sensitivity when compared to PCR and a lack of a widely available gold standard proxy for infectiousness, the performance and use of LFDs has been a source of debate. We conducted a literature review in PubMed and bioRxiv/medRxiv for all studies examining the performance of lateral flow devices between 01 January 2020 and 31 October 2022. We used the search terms ‘SARS-CoV-2’/’COVID-19’ and ‘antigen’/’lateral flow test’/’lateral flow device’. Multiple studies have examined the sensitivity and specificity of LFDs, including several systematic reviews. However, the majority of the studies are based on pre-Alpha infections. Large studies examining the test accuracy for different variants, including Delta and Omicron, and following vaccination are limited.Added value of this studyIn this large national LFD evaluation programme, we compared the performance of three different LFDs relative to PCR in various settings. Compared to PCR testing, sensitivity was 63.2% (95%CI 61.7-64.6%) overall, and 71.6% (95%CI 69.8-73.4%) in unselected communitybased testing. Specificity was 99.71% (99.66-99.74%). LFDs were more likely to be positive as viral loads increased. LFD sensitivity was similar during Alpha/pre-Alpha and Delta periods but increased during the Omicron period. There was no association between sensitivity and vaccination status. Sensitivity was higher in symptomatic participants, 68.7% (66.9-70.4%) than in asymptomatic participants, 52.8% (50.1-55.4%). Using national contact tracing data, we estimated that 79.4% (68.6-81.3%) of index cases resulting in probable onward transmission (i.e. with ≥1 PCR/LFD-positive contact) were detectable using LFDs. Symptomatic index cases were more likely to be detected than asymptomatic index cases due to higher viral loads and better LFD performance at a given viral load. The proportion of index cases detected remained relatively stable over time and with successive variants, with a slight increase in the proportion of asymptomatic index cases detected during Omicron.Implications of all the available evidenceOur data show that LFDs detect most SARS-CoV-2 infections, with findings broadly similar to those summarised in previous meta-analyses. We show that LFD performance has been relatively consistent throughout different variant-dominant phases of the pandemic and following the roll-out of vaccination. LFDs can detect most infections that transmit to others and can therefore be used as part of a risk reduction strategy. However, performance is lower in asymptomatic compared to symptomatic individuals and this needs to be considered when designing testing programmes.

The COVID-19 pandemic forced surprised governments worldwide to act fast and decisively, often revealing lack of preparation for this kind of situation. However, such crises are expected to occur far more frequently than ever before. To keep societies prospering, governments, administrations, and civil servants will have to adapt quickly and effectively—and hence need to develop the required capabilities (e.g., appropriate policies, strategies, knowledge, skills). To deepen our understanding of appropriate action in face of crises, resulting consequences for stability and required, demanded or enforced behavior of people, we propose the concept of resilience. Resilience, we argue by way of five propositions, helps articulating the underlying dynamics in society and its administrative systems in order to allow for a sustainable incorporation of the long-term perspective in the short-term strategy, particularly in times of disturbances and temporary perturbations.

A strong evidence-based case is made for a reduction in the drink driving blood alcohol concentration (BAC), currently in the UK 80 mg to 50 mg per 100 ml which worldwide has been shown to decrease the number of drink driving including fatal accidents. An even lower BAC of 20 mg per 100 ml is recommended for the younger novice representing 7% of driving licence holders in the UK but involved in 20% of fatal and serious collisions. The danger of binge drinking and of combining alcohol with other drugs such as cannabis and marijuana is emphasised and the harmful influence of simple energy drinks when combined with alcohol. The review also emphasises the need for enhanced police enforcement and more public awareness campaigns which to date have indicated growing public support for reducing the drink driving limits.

The efficacy of COVID-19 convalescent plasma (CCP) as a treatment for hospitalized patients with COVID-19 remains somewhat controversial; however, many studies have not evaluated CCP documented to have high neutralizing antibody titer by a highly accurate assay. To evaluate the correlation of the administration of CCP with titer determined by a live viral neutralization assay with 7- and 28-day death rates during hospitalization, a total of 23 118 patients receiving a single unit of CCP were stratified into two groups: those receiving high titer CCP (250 50% inhibitory dilution, ID50; n = 13 636) or low titer CCP (≤250 ID50; n = 9482). Multivariable Cox regression was performed to assess risk factors. Non-intubated patients who were transfused with high titer CCP showed 1.1% and 1.7% absolute reductions in overall 7- and 28-day death rates, respectively, compared to those non-intubated patients receiving low titer CCP. No benefit of CCP was observed in intubated patients. The relative benefit of high titer CCP was confirmed in multivariable Cox regression. Administration of CCP with high titer antibody content determined by live viral neutralization assay to non-intubated patients is associated with modest clinical efficacy. Although shown to be only of modest clinical benefit, CCP may play a role in the future should viral variants develop that are not neutralized by other available therapeutics.

Polymicrogyria is a heterogeneous malformation of cortical development microscopically defined by an excessive folding of the cortical mantle resulting in small gyri with a fused surface. Polymicrogyria is responsible for a wide range of neurological symptoms (e.g. epilepsy, intellectual disability, motor dysfunction). Most cases have a supposed environmental clastic vascular or infectious origin but progress in genomics has revealed new monogenic entities. We report four cases from two independent families sharing a common recognizable lethal syndromic polymicrogyria of autosomal recessive inheritance. Beyond diffuse polymicrogyria detected prenatally, pathological examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. In all affected cases, exome sequencing showed a pathogenic homozygous nonsense ATP1A2 variant. This resulted in absence of immunodetectable ATP1A2 protein in two brains analysed. ATP1A2 encodes the alpha-2 isoform of the Na+/K+-ATPase, which is highly expressed in brain tissues and has previously been related to familial hemiplegic migraine (MIM#602481) and alternating hemiplegia of childhood (MIM#104290). Through the description of this genetic entity, we emphasize the possibility of dual mode of transmission for disease-causing genes and provide the key neuropathological features that should prompt geneticists to test for mutations in the ATP1A2 gene.

textabstractWe set out to develop a method and research technique that could unite both modelling and case-based observations in order to analyse collective decision-making processes. Following Abbott’s (2001) recommendation regarding social processes, we have defined collective decision-making as an uninterrupted and non-directional process that is structured in sequences or lineages of events. To structure these processes, we re-modelled the basic components of Kauffman’s (1993) NK-model. We converted N to ‘problem and solution definitions’ (PSDs) and K to ‘connectedness’ between actors (c_score). An important modification is that we consider NK to be a dependent configuration; i.e., K entails both content and process. Fitness is defined as the probability of an actor achieving (elements of) its PSD as a result of its adaptive moves in relation to the adaptive moves of others. The model is put to the test in four different studies: (1) 20 years of decision-making in planning, building and servicing HSL-Zuid high-speed railways in the Netherlands; (2) the strategic search process of villages and cantons in the Gotthard region of Switzerland; (3) the redevelopment of a football stadium and the surrounding area in south Rotterdam, the Netherlands; and (4) the rise and fall of the Airport RailLink in Bangkok, Thailand. From these studies, we derived six archetypes in collection decision-making, subdivided into actor archetypes and interaction archetypes. For the actor archetypes, behavioural consistency is not just a trait for the actor but also affects the space of possibilities and/or behaviours of other actors. The interactions of individual actors combine to produce self-propagating dynamics that drive the further evolution of the collective decision-making process. The fitness field model enables researchers to investigate the various dimensions of the collective decision-making process – ranging from individual strategies and actions to variation, selection and retention of contents, from interactions to fitness gains and losses, and back again.