How people think about the truth of hypothetical impossibilities.

People can think about hypothetical impossibilities and a curious observation is that some impossible conditionals seem true and others do not. Four experiments test the proposal that people think about impossibilities just as they do possibilities, by attempting to construct a consistent simulation of the impossible conjecture with its suggested outcome, informed by their knowledge of the real world. The results show that participants judge some impossible conditionals true with one outcome, for example, "if people were made of steel, they would not bruise easily" and false with the opposite outcome, "if people were made of steel they would bruise easily", and others false with either outcome, for example, "if houses were made of spaghetti, their engines would (not) be noisy". However, they can sometimes judge impossible conditionals true with either outcome, for example, "if Plato were identical to Socrates, he would (not) have a small nose", or "if sheep and wolves were alike, they would (not) eat grass". The results were observed for judgments about what could be true (Experiments 1 and 4), judgments of degrees of truth (Experiment 2), and judgments of what is true (Experiment 3). The results rule out the idea that people evaluate the truth of a hypothetical impossibility by relying on cognitive processes that compare the probability of each conditional to its counterpart with the opposite outcome.

Switching Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide Fumarate (TAF) in Hepatitis B/HIV Co-Infection: A Feasibility Study.

PURPOSE: Tenofovir alafenamide (TAF) delivers the active metabolite more efficiently to target cells compared with tenofovir disoproxil fumarate (TDF). Recent studies suggest that TAF is efficacious in treatment naïve individuals who are co-infected with HBV/HIV and may have superior effects on HBV e antigen (HBeAg) seroconversion in this setting. The primary objective of this study was to explore the feasibility of switching from TDF to TAF in HBV/HIV co-infection. METHODS: In this single-arm, multicenter, open-label study, we recruited patients (n = 20) who were on stable TDF-based antiviral therapy for at least 12 months. All participants had undetectable HIV RNA and HBV DNA levels at the time of screening and were converted to a TAF-based treatment regimen (TAF + emtricitabine + third agent) for 48 weeks. FINDINGS: Twenty-seven individuals were invited to take part in the screening process; 3 met the exclusion criteria and a further 4 withdrew consent prior to enrolment. The remaining participants were predominantly male (70%), non-cirrhotic (95%) and of Afro-Caribbean ethnicity (60%). All were co-infected with HIV-1 and established on long-term antiretroviral treatment prior to enrolment (median 6.5 years). No adverse events related to the study drug were observed, and most patients (89.5%) maintained undetectable HIV RNA and HBV DNA throughout the follow-up period. IMPLICATIONS: Switching from TDF to TAF in HBV/HIV co-infection was safe, well tolerated and maintained virological suppression in most patients. Additional studies are needed to confirm these findings in larger cohorts and explore other endpoints.

Human verifications: Computable with truth values outside logic.

Cognitive scientists treat verification as a computation in which descriptions that match the relevant situation are true, but otherwise false. The claim is controversial: The logician Gödel and the physicist Penrose have argued that human verifications are not computable. In contrast, the theory of mental models treats verification as computable, but the two truth values of standard logics, true and false, as insufficient. Three online experiments (n = 208) examined participants' verifications of disjunctive assertions about a location of an individual or a journey, such as: 'You arrived at Exeter or Perth'. The results showed that their verifications depended on observation of a match with one of the locations but also on the status of other locations (Experiment 1). Likewise, when they reached one destination and the alternative one was impossible, their use of the truth value: could be true and could be false increased (Experiment 2). And, when they reached one destination and the only alternative one was possible, they used the truth value, true and it couldn't have been false, and when the alternative one was impossible, they used the truth value: true but it could have been false (Experiment 3). These truth values and those for falsity embody counterfactuals. We implemented a computer program that constructs models of disjunctions, represents possible destinations, and verifies the disjunctions using the truth values in our experiments. Whether an awareness of a verification's outcome is computable remains an open question.

How people reason with counterfactual and causal explanations for Artificial Intelligence decisions in familiar and unfamiliar domains.

Few empirical studies have examined how people understand counterfactual explanations for other people's decisions, for example, "if you had asked for a lower amount, your loan application would have been approved". Yet many current Artificial Intelligence (AI) decision support systems rely on counterfactual explanations to improve human understanding and trust. We compared counterfactual explanations to causal ones, i.e., "because you asked for a high amount, your loan application was not approved", for an AI's decisions in a familiar domain (alcohol and driving) and an unfamiliar one (chemical safety) in four experiments (n = 731). Participants were shown inputs to an AI system, its decisions, and an explanation for each decision; they attempted to predict the AI's decisions, or to make their own decisions. Participants judged counterfactual explanations more helpful than causal ones, but counterfactuals did not improve the accuracy of their predictions of the AI's decisions more than causals (Experiment 1). However, counterfactuals improved the accuracy of participants' own decisions more than causals (Experiment 2). When the AI's decisions were correct (Experiments 1 and 2), participants considered explanations more helpful and made more accurate judgements in the familiar domain than in the unfamiliar one; but when the AI's decisions were incorrect, they considered explanations less helpful and made fewer accurate judgements in the familiar domain than the unfamiliar one, whether they predicted the AI's decisions (Experiment 3a) or made their own decisions (Experiment 3b). The results corroborate the proposal that counterfactuals provide richer information than causals, because their mental representation includes more possibilities.

Acute Charcot arthropathy as a first presentation of type 2 diabetes mellitus.

Charcot arthropathy in people with diabetes is generally seen when diabetes has been well established, and therefore it is not routinely considered as a differential diagnosis in people presenting with erythematous and oedematous joints in primary care. We present two cases of acute Charcot arthropathy as a first presentation of type 2 diabetes mellitus. The first case describes a man in his 70s, who presented with a 5-week history of right foot pain, treated initially in the community as cellulitis. A diagnosis of acute Charcot arthropathy was made in the emergency department following review by the orthopaedic and podiatry department. The second case describes a woman in her 40s who presented with a 2-week history of ankle pain. Charcot arthropathy is associated with significant morbidity and mortality, and these cases highlight the importance of including Charcot arthropathy in the differential diagnosis when people present with atypical joint swelling.

COVAC1 phase 2a expanded safety and immunogenicity study of a self-amplifying RNA vaccine against SARS-CoV-2.

Background: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is well tolerated and immunogenic in SARS-CoV-2 seronegative and seropositive individuals aged 18-75. Methods: A phase 2a expanded safety and immunogenicity study of a saRNA SARS-CoV-2 vaccine candidate LNP-nCoVsaRNA, was conducted at participating centres in the UK between 10th August 2020 and 30th July 2021. Participants received 1 µg then 10 µg of LNP-nCoVsaRNA, ∼14 weeks apart. Solicited adverse events (AEs) were collected for one week post-each vaccine, and unsolicited AEs throughout. Binding and neutralisating anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, and SARS-CoV-2 pseudoneutralisation assay. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). Findings: 216 healthy individuals (median age 51 years) received 1.0 µg followed by 10.0 µg of the vaccine. 28/216 participants were either known to have previous SARS-CoV2 infection and/or were positive for anti-Spike (S) IgG at baseline. Reactogenicity was as expected based on the reactions following licensed COVID-19 vaccines, and there were no serious AEs related to vaccination. 80% of baseline SARS-CoV-2 naïve individuals (147/183) seroconverted two weeks post second immunization, irrespective of age (18-75); 56% (102/183) had detectable neutralising antibodies. Almost all (28/31) SARS-CoV-2 positive individuals had increased S IgG binding antibodies following their first 1.0 µg dose with a ≥0.5log10 increase in 71% (22/31). Interpretation: Encapsulated saRNA was well tolerated and immunogenic in adults aged 18-75 years. Seroconversion rates in antigen naïve were higher than those reported in our dose-ranging study. Further work is required to determine if this difference is related to a longer dosing interval (14 vs. 4 weeks) or dosing with 1.0 µg followed by 10.0 µg. Boosting of S IgG antibodies was observed with a single 1.0 µg injection in those with pre-existing immune responses. Funding: Grants and gifts from the Medical Research Council UKRI (MC_PC_19076), the National Institute for Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, and Restore the Earth.

Human monkeypox virus infection in women and non-binary individuals during the 2022 outbreaks: a global case series.

BACKGROUND: Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve identification and understanding of risk factors. METHODS: International collaborators in geographical locations with high numbers of diagnoses of monkeypox virus infection were approached and invited to contribute data on women and non-binary individuals with confirmed monkeypox virus infection. Contributing centres completed deidentified structured case-report spreadsheets, adapted and developed by participating clinicians, to include variables of interest relevant to women and non-binary individuals assigned female at birth. We describe the epidemiology and clinical course observed in the reported infections. FINDINGS: Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28-40; range 19-84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1-200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalised, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported. INTERPRETATION: The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high. FUNDING: None.

Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis.

BACKGROUND: Historically, human monkeypox virus cases in the UK have been limited to imported infections from west Africa. Currently, the UK and several other countries are reporting a rapid increase in monkeypox cases among individuals attending sexual health clinics, with no apparent epidemiological links to endemic areas. We describe demographic and clinical characteristics of patients diagnosed with human monkeypox virus attending a sexual health centre. METHODS: In this observational analysis, we considered patients with confirmed monkeypox virus infection via PCR detection attending open-access sexual health clinics in London, UK, between May 14 and May 25, 2022. We report hospital admissions and concurrent sexually transmitted infection (STI) proportions, and describe our local response within the first 2 weeks of the outbreak. FINDINGS: Monkeypox virus infection was confirmed in 54 individuals, all identifying as men who have sex with men (MSM), with a median age of 41 years (IQR 34-45). 38 (70%) of 54 individuals were White, 26 (48%) were born in the UK, and 13 (24%) were living with HIV. 36 (67%) of 54 individuals reported fatigue or lethargy, 31 (57%) reported fever, and ten (18%) had no prodromal symptoms. All patients presented with skin lesions, of which 51 (94%) were anogenital. 37 (89%) of 54 individuals had skin lesions affecting more than one anatomical site and four (7%) had oropharyngeal lesions. 30 (55%) of 54 individuals had lymphadenopathy. One in four patients had a concurrent STI. Five (9%) of 54 individuals required admission to hospital, mainly due to pain or localised bacterial cellulitis requiring antibiotic intervention or analgesia. We recorded no fatal outcomes. INTERPRETATION: Autochthonous community monkeypox virus transmission is currently observed among MSM in the UK. We found a high proportion of concomitant STIs and frequent anogenital symptoms, suggesting transmissibility through local inoculation during close skin-to-skin or mucosal contact, during sexual activity. Additional resources are required to support sexual health and other specialist services in managing this condition. A review of the case definition and better understanding of viral transmission routes are needed to shape infection control policies, education and prevention strategies, and contact tracing. FUNDING: None.

Cognitive processes in imaginative moral shifts: How judgments of morally unacceptable actions change.

How do people come to consider a morally unacceptable action, such as "a passenger in an airplane does not want to sit next to a Muslim passenger and so he tells the stewardess the passenger must be moved to another seat", to be less unacceptable? We propose they tend to imagine counterfactual alternatives about how things could have been different that transform the unacceptable action to be less unacceptable. Five experiments identify the cognitive processes underlying this imaginative moral shift: an action is judged less unacceptable when people imagine circumstances in which it would have been moral. The effect occurs for immediate counterfactuals and reflective ones, but is greater when participants create an immediate counterfactual first, and diminished when they create a reflective one first. The effect also occurs for unreasonable actions. We discuss the implications for alternative theories of the mental representations and cognitive processes underlying moral judgments.

Similarities and differences in understanding negative and affirmative counterfactuals and causal assertions: Evidence from eye-tracking.

Two eye-tracking experiments compared affirmative and negative counterfactuals, "if she had (not) arrived early, she would (not) have bought roses" and affirmative and negative causal assertions, "Because she arrived (did not arrive) early, she bought (did not buy) roses." When participants heard a counterfactual, they looked on screen at words corresponding to its conjecture ("roses"), and its presupposed facts ("no roses"), whereas for a causal assertion, they looked only at words corresponding to the facts. For counterfactuals, they looked at the conjecture first, and later the presupposed facts, and at the latter more than the former. The effect was more pronounced for negative counterfactuals than affirmative ones because the negative counterfactual's presupposed facts identify a specific item ("she bought roses"), whereas the affirmative counterfactual's presupposed facts do not ("she did not buy roses"). Hence, when participants were given a binary context, "she did not know whether to buy roses or carnations," they looked primarily at the presupposed facts for both sorts of counterfactuals. We discuss the implications for theories of negation, the dual meaning of counterfactuals, and their relation to causal assertions.

Establishment of a human three-dimensional chip-based chondro-synovial coculture joint model for reciprocal cross talk studies in arthritis research.

Rheumatoid arthritis is characterised by a progressive, intermittent inflammation at the synovial membrane, which ultimately leads to the destruction of the synovial joint. The synovial membrane as the joint capsule's inner layer is lined with fibroblast-like synoviocytes that are the key player supporting persistent arthritis leading to bone erosion and cartilage destruction. While microfluidic models that model molecular aspects of bone erosion between bone-derived cells and synoviocytes have been established, RA's synovial-chondral axis has not yet been realised using a microfluidic 3D model based on human patient in vitro cultures. Consequently, we established a chip-based three-dimensional tissue coculture model that simulates the reciprocal cross talk between individual synovial and chondral organoids. When co-cultivated with synovial organoids, we could demonstrate that chondral organoids induce a higher degree of cartilage physiology and architecture and show differential cytokine response compared to their respective monocultures highlighting the importance of reciprocal tissue-level cross talk in the modelling of arthritic diseases.

How people keep track of what is real and what is imagined: The epistemic status of counterfactual alternatives to reality.

When people understand a counterfactual such as "if it had been a good year, there would have been roses," they simulate the imagined alternative to reality, for example, "there were roses," and the actual reality, as known or presupposed, for example, "there were no roses." Seven experiments examined how people keep track of the epistemic status of these possibilities, by priming participants to anticipate a story would continue about one or the other. When participants anticipated the story would continue about how the current reality related to the past presupposed reality, they read a target description about reality more rapidly than one about the imagined alternative, indicating they had prioritized access to their mental representation of reality; but when they anticipated the story would continue about how the current reality related to the imagined alternative to reality, they read a target description about the imagined alternative and one about reality equally rapidly, indicating they had maintained access to both (Experiment 1), unlike for stories with no counterfactuals (Experiments 2 and 3). The tendency is not invariant: it appears immune to remote experience (Experiments 4 and 5), but it is influenced by immediate experience (Experiments 6 and 7). The results have implications for theories of reality monitoring, reasoning, and imagination. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Possibilities and the parallel meanings of factual and counterfactual conditionals.

The mental model theory postulates that the meanings of conditionals are based on possibilities. Indicative conditionals-such as "If he is injured tomorrow, then he will take some leave"-have a factual interpretation that can be paraphrased as It is possible, and remains so, that he is injured tomorrow, and in that case certain that he takes some leave. Subjunctive conditionals, such as, "If he were injured tomorrow, then he would take some leave," have a prefactual interpretation that has the same paraphrase. But when context makes clear that his injury will not occur, the subjunctive has a counterfactual paraphrase, with the first clause: It was once possible, but does not remain so, that he will be injured tomorrow. Three experiments corroborated these predictions for participants' selections of paraphrases in their native Spanish, for epistemic and deontic conditionals, for those referring to past and to future events, and for those with then clauses referring to what may or must happen. These results are contrary to normal modal logics. They are also contrary to theories based on probabilities, which are inapplicable to deontic conditionals, such as, "If you have a ticket, then you must enter the show."

The Suppression of Inferences From Counterfactual Conditionals.

We examine two competing effects of beliefs on conditional inferences. The suppression effect occurs for conditionals, for example, "if she watered the plants they bloomed," when beliefs about additional background conditions, for example, "if the sun shone they bloomed" decrease the frequency of inferences such as modus tollens (from "the plants did not bloom" to "therefore she did not water them"). In contrast, the counterfactual elevation effect occurs for counterfactual conditionals, for example, "if she had watered the plants they would have bloomed," when beliefs about the known or presupposed facts, "she did not water the plants and they did not bloom" increase the frequency of inferences such as modus tollens. We report six experiments that show that beliefs about additional conditions take precedence over beliefs about presupposed facts for counterfactuals. The modus tollens inference is suppressed for counterfactuals that contain additional conditions (Experiments 1a and 1b). The denial of the antecedent inference (from "she did not water the plants" to "therefore they did not bloom") is suppressed for counterfactuals that contain alternatives (Experiments 2a and 2b). We report a new "switched-suppression" effect for conditionals with negated components, for example, "if she had not watered the plants they would not have bloomed": modus tollens is suppressed by alternatives and denial of the antecedent by additional conditions, rather than vice versa (Experiments 3a and 3b). We discuss the implications of the results for alternative theories of conditional reasoning.

Monitoring tissue-level remodelling during inflammatory arthritis using a three-dimensional synovium-on-a-chip with non-invasive light scattering biosensing.

Rheumatoid arthritis is a chronic, systemic joint disease in which an autoimmune response translates into an inflammatory attack resulting in joint damage, disability and decreased quality of life. Despite recent introduction of therapeutic agents such as anti-TNFα, even the best current therapies fail to achieve disease remission in most arthritis patients. Therefore, research into the mechanisms governing the destructive inflammatory process in rheumatoid arthritis is of great importance and may reveal novel strategies for the therapeutic interventions. To gain deeper insight into its pathogensis, we have developed for the first time a three-dimensional synovium-on-a-chip system in order to monitor the onset and progression of inflammatory synovial tissue responses. In our study, patient-derived primary synovial organoids are cultivated on a single chip platform containing embedded organic-photodetector arrays for over a week in the absence and presence of tumor-necrosis-factor. Using a label-free and non-invasive optical light-scatter biosensing strategy inflammation-induced 3D tissue-level architectural changes were already detected after two days. We demonstrate that the integration of complex human synovial organ cultures in a lab-on-a-chip provides reproducible and reliable information on how systemic stress factors affect synovial tissue architectures.

If and or: Real and counterfactual possibilities in their truth and probability.

The theory of mental models postulates that conditionals and disjunctions refer to possibilities, real or counterfactual. Factual conditionals, for example, "If there's an apple, there's a pear," parallel counterfactual ones, for example, "If there had been an apple, there would have been a pear." A similar parallel underlies disjunctions. Individuals estimate the probabilities of conditionals by adjusting the probability of their then-clauses according to the effects of their if-clauses, and the probabilities of disjunctions by a rough average of the probabilities of their disjuncts. Hence, the theory predicts that estimates of the joint probabilities of these assertions with each of the four cases in their partitions will be grossly subadditive, summing to over 100%. Five experiments corroborated these predictions. Factual conditionals and disjunctions were judged true in the same cases as their counterfactual equivalents, and the sum of their joint probabilities with cases in the partition ranged from 240% to 270% (Experiments 1a, 1b). When participants were told these probabilities should not sum to more than 100%, estimates of the probability of A and C, as the model theory predicts, were higher for factual than counterfactual conditionals, whereas estimates of the probability of not-A and not-C had the opposite difference (Experiment 1c). Judgments of truth or falsity distinguished between conditionals that were certain and those that might have counterexamples (Experiment 2a), whereas judgments of the likelihood of truth reflected the probabilities of counterexamples (Experiment 2b). We discuss implications for alternative theories based on standard logic, suppositions, probabilistic logic, and causal Bayes networks. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The Comprehension of Counterfactual Conditionals: Evidence From Eye-Tracking in the Visual World Paradigm.

Three experiments tracked participants' eye-movements to examine the time course of comprehension of the dual meaning of counterfactuals, such as "if there had been oranges then there would have been pears." Participants listened to conditionals while looking at images in the visual world paradigm, including an image of oranges and pears that corresponds to the counterfactual's conjecture, and one of no oranges and no pears that corresponds to its presumed facts, to establish at what point in time they consider each one. The results revealed striking individual differences: some participants looked at the negative image and the affirmative one, and some only at the affirmative image. The first experiment showed that participants who looked at the negative image increased their fixation on it within half a second. The second experiment showed they do so even without explicit instructions, and the third showed they do so even for printed words.

Peripheral nerve transfers change target muscle structure and function.

Selective nerve transfers surgically rewire motor neurons and are used in extremity reconstruction to restore muscle function or to facilitate intuitive prosthetic control. We investigated the neurophysiological effects of rewiring motor axons originating from spinal motor neuron pools into target muscles with lower innervation ratio in a rat model. Following reinnervation, the target muscle's force regenerated almost completely, with the motor unit population increasing to 116% in functional and 172% in histological assessments with subsequently smaller muscle units. Muscle fiber type populations transformed into the donor nerve's original muscles. We thus demonstrate that axons of alternative spinal origin can hyper-reinnervate target muscles without loss of muscle force regeneration, but with a donor-specific shift in muscle fiber type. These results explain the excellent clinical outcomes following nerve transfers in neuromuscular reconstruction. They indicate that reinnervated muscles can provide an accurate bioscreen to display neural information of lost body parts for high-fidelity prosthetic control.