Freedom to err: The expanding cellular functions of translesion DNA polymerases.

Translesion synthesis (TLS) DNA polymerases were originally described as error-prone enzymes involved in the bypass of DNA lesions. However, extensive research over the past few decades has revealed that these enzymes play pivotal roles not only in lesion bypass, but also in a myriad of other cellular processes. Such processes include DNA replication, DNA repair, epigenetics, immune signaling, and even viral infection. This review discusses the wide range of functions exhibited by TLS polymerases, including their underlying biochemical mechanisms and associated mutagenicity. Given their multitasking ability to alleviate replication stress, TLS polymerases represent a cellular dependency and a critical vulnerability of cancer cells. Hence, this review also highlights current and emerging strategies for targeting TLS polymerases in cancer therapy.

US state laws on medical freedom and investigational stem cell procedures: a call to focus on state-based legislation.

The premature marketing of investigational stem cell interventions (SCIs) is a growing market in the US. Several US states have passed legislation to permit and promote unproven and experimental SCIs for individuals with terminal or chronic diseases. These SCI medical freedom laws, which are largely based on right-to-try legislation, increase access to experimental SCIs with little to no oversight. They undermine federal regulatory authority and can compromise patient safety and informed decision-making. SCI medical freedom laws have gone largely unnoticed by scientific societies interested in the responsible translation of stem cell medicine. In this article, we analyze state SCI medical freedom laws and describe their detrimental impact on patients and society. We contend that scientific and medical societies are uniquely poised to advocate against state-based policy promoting unproven SCIs but recognize resource and other constraints to advocate for or against legislation in 50 states. We recommend societies establish coalitions and share resources to address state-based SCI medical freedom laws and other legislation surrounding unproven SCIs.

Concerns about academic freedom caused by the Russia-Ukraine War.

Russia's war against Ukraine has raised concerns not about the fate of Ukrainian science and scientists but also academic freedom and international cooperation in science.

Keep biology weird: The freedom to be curious: On disobedient worms and scientific freedom.

Caenorhabditis elegans embodies the expectations of a solution-driven take on biology on the one hand, and the mysteries and wonders of life that drives biologists to go to their labs on the other hand.

Challenging local realism with human choices.

A Bell test is a randomized trial that compares experimental observations against the philosophical worldview of local realism 1 , in which the properties of the physical world are independent of our observation of them and no signal travels faster than light. A Bell test requires spatially distributed entanglement, fast and high-efficiency detection and unpredictable measurement settings2,3. Although technology can satisfy the first two of these requirements4-7, the use of physical devices to choose settings in a Bell test involves making assumptions about the physics that one aims to test. Bell himself noted this weakness in using physical setting choices and argued that human 'free will' could be used rigorously to ensure unpredictability in Bell tests 8 . Here we report a set of local-realism tests using human choices, which avoids assumptions about predictability in physics. We recruited about 100,000 human participants to play an online video game that incentivizes fast, sustained input of unpredictable selections and illustrates Bell-test methodology 9 . The participants generated 97,347,490 binary choices, which were directed via a scalable web platform to 12 laboratories on five continents, where 13 experiments tested local realism using photons5,6, single atoms 7 , atomic ensembles 10 and superconducting devices 11 . Over a 12-hour period on 30 November 2016, participants worldwide provided a sustained data flow of over 1,000 bits per second to the experiments, which used different human-generated data to choose each measurement setting. The observed correlations strongly contradict local realism and other realistic positions in bipartite and tripartite 12 scenarios. Project outcomes include closing the 'freedom-of-choice loophole' (the possibility that the setting choices are influenced by 'hidden variables' to correlate with the particle properties 13 ), the utilization of video-game methods 14 for rapid collection of human-generated randomness, and the use of networking techniques for global participation in experimental science.

Evaluation of the current use of MRI to aid the diagnosis of axial spondyloarthritis in the UK: results from a freedom of information request.

AIM: To evaluate the impact of recommendations from the 2019 consensus exercise conducted by radiologists and rheumatologists on the use of magnetic resonance imaging (MRI) to investigate axial spondyloarthritis (axSpA) in clinical practice. MATERIALS AND METHODS: A freedom of information (FOI) request was used to assess the use of MRI in the diagnosis of axSpA and radiologists' awareness of the 2019 guidance across all NHS Trusts and Health Boards in the UK, including England, Scotland, Northern Ireland, and Wales. RESULTS: The FOI request was sent to 150 Trusts/Health Boards, and 93 full responses were received. Of the 93 respondents (97%), 90 reported familiarity with the term axSpA and 70/93 (75%) reported familiarity with the 2019 recommendations. Awareness of recommendations regarding specific MRI features supportive of the diagnosis of axSpA was 74/93 (80%) for the sacroiliac joints (SIJs) and 66/93 (71%) for the spine. The median wait for MRI acquisition was 2-3 months. Fifty-two of the 93 (56%) reported at least some outsourcing of axSpA MRI (33%/29% for specialist/non-specialist outsourcing respectively); 32/93 (34%) reported some scans being reported in-house by non-musculoskeletal radiologists. CONCLUSION: There have been several positive developments in the understanding and use of MRI for the diagnosis of axSpA in the UK since the 2017 survey, although substantial scope for further improvement remains. Several new challenges have also emerged, including the increase in waiting times, reliance on outsourcing, and the reporting of MRI by non-musculoskeletal radiologists.

A human right to pleasure? Sexuality, autonomy and egalitarian strategies.

A growing focus on pleasure in human rights discourse has been used to address patterns of sexual exclusion, often when addressing the problems of people with disabilities (PWD). As convincingly argued by Liberman, however, not all PWD suffer from sexual exclusion, and not all who suffer from sexual exclusion are PWD. Danaher and Liberman have thus argued in various ways for a broader range of measures, addressing sexual exclusion. This article builds on previous research and offers a conceptual framework for addressing sexual pleasure and exclusion in terms of human rights. It argues that human rights aim to safeguard autonomy, which is interpreted as multidimensional. It, thus, divides autonomy into the four dimensions of liberty (freedom from threat and coercion), opportunity (options to choose between), capacity (what an agent is capable of doing) and authenticity (the extent to which choices are genuine). Furthermore, it distinguishes between distinct egalitarian strategies, which offer different problems and possibilities, and may be combined. Thus, there is direct egalitarian distribution, indirect egalitarian distribution, baseline or threshold strategies and general promotion strategies. By way of conclusion, the importance of sexual authenticity as the ultimate aim of sexual rights is emphasised.

The role of collectivism, liberty, COVID fatigue, and fatalism in public support for the zero-COVID policy and relaxing restrictions in China.

BACKGROUND: China was the last country in the world to relax COVID-19 restrictions. A successful public health policy requires public support. This analysis examined the factors associated with Chinese support for zero-COVID and relaxing COVID-19 restrictions in China. METHOD: Two online surveys were conducted among Chinese participants in mainland China on June 10-13 (N = 460) and December 2, 2022 (N = 450). These two samples were similar based on the participants' demographics. RESULTS: The results revealed that the perceived health consequences of a COVID-19 policy, perceived norms of approving a COVID-19 policy, and hope positively predicted the participants' support for the COVID-19 policy. The results further showed that collectivism and fatalism positively predicted support for zero-COVID and negatively predicted support for relaxing restrictions. COVID fatigue was negatively associated with support for zero-COVID and positively associated with support for relaxing restrictions. Liberty positively predicted support for relaxing restrictions in June and negatively predicted zero-COVID in December 2023. It did not positively or negatively predict support for the policy adopted by the government. CONCLUSION: Collectivism, liberty, COVID fatigue, and fatalistic beliefs are important considerations connected to public support for a COVID-19 policy. The role of liberty was more nuanced and depended on the survey's time and whether the government adopted the policy.

Euthanasia, consensual homicide, and refusal of treatment.

Consensual homicide remains a crime in jurisdictions where active voluntary euthanasia has been legalized. At the same time, both jurisdictions, in which euthanasia is legal and those in which it is not, recognize that all patients (whether severely ill or not) have the right to refuse or withdraw medical treatment (including life-saving treatment). In this paper, I focus on the tensions between these three norms (the permission of active euthanasia, the permission to reject life-saving treatment, and the prohibition of consensual homicide), assuming a justification of euthanasia based on the right to (personal) autonomy. I argue that the best way to provide a coherent account of these norms is to claim that patients have two distinct rights: the right to autonomy and the right to bodily integrity. This solution has some relevant implications for the discussion of the legalization of active euthanasia.

'It gives me more freedom': Family perspectives on travelling with children on nocturnal ventilation.

BACKGROUND: Children with neuromuscular weakness or central hypoventilation often require nocturnal ventilation. Children with these conditions are living longer and the numbers of children affected are increasing. The challenges associated with managing ventilation at home have been documented; however, there has been limited investigation into accessing wider experiences such as travel. Air travel, in particular, may be considered challenging for children with these conditions because oxygen levels are lower in airplane cabins than at sea levels. OBJECTIVE: We sought to understand experiences of and attitudes towards travel amongst families of children using nocturnal ventilation for neuromuscular weakness or central hypoventilation. METHODS: Two semi-structured interviews were conducted amongst participants enrolled in a trial of a new pre-flight assessment of their tolerance of reduced oxygen levels during flight (known as a hypoxic challenge test). Children participating in the trial were aged 19 months to 18 years. Parents were interviewed and provided proxy views for younger children, and older children were encouraged to present their own views during these interviews. One interview was conducted immediately after the assessment, and a second 3 months later. Data were analysed utilising the framework approach to thematic analysis. RESULTS: Seventeen families participated in the first interview with 14 of these families completing the follow-up interview. Three further families participated in the follow-up interview only. Here, we report three themes relating to participant experience of travel and how this is impacted by their condition. The three themes and their sub-themes were (1) insight into children's lives: hospital attendances, gaining knowledge and confidence, and child as a person; (2) travelling with your child: planes, trains and automobiles, rules of air travel, and uncertainty; and (3) the meaning of travel: normalisation, connection to extended family, expanded experiences, and freedom and equality. CONCLUSIONS: This population of children and their families aspire to travel but face challenges from clinical and social barriers. It is essential that we further our understanding of the physiological, social and cultural aspects of their experience to facilitate their access to broadened life experiences.

Insights into vertebral band pair deposition rate in the juvenile common thresher shark (Alopias vulpinus) in the northeastern Pacific Ocean.

Validation of band pair deposition rates in elasmobranch vertebrae is essential for accurate age estimation using band pair counting techniques. We present a validation study of the vertebral band pair deposition rate for juvenile common thresher sharks Alopias vulpinus in the northeastern Pacific Ocean (NEPO) using tag and recapture with oxytetracycline (OTC) injection. A total of 14 juvenile A. vulpinus marked with OTC from 1998 through 2013 were recaptured with times at liberty ranging from 1.08 to 3.81 years with an average of 2.14 years (±0.97 years standard deviation, SD). Shark size ranged from 80 to 128 cm fork length (LF) at the time of OTC injection and from 112 to 168 cm LF for those measured at recapture. The slopes of the relationships between band pairs post OTC and years at liberty for each reader ranged from 0.84 to 0.95, slightly lower than the 1.0 slope expected from annual band pair formation. These findings preliminarily support previous age and growth assumptions based on a one band pair per year deposition rate. However, high variation in band pair deposition rates between samples, coupled with regression slopes falling just under one band pair per year, indicates that further investigation is needed to refine band pair deposition rate estimates.

[Genetic studies on forensic-psychiatric inpatients? : Clinical, ethical and legal considerations]. / Genetische Studien an forensisch Untergebrachten? : Klinische, ethische und juristische Überlegungen.

BACKGROUND: Research on people deprived of liberty raises serious questions, especially concerning behavioral genetic studies. QUESTION: Does including criminally detained patients with mental disorders in genetic studies lead to a gain of new knowledge and can this be ethically and legally justified? METHOD: Evaluation of existing literature and interdisciplinary reflection. RESULTS: After a review of research ethics and legal norms, we consider the benefits and risks of behavioral genetic research, taking the unique situation of test persons deprived of their liberty into account. The fundamental right to freedom of research also justifies foundational research in forensic psychiatry and psychotherapy. The possible future benefits of improving treatment plans must be weighed against the risks resulting from potential data leaks and inappropriate public reception of research results. Then we analyze possible threats to voluntary and informed consent to study participation in more detail by the ethical concept of vulnerability. Alongside problems with grasping complex issues, above all dependencies and power dynamics in the correctional system play a pivotal role. Recommendations on the ethical and legal inclusion of this study population are given. CONCLUSION: Including criminally detained study participants can be ethically and legally justified when autonomous consent is supported by specific organizational and legal procedures and measures, for example via a clear professional and organizational separation of correction and research.

Effect of Emotional Freedom Technique Applied to Patients Before Laparoscopic Cholecystectomy on Surgical Fear and Anxiety: A Randomized Controlled Trial.

PURPOSE: No studies have investigated the effect of the Emotional Freedom Technique (EFT) on the surgical fears and anxieties of patients before laparoscopic cholecystectomy. This study aimed to determine the effect of EFT on patients' surgical fears and anxieties before laparoscopic cholecystectomy. DESIGN: The research was conducted using a pretest, post-test, and randomized controlled experimental research design. METHODS: A total of 112 patients (56 in the intervention group and 56 in the control group) were included in the study. While routine care and treatment practices were applied to the control group, EFT was applied to the intervention group. A Patient Information Form, an Anxiety Specific to Surgery Questionnaire, a Surgical Fear Questionnaire, and Subjective Units of Disturbance (SUD) were used to collect the research data. FINDINGS: There was no significant difference between the groups in terms of descriptive and clinical features (P > .05). The post-test score averages of EFT group in the Surgical Fear Questionnaire, Anxiety Specific to Surgery Questionnaire, and SUD were significantly lower than in the control group (P < .001). The EFT significantly reduced the SUD scores of the patients by 54.4% (η2 = 0.544, P < .001). CONCLUSIONS: EFT was found to be useful in clinical practice in the preoperative period, reducing surgery-specific anxiety and surgical fear. EFT can be recommended for application during the preoperative period in clinics.

Deprivation of liberty and the community nurse.

In this month's Policy column, Iwan Dowie discusses the 'deprivation of liberty' - which is used to safeguard patients who may be lacking sufficient mental capacity to manage their own safety. The author, through previous legal cases, shares how the Deprivation of Liberty Safeguards (DoLS)-an amendment to the Mental Capacity Act 2005-came into being, and the importance of community nurses in knowing the DoLS.

Prioritizing persons deprived of liberty in global guidelines for tuberculosis preventive treatment.

In this Policy Forum piece, Aditya Narayan and colleagues discuss the challenges and opportunities for tuberculosis preventive treatment in carceral settings.

One-year sac regression is associated with freedom from fatal adverse events after endovascular aneurysm repair.

OBJECTIVE: Although the predictors of long-term prognosis after endovascular aneurysm repair (EVAR) have been investigated, several reports have suggested that early sac shrinkage (ESS) is associated with superior long-term prognosis. However, it was not clear whether ESS was associated with aneurysm-related mortality. The aim of this study was to define fatal adverse events and to examine their association with ESS. METHODS: All consecutive patients who underwent EVAR for an abdominal aortic aneurysm at Nagoya University Hospital between June 2007 and August 2018 were identified. We defined ESS as an aneurysm diameter decrease of 10 mm or more at 1 year after EVAR, and we defined fatal adverse events as aneurysm-related death, aneurysm sac rupture, open conversion, secondary type Ia endoleak, or secondary type IIIa/b endoleak. Then, we evaluated the association between ESS and fatal adverse events and identified predictors of ESS. RESULTS: During the study period, 553 patients were identified and included. Fatal adverse events occurred in 42 patients (7.6%), and the details of the fatal adverse events were as follows: 13 aneurysm-related deaths, 17 aneurysm sac ruptures, 14 open conversions, 13 type Ia endoleaks, and 6 type III endoleaks. ESS occurred in 146 patients (26.4%). Kaplan-Meier curves showed that the ESS group had a significantly lower incidence of fatal adverse events (P < .001). Multivariate analysis showed that there were significant differences in terms of 5 or more preoperatively patent lumbar arteries (odds ratio [OR], 0.67; P = .049; 95% confidence interval [CI], 0.45-1.00), chronic kidney disease (OR, 0.49; P < .01; 95% CI, 0.29-0.84), and Zenith endograft use (OR, 1.76; P < .01; 95% CI, 1.16-2.67). Furthermore, the percentage of cases that achieved an aneurysm diameter of less than 40 mm was significantly higher in the ESS group (76.0% vs 15.5%; P < .01). The use of Zenith endografts showed a significantly higher rate of aneurysm disappearance than the use of Endurant endografts (P < .01) and Excluder endografts (P < .01). In addition, it was found that ESS was more likely to occur with the use of Zenith endografts, even when propensity score matching was performed for the neck morphology. CONCLUSIONS: ESS was associated with a lower rate of life-threatening adverse events after EVAR. The use of Zenith endografts was a predictor of ESS and was associated with increased rates of long-term sac shrinkage and aneurysm disappearance compared with the Endurant and Excluder endografts. Using the predictors of ESS identified in this study, we may be able to expand the indications for EVAR to patients with a longer life expectancy.

Levetiracetam as a first-line antiseizure medication in WHO grade 2 glioma: Time to seizure freedom and rates of treatment failure.

OBJECTIVE: The high seizure burden seen in World Health Association (WHO) grade 2 gliomas is well documented. This study aims to identify factors that influence the probability of seizure freedom (12 months of seizure remission) and treatment failure (antiseizure medication [ASM] cessation or introduction of an alternative) in patients with WHO grade 2 glioma. METHODS: This is a retrospective observational analysis of patients from a regional UK neurosurgical center with histologically proven (n = 146) WHO grade 2 glioma and brain tumor related epilepsy. Statistical analyses using both Kaplan-Meier and Cox proportional hazards models were undertaken, with a particular focus on treatment outcomes when the commonly prescribed ASM levetiracetam (n = 101) is used as first line. RESULTS: Treatment with levetiracetam as a first-line ASM resulted in a significant increase in the probability of seizure freedom (p < .05) at 2 years compared with treatment with an alternative ASM. Individuals presenting with focal seizures without bilateral tonic-clonic progression were between 39% and 42% significantly less likely to reach seizure freedom within 10 years (p < .05) and 132% more likely to fail treatment by 5 years (p < .01) when compared to individuals who had seizures with progression to bilateral tonic-clonic activity. ASM choice did not significantly affect treatment failure rates. SIGNIFICANCE: More than two-thirds of patients with WHO grade 2 glioma related epilepsy treated with levetiracetam first line achieve seizure freedom within 2 years and it is a reasonable first-choice agent. Experiencing mainly focal seizures without progression infers a significant long-term reduction in the chance of seizure freedom. Further studies are needed to inform ASM selection.