Differently increased volumes of multiple brain areas in Npc1 mutant mice following various drug treatments.

Background: Niemann-Pick disease type C1 (NPC1, MIM 257220) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. A murine model of Npc1-/- displays a rapidly progressing form of Npc1 disease, which is characterized by weight loss, ataxia, and increased cholesterol storage. Npc1-/- mice receiving a combined therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-ß-cyclodextrin (HPßCD) showed prevention of Purkinje cell loss, improved motor function and reduced intracellular lipid storage. Although therapy of Npc1-/- mice with COMBI, MIGLU or HPßCD resulted in the prevention of body weight loss, reduced total brain weight was not positively influenced. Methods: In order to evaluate alterations of different brain areas caused by pharmacotherapy, fresh volumes (volumes calculated from the volumes determined from paraffin embedded brain slices) of various brain structures in sham- and drug-treated wild type and mutant mice were measured using stereological methods. Results: In the wild type mice, the volumes of investigated brain areas were not significantly altered by either therapy. Compared with the respective wild types, fresh volumes of specific brain areas, which were significantly reduced in sham-treated Npc1-/- mice, partly increased after the pharmacotherapies in all treatment strategies; most pronounced differences were found in the CA1 area of the hippocampus and in olfactory structures. Discussion: Volumes of brain areas of Npc1-/- mice were not specifically changed in terms of functionality after administering COMBI, MIGLU, or HPßCD. Measurements of fresh volumes of brain areas in Npc1-/- mice could monitor region-specific changes and response to drug treatment that correlated, in part, with behavioral improvements in this mouse model.

Facilitating Access to Current, Evidence-Based Health Information for Non-English Speakers.

Scientific communication is crucial for the development of societies and the advancement of knowledge. However, many countries, and, consequently, their researchers, clinicians and community members, lack access to this information due to the information being disseminated in English rather than their native language. In this viewpoint, we aim to discuss the impacts of this problem and also outline recommendations for facilitating non-English speakers' access to current, evidence-based health information, thus extending the impact of science beyond academia. First, the authors discuss the barriers to accessing scientific health information for non-English speakers and highlight the negative impact of imposing English as a predominant language in academia. Next, the authors discuss the impacts of reduced access to clinical information for non-English speakers and how this reduced access impacts clinicians, clients, and health systems. Finally, the authors provide recommendations for enhancing access to scientific communication worldwide.

The Psychology of COVID-19 Booster Hesitancy, Acceptance and Resistance in Australia.

COVID-19 booster vaccinations have been recommended as a primary line of defence against serious illness and hospitalisation. This study identifies and characterises distinct profiles of attitudes towards vaccination, particularly the willingness to get a booster dose. A sample of 582 adults from Australia completed an online survey capturing COVID-related behaviours, beliefs and attitudes and a range of sociodemographic, psychological, political, social and cultural variables. Latent Profile Analysis (LPA) identified three subgroups: Acceptant (61%), Hesitant (30%) and Resistant (9%). Compared to the Acceptant group, the Hesitant and Resistant groups were less worried about catching COVID-19, used fewer official COVID-19 information sources, checked the news less, were lower on the agreeableness personality dimension and reported more conservatism, persecutory thinking, amoral attitudes and need for chaos. The Hesitant group also reported checking the legitimacy of information sources less, scored lower on the openness to new experiences personality dimension and were more likely than the Resistant and Acceptant groups to report regaining freedoms (e.g., travel) and work requirements or external pressures as reasons to get a booster. The Resistant group were higher on reactance, held more conspiratorial beliefs and rated their culture as being less tolerant of deviance than the Hesitant and Acceptant groups. This research can inform tailored approaches to increasing booster uptake and optimal strategies for public health messaging.

Heterogeneity of cGMP signalling in tumour cells and the tumour microenvironment: Challenges and chances for cancer pharmacology and therapeutics.

The second messenger cyclic guanosine monophosphate (cGMP) is an important regulator of human (patho-)physiology and has emerged as an attractive drug target. Currently, cGMP-elevating drugs are mainly used to treat cardiovascular diseases, but there is also increasing interest in exploring their potential for cancer prevention and therapy. In this review article, we summarise recent findings in cancer-related cGMP research, with a focus on melanoma, breast cancer, colorectal cancer, prostate cancer, glioma, and ovarian cancer. These studies indicate tremendous heterogeneity of cGMP signalling in tumour tissue. It appears that different tumour and stroma cells, and perhaps different sexes, express different cGMP generators, effectors, and degraders. Therefore, the same cGMP-elevating drug can lead to different outcomes in different tumour settings, ranging from inhibition to promotion of tumourigenesis or therapy resistance. These findings, together with recent evidence that increased cGMP signalling is associated with worse prognosis in several human cancers, challenge the traditional view that cGMP elevation generally has an anti-cancer effect. As cGMP pathways appear to be more stable in the stroma than in tumour cells, we suggest that cGMP-modulating drugs should preferentially target the tumour microenvironment. Indeed, there is evidence that phosphodiesterase 5 inhibitors like sildenafil enhance anti-tumour immunity by acting on immune cells. Moreover, many in vivo results obtained with cGMP-modulating drugs could be explained by effects on the tumour vasculature rather than on the tumour cells themselves. We therefore propose a model that incorporates the NO/cGMP signalling pathway in tumour vessels as a key target for cancer therapy. Deciphering the multifaceted roles of cGMP in cancer is not only a challenge for basic research, but also provides a chance to predict potential adverse effects of cGMP-modulating drugs in cancer patients and to develop novel anti-tumour therapies by precision targeting of the relevant cells and molecular pathways.

Reforming clinical negligence in England: lessons about patients' and providers' values from medical injury resolution in New Zealand and the United States of America.

England's current review of clinical negligence and consideration of alternatives (such as no-fault compensation) should be welcomed. Valuing what patients and families want, and need, after harm in healthcare necessitates a system that enables their needs to be met. Medical negligence litigation is misaligned with patients' needs after harm events. By contrast, alternatives (such as no-fault and communication-and-resolution programmes) offer opportunities to place patients', families' and providers' values at the forefront of resolution efforts. This article offers empirical insights and lessons from two alternative systems for resolving medical injuries: New Zealand's (NZ's) administrative compensation scheme, and the US communication-and-resolution programmes (CRPs). The review in England presents an exciting opportunity to design a system for responding to medical injuries that harnesses the strengths of alternative approaches for resolving medical injuries, while also improving on the challenges with treatment injury in NZ.