Facilitating Ukrainian Refugees' Continued Participation in Clinical Trials.

Russia's invasion of Ukraine and the ongoing armed conflict are having a hugely damaging effect on health services and the health infrastructure in Ukraine. Hundreds of clinical trials have been halted, leaving patients without access to treatment and jeopardizing the development of promising new drugs. There is a lack of clarity on dealing with protocol deviations and other disruptions caused by war. This article proposes guidance on facilitating Ukrainian refugees' continuation in clinical trials. The safety of study participants should be the main priority and guide every decision, regardless of any potential consequences for an ongoing trial. This commentary outlines policy recommendations regarding participants' reenrollment, the handover of participants and data to new principal investigators, and the consent process as well as the sponsor's obligations related to translation, data transfer, and support for Ukrainian investigators. To ensure data integrity, investigators should carry out risk assessments of the further use of refugees' data.

Supporting control programs on African swine fever in Ukraine through a knowledge, attitudes, and practices survey targeting backyard farmers.

A Knowledge, Attitudes, and Practices (KAP) questionnaire was designed to collect information on farmers' knowledge of ASF and their practices surrounding that could impact the spread of the disease. The questionnaire was distributed, and data collected, from 233 backyard farmers from five selected Oblasts (Rivne, Kharkiv, Odessa, Zakarpattia and Kiev). Kruskal-Wallis tests were conducted to identify factors that could influence knowledge, and Dunn tests were performed to determine differences between groups when the Kruskal-Wallis tests were significant. Spearman tests were carried out to explore the association between knowledge and risky practices. Results show that comprehensive knowledge on ASF is not common in backyard farmers and that risky practices that influence the spread of ASF are regularly performed. Of the respondents, 47% felt well-informed about how ASF can be transmitted and 31.8% felt confident about recognizing clinical signs of ASF. The independent variable "Oblast" was identified as a significant factor (p = 0.0015) associated with differences in knowledge on clinical signs. We demonstrated statistically significant differences of knowledge between backyard farmers from different Oblasts. Knowledge of preventive measures was positively correlated with risky handling practices related to edible pork products (p = 0.0053) and non-edible pork products (p = 0.0417). In conclusion, our results show that backyard farmers have knowledge gaps on ASF and practice various risky behaviours that might favour the spread of the disease in Ukraine. There are regional differences in ASF knowledge and risky practices that should be taken into consideration in future evidence-based ASF prevention and control programs, including public awareness activities.

In vivo stabilization of mutant human transthyretin in transgenic mice.

Transthyretin (TTR) is a 55 kD homotetrameric serum protein transporter of retinol binding protein charged with retinol and thyroxine (T4). The highly amyloidogenic human TTR variant in which leucine at position 55 is replaced by proline (L55P TTR) is responsible for aggressive fatal amyloidosis with peripheral and autonomic neuropathy, cardiomyopathy and nephropathy. Mice bearing one or two copies of a 19.2 kB human genomic fragment containing the entire coding sequence and the known control regions of the L55P TTR transgene, failed to develop TTR amyloidosis even though their sera contained mutant human TTR. The frequency of TTR tissue deposition was increased when the L55P TTR transgene was bred onto a murine TTR-null background. Denaturation of sera from the transgenic animals and murine TTR-knockouts expressing the human L55P TTR transgene revealed that the TTR tetramer was much more stable in the presence of the murine protein because the TTR circulates as hybrid human/murine heterotetramers. Intraperitoneal administration of diflunisal, a non-steroidal anti-inflammatory drug that binds to TTR in its T4-binding site and inhibits fibril formation in vitro, to human L55P TTR transgenic animals in which the murine TTR gene had been silenced, also stabilizes the circulating mutant protein to in vitro urea denaturation.

Preferential binding of human XPA to the mitomycin C-DNA interstrand crosslink and modulation by arsenic and cadmium.

The Xeroderma Pigmentosum A (XPA) protein is involved in the DNA damage recognition and repair complex formation steps of nucleotide excision repair (NER), and has been shown to preferentially bind to various forms of DNA damage including bulky lesions. DNA interstrand crosslinks are of particular interest as a form of DNA damage, since these lesions involve both strands of duplex DNA and present special challenges to the repair machinery, and mitomycin C (MMC) is one of several useful cancer chemotherapy drugs that induce these lesions. Purified XPA and the minimal DNA-binding domain of XPA are both fully capable of preferentially binding to MMC-DNA interstrand crosslinks in the absence of other proteins from the NER complex. Circular dichroism (CD) and gel shift assays were used to investigate XPA-DNA binding and to assess changes in secondary structure induced as a consequence of the interaction of XPA with model MMC-crosslinked and unmodified DNAs. These studies revealed that while XPA demonstrates only a modest increase in affinity for adducted DNA, it adopts a different conformation when bound to MMC-damaged DNA than when bound to undamaged DNA. This change in conformation may be more important in recruiting other proteins into a competent NER complex at damaged sites than preferential binding per se. Arsenic had little effect on XPA binding even at toxic concentrations, whereas cadmium reduced XPA binding to DNA to 10-15% that of Zn-XPA, and zinc addition could only partially restore activity. In addition, there was little or no change in conformation when Cd-XPA bound MMC-crosslinked DNA even though it demonstrated preferential binding, which may contribute to the mechanism by which cadmium can act as a co-mutagen and co-carcinogen.