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Background: COVID-19 care home outbreaks represent a significant proportion of COVID-19 morbidity and mortality in the UK. National testing initially focused on symptomatic care home residents, before extending to asymptomatic cohorts.Aim: The aim was to describe the epidemiology and transmission of COVID-19 in outbreak free care homes.Methods: A two-point prevalence survey of COVID-19, in 34 Liverpool care homes, was performed in April and May 2020. Changes in prevalence were analysed. Associations between care home characteristics, reported infection, prevention and control interventions, and COVID-19 status were described and analysed.Findings: No resident developed COVID-19 symptoms during the study. There was no significant difference between: the number of care homes containing at least one test positive resident between the first (17.6%, 95% confidence interval (CI) 6.8-34.5) and second round (14.7%, 95% CI 5.0-31.1) of testing (p>0.99); and the number of residents testing positive between the first (2.1%, 95% CI 1.2-3.4) and second round (1.0%, 95% CI 0.5-2.1) of testing (P=0.11). Care homes providing nursing care (risk ratio (RR) 7.99, 95% CI 1.1-57.3) and employing agency staff (RR 8.4, 95% CI 1.2-60.8) were more likely to contain test positive residents. Closing residents shared space was not associated with residents testing positive (RR 2.63, 95% CI 0.4-18.5).Conclusions: Asymptomatic COVID-19 care homes showed no evidence of disease transmission or development of outbreaks; suggesting that current infection prevention and control measures are effective in preventing transmission. Repeat testing at two to three weeks had limited or no public health benefits over regular daily monitoring of staff and residents for symptoms. These results should inform policies calling for regular testing of asymptomatic residents. [ABSTRACT FROM AUTHOR]

Background: COVID-19 placed a significant burden on the care home population during the first wave. Care Quality Commission's care quality ratings are given to all English care homes and could be used to identify whether care homes are at risk of COVID-19 outbreaks.Methods: An audit was performed, April 2020, of Liverpool care homes to identify associations between COVID-19 status and care quality ratings from the Care Quality Commission. Univariable logistic regression was performed to identify whether the Care Quality Commissions ratings were associated with a care home experiencing a COVID-19 outbreak, or a home having asymptomatic cases.Findings: Over half of the care homes (53.2%, n=41), had laboratory-confirmed clinical cases and 39 (95.1%) of these were reported as outbreaks. A small number of care homes (10.4%, n=8) had asymptomatic cases and over a third had no clinical or asymptomatic cases (36.4%, n=28). There was no significant difference between the overall Care Quality Commission rating of Liverpool and English care homes (p=0.57). There was no significant association between any of the Care Quality Commission rating domains and the presence of COVID-19 outbreaks and/or asymptomatic cases.Conclusions: During the first wave of the COVID-19 pandemic, Care Quality Commission ratings were not associated with COVID-19 outbreaks or asymptomatic cases in care homes. Infection prevention and control components of Care Quality Commission ratings need to be strengthened to identify care homes at a potential risk of infectious disease outbreaks that may require targeted support. Further large-scale studies will be required to test the findings from this study. [ABSTRACT FROM AUTHOR]

Myriad digital health interventions, applications, devices and technologies have, and are, being developed to help refine and personalise medicine from the patient, healthcare professional (HCP), healthcare system and industry perspectives. At a gathering of leaders in digital health, discussion included the current landscape of such digital health tools (DHTs), with specific examples from cardiology and respiratory medicine, and both the benefits and sometime downfalls of such tools. While DHTs can help patients and HCPs detect and monitor health conditions, the experts discussed how adoption of DHTs may be hampered by issues such as access to technology; data privacy and security concerns; technology integration into current healthcare systems; cost and reimbursement; and lack of guidelines and regulatory hurdles. The experts suggested solutions to such issues, including wider availability of healthcare 'booths' local to a patient; easy to understand and use phone applications; patient and HCP incentives to use DHTs and clear paths to adoption within a healthcare system. These should help with integration of DHTs into the healthcare system to aid shared decision-making and, ultimately, streamline and personalise healthcare for all., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2024.)

Background: Cyclin-dependent kinase 2 (CDK2) is an important target for structure-based design of antitumor agents. Monomeric CDK2 is inactive. Activation requires rearrangements to key structural elements of the enzyme's active site, which accompany cyclin binding and phosphorylation. To assess the validity of using monomeric CDK2 as a model for the active kinase in structure-based drug design, we have solved the structure of the inhibitor indirubin-5-sulphonate (E226) complexed with phospho-CDK2-cyclin A and compared it with the structure of E226 bound to inactive, monomeric CDK2., Results: Activation of monomeric CDK2 leads to a rotation of its N-terminal domain relative to the C-terminal lobe. The accompanying change in position of E226 follows that of the N-terminal domain, and its interactions with residues forming part of the adenine binding pocket are conserved. The environment of the ATP-ribose site, not explored by E226, is significantly different in the binary complex compared to the monomeric complex due to movement of the glycine loop. Conformational changes also result in subtle differences in hydrogen bonding and electrostatic interactions between E226's sulphonate and CDK2's phosphate binding site. Affinities calculated by LUDI for the interaction of E226 with active or inactive CDK2 differ by a factor of approximately ten., Conclusions: The accuracy of monomeric CDK2 as an inhibitor design template is restricted to the adenine binding site. The general flexibility observed for the glycine loop and subtle changes to the phosphate binding site suggest a need to study interactions between inhibitors and active CDK2 in structure-based drug design programs.

A new series of 2,6,9-trisubstituted purines, characterized by the presence of a common alkynyl substituent at C-2 and a range of different anilino/benzylamino groups at C-6, were synthesized. These compounds were evaluated for their capacity to inhibit cyclin-dependent kinase activity (CDK1-cyclin B) in vitro. Compounds 4e (N-6-p-Cl-benzylamino derivative) and 5e (N-6-m-Cl-anilino derivative) exhibited the strongest inhibitory activity with an IC(50) of 60 nM. The structure of compound 4b (N-6-p-methoxybenzylamino derivative) in complex with human CDK2 was determined by X-ray crystallography, revealing the molecular basis of inhibition by this molecule. Subsequent molecular modeling studies allowed us to rationalize the SAR observed for these compounds.

Indirubin is the active ingredient of Danggui Longhui Wan, a mixture of plants that is used in traditional Chinese medicine to treat chronic diseases. Here we identify indirubin and its analogues as potent inhibitors of cyclin-dependent kinases (CDKs). The crystal structure of CDK2 in complex with indirubin derivatives shows that indirubin interacts with the kinase's ATP-binding site through van der Waals interactions and three hydrogen bonds. Indirubin-3'-monoxime inhibits the proliferation of a large range of cells, mainly through arresting the cells in the G2/M phase of the cell cycle. These results have implications for therapeutic optimization of indigoids.