COSMIC Database and Structural Modeling Analysis of CYP2D6 Mutations in Human Cancers.

Single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP450) enzymes alter the metabolism of a variety of drugs. Numerous medications, including chemotherapies, are metabolized by CYP450 enzymes, making the expression of this suite of enzymes in tumor cells relevant to prescription regimens for cancer patients. We analyzed the characteristics of mutations of the CYP2D6 enzymes in cancer patients obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC), including mutation type, age of the patient, tissue type, and histology. Mutations were analyzed through the Cancer-Related Analysis of Variants Toolkit (CRAVAT) software along with CHASM and VEST4 algorithms to determine the likelihood of being a driver and/or pathogenic mutation. For mutations with significant CHASM and VEST4 scores, structural analysis of each corresponding mutant protein was performed. The effect of each mutation was evaluated for its impact on the overall protein stability and ligand binding using Foldit Standalone and SwissDock, respectively. Structural analysis revealed that several missense mutations in CYP2D6 resulted in altered stability after energy minimization. Three missense mutations of CYP2D6 significantly altered docking stability and those located on alpha-helices near the docking site had a more significant impact than those not found in secondary protein structures. In conclusion, we have identified a series of mutations to CYP2D6 enzymes with possible relevance to cancer pathologies. Significance Statement CYP2D6 is responsible for the metabolism of many anti-cancer drugs. This study identified and characterized a series of mutations in the CYP2D6 enzyme that occurred in tumors. We found it likely that many of these mutations would alter enzyme function, leading to changes in drug metabolism in the tumor. We provide a basis for predicting the likelihood of a patient carrying these mutations to identify patients who may benefit from a precision medicine approach to drug selection and dosing.

Improving preparedness for introducing and scaling up long-acting HIV pre-exposure prophylaxis in Asia.

Long-acting injectable PrEP, particularly cabotegravir (CAB-LA), has the potential to enhance HIV prevention in Asia, and was the topic of a roundtable held in Singapore in June 2023. Despite proven efficacy, CAB-LA's impact in Asia is hindered by regulatory, manufacturing, and cost barriers. There is an urgent need to address these challenges to expedite CAB-LA's introduction and scale-up, including collaborative research, streamlined regulatory processes, and increased manufacturing capacity. We call for better preparedness in long-acting PrEP in research and implementation science, product licensing and accessibility, and capacity readiness for scale-up, to meet the significant demand among key populations in Asia.

Evidence of SARS-CoV-2 Antibody in Mississippi White-Tailed Deer.

Background: Early detection and monitoring of SARS-CoV-2 infections in animal populations living in close proximity to humans is crucial for preventing reverse zoonosis of new viral strains. Evidence accumulated has revealed widespread SARS-CoV-2 infection among white-tailed deer (WTD), (Odocoileus virginianus) populations in the United States except in the southeast region. Therefore, the objective was to conduct surveillance for evidence of SARS-CoV-2 infection among WTD in Mississippi. Materials and Methods: Blood, kidney tissues, and nasal swab samples were collected in 17 counties from hunter-harvested deer during 2021-2022 and 2022-2023.Samples of kidney tissue were collected to evaluate for detecting antibody as a possible alternative to blood that is not always available from dead WTD. Nasal swab samples were tested for SARS-CoV-2 viral RNA by a RT-PCR assay. Sera and kidney tissue samples were tested for SARS-CoV-2 antibody by an enzyme-linked immunoassay (ELISA) and sera by a plaque reduction neutralization test (PRNT80). Results: The results of testing sera and kidney homogenate samples provided the first evidence of SARS-CoV-2 infection among WTD in Mississippi. The infection rate during 2021-2022 was 67% (10/15) based on the detection of neutralizing antibody by the PRNT80 and 26%(16/62) based on the testing of kidney tissue homogenates by an ELISA, and viral RNA was detected in 25% (3/12) of nasal swab samples. In 2022 to 2023, neutralizing antibody was detected in 62% (28/45) of WTD serum samples. In contrast, antibodies were not detected in 220 kidney homogenates by an ELISA nor was viral RNA detected in 220 nasal swab samples. Evidence of WTD activity was common in urban areas during the survey. Conclusion: Overall, the findings documented the first SARS-CoV-2 infection among WTD in Mississippi and showed that WTD commonly inhabited urban areas as a possible source of acquiring infection from humans infected with this virus.

'Seeing' the electromagnetic spectrum: spotlight on the cryptochrome photocycle.

Cryptochromes are widely dispersed flavoprotein photoreceptors that regulate numerous developmental responses to light in plants, as well as to stress and entrainment of the circadian clock in animals and humans. All cryptochromes are closely related to an ancient family of light-absorbing flavoenzymes known as photolyases, which use light as an energy source for DNA repair but themselves have no light sensing role. Here we review the means by which plant cryptochromes acquired a light sensing function. This transition involved subtle changes within the flavin binding pocket which gave rise to a visual photocycle consisting of light-inducible and dark-reversible flavin redox state transitions. In this photocycle, light first triggers flavin reduction from an initial dark-adapted resting state (FADox). The reduced state is the biologically active or 'lit' state, correlating with biological activity. Subsequently, the photoreduced flavin reoxidises back to the dark adapted or 'resting' state. Because the rate of reoxidation determines the lifetime of the signaling state, it significantly modulates biological activity. As a consequence of this redox photocycle Crys respond to both the wavelength and the intensity of light, but are in addition regulated by factors such as temperature, oxygen concentration, and cellular metabolites that alter rates of flavin reoxidation even independently of light. Mechanistically, flavin reduction is correlated with conformational change in the protein, which is thought to mediate biological activity through interaction with biological signaling partners. In addition, a second, entirely independent signaling mechanism arises from the cryptochrome photocycle in the form of reactive oxygen species (ROS). These are synthesized during flavin reoxidation, are known mediators of biotic and abiotic stress responses, and have been linked to Cry biological activity in plants and animals. Additional special properties arising from the cryptochrome photocycle include responsivity to electromagnetic fields and their applications in optogenetics. Finally, innovations in methodology such as the use of Nitrogen Vacancy (NV) diamond centers to follow cryptochrome magnetic field sensitivity in vivo are discussed, as well as the potential for a whole new technology of 'magneto-genetics' for future applications in synthetic biology and medicine.

The International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD) guidelines for prevention of traumatic dental injuries: Part 1: General introduction.

The Guidelines for Prevention of Traumatic Dental Injuries were reviewed and approved by the Board of Directors of the International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD).

The International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD) guidelines for prevention of traumatic dental injuries: Part 4: Faceshields for the prevention of dental and oral trauma.

The Guidelines for Prevention of Traumatic Dental Injuries were reviewed and approved by the Board of Directors of the International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD).

The International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD) guidelines for prevention of traumatic dental injuries: Part 5: Secondary prevention of dental injuries.

The Guidelines for Prevention of Traumatic Dental Injuries were reviewed and approved by the Board of Directors of the International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD).

The International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD) guidelines for prevention of traumatic dental injuries: Part 3: Mouthguards for the prevention of dental and oral trauma.

The Guidelines for Prevention of Traumatic Dental Injuries were reviewed and approved by the Board of Directors of the International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD).

The International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD) guidelines for prevention of traumatic dental injuries: Part 10: First aid education.

The Guidelines for Prevention of Traumatic Dental Injuries were reviewed and approved by the Board of Directors of the International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD).

The International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD) guidelines for prevention of traumatic dental injuries: Part 2: Primary prevention of dental trauma across the life course.

The Guidelines for Prevention of Traumatic Dental Injuries were reviewed and approved by the Board of Directors of the International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD).

The International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD) guidelines for prevention of traumatic dental injuries: Part 6: Education.

The Guidelines for Prevention of Traumatic Dental Injuries were reviewed and approved by the Board of Directors of the International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD).

The International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD) guidelines for prevention of traumatic dental injuries: Part 8: ToothSOS app.

The Guidelines for Prevention of Traumatic Dental Injuries were reviewed and approved by the Board of Directors of the International Association of Dental Traumatology (IADT) and the Academy for Sports Dentistry (ASD).

The Tooth Protector in Early Professional Baseball.

Protection of athletes during sporting activities was of some concern even in the late 1800s. That concern continues, over 140 years later. In baseball, safety for the catcher was of primary concern because of inherent risks of being "behind the plate" while balls are pitched, bats are swung, and runners attempting to score come barreling in. Doug Allison was the skilled catcher for the 1869 Cincinnati Red Stockings who was known to use certain objects for self-protection, including George Wright's rubber "Mouthpiece." This report reviews earliest development of mouth protection in baseball, as known through reports of the times, and Doug Allison's career.

Pooled Pharyngeal, Rectal, and Urine Specimens for the Point-of-Care Detection of Chlamydia trachomatis and Neisseria gonorrhoeae by Lay Providers in Key Population-Led Health Services in Thailand.

Routine testing for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) in people with heightened risk is lacking in Thailand. This study aimed to assess the performance of the Cepheid Xpert CT/NG assay, conducted by key population (KP) lay providers, for CT and NG detection on single-site and pooled specimens from the pharynx, rectum, and urine. Between August and October 2019, 188 men who have sex with men and 11 transgender women were enrolled. Participants collected urine specimens while trained KP lay providers obtained pharyngeal and rectal swabs. Compared to single-site testing with the Abbott RealTime CT/NG assay by medical technologists, the Xpert assay missed one pharyngeal NG infection out of 199 single-site specimens, giving a 93.3% sensitivity for pharyngeal NG and one missed pharyngeal NG infection out of fifty pooled specimens, giving an 88.9% sensitivity for pharyngeal NG. There was no discrepancy between the two assays for CT detection. The Cohen's Kappa coefficient of pooled specimen testing by the Xpert was 0.93 for NG and 1 for CT when compared to single-site testing by Abbott. Implementing pooled specimen testing by KP lay providers can be a cost-saving strategy to enhance the uptake of CT/NG services for populations facing increased risk.

Differentiated service delivery for HIV treatment models in Thailand: A cross-sectional assessment of real-world implementation and uptake.

OBJECTIVES: First, to describe the antiretroviral therapy (ART) delivery models available in Thailand to understand differentiated service delivery for further service system optimization and expansion of best practices; second, to determine the client characteristics associated with model uptake. METHODS: Across-sectional assessment using secondary data was conducted to describe ART models implemented as routine services at four public hospitals in three major provinces with a high-HIV burden in Thailand. From April to October 2020, ART clients were screened consecutively according to the inclusion criteria: Thai, aged ≥18 years, and on ART for ≥6 months. HIV treatment models were categorised based on the service type, location, provider, and frequency. Logistic regression was used to identify the associated factors. RESULTS: Seven individual ART delivery models were identified: four were facility-based and three were out-of-facility. No group models were identified. Of 3,366 records of ART clients reviewed, 3,213 (95.5%) met the study criteria and received ART through the following models: conventional (32.6%), nurse-led clinical consultation (10.0%), fast-track refill (29.0%), after-hours clinic (10.6%), pharmacist-led pickup center (3.6%), key population-led community-based organisation (2.7%), and mailing (11.5%). Age, population, duration on ART, and viral load were associated with the uptake of certain alternative service models when compared to the conventional model. CONCLUSIONS: Among the variety of ART delivery approaches available in Thailand, facility-based models remain the most prevalent. Future work should investigate the role of client preference and choice in choosing service models and service utilisation patterns over time, and assess the acceptability and effectiveness of these models.

Acceptability and retention of the key population-led HIV treatment service for men who have sex with men and transgender women living with HIV in Thailand.

INTRODUCTION: In Thailand, where the HIV epidemic is concentrated among key populations (KPs), particularly men who have sex with men (MSM) and transgender women (TGW), an HIV service delivery model tailored to KPs was piloted. This study evaluated the acceptability and retention of clients who accepted and declined the KP-led HIV treatment service. METHODS: A retrospective cohort study was conducted using secondary data from three community-based organizations (CBOs) and three hospitals in Thailand. KP lay providers were trained to lead HIV treatment service in which MSM and TGW living with HIV received counselling and a 3-month antiretroviral therapy (ART) supply at CBOs. Thai MSM and TGW who were at least 18 years, on ART for at least 6-12 months, without co-morbidities/co-infections, and virally suppressed were eligible and offered the service. Those who declined received ART via other service models offered by the hospitals and served as a comparison group. RESULTS: Of 220 clients screened between February 2019 and February 2020, 72% (159/220) were eligible of which 146 were MSM and 13 were TGW. Overall, 45% (72/159) accepted the KP-led service. Of those who declined, 98% (85/87) preferred to see the physician at the hospital. After 12 months of follow-up, among those accepted, 57% were in care at the CBO, 32% were referred back to and in care in other service models offered by the hospital, 10% were successfully transferred out to other hospital and 1% were lost to follow-up (LTFU); among those declined, 92% were in care in any service models offered by the hospital, 5% were successfully transferred out to other hospital, 2% were LTFU and 1% died (p-value<0.001). CONCLUSIONS: Despite moderate acceptability and retention in care at the CBO among the clients accepting the KP-led service, almost all clients were engaged in care overall. Multiple service models that meet the preferences and needs of KPs living with HIV should be available to optimize engagement in care.

Stephen Massey: a career in visual neuroscience.

This review is a memoir by Dr. Stephen C. Massey's longtime collaborator, Dr. Stephen L. Mills, and written, for the most part, in the first person. It also serves as an introduction to the virtual festschrift to celebrate Dr. Massey's retirement. and. The references cited here are only a few of the highlights of Dr. Massey's distinguished career. A complete list is found here: https://pubmed.ncbi.nlm.nih.gov/?term=massey+sc+%28retina+or+photoreceptors%29&sort=date.