Access, acceptance and adherence to cancer prehabilitation: a mixed-methods systematic review.

PURPOSE: The purpose of this systematic review is to better understand access to, acceptance of and adherence to cancer prehabilitation. METHODS: MEDLINE, CINAHL, PsychINFO, Embase, Physiotherapy Evidence Database, ProQuest Medical Library, Cochrane Library, Web of Science and grey literature were systematically searched for quantitative, qualitative and mixed-methods studies published in English between January 2017 and June 2023. Screening, data extraction and critical appraisal were conducted by two reviewers independently using Covidence™ systematic review software. Data were analysed and synthesised thematically to address the question 'What do we know about access, acceptance and adherence to cancer prehabilitation, particularly among socially deprived and minority ethnic groups?' The protocol is published on PROSPERO CRD42023403776 RESULTS: Searches identified 11,715 records, and 56 studies of variable methodological quality were included: 32 quantitative, 15 qualitative and nine mixed-methods. Analysis identified facilitators and barriers at individual and structural levels, and with interpersonal connections important for prehabilitation access, acceptance and adherence. No study reported analysis of facilitators and barriers to prehabilitation specific to people from ethnic minority communities. One study described health literacy as a barrier to access for people from socioeconomically deprived communities. CONCLUSIONS: There is limited empirical research of barriers and facilitators to inform improvement in equity of access to cancer prehabilitation. IMPLICATIONS FOR CANCER SURVIVORS: To enhance the inclusivity of cancer prehabilitation, adjustments may be needed to accommodate individual characteristics and attention given to structural factors, such as staff training. Interpersonal connections are proposed as a fundamental ingredient for successful prehabilitation.

Probing Ligand Binding Sites on Large Proteins by Nuclear Magnetic Resonance Spectroscopy of Genetically Encoded Non-Canonical Amino Acids.

N6-(((trimethylsilyl)-methoxy)carbonyl)-l-lysine (TMSK) and N6-trifluoroacetyl-l-lysine (TFAK) are non-canonical amino acids, which can be installed in proteins by genetic encoding. In addition, we describe a new aminoacyl-tRNA synthetase specific for N6-(((trimethylsilyl)methyl)-carbamoyl)-l-lysine (TMSNK), which is chemically more stable than TMSK. Using the dimeric SARS-CoV-2 main protease (Mpro) as a model system with three different ligands, we show that the 1H and 19F nuclei of the solvent-exposed trimethylsilyl and CF3 groups produce intense signals in the nuclear magnetic resonance (NMR) spectrum. Their response to active-site ligands differed significantly when positioned near rather than far from the active site. Conversely, the NMR probes failed to confirm the previously reported binding site of the ligand pelitinib, which was found to enhance the activity of Mpro by promoting the formation of the enzymatically active dimer. In summary, the amino acids TMSK, TMSNK, and TFAK open an attractive path for site-specific NMR analysis of ligand binding to large proteins of limited stability and at low concentrations.

Predicting Antiviral Resistance Mutations in SARS-CoV-2 Main Protease with Computational and Experimental Screening.

The main protease (Mpro) of SARS-CoV-2 is essential for viral replication and has been the focus of many drug discovery efforts since the start of the COVID-19 pandemic. Nirmatrelvir (NTV) is an inhibitor of SARS-CoV-2 Mpro that is used in the combination drug Paxlovid for the treatment of mild to moderate COVID-19. However, with increased use of NTV across the globe, there is a possibility that future SARS-CoV-2 lineages will evolve resistance to NTV. Early prediction and monitoring of resistance mutations could allow for measures to slow the spread of resistance and for the development of new compounds with activity against resistant strains. In this work, we have used in silico mutational scanning and inhibitor docking of Mpro to identify potential resistance mutations. Subsequent in vitro experiments revealed five mutations (N142L, E166M, Q189E, Q189I, and Q192T) that reduce the potency of NTV and of a previously identified non-covalent cyclic peptide inhibitor of Mpro. The E166M mutation reduced the half-maximal inhibitory concentration (IC50) of NTV 24-fold and 118-fold for the non-covalent peptide inhibitor. Our findings inform the ongoing genomic surveillance of emerging SARS-CoV-2 lineages.

Antiviral cyclic peptides targeting the main protease of SARS-CoV-2.

Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (Mpro) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 Mpro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of Mpro complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S1 and S2, respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these Mpro peptide inhibitors possessed antiviral activity against SARS-CoV-2 in vitro with EC50 values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2.

"We're talking about black men here, there's a difference"; cultural differences in socialised knowledge of prostate cancer risk: A qualitative research study.

PURPOSE: To detail social knowledge of prostate cancer risk amongst cultural groups. Prostate cancer is the most common cancer in men, and black men are at the highest risk. Despite this, black men are the least likely to be diagnosed early with prostate cancer. It is important to understand why this is so that these men can receive early access to effective treatment and support. METHODS: A constructivist grounded theory methodology was used. Data were collected between December 2015 and October 2017; seventeen men were interviewed, and eighteen men took part in focus groups. RESULTS: There were differences in the way the men constructed their understanding of risks for prostate cancer. The social construction of prostate cancer risk knowledge was mediated by the way the men were socialised to understand and accept this risk. The Somali and African Caribbean men placed social importance on the healthy body, whereas the white working class men seemed to find social value through the unwell body. This research proposes the theory that social constructions of knowledge mediate the way men perceive and accept their risk for prostate cancer. CONCLUSION: Understanding socially-derived knowledge of risk may mediate the acceptance of factors relating to prostate cancer. This knowledge may help health providers and third sector organisations produce targeted health-related information. Health practitioners may also benefit from understanding how socially constructed ideas of the body could influence the way men respond to conversations about prostate cancer so that tailored and culturally appropriate support can be offered.

Opportunity and the sexual abuse of adolescents.

OBJECTIVES: The risk of sexual abuse victimization was examined from a routine activity perspective. For comparison, predictors of sexual encounters with same-age peers were also examined. METHODS: Analyses were based on a nationally representative sample of 24,823 Finnish youth who responded to questions about their sexual encounters with peers and with someone outside their family who was at least five years older. RESULTS: Adolescents who had older friends and parents who did not monitor their social relationships were at greater risk of sexual abuse and peer encounters. In addition, delinquent youth had a higher risk of abuse than non-delinquents, controlling for exposure. Delinquent youth were also more likely to have favorable attitudes toward the abuse, to initiate the sexual encounter, and to experience repeat victimizations. Physical attractiveness, but not sexual maturity, was related to abuse. CONCLUSIONS: Risk of sexual abuse is positively related to exposure to older people, susceptibility to deviant influence, and the target's value to the offender. A full understanding of risk factors requires a consideration of the victims' characteristics and their compliant behavior.

Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming.

The contact system comprises a series of serine proteases that mediate procoagulant and proinflammatory activities via the intrinsic pathway of coagulation and the kallikrein-kinin system, respectively. Inhibition of Factor XIIa (FXIIa), an initiator of the contact system, has been demonstrated to lead to thrombo-protection and anti-inflammatory effects in animal models and serves as a potentially safer target for the development of antithrombotics. Herein, we describe the use of the Randomised Nonstandard Peptide Integrated Discovery (RaPID) mRNA display technology to identify a series of potent and selective cyclic peptide inhibitors of FXIIa. Cyclic peptides were evaluated in vitro, and three lead compounds exhibited significant prolongation of aPTT, a reduction in thrombin generation, and an inhibition of bradykinin formation. We also describe our efforts to identify the critical residues for binding FXIIa through alanine scanning, analogue generation, and via in silico methods to predict the binding mode of our lead cyclic peptide inhibitors.

Seeking synergies: understanding the evidence that links menstrual health and sexual and reproductive health and rights.

Global efforts to improve menstrual health and sexual and reproductive health and rights (SRHR) are fundamentally intertwined and share similar goals for improving health and well-being and increasing gender equality. Historically, however, the two fields have operated independently and missed opportunities to build upon their biological and sociocultural linkages. Biological touchpoints connecting the two fields include genital tract infections, menstrual disorders, contraception, and menopause. From a sociocultural perspective, intersections occur in relation to the experience of puberty and menarche, gender norms and equity, education, gender-based violence, and transactional sex. We describe evidence linking menstrual health and SRHR and offer recommendations for integration that could strengthen the impact of both fields.

Using Card Games to study cultural differences in men's social talk about prostate cancer.

AIM: To report the Card Games approach used to study men's talk about their risk for prostate cancer and as a method of data collection to analyse patterns of talk among distinct cultural groups. DESIGN: A constructivist grounded theory approach using focus groups to analyse men's social talk about prostate cancer. METHODS: Data were collected using three focus groups with African-Caribbean, Somali, and White British men. The focus groups were conducted in a location of the men's choice with a focus group facilitator and observer. Four Card Games were given to the men to encourage social talk. RESULTS: The African-Caribbean men had the most democratic talk with the use of agreement and disagreement and the Somali men were the most inclusive of others and used the most humour. The White British men were competitive in their talk and the least inclusive of each other's views. CONCLUSION: The Card Games revealed differences in the pattern of talk, which provided insight into how men may use social talk to develop their understanding of prostate cancer risk. This is useful for healthcare professionals as it provides a grounding for structuring discussions with men about prostate cancer, while understanding of how risk-related knowledge may be reconstructed in social talk and interactions. IMPACT: The methodology discussed in this paper addressed the use of focus group to analyse talk of men from culturally diverse groups. The use of Card Games allowed the talk between the men to take centre stage and this allowed differences in the social talk of the men to become apparent. The use of this methodology could have an impact on approaches to researching cultural understandings of cancer risk, which may provide evidence on effective delivery of sociocultural relevant health education relating to cancer screening.

A cross-sectional survey of the pharmacy workforce in general practice in Scotland.

BACKGROUND: In Scotland, there has been significant investment in pharmacy teams in general medical practices over recent years, aligned to current government policy. OBJECTIVES: To characterize the national pharmacy workforce including activities undertaken, perceived competence and confidence, as well as perception of integration of the intervention. METHODS: A cross-sectional survey of all pharmacists and pharmacy technicians in general practices. Survey items were demographics, activities undertaken and experiences. The NoMAD tool (Improving the Normalization of Complex Interventions) was included as a measure of perspectives of implementation. Post-piloting, a questionnaire link was sent to all pharmacists (n = 471) and pharmacy technicians (n = 112). A total NoMAD score was obtained by assigning 1 (strongly disagree) to 5 (strongly agree) to each item. RESULTS: Responses were received from 393 (83.4%) pharmacists and 101 (91.8%) pharmacy technicians. Three quarters of pharmacists (74.6%) and pharmacy technicians (73.3%) had been qualified for over 10 years. Two-thirds of pharmacists (68.4%) were independent prescribers, with three quarters (72.3%) currently prescribing. Respondents worked in a median of two practices and were providing a range of activities including medication/polypharmacy reviews, medicines reconciliation, prescribing efficiencies and training. Respondents reported high levels of competence and confidence (median 8, scale 0-10 highest). Median NoMAD total score (scale 20-100 highest, Cronbach's alpha 0.89) was 80 for pharmacists and 75 for pharmacy technicians, P ≤ 0.001. CONCLUSIONS: The general practice pharmacy workforce in Scotland is experienced, well-qualified and integrated within general practices, delivering a range of activities. These findings have implications for workforce planning and future education and training.

Reactions of Boys and Girls to Sexual Abuse and to Sexual Encounters with Peers.

To understand the etiology and consequences of child sexual abuse it is important to study the victims' subjective reactions to such incidents. Because researchers have not been able to survey children about sexual abuse, not much is known about how subjective reactions are related to gender, age, age difference, and the social relationship between the offender and victim. The present study fills this gap using data gathered from a large, nationally representative sample of Finnish children ages 11 to 17 (N = 32,145). Analyses of abuse are based on a sample of 1520 children (78% girls), while analyses of peer sexual experiences are based on a sample of 3551 children (55% girls). Multivariate analyses adjusted for the use of coercion, the intimacy of the sexual experience, and other incident characteristics. It was hypothesized that, as a result of sex differences in sexuality and attitudes toward deviant behavior, girls are more sensitive than boys to age and age difference. Three findings supported the hypothesis: (1) girls were more likely than boys to have a negative reaction to sexual encounters regardless of the age difference; (2) for girls, age was negatively associated with the likelihood of a negative reaction, but age had no effect for boys; and (3) girls reacted negatively to age difference while boys did not. However, girls did not react more negatively unless the offender was at least eight years older. The results highlight the susceptibility of adolescent boys to encounters with older women. They further suggest that ignoring the role of the victim limits understanding of the vulnerability of young people to sexual abuse.

Heteronormativity and prostate cancer: A discursive paper.

AIMS AND OBJECTIVES: To discuss the risks that heteronormative assumptions play in prostate cancer care and how these may be addressed. BACKGROUND: There is international evidence to support the case that LGBT patients with cancer are less likely to report poor health or self-disclose sexual orientation. Gender-specific cancers, such as prostate cancer, require particular interventions in terms of supportive care. These may include advice about side-effect management (such as incontinence or erectile dysfunction), treatment choices and social and emotional issues. In this paper, we discuss and analyse the heteronormative assumptions and culture that exist around this cancer. We argue that this situation may act as a barrier to effective supportive care for all Lesbian women, Gay, Transgender and Bisexual patients, in this case men who have sex with men. [Correction added on 21 September 2017, after first online publication: The first sentence of the Background section has been revised for clarity in this current version.] DESIGN: Theoretical exploration of heteronormativity considered against the clinical context of prostate cancer. METHODS: Identification and inclusion of relevant international evidence combined with clinical discussion. RESULTS: This paper posits a number of questions around heteronormativity in relation to prostate cancer information provision, supportive care and male sexuality. While assumptions regarding sexual orientation should be avoided in clinical encounters, this may be difficult when heteronormative assumptions dominate. Existing research supports the assertion that patient experience, including the needs of LGBT patients, should be central to service developments. CONCLUSION: Assumptions about sexual orientation should be avoided and recorded accurately and sensitively, and relational models of care should be promoted at the start of cancer treatment in an appropriate manner. These may assist in reducing the risks of embarrassment or offence to nonheterosexual patients, or to professionals who may adopt heteronormative assumptions. RELEVANCE TO CLINICAL PRACTICE: Having an awareness of the risks of making heteronormative assumptions in clinical practice will be useful for all health professionals engaged in prostate cancer care. This awareness can prevent embarrassment or upset for patients and ensure a more equitable provision of service, including men with prostate cancer who do not identify as heterosexual.

Sp2 DNA binding activity and trans-activation are negatively regulated in mammalian cells.

Previous studies have indicated that Sp2 binds poorly to GC-rich sequences bound by Sp1 and Sp3, and further functional analyses of Sp2 have been limited. To study Sp2-mediated transcription, we employed a PCR-based protocol to determine the Sp2 consensus DNA-binding sequence (5'-GGGCGGGAC-3') and performed kinetic experiments to show that Sp2 binds this consensus sequence with high affinity (225 pm) in vitro. To determine the functional consequence of Sp2 interaction with this sequence in vivo, we transformed well characterized Sp-binding sites within the dihydrofolate reductase (DHFR) promoter to consensus Sp2-binding sites. Incorporation of Sp2-binding sites within the DHFR promoter increased Sp2-mediated trans-activation in transient co-transfection experiments but also revealed Sp2 to be a relatively weak trans-activator with little or no capacity for additive or synergistic trans-activation. Using chimeric molecules prepared with portions of Sp1 and Sp2 and the human prostate-specific antigen promoter, we show that Sp2 DNA binding activity and trans-activation are negatively regulated in mammalian cells. Taken together, our data indicate that Sp2 is functionally distinct relative to other Sp family members and suggest that Sp2 may play a unique role in cell physiology.