Professionally led support groups for people living with advanced or metastatic cancer: a systematic scoping review of effectiveness and factors critical to implementation success within real-world healthcare and community settings.

PURPOSE: To examine the effectiveness of professionally led support groups for people with advanced or metastatic cancer, and identify factors critical to implementation success within real-world settings. METHODS: Databases (MEDLINE; PsychINFO; CINAHL) and grey literature were searched for empirical publications and evaluations. Articles were screened for eligibility and data systematically extracted, charted and summarised using a modified scoping review methodology. Implementation factors were mapped using Proctor's implementation framework and the Consolidated Framework for Implementation Research 2.0. RESULTS: A total of 1691 publications were identified; 19 were eligible for inclusion (8 randomised controlled trials, 7 qualitative studies, 2 cohort studies, 2 mixed methods studies). Most (n=18) studies focused on tumour-specific support groups. Evidence supported professionally led support groups in reducing mood disturbances (n=5), distress (i.e. traumatic stress, depression) (n=4) and pain (n=2). Other benefits included social connectedness (n=6), addressing existential distress (n=5), information and knowledge (n=6), empowerment and sense of control (n=2), relationships with families (n=2) and communication with health professionals (n=2). Thirteen studies identified factors predicting successful adoption, implementation or sustainment, including acceptability (n=12; 63%), feasibility (n=6; 32%) and appropriateness (n=1; 5%). Key determinants of successful implementation included group leaders' skills/experience, mode of operation, travelling distance, group composition and membership and resourcing. CONCLUSIONS: Professionally led tumour-specific support groups demonstrate effectiveness in reducing mood disturbances, distress and pain among patients. Successful implementation hinges on factors such as leadership expertise, operational methods and resource allocation. IMPLICATIONS FOR CANCER SURVIVORS: Professionally led support groups may fill an important gap in supportive care for people with advanced or metastatic cancer.

Pharmacokinetic Study of Islatravir and Etonogestrel Implants in Macaques.

The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the antiretroviral islatravir (ISL) and the contraceptive etonogestrel (ENG). Three implants were tested: ISL-62 mg, ISL-98 mg, and ENG-33 mg. Animals received one or two ISL-eluting implants, with doses of 42, 66, or 108 µg of ISL/day with or without an additional ENG-33 mg implant (31 µg/day). Drug release increased linearly with dose with median [range] plasma ISL levels of 1.3 [1.0-2.5], 1.9 [1.2-6.3] and 2.8 [2.3-11.6], respectively. The ISL-62 and 98 mg implants demonstrated stable drug release over three months with ISL-triphosphate (ISL-TP) concentr54ations in PBMCs above levels predicted to be efficacious for PrEP. Similarly, ENG implants demonstrated sustained drug release with median [range] plasma ENG levels of 495 [229-1110] pg/mL, which suppressed progesterone within two weeks and showed no evidence of altering ISL pharmacokinetics. Two of the six ISL-98 mg implants broke during the study and induced implant-site reactions, whereas no reactions were observed with intact implants. We show that ISL and ENG biodegradable implants are safe and yield sufficient drug levels to achieve prevention targets. The evaluation of optimized implants with increased mechanical robustness is underway for improved durability and vaginal efficacy in a SHIV challenge model.

Assessment of Anti-SARS-CoV-2 antibody levels among university students vaccinated with different COVID-19 primary and booster doses - fall 2021, Wisconsin.

BACKGROUND: University students commonly received COVID-19 vaccinations before returning to U.S. campuses in the Fall of 2021. Given likely immunologic variation among students based on differences in type of primary series and/or booster dose vaccine received, we conducted serologic investigations in September and December 2021 on a large university campus in Wisconsin to assess anti-SARS-CoV-2 antibody levels. METHODS: We collected blood samples, demographic information, and COVID-19 illness and vaccination history from a convenience sample of students. Sera were analyzed for both anti-spike (anti-S) and anti-nucleocapsid (anti-N) antibody levels using World Health Organization standardized binding antibody units per milliliter (BAU/mL). Levels were compared across categorical primary COVID-19 vaccine series received and binary COVID-19 mRNA booster status. The association between anti-S levels and time since most recent vaccination dose was estimated by mixed-effects linear regression. RESULTS: In total, 356 students participated, of whom 219 (61.5%) had received a primary vaccine series of Pfizer-BioNTech or Moderna mRNA vaccines and 85 (23.9%) had received vaccines from Sinovac or Sinopharm. Median anti-S levels were significantly higher for mRNA primary vaccine series recipients (2.90 and 2.86 log [BAU/mL], respectively), compared with those who received Sinopharm or Sinovac vaccines (1.63 and 1.95 log [BAU/mL], respectively). Sinopharm and Sinovac vaccine recipients were associated with a significantly faster anti-S decline over time, compared with mRNA vaccine recipients (P <.001). By December, 48/172 (27.9%) participants reported receiving an mRNA COVID-19 vaccine booster, which reduced the anti-S antibody discrepancies between primary series vaccine types. CONCLUSIONS: Our work supports the benefit of heterologous boosting against COVID-19. COVID-19 mRNA vaccine booster doses were associated with increases in anti-SARS-CoV-2 antibody levels; following an mRNA booster dose, students with both mRNA and non-mRNA primary series receipt were associated with comparable levels of anti-S IgG.

Learning, judgement and workforce tensions impact failure to fail in a medical postgraduate setting: A supervisor perspective.

PURPOSE: Medical training organisations have a duty to prepare medical graduates for future safe, competent practice. Decisions about underperformance are high stakes at the postgraduate level and failure to fail can occur. We aimed to explore this concept from a systems and supervisor perspective. METHOD: Supervisors of specialist physician trainees were invited to provide written feedback on failure to fail as part of a broader anonymous supervisor survey. They were provided with a trigger statement and responded in free-text format. A deductive content analysis was undertaken through the lenses of supervisor and institution. RESULTS: Of 663 supervisors who responded to the broader survey, 373 (56%) provided feedback on the failure to fail trigger statement. Analyses indicated an interplay between trainee and supervisor characteristics, and broader system elements. System elements that contributed to failure to fail trainees included lack of longitudinal monitoring and quality of assessment information. Supervisor characteristics included confident, conflicted and avoidant behaviours towards underperforming trainees. CONCLUSIONS: Individual and system challenges that contributed to failure to fail were identified in this study, and we propose a three-way tension among learning, judgement and workforce. Three potential mitigation strategies have been identified to reduce failure to fail, namely a stage-based approach to remediation, faculty development in supervisory skills and improved assessment-for-learning processes.

Distinct Antiretroviral Mechanisms Elicited by a Viral Mutagen.

5-aza-cytidine (5-aza-C) has been shown to be a potent human immunodeficiency virus type 1 (HIV-1) mutagen that induces G-to-C hypermutagenesis by incorporation of the reduced form (i.e., 5-aza-dC, 5-aza-dCTP). Evidence to date suggests that this lethal mutagenesis is the primary antiretroviral mechanism for 5-aza-C. To investigate the breadth of application of 5-aza-C as an antiretroviral mutagen, we have conducted a comparative, parallel analysis of the antiviral mechanism of 5-aza-C between HIV-1 and gammaretroviruses - i.e., murine leukemia virus (MuLV) and feline leukemia virus (FeLV). Intriguingly, in contrast to the hallmark G-to-C hypermutagenesis observed with HIV-1, MuLV and FeLV did not reveal the presence of a significant increase in mutational burden, particularly that of G-to-C transversion mutations. The effect of 5-aza-dCTP on DNA synthesis revealed that while HIV-1 RT was not inhibited by 5-aza-dCTP even at 100 µM, 5-aza-dCTP was incorporated and significantly inhibited MuLV RT, generating pause sites and reducing the fully extended product. 5-aza-dCTP was found to be incorporated into DNA by MuLV RT or HIV-1 RT, but only acted as a non-obligate chain terminator for MuLV RT. This biochemical data provides an independent line of experimental evidence in support of the conclusion that HIV-1 and MuLV have distinct primary mechanisms of antiretroviral action with 5-aza-C. Taken together, our data provides striking evidence that an antiretroviral mutagen can have strong potency via distinct mechanisms of action among closely related viruses, unlinking antiviral activity from antiviral mechanism of action.

The effect of depot medroxyprogesterone acetate on tenofovir alafenamide in rhesus macaques.

Prevention of HIV infection and unintended pregnancies are public health priorities. In sub-Saharan Africa, where HIV prevalence is highest, depot medroxyprogesterone acetate (DMPA) is widely used as contraception. Therefore, understanding potential interactions between DMPA and antiretrovirals is critical. Here, we use a macaque model to investigate the effect of DMPA on the pharmacology of the antiretroviral tenofovir alafenamide (TAF). Female rhesus macaques received 30 mg of DMPA (n = 9) or were untreated (n = 9). Macaques received a human equivalent dose of TAF (1.5 mg/kg) orally by gavage. Tenofovir (TFV) and TFV-diphosphate (TFV-DP) were measured in blood, secretions, and tissues over 72 h. The median area under the curve (AUC0-72h) values for TFV-DP in peripheral blood mononuclear cells were similar in DMPA-treated (6991 fmol*h/106 cells) and untreated controls (5256 fmol*h/106 cells) (P = 0.174). Rectal tissue TFV-DP concentrations from DMPA+ animals [median: 20.23 fmol/mg of tissue (range: 4.94-107.95)] were higher than the DMPA- group [median: below the limit of quantification (BLOQ-11.92)], (P = 0.019). TFV-DP was not detectable in vaginal tissue from either group. A high-dose DMPA treatment in macaques was associated with increased rectal TFV-DP levels, indicating a potential tissue-specific drug-drug interaction. The lack of detectable TFV-DP in the vaginal tissue warrants further investigation of PrEP efficacy with single-agent TAF products. DMPA did not affect systemic TAF metabolism, with similar PBMC TFV-DP in both groups, suggesting that DMPA use should not alter the antiviral activity of TAF.

Training rhesus macaques to take daily oral antiretroviral therapy for preclinical evaluation of HIV prevention and treatment strategies.

BACKGROUND: Macaque models of simian or simian/human immunodeficiency virus (SIV or SHIV) infection are critical for the evaluation of antiretroviral (ARV)-based HIV treatment and prevention strategies. However, modelling human oral ARV administration is logistically challenging and fraught by limited adherence. Here, we developed a protocol for administering daily oral doses of ARVs to macaques with a high rate of compliance. METHODS: Parameters of positive reinforcement training (PRT), behavioral responses and optimal drug delivery foods were defined in 7 male rhesus macaques (Macaca mulatta). Animals were trained to sit in a specified cage location prior to receiving ARVs, emtricitabine (FTC) and tenofovir alafenamide (TAF), in a blended food mixture, which was followed immediately with a juice chaser. Consistency of daily oral adherence was evaluated in 4 trained macaques receiving clinically equivalent doses of FTC and TAF (20 and 1.5 mg/kg, respectively) in a short-term (1 month) and an extended (6 month) trial. Adherence was monitored using medication diaries and by quantifying intracellular FTC-triphosphate (FTC-TP) and tenofovir-diphosphate (TFV-DP) concentrations in peripheral mononuclear blood cells (PBMCs). RESULTS: Trained macaques quickly and consistently took daily oral ARVs for 1 month with an average 99.8% observed adherence. Intracellular concentrations of TFV-DP (median = 845.8 fmol/million cells [range, 620.8-1031.3]) and FTC-TP (median = 367.0 fmol/million cells [range, 289.5-413.5) in PBMCs were consistent with high adherence. Extended treatment with select subjects yielded similar observations for three months (99.5% adherence, 352/356 complete doses taken), although a sudden drop in adherence was observed after splenic biopsy surgery. CONCLUSIONS: We demonstrate that trained macaques reliably adhere to a daily oral ARV regimen, although unexpected adherence issues are possible. Our approach, using clinical doses of oral FTC and TAF daily, further refines macaque models of HIV treatment and prevention by mimicking the human route and timing of ARV administration.

Optimizing Multisource Feedback Implementation for Australasian Physicians.

INTRODUCTION: Medical regulatory bodies in Australasia are encouraging greater use of continuing professional development activities, such as multisource feedback (MSF), which are practice-based, include facilitated feedback, and improve performance. The aim of this study was to explore the feasibility, effectiveness, and sustainability of an MSF process that includes a telephone/videoconference debrief, to better design future MSF implementation. METHOD: Thirty-seven Australasian physician participants sought feedback from patients and colleagues and debriefed their feedback report with a trained facilitator. The impact was evaluated using quantitative and qualitative measures including surveys and semistructured interviews. RESULTS: The feasibility of the MSF process was impacted by the level of support for the participant to complete the MSF, the nature and location of participants' work, and the use of telephone/videoconference to deliver the debrief. Regarding effectiveness, the MSF stimulated reflection on practice and action on areas identified for improvement. In addition, the quality of rater feedback and the inclusion of a debrief impacted participant and facilitator reports of effectiveness. The absence of a culture of feedback, the formative nature of the MSF, and the confidentiality of the results were factors impacting sustainability. DISCUSSION: Optimizing MSF is important to encourage broad uptake in the wider medical community in Australasia. Although several factors were identified as having an impact, it is clear that inclusion of a quality debrief will increase the perceived value and the effectiveness of MSF. Delivering that debrief through telephone/videoconference can be effective and will increase the overall feasibility and sustainability.

Learning relationships in community-based service-learning: a social network analysis.

BACKGROUND: Little is known about the social learning of students within community-based clinical placements and ways in which it can be supported. In an allied health service-learning program, we analysed students' learning relationships to quantify what, and from whom students learnt. METHODS: We conducted a social learning network survey in four domains of learning (clinical knowledge, procedural skills, professional development, and complex determinants of health) to explore learning relationships (ties) with other people (alters) that students (egos) formed during their placement. We quantified how different roles (supervisors, health professionals, administrators, peers, schoolteachers, and clients) contributed to the students' learning in each of the four domains. We used exponential random graph models (ERGMs) to test which relational processes contributed to the structure of the observed learning networks. RESULTS: Data was available from a complete cohort of 10 students on placement in a network of 69 members, thus providing information on 680 potential learning relations. Students engaged in similar ways in the domains of clinical knowledge, procedural skills, and professional development. Learning relations with academic supervisors were significantly more likely. Also students reported reciprocal learning relations with peers - i.e. they formed learning pairs. This effect was absent in learning networks about complex determinants of health (including socio-economic and cultural factors). Instead, local administrative staff were significantly more often the source of learning about the local contextual factors. CONCLUSIONS: Understanding the structure of student learning networks through social network analysis helps identify targeted strategies to enhance learning in community-based service-learning programs. Our findings suggest students recognised important learning from each other and from administrative personnel that is unrelated to the content of their placement. Based on this insight clinical educators could prepare students to become agentic learners, learning with each other and from sources outside their program.

A central role for PI3K-AKT signaling pathway in linking SAMHD1-deficiency to the type I interferon signature.

The autoimmune disorder Aicardi-Goutières syndrome (AGS) is characterized by a constitutive type I interferon response. SAMHD1 possesses both dNTPase and RNase activities and mutations in SAMHD1 cause AGS; however, how SAMHD1-deficiency causes the type I interferon response in patients with AGS remains unknown. Here, we show that endogenous RNA substrates accumulated in the absence of SAMHD1 act as a major immunogenic source for the type I interferon response. Reconstitution of SAMHD1-negative human cells with wild-type but not RNase-defective SAMHD1 abolishes spontaneous type I interferon induction. We further identify that the PI3K/AKT/IRF3 signaling pathway is essential for the type I interferon response in SAMHD1-deficient human monocytic cells. Treatment of PI3K or AKT inhibitors dramatically reduces the type I interferon signatures in SAMHD1-deficient cells. Moreover, SAMHD1/AKT1 double knockout relieves the type I interferon signatures to the levels observed for wild-type cells. Identification of AGS-related RNA sensing pathway provides critical insights into the molecular pathogenesis of the type I interferonopathies such as AGS and overlapping autoimmune disorders.

SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination.

DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.

A global probe into dental student perceptions about philanthropy, global dentistry and international student exchanges.

BACKGROUND: Training culturally competent graduates who can practice effectively in a multicultural environment is a goal of contemporary dental education. The Global Oral Health Initiative is a network of dental schools seeking to promote global dentistry as a component of cultural competency training. OBJECTIVE: Before initiating international student exchanges, a survey was conducted to assess students' awareness of global dentistry and interest in cross-national clerkships. METHODS: A 22-question, YES/NO survey was distributed to 3,487 dental students at eight schools in seven countries. The questions probed students about their school's commitment to enhance their education by promoting global dentistry, volunteerism and philanthropy. The data were analysed using Vassarstats statistical software. RESULTS: In total, 2,371 students (67.9%) completed the survey. Cultural diversity was seen as an important component of dental education by 72.8% of the students, with two-thirds (66.9%) acknowledging that their training provided preparation for understanding the oral health care needs of disparate peoples. A high proportion (87.9%) agreed that volunteerism and philanthropy are important qualities of a well-rounded dentist, but only about one-third felt that their school supported these behaviours (36.2%) or demonstrated a commitment to promote global dentistry (35.5%). In addition, 87.4% felt that dental schools are morally bound to improve oral health care in marginalised global communities and should provide students with international exchange missions (91%), which would enhance their cultural competency (88.9%) and encourage their participation in charitable missions after graduation (67.6%). CONCLUSION: The study suggests that dental students would value international exchanges, which may enhance students' knowledge and self-awareness related to cultural competence.

Social learning in a longitudinal integrated clinical placement.

Recent research has demonstrated that longitudinal integrated placements (LICs) are an alternative mode of clinical education to traditional placements. Extended student engagement in community settings provide the advantages of educational continuity as well as increased service provision in underserved areas. Developing and maintaining LICs require a differing approach to student learning than that for traditional placements. There has been little theoretically informed empirical research that has offered explanations of which are the important factors that promote student learning in LICs and the relationships between those factors. We explored the relationship between student learning, student perceptions of preparedness for practice and student engagement, in the context of a rural LIC. We used a sequential qualitative design employing thematic, comparative and relational analysis of data from student interviews (n = 18) to understand possible processes and mechanisms of student learning in the LIC. Through the theoretical lens of social learning systems, we identified two major themes; connectivity and preparedness for practice. Connectivity described engagement and relationship building by students, across formal and informal learning experiences, interprofessional interactions, social interactions with colleagues, interaction with patients outside of the clinical setting, and the extent of integration in the wider community. Preparedness for practice, reflected students' perceptions of having sufficient depth in clinical skills, personal and professional development, cultural awareness and understanding of the health system, to work in that system. A comparative analysis compared the nature and variation of learning across students. In a relational analysis, there was a positive association between connectivity and preparedness for practice. Connectivity is a powerful enabler of students' agentic engagement, collaboration, and learning within an LIC. It is related to student perceptions of preparedness for practice. These findings provide insight for institutions wishing to develop similar programmes, by encouraging health professional educators to consider all of the potential elements of the placements, which most promote connectivity.

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion.

We previously reported that combining a phosphoinositide 3-kinase (PI3K) inhibitor with a poly-ADP Rib polymerase (PARP)-inhibitor enhanced DNA damage and cell death in breast cancers that have genetic aberrations in BRCA1 and TP53. Here, we show that enhanced DNA damage induced by PI3K inhibitors in this mutational background is a consequence of impaired production of nucleotides needed for DNA synthesis and DNA repair. Inhibition of PI3K causes a reduction in all four nucleotide triphosphates, whereas inhibition of the protein kinase AKT is less effective than inhibition of PI3K in suppressing nucleotide synthesis and inducing DNA damage. Carbon flux studies reveal that PI3K inhibition disproportionately affects the nonoxidative pentose phosphate pathway that delivers Rib-5-phosphate required for base ribosylation. In vivo in a mouse model of BRCA1-linked triple-negative breast cancer (K14-Cre BRCA1(f/f)p53(f/f)), the PI3K inhibitor BKM120 led to a precipitous drop in DNA synthesis within 8 h of drug treatment, whereas DNA synthesis in normal tissues was less affected. In this mouse model, combined PI3K and PARP inhibition was superior to either agent alone to induce durable remissions of established tumors.

SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells.

SAMHD1 limits HIV-1 infection in non-dividing myeloid cells by decreasing intracellular dNTP pools. HIV-1 restriction by SAMHD1 in these cells likely prevents activation of antiviral immune responses and modulates viral pathogenesis, thus highlighting a critical role of SAMHD1 in HIV-1 physiopathology. Here, we explored the function of SAMHD1 in regulating cell proliferation, cell cycle progression and apoptosis in monocytic THP-1 cells. Using the CRISPR/Cas9 technology, we generated THP-1 cells with stable SAMHD1 knockout. We found that silencing of SAMHD1 in cycling cells stimulates cell proliferation, redistributes cell cycle population in the G1/G0 phase and reduces apoptosis. These alterations correlated with increased dNTP levels and more efficient HIV-1 infection in dividing SAMHD1 knockout cells relative to control. Our results suggest that SAMHD1, through its dNTPase activity, affects cell proliferation, cell cycle distribution and apoptosis, and emphasize a key role of SAMHD1 in the interplay between cell cycle regulation and HIV-1 infection.

Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase.

Although many compounds have been approved for the treatment of human immunodeficiency type-1 (HIV-1) infection, additional anti-HIV-1 drugs (particularly those belonging to new drug classes) are still needed due to issues such as long-term drug-associated toxicities, transmission of drug-resistant variants, and development of multi-class resistance. Lethal mutagenesis represents an antiviral strategy that has not yet been clinically translated for HIV-1 and is based on the use of small molecules to induce excessive levels of deleterious mutations within the viral genome. Here, we show that 5-azacytidine (5-aza-C), a ribonucleoside analog that induces the lethal mutagenesis of HIV-1, and multiple inhibitors of the enzyme ribonucleotide reductase (RNR) interact in a synergistic fashion to more effectively reduce the infectivity of HIV-1. In these drug combinations, RNR inhibitors failed to significantly inhibit the conversion of 5-aza-C to 5-aza-2'-deoxycytidine, suggesting that 5-aza-C acts primarily as a deoxyribonucleoside even in the presence of RNR inhibitors. The mechanism of antiviral synergy was further investigated for the combination of 5-aza-C and one specific RNR inhibitor, resveratrol, as this combination improved the selectivity index of 5-aza-C to the greatest extent. Antiviral synergy was found to be primarily due to the reduced accumulation of reverse transcription products rather than the enhancement of viral mutagenesis. To our knowledge, these observations represent the first demonstration of antiretroviral synergy between a ribonucleoside analog and RNR inhibitors, and encourage the development of additional ribonucleoside analogs and RNR inhibitors with improved antiretroviral activity.

Dual anti-HIV mechanism of clofarabine.

BACKGROUND: HIV-1 replication kinetics inherently depends on the availability of cellular dNTPs for viral DNA synthesis. In activated CD4(+) T cells and other rapidly dividing cells, the concentrations of dNTPs are high and HIV-1 reverse transcription occurs in an efficient manner. In contrast, nondividing cells such as macrophages have lower dNTP pools, which restricts efficient reverse transcription. Clofarabine is an FDA approved ribonucleotide reductase inhibitor, which has shown potent antiretroviral activity in transformed cell lines. Here, we explore the potency, toxicity and mechanism of action of clofarabine in the human primary HIV-1 target cells: activated CD4(+) T cells and macrophages. RESULTS: Clofarabine is a potent HIV-1 inhibitor in both activated CD4(+) T cells and macrophages. Due to its minimal toxicity in macrophages, clofarabine displays a selectivity index over 300 in this nondividing cell type. The anti-HIV-1 activity of clofarabine correlated with a significant decrease in both cellular dNTP levels and viral DNA synthesis. Additionally, we observed that clofarabine triphosphate was directly incorporated into DNA by HIV-1 reverse transcriptase and blocked processive DNA synthesis, particularly at the low dNTP levels found in macrophages. CONCLUSIONS: Taken together, these data provide strong mechanistic evidence that clofarabine is a dual action inhibitor of HIV-1 replication that both limits dNTP substrates for viral DNA synthesis and directly inhibits the DNA polymerase activity of HIV-1 reverse transcriptase.

5-Azacytidine Enhances the Mutagenesis of HIV-1 by Reduction to 5-Aza-2'-Deoxycytidine.

5-Azacytidine (5-aza-C) is a ribonucleoside analog that induces the lethal mutagenesis of human immunodeficiency virus type 1 (HIV-1) by causing predominantly G-to-C transversions during reverse transcription. 5-Aza-C could potentially act primarily as a ribonucleotide (5-aza-CTP) or as a deoxyribonucleotide (5-aza-2'-deoxycytidine triphosphate [5-aza-dCTP]) during reverse transcription. In order to determine the primary form of 5-aza-C that is active against HIV-1, Illumina sequencing was performed using proviral DNA from cells treated with 5-aza-C or 5-aza-dC. 5-Aza-C and 5-aza-dC were found to induce highly similar patterns of mutation in HIV-1 in terms of the types of mutations observed, the magnitudes of effects, and the distributions of mutations at individual sequence positions. Further, 5-aza-dCTP was detected by liquid chromatography-tandem mass spectrometry in cells treated with 5-aza-C, demonstrating that 5-aza-C was a substrate for ribonucleotide reductase. Notably, levels of 5-aza-dCTP were similar in cells treated with equivalent effective concentrations of 5-aza-C or 5-aza-dC. Lastly, HIV-1 reverse transcriptase was found to incorporate 5-aza-CTPin vitroat least 10,000-fold less efficiently than 5-aza-dCTP. Taken together, these data support the model that 5-aza-C enhances the mutagenesis of HIV-1 primarily after reduction to 5-aza-dC, which can then be incorporated during reverse transcription and lead to G-to-C hypermutation. These findings may have important implications for the design of new ribonucleoside analogs directed against retroviruses.

The emotional well-being of young people having a parent with younger onset dementia.

Younger onset dementia (YOD) not only affects the person with the diagnosis but the whole family, which often includes young people. A limited body of research on this group of young people indicates that they experience varying degrees of emotional trauma. We explored the lived experiences of young people having a parent with YOD from the perspective of the social model of disability. Data were available from semi-structured interviews with 12 young people who had a parent with YOD looking at their lived experiences between 8 and 24 years. Thematic analysis identified four main themes: the emotional toll of caring, keeping the family together, grief and loss and psychological distress The social model of disability theory provides a helpful framework for these families who experience significant emotional distress, demonstrating that the disability is often socially constructed by a society, which marginalizes and excludes them. A 'whole family' approach is proposed, where the needs of young people and their parents are respected and responded to age appropriately.

Empowerment of young people who have a parent living with dementia: a social model perspective.

BACKGROUND: Socially constructed disablement has marginalized young people in families where a parent has younger onset dementia (YOD). This has contributed to inadequate societal support for their complex situation. Impacts on such young people include significant involvement with mental health services for themselves. In this paper, we explored the young people's lived experiences in these families and the influencing factors to enable these young people to be included and supported within their community. METHODS: In this qualitative research study, the social model of disability was used as the theoretical framework in conducting a thematic analysis of interviews with 12 participants. RESULTS: Three themes emerged; invisibility highlighting the issues of marginalization; connectivity foregrounding the engagement of young people with family, friends and their social networks, and being empowered through claiming their basic human right to receive the age appropriate support they needed. CONCLUSION: The current plight of young people living with a parent with YOD demands a fundamental shift by society in developing inclusive cross-sectorial cooperation linking service providers across youth and dementia sectors. This requires working in partnership with the service users responding to the identified needs of individual family members.