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.

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.

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.

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.

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.

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.

Host SAMHD1 protein promotes HIV-1 recombination in macrophages.

Template switching can occur during the reverse transcription of HIV-1. Deoxynucleotide triphosphate (dNTP) concentrations have been biochemically shown to impact HIV-1 reverse transcriptase (RT)-mediated strand transfer. Lowering the dNTP concentrations promotes RT pausing and RNA template degradation by RNase H activity of the RT, subsequently leading to strand transfer. Terminally differentiated/nondividing macrophages, which serve as a key HIV-1 reservoir, contain extremely low dNTP concentrations (20-50 nm), which results from the cellular dNTP hydrolyzing sterile α motif and histidine aspartic domain containing protein 1 (SAMHD1) protein, when compared with activated CD4(+) T cells (2-5 µm). In this study, we first observed that HIV-1 template switching efficiency was nearly doubled in human primary macrophages when compared with activated CD4(+) T cells. Second, SAMHD1 degradation by viral protein X (Vpx), which elevates cellular dNTP concentrations, decreased HIV-1 template switching efficiency in macrophages to the levels comparable with CD4(+) T cells. Third, differentiated SAMHD1 shRNA THP-1 cells have a 2-fold increase in HIV-1 template switching efficiency. Fourth, SAMHD1 degradation by Vpx did not alter HIV-1 template switching efficiency in activated CD4(+) T cells. Finally, the HIV-1 V148I RT mutant that is defective in dNTP binding and has DNA synthesis delay promoted RT stand transfer when compared with wild type RT, particularly at low dNTP concentrations. Here, we report that SAMHD1 regulation of the dNTP concentrations influences HIV-1 template switching efficiency, particularly in macrophages.

Restricted 5'-end gap repair of HIV-1 integration due to limited cellular dNTP concentrations in human primary macrophages.

HIV-1 proviral DNA integration into host chromosomal DNA is only partially completed by the viral integrase, leaving two single-stranded DNA gaps with 5'-end mismatched viral DNA flaps. It has been inferred that these gaps are repaired by the cellular DNA repair machinery. Here, we investigated the efficiency of gap repair at integration sites in different HIV-1 target cell types. First, we found that the general gap repair machinery in macrophages was attenuated compared with that in dividing CD4(+) T cells. In fact, the repair in macrophages was heavily reliant upon host DNA polymerase ß (Pol ß). Second, we tested whether the poor dNTP availability found in macrophages is responsible for the delayed HIV-1 proviral DNA integration in this cell type because the Km value of Pol ß is much higher than the dNTP concentrations found in macrophages. Indeed, with the use of a modified quantitative AluI PCR assay, we demonstrated that the elevation of cellular dNTP concentrations accelerated DNA gap repair in macrophages at HIV-1 proviral DNA integration sites. Finally, we found that human monocytes, which are resistant to HIV-1 infection, exhibited severely restricted gap repair capacity due not only to the very low levels of dNTPs detected but also to the significantly reduced expression of Pol ß. Taken together, these results suggest that the low dNTP concentrations found in macrophages and monocytes can restrict the repair steps necessary for HIV-1 integration.

Anti-HIV host factor SAMHD1 regulates viral sensitivity to nucleoside reverse transcriptase inhibitors via modulation of cellular deoxyribonucleoside triphosphate (dNTP) levels.

Newly identified anti-HIV host factor, SAMHD1, restricts replication of lentiviruses such as HIV-1, HIV-2, and simian immunodeficiency virus in macrophages by enzymatically hydrolyzing and depleting cellular dNTPs, which are the substrates of viral DNA polymerases. HIV-2 and some simian immunodeficiency viruses express viral protein X (VPX), which counteracts SAMHD1 and elevates cellular dNTPs, enhancing viral replication in macrophages. Because nucleoside reverse transcriptase inhibitors (NRTIs), the most commonly used anti-HIV drugs, compete against cellular dNTPs for incorporation into proviral DNA, we tested whether SAMHD1 directly affects the efficacy of NRTIs in inhibiting HIV-1. We found that reduction of SAMHD1 levels with the use of virus-like particles expressing Vpx- and SAMHD1-specific shRNA subsequently elevates cellular dNTPs and significantly decreases HIV-1 sensitivity to various NRTIs in macrophages. However, virus-like particles +Vpx treatment of activated CD4(+) T cells only minimally reduced NRTI efficacy. Furthermore, with the use of HPLC, we could not detect SAMHD1-mediated hydrolysis of NRTI-triphosphates, verifying that the reduced sensitivity of HIV-1 to NRTIs upon SAMHD1 degradation is most likely caused by the elevation in cellular dNTPs.

Australian doctors' involvement in medicolegal matters: a cross-sectional self-report study.

OBJECTIVE: To investigate the frequency of, and factors associated with, Australian doctors' involvement in medicolegal matters. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional survey of Australian doctors (specialists, trainees and general practitioners) insured with the medical insurance company Avant. A self-report questionnaire was mailed to Avant members in September 2007 to gather data on their involvement in medicolegal matters. Information on psychiatric morbidity and alcohol consumption was also collected using the General Health Questionnaire and the Alcohol Use Disorders Identification Test. MAIN OUTCOME MEASURES: Occurrence and type of past and current medicolegal matters with which doctors have been involved. RESULTS: Of 8500 doctors invited to participate, 2999 returned completed surveys (36% response rate). Sixty-five per cent of respondents had been involved in a medicolegal matter at some time, and 14% were involved in a current matter. The two most common types of medicolegal matter were claims for compensation and complaints to a health care complaints body. Doctors were more likely to be involved in medicolegal matters if they were male, worked in high-intervention areas of medicine (surgery and obstretics/gynaecology), and worked longer hours. CONCLUSION: Our study concurs with other studies in finding an association between medicolegal matters and being male, working long hours and working in high-intervention areas of medicine. Unlike other studies, we found no association between age and involvement in a current medicolegal matter. Our findings also pose the question of whether psychiatric morbidity in doctors is a cause or effect of the medicolegal process.