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Understandings of disability are situated within social, political and economic circumstances. Internationally, medical conceptualisations of disability prevail, influencing policy and practice, creating a discourse which encourages categorisation, diagnosis and prescribed ways of understanding behaviour. This body of knowledge has a profound influence, providing powerful explanatory models of disability. Such discourse excludes other ways of knowing, with little attention paid to competences and the construction of worlds especially from the perspectives of disabled children themselves. This article draws upon a small number of UK qualitative studies which have examined disabled child abuse and included the experiences of disabled children. These studies have highlighted how medicalised notions of disability have led to both medicalised and psychiatrised responses to abuse, which have ill-served disabled children. It could be argued that medicalisation has led to disabled children being labelled as either 'too disabled' to be abused or 'not disabled enough' to receive an appropriate response which meets their needs; they are also sometimes regarded as showing signs of mental ill health when such signs are more likely to be an understandable manifestation of the trauma of abuse. Evidence collected indicate that much can be learnt from understanding the construction of disabled childhoods and how our current limited exploration of this affects how society prevents, identifies and responds to disabled child abuse and associated trauma. Drawing upon disabled children's recommendations to 'see me, hear me and understand me', this article will argue that in order to protect disabled children and support them to recover from abuse, we need to move away from a tick-box culture of medicalising, categorising, psychiatrising and 'othering' to a greater understanding of disabled children's worlds, and to a rights-based model of disabled child protection whereby we challenge the increased barriers to support faced by disabled children who have experienced abuse.

Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis‐related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK–STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady‐state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite‐to‐parent AUC ratio of 1.4–2.1. This review describes momelotinib's mechanism of action, detailing how the JAK–STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment. [ABSTRACT FROM AUTHOR]

Momelotinib—approved for treatment of myelofibrosis in adults with anemia—and its major active metabolite, M21, were assessed as drug–drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple‐dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single‐dose rifampin), and a strong CYP3A4 inducer (multiple‐dose rifampin). Momelotinib DDI perpetrator potential (multiple‐dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration–time curve (AUC), time to reach Cmax, and half‐life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single‐dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple‐dose rifampin compared with single‐dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple‐dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1′‐hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short‐term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments. [ABSTRACT FROM AUTHOR]

Establishing a dosing regimen that maximizes clinical benefit and minimizes adverse effects for novel therapeutics is a key objective for drug developers. Finding an optimal dose and schedule can be particularly challenging for compounds with a narrow therapeutic window such as in oncology. Modeling and simulation tools can be valuable to conduct in silico evaluations of various dosing scenarios with the goal to identify those that could minimize toxicities, avoid unscheduled dose interruptions, or minimize premature discontinuations, which all could limit the potential for therapeutic benefit. In this tutorial, we present a stepwise development of an adaptive dose simulation framework that can be used for dose optimization simulations. The tutorial first describes the general workflow, followed by a technical description with basic to advanced practical examples of its implementation in mrgsolve and is concluded with examples on how to use this in decision‐making around dose and schedule optimization. The adaptive simulation framework is built with pharmacokinetic, pharmacodynamic (i.e., biomarkers, activity markers, target engagement markers, efficacy markers), and safety models that include evaluations of unexplained interindividual and intraindividual variability and covariate impact, which can be replaced and expanded (e.g., combination setting, comparator setting) with user‐defined models. Subsequent adaptive simulations allow investigation of the impact of starting dose, dosing intervals, and event‐driven (exposure or effect) dose modifications on any end point. The resulting simulation‐derived insights can be used in quantitatively proposing dose and regimens that better balance benefit and adverse effects for further evaluation, aiding dose selection discussions, and designing dose modification recommendations, among others. [ABSTRACT FROM AUTHOR]

Belantamab mafodotin, a monomethyl auristatin F (MMAF)–containing monoclonal antibody‐drug conjugate (ADC), demonstrated deep and durable responses in the DRiving Excellence in Approaches to Multiple Myeloma (DREAMM)‐1 and pivotal DREAMM‐2 studies in patients with relapsed/refractory multiple myeloma. As with other MMAF‐containing ADCs, ocular adverse events were observed. To predict the effects of belantamab mafodotin dosing regimens and dose‐modification strategies on efficacy and ocular safety end points, DREAMM‐1 and DREAMM‐2 data across a range of doses were used to develop an integrated simulation framework incorporating two separate longitudinal models and the published population pharmacokinetic model. A concentration‐driven tumor growth inhibition model described the time course of serum M‐protein concentration, a measure of treatment response, whereas a discrete time Markov model described the time course of ocular events graded with the GSK Keratopathy and Visual Acuity scale. Significant covariates included baseline β2‐microglobulin on growth rate, baseline M‐protein on kill rate, extramedullary disease on the effect compartment rate constant, and baseline soluble B cell maturation antigen on maximal effect. Efficacy and safety end points were simulated for various doses with dosing intervals of 1, 3, 6, and 9 weeks and various event‐driven dose‐modification strategies. Simulations predicted that lower doses and longer dosing intervals were associated with lower probability and lower overall time with Grade 3+ and Grade 2+ ocular events compared with the reference regimen (2.5 mg/kg every 3 weeks), with a less‐than‐proportional reduction in efficacy. The predicted improved benefit–risk profiles of certain dosing schedules and dose modifications from this integrated framework has informed trial designs for belantamab mafodotin, supporting dose‐optimization strategies. [ABSTRACT FROM AUTHOR]

Through the creation of safe spaces in which to explore and challenge dominant negative views of disabled children and young people, this co‐written paper presents unique insight into the meaning and impact upon disabled young people's lives of medical lenses and deficit models of disability. Bodies of work and dominant debates in medical sociology, disability studies and childhood studies have so far largely overlooked the experiences and positioning of disabled children and young people and have rarely involved them in the development or discussion of theory. Drawing on empirical data, and through a series of creative, reflective workshops with a UK‐based disabled young researchers' collective (RIP:STARS), this paper discusses areas of theoretical importance identified by the disabled young researcher collective—the validation of their lives, negotiation of their identity and acceptance in society. The implications, and possibilities, of platforming disabled children and young people's voices in theoretical debates are deliberated and are achieved through the yielding of privileged academic voice and the development of a symbiotic, genuine partnership which resonates with disabled young people and recognises them as experts in their own lives. [ABSTRACT FROM AUTHOR]

In 2009 the National Society for the Protection of Cruelty to Children published "Partner Exploitation and Violence in Teenage Intimate Relationships". This publication reports on the first major study in the United Kingdom to systematically document the incidence rates and dynamics of intimate partner violence in the lives of young people. It also highlights the UK research communities' lack of attention to the issue of young people and partner violence; much of what is known about young people's experiences of violence within their intimate relationships has been informed by research undertaken in the USA. In this article we contribute to the growing body of research in the United Kingdom and present findings from a qualitative study that explored pregnant teenagers and young mothers' experience of power, control and domestic violence in their familial and intimate relationships. Our study highlights the complexities and contradictions relating to the notion of family support, with young women respondents sometimes identifying this "support" as controlling. Our findings also show how young mothers, like older adult women, are subject to a range of violent behaviours in their intimate relationships. We conclude that any attempt to minimise the "risks" this group face needs to recognise how familial and intimate relationships can negatively impact on the health and well-being of pregnant teenagers, of young mothers and that of their child/children.

The rise of social media use has been phenomenal, particularly during the recent COVID-19 pandemic. Furthermore, Facebook has also seen its share of users rise at a meteoric rate. At the same time, the academy is producing a growing body of literature concerning the use of online methods for primary data collection. Yet, despite the increase in the use of the internet as a research tool, very little still exists on the use of social media to recruit research participants, particularly those deemed "socially invisible". This paper addresses this gap. Another research project explored the experiences of South Asian women who had departed the social norms of arranged marriage to form an intimate relationship with a partner of choice and who then experienced forms of gender-related violence (GRV). The project encountered difficulties in recruiting participants from this marginalised and often invisible group in UK society, who are often too frightened or ashamed to come forward. This study demonstrates how to use Facebook ethically and methodologically, highlighting some of the methods used to overcome the challenges that were presented. The research was undertaken before the COVID-19 pandemic (which prompted a widespread use of social media in social science research). We argue that, despite the ethical challenges, the advantages of using social media to recruit participants when researching a highly sensitive topic such as GRV with 'invisible groups' was highly beneficial. We therefore suggest that social media should be an integral part of the research recruitment process, alongside non-digital methods, so that other 'invisible groups' are not created comprising those who cannot access technology. We share the lessons learned for the benefit of researchers using a similar approach today when recruiting research participants from invisible and marginalised groups. The authors caveat their recommendation of using social media with suggesting that those who do not have high levels of experience of data collection with such cohorts instead consider working with gatekeepers to facilitate the recruitment. [ABSTRACT FROM AUTHOR]

Molibresib (GSK525762) is an investigational orally bioavailable small‐molecule bromodomain and extraterminal (BET) protein inhibitor for the treatment of advanced solid tumors. In the first‐time‐in‐human BET115521 study of molibresib in patients with solid tumors, thrombocytopenia was the most frequent treatment‐related adverse event (AE), QT prolongation was an AE of special interest based on preclinical signals, and gastrointestinal (GI) AEs (nausea, vomiting, diarrhea, and dysgeusia) were often observed. The aims of this analysis were the following: (i) develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model capable of predicting platelet time courses in individual patients after administration of molibresib and identify covariates of clinical interest; (ii) evaluate the effects of molibresib (and/or its two active metabolites [GSK3529246]) exposure on cardiac repolarization by applying a systematic modeling approach using high‐quality, intensive, PK time‐matched 12‐lead electrocardiogram measurements; (iii) evaluate the exposure–response (ER) relationship between molibresib and/or GSK3529246 exposures and the occurrence of Grade 2 or higher GI AEs. Overall, the PK/PD model (including a maximal drug effect model and molibresib concentration) adequately described platelet counts following molibresib treatment and was used to simulate the impact of molibresib dosing on thrombocytopenia at different doses and regimens. ER analyses showed no clinically meaningful QT interval prolongation with molibresib at up to 100 mg q.d., and no strong correlation between molibresib exposure and the occurrence of Grade 2 or higher GI AEs. The models described here can aid dosing/schedule and drug combination strategies and may support a thorough QT study waiver request for molibresib. [ABSTRACT FROM AUTHOR]

Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration‐resistant prostate cancer (CRPC), triple‐negative breast cancer, estrogen receptor‐positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment‐related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted. What's new? Molibresib is a BET inhibitor currently being tested against various solid tumors. Part 1 of this study, published previously, established a recommended dosage in patients with nuclear protein in testis carcinoma. Here, the authors present part 2, reporting on the safety and efficacy of molibresib in a wider array of tumor types. While they found no unexpected toxicities, adverse events caused 83% of patients to pause treatment, and 29% to lower their dosage. Molibresib showed some anti‐tumor activity, although clinically meaningful response rates were not observed by the end of the trial. [ABSTRACT FROM AUTHOR]

Two patients achieved a morphologic leukemia-free state at the 12 mg dose level and with GSK2879552 + ATRA combination therapy, and improvement in leukemia cutis was observed in one patient following treatment with GSK2879552 12 mg (Supplementary Figure 2). Among the 10 patients who received GSK2879552 + ATRA combination therapy, treatment-related Grade 2 pruritus led to treatment discontinuation due to investigator discretion in one patient. Outcomes remain poor for patients with advanced myelodysplastic syndrome (MDS) or relapsed/refractory acute myeloid leukemia (AML) [[1]] due to a lack of effective treatment regimens [[3]], highlighting an unmet clinical need for novel treatments for these patients. [Extracted from the article]

Belantamab mafodotin is an antibody–drug conjugate comprising a humanized anti‐B‐cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F (MMAF) via a protease‐resistant maleimidocaproyl linker. Single‐agent belantamab mafodotin showed clinically meaningful activity and manageable safety in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM) in the phase I DREAMM‐1 and phase II DREAMM‐2 studies and is approved by the US Food and Drug Administration and European Medicines Agency for RRMM treatment. To support monotherapy dose selection, the relationship between Cycle 1 exposure (derived using a population pharmacokinetic model) and clinical response (for multiple efficacy and safety end points) was explored. In DREAMM‐2, efficacy end points (probability of response (PoR) and progression‐free survival (PFS)) were associated with exposure in univariate evaluation; however, once disease burden factors were included in the model (e.g., baseline soluble BCMA, ß2‐microglobulin), exposure was no longer significant. Patients with higher disease burden had lower exposure. In DREAMM‐1, belantamab mafodotin exposure was the only variable to correlate with PoR and PFS. Probability of corneal events (keratopathy), but not dry eye or blurred vision, was strongly associated with belantamab mafodotin exposure (DREAMM‐2). Higher cys‐mcMMAF maximum plasma drug concentration (Cmax) and lower baseline platelet count were associated with increased probability of thrombocytopenia (DREAMM‐1 and DREAMM ‐2). In general, safety end points were more strongly associated with belantamab mafodotin exposure than efficacy end points, particularly after disease factors and patient characteristics were taken into account. Overall, these findings supported the monotherapy dose recommendation of belantamab mafodotin as 2.5 mg/kg every 3 weeks in patients with RRMM who have received four or more prior therapies. [ABSTRACT FROM AUTHOR]

Belantamab mafodotin (belamaf) is an antibody–drug conjugate (ADC) targeting B‐cell maturation antigen (BCMA). Nonlinear mixed‐effects models were developed to characterize the population pharmacokinetics (PopPK) of ADC, total monoclonal antibody (mAb), and cysteine‐maleimidocaproyl‐MMAF (cys‐mcMMAF) after 0.03–4.6 mg/kg dosing every 3 weeks in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM; DREAMM‐1, n = 73; DREAMM‐2, n = 218). Sequential modeling methodology was used. Individual post hoc parameter estimates from the final ADC model were used to develop total mAb and cys‐mcMMAF models. Formal covariate selection used a modified stepwise forward inclusion method with backward elimination. A linear, two‐compartment PopPK model with a time‐varying clearance (CL) described ADC PK. Initial ADC typical value for CL for a DREAMM‐2 patient was 0.936 L/day with a half‐life of 11.5 days, over time CL was reduced by 28% resulting in a half‐life of 14.3 days. Time to 50% maximal CL change was ~ 50 days. Baseline soluble BCMA (sBCMA), immunoglobulin (IgG), albumin, and bodyweight impacted ADC CL. Cys‐mcMMAF concentrations were described with a linear two‐compartment model linked to ADC; input rate was governed by deconjugation/intracellular proteolytic degradation of ADC represented by an exponentially decreasing MMAF:mAb (drug antibody ratio [DAR]) after each dose. Time to 50% DAR reduction was 10.3 days. Baseline sBCMA and IgG impacted cys‐mcMMAF central volume of distribution. In conclusion, ADC, total mAb, and cys‐mcMMAF concentration–time profiles in RRMM were well‐described by PopPK models, and exposure was most strongly impacted by disease‐related characteristics. [ABSTRACT FROM AUTHOR]

Molibresib (GSK525762) is an investigational, orally bioavailable, small‐molecule bromodomain and extraterminal (BET) protein inhibitor for the treatment of advanced solid tumors. Molibresib was initially evaluated in a first‐time‐in‐human (FTIH) study BET115521 consisting of two parts: Part 1 of the study (dose escalation) was conducted in 94 patients with nuclear protein in testis midline carcinoma and other solid tumors, and Part 2 (expansion cohort) was conducted in 99 patients with different solid tumor types. Molibresib is metabolized by cytochrome P450 3A4 enzymes to produce two major active metabolites that are equipotent to the parent molecule. The metabolites are measured together after full conversion of one to the other and reported as an active metabolite composite (GSK3529246). The molibresib pharmacokinetic (PK) profile has been characterized by a decrease in exposure over time, with the decrease more pronounced at higher doses, and accompanied by a slight increase of the metabolite concentrations. Autoinduction of molibresib metabolism was suspected and confirmed in vitro. Here we report the development of a semimechanistic liver‐compartment population PK model using PK data from the FTIH study, which adequately describes the autoinduction of molibresib clearance and the PK of both molibresib and GSK3529246. Covariate analysis indicated body weight had a significant effect on the volume of distribution of molibresib and GSK3529246, and higher levels of aspartate aminotransferase resulted in the lower clearance of GSK3529246. This model was used to simulate individual patient exposures based on covariate information for use in future alternative dosing strategies and exposure–response analyses. [ABSTRACT FROM AUTHOR]

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

Molibresib (GSK525762), an orally bioavailable small molecule with 2 major equipotent active metabolites, is being developed for the treatment of cancers. Molibresib is a substrate of cytochrome P450 (CYP) 3A4 and P‐glycoprotein (P‐gp). To enable administering safe doses of molibresib to healthy volunteers, this 2‐part randomized, open‐label, crossover drug‐drug interaction trial was conducted as an adaptive design study using physiologically based pharmacokinetic (PBPK) modeling and simulation to predict the lowest doses of molibresib that could be safely administered alone (10 mg) or with itraconazole and rifampicin (strong inhibitors and inducers of CYP3A and P‐gp, respectively). PBPK simulation guided the molibresib dose (5 mg) to be administered along with itraconazole in part 1. Itraconazole increased total exposure (AUC) of molibresib by 4.15‐fold with a 66% increase in Cmax, whereas the total AUC and Cmax for the 2 major active metabolites of molibresib decreased by about 70% and 87%, respectively. A second PBPK simulation was conducted with part 1 data to also include the active metabolites to update the recommendation for the molibresib dose (20 mg) with rifampicin. With rifampicin, the AUC and Cmax of molibresib decreased by approximately 91% and 80%, respectively, whereas the AUC of the 2 active metabolites decreased to a lesser extent (8%), with a 2‐fold increase in Cmax. The results of this study confirmed the in vitro data that molibresib is a substrate for CYP3A4. The adaptive design, including Simcyp simulations, allowed evaluation of 2 drug interactions of an oncology drug in a single trial, thus minimizing time and exposures administered to healthy subjects. [ABSTRACT FROM AUTHOR]

Despite advances in HIV-1 management with antiretroviral therapy, drug resistance and toxicities with multidrug regimens can result in treatment failure. Hence, there is a continuing demand for antiretroviral agents (ARVs) with novel mechanisms of action. Maturation inhibitors inhibit HIV-1 replication via a unique mechanism of action and can be combined with other ARVs. Two phase I randomized clinical trials were conducted for a maturation inhibitor, GSK3640254, to determine safety, pharmacokinetics (NCT03231943), and relative bioavailability (NCT03575962) in healthy adults. The first trial was conducted in two parts. Part 1 was conducted in a two-cohort, interlocking, eight-period fashion in 20 participants with single ascending doses of GSK3640254 (1-700 mg) or placebo. In Part 2, 58 participants were randomized to receive GSK3640254 (n = 44) or placebo (n = 14). Four participants reported adverse events (AEs) leading to study discontinuation, with one adverse drug reaction (maculopapular rash). There was no relationship between frequency or severity of AEs and dose. Pharmacokinetic assessments showed that GSK3640254 was slowly absorbed, with time to maximum concentration (tmax) occurring between 3.5 and 4 hours and half-life of ~24 hours. In the relative bioavailability study of GSK3640254 mesylate salt vs bis-hydrochloride salt capsules in 14 healthy adults, the mesylate salt performed slightly better than the bis-hydrochloride formulation (12%-16% increase in area under the concentration-time curve and maximum concentration); tmax (5 hours) was similar between the formulations. Initial pharmacokinetic and safety data from these healthy-participant studies informed further development of GSK3640254 for once-daily dosing for the treatment of HIV-1 infection. Abbreviations: ART, antiretroviral therapy; ARV, antiretroviral; FTIH, first-time-in-human; MI, maturation inhibitor. [ABSTRACT FROM AUTHOR]

Collaborative research offers an opportunity to access experiential knowledge, rooted in a process that aims to move beyond traditional research relationships and boundaries. Collaborative research does not always change the power differential; nonetheless, it has the potential to lead to ethical relationships and for partnership working that supports 'change'. Working in this way aids in understanding and advancing ideas for change, grounded in the views and experiences of all involved. In this article, we share our experiences of carrying out two collaborative land-based prison-based evaluations. These programmes, delivered by third sector organisations, have both worked with men in prison but differed in relation to focus, approach, timescale and the specific group of men targeted within the prison population. This work highlights how working collaboratively lends itself to a way of engaging, through building a range of relationships with key stakeholders, men in prison, prison staff and practitioners, a channel to 'knowing differently' and potential for creating humanising spaces within the prison environment. This article details the rewards, tensions and challenges we have encountered when carrying out land-based studies, illuminating additional dimensions for consideration when adopting this approach. [ABSTRACT FROM AUTHOR]

Delineation of the full integration of quantitative and qualitative methods throughout all stages of multisite mixed methods case study projects remains a gap in the methodological literature. This article offers advances to the field of mixed methods by detailing the application and integration of mixed methods throughout all stages of one such project; a study of child welfare inequalities. By offering a critical discussion of site selection and the management of confirmatory, expansionary and discordant data, this article contributes to the limited body of mixed methods exemplars specific to this field. We propose that our mixed methods approach provided distinctive insights into a complex social problem, offering expanded understandings of the relationship between poverty, child abuse, and neglect. [ABSTRACT FROM AUTHOR]

Background Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors. Methods This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker. Results Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60–100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%–42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3–7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months. Conclusions Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC. [ABSTRACT FROM AUTHOR]

This novel paper critically addresses a currently popular sex education resource which compares sexual consent to tea drinking. Drawing from a study which considered the meaning of consent through focus groups and interviews with young people and professionals, we argue that the central 'risk avoidance' message of such resources individualises the potential risks of non‐consensual sex and ignores the gendered social structures which shape interpersonal relationships. We suggest that simplifying and extrapolating sexual consent from broader cultural understandings is problematic. Conversations with young people are important, but they need to address the complexity of sexual consent, coercion and gendered sexual norms. [ABSTRACT FROM AUTHOR]