Family carers' experience of the need for admission of their relative with an intellectual disability to an Assessment and Treatment Unit.

BACKGROUND: There is limited research that explores the experiences of family carers of individuals with an intellectual disability requiring admission to a specialist National Health Service Assessment and Treatment Unit. Accordingly, this study aimed to explore family carers' experience in respect of this phenomenon and their relationships with professionals at this time. METHODS: Interpretative phenomenological analysis was used. Six family carers (three mothers and three fathers) participated and were interviewed via the use of semi-structured interviews. FINDINGS: Five major themes were developed to represent how carers made sense and gave meaning to their experience. They illustrate how this experience had a significant influence on their sense of value and self-identity. It resulted in higher levels of anxiety, stress and uncertainty about the future of their relative and their identity as a carer. Significantly, professionals are identified as having a pivotal role in influencing how carers come to view their sense of self, identity, value and importance. CONCLUSION: The admission of their relative was a time of increased vulnerability for carers in respect of maintaining a sense of self-identity. Engaging with services and professionals had a major influence on situating them within the social structure that makes up the formal system of support. This had a pivotal role in influencing and determining how participants identified with their sense of self.

Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications.

BACKGROUND: Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy's clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. MATERIALS AND METHODS: We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). RESULTS: Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). CONCLUSION: Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. IMPLICATIONS FOR PRACTICE: Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies.

The formal support experiences of family carers of people with an intellectual disability who also display challenging behaviour and/or mental health issues: what do carers say?

This article reports the findings of a literature review of research that has explored the support experiences of family carers of a person with an intellectual disability who displays challenging behaviour and/or has a mental health problem. The purpose of this review is to provide an overview of the reported experiences of family carers from recent research studies, about their own support. Having discussed the search strategy, definitions of challenging behaviour and mental health/illness are presented. Evidence concerning the needs of carers and the extent to which they are met is explored, and the need for consistency and good communication are highlighted. Conclusions are drawn and recommendations made for the development of future research and practice.

Subtle or covert abuse within intimate partner relationships: a scoping review protocol.

OBJECTIVE: The objective of the review is to understand how academic literature on domestic violence has described or defined subtle, non-physical abuse in intimate heterosexual or same-sex relationships. INTRODUCTION: Academic literature frequently refers to subtle or covert abuse in intimate relationships; however, this kind of abuse, while recognized by therapists who work with victims, has not yet been researched. Without understanding how clients experiencing subtle abuse present in therapy, therapists may misunderstand the cause of their distress and do more harm than good. This scoping review aims to understand how the current literature describes or defines subtle or covert abuse to inform future research to enable therapists to recognize subtle abuse in their clients. INCLUSION CRITERIA: Academic work that describes or defines subtle or covert abuse in intimate partner relationships based on primary research or discussion papers published in English will be considered for inclusion. Work will be excluded if it only describes physical or overt non-physical abuse. METHODS: MeSH terms and keywords relating to domestic violence literature found in preliminary searches were used to design the initial search strategies. Search terms based on these were chosen in discussion with a librarian. The following databases will be searched: PsycINFO (EBSCO), MEDLINE Complete (EBSCO), CINAHL (EBSCO), PsycArticles (EBSCO), and Scopus. Searches will be conducted for studies published from 1950 onward. Studies meeting the inclusion criteria will be searched for descriptions or definitions of the terms "subtle" or "covert. Direct quotes will be entered in the data extraction form, along with details of study participants, concept, and context. Results will be presented in tabular format with quotes from original sources, and narratively in a discussion.

Impacts of offshore oil spill accidents on island bird communities: A test run study around Orkney and Svalbard archipelagos.

The sea area around the Orkney archipelago, Scotland is subjected to substantial maritime shipping activities. By contract, the Svalbard archipelago, Norway currently has a rather low marine traffic profile. Future projections, however, indicate that the Trans-Arctic route might change the whole transportation picture and Svalbard may be at the centre of maritime activities. Both archipelagos have sensitive environmental resources at sea and inland, including bird communities. There are, for instance, 13 Red Listed species present in Orkney and 2 in Svalbard. In this regard, it is important to address oil spill risks along existing and projected shipping routes. Hypothetical spills were simulated in twelve scenarios for both the Orkney and Svalbard archipelagos with the OpenDrift open-source software. The results indicate risks to seabird communities. For Orkney, the spills resulted in the most extensive contamination of the sea and land environments in autumn. For Svalbard, autumn spills on the contrary presented the lowest risk to seabirds. Based on the simulations, we recommend increased caution for shipping activities in the problematic seasons, improved local readiness for ship accidents and sufficient pre-incident planning.

Tracking the impacts of COVID-19 pandemic-related debris on wildlife using digital platforms.

Since the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic in December 2019, there have been global surges of single-use plastic use. Due to the importance of personal protective equipment (PPE) and sanitation items in protecting against virus transmission and from testing, facemasks, respirators, disposable gloves and disposable wet wipes have become global staples in households and institutions. Widespread use and insufficient infrastructure, combined with improper waste management have resulted in an emerging category of litter. With widespread presence in the environment, such items pose a direct threat to wildlife as animals can interact with them in a series of ways. We examined the scope of COVID-19 pandemic-related debris, including PPE and sanitation items, on wildlife from April 2020 to December 2021. We document the geographic occurrence of incidents, debris types, and consequences of incidents that were obtained from social media searches, unpublished reports from colleagues, and reports available from the citizen science database "Birds and Debris". There were 114 unique sightings of wildlife interactions with pandemic-related debris (38 from 2020 and 76 from 2021). Within the context of this dataset, most incidents involved birds (83.3 %), while fewer affected mammals (10.5 %), invertebrates (3.5 %), fish (1.8 %), and sea turtles (0.9 %). Sightings originated in 23 countries, and consisted mostly of entanglements (42.1 %) and nest incorporations (40.4 %). We verified sightings by contacting the original observers and were able to identify replicated sightings and increase the resolution of the data collected compared with previously published results. Due to the complexities associated with global use and accessibility of digital platforms, we likely underestimate the number of animals harmed by debris. Overall, the global scope of this study demonstrates that online and social media platforms are a valuable way to collect biologically relevant citizen science data and track rapidly emerging environmental challenges.

The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases.

Ovarian cancer is the deadliest gynecologic cancer, with a 5-year survival rate of 30%, when the disease has spread throughout the peritoneal cavity. We investigated the efficacy to delay disease progression by the DNA-dependent protein kinase (DNA-PK) inhibitor AZD7648, administered in combination with two of the therapeutic options for patient management: either pegylated liposomal doxorubicin (PLD) or the PARP inhibitor olaparib. Patient-derived ovarian cancer xenografts (OC-PDX) were transplanted subcutaneously to evaluate the effect of treatment on tumor growth, or orthotopically in the peritoneal cavity to evaluate the effect on metastatic spread. AZD7648 was administered orally in combination with PLD (dosed intravenously) or with olaparib (orally). To prove the inhibition of DNA-PK in the tumors, we measured pDNA-PKcs, pRPA32, and γH2AX, biomarkers of DNA-PK activity. AZD7648 enhanced the therapeutic efficacy of PLD in all the OC-PDXs tested, regardless of their BRCA status or sensitivity to cisplatin or PLD. The treatment caused disease stabilization, which persisted despite therapy discontinuation for tumors growing subcutaneously, and significantly impaired the abdominal metastatic dissemination, prolonging the lifespan of mice implanted orthotopically. AZD7648 potentiated the efficacy of olaparib in BRCA-deficient OC-PDXs but did not sensitize BRCA-proficient OC-PDXs to olaparib, despite an equivalent inhibition of DNA-PK, suggesting the need of a preexisting olaparib activity to benefit from the addition of AZD7648. This work suggests that AZD7648, an inhibitor of DNA-PK, dosed in combination with PLD or olaparib is an exciting therapeutic option that could benefit patients with ovarian cancer and should be explored in clinical trials.

The experience of occupational identity disruption post stroke: a systematic review and meta-ethnography.

PURPOSE: After a stroke, most individuals cannot participate in some of their valued occupations, disrupting their occupational identity. The aim of this interpretive synthesis is to systematically review the existing body of research to develop an understanding of the experience of occupational identity disruption post-stroke. METHODS: A systematic review of the literature that included nine electronic databases, reference lists screening and grey literature checking was completed. Ten studies published between January 2012 and October 2018 were included. Meta-ethnography was used for the interpretive synthesis. FINDINGS: A three-staged process model was created. Stage 1 illustrates the four factors involved in occupational identity disruption: "A fragmented and externalized body", "losing control, freedom and independence", "changed social and familial interactions", and "occupational participation loss". Stage two explains the experience of occupational identity disruption: "Occupational identity loss", "a de-valued self", and "threat to identity continuity". Stage three shows the individual's coping strategies: "protecting one's self", "social isolation", and "re-inventing one's occupational self". CONCLUSIONS: Stroke impacts on an individual's occupational identity, compromising the continuity of a stroke survivor's sense of self. However, occupational identity is fluid; this can be used to support individuals to re-invent the occupational self. A conceptual model was developed to support the application of these results in clinical practice.Implications for rehabilitationOccupational identity disruption impacts on stroke survivors' self-value and sense of self continuity.Health care professionals' understanding of stroke survivors experience of occupational identity disruption could contribute to realign stroke survivors and clinicians' rehabilitation goals.Occupational participation and social interaction should be core aspects of stroke rehabilitation.Occupation-focus rehabilitation could provide opportunities for stroke survivors to pursue their desired occupational identity.

Measuring nest incorporation of anthropogenic debris by seabirds: An opportunistic approach increases geographic scope and reduces costs.

Data on the prevalence of anthropogenic debris in seabird nests can be collected alongside other research or through community science initiatives to increase the temporal and spatial scale of data collection. To assess the usefulness of this approach, we collated data on nest incorporation of debris for 14 seabird species from 84 colonies across five countries in northwest Europe. Of 10,274 nests monitored 12% contained debris, however, there was large variation in the proportion of nests containing debris among species and colonies. For several species, the prevalence of debris in nests was significantly related to the mean Human Footprint Index (HFI), a proxy for human impact on the environment, within 100 km of the colony. Collecting opportunistic data on nest incorporation of debris by seabirds provides a cost-effective method of detecting changes in the prevalence of debris in the marine environment across a large geographic scale.

A standardised method for estimating the level of visible debris in bird nests.

Unlike records of plastic ingestion and entanglement in seabirds which date back to the 1960s, the literature regarding debris in bird nests is comparatively limited. It is important to identify standardised methods early so that data are collected in a consistent manner, ensuring that future studies can be comparable. Here, we outline a method that can be applied to photographs for estimating the proportion of visible debris at the surface of a nest. This method uses ImageJ software to superimpose a grid onto a photograph of a nest/s. The number of cells with and without debris are then counted. Our proposed method is repeatable, straightforward, and accessible. We optimised the method to estimate the level of visible debris in Northern Gannet (Morus bassanus) nests, however, with some modification (i.e., adjustment of grid cell size), it could be applied to other seabird species, and terrestrial birds, that incorporate debris within nests.

Inhibition of DNA-PK with AZD7648 Sensitizes Tumor Cells to Radiotherapy and Induces Type I IFN-Dependent Durable Tumor Control.

PURPOSE: Combining radiotherapy (RT) with DNA damage response inhibitors may lead to increased tumor cell death through radiosensitization. DNA-dependent protein kinase (DNA-PK) plays an important role in DNA double-strand break repair via the nonhomologous end joining (NHEJ) pathway. We hypothesized that in addition to a radiosensitizing effect from the combination of RT with AZD7648, a potent and specific inhibitor of DNA-PK, combination therapy may also lead to modulation of an anticancer immune response. EXPERIMENTAL DESIGN: AZD7648 and RT efficacy, as monotherapy and in combination, was investigated in fully immunocompetent mice in MC38, CT26, and B16-F10 models. Immunologic consequences were analyzed by gene expression and flow-cytometric analysis. RESULTS: AZD7648, when delivered in combination with RT, induced complete tumor regressions in a significant proportion of mice. The antitumor efficacy was dependent on the presence of CD8+ T cells but independent of NK cells. Analysis of the tumor microenvironment revealed a reduction in T-cell PD-1 expression, increased NK-cell granzyme B expression, and elevated type I IFN signaling in mice treated with the combination when compared with RT treatment alone. Blocking of the type I IFN receptor in vivo also demonstrated a critical role for type I IFN in tumor growth control following combined therapy. Finally, this combination was able to generate tumor antigen-specific immunologic memory capable of suppressing tumor growth following rechallenge. CONCLUSIONS: Blocking the NHEJ DNA repair pathway with AZD7648 in combination with RT leads to durable immune-mediated tumor control.

The Src inhibitor AZD0530 reversibly inhibits the formation and activity of human osteoclasts.

Tumor cells in the bone microenvironment are able to initiate a vicious cycle of bone degradation by mobilizing osteoclasts, multinucleated cells specialized in bone degradation. c-Src is highly expressed both in tumors and in osteoclasts. Therefore, drugs like AZD0530, designed to inhibit Src activity, could selectively interfere with both tumor and osteoclast activity. Here we explored the effects of AZD0530 on human osteoclast differentiation and activity. The effect on osteoclasts formed in vivo was assessed in mouse fetal calvarial explants and in isolated rabbit osteoclasts, where it dose-dependently inhibited osteoclast activity. Its effect on formation and activity of human osteoclasts in vitro was determined in cocultures of human osteoblasts and peripheral blood mononuclear cells. AZD0530 was most effective in inhibiting osteoclast-like cell formation when present at the onset of osteoclastogenesis, suggesting that Src activity is important during the initial phase of osteoclast formation. Formation of active phosphorylated c-Src, which was highly present in osteoclast-like cells in cocultures and in peripheral blood mononuclear cell monocultures, was significantly reduced by AZD0530. Furthermore, it reversibly prevented osteoclast precursor migration from the osteoblast layer to the bone surface and subsequent formation of actin rings and resorption pits. These data suggest that Src is pivotal for the formation and activity of human osteoclasts, probably through its effect on the distribution of the actin microfilament system. The reversible effect of AZD0530 on osteoclast formation and activity makes it a promising candidate to temper osteoclastic bone degradation in bone diseases with enhanced osteoclast activity such as osteolytic metastatic bone disease.

A review of the potential utilisation of plastic waste as adsorbent for removal of hazardous priority contaminants from aqueous environments.

There is growing global awareness of the presence and negative impacts of waste plastic in the marine environment. Risks to wildlife include ingestion and entanglement for macro-plastic (larger than 5 mm in length), alongside food chain transfer for micro-plastics (less than 5 mm in length). Plastics in the marine environment have also been shown to adsorb and accumulate contaminants from seawater, e.g., heavy metals and hydrophobic organic compounds. This means that plastics can additionally act as vectors for transport of contaminants, permitting ecotoxicological risks to be spatially extended. However, the ability of waste plastic to adsorb pollutants also offers potential opportunity, if they can be used for the decontamination of wastewater. Here, we provide an overview of marine plastic types and distribution, and then systematically assess their potential to be repurposed as novel adsorbents. Data published in recent years are interrogated to gain an overview of the interaction mechanisms between marine plastics and both organic and inorganic contaminants. In addition, factors that may be exploited to enhance their performance in removal of contaminants are also reviewed and prioritised, e.g., surface modification and activation. This paper highlights the novel potential of repurposing plastic waste for wastewater treatment applications and seeks to identify key knowledge gaps and future research priorities for scientists and engineers.

Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells.

The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1-2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib.

HPV-Related Neovaginal Squamous Cell Carcinoma Presenting as Lung Metastasis after Male-to-Female Gender Confirmation Surgery.

There have been 4 reported cases of squamous cell carcinoma (SCC) of the neovagina in transgender women. In this report, we present another case of neovaginal SCC in a transgender woman, which was HPV-related, with lung metastasis as the initial presentation, and which was also complicated by her previous history of metastatic renal cell carcinoma. This unique case highlights the diagnostic challenges in these unusual scenarios. Through this report, we hope to address the benefits of multidisciplinary tumor board rounds, provision of detailed clinical information, and familiarization of the transgender anatomy within the pelvis in this group of patients. We also propose that transgender women undergo a continuous annual follow-up after postoperative follow-up is completed.

Monitoring nest incorporation of anthropogenic debris by Northern Gannets across their range.

Anthropogenic marine debris is a recognised global issue, which can impact a wide range of organisms. This has led to a rise in research focused on plastic ingestion, but quantitative data on entanglement are still limited, especially regarding seabirds, due to challenges associated with monitoring entanglement in the marine environment. However, for seabird species that build substantial surface nests there is the opportunity to monitor nest incorporation of debris that individuals collect as nesting material. Here, we monitored nest incorporation of anthropogenic marine debris by Northern Gannets (Morus bassanus) from 29 colonies across the species' range to determine a) the frequency of occurrence of incorporated debris and b) whether the Northern Gannet is a suitable indicator species for monitoring anthropogenic debris in the marine environment within their range. Using data obtained from visual observations, digital photography and published literature, we recorded incorporated debris in 46% of 7280 Northern Gannet nests, from all but one of 29 colonies monitored. Significant spatial variation was observed in the frequency of occurrence of debris incorporated into nests among colonies, partly attributed to when the colony was established and local fishing intensity. Threadlike plastics, most likely from fishing activities, was most frequently recorded in nests, being present in 45% of 5842 nests, in colonies where debris type was identified. Comparisons with local beach debris indicate a preference for threadlike plastics by Northern Gannets. Recording debris in gannet nests provides an efficient and non-invasive method for monitoring the effectiveness of actions introduced to reduce debris pollution from fishing activities in the marine environment.

The Impact of the Cellular Origin in Acute Myeloid Leukemia: Learning From Mouse Models.

Acute myeloid leukemia (AML) is a genetically heterogeneous disease driven by a limited number of cooperating mutations. There is a long-standing debate as to whether AML driver mutations occur in hematopoietic stem or in more committed progenitor cells. Here, we review how different mouse models, despite their inherent limitations, have functionally demonstrated that cellular origin plays a critical role in the biology of the disease, influencing clinical outcome. AML driven by potent oncogenes such as mixed lineage leukemia fusions often seem to emerge from committed myeloid progenitors whereas AML without any major cytogenetic abnormalities seem to develop from a combination of preleukemic initiating events arising in the hematopoietic stem cell pool. More refined mouse models may serve as experimental platforms to identify and validate novel targeted therapeutic strategies.

AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity.

DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.