Care First-Fund Later (CareFFuL): an end-of-life home care quality improvement project.

Previous work found referrals for end-of-life care are made late in the dying process and assessment processes for care funding, through continuing healthcare fast-track funding often inhibit people being able to die at home. The average time to discharge was 6.3 days and 29% died in hospital, as median survival was only 15 days.We aimed to support discharge to home within 1 day by December 2023 for patients, wishing to die at home, referred to the end-of-life discharge team in a medium-sized district general hospital in Southwest England.In phase 1, we identified 13 people on a patient-by-patient basis, learning from obstacles. Barriers identified included sourcing of equipment, communication between teams and clunky paperwork. Median time to discharge was 2 days (range within 24 hours to 8 days) with 2/13 (15.4%) dying prior to discharge. In phase 2, we extended the pilot, and 104 patients were identified; 94 people were discharged to home, with a median of wait of 1 day (range 0-7) to discharge, and 10 (9.6%) died prior to discharge (median 1 day; range 0-4). Median survival from discharge for the 94 who achieved their wishes to go home to die was 9 days (range 1-205 days). Only 26/94 (27.7%) people survived more than 30 days.Rapid decision-making and structures to support home-based end-of-life care can support more people to die in their preferred place of care, by using a community-based rapid response team instead of, or in parallel with continuing healthcare fast-track funding referral applications. Current pathways and funding models are not fit for purpose in an urgent care scenario when we have only one chance to get it right.

Video feedback for young babies and maternal perinatal mental illness: intervention adaptation, feasibility and acceptability.

AIMS/BACKGROUND: We aimed to adapt, pilot and explore experiences of receiving and delivering the video feedback intervention for positive parenting (VIPP) for 2 to 6 month old babies, mothers experiencing moderate to severe perinatal mental health difficulties and perinatal mental health clinicians. DESIGN/METHODS: The VIPP intervention was adapted to include developmentally appropriate activities and developmental psychoeducation for 2 to 6 month olds, alongside psychoeducation on emotion regulation, and then piloted in 14 mothers experiencing moderate to severe perinatal mental health difficulties (registration ISRCTN64237883). Observational and self-reported pre-post outcome data on parenting and parent-infant mental health was collected, and post-intervention qualitative interviews were conducted with participating mothers and clinicians. RESULTS: Consent (67%), intervention completion (79%) and follow-up rates (93%) were high. Effect sizes on pre-post outcome measures indicated large improvements in parenting confidence and perceptions of the parent-infant relationship, and a medium-size improvement in maternal sensitivity. In qualitative interviews, clinicians and mothers described how mothers' initial anxieties about being filmed were allayed through receiving positive and strengths-focussed feedback, boosting their self-confidence, and that the video feedback facilitated identification of young babies' subtle behavioural cues and moments of mother-infant connection. Streamlining the information provided on maternal emotion regulation, and allowing increased use of clinical judgement to tailor intervention delivery, were suggested to optimise intervention feasibility and acceptability. CONCLUSION: It is feasible and acceptable to implement VIPP with very young babies and their mothers experiencing perinatal mental health difficulties. A fully powered randomised controlled trial is required to establish intervention efficacy.

Identification and treatment of individuals with attention-deficit/hyperactivity disorder and substance use disorder: An expert consensus statement.

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with substance use (SU) and/or substance use disorder (SUD). Individuals with concurrent ADHD and SU/SUD can have complex presentations that may complicate diagnosis and treatment. This can be further complicated by the context in which services are delivered. Also, when working with young people and adults with co-existing ADHD and SU/SUD, there is uncertainty among healthcare practitioners on how best to meet their needs. In February 2022, the United Kingdom ADHD Partnership hosted a meeting attended by multidisciplinary experts to address these issues. Following presentations providing attendees with an overview of the literature, group discussions were held synthesizing research evidence and clinical experience. Topics included: (1) A review of substances and reasons for use/misuse; (2) identification, assessment and treatment of illicit SU/SUD in young people and adults with ADHD presenting in community services; and (3) identification, assessment and treatment of ADHD in adults presenting in SU/SUD community and inpatient services. Dis-cussions highlighted inter-service barriers and fragmentation of care. It was concluded that a multimodal and multi-agency approach is needed. The consensus group generated a table of practice recommendations providing guidance on: identification and assessment; pharmacological and psychological treatment; and multi-agency interventions.

Patient-centered pharmacovigilance: priority actions from the inherited bleeding disorders community.

Pharmacovigilance, the science and practice of monitoring the effects of medicinals and their safety, is the responsibility of all stakeholders involved in the development, manufacture, regulation, distribution, prescription, and use of drugs and devices. The patient is the stakeholder most impacted by and the greatest source of information on safety issues. It is rare, however, for the patient to take a central role and exert leadership in the design and execution of pharmacovigilance. Patient organizations in the inherited bleeding disorders community are among the most established and empowered, particularly in the rare disorders. In this review, two of the largest bleeding disorders patient organizations, Hemophilia Federation of America (HFA) and National Hemophilia Foundation (NHF), offer insights into the priority actions required of all stakeholders to improve pharmacovigilance. The recent and ongoing increase in incidents raising safety concerns and a therapeutic landscape on the cusp of unprecedented expansion heighten the urgency of a recommitment to the primacy of patient safety and well-being in drug development and distribution. Plain Language Summary: Patients at the center of product safety Every medical device and therapeutic product has potential benefits and harms. The pharmaceutical and biomedical companies that develop them must demonstrate that they are effective, and the safety risks are limited or manageable, for regulators to approve them for use and sale. After the product has been approved and people are using it in their daily lives, it is important to continue to collect information about any negative side effects or adverse events; this is called pharmacovigilance. Regulators, like the United States (US) Food and Drug Administration, the companies that sell and distribute the products, and healthcare professionals who prescribe them are all required to participate in collecting, reporting, analyzing, and communicating this information. The people with the most firsthand knowledge of the benefits and harms of the drug or device are the patients who use them. They have an important responsibility to learn how to recognize adverse events, how to report them, and to stay informed of any news about the product from the other partners in the pharmacovigilance network. Those partners have a crucial responsibility to provide clear, easy-to-understand information to patients about any new safety concerns that come to light. The community of people with inherited bleeding disorders has recently encountered problems with poor communication of product safety issues, prompting two large US patient organizations, National Hemophilia Foundation and Hemophilia Federation of America, to hold a Safety Summit with all the pharmacovigilance network partners. Together they developed recommendations to improve the collection and communication of information about product safety so that patients can make well-informed, timely decisions about their use of drugs and devices. This article presents these recommendations in the context of how pharmacovigilance is supposed to work and some of the challenges encountered by the community.

Ultrasound-enhanced Magnéli phase Ti4O7 anodic oxidation of per- and polyfluoroalkyl substances (PFAS) towards remediation of aqueous film forming foams (AFFF).

Per-and polyfluoroalkyl substances (PFAS) remediation is still a challenge. In this study, we propose a hybrid system that combines electrochemical treatment with ultrasound irradiation, aiming for an enhanced degradation of PFAS. Equipped with a titanium suboxide (Ti4O7) anode, the electrochemical cell is able to remove perfluorooctanoic acid (PFOA) effectively. Under the optimal conditions (50 mA/cm2 current density, 0.15 M Na2SO4 supporting electrolyte, and stainless steel/Ti4O7/stainless steel electrode configuration with a gap of ∼10 mm), the electrochemical process achieves ∼100 % PFOA removal and 43 % defluorination after 6 h. Applying ultrasound irradiation (130 kHz) alone offers a limited PFOA removal, with 33 % PFOA removal and 5.5 % defluorination. When the electrochemical process is combined with ultrasound irradiation, we observe a significant improvement in the remediation performance, with ∼100 % PFOA removal and 63.5 % defluorination, higher than the sum of 48.5 % (43 % achieved by the electrochemical process, plus 5.5 % by the ultrasound irradiation), implying synergistic removal/oxidation effects. The hybrid system also consistently shows the synergistic defluorination during degradation of other PFAS and the PFAS constituents in aqueous film forming foam (AFFF). We attribute the synergistic effect to an activated/cleaned electrode surface, improved mass transfer, and enhanced production of radicals.

Achieving access to haemophilia care in low-income and lower-middle-income countries: expanded Humanitarian Aid Program of the World Federation of Hemophilia after 5 years.

Highly effective treatment of haemophilia A and B is primarily available to 15% of the world's population, in high-income countries. In low-income countries (LICs) and lower-middle-income countries (LMICs), morbidity and mortality are high because of greatly reduced access to diagnosis, care, and treatment. We report the challenges and impact after the first 5 years (mid-2015-2020) of the expanded World Federation of Hemophilia (WFH) Humanitarian Aid Program (HAP). WFH HAP donated coagulation products were used to treat more than 250 000 acute bleeding episodes, manage approximately 4000 surgeries, and establish bleeding preventive prophylaxis in about 2000 patients in 73 countries. Health-care providers worldwide learned optimal management of patients with complex needs through virtual and in-person training. In response to the programme, some governments increased investment in haemophilia care, including independent purchases of small amounts of treatment products. With unparalleled scope and complexity, and substantial benefits to people with haemophilia and society in general, the WFH HAP is an exemplar of partnership between for-profit and not-for-profit organisations advancing health-care equity in LICs and LMICs, which could be replicated by other organisations supporting people with different monogenic diseases.

A novel case of ocular cicatricial pemphigoid induced by levamisole-adulterated cocaine.

AIM: To report a case of ocular cicatricial pemphigoid caused by levamisole-adulterated cocaine. METHODS: Case report. RESULTS: A 54-year-old woman with multi-systemic levamisole-induced vasculitis which triggered bilateral cicatrizing conjunctivitis refractory to conventional immunosuppressants due to continued cocaine misuse. CONCLUSION: Levamisole-induced vasculitis is a significant public health issue due to its popularity as an adulterant to cocaine. Our report suggests that levamisole caused vasculitis and ocular cicatricial pemphigoid in this case. Ocular manifestation of this syndrome is rare.

Communicating deprescribing decisions made in hospital with general practitioners in the community.

BACKGROUND: Deprescribing, the supervised withdrawal of inappropriate medications, intends to manage polypharmacy, which is prevalent in older patients. AIMS: To examine general practitioner (GP) perceptions of communication processes between clinicians in hospital and GP in the community about deprescribing decisions made in hospital. METHODS: Focus groups and interviews were held with 15 GP, exploring deprescribing in hospitals, communication of deprescribing information and the format of communications. Sessions were audiotaped, transcribed and analysed using an inductive approach. RESULTS: GP stated that they should be involved in deprescribing decisions, especially for older complex patients, because of their good knowledge of their patients. Barriers to effective communication included the acute nature of hospital stays and lack of time. Facilitators included long-term relationships of GP with their patients and engaged patients. GP preferred communication of deprescribing decisions to be over the telephone while the patient was still in hospital, and with a concise, electronic discharge summary at the time of discharge. GP indicated that rationale for medication changes and recommended follow-up actions were crucial in a discharge summary to enable care post-discharge. CONCLUSIONS: GP welcome increased communication with hospital clinicians regarding deprescribing decisions made while patients are in hospital. Communication needs to be timely, transparent, succinct and accessible. Lack of time and difficulties contacting hospital clinicians challenge this process.

Rationalization of the X-ray photoelectron spectroscopy of aluminium phosphates synthesized from different precursors.

The aim of this paper is to clarify the assignments of X-ray photoelectron spectra of aluminium phosphate materials prepared from the reaction of phosphoric acid with three different aluminium precursors [Al(OH)3, Al(NO3)3 and AlCl3] at different annealing temperatures. The materials prepared have been studied by X-ray photoelectron spectroscopy (XPS), powder X-ray diffraction (XRD), infrared spectroscopy and high-resolution solid-state 31P NMR spectroscopy. A progressive polymerization from orthophosphate to metaphosphates is observed by XRD, ATR-FTIR and solid state 31P NMR, and on this basis the oxygen states observed in the XP spectra at 532.3 eV and 533.7 eV are assigned to P-O-Al and P-O-P environments, respectively. The presence of cyclic polyphosphates at the surface of the samples is also evident.

Orbital plasmablastic lymphoma.

Plasmablastic lymphoma is an unusual and aggressive form of diffuse large B-cell lymphoma, which arises more commonly within the oronasal mucosa. It should be considered as a differential diagnosis for rapidly growing periorbital lesions, particularly in the context of HIV positivity.

Oxytocin and opioid addiction revisited: old drug, new applications.

Opioid addiction has devastating health and socio-economic consequences, and current pharmacotherapy is limited and often accompanied by side effects, thus novel treatment is warranted. Traditionally, the neurohypophyseal peptide oxytocin (OT) is known for its effects on mediating reward, social affiliation and bonding, stress and learning and memory. There is now strong evidence that OT is a possible candidate for the treatment of drug addiction and depression-addiction co-morbidities. This review summarizes and critically discusses the preclinical evidence surrounding the consequences of pharmacological manipulation of the oxytocinergic system on opioid addiction-related processes, as well as the effects of opioids on the OT system at different stages of the addiction cycle. The mechanisms underlying the effects of OT on opioid addiction, including OT' interaction with the monoaminergic, glutamatergic, opioidergic systems and its effect on the amygdala, the hypothalamic-pituitary-adrenal axis and on memory consolidation of traumatic memories, are also reviewed. We also review clinical evidence on the effects of intranasal OT administration on opioid-dependent individuals and discuss the therapeutic potential along with the limitations that accompany OT-based pharmacotherapies. Review of these studies clearly indicates that the OT system is profoundly affected by opioid use and abstinence and points towards the OT system as an important target for developing pharmacotherapies for the treatment of opioid addiction and co-existing affective disorders, thereby preventing relapse. Therefore, there is a clear need for clinical studies assessing the efficacy of OT-based pharmacotherapies in opioid addiction. LINKED ARTICLES: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

Developing and piloting a peer mentoring intervention to reduce teenage pregnancy in looked-after children and care leavers: an exploratory randomised controlled trial.

BACKGROUND: Looked-after children (LAC) are at greater risk of teenage pregnancy than non-LAC, which is associated with adverse health and social consequences. Existing interventions have failed to reduce rates of teenage pregnancy in LAC. Peer mentoring is proposed as a means of addressing many of the factors associated with the increased risk of teenage pregnancy in this group. OBJECTIVE: To develop a peer mentoring intervention to reduce teenage pregnancy in LAC. DESIGN: Phase I and II randomised controlled trial of a peer mentoring intervention for LAC; scoping exercise and literature search; national surveys of social care professionals and LAC; and focus groups and interviews with social care professionals, mentors and mentees. SETTING: Three local authorities (LAs) in England. PARTICIPANTS: LAC aged 14-18 years (mentees/care as usual) and 19-25 years (mentors). INTERVENTION: Recruitment and training of mentors; randomisation and matching of mentors to mentees; and 1-year individual peer mentoring. PRIMARY OUTCOME: pregnancy in LAC aged 14-18 years. SECONDARY OUTCOMES: sexual attitudes, behaviour and knowledge; psychological health; help-seeking behaviour; locus of control; and attachment style. A health economic evaluation was also carried out. RESULTS: In total, 54% of target recruitment was reached for the exploratory trial and 13 out of 20 mentors (65%) and 19 out of 30 LAC aged 14-18 years (63%) (recruited during Phases I and II) were retained in the research. The training programme was acceptable and could be manualised and replicated. Recruitment and retention difficulties were attributed to systemic problems and LA lack of research infrastructure and lack of additional funding to support and sustain such an intervention. Mentees appeared to value the intervention but had difficulty in meeting weekly as required. Only one in four of the relationships continued for the full year. A future Phase III trial would require the intervention to be modified to include provision of group and individual peer mentoring; internal management of the project, with support from an external agency such as a charity or the voluntary sector; funds to cover LA research costs, including the appointment of a dedicated project co-ordinator; a reduction in the lower age for mentee recruitment and an increase in the mentor recruitment age to 21 years; and the introduction of a more formal recruitment and support structure for mentors. CONCLUSIONS: Given the problems identified and described in mounting this intervention, a new development phase followed by a small-scale exploratory trial incorporating these changes would be necessary before proceeding to a Phase III trial. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 85. See the NIHR Journals Library website for further project information.

Challenges to undertaking randomised trials with looked after children in social care settings.

BACKGROUND: Randomised controlled trials (RCTs) are widely viewed as the gold standard for assessing effectiveness in health research; however many researchers and practitioners believe that RCTs are inappropriate and un-doable in social care settings, particularly in relation to looked after children. The aim of this article is to describe the challenges faced in conducting a pilot study and phase II RCT of a peer mentoring intervention to reduce teenage pregnancy in looked after children in a social care setting. METHODS: Interviews were undertaken with social care professionals and looked after children, and a survey conducted with looked after children, to establish the feasibility and acceptability of the intervention and research design. RESULTS: Barriers to recruitment and in managing the intervention were identified, including social workers acting as informal gatekeepers; social workers concerns and misconceptions about the recruitment criteria and the need for and purpose of randomisation; resource limitations, which made it difficult to prioritise research over other demands on their time and difficulties in engaging and retaining looked after children in the study. CONCLUSIONS: The relative absence of a research infrastructure and culture in social care and the lack of research support funding available for social care agencies, compared to health organisations, has implications for increasing evidence-based practice in social care settings, particularly in this very vulnerable group of young people.

Women's engagement with mobile device applications in pregnancy and childbirth.

Childbearing women are increasingly engaging with social media and technology. The use of apps for pregnancy and childbirth advice is a new approach to maternity provision, and has potential to impact upon midwifery. Apps are ideally placed to provide opportunities for women to access information; however, there are concerns about the quality of mobile app data in relation to evidence based midwifery. This discussion paper presents a general overview of the use of apps as an information resource, and provides a platform for debate about their position in midwifery care.

Eukaryotic translation elongation factor 1-alpha 1 inhibits p53 and p73 dependent apoptosis and chemotherapy sensitivity.

The p53 family of transcription factors is a key regulator of cell proliferation and death. In this report we identify the eukaryotic translation elongation factor 1-alpha 1 (eEF1A1) to be a novel p53 and p73 interacting protein. Previous studies have demonstrated that eEF1A1 has translation-independent roles in cancer. We report that overexpression of eEF1A1 specifically inhibits p53-, p73- and chemotherapy-induced apoptosis resulting in chemoresistance. Short-interfering RNA-mediated silencing of eEF1A1 increases chemosensitivity in cell lines bearing wild type p53, but not in p53 null cells. Furthermore, silencing of eEF1A1 partially rescues the chemoresistance observed in response to p53 or p73 knockdown, suggesting that eEF1A1 is a negative regulator of the pro-apoptotic function of p53 and p73. Thus, in the context of p53-family signaling, eEF1A1 has anti-apoptotic properties. These findings identify a novel mechanism of regulation of the p53 family of proteins by eEF1A1 providing additional insight into potential targets to sensitize tumors to chemotherapy.

SATB2 augments ΔNp63α in head and neck squamous cell carcinoma.

ΔNp63α is a critical pro-survival protein overexpressed in 80% of head and neck squamous cell carcinomas (HNSCCs) where it inhibits TAp73ß transcription of p53-family target genes, which is thought to increase HNSCC resistance to chemotherapy-induced cell death. However, the mechanisms governing ΔNp63α function are largely unknown. In this study, we identify special AT-rich-binding protein 2 (SATB2) as a new ΔNp63α-binding protein that is preferentially expressed in advanced-stage primary HNSCC and show that SATB2 promotes chemoresistance by enhancing ΔNp63α-mediated transrepression by augmenting ΔNp63α engagement to p53-family responsive elements. Furthermore, SATB2 expression positively correlates with HNSCC chemoresistance, and RNA interference-mediated knockdown of endogenous SATB2 re-sensitizes HNSCC cells to chemotherapy- and γ-irradiation-induced apoptosis, irrespective of p53 status. These findings unveil SATB2 as a pivotal modulator of ΔNp63α that governs HNSCC cell survival.

Mice lacking both mixed-lineage kinase genes Mlk1 and Mlk2 retain a wild type phenotype.

The mitogen-activated protein kinase kinase kinases of the mixed-lineage kinase (MLK) family have been shown to activate the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway, and to regulate the other two principal MAPK cascades, p38 and extracellular signal-regulated kinase (ERK). Although there is growing evidence for their involvement in neuronal cell death leading to neurodegenerative disorders, little in vivo data is available for the members of this family of kinases. Here, we report that the inactivation of mouse Mlk1 and Mlk2 genes. Mlk1(-/-) and Mlk2(-/-) mice were found to be viable and healthy. Surprisingly, mice carrying the compound Mlk1/Mlk2 null mutations were also found to be viable, fertile and to have a normal life span. The nervous system, testis and kidney, the major sites of MLK1 and 2 expression, all appear normal, as do other organs where these kinases were found to be more weakly expressed. Surprisingly, developmental neuronal programmed cell death, another potential target for MLK family members, was also found to be unaffected. Our results suggest that there is extensive functional redundancy between MLK1/MLK2 and the other member of the family, MLK3, which is also not required for survival in mouse.

Expression of human nPTB is limited by extreme suboptimal codon content.

BACKGROUND: The frequency of synonymous codon usage varies widely between organisms. Suboptimal codon content limits expression of viral, experimental or therapeutic heterologous proteins due to limiting cognate tRNAs. Codon content is therefore often adjusted to match codon bias of the host organism. Codon content also varies between genes within individual mammalian species. However, little attention has been paid to the consequences of codon content upon translation of host proteins. METHODOLOGY/PRINCIPAL FINDINGS: In comparing the splicing repressor activities of transfected human PTB and its two tissue-restricted paralogs-nPTB and ROD1-we found that the three proteins were expressed at widely varying levels. nPTB was expressed at 1-3% the level of PTB despite similar levels of mRNA expression and 74% amino acid identity. The low nPTB expression was due to the high proportion of codons with A or U at the third codon position, which are suboptimal in human mRNAs. Optimization of the nPTB codon content, akin to the "humanization" of foreign ORFs, allowed efficient translation in vivo and in vitro to levels comparable with PTB. We were then able to demonstrate that all three proteins act as splicing repressors. CONCLUSIONS/SIGNIFICANCE: Our results provide a striking illustration of the importance of mRNA codon content in determining levels of protein expression, even within cells of the natural host species.

A splicing repressor domain in polypyrimidine tract-binding protein.

Polypyrimidine tract-binding protein (PTB) is an hnRNP with four RRM type domains. It plays roles as a repressive alternative splicing regulator of multilple target genes, as well as being involved in pre-mRNA 3' end processing, mRNA localization, stability, and internal ribosome entry site-mediated translation. Here we have used a tethered function assay, in which a fusion protein of PTB and the bacteriophage MS2 coat protein is recruited to a splicing regulatory site by binding to an artificially inserted MS2 binding site. Deletion mutations of PTB in this system allowed us to identify RRM2 and the following inter-RRM linker region as the minimal region of PTB that can act as splicing repressor domain when recruited to RNA. Splicing repression by the minimal repressor domain remained cell type-specific and dependent upon other defined regulatory elements in the alpha-tropomyosin test minigene. Our results highlight the fact that splicing repression by PTB can be uncoupled from the mode by which it binds to RNA.