Developing a core outcome set for evaluating medication adherence interventions for adults prescribed long-term medication in primary care.

BACKGROUND: Approximately half of people prescribed medications do not take them as prescribed. There is a significant unmet need regarding the barriers to medication adherence not being addressed in primary care. There is no agreement on which outcomes should be measured and reported in trials of medication adherence interventions. OBJECTIVE: To develop a core outcome set (COS) for trials of medication adherence interventions in primary care for adults prescribed medications for long-term health conditions. METHODS: A list of potentially relevant outcomes from the literature was developed. Using a two-round Delphi survey of stakeholder groups representing patients and their carers; primary care staff; and academic researchers with an interest in medication adherence; each outcome was scored in terms of importance for determining the effectiveness of medication adherence interventions in primary care. This was followed by two consensus workshops, where importance, as well as feasibility and acceptability of measurement, were considered in order to finalise the COS. RESULTS: One hundred and fifty people took part in Delphi Round 1 and 101 took part in Round 2. Eight people attended the workshops (four attendees per workshop). Seven outcomes were identified as most important, feasible and acceptable to collect in medication adherence trials: Health-related quality of life, number of doses taken, persistence with medicines, starting (initiating) a medicine, relevance of the medication adherence intervention for an individual, mortality, and adverse medicine events. CONCLUSIONS: This COS represents the minimum outcomes that should be collected and reported in all medication adherence trials undertaken in primary care. When developing and finalizing the COS, feasibility and acceptability of collection of outcomes has been considered. In addition to the COS, medication adherence trials can choose to include outcomes to suit their specific context such as the health condition associated with their medication adherence intervention.

Deep Learning in Image-Based Plant Phenotyping.

A major bottleneck in the crop improvement pipeline is our ability to phenotype crops quickly and efficiently. Image-based, high-throughput phenotyping has a number of advantages because it is nondestructive and reduces human labor, but a new challenge arises in extracting meaningful information from large quantities of image data. Deep learning, a type of artificial intelligence, is an approach used to analyze image data and make predictions on unseen images that ultimately reduces the need for human input in computation. Here, we review the basics of deep learning, assessment of deep learning success, examples of applications of deep learning in plant phenomics, best practices, and open challenges. Expected final online publication date for the Annual Review of Plant Biology, Volume 75 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Integrated health system intervention aimed at reducing type 2 diabetes risk in women after gestational diabetes in South Africa (IINDIAGO): a randomised controlled trial protocol.

INTRODUCTION: South Africa has a high prevalence of gestational diabetes mellitus (GDM; 15%) and many of these women (48%) progress to type 2 diabetes mellitus (T2DM) within 5 years post partum. A significant proportion (47%) of the women are not aware of their diabetes status after the index pregnancy, which may be in part to low postnatal diabetes screening rates. Therefore, we aim to evaluate a intervention that reduces the subsequent risk of developing T2DM among women with recent GDM. Our objectives are fourfold: (1) compare the completion of the nationally recommended 6-week postpartum oral glucose tolerance test (OGTT) between intervention and control groups; (2) compare the diabetes risk reduction between control and intervention groups at 12 months' post partum; (3) assess the process of implementation; and (4) assess the cost-effectiveness of the proposed intervention package. METHODS AND ANALYSES: Convergent parallel mixed-methods study with the main component being a pragmatic, 2-arm individually randomised controlled trial, which will be carried out at five major referral centres and up to 26 well-baby clinics in the Western Cape and Gauteng provinces of South Africa. Participants (n=370) with GDM (with no prior history of either type 1 or type 2 diabetes) will be recruited into the study at 24-36 weeks' gestational age, at which stage first data collection will take place. Subsequent data collection will take place at 6-8 weeks after delivery and again at 12 months. The primary outcome for the trial is twofold: first, the completion of the recommended 2-hour OGTT at the well-baby clinics 6-8 weeks post partum, and second, a composite diabetes risk reduction indicator at 12 months. Process evaluation will assess fidelity, acceptability, and dose of the intervention. ETHICS AND DISSEMINATION: Ethics approval has been granted from University of Cape Town (829/2016), University of the Witwatersrand, Johannesburg (M170228), University of Stellenbosch (N17/04/032) and the University of Montreal (2019-794). The results of the trial will be disseminated through publication in peer-reviewed journals and presentations to key South African Government stakeholders and health service providers. PROTOCOL VERSION: 1 December 2022 (version #2). Any protocol amendments will be communicated to investigators, Human Ethics Research Committees, trial participants, and trial registries. TRIAL REGISTRATION NUMBER: PAN African Clinical Trials Registry (https://pactr.samrc.ac.za) on 11 June 2018 (identifier PACTR201805003336174).

Heterogeneity and transcriptional drivers of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.

Nanoparticle delivery of innate immune agonists combines with senescence-inducing agents to mediate T cell control of pancreatic cancer.

Pancreatic ductal adenocarcinoma has quickly risen to become the 3rd leading cause of cancer-related death. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here we investigated an innovative immunotherapy approach combining local delivery of STING and TLR4 innate immune agonists via lipid-based nanoparticles (NPs) co-encapsulation with senescence-inducing RAS-targeted therapies that can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other pro-inflammatory signaling, increased antigen presentation by tumor cells and antigen presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and Type I interferon-dependent tumor regressions and long-term survival in preclinical PDAC models. STING and TLR4-mediated Type I interferon signaling were also associated with enhanced NK and CD8+ T cell immunity in human PDAC. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can synergize to orchestrate a coordinated innate and adaptive immune assault to overcome immune suppression and activate durable anti-tumor T cell responses against PDAC.

Ubuntu as a mediator in coping with multimorbidity treatment burden in a disadvantaged rural and urban setting in South Africa.

BACKGROUND: People living with multimorbidity in economically precarious circumstances in low- and middle-income countries (LMICs) experience a high workload trying to meet self-management demands. However, in countries such as South Africa, the availability of social networks and support structures may improve patient capacity, especially when networks are governed by cultural patterns linked to the Pan-African philosophy of Ubuntu, which promotes solidarity through humanness and human dignity. We explore the mediating role Ubuntu plays in people's ability to self-manage HIV/NCD multimorbidity in underprivileged settings in urban and rural South Africa. METHODS: We conducted semi-structured interviews with 30 patients living with HIV/NCD multimorbidity between February-April 2022. Patients attended public health clinics in Gugulethu, Cape Town and Bulungula, Eastern Cape. We analysed interviews using framework analysis, using the Cumulative Complexity Model (CuCoM) and Burden of Treatment Theory (BoTT) as frameworks through which to conceptualise the data. RESULTS: Despite facing economic hardship, people with multimorbidity in South Africa were able to cope with their workload. They actively used and mobilized family relations and external networks that supported them financially, practically, and emotionally, allowing them to better self-manage their chronic conditions. Embedded in their everyday life, patients, often unconsciously, embraced Ubuntu and its core values, including togetherness, solidarity, and receiving Imbeko (respect) from health workers. This enabled participants to share their treatment workload and increase self-management capacity. CONCLUSION: Ubuntu is an important mediator for people living with multimorbidity in South Africa, as it allows them to navigate their treatment workload and increase their social capital and structural resilience, which is key to self-management capacity. Incorporating Ubuntu and linked African support theories into current treatment burden models will enable better understandings of patients' collective support and can inform the development of context-specific social health interventions that fit the needs of people living with chronic conditions in African settings.

CompreHensive geriAtRician-led MEdication Review (CHARMER): protocol for a feasibility study of a hospital deprescribing behaviour change intervention.

INTRODUCTION: Over 50% of older adults are prescribed a medicine where the risk of harm outweighs the chances of benefit. During a hospital admission, older adults and carers expect medicines to be reviewed for appropriateness and any inappropriate medicines proactively deprescribed. While the principle of proactive deprescribing is an expectation of good prescribing practice, it is yet to become routine. The CompreHensive geriAtRician-led MEdication Review (CHARMER) study aims to develop and test a five-component behaviour change intervention to equip geriatricians and pharmacists to proactively deprescribe inappropriate medicines with older adults in hospital. This study aims to test the feasibility and acceptability of study processes and CHARMER implementation. METHODS AND ANALYSIS: A two-arm purposive allocation feasibility study is being undertaken at four acute hospitals in England, UK (three intervention and one control). The target sample is 400 patients across all hospitals. Primary outcome measures are: (1) participant recruitment rate and (2) participant attrition rate. Secondary outcome measures are: (1) hospital readmission rate; (2) mortality rate and (3) quality of life. Quantitative data will be checked for completeness and quality, and practitioner and patient demographics descriptively analysed. We will undertake a rapid qualitative analysis on observations, interviews and study meeting minutes data. A subsequent thematic analysis will be undertaken with codes mapped to the Theoretical Domains Framework and Normalisation Process Theory. Triangulation of qualitative and quantitative data will be undertaken. ETHICS AND DISSEMINATION: Ethics approval was obtained from Wales Research Ethics Committee 1 (IRAS ID 312494) and study approval from the Health Research Authority (22/WA/0087). Informed consent will be sought from all hospital staff involved in data collection activities and for patients involved in enhanced data collection activities. The findings of this study will be disseminated in peer-reviewed journals and conference presentations. TRIAL REGISTRATION: ISRCTN11899506.

Bladder-Sparing Treatment With Radical Dose Radiotherapy Is an Effective Alternative to Radical Cystectomy in Patients With Clinically Node-Positive Nonmetastatic Bladder Cancer.

PURPOSE: Bladder-sparing trimodal therapy (TMT) is an alternative to radical cystectomy (RC) according to international guidelines. However, there are limited data to guide management of nonmetastatic clinically node-positive bladder cancer (cN+ M0 BCa). We performed a multicenter retrospective analysis of survival outcomes in node-positive patients to inform practice. METHODS: Data from patients diagnosed with cN+ M0 BCa were collected from participating UK Oncology centers offering both TMT and RC. Overall survival (OS) and progression-free survival (PFS) outcomes were collected with details of treatment and clinical factors. RESULTS: A total of 287 patients with cN+ M0 BCa were included in the survival analysis. Median OS across all patients was 1.55 years (95% CI, 1.35 to 1.82 years). Receiving radical treatments was associated with improved OS (hazard ratio [HR], 0.32; 95% CI, 0.23 to 0.44; P < .001) compared with receiving palliative treatment. Radically treated patients (n = 163) received RC (n = 76) or radical dose radiotherapy (RT, n = 87); choice of radical treatment showed no association with OS (HR, 0.94; 95% CI, 0.63 to 1.41; P = .76) or PFS (HR, 0.74; 95% CI, 0.50 to 1.08; P = .12) on multivariable analysis. CONCLUSION: Patient cohorts with cN+ M0 BCa had equivalent survival outcomes whether treated with surgery or radical RT. Given the known morbidities of RC-in a patient group with poor survival-this study confirms that bladder-sparing TMT treatment should be a treatment option available to all patients with cN+ M0 BCa.

Advances in Making Cancer Mouse Models More Accessible and Informative through Non-Germline Genetic Engineering.

Genetically engineered mouse models (GEMMs) allow for modeling of spontaneous tumorigenesis within its native microenvironment in mice and have provided invaluable insights into mechanisms of tumorigenesis and therapeutic strategies to treat human disease. However, as their generation requires germline manipulation and extensive animal breeding that is time-, labor-, and cost-intensive, traditional GEMMs are not accessible to most researchers, and fail to model the full breadth of cancer-associated genetic alterations and therapeutic targets. Recent advances in genome-editing technologies and their implementation in somatic tissues of mice have ushered in a new class of mouse models: non-germline GEMMs (nGEMMs). nGEMM approaches can be leveraged to generate somatic tumors de novo harboring virtually any individual or group of genetic alterations found in human cancer in a mouse through simple procedures that do not require breeding, greatly increasing the accessibility and speed and scale on which GEMMs can be produced. Here we describe the technologies and delivery systems used to create nGEMMs and highlight new biological insights derived from these models that have rapidly informed functional cancer genomics, precision medicine, and immune oncology.

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance.

Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor natural killer (NK) cell and T cell immunity. In the present study, we found that the pancreas tumor microenvironment suppresses NK cell and T cell surveillance after therapy-induced senescence through enhancer of zeste homolog 2 (EZH2)-mediated epigenetic repression of proinflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK cell and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in patients with PDAC. These results demonstrate that EZH2 represses the proinflammatory SASP and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC.

Using the COM-B model and Behaviour Change Wheel to develop a theory and evidence-based intervention for women with gestational diabetes (IINDIAGO).

BACKGROUND: In South Africa, the prevalence of gestational diabetes (GDM) is growing, concomitant with the dramatically increasing prevalence of overweight/obesity among women. There is an urgent need to develop tailored interventions to support women with GDM to mitigate pregnancy risks and to prevent progression to type 2 diabetes post-partum. The IINDIAGO study aims to develop and evaluate an intervention for disadvantaged GDM women attending three large, public-sector hospitals for antenatal care in Cape Town and Soweto, SA. This paper offers a detailed description of the development of a theory-based behaviour change intervention, prior to its preliminary testing for feasibility and efficacy in the health system. METHODS: The Behaviour Change Wheel (BCW) and the COM-B model of behaviour change were used to guide the development of the IINDIAGO intervention. This framework provides a systematic, step-by-step process, starting with a behavioural analysis of the problem and making a diagnosis of what needs to change, and then linking this to intervention functions and behaviour change techniques to bring about the desired result. Findings from primary formative research with women with GDM and healthcare providers were a key source of information for this process. RESULTS: Key objectives of our planned intervention were 1) to address women's evident need for information and psychosocial support by positioning peer counsellors and a diabetes nurse in the GDM antenatal clinic, and 2) to offer accessible and convenient post-partum screening and counselling for sustained behaviour change among women with GDM by integrating follow-up into the routine immunisation programme at the Well Baby clinic. The peer counsellors and the diabetes nurse were trained in patient-centred, motivational counselling methods. CONCLUSIONS: This paper offers a rich description and analysis of designing a complex intervention tailored to the challenging contexts of urban South Africa. The BCW was a valuable tool to use in designing our intervention and tailoring its content and format to our target population and local setting. It provided a robust and transparent theoretical foundation on which to develop our intervention, assisted us in making the hypothesised pathways for behaviour change explicit and enabled us to describe the intervention in standardised, precisely defined terms. Using such tools can contribute to improving rigour in the design of behavioural change interventions. TRIAL REGISTRATION: First registered on 20/04/2018, Pan African Clinical Trials Registry (PACTR): PACTR201805003336174.

Genomics of Aminoglycoside Resistance in Pseudomonas aeruginosa Bloodstream Infections at a United States Academic Hospital.

Pseudomonas aeruginosa frequently becomes resistant to aminoglycosides by the acquisition of aminoglycoside modifying enzyme (AME) genes and the occurrence of mutations in the mexZ, fusA1, parRS, and armZ genes. We examined resistance to aminoglycosides in a collection of 227 P. aeruginosa bloodstream isolates collected over 2 decades from a single United States academic medical institution. Resistance rates of tobramycin and amikacin were relatively stable over this time, while the resistance rates of gentamicin were somewhat more variable. For comparison, we examined resistance rates to piperacillin-tazobactam, cefepime, meropenem, ciprofloxacin, and colistin. Resistance rates to the first four antibiotics were also stable, although uniformly higher for ciprofloxacin. Colistin resistance rates were initially quite low, rose substantially, and then began to decrease at the end of the study. Clinically relevant AME genes were identified in 14% of isolates, and mutations predicted to cause resistance were relatively common in the mexZ and armZ genes. In a regression analysis, resistance to gentamicin was associated with the presence of at least one gentamicin-active AME gene and significant mutations in mexZ, parS, and fusA1. Resistance to tobramycin was associated with the presence of at least one tobramycin-active AME gene. An extensively drug-resistant strain, PS1871, was examined further and found to contain five AME genes, most of which were within clusters of antibiotic resistance genes embedded in transposable elements. These findings demonstrate the relative contributions of aminoglycoside resistance determinants to P. aeruginosa susceptibilities at a United States medical center. IMPORTANCE Pseudomonas aeruginosa is frequently resistant to multiple antibiotics, including aminoglycosides. The rates of resistance to aminoglycosides in bloodstream isolates collected over 2 decades at a United States hospital remained constant, suggesting that antibiotic stewardship programs may be effective in countering an increase in resistance. Mutations in the mexZ, fusA1, parR, pasS, and armZ genes were more common than acquisition of genes encoding aminoglycoside modifying enzymes. The whole-genome sequence of an extensively drug resistant isolate indicates that resistance mechanisms can accumulate in a single strain. Together, these results suggest that aminoglycoside resistance in P. aeruginosa remains problematic and confirm known resistance mechanisms that can be targeted for the development of novel therapeutics.

FFAR4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome, but a predominant subset of HFpEF patients has metabolic syndrome (MetS). Mechanistically, systemic, nonresolving inflammation associated with MetS might drive HFpEF remodeling. Free fatty acid receptor 4 (Ffar4) is a GPCR for long-chain fatty acids that attenuates metabolic dysfunction and resolves inflammation. Therefore, we hypothesized that Ffar4 would attenuate remodeling in HFpEF secondary to MetS (HFpEF-MetS). To test this hypothesis, mice with systemic deletion of Ffar4 (Ffar4KO) were fed a high-fat/high-sucrose diet with L-NAME in their water to induce HFpEF-MetS. In male Ffar4KO mice, this HFpEF-MetS diet induced similar metabolic deficits but worsened diastolic function and microvascular rarefaction relative to WT mice. Conversely, in female Ffar4KO mice, the diet produced greater obesity but no worsened ventricular remodeling relative to WT mice. In Ffar4KO males, MetS altered the balance of inflammatory oxylipins systemically in HDL and in the heart, decreasing the eicosapentaenoic acid-derived, proresolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE), while increasing the arachidonic acid-derived, proinflammatory oxylipin 12-hydroxyeicosatetraenoic acid (12-HETE). This increased 12-HETE/18-HEPE ratio reflected a more proinflammatory state both systemically and in the heart in male Ffar4KO mice and was associated with increased macrophage numbers in the heart, which in turn correlated with worsened ventricular remodeling. In summary, our data suggest that Ffar4 controls the proinflammatory/proresolving oxylipin balance systemically and in the heart to resolve inflammation and attenuate HFpEF remodeling.

The impact of persistent precarity on patients' capacity to manage their treatment burden: A comparative qualitative study between urban and rural patients with multimorbidity in South Africa.

Background: People living with multimorbidity in low-and middle-income countries (LMICs) experience a high workload trying to meet the demands of self-management. In an unequal society like South Africa, many people face continuous economic uncertainty, which can impact on their capacity to manage their illnesses and lead to poor health outcomes. Using precariousness - the real and perceived impact of uncertainty - as a lens, this paper aims to identify, characterise, and understand the workload and capacity associated with self-management amongst people with multimorbidity living in precarious circumstances in urban and rural South Africa. Methods: We conducted qualitative semi-structured interviews with 30 patients with HIV and co-morbidities between February and April 2021. Patients were attending public clinics in Cape Town (Western Cape) and Bulungula (Eastern Cape). Interviews were transcribed and data analysed using qualitative framework analysis. Burden of Treatment Theory (BoTT) and the Cumulative Complexity Model (CuCoM) were used as theoretical lenses through which to conceptualise the data. Results: People with multimorbidity in rural and urban South Africa experienced multi-faceted precariousness, including financial and housing insecurity, dangerous living circumstances and exposure to violence. Women felt unsafe in their communities and sometimes their homes, whilst men struggled with substance use and a lack of social support. Older patients relied on small income grants often shared with others, whilst younger patients struggled to find stable employment and combine self-management with family responsibilities. Precariousness impacted access to health services and information and peoples' ability to buy healthy foods and out-of-pocket medication, thus increasing their treatment burden and reducing their capacity. Conclusion: This study highlights that precariousness reduces the capacity and increases treatment burden for patients with multimorbidity in low-income settings in South Africa. Precariousness is both accumulative and cyclic, as financial insecurity impacts every aspect of peoples' daily lives. Findings emphasise that current models examining treatment burden need to be adapted to accommodate patients' experiences in low-income settings and address cumulative precariousness. Understanding treatment burden and capacity for patients in LMICs is a crucial first step to redesign health systems which aim to improve self-management and offer comprehensive person-centred care.

Using qualitative study designs to understand treatment burden and capacity for self-care among patients with HIV/NCD multimorbidity in South Africa: A methods paper.

Background: Low- and middle-income countries (LMICs), including South Africa, are currently experiencing multiple epidemics: HIV and the rising burden of non-communicable diseases (NCDs), leading to different patterns of multimorbidity (the occurrence of two or more chronic conditions) than experienced in high income settings. These adversely affect health outcomes, increase patients' perceived burden of treatment, and impact the workload of self-management. This paper outlines the methods used in a qualitative study exploring burden of treatment among people living with HIV/NCD multimorbidity in South Africa. Methods: We undertook a comparative qualitative study to examine the interaction between individuals' treatment burden (self-management workload) and their capacity to take on this workload, using the dual lenses of Burden of Treatment Theory (BoTT) and Cumulative Complexity Model (CuCoM) to aid conceptualisation of the data. We interviewed 30 people with multimorbidity and 16 carers in rural Eastern Cape and urban Cape Town between February-April 2021. Data was analysed through framework analysis. Findings: This paper discusses the methodological procedures considered when conducting qualitative research among people with multimorbidity in low-income settings in South Africa. We highlight the decisions made when developing the research design, recruiting participants, and selecting field-sites. We also explore data analysis processes and reflect on the positionality of the research project and researchers. Conclusion: This paper illustrates the decision-making processes conducting this qualitative research and may be helpful in informing future research aiming to qualitatively investigate treatment burden among patients in LMICs.

A Prolonged Treatment Associated With Absent Septum Pellucidum in Neonatal Abstinence Syndrome: A Case Report.

Neonatal abstinence syndrome (NAS) involves a widely variable treatment course among affected individuals. Prognostic indicators that would help predict length of hospital stay and individualize treatment would be valuable to newborns, parents, and hospital staff, including advanced practice registered nurses. We describe a newborn with a prolonged NAS treatment course necessitating high doses of opioids and phenobarbital, found to have an isolated absent septum pellucidum (ASP). We hypothesize a mechanism for an association between an ASP and a difficult NAS treatment course. Should this be substantiated by other cases, it could provide a valuable prognosticator and indicate alternate treatment pathways.

A dolabralexin-deficient mutant provides insight into specialized diterpenoid metabolism in maize.

Two major groups of specialized metabolites in maize (Zea mays), termed kauralexins and dolabralexins, serve as known or predicted diterpenoid defenses against pathogens, herbivores, and other environmental stressors. To consider the physiological roles of the recently discovered dolabralexin pathway, we examined dolabralexin structural diversity, tissue-specificity, and stress-elicited production in a defined biosynthetic pathway mutant. Metabolomics analyses support a larger number of dolabralexin pathway products than previously known. We identified dolabradienol as a previously undetected pathway metabolite and characterized its enzymatic production. Transcript and metabolite profiling showed that dolabralexin biosynthesis and accumulation predominantly occur in primary roots and show quantitative variation across genetically diverse inbred lines. Generation and analysis of CRISPR-Cas9-derived loss-of-function Kaurene Synthase-Like 4 (Zmksl4) mutants demonstrated dolabralexin production deficiency, thus supporting ZmKSL4 as the diterpene synthase responsible for the conversion of geranylgeranyl pyrophosphate precursors into dolabradiene and downstream pathway products. Zmksl4 mutants further display altered root-to-shoot ratios and root architecture in response to water deficit. Collectively, these results demonstrate dolabralexin biosynthesis via ZmKSL4 as a committed pathway node biochemically separating kauralexin and dolabralexin metabolism, and suggest an interactive role of maize dolabralexins in plant vigor during abiotic stress.

Prior Spontaneous or Induced Abortion Is a Risk Factor for Cervical Dysfunction in Pregnant Women: a Systematic Review and Meta-analysis.

A history of abortion is associated with cervical dysfunction during pregnancy, but there remains uncertainty about whether risk can be stratified by the abortion type, the abortion procedure, or number of previous abortions. The objective of this study was to verify the relationship between cervical dysfunction measures in pregnancies with and without a history of termination. Embase and Medline databases were searched from 01 January 1960 to 01 March 2022 resulting in a full-text review of 28 studies. The Newcastle-Ottawa Scale (NOS) was used to assess the quality and risk of bias for non-randomized studies. The meta-analysis consisted of 6 studies that met all inclusion and exclusion criteria and included a combined total of 2,513,044 pregnancies. Cervical dysfunction was defined as either cervical insufficiency/incompetence in 4 of the studies and as short cervix in the others. Results from a random-effects model using reported adjusted odds ratios (aOR) estimated an increase in the odds of 2.71 (95% CI 1.76, 4.16) for cervical dysfunction in the current pregnancy related to a history of induced or spontaneous abortion. Subgroup analyses with only induced abortions (surgical/medical) estimated an aOR of 2.54 (95% CI 1.41, 4.57), while studies limited to surgical abortions had an aOR of 4.08 (95% CI 2.84, 5.86). The risk of cervical dysfunction in the current pregnancy was also found to be dependent on the number of previous abortions. In this meta-analysis, a prior history of abortion, and specifically induced abortions, was associated with cervical dysfunction. The protocol was registered in PROSPERO (CRD42020209723).

Co-design of a behaviour change intervention to equip geriatricians and pharmacists to proactively deprescribe medicines that are no longer needed or are risky to continue in hospital.

BACKGROUND: Trials of hospital deprescribing interventions have demonstrated limited changes in practitioner behaviour. Our previous research characterised four barriers and one enabler to geriatricians and pharmacists deprescribing in hospital that require addressing by a behaviour change intervention. Six behaviour change techniques (BCTs) have also been selected by the target audience using the hospital Deprescribing Implementation Framework (hDIF). This research aimed to co-design and operationalise the content, mode of delivery and duration/intensity of the six selected BCTs to develop the CompreHensive geriAtRician-led MEdication Review (CHARMER) deprescribing intervention. METHODS: We established co-design panels at three hospitals representing contextual factors likely to influence CHARMER implementation. Panels comprised geriatricians, pharmacists and other hospital staff likely to be involved in implementation. We convened two rounds of co-design workshops with each hospital to design a prototype for each BCT, which went for feedback at a final workshop attended by all three hospital panels. RESULTS: The six BCTs were co-designed into an intervention comprising:(1&2) Pharmacists' workshop with pros and cons of deprescribing activities, and videos of salient patient cases3 Regular geriatrician and pharmacist deprescribing briefings4 Videos of geriatricians navigating challenging deprescribing consultations5 Hospital deprescribing action plan6 Dashboard to benchmark deprescribing activitiesAutomated prompts to flag high-risk patients for deprescribing and a primary and secondary care deprescribing forum were proposed as additional BCTs by stakeholders. These were later excluded as they were not fidelitous to the theoretical determinants of geriatricians' and pharmacists' deprescribing behaviours. CONCLUSIONS: This study illustrates the integration of theory and co-design methodology with the target audience and staff likely to be involved in implementation of a hospital deprescribing behaviour change intervention. The development of an intervention that remains faithful to the underpinning mechanisms of action of behaviour change is a strength of this approach.