Scribble Deficiency Promotes Pancreatic Ductal Adenocarcinoma Development and Metastasis.

Perturbation of cell polarity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) progression. Scribble (SCRIB) is a well characterized polarity regulator that has diverse roles in the pathogenesis of human neoplasms. To investigate the impact of SCRIB deficiency on PDAC development and progression, Scrib was genetically ablated in well-established mouse models of PDAC. Scrib loss in combination with KrasG12D did not influence development of pancreatic intraepithelial neoplasms (PanIN) in mice. However, Scrib deletion cooperated with KrasG12D and concomitant Trp53 heterozygous deletion to promote invasive PDAC and metastatic dissemination, leading to reduced overall survival. Immunohistochemical and transcriptome analyses revealed that Scrib-null tumors display a pronounced reduction of collagen content and cancer associated fibroblast (CAF) abundance. Mechanistically, interleukin 1α (IL1α) levels were reduced in Scrib deficient tumors, and Scrib knockdown downregulated IL1α in mouse PDAC organoids (mPDOs), which impaired CAF activation. Furthermore, Scrib loss increased YAP activation in mPDOs and established PDAC cell lines, enhancing cell survival. Clinically, SCRIB expression was decreased in human PDAC, and SCRIB mislocalization was associated with poorer patient outcome. These results indicate that SCRIB deficiency enhances cancer cell survival and remodels the tumor microenvironment to accelerate PDAC development and progression, establishing the tumor suppressor function of SCRIB in advanced pancreatic cancer.

Mapping the cited evidence of ductal carcinoma in situ from the 5th edition of the World Health Organisation classification of tumours of the breast.

AIMS: Ductal carcinoma in situ (DCIS) is recognised by the World Health Organisation (WHO) Classification of Tumours (WCT) as a non-invasive neoplastic epithelial proliferation confined to the mammary ducts and lobules. This report categorises the references cited in the DCIS chapter of the 5th edition of the WCT (Breast Tumours) according to prevailing evidence levels for evidence-based medicine and the Hierarchy of Evidence for Tumour Pathology (HETP), identifying potential gaps that can inform subsequent editions of the WCT for this tumour. METHODS AND RESULTS: We included all citations from the DCIS chapter of the WCT (Breast Tumours, 5th edition). Each citation was appraised according to its study design and evidence level. We developed our map of cited evidence, which is a graphical matrix of tumour type (column) and tumour descriptors (rows). Spheres were used to represent the evidence, with size and colour corresponding to their number and evidence level respectively. Thirty-six publications were retrieved. The cited literature in the DCIS chapter comprised mainly case series and were regarded as low-level. We found an unequal distribution of citations among tumour descriptors. 'Pathogenesis' and 'prognosis and prediction' contained the most references, while 'clinical features', 'aetiology' and 'diagnostic molecular pathology' had only a single citation each. 'Prognosis and prediction' had the greatest proportion of moderate- and high-levels of evidence. CONCLUSION: Our findings align with the disposition for observational studies inherent in the field of pathology. Our map is a springboard for future efforts in mapping all available evidence on DCIS, potentially augmenting the editorial process and future editions of WCTs.

Effect of 48 Months of Closed-Loop Insulin Delivery on Residual C-Peptide Secretion and Glycemic Control in Newly Diagnosed Youth With Type 1 Diabetes: A Randomized Trial.

OBJECTIVE: We evaluated the effect of long-term intensive metabolic control with hybrid closed-loop (CL) on residual C-peptide secretion and glucose control compared with standard insulin therapy in youth with type 1 diabetes over 48 months. RESEARCH DESIGN AND METHODS: Following the 24-month primary phase of a multicenter, randomized, parallel trial of 96 newly diagnosed youth aged 10 to 16.9 years, participants were invited to an extension phase using treatment allocated at randomization. They continued with hybrid CL using the Cambridge algorithm or standard insulin therapy (control) until 48 months after diagnosis. Analysis was by intention-to-treat. RESULTS: At 24 months after diagnosis, 81 participants (mean ± SD age 14 ± 2 years) continued in the extension phase (47 CL, 34 control). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 5 ± 9 vs. control: 6 ± 14 pmol/L per mmol/L; mean adjusted difference -2 [95% CI -7, 4; P = 0.54]). Central laboratory HbA1c remained lower in the CL group by 0.9% (10 mmol/mol [95% CI 0.2, 1.5; 3, 17 mmol/mol); P = 0.009). Time in target range of 3.9 to 10.0 mmol/L was 12 percentage points (95% CI 3, 20; P = 0.008) higher in the CL group compared with control. There were 11 severe hypoglycemic events (6 CL, 5 control) and 7 diabetic ketoacidosis events (3 CL, 4 control) during the extension phase. CONCLUSIONS: Improved glycemic control was sustained over 48 months after diagnosis with CL insulin delivery compared with standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion.

Moving Forward on Tumor Pathology Research Reporting: A Guide for Pathologists From the World Health Organization Classification of Tumors Living Evidence Gap Map by Tumour Type Group.

Evidence-based medicine (EBM) can be an unfamiliar territory for those working in tumor pathology research, and there is a great deal of uncertainty about how to undertake an EBM approach to planning and reporting histopathology-based studies. In this article, reviewed and endorsed by the Word Health Organization International Agency for Research on Cancer's International Collaboration for Cancer Classification and Research, we aim to help pathologists and researchers understand the basics of planning an evidence-based tumor pathology research study, as well as our recommendations on how to report the findings from these. We introduce some basic EBM concepts, a framework for research questions, and thoughts on study design and emphasize the concept of reporting standards. There are many study-specific reporting guidelines available, and we provide an overview of these. However, existing reporting guidelines perhaps do not always fit tumor pathology research papers, and hence, here, we collate the key reporting data set together into one generic checklist that we think will simplify the task for pathologists. The article aims to complement our recent hierarchy of evidence for tumor pathology and glossary of evidence (study) types in tumor pathology. Together, these articles should help any researcher get to grips with the basics of EBM for planning and publishing research in tumor pathology, as well as encourage an improved standard of the reports available to us all in the literature.

Long-term assessment of the NHS hybrid closed-loop real-world study on glycaemic outcomes, time-in-range, and quality of life in children and young people with type 1 diabetes.

Hybrid closed-loop (HCL) systems seamlessly interface continuous glucose monitoring (CGM) with insulin pumps, employing specialised algorithms and user-initiated automated insulin delivery. This study aimed to assess the efficacy of HCLs at 12 months post-initiation on glycated haemoglobin (HbA1c), time-in-range (TIR), hypoglycaemia frequency, and quality of life measures among children and young people (CYP) with type 1 diabetes mellitus (T1DM) and their caregivers in a real-world setting. Conducted between August 1, 2021, and December 10, 2022, the prospective recruitment took place in eight paediatric diabetes centres across England under the National Health Service England's (NHSE) HCL pilot real-world study. A cohort of 251 CYP (58% males, mean age 12.3 years) with T1DM participated (89% white, 3% Asian, 4% black, 3% mixed ethnicity, and 1% other). The study utilised three HCL systems: (1) Tandem Control-IQ AP system, which uses the Tandem t:slim X2 insulin pump (Tandem Diabetes Care, San Diego, CA, USA) with the Dexcom G6® CGM (Dexcom, San Diego, CA, USA) sensor; (2) Medtronic MiniMed™ 780G with the Guardian 4 sensor (Medtronic, Northridge, CA, USA); and (3) the CamAPS FX (CamDiab, Cambridge, UK) with the Ypsomed insulin pump (Ypsomed Ltd, Escrick, UK) and Dexcom G6® CGM.All systems were fully funded by the NHS. Results demonstrated significant improvements in HbA1c (average reduction at 12 months 7 mmol/mol; P < 0.001), time-in-range (TIR) (average increase 13.4%; P < 0.001), hypoglycaemia frequency (50% reduction), hypoglycaemia fear, and quality of sleep (P < 0.001) among CYP over a 12-month period of HCL usage. Additionally, parents and carers experienced improvements in hypoglycaemia fear and quality of sleep after 6 and 12 months of use. In addition to the improvements in glycaemic management, these findings underscore the positive impact of HCL systems on both the well-being of CYP with T1DM and the individuals caring for them.

PROTOCOL: Methods used in the development, production and updating of evidence and gap maps: A scoping review.

Evidence and gap maps (EGMs) are an increasinly popular approach used in evidence synthesis. As an approach they address broad research questions, describing the existing evidence base, highlighting evidence gaps and providing an interactive visual tool for knowledge users. The purpose of this methodological study is to explore the the processes used in the development of EGM's and how they are reported. The aim is to better understand current practice and identify where clearer guidance is needed to support their production.

Diabetic Ketoacidosis at Onset of Type 1 Diabetes and Glycemic Outcomes with Closed-Loop Insulin Delivery.

The presence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) is associated with higher glycated hemoglobin levels over time. We evaluated whether hybrid-closed loop (HCL) therapy from onset of T1D could prevent the adverse impact of DKA at diagnosis on long-term glycemic outcomes. This was a posthoc analysis from 51 adolescents using HCL from diagnosis of T1D as part of the CLOuD trial (NCT02871089). We compared glycemic and insulin metrics between adolescents with (n = 17) and without (n = 34) DKA at diagnosis. Participants with and without DKA at diagnosis had similar time in target glucose range 3.9-10.0 mmol/L (70-180 mg/dL), time below range (<3.9 mmol/L, <70 mg/dL) and HbA1c at 6, 12, and 24 months. While insulin requirements at 6 months were higher in those with DKA at diagnosis, this was not statistically significant after adjusting for bodyweight. Residual C-peptide secretion was similar between groups. We conclude that HCL therapy may mitigate against the negative glycemic effects of DKA at T1D diagnosis.

The aetiology of fracture and nonunion in the hook of the hamate.

Fractures of the hook of the hamate are traditionally thought to be caused by direct trauma. A review of the anatomy and function of the hamate hook suggests that fracture is more likely as a result of a fatigue response that develops in the hook from repetitive load applied by the adjacent deep flexor tendons. Additional vascular compromise, from direct pressure of the tendons on critical local vessels, reduces blood flow leading to both mechanical and vascular effects that create pathological osseous change and weakening. These changes are likely to predispose to stress fracture and nonunion in repetitive gripping activities and are consistent with radiological findings.

Cost-Effectiveness of Closed-Loop Automated Insulin Delivery Using the Cambridge Hybrid Algorithm in Children and Adolescents with Type 1 Diabetes: Results from a Multicenter 6-Month Randomized Trial.

BACKGROUND/OBJECTIVE: The main objective of this study is to evaluate the incremental cost-effectiveness (ICER) of the Cambridge hybrid closed-loop automated insulin delivery (AID) algorithm versus usual care for children and adolescents with type 1 diabetes (T1D). METHODS: This multicenter, binational, parallel-controlled trial randomized 133 insulin pump using participants aged 6 to 18 years to either AID (n = 65) or usual care (n = 68) for 6 months. Both within-trial and lifetime cost-effectiveness were analyzed. Analysis focused on the treatment subgroup (n = 21) who received the much more reliable CamAPS FX hardware iteration and their contemporaneous control group (n = 24). Lifetime complications and costs were simulated via an updated Sheffield T1D policy model. RESULTS: Within-trial, both groups had indistinguishable and statistically unchanged health-related quality of life, and statistically similar hypoglycemia, severe hypoglycemia, and diabetic ketoacidosis (DKA) event rates. Total health care utilization was higher in the treatment group. Both the overall treatment group and CamAPS FX subgroup exhibited improved HbA1C (-0.32%, 95% CI: -0.59 to -0.04; P = .02, and -1.05%, 95% CI: -1.43 to -0.67; P < .001, respectively). Modeling projected increased expected lifespan of 5.36 years and discounted quality-adjusted life years (QALYs) of 1.16 (U.K. tariffs) and 1.52 (U.S. tariffs) in the CamAPS FX subgroup. Estimated ICERs for the subgroup were £19 324/QALY (United Kingdom) and -$3917/QALY (United States). For subgroup patients already using continuous glucose monitors (CGM), ICERs were £10 096/QALY (United Kingdom) and -$33 616/QALY (United States). Probabilistic sensitivity analysis generated mean ICERs of £19 342/QALY (95% CI: £15 903/QALY to £22 929/QALY) (United Kingdom) and -$28 283/QALY (95% CI: -$59 607/QALY to $1858/QALY) (United States). CONCLUSIONS: For children and adolescents with T1D on insulin pump therapy, AID using the Cambridge algorithm appears cost-effective below a £20 000/QALY threshold (United Kingdom) and cost saving (United States).

Rapid reviews methods series: guidance on rapid qualitative evidence synthesis.

This paper forms part of a series of methodological guidance from the Cochrane Rapid Reviews Methods Group and addresses rapid qualitative evidence syntheses (QESs), which use modified systematic, transparent and reproducible methodsu to accelerate the synthesis of qualitative evidence when faced with resource constraints. This guidance covers the review process as it relates to synthesis of qualitative research. 'Rapid' or 'resource-constrained' QES require use of templates and targeted knowledge user involvement. Clear definition of perspectives and decisions on indirect evidence, sampling and use of existing QES help in targeting eligibility criteria. Involvement of an information specialist, especially in prioritising databases, targeting grey literature and planning supplemental searches, can prove invaluable. Use of templates and frameworks in study selection and data extraction can be accompanied by quality assurance procedures targeting areas of likely weakness. Current Cochrane guidance informs selection of tools for quality assessment and of synthesis method. Thematic and framework synthesis facilitate efficient synthesis of large numbers of studies or plentiful data. Finally, judicious use of Grading of Recommendations Assessment, Development and Evaluation approach for assessing the Confidence of Evidence from Reviews of Qualitative research assessments and of software as appropriate help to achieve a timely and useful review product.

Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8+ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.

Advancing the methodology of mapping reviews: A scoping review.

This scoping review aims to identify and systematically review published mapping reviews to assess their commonality and heterogeneity and determine whether additional efforts should be made to standardise methodology and reporting. The following databases were searched; Ovid MEDLINE, Embase, CINAHL, PsycINFO, Campbell collaboration database, Social Science Abstracts, Library and Information Science Abstracts (LISA). Following a pilot-test on a random sample of 20 citations included within title and abstracts, two team members independently completed all screening. Ten articles were piloted at full-text screening, and then each citation was reviewed independently by two team members. Discrepancies at both stages were resolved through discussion. Following a pilot-test on a random sample of five relevant full-text articles, one team member abstracted all the relevant data. Uncertainties in the data abstraction were resolved by another team member. A total of 335 articles were eligible for this scoping review and subsequently included. There was an increasing growth in the number of published mapping reviews over the years from 5 in 2010 to 73 in 2021. Moreover, there was a significant variability in reporting the included mapping reviews including their research question, priori protocol, methodology, data synthesis and reporting. This work has further highlighted the gaps in evidence synthesis methodologies. Further guidance developed by evidence synthesis organisations, such as JBI and Campbell, has the potential to clarify challenges experienced by researchers, given the magnitude of mapping reviews published every year.

Streamlining search methods to update evidence and gap maps: A case study using intergenerational interventions.

Background: Evidence and Gap Maps (EGMs) should be regularly updated. Running update searches to find new studies for EGMs can be a time-consuming process. Search Summary Tables (SSTs) can help streamline searches by identifying which resources were most lucrative for identifying relevant articles, and which were redundant. The aim of this study was to use an SST to streamline search methods for an EGM of studies about intergenerational activities. Methods: To produce the EGM, 15 databases were searched. 8638 records were screened and 500 studies were included in the final EGM. Using an SST, we determined which databases and search methods were the most efficient in terms of sensitivity and specificity for finding the included studies. We also investigated whether any database performed particularly well for returning particular study types. For the best performing databases we analysed the search terms used to streamline the strategies. Results: No single database returned all of the studies included in the EGM. Out of 500 studies PsycINFO returned 40% (n = 202), CINAHL 39% (n = 194), Ageline 25% (n = 174), MEDLINE 23% (n = 117), ERIC 20% (n = 100) and Embase 19% (n = 98). HMIC database and Conference Proceedings Citation Index-Science via Web of Science returned no studies that were included in the EGM. ProQuest Dissertations & Theses (PQDT) returned the highest number of unique studies (n = 42), followed by ERIC (n = 33) and Ageline (n = 29). Ageline returned the most randomised controlled trials (42%) followed by CINAHL (34%), MEDLINE (29%) and CENTRAL (29%). CINAHL, Ageline, MEDLINE and PsycINFO performed the best for locating systematic reviews. (62%, 46% and 42% respectively). CINAHL, PsycINFO and Ageline performed best for qualitative studies (41%, 40% and 34%). The Journal of Intergenerational Relationships returned more included studies than any other journal (16%). No combinations of search terms were found to be better in terms of balancing specificity and sensitivity than the original search strategies. However, strategies could be reduced considerably in terms of length without losing key, unique studies. Conclusion: Using SSTs we have developed a method for streamlining update searches for an EGM about intergenerational activities. For future updates we recommend that MEDLINE, PsycINFO, ERIC, Ageline, CINAHL and PQDT are searched. These searches should be supplemented by hand-searching the Journal of Intergenerational Relationships and carrying out backwards citation chasing on new systematic reviews. Using SSTs to analyse database efficiency could be a useful method to help streamline search updates for other EGMs.

A New Hierarchy of Research Evidence for Tumor Pathology: A Delphi Study to Define Levels of Evidence in Tumor Pathology.

The hierarchy of evidence is a fundamental concept in evidence-based medicine, but existing models can be challenging to apply in laboratory-based health care disciplines, such as pathology, where the types of evidence and contexts are significantly different from interventional medicine. This project aimed to define a comprehensive and complementary framework of new levels of evidence for evaluating research in tumor pathology-introducing a novel Hierarchy of Research Evidence for Tumor Pathology collaboratively designed by pathologists with help from epidemiologists, public health professionals, oncologists, and scientists, specifically tailored for use by pathologists-and to aid in the production of the World Health Organization Classification of Tumors (WCT) evidence gap maps. To achieve this, we adopted a modified Delphi approach, encompassing iterative online surveys, expert oversight, and external peer review, to establish the criteria for evidence in tumor pathology, determine the optimal structure for the new hierarchy, and ascertain the levels of confidence for each type of evidence. Over a span of 4 months and 3 survey rounds, we collected 1104 survey responses, culminating in a 3-day hybrid meeting in 2023, where a new hierarchy was unanimously agreed upon. The hierarchy is organized into 5 research theme groupings closely aligned with the subheadings of the WCT, and it consists of 5 levels of evidence-level P1 representing evidence types that merit the greatest level of confidence and level P5 reflecting the greatest risk of bias. For the first time, an international collaboration of pathology experts, supported by the International Agency for Research on Cancer, has successfully united to establish a standardized approach for evaluating evidence in tumor pathology. We intend to implement this novel Hierarchy of Research Evidence for Tumor Pathology to map the available evidence, thereby enriching and informing the WCT effectively.

Revision of Failed Nonanatomic Extensor Retinacular Stabilization of the Unstable ECU Tendon: Surgical Technique and Case Series.

Nonanatomic surgical stabilization of the unstable extensor carpi ulnaris (ECU) tendon (where the subluxing tendon is re-routed away from the bony groove in the distal ulna) utilizes a flap of extensor retinaculum to create a new retaining sheath that will stabilize the tendon during forearm rotation movements. When this surgery fails, the extensor retinaculum tissue does not regenerate with sufficient structural strength to be used again. Previously, a different approach has then been needed for revision surgery, often using more complex surgical techniques with a substantially greater impact on recovery. We describe a highly reliable yet simple method of using local soft tissue to adequately restabilize the subluxing ECU tendon in cases where an extensor retinacular flap has already been used. We report the results of this technique in 4 patients, all of whom returned to jobs/hobbies where ECU instability was a considerable functional risk.

Association between stress, depression or anxiety and cancer: Rapid review of reviews.

Background: Several studies have suggested links between psychological stress, depression or anxiety, and cancer incidence or outcomes. Existing systematic reviews have addressed this question, with differing results. Aims: This rapid systematic umbrella review summarises existing reviews assessing the association between psychological stress, depression or anxiety and cancer incidence or cancer outcomes. Methods: Systematic reviews assessing stress, depression or anxiety and cancer were identified via searches of MEDLINE, PsycInfo and Cochrane Database of Systematic Reviews from 2010 to November 2020. Results: Twelve systematic reviews were included, summarising cohort and case-control studies, most of which adjusted for confounders. Regarding cancer incidence, one large meta-analysis reported a significant association between depression/anxiety and cancer incidence, while another showed a non-significant trend. Two further meta-analyses reported significant associations between stressful life events and cancer incidence. Conversely, two meta-analyses of work stress showed no significant association with cancer incidence. Regarding outcomes among cancer patients, three meta-analyses reported significant associations between depression/anxiety and cancer mortality, while another reported a non-significant trend for depression and cancer recurrence. One meta-analysis reported a significant association between partner bereavement and cancer mortality, while another showed no significant association between work stress and cancer mortality. Conclusions: There is consistent evidence for an association between psychological stress, depression or anxiety and cancer incidence in general populations, and some evidence for an association with mortality in cancer populations. Future research may focus on confirmation of these findings, as well as the role of social support and stress-reducing interventions in buffering against these effects.