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Objectives Diabetes mellitus is a chronic disease that entails significant burdens to patients, caregivers and society at large. While self-management behaviours like healthy eating and monitoring of blood glucose help to reduce the care burden, they are still perceived to be burdensome. Mobile applications have emerged as promising digital tools in helping patients to self-manage their conditions. We conducted systematic review to explore the perceptions and experiences of adults with types 1, 2 and gestational diabetes using mobile applications for self-management in diabetes.Design A systematic review of published primary studies exploring perceptions and experiences of adults living with types 1, 2 and gestational diabetes who used/have used mobile applications for self-management. The study was reported following the best practice guidelines defined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.Data sources We searched for articles published from January 2007 to December 2023 via MEDLINE (Ovid), Embase (Elsevier), CINAHL (Ovid) and Scopus (Elsevier).Eligibility criteria Primary qualitative studies that describe the perceptions and experiences of adults in using mobile applications in self-management of types 1, 2 and gestational diabetes published between January 2007 and December 2023.Data extraction and synthesis Two independent reviewers screened identified papers for eligibility, extracted data using a pre-defined data extraction form and applied the Critical Appraisal Skills Program tool to appraise the quality of the included studies. Data were narratively synthesised, guided by the ‘unified theory of acceptance and use of technology (UTAUT)’ framework.Results A total of 24 qualitative studies deploying interviews and surveys with open-ended questions were included in the review. We identified four major themes, which were mapped against the constructs of the ‘UTAUT’ framework: ‘performance expectancy’, ‘effort expectancy’, ‘social influence’ and ‘facilitating conditions’.More than 50% of the studies described favourable app features relating to monitoring blood glucose, diet and exercise while also emphasising the importance of customising these to patient needs. About 40% of the studies described unfavourable aspects related to uploading of excessive information, monitoring device incompatibility, episodic app crashes and telephone handling issues.Conclusion The review supports the favourable view of mobile applications as promising tools in helping patients with diabetes to self-manage. However, the challenges on the ease of use and non-customised features of the apps potentially hinder patients’ long-term engagement.

In Japan, the term shūkatsu—referred as the planning for later life and for the afterlife—has gained popularity due to high amount of mass media exposure in recent years. This paper examines shūkatsu from the active aging framework, contending that shūkatsu is an important activity that contributes to active aging, as the process of conscientious planning encourages older Japanese people to remain active. Data for this study were obtained from qualitative interviews that were conducted with 40 older middle-class Japanese citizens residing in Nagoya. Explored through a life course perspective, the study examined how salient factors, such as personal history, experiences, roles, anxieties, life-changing events, and cultural practices, have influenced older Japanese people in their shūkatsu decision-making process. In the process of understanding how the Japanese respond to changing family relationships and sociocultural transformations, the emphasis on living a “good old age” for better social, psychological, and physical well-being strongly reflects the agency to age actively. In a super-aged Japan, shūkatsu may be a vital strategy that not only ensures a better quality of life for the older population and their children, but it also contributes to individual’s sense of usefulness and satisfaction, as they are actively involved in the planning and management of their own later and afterlife choices.

Abstract Background The operating room (OR) of the hospital is a special unit that requires a relatively clean environment. The microbial concentration of an indoor OR extrinsically influences surgical site infection rates. The aim of this study was to use active sampling methods to assess microbial colony counts in working ORs and to determine the factors affecting air contamination in a tertiary referral medical center. Methods This study was conducted in 28 operating rooms located in a 3000-bed medical center in northern Taiwan. The microbiologic air counts were measured using an impactor air sampler from May to August 2015. Information about the procedure-related operative characteristics and surgical environment (environmental- and personnel-related factors) characteristics was collected. Results A total of 250 air samples were collected during surgical procedures. The overall mean number of bacterial colonies in the ORs was 78 ± 47 cfu/m3. The mean number of colonies was the highest for transplant surgery (123 ± 60 cfu/m3), followed by pediatric surgery (115 ± 30.3 cfu/m3). A total of 25 samples (10%) contained pathogens; Coagulase-negative staphylococcus (n = 12, 4.8%) was the most common pathogen. After controlling for potentially confounding factors by a multiple regression analysis, the surgical stage had the significantly highest correlation with bacterial counts (r = 0.346, p

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats., Competing Interests: Declarations. Ethics approval and consent to participate: Not Applicable. Consent for publication: We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all the authors. All figures are original and were drawn using BioRender by the authors for this review. Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work in this paper. M.H.A. is founder, shareholder and scientific advisor of IO Biotech ApS. LMC is a consultant for Evergreen Theragnostics. S.K. has consulted for Telix Pharmaceuticals Ltd., acknowledges support for investigator services from RayzeBio and holds the following patent: PCT/US2021/039418 (THOR cell (tumor homing radio-emitting cell)., (© 2025. The Author(s).)

Background: Gastric intestinal metaplasia (IM) is a precancerous stage spanning a morphological spectrum that is poorly represented by human cell line models., Objective: We aim to establish and characterise human IM cell models to better understand IM progression along the cancer spectrum., Design: A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established. Comprehensive multi-omics profiling and functional characterisation were performed., Results: Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation. Their lineage trajectories connected different cycling and quiescent stem and progenitors, highlighting differences in gastric to IM transition and the potential origin of IM from STMN1 cycling isthmus stem cells. Hybrid IMOs showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates and reactivation of a fetal gene programme.Cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature. Genomically, IMOs showed elevated mutation burden, frequent chromosome 20 gain and epigenetic deregulation of many intestinal and gastric genes. Functionally, IMOs were FGF10 independent and showed downregulated FGFR2. Several IMOs exhibited a cell-matrix adhesion independent subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, potentially representing the earliest neoplastic precursor of IM-induced gastric cancer., Conclusions: Overall, our IMO biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention., Competing Interests: Competing interests: SYL and STY have received research sponsorships from Pfizer, Merck, Servier. HC is an inventor on multiple patents related to organoid technology and one patent on a Matrigel replacement. He is also currently head of Roche’s R&D in Basel, as a member of the executive board. His full disclosures can be found on the following website: www.uu.nl/staff/JCClevers/Additional functions. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

BackgroundMaintaining durable immunity following vaccination represents a major challenge, but whether mRNA booster vaccination improves durability is unknown.MethodsWe measured antibody responses in 55 healthy adults, who received a booster dose of the Pfizer-BioNTech or Moderna vaccine against SARS-CoV-2 and calculated the half-life of the antibody titers. We also measured memory B and T cell responses in a subset of 28 participants. In 13 volunteers who received a second booster vaccine, we measured serum antibody titers and memory B and T cell responses.ResultsThe booster (third immunization) dose at 6 to 10 months increased the half-life of the serum-neutralizing antibody (nAb) titers to 76 days from 56 to 66 days after the primary 2-dose vaccination. A second booster dose (fourth immunization) a year after the primary vaccination further increased the half-life to 88 days. However, despite this modestly improved durability in nAb responses against the ancestral (WA.1) strain, there was a loss of neutralization capacity against the Omicron subvariants BA.2.75.2, BQ.1.1, and XBB.1.5 (48-, 71-, and 66-fold drop in titers, respectively, relative to the WA.1 strain). Although only 45% to 65% of participants demonstrated a detectable nAb titer against the newer variants after the booster (third dose), the response declined to below the detection limit in almost all individuals by 6 months. In contrast, booster vaccination induced antigen-specific memory B and T cells that persisted for at least 6 months.ConclusionThe durability of serum antibody responses improves only marginally following booster immunizations with the Pfizer-BioNTech or Moderna mRNA vaccines.

Objective: Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells., Design: We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence., Results: 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively., Conclusions: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity., Competing Interests: Competing interests: SYL and STY have received research sponsorships from Pfizer, Merck, Servier. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Waning immunity to vaccination represents a major challenge in vaccinology. Whether booster vaccination improves the durability of immune responses is unknown. Here we show, using a cohort of 55 adult vaccinees who received the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine against SARS-CoV-2, that a booster (i.e., 3 rd immunization) dose at 6 - 10 months increased the half-life of serum neutralizing antibody (nAb) titers to 76 days from 56 - 66 days estimated after the primary two-dose vaccination series. A second booster dose (i.e., 4 th immunization) more than a year after the primary vaccination increased the half-life further to 88 days. However, despite this modestly improved durability in nAb responses against the Wuhan strain, there was a loss in neutralization capacity against Omicron subvariants, especially the recently emerged variants, BA.2.75.2 and BQ.1.1 (35 and 50-fold drop in titers respectively, relative to the ancestral (WA.1) strain. While only 55 â€" 65% of participants demonstrated a detectable nAb titer against the newer variants after the booster (3 rd dose), the response declined to below the detection limit in almost all individuals by 6 months. Notably, even against BA.1 and BA.5, the titers declined rapidly in a third of the vaccinees and were below the detection limit at 6 months. In contrast, booster vaccination induced antigen-specific memory B and T cells that persisted for at least 6 months. Collectively, our data show that the durability of immune responses improves following subsequent booster immunizations; however, the emergence of immune evasive variants reduces the effectiveness of booster doses in preventing infection.

Objective: Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs., Design: We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed., Results: We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2 , but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time., Conclusions: These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity., Competing Interests: Competing interests: SYL and STY have received research sponsorship from Pfizer, Merck, Servier and Curegenix. HC is an inventor on several patents relating to Wnt activity in cancers and a pending patent on growing organoids from patients with colorectal cancer. He is a cofounder and SAB member of Surrozen, a start-up in Silicon Valley; a SAB member of Kallyope (New York), Merus (Utrecht) and Decibel (Boston); a non-executive board member of Roche (Basel) and SAB member of the Roche subsidiary Genentech (San Francisco) since 2019; a scientific advisor for and investor in Life Sciences Partners, a biotech venture capital firm located in Amsterdam., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Amyotrophic lateral sclerosis (ALS) presents with focal muscle weakness due to motor neuron degeneration that becomes generalized, leading to death from respiratory failure within 3-5 years from symptom onset. Despite the heterogeneity of aetiology, TDP-43 proteinopathy is a common pathological feature that is observed in >95% of ALS and tau-negative frontotemporal dementia (FTD) cases. TDP-43 is a DNA/RNA-binding protein that in ALS and FTD translocates from being predominantly nuclear to form detergent-resistant, hyperphosphorylated aggregates in the cytoplasm of affected neurons and glia. Mutations in TARDBP account for 1-4% of all ALS cases and almost all arise in the low complexity C-terminal domain that does not affect RNA binding and processing. Here we report an ALS/FTD kindred with a novel K181E TDP-43 mutation that is located in close proximity to the RRM1 domain. To offer predictive gene testing to at-risk family members, we undertook a series of functional studies to characterize the properties of the mutation. Spectroscopy studies of the K181E protein revealed no evidence of significant misfolding. Although it is unable to bind to or splice RNA, it forms abundant aggregates in transfected cells. We extended our study to include other ALS-linked mutations adjacent to the RRM domains that also disrupt RNA binding and greatly enhance TDP-43 aggregation, forming detergent-resistant and hyperphosphorylated inclusions. Lastly, we demonstrate that K181E binds to, and sequesters, wild-type TDP-43 within nuclear and cytoplasmic inclusions. Thus, we demonstrate that TDP-43 mutations that disrupt RNA binding greatly enhance aggregation and are likely to be pathogenic as they promote wild-type TDP-43 to mislocalize and aggregate acting in a dominant-negative manner. This study highlights the importance of RNA binding to maintain TDP-43 solubility and the role of TDP-43 aggregation in disease pathogenesis., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Starch consists of two types of molecules: amylose and amylopectin. The objective of this study was increase understanding about mechanisms related to starch accumulation in hulless barley (Hordeum vulgare L.) grain by measuring temporal changes in (i) grain amylose and amylopectin content, (ii) starch synthase activity, and (iii) the relative expressions of key starch-related genes., Results: The amylopectin/amylose ratio gradually declined in both Beiqing 6 and Kunlun 12. In both cultivars, the activities of adenosine diphosphate glucose pyrophosphorylase, soluble starch synthase (SSS), granule bound starch synthase (GBSS), and starch branching enzyme (SBE) increased steadily during grain filling, reaching their maximums 20-25 days after anthesis. The activities of SSS and SBE were greater in Ganken 5 than in either Beiqing 6 or Kunlun 12. The expression of GBSS I was greater in Beiqing 6 and Kunlun 12 than in Ganken 5. In contrast, the expression of SSS I, SSS II and SBE I was greater in Ganken 5 than in Beiqing 6 and Kunlun 12. The peak in GBSS I expression was later than that of SSS I, SSS II, SBE IIa and SBE IIb. The GBSS I transcript in Kunlun 12 was expressed on average 90 times more than the GBSS II transcript., Conclusions: The results suggest that SBE and SSS may control starch synthesis at the transcriptional level, whereas GBSS I may control starch synthesis at the post transcriptional level. GBSS I is mainly responsible for amylose synthesis whereas SSS I and SBE II are mainly responsible for amylopectin synthesis in amyloplasts.