Alternative translation initiation produces synaptic organizer proteoforms with distinct localization and functions.

While many mRNAs contain more than one translation initiation site (TIS), the functions of most alternative TISs and their corresponding protein isoforms (proteoforms) remain undetermined. Here, we showed that alternative usage of CUG and AUG TISs in neuronal pentraxin receptor (NPR) mRNA produced two proteoforms, of which the ratio was regulated by RNA secondary structure and neuronal activity. Downstream AUG initiation truncated the N-terminal transmembrane domain and produced a secreted NPR proteoform sufficient in promoting synaptic clustering of AMPA-type glutamate receptors. Mutations that altered the ratio of NPR proteoforms reduced AMPA receptors in parvalbumin-positive interneurons and affected learning behaviors in mice. In addition to NPR, upstream AUU-initiated N-terminal extension of C1q-like synaptic organizers anchored these otherwise secreted factors to the membrane. Together, these results uncovered the plasticity of N-terminal signal sequences regulated by alternative TIS usage as a potentially widespread mechanism in diversifying protein localization and functions.

Targeting immune-fibroblast cell communication in heart failure.

Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction1,2. However, the molecular mechanisms driving immune-fibroblast cell communication in human cardiac disease remain unexplored and there are at present no approved treatments that directly target cardiac fibrosis3,4. Here we performed multiomic single-cell gene expression, epitope mapping and chromatin accessibility profiling in 45 healthy donor, acutely infarcted and chronically failing human hearts. We identified a disease-associated fibroblast trajectory that diverged into distinct populations reminiscent of myofibroblasts and matrifibrocytes, the latter expressing fibroblast activator protein (FAP) and periostin (POSTN). Genetic lineage tracing of FAP+ fibroblasts in vivo showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model cardiac fibroblasts and demonstrated that three different in vivo mouse models of cardiac injury were superior compared with cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin-1ß (IL-1ß) signalling drove the emergence of FAP/POSTN fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts and the IL-1ß ligand in CCR2+ monocytes and macrophages, and inhibited IL-1ß signalling using a monoclonal antibody, and showed reduced FAP/POSTN fibroblasts, diminished myocardial fibrosis and improved cardiac function. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.

ANGPTL3 deficiency impairs lipoprotein production and produces adaptive changes in hepatic lipid metabolism.

Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins and low-density lipoprotein (LDL) cholesterol. Although ANGPTL3 modulates the metabolism of circulating lipoproteins, its role in triglyceride-rich lipoprotein assembly and secretion remains unknown. CRISPR-associated protein 9 (CRISPR/Cas9) was used to target ANGPTL3 in HepG2 cells (ANGPTL3-/-) whereupon we observed ∼50% reduction of apolipoprotein B100 (ApoB100) secretion, accompanied by an increase in ApoB100 early presecretory degradation via a predominantly lysosomal mechanism. Despite defective particle secretion in ANGPTL3-/- cells, targeted lipidomic analysis did not reveal neutral lipid accumulation in ANGPTL3-/- cells; rather ANGPTL3-/- cells demonstrated decreased secretion of newly synthesized triglycerides and increased fatty acid oxidation. Furthermore, RNA sequencing demonstrated significantly altered expression of key lipid metabolism genes, including targets of peroxisome proliferator-activated receptor α, consistent with decreased lipid anabolism and increased lipid catabolism. In contrast, CRISPR/Cas9 LDL receptor (LDLR) deletion in ANGPTL3-/- cells did not result in a secretion defect at baseline, but proteasomal inhibition strongly induced compensatory late presecretory degradation of ApoB100 and impaired its secretion. Additionally, these ANGPTL3-/-;LDLR-/- cells rescued the deficient LDL clearance of LDLR-/- cells. In summary, ANGPTL3 deficiency in the presence of functional LDLR leads to the production of fewer lipoprotein particles due to early presecretory defects in particle assembly that are associated with adaptive changes in intrahepatic lipid metabolism. In contrast, when LDLR is absent, ANGPTL3 deficiency is associated with late presecretory regulation of ApoB100 degradation without impaired secretion. Our findings therefore suggest an unanticipated intrahepatic role for ANGPTL3, whose function varies with LDLR status.

The mediating effect of dispositional mindfulness on the association between UPPS-P impulsivity traits and gaming disorder among Asia-Pacific young adults.

BACKGROUND: Little evidence is available to verify the mediating effect of dispositional mindfulness on the association between gaming disorder and various impulsivity traits. The present study aimed to investigate the mediating effect of dispositional mindfulness on the association between the five UPPS-P impulsivity traits and the risk of gaming disorder among young adults. METHODS: It was an inter-regional cross-sectional study using online survey in Australia, Japan, The Philippines and China. Impulsivity measured by the UPPS-P Impulsive Behavior Scale-Short version; dispositional mindfulness measured by the Mindfulness Attention Awareness Scale; and the risk of gaming disorder measured by the Internet Gaming Disorder Scale were collected in the focal regions. Structural equation modeling was performed by SPSS AMOS version 26 to verify the study hypotheses. Bootstrapped 95% confidence interval was reported. Statistical significance was indicated by the p-value below 0.05. RESULTS: Among the 1,134 returned questionnaires, about 40% of them aged 18-20 years and 21-23 years, respectively. 53.8% were male. 40.7% had been playing digital and video games for over 10 years. The prevalence of gaming disorder was 4.32%. The model fitness indices reflected that the constructed model had an acceptable model fit (χ2(118) = 558.994, p < 0.001; χ2/df = 4.737; CFI = 0.924; TLI = 0.890; GFI = 0.948; RMSEA = 0.058; SRMR = 0.0487). Dispositional mindfulness fully mediated the effect of positive urgency and negative urgency on the risk of gaming disorder. The effect of lack of premeditation on the risk of gaming disorder was partially mediated by dispositional mindfulness. However, dispositional mindfulness did not mediate the effect of sensation seeking on the risk of gaming disorder. CONCLUSIONS: The varied associations between dispositional mindfulness and the five impulsivity traits hints that improving some impulsive traits may increase dispositional mindfulness and so lower the risk of gaming disorder. Despite further studies are needed to verify the present findings, it sheds light on the need to apply interventions on gamers based on their impulsivity profile. Interventions targeting at emotion regulation and self-control such as mindfulness-based interventions seem to be effective to help gamers with dominant features of urgency and lack of premeditation only. Other interventions shall be considered for gamers with high sensation seeking tendency to enhance the effectiveness of gaming disorder prevention.

Ultralow-Dose Dynamic Expiratory CT and Repeated Imaging Enhance Evaluation for Tracheomalacia.

OBJECTIVE: This study aims to determine if a novel imaging protocol (ultralow-dose dynamic expiratory computed tomography [CT] with repeated imaging) identifies tracheomalacia (TM) more reliably than traditional dynamic tracheal CT. METHODS: We performed a retrospective evaluation of 184 consecutive ultralow-dose dynamic CTs for TM during 2017. The protocol obtains images during 1 inspiration and 2 forced expirations. Tracheal narrowing during both expirations (airway narrowing [percentage] during first dynamic expiration CT [DE1], airway narrowing [percentage] during second dynamic expiration CT [DE2]) was reported as a percentage of inspiratory area. We identified maximum narrowing of each patient's sequence (maximum narrowing [percentage] on either dynamic expiration CT [DEmax] = greatest narrowing of DE1 or DE2) and compared DE1, DE2, and DEmax in individual studies and between patients. Outcomes included frequency of TM, tracheal narrowing, and severity. Reliability was assessed by comparing tracheal area narrowing and TM grade. RESULTS: There was significantly more airway narrowing using 2 expiratory image acquisitions. Average DEmax tracheal area was 12% narrower than DE1 alone and 21% worse than DE2 alone (both P < 0.001). Using DEmax, TM was diagnosed 35% more often than DE1 alone and 31% more often than DE2 alone ( P < 0.001). DEmax identified more severe distribution of TM compared with DE1 or DE2 alone ( P < 0.001). Reliability between DE1 and DE2 was good for tracheal narrowing and moderate for TM grade. The mean effective radiation dose was 2.41 millisievert (mSv) for routine inspiration CT and 0.07 mSv for each dynamic expiration CT (total effective radiation, 2.55 mSv). CONCLUSIONS: Dynamic expiration CT with 2 expiratory image acquisitions enhanced evaluation of TM, minimally increased radiation dose, and should be considered as a noninvasive screening option.

Giant fronto-spheno-orbitary juvenile psammomatoid ossifying fibroma: Case report and literature review.

Juvenile psammomatoid ossifying fibroma (JPOF) is an osteofibrous neoplasm that originates in the craniofacial skeleton typically during the first three decades of life. JPOFs usually involve the orbit, paranasal sinuses or the jaws. Extensive involvement of the anterior cranial base with compromised visual function is a rare phenomenon. In such clinical context, a definite diagnosis can only be made on the basis of histopathological findings, given the absence of pathognomonic radiological features. Despite being considered a benign entity, JPOFs present a locally aggressive behavior. Therefore, these neoplasms must be included in the differential diagnosis in every patient harboring a skull base osteofibrous lesion, and, once diagnosed, gross total surgical removal should be attempted. In this study, we present our experience in the diagnosis and treatment of a patient diagnosed with a giant JPOF involving the cranial base.

Development and validation of a health literacy scale for family caregivers of older people with chronic illness.

BACKGROUND: Family caregivers (FCs) encounter a variety of health problems in older people with chronic illness, necessitating a certain level of health literacy to access, understand, appraise and apply health information and services. This study aimed to develop and validate a scale for measuring health literacy among FCs of older people with chronic illness. METHODS: Concept mapping was first employed to develop a conceptual model of health literacy of FCs. Scale domains were derived from the conceptual model, and item generation was performed using deductive and inductive methods. Quantitative methods, including merging scale dimensions and items, expert reviews, cognitive interviews, and item reduction analysis, were used to refine the scale. Confirmatory factor analysis was employed to validate the scale's structure. Concurrent validity, internal consistency, and test-retest reliability were also examined. RESULTS: A 20-dimension conceptual model was developed, and 60 items were generated for the scale. Expert review (content validity index > 0.85) and cognitive interview with FCs confirmed the relevance and clarity of the majority of the generated scale items. Confirmatory factor analysis with 451 FCs of older people with chronic illness supported a 5-factor structure (symptom management, daily personal care and household tasks, care coordination, communication and relationship with the care recipient, and self-care of caregivers) with 42 finalized scale items, including four levels of health literacy skills (accessing, understanding, appraising and applying health information). Concurrent validity with the European Health Literacy Questionnaire (HLS-EU-Q47) was satisfactory (r = 0.67, p < 0.01). The Cronbach's α coefficient of the scale was 0.96, with subscales ranging from 0.84 to 0.91. The two-week test-retest reliability was 0.77 (p < 0.01). CONCLUSION: This study developed a conceptual model explaining the concept and factors of health literacy among FCs of older people with chronic illness that could provide the groundwork for future studies in developing relevant evidence-based interventions. A new Health Literacy Scale-Family Caregiver (HLS-FC) with satisfactory psychometric properties was developed in this study, which can be utilized to identify caregivers with insufficient health literacy and facilitate timely interventions by healthcare professionals.

Insights into autoregulation of a membrane protein complex by its cytoplasmic domains.

Membrane transporters mediate the passage of molecules across membranes and are essential for cellular function. While the transmembrane region of these proteins is responsible for substrate transport, often the cytoplasmic regions are required for modulating their activity. However, it can be difficult to obtain atomic-resolution descriptions of these autoregulatory domains by classical structural biology techniques, especially if they lack a single, defined structure. The betaine permease, BetP, a homotrimer, is a prominent and well-studied example of a membrane protein whose autoregulation depends on cytoplasmic N- and C-terminal segments. These domains sense and transduce changes in K+ concentration and in lipid bilayer properties caused by osmotic stress. However, structural data for these terminal domains is incomplete, which hinders a clear description of the molecular mechanism of autoregulation. Here we used microsecond-scale molecular simulations of the BetP trimer to compare reported conformations of the 45-amino-acid long C-terminal tails. The simulations provide support for the idea that the conformation derived from electron microscopy (EM) data represents a more stable global orientation of the C-terminal segment under downregulating conditions while also providing a detailed molecular description of its dynamics and highlighting specific interactions with lipids, ions, and neighboring transporter subunits. A missing piece of the molecular puzzle is the N-terminal segment, whose dynamic nature has prevented structural characterization. Using Rosetta to generate ensembles of de novo conformations in the context of the EM-derived structure robustly identifies two features of the N-terminal tail, namely 1) short helical elements and 2) an orientation that would confine potential interactions to the protomer in the counterclockwise direction (viewed from the cytoplasm). Since each C-terminal tail only contacts the protomer in the clockwise direction, these results indicate an intricate interplay between the three protomers of BetP in the downregulated protein and a multidirectionality that may facilitate autoregulation of transport.

Desymmetrization of Vicinal Bis(boronic) Esters by Enantioselective Suzuki-Miyaura Cross-Coupling Reaction.

The development of an enantioselective catalytic Suzuki-Miyaura reaction that applies to meso 1,2-diborylcycloalkanes is described. This reaction provides a modular route to enantiomerically enriched substituted carbocycles and heterocycles that retain a synthetically versatile boronic ester. With appropriately constructed substrates, compounds bearing additional stereogenic centers and fully substituted carbon atoms can be generated in a straightforward fashion. Preliminary mechanistic experiments suggest that substrate activation arises from the cooperative effect of vicinal boronic esters during the transmetalation step.

Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection.

BACKGROUND: Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment. METHODS: We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (p<5×10-8) were investigated in additional independent studies, were fine-mapped and putative causal genes identified by gene expression analysis. GWASs of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease among the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWASs). RESULTS: From a GWAS of 9714 cases and 48 471 controls, we identified six novel genome-wide significant signals for chronic sputum production including signals in the human leukocyte antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2203 cases and 17 627 controls. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations including blood cell traits, liver biomarkers, infections, gastrointestinal and thyroid-associated diseases, and respiratory disease. CONCLUSIONS: Novel signals at the FUT2 and mucin loci suggest that mucin fucosylation may be a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.

Risks and benefits of anesthesia for combined pediatric procedures in the NIH undiagnosed diseases program.

PURPOSE: The NIH Undiagnosed Diseases Program (UDP) aims to provide diagnoses to patients who have previously received exhaustive evaluations yet remain undiagnosed. Patients undergo procedural anesthesia for deep phenotyping for analysis with genomic testing. METHODS: A retrospective chart review was performed to determine the safety and benefit of procedural anesthesia in pediatric patients in the UDP. Adverse perioperative events were classified as anesthesia-related complications or peri-procedural complications. The contribution of procedures performed under anesthesia to arriving at a diagnosis was also determined. RESULTS: From 2008 to 2020, 249 pediatric patients in the UDP underwent anesthesia for diagnostic procedures. The majority had a severe systemic disease (American Society for Anesthesiology status III, 79%) and/or a neurologic condition (91%). Perioperative events occurred in 45 patients; six of these were attributed to anesthesia. All patients recovered fully without sequelae. Nearly half of the 249 patients (49%) received a diagnosis, and almost all these diagnoses (88%) took advantage of information gleaned from procedures performed under anesthesia. CONCLUSIONS: The benefits of anesthesia involving multiple diagnostic procedures in a well-coordinated, multidisciplinary, research setting, such as in the pediatric UDP, outweigh the risks.

Acute promyelocytic leukaemia: population-based study of epidemiology and outcome with ATRA and oral-ATO from 1991 to 2021.

BACKGROUND: The epidemiology and treatment of acute promyelocytic leukaemia (APL) are changing. We have incorporated oral arsenic trioxide (oral-ATO) into induction/maintenance. METHODS: Newly-diagnosed APL from 1991 to 2021 divided into three 10-year periods were studied to define its epidemiology and how oral-ATO impacted on its outcome. Primary endpoints included APL incidence, early deaths (ED, first 30 days), and overall survival (OS). Secondary endpoints included post-30-day OS, relapse-free survival (RFS), and incidence of second cancers. RESULTS: APL occurred in 374 males and 387 females at a median age of 44 (1-97) years. Annual incidences increased progressively, averaging 0.32 per 100,000 people. All-trans retinoic acid (ATRA)-based and oral-ATO-based regimens were used in 469 and 282 patients. There were 144 EDs, occurring almost exclusively in ATRA-based inductions (N = 139), being more with males, age > 50 years, leucocyte > 10 × 109/L, diagnosis during 1991-2009 and fewer with oral-ATO-based regimens. After a median of 75 (interquartile range: 14-161) months, 5-year and 10-year OS were 68.1% and 63.3%, inferior with males, age > 50 years, leucocyte > 10 × 109/L, high-risk Sanz score and superior with oral-ATO-based regimens. Factoring out EDs, 5-year and 10-year post-30-day OS were 84.0% and 78.1%, inferior with males and superior with oral-ATO-based regimens. In 607 CR1 patients, the 5-year RFS was 83.8%, superior with diagnosis in 2010-2021 and oral-ATO-based regimens. Second cancers developed in 21 patients, unrelated to oral-ATO-based regimens. CONCLUSIONS: There was an increasing incidence of APL, and all survivals were superior with the use of oral-ATO-based regimens. This study formed part of the Acute Promyelocytic Leukaemia Asian Consortium Project (ClinicalTrials.gov identifier: NCT04251754).

Immune-mediated colitis associated with ocrelizumab: A new safety risk.

BACKGROUND: An association between certain immunomodulatory therapies (rituximab, ipilimumab, and other immune checkpoint inhibitors) and inflammatory (non-ischemic and non-infectious) colitis in oncologic and non-oncologic patient populations is well documented in the medical literature. OBJECTIVE: The purpose of this case series is to describe adverse event reports of new onset, inflammatory colitis in association with ocrelizumab in patients with multiple sclerosis submitted to U.S. Food and Drug Administration (FDA) or published in the medical literature. METHODS: The FDA Adverse Event Reporting System (FAERS) and medical literature were searched. RESULTS: A review of postmarketing cases from FAERS and published medical literature identified 38 cases consistent with inflammatory, non-ischemic, and non-infectious colitis in association with ocrelizumab. The median time-to-onset was 8 months. Cases were reported using the following diagnostic terms: Crohn's disease (13), unspecified colitis (11), microscopic colitis (5), ulcerative colitis (5), medication-induced colitis (3), and autoimmune colitis (2). CONCLUSIONS: This case series highlights ocrelizumab induced immune-mediated colitis that can be clinically severe and potentially life-threatening. Based on the findings of this review, the ocrelizumab Prescribing Information was amended to include immune-mediated colitis in the Warnings and Precautions section.

A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature.

AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

Allogeneic haematopoietic stem cell transplantation for myelofibrosis: prognostic indicators and the role of JAK2V617F measurable-residual disease monitoring by droplet-digital polymerase chain reaction.

Relapse after allogeneic haematopoietic stem cell transplantation (HSCT) is one of the key determinants of outcome in myelofibrosis (MF) and remains an important unmet need. In this retrospective single-centre study, we evaluated 35 consecutive patients with MF receiving allogeneic HSCT. At 30 days post-HSCT, full donor chimerism was achieved in 31 patients (88.6%). The median time to neutrophil engraftment was 16.8 (10-42) days and the median time to platelet engraftment was 26 (12-245) days. Four patients (11.4%) experienced primary graft failure. With a median duration of follow-up of 33 (1-223) months, with the 5-year overall survival (OS) and progression-free survival (PFS) were 51.6% and 46.3%, respectively. Relapse after HSCT (P < 0.001), leucocyte count ≥ 18 × 109/L at HSCT (P = 0.003) and accelerated/blast phase disease at HSCT (P < 0.001) were significantly associated with worse OS. Age at HSCT ≥ 54 years (P = 0.01), mutated ETV6 (P = 0.03), leucocyte count ≥ 18 × 109/L (P = 0.02), accelerated/blast phase MF (P = 0.001), and grade 2-3 bone marrow reticulin fibrosis at 12 months post-HSCT (P = 0.002) were significantly associated with worse PFS. JAK2V617F MRD ≥ 0.047 [sensitivity 85.7%; positive predictive value (PPV) 100%; AUC 0.984; P = 0.001] at 6 months and JAK2V617F MRD ≥ 0.009 (sensitivity 100%; PPV 100%; AUC 1.0; P = 0.001) at 12 months were highly predictive of post-HSCT relapse. Inferior OS and PFS were significantly associated with detectable JAK2V617F MRD at 12 months (P = 0.003 and P = 0.0001, respectively).

ILRUN Promotes Atherosclerosis Through Lipid-Dependent and Lipid-Independent Factors.

BACKGROUND: Common genetic variation in close proximity to the ILRUN gene are significantly associated with coronary artery disease as well as with plasma lipid traits. We recently demonstrated that hepatic inflammation and lipid regulator with ubiquitin-associated domain-like and NBR1-like domains (ILRUN) regulates lipoprotein metabolism in vivo in mice. However, whether ILRUN, which is expressed in vascular cells, directly impacts atherogenesis remains unclear. We sought to determine the role of ILRUN in atherosclerosis development in mice. METHODS: For our study, we generated global Ilrun-deficient (IlrunKO) male and female mice on 2 hyperlipidemic backgrounds: low density lipoprotein receptor knockout (LdlrKO) and apolipoprotein E knockout (ApoeKO; double knockout [DKO]). RESULTS: Compared with littermate control mice (single LdlrKO or ApoeKO), deletion of Ilrun in DKO mice resulted in significantly attenuated both early and advanced atherosclerotic lesion development, as well as reduced necrotic area. DKO mice also had significantly decreased plasma cholesterol levels, primarily attributable to non-HDL (high-density lipoprotein) cholesterol. Hepatic-specific reconstitution of ILRUN in DKO mice on the ApoeKO background normalized plasma lipids, but atherosclerotic lesion area and necrotic area remained reduced in DKO mice. Further analysis showed that loss of Ilrun increased efferocytosis receptor MerTK expression in macrophages, enhanced in vitro efferocytosis, and significantly improved in situ efferocytosis in advanced lesions. CONCLUSIONS: Our results support ILRUN as an important novel regulator of atherogenesis that promotes lesion progression and necrosis. It influences atherosclerosis through both plasma lipid-dependent and lipid-independent mechanisms. These findings support ILRUN as the likely causal gene responsible for genetic association of variants with coronary artery disease at this locus and suggest that suppression of ILRUN activity might be expected to reduce atherosclerosis.

Does bioabsorbable mesh reduce hiatal hernia recurrence rates? A meta-analysis.

INTRODUCTION: The use of bioabsorbable mesh at the hiatus is controversial. Long-term data are scant. We evaluated the world literature and performed a meta-analysis to determine if these meshes were effective in reducing recurrence. METHODS: A literature search was performed using PubMed, MEDLINE, and ClinicalKey. We evaluated articles reporting on both Bio-A™ (polyglycolic acid:trimethylene carbonate-PGA:TMC) and Phasix™ (poly-4-hydroxybutyrate-P4HB) used at the hiatus. The DerSimonian-Laird random effects model was used to estimate the overall pooled treatment effect along with a 95% confidence interval (CI). Similar analysis was conducted to compare the clinical outcomes, i.e., recurrence rate, mean surgical time, mean hospital stays and mean follow-up duration between non-Mesh and Mesh group. The I2 statistic was computed to assess the heterogeneity in effect sizes across the studies. RESULTS: A total of 21 studies (12 mesh studies with 963 subjects and 9 non-mesh studies with 617 subjects) were included to conduct the meta-analysis. There was one article reporting outcomes on P4HB mesh (73 subjects) and 11 on PGA:TMC mesh (890 subjects). The bioabsorbable mesh group had a significantly lower recurrence rate compared to the non-mesh group (8% vs. 18%; 95%CI 0.08-0.17), pooled p-value < 0.0001. Surgery time was shorter in the mesh group compared to the non-mesh group (136.4 min vs. 150 min) but not statistically significant (p = 0.54). There tended to be a more extended follow-up period after surgery in the non-mesh group compared to the mesh group (27 vs. 25.8 months, range 10.8-54 months); but not statistically significant (ES: 27.4; 95%CI 21.6-33.3; p = 0.92). CONCLUSIONS: Hiatal hernia repair with bioabsorbable mesh is more effective at reducing hernia recurrence rate in the mid-term than simple suture cruroplasty. Further studies investigating the long-term outcomes and P4HB mesh are needed.

Effects of an individualised exercise programme plus Behavioural Change Enhancement (BCE) strategies for managing fatigue in frail older adults: a cluster randomised controlled trial.

BACKGROUND: To the best of our knowledge, although ageing-induced fatigue could cause adverse outcomes such as frailty, there is currently no intervention for it. This study evaluated the effects of an individualised exercise programme with/without BCE strategies on reducing fatigue in older adults. METHODS: A three-armed cluster-randomised controlled trial (RCT) was conducted with 184 participants (mean age: 79.1 ± 6.4; mean frailty score: 2.8 + 0.8) from 21 community centres (ClinicalTrials.gov: NCT03394495). They were randomised into either: the COMB group (n = 64), receiving 16 weeks of exercise training plus the BCE programme; the EXER group (n = 65), receiving exercise training and health talks; or the control group (n = 55), receiving only health talks. Fatigue was assessed using the Multi-dimensional Fatigue Inventory (range: 20 to 100, with higher scores indicating higher fatigue levels) at baseline, and immediately, 6 months, and 12 months post-intervention. RESULTS: The GEE analyses showed significant interaction (time x group) between the COMB and control groups immediately (p < 0.001), 6 months (p < 0.001), and 12 months (p < 0.001) post-intervention. Comparing the COMB and EXER groups, there was a significant interaction immediately (p = 0.013) and at 12 months post-intervention (p = 0.007). However, no significant difference was seen between the EXER group and control group at any time point. CONCLUSIONS: The COMB intervention showed better immediate and sustainable effects (i.e., 12 months after the intervention) on reducing fatigue in frail older adults than exercise training or health education alone. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03394495), registered on 09/01/2018.

Changes in relative peripheral refraction in children who switched from single-vision lenses to Defocus Incorporated Multiple Segments lenses.

PURPOSE: To investigate changes in relative peripheral refraction (RPR) associated with myopia progression in children who wore single-vision (SV) lenses for 2 years and switched to Defocus Incorporated Multiple Segments (DIMS) lenses in the third year versus children who wore DIMS lenses for 3 years. METHODS: In the first 2 years, children were allocated randomly to wear either DIMS or SV lenses. In the third year, children in the DIMS group continued to wear these lenses, while those in the SV group were switched to DIMS lenses (Control-to-DIMS group). Central and peripheral refraction and axial length were monitored every 6 months. RESULTS: Over 3 years, the DIMS group (n = 65) showed good myopia control and maintained a relatively constant and symmetrical RPR profile without significant changes. In the first 2 years, children who wore SV lenses (n = 55) showed asymmetrical RPR changes, with significant increases in hyperopic RPR at 20° nasal (N) (mean difference: 0.88 ± 1.06 D, p < 0.0001) and 30N (mean difference: 1.07 ± 1.09 D, p < 0.0001). The Control-to-DIMS group showed significant myopia retardation after wearing DIMS lenses in the third year. When compared with the RPR changes in the first 2 years, significant reductions in hyperopic RPR were observed at 20N (mean difference: -1.14 ± 1.93 D, p < 0.0001) and 30N (mean difference: -1.07 ± 1.17 D, p < 0.0001) in the third year. However, no significant difference between the RPR changes found in the nasal retina and temporal retina (p > 0.05) was noted in the third year. CONCLUSION: Symmetrical changes in RPR were found in children switching from SV to DIMS lenses, and a symmetrical pattern of RPR was noted in children who wore DIMS for 3 years. Myopia control using myopic defocus in the mid-periphery influenced the RPR changes and retarded myopia progression by altering the eye's growth pattern.

Initial Evaluation and Management of Patients Presenting with Acute Chest Pain in the Emergency Department.

PURPOSE OF THE REVIEW: To review the initial evaluation of chest pain in the emergency department (ED), with a focus on coronary artery disease (CAD) and acute coronary syndromes (ACS), using consensus statements from major cardiovascular disease organizations. RECENT FINDINGS: Major cardiovascular organizations have released consensus statements on this topic, notably the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain and the 2022 ACC Expert Consensus Decision Pathway on the Evaluation and Disposition of Acute Chest Pain in the Emergency Department. Also, recent studies have evaluated the use of high sensitivity troponin (hs-cTn) to safely rule out myocardial infarction (MI), with the development of rule-out pathways designed to be utilized in the ED. This review highlights the comprehensive differential diagnoses of chest pain in the ED and urgent management of these etiologies, with a focus on cardiovascular etiologies. There exist a few rule-out pathways recommended by major cardiovascular organizations, notably the high-STEACS and the ESC 0/1 and 0/2 pathways that can safely and quickly discharge patients with low risk of MI.