Exacerbated atherosclerosis in progeria is prevented by progerin elimination in vascular smooth muscle cells but not endothelial cells.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by the expression of progerin, a mutant protein that accelerates aging and precipitates death. Given that atherosclerosis complications are the main cause of death in progeria, here, we investigated whether progerin-induced atherosclerosis is prevented in HGPSrev-Cdh5-CreERT2 and HGPSrev-SM22α-Cre mice with progerin suppression in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. HGPSrev-Cdh5-CreERT2 mice were undistinguishable from HGPSrev mice with ubiquitous progerin expression, in contrast with the ameliorated progeroid phenotype of HGPSrev-SM22α-Cre mice. To study atherosclerosis, we generated atheroprone mouse models by overexpressing a PCSK9 gain-of-function mutant. While HGPSrev-Cdh5-CreERT2 and HGPSrev mice developed a similar level of excessive atherosclerosis, plaque development in HGPSrev-SM22α-Cre mice was reduced to wild-type levels. Our studies demonstrate that progerin suppression in VSMCs, but not in ECs, prevents exacerbated atherosclerosis in progeroid mice.

Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic, Omalizumab, in Severe Asthma in Adults: Results of the SoMOSA Study.

BACKGROUND: The anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment. METHODS: 1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting ß-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. RESULTS: 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-ß-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions This is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Metabolic outcomes in obese mice undergoing one-anastomosis gastric bypass (OAGB) with a long or a short biliopancreatic limb.

One-anastomosis gastric bypass (OAGB) has gained importance as a simple, safe, and effective operation to treat morbid obesity. We previously found that Roux-en-Y gastric bypass surgery with a long compared with a short biliopancreatic limb (BPL) leads to improved weight loss and glucose tolerance in obese mice. However, it is not known whether a long BPL in OAGB surgery also results in beneficial metabolic outcomes. Five-week-old male C57BL/6J mice fed a high-fat diet (HFD) for 8 weeks underwent OAGB surgery with defined BPL lengths (5.5 cm distally of the duodenojejunal junction for short and 9.5 cm for long BPL), or sham surgery combined with caloric restriction. Weight loss, glucose tolerance, obesity-related comorbidities, endocrine effects, gut microbiota, and bile acids were assessed. Total weight loss was independent of the length of the BPL after OAGB surgery. However, a long BPL was associated with lower glucose-stimulated insulin on day 14, and an improved glucose tolerance on day 35 after surgery. Moreover, a long BPL resulted in reduced total cholesterol, while there were no differences in the resolution of metabolic dysfunction-associated steatotic liver disease (MASLD) and adipose tissue inflammation. Tendencies of an attenuated hypothalamic-pituitary-adrenal (HPA) axis and aldosterone were present in the long BPL group. With both the short and long BPL, we found an increase in primary conjugated bile acids (pronounced in long BPL) along with a loss in bacterial Desulfovibrionaceae and Erysipelotrichaceae and simultaneous increase in Akkermansiaceae, Sutterellaceae, and Enterobacteriaceae. In summary, OAGB surgery with a long compared with a short BPL led to similar weight loss, but improved glucose metabolism, lipid, and endocrine outcomes in obese mice, potentially mediated through changes in gut microbiota and related bile acids. Tailoring the BPL length in humans might help to optimize metabolic outcomes after bariatric surgery.NEW & NOTEWORTHY Weight loss following OAGB surgery in obese mice was not influenced by BPL length, but a longer BPL was associated with improved metabolic outcomes, including glucose and lipid homeostasis. These changes could be mediated by bile acids upon altered gut microbiota. Further validation of these findings is required through a randomized human study.

Nodule-specific Cu+ -chaperone NCC1 is required for symbiotic nitrogen fixation in Medicago truncatula root nodules.

Cu+ -chaperones are a diverse group of proteins that allocate Cu+ ions to specific copper proteins, creating different copper pools targeted to specific physiological processes. Symbiotic nitrogen fixation carried out in legume root nodules indirectly requires relatively large amounts of copper, for example for energy delivery via respiration, for which targeted copper deliver systems would be required. MtNCC1 is a nodule-specific Cu+ -chaperone encoded in the Medicago truncatula genome, with a N-terminus Atx1-like domain that can bind Cu+ with picomolar affinities. MtNCC1 is able to interact with nodule-specific Cu+ -importer MtCOPT1. MtNCC1 is expressed primarily from the late infection zone to the early fixation zone and is located in the cytosol, associated with plasma and symbiosome membranes, and within nuclei. Consistent with its key role in nitrogen fixation, ncc1 mutants have a severe reduction in nitrogenase activity and a 50% reduction in copper-dependent cytochrome c oxidase activity. A subset of the copper proteome is also affected in the ncc1 mutant nodules. Many of these proteins can be pulled down when using a Cu+ -loaded N-terminal MtNCC1 moiety as a bait, indicating a role in nodule copper homeostasis and in copper-dependent physiological processes. Overall, these data suggest a pleiotropic role of MtNCC1 in copper delivery for symbiotic nitrogen fixation.

Urinary incontinence increases risk of postpartum depression: systematic review and meta-analysis.

OBJECTIVE: Postpartum depression is one of the most common complications after childbearing. Urinary incontinence is a frequent symptom during pregnancy and the postnatal period, often being the first time that women experience it. This systematic review and meta-analysis aimed to synthesize the evidence on the association between urinary incontinence and postpartum depression and to assess whether this association becomes weaker at 6 months after childbirth. DATA SOURCES: MEDLINE, Embase, Cochrane Library, Web of Science, and PsycINFO were searched from inception to December 26, 2023. STUDY ELIGIBILITY CRITERIA: Cross-sectional and cohort studies addressing the association between urinary incontinence and postpartum depression were included. METHODS: Pooled odds ratios and their 95% confidence intervals, and 95% prediction intervals were estimated using a DerSimonian and Laird random-effects model for the association between urinary incontinence and postpartum depression. Subgroup analyses were conducted on the basis of time after delivery (<6 or ≥6 months). The risk of bias was assessed with the National Institutes of Health Quality Assessment Tool for Observational Cohort Studies. RESULTS: Eleven published studies were included in the systematic review and meta-analysis. Overall, the odds ratio for the association between urinary incontinence and postpartum depression was 1.45 (95% confidence interval, 1.11-1.79; 95% prediction interval, 0.49-2.40; I2=65.9%; P=.001). For the 7 cohort studies, the odds ratio was 1.63 (95% confidence interval, 1.35-1.91; 95% prediction interval, 1.14-2.13; I2=11.1%; P=.345). For the 4 cross-sectional studies, the odds ratio was 1.05 (95% confidence interval, 1.04-1.05; 95% prediction interval, 1.04-1.06; I2=0.0%; P=.413). According to the time after delivery, the odds ratio estimates for cohort studies with a postpartum period <6 months were 1.44 (95% confidence interval, 1.07-1.81; prediction interval, 0.63-2.25; I2=0.0%; P=.603) and 1.53 (95% confidence interval, 1.16-1.89; prediction interval, 0.41-2.65; I2=50.7%; P=.087) for those with a postpartum period ≥6 months. CONCLUSION: This systematic review and meta-analysis suggests that urinary incontinence may be a potential predictor of postpartum depression. Thus, it is important that health care professionals offer support and treatment options to women who experience these conditions.

Sodium-glucose cotransporter 2 inhibition in primary and secondary glomerulonephritis.

BACKGROUND: The role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the management glomerular/systemic autoimmune diseases with proteinuria in real-world clinical settings is unclear. METHODS: This is a retrospective, observational, international cohort study. Adult patients with biopsy-proven glomerular diseases were included. The main outcome was the percentage reduction in 24-h proteinuria from SGLT2i initiation to 3, 6, 9 and 12 months. Secondary outcomes included percentage change in estimated glomerular filtration rate (eGFR), proteinuria reduction by type of disease and reduction of proteinuria ≥30% from SGLT2i initiation. RESULTS: Four-hundred and ninety-three patients with a median age of 55 years and background therapy with renin-angiotensin system blockers were included. Proteinuria from baseline changed by -35%, -41%, -45% and -48% at 3, 6, 9 and 12 months after SGLT2i initiation, while eGFR changed by -6%, -3%, -8% and -10.5% at 3, 6, 9 and 12 months, respectively. Results were similar irrespective of the underlying disease. A correlation was found between body mass index (BMI) and percentage proteinuria reduction at last follow-up. By mixed-effects logistic regression model, serum albumin at SGLT2i initiation emerged as a predictor of ≥30% proteinuria reduction (odds ratio for albumin <3.5 g/dL, 0.53; 95% CI 0.30-0.91; P = .02). A slower eGFR decline was observed in patients achieving a ≥30% proteinuria reduction: -3.7 versus -5.3 mL/min/1.73 m2/year (P = .001). The overall tolerance to SGLT2i was good. CONCLUSIONS: The use of SGLT2i was associated with a significant reduction of proteinuria. This percentage change is greater in patients with higher BMI. Higher serum albumin at SGLT2i onset is associated with higher probability of achieving a ≥30% proteinuria reduction.

Cohort-based strategies as an in-house tool to evaluate and improve phenotyping robustness of LC-MS/MS lipidomics platforms.

In recent years, instrumental improvements have enabled the spread of mass spectrometry-based lipidomics platforms in biomedical research. In mass spectrometry, the reliability of generated data varies for each compound, contingent on, among other factors, the availability of labeled internal standards. It is challenging to evaluate the data for lipids without specific labeled internal standards, especially when dozens to hundreds of lipids are measured simultaneously. Thus, evaluation of the performance of these platforms at the individual lipid level in interlaboratory studies is generally not feasible in a time-effective manner. Herein, using a focused subset of sphingolipids, we present an in-house validation methodology for individual lipid reliability assessment, tailored to the statistical analysis to be applied. Moreover, this approach enables the evaluation of various methodological aspects, including discerning coelutions sharing identical selected reaction monitoring transitions, pinpointing optimal labeled internal standards and their concentrations, and evaluating different extraction techniques. While the full validation according to analytical guidelines for all lipids included in a lipidomics method is currently not possible, this process shows areas to focus on for subsequent method development iterations as well as the robustness of data generated across diverse methodologies.

Genomic Context of SARS-CoV-2 Outbreaks in Farmed Mink in Spain during Pandemic: Unveiling Host Adaptation Mechanisms.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects various mammalian species, with farmed minks experiencing the highest number of outbreaks. In Spain, we analyzed 67 whole genome sequences and eight spike sequences from 18 outbreaks, identifying four distinct lineages: B.1, B.1.177, B.1.1.7, and AY.98.1. The potential risk of transmission to humans raises crucial questions about mutation accumulation and its impact on viral fitness. Sequencing revealed numerous not-lineage-defining mutations, suggesting a cumulative mutation process during the outbreaks. We observed that the outbreaks were predominantly associated with different groups of mutations rather than specific lineages. This clustering pattern by the outbreaks could be attributed to the rapid accumulation of mutations, particularly in the ORF1a polyprotein and in the spike protein. Notably, the mutations G37E in NSP9, a potential host marker, and S486L in NSP13 were detected. Spike protein mutations may enhance SARS-CoV-2 adaptability by influencing trimer stability and binding to mink receptors. These findings provide valuable insights into mink coronavirus genetics, highlighting both host markers and viral transmission dynamics within communities.

Targeted therapy for lung cancer: Beyond EGFR and ALK.

Precision oncology comprises the set of strategies that aim to design the best cancer treatment based on tumor biology. A recognized subset of patients with non-small cell lung cancer (NSCLC) harbor actionable genomic aberrations that can benefit from targeted therapy. In lung cancer, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are well characterized oncogenic drivers for which the therapeutic use of tyrosine kinase inhibitors has demonstrated improved outcomes compared with chemotherapy. Other druggable targets are also well characterized, and effective inhibitors have been developed and commercialized, leading to a paradigm shift in NSCLC treatment. Here, the authors provide a review of the oncogenic role of the most relevant molecular alterations in NSCLC and emerging treatments in this setting beyond EGFR-driven and ALK-driven diseases.

Forging a symbiosis: transition metal delivery in symbiotic nitrogen fixation.

Symbiotic nitrogen fixation carried out by the interaction between legumes and rhizobia is the main source of nitrogen in natural ecosystems and in sustainable agriculture. For the symbiosis to be viable, nutrient exchange between the partners is essential. Transition metals are among the nutrients delivered to the nitrogen-fixing bacteria within the legume root nodule cells. These elements are used as cofactors for many of the enzymes controlling nodule development and function, including nitrogenase, the only known enzyme able to convert N2 into NH3 . In this review, we discuss the current knowledge on how iron, zinc, copper, and molybdenum reach the nodules, how they are delivered to nodule cells, and how they are transferred to nitrogen-fixing bacteria within.

CRISPR/Cas9-mediated knockout of a polyester synthase-like gene delays flowering time in alfalfa.

KEY MESSAGE: T-DNA and CRISPR/Cas9-mediated knockout of polyester synthase-like genes delays flowering time in Arabidopsis thaliana and Medicago sativa (alfalfa). Thus, we here present the first report of edited alfalfa with delayed flowering.

Identification of the haemoglobin level associated with a lower risk of complications after total hip and knee arthroplasty.

BACKGROUND: Preoperative anaemia is associated with poor outcomes in surgical patients, but the preoperative haemoglobin cut-off that determines lower morbidity in total knee arthroplasty (TKA) and total hip arthroplasty (THA) is not well established. METHODS: Planned secondary analysis of data collected during a multicentre cohort study of patients undergoing THA and TKA in 131 Spanish hospitals during a single 2-month recruitment period. Anaemia was defined as haemoglobin <12 g dl-1 for females and < 13 g dl-1 for males. The primary outcome was the number of patients with 30-day in-hospital postoperative complications according to European Perioperative Clinical Outcome definitions and specific surgical TKA and THA complications. Secondary outcomes included the number of patients with 30-day moderate-to-severe complications, red blood cell transfusion, mortality, and length of hospital stay. Binary logistic regression models were constructed to assess association between preoperative Hb concentrations and postoperative complications, and variables significantly associated with the outcome were included in the multivariate model. The study sample was divided into 11 groups based on preoperative Hb values in an effort to identify the threshold at which increased postoperative complications occurred. RESULTS: A total of 6099 patients were included in the analysis (3818 THA and 2281 TKA), of whom 8.8% were anaemic. Patients with preoperative anaemia were more likely to suffer overall complications (111/539, 20.6% vs. 563/5560, 10.1%, p < .001) and moderate-to-severe complications (67/539, 12.4% vs. 284/5560, 5.1%, p < .001). Multivariable analysis showed preoperative haemoglobin ≥14 g dl-1 was associated with fewer postoperative complications. CONCLUSION: Preoperative haemoglobin ≥14 g dl-1 is associated with a lower risk of postoperative complications in patients undergoing primary TKA and THA.

Biohydrogen Production in Microbial Electrolysis Cell Operating on Designed Consortium of Denitrifying Bacteria.

Research background: This study provides insight into the use of a designed microbial community to produce biohydrogen in simple, single-chamber microbial electrolysis cells (MECs). The ability of MECs to stably produce biohydrogen relies heavily on the setup and microorganisms working inside the system. Despite having the most straightforward configuration and effectively avoiding costly membranes, single-chamber MECs are prone to competing metabolic pathways. We present in this study one possible way of avoiding this problem using characteristically defined, designed microbial consortium. Here, we compare the performance of MECs inoculated with a designed consortium to MECs operating with a naturally occurring soil consortium. Experimental approach: We adapted a cost-effective and simple single-chamber MEC design. The MEC was gastight, 100 mL in volume, and equipped with continuous monitoring for electrical output using a digital multimeter. Microorganisms were sourced from Indonesian environmental samples, either as denitrifying bacterial isolates grouped as a designed consortium or natural soil microbiome used in its entirety. The designed consortium consisted of five species from the Pseudomonas and Acinetobacter genera. The headspace gas profile was monitored periodically with a gas chromatograph. At the end of the culture, the composition of the natural soil consortium was characterized by next generation sequencing and the growth of the bacteria on the surface of the anodes by field emission scanning electron microscopy. Results and conclusions: We found that MEC using a designed consortium presented a better H2 production profile, with the ability of the system to maintain headspace H2 concentration relatively stable for a long time after reaching stationary growth period. In contrast, MECs inoculated with soil microbiome exhibited a strong decline in headspace H2 profile within the same time frame. Novelty and scientific contribution: This work utilizes a designed, denitrifying bacterial consortium isolated from Indonesian environmental samples that can survive in a nitrate-rich environment. Here we propose using a designed consortium as a biological approach to avoid methanogenesis in MECs, as a simple and environmentally friendly alternative to current chemical/physical methods. Our findings offer an alternative solution to avoid the problem of H2 loss in single-chamber MECs along with optimizing biohydrogen production through bioelectrochemical routes.

Peritoneal tuberculosis mimicking colonic carcinomatosis.

Pulmonary Tuberculosis (TB) has increased in Spain in recent years due to multiple factors. Peritoneal tuberculosis represents the sixth cause of extrapulmonary tuberculosis, accounting for 11% of tuberculosis cases. We report a 28-year-old male from Mali, who arrived at our hospital with an acute abdomen due to intestinal perforation with a computed tomography scan (CT) performed peritoneal tuberculosis mimicking primary carcinomatosis. This presents a diagnostic and therapeutic challenge, since the surgical approach differs in both cases, and the prognosis is very different between them.

Importance of immunohistochemistry in the differential diagnosis of gastric mesenchymal tumors.

Although morphology is the key to histological diagnosis, gastric mesenchymal tumors can share very similar growth and cellularity patterns, sometimes being indistinguishable. Therefore, immunohistochemical techniques are going to be crucial in the definitive diagnosis. The objective of this work is to perform an immunohistochemical differential diagnosis of gastric mesenchymal tumors.

Evolution of two unusual radiological findings in a patient with mesenteric ischemia.

Portal pneumatosis has been considered an ominous sign associated with intestinal ischemia, with a mortality rate of up to 90% as long as it is associated with sepsis. However, the prognosis of mesenteric ischemia depends on the etiology rather than the presence of portal pneumatosis. We present a patient with portal pneumatosis that disappeared 24 hours after the first surgery, but irreversible ischemic lesions were established in the terminal ileum. It should be noted that the excretion of the intravenous contrast is mainly through the kidneys, and it can be eliminated through alternative routes such as the bile duct or the mucosa of the small intestine (vicariant excretion), especially in patients with renal pathology.

Recurrence of gastric schwannoma.

Gastric schwannoma can be malignant in 13.8% of cases. The prognosis of malignant schwannoma is usually poor, characterized by a rapidly progressive disease course and a poor response to chemotherapy. Normally, the recurrence of schwannoma is due to involvement of the surgical resection margin. In turn, recurrence of malignant gastric schwannoma GS is approximately 50%, 25% locoregional and 25% with liver metastases. Even after a complete gastric resection with associated lymphadenectomy, schwannoma may present liver metastases during follow-up.

Systematic review on the clinical management of chronic pain and comorbid opioid use disorder. / Revisión sistemática sobre el manejo clínico del dolor crónico y el trastorno por uso de opioides simultáneo.

The crisis caused by prescribed opioids and their related side effects are a public health problem worldwide. Most of these are prescribed for coping with chronic pain. The coexistence of opioid use disorder (OUD) in patients with chronic pain represents a complex challenge due to the need for managing both pain and OUD. The aim of this systematic review is to evaluate the efficacy of feasible treatments for this population with OUD and comorbid chronic pain for both conditions. A systematic database search has been performed using Cochrane Library, MEDLINE, PsycINFO and ClinicalTrials.gov in compliance with PRISMA guidelines. Eligible articles addressed the outcomes in chronic pain patients with comorbid opioid use disorder after treatment interventions were applied. Of 593 identified articles, nine were eligible for qualitative review (n = 7 pharmacological interventions; n = 2 psychological interventions). Methadone, buprenorphine, cognitive-behavioral and mindfulness showed promising results, but data were inconclusive (<2 RCT with low risk of bias). It is unclear whether the opioid agonist treatment should be maintained or tapered and which drug should be prescribed for the opioid substitution therapy (methadone or buprenorphine/naloxone). Mindfulness and cognitive behavioral therapy have a discrete effect on improving negative affect but not pain. The therapeutic approach might be individualized under a shared decision-making basis.

La crisis causada por los opioides recetados y sus efectos secundarios relacionados son un problema de salud pública en todo el mundo. La mayoría de estos medicamentos se recetan para el afrontamiento del dolor crónico. La coexistencia del trastorno por uso de opioides (TUO) en pacientes con dolor crónico representa un desafío complejo debido a la necesidad de controlar tanto el dolor como el TUO. El objetivo de esta revisión sistemática es evaluar la eficacia de los tratamientos posibles para dicha población con TUO y dolor crónico. Se ha realizado una revisión sistemática usando las bases de datos Cochrane Library, MEDLINE, PsycINFO y ClinicalTrials.gov, conforme a las pautas PRISMA. Los artículos elegibles abordaron los resultados en pacientes con dolor crónico y diagnóstico comórbido de TUO, después de aplicar una intervención. De 593 artículos identificados, nueve eran elegibles para la revisión cualitativa (n = 7 intervenciones farmacológicas; n = 2 intervenciones psicológicas). La metadona, la buprenorfina, la terapia cognitivo-conductual y el mindfulness mostraron resultados prometedores, pero los datos no eran concluyentes (<2 ECA con bajo riesgo de sesgo). No está claro si el tratamiento con agonistas opioides debe mantenerse o disminuirse y qué fármaco debe prescribirse para la terapia de sustitución de opioides (metadona o buprenorfina/naloxona). El mindfulness y la terapia cognitivo-conductual tienen un efecto discreto en la mejora del afecto negativo, pero no del dolor. El enfoque terapéutico podría individualizarse sobre la base de una toma de decisiones conjunta.

Faecal immunochemical tests safely enhance rational use of resources during the assessment of suspected symptomatic colorectal cancer in primary care: systematic review and meta-analysis.

OBJECTIVE: Implementation of faecal immunochemical tests (FIT) as a triage test in primary healthcare may improve the efficiency of referrals without missing cases of colorectal cancer (CRC). We aim to summarise the performance characteristics of FITs for CRC in symptomatic patients presenting to primary healthcare. DESIGN: We performed a systematic literature review of Medline and EMBASE databases from May 2018 to November 2020. Previous related systematic searches were also adapted to this aim and completed with reference screening. We identified studies performed on adult patients consulting for abdominal symptoms in primary care which reported data such that the FIT diagnostic performance parameters for CRC could be obtained. Bivariate models were used to synthesise available evidence. Meta-regression analysis was performed to evaluate the causes of heterogeneity. RESULTS: Twenty-three studies (69 536 participants) were included (CRC prevalence 0.3%-6.2%). Six studies (n=34 691) assessed FIT as rule in test (threshold of ≥150 µg Hb/g faeces) showing a sensitivity of 64.1% (95% CI 57.8% to 69.9%) and a specificity of 95.0% (95% CI 91.2% to 97.2%). A threshold of 10 µg/g (15 studies; n=48 872) resulted in a sensitivity of 87.2% (95% CI 81.0% to 91.6%) and a specificity of 84.4% (95% CI 79.4% to 88.3%) for CRC. At a 20 µg Hb/g faeces threshold (five studies; n=24 187) less than one additional CRC would be missed per 1000 patients investigated compared with 10 µg Hb/g faeces threshold (CRC prevalence 2%). CONCLUSION: FIT is the test of choice to evaluate patients with new-onset lower gastrointestinal symptoms in primary healthcare.

Cardiovascular Progerin Suppression and Lamin A Restoration Rescue Hutchinson-Gilford Progeria Syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder characterized by premature aging and death mainly because of myocardial infarction, stroke, or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Patients look healthy at birth, and symptoms typically emerge in the first or second year of life. Assessing the reversibility of progerin-induced damage and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies. METHODS: We used CRISPR-Cas9 technology to generate LmnaHGPSrev/HGPSrev (HGPSrev) mice engineered to ubiquitously express progerin while lacking lamin A and allowing progerin suppression and lamin A restoration in a time- and cell type-specific manner on Cre recombinase activation. We characterized the phenotype of HGPSrev mice and crossed them with Cre transgenic lines to assess the effects of suppressing progerin and restoring lamin A ubiquitously at different disease stages as well as specifically in vascular smooth muscle cells and cardiomyocytes. RESULTS: Like patients with HGPS, HGPSrev mice appear healthy at birth and progressively develop HGPS symptoms, including failure to thrive, lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electrocardiographic anomalies, and precocious death (median lifespan of 15 months versus 26 months in wild-type controls, P<0.0001). Ubiquitous progerin suppression and lamin A restoration significantly extended lifespan when induced in 6-month-old mildly symptomatic mice and even in severely ill animals aged 13 months, although the benefit was much more pronounced on early intervention (84.5% lifespan extension in mildly symptomatic mice, P<0.0001, and 6.7% in severely ill mice, P<0.01). It is remarkable that major vascular alterations were prevented and lifespan normalized in HGPSrev mice when progerin suppression and lamin A restoration were restricted to vascular smooth muscle cells and cardiomyocytes. CONCLUSIONS: HGPSrev mice constitute a new experimental model for advancing knowledge of HGPS. Our findings suggest that it is never too late to treat HGPS, although benefit is much more pronounced when progerin is targeted in mice with mild symptoms. Despite the broad expression pattern of progerin and its deleterious effects in many organs, restricting its suppression to vascular smooth muscle cells and cardiomyocytes is sufficient to prevent vascular disease and normalize lifespan.