Objectives: The Global Leadership Initiative on Malnutrition (GLIM) is a framework for diagnosing malnutrition. The applicability of GLIM in patients receiving dialysis remains insufficiently explored. This study aimed to identify the most prevalent phenotypic criteria, assess whether dialysis per se can be used as the sole etiological criterion, and evaluate dietitians' perceptions of GLIM's feasibility in clinical practice. Methods: In this exploratory mix-method study, adult patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) were recruited from six Swedish dialysis centers. Malnutrition was diagnosed and graded according to GLIM. Phenotypic criteria included unintentional weight loss, low body mass index, and low muscle mass assessed by calf or arm muscle circumference. Two etiologic models were applied: (I) reduced dietary intake or inflammation, and (II) dialysis as the sole disease-related burden. Renal dietitians conducted assessments and completed a questionnaire on feasibility. Results: Ninety-three patients were included (HD n = 57, PD n = 36), median age 74 y; 60% were male and 43% had diabetes. Low muscle mass was the most prevalent phenotypic criterion (49%). Malnutrition prevalence was 42% using model I and 55% using model II. Ten dietitians completed the assessments, with a median time of 15 minutes. Facilitators included clear guidelines, appropriate equipment, and organizational support. Assessment was also perceived as motivating for patients. Conclusions: The prevalence of malnutrition among dialysis patients using GLIM varied between 42% and 55% depending on the etiological model. Low muscle mass was the most common phenotypic criterion. GLIM appeared feasible for routine use in dialysis care.
Purpose: Clinical features of COPD and asthma overlap, complicating differential diagnosis. This study investigated the prevalence of comorbid asthma in COPD patients and its association with patient-related outcomes.Materials and methods: Patients with a doctor’s diagnosis of COPD were randomly selected in two cohorts 2005 (n = 1060) and 2014 (n = 1671), from primary and secondary care in Sweden. Data were collected from medical records and patient questionnaires at baseline and at follow-up (2012 and 2022, respectively). Questionnaires included data on exacerbations. Symptoms were assessed using the clinical COPD questionnaire (CCQ). Comorbid asthma was identified through medical records. Ten-year mortality data were obtained from national registers. Logistic and linear regression assessed associations with patient-reported outcomes; Cox regression was applied for mortality analyses.Results: Comorbid asthma was found in 22% of the 2005 cohort and 9% of the 2014 cohort (p < .001). In both cohorts, it was associated with an increased risk of exacerbations: OR (95% CI) 1.58 (1.07–2.32), p = .02, and 2.20 (1.38–3.52), p < .001, respectively. No associations were found between comorbid asthma and worsening of health status (CCQ). Mortality risk did not differ in the 2005 cohort, HR (95% CI) 0.92 (0.71–1.18), but was lower in the 2014 cohort, HR (95% CI) 0.67 (0.49–0.93), p = .02.Conclusion: Comorbid asthma in COPD has changed from 22 to 9%, potentially due to improved diagnostics. Comorbid asthma remains clinically relevant due to its association with an increased exacerbation risk.
Background Metabolic dysfunction–associated steatotic liver disease (MASLD) is highly prevalent and frequently undiagnosed, despite liver fibrosis being the strongest predictor of liver-related morbidity and mortality. We aimed to quantify Fibrosis-4 (FIB-4) index-based fibrosis risk and to evaluate guideline-recommended follow-up—FIB-4 documentation, confirmatory testing, and specialist referral—in a large US cohort. Methods We conducted a retrospective study of electronic health record data from the US All of Us Research Program. Among adults aged 35 years or older with sufficient laboratory data, FIB-4 scores were calculated from routinely captured biomarkers, classified as low (<1.3), indeterminate (1.3–2.67; 2.0–2.67 if aged ≥65 years), or high risk (>2.67), and described across sociodemographic and metabolic subgroups; associations with incident major adverse liver outcomes (MALO) were assessed with Cox proportional-hazards regression. We examined FIB-4 documentation, confirmatory testing, and specialty referrals within 365 days of the index FIB-4 date. Findings Among 136,004 participants (mean age 60.8 years [SD 13.5]; 79,365 [58.4%] female; 81,420 [59.9%] White, 21,779 [16.0%] Hispanic or Latino, 20,076 [14.8%] Black), 26,971 (19.8%, 95% CI 19.6–20.0) had indeterminate and 11,217 (8.2%, 8.1–8.4) high FIB-4–based fibrosis risk. Elevated risk was more frequent with cardiovascular disease (41.7% vs 25.6%), hypertension (30.7% vs 23.4%), and type 2 diabetes (29.7% vs 27.4%), rising from 25.6% with no metabolic comorbidities to 36.6% with four. FIB-4 documentation was rare, and fewer than 1% of high-risk participants underwent confirmatory testing or referral; referral was low across risk categories (0.19% high, 0.19% indeterminate, 0.25% low risk). MALO occurred in 1308 (11.7%) high-risk vs 830 (0.8%) low-risk participants (adjusted hazard ratio 19.68, 95% CI 17.88–21.67). Interpretation Routinely collected laboratory data identify substantial liver fibrosis risk in this volunteer US cohort, yet guideline-recommended follow-up is uncommon. Implementation strategies such as automated risk calculation and reflex-based testing pathways could reduce missed opportunities for earlier diagnosis and intervention. Funding No specific funding was received for this study.
Precise and flexible control of gene expression is essential for dissecting gene function in complex biological systems. Although recent developments in genetic engineering and CRISPR/Cas9 technology have expanded tools for gene activation, suppression and editing, their application in physiologically relevant models remains challenging, time consuming, and expensive. Here, we present a modular, doxycycline-inducible vector system that integrates gene overexpression, shRNA-mediated knockdown, and CRISPR/Cas9-mediated regulation within a single, lentivirus-compatible system. The modular design allows rapid exchange of selection markers, epitope tags and reporters via Gateway cloning, providing broad adaptability across experimental settings. In addition to standard fluorescent and luminescent reporters, the system includes advanced sensors, such as FUCCI cell cycle reporters, to enable monitoring of cellular processes. By combining fluorescence barcoding with combinatorial genetic perturbations, the platform supports multiplexed analysis of gene function and genetic interactions through phenotypic characterization by multiplex fluorescence imaging or flow cytometry. We demonstrate its utility in vivo with breast cancer intraductal xenografts to reveal that ER+ breast cancer cells (MCF7) rely on androgen (AR), estrogen (ER) and progesterone receptors (PR) for in vivo growth. This versatile gene perturbation system provides tight temporal control, streamlined implementation, and high-content phenotyping capacity facilitating efficient in vitro and in vivo studies while reducing the use of animals in in vivo validation experiments. It thus expands the experimental repertoire for dynamic, multigene interrogation in complex systems. ### Competing Interest Statement The authors have declared no competing interest. Barncancerfonden, https://ror.org/05072yv34, TJ2019-0036 Cancer Research KI Blue Sky Award Felix Mindus Contribution to Leukemia Research, 2019-01992 NCKV Loo and Hans Osterman Foundation, 2020-01208 Karolinska Institutet Research Foundation, 2020-01685, 2022-01749 Swedish Cancer Society, 21 0352 PT Hållsten Foundation SciLifeLab Technology Development Project Grant Novo Nordisk Pioneer Innovator Grant 1, NNF22OC0076798 Marie Skłodowska-Curie, 859860
LBA5500 Background: Optimal timing of cytoreduction in non-frail patients (pts) with seemingly resectable stage IIIB-IVB ovarian, tubal, and peritoneal carcinoma (OC) remains controversial. Methods: TRUST is an international randomized multicenter phase III trial in pts with stage IIIB-IVB OC and good performance status (ECOG 0/1) comparing primary cytoreductive surgery (PCS) followed by 6 cycles of intravenous (iv) chemotherapy to 3 cycles of neoadjuvant iv chemotherapy (NACT) followed by interval cytoreductive surgery (ICS) and 3 further iv cycles. Maintenance treatment with bevacizumab and/or PARP inhibitors was allowed if selection criteria was similar for both arms. Pts were eligible for the study if preoperative clinical and radiologic assessment identified them as potential candidates for PCS. To ensure surgical quality, participating centers complied with an onsite surgery quality assurance audit, had adequate infrastructure, surgical proficiency (complete resection rates ≥50% in PCS) and sufficient volume (≥36 PCS/year). The intent to treat analysis population included all eligible pts with confirmed stage IIIB-IVB disease. The primary endpoint was overall survival (OS). Superiority was tested using a two-sided stratified log-rank test with significance level 0.05. Secondary endpoints were progression-free survival (PFS) and surgical complications. Results: A total of 688 eligible pts (median age: 63y; range: 32-83) underwent randomization: 345 were assigned to PCS and 343 to NACT/ICS. 91% had high-grade serous histology. Complete resection was achieved in 61.7%/62.9% of all randomized/all operated pts in the PCS group and 72%/76.6% in the ICS group. Median PFS was 22.2 months in the PCS group, and 19.7 months in the ICS group (HR 0.80 95%CI: 0.66-0.96; p=0.02). Median OS was 54.3 months in the PCS group and 48.3 months in the ICS group (HR 0.89 95%CI: 0.74-1.08; p=0.24). Pts with complete cytoreduction after PCS had the most favorable outcome, with a median PFS and OS of 27.9 and 67.0 months, respectively. A long-term benefit from PCS was seen in all analyzed subgroups. The benefit of PCS was most prominent in stage III pts (n=468): median PFS for PCS vs ICS, 26.3 vs 21.4 mos; median OS for PCS vs ICS, 63.7 vs 53.2 months. Major postoperative complication rates were acceptable, with a 30-day postoperative mortality rate of < 1% in both groups. Conclusions: In expert centers with proven surgical quality, PCS followed by iv chemotherapy resulted in a significantly longer median PFS and a numerically longer OS compared to NACT/ICS in non-frail OC pts. Although statistical significance in the primary endpoint was not reached, this is the first randomized trial to show a benefit of PCS over ICS. This benefit is likely to be associated with the high complete resection rate, reinforcing PCS as a standard of care in non-frail pts with seemingly resectable advanced OC. Clinical trial information: NCT02828618 .
