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Abstract Quantitative assessment of the extent of radiological alterations in interstitial lung diseases is a promising field of application that goes beyond the limitations of qualitative scoring. Analysis of density histograms, i.e., skewness, kurtosis, and mean lung attenuation, is among the most studied approaches. We recently proposed their integration in a single parameter, the computerized integrated index (CII), to reduce their redundancy. The CII has proven effective in detecting subclinical lung involvement, correlates with lung function/disease activity, and predicts mortality in systemic sclerosis patients. Seventy-three newly diagnosed and therapy-naive IPF patients (M = 50; median age: 70.2 years) were prospectively enrolled from January 2014 to December 2022, and followed till December 2023. At baseline, all underwent lung function testing and volumetric high resolution chest CT. Density histograms were analyzed with an open-source automatic platform (Slicer 3D) and CII derived by means of Principal Component Analysis, as previously described. During a median follow-up of 5.8 years, 39 (53.4%) subjects died. Median overall survival (OS) was 4.9 years (95% CI 3.7 years-not estimable). The CII was significantly associated with OS (HR 0.49; 95% CI 0.35–0.68; P

Lipotoxicity refers to the harmful effects of excess fatty acids on metabolic health, and it can vary depending on the type of fatty acids involved. Saturated and unsaturated fatty acids exhibit distinct effects, though the precise mechanisms behind these differences remain unclear. Here, we investigated the lipotoxicity of palmitic acid (PA), a saturated fatty acid, compared with oleic acid (OA), a monounsaturated fatty acid, in the hepatic cell line HuH7. Our results demonstrated that PA, unlike OA, induces lipotoxicity, endoplasmic reticulum (ER) stress, and autophagy inhibition. Compared with OA, PA treatment leads to less lipid droplet (LD) accumulation and a significant reduction in the mRNA and protein level of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme of triacylglycerol synthesis. Using modulators of ER stress and autophagy, we established that DGAT1 downregulation by PA is closely linked to these cellular pathways. Notably, the ER stress inhibitor 4-phenylbutyrate can suppress PA-induced DGAT1 downregulation. Furthermore, knockdown of DGAT1 by siRNA or with A922500, a specific DGAT1 inhibitor, resulted in cell death, even with OA. Both PA and OA increased the oxygen consumption rate; however, the increase associated with PA was only partially coupled to ATP synthesis. Importantly, treatment with GW7647 a specific PPARα agonist mitigated the lipotoxic effects of PA, restoring PA-induced ER stress, autophagy block, and DGAT1 suppression. In conclusion, our study highlights the crucial role of DGAT1 in PA-induced lipotoxicity, broadening the knowledge of the mechanisms underlying hepatic lipotoxicity and providing the basis for potential therapeutic interventions.

Background:. To effectively counsel patients prior to shoulder arthroplasty, surgeons should understand the overall life trajectory and life expectancy of patients in the context of the patient’s shoulder pathology and medical comorbidities. Such an understanding can influence both operative and nonoperative decision-making and implant choices. This study evaluated 5-year mortality following shoulder arthroplasty in patients ≥65 years old and identified associated risk factors. Methods:. We utilized Centers for Medicare & Medicaid Services Fee-for-Service inpatient and outpatient claims data to investigate the 5-year mortality rate following shoulder arthroplasty procedures performed from 2014 to 2016. The impact of patient demographics, including fracture diagnosis, year fixed effects, and state fixed effects; patient comorbidities; and hospital-level characteristics on 5-year mortality rates were assessed with use of a Cox proportional hazards regression model. A p value of

Purpose: To evaluate patient-reported outcome measures (PROMs) following arthroscopic partial meniscectomy (APM) in patients with Kellgren-Lawrence (KL) grade 3 on preoperative knee radiographs and a symptomatic meniscal tear. Methods: This was a retrospective study design using prospectively collected data from a single institution. Patients were included if they had KL grade 3 osteoarthritis on preoperative radiographs of the knee and completed a trial of nonoperative treatment for at least 6 weeks prior to APM. Patients were excluded if they had inflammatory arthritis, incomplete preoperative and/or 1-year postoperative follow-up data, repeat knee arthroscopy, and concomitant ligamentous injury. Statistical analyses used PROMs, preoperatively and up to 2 years postoperatively, to assess improvement utilizing scales with previously established thresholds, including minimal clinically important difference (MCID) and substantial clinical benefit (SCB). Results: Eighty-two patients met the eligibility criteria (49 women [60%], mean [SD] age, 53.1 [9.3] years). At the 1-year follow-up, most patients achieved MCID: 73% in Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain, 66% in KOOS Symptoms, and 78% in KOOS Activities of Daily Living (ADL). These improvements were similar at the 2-year follow-up: 75%, 72%, and 79% in each subscale, respectively. SCB was also demonstrated 1 year postoperatively, with 56%, 73%, and 71% achieving SCB for the KOOS Pain, Symptoms, and ADL subscales, respectively. These results largely persisted at the 2-year follow-up. Visual analog scale scores for pain also improved at 1- and 2-year postoperative periods with mean improvements from baseline of 2.80 and 2.87 points, respectively. Marx Activity Score decreased on average from baseline to 1- and 2-year follow-up. Conclusions: At a minimum of 1-year follow-up, most patients with KL grade 3 and a meniscal tear achieved MCID and SCB in KOOS Pain, KOOS Symptoms, and KOOS ADL, indicating meaningful outcome improvement for these patients. Level of Evidence: Level IV, therapeutic case series.

Blake M Bacevich,1 Richard David James Smith,1 Alec M Reihl,1 Augustus D Mazzocca,1,2 Ian D Hutchinson1 1Division of Sports Medicine, Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Massachusetts General Brigham, Boston, MA, USA; 2Medical Director, Division of Sports Medicine, Department of Orthopaedic Surgery, Massachusetts General Brigham, Boston, MA, USACorrespondence: Ian D Hutchinson, Division of Sports Medicine, Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, Tel +1 781-487-6166, Fax +1 781-487-6826, Email ihutchinson@mgh.harvard.eduAbstract: Despite significant advances in the understanding and delivery of osteosynthesis, fracture non-union remains a challenging clinical problem in orthopaedic surgery. To bridge the gap, basic science characterization of fracture healing provides a platform to identify and target biological strategies to enhance fracture healing. Of immense interest, Platelet-rich plasma (PRP) is a point of care orthobiologic that has been extensively studied in bone and soft tissue healing given its relative ease of translation from the benchtop to the clinic. The aim of this narrative review is to describe and relate pre-clinical in-vitro and in-vivo findings to clinical observations investigating the efficacy of PRP to enhance bone healing for primary fracture management and non-union treatment. A particular emphasis is placed on the heterogeneity of PRP preparation techniques, composition, activation strategies, and delivery. In the context of existing data, the routine use of PRP to enhance primary fracture healing and non-union management cannot be supported. However, it is acknowledged that extensive heterogeneity of PRP treatments in clinical studies adds obscurity; ultimately, refinement (and consensus) of PRP treatments for specific clinical indications, including repetition studies are warranted.Keywords: platelet rich plasma, bone regeneration, fracture healing, fractures, ununited

Smart cities include complex ICT ecosystems, whose definition requires the cooperation of several software systems. Among them, Intelligent Public Transportation Systems (IPTS) aim to effectively exploit public transit resources. Still, adopting an IPTS is non-trivial. Off-the-shelf IPTS are often tied to specific technologies and, thus, not easy to integrate within existing software ecosystems. Moreover, despite IPTS introduce several peculiar issues, there is a lack of domain-specific reference architectures, which would significantly ease the work of practitioners. To fill this gap, starting from the experience gained with the Hitachi Rail company in deploying a large-scale IPTS, we identify a set of requirements for IPTS, and propose a domain-specific reference architecture, compliant with these requirements, whose primary objective is facilitating and standardizing the design of IPTS, by providing guidelines to IPTS designers. Consequently, it eases also the interoperability among different IPTSs. As an example of an IPTS obtainable from the architecture, we present a solution currently deployed by Hitachi in a major Italian city. Still, being independent from the specific considered urban scenario, the architecture can be easily instantiated in different cities with similar needs. Finally, we discuss some research challenges which should be further investigated in this domain.

Background: Connective tissue subacromial bursa-derived progenitor cells (SBDCs) have been suggested as a potent biologic augment to promote healing of the repaired rotator cuff tendon. Maximizing the amount of retained progenitor cells at the tendon repair site is essential for ensuring an optimal healing environment, warranting a search for proadhesive and proliferative adjuvants. The purpose was to evaluate the effect of magnesium (Mg), platelet-rich plasma (PRP), and a combination of both adjuvants on the in vitro cellular adhesion and proliferation potential of SBDCs on suture material commonly used in rotator cuff surgery. Methods: SBDCs were isolated from subacromial bursa samples harvested during rotator cuff repair and cultured in growth media. Commercially available collagen-coated nonabsorbable flat-braided suture was cut into 1-inch pieces, placed into 48-well culture dishes, and sterilized under ultraviolet light. Either a one-time dose of 5 mM sterile Mg, 0.2 mL of PRP, or a combination of both adjuvants was added, while a group without treatment served as a negative control. Cellular proliferation and adhesion assays on suture material were performed for each treatment condition. Results: Augmenting the suture with Mg resulted in a significantly increased cellular adhesion (total number of attached cells) of SBDCs compared to PRP alone (31,527 ± 19,884 vs. 13,619 ± 8808; P .05, respectively). Conclusion: Augmenting suture material with Mg resulted in a significantly increased cellular adhesion of SBDCs compared to untreated suture material, as well as augmentation with PRP alone or a combination of both adjuvants. Further, Mg with or without PRP augmentation achieved a significant increase in the cellular proliferation of SBDCs on suture material compared to untreated sutures and augmentation with PRP alone. Application of Mg may be a clinically feasible approach to optimizing the use of SBDCs as a biological augment in rotator cuff repair, while combined augmentation with PRP may harness the full potential for optimized tissue recovery due to the high concentration of PRP-derived growth factors.

Abstract Nuclear factors rapidly scan the genome for their targets, but the role of nuclear organization in such search is uncharted. Here we analyzed how multiple factors explore chromatin, combining live-cell single-molecule tracking with multifocal structured illumination of DNA density. We find that factors displaying higher bound fractions sample DNA-dense regions more exhaustively. Focusing on the tumor-suppressor p53, we demonstrate that it searches for targets by alternating between rapid diffusion in the interchromatin compartment and compact sampling of chromatin dense regions. Efficient targeting requires balanced interactions with chromatin: fusing p53 with an exogenous intrinsically disordered region potentiates p53-mediated target gene activation at low concentrations, but leads to condensates at higher levels, derailing its search and downregulating transcription. Our findings highlight the role of disordered regions on factors search and showcase a powerful method to generate traffic maps of the eukaryotic nucleus to dissect how its organization guides nuclear factors action.