Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy.

Introduction: Pompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels. Method: In a single-center, open-label prospective study, we assessed ITI therapy's efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI. Results: This study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea. Conclusion: ITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.

Oral Delivery of Photopolymerizable Nanogels Loaded with Gemcitabine for Pancreatic Cancer Therapy: Formulation Design, and in vitro and in vivo Evaluations.

Background: Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients. Methods: We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug. Results: Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91±7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07±19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM's AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙µg/mL) compared to oral free-GEM (19.04 hr∙µg/mL) after oral administration (p<0.01), highlighting NGs' efficacy in impeding rapid drug metabolism and enhancing retention. Conclusion: In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.

Insights into optimal surgical fixation for posterior malleolar fractures.

Aims: The optimal management of posterior malleolar ankle fractures, a prevalent type of ankle trauma, is essential for improved prognosis. However, there remains a debate over the most effective surgical approach, particularly between screw and plate fixation methods. This study aims to investigate the differences in outcomes associated with these fixation techniques. Methods: We conducted a comprehensive review of clinical trials comparing anteroposterior (A-P) screws, posteroanterior (P-A) screws, and plate fixation. Two investigators validated the data sourced from multiple databases (MEDLINE, EMBASE, and Web of Science). Following PRISMA guidelines, we carried out a network meta-analysis (NMA) using visual analogue scale and American Orthopaedic Foot and Ankle Score (AOFAS) as primary outcomes. Secondary outcomes included range of motion limitations, radiological outcomes, and complication rates. Results: The NMA encompassed 13 studies, consisting of four randomized trials and eight retrospective ones. According to the surface under the cumulative ranking curve-based ranking, the A-P screw was ranked highest for improvements in AOFAS and exhibited lowest in infection and peroneal nerve injury incidence. The P-A screws, on the other hand, excelled in terms of VAS score improvements. Conversely, posterior buttress plate fixation showed the least incidence of osteoarthritis grade progression, postoperative articular step-off ≥ 2 mm, nonunions, and loss of ankle dorsiflexion ≥ 5°, though it underperformed in most other clinical outcomes. Conclusion: The NMA suggests that open plating is more likely to provide better radiological outcomes, while screw fixation may have a greater potential for superior functional and pain results. Nevertheless, clinicians should still consider the fragment size and fracture pattern, weighing the advantages of rigid biomechanical fixation against the possibility of soft-tissue damage, to optimize treatment results.

Beyond traditional therapies: a network meta-analysis on the treatment efficacy for chronic phantom limb pain.

BACKGROUND: Phantom limb pain (PLP) frequently affects individuals with limb amputations. When PLP evolves into its chronic phase, known as chronic PLP, traditional therapies often fall short in providing sufficient relief. The optimal intervention for chronic PLP remains unclear. OBJECTIVE: The objectives of this network meta-analysis (NMA) were to examine the efficacy of different treatments on pain intensity for patients with chronic PLP. EVIDENCE REVIEW: We searched Medline, EMBASE, Cochrane CENTRAL, Scopus, and CINAHL EBSCO, focusing on randomized controlled trials (RCTs) that evaluated interventions such as neuromodulation, neural block, pharmacological methods, and alternative treatments. An NMA was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The primary outcome was pain score improvement, and the secondary outcomes were adverse events. FINDINGS: The NMA, incorporating 12 RCTs, indicated that neuromodulation, specifically repetitive transcranial magnetic stimulation, provided the most substantial pain improvement when compared with placebo/sham groups (mean difference=-2.9 points, 95% CI=-4.62 to -1.18; quality of evidence (QoE): moderate). Pharmacological intervention using morphine was associated with a significant increase in adverse event rate (OR=6.04, 95% CI=2.26 to 16.12; QoE: low). CONCLUSIONS: The NMA suggests that neuromodulation using repetitive transcranial magnetic stimulation may be associated with significantly larger pain improvement for chronic PLP. However, the paucity of studies, varying patient characteristics across each trial, and absence of long-term results underscore the necessity for more comprehensive, large-scale RCTs. PROSPERO REGISTRATION NUMBER: CRD42023455949.

Direct observation of single-atom defects in monolayer two-dimensional materials by using electron ptychography at 200 kV acceleration voltage.

Electron ptychography has emerged as a popular technology for high-resolution imaging by combining the high coherence of electron sources with the ultra-fast scanning electron coil. However, the limitations of conventional pixelated detectors, including poor dynamic range and slow data readout speeds, have posed restrictions in the past on conducting electron ptychography experiments. We used the Gatan STELA pixelated detector to capture sequential diffraction data of monolayer two-dimensional (2D) materials for ptychographic reconstruction. By using the pixelated detector and electron ptychography, we demonstrate the observation of the radiation damage at atomic resolution in Transition Metal Dichalcogenides (TMDs).

Effectiveness of sound and darkness interventions for critically ill patients' sleep quality: A systematic review and component network meta-analysis.

BACKGROUND: Noise and lighting are prime factors of poor sleep quality in critically ill patients, which impair recovery and increase the risk of delirium or complications. AIM: To identify and rank the effectiveness of sound and darkness interventions on the sleep quality of critically ill patients. STUDY DESIGN: This systematic review and component network meta-analysis was based on the Preferred Reporting Items for Systematic Reviews incorporating the Network Meta-Analyses (PRISMA-NMA) Statement. The Embase, MEDLINE, Cochrane CENTRAL, CINAHL, Airiti Library, and Google Scholar databases were searched from inception to August 10, 2021, for randomized controlled trials (RCTs) on sound and darkness interventions targeting critically ill patients' sleep quality. We applied standard and component NMA to determine the effects of interventions. The certainty of evidence was evaluated using the Cochrane risk-of-bias tool (V.2.0) and the online Confidence in Network Meta-Analysis (CINeMA) application. RESULTS: Twenty-four RCTs with 1507 participants who used combined interventions constituting seven competing interventions were included in the standard NMA. The combination of earplugs, eye masks, and music; eye masks alone; earplugs combined with eye masks; and music alone had beneficial intervention effects. The combination of earplugs, eye masks, and music was the best intervention, and these components had no interaction effect. An eye mask had the best relative effect, followed by music, quiet time, and earplugs. CONCLUSIONS: This study provides clinical evidence of the effectiveness of using eye masks, music, and earplugs to improve sleep quality in critically ill patients. We also recommend future research using bedtime music, nocturnal eye masks, and quiet time, which had the best relative effects on sleep quality. RELEVANCE TO CLINICAL PRACTICE: This study provides recommendations for interventions that nurses can use to improve critically ill patients' sleep quality.

Health and care workers in long-term care facilities and their role in preventing emerging infectious diseases: A scoping review.

BACKGROUND: The COVID-19 pandemic has had a tremendous impact on healthcare systems worldwide. In particular, long-term care facilities have proved more susceptible to infection as they care for vulnerable populations at high risk of chronic illness. How this impacts the role and core competencies of health and care workers in these facilities remains less understood. AIM: Describe how health and care workers contribute to the prevention of emerging infectious diseases in long-term care facilities. DESIGN: A scoping review. METHODS: A systematic search of literature dating from 2002 to 2022 was conducted in the following databases: EMBASE, Medline (Ovid), Cochrane Library, CINAHL Plus with Full Text (EBSCOhost), Web of Science, and AgeLine. Studies were selected if they focused on health and care workers in long-term care facilities, offered a perspective on the prevention of emerging infectious diseases or infection prevention and control, and were original qualitative or quantitative studies in English. Data were extracted, cross-checked and analyzed by two researchers, and any difference in views regarding the appropriateness of literature would be resolved by consulting a third researcher. An inductive descriptive approach was applied for the analysis of results, and themes were established via consensus meetings. RESULTS: A total of fourteen studies from Asia, Europe, and the Americas were included. Three themes emerged from the review: "The roles of health and care workers evolve with the times", "The core competencies of health and care workers are essential for preventing emerging infectious diseases in long-term care facilities" and "The key to successful prevention of emerging infectious diseases in long-term care facilities is through a systematic, comprehensive effort that mobilize health and care workers at all levels". Health and care workers had to take on increasingly complex roles and rely on their core competencies to cope with epidemic changes, and facility resources, employee quality and management models were found to have significantly improved infection prevention and control outcomes. CONCLUSIONS: The roles of health and care workers are evolving, and effective infection prevention within long-term care facilities depends on their ability to perform core competencies with skill and confidence. Moreover, a systematic, comprehensive framework, for which this paper proposes three guidelines, is urgently needed to ensure consistent policy implementation within the facility as well as support and access to resources for health and care workers. CLINICAL RELEVANCE: Infection prevention efforts within long-term care facilities must take into account the evolving roles of health and care workers, with a focus on guaranteeing access to resources, training and support that will help them gain the core competencies necessary for juggling those roles. In addition, there is an urgent need for research instruments that will help assess those competencies and identify areas of improvement.

Determining the Optimal Treatment for Idiopathic Clubfoot: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Clubfoot, or congenital talipes equinovarus deformity, is a common anomaly affecting the foot in infants. However, clinical equipoise remains between different interventions, especially those based on the Ponseti method. The aim of this study was to examine the clinical outcomes of the various interventions for treating idiopathic clubfoot. METHODS: Searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Scopus, and CINAHL were conducted. Randomized controlled trials comparing different interventions, including the Ponseti method, accelerated Ponseti method, Ponseti method with botulinum toxin type A (Botox) injection, Ponseti method with early tibialis anterior tendon transfer (TATT), Kite method, and surgical treatment, were included. Network meta-analyses (NMAs) were conducted according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) reporting guidelines. The primary outcomes were the change in total Pirani score and maximal ankle dorsiflexion. Secondary outcomes were the number of casts, time in casts, and rates of tenotomy, total complications, relapse, adverse events, and additional required major surgery. RESULTS: Eleven randomized controlled trials involving 740 feet were included. According to the SUCRA (surface under the cumulative ranking curve)-based relative ranking, the Ponseti method was associated with the best outcomes in terms of Pirani score changes, maximal ankle dorsiflexion, number of casts, adverse events, and total complications, whereas the accelerated Ponseti method was associated with the best outcomes in terms of time in casts and tenotomy rate. Early TATT ranked best in terms of relapse rate. The Ponseti method with Botox injection was associated with the best outcomes in terms of the need for additional major surgery. CONCLUSIONS: The NMAs suggest that the Ponseti method is the optimal treatment overall, despite potential drawbacks such as longer time in casts and higher rates of tenotomy, relapse, and the need for additional surgery compared with other modified approaches. Therefore, clinicians should consider how treatments can be tailored individually. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Bone-derived PDGF-BB drives brain vascular calcification in male mice.

Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue is well studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular calcification in male mice. Aged male mice had higher serum PDGF-BB levels and a higher incidence of brain calcification compared with young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevated serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA-Seq (scRNA-Seq) revealed that PDGF-BB upregulated multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRß (p-PDGFRß) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of osteoblast differentiation genes in PCs and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induced brain vascular calcification by activating the p-PDGFRß/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.

Differential cellular responses to FDA-approved nanomedicines: an exploration of albumin-based nanocarriers and liposomes in protein corona formation.

Albumin nanoparticles (NPs) and PEGylated liposomes have garnered tremendous interest as therapeutic drug carriers due to their unique physicochemical properties. These unique properties also have significant effects on the composition and structure of the protein corona formed around these NPs in a biological environment. Herein, protein corona formation on albumin NPs and liposomes was simultaneously evaluated through in vitro and simulation studies. The sizes of both types of NPs increased with more negatively charged interfaces upon being introduced into fetal bovine serum. Gel electrophoresis and label-free quantitative proteomics were performed to identify proteins recruited to the hard corona, and fewer proteins were found in albumin NPs than in liposomes, which is in accordance with isothermal titration calorimetry. The cellular uptake efficiency of the two NPs significantly differed in different serum concentrations, which was further scrutinized by loading an anticancer compound into albumin NPs. The presence of the hard protein corona increased the cellular uptake of albumin NPs in comparison with liposomes. In our simulation study, a specific receptor present in the membrane was greatly attracted to the albumin-apolipoprotein E complex. Overall, this study not only evaluated protein corona formation on albumin NPs, but also made promising advancements toward albumin- and liposome-based therapeutic systems.

A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment.

Doxorubicin is a widely-used chemotherapeutic drug, however its high toxicity poses a significant challenge for its clinical use. To address this issue, a physiologically-based pharmacokinetic (PBPK) model was implemented to quantitatively assess doxorubicin toxicity at cellular scale. Due to its unique pharmacokinetic behavior (e.g. high volume of distribution and affinity to extra-plasma tissue compartments), we proposed a modified PBPK model structure and developed the model with multispecies extrapolation to compensate for the limitation of obtaining clinical tissue data. Our model predicted the disposition of doxorubicin in multiple tissues including clinical tissue data with an overall absolute average fold error (AAFE) of 2.12. The model's performance was further validated with 8 clinical datasets in combined with intracellular doxorubicin concentration with an average AAFE of 1.98. To assess the potential cellular toxicity, toxicity levels and area under curve (AUC) were defined for different dosing regimens in toxic and non-toxic scenarios. The cellular concentrations of doxorubicin in multiple organ sites associated with commonly observed adverse effects (AEs) were simulated and calculated the AUC for quantitative assessments. Our findings supported the clinical dosing regimen of 75 mg/m2 with a 21-day interval and suggest that slow infusion and separated single high doses may lower the risk of developing AEs from a cellular level, providing valuable insights for the risk assessment of doxorubicin chemotherapy. In conclusion, our work highlights the potential of PBPK modelling to provide quantitative assessments of cellular toxicity and supports the use of clinical dosing regimens to mitigate the risk of adverse effects.

A risk stratification model modified from the U.S. guideline could be applied in an Asian population with or without ASCVD.

AIM: This study aimed to evaluate the performance of a modified US (MUS) model for risk prediction of cardiovascular (CV) events in Asian patients and compare it to European and Japanese models. MATERIAL AND METHODS: The MUS model, based on the US ACC/AHA 2018 lipid treatment guideline, was employed to stratify patients under primary or secondary prevention. Two multi-center prospective observational registry cohorts, T-SPARCLE and T-PPARCLE, were used to validate the scoring system, and the primary outcome was the time to first occurrence/recurrence of major adverse cardiac events (MACEs). The MUS model's performance was compared to other models from Europe and Japan. RESULTS: A total of 10,733 patients with the mean age of 64.2 (SD: 11.9) and 36.5% female were followed up for a median of 5.4 years. The MUS model was validated, with an AUC score of 0.73 (95% CI 0.68-0.78). The European and Japanese models had AUC scores ranging from 0.6 to 0.7. The MUS model categorized patients into four distinct CV risk groups, with hazard ratios (HRs) as follows: very high-vs. high-risk group (HR=1.91, 95% CI 1.53-2.39), high-vs. moderate-risk group (HR=2.08, 95% CI 1.60-2.69), and moderate-vs. low-risk group (HR=3.14, 95% CI 1.63-6.03). After adjusting for the MUS model, a history of ASCVD was not a significant predictor of adverse cardiovascular outcomes within each risk group. CONCLUSION: The MUS model is an effective tool for risk stratification in Asian patients with and without ASCVD, accurately predicting MACEs and performing comparably or better than other established risk models. Our findings suggest that patient management should focus on background risk factors instead of solely on primary or secondary prevention.

Effectiveness of outpatient geriatric evaluation and management intervention on survival and nursing home admission: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The benefit of inpatient comprehensive geriatric assessment on patient survival and function has been demonstrated among frail older patients. However, the influence of outpatient geriatric evaluation and management (GEM) on clinical outcomes remains debated. This study aimed to update the research evidence detailing the effect of outpatient GEM on survival and nursing-home admission through a comparison with conventional care. METHODS: Cochrane Library, EMBASE, and MEDLINE databases were searched up to January 29th, 2022, to identify randomized controlled trials (RCTs) including older people over age 55 that compared outpatient GEM with conventional care on mortality (primary outcome) and nursing-home admission (secondary outcome) during a follow-up period of 12 to 36 months. RESULTS: Nineteen reports from 11 studies that recruited 7,993 participants (mean age 70-83) were included. Overall, outpatient GEM significantly reduced mortality (risk ratio (RR) = 0.87, 95% confidence interval (CI) = 0.77-0.99, I2 = 12%). For the subgroup analysis categorized by different follow-up periods, its prognostic benefit was only disclosed for 24-month mortality (RR = 0.68, 95% CI = 0.51-0.91, I2 = 0%), but not for 12- or 15 to 18-month mortality. Furthermore, outpatient GEM had significantly trivial effects on nursing-home admission during the follow-up period of 12 or 24 months (RR = 0.91, 95% CI = 0.74-1.12, I2 = 0%). CONCLUSIONS: Outpatient GEM led by a geriatrician with a multidisciplinary team improved overall survival, specifically during the 24-month follow-up period. This trivial effect was demonstrated in rates of nursing-home admission. Future research on outpatient GEM involving a larger cohort is warranted to corroborate our findings.

"Bone-SASP" in Skeletal Aging.

Senescence is a complex cell state characterized by stable cell cycle arrest and a unique secretory pattern known as the senescence-associated secretory phenotype (SASP). The SASP factors, which are heterogeneous and tissue specific, normally include chemokines, cytokines, growth factors, adhesion molecules, and lipid components that can lead to multiple age-associated disorders by eliciting local and systemic consequences. The skeleton is a highly dynamic organ that changes constantly in shape and composition. Senescent cells in bone and bone marrow produce diverse SASP factors that induce alterations of the skeleton through paracrine effects. Herein, we refer to bone cell-associated SASP as "bone-SASP." In this review, we describe current knowledge of cellular senescence and SASP, focusing on the role of senescent cells in mediating bone pathologies during natural aging and premature aging syndromes. We also summarize the role of cellular senescence and the bone-SASP in glucocorticoids-induced bone damage. In addition, we discuss the role of bone-SASP in the development of osteoarthritis, highlighting the mechanisms by which bone-SASP drives subchondral bone changes in metabolic syndrome-associated osteoarthritis.

Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow.

The chronic use of glucocorticoids decreases bone mass and quality and increases bone-marrow adiposity, but the underlying mechanisms remain unclear. Here, we show that bone-marrow adipocyte (BMAd) lineage cells in adult mice undergo rapid cellular senescence upon glucocorticoid treatment. The senescent BMAds acquire a senescence-associated secretory phenotype, which spreads senescence in bone and bone marrow. Mechanistically, glucocorticoids increase the synthesis of oxylipins, such as 15d-PGJ2, for peroxisome proliferator-activated receptor gamma (PPARγ) activation. PPARγ stimulates the expression of key senescence genes and also promotes oxylipin synthesis in BMAds, forming a positive feedback loop. Transplanting senescent BMAds into the bone marrow of healthy mice is sufficient to induce the secondary spread of senescent cells and bone-loss phenotypes, whereas transplanting BMAds harboring a p16INK4a deletion did not show such effects. Thus, glucocorticoid treatment induces a lipid metabolic circuit that robustly triggers the senescence of BMAd lineage cells that, in turn, act as the mediators of glucocorticoid-induced bone deterioration.

Is implant choice associated with fixation strength for displaced radial neck fracture: a network meta-analysis of biomechanical studies.

The multitude of fixation options for radial neck fractures, such as pins, screws, biodegradable pins and screws, locking plates, and blade plates, has led to a lack of consensus on the optimal implant choice and associated biomechanical properties. This study aims to evaluate the biomechanical strength of various fixation constructs in axial, sagittal, and torsional loading directions. We included biomechanical studies comparing different interventions, such as cross/parallel screws, nonlocking plates with or without augmented screws, fixed angle devices (T or anatomic locking plates or blade plates), and cross pins. A systematic search of MEDLINE (Ovid), Embase, Scopus, and CINAHL EBSCO databases was conducted on September 26th, 2022. Data extraction was carried out by one author and verified by another. A network meta-analysis (NMA) was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Primary outcomes encompassed axial, bending, and torsional stiffness, while the secondary outcome was bending load to failure. Effect sizes were calculated for continuous outcomes, and relative treatment ranking was measured using the surface under the cumulative ranking curve (SUCRA). Our analysis encompassed eight studies, incorporating 172 specimens. The findings indicated that fixed angle constructs, specifically the anatomic locking plate, demonstrated superior axial stiffness (mean difference [MD]: 23.59 N/mm; 95% CI 8.12-39.06) in comparison to the cross screw. Additionally, the blade plate construct excelled in bending stiffness (MD: 32.37 N/mm; 95% CI - 47.37 to 112.11) relative to the cross screw construct, while the cross-screw construct proved to be the most robust in terms of bending load failure. The parallel screw construct performed optimally in torsional stiffness (MD: 139.39 Nm/degree; 95% CI 0.79-277.98) when compared to the cross screw construct. Lastly, the nonlocking plate, locking T plate, and cross-pin constructs were found to be inferior in most respects to alternative interventions. The NMA indicated that fixed angle devices (blade plate and anatomic locking plate) and screw fixations may exhibit enhanced biomechanical strength in axial and bending directions, whereas cross screws demonstrated reduced torsional stability in comparison to parallel screws. It is imperative for clinicians to consider the application of these findings in constraining forces across various directions during early range of motion exercises, taking into account the distinct biomechanical properties of the respective implants.

Elevated PDGF-BB from Bone Impairs Hippocampal Vasculature by Inducing PDGFRß Shedding from Pericytes.

Evidence suggests a unique association between bone aging and neurodegenerative/cerebrovascular disorders. However, the mechanisms underlying bone-brain interplay remain elusive. Here platelet-derived growth factor-BB (PDGF-BB) produced by preosteoclasts in bone is reported to promote age-associated hippocampal vascular impairment. Aberrantly elevated circulating PDGF-BB in aged mice and high-fat diet (HFD)-challenged mice correlates with capillary reduction, pericyte loss, and increased blood-brain barrier (BBB) permeability in their hippocampus. Preosteoclast-specific Pdgfb transgenic mice with markedly high plasma PDGF-BB concentration faithfully recapitulate the age-associated hippocampal BBB impairment and cognitive decline. Conversely, preosteoclast-specific Pdgfb knockout mice have attenuated hippocampal BBB impairment in aged mice or HFD-challenged mice. Persistent exposure of brain pericytes to high concentrations of PDGF-BB upregulates matrix metalloproteinase 14 (MMP14), which promotes ectodomain shedding of PDGF receptor ß (PDGFRß) from pericyte surface. MMP inhibitor treatment alleviates hippocampal pericyte loss and capillary reduction in the conditional Pdgfb transgenic mice and antagonizes BBB leakage in aged mice. The findings establish the role of bone-derived PDGF-BB in mediating hippocampal BBB disruption and identify the ligand-induced PDGFRß shedding as a feedback mechanism for age-associated PDGFRß downregulation and the consequent pericyte loss.

Biomechanical comparison of different suture anchors used in rotator cuff repair surgery-all-suture anchors are equivalent to other suture anchors: a systematic review and network meta-analysis.

PURPOSE: Suture anchors are commonly used to repair rotator cuff tendons in arthroscopy surgery, and several anchor materials have been created to maximize pull-out strength and minimize iatrogenic damage. We hypothesized that all-suture anchors have biomechanical properties equivalent to those of conventional anchors. Our purpose is to compare the biomechanical properties of different anchors used for rotator cuff repair. METHODS: The Embase, PubMed, Cochrane, and Scopus databases were searched for biomechanical studies on various suture anchors. The search keywords included rotator cuff tears and suture anchors, and two authors conducted study a selection, risk of bias assessment, and data extraction. The failure load, stiffness, and displacement were calculated using the mean differences with 95% confidence intervals (CIs). Failure modes were estimated using summary odds ratios with 95% CIs. The surface under the cumulative ranking curve was used for the relative ranking probabilities. A sensitivity analysis was performed by excluding studies using synthetic bones. RESULTS: The polyetheretherketone (PEEK) (p < 0.001) and all-suture anchors (p < 0.001) had higher failure loads than the biocomposite anchors, whereas no significant difference was observed in stiffness among the anchors. The all-suture (p = 0.006) and biocomposite anchors (p < 0.001) had displacements higher than the metal anchors. The relative ranking of the included anchors in failure loads and displacement changed in sensitivity analysis. The meta-analysis did not find significant differences, but the relative ranking probabilities suggested that all-suture anchor had a higher rate of anchor pull-out and a lower rate of eyelet or suture breakage. In contrast, the metal anchors were associated with a higher number of eyelet breakage episodes. CONCLUSIONS: All-suture anchors showed significantly higher failure loads than the biocomposite anchors and similar cyclic displacements to the biocomposite and PEEK anchors. There were no significant differences in stiffness between all-suture and conventional suture anchors. The relative ranking of biomechanical properties changed in sensitivity analysis, suggesting the potential effect of bone marrow density. LEVEL OF EVIDENCE: Level IV.

Combined Left Ventricular Ejection Fraction and N-Terminal pro-B-type Natriuretic Peptide after Sacubitril/Valsartan for Predicting Outcomes in Patients with Heart Failure with Reduced Ejection Fraction.

Background: The aim of this study was to determine whether a combined increase of ≥ 10% in left ventricular ejection fraction (LVEF) and decrease in N-terminal pro-B-type natriuretic peptide (NT pro-BNP) to < 1000 pg/mL after treatment with sacubitril/valsartan (SAC/VAL) in patients with heart failure with reduced ejection fraction (HFrEF) translated to better treatment outcomes in a real-world Taiwanese population. Methods: This is a single-center, prospective, non-randomized, observational study. Consecutive patients with HFrEF were treated with SAC/VAL and followed up for at least 12 months. The primary endpoint was a change in LVEF and reduction in NT pro-BNP at 12 months. The secondary outcomes were death and heart failure (HF) rehospitalization. Results: A total of 105 patients were analyzed after 12 months of SAC/VAL treatment. The mean age was 66.0 ± 11.6 years, and the mean LVEF and NT pro-BNP were 33.6 ± 6.7% and 4462.7 ± 5851.7 pg/mL respectively. The mean LVEF significantly increased to 50.5 ± 10.3% (p < 0.001), while NT pro-BNP decreased to 1270.3 ± 2368.2 pg/mL (p = 0.001) at 12 months, with the greatest changes occurring in the first 3 months of treatment (p < 0.001). Five patients died and 12 were rehospitalized for HF. None of the patients in the responder group died compared to 5 deaths in the non-responder group (p = 0.039). Combined ≥ 10% LVEF increase and NT pro-BNP of < 1000 pg/mL was an independent predictor of death and HF rehospitalization (p = 0.019). Conclusions: SAC/VAL treatment resulted in significant improvements in LVEF, reduced NT pro-BNP level, death and HF hospitalization. Taken separately, an NT pro-BNP level of < 1000 pg/mL was a better predictor than ≥ 10% LVEF increase. Combining both variables predicted fewer deaths and HF rehospitalizations. Even with failure to reach the target dose, SAC/VAL still had significantly beneficial treatment outcomes in Taiwanese patients.