Deep-learning generated B-line score mirrors clinical progression of disease for patients with heart failure.

BACKGROUND: Ultrasound can detect fluid in the alveolar and interstitial spaces of the lung using the presence of artifacts known as B-lines. The aim of this study was to determine whether a deep learning algorithm generated B-line severity score correlated with pulmonary congestion and disease severity based on clinical assessment (as identified by composite congestion score and Rothman index) and to evaluate changes in the score with treatment. Patients suspected of congestive heart failure underwent daily ultrasonography. Eight lung zones (right and left anterior/lateral and superior/inferior) were scanned using a tablet ultrasound system with a phased-array probe. Mixed effects modeling explored the association between average B-line score and the composite congestion score, and average B-line score and Rothman index, respectively. Covariates tested included patient and exam level data (sex, age, presence of selected comorbidities, baseline sodium and hemoglobin, creatinine, vital signs, oxygen delivery amount and delivery method, diuretic dose). RESULTS: Analysis included 110 unique subjects (3379 clips). B-line severity score was significantly associated with the composite congestion score, with a coefficient of 0.7 (95% CI 0.1-1.2 p = 0.02), but was not significantly associated with the Rothman index. CONCLUSIONS: Use of this technology may allow clinicians with limited ultrasound experience to determine an objective measure of B-line burden.

Analysis of correlation between medial joint line change and lower limb coronal alignment after Oxford unicompartmental knee arthroplasty.

BACKGROUND: Lower limb coronal alignment was thought to be a predictive factor for Unicompartmental Knee Arthroplasty (UKA) result. The tibial bony resection and implant position lead to joint line change postoperatively. Analysis was done to find out the correlation between these factors. METHODS: From 2019 to 2021, 90 medial Oxford UKA were implanted by a single surgeon. Hip Knee Ankle Angle (HKAA), Lateral Distal Femoral Angle (LDFA), Medial Proximal Tibial Angle (MPTA), and intraoperative bony resection thickness were measured. The medial joint line change was calculated. The correlation between joint line change and alignment change was evaluated. RESULTS: The mean tibial resection thickness was 4.3 mm. The mean tibial joint line was elevated by 2.3 mm, while the mean femoral joint line proximalized by 0.8 mm. HKAA changed from 8.4° varus preoperatively to 3.6° varus postoperatively. LDFA changed from 89.0° to 86.7°. MPTA changed from 85.6° to 86.6°. Preoperative HKAA showed a strong correlation with postoperative HKAA (p < 0.001), and preoperative MPTA showed a positive correlation with postoperative HKAA (p < 0.001). While preoperative LDFA had a negative correlation with postoperative HKAA (p < 0.001). The femoral joint line change and LDFA change had a significant correlation with HKAA change (p < 0.05). CONCLUSION: The change of joint line had no correlation with postoperative HKAA in Oxford UKA. Preoperative HKAA strongly correlated with postoperative HKAA; while preoperative smaller LDFA and larger MPTA had a moderate correlation with postoperative HKAA. The femoral joint line change and LDFA change had a weak to moderate correlation with HKAA change.

Fastball Quality After Ulnar Collateral Ligament Reconstruction in Major League Baseball Pitchers.

BACKGROUND: The ulnar collateral ligament (UCL) is essential for elbow stability during pitching. In professional baseball, the fastball (FB) is the most commonly used pitch, making postrecovery FB performance after UCL reconstruction (UCLR) a crucial aspect to consider. HYPOTHESES: (1) Pitchers undergoing UCLR would show no significant changes in performance metrics compared with nonoperated pitchers with similar FB velocity and spin rate, and (2) no significant variance would be found in these metrics within the operated pitchers concerning their preinjury anthropometric characteristics and pitching performance metrics. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The study included 91 Major League Baseball (MLB) pitchers who underwent primary UCLR between January 1, 2015, and December 31, 2021. A matched 1:1 control group of MLB pitchers without UCLR injuries was established. Publicly available pitch metrics and anthropometric data were compared between the study and control groups. RESULTS: Disparities in several performance metrics emerged during the first postreturn year (PRY1), including FB use percentage (P = .029), fielder independent pitching (FIP) (P = .021), and standardized FB runs above average per 100 pitches (wFB/C) (P < .001). Subgroup analysis within the UCLR group revealed a negative correlation between presurgery mean FB velocity and its subsequent change (P < .001) and a positive correlation with changes in FIP (P = .025) from the index year to PRY1. A negative correlation was observed between FB use percentage in the index year and its change by PRY1 (P = .002). By the second postreturn year, no significant differences were found in these performance metrics. No factors were significantly related to prolonged recovery time. CONCLUSION: Although FB velocity and spin rate remained consistent, significant differences were observed in FB use percentage, FIP, and wFB/C in PRY1. However, by second postreturn year, these differences were no longer significant. No specific risk factors were identified concerning prolonged recovery time between pre-UCLR FB pitching metrics and the physical anthropometric data. These results suggest that although the short-term postsurgery period may affect more specialized pitching metrics, the basic pitching performance metrics, as hypothesized, remain largely unaffected by UCLR.

Single-bundle ACL combined with ALL reconstruction yields comparable outcomes in patients with varied anatomical risk factors for ACL graft failure.

BACKGROUND: Anterior cruciate ligament (ACL) graft failure is influenced by factors such as meniscal tears and tibial plateau slope. Combined anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstruction has reduced failure rates; however, its efficacy in high-risk patients remains unclear. This study hypothesized that combined ACL and ALL reconstruction would yield similar clinical outcomes in patients with varying risks of ACL failure. PATIENTS AND METHODS: A total of 76 patients who underwent primary single-bundle ACL reconstruction combined with ALL reconstruction between June 2018 and June 2021 were included. The medial tibial slope (MTS), lateral tibial slope (LTS), and anterior tibial translation (ATT) were measured using magnetic resonance imaging and plain radiography of the knee joint. The meniscal lesions were assessed during surgery. Preoperative clinical assessments and final follow-up were conducted using patient-reported outcome measurements (PROMs), including the International Knee Documentation Committee (IKDC) evaluation, Lysholm knee scoring scale, and Tegner Activity scale. PROMs were collected at least two years postoperatively. RESULTS: The average follow-up was 32.5 ± 7.4 months. There were no significant differences in postoperative IKDC score, Lysholm score, or Tegner activity score between patients with or without medial meniscus injury (p = 0.155, 0.914, and 0.042, respectively), with or without lateral meniscus injury (p = 0.737, 0.569, and 0.942, respectively), medial tibial slope > 12° or ≤ 12° (p = 0.290, 0.496, and 0.988, respectively), or lateral tibial slope > 7.4° or ≤ 7.4° (p = 0.213, 0.625, and 0.922, respectively). No significant correlations were found between anterior tibial translation and postoperative IKDC (R = -0.058, p = 0.365), Lysholm (R = -0.017, p = 0.459), or Tegner activity scores (R = -0.147, p = 0.189). CONCLUSION: Our study demonstrates that single-bundle ACL reconstruction combined with ALL reconstruction provides reliable and comparable clinical outcomes in patients with high-risk factors for ACL graft failure, such as increased tibial slope or meniscal injury. Our results suggest that the indications for ALL reconstruction may be expanded to include patients with a high tibial slope or meniscal injury, because these factors have been shown to contribute to increased rotational instability and high rates of ACL graft failure. Future prospective randomized controlled trials with large patient cohorts and long follow-up periods are needed to validate these findings and establish clear guidelines for patient selection and surgical decision-making. LEVEL OF EVIDENCE: Level 3.

Nrf2-mediated adenylosuccinate lyase promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma cells through ferroptosis escape.

Pancreatic cancer has one of the highest fatality rates and the poorest prognosis among all cancer types worldwide. Gemcitabine is a commonly used first-line therapeutic drug for pancreatic cancer; however, the rapid development of resistance to gemcitabine treatment has been observed in numerous patients with pancreatic cancer, and this phenomenon limits the survival benefit of gemcitabine. Adenylosuccinate lyase (ADSL) is a crucial enzyme that serves dual functions in de novo purine biosynthesis, and it has been demonstrated to be associated with clinical aggressiveness, prognosis, and worse patient survival for various cancer types. In the present study, we observed significantly lower ADSL levels in gemcitabine-resistant cells (PANC-1/GemR) than in parental PANC-1 cells, and the knockdown of ADSL significantly increased the gemcitabine resistance of parental PANC-1 cells. We further demonstrated that ADSL repressed the expression of CARD-recruited membrane-associated protein 3 (Carma3), which led to increased gemcitabine resistance, and that nuclear factor erythroid 2-related factor 2 (Nrf2) regulated ADSL expression in parental PANC-1 cells. These results indicate that ADSL is a candidate therapeutic target for pancreatic cancer involving gemcitabine resistance and suggest that the Nrf2/ADSL/Carma3 pathway has therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Double-bundle ACL combined with ALL reconstruction for patients at high risk of ACL failure: clinical and radiological results.

BACKGROUND: We investigated whether double-bundle (DB) anterior cruciate ligament (ACL) reconstruction (ACLR) combined with anterolateral ligament reconstruction (ALLR) improved clinical and radiological outcomes in patients at high risk of ACL failure. The primary outcome was graft failure, and secondary outcomes included knee stability and patient-reported outcome measures (PROMs). PATIENTS AND METHODS: Fifty-two patients who underwent DB ACLR combined with ALLR were included in this retrospective cohort study. Preoperative risk factors, including femorotibial angle (FTA), lateral tibial slope (LTS), medial tibial slope (MTS), and meniscal tears, were assessed using X-ray and magnetic resonance imaging (MRI). The grade of post-operative pivot shift, Lysholm score, and Tegner activity score were used to assess clinical outcomes. The minimum follow up duration was 2 years. RESULTS: The cohort (mean age, 26.1 ± 9.4 years; 51.9% male) had a mean follow-up duration of 28.9 ± 3.4 months. Preoperatively, 57.8% had lateral meniscus (LM) tears, and 61.0% had a grade 2-3 pivot shift. Postoperatively, no graft failures or revision cases occurred during follow-up. Approximately 90.4% of the patients exhibited a negative pivot shift (p < 0.001), with Lysholm and Tegner activity scores of 92.5 ± 6.1 and 5.1 ± 2.0. The medial meniscus (MM) tear group had a significantly smaller FTA than the intact group (p = 0.043). No significant differences in PROMs were found between the LM tear and intact LM groups or between the high and low MTS or LTS groups (p = n.s.). CONCLUSION: DB ACLR combined with ALLR had satisfactory clinical outcomes in patients at high risk of ACL failure, with no graft failures observed during a mean follow-up duration of 2.4 years. The technique effectively reduced the postoperative pivot shift, regardless of preoperative risk factors. STUDY DESIGN: Level IV, retrospective therapeutic case-series. TRAIL REGISTRATION: ethical approval number, 202300134B0; ethical committee, the Institutional Review Board of Chang Gung Medical Foundation.

Failure of the linkage mechanism in a semi-constrained total elbow arthroplasty is a rare and unpredictable event: a review of seven cases.

PURPOSE: Linked component of total elbow arthroplasty (TEA) consisted of bushing and locking pins. Failure of linked components is a rare complication of TEA. This study aims to investigate the mechanism and consequence of failure of the linkage mechanism in TEA surgeries. METHODS: Between 2010 and 2021, five patients received revision operation due to linked component failure. Besides, two patients underwent primary operation at another institute were also analyzed due to failure of the linkage mechanism. RESULTS: All seven patients underwent primary TEA and mean age for primary TEA was 48 (range, 27-62). Two patients had TEA for post-traumatic arthritis, three patients for rheumatoid arthritis, and two patients for comminuted distal humerus fracture. The average time between primary TEA and revision TEA for linked component failure was 13.6 years. Three bushing wear and four locking pin dissociation were diagnosed according to pre-operative radiography. Elbow pain and swelling are the most common clinical symptoms. Severe osteolysis, periprosthetic fracture, and stem loosening were noted in three bushing wear cases. In four dissociation of locking pin cases, breakage of male locking pin phalanges was demonstrated in two patients. For revision procedures, both the locking pins and bushings were replaced. No patients in the study required additional surgery after the revision operation for linked component failure. CONCLUSION: Osteolysis, component loosening, periprosthetic fracture may be expected after linked component failure. Patients should be regularly followed up from short-term to long-term with radiography. Early diagnosis and intervention with linked component exchange can prevent extensive revision surgery.

Analysis of correlation between medial joint line change and lower limb coronal alignment after Oxford unicompartmental knee arthroplasty

Abstract Background: Lower limb coronal alignment was thought to be a predictive factor for Unicompartmental Knee Arthroplasty (UKA) result. The tibial bony resection and implant position lead to joint line change postoperatively. Analysis was done to find out the correlation between these factors. Methods: From 2019 to 2021, 90 medial Oxford UKA were implanted by a single surgeon. Hip Knee Ankle Angle (HKAA), Lateral Distal Femoral Angle (LDFA), Medial Proximal Tibial Angle (MPTA), and intraoperative bony resection thickness were measured. The medial joint line change was calculated. The correlation between joint line change and alignment change was evaluated. Results: The mean tibial resection thickness was 4.3 mm. The mean tibial joint line was elevated by 2.3 mm, while the mean femoral joint line proximalized by 0.8 mm. HKAA changed from 8.4° varus preoperatively to 3.6° varus postoperatively. LDFA changed from 89.0° to 86.7°. MPTA changed from 85.6° to 86.6°. Preoperative HKAA showed a strong correlation with postoperative HKAA (p < 0.001), and preoperative MPTA showed a positive correlation with postoperative HKAA (p < 0.001). While preoperative LDFA had a negative correlation with postoperative HKAA (p < 0.001). The femoral joint line change and LDFA change had a significant correlation with HKAA change (p < 0.05). Conclusion: The change of joint line had no correlation with postoperative HKAA in Oxford UKA. Preoperative HKAA strongly correlated with postoperative HKAA; while preoperative smaller LDFA and larger MPTA had a moderate correlation with postoperative HKAA. The femoral joint line change and LDFA change had a weak to moderate correlation with HKAA change.

Early versus delayed mobilization for arthroscopic rotator cuff repair (small to large sized tear): a meta-analysis of randomized controlled trials.

BACKGROUND: The timing to start passive or active range of motion (ROM) after arthroscopic rotator cuff repair remains unclear. This systematic review and meta-analysis evaluated early versus delayed passive and active ROM protocols following arthroscopic rotator cuff repair. The aim of this study is to systematically review the literature on the outcomes of early active/passive versus delayed active/passive postoperative arthroscopic rotator cuff repair rehabilitation protocols. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) published up to April 2022 comparing early motion (EM) versus delayed motion (DM) rehabilitation protocols after arthroscopic rotator cuff repair for partial and full-thickness tear was conducted. The primary outcome was range of motion (anterior flexion, external rotation, internal rotation, abduction) and the secondary outcomes were Constant-Murley score (CMS), Simple Shoulder Test Score (SST score) and Visual Analogue Scale (VAS). RESULTS: Thirteen RCTs with 1,082 patients were included in this study (7 RCTs for early passive motion (EPM) vs. delayed passive motion (DPM) and 7 RCTs for early active motion (EAM) vs. delayed active motion (DAM). Anterior flexion (1.40, 95% confidence interval (CI), 0.55-2.25) and abduction (2.73, 95%CI, 0.74-4.71) were higher in the EPM group compared to DPM. Similarly, EAM showed superiority in anterior flexion (1.57, 95%CI, 0.62-2.52) and external rotation (1.59, 95%CI, 0.36-2.82), compared to DAM. There was no difference between EPM and DPM for external rotation, retear rate, CMS and SST scores. There was no difference between EAM and DAM for retear rate, abduction, CMS and VAS. CONCLUSION: EAM and EPM were both associated with superior ROM compared to the DAM and DPM protocols. EAM and EPM were both safe and beneficial to improve ROM after arthroscopic surgery for the patients with small to large sized tears.

Analysis of Cellular Crosstalk and Molecular Signal between Periosteum-Derived Precursor Cells and Peripheral Cells During Bone Healing Process Using a Paper-Based Osteogenesis-On-A-Chip Platform.

Periosteum-derived progenitor cells (PDPCs) are highly promising cell sources that are indispensable in the bone healing process. Adipose-derived stem cells (ADSCs) are physiologically close to periosteum tissue and release multiple growth factors to promote the bone healing process. Co-culturing PDPCs and ADSCs can construct periosteum-bone tissue microenvironments for the study of cellular crosstalk and molecular signal in the bone healing process. In the current work, a paper-based osteogenesis-on-a-chip platform was successfully developed to provide an in vitro three-dimensional coculture model. The platform was a paper substrate sandwiched between PDPC-hydrogel and ADSC-hydrogel suspensions. Cell secretion could be transferred through the paper substrate from one side to another side. Growth factors including BMP2, TGF-ß, POSTN, Wnt proteins, PDGFA, and VEGFA were directly analyzed by a paper-based immunoassay. Cellular crosstalk was studied by protein expression on the paper substrate. Moreover, osteogenesis of PDPCs was investigated by examining the mRNA expressions of PDPCs after culture. Neutralizing and competitive assays were conducted to understand the correlation between growth factors secreted from ADSCs and the osteogenesis of PDPCs. In vitro periosteum-bone tissue microenvironment was established by the paper-based osteogenesis-on-a-chip platform. The proposed approach provides a promising assay of cellular crosstalk and molecular signal in 3D coculture microenvironment that may potentially lead to the development of effective bone regeneration therapy.

Robotic versus laparoscopic hepatectomy: A single-center, propensity score- matched study.

BACKGROUND: Although the effectiveness of robotic hepatectomy (RH) has been evaluated in several studies, the superiority of RH over other approaches has not been definitely established. Therefore, in the present propensity score-matched cohort study, we compared RH and laparoscopic hepatectomy (LH) in terms of perioperative and oncologic outcomes. METHODS: This retrospective study included patients who underwent RH or LH for benign and malignant liver lesions at a single center in Taiwan at any time between 2014 and 2020. Confounding factors, specifically age, sex, body mass index, American Society of Anesthesiologists score, IWATE criteria, and Charlson comorbidity index, were adjusted through propensity score matching (PSM). RESULTS: A total of 329 patients were finally included in this study. Two homogeneous groups (RH and LH; n, 72 each) were formed using PSM. The RH group had a longer operative time (median: 231 vs.180 min, respectively; P = .001) and lower conversion (to open surgery) rate (9.7% vs.0.0%, respectively; P = .013) than did the LH group. However, the two groups did not differ in terms of other perioperative outcomes, specifically blood loss, hospital stay, intensive care unit admission, mortality, morbidity, or tumor margin status. CONCLUSIONS: The rate of conversion to open surgery is lower in RH than in LH. Although operative time is longer in RH than in LH, RH is feasible and safe for patients with benign or malignant liver lesion. Our study also demonstrated comparable oncological results in patients with hepatocellular carcinoma between LH and RH group.

Using Single Peroneal Longus Tendon Graft for Segmental Meniscus Transplantation and Revision Anterior Cruciate Ligament Combined Anterolateral Reconstruction.

This case report describes a new approach to segmental meniscal reconstruction using a peroneal longus autograft in a patient with recurrent traumatic medial meniscus tear and anterior cruciate ligament reconstruction (ACLR) failure. While allograft meniscal transplantation is the preferred method for treating meniscal deficiency, its high cost and various legal regulations have limited its widespread use. Autologous tendon grafts have been proposed as a substitute for allograft meniscus transplantation, but their initial results were poor, leading to little progress in this area. However, recent animal experiments and clinical studies have demonstrated promising results in using autologous tendon grafts for meniscal transplantation, including improvements in pain and quality of life for patients. Further research is needed to evaluate the effectiveness of segmental meniscal reconstruction using autologous tendon grafts, but it could potentially lead to more accessible and cost-effective treatment options for patients with meniscal deficiency.

Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis.

Sorafenib, a small-molecule inhibitor targeting several tyrosine kinase pathways, is the standard treatment for advanced hepatocellular carcinoma (HCC). However, not all patients with HCC respond well to sorafenib, and 30% of patients develop resistance to sorafenib after short-term treatment. Galectin-1 modulates cell-cell and cell-matrix interactions and plays a crucial role in HCC progression. However, whether Galectin-1 regulates receptor tyrosine kinases by sensitizing HCC to sorafenib remains unclear. Herein, we established a sorafenib-resistant HCC cell line (Huh-7/SR) and determined that Galectin-1 expression was significantly higher in Huh-7/SR cells than in parent cells. Galectin-1 knockdown reduced sorafenib resistance in Huh-7/SR cells, whereas Galectin-1 overexpression in Huh-7 cells increased sorafenib resistance. Galectin-1 regulated ferroptosis by inhibiting excessive lipid peroxidation, protecting sorafenib-resistant HCC cells from sorafenib-mediated ferroptosis. Galectin-1 expression was positively correlated with poor prognostic outcomes for HCC patients. Galectin-1 overexpression promoted the phosphorylation of AXL receptor tyrosine kinase (AXL) and MET proto-oncogene, receptor tyrosine kinase (MET) signaling, which increased sorafenib resistance. MET and AXL were highly expressed in patients with HCC, and AXL expression was positively correlated with Galectin-1 expression. These findings indicate that Galectin-1 regulates sorafenib resistance in HCC cells through AXL and MET signaling. Consequently, Galectin-1 is a promising therapeutic target for reducing sorafenib resistance and sorafenib-mediated ferroptosis in patients with HCC.

Machine Learning Algorithm Detection of Confluent B-Lines.

OBJECTIVE: B-lines are a ring-down artifact of lung ultrasound that arise with increased alveolar water in conditions such as pulmonary edema and infectious pneumonitis. Confluent B-line presence may signify a different level of pathology compared with single B-lines. Existing algorithms aimed at B-line counting do not distinguish between single and confluent B-lines. The objective of this study was to test a machine learning algorithm for confluent B-line identification. METHODS: This study used a subset of 416 clips from 157 subjects, previously acquired in a prospective study enrolling adults with shortness of breath at two academic medical centers, using a hand-held tablet and a 14-zone protocol. After exclusions, random sampling generated a total of 416 clips (146 curvilinear, 150 sector and 120 linear) for review. A group of five experts in point-of-care ultrasound blindly evaluated the clips for presence/absence of confluent B-lines. Ground truth was defined as majority agreement among the experts and used for comparison with the algorithm. RESULTS: Confluent B-lines were present in 206 of 416 clips (49.5%). Sensitivity and specificity of confluent B-line detection by algorithm compared with expert determination were 83% (95% confidence interval [CI]: 0.77-0.88) and 92% (95% CI: 0.88-0.96). Sensitivity and specificity did not statistically differ between transducers. Agreement between algorithm and expert for confluent B-lines measured by unweighted κ was 0.75 (95% CI: 0.69-0.81) for the overall set. CONCLUSION: The confluent B-line detection algorithm had high sensitivity and specificity for detection of confluent B-lines in lung ultrasound point-of-care clips, compared with expert determination.

Radiographic Analysis in Extra-Articular and Intra-Articular Distal Radius Fractures Treated with Variable-Angle Volar Locking Plate Fixation.

(1) Background: Different distal radial fracture types have different prognosis after fixation. Our study aim is to evaluate the differences in radiographic parameters by using variable-angle volar locking plate (VAVLP) fixation according to extra-articular and intra-articular distal radial fracture. (2) Methods: There are two groups: extra-articular group (21) and intra-articular group (25). Forearm radiographs immediately after surgery and at 3 months after operation were reviewed for analyzing radial height (RH), ulnar variance (UV), radial inclination (RI), volar tilt (VT), tear drop angle (TDA), distal dorsal cortical distance (DDD), and Soong classification (SC). (3) Results: There were no significant differences in the above parameters between two groups at either immediately post-operative or at 3-month follow-up, except for TDA (p = 0.048). Most patients in both groups were at low risk of flexor tendon rupture, except for two cases. We observed a positive correlation between post-operative DDD and 3-month change in the intra-articular group, but not the extra-articular group. (4) Conclusions: Our study demonstrates that VAVLP fixation is effective in maintaining the stability of most radiographic parameters and reduces the risk of tendon rupture in both extra-articular and intra-articular distal radial fractures. Post-operative DDD can be used to predict the degree of subsequent displacement in patients with intra-articular fractures fixed with VAVLP.

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia.

Friedreich's ataxia (FA) is a life-threatening autosomal recessive disorder characterized by neurological and cardiac dysfunction. Arrhythmias and heart failure are the main cause of premature death. From prior studies in murine models of FA, adeno-associated virus encoding the normal human frataxin gene (AAVrh.10hFXN) effectively treated the cardiac manifestations of the disease. However, the therapeutic dose window is limited by high level of human frataxin (hFXN) gene expression associated with toxicity. As a therapeutic goal, since FA heterozygotes have no clinical manifestations of FA, we estimated the level of frataxin (FXN) necessary to convert the heart of a homozygote to that of a heterozygote. In noncardiac cells, FA heterozygotes have 30-80% of normal FXN levels (17.7-47.2 ng/mg, average 32.5 ng/mg) and FA homozygotes 2-30% normal levels (1.2-17.7 ng/mg, average 9.4 ng/mg). Therefore, an AAV vector would need to augment endogenous in an FA homozygote by >8.3 ng/mg. To determine the required dose of AAVrh.10hFXN, we administered 1.8 × 1011, 5.7 × 1011, or 1.8 × 1012 gc/kg of AAVrh.10hFXN intravenously (IV) to muscle creatine kinase (mck)-Cre conditional knockout Fxn mice, a cardiac and skeletal FXN knockout model. The minimally effective dose was 5.7 × 1011 gc/kg, resulting in cardiac hFXN levels of 6.1 ± 4.2 ng/mg and a mild (p < 0.01 compared with phosphate-buffered saline controls) improvement in mortality. A dose of 1.8 × 1012 gc/kg resulted in cardiac hFXN levels of 33.7 ± 6.4 ng/mg, a significant improvement in ejection fraction and fractional shortening (p < 0.05, both comparisons) and a 21.5% improvement in mortality (p < 0.001). To determine if the significantly effective dose of 1.8 × 1012 gc/kg could achieve human FA heterozygote levels in a large animal, this dose was administered IV to nonhuman primates. After 12 weeks, the vector-expressed FXN in the heart was 17.8 ± 4.9 ng/mg, comparable to the target human levels. These data identify both minimally and significantly effective therapeutic doses that are clinically relevant for the treatment of the cardiac manifestations of FA.

Two- Versus 8-Zone Lung Ultrasound in Heart Failure: Analysis of a Large Data Set Using a Deep Learning Algorithm.

OBJECTIVE: Scanning protocols for lung ultrasound often include 8 or more lung zones, which may limit real-world clinical use. We sought to compare a 2-zone, anterior-superior thoracic ultrasound protocol for B-line artifact detection with an 8-zone approach in patients with known or suspected heart failure using a deep learning (DL) algorithm. METHODS: Adult patients with suspected heart failure and B-lines on initial lung ultrasound were enrolled in a prospective observational study. Subjects received daily ultrasounds with a hand-held ultrasound system using an 8-zone protocol (right and left anterior/lateral and superior/inferior). A previously published deep learning algorithm that rates severity of B-lines on a 0-4 scale was adapted for use on hand-held ultrasound full video loops. Average severities for 8 and 2 zones were calculated utilizing DL ratings. Bland-Altman plot analyses were used to assess agreement and identify bias between 2- and 8-zone scores for both primary (all patients, 5728 videos, 205 subjects) and subgroup (confirmed diagnosis of heart failure or pulmonary edema, 4464 videos, 147 subjects) analyses. RESULTS: Bland-Altman plot analyses revealed excellent agreement for both primary and subgroup analyses. The absolute difference on the 4-point scale between 8- and 2-zone average scores was not significant for the primary dataset (0.03; 95% CI -0.01 to 0.07) or the subgroup (0.01; 95% CI -0.04 to 0.06). CONCLUSION: Utilization of a 2-zone, anterior-superior thoracic ultrasound protocol provided similar severity information to an 8-zone approach for a dataset of subjects with known or suspected heart failure.

Medical-Legal Partnership Effects on Mental Health, Health Care Use, and Quality of Life in Primary Care: A Randomized Clinical Trial.

PURPOSE: To determine whether an immediate referral to a medical-legal partnership (MLP), compared with a 6-month waitlist control, improved mental health, health care use, and quality of life. METHODS: This trial randomly assigned individuals to an immediate referral or a wait-list control. The MLP involved a collaboration between the primary care clinic and a legal services organization. The primary outcome was stress (6 months) as measured by the Perceived Stress Scale (PSS). Secondary measures included the Center for Epidemiologic Studies Depression Scale; Generalized Anxiety Disorder scale (GAD-7); Patient-Reported Outcomes Measurement Information System (PROMIS); and emergency department (ED), urgent care, and hospital visits. Assessments were at baseline and 3-, 6-, and 9-month follow-ups. Bayesian statistical inference and a 75% posterior probability threshold were used to identify noteworthy differences. RESULTS: Immediate referral was associated with lower PSS scores and higher GAD-7 scores. PROMIS scores were higher for the immediate referral group with respect to several subdomains. At 6 months, the immediate referral group demonstrated 21% fewer ED visits and 75.6% more hospital visits. CONCLUSION: Immediate referral to the MLP was associated with lower stress and a lower rate of ED visits but higher anxiety and a higher rate of hospital visits. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03805126.

Sessile Trichomes Play Major Roles in Prey Digestion and Absorption, While Stalked Trichomes Function in Prey Predation in Byblis guehoi.

Carnivorous plants in the genus Byblis obtain nutrients by secreting viscous glue drops and enzymes that trap and digest small organisms. Here, we used B. guehoi to test the long-held theory that different trichomes play different roles in carnivorous plants. In the leaves of B. guehoi, we observed a 1:2.5:14 ratio of long-stalked, short-stalked, and sessile trichomes. We demonstrated that the stalked trichomes play major roles in the production of glue droplets, while the sessile trichomes secrete digestive enzymes, namely proteases and phosphatases. In addition to absorbing digested small molecules via channels/transporters, several carnivorous plants employ a more efficient system: endocytosis of large protein molecules. By feeding B. guehoi fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) to monitor protein transport, we found that sessile trichomes exhibited more endocytosis than long- and short-stalked trichomes. The uptaken FITC-BSA was delivered to the neighboring short epidermal cells in the same row as the sessile trichomes, then to the underlying mesophyll cells; however, no signals were detected in the parallel rows of long epidermis cells. The FITC control could be taken up by sessile trichomes but not transported out. Our study shows that B. guehoi has developed a well-organized system to maximize its food supply, consisting of stalked trichomes for prey predation and sessile trichomes for prey digestion. Moreover, the finding that sessile trichomes transfer large, endocytosed protein molecules to the underlying mesophyll, and putatively to the vascular tissues, but not laterally to the terminally differentiated epidermis, indicates that the nutrient transport system has evolved to maximize efficiency.

Comparison of suture-bridge and independent double-row techniques for medium to massive posterosuperior cuff tears: a two-year retrospective study.

BACKGROUND: Transosseous-equivalent suture-bridge (TOE-SB) and independent double-row (IDR) repair techniques were developed to treat rotator cuff tears. The study was designed to prove that both TOE-SB and IDR techniques provided comparable clinical results and retear rate for medium to massive posterosuperior rotator cuff tears, while the surgical time and number of suture anchor used were less in the IDR group. STUDY DESIGN: Level of evidence: level III, Retrospective comparative study. METHODS: Patients with medium to massive posterosuperior rotator cuff tears receiving arthroscopic TOE-SB and IDR between November 2016 to October 2019 were retrospectively enrolled. All patients were confirmed to have grade ≤ 2 fatty infiltration in the muscles of the torn tendons. Revision, concomitant subscapularis tear, acromiohumeral distance < 7 mm, glenohumeral osteoarthritis, partial repair, incomplete repair, partial thickness, or irreparable posterosuperior cuff tear were excluded. Surgical time, number of suture anchor used for the surgery, pre-operative, and post-operative clinical scores such as Constant-Murley score, subjective shoulder value (SSV), and visual analog scale (VAS) were compared. The retear rates between groups were evaluated by ultrasound. RESULTS: Thirty-five IDR and thirty-five TOE-SB repairs were enrolled. The IDR technique required much fewer anchors than TOE-SB did to complete the cuff repair. The mean operation time in IDR and TOE-SB group were 86(18.23), and 114(18.7) (min), respectively (P <  0.01). The mean number of anchors used to complete the cuff repair was 2(0.17) in IDR and 3(0.61) in TOE-SB (P <  0.01). The Constant-Murley score improved from 34.9 ± 6.6 to 80.6 ± 9.4 in the IDR group, and 37.4 ± 6 to 81.9 ± 4.6 in the TOE-SB group (both P <  0.001). SSV improved from 24.6 ± 9.6 to 79.3 ± 10.6 in the IDR, and 27.9 ± 9 to 82.9 ± 6.9 in the TOE-SB group (both P <  0.001). VAS improved from 7.9 ± 0.6 to 1.5 ± 0.7 in the IDR, and 8 ± 0.5 to 1.3 ± 0.6 in the TOE-SB group (both P <  0.001) at final follow-up. No significant difference was found between the retear rates (14.3% in the IDR vs. 17.1% in the TOE-SB, respectively) in the 2-year follow-up. CONCLUSIONS: Both IDR and TOE-SB group provided comparable clinical results and retear rates for medium to massive posterosuperior rotator cuff tears. The surgical time and number of anchors used were less in the IDR group than in the TOE-SB group.