Structure and dynamics of a pentameric KCTD5/CUL3/Gßγ E3 ubiquitin ligase complex.

Heterotrimeric G proteins can be regulated by posttranslational modifications, including ubiquitylation. KCTD5, a pentameric substrate receptor protein consisting of an N-terminal BTB domain and a C-terminal domain, engages CUL3 to form the central scaffold of a cullin-RING E3 ligase complex (CRL3KCTD5) that ubiquitylates Gßγ and reduces Gßγ protein levels in cells. The cryo-EM structure of a 5:5:5 KCTD5/CUL3NTD/Gß1γ2 assembly reveals a highly dynamic complex with rotations of over 60° between the KCTD5BTB/CUL3NTD and KCTD5CTD/Gßγ moieties of the structure. CRL3KCTD5 engages the E3 ligase ARIH1 to ubiquitylate Gßγ in an E3-E3 superassembly, and extension of the structure to include full-length CUL3 with RBX1 and an ARIH1~ubiquitin conjugate reveals that some conformational states position the ARIH1~ubiquitin thioester bond to within 10 Å of lysine-23 of Gß and likely represent priming complexes. Most previously described CRL/substrate structures have consisted of monovalent complexes and have involved flexible peptide substrates. The structure of the KCTD5/CUL3NTD/Gßγ complex shows that the oligomerization of a substrate receptor can generate a polyvalent E3 ligase complex and that the internal dynamics of the substrate receptor can position a structured target for ubiquitylation in a CRL3 complex.

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-ß. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-ß production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

Formation, Selective Encapsulation, and Tautomerization Control of Isoindolone Utilizing Guanidinium Sulfonate Frameworks.

Herein we report the use of tetrakis (guanidinium) pyrenetetrasulfonate (G4PYR) and bis (guanidinium) 1,5-napthalene disulfonate (G2NDS) to catalyze the cyclization of 2-cyanobenzamide (1) to isoindolone (2). Moreover, we demonstrate the remarkable selectivity of these guanidinium organosulfonate hosts in encapsulating 2 over 1. By thoroughly investigating the intramolecular cyclization reaction, we determined that guanidinium and the organosulfonate moiety acts as the catalyst in this process. Additionally, 2 is selectively encapsulated, even in mixtures of other structurally similar heterocycles like indole. Furthermore, the tautomeric state of 2 (amino isoindolone (2-A) and imino isoindolinone forms (2-I)) can be controlled by utilizing different guanidinium organosulfonate frameworks.

Structure Elucidation of Pharmaceutically Relevant Compounds within Pyrene-based Frameworks.

Single crystal X-ray diffraction (SCXRD) is the preferred and most accurate technique for determining molecular structures. However, it can present challenges when dealing with specific small molecules and active pharmaceutical ingredients (APIs), as many do not form quality crystals without coformers or can be unstable. In this study, we introduce tetrakis(guanidinium) pyrenetetrasulfonate (G4PYR), a robust guanidinium-organosulfonate (GS) framework that efficiently encapsulates small molecules and APIs rich in functional groups. The hydrogen bonding frameworks formed by G4PYR display well-ordered structures with predictable pyrene-pyrene distances, making them ideally suited for targeting arene-based APIs with pendant groups. Successful encapsulation of various guests, including benzaldehyde, benzamide, and arenes containing multiple hydrogen bond donors and acceptors like uracil and thymine, was achieved. Furthermore, we successfully encapsulated important pharmaceutical and biologically relevant compounds, such as lidocaine, ropinirole, adenosine, thymidine, and others. Notably, we present a workflow for investigating host-guest complex formation using powder X-ray diffraction and high throughput experimentation.

Development and Validation of Matrix of Chemistry, Manufacturing, and Control (MoCMC) System for Intramammary Drug Products (IMM).

PURPOSE: Products formulated for intramammary (IMM) infusion are intended for the delivery of therapeutic moieties directly into the udder through the teat canal to maximize drug exposure at the targeted clinical site, the mammary gland, with little to no systemic drug exposure. Currently, to our knowledge, there has been no in-vitro matrix system available to differentiate between IMM formulations. Our goal is to develop A custom tailored in-vitro "Matrix of Chemistry, Manufacturing and Control" (MoCMC) System to be a promising future tool for identifying inequivalent IMM formulations. MoCMC can detect inter and intra batch variabilities, thereby identifying potential generics versus brand product similarities or differences with a single numeric value and a specific & distinctive fingerprint. METHODS: The FDA-approved IMM formulation, SPECTRAMASTⓇ LC, was selected as the reference product for the MoCMC. Twelve in-house test formulations containing ceftiofur hydrochloride were formulated and characterized. The MoCMC was developed to include six input parameters and three output parameters. The MoCMC system was used to evaluate and compare SPECTRAMASTⓇ LC with its in-house formulations. RESULTS: Based on the MoCMC generated parameters, the distinctive fingerprints of MoCMC for each IMM formulations, and the statistical analyses of MCI and PPI values, in-house formulations, F-01 and F-02 showed consistency while the rest of in-house formulations (F-03-F-12) were significantly different as compared to SPECTRAMASTⓇ LC. CONCLUSION: This research showed that the MoCMC approach can be used as a tool for intra batch variabilities, generics versus brand products comparisons, post-approval formulations changes, manufacturing changes, and formulation variabilities.

Development and Validation of Discriminatory In-vitro Release Method for Intramammary Drug Product.

PURPOSE: Intramammary (IMM) formulations are locally acting and delivered intracisternally into the udder. No pharmacopeial in-vitro release method is available to differentiate between the IMM formulations. Our research aim is to develop in-vitro release methods that discriminate different IMM formulations (SPECTRAMAST® LC and in-house formulations). METHODOLOGY: Different in-house formulations were developed to simulate SPECTRAMAST® LC generics. SPECTRAMAST® LC and the in-house formulations were characterized for physicochemical attributes, such as particle size, rheology, drug content, sedimentation rate, and flocculation rate. The in-vitro release method was optimized by evaluating drug release using USP apparatuses 1, 2 (with and without enhancer/customized cells), and 4. Various test parameters, including medium effect (whole homogenized bovine milk versus aqueous buffer), medium volume (200-900 mL), and rotational speed (50-200 rpm) were investigated. RESULTS: Two potential in-vitro systems can be used as discriminatory methods for IMM formulations: USP apparatus 2 with the IMM formulation loaded into two containers a) customized formulation container (83.1 cm in height and 56.4 cm in width) or b) enhancer cells with their top adapted with mesh #40 (rotation speed:125 rpm and 900 mL of whole homogenized bovine milk). The release profile of SPECTRAMAST® LC at 1 h (99.8%) was not significantly different from formulations with similar physicochemical characteristics F-01 (99.1%) and F-02 (100.5%). Formulation with different physicochemical characteristics F-03 (44.3%) and F-04 (57.2%) showed slower release (1 h) than SPECTRAMAST® LC (98.8%). CONCLUSION: The developed in-vitro release methods can be used as a potential tool for in-vitro comparability evaluations for IMM formulations.

Correlation of miR-155-5p, KRAS, and CREB Expression in Patients with Acute Myeloid Leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a type of blood cancer involving numerous aberrant genes and microRNAs. MiRNAs are non-coding sequences that have been proven to be players in the biological processes of various cancers. The present study is designed to illustrate the relationship between miR-155, KRAS, and CREB. METHODS: This case-control study was conducted on 21 patients with AML and 9 healthy individuals. The expressions of miR-155, KRAS, and CREB were measured using RT-PCR. Demographic data were extracted from the documents of individuals. SPSS and GraphPad Prism software were used to analyze the data. RESULTS: The expression of miR-155 in patients with AML was 35 times higher than in the control group (p < 0.0001). Also, CREB fold change increased by 1.92-fold in patients compared to the controls (p = 0.034), but no difference in KRAS was observed between the control and AML groups (p > 0.05). There was no change in miR-155, CREB, and KRAS expression based on gender, age, and blast percentage (p > 0.5). Nevertheless, there was a direct correlation between CREB and KRAS expressions (p = 0.0002). Our result showed that overexpression of CREB and KRAS would cause an increase in white blood cells (WBCs) (p = 0.001, 0.045 respectively), but there was no correlation between miR-155 with WBCs (p > 0.5). CONCLUSIONS: Our study revealed that miR-155 and CREB had overexpression compared to the control group.

A Predefined Rule-Based Multi-Factor Risk Stratification Is Associated With Improved Outcomes at a Rural Primary Care Practice.

This study built a predefined rule-based risk stratification paradigm using 19 factors in a primary care setting that works with rural communities. The factors include medical and nonmedical variables. The nonmedical variables represent 3 demographic attributes and one other factor represents transportation availability. Medical variables represent major clinical variables such as blood pressure and BMI. Many risk stratification models are found in the literature but few integrate medical and nonmedical variables, and to our knowledge, no such model is designed specifically for rural communities. The data used in this study contain the associated variables of all medical visits in 2021. Data from 2022 were used to evaluate the model. After our risk stratification model and several interventions were adopted in 2022, the percentage of patients with high or medium risk of deteriorating health outcomes dropped from 34.9% to 24.4%, which is a reduction of 30%. The medium-complex patient population size, which had been 29% of all patients, decreased by about 4% to 5.7%. According to the analysis, the total risk score showed a strong correlation with 3 risk factors: dual diagnoses, the number of seen providers, and PHQ9 (0.63, 0.54, and 0.45 correlation coefficients, respectively).

Particulated juvenile cartilage allograft for the treatment of osteochondral lesions of the talus is associated with a high complication rate and a high failure rate at short-term follow-up: A systematic review.

PURPOSE: The purpose of this systematic review was to evaluate the clinical and radiological outcomes together with the complication rates and failure rates at short-term follow-up following particulated juvenile cartilage allograft (PJCA) for the management of osteochondral lesions of the talus (OLT). METHODS: During October 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies examining outcomes following PJCA for the management of OLTs. Data regarding study characteristics, patient demographics, lesion characteristics, subjective clinical outcomes, radiological outcomes, complications and failures were extracted and analysed. RESULTS: Twelve studies were included. In total, 241 patients underwent PJCA for the treatment of OLT at a weighted mean follow-up of 29.0 ± 24.9 months. The weighted mean lesion size was 138.3 ± 59.6 mm2 . Prior surgical intervention was recorded in seven studies, the most common of which was microfracture (65.9%). The weighted mean American Orthopaedic Foot and Ankle Society score improved from a preoperative score of 58.5 ± 3.2 to a postoperative score of 83.9 ± 5.3. The weighted mean postoperative magnetic resonance observation of cartilage repair tissue (MOCART) score was 48.2 ± 3.3. The complication rate was 25.2%, the most common of which was allograft hypertrophy (13.2%). Thirty failures (12.4%) were observed at a weighted mean time of 9.8 ± 9.6 months following the index procedure. CONCLUSION: This systematic review demonstrated a moderate improvement in subjective clinical outcomes following PJCA for the treatment of OLT at short term follow-up. However, postoperative MOCART scores were reported as poor. In addition, a high complication rate (25.2%) and a high failure rate (12.4%) at short-term follow-up was observed, calling into question the efficacy of PJCA for the treatment of large OLTs. In light of the available evidence, PJCA for the treatment of large OLTs cannot be currently recommended. LEVEL OF EVIDENCE: Level IV.

Oral Bioavailability Enhancement of Poorly Soluble Drug by Amorphous Solid Dispersion Using Sucrose Acetate Isobutyrate.

The focus of the present work was to develop amorphous solid dispersion (ASD) formulation of aprepitant (APT) using sucrose acetate isobutyrate (SAIB) excipient, evaluate for physicochemical attributes, stability, and bioavailability, and compared with hydroxypropyl methylcellulose (HPMC) based formulation. Various formulations of APT were prepared by solvent evaporation method and characterized for physiochemical and in-vivo performance attributes such as dissolution, drug phase, stability, and bioavailability. X-ray powder diffraction indicated crystalline drug conversion into amorphous phase. Dissolution varied as a function of drug:SAIB:excipient proportion. The dissolution was more than 80% in the optimized formulation (F10) and comparable to HPMC based formulation (F13). Stability of F10 and F13 formulations stored at 25 C/60% and 40°C/75% RH for three months were comparable. Both ASD formulations (F10 and F13) were bioequivalent as indicated by the pharmacokinetic parameters Cmax and AUC0-∞. Cmax and AUC0-∞ of F10 and F13 formulations were 2.52 ± 0.39, and 2.74 ± 0.32 µg/ml, and 26.59 ± 0.39, and 24.79 ± 6.02 µg/ml.h, respectively. Furthermore, the bioavailability of ASD formulation was more than twofold of the formulation containing crystalline phase of the drug. In conclusion, stability and oral bioavailability of SAIB based ASD formulation is comparable to HPMC-based formulation of poorly soluble drugs.

The influence of telemedicine in primary healthcare on diabetes mellitus control and treatment adherence in Riyadh region.

Several studies have found that telemedicine has the potential to enhance the outcomes of patients with diabetes. This study aimed to determine the impact of telemedicine on the clinical outcomes of patients with type 2 diabetes mellitus (T2DM) in Saudi Arabia. We conducted a cross-sectional study among T2DM patients in selected primary healthcare centers in Riyadh, Saudi Arabia, from March 1, 2023, to August 20, 2023. We looked at how telemedicine affected HbA1c control, adherence, the number of diabetic complications, and polypharmacy using adjusted multivariable logistic regression models. Among the 583 patients, 140 (24.05 %) received care via telemedicine, while 442 (75.95 %) received in-person care. Patients who utilized telemedicine had significantly better glycemic control than those who received in-person care only (AOR = 5.123, 95 % CI = 3.107-8.447). Telemedicine also showed positive effects on treatment adherence (AOR = 2.552, 95 % CI = 1.6284-4.2414). Telemedicine can effectively reduce diabetic complications (AOR = 0.277, 95 % CI = 0.134-0.571). Regarding polypharmacy, patients with telemedicine use were less likely to report polypharmacy (AOR = 0.559, 95 % CI = 0.361-0.866). Telemedicine is considered one of the factors that improve HbA1c management and might increase therapeutic adherence and reduce diabetic complications and polypharmacy.

The significance of heterotopic ossification following total ankle arthroplasty: a systematic review and meta-analysis.

PURPOSE: The purpose of this systematic review and meta-analysis was to evaluate the prevalence and clinical significance of heterotopic ossification (HO) following total ankle replacement (TAR). METHODS: During August 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies reporting HO following TAR. Data regarding surgical characteristics, pathological characteristics, subjective clinical outcomes, ankle range of motion, radiographic outcomes, reoperation rates were extracted and analysed. RESULTS: Twenty-seven studies with 2639 patients (2695 ankles) at a weighed mean follow-up time of 52.8 ± 26.9 months were included. The pooled prevalence rate was 44.6% (0.25; 0.66). The implant with the highest rate of HO was the INBONE I (100%) and BOX (100%) implants. The most common modified Brooker staging was grade 1 (132 patients, 27.0%). Random effects models of standardized mean differences found no difference in American orthopedic foot and ankle society (AOFAS) scores, visual analog scale scores (VAS) and ankle range of motion (ROM) between patients with HO and patients without HO. Random effects models of correlation coefficients found no correlation between AOFAS, VAS and ROM and the presence of HO. The surgical intervention rate for symptomatic HO was 4.2%. CONCLUSION: This systematic review and meta-analysis found that HO is a common finding following TAR that is not associated with inferior clinical outcomes. Surgical intervention was required only for moderate-to-severe, symptomatic HO following TAR. This study is limited by the marked heterogeneity and low level and quality of evidence of the included studies. Further higher quality studies are warranted to determine the precise prevalence and impact of HO on outcomes following TAR.

Polyvinyl alcohol hydrogel implant for the treatment of hallux rigidus is associated with a high complication rate and moderate failure rate at short-term follow-up: a systematic review.

PURPOSE: Moderate-to-severe hallux rigidus is a debilitating pathology that is optimally treated with surgical intervention. Arthrodesis produces reliable clinical outcomes but is limited by restriction in 1st metatarsophalangeal joint range of motion. The advent of polyvinyl alcohol hydrogel (PVA) implants have produced early promise based on initial trials, but more recent studies have called into question the efficacy of this procedure. The purpose of this systematic review was to evaluate the clinical and radiological outcomes following the use of PVA for hallux rigidus. METHODS: The MEDLINE, EMBASE and Cochrane library databases were systematically reviewed using the preferred reporting items for systematic reviews and meta-analyses guidelines. 18 studies were included. RESULTS: In total, 1349 patients (1367 feet) underwent PVA at a weighted mean follow-up of 24.1 ± 11.1 months. There were 168 patients (169 feet) included in the cheilectomy cohort and 322 patients (322 feet) included in the arthrodesis cohort. All 3 cohorts produced comparable improvements in subjective clinical outcomes. Postoperative imaging findings in the PVA cohort included joint space narrowing, peri-implant fluid, peri-implant edema and erosion of the proximal phalanx. The complication rate in the PVA cohort, cheilectomy cohort and arthrodesis cohort was 27.9%, 11.8% and 24.1%, respectively. The failure rates in the PVA cohort, cheilectomy cohort and arthrodesis cohort was 14.8%, 0.3% and 9.0%, respectively. CONCLUSION: This systematic review demonstrated that PVA produced a high complication rate (27.9%) together with concerning postoperative imaging findings at short-term follow-up. In addition, a moderate failure rate (14.8%) and secondary surgical procedure rate (9.5%) was noted for the PVA cohort. The findings of this review calls into question the efficacy and safety of PVA for the treatment of hallux rigidus. LEVEL OF EVIDENCE: IV.

Altered hepatic and intestinal homeostasis in a neonatal murine model of short-term total parenteral nutrition and antibiotics.

Parenteral nutrition (PN) prevents starvation and supports metabolic requirements intravenously when patients are unable to be fed enterally. Clinically, infants are frequently provided PN in intensive care settings along with exposure to antibiotics (ABX) to minimize infection during care. Unfortunately, neonates experience extremely high rates of hepatic complications. Adult rodent and piglet models of PN are well-established but neonatal models capable of leveraging the considerable transgenic potential of the mouse remain underdeveloped. Utilizing our newly established neonatal murine PN mouse model, we administered ABX or controlled drinking water to timed pregnant dams to disrupt the maternal microbiome. We randomized mouse pups to PN or sham surgery controls +/- ABX exposure. ABX or short-term PN decreased liver and brain organ weights, intestinal length, and mucosal architecture (vs. controls). PN significantly elevated evidence of hepatic proinflammatory markers, neutrophils and macrophage counts, bacterial colony-forming units, and evidence of cholestasis risk, which was blocked by ABX. However, ABX uniquely elevated metabolic regulatory genes resulting in accumulation of hepatocyte lipids, triglycerides, and elevated tauro-chenoxycholic acid (TCDCA) in serum. Within the gut, PN elevated the relative abundance of Akkermansia, Enterococcus, and Suterella with decreased Anaerostipes and Lactobacillus compared with controls, whereas ABX enriched Proteobacteria. We conclude that short-term PN elevates hepatic inflammatory stress and risk of cholestasis in early life. Although concurrent ABX exposure protects against hepatic immune activation during PN, the dual exposure modulates metabolism and may contribute toward early steatosis phenotype, sometimes observed in infants unable to wean from PN.NEW & NOTEWORTHY This study successfully established a translationally relevant, murine neonatal parenteral nutrition (PN) model. Short-term PN is sufficient to induce hepatitis-associated cholestasis in a neonatal murine model that can be used to understand disease in early life. The administration of antibiotics during PN protects animals from bacterial translocation and proinflammatory responses but induces unique metabolic shifts that may predispose the liver toward early steatosis.

Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries.

BACKGROUND: The safety and efficacy of antenatal glucocorticoids in women in low-resource countries who are at risk for preterm birth are uncertain. METHODS: We conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at risk for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal death, and possible maternal bacterial infection; neonatal death alone and stillbirth or neonatal death were evaluated with superiority analyses, and possible maternal bacterial infection was evaluated with a noninferiority analysis with the use of a prespecified margin of 1.25 on the relative scale. RESULTS: A total of 2852 women (and their 3070 fetuses) from 29 secondary- and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan underwent randomization. The trial was stopped for benefit at the second interim analysis. Neonatal death occurred in 278 of 1417 infants (19.6%) in the dexamethasone group and in 331 of 1406 infants (23.5%) in the placebo group (relative risk, 0.84; 95% confidence interval [CI], 0.72 to 0.97; P = 0.03). Stillbirth or neonatal death occurred in 393 of 1532 fetuses and infants (25.7%) and in 444 of 1519 fetuses and infants (29.2%), respectively (relative risk, 0.88; 95% CI, 0.78 to 0.99; P = 0.04); the incidence of possible maternal bacterial infection was 4.8% and 6.3%, respectively (relative risk, 0.76; 95% CI, 0.56 to 1.03). There was no significant between-group difference in the incidence of adverse events. CONCLUSIONS: Among women in low-resource countries who were at risk for early preterm birth, the use of dexamethasone resulted in significantly lower risks of neonatal death alone and stillbirth or neonatal death than the use of placebo, without an increase in the incidence of possible maternal bacterial infection. (Funded by the Bill and Melinda Gates Foundation and the World Health Organization; Australian and New Zealand Clinical Trials Registry number, ACTRN12617000476336; Clinical Trials Registry-India number, CTRI/2017/04/008326.).

Hepatitis C care cascade before and during the direct-acting antiviral eras in New South Wales, Australia: A population-based linkage study.

The hepatitis C virus (HCV) care cascade characterization is important for monitoring progress towards HCV elimination. This study evaluated HCV care cascade and factors associated with treatment during pre-DAA (2011-2012 and 2013-2015) and DAA (2016-2018) eras in New South Wales (NSW), Australia. We conducted a cohort study of people with an HCV notification (1993 to 2017) through end 2018, linked to administrative datasets, including HCV treatment and non-hospital services. Those aged <18 years, died within first 6 months of study period or notification, and who had successful HCV treatment in period before were excluded. Sex-specific spontaneous viral clearance was incorporated to estimate treatment-eligible population. The study population in each period were cumulative and brought forward from one period to the next. Among 115,667 people with HCV notification, 87,063 fulfilled eligibility criteria. During 2011 to 2012, 2013 to 2015, and 2016 to 2018, cumulative HCV notifications were 71,677, 77,969, and 80,017; 52,016, 56,793, and 57,467 were eligible for treatment; 29%, 48%, and 64% confirmed HCV RNA positive; and 0.6%, 5%, and 38% initiated HCV treatment, respectively. Birth cohort 1945 to 1964 (vs. ≥1965), males, non-Aboriginal ethnicity, regional/rural area of residence, and HCV/HIV co-infection were associated with higher treatment uptake. Incarceration and drug dependence were associated with higher treatment uptake during the DAA era. In Australia, many marginalized populations including those incarcerated and those with drug dependence have equitable treatment uptake in the DAA era. Targeted strategies are required to enhance treatment uptake for females and Aboriginal populations.

Endocardial fibroelastosis in infants and young children: a state-of-the-art review.

Endocardial fibroelastosis (EFE) is a rare cardiac condition characterized by excessive endocardial thickening secondary to fibroelastic tissues that commonly present in infants and young children. Most of endocardial fibroelastosis cases are secondary forms, which occur in conjunction with other cardiac diseases. Endocardial fibroelastosis has been associated with poor prognosis and outcomes. In light of recent advancements in understanding pathophysiology, several new data have revealed compelling evidence that abnormal endothelial-to-mesenchymal transition is the root cause of endocardial fibroelastosis. This article aims to review the recent development in pathophysiology, diagnostic workup, and management, and to discuss possible differential diagnoses.

In-Office Needle Arthroscopy for the Foot and Ankle.

In-office needle arthroscopy (IONA) has been a readily available tool dating back to the 1990s, primarily for diagnostic purposes. This technique was not fully accepted and implemented because of significant limitations with the image quality and lack of instrumentation available to simultaneously treat the identified pathologies. However, recent advancements in IONA technology have made it possible to perform arthroscopic procedures under local anesthesia in the office setting, which once required a full operating suite. IONA has revolutionized how we treat foot and ankle pathologies in our practice. IONA allows the patient to be an active participant in the procedure and provides an interactive experience. IONA can be used to treat a range of foot and ankle pathologies, including anterior ankle impingement, posterior ankle impingement, osteochondral lesions of the ankle joint, hallux rigidus, lateral ankle ligament repair, and tendoscopic treatment of Achilles, peroneal, and posterior tibial tendon disorders. Excellent outcomes with regard to subjective clinical outcomes, return to play times, and complications have been reported following IONA for these pathologies.

Supramalleolar osteotomy for the treatment of ankle osteoarthritis leads to favourable outcomes and low complication rates at mid-term follow-up: a systematic review.

PURPOSE: The purpose of this systematic review was to evaluate both the clinical and radiographic outcomes following supramalleolar osteotomy (SMO) in patients with ankle osteoarthritis, and to analyse the level of evidence (LOE) and quality of evidence (QOE) of the included studies. METHODS: A systematic review of the MEDLINE, EMBASE, and Cochrane Library databases was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies reporting clinical data following SMO for the treatment of ankle osteoarthritis were included and assessed. The level and quality of evidence of the included studies were also evaluated. RESULTS: Twenty-four studies with 1160 patients (1182 ankles) were included. Overall, 78.8% patients presented with post-traumatic ankle osteoarthritis. The weighted mean AOFAS score improved from 52.6 ± 9.7 (range 33.8-78.4) preoperatively to 78.1 ± 5.7 postoperatively at weighted mean follow-up of 50.4 ± 18.6 months (range 24.5-99.0). The most frequently utilised radiographic parameter was the tibial anterior surface angle, which improved from a preoperative weighted mean of 86.3° ± 5.6° (range 76.0°-102.0°) to a postoperative weighted mean of 89.9° ± 3.7° (range 84.9°-99.6°). The complication rate was 5.1% with non-union as the most commonly reported complication (1.6%). Secondary procedures were carried out in 28.2% of patients, the most common of which was implant and hardware removal (17.6%). The failure rate was 6.8%. Two studies were LOE II, 3 studies were LOE III, and 19 studies were LOE IV. The mean Modified Coleman Methodology Score was 59.3 ± 6.6 and the mean MINORS criteria score of all the included studies was 9.5 ± 3.7. CONCLUSION: This systematic review demonstrates good clinical and radiological outcomes, together with a low failure rate at mid-term follow-up following supramalleolar osteotomy in patients with ankle osteoarthritis. However, a moderate reoperation rate (28.2%) was reported. A low failure rate (6.8%) was reported, which must be interpreted in light of the shortcomings of the design of the included studies and a relatively short follow-up period. In addition, there is a low level and quality of evidence in the current literature with inconsistent reporting of data which underscores the need for further higher quality research to be conducted. Our review highlights that SMO may be an effective and safe procedure in the setting of early-to-intermediate-stage ankle osteoarthritis. LEVEL OF EVIDENCE: IV.

Lower re-rupture rates but higher complication rates following surgical versus conservative treatment of acute achilles tendon ruptures: a systematic review of overlapping meta-analyses.

PURPOSE: To systematically review and evaluate the current meta-analyses for the treatment of acute Achilles tendon rupture (AATR). This study can provide clinicians with a clear overview of the current literature to aid clinical decision-making and the optimal formulation of treatment plans for AATR. METHODS: Two independent reviewers searched PubMed and Embase on June 2, 2022 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Assessment of evidence was twofold: level of evidence (LoE) and quality of evidence (QoE). LoE was evaluated using published criteria by The Journal of Bone and Joint Surgery and the QoE by the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) scale. Pooled complication rates were highlighted for significance in favour of one treatment arm or no significance. RESULTS: There were 34 meta-analyses that met the eligibility criteria, with 28 studies of LoE 1, and the mean QoE was 9.8 ± 1.2. Significantly lower re-rupture rates were reported with surgical (2.3-5%) versus conservative treatment (3.9-13%), but conservative treatment was favoured in terms of lower complication rates. The re-rupture rates were not significantly different between percutaneous repair or minimally invasive surgery (MIS) compared to open repair, but MIS was favoured in terms of lower complication rates (7.5-10.4%). When comparing rehabilitation protocols following open repair (four studies), conservative treatment (nine studies), or combined (three studies), there was no significant difference in terms of re-rupture or obvious advantage in terms of lower complication rates between early versus later rehabilitation. CONCLUSION: This systematic review found that surgical treatment was significantly favoured over conservative treatment for re-rupture, but conservative treatment had lower complication rates other than re-rupture, notably for infections and sural nerve injury. Open repair had similar re-rupture rates to MIS, but lower complication rates; however, the rate of sural nerve injuries was lower in open repair. When comparing earlier versus later rehabilitation, there was no difference in re-rupture rates or obvious advantage in complications between open repair, conservative treatment, or when combined. The findings of this study will allow clinicians to effectively counsel their patients on the postoperative outcomes and complications associated with different treatment approaches for AATR. LEVEL OF EVIDENCE: IV.