Low Failure Rate Research Articles

G2P2C — A modular reinforcement learning algorithm for glucose control by glucose prediction and planning in Type 1 Diabetes

Developing diagnostic and treatment solutions for medical applications is often challenging due to the complex dynamics, partial observability, high inter- and intra-population variability, and the presence of unknown delays and disturbances. A characteristic case is the control of glucose concentration in people with Type 1 Diabetes (T1D) through the administration of exogenous insulin. The above complexities, enhanced by the significant cognitive burden associated with the estimation of optimal insulin dosing related to daily activities such as food intake and exercise, call for advanced insulin administration solutions towards a fully automated Artificial Pancreas System (APS). Reinforcement Learning (RL) is currently being explored in the development of APSs thanks to its demonstrated potential in problems characterized by complex dynamics and uncertainties. Despite the progress, RL algorithms in T1D still require manual estimation and announcement of meal carbohydrate (CHO) content or rely on small meal scenarios. In this study, we proposed G2P2C, a modular deep RL algorithm, which aims to fully automate glucose control in T1D, eliminating the need for CHO estimation and announcement. G2P2C was designed based on the state-of-the-art Proximal Policy Optimization (PPO) algorithm, augmented by two novel optimization phases: (i) model learning and (ii) planning. The former integrated an auxiliary learning task to learn a glucose dynamics model. The latter fine-tuned the learned control strategy to a short-time horizon by simulating glucose trajectories into the future. We evaluated the performance of G2P2C in-silico on a challenging meal protocol (180 g of CHO per day) for 20 subjects (10 adults and 10 adolescents) using an open-source version of a T1D simulator approved by the United States Food and Drug Administration (FDA). G2P2C was compared with state-of-the-art RL algorithms and two basal-bolus (BB) clinical treatment strategies, which involve manual meal announcement and CHO estimation with automated correction insulin boli for elevated glucose. G2P2C obtained statistically significant (P<0.05) reward improvements compared to PPO in 18 out of 20 subjects, while maintaining a lower failure rate. In addition, G2P2C achieved a time in range of 73% and 64% for the adult and adolescent cohorts, respectively, outperforming BB strategies in the adult cohort although no meal announcement was performed. The control performance and algorithmic characteristics of G2P2C show promise as a candidate algorithm for glucose control in APSs. We released the codebase of G2P2C (https://github.com/chirathyh/G2P2C) and an online demonstration tool (https://capsml.com/), where users can perform custom simulations to compare G2P2C with BB strategies, under the MIT license.

Failure Rate and Early Complications of Thumb Carpometacarpal Joint Replacement-A Multicenter Retrospective Study of Two Modern Implant Designs.

Joint replacement arthroplasty for the treatment of thumb osteoarthritis is gaining popularity as recent studies have demonstrated better pinch and grip strength and faster rehabilitation. Our aim was to identify early complications in modern implant designs using a multicenter study. A total of 381 patients who underwent thumb carpometacarpal replacement surgery in six participating hospitals were enrolled. The complications included were fractures, dislocations, infections, tendon and nerve injuries, and complex regional pain syndrome. Major complications were defined as a failure to implant the prosthesis, revision surgery to remove the implant, and any other need for further surgical intervention. The secondary outcomes were any other complications treated non-surgically and the timing of the complications. Eleven procedures failed, and these patients were treated with trapeziectomies. Twelve other patients required repeat surgical interventions. Minor adverse events occurred in 25.4% of the cases, and transient irritation of the superficial radial nerve and De Quervain tendinopathy were the most prevalent complications. Although this cohort depicted the learning curves of multiple surgeons, our study demonstrated low short-term failure rates. An inability to achieve primary stability of the cup in the trapezium was the leading cause of failure. Dislocations and other major complications with modern implants were very few.

Effects of immersion in 4-methacryloyloxyethyl trimellitate anhydride/methyl methacrylate-tri-n-butyl borane resin-activated liquid on microtensile bond strength of root canal dentin

Background/purpose4-methacryloyloxyethyl trimellitate anhydride/methyl methacrylate-tri-n-butyl borane (4-META/MMA-TBB) resin is used for indirect restorations. We aimed to evaluate effects of immersion in 4-META/MMA-TBB-activated liquid on the bond strength of root canal dentin. Materials and methodsWe used freshly extracted single-rooted human teeth. After decoronation, each root was vertically sectioned into halves; their dentin walls were polished and flattened. The control group underwent dentin treatment with Green Activator. The immersion group was treated with Green Activator and Teeth Primer and immersed in 4-META/MMA-TBB-activated liquid. After bonding the resin blocks with Super-Bond, microtensile bond strength (μTBS) tests were performed (n = 6), and fracture surfaces were analyzed. Before surface treatment, dentin was immersed in a sodium fluorescein solution for 3 h, and resin blocks were bonded with Super-Bond with rhodamine B as in the bond strength test. The bonded cross section was observed using confocal laser scanning microscopy (CLSM). ResultsμTBS was significantly higher in the immersion group than in the control group (61.5 [51.3–66.7] vs. 33.0 [20.4–57.8] MPa; P < 0.05). Fracture mode analysis showed that, compared with the control group, the immersion group had a significantly lower rate of adhesive failure at the dentin interface and a significantly higher rate of cohesive failure in Super-Bond (P < 0.01). CLSM showed a water droplet-like accumulation of fluorescein dye above the hybrid layer in the control group, not in the immersion group. ConclusionImmersion in a 4-META/MMA-TBB-activated liquid inhibited water exudation from the root canal dentin and improved the bond strength.

Lower Perioperative Complication Rates and Shorter Lengths of Hospital Stay Associated With Technology-Assisted Total Knee Arthroplasty Versus Conventional Instrumentation in Primary Total Knee Arthroplasty

BackgroundThe use of technology allows increased precision in component positioning in total knee arthroplasty (TKA). The objectives of this study were to compare (1) perioperative complications and (2) resource utilization between robotic-assisted (RA) and computer-navigated (CN) versus conventional (CI) TKA. MethodsA retrospective cohort study was performed using a national database to identify patients undergoing unilateral, primary elective TKA from January 2016 to December 2019. A total of 2,174,685 patients were identified and included RA (69,445), CN (112,225), or CI (1,993,015) TKA. Demographics, complications, lengths of stay, dispositions, and costs were compared between the cohorts. Binary logistic regression analysis was performed. ResultsThe RA TKA cohort had lower rates of intraoperative fracture (0.05 versus 0.08%, P < .05), respiratory complications (0.6 versus 1.1%, P < .05), renal failure (1.3 versus 1.7%, P < .05), delirium (0.1 versus 0.2%, P < .05), gastrointestinal complications (0.04 versus 0.09%, P < .05), postoperative anemia (8.9 versus 13.9%, P < .05), blood transfusion (0.4 versus 0.9%, P < .05), pulmonary embolism, and deep vein thrombosis (0.1 versus 0.2%, P < .05), and mortality (0.01 versus 0.02%, P < .05) compared to conventional TKA, though the cohort did have higher rates of myocardial infarction (0.09 versus 0.07%, P < .05). The CN cohort had lower rates of myocardial infarction (0.02 versus 0.07%, P < .05), respiratory complications (0.8 versus 1.1%, P < .05), renal failure (1.5 versus 1.7%, P < .05), blood transfusion (0.8 versus 0.9%, P < .05), pulmonary embolism (0.08 versus 0.2%, P < .05), and deep vein thrombosis (0.2 versus 0.2%, P < .05) over CI TKA. Total cost was increased in RA (16,190 versus $15,133, P < .05) and CN (17,448 versus $15,133, P < .05). However, the length of hospital stay was decreased in both RA (1.8 versus 2.2 days, P < .05) and CN (2.1 versus 2.2 days, P < .05). ConclusionsTechnology-assisted TKA was associated with lower perioperative complication rates and faster recovery.

Varying Complication Rates and Increased Costs in Technology-Assisted Total Hip Arthroplasty Versus Conventional Instrumentation in 1,372,300 Primary Total Hips

BackgroundThe use of technology allows surgeons increased precision in component positioning in total hip arthroplasty (THA). The objective of this study was to compare (1) perioperative complications and (2) resource utilizations between robotic-assisted (RA) and computer-navigated (CN) versus conventional instrumenttaion (CI) THA. MethodsA retrospective cohort study was performed using a large national database to identify patients undergoing unilateral, primary elective THA from January 1, 2016 to December 31, 2019 using RA, CN, or CI. There were 1,372,300 total patients identified and included RA (29,735), CN (28,480), and CI (1,314,085) THA. Demographics, complications, lengths of stay, dispositions, and costs were compared between the cohorts. Binary logistic regression analyses were performed. ResultsThe use of RA THA led to lower rates of intraoperative fracture (0.22% versus 0.39%), delirium (0.1% versus 0.2%), postoperative anemia (14.4% versus 16.7%), higher myocardial infarction (0.13% versus 0.08%), renal failure (1.7% versus 1.6%), blood transfusion (2.0% versus 1.9%), and wound dehiscence (0.02% versus 0.01%) compared to CI THA. The use of CN led to lower rates of respiratory complication (0.5% versus 0.8%), renal failure (1.1% versus 1.6%), blood transfusion (1.3% versus 1.9%), and pulmonary embolism (0.02% versus 0.1%) compared to CI THA. Total costs were increased in RA ($17,729 versus $15,977) and CN ($22,529 versus $15,977). Lengths of hospital stay were decreased in RA (1.8 versus 1.9 days) and CN (1.7 versus 1.9 days). ConclusionsPerioperative complication rates vary in technology-assisted THA, with higher rates in RA THA and lower rates in CN THA, relative to CI THA. Both RA THA and CN THA were associated with more costs, shorter postoperative hospital stays, and higher rates of discharge home compared to CI THA.

All-suture fixation of syndesmotic injuries: a case series.

To retrospectively evaluate the clinical outcomes of patients treated for syndesmotic injuries with an all-suture construct technique and compare their patient reported outcome scores with historically published outcomes of syndesmotic injuries fixed with suspensory suture buttons. This was a retrospective case series of patients treated at a Level 1 Trauma Center from May 1, 2018, to June 30, 2022. Ten patients aged 18 and older with unstable syndesmotic injuries treated with all-suture repair. Patients were excluded if they were treated with trans-osseous screws, had previous failed syndesmotic fixation, or suspensory suture button fixation. Patient-reported outcomes including Visual Analog Scale (VAS) pain scores, American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot scores, and complications were recorded. In the patients with 6weeks or more of radiographic follow-up (N = 9), there was no evidence of nonunion, loss of fixation, hardware complication, or whitling of the fibula by the suture. At final follow-up average VAS pain scores were 1.5 out of 10 (range 0-4; SD 1.2), AOFAS ankle and hindfoot scores averaged 89.6 out of 100 (range 86-100; SD 6.1). The pain subscale of the AOFAS score averaged 37.5 out of 40 (range 35-40; SD 2.5). The functional subscale of the AOFAS score averaged 46 out of 50 (range 44-50; SD 3.0). Stiffness was reported in one patient at their follow-up visits, which resolved with continued physical therapy. There were no superficial or deep infections. In conclusion, this case series presents the first clinical outcomes of an all-suture fixation technique for treatment of unstable syndesmotic ankle injuries. Our results suggest that the all-suture fixation technique results in similar patient reported outcomes when compared with historically reported patient reported outcomes of suspensory suture button fixation, and low rates of complication or hardware failure.

1306. Lower Treatment Failure Rates in Patients with Non-Staphylococcal Prosthetic Joint Infections (PJI) Treated with Debridement and Implant Retention (DAIR) Receiving Chronic Antibiotic Suppression (CAS)

Abstract Background PJI occurs in 0.5-2% of Joint Arthroplasty. Patients with acute non-Staphylococcal PJI who undergo DAIR are treated with 6 weeks of antimicrobials after which CAS may be considered. We aimed to compare the incidence of treatment failure between people who received CAS and those who did not. Methods This is a retrospective cohort study of patients admitted to Veterans Affairs (VA) hospitals from 2003-2017 with a non-Staphylococcal PJI, underwent DAIR and received 6 weeks of antimicrobial treatment (Table 1). CAS was defined as at least 30 days of oral antibiotics after 6 weeks of antimicrobial treatment. Duration of CAS was categorized as short (1-3 months), moderate (3-6 months) and long ( &amp;gt;6 months) (Fig 1). Patients were followed for 5 years. Treatment failure was defined as microbiologically confirmed recurrent PJI, additional debridement or re-operation at the same site. Cause-specific Kaplan-Meier curves were used to compare treatment failure rates between those who did and did not receive CAS, censoring on death. Results Among 468 patients with non-staphylococcal PJI who underwent DAIR, 208 (44.4%) received CAS. Patients with Enterococcus PJI were statistically more likely to receive CAS. K-M curves showed patients on CAS had a higher estimated failure free survival probability at 5 years when compared to those who did not get CAS (66% vs. 55%, p&amp;lt; 0.01) (Fig 2). When antibiotic use was considered as a time-dependent covariate, CAS was associated with a decreased hazard of treatment failure (hazard ratio (HR): .47 (95% confidence interval [CI]: 0.29, 0.76). After statistically adjusting for surgical site, severity of illness, and alcohol abuse, a short duration of CAS was significantly associated with decreased treatment failure (HR=0.24; 95% CI: 0.11, 0.52). There was no significant association between moderate or long duration of CAS and treatment failure (Table 2) Table 2 Conclusion A short duration of CAS may be beneficial among patients with non-Staphylococcal PJI who underwent DAIR. However, there was not a statistically significant association between longer duration of CAS use and treatment failure. Thus, the risks and benefits of long-term antibiotics should be weighed when aiming to prevent recurrence of PJI. Disclosures Mireia Puig-Asensio, MD, GILEAD: Honoraria Andrew Pugely, MD, MBA, Globus Medical: Advisor/Consultant|Globus Medical: Grant/Research Support|Globus Medical: IP royalties|Medtronic: Advisor/Consultant|Medtronic: Grant/Research Support|RDB Bioinformatics: Grant/Research Support|United Healthcare: Advisor/Consultant

Similar Clinical Outcomes for Arthroscopic Labral Reconstruction in Irreparable Cases Using the Indirect Head of the Rectus Femoris Tendon With an All-Inside Technique for Small Defects and the Iliotibial Band for Large Defects

To evaluate the clinical outcomes and satisfaction rate of patients who underwent arthroscopic labral reconstruction for an irreparable labral tear with a minimum follow-up period of 2 years. Additionally, this study aimed to compare 2 different reconstructive techniques for small and large labral defects: the indirect head of the rectus femoris tendon (IHRFT) autograft with an all-inside technique used to repair small defects (≤3 hours) and the iliotibial band (ITB) autograft for large defects (>3 hours). A total of 24 hips treated with the IHRFT were compared with 24 hips treated with the ITB. All patients underwent clinical evaluation before surgery and during the most recent follow-up (42 ± 18 months). The evaluation included patient satisfaction, the modified Harris Hip Score, the Non-Arthritic Hip Score, the Hip Outcome Score, the Hip Outcome Score-sport subscale, the 12-item International Hip Outcome Tool, and the visual analog scale pain score. All clinical scores were significantly improved (P < .001) at the latest follow-up in both groups. The final satisfaction was 7.1 ± 2.8 and 8.8 ± 1.6 for the IHRFT and ITB groups, respectively (P= .006). There was a significant difference in age (41.2 ± 6.0 years for the IHRFT group and 33 ± 8.5 for the ITB group; P= .004) and in surgery time (147.3 ± 39.4 minutes for the ITB group and 105.3 ± 25.7 for the IHRFT group; P < .001). One patient (4.2%) in the IHRFT group underwent total hip arthroplasty after 21.3 months (P= .999). At the 2-year follow-up, treating small defects using IHRFT and larger defects using ITB resulted in good patient-reported outcome measures with a low rate of complications and failures. The ITB group reported a higher level of satisfaction at the final follow-up. Level III, retrospective comparative therapeutic trial.

Scrutinate proclivity of regional aquifer hydraulic parameters: apriorisms for borehole failures within parts of the middle Benue Trough, Nigeria

Abstract Water borehole failures in Nigeria's middle Benue Trough are caused by imprecise aquifer features. This study employed empirical data to understand hydraulic parameters, anticipate regional groundwater potential, and explain borehole failures in difficult geological locations. 89 VES stations and quantitative data interpretation were required to determine the geoelectric properties beneath each station. Aquifer layers were delineated and their resistivity and thickness combined using geo-environment specific relations to yield transmissivity, hydraulic conductivity for both basement complex and sedimentary environments variously. Results show that aquifer resistivity ranges from 4.5 – 984.4 ohm-m; aquifer layer thickness varies from 4.4 m – 96.7 m with average thicknesses in sedimentary environment considerably greater; hydraulic conductivities range from 0.056 – 30.15 m/day, Transmissivity values range from 0.31 – 1281.36 m2/day. Log transformed transmissivity values range from 3.51 – 7.1 m2/day. Approximately 60.34% of the entire study area falls within transmissivity magnitude III and IV and can only support withdrawals for local water supply adequate for small communities and private consumption only and this may be the inferred cause for the low yield and high borehole failure rates. Understanding hydraulic characteristics is critical for 6controlling groundwater; research advances knowledge of transmissivity and conductivity in complex terrain.

Intracranial Outcomes of De Novo Brain Metastases Treated With Osimertinib Alone in Patients With Newly Diagnosed EGFR-Mutant NSCLC

IntroductionPatients with EGFR-mutant NSCLC have a high incidence of brain metastases. The EGFR-directed tyrosine kinase inhibitor osimertinib has intracranial activity, making the role of local central nervous system (CNS)-directed therapies, such as radiation and surgery, less clear. MethodsPatients with EGFR-mutant NSCLC and brain metastases who received osimertinib as initial therapy after brain metastasis diagnosis were included. Individual lesion responses were assessed using adapted RANO-BM criteria. CNS progression and local progression of brain metastasis from osimertinib start were analyzed using cumulative incidence treating death as a competing risk. Overall survival was estimated using Kaplan-Meier methodology. ResultsThere were 36 patients who had a median interval from brain metastasis diagnosis to first-line osimertinib initiation of 25 days. In total, 136 previously untreated brain metastases were tracked from baseline. Overall, 105 lesions (77.2%) had complete response and 31 had partial response reflecting best objective response of 100%. Best response occurred at a median of 96 days (range: 28–1113 d) from baseline magnetic resonance imaging. This reflects a best objective response rate of 100%. Two-year overall survival was 80%. CNS progression rates at 1-, 2-, and 3-years post-osimertinib were 21%, 32%, and 41%, respectively. Lesion-level local failure was estimated to be 0.7% and 4.7% at 1- and 2-years post-osimertinib, respectively. No clinicodemographic factors including brain metastasis number were associated with post-osimertinib progression. ConclusionsIntracranial response to osimertinib is excellent for patients with EGFR-mutant NSCLC with de novo, previously untreated brain metastases. Very low local failure rates support a strategy of upfront osimertinib alone in selected patients.

Loss of chondroprotection of medial collagen meniscus implant (CMI) at 20-year follow-up

ObjectiveThe mid-term results of the collagen meniscus implant (CMI) procedure for the replacement of partial meniscus defects have already been described. However, there is a paucity of long-term comparative studies. This study aimed to compare the clinical outcomes, failures, and osteoarthritis progression of patients who underwent partial medial meniscectomy and medial CMI implantation. MethodsThirty-six nonconsecutive patients with medial meniscus injuries that underwent medial CMI (MCMI) implantation or partial medial meniscectomy (PMM) between 1997 and 2000 were included in a prospective study with an intermediate 10-year follow-up examination and a final follow-up examination at 20-year follow-up. Outcome measures at the 20-year follow-up included the Lysholm score, visual analogue scale (VAS) for pain, International Knee Documentation Committee (IKDC) knee form , and Tegner activity level. Bilateral weight-bearing radiographs were also performed to evaluate hip-knee-angle (HKA) and the medial joint line height (JL). Data regarding complications and failures were also collected. ResultsAt the 20-year follow-up, 31 patients (83% follow-up rate) with a mean age of 60.7 ​± ​8.9 years were included in the final analysis (21.1 ​± ​1.2 years follow-up). Four reoperations and one failure per group were reported. When comparing the clinical results of the two groups, no difference was found considering the Lysholm score, Knee Injury and Osteoarthritis Outcome Score (KOOS), Tegner, and the IKDC. Moreover, 20 patients underwent radiographic examination (10 MCMI, 10 ​MM), and no statistically significant difference was reported concerning the JL, HKA, and the presence and incidence of osteoarthritis between the two groups. ConclusionThe CMI implant for partial medial meniscectomy provided good long-term results and a low failure rate. However, differently from the 10 years follow-up, the clinical and the radiological outcomes were not superior compared to the medial meniscectomy group. The present study's result suggests that using a medial scaffold is not chondroprotective. Level of evidenceIII, Prospective case–control study.

Computer-guided miniscrew insertion in the paramedian and parapalatal area of the palatal vault: low failure rate and no learning curve required to obtain predictable results?

To evaluate the failure rate of palatal computer-guided miniscrews, placed in paramedian and parapalatal regions for orthodontic purposes. In addition, to investigate the presence of a learning curve using computer guided miniscrew insertion, and to evaluate the peri-implant soft tissues response at 2-, 6- and 12- month follow-ups. 202 palatal computer-guided miniscrews were inserted in 78 subjects for orthodontic purposes. A surgical guide was designed after planning the appropriate insertion sites on three-dimensional images created by the fusion of cone-beam computed tomography (CBCT) and digital dental model images. The devices were disassembled monthly to perform the percussion test and to evaluate the mobility of each miniscrew. To determine the presence of a learning curve, the time of miniscrew failures and the number of surgeries were evaluated. Bleeding on probing (BOP) and probing pocket depth (PPD) were recorded for each miniscrew, at 2- (T0), 6- (T1), and 12-month follow ups (T2). An immediate failure rate of 4.95%, due to lack of primary stability immediately following miniscrew insertion, was recorded, with statistically significant higher failure rate of parapalatal miniscrews (P&#61; 0.00). Miniscrew failure occurred at random time, with an absence of a learning curve. The BOP (mean: 3.13%) and PPD (mean: 1.68mm) measurements remained stable over time. Computer-guided miniscrew insertion in the palatal vault showed a low failure rate without a determined learning curve to obtain predictable results and with long-term stability of peri-implant soft tissues indexes.

RADT-21. LINEAR ACCELERATOR BASED RADIOSURGERY WITH DYNAMIC CONFORMAL ARCS FOR PATIENTS WITH MULTIPLE BRAIN METASTASES: A PROSPECTIVE COHORT STUDY

Abstract PURPOSE Linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) is gaining popularity as an alternative due to its high delivery efficiency and improved accessibility. This study focuses on the radiosurgery protocol of a single institution, utilizing single-isocenter multi-target SRS treatment with an inverse-optimized dynamic conformal arc technique. Materials &amp; METHODS A prospective cohort study was conducted from August 2020. The study protocol was approved by the Research Ethics Committee. Patients with brain tumors referred for SRS were treated based on the indications. Prescription doses were determined by target size and radiation oncologists. The protocol included a 1-2 mm expansion of tumors for the planning target volume (PTV), with a requirement of at least 85% PTV coverage. At least three non-coplanar arcs are needed. Competing risk survival analysis was used to assess the cumulative incidence of failure. RESULTS A total of 57 patients with 190 brain tumors underwent SRS in this study. 12 patients (21.1%) received at least 2 radiation courses for recurrent lesions. Tumor sizes ranged from 0.45 to 8.0 cm (median 1.41 cm). The maximal dose relation ranged between 71.5% and 91.4% (median 81.6). The conformal index ranged from 1.08 to 2.19 (median 1.19), and the dose gradient index ranged from 2.19 to 6.95 (median 3.59). The 1-year cumulative incidence of local failure and intracranial distant failure rates were 10.8% and 35.6%, respectively. CONCLUSION LINAC-based SRS using dynamic conformal arcs achieves optimal tumor coverage and a high dose gradient with ease. It demonstrates a low rate of local failure, effectively protects normal brain tissue, and allows for the postponement of whole brain radiotherapy, enabling patients to maintain a normal quality of life. In conclusion, LINAC-based SRS with dynamic conformal arcs may be a beneficial treatment option for brain metastases, even with a high lesion count, particularly in institutions equipped with LINAC.

The effect of sodium-glucose co-transporter-2 inhibitors following anterior ST-segment elevation myocardial infarction

Abstract Background Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been clearly demonstrated to be associated with lower rate of new-onset heart failure(HF) in patients under risk of HF. In addition, due to lower rehospitalisation and better functional status in HF patients, SGLT-2 inhibitors have became the cornerstone of treatment regardless of the diabetes status. New-onset HF is very common in survivors of anterior ST-segment elevation myocardial infarction(STEMI) and requires preventive strategies, however the role of SGLT-2 inhibition in this population is not well established yet. Purpose In this study, we aimed to demonstrate the role of the SGLT-2 inhibitors in patients with anterior STEMI. Methods We prospectively enrolled patients with diabetes mellitus who had anterior STEMI, which was managed with primary percutaneous coronary intervention. Patients with previous myocardial infarction, heart failure, under SGLT-2 inhibitor treatment and chronic kidney disease were excluded. Patients were divided into two groups according to SGLT-2 inhibitor treatment; group 1 patients treated with empaglifosine or dapaglifosine and group 2 received other classes of diabetes medicine. Comorbidities regarding smoking history (p: 0.871), hypertension (p: 0.064), previous cerebrovascular accident(p: 0,348) and coronary artery disease(p: 0.201) were comparable between groups. Presence of multivessel coronary artery disease (p: 0.259) and left main coronary artery involvement (p: 0.062) were also similar between groups. Glucose level on admission was similar (p: 0.782) between groups, however HBa1C level was significantly higher in group 1(p: &amp;lt;0.001). Left ventricular ejection fraction which was calculated prior to hospital discharge was also similar between groups(p: 0.297). Mean follow-up duration was 12 months and new-onset heart failure was significantly lower in group 1 patients(p:&amp;lt;0.001). In line with the rate of new onset-heart failure, pro-BNP levels at the 12th month visit were lower in group 1 patients (p: 0.042) which was similar during the STEMI hospitalization (p: 0.668). Multivariate analyses demonstrated that the use of SGLT-2 inhibitors independently associated with lower rate of new-onset HF. Conclusion Our results indicate that SGLT-2 inhibitors decrease the rate of new-onset heart failure during the follow-up in patients with previous myocardial infarction.Baseline characteristicsUnivariate and multivariate analysis

Atrial and ventricular arrhythmias with immune checkpoint inhibitor therapy in patients without evidence of myocarditis

Abstract Background Immune checkpoint inhibitor (ICI) therapy has improved the prognosis of many cancer types. Immune-related adverse events (irAEs) are common and recent studies suggest ICI therapy may be associated with an increased risk of arrhythmias. However, data on arrhythmias after ICI therapy has been limited by small sample sizes, the inclusion of patients with ICI myocarditis, or an incomplete characterization of the factors that drive arrhythmias with an ICI. Purpose This study aimed to characterize the association between ICIs and arrhythmias in patients without evidence of myocarditis. Methods We conducted a hospital network-wide retrospective cohort study on all patients treated with ICI who were free from arrhythmias at the start of ICI therapy, and had no evidence of immune-related myocarditis. We used a historical pre-ICI therapy era cohort of cancer patients of similar age and tumor types, diagnosed between 2008-2012. The main study outcome was the incidence of atrial fibrillation, atrial flutter, supraventricular tachycardia, and ventricular tachycardia after ICI therapy. International Classification of Diseases 9th and 10th edition codes were used to ascertain baseline characteristics and to detect the study outcomes. Myocarditis cases were identified through the application of natural language processing techniques to electronic health records. Patients on ICI therapy and controls were followed from the start of ICI therapy, and from the first visit after 2008, respectively, up to three years after the index date. Results The study population consisted of 7441 patients on ICI therapy and 2311 controls. Patients on ICI therapy were older (65±13 vs. 63±13 years, p&amp;lt;0.001) and more frequently had arterial hypertension (52% vs. 47%, p&amp;lt;0.001), but had lower rates of prior congestive heart failure (6% vs. 11%, p&amp;lt;0.001). Over a median follow-up period of 36 months, 9.8% on ICI therapy were diagnosed with any incident atrial or ventricular arrhythmia, compared to 7.1% in the control group (p&amp;lt;0.001) with corresponding incidence rates of 4.4 and 2.3 cases per 100 person-years, respectively (Fig. 1). When correcting for age, sex, cancer type, prior congestive heart failure, and cardiovascular risk factors, patients on ICI therapy had a higher risk of a composite outcome of any arrhythmia (hazard ratio [HR] 1.68, 95% confidence interval [CI]: 1.39-2.04, p&amp;lt;0.001), atrial fibrillation (HR 1.29, 95%CI: 1.02-1.63, p=0.034) and ventricular tachycardia (HR 2.01, 95%CI: 1.34-3.04, p&amp;lt;0.001). In a multivariable logistic regression model, the occurrence of a non-cardiovascular irAE was a predictor of an incident arrhythmia (odds ratio 1.81, 95%CI: 1.56-2.23, p&amp;lt;0.001). Conclusion This study, to the best of our knowledge, is the largest to report on ICI therapy-related arrhythmias and the first to show the occurrence of non-cardiovascular irAEs as a predictor of arrhythmia risk in patients on ICI therapy without evidence of myocarditis.Fig. 1

Efficacy and safety of intravenous iron repletion in patients with heart failure: a systematic review and meta-analysis

Abstract Introduction AFFIRM-AHF and IRONMAN demonstrated lower rates of the combined endpoint recurrent heart failure (HF) hospitalizations and cardiovascular death (CVD) by using intravenous (IV) ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), respectively in patients with HF and iron deficiency (ID) utilizing prespecified COVID-19 analyses. Material and methods We meta-analyzed efficacy, between trial heterogeneity and data robustness for the primary endpoint and CVD in AFFIRM-AHF and IRONMAN. As sensitivity analysis, we analyzed data from all eligible exploratory trials investigating FCM/FDI in HF. Results FCM/FDI reduced the primary endpoint (RR = 0.81, 95% CI 0.69-0.95, p = 0.01, I2 = 0%), with the number needed to treat (NNT) being 7. Power was 73% and findings were robust with fragility index (FI) of 94 and fragility quotient (FQ) of 0.041. Effects of FCM/FDI were neutral concerning CVD (OR = 0.88, 95% CI 0.71-1.09, p = 0.24, I2 = 0%). Power was 21% while findings were fragile with reverse FI of 14 and reversed FQ of 0.006. The sensitivity analysis from all eligible trials (n = 3,258) confirmed positive effects of FCM/FDI on the primary endpoint (RR = 0.77, 95% CI 0.66-0.90, p = 0.0008, I2 = 0%), with NNT being 6. Power was 91% while findings were robust (FI of 147 and FQ of 0.045). Effect on CVD was neutral (RR = 0.87, 95% CI 0.71-1.07, p = 0.18, I2 = 0%). Power was 10% while findings were fragile (reverse FI of 7 and reverse FQ of 0.002). Rate of infections (OR = 0.85, 95% CI 0.71-1.02, p = 0.09, I2 = 0%), vascular disorder (OR = 0.84, 95% CI 0.57-1.25, p = 0.34, I2 = 0%) and general or injection-site related disorders (OR = 1.39, 95% CI 0.88-1.29, p = 0.16, I2 = 30%) were comparable between groups. There was no relevant heterogeneity (I2&amp;gt;50%) between the trials for any of the analyzed outcomes. Conclusions Use of FCM/FDI is safe and reduces the composite of recurrent HF hospitalizations and CVD without benefit on CVD. Findings concerning composite outcomes exhibit a high level of robustness without heterogeneity between trials with FCM and FDI.Summary

Impact of Transcatheter Edge-to-Edge Mitral Valve Repair on Atrial Functional Mitral Regurgitation from the GIOTTO Registry

Atrial functional mitral regurgitation (aFMR) has a peculiar pathophysiology that may have distinctive outcomes. We investigated the impact of transcatheter edge-to-edge repair in aFMR compared with other FMR etiologies. The GIOTTO (GIse registry Of Transcatheter treatment of MR) is a multicenter, prospective study enrolling patients with symptomatic MR treated with MitraClip up to 2020. We categorized patients with FMR as aFMR, ischemic FMR (iFMR), and nonischemic ventricular FMR (niFMR). The clinical end points were defined according to the Mitral Valve Academic Research Consortium. Of 1,153 patients, 6% had aFMR, 47% iFMR, and 47% niFMR. Patients with aFMR were older, mostly women, and had a higher atrial fibrillation rate. They had better left ventricular ejection fraction and smaller left ventricular volumes, with no difference in mitral effective regurgitant orifice area. The acute device and procedural success rates were similar among the groups. At the longest available follow-up (median 478days, interquartile range 91 to 741 days), the rate of MR ≥2+ was similar among the groups. Patients with aFMR had a lower rate of cardiovascular death and heart failure than patients with iFMR (hazard ratio [HR] 0.43, p = 0.02) and niFMR (HR 0.45, p = 0.03). The aFMR etiology remained independently associated with the composite outcome, together with postprocedural MR ≤1+ (HR 0.63, p <0.01) and peripheral arteriopathy (HR 1.82, p = 0.003). The results of this GIOTTO subanalysis suggested that aFMR is less prevalent and associated with better outcomes compared with other causes of FMR treated by transcatheter edge-to-edge repair. Postprocedural MR >1+, peripheral vasculopathy, non-aFMR were independent predictors of worse outcomes.

Outcomes of Meniscal Repair in Patients Aged 40 and Above: A Systematic Review.

Meniscal injuries are increasingly common in older age groups. Age is often cited as a contraindication to undergoing meniscal repair due to concerns regarding failure rates. There has recently, however, been an increasing shift towards repair in older populations. The purpose of this study was to review outcomes of meniscal repair in patients over the age of 40. A systematic search of the following databases was conducted of PubMed, SCOPUS, Web of Science, and Cochrane Library to identify studies reporting failure rates of patients over 40 with meniscal injuries undergoing repair. The definition of meniscus failure was noted for each study evaluated in this systematic review. Further data surrounding clinical and radiological outcomes were recorded and evaluated, when available. Thirteen studies were included in this review, encompassing a total of 316 meniscal repairs in patients over the age of 40 years. The overall failure rate was found to be 15.5% (49/316) (range 0-33.3%). There was no difference in the failure rate in those over 40 vs. under 40, and the two groups had equivalent functional outcomes. Age should not be considered a contra-indication for meniscal repair. Appropriately selected older patients can have acceptably low failure rates with meniscal repair and similar functional outcomes to those under the age of forty. Meniscal repairs in those over 40 achieved better functional outcomes than patients of the same age group who underwent meniscectomy.

Haploidentical Hematopoietic Cell Transplant with Post-Transplant Cyclophosphamide Expedites Donor-Derived Immune Reconstitution in a Pediatric Severe Aplastic Anemia Cohort

Severe aplastic anemia (SAA) is a life-threatening, idiopathic process involving the immune-mediated destruction of hematopoietic stem cells. Treatment involves immunosuppressive therapy (IST) and/or allogeneic hematopoietic cell transplantation (HCT). The latter has recently been optimized with use of a post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GvHD) platform, permitting successful HCT with only half-HLA-matched haploidentical donors. In pediatrics, this platform results in &amp;gt;90% overall survival with low rates of GvHD and graft failure. However, reports on donor chimerism and immune reconstitution are limited. We hypothesized that a PTCy platform would expedite CD3 donor engraftment and CD4 T cell recovery. In a phase III clinical trial, we treated three cohorts of pediatric (age &amp;lt;/=25 years) patients with SAA requiring alloHCT: MUD, MSD, and HAPLO. The MUD cohort included n=15 recipients of 7-8/8 HLA-matched unrelated donor grafts (n=5 7/8, n=10 8/8) with median age 14 years (range 2-17 years), following cyclophosphamide (Cy) 50 mg/kg, fludarabine (Flu) 200 mg/m 2, rabbit anti-thymocyte globulin (rATG) 9 mg/kg total dose rabbit and low dose total body irradiation (TBI) at 200 cGy. The MSD cohort included n=9 recipients of 8/8 HLA-matched sibling donor grafts with median age 15 years (range 12-24 years), following Cy 200 mg/kg and 9 mg/kg rATG. The HAPLO cohort included n=4 recipients of 4/8 HLA-matched related donor grafts with median age 8.5 years (range 2-21 years) following Cy 29 mg/kg, Flu 150 mg/m 2, 9 mg/kg rATG, and low dose TBI at 200 cGy. GvHD prophylaxis consisted of 30 days of mycophenolate mofetil, and 100 days of a calcineurin inhibitor (followed by an 8-10 week taper), with the HAPLO cohort additionally receiving post-transplant Cy (PTCy) 50 mg/kg/day on days +3 and +4. Peripheral blood lymphocyte counts and peripheral blood and bone marrow donor chimerism were evaluated on days +100, +180 and +365. Recipient characteristics were largely equivalent between cohorts, with 43% receiving IST prior to HCT. Clonality was overrepresented in the HAPLO cohort (2 of 4, 1 with monosomy 7 myelodysplastic syndrome and 1 with a large PNH clone), with only 2 of 15 in the MUD and none in the MSD cohorts. Active controlled infections at the time of HCT were additionally overrepresented in the HAPLO cohort, with disseminated pseudomonas in 1. The MUD cohort had 1 with Rhizopus invasive sinusitis (none in the MSD cohort). Achievement of neutrophil engraftment was statistically significantly delayed in the HAPLO cohort at a median of 17 days compared to 12 for MSD and 14 for MUD, p=0.004), however there were no episodes of primary or secondary graft failure. With only a single late death from intracranial hemorrhage in the MUD cohort, OS was equivalent at 2 years (100% in MSD and HAPLO cohorts, 93.3% in MUD). GvHD rates were low with only 1 (MUD) experiencing grade II acute GvHD, and 1 (MUD) experiencing mild chronic GvHD. Immune reconstitution varied by cohort with statistically significantly greater CD3 peripheral blood donor chimerism (p&amp;lt;0.001) as well as CD4 (p=0.04) and CD8 (p=0.03) T cell counts over time for the HAPLO recipients (CD3 chimerism in Fig 1, CD4 count in Fig 2; 2-way ANOVA fixed effects model). Considering a CD4 &amp;gt;200 cell/uL as clinically meaningful, we assessed the proportion of each cohort achieving this milestone at each timepoint. While each cohort had an increase in proportion achieving CD4&amp;gt;200 over time, the HAPLO cohort reached 50% with CD4 &amp;gt;200 at day +100, compared to 11% MUD and 0% MSD (p=0.09). At day +180, the proportion with CD4 &amp;gt;200 were 36% MUD, 25% MSD and 75% HAPLO (1 yr: 90% MUD, 100% MSD and HAPLO). Donor availability remains a challenge to successful transplant for patients with SAA, and haploidentical matches overcome donor limited accessibility. PTCy as GvHD prophylaxis is associated with low incidences of graft failure and severe GvHD. While PTCy might be anticipated to inhibit donor T cells and immune reconstitution, our data, albeit limited by small cohorts, demonstrates superior and more efficient CD3 donor engraftment and CD4 T cell count recovery following HAPLO HCT with PTCy compared to non-PTCy based MUD and MSD cohorts.

Low contralateral failure rate with unilateral proton beam radiotherapy for oropharyngeal squamous cell carcinoma: A multi-institutional prospective study from the proton collaborative group

IntroductionUnilateral radiation therapy is appropriate for select patients with oropharyngeal squamous cell carcinoma (OPSCC). The use of proton beam therapy (PBT) in the unilateral setting decreases the dose to the contralateral neck and organs at risk. This study aims to evaluate contralateral recurrences in patients who received ipsilateral PBT. MethodsWe evaluated the Proton Collaborative Group database for patients treated with PBT for head and neck squamous cell carcinoma between the years 2015–2020 at 12 institutions. Dosimetric analysis was performed in five cases. ResultsOur analysis included 41 patients that received ipsilateral PBT with a mean follow-up of 14.7 months. 37% patients (n = 15) were treated for recurrent disease, and 63% (n = 26) were treated for de novo disease. Oropharyngeal sites included tonsillar fossa (n = 30) and base of tongue (n = 11). The median dose and BED delivered were 69.96 CGE and 84 Gy, respectively. Eight (20%) patients experienced at least one grade 3 dysphagia (n = 4) or esophagitis (n = 4) toxicity. No grade ≥ 4 toxicities were reported. There was one (2.4%) failure in the contralateral neck. The 1-year locoregional control was 88.9% and the freedom from distant metastasis was 95.5% (n = 2). The dosimetric analysis demonstrated similar ipsilateral level II cervical nodal region doses, whereas contralateral doses were higher with photon plans, mean: 15.5 Gy and 0.7CGE, D5%: 25.1 Gy and 6.6CGE. ConclusionsOur series is the first to report outcomes for patients with OPSCC receiving unilateral PBT. The contralateral neck failure rate was excellent and comparable to failure rates with photon irradiation.