Left bundle branch area pacing for heart failure patients requiring cardiac resynchronization therapy: A meta-analysis.

INTRODUCTION: Left bundle branch area pacing (LBBP) is a novel conduction system pacing method to achieve effective physiological pacing and an alternative to cardiac resynchronization therapy (CRT) with biventricular pacing (BVP) for patients with heart failure with reduced ejection fraction (HFrEF). We conduted this meta-analysis and systemic review to review current data comparing BVP and LBBP in patients with HFrEF and indications for CRT. METHODS: We searched PubMed/Medline, Web of Science, and Cochrane Library from the inception of the database to November 2022. All studies that compared LBBP with BVP in patients with HFrEF and indications for CRT were included. Two reviewers performed study selection, data abstraction, and risk of bias assessment. We calculated risk ratios (RRs) with the Mantel-Haenszel method and mean difference (MD) with inverse variance using random effect models. We assessed heterogeneity using the I2 index, with I2 > 50% indicating significant heterogeneity. RESULTS: Ten studies (9 observational studies and 1 randomized controlled trial; 616 patients; 15 centers) published between 2020 and 2022 were included. We observed a shorter fluoroscopy time (MD: 9.68, 95% confidence interval [CI]: 4.49-14.87, I2 = 95%, p < .01, minutes) as well as a shorter procedural time (MD 33.68, 95% CI: 17.80-49.55, I2 = 73%, p < .01, minutes) during the implantation of LBBP CRT compared to conventional BVP CRT. LBBP was shown to have a greater reduction in QRS duration (MD 25.13, 95% CI: 20.06-30.20, I2 = 51%, p < .01, milliseconds), a greater left ventricular ejection fraction improvement (MD: 5.80, 95% CI: 4.81-6.78, I2 = 0%, p < .01, percentage), and a greater left ventricular end-diastolic diameter reduction (MD: 2.11, 95% CI: 0.12-4.10, I2 = 18%, p = .04, millimeter). There was a greater improvement in New York Heart Association function class with LBBP (MD: 0.37, 95% CI: 0.05-0.68, I2 = 61%, p = .02). LBBP was also associated with a lower risk of a composite of heart failure hospitalizations (HFH) and all-cause mortality (RR: 0.48, 95% CI: 0.25-0.90, I2 = 0%, p = .02) driven by reduced HFH (RR: 0.39, 95% CI: 0.19-0.82, I2 = 0%, p = .01). However, all-cause mortality rates were low in both groups (1.52% vs. 1.13%) and similar (RR: 0.98, 95% CI: 0.21-4.68, I2 = 0%, p = .87). CONCLUSION: This meta-analysis of primarily nonrandomized studies suggests that LBBP is associated with a greater improvement in left ventricular systolic function and a lower rate of HFH compared to BVP. There was uniformity of these findings in all of the included studies. However, it would be premature to conclude based solely on the current meta-analysis alone, given the limitations stated. Dedicated, well-designed, randomized controlled trials and observational studies are needed to elucidate better the comparative long-term efficacy and safety of LBBP CRT versus BIV CRT.

Patient-reported experience measures in deprescribing for hospitalised older patients: a prospective, multicentre, observational study.

BACKGROUND: Hospitalisation provides an opportunity for medication review and deprescribing. Patient-reported experience measures (PREM) for deprescribing in older patients in hospital are not well described. AIMS: To pilot test and describe PREM for deprescribing in older patients, compare PREM by patient characteristics and investigate patients' awareness of medication changes on hospital discharge. METHODS: This prospective, multicentre, observational cohort study at two tertiary hospitals in Sydney, Australia, evaluated the PREM questionnaire developed by the NSW Therapeutic Advisory Group. It was completed by patients (or their next of kin) recruited from acute geriatric medicine and orthogeriatric services. Association with nine patient characteristics was analysed using the Chi-squared test and multivariable regression. Awareness of medication changes and test-retest reliability were analysed using descriptive statistics. RESULTS: Overall, 201 participants completed the questionnaire, with 170 eligible for analysis; 34 (20%) of 170 were aware of reduction or cessation of their usual medications on discharge and reported involvement in decision-making and receiving enough information to reduce or stop one or more of their usual medications (positive PREM). Independent predictors of positive PREM included respondent (next of kin), hospital (Hospital 1), language (English) and specialty (acute geriatric medicine). Overall, 92 (59.4%) of 155 patients with medication changes were aware of those changes on hospital discharge. CONCLUSIONS: These PREM are a feasible tool to examine older patients' experiences of deprescribing in hospital and might be applied to evaluate interventions to improve awareness, shared decision-making and provision of information when deprescribing for older patients.

A Systematic Temporal Assessment of Changes in Tendon Stiffness Following Rotator Cuff Repair.

OBJECTIVES: How the material properties of the human supraspinatus tendon change following arthroscopic rotator cuff repair is undetermined. Shear wave elastography ultrasound is a relatively new, noninvasive measure of tissue stiffness. We aimed to evaluate any temporal changes in stiffness and/or thickness of supraspinatus tendons in humans following primary arthroscopic rotator cuff repair. METHODS: Shear wave elastography was performed at three predetermined regions by a single sonographer at 1-, 6-, 12-, 24-, and 52 weeks postoperatively in 50 consecutive single-row inverted mattress primary arthroscopic rotator cuff repairs. One-way ANOVA with Tukey's correction and Spearman's correlation tests was performed. RESULTS: Of 50 patients, two retore by 1-week and were excluded. Two patients retore at 6 weeks, two at 12 weeks, and one at 24 weeks. The mean tendon stiffness in 48 patients at the tendon footprint increased by 21% (1.32 m/s) at 6 months (P < .001), with the lateral tendon stiffening before the medial tendon. Tendon thickness decreased by 11% (0.6 mm) at 6 weeks (P = .008), then stabilized to 24 weeks. Tendons that were less elastographically stiff at 1 week were more likely to be thinner at 6-weeks (r = .38, P = .010). CONCLUSIONS: The data supports the hypothesis that rotator cuff tendons repaired using the single-row inverted-mattress technique take 6 weeks to heal to bone. Unlike in other tendons, there was no hypertrophic healing response. Prior to 6 weeks, the tendon may stretch/thin-out, particularly if its material properties, as assessed by shear wave elastography, are inferior. The material properties of the tendon improved at the tendon insertion site first, then medially out to 12 months post-repair.

An evaluation of shear wave elastographic characteristics of the supraspinatus tendon after rotator cuff repair.

BACKGROUND: The main complication of rotator cuff repair is retear, which is most common in older patients and patients with greater tear sizes. However, it is unknown why these factors are associated with increased rates of retear. The aim of this study was to determine whether the factors associated with rotator cuff retear (age, tear size, sex, history of trauma, and duration of symptoms) are also associated with decreased mechanical stiffness of the supraspinatus tendon after repair, as assessed by shear wave elastography. METHODS: This was a prospective study of 50 patients undergoing primary rotator cuff repair. A sonographer conducted shear wave elastography ultrasound in all patients at 1, 6, 12, 26, and 52 weeks after repair. The shear wave velocity of the supraspinatus tendon was measured at the tendon-bone interface, 3 mm medial to the interface, and 6 mm medial to the interface. A multiple linear regression analysis was performed with calculation of Cohen F2 values to determine the factors that independently affected supraspinatus tendon stiffness postoperatively. RESULTS: For every decade increase in age, the shear wave velocity of the supraspinatus tendon decreased by 0.5 m/s (P = .004). Greater tear size correlated with reduced supraspinatus shear wave velocity (P < .03 at 6 weeks). Male patients had greater supraspinatus tendon stiffness than female patients (8.2 m/s vs. 6.9 m/s, P = .04). Tendons in patients with a history of trauma were approximately 16% stiffer postoperatively than those in patients with no trauma history (P < .001). Duration of symptoms had no impact on the mechanical stiffness of the supraspinatus tendon. CONCLUSION: Older age, larger tear size, female sex, and nontraumatic tear causation were independently associated with reduced shear wave velocity of the supraspinatus tendon postoperatively. The findings of our study correlate with the results of cohort studies assessing the influence of these variables on rotator cuff retear rates, suggesting that the mechanical stiffness of the supraspinatus tendon, as assessed by shear wave elastography, may have an important association with a successful repair.

Synthetic polytetrafluoroethylene patches for irreparable rotator cuff tears-how are they doing at 5 years?

BACKGROUND: Treating massive and irreparable rotator cuff tears are problematic. Several studies have reported that polytetrafluoroethylene (PTFE) patches demonstrated excellent construct integrity and positive clinical and patient outcomes. However, these studies either had small sample sizes or short follow-up periods. PURPOSE: To determine the survivorship, efficacy, and medium-term (2-19 years) outcomes of PTFE patch repairs. METHODS: This retrospective study used prospectively collected data to establish the medium-term outcomes of PTFE interposition patch repairs for massive rotator cuff tears that could not be repaired by the standard technique. Patients included those who met the ≥2-year follow-up criteria post repair. Standardized assessments of patient-ranked shoulder pain and function and shoulder strength and passive range of motion (ROM) were performed preoperatively and at follow-up visits. Radiographs and ultrasonography were used to evaluate repair integrity, measure proximal humeral head migration, and determine glenohumeral arthritis scores. RESULTS: Forty-one shoulders formed the study cohort at a mean follow-up period of 5 years (range: 2-19 years). The mean age of this group was 72 (standard deviation: 10; range: 50-88) and had 14 cm2 tears at surgery. Twenty-five of 41 (61%) PTFE interposition patch repairs remained intact at an average of 5 years postrepair. Thirteen patches failed at the patch-tendon junction, 1 was removed, and 2 patients underwent reverse total shoulder replacement. Patient-ranked shoulder stiffness (P < .05), frequency of pain during activity and sleep (P < .001), pain levels during overhead activity and rest (P < .001), and overall shoulder function significantly improved from bad preoperatively to fair at the mean 5-year postoperative visit (P < .001). No significant improvements were demonstrated in dynamometer-measured shoulder strength maneuvers and passive ROM. All patients demonstrated proximal humeral head migration on shoulder radiographs regardless of repair integrity (mean Upper Migration Index = 1.2). Failed repairs were associated with higher mean preoperative glenohumeral arthritis grades compared with intact repairs (grade 2 in failed repairs compared with grade 1 in intact repairs) (P < .01). CONCLUSION: PTFE interposition patch repairs for massive and irreparable tears had good construct integrity and clinical outcomes at 2 years. These outcomes were not maintained. PTFE patch repairs often failed at the patch-tendon junction at 4 years and beyond and were ineffective in (1) preventing proximal humeral head migration, (2) stopping progression of glenohumeral arthritis, and (3) improving shoulder strength and ROM.

Fibrillar matrix, Echogenicity, Contour, Thickness, and Suture (FECTS) vs. Global: A comparison of 2 scales developed to assess ultrasound images post rotator cuff repair.

BACKGROUND: Ultrasound is commonly used to assess rotator cuff repair (RCR), but no standardized criterion exists to characterize the tendon. PURPOSE: The aims of this study were to (1) develop content validity for ultrasound specific criteria to grade the postoperative appearance of a tendon after RCR, (2) assess the reliability of the criteria, and (3) assess the feasibility to use these assessments. METHODOLOGY: Following expert consultation and literature review for content validity, 2 scales were created: 1) the Fibrillar matrix, Echogenicity, Contour, Thickness, and Suture (FECTS) scale and 2) the Rotator Cuff Repair-Investigator Global Assessment (RCR-IGA). A prospective cohort study was undertaken on patients who had received a RCR and serial B-mode ultrasound images. Four raters assessed the 64-ultrasound images using the scales created in a blinded fashion using intraclass correlation coefficients. RESULTS: The FECTS scale was a composite score with 5 key parameters and the RCR-IGA scale was a 5-point global score. The intrarater reliability for the FECTS scale was excellent for the most experienced rater (0.92) and fair for the rater with no experience (0.72). The intrarater reliability for the RCR-IGA scale was excellent for 3 of the 4 raters (0.80-0.87) and fair when used by the least experienced rater (0.56). Inter-rater testing for all the FECTS scale parameters had excellent reliability (0.82-0.92) except for Fibrillar matrix (0.73). The average time to complete the FECTS scale per image was 23 seconds and 11 seconds for the RCR-IGA scale. CONCLUSION: The FECTS scale and the RCR-IGA scale are reliable tools to assess the ultrasonic appearance of the repaired rotator cuff tendon. The FECTS scale was more reliable for less experienced assessors. The RCR-IGA scale was easier, more time efficient and reliable for those with experience.

Synthesis and evaluation of potent novel inhibitors of human sulfide:quinone oxidoreductase.

Here we report the first small-molecule inhibitors of human sulfide:quinone oxidoreductase (SQOR) that decrease the rate of breakdown of hydrogen sulfide (H2S), a potent cardioprotective signaling molecule. SQOR is a mitochondrial membrane-bound protein that catalyzes a two-electron oxidation of H2S to sulfane sulfur (S0), using glutathione (or sulfite) and coenzyme Q (CoQ) as S0 and electron acceptor, respectively. Inhibition of SQOR may constitute a new approach for the treatment of heart failure with reduced ejection fraction. Starting from top hits identified in a high-throughput screen, we conducted SAR development guided by docking of lead candidates into our crystal structure of SQOR. We identified potent SQOR inhibitors such as 19 which has an IC50 of 29 nM for SQOR inhibition and favorable pharmacokinetic and ADME properties required for in vivo efficacy testing.

Anteroposterior tear size, age, hospital, and case number are important predictors of repair integrity: an analysis of 1962 consecutive arthroscopic single-row rotator cuff repairs.

BACKGROUND: Retear or nonhealing of a surgically repaired rotator cuff is common, but the determinants of retear are poorly understood. We aimed to determine the relationship between preoperative and intraoperative factors and retear rate following rotator cuff repair and to formulate a predictive model based on this relationship, including any interaction effects between tear size, patient age, and surgical experience in contributing to the retear rate. METHODS: We performed a post hoc analysis of prospectively collected data from 1962 consecutive patients who underwent a primary arthroscopic single-row rotator cuff repair performed by the senior author from 2007 through 2018 and postoperatively returned for 6-month follow-up ultrasonography. RESULTS: Multiple logistic regression analysis revealed anteroposterior tear length to be the most important independent predictor of retear (Wald statistic, 90; P < .001). Other independent predictors included case number (Wald statistic, 59; P < .001), patient age at surgery (Wald statistic, 30; P < .001), and type of hospital (public vs. private) (Wald statistic, 17; P < .001). The data indicated that following rotator cuff repair, there was a 4-fold increase in the retear rate as the anteroposterior tear size increased from 1 cm to 3 cm; a 8-fold decrease when comparing case number 1000 with case number 3000; a 2-fold increase as patient age increased from 50 years to 70 years; and a 3-fold increase when comparing surgery performed in a public hospital vs. a private hospital. The area under the receiver operating characteristic curve was 0.81 (95% confidence interval, 0.78-0.84), indicating that our equation could predict 81% of retears. CONCLUSIONS: Anteroposterior tear length was the most important independent predictor of retear or nonhealing. Other predictive factors included case number, patient age at surgery, and hospital type. The predictive effect of anteroposterior tear length, patient age, and case number in contributing to retear was additive. Our regression equation may be used to calculate patient rotator cuff retear risk at 6 months after repair.

Stiffness: friend or foe? A cohort study evaluating the effect of early postoperative stiffness on the outcomes of patients who underwent superior labral repair.

BACKGROUND AND HYPOTHESIS: Postoperative stiffness is a commonly reported complication after type II superior labrum anterior-posterior (SLAP) repair. It is unclear whether patients with postoperative stiffness, classified as external rotation to the side of ≤20°, ultimately will have greater functional outcomes at ≥2 years after surgery. We hypothesized that postoperative stiffness would result in improved functional outcomes at ≥2 years after surgery. METHODS: Sixty-five consecutive arthroscopic SLAP repair cases performed by a single surgeon were retrospectively reviewed using prospectively collected patient-ranked outcomes and examiner-determined assessments preoperatively and at 1 week, 6 weeks, 24 weeks, and a minimum of 2 years after surgery. Patients were allocated to the stiff group and the non-stiff group based on their external rotation at 6 weeks after repair. RESULTS: Of the patients, 16 (27%) had ≤20° of external rotation at 6 weeks postoperatively. These patients, comprising the stiff group, had more pain and more difficulty with overhead activities early on than patients in the non-stiff group (very severe vs. severe, P < .05), but by 2 years, they had less difficulty and less pain with overhead activities, less patient-reported stiffness, and less severe pain at night than isolated SLAP repair patients with >20° of external rotation at 6 weeks (P < .05). CONCLUSION: This study suggests that in patients who underwent SLAP repair, early postoperative stiffness (at 6 weeks as assessed by ≤20° of external rotation), while problematic early, is associated with improved functional outcomes in the longer term, with patients in the stiff group reporting less pain and difficulty with overhead activities at ≥2 years after surgery.

The fate of sutures post rotator cuff repair.

BACKGROUND: Ultrasonographic imaging has been widely used as a diagnostic tool for rotator cuff tears. Several studies have explored the changes in rotator cuff tendon morphology after arthroscopic cuff repair; however, none have addressed the fate of sutures. The aim of this study was to determine (1) if the sutures migrate through the tendon during the postoperative healing period in patients who have had arthroscopic rotator cuff repair; (2) if the sutures do migrate, the time point at which it does; and (3) if the quality of the tendon, in terms of tendon stiffness, modulus of elasticity, bursal thickness, and anatomic footprint, affects suture migration. METHODS: This was a prospective study involving 21 patients who had primary arthroscopic rotator cuff repair performed by a single surgeon. All patients were assessed at 8 days, 6 weeks, 12 weeks, and 24 weeks postrepair; during each assessment, patients underwent an ultrasonographic examination (using a Siemens ACUSON S3000 ultrasonographic system, following a standardized protocol), where supraspinatus tendon thickness and thickness of tendon tissues below and above the suture were measured. Measurements of anatomic footprint, bursal thickness, tendon stiffness, and modulus of elasticity were obtained to assess tendon quality. RESULTS: Of the 21 participants, 14 (67%) had full-thickness tears and 7 (33%) had partial-thickness tears. Between the 12th- and 24th-week follow-up, 2 patients' tendons were found to be not intact. Within the first 12 weeks of the postrepair healing period, the sutures migrated inferiorly, through to the middle of the tendon at the footprint-articular junction (ie, ratio of tendon tissue thickness below the suture to the total tendon thickness = 0.5) (P = .03). The mean anatomic footprint increased from 8.4 ± 1.6 mm to 9.1 ± 1.2 mm between 8 days and 6 weeks (P = .04); bursal thickness decreased during the 24-week period from 1.5 ± 0.9 mm to 0.7 ± 0.4 mm (P = .005); tendon modulus of elasticity increased from 154 ± 75 kPa to 205 ± 96 kPa between 8 days and 24 weeks (P = .05). DISCUSSION: This is the first study to investigate suture position and migration post arthroscopic rotator cuff repair. The findings of this study suggest that sutures migrating to the middle of the tendon during the postoperative healing process is a normal phenomenon observed on ultrasonography.

Synthesis of 4-oxotetrahydropyrimidine-1(2H)-carboxamides derivatives as capsid assembly modulators of hepatitis B virus.

We report herein the synthesis and evaluation of phenyl ureas derived from 4-oxotetrahydropyrimidine as novel capsid assembly modulators of hepatitis B virus (HBV). Among the derivatives, compound 27 (58031) and several analogs showed an activity of submicromolar EC50 against HBV and low cytotoxicities (>50 µM). Structure-activity relationship studies revealed a tolerance for an additional group at position 5 of 4-oxotetrahydropyrimidine. The mechanism study indicates that compound 27 (58031) is a type II core protein allosteric modulator (CpAMs), which induces core protein dimers to assemble empty capsids with fast electrophoresis mobility in native agarose gel. These compounds may thus serve as leads for future developments of novel antivirals against HBV.

Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa.

The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.

The Critical Shoulder Angle Shows a Reciprocal Change in Magnitude When Evaluating Symptomatic Full-Thickness Rotator Cuff Tears Versus Primary Glenohumeral Osteoarthritis as Compared With Control Subjects: A Systematic Review and Meta-analysis.

PURPOSE: To determine whether a high critical shoulder angle (CSA) is associated with symptomatic full-thickness rotator cuff (RC) tears and/or whether a low CSA is associated with primary glenohumeral osteoarthritis (GHOA). METHODS: A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All observational studies that examined an association between CSA and full-thickness RC tears and/or primary GHOA were included. A primary meta-analysis was performed including all studies that met the inclusion criteria regardless of radiographic quality. A secondary meta-analysis was performed to explore the hypothesis that radiographic quality was a source of heterogeneity, which excluded those studies in which radiograph quality was not strictly defined and controlled. RESULTS: For the primary meta-analysis, 11 studies met the inclusion criteria for RC tears and 5 for primary GHOA. The CSA was greater in the RC tear group than the control group (mean difference 4.03°, 95% confidence interval 2.95°-5.11, 95% prediction interval 0.0487°-8.01°; P < .001). The CSA was lower in the GHOA group than the control group (mean difference -3.98°, 95% confidence interval -5.66° to -2.31°, 95% prediction interval -10.2° to -2.19°; P < .001).A high level of heterogeneity was observed in the RC tear analysis (I2 = 88.4), which decreased after the exclusion of 5 studies based on radiographic quality (I2 = 75.3). A high level of heterogeneity also was observed in the primary GHOA analysis (I2 = 87.3), which decreased after the exclusion of 2 studies based on the radiographic quality (I2 = 48.2). CONCLUSIONS: There is a reciprocal change in magnitude of the CSA when evaluating symptomatic full-thickness RC tears versus primary GHOA as compared with control subjects. Radiographic quality is a source of heterogeneity in studies that investigate a link between CSA and RC tears and primary GHOA. LEVEL OF EVIDENCE: Level III, systematic review and meta-analysis of Level III studies.

Shoulder stiffness after rotator cuff repair: the fate of stiff shoulders up to 9 years after rotator cuff repair.

BACKGROUND: Stiffness and retear are 2 common complications of rotator cuff repair. McNamara et al found that postoperative stiffness was associated with lower retear rates at 6 months. This study aimed to determine if stiffness after rotator cuff repair protects the individual from retear up to 9 years after surgery. MATERIALS AND METHODS: Two groups of patients, 69 with stiff and 63 with nonstiff shoulder, who underwent arthroscopic rotator cuff repair were created based on external rotation measurements at 6 weeks postoperatively. Patients had regular follow-up assessments at 6, 12, and 24 weeks and were instructed to return for a follow-up at least 2 years after surgery. Patients were assessed for range of motion, shoulder function, strength, and rotator cuff integrity using ultrasound. RESULTS: For patients with postoperative stiffness at 6 weeks, the retear rate at 6 months was 3%, whereas the rate for nonstiff patients was 19% (P = .004). This protective effect of postoperative stiffness persisted up to 9 years after surgery (P = .002). Postoperative stiffness resolved by 5 years after surgery for all measurements except external rotation (50° vs. 61°) (P = .006). Patients with postoperative stiffness had continued improvements in abduction (P < .001), internal rotation (P = .020), and all patient-ranked measurements from the 6-month follow-up to 5 years after surgery. Patients with stiff shoulder had greater overall satisfaction by the final follow-up (P = .028). CONCLUSIONS: In patients experiencing stiffness after rotator cuff surgery, the repair is less likely to fail at 6 months. Although the stiffness generally resolves by 5 years, this protective effect still persists at 9 years after surgery.

Can handheld dynamometry predict rotator cuff tear size? A study in 2100 consecutive patients.

BACKGROUND: This study aimed to determine whether handheld dynamometry measurements could predict rotator cuff tear size in patients who required surgical treatment of their shoulder pathology. METHODS: Handheld dynamometer readings were collected prior to surgery and analyzed retrospectively for 2100 consecutive patients. Post hoc, the cohort was divided into patients with rotator cuff tears (n = 1747) and those without rotator cuff tears (n = 353). The tear group was stratified into partial- vs. full-thickness tears and into 4 groups based on tear size area. RESULTS: Patients with partial-thickness tears had greater internal rotation (P = .03), external rotation (P < .001), and supraspinatus (P < .001) strength than patients with full-thickness tears. Patients with tears had lower supraspinatus strength than patients without tears (r = -0.82, P < .001). Patients with a larger tear size had lower values of external rotation (r = -1.46, P < .001) and supraspinatus (r = -1.18, P < .001) strength. A model involving internal rotation and supraspinatus strength could predict the presence of a tear with a sensitivity of 82% and specificity of 29%. The correct prediction rate was 73% overall (82% in tear group and 29% in no-tear group). The following formula was found to predict rotator cuff tear size, showing modest correlation with our raw data (r = 0.25, P < .001): Tear size = 482.8 + (3.9 × Internal rotation strength) + (1.6 × Adduction strength) - (7.2 × External rotation strength) - (2.0 × Supraspinatus strength). CONCLUSIONS: Handheld dynamometer readings could not reliably predict rotator cuff tear size, showing only modest correlation with our raw data. Handheld dynamometry readings could predict the presence of a tear, although tears in the intact cohort were overestimated (a specificity of 29% and negative predictive value of 25%).

Biomechanical comparison of knotless wide suture double-row SutureBridge rotator cuff repair to double-row standard suture repair.

BACKGROUND: A comparison of self-reinforcement and footprint compression between standard- and wide-diameter suture material in double-row SutureBridge repair techniques has not been performed. The aim of this study was to compare the self-reinforcement and footprint contact pressure generated under progressive tensile loads between 2 double-row SutureBridge rotator cuff repair techniques: 1 performed with FiberWire and 1 performed with FiberTape in a knotless technique. MATERIALS AND METHODS: Rotator cuff repairs were performed in 10 pairs of ovine shoulders. One group underwent a double-row SutureBridge repair using FiberWire. The other group underwent an identical repair with FiberTape. Footprint contact pressure was measured from 0° to 60° of abduction under loads of 0-60 N. Pull-to-failure tests were then performed. RESULTS: In both repair constructs at 0° of abduction, each 10-N increase in rotator cuff tensile load led to a significant increase in footprint contact pressure (P < .05). The rate of increase in footprint contact pressure was greater in the FiberTape construct (ratio, 1.68; P = .00035). In both repair constructs, the highest values for footprint contact pressure were seen at 0° of abduction. No difference in pull to failure, peak load, or total energy was found between the groups. CONCLUSION: Self-reinforcement was seen in both double-row SutureBridge repairs with standard- and wide-diameter suture material but was greater in the repair with the wide-diameter suture material construct. Footprint compression is greater in a knotless double-row SutureBridge repair with wide-diameter suture material than in a knotted double-row SutureBridge repair with standard-diameter suture material at 20° of abduction.

Pancreatitis-Induced Depletion of Syntaxin 2 Promotes Autophagy and Increases Basolateral Exocytosis.

BACKGROUND & AIMS: Pancreatic acinar cells are polarized epithelial cells that store enzymes required for digestion as inactive zymogens, tightly packed at the cell apex. Stimulation of acinar cells causes the zymogen granules to fuse with the apical membrane, and the cells undergo exocytosis to release proteases into the intestinal lumen. Autophagy maintains homeostasis of pancreatic acini. Syntaxin 2 (STX2), an abundant soluble N-ethyl maleimide sensitive factor attachment protein receptor in pancreatic acini, has been reported to mediate apical exocytosis. Using human pancreatic tissues and STX2-knockout (KO) mice, we investigated the functions of STX2 in zymogen granule-mediated exocytosis and autophagy. METHODS: We obtained pancreatic tissues from 5 patients undergoing surgery for pancreatic cancer and prepared 80-µm slices; tissues were exposed to supramaximal cholecystokinin octapeptide (CCK-8) or ethanol and a low concentration of CCK-8 and analyzed by immunoblot and immunofluorescence analyses. STX2-KO mice and syntaxin 2+/+ C57BL6 mice (controls) were given intraperitoneal injections of supramaximal caerulein (a CCK-8 analogue) or fed ethanol and then given a low dose of caerulein to induce acute pancreatitis, or saline (controls); pancreata were isolated and analyzed by histology and immunohistochemistry. Acini were isolated from mice, incubated with CCK-8, and analyzed by immunofluorescence microscopy or used in immunoprecipitation experiments. Exocytosis was quantified using live-cell exocytosis and Ca2+ imaging analyses and based on formation of exocytotic soluble N-ethyl maleimide sensitive factor attachment protein receptor complexes. Dysregulations in autophagy were identified using markers, electron and immunofluorescence microscopy, and protease activation assays. RESULTS: Human pancreatic tissues and dispersed pancreatic acini from control mice exposed to CCK-8 or ethanol plus CCK-8 were depleted of STX2. STX2-KO developed more severe pancreatitis after administration of supramaximal caerulein or a 6-week ethanol diet compared with control. Acini from STX2-KO mice had increased apical exocytosis after exposure to CCK-8, as well as increased basolateral exocytosis, which led to ectopic release of proteases. These increases in apical and basolateral exocytosis required increased formation of fusogenic soluble N-ethyl maleimide sensitive factor attachment protein receptor complexes, mediated by STX3 and STX4. STX2 bound ATG16L1 and prevented it from binding clathrin. Deletion of STX2 from acini increased binding of AT16L1 to clathrin, increasing formation of pre-autophagosomes and inducing autophagy. Induction of autophagy promoted the CCK-8-induced increase in autolysosome formation and the activation of trypsinogen. CONCLUSIONS: In studies of human pancreatic tissues and pancreata from STX2-KO and control mice, we found STX2 to block STX3- and STX4-mediated fusion of zymogen granules with the plasma membrane and exocytosis and prevent binding of ATG16L1 to clathrin, which contributes to induction of autophagy. Exposure of pancreatic tissues to CCK-8 or ethanol depletes acinar cells of STX2, increasing basolateral exocytosis and promoting autophagy induction, leading to activation of trypsinogen.

Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability.

This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.

Shoulder abduction diminishes self-reinforcement in transosseous-equivalent rotator cuff repair in both knotted and knotless techniques.

PURPOSE: The self-reinforcement mechanism after double row suturebridge rotator cuff repair generates increasing compressive forces at the tendon footprint with increasing tendon load. Passive range of motion is usually allowed after rotator cuff repair. The mechanism of self-reinforcement could be adversely affected by shoulder abduction. METHODS: Rotator cuff tears were created ex vivo in nine pairs of ovine shoulders. Two different repair techniques were used. One group was repaired using a double row 'suturebridge' construct with tied horizontal medial row mattress sutures (Knotted repair group). The other group was repaired identically except that medial row knots were not tied (Knotless repair group). Footprint compression was measured at varying amounts of abduction and under tendon loads of 0, 10, 20, 30, 40, 50 and 60N. The rate of increase of contact pressure (degree of self-reinforcement) was calculated for each abduction angle. RESULTS: Abduction diminishes footprint contact pressure in both knotted and knotless double row suturebridge constructs. Progressive abduction from 0 to 40 abduction in the knotless group and 0-30 in the knotted group results in a decrease in self-reinforcement. Abduction beyond this does not cause a further decrease in self-reinforcement. There was no difference in the rate of increase of footprint contact pressure at each angle of abduction when comparing the knotted and knotless groups. CONCLUSION: In the post-operative period, high tendon load combined with minimal abduction would be expected to generate the greatest amount of footprint compression which may improve tendon healing. Therefore, to maximize footprint compression the use of abduction pillows should be avoided while early isometric strengthening should be used.

Preventing brachial plexus injury during shoulder surgery: a real-time cadaveric study.

BACKGROUND: Brachial plexopathy is not uncommon after shoulder surgery. Although thought to be due to stretch neuropathy, its etiology is poorly understood. This study aimed to identify arm positions and maneuvers that may risk causing brachial plexopathy during shoulder arthroplasty. METHODS: Tensions in the cords of the brachial plexuses of 6 human cadaveric upper limbs were measured using load cells while each limb was placed in different arm positions and while they underwent shoulder hemiarthroplasty and revision reverse arthroplasty. Arthroplasty procedures in 4 specimens were performed with standard limb positioning (unsupported), and 2 specimens were supported from under the elbow (supported). Each cord then underwent biomechanical testing to identify tension corresponding to 10% strain (the stretch neuropathy threshold in animal models). RESULTS: Tensions exceeding 15 N, 11 N, and 9 N in the lateral, medial, and posterior cords, respectively, produced 10% strain. Shoulder abduction >70° and combined external rotation >60° with extension >50° increased medial cord tension above the 10% strain threshold. Medial cord tensions (mean ± standard error of the mean) in unsupported specimens increased over baseline during hemiarthroplasty (sounder insertion [4.7 ± 0.6 N, P = .04], prosthesis impaction [6.1 ± 0.8 N, P = .04], and arthroplasty reduction [5.0 ± 0.7 N, P = .04]) and revision reverse arthroplasty (retractor positioning [7.2 ± 0.8 N, P = .02]). Supported specimens experienced lower tensions than unsupported specimens. CONCLUSIONS: Shoulder abduction >70°, combined external rotation >60° with extension >50°, and downward forces on the humeral shaft may risk causing brachial plexopathy. Retractor placement, sounder insertion, humeral prosthesis impaction, and arthroplasty reduction increase medial cord tensions during shoulder arthroplasty. Supporting the arm from under the elbow protected the brachial plexus in this cadaveric model.