8-l-Cystinyl Bis(1,8-diazaspiro[4.5]decane) as an Orally Bioavailable l-Cystine Crystallization Inhibitor for Cystinuria.

Cystinuria, a rare genetic disorder, is characterized by defective l-cystine reabsorption from the renal proximal tubule, resulting in abnormally high concentrations of l-cystine and subsequent l-cystine crystallization in urine and stone formation in the urinary tract. Inhibition of l-cystine crystallization by l-cystine diamides such as LH708 (2) represents a promising new approach to prevent stone formation in patients with cystinuria. While 2 shows promising in vivo efficacy and a good safety profile in a Slc3a1-knockout mouse model of cystinuria, further structural modification of 2 led to the discovery of 8-l-cystinyl bis(1,8-diazaspiro[4.5]decane) (LH1753, 3) incorporating a bioisosteric spiro bicyclic diamine 1,8-diazaspiro[4.5]decane for the N-methylpiperazine terminal groups in 2 as a promising candidate with 3 being about 120× more potent than l-cystine dimethyl ester (CDME, 1) and about 2× more potent than 2 in inhibiting l-cystine crystallization. Furthermore, 3 demonstrated good oral bioavailability and in vivo efficacy in preventing l-cystine stone formation in the Slc3a1-knockout mouse model of cystinuria.

Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2.

CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity. In this report, we describe the discovery of (4-pyrazolyl)-2-aminopyrimidines as a potent class of CDK2 inhibitors that display selectivity over CDKs 1, 4, 6, 7, and 9. SAR studies led to the identification of compound 17, a kinase selective and highly potent CDK2 inhibitor (IC50 = 0.29 nM). The evaluation of 17 in CCNE1-amplified mouse models shows the pharmacodynamic inhibition of CDK2, measured by reduced Rb phosphorylation, and antitumor activity.

Clinical presentation and outcomes in patients with antiphospholipid syndrome-associated adrenal hemorrhage. A multicenter cohort study and systematic literature review.

BACKGROUND: Adrenal hemorrhage (AH) can occur in patients with antiphospholipid Syndrome (APS). We aimed to characterize the clinical manifestations, treatments, and outcomes of patients presenting with APS-associated AH (APS-AH) through a retrospective cohort and a systematic literature review (SLR). METHODS: We performed a mixed-source approach combining a multicenter cohort with an SLR of patients with incident APS-AH. We included patients from Mayo Clinic and published cases with persistent positivity for antiphospholipid antibodies and presenting with AH, demonstrated by imaging or biopsy. We extracted demographics, clinical characteristics, laboratory findings, treatment strategies, and outcomes (primary adrenal insufficiency and mortality). We used Kaplan-Meier and Cox models for survival analysis. RESULTS: We included 256 patients in total, 61 (24%) from Mayo Clinic and 195 (76%) from the SLR. The mean age was 46.8 (SD 15.2) years, and 45% were female. 69% of patients had bilateral adrenal involvement and 64% presented adrenal insufficiency. The most common symptoms at presentation were abdominal pain in 79%, and nausea and vomiting 46%. Hyponatremia (77%) was the most common electrolyte abnormality. Factors associated with primary adrenal insufficiency were bilateral adrenal involvement at initial imaging (OR 3.73, CI; 95%, 1.47-9.46) and anticardiolipin IgG positivity (OR 3.80, CI; 95%, 1.30-11.09). The survival rate at five years was 82%. History of stroke was associated with 3.6-fold increase in mortality (HR 3.62, 95% CI; 1.33-9.85). CONCLUSION: AH is a severe manifestation of APS with increased mortality. Most patients developed permanent primary adrenal insufficiency, particularly those positive for anticardiolipin IgG and bilateral adrenal involvement.

Impact of Injection-Based Delivery Parameters on Local Distribution Volume of EthylCellulose Ethanol Gel in Tissue and Tissue Mimicking Phantoms.

: Local drug delivery aims to minimize systemic toxicity by preventing off-target effects; however, injection parameters influencing depot formation of injectable gels have yet to be thoroughly studied. We explored the effects of needle characteristics, injection depth, rate, volume, and polymer concentration on gel ethanol distribution in both tissue and phantoms. METHODS: The polymer ethyl cellulose (EC) was added to ethanol to form an injectable gel to ablate cervical precancer and cancer. Tissue mimicking phantoms composed of 1% agarose dissolved in deionized water were used to establish overall trends between various injection parameters and the resulting gel distribution. Additional experiments were performed in excised swine cervices with a CT-imageable injectate formulation, which enabled visualization of the distribution without tissue sectioning. RESULTS: Needle type and injection rate had minimal impact on gel distribution, while needle depths ≥13 mm yielded significantly larger distributions. Needle gauge and EC concentration impacted injection pressure with maximum gel distribution achieved when the pressure was 70-250 kPa. Injection volumes ≤3 mL of 6% ECethanol minimized fluid leakage away from the injection site. Results guided the development of a speculum-compatible handheld injector to deliver gel ethanol into the cervix. CONCLUSION: Needle depth, gauge, and polymer concentration are critical to consider when delivering injectable gels. SIGNIFICANCE: This study addressed key questions related to the impact of injection-based parameters on gel distribution at a scale relevant to human applications including: 1) how best to deliver EC-ethanol into the cervix and 2) general insights about injection protocols relevant to the delivery of injectable gels in tissue.

In Vivo Evaluation of Safety and Efficacy of Ethyl Cellulose-Ethanol Tissue Ablation in a Swine Cervix Model.

Current therapies for treating cervical dysplasia are often inaccessible in low and middle-income countries (LMICs), highlighting the need for novel low-cost therapies that can be delivered at the point of care. Ethanol ablation is a low-cost therapy designed to treat locoregional cancers, which we augmented into an ethyl cellulose (EC)-ethanol gel formulation to enhance its efficacy. Here, we evaluated whether EC-ethanol ablation is able to safely achieve an ablation zone comparable to thermocoagulation, a commonly used therapy for cervical dysplasia. The study was performed in 20 female Yorkshire pigs treated with either a single 500 µL injection of EC-ethanol into the 12 o'clock position of the cervix or a single application of thermocoagulation at 100 °C for 20 s. The average temperature, heart rate, respiratory rate, and blood oxygen remained within normal ranges throughout the EC-ethanol procedure and were similar to the thermocoagulation group. No major side effects were observed. The reproductive tracts were excised after 24 h to examine ablation zones. Comparable depths of necrosis were seen for EC-ethanol (18.6 ± 1.6 mm) and thermocoagulation (19.7 ± 4.1 mm). The volumes of necrosis induced by a single injection of EC-ethanol (626.2 ± 122.8 µL) were comparable to the necrotic volumes induced by thermocoagulation in the top half of the cervices (664.6 ± 168.5 µL). This suggests that two EC-ethanol injections could be performed (e.g., at the 12 and 6 o'clock positions) to achieve comparable total necrotic volumes to thermocoagulation and safely and effectively treat women with cervical dysplasia in LMICs. This is the first study to systematically evaluate EC-ethanol ablation in a large animal model and compare its safety and efficacy to thermocoagulation, a commonly used ablative therapy for cervical dysplasia.

Development of convenient crystallization inhibition assays for structure-activity relationship studies in the discovery of crystallization inhibitors.

Kidney stone diseases are increasing globally in prevalence and recurrence rates, indicating an urgent medical need for developing new therapies that can prevent stone formation. One approach we have been working on is to develop small molecule inhibitors that can interfere with the crystallization process of the chemical substances that form the stones. For these drug discovery efforts, it is critical to have available easily accessible assay methods to evaluate the potential inhibitors and rank them for structure-activity relationship studies. Herein, we report a convenient, medium-to-high throughput assay platform using, as an example, the screening and evaluation of inhibitors of L-cystine crystallization for the prevention of kidney stones in cystinuria. The assay involves preparing a supersaturated solution, followed by incubating small volumes (<1 mL) of the supersaturated solution with test inhibitors for 72 hours, and finally measuring L-cystine concentrations in the supernatants after centrifugation using either a colorimetric or fluorometric method. Compared to traditional techniques for studying crystallization inhibitors, this miniaturized multi-well assay format is simple to implement, cost-effective, and widely applicable in determining and distinguishing the activities of compounds that inhibit crystallization. This assay has been successfully employed to discover L-cystine diamides as highly potent inhibitors of L-cystine crystallization such as LH708 with an EC50 of 0.058 µM, 70-fold more potent than L-CDME (EC50 = 4.31 µM).

The American Association for Thoracic Surgery (AATS) 2023 Expert Consensus Document: Staging and multidisciplinary management of patients with early-stage non-small cell lung cancer.

Novel targeted therapy and immunotherapy drugs have recently been approved for use in patients with surgically resectable lung cancer. Accurate staging, early molecular testing, and knowledge of recent trials are critical to optimize oncologic outcomes in these patients.

Utilization of preventive services in a systemic lupus erythematosus population-based cohort: a Lupus Midwest Network (LUMEN) study.

BACKGROUND: Systemic lupus erythematosus (SLE) is a disease that can lead to damage of multiple organs and, along with certain treatments, increase the risk of developing cancer, cardiovascular disease, diabetes, osteoporosis, and infections. Preventive services are particularly important in patients with SLE to mitigate the aforementioned risks. We aimed to evaluate the trends of preventive services utilization in patients with systemic lupus erythematosus, compared with non-SLE population. METHODS: All ≥19-year-old patients in the Lupus Midwest Network (LUMEN) registry, a population-based cohort, with SLE on January 1, 2015, were included and matched (1:1) by sex, age, race, and county to non-SLE comparators. Among both groups, we compared the rates of screenings for breast and cervical cancer, hypertension, hyperlipidemia, diabetes mellitus, and osteoporosis as well as immunizations. RESULTS: We included 440 SLE patients and 430 non-SLE comparators. The probability of breast cancer screening among women with SLE was similar to comparators (hazard ratio [HR] 1.09, 95% CI 0.85-1.39), while cervical cancer screening was lower (HR 0.75, 95% CI 0.58-0.96). Hypertension screening was higher among patients with SLE (HR 1.35, 95% CI 1.13-1.62); however, hyperlipidemia screening was similar to comparators (HR 1.16, 95% CI 0.96-1.41). Diabetes and osteoporosis screenings were more likely to be performed for SLE patients than for comparators (HR 2.46, 95% CI 2.11-2.87; and HR 3.19, 95% CI 2.31-4.41; respectively). Influenza and pneumococcal immunizations were higher among SLE patients (HR 1.31, 95% CI 1.12-1.54; and HR 2.06, 95% CI 1.38-3.09; respectively), while zoster vaccination was similar (HR 1.17, 95% CI 0.81-1.69). CONCLUSIONS: The trends of utilization of preventive services by SLE patients vary according to screening or vaccine compared with the general population. Considering these differences, we demonstrate an opportunity for improvement, particularly in cervical cancer, hyperlipidemia, and osteoporosis screenings and vaccinations.

Discovery of mobocertinib, a new irreversible tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer harboring EGFR exon 20 insertion mutations.

Epidermal growth factor receptor (EGFR) is essential for normal cellular functions. Mutations of EGFR's kinase domain can cause dysregulation leading to non-small cell lung cancer (NSCLC). Exon 20 insertion (ex20ins) mutations in EGFR are one of the leading contributors to oncogenesis and confer insensitivity to most available therapeutics. Mobocertinib is a novel tyrosine kinase inhibitor (TKI) recently approved by the US FDA as a first-in-class small molecule therapeutic for EGFR ex20ins-positive NSCLC. When compared to osimertinib, a TKI indicated for the treatment of EGFR T790M-positive NSCLC, mobocertinib differs only by the presence of an additional C5-carboxylate isopropyl ester group on the middle pyrimidine core. Together with the acrylamide side chain that is responsible for irreversible inhibition, this additional C5-substituent affords mobocertinib high anticancer potency and specificity to EGFR ex20ins-positive lung cancer that is resistant to other EGFR TKIs. This review article provides an overview of the discovery of mobocertinib from osimertinib including their structure-activity relationships, mechanisms of action, preclinical pharmacology, pharmacokinetics, and clinical applications. The discovery and use of mobocertinib and other EGFR TKIs demonstrate the power of structure-based drug design and promising therapeutic outcomes of using precision medicine approaches in the management of molecularly defined tumors. Graphical abstract.

Imaging of the Postoperative Skull Base and Cerebellopontine Angle.

For pathologic conditions affecting the skull base and cerebellopontine angle, imaging techniques have advanced to assess for residual disease, disease progression, and postoperative complications. Knowledge regarding various surgical approaches of skull base tumor resection, expected postoperative appearance, and common postsurgical complications guides radiologic interpretation. Complexity of skull base anatomy, small size of the relevant structures, lack of familiarity with surgical techniques, and postsurgical changes confound radiologic evaluation. This article discusses the imaging techniques, surgical approaches, expected postoperative changes, and complications after surgery of the skull base, with emphasis on the cerebellopontine angle, anterior cranial fossa, and central skull base regions.

Early Functional Status After Surgery for Congenital Heart Disease: A Single-Center Retrospective Study.

OBJECTIVES: The objective of this study is to investigate the change in functional status in infants, children, and adolescents undergoing congenital heart surgery using the Functional Status Scale. DESIGN: A single-center retrospective study. SETTING: A 26-bed cardiac ICU in a free-standing university-affiliated tertiary children's hospital. PATIENTS: All patients 0-18 years who underwent congenital heart surgery from January 1, 2014, to December 31, 2017. INTERVENTIONS: None. MEASUREMENTS AND MIN RESULTS: The primary outcome variable was change in Functional Status Scale scores from admission to discharge. Additionally, two binary outcomes were derived from the primary outcome: new morbidity (change in Functional Status Scale ≥ 3) and unfavorable functional outcome (change in Functional Status Scale ≥ 5); their association with risk factors was assessed using modified Poisson regression. Out of 1,398 eligible surgical encounters, 65 (4.6%) and 15 (1.0%) had evidence of new morbidity and unfavorable functional outcomes, respectively. Higher Surgeons Society of Thoracic and the European Association for Cardio-Thoracic Surgery score, single-ventricle physiology, and longer cardiopulmonary bypass time were associated with new morbidity. Longer hospital length of stay was associated with both new morbidity and unfavorable outcome. CONCLUSIONS: This study demonstrates the novel application of the Functional Status Scale on patients undergoing congenital heart surgery. New morbidity was noted in 4.6%, whereas unfavorable outcome in 1%. There was a small change in the total Functional Status Scale score that was largely attributed to changes in the feeding domain. Higher Society of Thoracic and the European Association for Cardio-Thoracic Surgery score, single-ventricle physiology, and longer cardiopulmonary bypass times were associated with new morbidity, whereas longer hospital length of stay was associated with both new morbidity and unfavorable outcome. Further studies with larger sample size will need to be done to confirm our findings and to better ascertain the utility of Functional Status Scale on this patient population.

Intratumoral Photosensitizer Delivery and Photodynamic Therapy.

Photodynamic therapy (PDT) is a two-step procedure that involves the administration of special drugs, commonly called photosensitizers, followed by the application of certain wavelengths of light. The light activates these photosensitizers to produce reactive molecular species that induce cell death in tissues. There are numerous factors to consider when selecting the appropriate photosensitizer administration route, such as which part of the body is being targeted, the pharmacokinetics of photosensitizers, and the formulation of photosensitizers. While intravenous, topical, and oral administration of photosensitizers are widely used in preclinical and clinical applications of PDT, other administration routes, such as intraperitoneal, intra-arterial, and intratumoral injections, are gaining traction for their potential in treating advanced diseases and reducing off-target toxicities. With recent advances in targeted nanotechnology, biomaterials, and light delivery systems, the exciting possibilities of targeted photosensitizer delivery can be fully realized for preclinical and clinical applications. Further, in light of the growing burden of cancer mortality in low and middle-income countries and development of low-cost light sources and photosensitizers, PDT could be used to treat cancer patients in low-income settings. This short article introduces aspects of interfaces of intratumoral photosensitizer injections and nano-biomaterials for PDT applications in both high-income and low-income settings but does not present a comprehensive review due to space limitations.

Optimizing ethyl cellulose-ethanol delivery towards enabling ablation of cervical dysplasia.

In low-income countries, up to 80% of women diagnosed with cervical dysplasia do not return for follow-up care, primarily due to treatment being inaccessible. Here, we describe development of a low-cost, portable treatment suitable for such settings. It is based on injection of ethyl cellulose (EC)-ethanol to ablate the transformation zone around the os, the site most impacted by dysplasia. EC is a polymer that sequesters the ethanol within a prescribed volume when injected into tissue, and this is modulated by the injected volume and delivery parameters (needle gauge, bevel orientation, insertion rate, depth, and infusion rate). Salient injection-based delivery parameters were varied in excised swine cervices. The resulting injection distribution volume was imaged with a wide-field fluorescence imaging device or computed tomography. A 27G needle and insertion rate of 10 mm/s achieved the desired insertion depth in tissue. Orienting the needle bevel towards the outer edge of the cervix and keeping infusion volumes ≤ 500 µL minimized leakage into off-target tissue. These results guided development of a custom hand-held injector, which was used to locate and ablate the upper quadrant of a swine cervix in vivo with no adverse events or changes in host temperature or heart rate. After 24 h, a distinct region of necrosis was detected that covered a majority (> 75%) of the upper quadrant of the cervix, indicating four injections could effectively cover the full cervix. The work here informs follow up large animal in vivo studies, e.g. in swine, to further assess safety and efficacy of EC-ethanol ablation in the cervix.

Pectoral nerve blocks decrease postoperative pain and opioid use after pacemaker or implantable cardioverter-defibrillator placement in children.

BACKGROUND: Pectoral nerve blocks (PECs) can reduce intraprocedural anesthetic requirements and postoperative pain. Little is known about the utility of PECs in reducing pain and narcotic use after pacemaker (PM) or implantable cardioverter-defibrillator (ICD) placement in children. OBJECTIVE: The purpose of this study was to determine whether PECs can decrease postoperative pain and opioid use after PM or ICD placement in children. METHODS: A single-center retrospective review of pediatric patients undergoing transvenous PM or ICD placement between 2015 and 2020 was performed. Patients with recent cardiothoracic surgery or neurologic/developmental deficits were excluded. Demographics, procedural variables, postoperative pain, and postoperative opioid usage were compared between patients who had undergone PECs and those who had undergone conventional local anesthetic (Control). RESULTS: A total of 74 patients underwent PM or ICD placement; 20 patients (27%) underwent PECs. There were no differences between PECs and Control with regard to age, weight, gender, type of device placed, presence of congenital heart disease, type of anesthesia, procedural time, or complication rates. Patients who underwent PECs had lower pain scores at 1, 2, 6, 18, and 24 hours compared to Control. PECs patients had a lower mean cumulative pain score [PECs 1.5 (95% confidence interval [CI] 0.8-2.2) vs Control 3.1 (95% CI 2.7-3.5); P <.001] and lower total opioid use [PECs 6.0 morphine milligram equivalent (MME)/m2 (95% CI 3.4-8.6) vs Control 15.0 MME/m2 (95% CI 11.8-18.2); P = .001] over the 24 hours postimplant. CONCLUSION: PECs reduce postoperative pain scores and lower total opioid usage after ICD or PM placement. PECs should be considered at the time of transvenous device placement in children.

Tight Junction Protein Claudin-7 Is Essential for Intestinal Epithelial Stem Cell Self-Renewal and Differentiation.

BACKGROUND & AIMS: Claudin-7 (Cldn7) is a tight junction (TJ) membrane protein located at the apical TJ and basolateral side of intestinal epithelial cells. Deletion of Cldn7 by gene targeting leads to the inflammatory bowel disease-like phenotype in mice, which includes weight loss, diarrhea, mucosa ulceration, and severe intestinal epithelial damage. In this study, we test our hypothesis that Cldn7 plays a critical role in regulating intestinal crypt stem cell functions. METHODS: Gene expression microarray, quantitative reverse-transcription polymerase chain reaction, in situ hybridization, histologic examinations, immunoblotting, 3-dimensional organoid culture, and various treatments to rescue Cldn7-deficient organoid defects were conducted using global Cldn7 knockout mice and inducible, conditional Cldn7 knockout mice. RESULTS: Gene deletion of Cldn7 in intestines showed significant alteration of expression profiles with striking down-regulation of intestinal crypt stem cell markers such as Olfm4, dislocated proliferative cells, and disrupted epithelial cell differentiation. In addition, the isolated Cldn7-deficient crypts where the stem cells reside were either unable to survive at all or formed defective spheroids, highlighting the functional impairment of crypt stem cells in the absence of Cldn7. Remarkably, the Cldn7-expressing organoids with buddings underwent rapid cell degeneration within days after turning off Cldn7 expression in the culture. We identified that activation of Wnt/ß-catenin signaling rescued the organoid defects caused by Cldn7 deletion. CONCLUSIONS: In this study, we show that Cldn7 is indispensable in controlling Wnt/ß-catenin signaling-dependent intestinal epithelial stem cell survival, self-renewal, and cell differentiation. This study could open a door to study roles of TJ proteins in stem cell regulations in other tissues and organs.

Immunomodulators targeting the PD-1/PD-L1 protein-protein interaction: From antibodies to small molecules.

Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.

Global Spinal Alignment in Cervical Kyphotic Deformity: The Importance of Head Position and Thoracolumbar Alignment in the Compensatory Mechanism.

BACKGROUND: Previous studies have evaluated cervical kyphosis (C-kypho) using cervical curvature or chin-brow vertical angle, but the relationship between C-kypho and global spinal alignment is currently unknown. OBJECTIVE: To elucidate global spinal alignment and compensatory mechanisms in primary symptomatic C-kypho using full-spine radiography. METHODS: In this retrospective multicenter study, symptomatic primary C-kypho patients (Cerv group; n = 103) and adult thoracolumbar deformity patients (TL group; n = 119) were compared. We subanalyzed Cerv subgroups according to sagittal vertical axis (SVA) values of C7 (SVAC7 positive or negative [C7P or C7N]). Various Cobb angles (°) and SVAs (mm) were evaluated. RESULTS: SVAC7 values were -20.2 and 63.6 mm in the Cerv group and TL group, respectively (P < .0001). Various statistically significant compensatory curvatures were observed in the Cerv group, namely larger lumbar lordosis (LL) and thoracic kyphosis. The C7N group had significantly lower SVACOG (center of gravity of the head) and SVAC7 (32.9 and -49.5 mm) values than the C7P group (115.9 and 45.1 mm). Sagittal curvatures were also different in T4-12, T10-L2, LL4-S, and LL. The value of pelvic incidence (PI)-LL was different (C7N vs C7P; -2.2° vs 9.9°; P < .0003). Compensatory sagittal curvatures were associated with potential for shifting of SVAC7 posteriorly to adjust head position. PI-LL affected these compensatory mechanisms. CONCLUSION: Compensation in symptomatic primary C-kypho was via posterior shifting of SVAC7, small T1 slope, and large LL. However, even in C-kypho patients, lumbar degeneration might affect global spinal alignment. Thus, global spinal alignment with cervical kyphosis is characterized as head balanced or trunk balanced.

The Clinical Effect of a Rotator Cuff Retear: A Meta-analysis of Arthroscopic Single-Row and Double-Row Repairs.

BACKGROUND: The clinical effect of a retear after rotator cuff repair remains unclear. While some studies have indicated clinical deficits due to a retear, others have stated that a retear does not detrimentally affect outcomes. PURPOSE: To conduct a meta-analysis comparing clinical outcomes between intact and retorn rotator cuffs after arthroscopic repair. STUDY DESIGN: Meta-analysis. METHODS: A literature search using the terms "arthroscopic," "rotator cuff," "repair," "retear," "re-tear," "defect," "single-row," "double-row," "clinical outcomes," and "functional outcomes" was conducted. Article inclusion criteria were an adequate description of the surgical technique, stratification of outcomes by intact rotator cuff versus retear with a minimum of 1 year of follow-up, and documentation of the presence/absence of a full-thickness retear using imaging. Exclusion criteria were isolated subscapularis tears/repairs, labral repairs, infections, postoperative fractures, insufficient data or statistical indications, and postoperative data not stratified by retear versus intact rotator cuff. A meta-analysis was performed using a random-effects model on variables that had comparisons from at least 3 studies. Single-row (SR) and double-row (DR) studies were analyzed both separately and together in an "all arthroscopic repairs" (AAR) comparison. The calculated effect was considered significant at a P value <.05. RESULTS: Within the SR group, patients with a rotator cuff retear had a significantly lower Constant score (mean difference [95% CI], -6.79 [-8.94 to -4.65]; P < .001) and lower University of California, Los Angeles (UCLA) score (-3.21 [-5.27 to -1.15]; P = .002) but not higher pain (0.071 [-0.34 to 0.49]; P = .739). Within the DR group, patients with a rotator cuff retear had a significantly lower Constant score (mean difference [95% CI], -9.35 [-12.2 to -6.50]; P < .001), lower American Shoulder and Elbow Surgeons (ASES) score (-12.1 [-17.1 to -7.26]; P < .001), lower UCLA score (-3.07 [-4.85 to -1.29]; P < .001), higher pain (0.622 [0.19 to 1.05]; P = .005), and lower abduction strength ( P < .001). In the AAR comparison, patients with a retear had a significantly lower Constant score (mean difference [95% CI], -7.56 [-9.55 to -5.57]; P < .001), lower ASES score (-10.1 [-15.5 to -4.64]; P < .001), lower UCLA score (-3.00 [-4.47 to -1.53]; P < .001), and lower abduction strength (in kg·f) (-3.32 [-4.53 to -2.12]; P < .001) but not higher pain (0.332 [-0.014 to 0.680]; P = .060). CONCLUSION: Patients with a full-thickness rotator cuff retear exhibited significantly lower clinical outcome scores and strength compared with patients with an intact or partially torn rotator cuff.

Block Copolymer Membranes for Efficient Capture of a Chemotherapy Drug.

We introduce the use of block copolymer membranes for an emerging application, "drug capture". The polymer is incorporated in a new class of biomedical devices, referred to as ChemoFilter, which is an image-guided temporarily deployable endovascular device designed to increase the efficacy of chemotherapy-based cancer treatment. We show that block copolymer membranes consisting of functional sulfonated polystyrene end blocks and a structural polyethylene middle block (S-SES) are capable of capturing doxorubicin, a chemotherapy drug. We focus on the relationship between morphology of the membrane in the ChemoFilter device and efficacy of doxorubicin capture measured in vitro. Using small-angle X-ray scattering and cryogenic scanning transmission electron microscopy, we discovered that rapid doxorubicin capture is associated with the presence of water-rich channels in the lamellar-forming S-SES membranes in aqueous environment.