Radiographic and Advanced Imaging Evaluation of Posterior Shoulder Instability.

PURPOSE OF REVIEW: Posterior shoulder instability is an uncommon but important cause of shoulder dysfunction and pain which may occur as the result of seizure, high energy trauma, or repetitive stress related to occupational or sport-specific activities. This current review details the imaging approach to the patient with posterior shoulder instability and describes commonly associated soft tissue and bony pathologies identified by radiographs, CT, and MR imaging. RECENT FINDINGS: Advances in MR imaging technology and techniques allow for more accurate evaluation of bone and soft tissue pathology associated with posterior shoulder instability while sparing patients exposure to radiation. Imaging can contribute significantly to the clinical management of patients with posterior shoulder instability by demonstrating the extent of associated injuries and identifying predisposing anatomic conditions. Radiologic evaluation should be guided by clinical history and physical examination, beginning with radiographs followed by CT and/or MRI for assessment of osseous and soft tissue pathology. Synthesis of a patient's clinical history, physical exam findings, and radiologic examinations should guide clinical management.

A novel approach to saline/contrast delivery in excimer laser coronary atherectomy (ELCA) to enhance efficacy: MAXCon ELCA technique.

The advent of excimer laser coronary atherectomy (ELCA) nearly four decades ago heralded a novel way to treat complex lesions, both coronary and peripheral, which were previously untraversable and thus untreatable. These complex lesions include heavily calcified lesions, ostial lesions, bifurcation lesions, chronic total occlusions, in-stent restenosis (including stent underexpansion), and degenerative saphenous vein grafts. We discuss the technology of ELCA, its indications, applications, and complications, and suggest the "MAXCon ELCA" technique for better outcomes without increased risk. Lastly, we present a case of MAXCon ELCA effectively treating a complex lesion.

Is There Utility in Preoperative Testing of Hemoglobin Before Primary Cheiloplasty?

OBJECTIVE: To examine whether a preoperative hemoglobin of less than 10 g/dL is associated with a higher rate of perioperative complications. DESIGN: Retrospective review. SETTING: Tertiary academic hospital at Arkansas Children's Hospital of Little Rock, Arkansas. PATIENTS: A retrospective chart review evaluated patients undergoing primary cleft lip surgery from 2012 to 2017. INTERVENTIONS: No prospective intervention was performed for this study care. MAIN OUTCOME MEASURES: Age, sex, medical history, weight, and perioperative complications. Hemoglobin level was collected in the preoperative area. The primary outcome was rate of perioperative complications including infection, dehiscence, return to the operating room, unplanned admission, and emergency department visit within two weeks postoperatively. RESULTS: 105 patients undergoing primary cheiloplasty met inclusion criteria. Hemoglobin levels were obtained on all patients. 93.3% (n = 98) of patients had a hemoglobin of >10 g/dL before surgery, and 6.6% (n = 7) had levels <10 g/dL. 1 of 7 patients with a hemoglobin of <10 g/dL experienced a postoperative complication (Tet spell) and one patient with a hemoglobin of >10 g/dL experienced a postoperative complication (unplanned intensive care admission for respiratory distress). CONCLUSIONS: Post-operative complications are rare after primary cheiloplasty in patients with low or normal hemoglobin levels. The results of this study show that a preoperative hemoglobin of <10 g/dL does not predict perioperative complications in patients undergoing primary cheiloplasty.

Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong in vivo target engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters. Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivo are hypothesized to be manifested by a metabolite─generated by aldehyde oxidase (AO)─possessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications.

Molecular pharmacodynamics of meropenem for nosocomial pneumonia caused by Pseudomonas aeruginosa.

Hospital-acquired pneumonia (HAP) is a leading cause of morbidity and mortality, commonly caused by Pseudomonas aeruginosa. Meropenem is a commonly used therapeutic agent, although emergent resistance occurs during treatment. We used a rabbit HAP infection model to assess the bacterial kill and resistance pharmacodynamics of meropenem. Meropenem 5 mg/kg administered subcutaneously (s.c.) q8h (±amikacin 3.33-5 mg/kg q8h administered intravenously[i.v.]) or meropenem 30 mg/kg s.c. q8h regimens were assessed in a rabbit lung infection model infected with P. aeruginosa, with bacterial quantification and phenotypic/genotypic characterization of emergent resistant isolates. The pharmacokinetic/pharmacodynamic output was fitted to a mathematical model, and human-like regimens were simulated to predict outcomes in a clinical context. Increasing meropenem monotherapy demonstrated a dose-response effect to bacterial kill and an inverted U relationship with emergent resistance. The addition of amikacin to meropenem suppressed the emergence of resistance. A network of porin loss, efflux upregulation, and increased expression of AmpC was identified as the mechanism of this emergent resistance. A bridging simulation using human pharmacokinetics identified meropenem 2 g i.v. q8h as the licensed clinical regimen most likely to suppress resistance. We demonstrate an innovative experimental platform to phenotypically and genotypically characterize bacterial emergent resistance pharmacodynamics in HAP. For meropenem, we have demonstrated the risk of resistance emergence during therapy and identified two mitigating strategies: (i) regimen intensification and (ii) use of combination therapy. This platform will allow pre-clinical assessment of emergent resistance risk during treatment of HAP for other antimicrobials, to allow construction of clinical regimens that mitigate this risk.IMPORTANCEThe emergence of antimicrobial resistance (AMR) during antimicrobial treatment for hospital-acquired pneumonia (HAP) is a well-documented problem (particularly in pneumonia caused by Pseudomonas aeruginosa) that contributes to the wider global antimicrobial resistance crisis. During drug development, regimens are typically determined by their sufficiency to achieve bactericidal effect. Prevention of the emergence of resistance pharmacodynamics is usually not characterized or used to determine the regimen. The innovative experimental platform described here allows characterization of the emergence of AMR during the treatment of HAP and the development of strategies to mitigate this. We have demonstrated this specifically for meropenem-a broad-spectrum antibiotic commonly used to treat HAP. We have characterized the antimicrobial resistance pharmacodynamics of meropenem when used to treat HAP, caused by initially meropenem-susceptible P. aeruginosa, phenotypically and genotypically. We have also shown that intensifying the regimen and using combination therapy are both strategies that can both treat HAP and suppress the emergence of resistance.

Retrospective evaluation of MRI findings in arthroscopically confirmed cases of hypermobile lateral meniscus.

OBJECTIVE: To identify preoperative MRI findings in patients with arthroscopically confirmed hypermobile lateral meniscus utilizing a standard MRI knee protocol, with comparison to normal control and lateral meniscal tear groups. SUBJECTS AND METHODS: All patients with arthroscopically confirmed hypermobile lateral meniscus diagnosed at our institution were retrospectively identified. The following structures were evaluated on preoperative knee MRIs: superior and inferior popliteomeniscal fascicles, lateral meniscus and meniscocapsular junction, popliteal hiatus, and soft tissue edema around the popliteal hiatus. The same MRI features were evaluated in the normal control and lateral meniscal tear groups. RESULTS: Study, normal control, and lateral meniscal tear patients (18 each) were included. In the study group, 94.4% had superior popliteomeniscal fascicle abnormality, 89.0% had inferior popliteomeniscal fascicle abnormality, and 72.2% had lateral meniscal abnormality. Incidence of these abnormalities was significantly higher than in the normal control group. Meniscal abnormalities in the study group all involved the posterior horn meniscocapsular junction, 12/13 of which had vertical signal abnormality at the junction and 1/13 with anterior subluxation of the entire posterior horn. Popliteus hiatus measurements were largest in the lateral meniscal tear group. CONCLUSION: In patients with hypermobile lateral meniscus, the combination of popliteomeniscal fascicle abnormality and vertical signal abnormality at the meniscocapsular junction was seen in the majority of patients. Popliteomeniscal fascicle signal abnormality without identifiable lateral meniscal injury was the next most common imaging appearance. Radiologists may provide valuable information by suggesting the diagnosis of hypermobile lateral meniscus in such cases.

Treatment of calcific arterial disease via enhancement of autophagy using GSK343.

Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp-/-) and small (Abcc6-/-) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.

Context-specific synthetic T cell promoters from assembled transcriptional elements.

Genetic engineering of human lymphocytes for therapeutic applications is constrained by a lack of transgene transcriptional control, resulting in a compromised therapeutic index. Incomplete understanding of transcriptional logic limits the rational design of contextually responsive genetic modules1. Here, we juxtaposed rationally curated transcriptional response element (TRE) oligonucleotides by random concatemerization to generate a library from which we selected context-specific inducible synthetic promoters (iSynPros). Through functional selection, we screened an iSynPro library for "IF-THEN" logic-gated transcriptional responses in human CD8+ T cells expressing a 4-1BB second generation chimeric antigen receptor (CAR). iSynPros exhibiting stringent off-states in quiescent T cells and CAR activation-dependent transcriptional responsiveness were cloned and subjected to TRE composition and pattern analysis, as well as performance in regulating candidate antitumor potency enhancement modules. These data reveal synthetic TRE grammar can mediate logic-gated transgene transcription in human T cells that, when applied to CAR T cell engineering, enhance potency and improve therapeutic indices.

Pre-clinical validation of a pan-cancer CAR-T cell immunotherapy targeting nfP2X7.

Chimeric antigen receptor (CAR)-T cell immunotherapy is a novel treatment that genetically modifies the patients' own T cells to target and kill malignant cells. However, identification of tumour-specific antigens expressed on multiple solid cancer types, remains a major challenge. P2X purinoceptor 7 (P2X7) is a cell surface expressed ATP gated cation channel, and a dysfunctional version of P2X7, named nfP2X7, has been identified on cancer cells from multiple tissues, while being undetectable on healthy cells. We present a prototype -human CAR-T construct targeting nfP2X7 showing potential antigen-specific cytotoxicity against twelve solid cancer types (breast, prostate, lung, colorectal, brain and skin). In xenograft mouse models of breast and prostate cancer, CAR-T cells targeting nfP2X7 exhibit robust anti-tumour efficacy. These data indicate that nfP2X7 is a suitable immunotherapy target because of its broad expression on human tumours. CAR-T cells targeting nfP2X7 have potential as a wide-spectrum cancer immunotherapy for solid tumours in humans.

Crystal structure of bis(3,5-dichloro-2-hydroxybenzyl)(2-methoxyethyl)amine.

The title compound, systematic name 4,4',6,6'-tetrachloro-2,2'-{[(2-methoxy-ethyl)azanediyl]bis(methylene)}diphenol (C17H17Cl4NO, 1), was prepared via a modified Mannich reaction between 2-meth-oxy-ethyl-amine, 2,4-di-chloro-phenol, and aqueous formaldehyde. The resulting amine bis-(phenol) provides an inter-esting comparison to related species as a result of the electron-withdrawing substituents on the phenol rings, in combination with similar steric parameters. One of the Cl atoms was modeled as a two-component disorder with partial occupancies of 0.49 (3) and 0.51 (3), while the pendant ether group was modeled as a two-component disorder with partial occupancies of 0.867 (3) and 0.133 (3). A comparison of metrical parameters for the title compound and closely related structures provides insight into the use of these species as ligands to support transition-metal complexes for applications as homogeneous catalysts.

Ergonomics for Cleft Providers: A Brief Communication.

Musculoskeletal (MSK) injuries are the most common and debilitating work-related injuries among healthcare providers. These injuries often occur due to a lack of awareness and insufficient guidance during the early years of medical training. Recognizing the need to address this issue, the Comprehensive Cleft Care Workshop (CCCW) has taken steps to integrate an ergonomics session into its curriculum. The goal of this initiative is to enhance awareness on ergonomics, improve the integration of ergonomics into daily routine, and ultimately reduce the occurrence of MSK injuries among healthcare professionals.

Management of Partial-Thickness Tears of the Distal Bicep Tendon: Evaluation of 111 Patients With 10-Year Follow-up.

Background: There is a paucity of research on the management of partial-thickness tears of the distal bicep tendon, and even less is known about the long-term outcomes of this condition. Purpose: To identify patients with partial-thickness distal bicep tendon tears and determine (1) patient characteristics and treatment strategies, (2) long-term outcomes, and (3) any identifiable risk factors for progression to surgery or complete tear. Study Design: Case-control study; Level of evidence, 3. Methods: A fellowship-trained musculoskeletal radiologist identified patients diagnosed with a partial-thickness distal bicep tendon tear on magnetic resonance imaging between 1996 and 2016. Medical records were reviewed to confirm the diagnosis and record study details. Multivariate logistic regression models were created using baseline characteristics, injury details, and physical examination findings to predict operative intervention. Results: In total, 111 patients met inclusion criteria (54 treated operatively, 57 treated nonoperatively), with 53% of tears in the nondominant arm and a mean follow-up time after surgery of 9.7 ± 6.5 years. Only 5% of patients progressed to full-thickness tears during the study period, at a mean of 35 months after the initial diagnosis. Patients who were nonoperatively treated were less likely to miss time from work (12% vs 61%; P < .001) and missed fewer days (30 vs 97 days; P < .016) than those treated surgically. Multivariate regression analyses demonstrated increased risk of progression to surgery with older age at initial consult (unit odds ratio [OR], 1.1), tenderness to palpation (OR, 7.5), and supination weakness (OR, 24.8). Supination weakness at initial consult was a statistically significant predictor for surgical intervention (OR, 24.8; P = .001). Conclusion: Clinical outcomes were favorable for patients regardless of treatment strategy. Approximately 50% of patients were treated surgically; patients with supination weakness were 24 times more likely to undergo surgery than those without. Progression to full-thickness tear was a relatively uncommon reason for surgical intervention, with only 5% of patients progressing to full-thickness tears during the study period and the majority occurring within 3 months of initial diagnosis.

Outcomes After Pharyngeal Flap Surgery in Children: A Comparison of Lined Versus Unlined Flaps.

OBJECTIVE: The addition of a uvular flap (PFU) was hypothesized to improve outcomes over standard pharyngeal flap (PF) for correction of velopharyngeal dysfunction. We report differences in outcomes of PF vs PFU at our institution. DESIGN: Retrospective cohort study. SETTING: Tertiary children's hospital. PATIENTS: Children who underwent PF or PFU with the three highest-volume surgeons at our institution in 2004-2017. OUTCOME MEASURES: We examined differences in complications between groups, frequency and type of revision surgery, and speech-related measures including nasometry, pressure-flow testing (PFT) and perceptual speech analysis (PSA). RESULTS: 160 patients were included, 41 PF and 119 PFU (including 18 with Hogan technique). Patients undergoing PFU were older (7.6 yr vs 6.0 yr; p = 0.037) and more likely to have cleft palate (63/119 vs 14/41; p = 0.047). There was no significant difference in complications. With PFU, a decrease in airspace contracting revision surgeries was noted, (4/119 vs 8/41; p = 0.002) which drove a reduction in revision surgery of all types (7/119 vs 13/41; p = 0.033). However, patients that did undergo revision surgery after PFU underwent more revision procedures (p = 0.032). PSA scores were found to be lower (less hypernasal) after PFU (p = 0.009) compared to PF. Objective speech measures had varying results, with nasometry demonstrating a significant difference between groups (p = 0.001), while PFT (p = 0.525) did not demonstrate a statistical difference. CONCLUSION: The use of a uvular lining flap in pharyngeal flap surgery may be associated with improved long term surgical outcomes, including both improvements in subjective and objective testing and a lower rate of revision surgery, without increased complications.

Discovery of arylsulfonamides as a novel class of allosteric integrase inhibitors with antiviral activity.

Lens epithelial-derived growth factor (LEDGF) increases the efficiency of proviral DNA integration into the host genome by interacting with HIV integrase (IN) and directing it to a chromatin environment that favors viral transcription. Allosteric integrase inhibitors (ALLINIs), such as known 2-(tert-butoxy)acetic acid (1), bind to the LEDGF pocket on the catalytic core domain (CCD) of IN, but exert more potent antiviral activities by inhibition of late-stage HIV-1 replication events than through disruption of proviral integration at an earlier phase. A high-throughput screen (HTS) for compounds that disrupt IN-LEDGF interaction led to the identification of a novel arylsulfonamide series, as exemplified by 2, possessing ALLINI-like properties. Further SAR studies led to more potent compound 21 and provided key chemical biology probes revealing that arylsulfonamides are a novel class of ALLINIs with a distinct binding mode than that of 2-(tert-butoxy)acetic acids.

Single-Stage Posterior Vomerine Ostectomy and Primary Cheiloplasty in Patients with Bilateral Cleft Lip & Palate and Protuberant Premaxilla.

OBJECTIVE: A protruded premaxilla has always been challenging to care for by cleft care professionals. This study aims to fortify the use of a single-stage premaxillary setback, with posterior vomerine ostectomy and primary cheiloplasty to achieve proper care for patients with bilateral cleft lip and palate (BCLP) and protruded premaxilla. DESIGN: Longitudinal retrospective analysis. SETTING: Twenty-three outreach programs to four countries (Ecuador, Lebanon, Peru, and El-Salvador) between 2016-2022. PATIENTS/PARTICIPANTS: Sixty-five patients between the ages of 3 months and 6 years and 5 months, with BCLP and severely protruded premaxilla underwent premaxillary setback via posterior vomerine ostectomy and primary cheiloplasty. Patients with diagnosed syndromes and inaccessible vomer bone due to fused palates were excluded from the study. INTERVENTIONS: Premaxillary setback with posterior vomerine ostectomy, bilateral gingivoperiosteoplasties (GPP), and primary cheiloplasty. MAIN OUTCOME MEASURE(S): Postoperative complications and aesthetic outcomes. RESULTS: The mean age at surgery was 13.17 ± 14.1 months, with an average follow-up time of 26 ± 17 months. Patients underwent their procedures in Ecuador (72%), Peru (9%), Lebanon (8%) and El-Salvador (1%). The majority of patients were aged 1 year or less (66.7%) and were males (58.5%). All patients were operated on successfully and had good aesthetic outcomes. Only one patient developed partial necrosis. CONCLUSION: Patients with BCLP and severe premaxillary protrusion have always carried immense social, psychological, and financial burdens, especially in outreach settings. Our described single-stage technique has proven to be safe and effective with good aesthetic results. Further follow-up after primary repair should be done to document and ensure proper facial growth and normal nasolabial maturation.

Direct haplotype-resolved 5-base HiFi sequencing for genome-wide profiling of hypermethylation outliers in a rare disease cohort.

Long-read HiFi genome sequencing allows for accurate detection and direct phasing of single nucleotide variants, indels, and structural variants. Recent algorithmic development enables simultaneous detection of CpG methylation for analysis of regulatory element activity directly in HiFi reads. We present a comprehensive haplotype resolved 5-base HiFi genome sequencing dataset from a rare disease cohort of 276 samples in 152 families to identify rare (~0.5%) hypermethylation events. We find that 80% of these events are allele-specific and predicted to cause loss of regulatory element activity. We demonstrate heritability of extreme hypermethylation including rare cis variants associated with short (~200 bp) and large hypermethylation events (>1 kb), respectively. We identify repeat expansions in proximal promoters predicting allelic gene silencing via hypermethylation and demonstrate allelic transcriptional events downstream. On average 30-40 rare hypermethylation tiles overlap rare disease genes per patient, providing indications for variation prioritization including a previously undiagnosed pathogenic allele in DIP2B causing global developmental delay. We propose that use of HiFi genome sequencing in unsolved rare disease cases will allow detection of unconventional diseases alleles due to loss of regulatory element activity.

Filling a nick in NIK: Extending the half-life of a NIK inhibitor through structure-based drug design.

Inhibition of NF-κB inducing kinase (NIK) has been pursued as a promising therapeutic target for autoimmune disorders due to its highly regulated role in key steps of the NF-κB signaling pathway. Previously reported NIK inhibitors from our group were shown to be potent, selective, and efficacious, but had higher human dose projections than desirable for immunology indications. Herein we report the clearance-driven optimization of a NIK inhibitor guided by metabolite identification studies and structure-based drug design. This led to the identification of an azabicyclo[3.1.0]hexanone motif that attenuated in vitro and in vivo clearance while maintaining NIK potency and increasing selectivity over other kinases, resulting in a greater than ten-fold reduction in predicted human dose.

Prophylactic Surgery for Thoracic Aortic Aneurysm: Asking Family for Help.

A 68-year-old man presented for evaluation of a 5.0-cm asymptomatic ascending aortic aneurysm. He was managed medically until a family member was also diagnosed with a thoracic aortic aneurysm. His aneurysm was, therefore, likely to be genetically predisposed, and he underwent early prophylactic ascending aorta replacement. (Level of Difficulty: Beginner.).

KaryoCreate: A CRISPR-based technology to study chromosome-specific aneuploidy by targeting human centromeres.

Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer. Here, we describe KaryoCreate (karyotype CRISPR-engineered aneuploidy technology), a system that enables the generation of chromosome-specific aneuploidies by co-expression of an sgRNA targeting chromosome-specific CENPA-binding ɑ-satellite repeats together with dCas9 fused to mutant KNL1. We design unique and highly specific sgRNAs for 19 of the 24 chromosomes. Expression of these constructs leads to missegregation and induction of gains or losses of the targeted chromosome in cellular progeny, with an average efficiency of 8% for gains and 12% for losses (up to 20%) validated across 10 chromosomes. Using KaryoCreate in colon epithelial cells, we show that chromosome 18q loss, frequent in gastrointestinal cancers, promotes resistance to TGF-ß, likely due to synergistic hemizygous deletion of multiple genes. Altogether, we describe an innovative technology to create and study chromosome missegregation and aneuploidy in the context of cancer and beyond.

Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach.

Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host's immune system leading to acquired immunodeficiency syndrome and potentially death. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Continued emergence of drug-resistance mutations drives the need for novel drugs that can inhibit HIV-1 replication through new pathways. The viral protein reverse transcriptase (RT) plays a fundamental role in the HIV-1 replication cycle, and multiple approved medications target this enzyme. In this study, fragment-based drug discovery was used to optimize a previously identified hit fragment (compound B-1), which bound RT at a novel site. Three series of compounds were synthesized and evaluated for their HIV-1 RT binding and inhibition. These series were designed to investigate different vectors around the initial hit in an attempt to improve inhibitory activity against RT. Our results show that the 4-position of the core scaffold is important for binding of the fragment to RT, and a lead compound with a cyclopropyl substitution was selected and further investigated. Requirements for binding to the NNRTI-binding pocket (NNIBP) and a novel adjacent site were investigated, with lead compound 27-a minimal but efficient NNRTI-offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors.