Tissue-engineered smooth muscle cell and endothelial progenitor cell bi-level cell sheets prevent progression of cardiac dysfunction, microvascular dysfunction, and interstitial fibrosis in a rodent model of type 1 diabetes-induced cardiomyopathy.

BACKGROUND: Diabetes mellitus is a risk factor for coronary artery disease and diabetic cardiomyopathy, and adversely impacts outcomes following coronary artery bypass grafting. Current treatments focus on macro-revascularization and neglect the microvascular disease typical of diabetes mellitus-induced cardiomyopathy (DMCM). We hypothesized that engineered smooth muscle cell (SMC)-endothelial progenitor cell (EPC) bi-level cell sheets could improve ventricular dysfunction in DMCM. METHODS: Primary mesenchymal stem cells (MSCs) and EPCs were isolated from the bone marrow of Wistar rats, and MSCs were differentiated into SMCs by culturing on a fibronectin-coated dish. SMCs topped with EPCs were detached from a temperature-responsive culture dish to create an SMC-EPC bi-level cell sheet. A DMCM model was induced by intraperitoneal streptozotocin injection. Four weeks after induction, rats were randomized into 3 groups: control (no DMCM induction), untreated DMCM, and treated DMCM (cell sheet transplant covering the anterior surface of the left ventricle). RESULTS: SMC-EPC cell sheet therapy preserved cardiac function and halted adverse ventricular remodeling, as demonstrated by echocardiography and cardiac magnetic resonance imaging at 8 weeks after DMCM induction. Myocardial contrast echocardiography demonstrated that myocardial perfusion and microvascular function were preserved in the treatment group compared with untreated animals. Histological analysis demonstrated decreased interstitial fibrosis and increased microvascular density in the SMC-EPC cell sheet-treated group. CONCLUSIONS: Treatment of DMCM with tissue-engineered SMC-EPC bi-level cell sheets prevented cardiac dysfunction and microvascular disease associated with DMCM. This multi-lineage cellular therapy is a novel, translatable approach to improve microvascular disease and prevent heart failure in diabetic patients.

A novel protein-engineered hepatocyte growth factor analog released via a shear-thinning injectable hydrogel enhances post-infarction ventricular function.

In the last decade, numerous growth factors and biomaterials have been explored for the treatment of myocardial infarction (MI). While pre-clinical studies have demonstrated promising results, clinical trials have been disappointing and inconsistent, likely due to poor translatability. In the present study, we investigate a potential myocardial regenerative therapy consisting of a protein-engineered dimeric fragment of hepatocyte growth factor (HGFdf) encapsulated in a shear-thinning, self-healing, bioengineered hydrogel (SHIELD). We hypothesized that SHIELD would facilitate targeted, sustained intramyocardial delivery of HGFdf thereby attenuating myocardial injury and post-infarction remodeling. Adult male Wistar rats (n = 45) underwent sham surgery or induction of MI followed by injection of phosphate buffered saline (PBS), 10 µg HGFdf alone, SHIELD alone, or SHIELD encapsulating 10 µg HGFdf. Ventricular function, infarct size, and angiogenic response were assessed 4 weeks post-infarction. Treatment with SHIELD + HGFdf significantly reduced infarct size and increased both ejection fraction and borderzone arteriole density compared to the controls. Thus, sustained delivery of HGFdf via SHIELD limits post-infarction adverse ventricular remodeling by increasing angiogenesis and reducing fibrosis. Encapsulation of HGFdf in SHIELD improves clinical translatability by enabling minimally-invasive delivery and subsequent retention and sustained administration of this novel, potent angiogenic protein analog. Biotechnol. Bioeng. 2017;114: 2379-2389. © 2017 Wiley Periodicals, Inc.

Extremely large sinus pericranii with involvement of the torcular and associated with Crouzon's syndrome.

INTRODUCTION: Sinus pericranii is a rare vascular malformation that connects the intracranial dural sinuses to the extracranial venous drainage system and is caused by either trauma or congenital defects. Although the majority of these vascular structures are due to trauma, some are congenital. CASE REPORT: Herein, we report a 5-month-old patient with a very large and fluctuating subcutaneous mass over the occiput and the diagnosis of Crouzon's syndrome. The child presented with a large midline mass that on imaging, connected to the underlying torcular and was diagnosed as a sinus pericranii. At long-term follow-up and without operative intervention, the sinus pericranii resolved. This uncommon relationship is reviewed. CONCLUSION: Premature closure of posterior fossa sutures as part of Crouzon's syndrome can present with large sinus pericranii. Such subcutaneous swellings might resolve spontaneously.

Aortic arch origin of the left vertebral artery: An Anatomical and Radiological Study with Significance for Avoiding Complications with Anterior Approaches to the Cervical Spine.

Complications from anterior approaches to the cervical spine are uncommon with normal anatomy. However, variant anatomy might predispose one to an increased incidence of injury during such procedures. We hypothesized that left vertebral arteries that arise from the aortic arch instead of the subclavian artery might take a more medial path in their ascent making them more susceptible to iatrogenic injury. Fifty human adult cadavers were examined for left vertebral arteries having an aortic arch origin and these were dissected along their entire cervical course. Additionally, two radiological databases of CTA and arteriography procedures were retrospectively examined for cases of aberrant left vertebral artery origin from the aortic arch over a two-year period. Two cadaveric specimens (4%) were found to have a left vertebral artery arising from the aortic arch. The retrospective radiological database analysis identified 13 cases (0.87%) of left vertebral artery origin from the aortic arch. Of all cases, vertebral arteries that arose from the aortic arch were much more likely to not only have a more medial course (especially their preforaminal segment) over the cervical vertebral bodies but also to enter a transverse foramen that was more cranially located than the normal C6 entrance of the vertebral artery. Spine surgeons who approach the anterior cervical spine should be aware that an aortic origin of the left vertebral artery is likely to be closer to the midline and less protected above the C6 vertebral level. Clin. Anat. 30:811-816, 2017. © 2017Wiley Periodicals, Inc.

Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb.

BACKGROUND: Despite promising therapeutic innovation over the last decade, peripheral arterial disease remains a prevalent morbidity, as many patients are still challenged with peripheral ischemia. We hypothesized that delivery of engineered stromal cell-derived factor 1-alpha (ESA) in an ischemic hind limb will yield significant improvement in perfusion. METHODS: Male rats underwent right femoral artery ligation, and animals were randomized to receive a 100 µL injection of saline (n = 9) or 6 µg/kg dosage of equal volume of ESA (n = 12) into the ipsilateral quadriceps muscle. Both groups of animals were also given an intraperitoneal injection of 40 µg/kg of granulocyte macrophage colony-stimulating factor (GMCSF). Perfusion was quantified using a laser Doppler imaging device preoperatively, and on postoperative days 0, 7, and 14. Immunohistochemistry was performed to quantify angiogenesis on day 14, and an mRNA profile was evaluated for angiogenic and inflammatory markers. RESULTS: Compared with the saline/GMCSF group at day 14, the ESA/GMCSF-injected animals had greater reperfusion ratios (Saline/GMCSF, 0.600 ± 0.140 vs ESA/GMCSF, 0.900 ± 0.181; group effect P = .006; time effect P < .0001; group×time effect P < .0001), elevated capillary density (10×; Saline/GMCSF, 6.40 ± 2.01 vs ESA/GMCSF, 18.55 ± 5.30; P < .01), and increased mRNA levels of vascular endothelial growth factor-A (Saline/GMCSF [n = 6], 0.298 ± 0.205 vs ESA/GMCSF [n = 8], 0.456 ± 0.139; P = .03). CONCLUSIONS: Delivery of ESA significantly improves perfusion in a rat model of peripheral arterial disease via improved neovasculogenesis, a finding which may prove beneficial in the treatment strategy for this debilitating disease.

Isolation and trans-differentiation of mesenchymal stromal cells into smooth muscle cells: Utility and applicability for cell-sheet engineering.

BACKGROUND: Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) have shown potential to differentiate into various cell types, including smooth muscle cells (SMCs). The extracellular matrix (ECM) represents an appealing and readily available source of SMCs for use in tissue engineering. In this study, we hypothesized that the ECM could be used to induce MSC differentiation to SMCs for engineered cell-sheet construction. METHODS: Primary MSCs were isolated from the BM of Wistar rats, transferred and cultured on dishes coated with 3 different types of ECM: collagen type IV (Col IV), fibronectin (FN), and laminin (LM). Primary MSCs were also included as a control. The proportions of SMC (a smooth muscle actin [aSMA] and SM22a) and MSC markers were examined with flow cytometry and Western blotting, and cell proliferation rates were also quantified. RESULTS: Both FN and LM groups were able to induce differentiation of MSCs toward smooth muscle-like cell types, as evidenced by an increase in the proportion of SMC markers (aSMA; Col IV 42.3 ± 6.9%, FN 65.1 ± 6.5%, LM 59.3 ± 7.0%, Control 39.9 ± 3.1%; P = 0.02, SM22; Col IV 56.0 ± 7.7%, FN 74.2 ± 6.7%, LM 60.4 ± 8.7%, Control 44.9 ± 3.6%) and a decrease in that of MSC markers (CD105: Col IV 64.0 ± 5.2%, FN 57.6 ± 4.0%, LM 60.3 ± 7.0%, Control 85.3 ± 4.2%; P = 0.03). The LM group showed a decrease in overall cell proliferation, whereas FN and Col IV groups remained similar to control MSCs (Col IV, 9.0 ± 2.3%; FN, 9.8 ± 2.5%; LM, 4.3 ± 1.3%; Control, 9.8 ± 2.8%). CONCLUSIONS: Our findings indicate that ECM selection can guide differentiation of MSCs into the SMC lineage. Fibronectin preserved cellular proliferative capacity while yielding the highest proportion of differentiated SMCs, suggesting that FN-coated materials may be facilitate smooth muscle tissue engineering.

Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1α analog in a translational ovine myocardial infarction model.

RATIONALE: After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile. OBJECTIVE: To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility. METHODS AND RESULTS: Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01). CONCLUSIONS: The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

Bioengineered stromal cell-derived factor-1α analogue delivered as an angiogenic therapy significantly restores viscoelastic material properties of infarcted cardiac muscle.

Ischemic heart disease is a major health problem worldwide, and current therapies fail to address microrevascularization. Previously, our group demonstrated that the sustained release of novel engineered stromal cell-derived factor 1-a analogue (ESA) limits infarct spreading, collagen deposition, improves cardiac function by promoting angiogenesis in the region surrounding the infarct, and restores the tensile properties of infarcted myocardium. In this study, using a well-established rat model of ischemic cardiomyopathy, we describe a novel and innovative method for analyzing the viscoelastic properties of infarcted myocardium. Our results demonstrate that, compared with a saline control group, animals treated with ESA have significantly improved myocardial relaxation rates, while reducing the transition strain, leading to restoration of left ventricular mechanics.

Preoperative prediction model for risk of readmission after total joint replacement surgery: a random forest approach leveraging NLP and unfairness mitigation for improved patient care and cost-effectiveness.

BACKGROUND: The Center for Medicare and Medicaid Services (CMS) imposes payment penalties for readmissions following total joint replacement surgeries. This study focuses on total hip, knee, and shoulder arthroplasty procedures as they account for most joint replacement surgeries. Apart from being a burden to healthcare systems, readmissions are also troublesome for patients. There are several studies which only utilized structured data from Electronic Health Records (EHR) without considering any gender and payor bias adjustments. METHODS: For this study, dataset of 38,581 total knee, hip, and shoulder replacement surgeries performed from 2015 to 2021 at Novant Health was gathered. This data was used to train a random forest machine learning model to predict the combined endpoint of emergency department (ED) visit or unplanned readmissions within 30 days of discharge or discharge to Skilled Nursing Facility (SNF) following the surgery. 98 features of laboratory results, diagnoses, vitals, medications, and utilization history were extracted. A natural language processing (NLP) model finetuned from Clinical BERT was used to generate an NLP risk score feature for each patient based on their clinical notes. To address societal biases, a feature bias analysis was performed in conjunction with propensity score matching. A threshold optimization algorithm from the Fairlearn toolkit was used to mitigate gender and payor biases to promote fairness in predictions. RESULTS: The model achieved an Area Under the Receiver Operating characteristic Curve (AUROC) of 0.738 (95% confidence interval, 0.724 to 0.754) and an Area Under the Precision-Recall Curve (AUPRC) of 0.406 (95% confidence interval, 0.384 to 0.433). Considering an outcome prevalence of 16%, these metrics indicate the model's ability to accurately discriminate between readmission and non-readmission cases within the context of total arthroplasty surgeries while adjusting patient scores in the model to mitigate bias based on patient gender and payor. CONCLUSION: This work culminated in a model that identifies the most predictive and protective features associated with the combined endpoint. This model serves as a tool to empower healthcare providers to proactively intervene based on these influential factors without introducing bias towards protected patient classes, effectively mitigating the risk of negative outcomes and ultimately improving quality of care regardless of socioeconomic factors.

Effect of Electronic Portal Messaging With Embedded Asynchronous Care on Physician-Assisted Smoking Cessation Attempts: A Randomized Clinical Trial.

IMPORTANCE: Despite the substantial health and financial burdens of smoking and the availability of effective, evidence-based interventions in primary care settings, few smokers and physicians use these strategies for smoking cessation. OBJECTIVE: To evaluate whether electronic outreach to smokers with embedded asynchronous care increases the number of quit attempts and explore the roles of the message sender (ie, primary care physician [PCP] vs health care system) and patient-related characteristics. DESIGN, SETTING, AND PARTICIPANTS: This quality improvement randomized clinical trial was designed to measure 2 factors: (1) electronic outreach messaging with and without a survey link to asynchronous care and (2) messaging by a personal PCP or health system. The study was conducted within the electronic health record and portal messaging platform of a large health system in the South Central US. Participants were adult patients 18 years or older who were designated as smokers in their electronic health records. Data were collected from January 13 to February 24, 2020, with participating PCPs surveyed in July 2020. INTERVENTIONS: Portal messages encouraging a quit attempt and offering physician assistance were sent to smokers who were randomly selected and assigned to 1 of 4 conditions (message with or without embedded asynchronous care and PCP or system as sender). Half of the messages contained an invitation to come to clinics and the other half contained a link to access asynchronous care. MAIN OUTCOMES AND MEASURES: The primary outcome was electronic health record-documented quit attempts (1 indicates quit attempt; 0, no quit attempt), which were tracked 30 days after the electronic outreach. Secondary outcomes included physician perceptions of the electronic outreach intervention, using a 5-point scale to assess perceptions of workload, comfort with providing medication from survey information, and further interest in the program 6 months after the intervention. RESULTS: A total of 188 participants (99 women [52.4%] and 89 men [47.3%]) with mean (SD) age of 55.2 (13.9) years were randomized to 1 of 4 conditions. Group 1 (n = 46) received a message from the PCP without a link to the survey; group 2 (n = 48) received a message from the PCP with a link to asynchronous care in the form of the survey. Group 3 (n = 47) received a message from the health system without a link to the survey; group 4 (n = 47) received a message from the health system with a link to the survey. No statistically significant difference in documented quite attempts was found among the 4 study groups. There was also no statistically significant difference in quit attempts between the group that received the asynchronous care survey link and the group that did not (odds ratio, 2.50 [95% CI, 0.72-8.72]). However, the quit attempt rate for those with asynchronous care offered (9 of 95 [9.5%]) was more than double the quit attempt rate for those with in-person care offered (4 of 93 [4.3%]). CONCLUSIONS AND RELEVANCE: This quality improvement randomized clinical trial did not find a statistically significant difference in physician-assisted quit attempts among patients who received electronic with asynchronous care vs those who received outreach alone, regardless of whether the message source was a PCP or a health system. However, the program engaged patients in difficult-to-reach rural areas as well as younger patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05172219.

Selecting response anchors with equal intervals for summated rating scales.

Summated rating scales are ubiquitous in organizational research, and there are well-delineated guidelines for scale development (e.g., Hinkin, 1998). Nevertheless, there has been less research on the explicit selection of the response anchors. Constructing survey questions with equal-interval properties (i.e., interval or ratio data) is important if researchers plan to analyze their data using parametric statistics. As such, the primary objectives of the current study were to (a) determine the most common contexts in which summated rating scales are used (e.g., agreement, similarity, frequency, amount, and judgment), (b) determine the most commonly used anchors (e.g., strongly disagree, often, very good), and (c) provide empirical data on the conceptual distance between these anchors. We present the mean and standard deviation of scores for estimates of each anchor and the percentage of distribution overlap between the anchors. Our results provide researchers with data that can be used to guide the selection of verbal anchors with equal-interval properties so as to reduce measurement error and improve confidence in the results of subsequent analyses. We also conducted multiple empirical studies to examine the consequences of measuring constructs with unequal-interval anchors. A clear pattern of results is that correlations involving unequal-interval anchors are consistently weaker than correlations involving equal-interval anchors. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model.

The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy's potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (n = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure-volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (p = 0.006) and contractility based on the slope of the end-systolic pressure-volume relationship (p = 0.006). NRG-HG also significantly reduced infarct scar size (p = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.

Diverse human VH antibody fragments with bio-therapeutic properties from the Crescendo Mouse.

We describe the 'Crescendo Mouse', a human VH transgenic platform combining an engineered heavy chain locus with diverse human heavy chain V, D and J genes, a modified mouse Cγ1 gene and complete 3' regulatory region, in a triple knock-out (TKO) mouse background devoid of endogenous immunoglobulin expression. The addition of the engineered heavy chain locus to the TKO mouse restored B cell development, giving rise to functional B cells that responded to immunization with a diverse response that comprised entirely 'heavy chain only' antibodies. Heavy chain variable (VH) domain libraries were rapidly mined using phage display technology, yielding diverse high-affinity human VH that had undergone somatic hypermutation, lacked aggregation and showed enhanced expression in E. coli. The Crescendo Mouse produces human VH fragments, or Humabody® VH, with excellent bio-therapeutic potential, as exemplified here by the generation of antagonistic Humabody® VH specific for human IL17A and IL17RA.

Multistage selection strategies: simulating the effects on adverse impact and expected performance for various predictor combinations.

Examination of the trade-off between mean performance and adverse impact has received empirical attention for single-stage selection strategies; however, research for multistage selection strategies is almost nonexistent. The authors used Monte Carlo simulation to explore the trade-off between expected mean performance and minority hiring in multistage selection strategies and to identify those strategies most effective in balancing the trade-off. In total, 43 different multistage selection strategies were modeled; they reflected combinations of predictors with a wide range of validity, subgroup differences, and predictor intercorrelations. These selection models were examined across a variety of net and stage-specific selection ratios. Though it was still the case that an increase in minority hiring was associated with a decrease in predicted performance for many scenarios, the current results revealed that certain multistage strategies are much more effective than others for managing the performance and adverse impact trade-offs. The current study identified several multistage strategies that are clearly more desirable than those strategies previously suggested in the literature for practitioners who seek a practical selection system that will yield a high-performing and highly representative workforce.

Work stressors, role-based performance, and the moderating influence of organizational support.

As a test of the 2-dimensional model of work stressors, the present study proposed differential relationships between challenge stressors and hindrance stressors and role-based performance, which were expected to be moderated by organizational support. In a sample of 215 employees across 61 offices of a state agency, the authors obtained a positive relationship between challenge stressors and role-based performance and a negative relationship between hindrance stressors and role-based performance. In addition, organizational support moderated the relationship between challenge stressors and role-based performance but did not moderate the relationship between hindrance stressors and role-based performance. This suggests that organizations would benefit from increasing challenges in the workplace as long as they are supportive of employees and removing hindrances. Further implications for organizational theory and practice are discussed. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

Ex Vivo Biomechanical Study of Apical Versus Papillary Neochord Anchoring for Mitral Regurgitation.

BACKGROUND: Neochordoplasty is an important repair technique, but optimal anchoring position is unknown. Although typically anchored at papillary muscles, new percutaneous devices anchor the neochordae at or near the ventricular apex, which may have an effect on chordal forces and the long-term durability of the repair. METHODS: Porcine mitral valves (n = 6) were mounted in a left heart simulator that generates physiologic pressure and flow through the valves, and chordal forces were measured with Fiber Bragg Grating strain gauge sensors. Isolated mitral regurgitation was induced by cutting P2 primary chordae, and the regurgitant valve was repaired with polytetrafluoroethylene neochord with apical anchoring, followed by papillary muscle fixation for comparison. In both situations, the neochord was anchored to a customized force-sensing post positioned to mimic the relevant in vivo placement. RESULTS: Echocardiographic and hemodynamic data confirmed that the repairs restored physiologic hemodynamics. Forces on the chordae and neochord were lower for papillary fixation than for the apical fixation (p = 0.003). In addition, the maximum rate of change of force on the chordae and neochordae was higher for apical fixation than for papillary fixation (p = 0.028). CONCLUSIONS: Apical neochord anchoring results in effective repair of mitral regurgitation, albeit with somewhat higher forces on the chordae and neochord suture, as well as an increased rate of loading on the neochord compared with the papillary muscle fixation. These results may guide strategies to reduce stresses on neochordae as well as aid optimal patient selection.

Cranial Nerve Foramina: Part II - A Review of the Anatomy and Pathology of Cranial Nerve Foramina of the Posterior Cranial Fossa.

Cranial nerve foramina are integral exits from the confines of the skull. Despite their significance in cranial nerve pathologies, there has been no comprehensive anatomical review of these structures. Owing to the extensive nature of this topic we have divided our review into two parts; Part II, presented here, focuses on the foramina of the posterior cranial fossa and discusses each foramen's shape, orientation, size, surrounding structures, and structures that pass through it. Furthermore, by comparing foramen sizes against the cross-sectional areas of their contents, we determine the amount of free space available within each. We also review lesions that can obstruct each foramen and discuss the clinical consequences.

Cranial Nerve Foramina Part I: A Review of the Anatomy and Pathology of Cranial Nerve Foramina of the Anterior and Middle Fossa.

Cranial nerve foramina are integral exits from the confines of the skull. Despite their significance in cranial nerve pathologies, there has been no comprehensive anatomical review of these structures. Owing to the extensive nature of this topic, Part I of our review, presented here, focuses on the foramina of the anterior and middle cranial fossae, discussing each foramen's shape, orientation, size, surrounding structures, and structures that traverse them. Furthermore, by comparing the size of each foramen against the cross-sectional areas of its contents, we estimate the amount of free space in each. We also review lesions that can obstruct the foramina and discuss their clinical consequences.

Supernumerary Abducens Nerves: A Comprehensive Review.

BACKGROUND: Branching and/or replication of the abducens nerve is not an uncommon occurrence. Although numerous variations have been documented, the rarest forms are duplicated or triplicated nerves, where multiple nerve roots originate from the brainstem, travel intracranially, and attach to the lateral rectus as separate entities. METHODS: We conducted a systematic literature search on the topic of supernumerary abducens nerve, using PubMed and Google Scholar. RESULTS: After screening, 16 studies were included: 11 cadaveric studies and 6 case reports. CONCLUSIONS: In this paper, we review the literature on variations found, discuss current hypotheses and clinical relevance, and propose future studies. Neurosurgeons should be aware of such nerve variants when viewing imaging or operating in the regions traversed by the abducens nerve.

Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours?

Antibody-Drug Conjugates (ADCs) have been through multiple cycles of technological innovation since the concept was first practically demonstrated ~40 years ago. Current technology is focusing on large, whole immunoglobulin formats (of which there are approaching 100 in clinical development), many with site-specifically conjugated payloads numbering 2 or 4. Despite the success of trastuzumab-emtansine in breast cancer, ADCs have generally failed to have an impact in solid tumours, leading many to explore alternative, smaller formats which have better penetrating properties as well as more rapid pharmacokinetics (PK). This review describes research and development progress over the last ~10 years obtained from the primary literature or conferences covering over a dozen different smaller format-drug conjugates from 80 kDa to around 1 kDa in total size. In general, these agents are potent in vitro, particularly more recent ones incorporating ultra-potent payloads such as auristatins or maytansinoids, but this potency profile changes when testing in vivo due to the more rapid clearance. Strategies to manipulate the PK properties, whilst retaining the more effective tumour penetrating properties could at last make small-format drug conjugates viable alternative therapeutics to the more established ADCs.