Path-dependence of the Plio-Pleistocene glacial/interglacial cycles.

We find strong path dependence in the evolution of the Plio-Pleistocene glaciations using CLIMBER-2 Earth System Model simulations from the mid-Pliocene to modern preindustrial (3 My-0 My BP) driven by a gradual decrease in volcanic carbon dioxide outgassing and regolith removal from basal ice interaction. Path dependence and hysteresis are investigated by alternatively driving the model forward and backward in time. Initiating the model with preindustrial conditions and driving the model backward using time-reversed forcings, the increase in volcanic outgassing back-in-time (BIT) does not generate the high CO2 levels and relatively ice-free conditions of the late Pliocene seen in forward-in-time (FIT) simulations of the same model. This behavior appears to originate from nonlinearities and initial state dependence in the carbon cycle. A transition from low-amplitude sinusoidal obliquity (~41 ky) and precession (~23 ky) driven glacial/interglacial cycles to high-amplitude ~100 ky likely eccentricity-related sawtooth cycles seen between -1.25 My and -0.75 My BP (the Mid-Pleistocene transition or "MPT") in FIT simulations disappears in BIT integrations depending on the details of how the regolith removal process is treated. A transition toward depleted regolith and lowered atmospheric CO2 levels are both required to reproduce the MPT.

CAR expression in invasive breast carcinoma and its effect on adenovirus transduction efficiency.

BACKGROUND: Breast cancer is the second leading cause of death in women, with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) as the two most common forms of invasive breast cancer. While estrogen receptor positive (ER+) IDC and ILC are treated similarly, the multifocality of ILC presents challenges in detection and treatment, worsening long-term clinical outcomes in patients. With increasing documentation of chemoresistance in ILC, additional treatment options are needed. Oncolytic adenoviral therapy may be a promising option, but cancer cells must express the coxsackievirus & adenovirus receptor (CAR) for adenoviral therapy to be effective. The present study aims to evaluate the extent to which CAR expression is observed in ILC in comparison to IDC, and how the levels of CAR expression correlate with adenovirus transduction efficiency. The effect of liposome encapsulation on transduction efficiency is also assessed. METHODS: To characterize CAR expression in invasive breast carcinoma, 36 formalin-fixed paraffin-embedded (FFPE) human breast tumor samples were assayed by CAR immunohistochemistry (IHC). Localization of CAR in comparison to other junctional proteins was performed using a multiplex immunofluorescence panel consisting of CAR, p120-catenin, and E-cadherin. ILC and IDC primary tumors and cell lines were transduced with E1- and E3-deleted adenovirus type 5 inserted with a GFP transgene (Ad-GFP) and DOTAP liposome encapsulated Ad-GFP (DfAd-GFP) at various multiplicities of infection (MOIs). Transduction efficiency was measured using a fluorescence plate reader. CAR expression in the human primary breast carcinomas and cell lines was also evaluated by IHC. RESULTS: We observed membranous CAR, p120-catenin and E-cadherin expression in IDC. In ILC, we observed cytoplasmic expression of CAR and p120-catenin, with absent E-cadherin. Adenovirus effectively transduced high-CAR IDC cell lines, at MOIs as low as 12.5. Ad-GFP showed similar transduction as DfAd-GFP in high-CAR IDC cell lines. Conversely, Ad-GFP transduction of ILC cell lines was observed only at MOIs of 50 and 100. Furthermore, Ad-GFP did not transduce CAR-negative IDC cell lines even at MOIs greater than 100. Liposome encapsulation (DfAd-GFP) improved transduction efficiency 4-fold in ILC and 17-fold in CAR-negative IDC cell lines. CONCLUSION: The present study demonstrates that oncolytic adenoviral therapy is less effective in ILC than IDC due to differences in spatial CAR expression. Liposome-enhanced delivery may be beneficial for patients with ILC and tumors with low or negative CAR expression to improve adenoviral therapeutic effectiveness.

Editorial Commentary: Trends in Hip Arthroscopy Require Rapid Dissemination From Higher-Volume and Academic Surgeons to the Greater Orthopaedic Community.

Trends in hip arthroscopy show that labral repair and preservation, capsular repair and preservation, and treatment of femoroacetabular impingement during hip arthroscopy are associated with superior short-term and mid- to longer-term outcomes. Hip arthroscopy, and in particular arthroscopic femoroacetabular impingement correction, is in its infancy compared with many other orthopaedic procedures. As we assimilate knowledge, data, and evidence-based research, it is critical to evaluate surgical trends and how they affect our management of these patients and pathologies. However, it is important to recognize that there is great variability with regards to surgical volume and awareness of impending evidence-based research for relatively newer procedures such as hip arthroscopy. This can lead to delays for incorporating newer evidence-based techniques. The gap is closing, but the time required to close this disparity in management trends between higher-volume/academic surgeons and the orthopaedic community as a whole could be shorter. Whether this delay for adapting evidence-based trends is consistent across the spectrum of orthopaedic surgery or specific to smaller subspecialty areas such as hip arthroscopy is unclear. Regardless, it is essential that those who are performing the larger volume of cases and research must raise our voices, turn up our loudspeakers, and publish, present, and use social media platforms to spread the word of the latest evidence-based trends quickly! It is equally critical for the greater orthopaedic community to listen for the benefit of patients. If all parties collaborate, we can get up to speed in a timelier manner and achieve the best-possible outcomes together.

Editorial Commentary: Minimizing Traction Force and Time as Well as Application of Specific Technical Pearls Might Trump the Importance of Choosing Between Post or Postless Hip Arthroscopy With Regards to Complications.

Recently, there has been a trend toward performing hip arthroscopy without a post (postless) in an effort to decrease perineal post-related complications. Previous studies have revealed a variable risk of pudendal nerve neuralgia and perineal soft-tissue injury when using a post. There is emerging evidence that arthroscopic hip procedures can be done without the use of a post, with less traction force on the perineal region, and with adequate exposure to safely accomplish a well-done femoroacetabular impingement corrective procedure. Prospective comparative studies with conclusive evidence of the superiority of either technique, however, are lacking. Complications with a post are likely associated with high traction forces, prolonged traction times, and potentially suboptimal technique and patient positioning. In addition, postless traction is in its infancy and new adverse events/outcomes are likely to emerge. There are likely specific situations and patient populations in which one technique might be superior to the other. We are the carpenters of medicine and rather than blaming our tools and throwing out a technique that has served us well for decades, we should better understand some important pearls and pitfalls that might allow either method to be safely performed.

Radiographic and Dynamic Assessment for Resection of Cam Lesions in Patients With Femoroacetabular Impingement.

Cam-type femoroacetabular impingement is characterized by a pathologic asphericity of the femoral head-neck junction, and arthroscopic femoral osteoplasty is indicated to correct the bony abnormality and restore normal hip mechanics when symptomatic. Residual femoroacetabular impingement deformity after arthroscopy is a leading cause of failure, and it is therefore critical to perform a thorough fluoroscopic and dynamic assessment when addressing cam deformities arthroscopically. The fluoroscopic assessment uses 6 anteroposterior views, including 3 in hip extension (30° internal rotation, neutral rotation, and 30° external rotation) and 3 in 50° flexion (neutral rotation, 40° external rotation, 60° of external rotation), performed before, during, and after the femoral resection. The dynamic assessment includes evaluation of impingement-free range of motion and "end feel" (a subjective description of the tactile feedback during assessment of hip motion), and should be performed before and after the femoral resection in 3 specific positions (extension/abduction, flexion/abduction, and flexion/internal rotation). Although the anterior aspect of the head-neck junction is readily accessed through standard arthroscopic portals with the hip in 30 to 50° of flexion, the posterolateral, posteromedial, and posterior extent of the femoral head-neck junction are challenging to address. The natural external rotation of the proximal femur during flexion and internal rotation during extension can be used to gain posterior lateral and medial access. Antero/posteromedial femoral access can be obtained with >50° of hip flexion with the burr in the anteromedial portal. Posterolateral femoral access is achieved with hip extension with the burr in the anterolateral portal, and further posterolateral access can be achieved with the addition of traction, allowing resection of posterolateral deformities extending beyond the lateral retinacular vessels while remaining proximal to the vessels. This comprehensive intraoperative fluoroscopic and dynamic assessment and surgical technique can lead to a predictable correction of most cam-type deformities.

BETA PRIME: Phase I study of AdAPT-001 as monotherapy and combined with a checkpoint inhibitor in superficially accessible, treatment-refractory solid tumors.

AdAPT-001 is an investigational therapy consisting of a replicative type 5 adenovirus armed with a TGF-ß receptor-immunoglobulin Fc fusion trap, designed to neutralize isoforms 1 and 3 of the profibrotic and immunosuppressive cytokine, TGF-ß. In preclinical studies with an immunocompetent mouse model, AdAPT-001 eradicated directly treated 'cold' tumors as well as distant untreated tumors, and, from its induction of systemic CD8+ T cell-mediated antitumor immunity, protected the mice from rechallenge with tumor cells. AdAPT-001 also sensitized resistant tumors to checkpoint blockade. This manuscript describes the rationale and design of the first-in-human phase I, dose-escalation and dose-expansion study of AdAPT-001 alone and in combination with a checkpoint inhibitor in adults with treatment-refractory superficially accessible solid tumors.

The purpose of this study is to find out more about the experimental oncolytic virus called AdAPT-001 that has been designed to selectively eliminate cancer cells. The virus is also designed to make a particular protein called a TGF-ß trap, which neutralizes TGF-ß, an overproduced chemical in cancer cells that puts the immune system into a comatose state. This article discusses a clinical trial called BETA PRIME for patients with no other standard treatment options. The trial will explore different doses of AdAPT-001 both alone and in combination with an approved checkpoint inhibitor or another immunotherapy, which blocks the 'off' signal on immune cells, to determine the safest and best dose. Clinical Trial Registration: NCT04673942 (ClinicalTrials.gov).

Editorial Commentary: Routine Preoperative Magnetic Resonance Imaging for Hip Arthroscopy Is Wasting Health Care Dollars and Delaying Surgical Intervention: Decision Making Should Be at the Discretion of the Health Care Provider Not Mandated by Health Care Insurers.

Making an accurate preoperative diagnosis is critical to optimizing outcomes after hip arthroscopy. A detailed history, thorough physical examination, imaging studies, and diagnostic injections must all be considered in the decision-making process. In today's health care climate, it is imperative to obtain essential and indicated preoperative information while being mindful of health care dollars. Magnetic resonance imaging (MRI) of the hip has been shown to be a highly sensitive modality for hip and pelvis disorders. However, it is critical to recognize that acetabular labral tears and other hip pathology are highly prevalent in an asymptomatic young adult population. There are certainly situations when an MRI should be obtained (suspected arthritic symptoms, avascular necrosis, synovial disorders, uncommon osseous tumors); however, these patients generally present with atypical symptoms. In addition, obtaining an MRI can delay surgical intervention, which has been shown to lead to inferior outcomes in prior studies. MRI is not imperative when patients present with typical intermittent, deep anterior, lateral, groin pain with prolonged sitting, twisting and pivoting, and transitioning from sitting to standing. The typical physical examination includes positive hip impingement testing (FADIR / anterior impingement test) that recreates the patients presenting complaints. Appropriate imaging includes plain radiographs revealing adequate acetabular coverage (not significantly dysplastic) or acetabular overcoverage (pincer-type femoracetabular impingement), cam-type femoracetabular impingement, and well-maintained joint space on all views, including a false profile radiograph to further evaluate the anterior joint space. Finally, a diagnostic injection can be invaluable to further confirm the hip joint proper as the source of pain. If all of the above criteria are met, I strongly believe an MRI is unlikely to alter the surgical decision-making process. In the end, the treating clinician should determine when an MRI is necessary based on the presenting symptoms and examination, rather than insurers applying a blanket requirement for preauthorization. This physician autonomy would ultimately lead to more efficient and cost-effective patient care. Medicine is an art, and unjustified handcuffing of the artist without evidence could result in inferior results.

Editorial Commentary: Restoration of Hip Capsular Tension Is More Important Than Repair Construct Configuration.

The debate regarding optimal capsular management during hip arthroscopy has been evolving for over 20 years. Femoroacetabular impingement emerged in the arthroscopic world in the early 2000s. However, the ability to address osseous deformities and decompress and/or reshape them was limited by the hip capsular structures and small capsulotomies. Some surgeons attempted to arthroscopically manage these deformities with limited capsulotomies, with not surprisingly limited success. Others made larger capsular windows (capsulectomies) to more accurately manage these deformities but potentially left some patients with varying degrees of iatrogenic microinstability or macroinstability. Over time, an increasing awareness of post-arthroscopy instability in the form of case reports, case series, and backroom chatter among the hip arthroscopy thought leaders brought the idea of routine capsular closure to the forefront. Biomechanical studies defined the role of the hip capsular ligaments, the deficits created with various capsulotomies during surgery, and the ability to restore stability after capsular repair. Clinical studies revealed better outcomes and lower revision rates after capsular repair for subtle osseous and soft-tissue instability, revision cases, and athletes compared with unrepaired capsulotomies. Various capsular repair constructs (side-to-side repairs, capsular shifts, and various suture configurations and suture materials) have been proposed, without evidence to support a superior technique or suture material. In the end, capsular management is an evolving art that takes into account various patient-specific factors (i.e., individual activity requirements, soft-tissue and osseous parameters, and intraoperative impressions) with the end goal of achieving a stable, impingement-free joint. There might be various capsular management roads to travel, but the destination remains the same.

Atrial Fibrillation Genomics: Discovery and Translation.

PURPOSE OF REVIEW: Our understanding of the fundamental cellular and molecular factors leading to atrial fibrillation (AF) remains stagnant despite significant advancement in ablation and device technologies. Diagnosis and prevention strategies fall behind that of treatment, but expanding knowledge in AF genetics holds the potential to drive progress. We aim to review how an understanding of the genetic contributions to AF can guide an approach to individualized risk stratification and novel avenues in drug discovery. RECENT FINDINGS: Rare familial forms of AF identified monogenic contributions to the development of AF. Genome-wide association studies (GWAS) further identified single-nucleotide polymorphisms (SNPs) suggesting polygenic and multiplex nature of this common disease. Polygenic risk scores accounting for the multitude of associated SNPs that each confer mildly elevated risk have been developed to translate genetic information into clinical practice, though shortcomings remain. Additionally, novel laboratory methods have been empowered by recent genetic findings to enhance drug discovery efforts. AF is increasingly recognized as a disease with a significant genetic component. With expanding sequencing technologies and accessibility, polygenic risk scores can help identify high risk individuals. Advancement in digital health tools, artificial intelligence and machine learning based on standard electrocardiograms, and genomic driven drug discovery may be integrated to deliver a sophisticated level of precision medicine in this modern era of emphasis on prevention. Randomized, prospective studies to demonstrate clinical benefits of these available tools are needed to validate this approach.

Editorial Commentary: Psoas Tenotomy in the Setting of a Borderline Dysplastic Hip Risks Iatrogenic Instability: Be Extremely Cautious and Particularly in Athletes.

Successful outcomes after psoas tenotomies have been reported and proposed in the setting of recalcitrant internal snapping and psoas impingement. However, case reports citing hip flexion weakness and iatrogenic instability created concern regarding the role for psoas tenotomies. Despite these concerns, some recent studies reporting improved outcomes after endoscopic psoas tenotomies breathe further life into this controversial topic. Psoas tenotomy in the setting of a borderline dysplastic hip likely carries an even greater risk for iatrogenic instability. It might be critical to evaluate for clinical signs and symptoms of instability in addition to radiographic parameters to avoid this potentially devastating complication. In addition, the traditional definition of borderline dysplasia is based on lateral acetabular coverage that might be less important than anterior acetabular coverage and femoral version when contemplating psoas tenotomies on the basis of the dynamic anterior stabilizing effect of the iliopsoas myotendinous unit. Surgeons should also be extremely cautious when considering psoas tenotomy in an athletic population with the potential for persistent weakness and limited data hinting at inferior sports specific outcomes. In the end, it is not clear whether the psoas tenotomy "drives" the improvements seen in some studies, or whether many of these patients ultimately battle their way into a minimally clinically important difference "despite" the psoas tenotomy.

Editorial Commentary: Ultrasound-Guided Injection With Dynamic Assessment Could Improve Outcomes in Atypical and Revision Hip Arthroscopy Patients: But Today, Few Are Trained to Hear at Such High Frequencies.

Imaging modalities for hip disorders all have their strengths and weaknesses. Magnetic resonance imaging is superior for evaluating soft tissue pathology, computerized tomography best characterizes osseous morphology, and plain radiographs can accurately depict 2-dimensional anatomy and are familiar to most clinicians. Ultrasound-guided injections have become commonplace in the musculoskeletal arena. Ultrasound evaluation of musculoskeletal anatomy has received increased attention, has the ability to image soft tissue and osseous structures, and more importantly, has the ability to dynamically evaluate these structures in real time. A noninvasive dynamic assessment of the hip region could be an absolute game changer for the hip preservation/sports medicine community in the diagnosis of atypical hip pain, femoroacetabular impingement, and labral tears. Widespread ability and expertise to perform these dynamic ultrasound assessments, however, is not in place at this time. We need more training and studies to best harness the potential benefits of these sound waves.

Posterior Tibial Slope: Understand Bony Morphology to Protect Knee Cruciate Ligament Grafts.

Improved understanding of the biomechanical significance and clinical repercussions of tibial slope on cruciate ligament function has sparked a newfound clinical interest in this morphological feature. Using either magnetic resonance imaging or lateral tibia radiographs, the anterior-posterior angulation of the tibial plateau relative to the tibial shaft can be measured. Clinical and biomechanical studies have reported that increased posterior tibial slope (PTS) places significantly increased tension on the native and reconstructed anterior cruciate ligament (ACL), leading to an increased risk of failure. It has also been suggested that increased PTS of the lateral tibial plateau has a greater impact on ACL forces and anterior tibial translation than PTS of the medial tibial plateau. Conversely, a decreased PTS has been shown to be a risk factor for recurvatum deformity, posterior cruciate ligament (PCL) injury, and posterior tibial translation and has been linked to single bundle PCL reconstruction failure. In the setting of ACL insufficiency with a PTS greater than 12°, anterior closing wedge osteotomy has been shown to be protective for ACL reconstructions. Alternatively, some surgeons have advocated for the addition of lateral extraarticular stabilization procedures in the setting of increased PTS. Further, in the setting of PCL insufficiency with an anteriorly directed, or flat, PTS, anterior opening wedge osteotomy has shown encouraging results. In addition, double bundle PCL reconstructions should be strongly considered in the setting of anteriorly directed, or flat, tibial slope.

Posterior Tibial Slope Measurements Using the Anatomic Axis Are Significantly Increased Compared With Those That Use the Mechanical Axis.

PURPOSE: To compare posterior tibial slope (PTS) measurements from standard lateral knee radiographs with measurements from full-length lateral tibia radiographs. METHODS: We performed a multicenter, prospective study. Lateral knee and full-length lateral tibia radiographs were obtained for each patient, and PTS was measured. Slope measurements were obtained by measuring the angle between an average of the medial and lateral tibial plateaus and a representative tibial diaphysis line. The proximal anatomic axis was measured on lateral knee radiographs, and both the mechanical axis and anatomic axis were measured on full-length lateral tibia radiographs. The mechanical axis was defined as the center of the plateau to the center of the plafond, and the anatomic axis was defined as the center of the tibial diaphysis. The minimal clinically significant difference was defined a priori as 2° of PTS or greater. RESULTS: A total of 140 patients met the inclusion criteria. The average PTS using the proximal anatomic axis was 11.6° ± 3.2° on lateral knee radiographs; the PTS measured on full-length lateral tibia radiographs was 9.5° ± 3.4° using the mechanical axis and 11.8° ± 3.1° using the anatomic axis. There was a significant difference between the measurements with the mechanical axis and both anatomic axis measurements (P < .01) but no significant difference between the 2 anatomic axis measurement techniques (P = .574). In total, 55% of patients (n = 77) had a 2° or greater difference between the proximal anatomic axis and mechanical axis PTS measurement techniques. CONCLUSIONS: There was no significant difference between PTS measurements that used the proximal anatomic axis from lateral knee radiographs and those that used the anatomic axis from full-length lateral tibia radiographs. Thus, lateral knee radiographs are adequate to accurately obtain tibial slope measurements. However, there was a significant difference between PTS measurements that used the anatomic axis and those that used the mechanical axis of the tibia. CLINICAL RELEVANCE: It is recommended that future studies report tibial slope based upon measurements that utilize the anatomic axis in order to ensure that subsequent conclusions are comparable, independent of the radiographic view.

A Systematic Review Shows High Variation in Terminology, Surgical Techniques, Preoperative Diagnostic Measures, and Geographic Differences in the Treatment of Athletic Pubalgia/Sports Hernia/Core Muscle Injury/Inguinal Disruption.

PURPOSE: To perform a systematic review of reported terminologies, surgical techniques, preoperative diagnostic measures, and geographic differences in the treatment of core muscle injury (CMI)/athletic pubalgia/inguinal disruption. METHODS: A systematic review was performed by searching PubMed, the Cochrane Library, and Embase to identify clinical studies or articles that described a surgical technique to treat CMI refractory to nonoperative treatment. The search phrase used was "core muscle injury" OR "sports hernia" OR "athletic pubalgia" OR "inguinal disruption." The diagnostic terminology, country of publication, preoperative diagnostic measures, surgical technique, and subspecialty of the operating surgeons described in each article were extracted and reported. RESULTS: Thirty-one studies met the inclusion and exclusion criteria, including 3 surgical technique articles and 28 clinical articles (2 Level I evidence, 1 Level II, 4 Level III, and 21 Level IV). A total of 1,571 patients were included. The most common terminology used to describe the diagnosis was "athletic pubalgia," followed by "sports hernia." Plain radiographs and magnetic resonance imaging of the pelvis were the most common imaging modalities used in the preoperative evaluation of CMI/athletic pubalgia/inguinal disruption. Tenderness-to-palpation testing was the most common technique performed during physical examination, although the specific locations assessed with this technique varied substantially. The operating surgeons were general surgeons (16 articles), a combination of orthopaedic and general surgeons (7 articles), or orthopaedic surgeons (5 articles). The most common procedures performed were open or laparoscopic mesh repair, adductor tenotomy, primary tissue (hernia) repair, and rectus abdominis repair. The procedures performed differed on the basis of surgeon subspecialty, geographic location, and year of publication. CONCLUSIONS: A variety of diagnostic methods and surgical procedures have been used in the treatment of a CMI/athletic pubalgia/sports hernia/inguinal disruption. These procedures are performed by orthopaedic and/or general surgeons, with the procedures performed differing on the basis of surgeon subspecialty and geographic location. LEVEL OF EVIDENCE: Level V, systematic review of Level I to V studies.

Is Arthroscopic Hip Labral Repair/Reconstruction Surgery Effective for Treating Femoroacetabular Impingement in the Presence of Osteoarthritis?

OBJECTIVE: To investigate clinical outcomes after arthroscopic labral preservation surgery for femoroacetabular impingement (FAI) in the presence of osteoarthritis (OA) compared with FAI without significant OA. DESIGN: Retrospective case-control study. SETTING: Department of Orthopaedic Surgery and Sports Medicine, Hospital of Academic Institute. PATIENTS: Femoroacetabular impingement patients (n = 97; ≥35 years) undergoing arthroscopic FAI correction with labral preservation surgery from March 2009 to April 2014 were enrolled in this study. INTERVENTIONS: Patients were divided into 2 groups: FAI group (79 patients), with Tonnis grade 0 or 1, and FAI + OA group (18 patients), with Tonnis grade 2 or 3. MAIN OUTCOME MEASURES: We examined the clinical outcomes using the Modified Harris Hip Score (MHHS), Nonarthritic Hip Score (NAHS), and the conversion rate to total hip arthroplasty (THA). RESULTS: No significant differences existed between the 2 groups with respect to age, sex, follow-up period, or preoperative MHHS or NAHS. The mean MHHS and NAHS at the final follow-up were significantly lower in the FAI + OA group than in the FAI group. There was a significant difference in the rate of conversion to THA and failure between the 2 groups (THA 5% vs 50%) (failure 15% vs 67%). CONCLUSION: Patients with FAI in the presence of OA did not improve after arthroscopic labral preservation surgery and had a high conversion rate to THA. LEVEL OF EVIDENCE: Level III.

Understanding the key processes of excellence as a prerequisite to establishing academic centres of excellence in Africa.

BACKGROUND: Africa's economic transformation relies on a radical transformation of its higher education institutions. The establishment of regional higher education Centres of Excellence (CoE) across Africa through a World Bank support aims to stimulate the needed transformation in education and research. However, excellence is a vague, and often indiscriminately used concept in academic circles. More importantly, the manner in which aspiring institutions can achieve academic excellence is described inadequately. The main objective of this paper is to describe the core processes of excellence as a prerequisite to establishing academic CoE in Africa. METHODS: The paper relies on our collaborative discussions and real-world insight into the pursuit of academic excellence, a narrative review using Pubmed search for a contextual understanding of CoEs in Africa supplemented by a Google search for definitions of CoEs in academic contexts. RESULTS: We identified three key, synergistic processes of excellence central to institutionalizing academic CoEs: participatory leadership, knowledge management, and inter-disciplinary collaboration. (1) Participatory leadership encourages innovations to originate from the different parts of the organization, and facilitates ownership as well as a culture of excellence. (2) Centers of Excellence are future-oriented in that they are constantly seeking to achieve best practices, informed by the most up-to-date and cutting-edge research and information available. As such, the process by which centres facilitate the flow of knowledge within and outside the organization, or knowledge management, is critical to their success. (3) Such centres also rely on expertise from different disciplines and 'engaged' scholarship. This multidisciplinarity leads to improved research productivity and enhances the production of problem-solving innovations. CONCLUSION: Participatory leadership, knowledge management, and inter-disciplinary collaborations are prerequisites to establishing academic CoEs in Africa. Future studies need to extend our findings to understand the processes key to productivity, competitiveness, institutionalization, and sustainability of academic CoEs in Africa.

Pandemic-Proofing Your Library: Disaster Response and Lessons Learned from COVID-19.

The COVID-19 pandemic has affected libraries across the globe, including academic health sciences libraries, in many ways. This manuscript describes the challenges, solutions, and practices employed by the Stony Brook University Health Sciences Library in order to maintain continuity of services to patrons including faculty, hospital staff, students, and clinicians while operating in one of the earliest epicenters of the pandemic. Some of the major changes the library underwent in response to the pandemic included implementing new online anatomy resources, contactless circulation, remote interlibrary loan services and modified operating practices.

MetAP2 inhibition increases energy expenditure through direct action on brown adipocytes.

Inhibitors of methionine aminopeptidase 2 (MetAP2) have been shown to reduce body weight in obese mice and humans. The target tissue and cellular mechanism of MetAP2 inhibitors, however, have not been extensively examined. Using compounds with diverse chemical scaffolds, we showed that MetAP2 inhibition decreases body weight and fat mass and increases lean mass in the obese mice but not in the lean mice. Obesity is associated with catecholamine resistance and blunted ß-adrenergic receptor signaling activities, which could dampen lipolysis and energy expenditure resulting in weight gain. In the current study, we examined effect of MetAP2 inhibition on brown adipose tissue and brown adipocytes. Norepinephrine increases energy expenditure in brown adipose tissue by providing fatty acid substrate through lipolysis and by increasing expression of uncoupled protein-1 (UCP1). Metabolomic analysis shows that in response to MetAP2 inhibitor treatment, fatty acid metabolites in brown adipose tissue increase transiently and subsequently decrease to basal or below basal levels, suggesting an effect on fatty acid metabolism in this tissue. Treatment of brown adipocytes with MetAP2 inhibitors enhances norepinephrine-induced lipolysis and energy expenditure, and prolongs the activity of norepinephrine to increase ucp1 gene expression and energy expenditure in norepinephrine-desensitized brown adipocytes. In summary, we showed that the anti-obesity activity of MetAP2 inhibitors can be mediated, at least in part, through direct action on brown adipocytes by enhancing ß-adrenergic-signaling-stimulated activities.

A 512-Channel Multi-Layer Polymer-Based Neural Probe Array.

We present for the first time the design, fabrication, and preliminary bench-top characterization of a high-density, polymer-based penetrating microelectrode array, developed for chronic, large-scale recording in the cortices and hippocampi of behaving rats. We present two architectures for these targeted brain regions, both featuring 512 Pt recording electrodes patterned front-and-back on micromachined eight-shank arrays of thin-film Parylene C. These devices represent an order of magnitude improvement in both number and density of recording electrodes compared with prior work on polymer-based microelectrode arrays. We present enabling advances in polymer micro-machining related to lithographic resolution and a new method for back-side patterning of electrodes. In vitro electrochemical data verifies suitable electrode function and surface properties. Finally, we describe next steps toward the implementation of these arrays in chronic, large-scale recording studies in free-moving animal models.

Editorial Commentary: "The Earth is Not Flat": Progressing From Plain Radiographs to Three-Dimensional Imaging When Evaluating Hip Disorders.

Dysplastic hip morphologies have received increasing attention in the hip preservation community. Defining and characterizing "transitional acetabular coverage" or "borderline" dysplasia has been extraordinarily challenging, and these hips have been lumped together based on focal radiographic measurements such as the lateral center edge and Tonnis angles. Some of these hips are treated with arthroscopy and some with corrective osteotomies without definitive patient-related outcome measure winners in our literature. Three-dimensional imaging evaluation of these hips with regard to acetabular and femoral-sided anatomy will be required to more clearly define any consistent anatomic variants and their respective optimal surgical approaches.