Fear of cancer recurrence and change in hair cortisol concentrations in partners of breast cancer survivors.

PURPOSE: Partners of breast cancer (BC) survivors report high rates of psychological distress including fear of cancer recurrence (FCR). Research suggests that partners may have poorer physical health outcomes than the general population, but little research has examined the physiological biomarkers by which distress may impact partner health outcomes. The current study examined the associations between FCR and changes in hair cortisol among BC partners. METHODS: Male partners (N = 73) of early-stage BC survivors provided hair samples during two visits, one after completion of survivors' adjuvant treatment (T1) and again 6 months later (T2). Two subscales from the Fear of Cancer Recurrence Inventory and one subscale from the Concerns about Recurrence Scale comprised a latent FCR factor at T1. A latent change score model was used to examine change in cortisol as a function of FCR. RESULTS: Partners were on average 59.65 years of age (SD = 10.53) and non-Hispanic White (83%). Latent FCR at T1 was positively associated (b = 0.08, SE = 0.03, p = .004, standardized ß = .45) with change in latent hair cortisol from T1 to T2. CONCLUSIONS: Results indicated that greater FCR was associated with increases in hair cortisol in the months following adjuvant treatment. This is one of the first studies to examine the physiological correlates of FCR that may impact health outcomes in BC partners. IMPLICATIONS FOR CANCER SURVIVORS: Findings highlight the need for further research into the relationship between FCR and its physiological consequences. Interventions to address partner FCR are needed and may aid in improving downstream physical health outcomes.

Some Perceptions Differ, Match Outcomes Do Not: A Multisite Retrospective Cross-Sectional Comparison of Virtual vs. In-Person Recruitment.

BACKGROUND: Virtual interviewing for residency provides considerable savings. Its impact on match outcomes remains unclear. OBJECTIVE: Evaluate the impact of virtual residency recruitment on program and applicant assessment and match outcomes. DESIGN: Cross-sectional survey, September 2020-July 2021 PARTICIPANTS: Faculty interviewers and 2019 and 2020 PGY-1 classes at three academic internal medicine residencies. MAIN MEASURES: Survey items rating effectiveness of interview format, preference for future interview format, and perceived impact on diversity. KEY RESULTS: A total of 247/436 faculty (57%) interviewers responded. Faculty perceived that in-person interviews enhanced applicant assessment (3.23 ± 0.38, p < 0.01) and recruitment of the most qualified applicants (p < 0.01) but did not impact recruitment of a racially or gender diverse class (3.03 ± 0.99, p = 0.95 and 3.09 ± 0.76, p = 0.14 respectively). They also did not demonstrate a preference for future interview formats. A total of 259/364 matched applicants responded, corresponding to a 76% response rate in the in-person cohort and a 66% response rate for virtual. Trainees were equally likely to match at their top choice when interviewing virtually vs. in-person (p = 0.56), and racial/ethnic and gender composition of the incoming class also did not differ (p = 0.81 and p = 0.19 respectively). Trainees perceived many aspects of the institution were better assessed in-person, though the impact varied according to assessment domain. Trainees who interviewed in-person preferred in-person formats. Of those who interviewed virtually, 47% preferred virtual and 54% preferred in-person. There were no predictors of virtual preference for future interview formats. CONCLUSIONS: Faculty and applicants who experienced virtual recruitment had no preference for future recruitment format. Virtual recruitment had no impact on the racial/gender diversity of matched classes or on applicants matching at their top-ranked institution. Institutions should consider the potential non-inferiority of virtual interviews with financial and other benefits when making decisions about future interview formats.

The Epidemiology of Ocular Chlamydia trachomatis Infection within Districts Persistently Endemic for Trachoma in Amhara, Ethiopia.

Persistent trachoma is a growing concern to trachoma control programs globally and programs serving Ethiopia specifically. Persistent trachoma is defined as a district with two or more trachoma impact surveys (TISs) at which the prevalence of trachomatous inflammation-follicular (TF) among children ages 1-9 years is ≥5%, the elimination threshold. Because the global target for trachoma elimination as a public health problem is 2030, research is needed to better characterize persistent trachoma. This study described the epidemiology of ocular Chlamydia trachomatis infection, the causative bacteria of trachoma, in seven contiguous districts experiencing persistent trachoma. In 2019, multistage cluster random sampling TISs were conducted in the seven districts after 10 years of interventions. All individuals ages ≥1 year were examined for trachoma clinical signs by certified graders, and conjunctival swabs were collected from children ages 1-5 years to test for C. trachomatis infection. The district TF prevalence ranged from 11.8% (95% CI:7.6-16.0%) to 36.1% (95% CI:27.4-44.3%). The range of district-level C. trachomatis infection prevalence was between 2.7% and 34.4%. Statistically significant spatial clustering of high-infection communities was observed in the study districts, and children with infection were more likely than those without to be found in households with clinical signs of trachoma and those without latrines. These seven districts appear to constitute a persistent hotspot in Amhara, where an additional 3-5 years or more of interventions will be required. The global program will need to strengthen and enhance intervention strategies within persistent districts if elimination by 2030 is to be achieved.

Cardiac Mechanics and the Risk of Atrial Fibrillation in a Community-Based Cohort of Older Adults.

BACKGROUND: Assessment of cardiac structure and function improves risk prediction of new-onset atrial fibrillation (AF) in different populations. We aimed to comprehensively compare standard and newer measures of cardiac structure and function in improving prediction of AF in a cohort of older adults without history of AF and stroke. METHODS: We included 5050 participants without prevalent AF and stroke (mean age 75 ± 5 years, 59% women and 22% Black) from the Atherosclerosis Risk in Communities (ARIC) study who underwent complete 2-dimensional echocardiography, including speckle-tracking analysis of the left ventricle (LV) and left atrium (LA). We assessed the association of cardiac measures with incident AF (including atrial flutter) and quantified the extent to which these measures improved model discrimination and risk classification of AF compared with the CHARGE-AF score. RESULTS: Over a median follow-up time of 7 years, 676 participants developed AF (incidence rate, 2.13 per 100 person-years). LV mass index and wall thickness, E/e' and measures of LA structure and function, but not LV systolic function, were associated with incident AF, after accounting for confounders. Above all, LA reservoir strain, contraction strain, and LA minimal volume index (C-statistics [95%Confidence interval]: 0.73 [0.70,0.75], 0.72 [0.70,0.75] and 0.72 [0.69,0.75], respectively) significantly improved the risk discrimination of the CHARGE-AF score (baseline C-statistic: 0.68 [0.65,0.70]) and achieved the highest category-based net reclassification improvement (29%, 24% and 20%, respectively). CONCLUSIONS: In a large cohort of older adults without prevalent AF and stroke, measures of LA function improved the prediction of AF more than other conventional cardiac measures.

Industry perspective on regulatory authority (RA) quality reviews of biosimilar applications - an evaluation of RA guidance and expectations for chemical, manufacturing, and controls information through in-depth query analysis.

PURPOSE: Evaluate the type and quantity of quality information (i.e. Chemistry, Manufacturing, and Control) requested by the US FDA and EMA in queries pertaining to biosimilar applications. METHODS: Numbers/types of queries received following regulatory submissions (FDA/EMA, n = 7/n = 5) for seven biosimilars (PF-filgrastim [Nivestym], PF-rituximab [Ruxience®], PF-trastuzumab [Trazimera®], PF-bevacizumab [Zirabev®], PF-pegfilgrastim [Nyvepria®], PF-adalimumab [Abrilada™/Amsparity®], PF-infliximab [Ixifi]) from a single product portfolio were analyzed considering published regulatory authority (RA) guidance and in relation to sections/subsections of Module 3: Quality from the Common Technical Document regulatory dossier and topics based on keyword assignment. RESULTS: Queries were most frequently assigned (FDA/EMA %, range) to Drug Substance Manufacture (subsection 3.2.S.2; 21-35%/13-50%), Control of Drug Substance (3.2.S.4; 3-11%/5-17%), Drug Product Pharmaceutical Development (3.2.P.2; 1-12%/1-15%) and Manufacture (3.2.P.3; 17-41%/2-13%), and Analytical Similarity (3.2.R; 4-21%/4-20%). The proportion of Drug Substance and Drug Product queries was significantly different between RAs (n1 = 952, n2 = 468, p-value <0.001; two-sample proportion z-test). Topic assignments included: Control (12-27%/12-28%), Manufacturing (56-72%/34-66%), Stability (1-12%/2-24%), Biosimilarity (5-16%/5-25%), and Container Closure (0-3%/0-9%). CONCLUSION: The focus of both RAs on topics related to manufacturing and controls is valuable in understanding expectations for scientific and technical content related to gaining biosimilar approval.

Selected phytocannabinoids inhibit SN-38- and cytokine-evoked increases in epithelial permeability and improve intestinal barrier function in vitro.

Irinotecan use is linked to the development of gastrointestinal toxicity and inflammation, or gastrointestinal mucositis. Selected phytocannabinoids have been ascribed anti-inflammatory effects in models of gastrointestinal inflammation, associated with maintaining epithelial barrier function. We characterised the mucoprotective capacity of the phytocannabinoids: cannabidiol, cannabigerol, cannabichromene and cannabidivarin in a cell-based model of intestinal epithelial stress occurring in mucositis. Transepithelial electrical resistance (TEER) was measured to determine changes in epithelial permeability in the presence of SN-38 (5 µM) or the pro-inflammatory cytokines TNFα and IL-1ß (each at 100 ng/mL), alone or with concomitant treatment with each of the phytocannabinoids (1 µM). The DCFDA assay was used to determine the ROS-scavenging ability of each phytocannabinoid following treatment with the lipid peroxidant tbhp (200 µM). Each phytocannabinoid provided significant protection against cytokine-evoked increases in epithelial permeability. Cannabidiol, cannabidivarin and cannabigerol were also able to significantly inhibit SN-38-evoked increases in permeability. None of the tested phytocannabinoids inhibited tbhp-induced ROS generation. These results highlight a novel role for cannabidiol, cannabidivarin and cannabigerol as inhibitors of SN-38-evoked increases in epithelial permeability and support the rationale for the further development of novel phytocannabinoids as supportive therapeutics in the management of irinotecan-associated mucositis.

Standard Orbitozygomatic Craniotomy versus Mini Orbitozygomatic Craniotomy via an Eyebrow Incision for Microsurgical Treatment of Anterior Communicating Artery Aneurysms.

Background Skull base approaches are utilized to improve microsurgical treatment of cerebral aneurysms. Advantages include early proximal and distal control, increased visualization, and minimal brain retraction. Orbitozygomatic (OZ) craniotomies via pterional incision are commonly used for the treatment of anterior communicating artery (ACoA) aneurysms. A smaller, less invasive OZ craniotomy performed through an eyebrow incision may provide several advantages over a standard OZ approach. Objective We compare surgical outcomes of the standard and eyebrow OZ for the treatment of ACoA aneurysms. Design All patients who underwent microsurgical treatment for ACoA aneurysms by a single surgeon over an 8-year period were included in this retrospective analysis. Patient demographics and clinical data were collected. Participants Thirty-seven consecutive patients were identified, with 15 receiving eyebrow OZ and 22 receiving standard OZ. Main Outcome Measures Data were collected on patient demographics, pathology, intraoperative and perioperative data, and 30-day morbidity. Results A total of 100% of the eyebrow OZ group and 95.5% of the standard OZ group had complete aneurysmal occlusion. Four eyebrow OZ and six standard OZ patients had an intraoperative rupture. All were managed without complication. Two eyebrow OZ and one standard OZ patient died within 30 days of surgery. No patients in either group had aneurysm recurrence, required retreatment, or were limited intraoperatively by exposure. Conclusions The OZ approach via an eyebrow incision has similar outcomes to a standard OZ approach and is a safe option for the treatment of ACoA aneurysms.

Multimodality assessment of the coronary microvasculature with TIMI frame count versus perfusion PET highlights coronary changes characteristic of coronary microvascular disease.

Background: The diagnosis of coronary microvascular disease (CMVD) remains challenging. Perfusion PET-derived myocardial blood flow (MBF) reserve (MBFR) can quantify CMVD but is not widely available. Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC) is an angiography-based method that has been proposed as a measure of CMVD. Here, we compare TFC and PET-derived MBF measurements to establish the role of TFC in assessing for CMVD. We use coronary modeling to elucidate the relationship between MBFR and TFC and propose TFC thresholds for identifying CMVD. Methods: In a cohort of 123 individuals (age 58 ± 12.1, 63% women, 41% Caucasian) without obstructive coronary artery disease who had undergone perfusion PET and coronary angiography for clinical indications, we compared TFC and perfusion PET parameters using Pearson correlation (PCC) and linear regression modeling. We used mathematical modeling of the coronary circulation to understand the relationship between these parameters and performed Receiver Operating Curve (ROC) analysis. Results: We found a significant negative correlation between TFC and MBFR. Sex, race and ethnicity, and nitroglycerin administration impact this relationship. Coronary modeling showed an uncoupling between TFC and flow in epicardial vessels. In ROC analysis, TFC performed well in women (AUC 0.84-0.89) and a moderately in men (AUC 0.68-0.78). Conclusions: We established an inverse relationship between TFC and PET-derived MBFR, which is affected by patient selection and procedural factors. TFC represents a measure of the volume of the epicardial coronary compartment, which is increased in patients with CMVD, and performs well in identifying women with CMVD.

High-dimensional mapping of human CEACAM1 expression on immune cells and association with melanoma drug resistance.

BACKGROUND: Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. METHODS: An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. RESULTS: CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. CONCLUSIONS: To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.

Some proteins, such as programmed cell death protein 1 (PD1), can stop the immune system from attacking cancer cells, allowing cancers to grow. Therapies targeting these proteins can be highly effective, but tumors can become resistant. It is important to identify factors involved in this resistance to develop improved cancer therapies. Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is a protein that inhibits an immune response and its levels have been associated with poor patient outcomes. We applied a method that allows for the detection of proteins on a single cell to uncover CEACAM1 patterns in melanoma. We found that increased CEACAM1 expression levels on multiple different immune cell types was associated with tumors that were resistant to therapy. These findings may help us to understand the role of CEACAM1 in cancer and to develop better cancer therapies.

Estimating the potential value of MSM-focused evidence-based implementation interventions in three Ending the HIV Epidemic jurisdictions in the United States: a model-based analysis.

INTRODUCTION: Improving the delivery of existing evidence-based interventions to prevent and diagnose HIV is key to Ending the HIV Epidemic in the United States. Structural barriers in the access and delivery of related health services require municipal or state-level policy changes; however, suboptimal implementation can be addressed directly through interventions designed to improve the reach, effectiveness, adoption or maintenance of available interventions. Our objective was to estimate the cost-effectiveness and potential epidemiological impact of six real-world implementation interventions designed to address these barriers and increase the scale of delivery of interventions for HIV testing and pre-exposure prophylaxis (PrEP) in three US metropolitan areas. METHODS: We used a dynamic HIV transmission model calibrated to replicate HIV microepidemics in Atlanta, Los Angeles (LA) and Miami. We identified six implementation interventions designed to improve HIV testing uptake ("Academic detailing for HIV testing," "CyBER/testing," "All About Me") and PrEP uptake/persistence ("Project SLIP," "PrEPmate," "PrEP patient navigation"). Our comparator scenario reflected a scale-up of interventions with no additional efforts to mitigate implementation and structural barriers. We accounted for potential heterogeneity in population-level effectiveness across jurisdictions. We sustained implementation interventions over a 10-year period and evaluated HIV acquisitions averted, costs, quality-adjusted life years and incremental cost-effectiveness ratios over a 20-year time horizon (2023-2042). RESULTS: Across jurisdictions, implementation interventions to improve the scale of HIV testing were most cost-effective in Atlanta and LA (CyBER/testing cost-saving and All About Me cost-effective), while interventions for PrEP were most cost-effective in Miami (two of three were cost-saving). We estimated that the most impactful HIV testing intervention, CyBER/testing, was projected to avert 111 (95% credible interval: 110-111), 230 (228-233) and 101 (101-103) acquisitions over 20 years in Atlanta, LA and Miami, respectively. The most impactful implementation intervention to improve PrEP engagement, PrEPmate, averted an estimated 936 (929-943), 860 (853-867) and 2152 (2127-2178) acquisitions over 20 years, in Atlanta, LA and Miami, respectively. CONCLUSIONS: Our results highlight the potential impact of interventions to enhance the implementation of existing evidence-based interventions for the prevention and diagnosis of HIV.

Molecular insights into Sertoli cell function: how do metabolic disorders in childhood and adolescence affect spermatogonial fate?

Male infertility is a major public health concern globally with unknown etiology in approximately half of cases. The decline in total sperm count over the past four decades and the parallel increase in childhood obesity may suggest an association between these two conditions. Here, we review the molecular mechanisms through which obesity during childhood and adolescence may impair future testicular function. Several mechanisms occurring in obesity can interfere with the delicate metabolic processes taking place at the testicular level during childhood and adolescence, providing the molecular substrate to hypothesize a causal relationship between childhood obesity and the risk of low sperm counts in adulthood.

Association of Left Atrial Function With Incident Chronic Kidney Disease in Older Adults.

Objective: To examine the association of left atrial (LA) function with incident chronic kidney disease (CKD) and assess the clinical utility of adding LA function to a CKD risk prediction equation. Patients and Methods: We included 4002 Atherosclerosis Risk in Communities study participants without prevalent CKD (mean ± SD age, 75±5 years; 58% female, 18% Black). Left atrial function (reservoir, conduit, and contractile strain) was evaluated by 2D-echocardiograms on 2011 to 2013. Chronic kidney disease was defined as greater than 25% decline in estimated glomerular filtration rate of less than 60 mL/min/1.73 m2, end-stage kidney disease, or hospital records. Cox proportional hazards models were used. Risk prediction and decision curve analyses evaluated 5-year CKD risk by diabetes status. Results: Median follow-up was 7.2 years, and 598 participants developed incident CKD. Incidence rate for CKD was 2.29 per 100 person-years. After multivariable adjustments, the lowest quintile of LA reservoir, conduit, and contractile strain (vs highest quintile) had a higher risk of CKD (hazard ratios [95% CIs]: 1.94 [1.42-2.64], 1.62 [1.19-2.20], and 1.49 [1.12-1.99]). Adding LA reservoir strain to the CKD risk prediction equation variables increased the C-index by 0.026 (95% CI: 0.005-0.051) and 0.031 (95% CI: 0.006-0.058) in participants without and with diabetes, respectively. Decision curve analysis found the model with LA reservoir strain had a higher net benefit than the model with CKD risk prediction equation variables alone. Conclusion: Lower LA function is independently associated with incident CKD. Adding LA function to the CKD risk prediction enhances prediction and yields a higher clinical net benefit. These findings suggest that impaired LA function may be a novel risk factor for CKD.

Eighteen-Year Follow-up After Autologous Chondrocyte Implantation on Medial and Lateral Femoral Condyles: A Case Report.

Articular cartilage defects are common injuries of the knee. The defects often progress in size and produce significant clinical symptoms due to the lack of intrinsic repair or regenerative capacity of articular cartilage. With the failure of nonoperative treatment options, surgical treatment is indicated and includes palliative, reparative, and regenerative options. For large defects of the femoral condyles, trochlea, or patella, autologous chondrocyte implantation can provide successful and long-lasting results. Presented is the case of a 37-year-old male with an 18-year follow-up to autologous chondrocyte implantation for extensive left knee articular cartilage defects of the medial and lateral femoral condyles. Recovery from articular cartilage defects is shown through both clinical improvement of the patient and arthroscopic photographs of robust autologous articular cartilage on the medial femoral condyle. This case supports the long-term benefits of autologous chondrocyte implantation as a surgical intervention for large, full-thickness articular cartilage defects of the knee.

Using group level factor models to resolve high dimensionality in model-based sampling.

Joint modeling of decisions and neural activation poses the potential to provide significant advances in linking brain and behavior. However, methods of joint modeling have been limited by difficulties in estimation, often due to high dimensionality and simultaneous estimation challenges. In the current article, we propose a method of model estimation that draws on state-of-the-art Bayesian hierarchical modeling techniques and uses factor analysis as a means of dimensionality reduction and inference at the group level. This hierarchical factor approach can adopt any model for the individual and distill the relationships of its parameters across individuals through a factor structure. We demonstrate the significant dimensionality reduction gained by factor analysis and good parameter recovery, and illustrate a variety of factor loading constraints that can be used for different purposes and research questions, as well as three applications of the method to previously analyzed data. We conclude that this method provides a flexible and usable approach with interpretable outcomes that are primarily data-driven, in contrast to the largely hypothesis-driven methods often used in joint modeling. Although we focus on joint modeling methods, this model-based estimation approach could be used for any high dimensional modeling problem. We provide open-source code and accompanying tutorial documentation to make the method accessible to any researchers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy.

BACKGROUND: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. METHODS AND RESULTS: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (ß-2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein-outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity cardiac troponin. CONCLUSIONS: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON-HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

Technical Note on the Role of Kambin's Triangle in the Evolution of Total Joint Replacement of the Lumbar Spine.

We provide a historical and technical perspective on the evolution of Kambin's triangle as a safe working corridor for percutaneous access to the intervertebral disc to an anatomically expanded space to accommodate and facilitate open lumbar total joint replacement. The nearly 6-decade progression from intradiscal access in the intact lumbar spine to an enlarged working space following facetectomy to accommodate a transforaminal lumbar interbody fusion, and eventual further expansion via pedicle vertebral body osteotomy to support motion preservation with total joint replacement, represents a unique evolutionary pathway in surgical technique development. For each of these steps in evolution, we detail and provide the historical context of the corresponding surgical modifications required to expand the original anatomical boundaries of Kambin's triangle. It is postulated that the introduction of machine learning technologies coupled with innovations in robotics, materials science, and advanced imaging will further accelerate and refine the adaptation of more complex, precise, and efficacious surgical procedures to treat spinal degeneration via this working corridor.

Developing a PmSLP3-based vaccine formulation that provides robust long-lasting protection against hemorrhagic septicemia-causing serogroup B and E strains of Pasteurella multocida in cattle.

Background: Pasteurella multocida is a bacterial pathogen that causes a variety of infections across diverse animal species, with one of the most devastating associated diseases being hemorrhagic septicemia. Outbreaks of hemorrhagic septicemia in cattle and buffaloes are marked by rapid progression and high mortality. These infections have particularly harmful socio-economic impacts on small holder farmers in Africa and Asia who are heavily reliant on a small number of animals kept as a means of subsistence for milk and draft power purposes. A novel vaccine target, PmSLP-3, has been identified on the surface of hemorrhagic septicemia-associated strains of P. multocida and was previously shown to elicit robust protection in cattle against lethal challenge with a serogroup B strain. Methods: Here, we further investigate the protective efficacy of this surface lipoprotein, including evaluating the immunogenicity and protection upon formulation with a variety of adjuvants in both mice and cattle. Results: PmSLP-3 formulated with Montanide ISA 61 elicited the highest level of serum and mucosal IgG, elicited long-lasting serum antibodies, and was fully protective against serogroup B challenge. Studies were then performed to identify the minimum number of doses required and the needed protein quantity to maintain protection. Duration studies were performed in cattle, demonstrating sustained serum IgG titres for 3 years after two doses of vaccine and full protection against lethal serogroup B challenge at 7 months after a single vaccine dose. Finally, a serogroup E challenge study was performed, demonstrating that PmSLP-3 vaccine can provide protection against challenge by the two serogroups responsible for hemorrhagic septicemia. Conclusion: Together, these data indicate that PmSLP-3 formulated with Montanide ISA 61 is an immunogenic and protective vaccine against hemorrhagic septicemia-causing P. multocida strains in cattle.