Coronary Artery Origins Pattern in Pediatric Patients with Right-Left Fusion Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV) is a common congenital heart defect associated with coronary artery (CA) variants, including higher incidence of left CA dominance and shorter left main CA length. We observed by transthoracic echocardiography that left and right CA origins appear closer together in pediatric patients with right-left fusion (R/L) BAV compared to patients with trileaflet aortic valves. We sought to objectively confirm this observation. A retrospective review of pediatric echocardiograms with R/L BAV at a single institution (12/2010-11/2018) was performed. The 'coronary angle' was defined as the angle between the left and right coronary artery origins in the parasternal short axis view relative to the center of the aortic valve orifice. Values were compared to age-matched controls. Patients with inadequate images, anomalous coronary origins, or predefined significant congenital heart defects were excluded. We compared 191 R/L BAV patients (64% male) to 136 controls (57% male). Coronary angle was significantly more acute in R/L BAV than in controls (117.9° ± 16.7° vs 139.0° ± 10.1°, p < 0.0001). This was independent of age and gender. The difference persisted when BAV patients with abnormal aortic annulus/root diameters were removed from analysis (119.5° ± 15.1° vs 139.0° ± 10.1°, p < 0.0001). CA origins are closer together in R/L BAV independent of age, gender, or annulus/root size. This new anatomical description may aid in the diagnosis of subtle ('forme fruste') R/L BAV, assist in interventional planning, and improve understanding of the relationship between BAV and CA development.

Transforming Growth Factor ß Superfamily Signaling in Development of Colorectal Cancer.

Transforming growth factor (TGF)-ß cytokines signal via a complex network of pathways to regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. A high percentage of colorectal tumors contain mutations that disrupt TGF-ß family member signaling. We review how TGF-ß family member signaling is altered during development of colorectal cancer, models of study, interaction of pathways, and potential therapeutic strategies.

A Pathophysiological Approach for Selecting Medications to Treat Nociceptive and Neuropathic Pain in Servicemembers.

INTRODUCTION: The prevalence of chronic pain of service members (SMs) in the U.S. is estimated to be higher (roughly 31-44%) compared to that of civilian population (26%). This higher prevalence is likely due to the high physical demands related combat and training injuries that are not immediately resolved and worsen over time. Mental Health America reports that chronic pain can lead to other mental health conditions such as severe anxiety, depression, bipolar disorder, and post-traumatic stress disorder. Such mental health conditions can negatively affect job performance, reduce readiness for military duties, and often lead to patterns of misuse of opioid after SMs entering civilian life. The primary objective of this narrative review is to present a summarized guideline for the treatment of two types of pain that likely affect SMs, namely nociceptive somatic pain and neuropathic pain. This review focused on a stepwise approach starting with nonopioid interventions prior to opioid therapy. The secondary objective of this review is to elucidate the primary mechanisms of action and pathways associated with these two types of pain. METHODS: We followed the Scale for Assessment of Narrative Review Articles when transcribing this narrative review article to enhance the quality and brevity of this review. This Scale has 0.77% an intra-class coefficient of correlation, 95% confidence interval and 0.88 inter-rater reliability. We searched PubMed, Google Scholar, WorldCAT, and the Cochrane Library for the primary and secondary articles that targeted mechanisms of action, pathways, and pharmacological modalities for nociceptive somatic and neuropathic pain that were published from 2011 to 2022. We excluded articles related to pediatric, some specific pain conditions such as cancer-related pain, palliative care, end-of-life care, and articles that were not written in English language. For pharmacologic selection, we adopted the guidelines from the Policy for Implementation of a Comprehensive Policy on Pain Management by the Military Health Care system for the Fiscal Year 2021; the Clinical Practice Guidance for Opioid Therapy for Chronic Pain by the Department of Defense/Veterans Health Administration (2022); the (2021) Implementation of a Comprehensive Policy on Pain Management by the Military Health Care System; and the (2022) Guideline for Prescribing Opioids for Chronic Painby the Centers for Disease Control. DISCUSSION: From the knowledge of the mechanisms of action and pathways, we can be more likely to identify the causative origins of pain. As a result, we can correctly diagnose the type of pain, properly develop an efficient and personalized treatment plan, minimize adverse effects, and optimize clinical outcomes. The guideline, however, does not serve as a substitute for clinical judgment in patient-centered decision-making. Medication choices should be individualized judiciously based on the patient's comorbid conditions, available social and economic resources, and the patient's preferences to balance the benefits and risks associated with various pain medications and to achieve optimal pain relief and improve the patient's quality of life.

Identification and characterization of a first-generation inhibitor of claudin-1 in colon cancer progression and metastasis.

Colorectal cancer (CRC) is a leading cause of the cancer-related deaths worldwide. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is urgent. Several studies, including ours, have reported a causal role for an upregulated claudin-1 expression in promoting CRC metastasis through the activation of the Src and ß-catenin-signaling. In murine models of colon tumorigenesis, claudin-1 overexpression promotes oncogenic properties such as transformation and invasiveness. Conversely, the downregulation of claudin-1 inhibits colon tumorigenesis. Despite being a desirable target for cancer treatment, there are currently no known claudin-1 inhibitors with antitumor efficacy. Using a rigorous analytical design and implementing in- vitro and in-vivo testing and a brief medicinal chemistry campaign, we identified a claudin-1-specific inhibitor and named it I-6. Despite its high potency, I-6 was rapidly cleared in human liver microsomes. We, therefore, synthesized I-6 analogs and discovered a novel small molecule, PDS-0330. We determined that PDS0330 inhibits claudin-1-dependent CRC progression without exhibiting toxicity in in-vitro and in-vivo models of CRC and that it binds directly and specifically to claudin-1 with micromolar affinity. Further analyses revealed that PDS-0330 exhibits antitumor and chemosensitizer activities with favorable pharmacokinetic properties by inhibiting the association with metastatic oncogene Src. Overall, our data propose that PDS-0330 interferes with claudin-1/Src association to inhibit CRC progression and metastasis. Our findings are of direct clinical relevance and may open new therapeutic opportunities in colon cancer treatment and/or management by targeting claudin-1.

Evaluation of a Functional Restoration Program at Fort Bliss Interdisciplinary Pain Management Clinic.

INTRODUCTION: In partnership with the Veterans Health Administration, in 2010, the Department of Defense/Veterans Health Administration Pain Management Task Force Final Report recommended a comprehensive pain management plan. Consequently, each Army medical center established an Interdisciplinary Pain Management Clinic (IPMC) for pain treatment, and each IPMC implements a multidisciplinary outpatient functional restoration program (FRP) as an alternative to or in addition to pharmacological therapy. This article reports our first-year FRP results at William Beaumont Army Medical Center IPMC. MATERIALS AND METHODS: The FRP is designed to improve the participants' functionality and quality of life, both personally and professionally. Service members with chronic pain were evaluated for psychological and physical clearance before enrollment in an intense and structured FRP for 8 hours a day over 3 weeks. The program focused on physical and occupational exercises, yoga, acupuncture, and educational classes regarding pain medications, nutrition, and coping skills. The resulting data were analyzed using paired two-tailed t-tests with a predetermined significance level of 0.05 to examine the participants' mean changes upon completion of the FRP. RESULTS: The pre-post comparison indicated significant improvement after completion of the FRP. The fear-avoidance of physical activities and the fear of movement scores were reduced significantly (P < 0.05); the Canadian occupational performance and satisfaction, physical strength and endurance were improved significantly (P < 0.0001) in sit-to-stand, plank balance, lifting and carrying, and 10-minute 7-to-1 Pyramid tests; however, fear-avoidance of work was not significantly reduced (P = 0.2319). CONCLUSIONS: Because of the lack of randomization and the small number of subjects (N = 32, 7 cohorts), unknown sources of bias may have influenced the results. Despite these limitations, the results from this report support the program's effectiveness and are consistent with the outcomes from FRP programs in other military facilities and in civilian studies.

Current patterns of primary care provider practices for the treatment of post-traumatic headache in active duty military settings.

OBJECTIVE: To provide a preliminary assessment of the current clinical practice for the treatment of post-traumatic headache following concussion in military primary health care settings. BACKGROUND: Headache is one of the most common symptoms post-concussion; however, little is known of the current clinical practices of primary care providers (on the treatment of post-traumatic headache), particularly in military settings. METHODS: Study participants were primary care providers (n = 65) who treated active duty Service members suffering from post-traumatic headache at two military installations. Qualitative data gathered via semi-structured interviews were used to describe provider practices and experience in treating patients with post-traumatic headache. RESULTS: Some patterns of care across primary care providers treating post-traumatic headache were consistent with the Department of Defense-recommended clinical recommendation (e.g., recommendation of both pharmacological and non-pharmacological treatment [89.4%]; engaging in follow-up care [100%]). Differences existed in timing of follow-up from initial visit [16.9% reporting within 24 hours; 21.5% reporting within 48-72 hours; and 26.2% reporting more than 1 week], the factors contributing to the type of care given (e.g., symptomatology [33.0%], injury characteristic [24.2%], patient characteristic [13.2%]) and the need for referral to higher level of care (e.g., symptomatology [44.6%], treatment failure [25.0%]). These variations may be indicative of individualized treatment which would be compliant with best clinical practice. CONCLUSION: The results of this study demonstrate the current clinical practice in military primary care settings for the treatment of post-traumatic headache which can potentially inform and improve implementation of provider training and education.

Provider Training in the Management of Headache Following Concussion Clinical Recommendation: Promoting a Standardized Means for Efficient Patient Recovery and Timely Return to Duty.

Background: Headache is a common symptom reported following concussion/mild traumatic brain injury. The Department of Defense's clinical recommendation (CR) describes guidance for primary care providers for the management of post-traumatic headache (PTH) in Service members. Objective: The objective of this study is to examine the association between training on the CR with provider clinical practice, patient behaviors, and symptom recovery. Methods: Participants were healthcare providers and two patient groups (one receiving care as usual [CAU] and another receiving care after provider training on PTH CR [CR+]). Providers were interviewed at three time points: (1) prior to CAU enrollment; (2) after CAU enrollment, but prior to training; and (3) after CR+ follow-up. Data from the second and third provider interview were used to evaluate a potential difference between provider practices pre- and post-training (n = 13). Patients were enrolled within 6 months of concussion. Patient outcomes (including neurobehavioral and headache symptoms) were assessed at three time-points: within 72 h (n = 35), at 1-week (n = 34) and at 1-month post-enrollment (n = 27). Results: Most follow-up care reported by providers were recommended within 72 h of initial visit post-training vs. >1 week pre-training. Additionally, providers reported a greater number of visits based on patient symptoms after training than before. Post-training, most providers reported referring patients to higher level of care "as needed," if not "very rarely," compared to 25% reported referrals prior to training. At 1-week post-enrollment the CR+ patient group reported more frequent medical provider visits compared to the CAU group. This trend was reversed at the 1-month follow-up whereby more CAU reported seeing a medical provider compared to CR+. By 1-week post-enrollment, fewer patients in the CR+ group reported being referred to any other providers or specialists compared to the CAU group. No differences in patient outcomes by provider training was found. Conclusion: The study results demonstrate the feasibility of training on the Management of Headache Following Concussion CR in order to change provider practices by promoting timely care, and promoting patient compliance as shown through improvement in follow-up visits and more monitoring within the primary care clinic.

Deep Learning Convolutional Neural Networks for the Estimation of Liver Fibrosis Severity from Ultrasound Texture.

Diagnosis and staging of liver fibrosis is a vital prognostic marker in chronic liver diseases. Due to the inaccuracies and risk of complications associated with liver core needle biopsy, the current standard for diagnosis, other less invasive methods are sought for diagnosis. One such method that has been shown to correlate well with liver fibrosis is shear wave velocity measured by ultrasound (US) shear wave elastography; however, this technique requires specific software, hardware, and training. A current perspective in the radiology community is that the texture pattern from an US image may be predictive of the stage of liver fibrosis. We propose the use of convolutional neural networks (CNNs), a framework shown to be well suited for real world image interpretation, to test whether the texture pattern in gray scale elastography images (B-mode US with fixed, subject-agnostic acquisition settings) is predictive of the shear wave velocity (SWV). In this study, gray scale elastography images from over 300 patients including 3,500 images with corresponding SWV measurements were preprocessed and used as input to 100 different CNN architectures that were trained to regress shear wave velocity. In this study, even the best performing CNN explained only negligible variation in the shear wave velocity measures. These extensive test results suggest that the gray scale elastography image texture provides little predictive information about shear wave velocity and liver fibrosis.

Final results of the Department of Defense multicenter breast lymphatic mapping trial.

BACKGROUND: Lymphatic mapping and sentinel lymph node (SLN) biopsy have the potential to become the standard of care for nodal staging in breast cancer patients, but their widespread utility outside of university-based centers has not been determined. This study describes the final results from a national multi-institutional trial designed to determine the role of preoperative lymphoscintigraphy in breast lymphatic mapping, the rate of success for finding an SLN, and the rate of skip metastasis for patients with invasive breast cancer across all practice scenarios. METHODS: Lymphatic mapping techniques involving the combined use of blue dye and radiocolloid were taught to participating surgeons through a formal 2-day training course at the Moffitt Cancer Center. In protocol 1, surgeons performed their first 20 to 25 cases of breast mapping with SLN biopsy followed by complete axillary lymph node dissection. In protocol 2, after the learning phase, surgeons did not perform axillary lymph node dissection unless a SLN was positive for metastatic disease. RESULTS: Forty-two institutions, including 12 university-based research centers, participated in the trial. From July 1, 1997, through January 31, 1999, a total of 965 patients were accrued. Lymphoscintigraphy identified drainage to an axillary SLN 64% of the time, but by using sensitive handheld gamma probes at the time of the operation, an axillary SLN could be identified 86% of the time. The rate of success for finding an axillary SLN was 92.8% for cases performed at the Moffitt Cancer Center. For other university centers, the rate of success of identifying an axillary SLN was 91.4%, and for other community/regional hospitals in the study, it was 85.2%. For cases in which protocol 1 was followed, the rate of false-negative SLN biopsy was 4%. There was no axillary nodal recurrence after a negative SLN in protocol 2 when a negative SLN biopsy was followed by observation. The median follow-up for the patients on protocol 2 was 16 months. CONCLUSIONS: These data show a high rate of success for finding an axillary SLN and a low rate of skip metastasis in a national multicenter study of lymphatic mapping for breast cancer. This study suggests that SLN biopsy for breast cancer can be performed successfully in community/regional hospitals, as well as in major university-based centers.