Incidental detection of multiple endocrine neoplasia and medullary thyroid carcinoma before starting GLP-1 agonist: A case report.

A man, in his 30s, with a history of obesity and hypothyroidism planned to begin taking a new Glucagon-like peptide-1 (GLP-1) agonist for weight loss. As these medications have been associated with C-cell hyperplasia, a calcitonin level was checked as evaluation prior to starting the drug. This returned at 131 pg/mL (upper limit of normal<10 pg/mL), and a subsequent carcinoembryonic antigen was 5.2 ng/mL (ref<3 ng/mL). Thyroid ultrasound was performed and demonstrated bilateral subcentimeter nodules. After total thyroidectomy, final pathology demonstrated bilateral 0.8 cm medullary thyroid carcinoma. Genetic testing revealed a NM_020975.6: c.1826G > A; p.Cys609Tyr. germline RET mutation, confirming the diagnosis of multiple endocrine neoplasia 2 syndrome. The patient recovered well from treatment. His first-degree relatives also underwent genetic testing. This case represents a surprising diagnosis of familial multiple endocrine neoplasia 2A prior to starting a Glucagon-like peptide-1 agonist.

Health System Integration and Cancer Center Access for Rural Hospitals.

BACKGROUND: Cancer centers provide superior care but are less accessible to rural populations. Health systems that integrate a cancer center may provide broader access to quality surgical care, but penetration to rural hospitals is unknown. METHODS: Cancer center data were linked to health system data to describe health systems based on whether they included at least one accredited cancer center. Health systems with and without cancer centers were compared based on rural hospital presence. Bivariate tests and multivariable logistic regression were used with results reported as P-values and odds ratios (OR) with 95% confidence intervals (CIs). RESULTS: Ninety percent of cancer centers are in a health system, and 72% of health systems (434/607) have a cancer center. Larger health systems (P = .03) with more trainees (P = .03) more often have cancer centers but are no more likely to include rural hospitals (11% vs 6%, P = .43; adjusted OR .69, 95% CI .28-1.70). The minority of cancer centers not in health systems (N = 95) more often serve low complexity patient populations (P = .02) in non-metropolitan areas (P = .03). DISCUSSION: Health systems with rural hospitals are no more likely to have a cancer center. Ongoing health system integration will not necessarily expand rural patients' access to surgical care under existing health policy infrastructure and incentives.

Unique Usages of Dehydrated Human Amnion Chorion Membrane Allografts in Dermatology.

Dehydrated human amnion chorion membrane (dHACM) allografts are synthetic skin substitutes derived from placental tissue. dHACM allografts are used for replacing lost or damaged dermal tissue, as they contain many of the components found within the extracellular matrix that are beneficial in wound healing. Common uses of dHACM allografts include the healing of diabetic and non-diabetic foot and leg ulcers, decubitus ulcers, and wounds following debridement. While these grafts have been proven to be beneficial in other disciplines of medicine, their potential for use in the field of dermatology is emerging. Current clinical cases and research have shown dHACM allografts to be beneficial in repairing damaged tissue due to dermatologic conditions. They could play a role in the treatment of conditions causing chronic wounds, including dermal scarring or loss, and the repair of fragile skin. Examples of dHACM allograft use in dermatology include cases of pyoderma gangrenosum, Netherton syndrome, and wound healing with Mohs micrographic surgery. This literature review explores the efficacy of using dHACM allografts for the treatment of healing wounds within the field of dermatology. J Drugs Dermatol. 2023;22(12):1228-1231. doi:10.36849/JDD.7115.

Effect of Perioperative Antithrombotics on Postoperative Transfusion and Hematoma in Head and Neck Free Flaps.

Objective: To explore if antiplatelet or anticoagulant therapy increases the risk of transfusion requirement or postoperative hematoma formation in patients undergoing microvascular reconstruction for head and neck defects. Study Design: Retrospective cohort study. Setting: Departments of Otolaryngology-Head and Neck Surgery at the University of Alabama at Birmingham, the University of Colorado, and the University of California Irvine. Methods: A multi-institutional, retrospective review on microvascular reconstruction of the head and neck between August 2013 to July 2021. Perioperative antithrombotic data were collected to examine predictors of postoperative transfusion and hematoma. Results: A total of 843 free flaps were performed. Preoperative hemoglobin, hematocrit, operative time, and flap type were positive predictors of postoperative transfusion in both bivariate (P < .0001) and multivariate analyses (P < .0001). However, neither anticoagulation nor antiplatelet therapy were predictive of postoperative transfusion rates and hematoma formation. Conclusion: Antithrombotic regimens do not increase the risk of postoperative transfusion or hematoma in head and neck microvascular reconstruction. Based on this limited data, perioperative antithrombotic regimens can be considered in patients who may otherwise be at risk for these postoperative complications.

Do Socioeconomic Status and Race Impact the Safety and Efficacy of Breast Reconstruction?

INTRODUCTION: Immediate breast reconstruction after mastectomy has increased in recent years when compared with delayed reconstruction. Despite this encouraging trend, racial and socioeconomic disparities in the receipt of postmastectomy breast reconstruction have been well documented. We sought to assess the effect of race, socioeconomic status, and patient comorbidities on muscle sparing transverse rectus abdominis myocutaneous outcomes at our safety net hospital institution in the southeast. METHODS: The database of a tertiary referral center was queried for patients who received free transverse rectus abdominis myocutaneous flaps for immediate reconstruction after mastectomy meeting inclusion criteria from 2006 to 2020. Patient demographics and outcomes were compared based on socioeconomic status. The primary outcome (reconstructive success) was defined as breast reconstruction without flap loss. Statistical analysis included analysis of variance and χ2 tests were appropriate using Rstudio. RESULTS: Three-hundred fourteen patients were included in the study, with 76% White, 16% Black, and 8% other. Overall complication rate at our institution was 17% and reconstructive success was 94%. Non-White race, older age at time of breast cancer diagnosis, higher body mass index, and presence of comorbid conditions including current smoking and hypertension were all associated with low socioeconomic status. Despite this, surgical complication rates were not predicted by non-White race, older age, or presence of diabetes mellitus. When analyzing major and minor complications based on radiation received or reconstructive success, there was no significant difference regardless of radiation treatment with the group overall achieving a 94% success rate (P = 0.229). CONCLUSIONS: This study aimed to characterize the impact of socioeconomic status and race/ethnic status of patients on breast reconstruction outcomes at an institution in the South. We found that despite the greater morbidity in low income and ethnic/minority patients that when treated by a comprehensive safety net institution, they had excellent reconstructive outcomes due to low complications and minimal reoperations.

Structural dynamics reveal subtype-specific activation and inhibition of influenza virus hemagglutinin.

Influenza hemagglutinin (HA) is a prototypical class 1 viral entry glycoprotein, responsible for mediating receptor binding and membrane fusion. Structures of its prefusion and postfusion forms, embodying the beginning and endpoints of the fusion pathway, have been extensively characterized. Studies probing HA dynamics during fusion have begun to identify intermediate states along the pathway, enhancing our understanding of how HA becomes activated and traverses its conformational pathway to complete fusion. HA is also the most variable, rapidly evolving part of influenza virus, and it is not known whether mechanisms of its activation and fusion are conserved across divergent viral subtypes. Here, we apply hydrogen-deuterium exchange mass spectrometry to compare fusion activation in two subtypes of HA, H1 and H3. Our data reveal subtype-specific behavior in the regions of HA that undergo structural rearrangement during fusion, including the fusion peptide and HA1/HA2 interface. In the presence of an antibody that inhibits the conformational change (FI6v3), we observe that acid-induced dynamic changes near the epitope are dampened, but the degree of protection at the fusion peptide is different for the two subtypes investigated. These results thus provide new insights into variation in the mechanisms of influenza HA's dynamic activation and its inhibition.

Effect of Perioperative Antithrombotics on Head and Neck Microvascular Free Flap Survival After Anastomotic Revision.

OBJECTIVE: To determine if antithrombotic therapy improves head and neck microvascular free flap survival following anastomotic revision. STUDY DESIGN: A retrospective review of all patients with microvascular free tissue transfer to the head and neck between August 2013 and July 2021. SETTING: Otolaryngology-Head and Neck Surgery Departments at University of Alabama at Birmingham, University of Colorado, and University of California Irvine. METHODS: Perioperative use of anticoagulation, antiplatelets, intraoperative heparin bolus, tissue plasminogen activator (tPA) and vasopressor use, and leech therapy were collected plus microvascular free flap outcomes. The primary endpoint was free flap failure. Analyses of free flaps that underwent anastomotic revision with or without thrombectomy were performed. RESULTS: A total of 843 microvascular free flaps were included. The overall rate of flap failure was 4.0% (n = 34). The overall rate of pedicle anastomosis revision (artery, vein, or both) was 5.0% (n = 42) with a failure rate of 47.6% (n = 20) after revision. Anastomotic revision significantly increased the risk of flap failure (odds ratio [OR] 52.68, 95% confidence interval [CI] [23.90, 121.1], p < .0001) especially when both the artery and vein were revised (OR 9.425, 95% CI [2.117, 52.33], p = .005). Free flap failure after the anastomotic revision was not affected by postoperative antiplatelet therapy, postoperative prophylactic anticoagulation, intraoperative heparin bolus, tPA, and therapeutic anticoagulation regardless of which vessels were revised and if a thrombus was identified. CONCLUSION: In cases of microvascular free tissue transfer pedicle anastomotic revision, the use of antithrombotic therapy does not appear to significantly change free flap survival outcomes.

Long-duration pain block for postoperative anesthesia after endoscopic sinus surgery.

KEY POINTS: A long-duration pain block did not decrease postoperative pain or opioid consumption. Extended sinus procedures do not lead to additional postoperative pain or opioid consumption.

Novel pain management therapies for patients with pemphigus.

Pemphigus is a class of rare autoimmune diseases that causes incredibly painful blistering of the skin and significantly impacts patients' day-to-day lives and well-being. Many strides have been made in treating pemphigus; however, no comprehensive literature exists on how to treat the pain that accompanies the disease. It is important to remember that treating pemphigus involves a two-fold treatment plan assessing both the underlying autoimmune disease and the pain involved with the lesions. This literature review explores novel therapies that have been shown to be effective in treating pain in pemphigus.

Incidence and Risk Factors for Incidental Cancer on Melanoma Wide Excisions.

INTRODUCTION: Cancer patients and survivors have a high risk of developing additional malignancies. Patients who undergo melanoma excision often have sun-damaged skin and are predisposed to concurrent and subsequent skin cancers. The unexpected finding of an incidental cancer on melanoma wide excisions can require further surgery and delays adjuvant treatment. We aimed to determine the incidence and risk factors for incidental skin cancers in patients who had surgical excision of melanoma. METHODS: Our single-center retrospective study analyzed all patients diagnosed with primary melanoma at our institution from July 1, 2019 through June 30, 2020. We included patients with localized cutaneous melanoma who underwent surgical excision and had relevant pathology data available. Descriptive statistics and univariate analyses were performed on the demographic, clinical, and pathological data collected. We analyzed differences between the groups with and without incidental cancer to ascertain risk factors using chi-squared tests and Wilcoxon rank sum tests. Dunn's tests with Bonferroni correction were performed for multiple pairwise comparisons. RESULTS: There were 642 patients who met the criteria for inclusion, of whom 13 (2.0%) had incidental cancers identified on a pathologic assessment. Six (46%) had incidental squamous cell carcinoma and seven (54%) had basal cell carcinoma. With regard to management of incidental cancer, three (23%) patients required additional surgery for margin re-excision. Risk factors for incidental cancers in melanoma excision included older age (median 79 versus 62 y, P < 0.001), male sex (P = 0.042), and primary tumor location in the head/neck region relative to trunk (P < 0.01) or extremity (P < 0.01) primary sites. CONCLUSIONS: Although the frequency of incidental findings on melanoma excision is low, certain patients are at a greater risk including older male individuals with head/neck melanomas. These findings can be used to improve preoperative counseling of at-risk patients when melanoma excision is planned.

Burden of Care for Patients With In-Transit Melanoma.

INTRODUCTION: Patient burden of cancer care can be significant, especially for cancers like melanoma where patients are living longer, even with advanced disease. The purpose of this study is to compare the burden of treatment of melanoma patients with in-transit metastases (ITM). There are multiple treatment options for ITM, but no standard due to lack of large cohort comparative studies; thus, the anticipated burden of care may influence therapy choice. METHODS: Included patients had in-transit melanoma without distant metastasis and were managed at our institution from July 1, 2015 through December 31, 2020 using a combination of surgery, systemic, intralesional, and radiation therapy. We compared treatment burden, (number of treatments, clinic visits, inpatient hospital days, and distance traveled) and response rates using Kruskal-Wallis and chi-squared tests. Recurrence-free survival and estimated charges were exploratory endpoints. RESULTS: There were 42 patients who met the inclusion criteria. As initial treatment, patients had surgery (n = 20), surgery with adjuvant (n = 6), systemic (n = 9), and intralesional therapy (n = 2). Surgery had the lowest treatment burden (median of 1 treatment, 3 clinic visits, and 0 inpatient days) while surgery with adjuvant systemic therapy had the highest burden (median of 13 treatments, 12 clinic visits, and 0 inpatient days). Systemic, intralesional, and radiation therapy were used more often for recurrent ITM. Travel distance (P = 0.88) and response rates did not statistically differ between the four options for first line therapy (P = 0.99). At a median follow-up time of 8.8 mo, 22 (52%) of the cohort required more than 1 therapy to manage recurrent or progressive disease and 14 (33%) progressed to distant disease. CONCLUSIONS: Treatment of in-transit melanoma is associated with high burden of care and often requires multiple therapies, even with maximally effective first treatment choice. Factors evaluated in this study may be used to set expectations of treatment course for newly diagnosed patients and may aid in patients' decisions on therapy selection.

Attention Deficit Hyperactivity Disorder Increases Nicotine Addiction Severity in Adults Seeking Treatment for Substance Use Disorders: The Role of Personality Disorders.

AIMS: To examine the role of attention deficit/hyperactivity disorder (ADHD) and impulsive personality disorders in nicotine addiction severity among treatment-seeking substance use disorder (SUD) patients. METHODS: In a cross-sectional study, we examined data from the second International ADHD in Substance Use Disorders Prevalence Study (IASP-2) on 402 adults in SUD treatment from Puerto Rico, Hungary, and Australia using diagnostic interviews for ADHD, antisocial (ASP) and borderline (BPD) personality disorders, and the self-report Fagerström Test of Nicotine Dependence (FTND). We compared SUD patients with and without ADHD on nicotine addiction severity. We tested direct and indirect pathways from ADHD to nicotine addiction and mediation through ASP and BPD. RESULTS: Overall, 81.4% of SUD patients reported current cigarette smoking. SUD patients with ADHD had higher FTND scores and smoked more cigarettes than those without ADHD, with an earlier onset and more years of smoking. ASP mediated the effect of ADHD on all aspects of nicotine addiction severity, whereas BPD did so only on some aspects of nicotine addiction severity. CONCLUSIONS: SUD patients with comorbid ADHD show more severe nicotine addiction than those without, which is largely explained by comorbid impulsive personality disorders. In SUD patients, it is important to screen for adult ADHD and other psychiatric disorders, especially those with impulse control deficits such as ASP and BPD.

Optimizing Hydroxyl Radical Footprinting Analysis of Biotherapeutics Using Internal Standard Dosimetry.

Hydroxyl radical footprinting-mass spectrometry (HRF-MS) is a powerful technique for measuring protein structure by quantitating the solvent accessibility of amino acid side-chains; and when used in comparative analysis, HRF-MS data can provide detailed information on changes in protein structure. However, consistently controlling the amount of hydroxyl radical labeling of a protein requires the precise understanding of both the amount of radicals generated and half-life of the radicals in solution. The latter is particularly important for applications such as protein-protein and protein-ligand interactions, which may have different characteristics such as intrinsic reactivity and buffer components, and can cause differences in radical scavenging (herein termed "scavenging potential") between samples. To address this inherent challenge with HRF-MS analysis, we describe the comprehensive implementation of an internal standard (IS) dosimeter peptide leucine enkephalin (LeuEnk) for measuring the scavenging potential of pharmaceutically relevant proteins and formulation components. This further enabled evaluation of the critical method parameters affecting the scavenging potential of samples subjected to HRF-MS using fast photochemical oxidation of proteins. We demonstrate a direct correlation between the oxidation of the IS peptide and biotherapeutic target proteins, and show the oxidation of the IS can be used as a guide for ensuring equivalent scavenging potentials when comparing multiple samples. Establishing this strategy enables optimization of sample parameters, a system suitability approach, normalization of data, and comparison/harmonization of HRF-MS analysis across different laboratories.

Development of Photocrosslinking Probes Based on Huwentoxin-IV to Map the Site of Interaction on Nav1.7.

Voltage-gated sodium (Nav) channels respond to changes in the membrane potential of excitable cells through the concerted action of four voltage-sensor domains (VSDs). Subtype Nav1.7 plays an important role in the propagation of signals in pain-sensing neurons and is a target for the clinical development of novel analgesics. Certain inhibitory cystine knot (ICK) peptides produced by venomous animals potently modulate Nav1.7; however, the molecular mechanisms underlying their selective binding and activity remain elusive. This study reports on the design of a library of photoprobes based on the potent spider toxin Huwentoxin-IV and the determination of the toxin binding interface on VSD2 of Nav1.7 through a photocrosslinking and tandem mass spectrometry approach. Our Huwentoxin-IV probes selectively crosslink to extracellular loop S1-S2 and helix S3 of VSD2 in a chimeric channel system. Our results provide a strategy that will enable mapping of sites of interaction of other ICK peptides on Nav channels.

Current Trends in Biotherapeutic Higher Order Structure Characterization by Irreversible Covalent Footprinting Mass Spectrometry.

BACKGROUND: Biotherapeutics, particularly monoclonal antibodies (mAbs), are a maturing class of drugs capable of treating a wide range of diseases. Therapeutic function and solutionstability are linked to the proper three-dimensional organization of the primary sequence into Higher Order Structure (HOS) as well as the timescales of protein motions (dynamics). Methods that directly monitor protein HOS and dynamics are important for mapping therapeutically relevant protein-protein interactions and assessing properly folded structures. Irreversible covalent protein footprinting Mass Spectrometry (MS) tools, such as site-specific amino acid labeling and hydroxyl radical footprinting are analytical techniques capable of monitoring the side chain solvent accessibility influenced by tertiary and quaternary structure. Here we discuss the methodology, examples of biotherapeutic applications, and the future directions of irreversible covalent protein footprinting MS in biotherapeutic research and development. CONCLUSION: Bottom-up mass spectrometry using irreversible labeling techniques provide valuable information for characterizing solution-phase protein structure. Examples range from epitope mapping and protein-ligand interactions, to probing challenging structures of membrane proteins. By paring these techniques with hydrogen-deuterium exchange, spectroscopic analysis, or static-phase structural data such as crystallography or electron microscopy, a comprehensive understanding of protein structure can be obtained.

Managing the risk of intimacy: accounts of disclosure and responsiveness among people with HIV and intimate partners of people with HIV.

It is well known that concerns about sexual risk tend to decline among people in intimate relationships where there is established commitment and trust. In the context of relationships at increased risk for HIV transmission, interactions involving disclosure and partner responsiveness are key to maintaining intimacy and physical safety. This paper explores concepts of risk and sexual intimacy articulated by a community sample of 30 people living with HIV and their intimate relationship partners. Data revealed the shifts in intimate relationship dynamics upon the disclosure of an HIV diagnosis, the importance of intimacy in the context of managing one or both partners' HIV care and responses to new advances in HIV prophylaxis. Findings suggest that participants' experiences of self-disclosure and partner responsiveness most often resulted in an increased sense of protectiveness from and for partners. This suggests that health-promoting messaging should be adapted to be more relevant to intimate couple communication and mutual support.

Structural basis for dual-mode inhibition of the ABC transporter MsbA.

The movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.9 Å resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains. This study establishes a framework for the selective modulation of ABC transporters and provides rational avenues for the design of new antibiotics and other therapeutics targeting this protein family.