Heterogeneous Fe-N-C Catalyst for Aerobic Dehydrogenation of Hydrazones to Diazo Compounds Used for Carbene Transfer.

Organic diazo compounds are versatile reagents in chemical synthesis and would benefit from improved synthetic accessibility, especially for larger scale applications. Here, we report a mild method for the synthesis of diazo compounds from hydrazones using a heterogeneous Fe-N-C catalyst, which has Fe ions dispersed within a graphitic nitrogen-doped carbon support. The reactions proceed readily at room temperature using O2 (1 atm) as the oxidant. Aryl diazoesters, ketones, and amides are accessible, in addition to less stable diaryl diazo compounds. Initial-rate data show that the Fe-N-C catalyst achieves faster rates than a heterogeneous Pt/C catalyst. The oxidative dehydrogenation of hydrazones may be performed in tandem with Rh-catalyzed enantioselective C-H insertion and cyclopropanation of alkenes, without requiring isolation of the diazo intermediate. This sequence is showcased by using a flow reactor for continuous synthesis of diazo compounds.

Copper-Nitroxyl-Catalyzed α-Oxygenation of Cyclic Secondary Amines Including Application to Late-Stage Functionalization.

Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N-unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, we report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.

Effect of ear cleaning on treatment outcome for canine otitis externa.

BACKGROUND: Ear cleaning is often recommended for management of canine otitis externa (OE). Few in vivo studies evaluate how ear cleaning affects treatment outcome. HYPOTHESIS/OBJECTIVES: To determine the effect of ear cleaning on canine OE by comparing treatment outcome in cleaned versus noncleaned ears. ANIMALS: Twenty-three client-owned dogs with ceruminous or purulent OE. MATERIALS AND METHODS: Forty ears were randomised to one of two groups: 20 ears were wiped with dry or saline-moistened gauze (grp1), and 20 external ear canals received manual cleaning (grp2) with a commercial product. One millilitre of a commercial otic suspension containing hydrocortisone aceponate, miconazole nitrate and gentamicin sulfate was applied to affected ears every 24 h for five days. Cytological scores, modified otitis index score (OTIS3), pruritus Visual Analog Scale (PVAS), modified PVAS and client questionnaire were compared on Day (D)0 and D7. RESULTS: There were no statistical differences between cytological scores, modified OTIS3, PVAS, modified PVAS or client assessments between groups at D7. Both groups had significant reduction in all treatment parameters from D0 to D7 with the exception of cytological rod scores that were only significantly decreased in cleaned ears. There was a significant difference in OTIS3 before and after cleaning on D0. CONCLUSIONS AND CLINICAL RELEVANCE: Both groups achieved successful outcome regardless of cleaning. Ear cleaning may be more important when rod-shaped bacteria are present.

Chemical Kinetic Method for Active-Site Quantification in Fe-N-C Catalysts and Correlation with Molecular Probe and Spectroscopic Site-Counting Methods.

Mononuclear Fe ions ligated by nitrogen (FeNx) dispersed on nitrogen-doped carbon (Fe-N-C) serve as active centers for electrocatalytic O2 reduction and thermocatalytic aerobic oxidations. Despite their promise as replacements for precious metals in a variety of practical applications, such as fuel cells, the discovery of new Fe-N-C catalysts has relied primarily on empirical approaches. In this context, the development of quantitative structure-reactivity relationships and benchmarking of catalysts prepared by different synthetic routes and by different laboratories would be facilitated by the broader adoption of methods to quantify atomically dispersed FeNx active centers. In this study, we develop a kinetic probe reaction method that uses the aerobic oxidation of a model hydroquinone substrate to quantify the density of FeNx centers in Fe-N-C catalysts. The kinetic method is compared with low-temperature Mössbauer spectroscopy, CO pulse chemisorption, and electrochemical reductive stripping of NO derived from NO2- on a suite of Fe-N-C catalysts prepared by diverse routes and featuring either the exclusive presence of Fe as FeNx sites or the coexistence of aggregated Fe species in addition to FeNx. The FeNx site densities derived from the kinetic method correlate well with those obtained from CO pulse chemisorption and Mössbauer spectroscopy. The broad survey of Fe-N-C materials also reveals the presence of outliers and challenges associated with each site quantification approach. The kinetic method developed here does not require pretreatments that may alter active-site distributions or specialized equipment beyond reaction vessels and standard analytical instrumentation.

Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence. METHODS: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples. RESULTS: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1ß, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here. CONCLUSIONS: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.

Outcomes and technical modifications of vascularized lymph node transplantation from the lateral thoracic region for treatment of lymphedema.

BACKGROUND AND OBJECTIVES: This study evaluates clinical outcomes of vascularized lymph node transplantation (VLNT) from the lateral thoracic region and technical modifications. METHODS: Consecutive patients that underwent lateral thoracic VLNT to treat extremity lymphedema were included. Demographic and treatment data were recorded, and outcomes data including limb volume, LDex score, and Lymphedema Life Impact Scale (LLIS), QuickDASH, and LEFS questionnaires, were collected prospectively. Consecutive patients that underwent single-photon emission computed tomography (SPECT/CT) lymphoscintigraphy axillary reverse lymphatic mapping (RLM) were analyzed to characterize the physiological drainage of the normal upper extremity. RESULTS: A consecutive series of 32 flaps were included. At 24 months postoperatively mean reduction in limb volume excess was 47.2% (±11.6; p = 0.0085), LDex score was 63.1% (±8.5; p < 0.001), and LLIS score was 65.1% (±7.4; p < 0.001). Preoperatively 14/31 patients (45.2%) reported cellulitis, and postoperatively there were no episodes at up to 24 months (p < 0.001). No patient developed donor extremity lymphedema at mean 18.6 (±8.3) months follow-up. SPECT/CT-RLM of 182 normal axillae demonstrated that the sentinel lymph node(s) of the upper extremity was consistently anatomically located in the upper outer quadrant of the axilla (97%). CONCLUSIONS: VLNT from the lateral thoracic region is effective and versatile for the treatment of lymphedema with a low donor site complication rate.

Targeting cognitive control to reduce anxiety in very young children: A proof of concept study.

OBJECTIVE: Underdeveloped cognitive control (CC)-the capacity to flexibly adjust to changing environments-may predispose some children to early onset anxiety disorders and represents a promising intervention target. The current study established and pilot-tested "Camp Kidpower"-a novel group-based, interactive CC training intervention-and assessed its impacts on behavioral and neurophysiological indices of CC among preschool children with elevated anxiety symptoms. METHODS: Forty-four anxious children (4-6 years) were enrolled in Camp Kidpower, delivered in four sessions over 10 days. Before and after camp, children's capacity for CC was measured using well-validated, non-trained behavioral tasks and error-related negativity (ERN). Child anxiety symptoms were measured by parent report on the Spence Preschool Anxiety Scale. RESULTS: Thirty-two children completed the study, as defined by completion of pre- and follow-up assessments and at least three camp sessions. From baseline to after camp, performance on behavioral tests of CC improved, ERN amplitude increased, and anxiety symptoms decreased. CONCLUSION: Results provide initial evidence that play-based cognitive training targeted to behavioral and brain markers of CC reduces anxiety in preschoolers.

Decoding Billing Practices in Cochlear Implant Programs.

OBJECTIVES: The purpose of this study was to examine current cochlear implant (CI) billing practices across CI audiologists in the United States, to determine if CI audiologists are following the National Correct Coding Initiative (NCCI) edits, and to assess the CI audiologist's exposure to billing education. DESIGN: A 48-question survey was electronically distributed to and completed by audiologists who bill for CI services. Demographic data including work setting, population served, years of experience, number of CI patients managed per week, and exposure to billing education were collected. Data were analyzed to identify codes and modifiers used to bill for commonly performed CI procedures such as unilateral and bilateral CI programming, preoperative and postoperative testing, and objective measures. RESULTS: Data were obtained from 96 audiologists. The majority (86.3%, n = 82) of respondents agreed or strongly agreed they understand billing and coding practices for cochlear implants and 94.7% (n = 89) rated themselves as somewhat to highly efficient when performing these practices. Only 16.8% (n = 16) of respondents reported receiving formal training for practice management, and half of the respondents (51.1%, n = 48) reported unfamiliarity with national billing guidelines. Those who received formal training reported higher billing efficiency. Wide variability was seen for various billing scenarios. Billing questions were presented, and answers were coded as correct or incorrect based on the NCCI edits. Respondents who reported higher agreement with understanding billing and who received formal training scored better on common billing questions related to the NCCI edits. CONCLUSIONS: Most CI audiologists rated themselves as efficient in billing; however, wide variance in billing practices was observed. Incorporating practice management and current billing education into daily practice and into audiology training programs is essential to clinic efficiency, practice management, and CI program viability. CI audiologists should be knowledgeable about appropriate billing practices to ensure long-term sustainability of programs.

Conducting EEG research in clinically anxious preschoolers: A pilot study and preliminary recommendations.

Electroencephalography (EEG) data collection can be challenging in preschoolers with anxiety who are often debilitated by fear of the unknown. Thus, we iteratively refined techniques for EEG collection in three cohorts of children with anxiety enrolled in our study of a novel intervention. Techniques involved directing child attention away from the EEG setup (Cohort 1, N = 18), open discussion of equipment and processes during setup (Cohort 2, N = 21), and a preparatory EEG-exposure session prior to data collection (Cohort 3, N = 6). Children (N = 45, 4-7 years) attempted a Time 1 EEG before intervention, and those who completed intervention (N = 28) were invited to a Time 2 EEG. The percentages who provided analyzable EEGs were assessed by cohort. Cohort 3 provided more Time 1 EEGs (83.3%) than Cohorts 1 or 2 (66.7% each), suggesting that the preparatory session supported first-time EEG collection. More children provided Time 2 EEG data across successive cohorts (Cohort 1: 66.7%, Cohort 2: 82%, Cohort 3: 100%), suggesting that more open communication facilitated repeat EEG collection. Ultimately, increased EEG exposure and child-friendly communication about procedures improved data acquisition in this sample of clinically anxious preschoolers. Detailed study procedures are shared to support future EEG research in young children with anxiety.

Development and Evaluation of an Atopic Dermatitis Care Plan for Providers.

Background/Significance of problem: Atopic Dermatitis (AD) is a common, chronic, inflammatory dermatosis and skin disease that follows a relapsing pattern and requires a dynamic stepwise approach to management. Providers feel comfortable treating chronic disease states with a guided tool or care plan in many chronic diseases. Care plans used in many chronic diseases such as asthma, diabetes, and COPD have demonstrated effectiveness in disease and healthcare provider management. There is an unmet need for a universal AD care plan for providers. Clinical question/project purpose: A universal AD care plan was developed to improve AD disease management and patient outcomes. Post-implementation of providers & perceptions was assessed for how the AD universal care plan affected their ability to provide patient education. Search of literature/best evidence: Review of literature includes: CINAHL, ProQuest Health, PubMed, Fusion, and UpToDate databases from 2008-2018.Search terms included: Atopic Dermatitis, Eczema, care plans, care plan use in chronic disease. Clinical appraisal of literature/best evidence: Analysis of the evidence supported the need for AD education, which then supported the need for a universal AD care plan for providers. Integration into practice: "Your Eczema Care Plan" was used by thirty-five healthcare providers to improve patient outcomes in a similar manner as other evidence-based care plans.Evaluation of evidenced-based practice: Post-implementation of providers & perceptions were evaluated on how the AD care plan tool affected their ability to provide patient education. Results suggest patient education, disease management, and QOL are all improved when utilizing "Your Eczema Action Plan." J Drugs Dermatol. 2020;19(10): 950-955. doi:10.36849/JDD.2020.5090.

Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.

Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes. Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function. Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities. Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations. The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy. In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype. Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.

Proton Pump Inhibitor Use Is Associated with an Increased Frequency of New or Worsening Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt Creation.

PURPOSE: To determine whether proton pump inhibitor (PPI) use increases the rate of new or worsening hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS: In this retrospective study, 284 of 365 patients who underwent TIPS creation from January 1, 2005, to December 31, 2016, were analyzed (186 male, mean age 56 y, range 19-84 y). Dates of PPI use and dates of new or worsening HE, defined as hospitalization or escalation in outpatient medical management, were extracted from medical records. Mixed-effects negative binomial regression was used to test for an association between PPI usage and HE. RESULTS: After TIPS creation, among 168 patients on PPIs chronically, there were 235 episodes of new or worsening HE in 106,101 person-days (0.81/person-year). Among 55 patients never on PPIs, there were 37 episodes in 31,066 person-days (0.43/person-year). Among 61 patients intermittently taking PPIs, there were 78 episodes in 37,710 person-days while on PPIs (0.75/person-year) and 25 episodes in 35,678 person-days while off PPIs (0.26/person-year). In univariate regression, PPI usage was associated with a 3.34-fold increased rate of new or worsening HE (incidence rate ratio [IRR] 3.34; P < .001). In multivariate regression, older age (IRR 1.05; P < .001), male sex (IRR 1.58; P = .023), higher Model for End-Stage Liver Disease score (IRR 1.06; P = .015), previous HE or HE-preventive medication use (IRR 1.51; P = .029), and PPI use (IRR 3.19; P < .001) were significant risk factors. Higher PPI doses were associated with higher rates of HE (IRR 1.16 per 10 mg omeprazole equivalent; P = .046). CONCLUSIONS: PPI usage is associated with increased rates of new or worsening HE after TIPS creation.

Thermal liquid biopsy for monitoring melanoma patients under surveillance during treatment: A pilot study.

BACKGROUND: Differential Scanning Calorimetry (DSC) is a technique traditionally used to study thermally induced macromolecular transitions, and it has recently been proposed as a novel approach for diagnosis and monitoring of several diseases. We report a pilot study applying Thermal Liquid Biopsy (TLB, DSC thermograms of plasma samples) as a new clinical approach for diagnostic assessment of melanoma patients. METHODS: Multiparametric analysis of DSC thermograms of patient plasma samples collected during treatment and surveillance (63 samples from 10 patients) were compared with clinical and diagnostic imaging assessment to determine the utility of thermograms for diagnostic assessment in melanoma. Nine of the ten patients were stage 2 or 3 melanoma subjects receiving adjuvant therapy after surgical resection of their melanomas. The other patient had unresectable stage 4 melanoma and was treated with immunotherapy. Two reference groups were used: (A) 36 healthy subjects and (B) 13 samples from 8 melanoma patients who had completed successful surgical management of their disease and were determined by continued clinical assessment to have no evidence of disease. RESULTS: Plasma thermogram analysis applied to melanoma patients generally agrees with clinical evaluation determined by physical assessment or diagnostic imaging (~80% agreement). No false negatives were obtained from DSC thermograms. Importantly, this methodology was able to detect changes in disease status before it was identified clinically. CONCLUSIONS: Thermal Liquid Biopsy could be used in combination with current clinical assessment for the earlier detection of melanoma recurrence and metastasis. GENERAL SIGNIFICANCE: TLB offers advantages over current diagnostic techniques (PET/CT imaging), limited in frequency by radiation burden and expense, in providing a minimally-invasive, low-risk, low-cost clinical test for more frequent personalized patient monitoring to assess recurrence and facilitate clinical decision-making.

Corresponding ctDNA and tumor burden dynamics in metastatic melanoma patients on systemic treatment.

Radiographic imaging is the current standard for monitoring progression of tumor-burden and therapeutic resistance in patients with metastatic melanoma. Plasma circulating tumor DNA (ctDNA) has shown promise as a survelience tool, but longitudinal data on the dynamics between plasma ctDNA concentrations and radiographic imaging is lacking. We evaluated the relationship between longitudinal radiographic measures of tumor burden and ctDNA concentrations in plasma on 30 patients with metastatic melanoma on systemic treatment. In 9 patients with no radiographic evidence of disease over a total of 15 time points, ctDNA concentrations were undetectable. In 21 patients with radiographic tumor burden, ctDNA was detected in 81 % of 58 time points. Plasma ctDNA concentrations demonstrated a modest positive correlation with total tumor burden (TTB) measurements (R2= 0.49, p < 0.001), with the greatest degree of correlation observed under conditions of progressive disease (PD) (R2 = 0.91, p = 0.032). Plasma ctDNA concentrations were significantly greater at times of RECIST v1.1 progression (PD; 22.1 % ± 5.7 %) when compared to samples collected during stable disease (SD; 4.99 % ± 3.0 %) (p = 0.012); this difference was independent of total tumor burden (p = 0.997). Changes in plasma ctDNA showed a strong correlation with changes in TTB (R2= 0.88, p<0.001). These data suggest that measurements of plasma ctDNA during therapy are a better surrogate for responding versus non-responding disease compared to absolute tumor burden.

Brain response to errors in children who stutter.

PURPOSE: Heightened rates of social anxiety have been reported in adults who stutter (AWS), but it is unclear whether anxiety is heightened also in children who stutter (CWS). Objective neurophysiological responses such as the error-related negativity (ERN) have been associated with anxiety, and ERN was reported to be increased in AWS. In this study, we examined whether ERN and error positivity (Pe) are increased in CWS. We further characterized ERN associations with age and anxiety in CWS relative to children who do not stutter (CWNS). METHODS: EEG data were recorded from twenty-four CWS and twenty-four matched CWNS aged 3-9 years as they performed a Go/No-Go task. Parent-reported anxiety, and child-reported speech-associated attitude measures were collected. Linear regression models tested the effects of age, group, and their interaction, and the effects of anxiety, group, and their interaction on ERN and Pe. RESULTS: Contrary to expectations, no ERN or Pe difference were observed between CWS and CWNS. However, larger ERN amplitudes were associated with older age in CWS but not CWNS, suggesting altered development of the error monitoring system in CWS. Association of Pe with anxiety also differed between groups: smaller Pe amplitudes were associated with higher level of parent-reported child anxiety in CWNS but not in CWS. Neither anxiety nor self-reported communication attitude differed between groups. CONCLUSIONS: Brain responses to errors were overall comparable between CWS and CWNS. However, CWS differed in how error monitoring responses varied with age and with anxiety levels. More research is warranted to examine how these factors contribute to persistent stuttering.

A Consensus to Revise the Minimum Speech Test Battery-Version 3.

PURPOSE: The Minimum Speech Test Battery (MSTB) for adults was introduced in 1996 (Nilsson et al., 1996) and subsequently updated in 2011 (Advanced-Bionics et al., 2011). The MSTB has been widely used by clinicians as a guide for cochlear implant (CI) candidacy evaluations and to document post-operative speech recognition performance. Due to changes in candidacy over the past 10 years, a revision to the MSTB was needed. METHOD: In 2022, the Institute for Cochlear Implant Training (ICIT) recruited a panel of expert CI audiologists to update and revise the MSTB. This panel utilized a modified Delphi consensus process to revise the test battery and to improve its applicability considering recent changes in CI care. RESULTS: This resulted in the MTSB-Version 3 (MSTB-3), which includes test protocols for identifying not only traditional CI candidates but also possible candidates for electric-acoustic stimulation and patients with single-sided deafness and asymmetric hearing loss. The MSTB-3 provides information that supplements the earlier versions of the MSTB, such as recommendations of when to refer patients for a CI, recommended patient-reported outcome measures, considerations regarding the use of cognitive screeners, and sample report templates for clinical documentation of pre- and post-operative care. Electronic versions of test stimuli, along with all the materials described above, will be available to clinicians via the ICIT website (https://www.cochlearimplanttraining.com). CONCLUSION: The goal of the MSTB-3 is to be an evidence-based test battery that will facilitate a streamlined standard of care for adult CI candidates and recipients that will be widely used by CI clinicians.

Plasma Thermogram Parameters Differentiate Status and Overall Survival of Melanoma Patients.

Melanoma is the fifth most common cancer in the United States and the deadliest of all skin cancers. Even with recent advancements in treatment, there is still a 13% two-year recurrence rate, with approximately 30% of recurrences being distant metastases. Identifying patients at high risk for recurrence or advanced disease is critical for optimal clinical decision-making. Currently, there is substantial variability in the selection of screening tests and imaging, with most modalities characterized by relatively low accuracy. In the current study, we built upon a preliminary examination of differential scanning calorimetry (DSC) in the melanoma setting to examine its utility for diagnostic and prognostic assessment. Using regression analysis, we found that selected DSC profile (thermogram) parameters were useful for differentiation between melanoma patients and healthy controls, with more complex models distinguishing melanoma patients with no evidence of disease from patients with active disease. Thermogram features contributing to the third principal component (PC3) were useful for differentiation between controls and melanoma patients, and Cox proportional hazards regression analysis indicated that PC3 was useful for predicting the overall survival of active melanoma patients. With the further development and optimization of the classification method, DSC could complement current diagnostic strategies to improve screening, diagnosis, and prognosis of melanoma patients.

Monocytic MDSCs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy.

Immune checkpoint inhibitor (ICI) therapy is effective against many cancers for a subset of patients; a large percentage of patients remain unresponsive to this therapy. One contributing factor to ICI resistance is accumulation of monocytic myeloid-derived suppressor cells (M-MDSCs), a subset of innate immune cells with potent immunosuppressive activity against T lymphocytes. Here, using lung, melanoma, and breast cancer mouse models, we show that CD73-expressing M-MDSCs in the tumor microenvironment (TME) exhibit superior T cell suppressor function. Tumor-derived PGE2, a prostaglandin, directly induces CD73 expression in M-MDSCs via both Stat3 and CREB. The resulting CD73 overexpression induces elevated levels of adenosine, a nucleoside with T cell-suppressive activity, culminating in suppression of antitumor CD8+ T cell activity. Depletion of adenosine in the TME by the repurposed drug PEGylated adenosine deaminase (PEG-ADA) increases CD8+ T cell activity and enhances response to ICI therapy. Use of PEG-ADA can therefore be a therapeutic option to overcome resistance to ICIs in cancer patients.

Jejunal Mesenteric Vascularized Lymph Node Transplantation for Lymphedema: Outcomes and Technical Modifications.

BACKGROUND: The jejunal mesentery supplied by the superior mesenteric vascular tree has emerged as a viable site for vascularized lymph node transplantation. Among other benefits, it has the advantage of avoidance of the risk of donor-site lymphedema. This article reports the technique and outcomes of a novel approach to jejunal mesenteric vascularized lymph node transplantation with flap harvest from the mesenteric root to reduce the risk of small bowel ischemic complications. METHODS: A consecutive series of patients that underwent jejunal mesenteric vascularized lymph node transplantation to treat upper extremity lymphedema were included. Preoperative and postoperative measurements were taken at fixed intervals using standardized techniques including Perometer volumetry, LDex bioimpedance spectroscopy, the Lymphedema Life Impact Scale, and the Quick Disabilities of the Arm, Shoulder and Hand tool. Demographic, treatment, and outcomes data were collected, and descriptive statistics were used. RESULTS: There were 25 patients included, all of whom had maximized their conservative therapy before undergoing surgery. At 12 months postoperatively reduction in limb volume difference was 36.7 percent (p < 0.001), reduction in LDex score was 41.4 percent (p = 0.0015), and reductions in the Lymphedema Life Impact Scale and Quick Disabilities of the Arm, Shoulder and Hand scores were 55.7 percent (p = 0.0019) and 47.5 percent (p = 0.027), respectively. In 11 patients, there was a history of cellulitis (multiple episodes in eight), and at up to 24 months' follow-up postoperatively there were no episodes reported (p < 0.001). CONCLUSION: Upper extremity lymphedema can be effectively treated surgically using the jejunal mesenteric vascularized lymph node transplantation, resulting in reduced limb volume and extracellular fluid, and improved patient-reported limb function and outcomes measures compared with optimized conservative therapy alone. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Trending Anti-E7 Serology Predicts Mortality and Recurrence of HPV-Associated Cancers of the Oropharynx.

High-risk human papillomavirus (HPV) is among the most common causes of head and neck cancer (HNC) with increasing incidence. HPV-associated HNC patients' clinical response to treatment varies drastically, which has made treatment de-escalation clinical trials challenging. To address the need for noninvasive biomarkers that differentiate patient outcomes, serum antibodies to E7 oncoprotein levels were evaluated in serial serum specimens from HPV-positive HNC patients (n = 48). We have found that increasing antibodies to E7 throughout treatment correlates with increased cancer recurrence or progression to mortality (p = .004) with 100% specificity as a predictive test.