Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.

Deep-Learning-Based Screening and Ancillary Testing for Thyroid Cytopathology.

Thyroid cancer is the most common malignant endocrine tumor. The key test to assess preoperative risk of malignancy is cytologic evaluation of fine-needle aspiration biopsies (FNABs). The evaluation findings can often be indeterminate, leading to unnecessary surgery for benign post-surgical diagnoses. We have developed a deep-learning algorithm to analyze thyroid FNAB whole-slide images (WSIs). We show, on the largest reported data set of thyroid FNAB WSIs, clinical-grade performance in the screening of determinate cases and indications for its use as an ancillary test to disambiguate indeterminate cases. The algorithm screened and definitively classified 45.1% (130/288) of the WSIs as either benign or malignant with risk of malignancy rates of 2.7% and 94.7%, respectively. It reduced the number of indeterminate cases (N = 108) by reclassifying 21.3% (N = 23) as benign with a resultant risk of malignancy rate of 1.8%. Similar results were reproduced using a data set of consecutive FNABs collected during an entire calendar year, achieving clinically acceptable margins of error for thyroid FNAB classification.

Access to Benzathine Penicillin G Treatment for Persons With Syphilis, Maricopa County, Arizona, 2021.

BACKGROUND: As the incidence of syphilis continues to increase, examining benzathine penicillin G (BPG) treatment data provides valuable insight for public health strategies. This study analyzed the trends of where BPG is administered relative to the initial clinical site of syphilis diagnosis. Our findings are timely in the context of recent national BPG shortages. METHODS: The analysis included persons diagnosed with any syphilis stage in Maricopa County, Arizona, from January 1, 2021, to December 31, 2021. The Arizona surveillance database (PRISM) was the source of demographic, testing, and treatment data. RESULTS: Of a total of 4028 persons with syphilis, 3038 (75.4%) received at least 1 injection of BPG. Among persons who received an initial BPG injection, only 1719 (56.6%) were diagnosed and treated at the same clinical site type. The Maricopa County Sexually Transmitted Disease Clinic administered BPG to 48.8% (n = 1483) of persons with syphilis who received an initial injection. CONCLUSIONS: Our findings analyze trends in BPG administration that are likely due to treatment referral practices and medication cost. Administration of BPG is not guaranteed at the clinical site of diagnosis, highlighting concerns regarding access to BPG. A burden is placed on patients who are required to leave their diagnosing provider to seek syphilis treatment at other health facilities that administer BPG.

Treatment Completion With Three-Dose Series of Benzathine Penicillin Among People Diagnosed With Late Latent and Unknown Duration Syphilis, Maricopa County, Arizona.

BACKGROUND: Syphilis is a public health concern as cases are rising each year. If untreated, syphilis is associated with significant morbidity and risk of vertical transmission during pregnancy. For people with late latent and unknown duration stages, 3 injections of benzathine penicillin G (BPG) at 1-week intervals are recommended. Our study quantified treatment for people diagnosed with late latent and unknown duration syphilis in Maricopa County, Arizona with a secondary analysis of pregnant women to assess completion of 3 injections of BPG in multiple time intervals. METHODS: Maricopa County syphilis case data were extracted from the state-run database (PRISM). Records were reviewed for people with late latent and unknown duration syphilis during January 1, 2016, to December 31, 2021. Treatment types and time intervals between treatments were analyzed. RESULTS: Of a total of 14,924 people with syphilis reported in Maricopa County, 5372 (36.0%) were staged as late latent or unknown duration syphilis. Completion of 3 BPG injections in the time frame of 7 to 9 days was 42.9% (n = 2302). Completion among pregnant women (n = 406) with 3 injections was 68.7% (n = 279). CONCLUSIONS: The completion rate of 3 BPG injections for people with late latent or unknown duration syphilis is low. An unmet need exists to identify barriers to treatment including access to BPG and public health follow-up after the first injection. Prioritized effort is needed to identify and classify patients as having earlier stages of syphilis that require only 1 BPG injection.

Recent advances in visible light-activated radical coupling reactions triggered by (i) ruthenium, (ii) iridium and (iii) organic photoredox agents.

Photoredox chemistry with organic or transition metal agents has been reviewed in earlier years, but such is the pace of progress that we will overlap very little with earlier comprehensive reviews. This review first presents an overview of the area of research and then examines recent examples of C-C, C-N, C-O and C-S bond formations via radical intermediates with transition metal and organic radical promoters. Recent successes with Birch reductions are also included. The transition metal chemistry will be restricted to photocatalysts based on the most widely used metals, Ru and Ir, but includes coupling chemistries that take advantage of low-valent nickel, or occasionally copper, complexes to process the radicals that are formed. Our focus is on developments in the past 10 years (2011-2021). This period has also seen great advances in the chemistry of organic photoredox reagents and the review covers this area. The review is intended to present highlights and is not comprehensive.

A model of the burglar alarm hypothesis of prey alarm calls.

When approached by a predator many prey species will emit an "alarm call" as a form of anti-predator behavior. One hypothesis for the function of alarm calls is the "burglar alarm" hypothesis whereby upon attack, a prey renders itself dangerous to a predator by generating an alarm call that attracts a predator at higher trophic levels in the food chain; that is, attracts a predator to the prey's own predator. This paper concerns a model incorporating a mechanism to test the burglar alarm hypothesis. We prove in one space dimension global existence, of positive bounded classical solutions, and establish existence of non-constant equilibrium solutions and assess their stability. We provide some representative numerical simulations to emphasize the nature of pattern formation for this model and demonstrate the benefit achieved by a signal inducing prey species under the burglar alarm hypothesis.

Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells.

OBJECTIVE: The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells. DESIGN: To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD. RESULTS: As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn's disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. CONCLUSIONS: Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis. TRIAL REGISTRATION NUMBER: NCT02749630.

Supporting Health Among Young Men Who Have Sex With Men and Transgender Women With HIV: Lessons Learned From Implementing the weCare Intervention.

Young gay, bisexual, and other men who have sex with men and transgender women with HIV, particularly those who are racial or ethnic minorities, often have poor health outcomes. They also utilize a wide array of social media. Accordingly, we developed and implemented weCare, an mHealth (mobile health) intervention where cyberhealth educators utilize established social media platforms (e.g., Facebook, texting, and GPS-based mobile applications ["apps"]) designed for social and sexual networking) to improve HIV-related care engagement and health outcomes. As part of the process evaluation of weCare, we conducted 32 interviews with intervention participants (n = 18) and HIV clinic providers and staff (n = 14). This article highlights three key intervention characteristics that promoted care engagement, including that weCare is (1) targeted (e.g., using existing social media platforms, similarity between intervention participants and cyberhealth educator, and implementation within a supportive clinical environment), (2) tailored (e.g., bidirectional messaging and trusting relationship between participants and cyberhealth educators to direct interactions), and (3) personalized (e.g., addressing unique care needs through messaging content and flexibility in engagement with intervention). In addition, interviewees' recommendations for improving weCare focused on logistics, content, and the ways in which the intervention could be adapted to reach a larger audience. Quality improvement efforts to ensure that mHealth interventions are relevant for young gay, bisexual, and other men who have sex with men and transgender women are critical to ensure care engagement and support health outcomes.

Synthesis and Fluorescent Properties of ß-Pyridyl α-Amino Acids.

The preparation of a new class of ß-pyridyl α-amino acid is described using a highly regioselective, ytterbium-catalyzed hetero-Diels-Alder reaction of enones with vinyl ethers followed by a modified Knoevenagel-Stobbe reaction as the key heterocycle forming steps. Investigation of the properties and applications of these amino acids showed that they could be utilized in solid phase peptide synthesis for the preparation of a biologically relevant hexapeptide, while pyridines bearing electron-rich substituents exhibited strongly fluorescent properties with high quantum yields and MegaStokes shifts. A solvatochromic study with the most fluorogenic amino acid, a p-methoxyphenyl analogue, revealed that this charge-transfer based chromophore is highly sensitive to solvent polarity with a bathochromic shift of 115 nm on changing from THF to phosphate-buffered saline.

Synthesis and Photophysical Properties of Benzotriazole-Derived Unnatural α-Amino Acids.

The synthesis of a new class of benzotriazole-derived α-amino acid is described using a highly efficient nucleophilic aromatic substitution of ortho-fluoronitrobenzenes with l-3-aminoalanine and a polymer-supported nitrite reagent-mediated diazotization and cyclization of the subsequent 1,2-aryldiamines as the key steps. Further functionalization of the benzotriazole unit by preparation of halogenated analogues and Suzuki-Miyaura cross-coupling with aryl boronic acids allowed the synthesis of α-amino acids with conjugated side chains. Analysis of the photophysical properties of these α-amino acids revealed that incorporation of electron-rich substituents results in charge-transfer-based, fluorescent compounds with MegaStokes shifts.

Stereoselective synthesis of 2,6-trans-4-oxopiperidines using an acid-mediated 6-endo-trig cyclisation.

An acid-mediated 6-endo-trig cyclisation of amine-substituted enones has been developed for the stereoselective synthesis of trans-6-alkyl-2-methyl-4-oxopiperidines. Performed under conditions that prevent removal of the Boc-protecting group or acetal formation, the key cyclisation was found to generate cleanly the 4-oxopiperidine products in high overall yields from a wide range of alkyl substituted enones. The synthetic utility of the trans-6-alkyl-2-methyl-4-oxopiperidines formed from this process was demonstrated with the total synthesis of the quinolizidine alkaloid, (+)-myrtine and the piperidine alkaloid, (-)-solenopsin A.

Stereotactic radiosurgery for brain metastases from primary head and neck carcinomas: a retrospective analysis.

Patients with head and neck malignancies commonly develop metastatic disease, yet rarely do these carcinomas metastasize to the brain. Stereotactic radiosurgery (SRS) is routinely employed to treat brain metastases (BM). This study was undertaken to examine the efficacy of SRS for BM from primary head and neck carcinomas. From 2000 to 2016, a total of 19 patients with 38 lesions were retrospectively identified. All patients presented with a primary head and neck malignancy and subsequently developed metastatic disease to the brain treated with SRS at our institution. Actuarial rates for overall survival (OS), local control (LC) and distant brain metastases (DBM) were calculated using Kaplan-Meier estimates. Median follow up was 6.8 months and median survival was 15.8 months. Eleven lesions received post-operative SRS to a surgical cavity and 27 lesions received definitive SRS to a metastasis. The median dose prescribed was 18 Gy. One-year actuarial rate for LC was 77.3% (95% confidence interval [CI] 44-92%) while 1 year and 2 year rates of OS were 52.9% (CI 28-73%) and 31.7% (CI 11-55%) respectively. The median time to develop DBM was 8.4 months. Three patients (16%) underwent repeat SRS following development of new BM and three patients (16%) underwent salvage whole brain radiotherapy (WBRT). SRS may be utilized in the treatment of patients with primary head and neck malignancies metastasized to the brain with high efficacy. Patients with well-controlled systemic disease and good performance status may benefit the most from definitive SRS while avoiding WBRT.

Suborgan Level Quantitation of Proteins in Tissues Delivered by Polymeric Nanocarriers.

Amidst the rapid growth of protein therapeutics as a drug class, there is an increased focus on designing systems to effectively deliver proteins to target organs. Quantitative monitoring of protein distributions in tissues is essential for optimal development of delivery systems; however, existing strategies can have limited accuracy, making it difficult to assess suborgan dosing. Here, we describe a quantitative imaging approach that utilizes metal-coded mass tags and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to quantify the suborgan distributions of proteins in tissues that have been delivered by polymeric nanocarriers. Using this approach, we measure nanomole per gram levels of proteins as delivered by guanidinium-functionalized poly(oxanorborneneimide) (PONI) polymers to various tissues, including the alveolar region of the lung. Due to the multiplexing capability of the LA-ICP-MS imaging, we are also able to simultaneously quantify protein and polymer distributions, obtaining valuable information about the relative excretion pathways of the protein cargo and carrier. This imaging approach will facilitate quantitative correlations between nanocarrier properties and protein cargo biodistributions.

Salvage Stereotactic Radiosurgery for Recurrent WHO Grade 2 and 3 Meningiomas: A Multicenter Study (STORM).

PURPOSE: The role of stereotactic radiosurgery (SRS) in the management of grade 2 and 3 meningiomas is not well elucidated. Unfortunately, local recurrence rates are high, and guidelines for management of recurrent disease are lacking. To address this knowledge gap, we conducted STORM (Salvage Stereotactic Radiosurgery for Recurrent WHO Grade 2 and 3 Meningiomas), a multicenter retrospective cohort study of patients treated with primary SRS for recurrent grade 2 and 3 meningiomas. METHODS AND MATERIALS: Data on patients with recurrent grade 2 and 3 meningioma treated with SRS at first recurrence were retrospectively collected from 8 academic centers in the United States. Patients with multiple lesions at the time of initial diagnosis or more than 2 lesions at the time of first recurrence were excluded from this analysis. Patient demographics and treatment parameters were extracted at time of diagnosis, first recurrence, and second recurrence. Oncologic outcomes, including progression-free survival (PFS) and overall survival, as well as toxicity outcomes, were reported at the patient level. RESULTS: From 2000 to 2022, 108 patients were identified (94% grade 2, 6.0% grade 3). A total of 106 patients (98%) had upfront surgical resection (60% gross-total resection) with 18% receiving adjuvant radiation therapy (RT). Median time to first progression was 2.5 years (IQR, 1.34-4.30). At first recurrence, patients were treated with single or fractionated SRS to a median marginal dose of 16 Gy to a maximum of 2 lesions (87% received single-fraction SRS). The median follow-up time after SRS was 2.6 years. The 1-, 2-, and 3-year PFS was 90%, 75%, and 57%, respectively, after treatment with SRS. The 1-, 2-, and 3-year overall survival was 97%, 94%, and 92%, respectively. In the multivariable analysis, grade 3 disease (HR, 6.80; 95% CI, 1.61-28.6), male gender (HR, 3.48; 95% CI, 1.47-8.26), and receipt of prior RT (HR, 2.69; 95% CI, 1.23-5.86) were associated with worse PFS. SRS dose and tumor volume were not correlated with progression. Treatment was well tolerated, with a 3.0% incidence of grade 2+ radiation necrosis. CONCLUSIONS: This is the largest multicenter study to evaluate salvage SRS in recurrent grade 2 and 3 meningiomas. In this select cohort of patients with primarily grade 2 meningioma with a potentially more favorable natural history of delayed, localized first recurrence amenable to salvage SRS, local control rates and toxicity profiles were favorable, warranting further prospective validation.

Determining a distributed parameter in a neural cable model via a boundary control method.

Dendrites of nerve cells have membranes with spatially distributed densities of ionic channels and hence non-uniform conductances. These conductances are usually represented as constant parameters in neural models because of the difficulty in experimentally estimating them locally. In this paper we investigate the inverse problem of recovering a single spatially distributed conductance parameter in a one-dimensional diffusion (cable) equation through a new use of a boundary control method. We also outline how our methodology can be extended to cable theory on finite tree graphs. The reconstruction is unique.

Outcomes of total knee replacement after patellofemoral arthroplasty.

There is increasing interest in the use of patellofemoral joint replacements and the cohort receiving them are the youngest of any of the groups of patients undergoing a knee arthroplasty. With more contemporary prostheses, progression of arthritis in other parts of the knee joint is becoming the predominant mechanism of failure. We conducted a multicenter retrospective comparative cohort study to discover whether the outcome of total knee replacement is compromised by prior patellofemoral joint arthroplasty. A total of 21 patients with a mean age of 61 years, who were revised from a patellofemoral joint replacement to a total knee replacement, were compared with a matched cohort of patients who underwent primary total knee replacement. At a mean follow-up of 2.4 years, the primary total knee replacement cohort had significantly better Oxford Knee Scores, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function scores, pain visual analog scores, and EQ-5D scores. There was no significant difference in patient satisfaction or EQ-5D visual analog scale.Our results indicate that although the revision of a patellofemoral joint replacement to a total knee replacement is a technically straightforward procedure, the eventual outcome may be less satisfactory when compared with a primary total knee replacement.

Practical Considerations During Brachytherapy Applicator Placement for Locally Advanced Cervical Cancer.

Brachytherapy is an integral part of the definitive treatment for locally advanced cervical cancer following external beam radiation therapy. Placement of brachytherapy applicators is an important skill for radiation oncologists and care must be taken to place applicators appropriately to limit complications associated with the procedure and ensure that the radiation dose sufficiently covers the target while sparing the surrounding organs at risk. Using example cases, we discuss strategies for the placement of brachytherapy applicators in patients with anatomical considerations such as large obstructing uterine fibroids and the retroverted uterus. We also discuss the management of uterine perforation during applicator placement and approaches to patients with a poor response to external beam radiation therapy before brachytherapy delivery. We draw upon the available literature and our clinical experience to suggest approaches to these challenging scenarios.

Delineation of recurrent glioblastoma by whole brain spectroscopic magnetic resonance imaging.

BACKGROUND: Glioblastoma (GBM) cellularity correlates with whole brain spectroscopic MRI (sMRI) generated relative choline to N-Acetyl-Aspartate ratio (rChoNAA) mapping. In recurrent GBM (rGBM), tumor volume (TV) delineation is challenging and rChoNAA maps may assist with re-RT targeting. METHODS: Fourteen rGBM patients underwent sMRI in a prospective study. Whole brain sMRI was performed to generate rChoNAA maps. TVs were delineated by the union of rChoNAA ratio over 2 (rChoNAA > 2) on sMRI and T1PC. rChoNAA > 2 volumes were compared with multiparametric MRI sequences including T1PC, T2/FLAIR, diffusion-restriction on apparent diffusion coefficient (ADC) maps, and perfusion relative cerebral blood volume (rCBV). RESULTS: rChoNAA > 2 (mean 27.6 cc, range 6.6-79.1 cc) was different from other imaging modalities (P ≤ 0.05). Mean T1PC volumes were 10.7 cc (range 1.2-31.4 cc). The mean non-overlapping volume of rChoNAA > 2 and T1PC was 29.2 cm3. rChoNAA > 2 was 287% larger (range 23% smaller-873% larger) than T1PC. T2/FLAIR volumes (mean 111.7 cc, range 19.0-232.7 cc) were much larger than other modalities. rCBV volumes (mean 6.2 cc, range 0.2-19.1 cc) and ADC volumes were tiny (mean 0.8 cc, range 0-3.7 cc). Eight in-field failures were observed. Three patients failed outside T1PC but within rChoNAA > 2. No grade 3 toxicities attributable to re-RT were observed. Median progression-free and overall survival for re-RT patients were 6.5 and 7.1 months, respectively. CONCLUSIONS: Treatment of rGBM may be optimized by sMRI, and failure patterns suggest benefit for dose-escalation within sMRI-delineated volumes. Dose-escalation and radiologic-pathologic studies are underway to confirm the utility of sMRI in rGBM.