Cytochrome P450-soluble epoxide hydrolase oxylipins, depression and cognition in type 2 diabetes.

AIMS: This study examined serum cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) oxylipins and depressive symptoms together in relation to cognitive performance in individuals with type 2 diabetes mellitus (T2DM). METHODS: Clinically cognitively normal T2DM individuals were recruited (NCT04455867). Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II; total scores ≤13 indicated minimal depressive symptoms and ≥ 14 indicated significant depressive symptoms). Executive function and verbal memory were assessed. Fasting serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass-spectrometry. RESULTS: The study included 85 participants with minimal depressive symptoms and 27 with significant symptoms (mean age: 63.3 ± 9.8 years, 49 % women). In all participants, higher concentrations of linoleic acid derived sEH (12,13-dihydroxyoctadecamonoenoic acid; DiHOME) and CYP450 (12(13)-epoxyoctadecamonoenoic acid; EpOME) metabolites were associated with poorer executive function (F1,101 = 6.094, p = 0.015 and F1,101 = 5.598, p = 0.020, respectively). Concentrations of multiple sEH substrates interacted with depressive symptoms to predict 1) poorer executive function, including 9(10)-EpOME (F1,100 = 12.137, p < 0.001), 5(6)-epoxyeicosatrienoic acid (5(6)-EpETrE; F1,100 = 6.481, p = 0.012) and 11(12)-EpETrE (F1,100 = 4.409, p = 0.038), and 2) verbal memory, including 9(10)-EpOME (F1,100 = 4.286, p = 0.041), 5(6)-EpETrE (F1,100 = 6.845, p = 0.010), 11(12)-EpETrE (F1,100 = 3.981, p = 0.049) and 14(15)-EpETrE (F1,100 = 5.019, p = 0.027). CONCLUSIONS: Associations of CYP450-sEH metabolites and depressive symptoms with cognition highlight the biomarker and therapeutic potential of the CYP450-sEH pathway in T2DM.

Normal and malaligned talonavicular fusion alters cadaveric foot pressure and kinematics.

Talonavicular (TN) fusion is a common treatment for TN arthritis or deformity correction. There is incongruous evidence regarding remaining motion at the talocalcaneal and calcaneocuboid joints after TN fusion. Additionally, the effects of a malaligned TN fusion are not well understood and alignment of the fusion may be important for overall foot integrity. This project assessed the kinematic and kinetic effects of neutral and malaligned TN fusions. Ten cadaveric feet were tested on a gait simulator in four conditions: unfused, fused in neutral, fused in varus, and fused in valgus. The fusions were simulated with external fixation hardware. An eight-camera motion analysis system and a 10-segment foot model generated kinematic data, and a pressure mat captured pressure data. Simulated TN fusion was achieved in eight feet. From unfused to fused-neutral, range of motion (ROM) was not eliminated in the adjacent joints, but the positions of the joints changed significantly throughout stance phase. Furthermore, the ROM increased at the tibiotalar joint. Plantar pressure and center of pressure shifted laterally with neutral fusion. The malalignments marginally affected the ROM but changed joint positions throughout stance phase. Pressure patterns were shifted laterally in varus malalignment and medially in valgus malalignment. The residual motion and the altered kinematics at the joints in the triple joint complex after TN fusion may subsequently increase the incidence of arthritis. Clinical significance: This study quantifies the effects of talonavicular fusion and malalignment on the other joints of the triple joint complex.

Genetic retargeting of E3 ligases to enhance CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapies are medical breakthroughs in cancer treatment. However, treatment failure is often caused by CAR T cell dysfunction. Additional approaches are needed to overcome inhibitory signals that limit anti-tumor potency. Here, we developed bifunctional fusion "degrader" proteins that bridge one or more target proteins and an E3 ligase complex to enforce target ubiquitination and degradation. Conditional degradation strategies were developed using inducible degrader transgene expression or small molecule-dependent E3 recruitment. We further engineered degraders to block SMAD-dependent TGFß signaling using a domain from the SARA protein to target both SMAD2 and SMAD3. SMAD degrader CAR T cells were less susceptible to suppression by TGFß and demonstrated enhanced anti-tumor potency in vivo. These results demonstrate a clinically suitable synthetic biology platform to reprogram E3 ligase target specificity for conditional, multi-specific endogenous protein degradation, with promising applications including enhancing the potency of CAR T cell therapy.

Extensive Perineural Invasion vs Nerve Caliber to Assess Cutaneous Squamous Cell Carcinoma Prognosis.

Importance: Perineural invasion (PNI) is an adverse risk feature in cutaneous squamous cell carcinoma (CSCC) that affects patient prognosis and disease management. However, research comparing different PNI patterns on patient outcomes is limited. Objective: To compare 4 assessments of PNI in CSCC, their associations with poor outcomes, and implications for their inclusion in the Brigham and Women's Hospital (BWH) staging system. Design, Setting, and Participants: This retrospective cohort study was performed at a single tertiary care institution and compared 4 PNI assessments: nerve caliber, number of involved nerves per section, PNI maximal depth, and PNI location with respect to tumor. Patients with primary, localized, invasive CSCC with PNI diagnosed between January 1, 2000, and December 31, 2017, were identified via an electronic in-house database. Available pathology slides were secondarily reviewed by study authors. Relevant patient and tumor characteristics and outcomes were abstracted from the medical record. Data analysis was performed between September 6 and October 20, 2022. Main Outcomes and Measures: Risks of recurrence, disease-specific death, and a composite end point (any poor outcome) were calculated via multivariable stepwise Fine and Gray competing-risks regression. Considered revisions to the BWH staging system were assessed via receiver operating characteristic curves and test characteristics. Results: This study included 140 patients with CSCC, with a mean (SD) age of 75.1 (11.2) years. More than half of the patients were men (93 [66.4%]), and most identified as White (132 [94.3%]). Of the 4 PNI assessments studied, only involvement of multiple nerves was associated with poor outcomes. Perineural invasion of 5 or more distinct nerves (extensive PNI [ePNI]) was independently associated with local recurrence (subhazard ratio [SHR], 13.83 [95% CI, 3.50-54.62]; P < .001), disease-specific death (SHR, 6.20 [95% CI, 1.59-24.21]; P = .009), and any poor outcome (SHR, 10.21 [95% CI, 2.88-36.15]; P < .001). A revised BWH staging system with substitution of ePNI for large-caliber PNI resulted in improved area under the curve and test characteristics compared with current BWH staging criteria that use nerve caliber as the measure of PNI. Conclusions and Relevance: The findings of this cohort study suggest that ePNI is the best prognostic measure of PNI. Because ePNI obviated the need for a micrometer and had superior prognostic capacity to nerve caliber in this cohort, ePNI should be considered for inclusion in CSCC tumor staging. Inclusion of ePNI as a high-risk factor in CSCC staging systems may optimize patient selection for primary treatment and adjuvant interventions.

Persistence of long-term insulin independence after islet transplantation and two subsequent pregnancies.

Pregnancy increases metabolic demand for insulin and may lead to the exhaustion of intraportally transplanted islets and post-gestational hyperglycemia. To prevent these complications, we implemented preemptive insulin supplementation during two subsequent pregnancies in an insulin-independent islet transplant recipient. This strategy resulted in optimal blood glucose control during the pregnancies, the preservation of the optimal islet graft function and the postpartum maintenance of long-term insulin independence.

Adrenergic nerves regulate intestinal regeneration through IL-22 signaling from type 3 innate lymphoid cells.

The intestinal epithelium has high intrinsic turnover rate, and the precise renewal of the epithelium is dependent on the microenvironment. The intestine is innervated by a dense network of peripheral nerves that controls various aspects of intestinal physiology. However, the role of neurons in regulating epithelial cell regeneration remains largely unknown. Here, we investigated the effects of gut-innervating adrenergic nerves on epithelial cell repair following irradiation (IR)-induced injury. We observed that adrenergic nerve density in the small intestine increased post IR, while chemical adrenergic denervation impaired epithelial regeneration. Single-cell RNA sequencing experiments revealed a decrease in IL-22 signaling post IR in denervated animals. Combining pharmacologic and genetic tools, we demonstrate that ß-adrenergic receptor signaling drives IL-22 production from type 3 innate lymphoid cells (ILC3s) post IR, which in turn promotes epithelial regeneration. These results define an adrenergic-ILC3 axis important for intestinal regeneration.

Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases.

Type 2 diabetes mellitus (T2DM) and hypertension are risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, PVS in the white matter (wmPVS) or basal ganglia (bgPVS), and diffusion metrics in white matter. Patients with T2DM had greater wmPVS volume and there were greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found indirect effects of T2DM on volumes of other SVD and diffusion markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, and progression of deep lacunes over 1 year, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal mechanisms that mediate the impact of T2DM on cerebral small vessels.

Cytochrome P450-soluble epoxide hydrolase derived linoleic acid oxylipins and cognitive performance in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) increases the risk of cognitive decline and dementia. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been reported in T2DM, obesity and cognitive impairment. We examine linoleic acid (LA)-derived CYP450-sEH oxylipins and cognition in T2DM and explore potential differences between obese and nonobese individuals. The study included 51 obese and 57 nonobese participants (mean age 63.0 ± 9.9, 49% women) with T2DM. Executive function was assessed using the Stroop Color-Word Interference Test, FAS-Verbal Fluency Test, Digit Symbol Substitution Test, and Trails Making Test-Part B. Verbal memory was assessed using the California Verbal Learning Test, second Edition. Four LA-derived oxylipins were analyzed by ultra-high-pressure-LC/MS, and the 12,13-dihydroxyoctadecamonoenoic acid (12,13-DiHOME) considered the main species of interest. Models controlled for age, sex, BMI, glycosylated hemoglobin A1c, diabetes duration, depression, hypertension, and education. The sEH-derived 12,13-DiHOME was associated with poorer executive function scores (F1,98 = 7.513, P = 0.007). The CYP450-derived 12(13)-epoxyoctadecamonoenoic acid (12(13)-EpOME) was associated with poorer executive function and verbal memory scores (F1,98 = 7.222, P = 0.008 and F1,98 = 4.621, P = 0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F1,97 = 5.498, P = 0.021) and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F1,97 = 4.126, P = 0.045), predicting executive function such that relationships were stronger in obese individuals. These findings suggest that the CYP450-sEH pathway as a potential therapeutic target for cognitive decline in T2DM. For some markers, relationships may be obesity dependent.

Localised chronic fibrosing vasculitis versus erythema elevatum diutinum.

A woman in her 70s was referred for a painless plaque on the shin, present for 2 years and progressing in thickness. Examination revealed a large erythematous to violaceous indurated plaque with cobblestone appearance. Biopsy revealed an inflammatory infiltrate of neutrophils with scattered histiocytes, lymphocytes, eosinophils and plasma cells interspersed with areas of lamellar fibrosis and focal areas of vascular damage, suggestive of a localised chronic fibrosing vasculitis of the skin. Localised chronic fibrosing vasculitis is a rare dermatosis, typically presenting as ulcerated violet-red nodules, which can appear histologically similar to erythema elevatum diutinum (EED), which typically presents as red-brown annular plaques. EED may have a predominance of neutrophils and granulomas, while chronic fibrosing vasculitis may have a sparse infiltrate of mixed inflammatory cells without granulomas. While dapsone is a first-line treatment for EED, there are no formal guidelines on the treatment of localised chronic fibrosing vasculitis. Given the neutrophils in this sample and similarities with EED, this patient was treated with oral dapsone, resulting in plaque improvement.

Unsupervised Phenotype-Based Clustering of Clinicopathologic Features in Cutaneous Melanoma.

Pathogenic phenotypes in cutaneous melanoma have been vastly cataloged, although these classifications lack concordance and are confined to either morphological or molecular contexts. In this study, we perform unsupervised k-medoids clustering as a machine learning technique of 2,978 primary cutaneous melanomas at Mass General Brigham and apply this information to elucidate computer-defined subsets within the clinicopathologic domain. We identified five optimally separated clusters of melanoma that occupied two distinct clinicopathologic subspaces: a lower-grade partition associated with common or dysplastic nevi (i.e., nevus-associated melanomas) and a higher-grade partition lacking precursor lesions (i.e., de novo melanomas). Our model found de novo melanomas to be more mitogenic, more ulcerative, and thicker than nevus-associated melanomas, in addition to harboring previously unreported differences in radial and vertical growth phase status. The utilization of mixed clinicopathologic variables, reflective of actual clinical data contained in surgical pathology reports, has the potential to increase the biological relevance of existing melanoma classification schemes and facilitate the discovery of new genomic subtypes.

Improving timeliness in the neglected tropical diseases preventive chemotherapy donation supply chain through information sharing: A retrospective empirical analysis.

BACKGROUND: Billions of doses of medicines are donated for mass drug administrations in support of the World Health Organization's "Roadmap to Implementation," which aims to control, eliminate, and eradicate Neglected Tropical Diseases (NTDs). The supply chain to deliver these medicines is complex, with fragmented data systems and limited visibility on performance. This study empirically evaluates the impact of an online supply chain performance measurement system, "NTDeliver," providing understanding of the value of information sharing towards the success of global health programs. METHODS: Retrospective secondary data were extracted from NTDeliver, which included 1,484 shipments for four critical medicines ordered by over 100 countries between February 28, 2006 and December 31, 2018. We applied statistical regression models to analyze the impact on key performance metrics, comparing data before and after the system was implemented. FINDINGS: The results suggest information sharing has a positive association with improvement for two key performance indicators: purchase order timeliness (ß = 0.941, p = 0.003) and-most importantly-delivery timeliness (ß = 0.828, p = 0.027). There is a positive association with improvement for three variables when the data are publicly shared: shipment timeliness (ß = 2.57, p = 0.001), arrival timeliness (ß = 2.88, p = 0.003), and delivery timeliness (ß = 2.82, p = 0.011). CONCLUSIONS: Our findings suggest that information sharing between the NTD program partners via the NTDeliver system has a positive association with supply chain performance improvements, especially when data are shared publicly. Given the large volume of medicine and the significant number of people requiring these medicines, information sharing has the potential to provide improvements to global health programs affecting the health of tens to hundreds of millions of people.

Associations of Endometriosis and Hormone Therapy With Risk of Hyperlipidemia.

Using claims data from the universal health insurance program of Taiwan, we conducted a retrospective cohort study to investigate whether endometriosis and hormone therapy are associated with the risk of developing hyperlipidemia. We selected 9,155 women aged 20-55 years with endometriosis diagnosed during the period 2000-2013 and 212,641 women without endometriosis with a median follow-up time of 7 years. Among patients with endometriosis, 86% of cases were identified on the basis of diagnosis codes with an ultrasound claim, and 14% were defined by diagnostic laparoscopy or surgical treatments. In a Cox proportional hazards model, the adjusted hazard ratio was 1.30 (95% confidence interval (CI): 1.19, 1.41) for all women, 1.04 (95% CI: 0.81, 1.32) for women under 35 years of age, 1.17 (95% CI: 1.03, 1.32) for women aged 35-44 years, and 1.34 (95% CI: 1.18, 1.52) for women aged 45-54 years. Hysterectomy and/or bilateral oophorectomy accounted for 46.9% of the association between endometriosis and hyperlipidemia, and hormone therapy accounted for 21.6%. Among women with endometriosis, the marginal structural model approach adjusting for time-varying hysterectomy/bilateral oophorectomy showed no association between use of hormone medications and risk of hyperlipidemia. We concluded that women with endometriosis are at increased risk of hyperlipidemia; use of hormone therapy by these women was not independently associated with the development of hyperlipidemia.

Novel gel bolus to improve impedance-based measurements of esophageal cross-sectional area during primary peristalsis.

INTRODUCTION: Intraluminal esophageal impedance (ILEE) has the potential to measure esophageal luminal distension during swallow-induced peristalsis in the esophagus. A potential cause of inaccuracy in the ILEE measurement is the swallow-induced air in the bolus. AIM: Compare a novel gel bolus to the current alternatives for the measurement of impedance-based luminal distension (cross-sectional area, CSA) during primary peristalsis. METHODS: 12 healthy subjects were studied using high-resolution impedance manometry (HRMZ) and concurrently performed intraluminal ultrasound (US) imaging of the esophagus. Three test bolus materials were used: 1) novel gel, 2) 0.5 N saline, and 3) commercially available Diversatek EFTV viscous. Testing was performed in the supine and Trendelenburg (-15°) positions. US imaging assessed air in the bolus and luminal CSA. The Nadir impedance values were correlated to the US measured CSA. A custom Matlab software was used to assess the bolus travel times and impedance-based luminal CSA. RESULTS: The novel gel bolus had the least amount of air in the bolus during its passage through the esophagus, as assessed by US image analysis. The novel gel bolus in the supine and Trendelenburg positions had the best linear fit between the US measured CSA and nadir impedance value (R2  = 0.88 & R2  = 0.90). The impedance-based calculation of the CSA correlated best with the US measured CSA with the use of the novel gel bolus. CONCLUSION: We suggest the use of novel gel to assess distension along with contraction during routine clinical HRM testing.

Use of Targeted Next-Generation Sequencing to Identify Activating Hot Spot Mutations in Cherry Angiomas.

Importance: Shared gene variants in benign-malignant process pairs, such as BRAF mutations common to benign nevi and melanoma, are associated with differing phenotypic manifestations. Study of gene mechanisms underlying cherry angioma may uncover previously unknown disease relationships. Objective: To identify somatic mutations present in cherry angioma specimens by using targeted next-generation sequencing. Design, Setting, and Participants: In a single-center case series, 10 formalin-fixed, paraffin-embedded cherry angioma specimens from biopsies performed at Massachusetts General Hospital in Boston from July 10, 2016, to January 23, 2018, were obtained and underwent sequencing across a panel of 323 genes most relevant to cancer. Somatic mutations were curated by excluding variants that were presumed to be germline or of low mapping quality. Main Outcomes and Measures: Identification of somatic mutations associated with cherry angiomas. Results: In 10 cherry angioma tissue samples originating from 6 female and 4 male patients with a median (range) age of 54 (26-79) years, 5 samples (50%) revealed somatic missense mutations in GNAQ (Q209H, Q209R, and R183G) and GNA11 (Q209H). Individually, these mutational hot spots are known to be involved in entities that include congenital and anastomosing hemangiomas, hepatic small-vessel neoplasms (Q209), port-wine stains, and Sturge-Weber syndrome (R183). Both hot spots are associated with blue nevi, melanoma associated with blue nevus, and uveal melanoma. Conclusions and Relevance: In this case series study, the high prevalence of 5 known genetic drivers within the benign cherry angioma entity appears to support the context-dependent role of gene alterations in both benign and malignant proliferations from various cellular origins.

Clinical spectrum of cutaneous melanoma morphology.

BACKGROUND: Melanoma can mimic other cutaneous lesions, but the full spectrum and prevalence of these morphologic variants remain largely unknown. OBJECTIVE: To classify nonacral cutaneous melanomas into distinct morphologic clusters and characterize clusters' clinicopathologic features. METHODS: All pathologic melanoma diagnoses (occurring during 2011-2016) were reviewed for routine prebiopsy digital photographs (n = 400). Six dermatologists independently assigned lesions into 1 of 14 diagnostic classes on the basis of morphology. Image consensus clusters were generated by K-means; clinicopathologic features were compared with analysis of variance and χ2. RESULTS: Five morphologic clusters were identified: typical (n = 136), nevus-like (n = 81), amelanotic/nonmelanoma skin cancer (NMSC)-like (n = 70), seborrheic keratosis (SK)-like (n = 68), and lentigo/lentigo maligna (LM)-like (n = 45) melanomas. Nevus-like melanomas were found in younger patients. Nevus-like and lentigo/LM-like melanomas tended to be thinner and more likely identified on routine dermatologic examinations. NMSC-like melanomas were tender, thicker, more mitotically active, and associated with prior NMSC. Typical and SK-like melanomas had similar clinicopathologic features. LIMITATIONS: Cluster subdivision yielded diminished sample sizes. Visual assignment was performed without clinical context. CONCLUSION: When primary cutaneous melanomas were assigned into diagnostic groups and subjected to novel consensus clustering, recurrent morphologic patterns emerged. The spectrum of these morphologies was unexpectedly diverse, which might have implications for visual training and possibly clinical diagnosis.

PROMISE international; a clinical post marketing trial investigating the percutaneous deep vein arterialization (LimFlow) in the treatment of no-option chronic limb ischemia patient.

BACKGROUND: Critical limb ischemia (CLI) is the clinical end stage of peripheral artery disease and is associated with high amputation, mortality rates and poor quality of life. For CLI patients with no revascularization options, venous arterialization could be an alternative technique for limb salvage. A systematic review and meta-analysis published in 2017 concluded that venous arterialization may be considered a viable alternative. A recent development, is the Percutaneous Deep Vein Arterialization (pDVA), that is CE-marked and currently under investigation of the FDA. This procedure, called LimFlow, is a novel, minimally invasive, endovascular approach to perform a venous arterialization procedure. The limited evidence for its use necessitates a scientific judgement of the pDVA. Therefore, we initiated a prospective clinical post market trial to investigate the outcome of the pDVA in no-option critical limb ischemia. METHODS/DESIGN: The objective of this prospective study is to collect "real-life" clinical data among a population of patients treated with the pDVA in order to evaluate the clinical effectiveness and safety of the LimFlow System in patients with no-option critical limb ischemia. This study is a single-arm, open-label, prospective, post-market follow-up study to be conducted on up to fifty (50) eligible patients with a twelve-month follow-up period. The Primary endpoint is measured by amputation free survival. Secondary endpoints are complete wound healing, primary and secondary patency, limb salvage, renal function and technical and procedural success. Patients will be assessed at regular intervals during one year after the initial percutaneous deep vein arterialization procedure through clinical evaluation and self-completed questionnaires. DISCUSSION: The last decade several studies have been published with promising results and the number of treated patients has considerably grown. Venous arterialization could be a valuable treatment option in patients with often no other options than amputation of the affected limb. The first results in men are promising although more research and long term follow up is needed to establish the efficacy of this new treatment modality. With this prospective study, we evaluate the clinical effectiveness and safety in patients with no-option CLI treated with the pDVA (LimFlow System). TRIAL REGISTRATION: NCT03321552 .

Sustainable access to deworming drugs in a changing landscape.

The global effort to control and eliminate soil-transmitted helminthiasis (STH) currently depends on donations of albendazole and mebendazole, which reached more than 530 million children in 2016. As we approach 2020, the WHO goal of eliminating STH as a public health problem will not be met in most endemic countries, and ongoing treatment will be necessary. Additionally, the volume of drugs required might increase because global strategies for STH aim to interrupt transmission. Under the 2012 London Declaration on Neglected Tropical Diseases, pharmaceutical company commitments to donate drugs to control or eliminate neglected tropical diseases extend to 2020. We are approaching a period of uncertainty regarding different strategies for control and elimination of STH, the size and target populations for future donations, and optimum drugs and drug combinations. Long-term reliance on large-scale donation of deworming drugs is not sustainable. The global STH community need to develop a strategy to secure a sustainable global supply of affordable and effective anthelmintic drugs. This strategy should include improvement of the quality of generic drugs through innovative technical partnerships.