Increased mTORC2 pathway activation in lymph nodes of iMCD-TAFRO.

Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening haematologic disorder involving polyclonal lymphoproliferation and organ dysfunction due to excessive cytokine production, including interleukin-6 (IL-6). Clinical trial and real-world data demonstrate that IL-6 inhibition is effective in 34-50% of patients. mTOR, which functions through mTORC1 and mTORC2, is a recently discovered therapeutic target. The mTOR inhibitor sirolimus, which preferentially inhibits mTORC1, has led to sustained remission in a small cohort of anti-IL-6-refractory iMCD patients with thrombocytopenia, anasarca, fever, renal dysfunction and organomegaly (iMCD-TAFRO). However, sirolimus has not shown uniform effect, potentially due to its limited mTORC2 inhibition. To investigate mTORC2 activation in iMCD, we quantified the mTORC2 effector protein pNDRG1 by immunohistochemistry of lymph node tissue from six iMCD-TAFRO and eight iMCD patients who do not meet TAFRO criteria (iMCD-not-otherwise-specified; iMCD-NOS). mTORC2 activation was increased in all regions of iMCD-TAFRO lymph nodes and the interfollicular space of iMCD-NOS compared with control tissue. Immunohistochemistry also revealed increased pNDRG1 expression in iMCD-TAFRO germinal centres compared with autoimmune lymphoproliferative syndrome (ALPS), an mTOR-driven, sirolimus-responsive lymphoproliferative disorder, and comparable staining between iMCD-NOS and ALPS. These results suggest increased mTORC2 activity in iMCD and that dual mTORC1/mTORC2 inhibitors may be a rational therapeutic approach.

Synthetically Tunable White-, Green-, and Yellow-Green-Light Emission in Dual-Luminescent Gold(I) Complexes Bearing a Diphenylamino-2,7-fluorenyl Moiety.

The syntheses and photophysical characterization of five new gold(I) complexes bearing diphenylamine-substituted fluorenyl moieties are reported; four are characterized by X-ray diffraction crystallography. Ancillary ligation on gold(I) is provided by organophosphine and N-heterocyclic carbene ligands. Two complexes, Au-DPA0 and Au-DPA1, are σ-aryls, two, Au-ADPA0 and Au-ADPA1, are σ-alkynyls, and one, Au-TDPA1, is a σ-triazolyl bound through carbon. All complexes show vibronically structured absorption and luminescence bands that are assignable to π-π* transitions localized on the diphenylamine-substituted fluorenyl π system. The excited-state dynamics of all five chromophores are governed by selection of the ancillary ligand and σ attachment of the diphenylamine-substituted fluorenyl moiety. All of these chromophores are dual luminescent in a toluene solution at 298 K. The luminescence from the aryl derivatives, Au-ADPA0 and Au-DPA1, appears green. The alkynyl derivative containing a phosphine ancillary ligand, Au-ADPA0, is a white-light emitter, while the alkynyl derivative containing an N-heterocyclic carbene ancillary ligand, Au-ADPA1, is a yellow-light emitter. The luminescence from the triazolyl-linked chromophore, Au-TDPA1, appears as yellow-green. Spin-restricted density functional theory calculations support the assignments of ligand-centric optical transitions but with contributions of ligand-to-metal charge transfer involving the vacant Au 6p orbital.

Novel somatic alterations in unicentric and idiopathic multicentric Castleman disease.

OBJECTIVES: Castleman disease (CD) is a heterogeneous group of disorders involving systemic inflammation and lymphoproliferation. Recently, clonal mutations have been identified in unicentric CD (UCD) and idiopathic multicentric CD (iMCD), suggesting a potential underlying neoplastic process. METHODS: Patients with UCD or iMCD with next generation sequencing (NGS) data on tissue DNA and/or circulating tumor DNA (ctDNA) were included. RESULTS: Five patients were included, 4 with iMCD and 1 with UCD. Four patients (80%) were women; median age was 40 years. Three of five patients (60%) had ≥1 clonal mutation detected on biopsy among the genes included in the panel. One patient with iMCD had a 14q32-1p35 rearrangement and a der(1)dup(1)(q42q21)del(1)(q42) (1q21 being IL-6R locus) on karyotype. This patient also had a NF1 K2459fs alteration on ctDNA (0.3%). Another patient with iMCD had a KDM5C Q836* mutation, and one patient with UCD had a TNS3-ALK fusion but no ALK expression by immunohistochemistry. CONCLUSIONS: We report 4 novel somatic alterations found in patients with UCD or iMCD. The 1q21 locus contains IL-6R, and duplication of this locus may increase IL-6 expression. These findings suggest that a clonal process may be responsible for the inflammatory phenotype in some patients with UCD and iMCD.

Zn Coordination and the Identity of the Halide Ancillary Ligand Dramatically Influence the Excited-State Dynamics and Bimolecular Reactions of 2,3-Di(pyridin-2-yl)benzo[g]quinoxaline.

The optical properties of coordination complexes with ligands containing nitrogen heterocycles have been extensively studied for decades. One subclass of these materials, metal complexes utilizing substituted pyrazines and quinoxalines as ligands, has been employed in a variety of photochemical applications ranging from photodynamic therapy to organic light-emitting diodes. A vast majority of this work focuses on characterization of the metal-to-ligand charge-transfer states in these metal complexes; however, literature reports rarely investigate the photophysics of the parent pyrazine or quinoxaline ligand or perform control experiments utilizing metal complexes that lack low-lying charge-transfer (CT) states in order to determine how metal-atom coordination influences the photophysical properties of the ligand. With this in mind, we examined the steady-state and time-resolved photophysics of 2,3-di(pyridin-2-yl)benzo[g]quinoxaline (dpb) and explored how the coordination of ZnX2 (X = Cl-, Br-, I-) affects the photophysical properties of dpb. In dpb, we find that the dominant mode of deactivation from the singlet excited state is intersystem crossing (ISC). Coordination of ZnX2 perturbs the relative energies of the ππ* and nπ* excited states of dpb, leading to drastically different rates of ISC as well as radiative and nonradiative decay in the [Zn(dpb)X2] complexes compared to dpb. These differences in the rates change the dominant singlet-excited-state decay pathway from ISC in dpb to a mixture of ISC and fluorescence in [Zn(dpb)Cl2] and [Zn(dpb)Br2] and to nonradiative decay in [Zn(dpb)I2]. Coordination of ZnX2 and the choice of the halide ligand also have profound effects on the rate constants for excited-state bimolecular reactions, including triplet-triplet annihilation and oxygen quenching. These results demonstrate that metal coordination, even in complexes lacking low-lying CT states, and the choice of the ancillary ligand can dramatically alter the photophysical properties of chromophores containing nitrogen heterocycles.

From Dipyrrolonaphthyridinediones to Quinazolinoindolizinoindolizinoquinazolines.

The dipyrrolonaphthyridinedione (DPND) core can be readily converted into a series of acid-responsive quinazolinoindolizinoindolizinoquinazolines through a two-step route involving direct arylation followed by acid-catalyzed condensation. Unlike the majority of previously obtained DPNDs, these nonplanar dyes bearing eight fused rings are almost nonfluorescent, which is attributed to fast internal conversion relative to radiative decay and intersystem crossing.

Synthesis and photophysics of gold(i) alkynyls bearing a benzothiazole-2,7-fluorenyl moiety: a comparative study analyzing influence of ancillary ligand, bridging moiety, and number of metal centers on photophysical properties.

Three new gold(i) alkynyl complexes (Au-ABTF(0-2)) containing a benzothiazole fluorenyl moiety, with either an organic phosphine or N-heterocyclic carbene as ancillary ligand, have been synthesized and photophysically characterized. All three complexes display highly structured ground-state absorption and luminescence spectra. Dual-luminescence is observed in all three complexes at room temperature in toluene after three freeze-pump-thaw cycles. The phosphine complexes (Au-ABTF(0-1)) exhibit similar photophysics with fluorescent quantum yields ∼0.40, triplet-state quantum yields ∼0.50, and fluorescent lifetimes ∼300 ps. The carbene complex Au-ABTF2 displays different behavior; having a fluorescent quantum yield of 0.23, a triplet-state quantum yield of 0.61, and a fluorescent lifetime near 200 ps, demonstrating that the ancillary ligand alters excited-state dynamics. The compounds exhibit strong (on the order of 105 M-1 cm-1) and positive excited-state absorption in both their singlet and triplet excited states spanning the visible region. Delayed fluorescence resulting from triplet-triplet annihilation is also observed in freeze-pump-thaw deaerated samples of all the complexes in toluene. DFT calculations (both static and time-resolved) agree with the photophysical data where phosphine complexes have slightly larger S1-T2 energy gaps (0.28 eV and 0.26 eV) relative to the carbene complex (0.21 eV). Comparison of the photophysical properties of Au-ABTF(0-2) to previously published dinuclear gold(i) complexes and mononuclear gold(i) aryl complexes bearing the same benzothiazole-2,7-fluorenyl moiety are made. Structure-property relationships regarding ancillary ligand, bridging moiety, and number of metal centers are drawn.

Influence of Structural Isomerism on the Photophysical Properties of a Series of Donor-Acceptor 1-Naphthalenecarbonitrile Derivatives Possessing Amine Substituents.

In an effort to probe the influence of structural isomerism on the excited-state properties of a naphthalene-based donor-acceptor (D-A) system, four 1-naphthalenecarbonitrile compounds with amine substituents in the 2-, 3-, and 4-positions were synthesized and their photophysical properties were examined. Specifically, the molecules 2-dimethylamino-1-naphthalenecarbonitrile (2DA), 2-(1-piperidinyl)-1-naphthalenecarbonitrile (2P), 3-dimethylamino-1-naphthalenecarbonitrile (3DA), and 4-(1-piperidinyl)-1-naphthalenecarbonitrile (4P) were studied. The substitution position of the amine donor has a significant impact on both the ground-state absorption and excited-state properties of the complexes in toluene solution. The energy, band shape, and extinction coefficient of the ground-state absorption spectra are highly dependent on the substitution position of the amine donor. All of the derivatives exhibit fluorescence at room temperature. The fluorescence observed from 2DA, 2P, and 3DA demonstrates a vibronic structure with all three molecules possessing Stokes shifts on the order of 40 nm, whereas the fluorescence observed from 4P is broad and has a Stokes shift 2 times greater than the other derivatives. The fluorescence lifetimes, fluorescence quantum yields, and intersystem crossing quantum yields vary greatly with the substitution position of the amine donor. 2DA and 2P display intermediate fluorescence lifetimes (2.7 ns) and fluorescence quantum yields (0.20) while possessing the greatest intersystem quantum yield (0.80). 3DA has a much greater fluorescence lifetime (16.9 ns) and fluorescence quantum yield (0.82) at the expense of the intersystem crossing quantum yield (0.12). 4P has the shortest lifetime (0.53 ns), with the lowest fluorescence and intersystem crossing quantum yields (<0.05). The singlet-triplet energy gaps are nearly identical for 2DA, 2P, and 3DA with values on the order of 0.70 eV. This singlet-triplet gap is larger in 4P, with a calculated value of 0.94 eV. The triplet-triplet absorption spectra of 2DA, 2P, and 3DA are similar. Broad peaks in the UV and visible regions with maxima around 330 and 500 nm characterize all three spectra. The triplet excited-state extinction coefficient values for 3DA were found to be 1.5 times larger than those in 2DA and 2P. The triplet-triplet absorption spectrum of 4P is markedly different from the triplet-triplet absorption spectra of the other derivatives. The spectrum is broad, with the four local maxima observed at 374, 445, 624, and 774 nm. All four molecules display delayed fluorescence and laser-power-dependent triplet excited-state decay kinetics, indicating the involvement of triplet-triplet annihilation in the deactivation of the triplet excited states. Both the intrinsic triplet lifetimes and triplet-triplet annihilation rate constants were determined. These values are similar for all of the derivatives with triplet lifetimes on the order of 100 µs and diffusion-controlled rates of triplet-triplet annihilation.

Adolescent Preferences for a Pediatric Primary Care-based Sexually Transmitted Infection and HIV Prevention Intervention.

PURPOSE: We sought to elicit perspectives on HIV and sexually transmitted infection (STI) prevention among adolescents with recent STIs in primary care to optimize acceptability and effectiveness in designing a novel HIV/STI prevention intervention. METHODS: We enrolled 13-19 year-olds with recent gonorrhea, chlamydia, trichomonas, and/or syphilis in a multimethods cross-sectional study at two primary care clinics. Participants completed surveys and interviews. We used an integrated analytic approach deductively coding data using the Integrated Behavioral Model, then inductively coding to identify themes not represented in the Integrated Behavioral Model. RESULTS: Participants (n = 35) were 85% cisgender female, 14% cisgender male, 1% transgender female; 25% identified as lesbian, bisexual, or queer. Most (97%) identified as non-Latinx Black. None used condoms consistently, 26% were aware of pre-exposure prophylaxis (PrEP), and 31% were never HIV tested. Five key themes emerged. 1) Mental health was central to HIV prevention behavior uptake and coping with STI diagnosis. 2) Youth desired prevention counseling that allowed decisional autonomy and individualized goal setting. 3) Negative social norms around condoms and absent norms around HIV testing and PrEP limited method uptake. 4) Both confidence and concrete skills were needed to initiate prevention methods. 5) Youth desired education at the time of STI diagnosis to improve subsequent prevention decision making. DISCUSSION: Key intervention design considerations included 1) integrating mental health assessment and referral to services, 2) promoting individualized goal setting, 4) building communication skills, 4) providing navigation and material support for PrEP uptake and HIV testing, and 5) augmenting comprehensive STI and HIV prevention education.

Evaluation of secondary electronic cigarette inhalation on lipid metabolism in C57BL/6J mice using indirect calorimetry.

The disruption of glucose homeostasis associated with the use of nicotine delivery systems may be due to a shift to lipid metabolism. Indirect calorimetry was used to measure the respiratory exchange ratio (RER) in female (N = 21) and male (N = 21) C57BL/6J mice exposed to room air (control) or e-cigarette vapor in a 1L chamber to test the hypothesis that lipid metabolism predominates in vaped mice. Metabolism was quantified via RER using a GA-200 gas analyzer (iWorx, Inc) and LabScribe v.4 (iWorx, Inc.) software. Blood glucose levels were assessed from a subset of the population using an Accu-Check glucometer (Roche Diagnostics, Inc.). Statistical analyses were conducted using R v.4.0.3. Median RER for controls was lower in females. Older females showed a reduction in RER when exposure occurred in the afternoon (p < 0.001), and in males when exposure occurred in the morning (p = 0.007). Glucose concentrations (mg/dL) were higher after e-cigarette inhalation compared with controls, but this difference was not significant (p = 0.464). The reduction in the respiratory exchange ratio supports the hypothesis that e-cigarette inhalation promotes lipid metabolism, and the magnitude of the effect is influenced by gender, age and time of day.

TAFRO Syndrome and Elusive Diagnosis of Idiopathic Multicentric Castleman Disease Treated with Empiric Anti-Interleukin-6 Therapy.

TAFRO syndrome is defined by the presence of thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis/renal dysfunction (R), and organomegaly (O) and can be seen with idiopathic multicentric Castleman disease (iMCD) or as an isolated process without iMCD. Although the diagnosis of iMCD in patients with TAFRO can be challenging to make, iMCD should remain high on the differential diagnosis. Similar to iMCD, the pathophysiology of TAFRO is not well understood but is thought to be related to hypercytokinemia, with interleukin (IL)-6 playing a pivotal role. Anti-IL-6 monoclonal antibody therapy is an effective treatment modality for iMCD, but to date, there is no clear guidance on treatment of TAFRO in the absence of definitive diagnosis of iMCD, leading to suboptimal management and high morbidity. We report a case of TAFRO syndrome and demonstrate benefit with the empiric use of anti-IL-6 antibody therapy in the context of delayed diagnosis of iMCD.

Acceptability, Feasibility, and Quality of Telehealth for Adolescent Health Care Delivery During the COVID-19 Pandemic: Cross-sectional Study of Patient and Family Experiences.

BACKGROUND: Data regarding the acceptability, feasibility, and quality of telehealth among adolescents and young adults (AYA) and their parents and caregivers (caregivers) are lacking. OBJECTIVE: The aim of this study was to assess the noninferiority of telehealth versus in-person visits by comparing acceptability with respect to efficiency, effectiveness, equity, patient-centeredness, and confidentiality. METHODS: Cross-sectional web-based surveys were sent to caregivers and AYA following video visits within an Adolescent Medicine subspecialty clinic in May-July 2020. Proportions of AYA and caregivers who rated telehealth as noninferior were compared using chi-squared tests. Feasibility was assessed via items measuring technical difficulties. Deductive thematic analysis using the Institute of Medicine dimensions of health care quality was used to code open-ended question responses. RESULTS: Survey response rates were 20.5% (55/268) for AYA and 21.8% (123/563) for caregivers. The majority of the respondents were White cisgender females. Most AYA and caregivers rated telehealth as noninferior to in-person visits with respect to confidentiality, communication, medication management, and mental health care. A higher proportion of AYA compared to caregivers found telehealth inferior with respect to confidentiality (11/51, 22% vs 3/118, 2.5%, P<.001). One-quarter (14/55) of the AYA patients and 31.7% (39/123) of the caregivers reported technical difficulties. The dominant themes in the qualitative data included advantages of telehealth for efficiency and equity of health care delivery. However, respondents' concerns included reduced safety and effectiveness of care, particularly for patients with eating disorders, owing to lack of hands-on examinations, collection of vital signs, and laboratory testing. CONCLUSIONS: Telehealth was highly acceptable among AYA and caregivers. Future optimization should include improving privacy, ameliorating technical difficulties, and standardizing at-home methods of obtaining patient data to assure patient safety.

Photophysical properties of organogold(i) complexes bearing a benzothiazole-2,7-fluorenyl moiety: selection of ancillary ligand influences white light emission.

Herein we report three new gold(i) complexes with a benzothiazole-2,7-fluorenyl moiety bound through a gold-carbon σ-bond and either an N-heterocyclic carbene or organophosphine as ancillary ligands. The complexes have been characterized by NMR spectroscopy, X-ray crystallography, high resolution mass spectrometry, elemental analysis, and static and time-resolved optical spectroscopy. These compounds absorb almost strictly in the ultraviolet region and exhibit dual-luminescence following three freeze-pump-thaw cycles in toluene. The selection of the ancillary ligand significantly influences the excited-state dynamics of the complexes. The two phosphine containing complexes have similar fluorescence and phosphorescence quantum yields leading to generation of white light emission. The carbene containing complex exhibits a higher fluorescence quantum yield compared to its phosphorescence quantum yield resulting in a violet emission. Extensive photophysical characterization of these compounds suggests that the phosphine complexes undergo intersystem crossing more efficiently than the carbene complex. This is supported by a three-fold increase in luminescence lifetime, a halving in fluorescence quantum yield, and an increase in intersystem crossing efficiency by 25 percent for the phosphine complexes. Density-functional theory calculations support these observations where the energy gap between the S1 and T2 states for the carbene is roughly twice that of the phosphine complexes. To our knowledge this is the first example of single-component mononuclear gold(i) complexes exhibiting non-excimeric state white light emission, although a similar phenomenon has been realized for gold(iii) aryl compounds. Further, the triplet lifetimes of all three complexes are on the order of one ms in freeze-pump-thaw degassed toluene. These molecules also exhibit delayed fluorescence; all of the complexes display diffusion-controlled rate constants for triplet-triplet annihilation. Strong excited-state absorption is observed from the singlet and triplet excited-states in these molecules as well. The singlet states have excited-state extinction coefficients on the order of 1.5 × 105 M-1 cm-1 and the triplet states have excited-state extinction coefficients on the order of 1.0 × 105 M-1 cm-1.

A patient advocate to facilitate access and improve communication, care, and outcomes in adults with moderate or severe asthma: Rationale, design, and methods of a randomized controlled trial.

Few interventions to improve asthma outcomes have targeted low-income minority adults. Even fewer have focused on the real-world practice where care is delivered. We adapted a patient navigator, here called a Patient Advocate (PA), a term preferred by patients, to facilitate and maintain access to chronic care for adults with moderate or severe asthma and prevalent co-morbidities recruited from clinics serving low-income urban neighborhoods. We describe the planning, design, methodology (informed by patient and provider focus groups), baseline results, and challenges of an ongoing randomized controlled trial of 312 adults of a PA intervention implemented in a variety of practices. The PA coaches, models, and assists participants with preparations for a visit with the asthma clinician; attends the visit with permission of participant and provider; and confirms participants' understanding of what transpired at the visit. The PA facilitates scheduling, obtaining insurance coverage, overcoming patients' unique social and administrative barriers to carrying out medical advice and transfer of information between providers and patients. PA activities are individualized, take account of comorbidities, and are generalizable to other chronic diseases. PAs are recent college graduates interested in health-related careers, research experience, working with patients, and generally have the same race/ethnicity distribution as potential participants. We test whether the PA intervention, compared to usual care, is associated with improved and sustained asthma control and other asthma outcomes (prednisone bursts, ED visits, hospitalizations, quality of life, FEV1) relative to baseline. Mediators and moderators of the PA-asthma outcome relationship are examined along with the intervention's cost-effectiveness.