Effect of Coffee and Chocolate Ingestion on Clozapine Dose and on Plasma Clozapine and Norclozapine Concentrations in Clinical Practice.

BACKGROUND: Some reports point to dietary caffeine intake as a cause of increased plasma clozapine concentrations in certain patients. METHODS: We compared clozapine dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in male and female smokers and nonsmokers in relation to reported (i) coffee (caffeine) and (ii) chocolate (caffeine and theobromine) intake in samples submitted for clozapine therapeutic drug monitoring, 1993-2017. RESULTS: There was information on coffee ingestion for 16,558 samples (8833 patients) from males and 5886 samples (3433 patients) from females and on chocolate ingestion for 12,616 samples (7568 patients) from males and 4677 samples (2939 patients) from females. When smoking was considered, there was no discernible effect of either coffee or chocolate ingestion either on the median dose of clozapine or on the median plasma clozapine and norclozapine concentrations in men and in women. However, cigarette smoking was associated with higher coffee and chocolate consumption. Although male nonsmokers who reported drinking 3 or more cups of coffee daily had significantly higher median plasma clozapine and norclozapine concentrations than those who drank less coffee, they were also prescribed a significantly higher clozapine dose. There was no clear effect of coffee ingestion on plasma clozapine and norclozapine in female nonsmokers. IMPLICATIONS: Inhibition of clozapine metabolism by caffeine at the doses of caffeine normally encountered in those treated with clozapine is unlikely even in male nonsmokers. Measurement of plasma caffeine in an appropriate sample should be considered in any future investigation into a presumed clozapine-caffeine interaction.

Differences between human and machine perception in medical diagnosis.

Deep neural networks (DNNs) show promise in image-based medical diagnosis, but cannot be fully trusted since they can fail for reasons unrelated to underlying pathology. Humans are less likely to make such superficial mistakes, since they use features that are grounded on medical science. It is therefore important to know whether DNNs use different features than humans. Towards this end, we propose a framework for comparing human and machine perception in medical diagnosis. We frame the comparison in terms of perturbation robustness, and mitigate Simpson's paradox by performing a subgroup analysis. The framework is demonstrated with a case study in breast cancer screening, where we separately analyze microcalcifications and soft tissue lesions. While it is inconclusive whether humans and DNNs use different features to detect microcalcifications, we find that for soft tissue lesions, DNNs rely on high frequency components ignored by radiologists. Moreover, these features are located outside of the region of the images found most suspicious by radiologists. This difference between humans and machines was only visible through subgroup analysis, which highlights the importance of incorporating medical domain knowledge into the comparison.

Management of nontuberculous mycobacterial infections of the eye and orbit: A retrospective case series.

PURPOSE: To provide an update on different management approaches for Nontuberculous Mycobacterial (NTM) infections of the eye and orbit. OBSERVATIONS: A total of 9 eyes from 8 patients were found to meet study criteria. Of these 9 eyes, 6 eyes (66%) involved Mycobacterium abscessus, 2 (22%) involved M. chelonae, and 1 (11%) involved M. fortuitum. In 8 (88%) eyes, NTM infection was treated with a combination of antibiotics and removal of involved foreign body or tissue (e.g. scleral buckle, intraocular lens, orbital implant, or granuloma). One case was observed on topical therapy alone due to low suspicion for clinically significant infection. In 1 patient, a second culture-positive infection was found in the contralateral eye requiring treatment. CONCLUSIONS AND IMPORTANCE: Depending on the clinical presentation, optimal treatment of ocular and orbital NTM infections may require combination anti-mycobacterial antibiotics (topical and systemic), surgical removal of implanted material or tissue, or both.

An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy1-8. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.

Behavioral economics-based incentives supported by mobile technology on HIV knowledge and testing frequency among Latino/a men who have sex with men and transgender women: Protocol for a randomized pilot study to test intervention feasibility and acceptability.

BACKGROUND: Mobile Technology and Incentives (MOTIVES) is a randomized pilot study of a mobile technology-based and behavioral economics-supported HIV prevention intervention. Behavioral economics (BE) uses financial incentives in a way that departs from the traditional focus on large monetary payments. Instead, BE suggests that relatively small "nudges" can effectively initiate and sustain behavior change. This pilot study examines the feasibility and acceptability of an HIV prevention intervention that uses text messages in combination with BE incentives to improve retention of HIV prevention information and increase frequency of HIV testing among Latino/a men who have sex with men (MSM) and transgender women (TGW). The pilot will also estimate mission-critical design parameters with point and confidence interval estimates of the intervention to inform a future, fully powered effectiveness study. METHODS: The project will be conducted in collaboration with Bienestar Human Services, Inc. (Bienestar), a non-profit community-based service organization. The intervention is being tested in a small, randomized controlled trial to pilot the intervention's feasibility and acceptability among 200 Latino/a MSM and TGW from Bienestar's HIV testing sites. Information on feasibility will include recruitment, refusal, and retention rates as well as message sending success rates; acceptability will include perceived appropriateness based on responses to the intervention. Participants will be randomized into either the "information only" control group (e.g. receiving text messages with HIV prevention information) or the "information plus" intervention group (e.g. additionally receiving quiz questions that provide the possibility of winning prizes). Participants will be followed for 12 months from enrollment. In addition to using data abstracted from Bienestar's routine data collection mechanisms, we will also collect survey data (blinded outcome assessment) from participants at 0, 6, and 12 months to provide an initial assessment of whether incentives affect their level of HIV knowledge and testing frequency. DISCUSSION: If shown to be acceptable, feasible, and resource-efficient, MOTIVES will provide an innovative way to communicate the latest HIV prevention information and support trimestral HIV screening among Latino/a MSM and TGW. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03144336 . Registered on 5 May 2017.

Increased Cathepsin S activity associated with decreased protease inhibitory capacity contributes to altered tear proteins in Sjögren's Syndrome patients.

Cathepsin S (CTSS) activity is elevated in Sjögren's Syndrome (SS) patient tears. Here we tested whether protease inhibition and cystatin C (Cys C) levels are reduced in SS tears, which could lead to enhanced CTSS-driven degradation of tear proteins. CTSS activity against Cys C, LF and sIgA was tested in SS or healthy control tears. Tears from 156 female subjects (33, SS; 33, rheumatoid arthritis; 31, other autoimmune diseases; 35, non-autoimmune dry eye (DE); 24, healthy controls) were analyzed for CTSS activity and Cys C, LF, and sIgA levels. Cys C and LF showed enhanced degradation in SS tears supplemented with recombinant CTSS, but not supplemented healthy control tears. CTSS activity was significantly increased, while Cys C, LF and sIgA levels were significantly decreased, in SS tears compared to other groups. While tear CTSS activity remained the strongest discriminator of SS in autoimmune populations, combining LF and CTSS improved discrimination of SS beyond CTSS in DE patients. Reductions in Cys C and other endogenous proteases may enhance CTSS activity in SS tears. Tear CTSS activity is reconfirmed as a putative biomarker of SS in an independent patient cohort while combined LF and CTSS measurements may distinguish SS from DE patients.

En Face Optical Coherence Tomography Angiography Imaging Versus Fundus Photography in the Measurement of Choroidal Nevi.

BACKGROUND AND OBJECTIVES: Choroidal nevi are common benign intraocular tumors with a small risk of malignant transformation. This retrospective study investigates the use of en face spectral-domain optical coherence tomography angiography (SD-OCTA) in determining the clinical features and measurement of choroidal nevi. PATIENTS AND METHODS: Patients with choroidal nevi were imaged with both OCTA and a fundus photography device. Greatest longitudinal dimension (GLD), perpendicular dimension (PD), and the GLD/PD ratio were assessed on each device. Inter-device variation and intra- and inter-rater reliability analyses were performed. RESULTS: Fourteen patients with choroidal nevi were included. No significant difference between the GLD/PD ratio as measured by all three devices was found (Chi-square = 2.8, 2 df, P = .247). Intraclass correlation coefficients were greater than 0.7 for repeated measures on all devices, suggesting good repeatability and reproducibility. CONCLUSION: This study demonstrated inter-device consistency and high intra- and inter-rater reliability when measuring choroidal nevi. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:741-747.].

Racial disparities in cancer-related survival in patients with squamous cell carcinoma of the esophagus in the US between 1973 and 2013.

BACKGROUND: Esophageal cancer makes up approximately 1% of all diagnosed cancers in the US. There is a persistent disparity in incidence and cancer-related mortality rates among different races for esophageal squamous cell carcinoma (SCC). Most previous studies investigated racial disparities between black and white patients, occasionally examining disparities for Hispanic patients. Studies including Asians/Pacific Islanders (API) as a subgroup are rare. Our objective was to determine whether there is an association between race and cancer-related survival in patients with esophageal SCC. METHODS AND FINDINGS: This was a retrospective cohort study using the National Cancer Institute's Surveillance, Epidemiology, and End Result (SEER) database. The SEER registry is a national database that collects information on all incident cancer cases in 13 states of the United States and covers nearly 26% of the US population Patients aged 18 and over of White, Black, or Asian/Pacific Islander (API) race with diagnosed esophageal SCC from 1973 to 2013 were included (n = 13,857). To examine overall survival, Kaplan-Meier curves were estimated for each race and the log-rank test was used to compare survival distributions. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios with 95% confidence intervals. The final adjusted model controlled for sex, marital status, age at diagnosis, decade of diagnosis, ethnicity, stage at diagnosis, and form of treatment. Additional analyses stratified by decade of diagnosis were conducted to explore possible changes in survival disparities over time. After adjustment for potential confounders, black patients had a statistically significantly higher hazard ratio compared to white patients (HR 1.08; 95% confidence interval (CI) 1.03-1.13). However, API patients did not show a statistically significant difference in survival compared with white patients (HR 1.00; 95% CI 0.93-1.07). Patients diagnosed between 1973 and 1979 had twice the hazard of death compared to those diagnosed between 2000 and 2013 (HR 2.05, 95% CI 1.93-2.19). Patients diagnosed in 1980-1989 and 1990-1999 had had HRs of 1.59 (95% CI 1.51-1.68) and 1.33 (95% CI 1.26-1.41), respectively. After stratification according to decade of diagnosis, the HR for black patients compared with white patients was 1.14 (95% CI 1.02-1.29) in 1973-1979 and 1.12 (95% CI 1.03-1.23) in 1980-1989. These disparities were not observed after 1990; the HR for black patients compared with white patients was 1.03 (95% CI 0.93-1.13) in 1990-1999 and 1.05 (95% CI 0.96-1.15) in 2000-2013. CONCLUSIONS: Black patients with esophageal SCC were found to have a higher hazard of death compared to white and API patients. Survival disparities between races appear to have decreased over time. Future research that takes insurance status and other social determinants of health into account should be conducted to further explore possible disparities by race.

Widefield OCT Findings of a Patient With Stellate Nonhereditary Idiopathic Foveomacular Retinoschisis.

The authors report extensive peripheral retinoschisis in a patient with stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR) detected by widefield optical coherence tomography (OCT). A 64-year-old woman diagnosed with foveomacular retinoschisis 3 years prior presented for evaluation after being seen by multiple other retina specialists. Standard macular spectral-domain OCT (6 mm) revealed typical foveomacular schisis involving only the outer retina. However, widefield OCT (12 mm) revealed diffuse bilateral retinoschisis involving both inner and outer retinal layers in the macula and midperiphery. Widefield imaging is important to evaluate and monitor complex peripheral retinoschisis that may be otherwise undetectable using conventional techniques. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:774-777.].

Quantifying Microvascular Density and Morphology in Diabetic Retinopathy Using Spectral-Domain Optical Coherence Tomography Angiography.

PURPOSE: To quantify changes in retinal microvasculature in diabetic retinopathy (DR) by using spectral-domain optical coherence tomography angiography (SD-OCTA). METHODS: Retrospective, cross-sectional, observational study of healthy and diabetic adult subjects with and without DR. Retinal microvascular changes were assessed by using SD-OCTA images and an intensity-based optical microangiography algorithm. A semiautomated program was used to calculate indices of microvascular density and morphology in nonsegmented and segmented SD-OCTA images. Microvascular density was quantified by using skeleton density (SD) and vessel density (VD), while vessel morphology was quantified as fractal dimension (FD) and vessel diameter index (VDI). Statistical analyses were performed by using the Student's t-test or analysis of variance with post hoc Tukey honest significant difference tests for multiple comparisons. RESULTS: Eighty-four eyes with DR and 14 healthy eyes were studied. Spearman's rank test demonstrated a negative correlation between DR severity and SD, VD, and FD, and a positive correlation with VDI (ρ = -0.767, -0.7166, -0.768, and +0.5051, respectively; P < 0.0001). All parameters showed high reproducibility between graders (ICC = 0.971, 0.962, 0.937, and 0.994 for SD, VD, FD, and VDI, respectively). Repeatability (κ) was greater than 0.99 for SD, VD, FD, and VDI. CONCLUSIONS: Vascular changes in DR can be objectively and reliably characterized with SD, VD, FD, and VDI. In general, decreasing capillary density (SD and VD), branching complexity (FD), and increasing average vascular caliber (VDI) were associated with worsening DR. Changes in capillary density and morphology were significantly correlated with diabetic macular edema.

An ABA-increased interaction of the PYL6 ABA receptor with MYC2 Transcription Factor: A putative link of ABA and JA signaling.

Abscisic acid (ABA) is a plant hormone that mediates abiotic stress tolerance and regulates growth and development. ABA binds to members of the PYL/RCAR ABA receptor family that initiate signal transduction inhibiting type 2C protein phosphatases. Although crosstalk between ABA and the hormone Jasmonic Acid (JA) has been shown, the molecular entities that mediate this interaction have yet to be fully elucidated. We report a link between ABA and JA signaling through a direct interaction of the ABA receptor PYL6 (RCAR9) with the basic helix-loop-helix transcription factor MYC2. PYL6 and MYC2 interact in yeast two hybrid assays and the interaction is enhanced in the presence of ABA. PYL6 and MYC2 interact in planta based on bimolecular fluorescence complementation and co-immunoprecipitation of the proteins. Furthermore, PYL6 was able to modify transcription driven by MYC2 using JAZ6 and JAZ8 DNA promoter elements in yeast one hybrid assays. Finally, pyl6 T-DNA mutant plants show an increased sensitivity to the addition of JA along with ABA in cotyledon expansion experiments. Overall, the present study identifies a direct mechanism for transcriptional modulation mediated by an ABA receptor different from the core ABA signaling pathway, and a putative mechanistic link connecting ABA and JA signaling pathways.

Evidence for Retromutagenesis as a Mechanism for Adaptive Mutation in Escherichia coli.

Adaptive mutation refers to the continuous outgrowth of new mutants from a non-dividing cell population during selection, in apparent violation of the neo-Darwinian principle that mutation precedes selection. One explanation is that of retromutagenesis, in which a DNA lesion causes a transcriptional mutation that yields a mutant protein, allowing escape from selection. This enables a round of DNA replication that establishes heritability. Because the model requires that gene expression precedes DNA replication, it predicts that during selection, new mutants will arise from damage only to the transcribed DNA strand. As a test, we used a lacZ amber mutant of Escherichia coli that can revert by nitrous acid-induced deamination of adenine residues on either strand of the TAG stop codon, each causing different DNA mutations. When stationary-phase, mutagenized cells were grown in rich broth before being plated on lactose-selective media, only non-transcribed strand mutations appeared in the revertants. This result was consistent with the known high sensitivity to deamination of the single-stranded DNA in a transcription bubble, and it provided an important control because it demonstrated that the genetic system we would use to detect transcribed-strand mutations could also detect a bias toward the non-transcribed strand. When residual lacZ transcription was blocked beforehand by catabolite repression, both strands were mutated about equally, but if revertants were selected immediately after nitrous acid exposure, transcribed-strand mutations predominated among the revertants, implicating retromutagenesis as the mechanism. This result was not affected by gene orientation. Retromutagenesis is apt to be a universal method of evolutionary adaptation, which enables the emergence of new mutants from mutations acquired during counterselection rather than beforehand, and it may have roles in processes as diverse as the development of antibiotic resistance and neoplasia.

Pelvic ultrasound immediately following MDCT in female patients with abdominal/pelvic pain: is it always necessary?

To determine the added value of reimaging the female pelvis with ultrasound (US) immediately following multidetector CT (MDCT) in the emergent setting. CT and US exams of 70 patients who underwent MDCT for evaluation of abdominal/pelvic pain followed by pelvic ultrasound within 48 h were retrospectively reviewed by three readers. Initially, only the CT images were reviewed followed by evaluation of CT images in conjunction with US images. Diagnostic confidence was recorded for each reading and an exact Wilcoxon signed rank test was performed to compare the two. Changes in diagnosis based on combined CT and US readings versus CT readings alone were identified. Confidence intervals (95%) were derived for the percentage of times US reimaging can be expected to lead to a change in diagnosis relative to the diagnosis based on CT interpretation alone. Ultrasound changed the diagnosis for the ovaries/adnexa 8.1% of the time (three reader average); the majority being cases of a suspected CT abnormality found to be normal on US. Ultrasound changed the diagnosis for the uterus 11.9% of the time (three reader average); the majority related to the endometrial canal. The 95% confidence intervals for the ovaries/adnexa and uterus were 5-12.5% and 8-17%, respectively. Ten cases of a normal CT were followed by a normal US with 100% agreement across all three readers. Experienced readers correctly diagnosed ruptured ovarian cysts and tubo-ovarian abscesses (TOA) based on CT alone with 100% agreement. US reimaging after MDCT of the abdomen and pelvis is not helpful: (1) following a normal CT of the pelvic organs or (2) when CT findings are diagnostic and/or characteristic of certain entities such as ruptured cysts and TOA. Reimaging with ultrasound is warranted for (1) less-experienced readers to improve diagnostic confidence or when CT findings are not definitive, (2) further evaluation of suspected endometrial abnormalities. A distinction should be made between the need for immediate vs. follow-up imaging with US after CT.

Isolated sixth cranial nerve palsy as the presenting symptom of a rapidly expanding ACTH positive pituitary adenoma: a case report.

BACKGROUND: Pituitary adenoma may present with neuro-ophthalmic manifestations and, typically, rapid tumor expansion is the result of apoplexy. Herein, we present the first case of an isolated sixth cranial nerve palsy as initial feature of a rapidly expanding ACTH positive silent tumor without apoplexy. CASE PRESENTATION: A 44 year old female with a history of sarcoidosis presented with an isolated sixth cranial nerve palsy as the initial clinical feature of a rapidly expanding ACTH positive silent pituitary adenoma. The patient underwent emergent transsphenoidal hypophysectomy for this rapidly progressive tumor and subsequently regained complete vision and ocular motility. Despite tumor extension into the cavernous sinus, the other cranial nerves were spared during the initial presentation. CONCLUSIONS: This case illustrates the need to consider a rapidly growing pituitary tumor as a possibility when presented with a rapidly progressive ophthalmoplegia.

Solitary orbital plasmacytoma associated with chronic hepatitis C: a case report.

PURPOSE: To report a rare case of solitary orbital plasmacytoma associated with chronic hepatitis C. METHODS: We have reviewed the case of a man who presented with soft tissue mass in the superolateral orbit. Biopsy demonstrated immunohistochemical positivity of plasma cells for lambda light chains and CD56. Systemic evaluation was negative for multiple myeloma, and the diagnosis of solitary orbital plasmacytoma was made. RESULTS: We comment on the rarity of the case according to the reviewed literature. CONCLUSIONS: Given the correlation between hepatitis C and other lymphoproliferative disorders, we conclude hepatitis C may also be associated with solitary plasmacytomas.

Cyclic adenosine 3',5'-monophosphate responsive element binding protein phosphorylation is required but not sufficient for activation of corticotropin-releasing hormone transcription.

cAMP is a major regulator of CRH transcription. However, receptors activating CRH neurons (alpha-adrenergic and glutamatergic) do not signal through cAMP, suggesting that calcium phospholipid-dependent signaling synergizes with small elevations of intracellular cAMP. To test this hypothesis, we examined the relationship between activation of CRH transcription, cAMP production, and cAMP response element binding protein (CREB) phosphorylation in neuronal cultures treated with the adenylyl cyclase stimulator, forskolin, the phorbol ester, phorbol-12-myristate-13-acetate (PMA), or their combination. Forskolin, at threshold concentrations for cAMP production and CREB phosphorylation, induced CRH promoter-driven luciferase activity in 4B cells (EC(50) = 0.7 microm) and CRH primary transcript in hypothalamic neurons (EC(50) = 0.6 microm). PMA alone failed to activate CRH transcription despite being as effective as forskolin in phosphorylating CREB (Ser133 and Ser121). Although PMA potentiated the effect of low forskolin concentrations on CRH transcription and CREB phosphorylation, there was no correlation between phosphorylated CREB levels and activation of CRH transcription. Similarly, the calcium/calmodulin-dependent kinase inhibitor, KN-93, enhanced PMA plus forskolin-stimulated CREB phosphorylation and inhibited CRH transcription. Suppression of CREB phosphorylation by the protein kinase A inhibitor, H89, or the CREB dominant negative, A-CREB, did not affect basal but blocked forskolin-stimulated transcription. This study shows that calcium phospholipid-dependent pathways potentiate the ability of small elevations of intracellular cAMP to activate CRH transcription, providing a mechanism by which non-cAMP-dependent regulators induce CRH gene expression. In addition, the data indicate that phosphorylated CREB is essential but not sufficient for activation of CRH transcription, suggesting that full promoter stimulation requires the interaction of phosphorylated CREB with a coactivator.

Inhibition, escape, and attenuated growth of severe acute respiratory syndrome coronavirus treated with antisense morpholino oligomers.

The recently emerged severe acute respiratory syndrome coronavirus (SARS-CoV) is a potent pathogen of humans and is capable of rapid global spread. Peptide-conjugated antisense morpholino oligomers (P-PMO) were designed to bind by base pairing to specific sequences in the SARS-CoV (Tor2 strain) genome. The P-PMO were tested for their capacity to inhibit production of infectious virus as well as to probe the function of conserved viral RNA motifs and secondary structures. Several virus-targeted P-PMO and a random-sequence control P-PMO showed low inhibitory activity against SARS coronavirus. Certain other virus-targeted P-PMO reduced virus-induced cytopathology and cell-to-cell spread as a consequence of decreasing viral amplification. Active P-PMO were effective when administered at any time prior to peak viral synthesis and exerted sustained antiviral effects while present in culture medium. P-PMO showed low nonspecific inhibitory activity against translation of nontargeted RNA or growth of the arenavirus lymphocytic choriomeningitis virus. Two P-PMO targeting the viral transcription-regulatory sequence (TRS) region in the 5' untranslated region were the most effective inhibitors tested. After several viral passages in the presence of a TRS-targeted P-PMO, partially drug-resistant SARS-CoV mutants arose which contained three contiguous base point mutations at the binding site of a TRS-targeted P-PMO. Those partially resistant viruses grew more slowly and formed smaller plaques than wild-type SARS-CoV. These results suggest PMO compounds have powerful therapeutic and investigative potential toward coronavirus infection.

Inactivation of TNF signaling by rationally designed dominant-negative TNF variants.

Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.