Two-step screening for depressive symptoms in patients treated with kidney replacement therapies: a cross-sectional analysis.

BACKGROUND: Systematic screening for depressive symptoms may identify patients who may benefit from clinical assessment and psychosocial support. Here we assess a two-step screening using ultrabrief pre-screeners [Edmonton Symptom Assessment Survey-revised Depression item (ESASr-D) or Patient Health Questionnaire-2 (PHQ-2)] followed by the Patient-Reported Outcomes Measurement Information System Depression questionnaire (PROMIS-D) to identify depressive symptoms in patients on kidney replacement therapies. METHODS: We conducted a cross-sectional study of adults (kidney transplant recipients or treated with dialysis) in Toronto, ON, Canada. We simulated various two-step screening scenarios where only patients above a pre-screening cut-off score on the ESASr-D or PHQ-2 would move to step 2 (PROMIS-D). Screening performance was evaluated by sensitivity, specificity and positive and negative predictive values using the Patient Health Questionnaire-9 (PHQ-9) as the referent. The average number of items completed by patients in different scenarios was reported. RESULTS: Of 480 participants, 60% were male with a mean age of 55 years. Based on PHQ-9, 19% of patients had moderate or severe depressive symptoms. Pre-screening with a PHQ-2 score ≥1 combined with a PROMIS-D score of ≥53 provided the best two-step results (sensitivity 0.81, specificity 0.84, NPV 0.95). Two-step screening also reduces question burden. CONCLUSIONS: A two-step screening using a PHQ-2 score ≥1 followed by a PROMIS-D score ≥53 has good sensitivity and specificity for identifying potentially significant depressive symptoms among patients on kidney replacement therapies. This approach has lower question burden. Screened-in patients will need further clinical assessment to establish a diagnosis.

Misdiagnosis of lymphoma as vasculitis: A case report.

NK/T-cell lymphoma (NKTCL) is a highly aggressive malignant tumour with a very poor prognosis, which often poses diagnostic difficulties due to the non-specificity of its clinical presentation. NK/T-cell lymphoma with eosinophilic hyperplasia syndrome is extremely rare. This article describes a patient with NKTCL misdiagnosed as vasculitis who presented with sinusitis, abdominal pain, anorexia, and lung shadows. Additionally, the patient exhibited extremely high eosinophilia levels, which led to a further misdiagnosis of eosinophilic granuloma. We describe the clinical features, diagnostic methods and differential diagnosis of lymphoma and highlights the importance of a multidisciplinary approach in accurate diagnosis and treatment.

Systematic Evaluation of the Distribution of Immune Cells following Subcutaneous Administration of Haemophilus Influenzae Type B Vaccine to Mice.

The Haemophilus influenzae type B (Hib) conjugate vaccine is the most effective way to prevent Hib infection in infants and young children, and it is designed to induce the production of antibodies against polyribosylribitol phosphate (PRP) to protect babies from infection. However, the mechanism of immunity induced by the Hib vaccine is not fully understood. Recently, with the development of the combination diphtheria and tetanus toxoids and acellular pertussis vaccines (DTaP), increasing numbers of manufacturers have begun to develop DTaP-based combination vaccines, like the combination vaccine diphtheria and tetanus toxoids and acellular pertussis and Hib conjugate vaccine (DTaP-Hib), which contains adjuvants. However, the Hib vaccine does not contain adjuvants. It was theorized that the Hib antigen has poor compatibility with aluminum adjuvants for unclear reasons. Therefore, understanding the mechanism of the Hib-vaccine-induced immune response and the influence of adjuvants on the Hib vaccine is of great significance. In this paper, we immunized BalBc mice with either the Hib vaccine or the Hib vaccine that adsorbs aluminum adjuvants (Hib-Al). Here, we analyzed the anti-PRP antibody level and immune response of different cells using cell and cytokine levels. We found that the Hib vaccine could induce a humoral and cellular immune response, and the Hib-Al vaccine could induce greater quantities of IFN-γ, IL-4, and IL-6 and more antigen-specific antibodies through B cells, Th1, Th2, and ILC3s in the spleen. Together, our findings demonstrate the serologic responses and immune response in terms of cell and cytokine levels induced by the Hib vaccine, and they also imply that the addition of aluminum hydroxide adjuvant could enhance the function of the Hib vaccine, which preliminarily reveals the mechanism of immune response induced by the Hib-related vaccine.

BBB pathophysiology-independent delivery of siRNA in traumatic brain injury.

Small interfering RNA (siRNA)-based therapeutics can mitigate the long-term sequelae of traumatic brain injury (TBI) but suffer from poor permeability across the blood-brain barrier (BBB). One approach to overcoming this challenge involves treatment administration while BBB is transiently breached after injury. However, it offers a limited window for therapeutic intervention and is applicable to only a subset of injuries with substantially breached BBB. We report a nanoparticle platform for BBB pathophysiology-independent delivery of siRNA in TBI. We achieved this by combined modulation of surface chemistry and coating density on nanoparticles, which maximized their active transport across BBB. Engineered nanoparticles injected within or outside the window of breached BBB in TBI mice showed threefold higher brain accumulation compared to nonengineered PEGylated nanoparticles and 50% gene silencing. Together, our data suggest that this nanoparticle platform is a promising next-generation drug delivery approach for the treatment of TBI.

A cell-based drug delivery platform for treating central nervous system inflammation.

Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4+ T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases. KEY MESSAGES: MSCs can spontaneously take up the ATP-competitive kinase inhibitor Ro-31-8425. Ro-31-8425-loaded MSCs gradually release Ro-31-8425 and exhibit sustained suppression of T cells. Ro-31-8425-loaded MSCs have more sustained serum levels of Ro-31-8425 than free Ro-31-8425. Ro-31-8425-loaded MSCs are more effective than MSCs and free Ro-31-8425 for EAE therapy.

Microparticle Encapsulation of a Prostate-targeted Biologic for the Treatment of Liver Metastases in a Preclinical Model of Castration-resistant Prostate Cancer.

PRX302 is a highly potent, mutant bacterial pore-forming biologic protoxin engineered for selective activation by PSA, a serine protease expressed by benign and malignant prostate epithelial cells. Although being developed as a local therapy for benign prostatic hyperplasia and localized prostate cancer, PRX302 cannot be administered systemically as a treatment for metastatic disease due to binding to ubiquitously expressed glycosylphosphatidylinositol (GPI)-anchored proteins, which leads to poor accumulation within the tumor microenvironment. To overcome this limitation, poly-lactic-co-glycolic acid (PLGA) microparticles encapsulating the protoxin were developed, which are known to accumulate in the liver, a major site of metastasis for prostate cancer and other solid tumors. A highly sensitive and reproducible sandwich ELISA to quantify PRX302 released from microparticles was developed. Utilizing this assay, PRX302 release from different microparticle formulations was assessed over multiple days. Hemolysis assays documented PSA-dependent pore formation and lytic potential (i.e., function) of the released protoxin. MTT assays demonstrated that conditioned supernatant from PRX302-loaded, but not blank (i.e., unloaded), PLGA microparticles was highly cytotoxic to PC3 and DU145 human prostate cancer cells in the presence of exogenous PSA. Microparticle encapsulation prevented PRX302 from immediately interacting with GPI-anchored proteins as demonstrated in a competition assay, which resulted in an increased therapeutic index and significant antitumor efficacy following a single dose of PRX302-loaded microparticles in a preclinical model of prostate cancer liver metastasis with no obvious toxicity. These results document that PRX302 released from PLGA microparticles demonstrate in vivo antitumor efficacy in a clinically relevant preclinical model of metastatic prostate cancer.