Patient clinical and demographic factors associated with involuntary psychiatric admission in the northern territory top end.

OBJECTIVE: Australia has inadequate publicly available data regarding the use of involuntary psychiatric care. This study examined the association between patient clinical/demographic factors and involuntary psychiatric admission following initial psychiatric assessment in Royal Darwin Hospital. METHOD: Retrospective review of 638 psychiatric assessments followed by covariate analysis of patient variables associated with involuntary psychiatric admission. RESULTS: Most of the 225 psychiatric admissions were involuntary (92%). Male patients and those with a preferred language other than English had the highest risk of being admitted involuntarily (RR 1.09, χ2 [1] = 3.9, p = .048, and RR 1.11, p = .036, respectively). CONCLUSIONS: Further research regarding the influence of patient demographics and clinical factors on rates of involuntary admissions, particularly for Aboriginal patients, is recommended. The findings prompt discussion on strategies to improve monitoring of involuntary care and barriers to voluntary treatment.

The Comparison of Machine Learning and Mechanistic In Vitro-In Vivo Extrapolation Models for the Prediction of Human Intrinsic Clearance.

Accurate prediction of human pharmacokinetics (PK) remains one of the key objectives of drug metabolism and PK (DMPK) scientists in drug discovery projects. This is typically performed by using in vitro-in vivo extrapolation (IVIVE) based on mechanistic PK models. In recent years, machine learning (ML), with its ability to harness patterns from previous outcomes to predict future events, has gained increased popularity in application to absorption, distribution, metabolism, and excretion (ADME) sciences. This study compares the performance of various ML and mechanistic models for the prediction of human IV clearance for a large (645) set of diverse compounds with literature human IV PK data, as well as measured relevant in vitro end points. ML models were built using multiple approaches for the descriptors: (1) calculated physical properties and structural descriptors based on chemical structure alone (classical QSAR/QSPR); (2) in vitro measured inputs only with no structure-based descriptors (ML IVIVE); and (3) in silico ML IVIVE using in silico model predictions for the in vitro inputs. For the mechanistic models, well-stirred and parallel-tube liver models were considered with and without the use of empirical scaling factors and with and without renal clearance. The best ML model for the prediction of in vivo human intrinsic clearance (CLint) was an in vitro ML IVIVE model using only six in vitro inputs with an average absolute fold error (AAFE) of 2.5. The best mechanistic model used the parallel-tube liver model, with empirical scaling factors resulting in an AAFE of 2.8. The corresponding mechanistic model with full in silico inputs achieved an AAFE of 3.3. These relative performances of the models were confirmed with the prediction of 16 Pfizer drug candidates that were not part of the original data set. Results show that ML IVIVE models are comparable to or superior to their best mechanistic counterparts. We also show that ML IVIVE models can be used to derive insights into factors for the improvement of mechanistic PK prediction.

PSMA-targeted Radiotracers versus 18F Fluciclovine for the Detection of Prostate Cancer Biochemical Recurrence after Definitive Therapy: A Systematic Review and Meta-Analysis.

Background National guidelines endorse fluorine 18 (18F) fluciclovine PET/CT for the detection of prostate cancer (PCa) in men with biochemically recurrent PCa. The comparative performance between fluciclovine and gallium 68 or 18F prostate-specific membrane antigen (PSMA) PET/CT, a newer examination, is unclear. Purpose To compare the detection of biochemical recurrence using fluciclovine versus PSMA-targeted radiotracers in patients with a prostate-specific antigen (PSA) level less than 2 ng/mL. Materials and Methods With use of the Preferred Reporting Items for a Systematic Review and Meta-Analysis of Diagnostic Test Accuracy, or PRISMA-DTA, guidelines, a systematic review of PubMed and EMBASE databases between 2012 and 2019 was performed. Studies of fluciclovine PET/CT or PSMA PET/CT in biochemical recurrence were identified. PSA levels, clinical data, and reference standards were obtained when available. A random-effects model was applied to pooled estimates and 95% confidence intervals (CIs) around the prevalence of a positive examination, stratified according to PSA tier. Results Quantitative analysis included 482 patients (median age, 67 years; interquartile range, 67-67 years) in six fluciclovine studies and 3217 patients (median age, 68 years; interquartile range, 67-70 years) in 38 PSMA studies. Pooled detection rates for PSMA and fluciclovine were 45% (95% CI: 38%, 52%) and 37% (95% CI: 25%, 49%), respectively, for a PSA level less than 0.5 ng/mL (P = .46); 59% (95% CI: 52%, 66%) and 48% (95% CI: 34%, 61%) for a PSA level of 0.5-0.9 ng/mL (P = .19); and 80% (95% CI: 75%, 85%) and 62% (95% CI: 54%, 70%) for a PSA level of 1.0-1.9 ng/mL (P = .01). A reference standard was positive in 703 of 735 patients (96%) in the PSMA cohort and 247of 256 (97%) in the fluciclovine cohort. Conclusion Patient-level detection rates for biochemically recurrent prostate cancer were greater for prostate-specific membrane antigen-targeted radiotracers than fluciclovine for prostate specific antigen levels of 1.0-1.9 ng/mL. © RSNA, 2020 Online supplemental material is available for this article.

Extrapulmonary, Chronic Septic Arthritis From Mycobacterium tuberculosis in the Ankle and Subtalar Joints.

In the United States, rates of Mycobacterium tuberculosis infection have been declining for decades. Osteoarticular tuberculosis of the ankle is rarely observed. We present the case of a 65-year-old man who immigrated to the United States from India 24 years before the onset of symptoms. The patient initially reported atraumatic swelling and pain of the left ankle and foot and was treated for venous insufficiency. Later, the patient was referred to a nonsurgical orthopaedic clinic for additional workup and was found to have elevated inflammatory markers. MRI showed septic arthritis and osteomyelitis of the talus, distal tibia, and calcaneus. Joint aspiration revealed elevated white blood cell counts with predominately PMNs. The patient was then referred to an orthopaedic foot and ankle surgeon and underwent extensive irrigation and débridement. The patient was discharged on empiric antibiotics. Culture results from the original joint aspirate returned 14 days after surgery as positive for acid-fast bacillus, later identified as M tuberculosis by sequencing. Empiric antibiotics were discontinued, and the patient was started on appropriate antituberculotic therapy. This case report illustrates the challenge in the diagnosis of skeletal tuberculosis and the importance of including this condition on the differential for patients with atypical foot and ankle presentations.

Conditional over-expression of RAGE by embryonic alveolar epithelium compromises the respiratory membrane and impairs endothelial cell differentiation.

BACKGROUND: Receptors for advanced glycation end-products (RAGE) are cell surface receptors prominently expressed by lung epithelium. Previous research demonstrated that over-expression of RAGE by murine alveolar epithelial cells during embryogenesis caused severe lung hypoplasia and neonatal lethality. However, the effects of RAGE over-expression on adjacent matrix and endothelial cells remained unknown. METHODS: RAGE transgenic (TG) mice were generated that conditionally over-expressed RAGE in alveolar type II cells when fed doxycycline (dox) from conception to E18.5. To evaluate effects on the basement membrane, immunostaining and immunoblotting were performed for collagen IV and MMP-9, a matrix metalloprotease capable of degrading basement membranes. To assess changes in vasculature, immunostaining, immunoblotting and qRT-PCR were performed for Pecam-1, a platelet endothelial cell adhesion marker also known as CD31. Lastly, to characterize potential regulatory mechanisms of endothelial cell differentiation, immunoblotting and qRT-PCR for FoxM1, a key endothelium-specific transcription factor of the Forkhead Box (Fox) family, were completed. RESULTS: Qualitative immunostaining for collagen IV was less in RAGE TG mice compared to controls and immunoblotting revealed decreased collagen IV in the RAGE TG mouse lung. Additionally, elevated MMP-9 detected via immunostaining and immunoblotting implicated MMP-9 as a possible down stream effector in matrix destabilization mediated by RAGE signaling. Lastly, Pecam-1 assessment revealed a decrease in the prevalence of microvascular endothelial cells coincident with FoxM1 abrogation in RAGE TG mice compared to controls. CONCLUSIONS: RAGE over-expression by alveolar epithelium weakened the basement membrane and associated matrix via increased MMP-9 activity. Furthermore, over-expression of RAGE inhibited FoxM1, suggesting that anomalous transcriptional control contributes to decreased endothelial cell prevalence in the TG mouse lung.

Systemic DNA damage accumulation under in vivo tumor growth can be inhibited by the antioxidant Tempol.

Recently we found that mice bearing subcutaneous non-metastatic tumors exhibited elevated levels of two types of complex DNA damage, i.e., double-strand breaks and oxidatively-induced clustered DNA lesions in various tissues throughout the body, both adjacent to and distant from the tumor site. This DNA damage was dependent on CCL2, a cytokine involved in the recruitment and activation of macrophages, suggesting that this systemic DNA damage was mediated via tumor-induced chronic inflammatory responses involving cytokines, activation of macrophages, and consequent free radical production. If free radicals are involved, then a diet containing an antioxidant may decrease the distant DNA damage. Here we repeated our standard protocol in cohorts of two syngeneic tumor-bearing C57BL/6NCr mice that were on a Tempol-supplemented diet. We show that double-strand break and oxidatively-induced clustered DNA lesion levels were considerably decreased, about two- to three fold, in the majority of tissues studied from the tumor-bearing mice fed the antioxidant Tempol compared to the control tumor-bearing mice. Similar results were also observed in nude mice suggesting that the Tempol effects are independent of functioning adaptive immunity. This is the first in vivo study demonstrating the effect of a dietary antioxidant on abscopal DNA damage in tissues distant from a localized source of genotoxic stress. These findings may be important for understanding the mechanisms of genomic instability and carcinogenesis caused by chronic stress-induced systemic DNA damage and for developing preventative strategies.