Therapeutic effects of 7- to 14-day subanesthetic ketamine infusions for chronic pain on standardized psychiatric measures.

Background: We have previously shown that subanesthetic ketamine infusions effectively reduce refractory pain. However, the effects of ketamine infusions on comorbid conditions of depression and anxiety have not been explored in this patient population. Methods: We investigated the effects of ketamine on mood and anxiety in patients with refractory chronic pain treated with 7-14 days of subanesthetic continuous intravenous ketamine infusions, using well-validated clinical scales. Results: There was a significant 52% reduction in pain severity and 33% reduction in pain interference scores following ketamine treatment. Ketamine treatment also reduced scores on the depression module of the Patient Health Questionnaire (PHQ-9) by 28% and scores on the Generalised Anxiety and Depression Assessment (GAD-7) by 36%. Conclusion: Multiday subanesthetic ketamine infusions effectively reduce pain, anxiety and depression in patients with complex chronic pain.

What questions did we seek to answer? Chronic pain is a common problem with limited effective treatments. We have previously shown that supervised, multiday ketamine treatments given in the hospital can effectively reduce pain levels, with benefit for months for patients with persistent chronic pain. However, pain is quite complex and often co-occurs with other conditions, particularly depression and anxiety. We aimed to investigate how our ketamine infusions would impact these two important classes of disorder. We assessed our patients with chronic pain undergoing ketamine treatments using thoroughly researched clinical measures of pain, mood and anxiety before and after the infusions. What were the results? Patients had significant reductions in the standardized measures of pain and anxiety, and improvements in mood. We statistically checked whether these reductions were related, and found that reduced pain levels did not correlate with improvements in mood and anxiety levels. What do the results suggest? Ketamine treatments given in a carefully monitored hospital setting are effective in reducing anxiety and improving mood in patients undergoing treatment for chronic pain. The absence of a correlation between the change in pain levels and the change in anxiety and depression levels suggests that ketamine might affect different parts of the brain to achieve these independent effects.

Disentangling the cognitive, physical, and mental health sequelae of COVID-19.

As COVID-19 cases exceed hundreds of millions globally, many survivors face cognitive challenges and prolonged symptoms. However, important questions about the cognitive effects of COVID-19 remain unresolved. In this cross-sectional online study, 478 adult volunteers who self-reported a positive test for COVID-19 (mean = 30 days since most recent test) perform significantly worse than pre-pandemic norms on cognitive measures of processing speed, reasoning, verbal, and overall performance, but not short-term memory, suggesting domain-specific deficits. Cognitive differences are even observed in participants who did not require hospitalization. Factor analysis of health- and COVID-related questionnaires reveals two clusters of symptoms-one that varies mostly with physical symptoms and illness severity, and one with mental health. Cognitive performance is positively correlated with the global measure encompassing physical symptoms, but not the one that broadly describes mental health, suggesting that the subjective experience of "long COVID" relates to physical symptoms and cognitive deficits, especially executive dysfunction.

Correlation Between Subjective and Objective Severity of Oral and Ocular Dryness in Primary Sjögren Syndrome.

OBJECTIVE: Sjögren syndrome (SS) is a common autoimmune disease primarily affecting the eyes and mouth. With no single gold standard test for its diagnosis, accurate identification of patients with SS continues to be challenging. We aimed to assess the correlation of ocular and oral symptoms of dryness with objective measures in order to evaluate reliability in the screening of primary SS (pSS) in clinical practice. METHODS: We conducted a cross-sectional analysis of pre-screened pSS and sicca control patients assessed in the Multidisciplinary Sjögren's Clinic at the University Health Network in Toronto. The signs, symptoms, and objective measure of oral and ocular dryness and damage of each patient were prospectively recorded using a standardized protocol. RESULTS: Subjective measures of severity for xerophthalmia and xerostomia correlated in general with objective severity. Oral symptoms tend to have a stronger correlation with objective findings than ocular symptoms. Many patients with few or insignificant eye symptoms had profound ocular dryness and damage. Similarly, some patients with few or no symptoms of oral dryness had profound objective salivary hypofunction. The absence of symptoms does not rule out profound eye and mouth dryness or damage. CONCLUSION: Although objective measures of xerostomia may not be practical for general population screening, it is crucial that practicing specialists perform objective testing of all patients suspected of pSS, instead of relying on symptoms. Without objective testing, the physician cannot ensure the diagnosis of pSS and that the existence of significant damage is not overlooked and left untreated.

Identifying and understanding factors that affect the translation of therapies from the laboratory to patients: a study protocol.

Background: The process of translating preclinical findings into a clinical setting takes decades. Previous studies have suggested that only 5-10% of the most promising preclinical studies are successfully translated into viable clinical applications. The underlying determinants of this low success rate (e.g. poor experimental design, suboptimal animal models, poor reporting) have not been examined in an empirical manner. Our study aims to determine the contemporary success rate of preclinical-to-clinical translation, and subsequently determine if an association between preclinical study design and translational success/failure exists. Methods: Established systematic review methodology will be used with regards to the literature search, article screening and study selection process. Preclinical, basic science studies published in high impact basic science journals between 1995 and 2015 will be included. Included studies will focus on publicly available interventions with potential clinical promise. The primary outcome will be successful clinical translation of promising therapies - defined as the conduct of at least one Phase II trial (or greater) with a positive finding. A case-control study will then be performed to evaluate the association between elements of preclinical study design and reporting and the likelihood of successful translation. Discussion: This study will provide a comprehensive analysis of the therapeutic translation from the laboratory bench to the bedside. Importantly, any association between factors of study design and the success of translation will be identified. These findings may inform future research teams attempting preclinical-to-clinical translation. Results will be disseminated to identified knowledge users that fund/support preclinical research.

A systematic review on the efficacy and safety of low molecular weight heparin as an anticancer therapeutic in preclinical animal models.

OBJECTIVE: The therapeutic effects of low molecular weight heparins (LMWH) may extend past thrombosis prevention, with preclinical evidence demonstrating anti-metastatic properties. Clinical evidence on the topic, however, remains controversial. A systematic review of preclinical evidence may help elucidate reasons for this contradictory evidence. The objective of our systematic review is to assess the anti-metastatic properties of LMWHs in solid tumour animal models. METHODS: MEDLINE, Embase, Web of Science and PubMed were searched from inception to May 12th, 2020. All articles were screened independently and in duplicate. Studies that compared LMWH to a placebo or no treatment arm in solid tumour animal models were included. The primary outcome was the burden of metastasis. Secondary outcomes included primary tumour growth and mortality. The risk of bias was assessed in duplicate using a modified Cochrane Risk of Bias tool. RESULTS: Forty-two studies were included in the review. Administration of a LMWH was associated with a significant decrease in the burden of metastasis (SMD -2.18; 95% CI -2.66 to -1.70). Additionally, the administration of a LMWH was also associated with a significant reduction in primary tumour growth (SMD -1.95; 95% CI -2.56 to -1.34) and risk of death (RR 0.39; 95% CI 0.16-0.97). All included studies were deemed to be at an unclear risk of bias for at least one methodological criterion. CONCLUSIONS: Our results demonstrate that LMWH can effectively reduce metastatic burden and reduce tumour growth in preclinical animal models of solid tumour malignancies. Reasons for the contradiction with clinical evidence require further exploration.

The air-stable carbocation salt [(MeOC6H4)CPh2][BF4] in Lewis acid catalyzed hydrothiolation of alkenes.

Markovnikov hydrothiolation of 1,1-disubstituted and trisubstituted olefins (20 examples) is catalyzed by Lewis acids, including the air-stable trityl-cation salt [(MeOC6H4)CPh2][BF4] 3.

Identification of RNF168 as a PML nuclear body regulator.

Promyelocytic leukemia (PML) protein forms the basis of PML nuclear bodies (PML NBs), which control many important processes. We have screened an shRNA library targeting ubiquitin pathway proteins for effects on PML NBs, and identified RNF8 and RNF168 DNA-damage response proteins as negative regulators of PML NBs. Additional studies confirmed that depletion of either RNF8 or RNF168 increased the levels of PML NBs and proteins, whereas overexpression induced loss of PML NBs. RNF168 partially localized to PML NBs through its UMI/MIU1 ubiquitin-interacting region and associated with NBs formed by any PML isoform. The association of RNF168 with PML NBs resulted in increased ubiquitylation and SUMO2 modification of PML. In addition, RNF168 was found to associate with proteins modified by SUMO2 and/or SUMO3 in a manner dependent on its ubiquitin-binding sequences, suggesting that hybrid SUMO-ubiquitin chains can be bound. In vitro assays confirmed that RNF168, preferentially, binds hybrid SUMO2-K63 ubiquitin chains compared with K63-ubiquitin chains or individual SUMO2. Our study identified previously unrecognized roles for RNF8 and RNF168 in the regulation of PML, and a so far unknown preference of RNF168 for hybrid SUMO-ubiquitin chains.