JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian Consensus Conference on Pain in Neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy

Pharmacological and non-pharmacological strategies in the integrated treatment of pain in neurorehabilitation. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation

The interplay between pain and neurorehabilitation is very complex, in that pain may be a target for treatment, but can also have negative effects on neurorehabilitation procedures. Moreover, side effects of drugs, which are currently used to treat pain, may negatively influence rehabilitation outcomes. Because of the lack of guidelines or consensus, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) was aimed to answer some open questions on the treatment of pain in this setting. To this aim, we collected evidence on the pharmacological and non-pharmacological strategies and their role in the integrated approach to pain. Despite the lack of studies in patients undergoing neurorehabilitation, current guidelines on the pharmacological treatment of nociceptive and neuropathic pain may be applied in this setting. Non-pharmacological strategies include physical therapy, invasive procedures, psychological treatments and psychotherapy, which together with pharmacological therapies play a key role in the integrated approach to pain. The ICCPN recommendations offer information to ameliorate the current treatment of pain in neurorehabilitation, and to design future studies to answer the still open questions on this topic

Pharmacological and non-pharmacological strategies in the integrated treatment of pain in neurorehabilitation. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation

The interplay between pain and neurorehabilitation is very complex, in that pain may be a target for treatment, but can also have negative effects on neurorehabilitation procedures. Moreover, side effects of drugs, which are currently used to treat pain, may negatively influence rehabilitation outcomes. Because of the lack of guidelines or consensus, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) was aimed to answer some open questions on the treatment of pain in this setting. To this aim, we collected evidence on the pharmacological and non-pharmacological strategies and their role in the integrated approach to pain. Despite the lack of studies in patients undergoing neurorehabilitation, current guidelines on the pharmacological treatment of nociceptive and neuropathic pain may be applied in this setting. Non-pharmacological strategies include physical therapy, invasive procedures, psychological treatments and psychotherapy, which together with pharmacological therapies play a key role in the integrated approach to pain. The ICCPN recommendations offer information to ameliorate the current treatment of pain in neurorehabilitation, and to design future studies to answer the still open questions on this topic