Effects of immunosuppressive drugs on COVID-19 severity in patients with autoimmune hepatitis.

BACKGROUND: We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH). PATIENTS AND METHODS: Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression. RESULTS: We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients. CONCLUSION: Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH.

Role of Self-Association and Supersaturation in Oral Absorption of a Poorly Soluble Weakly Basic Drug.

PURPOSE: Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated. METHODS: Self-association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables. RESULTS: Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data. CONCLUSIONS: Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation.

Calm, irritated or infected? The experience of the inflammatory states and symptoms of pin site infection and irritation during external fixation: a grounded theory study.

AIM: To explore patients' experiences of the symptoms of suspected wound infection in external fixator pin sites. BACKGROUND: Pin site infection is painful and distressing and can threaten the success of treatment. It is difficult for patients and clinicians to differentiate between pin site infection and irritation or foreign body reaction to the pin. There is no validated outcome measure for infection that enables the success of interventions for prevention and management to be evaluated. There is a need to develop accurate patient-orientated assessment criteria. DESIGN: Qualitative design, using grounded theory. METHOD: Following written informed consent, a theoretical sample of 16 adults with an external fixation device that had been in situ for at least 12 weeks was recruited. They had experienced a pin site infection in the previous four weeks. Data were collected using semistructured interviews, and data collection was stopped when saturation was achieved. Analysis took place using constant comparative analysis. RESULTS: Participants described three 'clinical states' of pin site wounds: calm, irritated and infected. They described the differences in each state in relation to pain, redness, swelling, discharge and general symptoms. Symptoms were absent or varied in intensity depending on whether the pin sites were calm, irritated or infected. CONCLUSION: This study provides insight into patients' experiences of the symptoms of pin site infection resulting in an emerging theory based on conceptualisation of this experience, which is that of dimensions of inflammatory pin site states. The detail given will enable clinicians and researchers to be more accurate in recognising infection and begins to clarify the difference between a wound that is irritated and a wound that is infected. The findings will enable the development of a patient-orientated outcome questionnaire for pin site infection. RELEVANCE TO CLINICAL PRACTICE: There is a need for patients and clinicians to be able to differentiate between infected, not infected and irritated pin sites.

Differing time dependencies of object recognition memory impairments produced by nicotinic and muscarinic cholinergic antagonism in perirhinal cortex.

The roles of muscarinic and nicotinic cholinergic receptors in perirhinal cortex in object recognition memory were compared. Rats' discrimination of a novel object preference test (NOP) test was measured after either systemic or local infusion into the perirhinal cortex of the nicotinic receptor antagonist methyllycaconitine (MLA), which targets alpha-7 (α7) amongst other nicotinic receptors or the muscarinic receptor antagonists scopolamine, AFDX-384, and pirenzepine. Methyllycaconitine administered systemically or intraperirhinally before acquisition impaired recognition memory tested after a 24-h, but not a 20-min delay. In contrast, all three muscarinic antagonists produced a similar, unusual pattern of impairment with amnesia after a 20-min delay, but remembrance after a 24-h delay. Thus, the amnesic effects of nicotinic and muscarinic antagonism were doubly dissociated across the 20-min and 24-h delays. The same pattern of shorter-term but not longer-term memory impairment was found for scopolamine whether the object preference test was carried out in a square arena or a Y-maze and whether rats of the Dark Agouti or Lister-hooded strains were used. Coinfusion of MLA and either scopolamine or AFDX-384 produced an impairment profile matching that for MLA. Hence, the antagonists did not act additively when coadministered. These findings establish an important role in recognition memory for both nicotinic and muscarinic cholinergic receptors in perirhinal cortex, and provide a challenge to simple ideas about the role of cholinergic processes in recognition memory: The effects of muscarinic and nicotinic antagonism are neither independent nor additive.

The principles of caring for patients with Ilizarov external fixation.

External fixation is an important aspect of complex fracture management. Ilizarov fixation is a specialised type of external fixator consisting of numerous wires that penetrate the limb and are attached to a circular metal frame. Ilizarov fixation is used for fracture fixation and stabilisation, limb reconstruction, deformity correction and limb lengthening. The external fixator can be in place for many months and patients will need to adapt to the device and demonstrate an understanding of the principles of pin site care. Psychosocial issues also need to be considered.