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Aims St John's Wort (SJW) is widely used in the treatment of depression but concerns have been raised about its potential to interact with other drugs. Co-administration with SJW has resulted in signi®cant reductions in trough plasma concentrations of indinavir and cyclosporin [1,2]. Induction of cytochrome P450 3A4 (CYP3A4) has been implicated as the most likely interaction mechanism. However, the magnitude of the interaction seen in clinical practice is greater than that predicted by in vitro studies suggesting additional interaction mechanisms may exist. As indinavir and cyclosporin are substrates for both CYP3A4 and the multi drug transporter P-glycoprotein we hypothesized that modulation of P-glycoprotein expression and function by SJW may contribute to the development of potentially harmful drug±drug interactions. Methods Healthy volunteers were randomized to either SJW (0.15%) 600 mg three times daily for 16 days (n=15) or placebo (n=7). Blood samples were obtained for P-glycoprotein expression and function at baseline, 16 and 32 days post treatment. Peripheral blood lymphocytes (PBMCs) were isolated by Ficoll density gradient centrifugation, ®xed and permeabilized. Cells were stained with a P-glycoprotein speci®c antibody, quanti®ed by¯ow cytometry and median¯uorescence intensity (MFI) values obtained. Vimentin and IE (nonsense antibody) were used as controls. The presence of the MDR 1 gene product was con®rmed by RT-PCR. P-glycoprotein mediated drug ef¯ux was determined as a function of rhodamine ef¯ux in the absence and presence of ritonavir. Data are expressed as meants.d. and were subjected to nonparametric analysis. Results P-glycoprotein expression increased 4.2 fold from baseline in subjects treated with SJW (7.0t1.9 vs 29.5t14.3 (MFI); P<0.05). There was no effect with placebo (5.1t1.3 vs 6.0t1.9 MFI). SJW increased P-glycoprotein mediated rhodamine ef¯ux (reduced ratio) compared with baseline (0.12t0.04 vs 0.24t0.18 P<0.05).There was no change with placebo. Ritonavir (5 mM) inhibited P-glycoprotein mediated ef¯ux in both groups producing greater intracellular accumulation of rhodamine. However, this effect was attenuated following treatment with SJW (23.9t15.3% vs 75.4t16.4% P<0.05). Conclusions SJW increased expression and enhanced the drug ef¯ux function of the multi drug transporter P-glycoprotein in PBMCs of healthy volunteers. This may represent a second mechanism for the drug±herb interactions seen in clinical practice and account for the discrepancies between in vitro and in vivo data. Since P-glycoprotein and CYP3A4 have distinct though overlapping substrates, patients receiving drugs, which are P-glycoprotein substrates should be warned against self-medication with SJW as clinically signi®cant drug interactions may occur.

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The presence of NR1I2 polymorphisms can alter the induction of CYP3A4 and CYP2B6 promoter activity, potentially adding to the unpredictable nature of antiretroviral drug interactions. These polymorphisms differ in prevalence between whites and sub-Saharan Africans.

Co-administration of sildenafil 25 mg did not significantly alter the plasma indinavir levels. However, plasma sildenafil AUC was markedly increased in the presence of indinavir compared with historical controls. From the in vitro data, the mechanism of increase is indinavir inhibition of the hepatic metabolism of sildenafil. The magnitude of this interaction suggests a lower starting dose of sildenafil may be more appropriate in this clinical setting.

Background Nursing homes for older adults have been disproportionately affected by the Covid‐19 pandemic with increased mortality of residents and staff distress. Objective To quantify the mental health of nursing home staff during the Covid‐19 pandemic in the Republic of Ireland. Design/Methods Cross‐sectional anonymous study of Republic of Ireland nursing home staff ( n = 390) during the third wave of the Covid‐19 pandemic. Online survey collecting demographic information, Covid‐19 exposure history and mental health measures. Results There were significant differences between nurses, healthcare assistants (HCA) and non‐clinical staff history in age, ethnicity, years' experience, history of Covid‐19 infection and contact with Covid‐19 positive acquaintances. Moderate–severe post‐traumatic stress disorder symptoms were found in 45.1% (95% confidence interval [CI] 40.2%–50.1%) of all staff. A World Health Organisation‐5 (WHO‐5) wellbeing index score ≤32, indicating low mood, was reported by 38.7% (95% CI, 33.9%–43.5%) of staff; significantly more nurses reported low mood. Suicidal ideation and suicide planning were reported, respectively, by 13.8% (95% CI, 10.4%–17.3%) and 9.2% (95% CI, 6.4%–12.1%) of participants with no between‐group differences. HCAs reported a significantly higher degree of moral injury than non‐clinical staff. Nurses were more likely to use approach coping styles than non‐clinical staff. Work ability was insufficient in 24.6% (95% CI 20.3%–28.9%) of staff. Conclusion Nursing home staff report high levels of post‐traumatic stress, mood disturbance and moral injury during the Covid‐19 pandemic. Differences in degree of moral injury, wellbeing and coping styles were found between staff groups, which need to be incorporated into planning supports for this neglected workforce.

BackgroundTo provide the optimum level of healthcare, it is important that the supply of well-trained doctors meets the demand. However, despite many initiatives, Ireland continues to have a shortfall of physicians, which has been projected to persist. Our study aimed to investigate the migration intentions of Irish medical students and identify the factors that influence their decisions in order to design appropriate interventions to sustain the supply of trained doctors in order to maintain a viable medical system.MethodsAn online cross-sectional survey was undertaken of all Irish medical students studying in the Republic of Ireland. The survey included nominal, ordinal, and scale items to determine migration intentions, factors influencing their decisions, and understanding of the Irish healthcare system.ResultsA total of 2 273 medical students responded (37% response rate), of whom 1 519 were classified as Irish medical students (having completed secondary school in Ireland). Of these, 88% indicated they were either definitely migrating or contemplating migrating following graduation or completion of the pre-registration intern year. Forty percent expressed an intention of returning to Ireland within 5 years. The factors most influencing their decision to leave were career opportunities (85%), working conditions (83%), and lifestyle (80%).ConclusionThe migration intentions expressed in this study predict an immediate and severe threat to the sustainability of the Irish healthcare service. Urgent interventions such as providing information about career options and specialty training pathways are required. These must begin in the undergraduate phase and continue in postgraduate training and are needed to retain medical school graduates.

Background The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.