The re-emergence of influenza following the COVID-19 pandemic in Victoria, Australia, 2021 to 2022.

BackgroundCOVID-19 pandemic mitigation measures, including travel restrictions, limited global circulation of influenza viruses. In Australia, travel bans for non-residents and quarantine requirements for returned travellers were eased in November 2021, providing pathways for influenza viruses to be re-introduced.AimWe aimed to describe the epidemiological and virological characteristics of the re-emergence of influenza in Victoria, Australia to inform public health interventions.MethodsFrom 1 November 2021 to 30 April 2022, we conducted an epidemiological study analysing case notification data from the Victorian Department of Health to describe case demographics, interviewed the first 200 cases to establish probable routes of virus reintroduction and examined phylogenetic and antigenic data to understand virus diversity and susceptibility to current vaccines.ResultsOverall, 1,598 notifications and 1,064 positive specimens were analysed. The majority of cases (61.4%) occurred in the 15-34 years age group. Interviews revealed a higher incidence of international travel exposure during the first month of case detections, and high levels of transmission in university residential colleges were associated with return to campus. Influenza A(H3N2) was the predominant subtype, with a single lineage predominating despite multiple importations.ConclusionEnhanced testing for respiratory viruses during the COVID-19 pandemic provided a more complete picture of influenza virus transmission compared with previous seasons. Returned international travellers were important drivers of influenza reemergence, as were young adults, a group whose role has previously been under-recognised in the establishment of seasonal influenza epidemics. Targeting interventions, including vaccination, to these groups could reduce future influenza transmission.

Exercising for mass casualty preparedness.

Exercising for mass casualty incidents is mandated by governing organisations with the aim of maintaining readiness within the healthcare sector for the many challenges these incidents bring. This readiness is delivered through a combination of discussion-based and operation-based exercises that are targeted to the needs of both the individuals delivering care and the needs of the overall system of patient flow and treatment. Although exercising for disaster preparedness is resource intensive, it is the repetitive, iterative nature that allows for wide staff capture and exposure along with continual improvement of plans. Having been recently involved in exercising is also likely to increase the confidence of staff and makes them feel better prepared. Exercising should be tailored to the needs and likely challenges of each healthcare system. A cycle of design, challenge, and redesign should target areas of greatest need and greatest benefit. The conventional advice, when introducing exercising, is to start small and build up over time with repeated exercises that demonstrate increasing response capability. However, some organisations would benefit from an exercise that lays bare shortcomings and acts to galvanise change.

Development and Validation of Forecasting Next Reported Seizure Using e-Diaries.

OBJECTIVE: There are no validated methods for predicting the timing of seizures. Using machine learning, we sought to forecast 24-hour risk of self-reported seizure from e-diaries. METHODS: Data from 5,419 patients on SeizureTracker.com (including seizure count, type, and duration) were split into training (3,806 patients/1,665,215 patient-days) and testing (1,613 patients/549,588 patient-days) sets with no overlapping patients. An artificial intelligence (AI) program, consisting of recurrent networks followed by a multilayer perceptron ("deep learning" model), was trained to produce risk forecasts. Forecasts were made from a sliding window of 3-month diary history for each day of each patient's diary. After training, the model parameters were held constant and the testing set was scored. A rate-matched random (RMR) forecast was compared to the AI. Comparisons were made using the area under the receiver operating characteristic curve (AUC), a measure of binary discrimination performance, and the Brier score, a measure of forecast calibration. The Brier skill score (BSS) measured the improvement of the AI Brier score compared to the benchmark RMR Brier score. Confidence intervals (CIs) on performance statistics were obtained via bootstrapping. RESULTS: The AUC was 0.86 (95% CI = 0.85-0.88) for AI and 0.83 (95% CI = 0.81-0.85) for RMR, favoring AI (p < 0.001). Overall (all patients combined), BSS was 0.27 (95% CI = 0.23-0.31), also favoring AI (p < 0.001). INTERPRETATION: The AI produced a valid forecast superior to a chance forecaster, and provided meaningful forecasts in the majority of patients. Future studies will be needed to quantify the clinical value of these forecasts for patients. ANN NEUROL 2020;88:588-595.

Perspectives and Update on the Global Shortage of Verteporfin (Visudyne®).

An ongoing global shortage of verteporfin (Visudyne®) limits the treatment possibilities for several chorioretinal diseases, including central serous chorioretinopathy, choroidal hemangioma, and polypoidal choroidal vasculopathy. Verteporfin is required to perform photodynamic therapy in these ocular diseases. Therefore, the current situation has a substantial impact on eye care worldwide. The worldwide supply of verteporfin appears to be manufactured by a single factory, which is situated in the United States. The distribution of verteporfin is done by different companies for different regions of the world. Official communication on the shortage by the responsible companies has been scarce and over the past years several promises with regards to resolution of the shortage have not been fulfilled. The delivery of new batches of verteporfin is at irregular intervals, unpredictable, and may not be fairly balanced between different regions or countries in the world. To ensure a fair distribution of available verteporfin within a country, several measures can be taken. In the Netherlands, a national committee, consisting of ophthalmologists, is in place to arrange this. On the European level, the European Union and European Medicine Agency have plans to monitor medicine shortages more closely and to intervene if necessary. With a more intensified monitoring and regulation of medicine supplies, future impending shortages may be prevented. Remarkably, the amount of medicine shortages is increasing, having a significant and sometimes irreversible impact on patient care. Thus, efforts should be undertaken to minimize the consequences and, whenever possible, to prevent future medicine shortages.

A comparison of the effectiveness of different doses of tocilizumab and sarilumab in the treatment of severe COVID-19: a natural experiment due to drug shortages.

OBJECTIVES: Interleukin (IL)-6 inhibitors are administered to treat patients hospitalized with COVID-19. In 2021, due to shortages, different dosing regimens of tocilizumab, and a switch to sarilumab, were consecutively implemented. Using real-world data, we compare the effectiveness of these IL-6 inhibitors. METHODS: Hospitalized patients with COVID-19, treated with IL-6 inhibitors, were included in this natural experiment study. Sixty-day survival, hospital- and intensive care unit (ICU) length of stay, and progression to ICU or death were compared between 8 mg/kg tocilizumab, fixed-dose tocilizumab, low-dose tocilizumab, and fixed-dose sarilumab treatment groups. RESULTS: A total of 5485 patients from 49 hospitals were included. After correction for confounding, increased hazard ratios (HRs) for 60-day mortality were observed for fixed-dose tocilizumab (HR 1.20, 95% confidence interval [CI] 1.04-1.39), low-dose tocilizumab (HR 1.12, 95% CI 0.97-1.31), and sarilumab (HR 1.24, 95% CI 1.08-1.42), all relative to 8 mg/kg. The 8 mg/kg dosing regimen had lower odds of progression to ICU or death. Both hospital- and ICU length of stay were shorter for low-dose tocilizumab than for the 8 mg/kg group. CONCLUSION: We found differences in the probability of 60-day survival and the incidence of the combined outcome of mortality or ICU admission, mostly favoring 8 mg/kg tocilizumab. Because of potential time-associated residual confounding, further clinical studies are warranted.

Valve-in-Valve Transcatheter Mitral Valve Replacement: A Large First-in-Human 13-Year Experience.

BACKGROUND: Favourable early outcomes have been reported following valve-in-valve transcatheter mitral valve replacement (TMVR). However, reports of long-term outcomes are lacking. We aimed to evaluate early and late outcomes in a large first-in-human valve-in-valve TMVR 13-year experience. METHODS: All patients undergoing valve-in-valve TMVR in our centre from 2008 to 2021 were included. Clinical and echocardiographic outcomes, defined according to the Mitral Valve Academic Research Consortium, were reported. RESULTS: A total of 119 patients were analysed: mean age 76.8 ± 10.2 years, mean Society of Thoracic Surgeons score 10.7 ± 6.8%, 55.4% female, 63.9% transapical access. Thirty-day mortality was 2.5% for the total population and 0.0% after transseptal TMVR. Maximum follow-up was 13.1 years. During a median follow-up of 3.4 years (interquartile range 1.8-5.3 years), 55 patients (46.2%) died, mainly from noncardiovascular causes. Valve hemodynamics were acceptable at 5 years, with 2.5% structural dysfunction. Patients treated from 2016 on (n = 68; 57.1%), following the advent of routine use of the Sapien 3 valve, CT screening, and transseptal access, were compared with those treated before 2016 (n = 51; 42.9%). Patients from 2016 on had a higher technical success rate (100.0% vs 94.1%; P = 0.04), shorter hospitalisation (P < 0.001), trending lower 30-day mortality (1.5% vs 3.9%; P = 0.4) and better 5-year survival (74.7% vs 41.1%; P = 0.03). CONCLUSIONS: Valve-in-valve TMVR can be performed with little morbidity and low mortality. Mid- to long-term survival remains limited owing to advanced age and comorbidities. Structural bioprosthetic valve dysfunction was rare and redo TMVR feasible in selected patients. Outcomes continue to improve, but the role for valve-in-valve TMVR in lower surgical risk patients remains unclear.

Late Balloon Valvuloplasty for Transcatheter Heart Valve Dysfunction.

BACKGROUND: Transcatheter heart valve (THV) dysfunction with an elevated gradient or paravalvular leak (PVL) may be documented late after THV implantation. Medical management, paravalvular plugs, redo THV replacement, or surgical valve replacement may be considered. However, late balloon dilatation is rarely utilized because of concerns about safety or lack of efficacy. OBJECTIVES: We aimed to evaluate the safety and efficacy of late dilatation in the management of THV dysfunction. METHODS: All patients who underwent late dilatation for symptomatic THV dysfunction at 2 institutions between 2016 and 2021 were identified. Baseline, procedural characteristics, and clinical and echocardiographic outcomes were documented. THV frame expansion was assessed by multislice computed tomography before and after late dilatation. RESULTS: Late dilatation was performed in 30 patients a median of 4.6 months (IQR: 2.3-11.0 months) after THV implantation in the aortic (n = 25; 83.3%), mitral (n = 2; 6.7%), tricuspid (n = 2; 6.7%) and pulmonary (n = 1; 3.3%) position. THV underexpansion was documented at baseline, and frame expansion substantially improved after late dilatation. The mean transvalvular gradient fell in all patients. For aortic THVs specifically, mean transaortic gradient fell from 25.4 ± 13.9 mm Hg to 10.8 ± 4.1 mm Hg; P < 0.001. PVL was reduced to ≤mild in all 11 patients with a previous >mild PVL. Embolic events, stroke, annular injury, and bioprosthetic leaflet injury were not observed. Symptomatic benefit was durable at 19.6 months (IQR: 14.8-36.1 months) follow-up. CONCLUSIONS: Balloon dilatation late after THV implantation appears feasible and safe in appropriately selected patients and may result in THV frame expansion resulting in improvements in hemodynamic performance and PVL.

Tackling the challenges of nanomedicines: are we ready?

PURPOSE: This review provides an overview of the proceedings of the symposium "Tackling the Challenges of Nanomedicines: Are We Ready?" organized by the International Pharmaceutical Federation (FIP) Hospital Pharmacy Section and Non-Biological Complex Drugs (NBCDs) Working Group at the 2019 FIP World Congress of Pharmacy and Pharmaceutical Sciences. Debate centered on reasons underlying the current complex regulatory landscape for nanomedicines and their follow-on products (referred to as nanosimilars) and the pivotal role of hospital pharmacists in selecting, handling, and guiding usage of nanomedicines and nanosimilars. SUMMARY: The evaluation and use of nanomedicines are recognized among scientific, pharmaceutical, and regulatory bodies as complex. Interchangeability and substitutability of nanomedicines and nanosimilars are confounded by a lack of pharmaceutical and pharmacological equivalence, reflecting the inherent complex nature of these drug products and manufacturing processes. Consequences include implications for clinical safety and efficacy and, ultimately, comparability. Local regulatory approvals of some nanomedicines have occurred, but there is no standard to ensure streamlined evaluation and use of consistent measures of therapeutic equivalence of reference products and their nanosimilars. Hospital pharmacists are expected to be experts in the selection, handling, and substitution of nanomedicines and familiarize themselves with the limitations of current methods of assessing pharmaceutical and clinical equivalence of nanosimilars in order to ensure informed formulary decision-making and eventual patient benefit. CONCLUSION: Supportive guidance for pharmacists focusing on the substitutability and/or interchangeability of nanomedicines and their nanosimilars is needed. Current FIP guidance for pharmacists on therapeutic interchange and substitution should be extended to include nanomedicines and nanosimilars.

Proportional multistate lifetable modelling of preventive interventions: concepts, code and worked examples.

Burden of Disease studies-such as the Global Burden of Disease (GBD) Study-quantify health loss in disability-adjusted life-years. However, these studies stop short of quantifying the future impact of interventions that shift risk factor distributions, allowing for trends and time lags. This methodology paper explains how proportional multistate lifetable (PMSLT) modelling quantifies intervention impacts, using comparisons between three tobacco control case studies [eradication of tobacco, tobacco-free generation i.e. the age at which tobacco can be legally purchased is lifted by 1 year of age for each calendar year) and tobacco tax]. We also illustrate the importance of epidemiological specification of business-as-usual in the comparator arm that the intervention acts on, by demonstrating variations in simulated health gains when incorrectly: (i) assuming no decreasing trend in tobacco prevalence; and (ii) not including time lags from quitting tobacco to changing disease incidence. In conjunction with increasing availability of baseline and forecast demographic and epidemiological data, PMSLT modelling is well suited to future multiple country comparisons to better inform national, regional and global prioritization of preventive interventions. To facilitate use of PMSLT, we introduce a Python-based modelling framework and associated tools that facilitate the construction, calibration and analysis of PMSLT models.

Role of multislice computed tomography in transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) required precise knowledge of the anatomic dimensions and physical characteristics of the aortic valve, annulus, and aortic root. Most groups currently use angiography, transthoracic echocardiography (TTE), or transesophageal echocardiography (TEE) to assess aortic annulus dimensions and anatomy. However, multislice computed tomography (MSCT) may allow more detailed 3-dimensional assessment of the aortic root. Twenty-six patients referred for TAVR underwent MSCT. Scans were also obtained for 18 patients after TAVR. All patients underwent pre- and postprocedural aortic root angiography, TTE, and TEE. Mean differences in measured aortic annular diameters were 1.1 mm (95% confidence interval 0.5, 1.8) for calibrated angiography and TTE, -0.9 mm (95% confidence interval -1.7, -0.1 mm) for TTE and TEE, -0.3 mm (95% confidence interval -1.1, 0.6 mm) for MSCT (sagittal) and TTE, and -1.2 mm (95% confidence interval -2.2, -0.2 mm) for MSCT (sagittal) and TEE. Coronal systolic measurements using MSCT, which corresponded to angiographic orientation, were 3.2 mm (1st and 3rd quartiles 2.6, 3.9) larger than sagittal systolic measurements, which were in the same anatomic plane as standard TTE and TEE views. There was no significant association between either shape of the aortic annulus or amount of aortic valve calcium and development of perivalvular aortic regurgitation. After TAVR, the prosthesis extended to or beyond the inferior border of the left main ostium in 9 of 18 patients (50%), and in 11 patients (61%), valvular calcium was <5 mm from the left main ostium. In conclusion, MSCT identified that the aortic annulus was commonly eccentric and often oval. This may in part explain the small, but clinically insignificant, differences in measured aortic annular diameters with other imaging modalities. MSCT after TAVR showed close proximity of both the prosthesis and displaced valvular calcium to the left main ostium in most patients. Neither eccentricity nor calcific deposits appeared to contribute significantly to severity of paravalvular regurgitation after TAVR.