On the role of excipients in biopharmaceuticals manufacture: Modelling-guided formulation identifies the protective effect of arginine hydrochloride excipient on spray-dried Olipudase alfa recombinant protein.

Biopharmaceuticals are labile biomolecules that must be safeguarded to ensure the safety, quality, and efficacy of the product. Batch freeze-drying is an established means of manufacturing solid biopharmaceuticals but alternative technologies such as spray-drying may be more suitable for continuous manufacturing of inhalable biopharmaceuticals. Here we assessed the feasibility of spray-drying Olipudase alfa, a novel parenteral therapeutic enzyme, by evaluating some of its critical quality attributes (CQAs) in a range of excipients, namely, trehalose, arginine (Arg), and arginine hydrochloride (Arg-HCl) in the sucrose/methionine base formulation. The Arg-HCl excipient produced the best gain in CQAs of spray-dried Olipudase with a 63% reduction in reconstitution time and 83% reduction in the optical density of the solution. Molecular dynamics simulations revealed the atomic-scale mechanism of the protein-excipient interactions, substantiating the experimental results. The Arg-HCl effect was explained by the calculated thermal stability and structural order of the protein wherein Arg-HCl acted as a crowding agent to suppress protein aggregation and promote stabilization of Olipudase post-spray-drying. Therefore, by rational selection of appropriate excipients, our experimental and modelling dataset confirms spray-drying is a promising technology for the manufacture of Olipudase and demonstrates the potential to accelerate development of continuous manufacturing of parenteral biopharmaceuticals.

Comparison of Telemedicine Usage at Two Distinct Medicaid-Focused Pediatric Clinics.

Objective: To compare telemedicine versus office visit use at two Medicaid-focused pediatric primary care clinics. Methods: Retrospective cohort study from March 15, 2020 - March 15, 2021 at two Medicaid-focused pediatric primary care clinics. Site A and Site B care for different populations (Site B care for mostly immigrant families with preferred language Spanish). Outcomes included the percent of visits conducted through telemedicine and reason for visit. Descriptive statistics, univariable and multivariable mixed multilevel logistic regression, were used to assess relationship between patient demographics and telemedicine use. Results: Out of 17,142 total visits, 13% of encounters at Site A (n = 987) and 25% of encounters at Site B (n = 2,421) were conducted using telemedicine. Around 13.8% of well-child care (n = 1,515/10,997), 36.2% of mental health care (n = 572/1,581), and 25.0% of acute care/follow-up (n = 1,893/7,562) were telemedicine visits. After adjustment for covariates, there was no difference in odds of a patient having any telemedicine use by preferred language, sex, or payor. Patients 1-4 years of age had the lowest odds of telemedicine use. At Site A, patients who identified as Non-Hispanic Black (odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.24-0.45), Hispanic/Latinx (OR = 0.40, 95% CI = 0.24-0.66), or other race/ethnicity (OR = 0.35, 95% CI = 0.23-0.55) had lower odds of telemedicine use in comparison to Non-Hispanic White. Conclusions: Telemedicine was successfully accessed by Medicaid enrollees for different types of pediatric primary care. There was no difference in telemedicine use by preferred language and payor. However, differences existed by age at both sites and by race/ethnicity at one site. Future research should explore operational factors that improve telemedicine access for marginalized groups.

Improving corneal permeability of dexamethasone using penetration enhancing agents: First step towards achieving topical drug delivery to the retina.

With an ever-increasing burden of vision loss caused by diseases of the posterior ocular segment, there is an unmet clinical need for non-invasive treatment strategies. Topical drug application using eye drops suffers from low to negligible bioavailability to the posterior segment as a result of static and dynamic defensive ocular barriers to penetration, while invasive delivery systems are expensive to administer and suffer potentially severe complications. As the cornea is the main anatomical barrier to uptake of topically applied drugs from the ocular surface, we present an approach to increase corneal permeability of a corticosteroid, dexamethasone sodium-phosphate (DSP), using a novel penetration enhancing agent (PEA). We synthesised a novel polyacetylene (pAc) polymer and compared its activity to two previously described cell penetrating peptide (CPP) based PEAs, TAT and penetratin, with respect to increasing transcorneal permeability of DSP in a rapid ex-vivo porcine corneal assay over 60 min. The transcorneal apparent permeability coefficients (Papp) for diffusion of pAc, and fluorescein isothiocyanate (FITC) conjugated TAT and penetratin were up to 5 times higher (p < 0.001), when compared to controls. When pAc was used in formulation with DSP, an almost 5-fold significant increase was observed in Papp of DSP across the cornea (p = 0.0130), a significant 6-fold increase with TAT (p = 0.0377), and almost 7-fold mean increase with penetratin (p = 0.9540). Furthermore, we investigated whether the PEAs caused any irreversible damage to the barrier integrity of the corneal epithelium by measuring transepithelial electrical resistance (TEER) and immunostaining of tight junction proteins using zonula occludens-1 (ZO-1) and occludin antibodies. There was no damage or structural toxicity, and the barrier integrity was preserved after PEA application. Finally, an in-vitro cytotoxicity assessment of all PEAs in human retinal pigment epithelium cells (ARPE-19) demonstrated that all PEAs were very well-tolerated, with IC50 values of 64.79 mM for pAc and 1335.45 µM and 87.26 µM for TAT and penetratin, respectively. Our results suggest that this drug delivery technology could potentially be used to achieve a significantly higher intraocular therapeutic bioavailability after topical eye drop administration, than currently afforded.

Early Detection and Monitoring of Gastrointestinal Infections Using Syndromic Surveillance: A Systematic Review.

The underreporting of laboratory-reported cases of community-based gastrointestinal (GI) infections poses a challenge for epidemiologists understanding the burden and seasonal patterns of GI pathogens. Syndromic surveillance has the potential to overcome the limitations of laboratory reporting through real-time data and more representative population coverage. This systematic review summarizes the utility of syndromic surveillance for early detection and surveillance of GI infections. Relevant articles were identified using the following keyword combinations: 'early warning', 'detection', 'gastrointestinal activity', 'gastrointestinal infections', 'syndrome monitoring', 'real-time monitoring', 'syndromic surveillance'. In total, 1820 studies were identified, 126 duplicates were removed, and 1694 studies were reviewed. Data extraction focused on studies reporting the routine use and effectiveness of syndromic surveillance for GI infections using relevant GI symptoms. Eligible studies (n = 29) were included in the narrative synthesis. Syndromic surveillance for GI infections has been implemented and validated for routine use in ten countries, with emergency department attendances being the most common source. Evidence suggests that syndromic surveillance can be effective in the early detection and routine monitoring of GI infections; however, 24% of the included studies did not provide conclusive findings. Further investigation is necessary to comprehensively understand the strengths and limitations associated with each type of syndromic surveillance system.

Individual- and Neighborhood-Level Disparities in Audio-Only Telemedicine Utilization Across a Large Academic Health System.

Introduction: The objective of this study was to understand whether use of audio-only telemedicine visits differed by individual- and neighborhood-level patient characteristics during the COVID-19 pandemic. Methods: We conducted a retrospective cross-sectional study of telemedicine encounter data from a large academic health system. The primary outcome was rate of audio-only versus video visits. The exposures of interest were individual- (age, race, insurance, preferred language) and neighborhood-level (Social Deprivation Index [SDI]) patient characteristics. Results: Our study included 1,054,465 patient encounters from January 1, 2020 to December 31, 2021, of which 18.33% were completed via audio-only. Encounters among adults 75 years or older, Black patients, Spanish-speakers, and those with public insurance were more frequently conducted by audio-only (p < 0.001). Overall, populations showed decreasing rates of audio-only visits over time. We also observed an increase in the rate of audio-only encounters as SDI scores increased. Discussion: We found that audio-only disparities exist in telemedicine utilization by individual and zip code level characteristics. Though these disparities have improved over time as seen by our temporal analysis, marginalized and minority groups still showed the lowest rates of video utilization. In conclusion, access to audio-only care is a critical component to ensure that telemedicine is accessible to all populations. State and federal policy should support continued reimbursement of audio-only care to ensure equitable access to care while the implications of different care modalities are further studied.

Public inquiries, patient safety and the implementation gap.

A decade on from the Francis report, avoidable patient harm continues to occur and we have continued to see new inquiries and reviews into serious patient safety scandals. A failure to listen to patients or learn from previous investigations, a corrosive blame culture, a lack of effective leadership and an unresponsive regulatory framework are alarming and often reported themes that we review here.

Non-contact Laser Interferometer Method to Characterize Tablet Punches: New Methodology to Assess Surface Roughness.

Sticking to tablet punches is a major issue during drug product manufacturing. Research has shown that sticking involves the interrelationship of powder properties, compression force, length of manufacturing runs and punch quality. Here, we present a novel non-destructive methodology to study the surface metrology of punches to monitor them over their lifetime. This investigation used a non-contact laser interferometer to characterise roughness of commercial standard S7 steel punches coated with chrome that were originally used for commercial scale production that developed a sticking issue. During the development, this phenomenon had not been observed and was not considered a scale-up risk. The profilometer was used to examine the complete surface of these punches to investigate whether they met the acceptability criteria based on BS_ISO_18804 tooling standard. To improve data analysis during changeover, a 3D-printed holder was designed to enable analysis with minimal set-up requirements. Upon investigation, the punches were found to be of an unacceptable roughness and, particularly rough areas of the punch surface profiled, correlated well with areas of visually pronounced sticking. This non-destructive method can be used to produce a more detailed characterisation of punch roughness to ensure surfaces are of an acceptable quality after treatment with coatings.

Understanding the impact of the COVID-19 pandemic response on GI infection surveillance trends in England, January 2020-April 2022.

Stepwise non-pharmaceutical interventions and health system changes implemented as part of the COVID-19 response have had implications on the incidence, diagnosis, and reporting of other communicable diseases. Here, we established the impact of the COVID-19 outbreak response on gastrointestinal (GI) infection trends using routinely collected surveillance data from six national English laboratory, outbreak, and syndromic surveillance systems using key dates of governmental policy to assign phases for comparison between pandemic and historic data. Following decreases across all indicators during the first lockdown (March-May 2020), bacterial and parasitic pathogens associated with foodborne or environmental transmission routes recovered rapidly between June and September 2020, while those associated with travel and/or person-to-person transmission remained lower than expected for 2021. High out-of-season norovirus activity was observed with the easing of lockdown measures between June and October 2021, with this trend reflected in laboratory and outbreak systems and syndromic surveillance indicators. Above expected increases in emergency department (ED) attendances may have reflected changes in health-seeking behaviour and provision. Differential reductions across specific GI pathogens are indicative of the underlying routes of transmission. These results provide further insight into the drivers for transmission, which can help inform control measures for GI infections.

Telehealth Curricula in the Pediatric Core Clerkship: Results From a Survey of Clerkship Directors.

OBJECTIVE: Given the increasing prevalence of telehealth, medical students require dedicated instruction in the practice of high-quality telehealth. This study characterizes telehealth practices and curricula in pediatric core clerkships across the United States and Canada. METHODS: We surveyed pediatric core clerkship directors and site directors through the 2020 Council on Medical Student Education in Pediatrics (COMSEP) annual member survey. We analyzed the results using descriptive statistics. RESULTS: Of 104 medical schools represented, 28 responded (26.9%). Directors reported students spent little time on telehealth during their pediatric core clerkships (average 8.2% of clerkship; SD 10.4). Only 10.7% (n=3) of clerkships had dedicated telehealth curricula. The instructional methods, content, and modes of evaluation varied across the clerkships' curricula. Barriers to implementation of telehealth curricula included lack of dedicated time in the existing curriculum (64.0%), lack of faculty time to teach (44.0%), lack of curricular materials (44.0%), students not participating in telehealth activities (40.0%) and lack of faculty expertise (36.0%). CONCLUSIONS: Most pediatric core clerkships do not include dedicated telehealth curricula, and the characteristics of existing curricula vary. Considering the rapid adoption of telemedicine, pediatric core clerkships merit additional support and guidance for the training of medical students in telehealth practice.

Predicting Norovirus in England Using Existing and Emerging Syndromic Data: Infodemiology Study.

BACKGROUND: Norovirus is associated with approximately 18% of the global burden of gastroenteritis and affects all age groups. There is currently no licensed vaccine or available antiviral treatment. However, well-designed early warning systems and forecasting can guide nonpharmaceutical approaches to norovirus infection prevention and control. OBJECTIVE: This study evaluates the predictive power of existing syndromic surveillance data and emerging data sources, such as internet searches and Wikipedia page views, to predict norovirus activity across a range of age groups across England. METHODS: We used existing syndromic surveillance and emerging syndromic data to predict laboratory data indicating norovirus activity. Two methods are used to evaluate the predictive potential of syndromic variables. First, the Granger causality framework was used to assess whether individual variables precede changes in norovirus laboratory reports in a given region or an age group. Then, we used random forest modeling to estimate the importance of each variable in the context of others with two methods: (1) change in the mean square error and (2) node purity. Finally, these results were combined into a visualization indicating the most influential predictors for norovirus laboratory reports in a specific age group and region. RESULTS: Our results suggest that syndromic surveillance data include valuable predictors for norovirus laboratory reports in England. However, Wikipedia page views are less likely to provide prediction improvements on top of Google Trends and Existing Syndromic Data. Predictors displayed varying relevance across age groups and regions. For example, the random forest modeling based on selected existing and emerging syndromic variables explained 60% variance in the ≥65 years age group, 42% in the East of England, but only 13% in the South West region. Emerging data sets highlighted relative search volumes, including "flu symptoms," "norovirus in pregnancy," and norovirus activity in specific years, such as "norovirus 2016." Symptoms of vomiting and gastroenteritis in multiple age groups were identified as important predictors within existing data sources. CONCLUSIONS: Existing and emerging data sources can help predict norovirus activity in England in some age groups and geographic regions, particularly, predictors concerning vomiting, gastroenteritis, and norovirus in the vulnerable populations and historical terms such as stomach flu. However, syndromic predictors were less relevant in some age groups and regions likely due to contrasting public health practices between regions and health information-seeking behavior between age groups. Additionally, predictors relevant to one norovirus season may not contribute to other seasons. Data biases, such as low spatial granularity in Google Trends and especially in Wikipedia data, also play a role in the results. Moreover, internet searches can provide insight into mental models, that is, an individual's conceptual understanding of norovirus infection and transmission, which could be used in public health communication strategies.

Provider Perspectives Regarding Ambulatory Telemedicine at a Large Academic Health System During the COVID-19 Pandemic.

Purpose: To understand provider preferences regarding telemedicine across clinical departments and provider demographic groups. Methods: A cross-sectional online survey was distributed to providers at Johns Hopkins Medicine who had completed at least one outpatient telemedicine encounter. The survey included questions about clinical appropriateness and preferred use of telemedicine. Demographic data were obtained from institutional records. Descriptive statistics provided a profile of provider responses. Wilcoxon rank sum tests evaluated departmental and demographic differences. Results: A total of 1,342 of 3,576 providers responded (37.5%). Providers indicated that telemedicine was clinically appropriate for new patients a median of 31.5% of the time (Range: 20% in pediatrics, 80% in psychiatry/behavioral sciences). For existing patients, providers indicated that telemedicine was clinically appropriate a median of 70% of the time (Range: 50% in physical medicine, 90% in psychiatry/behavioral sciences). Providers desired a median of 30% of their schedule template be dedicated to telemedicine (Range: 20% in family medicine, 70% in psychiatry/behavioral sciences). Providers who were female, had fewer than 15 years in practice, or were psychiatrists/psychologists tended to find telemedicine more clinically appropriate (p < 0.05). Conclusions: A majority of providers across clinical departments felt that high-quality care could be delivered through telemedicine, although the amount of care varied widely based on department and patient type. Preferences for future telemedicine similarly showed wide variety across and within departments. These findings indicate that in this early adoption phase of widespread telemedicine integration, there is lack of consensus among providers about the amount of telemedicine appropriate for everyday practice.

Evaluation and Screening of Biopharmaceuticals using Multi-Angle Dynamic Light Scattering.

Biopharmaceuticals are large, complex and labile therapeutic molecules prone to instability due to various factors during manufacturing. To ensure their safety, quality and efficacy, a wide range of critical quality attributes (CQAs) such as product concentration, aggregation, particle size, purity and turbidity have to be met. Size exclusion chromatography (SEC) is the gold standard to measure protein aggregation and degradation. However, other techniques such as dynamic light scattering (DLS) are employed in tandem to measure the particle size distribution (PSD) and polydispersity of biopharmaceutical formulations. In this study, the application of multi-angle dynamic light scattering (MADLS) was evaluated for the determination of particle size, particle concentration and aggregation in 3 different protein modalities, namely bovine serum albumin (BSA) and two biopharmaceuticals including a monoclonal antibody (mAb) and an enzyme. The obtained calibration curve (R2 > 0.95) for the particle number concentration of the 3 proteins and the observed correlation between MADLS and SEC (R2 = 0.9938) for the analysis of aggregation in the enzyme can be employed as a 3-in-1 approach to assessing particle size, concentration and aggregation for the screening and development of products while also reducing the number of samples and experiments required for analysis prior to other orthogonal tests.

Increase in invasive group A streptococcal infection notifications, England, 2022.

Increases in invasive group A streptococcal (iGAS) infection and associated deaths, particularly in children, above seasonally expected levels are being seen this season (772 notifications reported in weeks 37 to 48 in 2022) across England. Diagnoses of iGAS infection from lower respiratory tract specimens in children under 15 years increased to 28% in November 2022. Medical practitioners have been alerted to the exceptional increase in incidence, including unusual numbers of children presenting with pulmonary empyema.

Resident Perceptions of Continuity Clinic Patient Metrics Differ From EHR Data: Pilot Use of Population Health Dashboards.

BACKGROUND AND OBJECTIVES: Population health management (PHM) dashboards using electronic health record (EHR) data can teach trainees about the population they serve while also delivering data on their clinical practice. Yet, few studies have demonstrated their use. In this pilot study, we assessed baseline resident perceptions of population health metrics for continuity clinic panels by comparing resident estimates with EHR-reported values delivered by individualized PHM dashboards. METHODS: A descriptive, comparative study was conducted at a primary continuity clinic site for pediatric residents in January 2018. Residents were surveyed about population health metrics for their patient panels, including demographics, utilization, and medical diagnoses. We compared resident estimates to corresponding EHR-reported values using 2-tailed paired t tests. RESULTS: A total of 42 out of 55 eligible residents (76%) completed the survey. Compared with EHR-reported values, residents estimated higher percentages of emergency department utilization (22.1% vs 10.3%, P < .01) and morbidity, including medical complexity (15.6% vs 5.9%, P < .01), overweight (38.1% vs 11.7%, P < .01), obesity (20.5% vs 15.8%, P = .02), and asthma (34.6% vs 21.4%, P < .01). CONCLUSIONS: In this pilot study of PHM dashboards, resident perceptions of continuity clinic population health metrics did not align with EHR data. Estimates were higher for measures of utilization and morbidity. PHM dashboards may help trainees better understand their patient populations and serve as a consistent source of objective practice data. However, further research and investment is needed to evaluate dashboard implementation and impact on trainee and patient outcomes.

Additional consensus recommendations for conducting complex innovative trials of oncology agents: a post-pandemic perspective.

In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation.

Epidemiology of respiratory syncytial virus in children younger than 5 years in England during the COVID-19 pandemic, measured by laboratory, clinical, and syndromic surveillance: a retrospective observational study.

BACKGROUND: Seasonal epidemics of respiratory syncytial virus (RSV) cause a clinically significant burden of disease among young children. Non-pharmaceutical interventions targeted at SARS-CoV-2 have affected the activity of other respiratory pathogens. We describe changes in the epidemiology of RSV among children younger than 5 years in England since 2020. METHODS: Surveillance data on RSV infections, comprising laboratory-confirmed cases, proportion of positive tests, hospital admissions for RSV-attributable illness, and syndromic indicators for RSV-associated disease (emergency department attendances for acute bronchitis or bronchiolitis, non-emergency health advice telephone service [NHS 111] calls for cough, general practitioner [GP] in-hours consultations for respiratory tract infections, and GP out-of-hours contacts for acute bronchitis or bronchiolitis) were analysed from Dec 29, 2014 to March 13, 2022, for children younger than 5 years. Data were extracted from national laboratory, clinical, and syndromic surveillance systems. Time-series analyses using generalised linear models were used to estimate the effect of non-pharmaceutical interventions targeting SARS-CoV-2 on RSV indicators, with absolute and relative changes calculated by comparing observed and predicted values. FINDINGS: RSV-associated activity was reduced for all RSV indicators during winter 2020-21 in England, with 10 280 (relative change -99·5% [95% prediction interval -100·0 to -99·1]) fewer laboratory-confirmed cases, 22·2 (-99·6%) percentage points lower test positivity, 92 530 (-80·8% [-80·9 to -80·8]) fewer hospital admissions, 96 672 (-73·7% [-73·7 to -73·7]) fewer NHS 111 calls, 2924 (-88·8% [-90·4 to -87·2]) fewer out-of-hours GP contacts, 91 304 (-89·9% [-90·0 to -89·9]) in-hours GP consultations, and 27 486 (-85·3% [-85·4 to -85·2]) fewer emergency department attendances for children younger than 5 years compared with predicted values based on winter seasons before the COVID-19 pandemic. An unprecedented summer surge of RSV activity occurred in 2021, including 11 255 (1258·3% [1178·3 to 1345·8]) extra laboratory-confirmed cases, 11·6 percentage points (527·3%) higher test positivity, 7604 (10·7% [10·7 to 10·8]) additional hospital admissions, 84 425 (124·8% [124·7 to 124·9]) more calls to NHS 111, 409 (39·0% [36·6 to 41·8]) more out-of-hours GP contacts, and 9789 (84·9% [84·5 to 85·4]) more emergency department attendances compared with the predicted values, although there were 21 805 (-34·1% [-34·1 to -34·0]) fewer in-hours GP consultations than expected. Most indicators were also lower than expected in winter 2021-22, although to a lesser extent than in winter 2020-21. INTERPRETATION: The extraordinary absence of RSV during winter 2020-21 probably resulted in a cohort of young children without natural immunity to RSV, thereby raising the potential for increased RSV incidence, out-of-season activity, and health-service pressures when measures to restrict SARS-CoV-2 transmission were relaxed. FUNDING: None.

BIR POSITION STATEMENT: Governance requirements for Non-Medical referrers to radiology.

The ability to request clinical imaging is included in many advanced roles of health-care professionals in the UK and is seen as a useful component in ensuring patients receive the right care, by the right person, at the right time. In order that diagnostic imaging referrals are appropriate, timely and safely made, the British Institute of Radiology has produced a position statement on the governance requirements covering clinical imaging requests from non-medical referrers (NMRs). This document is intended to help define the role of a NMR and to ensure they are practising responsibly and safely, within professional and legal frameworks, as part of the wider interprofessional team.