Descriptive analysis to assess seasonal patterns of COVID-19 and influenza in low-income and middle-income countries in Asia, the Middle East and Latin America.

OBJECTIVES: Understanding disease seasonality can help predict the occurrence of outbreaks and inform public health planning. Respiratory diseases typically follow seasonal patterns; however, knowledge regarding the seasonality of COVID-19 and its impact on the seasonality of influenza remains limited. The objective of this study was to provide more evidence to understand the circulation of SARS-CoV-2, the virus responsible for COVID-19, in an endemic scenario to guide potential preventive strategies. DESIGN: In this study, a descriptive analysis was undertaken to describe seasonality trends and/or overlap between COVID-19 and influenza in 12 low-income and middle-income countries using Our World in Data and FluMart data sources. Plots of COVID-19 and influenza cases were analysed. SETTING: Singapore, Thailand, Malaysia, the Philippines, Argentina, Brazil, Mexico, South Africa, Morocco, Bahrain, Qatar and Saudi Arabia. OUTCOME MEASURES: COVID-19 cases and influenza cases. RESULTS: No seasonal patterns of SARS-CoV-2 or SARS-CoV-2/influenza cocirculation were observed in most countries, even when considering the avian influenza pandemic period. CONCLUSIONS: These results can inform public health strategies. The lack of observed seasonal behaviour highlights the importance of maintaining year-round vaccination rather than implementing seasonal campaigns. Further research investigating the influence of climate conditions, social behaviour and year-round preventive measures could be fundamental for shaping appropriate policies related to COVID-19 and respiratory viral disease control in low-income and middle-income countries as COVID-19 variant data and epidemiologic patterns accrue over time.

Clinician and patient views on janus kinase inhibitors in the treatment of inflammatory arthritis: a mixed methods study.

BACKGROUND: Janus kinase inhibitors (JAKi) are new targeted synthetic disease-modifying antirheumatic drugs (DMARDs) licenced in the UK to treat rheumatoid and psoriatic arthritides. Unlike currently often prescribed biological DMARDs, they target a different part of the inflammatory pathway and are taken orally. The aim of this study was to explore what UK-based rheumatology clinicians and inflammatory arthritis (IA) patients think about the awareness, prescription and use of JAKi; how they compare with biologics; and how the COVID-19 pandemic has affected how JAKi are viewed and prescribed. METHODS: Rheumatology clinicians and IA patients completed online surveys and participated in interviews/focus groups between September 2021 and January 2022. Survey data were analysed descriptively, and interview/focus group data underwent an inductive thematic analysis. RESULTS: 66.6% of patients had at least some awareness of JAKi, 73.0% from their rheumatology team. Problems getting earlier access to these drugs were raised by some patients, with many being prescribed JAKi after multiple other therapies had failed. 91.5% of clinicians prescribed JAKi in keeping with their local guidelines, with 72.3% prescribing them frequently as a monotherapy. Some clinicians had lingering safety concerns over JAKi use. Despite experiencing side effects and knowing of possible long-term risks, patients felt overall the benefits of JAKi outweighed the risks. 39.3% of patients were 'very satisfied' on JAKi, compared with 25.0% on biologics. Patients on JAKi appreciated their short half-life when it comes to infections, and their convenience as an oral therapy. When JAKi were discontinued in patients, it was predominantly due to inefficacy and non-cardiovascular adverse events. The COVID-19 pandemic resulted in increased prescription of JAKi as an alternative to injections and infusions, primarily to avoid potentially exposing patients to the coronavirus. Some patients believed their JAKi may confer some protection against developing severe COVID-19. CONCLUSION: JAKi are an effective treatment option for IA and are liked by patients. The COVID-19 pandemic appears to have impacted their prescription favourably. However, clinicians have safety concerns over JAKi use. Any decision to go on a JAKi should be informed and take into account individual patient risk factors, circumstances and preferences.

Proteomic profiling of paired human liver homogenate and tissue derived extracellular vesicles.

Advances in technologies to isolate extracellular vesicles (EVs) and detect/quantify their cargo underpin the novel potential of these circulating particles as a liquid biopsy to understand physiology and disease. One organ of particular interest in terms of utilizing EVs as a liquid biopsy is the liver. The extent to which EVs originating from the liver reflect the functional status of this organ remains unknown. This is an important knowledge gap that underpins the utility of circulating liver derived EVs as a liquid biopsy. The primary objective of this study was to characterize the proteomic profile of EVs isolated from the extracellular space of liver tissue (LEV) and compare this profile to that of paired tissue (LH). LCMS analyses detected 2892 proteins in LEV and 2673 in LH. Of the 2673 proteins detected in LH, 1547 (58%) were also detected in LEV. Bioinformatic analyses demonstrated comparable representation of proteins in terms of biological functions and cellular compartments. Although, enriched representation of membrane proteins and associated functions was observed in LEV, while representation of nuclear proteins and associated functions was depleted in LEV. These data support the potential use of circulating liver derived EVs as a liquid biopsy for this organ.

Spatiotemporal Trends Spanning Three Decades Show Toxic Levels of Chemical Contaminants in Marine Mammals.

Despite their ban and restriction under the 2001 Stockholm Convention, persistent organic pollutants (POPs) are still widespread and pervasive in the environment. Releases of these toxic and bioaccumulative chemicals are ongoing, and their contribution to population declines of marine mammals is of global concern. To safeguard their survival, it is of paramount importance to understand the effectiveness of mitigation measures. Using one of the world's largest marine mammals strandings data sets, we combine published and unpublished data to examine pollutant concentrations in 11 species that stranded along the coast of Great Britain to quantify spatiotemporal trends over three decades and identify species and regions where pollutants pose the greatest threat. We find that although levels of pollutants have decreased overall, there is significant spatial and taxonomic heterogeneity such that pollutants remain a threat to biodiversity in several species and regions. Of individuals sampled within the most recent five years (2014-2018), 48% of individuals exhibited a concentration known to exceed toxic thresholds. Notably, pollutant concentrations are highest in long-lived, apex odontocetes (e.g., killer whales (Orcinus orca), bottlenose dolphins (Tursiops truncatus), and white-beaked dolphins (Lagenorhynchus albirostris)) and were significantly higher in animals that stranded on more industrialized coastlines. At the present concentrations, POPs are likely to be significantly impacting marine mammal health. We conclude that more effective international elimination and mitigation strategies are urgently needed to address this critical issue for the global ocean health.

Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial.

BACKGROUND: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. METHODS: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. FINDINGS: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. INTERPRETATION: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. FUNDING: National Institute for Health and Care Research.

Impact of COVID-19 on disease (self) management and well-being in people with Rheumatic or Musculoskeletal diseases across four European countries: a mixed methods study.

BACKGROUND: Qualitative data on how the COVID-19 pandemic has affected the lives of people with rheumatic and musculoskeletal diseases (RMDs) in different European countries are lacking. OBJECTIVES: To describe the impact of the first two waves of the COVID-19 pandemic on people with inflammatory RMDs concerning (self)management of their disease, interaction with the health care team, emotional well-being and overall health. METHODS: A mixed-methods study of adults (>18 years) with RMDs on immunosuppression from Cyprus, England, Greece, and Portugal took part on online focus groups (FG) after the first wave (July-August, 2020). The data was transcribed verbatim and thematically analyzed. Informed by the qualitative findings, a follow-up survey was developed for the same participants after the second wave, allowing to compare the perceived impact. RESULTS: Twenty-four patients (6 from each country; 21 women; 33-74 years range) participated. Three key themes were identified (with 3-7 subthemes each), focusing on the impact of COVID-19 on the: (i) individual, (ii) health settings, and (iii) work and community. Overall, qualitative results were similar across countries. The follow-up survey during the second wave highlighted a worsening of psychosocial aspects, e.g. sleep problems, stress, and isolation. CONCLUSIONS: People with RMDs felt vulnerable and anxious, specifically about how to cope with isolation and difficulties in communicating with healthcare providers. The second wave had a more significant impact on patients. Healthcare providers and policymakers need to consider measures to ameliorate the longer-term impact that many may still face.

Comparison Theorems for Stochastic Chemical Reaction Networks.

Continuous-time Markov chains are frequently used as stochastic models for chemical reaction networks, especially in the growing field of systems biology. A fundamental problem for these Stochastic Chemical Reaction Networks (SCRNs) is to understand the dependence of the stochastic behavior of these systems on the chemical reaction rate parameters. Towards solving this problem, in this paper we develop theoretical tools called comparison theorems that provide stochastic ordering results for SCRNs. These theorems give sufficient conditions for monotonic dependence on parameters in these network models, which allow us to obtain, under suitable conditions, information about transient and steady-state behavior. These theorems exploit structural properties of SCRNs, beyond those of general continuous-time Markov chains. Furthermore, we derive two theorems to compare stationary distributions and mean first passage times for SCRNs with different parameter values, or with the same parameters and different initial conditions. These tools are developed for SCRNs taking values in a generic (finite or countably infinite) state space and can also be applied for non-mass-action kinetics models. When propensity functions are bounded, our method of proof gives an explicit method for coupling two comparable SCRNs, which can be used to simultaneously simulate their sample paths in a comparable manner. We illustrate our results with applications to models of enzymatic kinetics and epigenetic regulation by chromatin modifications.

Buffy Coat Score as a Biomarker of Treatment Response in Neuronal Ceroid Lipofuscinosis Type 2.

The introduction of intracerebroventricular (ICV) enzyme replacement therapy (ERT) for treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease has produced dramatic improvements in disease management. However, assessments of therapeutic effect for ICV ERT are limited to clinical observational measures, namely the CLN2 Clinical Rating Scale, a subjective measure of motor and language performance. There is a need for an objective biomarker to enable assessments of disease progression and response to treatment. To address this, we investigated whether the proportion of cells with abnormal storage inclusions on electron microscopic examination of peripheral blood buffy coats could act as a biomarker of disease activity in CLN2 disease. We conducted a prospective longitudinal analysis of six patients receiving ICV ERT. We demonstrated a substantial and continuing reduction in the proportion of abnormal cells over the course of treatment, whereas symptomatic scores revealed little or no change over time. Here, we proposed the use of the proportion of cells with abnormal storage as a biomarker of response to therapy in CLN2. In the future, as more tissue-specific biomarkers are developed, the buffy coats may form part of a panel of biomarkers in order to give a more holistic view of a complex disease.

Perspectives of family-centred care at the end of life during the COVID-19 pandemic: A qualitative descriptive study.

AIM: To explore nurses' and family members' perspectives of family care at the end of life, during restricted visitation associated with the COVID-19 pandemic. BACKGROUND: To minimise the transmission of COVID-19, stringent infection prevention and control measures resulted in restricted hospital access for non-essential workers and visitors, creating challenges for the provision of family-centred care at the end of life. DESIGN: Qualitative descriptive approach based on naturalistic inquiry. METHODS: At a large public hospital in Melbourne, Australia, individual semi-structured interviews were undertaken with 15 registered nurses who cared for patients who died during restricted visitation associated with the COVID-19 pandemic, and 21 bereaved family members. COREQ guidelines informed analysis and reporting. RESULTS: Five themes developed from the data: (i) impact of visitor restrictions, which describes uncertain, ambiguous and arbitrary rules, onerous and inconsistent requirements; (ii) nurse-family communication; (iii) family-centred care and interrupted connections; (iv) well-being and negative emotions; and (v) suggestions for a better way, such as moving away from the black and whiteness of the rules, prioritising communication, compassion and advocacy. CONCLUSIONS: Negative consequences for communication and the patient-family connection at the end of life were felt deeply. The evolving COVID-19 rules that were frequently revised and applied at short notice, and the subsequent consequences for clinical practices and care were felt deeply. RELEVANCE TO CLINICAL PRACTICE: Technology-facilitated communication, innovation and increased resources must be prioritised to overcome the challenges described in this study. A family-centred approach to care and emphasising the patient-family connection at the end of life is fundamental to minimising trauma and distress associated with future public health emergencies. PATIENT OR PUBLIC CONTRIBUTION: Bereaved family members contributed their first-hand experience. Members of the health service's patient experience team ensured the research was conducted in accordance with health service guidelines for patient and public contribution.

An investigation into the effects of climate change on baleen whale distribution in the British Isles.

Climate change is predicted to impact the distribution of many marine species. In the North-East Atlantic and elsewhere in the world, studies indicate that climate change is leading to poleward shifts in cetacean distribution. Here, strandings data collected in the British Isles from 1990 to 2020 were used to assess whether there is evidence of a shift in baleen whale distribution. Linear regression models were used to compare the number of strandings over time between six regions of the British Isles and, whilst the results indicate no significant change in the number of strandings in the most southerly region of the British Isles, there have been significant increases in more northern regions. Data related to stranded minke whales is the primary driver of these increases, with a number of potential variables affecting this trend, including observer effort. These variables are discussed and further research to explore this potential association is suggested.

Patient perceptions of care quality and discharge information following same-day cardiac catheterization laboratory procedures: A mixed-methods study.

AIMS: To examine patients' perceptions of care quality following a same-day procedure in the cardiac catheterization laboratory and understand the extent to which they were prepared for discharge. DESIGN: Single-centre, mixed-methods study. METHODS: Postdischarge, online survey of patients who underwent a same-day procedure in the cardiac catheterization laboratory (n = 150) and one-on-one interviews with 13 of these patients. RESULTS: Survey responses were positive with mean scores between 4.39-4.83 out of five and 63.3% of respondents (n = 95) extremely likely to recommend the service to others. Interview data analysis identified three themes: the care experience, information and education for safe discharge, and follow-up needs. Participants spoke highly of their interactions with clinicians and were satisfied with their care experience. Mode and content of information delivered varied, with some participants lacking guidance about postdischarge health management and clarity about follow-up plans. PATIENT OR PUBLIC CONTRIBUTION: Participants were patients.

Evaluation of a marine mammal status and trends contaminants indicator for European waters.

Marine mammals are vulnerable to the bioaccumulation, biomagnification and lactational transfer of specific types of pollutants, such as industrial polychlorinated biphenyls (PCBs), due to their long-life spans, feeding at a high trophic level and unique fat stores that can serve as depots for these lipophilic contaminants. Currently, European countries are developing indicators for monitoring pollutants in the marine environment and assessing the state of biodiversity, requirements under both Regional Seas Conventions and European legislation. As sentinel species for marine ecosystem and human health, marine mammals can be employed to assess bioaccumulated contaminants otherwise below current analytical detection limits in water and lower trophic level marine biota. To aid the development of Regional Seas marine mammal contaminants indicators, as well as Member States obligations under descriptor 8 of the EU Marine Strategy Framework Directive, the current study aims to further develop appropriate methodological standards using data collected by the established UK marine mammal pollutant monitoring programme (1990 to 2017) to assess the trends and status of PCBs in harbour porpoises. Within this case study, temporal trends of PCB blubber concentration in juvenile harbour porpoises were analysed using multiple linear regression models and toxicity thresholds for the onset of physiological (reproductive and immunological) endpoints were applied to all sex-maturity groups. Mean PCB blubber concentrations were observed to decline in all harbour porpoise Assessment Units and OSPAR Assessment Areas in UK waters. However, a high proportion of animals were exposed to concentrations deemed to be a toxicological threat, though the relative proportion declined in most Assessment Units/Areas over the last 10 years of the assessment. Recommendations were made for improving the quality of the assessment going forward, including detailing monitoring requirements for the successful implementation of such an indicator.

The use of metaphors by service users with diverse long-term conditions: a secondary qualitative data analysis.

Long-term conditions and accompanied co-morbidities now affect about a quarter of the UK population. Enabling patients and caregivers to communicate their experience of illness in their own words is vital to developing a shared understanding of the condition and its impact on patients' and caregivers' lives and in delivering person-centred care. Studies of patient language show how metaphors provide insight into the physical and emotional world of the patient, but such studies are often limited by their focus on a single illness. The authors of this study undertook a secondary qualitative data analysis of 25 interviews, comparing the metaphors used by patients and parents of patients with five longterm conditions. Analysis shows how similar metaphors can be used in empowering and disempowering ways as patients strive to accept illness in their daily lives and how metaphor use depends on the manifestation, diagnosis, and treatment of individual conditions. The study concludes with implications for how metaphorical expressions can be attended to by healthcare professionals as part of shared care planning.

Development of a patient-led clinic visit framework: a case study navigating a patient's journey for rheumatology outpatient clinic consultations in England and Wales.

BACKGROUND: Involving patients and members of the public in healthcare planning is beneficial for many reasons including that the outcomes focus on topics relevant to service users. The National Early Inflammatory Arthritis Audit (NEIAA) aims to improve care quality for patients with inflammatory arthritis. CASE STUDY: This paper presents a case study detailing how the NEIAA Patient Panel worked with NEIAA governance groups, the National Rheumatoid Arthritis Society and the National Axial Spondyloarthritis Society to co-create an outpatient clinic visit framework for rheumatology professionals. A framework was co-created, divided into nine sections: pre-appointment preparation, waiting area (face-to-face appointments), face-to-face consultations, physical examination, establishing a forward plan, post consultation, annual holistic reviews, virtual appointments and key considerations. Providing insight into how the multi-disciplinary team can meet the diverse needs of patients with inflammatory arthritis, this framework now informs the teaching content about people who live with physical and mental disability for Year 3 and 4 undergraduate medical students at King's College London. CONCLUSION: Patients play an important role in helping to address gaps in health service provision in England/Wales. The co-production of a clinic visit framework, informed by their own lived experience and their own expectations can lead to improved and relevant outcomes for the benefit of patients and raises awareness to medical students what matters to patients with physical disabilities when attending outpatient care.

Patient and public involvement in an international rheumatology translational research project: an evaluation.

BACKGROUND: Rheuma Tolerance for Cure (RTCure) is a five-year international collaboration between academia, industry and patients/members of the public. It focuses on developing approaches to predict the onset of rheumatoid arthritis (RA) and designing clinical trials to reduce the risk of disease development through immune-tolerising and other treatments. We conducted a mid-term evaluation of patient and public involvement (PPI) within the project. METHODS: Two surveys on PPI were co-designed by the PPI Coordinator, Patient/Public Research Partners (PRPs) and a researcher. Both anonymous, electronic surveys were distributed to 61 researchers and 9 PRPs. Quantitative survey data were analysed using descriptive statistics and free text responses underwent inductive thematic analysis. RESULTS: Researcher and Patient response rates were 33% and 78%, respectively. Quantitative Researcher Survey data highlighted that (i) responding researchers represented all seven Work Packages (WPs), (ii) 40% thought PRPs had made a large or extremely large contribution to their own WPs, (iii) 55% thought PPI has had a moderate or large impact on RTCure, (iv) 75% worked with PRPs in RTCure, and (v) 60% said PRPs had affected their research thinking. Quantitative PRP Survey data highlighted that (i) PRPs were most involved in four WPs, (ii) 43% thought they had made a minor contribution to their main WP, (iii) 57% thought PPI has had a small impact on RTCure, and (iv) 57% thought they received too little feedback on the outcome of their contribution to different tasks. Four main themes were identified in both surveys: 'PRP contributions', 'Experiences of PPI', 'Impact of PPI on RTCure', and 'How PPI can be improved'. Two additional themes from the Researcher Survey were 'Impact of PPI on researchers' and 'Influence on Future Projects', and from the PRP Survey were 'Impact of PPI on PRPs' and 'Engagement with PRPs'. CONCLUSION: PPI seemed to have a significant impact on RTCure, however, PRPs were less aware. A focus on improving communication between PRPs and researchers (facilitated by the PPI Coordinator), and providing PPI training for researchers is likely to improve involvement. Complex legal agreements for PRPs should be avoided and careful attention paid to appropriate PRP compensation.

To sell or not to sell: considerations when evaluating private equity acquisitions.

PURPOSE OF REVIEW: Many private practice ophthalmology groups are considering a partnership with private equity. When evaluating whether to remain independent or to engage an equity partner, practice leaders must analyze their existing practice, address issues of equity transitions, management, and governance, and determine strategic goals. This paper discusses the factors that need to be considered when evaluating the possibility of an acquisition model. SUMMARY: When considering a partnership with private equity, a thriving and mature private practice must conduct an in-depth analysis of four factors: how to transition the equity of a mature practice, how to continue growth, how to manage an increasingly complex organization, and the after-effects of a sale. These same issues must be addressed whether the group decides to pursue private equity or decides to remain independent.

Preservation of lymphocyte functional fitness in perinatally-infected and treated HIV+ pediatric patients displaying sub-optimal viral control.

Background: Host-pathogen dynamics associated with HIV infection are quite distinct in children versus adults. We interrogated the functional fitness of the lymphocyte responses in two cohorts of perinatally infected HIV+ pediatric subjects with early anti-retroviral therapy (ART) initiation but divergent patterns of virologic control. We hypothesized that sub-optimal viral control would compromise immune functional fitness. Methods: The immune responses in the two HIV+ cohorts (n = 6 in each cohort) were benchmarked against the responses measured in age-range matched, uninfected healthy control subjects (n = 11) by utilizing tests for normality, and comparison [the Kruskal-Wallis test, and the two-tailed Mann-Whitney U test (where appropriate)]. Lymphocyte responses were examined by intra-cellular cytokine secretion, degranulation assays as well as phosflow. A subset of these data were further queried by an automated clustering algorithm. Finally, we evaluated the humoral immune responses to four childhood vaccines in all three cohorts. Results: We demonstrate that contrary to expectations pediatric HIV+ patients with sub-optimal viral control display no significant deficits in immune functional fitness. In fact, the patients that display better virologic control lack functional Gag-specific T cell responses and compared to healthy controls they display signaling deficits and an enrichment of mitogen-stimulated CD3 negative and positive lymphocyte clusters with suppressed cytokine production. Conclusions: These results highlight the immune resilience in HIV+ children on ART with sub-optimal viral control. With respect to HIV+ children on ART with better viral control, our data suggest that this cohort might potentially benefit from targeted interventions that might mitigate cell-mediated immune functional quiescence.