Costs of UK community care for individuals with recessive dystrophic epidermolysis bullosa: Findings of the Prospective Epidermolysis Bullosa Longitudinal Evaluation Study.

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin fragility disorder requiring multidisciplinary management. Information regarding costs of current standard treatment is scant. Objectives: As part of a longitudinal natural history study, we explored the community care costs of UK patients with different forms of RDEB. Methods: Fifty-nine individuals with RDEB provided detailed information on multiple facets of RDEB including disease severity scores (iscorEB, BEBS) and patient reported outcomes (quality of life evaluation in epidermolysis bullosa, iscorEB patient questionnaire). Costs data included time spent doing dressings, frequency of dressing changes, details of materials used, and paid and unpaid care. Results: Overall costs of dressing materials and associated care were high in RDEB. Median annual costs across all subtypes for those using dressings (n = 51) were over £26 000. For severe RDEB (RDEB-S), median costs were almost £90 000 per annum, with a median of 18 h per week spent on dressing changes. Half of working-age adults with RDEB were unemployed and 39% of carers were unable to take on full-time or part-time paid employment, adding to indirect costs and the financial burden from RDEB on families and society. Conclusions: The findings demonstrate the high costs of care of RDEB, particularly for RDEB-S. The current expense supports the drive to develop new therapies which accelerate wound healing and diminish total wound burden, thereby reducing costs of dressings and care. While costly to bring to market, these might ultimately reduce the overall cost of treatment and also the impact on individuals living with this rare disease. The data also highlight the need for adequate reimbursement for EB care which can place significant financial strain on families.

Program-Based Lung Cancer Care: A Prospective Observational Tumor Registry Linkage Study.

Introduction: Low-dose computed tomography screening (LDCT) and lung nodule programs (LNP) promote early lung cancer detection, improve survival; Multidisciplinary Care Programs (MDC) promote guideline-concordant care. The impact of such program-based care on "real-world" lung cancer survival is unquantified. We evaluated outcomes of lung cancer care delivered through structured programs in a community health care system. Methods: We conducted a cohort study linking institutional prospective observational LDCT, LNP and MDC databases with Tumor Registry of Baptist Cancer Center facilities. We categorized all patients diagnosed with lung cancer between 2011 and 2021 into program-based care versus non-program-based care cohorts. We compared patient characteristics, stage distribution, treatment modalities, survival and mortality in each pathway of care. Results: Of 12,148 patients, 237, 1,165, 1,140 and 9,606 were diagnosed through the LDCT, LNP, MDC or no program, respectively; non-program-based care sequentially diminished from 96.3% to 66.5%, diagnosis through LDCT increased from 0.5% to 7.1%, LNP from 3.5% to 20.8%; and MDC alone decreased from a high of 12.8% in 2014 to 5.6% in 2021. Program-based care was associated with earlier stage (p < 0.001), higher surgical resection rates (p < 0.001), greater use of adjuvant therapy (p < 0.001), better aggregate and stage-stratified survival (p < 0.001), and lower all-cause and lung cancer-specific mortality (p < 0.001). Recipients of non-program-based care were considerably less likely to receive lung cancer treatment; results remained consistent when patients receiving no treatment were excluded. Conclusions: Program-based care was associated with substantially better survival. Increasing access to program-based care should be explored as a matter of urgent public policy.

Getting up With Lateral Thinking.

Introduction: Falls in the community can have major impacts on patient lives. There can be long lasting physical and psychological consequences of a fall and subsequent long lie. The annual burden to ambulance services responding to falls at home is high. Affordable devices to help people get up from the floor, or reduce the risk of a long lie, would be useful and widely applicable. Case report: We present the case of 2 families who successfully used an air mattress and a bath lift to get the fallen person up off the floor following a fall, when they had previously called an ambulance. This has reduced their dependence on the ambulance service and has improved their confidence following falls. Discussion/conclusion: Affordable devices such as air mattresses can help people off the floor following a fall and prevent long lies as well as reduce the number of ambulance call outs.

Advancing public health informatics during the COVID-19 pandemic: Lessons learned from a public-private partnership with pharmacies.

To support efforts to vaccinate millions of Americans across the United States (US) against COVID-19, the US federal government (USG) launched the Pharmacy Partnership for Long-Term Care Program (PPP) in December 2020 and the Federal Retail Pharmacy Program (FRPP) in February 2021. These programs consisted of a collaborative partnership with the USG and 21 pharmacy organizations, including large retail chains, coordinating pharmacy services administrative organizations (PSAOs) representing independent retail and long-term care pharmacies, and pharmacy network administrators. These pharmacy organizations represented over 46,000 providers and created a robust channel for far-reaching COVID-19 vaccination across 56 state and local jurisdictions. PPP reported more than 8 million COVID-19 doses administered to residents and staff in long-term care facilities (LTCFs) as of June 2021. In addition, FRPP was responsible for administering more than 304 million doses, accounting for approximately 49% of all COVID-19 doses administered as of June 2023. This unprecedented public-private partnership allowed USG to rapidly adapt, expand, and aim to provide equitable access to vaccines for adults and eligible-aged children during the COVID-19 pandemic. As the largest federal COVID-19 vaccination program, the FRPP exemplifies how public-private partnerships can expand access to immunizations during a public health emergency. End-to-end informatics support helped pharmacies meet critical national public health goals and served as convenient access points for sustained health services. This manuscript describes lessons learned regarding informatics coordination with participating pharmacy partners to support the rapid and safe administration of COVID-19 vaccines across the US. The processes of onboarding to CDC's complex data network, establishing connections to state and local immunization information systems (IIS), and monitoring the quality of data pharmacy partners submitted to the CDC Data Clearinghouse (DCH) in alignment with the COVID-19 Vaccine Reporting Specifications (CVRS) are highlighted.

Establishing initial resting abdominal pressure in children undergoing urodynamics.

INTRODUCTION: The International Continence Society recommends zeroing of transducers to the atmospheric pressure for invasive urodynamics. The range of abdominal pressure relative to atmospheric pressure is well-known in adults but has not been described in children. This prospective observational study was carried out to establish baseline abdominal in children. MATERIALS AND METHODS: Prospective, multicenter, observational study of 100 children aged 0-18 years undergoing invasive urodynamics using water-filled systems. Initial resting abdominal pressure, intravesical pressure and detrusor pressure were recorded in supine, sitting, and standing position (as age- and diagnosis-appropriate). This data was analyzed using SPSS 20.0.0 with regard to age, gender, height, weight, body mass index, and underlying diagnosis (classified as neurogenic or non-neurogenic). Nonparametric tests were used (2-sided p < 0.05, significant). RESULTS: Initial resting abdominal pressure (inter-quartile range) in children was between 5 and 15 cmH2 O in the supine, 13-20 cmH2 O in the sitting, and 15-21 cmH2 O in the standing position. These pressures were not consistently influenced by age, gender, height, weight or underlying diagnosis. The initial resting detrusor pressure was noted to be 0-4 cmH2 O without any difference based on posture. Limitations include use of two-tube technique, relatively small number of subjects across each age group, wide range of underlying diagnoses and need for manual smoothing of some traces. CONCLUSION: This study defines initial resting abdominal pressure at urodynamics in children and notes that, as with adults, it is possible to define widely applicable ranges regardless of individual characteristics. These pressures appear lower than those noted historically in adults.

External evaluation of the Dynamic Criticality Index: A machine learning model to predict future need for ICU care in hospitalized pediatric patients.

OBJECTIVE: To assess the single site performance of the Dynamic Criticality Index (CI-D) models developed from a multi-institutional database to predict future care. Secondarily, to assess future care-location predictions in a single institution when CI-D models are re-developed using single-site data with identical variables and modeling methods. Four CI-D models were assessed for predicting care locations >6-12 hours, >12-18 hours, >18-24 hours, and >24-30 hours in the future. DESIGN: Prognostic study comparing multi-institutional CI-D models' performance in a single-site electronic health record dataset to an institution-specific CI-D model developed using identical variables and modelling methods. The institution did not participate in the multi-institutional dataset. PARTICIPANTS: All pediatric inpatients admitted from January 1st 2018 -February 29th 2020 through the emergency department. MAIN OUTCOME(S) AND MEASURE(S): The main outcome was inpatient care in routine or ICU care locations. RESULTS: A total of 29,037 pediatric hospital admissions were included, with 5,563 (19.2%) admitted directly to the ICU, 869 (3.0%) transferred from routine to ICU care, and 5,023 (17.3%) transferred from ICU to routine care. Patients had a median [IQR] age 68 months (15-157), 47.5% were female and 43.4% were black. The area under the receiver operating characteristic curve (AUROC) for the multi-institutional CI-D models applied to a single-site test dataset was 0.493-0.545 and area under the precision-recall curve (AUPRC) was 0.262-0.299. The single-site CI-D models applied to an independent single-site test dataset had an AUROC 0.906-0.944 and AUPRC range from 0.754-0.824. Accuracy at 0.95 sensitivity for those transferred from routine to ICU care was 72.6%-81.0%. Accuracy at 0.95 specificity was 58.2%-76.4% for patients who transferred from ICU to routine care. CONCLUSION AND RELEVANCE: Models developed from multi-institutional datasets and intended for application to individual institutions should be assessed locally and may benefit from re-development with site-specific data prior to deployment.

Hospital survival following pediatric HSCT: changes in complications, ICU therapies and outcomes over 10 years.

Introduction: Hematopoietic stem cell transplantation (HSCT) is an increasingly utilized therapy for malignant and non-malignant pediatric diseases. HSCT complications, including infection, organ dysfunction, and graft-versus-host-disease (GVHD) often require intensive care unit (ICU) therapies and are associated with mortality. Our aims were to identify the HSCT characteristics, complications and ICU therapies associated with (1) survival, and (2) survival changes over a ten-year period in a national dataset. Methods: A national sample from the Health Facts (Cerner Corporation, Kansas City, MO) database from 2009 to 2018 was utilized. Inclusion criteria were age 30 days to <22 years and HSCT procedure code. For patients with >1 HSCT, the first was analyzed. Data included demographics, hospital length of stay (LOS), hospital outcome, transplant type and indication. HSCT complications included GVHD and infections. ICU therapies were positive pressure ventilation (PPV), vasoactive infusion, and dialysis. Primary outcome was survival to discharge. Statistical methods included bivariate analyses and multivariate logistic regression. Results: 473 patients underwent HSCT with 93% survival. 62% were allogeneic (89% survival) and 38% were autologous (98% survival). GVHD occurred in 33% of allogeneic HSCT. Infections occurred in 26% of all HSCT. ICU therapies included PPV (11% of patients), vasoactive (25%), and dialysis (3%). Decreased survival was associated with allogeneic HSCT (p < 0.01), GVHD (p = 0.02), infection (p < 0.01), and ICU therapies (p < 0.01). Survival improved from 89% (2009-2013) to 96% (2014-2018) (p < 0.01). Allogeneic survival improved (82%-94%, p < 0.01) while autologous survival was unchanged. Survival improvement over time was associated with decreasing infections (33%-21%, p < 0.01) and increasing vasoactive infusions (20%-28%, p = 0.05). On multivariate analysis, later time period was associated with improved survival (p < 0.01, adjusted OR 4.28). Discussion: Hospital survival for HSCT improved from 89% to 96% from 2009 to 2018. Factors associated with mortality included allogeneic HSCT, GVHD, infections and ICU therapies. Improving survival coincided with decreasing infections and increasing vasoactive use.

Burden of mental disorders by gender in Pakistan: analysis of Global Burden of Disease Study data for 1990-2019.

AIMS AND METHOD: We aimed to examine the burden of mental disorders in Pakistan over the past three decades. We used the crude data of disability-adjusted life-years (DALYs) obtained from the Global Burden of Disease Study database (1990-2019) to represent burden. Data were retrieved on 26 January 2021. Data for adults of reproductive age (aged 15-49 years) were analysed to discuss and interpret the disease burden. An analysis was conducted on total DALYs separately for the genders for ten mental disorders reported in Pakistan. RESULTS: DALYs increased drastically with the onset of reproductive age. Depressive disorder was the most reported mental disorder, contributing 3.13% (95% CI 2.25-4.24) of total DALYs, and varied significantly between genders: females 3.89% (95% CI 2.73-5.29) versus males 2.37% (95% CI 1.62-3.25). CLINICAL IMPLICATIONS: A nationwide high-quality epidemiological surveillance system should be implemented to monitor mental disorders and offer culturally appropriate preventive services.

Economic burden of mental illness in Pakistan: an estimation for the year 2020 from existing evidence.

This report is based on the extrapolation to 2020 of data on the economic burden of mental illnesses in Pakistan in 2006. Given the resultant estimated high economic burden of mental illness in the country (£2.97 billion in 2020), we advocate a revised budget allocation to mental healthcare. As a resource-scarce nation that is entangled in natural disasters, Pakistan needs cost-effective psychological interventions such as culturally adapted manual-assisted problem-solving training (C-MAP) for the prevention of self-harm and suicide and to move towards attaining the United Nations' Sustainable Development Goals (SDGs). Although government has taken initiatives to support healthcare services (such as the Sehat Sahulat Program for universal health coverage), there is still a need to implement a cost-effective national digital model for mental healthcare such as the Agha Khan Development Network Digital Health Programme.

The US Federal Retail Pharmacy Program: Optimizing COVID-19 Vaccine Delivery Through a Strategic Public-Private Partnership.

To help achieve the initial goal of providing universal COVID-19 vaccine access to approximately 258 million adults in 62 US jurisdictions, the federal government launched the Federal Retail Pharmacy Program (FRPP) on February 11, 2021. We describe FRPP's collaboration among the federal government, US jurisdictions, federal entity partners, and 21 national chain and independent pharmacy networks to provide large-scale access to COVID-19 vaccines, particularly in communities disproportionately affected by COVID-19 (eg, people aged ≥65 years, people from racial and ethnic minority groups). FRPP initially provided 10 000 vaccination sites for people to access COVID-19 vaccines, which was increased to >35 000 vaccination sites by May 2021 and sustained through January 31, 2022. From February 11, 2021, through January 31, 2022, FRPP vaccination sites received 293 million doses and administered 219 million doses, representing 45% of all COVID-19 immunizations provided nationwide (38% of all first doses, 72% of all booster doses). This unprecedented public-private partnership allowed the federal government to rapidly adapt and scale up an equitable vaccination program to reach adults, later expanding access to vaccine-eligible children, during the COVID-19 pandemic. As the largest federal COVID-19 vaccination program, FRPP exemplifies how public-private partnerships can expand access to immunizations during a public health emergency. Pharmacies can help meet critical national public health goals by serving as convenient access points for sustained health services. Lessons learned from this effort-including the importance of strong coordination and communication, efficient reporting systems and data quality, and increasing access to and demand for vaccine, among others-may help improve future immunization programs and support health system resiliency, emphasizing community-level access and health equity during public health emergencies.

RECREATE: a study protocol for a multicentre pilot cluster randomised controlled trial (cRCT) in UK stroke services evaluating an intervention to reduce sedentary behaviour in stroke survivors (Get Set Go) with embedded process and economic evaluations.

INTRODUCTION: Sedentary behaviour (sitting or lying during waking hours without being otherwise active) is strongly associated with adverse health outcomes, including all-cause, cancer and cardiovascular mortality in adults. Stroke survivors are consistently reported as being more sedentary than healthy age-matched controls, spending more hours sedentary daily and sustaining longer unbroken bouts of sedentary time. An evidence-based and clinically feasible intervention ('Get Set Go') was developed. A pragmatic definitive trial to evaluate Get Set Go was planned; however, due to the unprecedented effects of the COVID-19 pandemic on National Health Service (NHS) services this study was reduced in size and scope to become an external pilot trial. We report the protocol for this external pilot trial, which aims to undertake a preliminary exploration of whether Get Set Go is likely to improve ability to complete extended activities of daily living in the first year post-stroke and inform future trial designs in stroke rehabilitation. METHODS AND ANALYSIS: This study is a pragmatic, multicentre, two-arm, external pilot cluster randomised controlled trial with embedded process and economic evaluations. UK-based stroke services will be randomised 1:1 to the intervention (usual care plus Get Set Go) or control (usual care) arm. Fifteen stroke services will recruit 300-400 stroke inpatient and carer participants, with follow-up at 6, 12 and 24 months. The proposed primary endpoint is stroke survivor self-reported Nottingham Extended Activities of Daily Living scale at 12 months. Endpoint analyses will be exploratory and provide preliminary estimates of intervention effect. The process evaluation will provide valuable information on intervention fidelity, acceptability and how it can be optimised. ETHICS AND DISSEMINATION: The study has been approved by Yorkshire and The Humber - Bradford-Leeds Research Ethics Committee (Ref: 19/YH/0403). Results will be disseminated through journal publications and conference presentations. TRIAL REGISTRATION NUMBER: This trial was registered prospectively on 01 April 2020 (ISRCTN ref: ISRCTN82280581).

Best practice considerations on the assessment of robotic assisted surgical systems: results from an international consensus expert panel.

BACKGROUND: Health technology assessments (HTAs) of robotic assisted surgery (RAS) face several challenges in assessing the value of robotic surgical platforms. As a result of using different assessment methods, previous HTAs have reached different conclusions when evaluating RAS. While the number of available systems and surgical procedures is rapidly growing, existing frameworks for assessing MedTech provide a starting point, but specific considerations are needed for HTAs of RAS to ensure consistent results. This work aimed to discuss different approaches and produce guidance on evaluating RAS. METHODS: A consensus conference research methodology was adopted. A panel of 14 experts was assembled with international experience and representing relevant stakeholders: clinicians, health economists, HTA practitioners, policy makers, and industry. A review of previous HTAs was performed and seven key themes were extracted from the literature for consideration. Over five meetings, the panel discussed the key themes and formulated consensus statements. RESULTS: A total of ninety-eight previous HTAs were identified from twenty-five total countries. The seven key themes were evidence inclusion and exclusion, patient- and clinician-reported outcomes, the learning curve, allocation of costs, appropriate time horizons, economic analysis methods, and robotic ecosystem/wider benefits. CONCLUSIONS: Robotic surgical platforms are tools, not therapies. Their value varies according to context and should be considered across therapeutic areas and stakeholders. The principles set out in this paper should help HTA bodies at all levels to evaluate RAS. This work may serve as a case study for rapidly developing areas in MedTech that require particular consideration for HTAs.

Enhancing the dissolution rate of poorly soluble drug Febuxostat using spray dried amorphous solid dispersion technique / Mejora de la tasa de disolución del fármaco poco soluble Febuxostat utilizando la técnica de dispersión de sólido amorfo secado por aspersión

Introducción: El febuxostat pertenece a los fármacos clase II del Sistema de Clasificación Biofarmacéutica, los cuales presentan baja solubilidad y alta permeabilidad. La dispersión sólida amorfa es una de las técnicas que pueden ser útiles para mejorar la solubilidad y las características del polvo. Objetivo: optimizar la concentración de polímeros hidrofílicos e hidrofóbicos para mejorar la velocidad de disolución y la solubilidad de las tabletas de febuxostat. Métodos: La dispersión sólida amorfa de febuxostat se preparó mediante el método de secado por aspersión utilizando Kolliphor P237 (1:2). Esta dispersión sólida amorfa se utilizó además para comprimir el comprimido. Para mejorar la solubilidad y la tasa de disolución, se aplicó un diseño factorial completo para optimizar la concentración crítica de KollidonSR e hidroxi propil metil celulosa (HPMC K4M). Los comprimidos preparados se caracterizaron por parámetros de precompresión y poscompresión. Resultados: La velocidad de liberación del fármaco se mantuvo mediante la formulación de una técnica de dispersión sólida amorfa. Se encontró que el lote optimizado (FSRT-OB) era apto para la liberación promedio del 93,30 % del fármaco en forma de liberación sostenida hasta 12 horas. Los datos de la cinética de liberación sugieren que la liberación del fármaco estuvo controlada por una combinación de mecanismo de relajación de cadena y difusión. Se encontró que la concentración optimizada para Kollidon SR y HPMC K4M era 38,50 % y 7,72 % respectivamente. Conclusión: La técnica de dispersión sólida amorfa es útil para mejorar la solubilidad, la velocidad de disolución y la biodisponibilidad de la tableta de Febuxostat. (AU)

Introduction: Febuxostat belongs to Biopharmaceutical classification system (BCS) class II drugs, which have low solubility and high permeability. Amorphous solid dispersion is one of the techniques which can be useful to improve solubility and powder characteristics. Objective: To optimize the concentration of hydrophilic and hydrophobic polymers to improve the dissolution rate and solubility of febuxostat tablets. Methods: The amorphous solid dispersion of febuxostat was prepared by spray drying method using Kolliphor P237 (1:2). This amorphous solid dispersion was further used to compress the tablet. To improve solubility and dissolu-tion rate, a full factorial design was applied to optimize the critical concentration of Kollidon SR and hydroxypropyl methyl cellulose (HPMC K4M). The prepared tablets were characterized by pre-compression and post-compression parameters. Result: The rate of drug release was sustained by formulating an amorphous solid dispersion technique. The optimized batch (FSRT-OB) was found to be fit for release average 93.30 % of the drug in sustain release manner up to 12hrs. The release kinetic data suggests that the drug release was controlled by combination of diffusion and chain relaxation mechanism. The optimized concentration for Kollidon SR and HPMC K4Mwas found to be 38.50 % and 7.72 % respectively. Conclusion: Amorphous solid dispersion technique is useful to enhance solubility, dissolution rate, and bioavail-ability of the Febuxostat tablet. (AU)

The Association of the Lactate-Albumin Ratio With Mortality and Multiple Organ Dysfunction in PICU Patients.

OBJECTIVES: To compare the relative associations of lactate, albumin, and the lactate-albumin ratio (LAR) measured early in disease course against mortality and prevalence of multiple organ dysfunction syndrome (MODS) in a general sample of critically ill pediatric patients. DESIGN: Retrospective analysis of the Health Facts (Cerner Corporation, Kansas City, MO) national database. SETTING: U.S. hospitals with PICUs. PATIENTS: Children admitted to the ICU ( n = 648) from 2009 to 2018 who had lactate and albumin measured within 6 hours of admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 648 admissions were included, with an overall mortality rate of 10.8% ( n = 70) and a MODS prevalence of 29.3% ( n = 190). Compared with survivors, deaths had higher initial lactates (7.3 mmol/L [2.6-11.7 mmol/L] vs 1.9 mmol/L [1.2-3.1 mmol/L]; p < 0.01), lower initial albumins (3.3 g/dL [2.7-3.8 g/dL] vs 4.2 g/dL [3.7-4.7 g/dL]; p < 0.01), and higher LARs (2.2 [1.0-4.2] vs 0.5 [0.3-0.8]; p < 0.01), with similar trends in patients with MODS versus those without MODS. LAR demonstrated a higher odds ratio (OR) for death than initial lactate alone (2.34 [1.93-2.85] vs 1.29 [1.22-1.38]) and a higher OR for MODS than initial lactate alone (2.10 [1.73-2.56] vs 1.22 [1.16-1.29]). Area under the receiver operating characteristic (AUROC) curve of LAR for mortality was greater than initial lactate (0.86 vs 0.82; p < 0.01). The LAR AUROC for MODS was greater than the lactate AUROC (0.71 vs 0.66; p < 0.01). Trends of lactate, albumin, and LAR for mortality were consistent across several diagnostic subgroups (trauma, primary respiratory failure, toxicology), but not all. CONCLUSIONS: LAR measured early in the course of critical illness is significantly associated with mortality and development of MODS when compared with initial lactate or initial albumin alone in critically ill pediatric patients.

Clinical Instability Is a Sign of Severity of Illness: A Cohort Study.

OBJECTIVES: Test the hypothesis that within patient clinical instability measured by deterioration and improvement in mortality risk over 3-, 6-, 9-, and 12-hour time intervals is indicative of increasing severity of illness. DESIGN: Analysis of electronic health data from January 1, 2018, to February 29, 2020. SETTING: PICU and cardiac ICU at an academic children's hospital. PATIENTS: All PICU patients. Data included descriptive information, outcome, and independent variables used in the Criticality Index-Mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 8,399 admissions with 312 deaths (3.7%). Mortality risk determined every three hours using the Criticality Index-Mortality, a machine learning algorithm calibrated to this hospital. Since the sample sizes were sufficiently large to expect statical differences, we also used two measures of effect size, the proportion of time deaths had greater instability than survivors, and the rank-biserial correlation, to assess the magnitude of the effect and complement our hypothesis tests. Within patient changes were compared for survivors and deaths. All comparisons of survivors versus deaths were less than 0.001. For all time intervals, two measures of effect size indicated that the differences between deaths and survivors were not clinically important. However, the within-patient maximum risk increase (clinical deterioration) and maximum risk decrease (clinical improvement) were both substantially greater in deaths than survivors for all time intervals. For deaths, the maximum risk increase ranged from 11.1% to 16.1% and the maximum decrease ranged from -7.3% to -10.0%, while the median maximum increases and decreases for survivors were all less than ± 0.1%. Both measures of effect size indicated moderate to high clinical importance. The within-patient volatility was greater than 4.5-fold greater in deaths than survivors during the first ICU day, plateauing at ICU days 4-5 at 2.5 greater volatility. CONCLUSIONS: Episodic clinical instability measured with mortality risk is a reliable sign of increasing severity of illness. Mortality risk changes during four time intervals demonstrated deaths have greater maximum and within-patient clinical instability than survivors. This observation confirms the clinical teaching that clinical instability is a sign of severity of illness.

UK-based multicentre cross-sectional study assessing advice requests veterinary dermatologists received from general practitioners.

BACKGROUND: There is little currently little information available regarding the nature of the advice requests veterinary dermatologists receive from general practitioners. Collation of such data could direct continuing veterinary development in the future. METHODS: Dermatologists completed hand-written recording sheets during or after enquiries. Information recorded included the route of enquiry, nature of advice, material provided, practice type and location, animal signalment, presenting signs, diagnosis/differential diagnosis, treatment and referral recommendations, time taken and if charges were made. RESULTS: Twelve dermatology services recorded 768 advice requests over a 6-month period. Most requests were submitted via email and related to canine dermatology (81%). An average of 9.5 minutes was spent replying to requests. Charges were made in 2% of cases. Advice regarding otitis was most commonly sought, followed by pruritus, alopecia and crusting. The most frequently discussed diagnoses included allergy, otitis, pyoderma, demodicosis, dermatophytosis and neoplasia. Antibiotics, anti-pruritics and topical otic medications were the most commonly discussed therapeutics. LIMITATIONS: This is an initial study and therefore there are limitations involving the depth of the data. Additional studies should be completed which identify why advice is sought, decision-making regarding referral, and if advice should be charged similarly to other disciplines. CONCLUSIONS: These findings highlight that veterinarians mostly frequently seek advice on management of common dermatological problems, including allergy, otitis and pyoderma.

Neither GLP-1 receptors nor GFRAL neurons are required for aversive or anorectic response to DON (vomitoxin).

Deoxynivalenol (DON), a type B trichothecene mycotoxin contaminating grains, promotes nausea, emesis and anorexia. With DON exposure, circulating levels of intestinally derived satiation hormones, including glucagon-like peptide 1 (GLP-1) are elevated. To directly test whether GLP-1 signaling mediates the effects of DON, we examined the response of GLP-1 or GLP-1R-deficient mice to DON injection. We found comparable anorectic and conditioned taste avoidance learning responses in GLP-1/GLP-1R deficient mice compared to control littermates, suggesting that GLP-1 is not necessary for the effects of DON on food intake and visceral illness. We then used our previously published data from translating ribosome affinity purification with RNA sequencing (TRAP-seq) analysis of area postrema neurons that express the receptor for the circulating cytokine growth differentiation factor (GDF15), growth differentiation factor a-like (GFRAL). Interestingly, this analysis showed that a cell surface receptor for DON, calcium sensing receptor (CaSR), is heavily enriched in GFRAL neurons. Given that GDF15 potently reduces food intake and can cause visceral illness by signaling through GFRAL neurons, we hypothesized that DON may also signal by activating CaSR on GFRAL neurons. Indeed, circulating GDF15 levels are elevated after DON administration but both GFRAL knockout and GFRAL neuron-ablated mice exhibited similar anorectic and conditioned taste avoidance responses compared to WT littermates. Thus, GLP-1 signaling and GFRAL signaling and neurons are not required for DON-induced visceral illness or anorexia.

Engagement With the Centers for Disease Control and Prevention Coronavirus Self-Checker and Guidance Provided to Users in the United States From March 23, 2020, to April 19, 2021: Thematic and Trend Analysis.

BACKGROUND: In 2020, at the onset of the COVID-19 pandemic, the United States experienced surges in healthcare needs, which challenged capacity throughout the healthcare system. Stay-at-home orders in many jurisdictions, cancellation of elective procedures, and closures of outpatient medical offices disrupted patient access to care. To inform symptomatic persons about when to seek care and potentially help alleviate the burden on the healthcare system, Centers for Disease Control and Prevention (CDC) and partners developed the CDC Coronavirus Self-Checker ("Self-Checker"). This interactive tool assists individuals seeking information about COVID-19 to determine the appropriate level of care by asking demographic, clinical, and nonclinical questions during an online "conversation." OBJECTIVE: This paper describes user characteristics, trends in use, and recommendations delivered by the Self-Checker between March 23, 2020, and April 19, 2021, for pursuing appropriate levels of medical care depending on the severity of user symptoms. METHODS: User characteristics and trends in completed conversations that resulted in a care message were analyzed. Care messages delivered by the Self-Checker were manually classified into three overarching conversation themes: (1) seek care immediately; (2) take no action, or stay home and self-monitor; and (3) conversation redirected. Trends in 7-day averages of conversations and COVID-19 cases were examined with development and marketing milestones that potentially impacted Self-Checker user engagement. RESULTS: Among 16,718,667 completed conversations, the Self-Checker delivered recommendations for 69.27% (n=11,580,738) of all conversations to "take no action, or stay home and self-monitor"; 28.8% (n=4,822,138) of conversations to "seek care immediately"; and 1.89% (n=315,791) of conversations were redirected to other resources without providing any care advice. Among 6.8 million conversations initiated for self-reported sick individuals without life-threatening symptoms, 59.21% resulted in a recommendation to "take no action, or stay home and self-monitor." Nearly all individuals (99.8%) who were not sick were also advised to "take no action, or stay home and self-monitor." CONCLUSIONS: The majority of Self-Checker conversations resulted in advice to take no action, or stay home and self-monitor. This guidance may have reduced patient volume on the medical system; however, future studies evaluating patients' satisfaction, intention to follow the care advice received, course of action, and care modality pursued could clarify the impact of the Self-Checker and similar tools during future public health emergencies.

Making Sense of Late Tissue Nodules Associated With Hyaluronic Acid Injections.

BACKGROUND: The pathogenesis of delayed-onset tissue nodules (DTNs) due to hyaluronic acid (HA) injections is uncertain. OBJECTIVES: To formulate a rational theory for DTN development and their avoidance and treatment. METHODS: A multidisciplinary and multicountry DTN consensus panel was established, with 20 questions posed and consensus sought. Consensus was set at 75% agreement. RESULTS: Consensus was reached in 16 of 20 questions regarding the pathogenesis of DTNs, forming the basis for a classification and treatment guide. CONCLUSIONS: The group believes that filler, pathogens, and inflammation are all involved in DTNs and that DTNs most likely are infection initiated with a variable immune response. Injected filler may incorporate surface bacteria, either a commensal or a true pathogen, if the skin barrier is altered. The initially high molecular weight HA filler is degraded to low molecular weight HA (LMWHA) at the edge of the filler. Commensals positioned within the filler bolus may be well tolerated until the filler is degraded and the commensal becomes visible to the immune system. LMWHA is particularly inflammatory in the presence of any local bacteria. Commensals may still be tolerated unless the immune system is generally heightened by viremia or vaccination. Systemic pathogenic bacteremia may also interact with the filler peripheral LMWHA, activating Toll-like receptors that induce DTN formation. Given this scenario, attention to practitioner and patient hygiene and early systemic infection treatment deserve attention. Classification and treatment systems were devised by considering each of the 3 factors-filler, inflammation, and infection-separately.