A multiconsistent computational methodology to resolve a diffusive epidemiological system with effects of migration, vaccination and quarantine.

BACKGROUND: We provide a compartmental model for the transmission of some contagious illnesses in a population. The model is based on partial differential equations, and takes into account seven sub-populations which are, concretely, susceptible, exposed, infected (asymptomatic or symptomatic), quarantined, recovered and vaccinated individuals along with migration. The goal is to propose and analyze an efficient computer method which resembles the dynamical properties of the epidemiological model. MATERIALS AND METHODS: A non-local approach is utilized for finding approximate solutions for the mathematical model. To that end, a non-standard finite-difference technique is introduced. The finite-difference scheme is a linearly implicit model which may be rewritten using a suitable matrix. Under suitable circumstances, the matrices representing the methodology are M-matrices. RESULTS: Analytically, the local asymptotic stability of the constant solutions is investigated and the next generation matrix technique is employed to calculate the reproduction number. Computationally, the dynamical consistency of the method and the numerical efficiency are investigated rigorously. The method is thoroughly examined for its convergence, stability, and consistency. CONCLUSIONS: The theoretical analysis of the method shows that it is able to maintain the positivity of its solutions and identify equilibria. The method's local asymptotic stability properties are similar to those of the continuous system. The analysis concludes that the numerical model is convergent, stable and consistent, with linear order of convergence in the temporal domain and quadratic order of convergence in the spatial variables. A computer implementation is used to confirm the mathematical properties, and it confirms the ability in our scheme to preserve positivity, and identify equilibrium solutions and their local asymptotic stability.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

The Modernization of Clozapine: A Recapitulation of the Past in the United States and the View Forward.

PURPOSE: Although clozapine was Food and Drug Administration (FDA) approved more than 3 decades ago, major barriers and gaps in knowledge continue to prevent its effective and safe use. We review modern-day problems encountered with clozapine in the United States (US). METHODS: Information surrounding current administrative, clinical, research, and technological gaps or barriers related to clozapine use in the US was reviewed. FINDINGS: The history of how clozapine became FDA approved likely contributes to gaps in knowledge. The frequency of safety warnings added to the FDA prescribing information may add to fears about clozapine, as evidence by numerous published survey studies. The clozapine Risk Evaluation and Mitigation Strategy (REMS) program has been modified several times in the last decade, causing access and safety issues for patients, which are discussed. Evidence may suggest that the FDA REMS requirements for hematologic monitoring are too cumbersome, and there may be ability to safely loosen requirements. The COVID-19 pandemic brought forth the ability for extended interval monitoring but also greater awareness of the clozapine-inflammation interaction. Newer guidelines published describe considerations in personalizing clozapine titration based on principles of ethnopsychopharmacology. Emerging technologies to support the use of clozapine are not widely available. IMPLICATIONS: Clozapine is a unique life-saving drug but it is underused in the US, despite its established efficacy. The 2021 REMS changes led to significant difficulties for providers and patients. We highlight the importance of the clozapine-inflammation interaction, therapeutic drug monitoring, and the ability for individual care based on patient-specific factors. There is an urgent need for advancing technology used for clozapine monitoring, evaluating barriers created by REMS, and establishing consistent practices throughout the US.

Automated ELISA On-Chip for the Detection of Anti-SARS-CoV-2 Antibodies.

The COVID-19 pandemic has been the most critical public health issue in modern history due to its highly infectious and deathly potential, and the limited access to massive, low-cost, and reliable testing has significantly worsened the crisis. The recovery and the vaccination of millions of people against COVID-19 have made serological tests highly relevant to identify the presence and levels of SARS-CoV-2 antibodies. Due to its advantages, microfluidic-based technologies represent an attractive alternative to the conventional testing methodologies used for these purposes. In this work, we described the development of an automated ELISA on-chip capable of detecting anti-SARS-CoV-2 antibodies in serum samples from COVID-19 patients and vaccinated individuals. The colorimetric reactions were analyzed with a microplate reader. No statistically significant differences were observed when comparing the results of our automated ELISA on-chip against the ones obtained from a traditional ELISA on a microplate. Moreover, we demonstrated that it is possible to carry out the analysis of the colorimetric reaction by performing basic image analysis of photos taken with a smartphone, which constitutes a useful alternative when lacking specialized equipment or a laboratory setting. Our automated ELISA on-chip has the potential to be used in a clinical setting and mitigates some of the burden caused by testing deficiencies.

Creating a Colocation Unit for End-of-Life Care during a Pandemic.

Background: Palliative care seeks to support the physical, psycho-social and spiritual needs of patients and families who are facing life threatening diseases. Advantages of establishing a palliative care unit, or alternatively co-locating patients, include promoting optimal physical and psychological symptom management; increased family satisfaction; and facilitating resource allocation. Objective: To design a stand-alone hospital unit to provide end of life care during a pandemic. Setting: Mount Sinai Hospital (MSH), a 1,144 bed tertiary- and quaternary-care teaching facility and Brookdale Department of Geriatrics and Palliative Medicine of the Icahn School of Medicine at Mt Sinai. Method: Tracking key indicators signaling the need for conversion to a COVID-19 unit, and identifying factors to facilitate a successful conversion. Result/Implementation: Using previously identified key focused action categories as framework, we describe our successful palliative care unit (PCU) conversion into a COVID-19 care unit. Conclusion: We believe that these operational insights gained from transforming our unit during COVID-19 will be helpful to other programs and institutions during a pandemic, or public health emergencies.

A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology.

Using Richardson and Davidson's model and the sciences of pharmacokinetics and clinical pharmacopsychology, this article reviewed the: (1) poor life expectancy associated with treatment-resistant schizophrenia (TRS), which may be improved in patients who adhere to clozapine; (2) findings that clozapine is the best treatment for TRS (according to efficacy, effectiveness and well-being); and (3) potential for clozapine to cause vulnerabilities, including potentially lethal adverse drug reactions such as agranulocytosis, pneumonia, and myocarditis. Rational use requires: (1) modification of the clozapine package insert worldwide to include lower doses for Asians and to avoid the lethality associated with pneumonia, (2) the use of clozapine levels for personalizing dosing, and (3) the use of slow and personalized titration. This may make clozapine as safe as possible and contribute to increased life expectancy and well-being. In the absence of data on COVID-19 in clozapine patients, clozapine possibly impairs immunological mechanisms and may increase pneumonia risk in infected patients. Psychiatrists should call their clozapine patients and families and explain to them that if the patient develops fever or flu-like symptoms, the psychiatrist should be called and should consider halving the clozapine dose. If the patient is hospitalized with pneumonia, the treating physician needs to assess for symptoms of clozapine intoxication since halving the dose may not be enough for all patients; consider decreasing it to one-third or even stopping it. Once the signs of inflammation and fever have disappeared, the clozapine dose can be slowly increased to the prior dosage level.