Application of user-centered co-design principles to address barriers in therapeutic drug monitoring.

BACKGROUND: Different software applications have been developed to support healthcare professionals in individualized drug dosing. However, their translation into clinical practice is limited, partly because of poor usability and integration into workflow, which can be attributed to the limited involvement of healthcare professionals in the development and implementation of drug dosing software. This study applied co-design principles to inform the design of a drug dosing software to address barriers in therapeutic drug monitoring (TDM) using vancomycin as an example. METHODS: Three workshops (face-to-face and online) were conducted by design researchers with pharmacists and prescribers. User journey storyboards, user personas, and prototyping tools were used to explore existing barriers to practice and opportunities for innovation through drug dosing software design. A prototype of the software interface was developed for further evaluation. RESULTS: Healthcare professionals (11 hospital pharmacists and 6 prescribers) with ≥2 years of clinical experience were recruited. Confidence and software usability emerged as the main themes. Participants identified a lack of confidence in vancomycin dosing and pharmacokinetic understanding and difficulty in accessing practice guidelines as key barriers that could be addressed through software implementation. Accessibility to information (e.g., guidelines and pharmacokinetic resources) and information presentation (e.g., graphical) within the dosing software were dependent on the needs and experience of the user. A software prototype with a speedometer-dial visual to convey optimal doses was well received by participants. CONCLUSION: The perspectives of healthcare professionals highlight the need for drug dosing software to be user-centred and adaptable to the needs and workflow of end users. Continuous engagement with stakeholders on tool usability, training, and education is needed to promote the implementation in practice.

Does insomnia treatment prevent depression?

Rates of major depressive disorder (MDD) are increasing globally, in part due to the coronavirus disease 2019 pandemic, contributing to disease burden. It has long been known that insomnia is intricately connected with depression as indicated by greater depression severity and lower treatment response. Furthermore, insomnia is a significant risk factor for new-onset depression. Treatment of insomnia is thus a logical target for prevention of incidents and recurrent MDD. This systematic review sought to evaluate the current evidence for the preventive effects of insomnia treatment on depression onset. A database search yielded 186 studies, six of which met criteria for inclusion in this review. All of the studies utilized cognitive behavioral treatment for insomnia (CBT-I) as the target intervention and most delivered treatment via a digital platform. Four of the studies found significantly lower rates of MDD onset in those who received CBT-I compared to a control condition. The two remaining studies failed to confirm these effects in primary analyses but secondary analyses suggested evidence of a preventive effect. There was significant methodologic heterogeneity across studies in terms of sample selection, outcomes, and follow-up periods, limiting the ability to draw firm conclusions. The evidence overall is in the direction of insomnia treatment reducing the risk for onset of MDD, but further research is warranted.

Left Ventricular Recruitment Utilizing Serial Upsizing of Blalock-Taussig-Thomas Shunt to Achieve Successful Biventricular Repair

Background Surgical strategies to achieve biventricular (BiV) repair in children with borderline left ventricle (LV) continue to evolve. We report our innovative strategy of LV recruitment utilizing systemic to pulmonary artery shunt upsizing along with fenestrated atrial septation (FAS). Case The case is a 22mo old with hypoplastic left heart variant with type A aortic arch interruption and bilateral SVC. The LV, aortic and mitral valve were hypoplastic not meeting criteria for BiV repair. He underwent stage 1 palliation (Norwood with 4mm BTT shunt). Frequent COVID infections and over-circulation led to BiV dysfunction and cardiogenic shock requiring ECMO support for 4 days. At 5 months of age cardiac catheterization (CC) revealed good hemodynamic parameters for a stage 2 Glenn. An MRI also revealed growth of the left ventricle. Decision-making A decision was made to engage in a staged LV recruitment process to achieve BiV repair. We elected to avoid a volume offloading procedure in the form of a Glenn. To optimize continued volume loading on the LV, Stage 2 palliation consisted of upsizing to a 5mm BTT shunt with 4mm FAS. MRI at 22 months showed an LV volume of 60ml/m2 associated with CC hemodynamics showing LA pressure of 13mmHg, and LV end-diastolic pressure of 12mmHg. He underwent BiV repair with takedown of DKS, with primary anastomosis of the aorta and the pulmonary artery to their respective circulations. The postoperative echocardiogram illustrated a gradient of 5mmHg and 3mmHg through the mitral and aortic valve respectively. The pt was placed on a beta blocker and discharged on day 5 following BiV conversion. This strategy provides increased pulmonary blood flow with increased bloodflow across the mitral valve and inflow into the LV. In so doing may enhance the rate of LV growth. Furthermore, this strategy avoids the bidirectional Glenn (BDG), a volume offloading operation. Conclusion Shunt upsizing with FAS is well tolerated. It has the potential advantage for fewer operations to achieve BiV circulation due to rapid LV growth in comparison to other staged LV recruitment strategies involving the BDG.Copyright © 2023 American College of Cardiology Foundation

Child Maltreatment and Long-Term Physical and Mental Health Outcomes: An Exploration of Biopsychosocial Determinants and Implications for Prevention.

Child maltreatment rates remain unacceptably high and rates are likely to escalate as COVID-related economic problems continue. A comprehensive and evidence-building approach is needed to prevent, detect and intervene where child maltreatment occurs. This review identifies key challenges in definitions, overviews the latest data on prevalence rates, reviews risk and protective factors, and examines common long-term mental health outcomes for children who experience maltreatment. The review takes a systems approach to child maltreatment outcomes through its focus on the overall burden of disease, gene-environment interactions, neurobiological mechanisms and social ecologies linking maltreatment to mental ill-health. Five recommendations relating to the accurate measurement of trends, research on brain structures and processes, improving the reach and impact of teleservices for detecting, preventing and treating child maladjustment, community-based approaches, and building population-focused multidisciplinary alliances and think tanks are presented.

Approaches to demonstrating the effectiveness of filovirus vaccines: Lessons from Ebola and COVID-19.

Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV) and Marburg virus (MARV), are members of the Filoviridae family that can cause severe disease and death in humans and animals. The reemergence of Ebola, Sudan and Marburg virus disease highlight the need for continued availability of safe and effectives vaccines as well as development of new vaccines. While randomized controlled trials using disease endpoints provide the most robust assessment of vaccine effectiveness, challenges to this approach include the unpredictable size, location, occurrence and duration of filovirus disease outbreaks. Thus, other approaches to demonstrating vaccine effectiveness have been considered. These approaches are discussed using examples of preventive vaccines against other infectious diseases. In addition, this article proposes a clinical immunobridging strategy using licensed EBOV vaccines as comparators for demonstrating the effectiveness of filovirus vaccine candidates that are based on the same licensed vaccine platform technology.

Tender Nasal Traumatic (TNT) Neuroma: Case Report and Review.

A traumatic neuroma occurs at the injury site of a peripheral nerve; however, albeit rarely, this variant of a neuroma can involve a nerve that has not experienced penetrating trauma. A lower extremity amputation stump is the most common location of a traumatic neuroma. Traumatic neuromas may be symptomatic; tumor-associated pain can be severe and significantly affect the patient's quality of life. Several hypotheses have been postulated for the pathogenesis of neuroma-related pain, including alpha-smooth muscle actin, neural fiber structural changes, nerve growth factor, and/or sensitization of the affected nerve. In addition to prevention, non-surgical treatment (such as chemical interventions, cryotherapy, neuromodulation, pharmacologic agents, and physiotherapy) and surgical interventions (such as direct nerve repair at the time of injury or ligation of the nerve proximal to the neuroma and various potential methods to minimize subsequent irritation of the distal free end of the proximal nerve) have been used to manage neuroma-associated pain. A traumatic neuroma of the nose is rare. Indeed, it has only been described in three individuals: two women (including the Caucasian woman in this report and a Turkish woman) and one man. The benign tumor was extremely painful in both women; however, the man's lesion was non-tender. Prior trauma to the nasal site included either a laceration or elective surgery; however, the reported woman did not experience any penetrating trauma to her nose. The diagnosis was established following an excisional (for the man), incisional (for the Turkish woman), or punch (for the Caucasian woman) biopsy. Follow-up was provided for two of the patients. The man's neuroma had been completely excised, and he never developed tumor-associated tenderness. However, the pain persisted after the biopsy healed for the reported woman whose neuroma was not entirely removed. The explosive and markedly severe character of the reported patient's lesion-related tenderness prompted us to propose an acronym for this uncommon yet exquisitely painful variant of a neuroma: tender nasal traumatic (TNT) neuroma.

SARS-CoV-2 Induces Epithelial-Enteric Neuronal Crosstalk Stimulating VIP Release.

BACKGROUND: Diarrhea is present in up to 30-50% of patients with COVID-19. The mechanism of SARS-CoV-2-induced diarrhea remains unclear. We hypothesized that enterocyte-enteric neuron interactions were important in SARS-CoV-2-induced diarrhea. SARS-CoV-2 induces endoplasmic reticulum (ER) stress in enterocytes causing the release of damage associated molecular patterns (DAMPs). The DAMPs then stimulate the release of enteric neurotransmitters that disrupt gut electrolyte homeostasis. METHODS: Primary mouse enteric neurons (EN) were exposed to a conditioned medium from ACE2-expressing Caco-2 colonic epithelial cells infected with SARS-CoV-2 or treated with tunicamycin (ER stress inducer). Vasoactive intestinal peptides (VIP) expression and secretion by EN were assessed by RT-PCR and ELISA, respectively. Membrane expression of NHE3 was determined by surface biotinylation. RESULTS: SARS-CoV-2 infection led to increased expression of BiP/GRP78, a marker and key regulator for ER stress in Caco-2 cells. Infected cells secreted the DAMP protein, heat shock protein 70 (HSP70), into the culture media, as revealed by proteomic and Western analyses. The expression of VIP mRNA in EN was up-regulated after treatment with a conditioned medium of SARS-CoV-2-infected Caco-2 cells. CD91, a receptor for HSP70, is abundantly expressed in the cultured mouse EN. Tunicamycin, an inducer of ER stress, also induced the release of HSP70 and Xbp1s, mimicking SARS-CoV-2 infection. Co-treatment of Caco-2 with tunicamycin (apical) and VIP (basolateral) induced a synergistic decrease in membrane expression of Na+/H+ exchanger (NHE3), an important transporter that mediates intestinal Na+/fluid absorption. CONCLUSIONS: Our findings demonstrate that SARS-CoV-2 enterocyte infection leads to ER stress and the release of DAMPs that up-regulates the expression and release of VIP by EN. VIP in turn inhibits fluid absorption through the downregulation of brush-border membrane expression of NHE3 in enterocytes. These data highlight the role of epithelial-enteric neuronal crosstalk in COVID-19-related diarrhea.

Nirmatrelvir Resistance in SARS-CoV-2 Omicron_BA.1 and WA1 Replicons and Escape Strategies (preprint)

The antiviral component of Paxlovid, nirmatrelvir (NIR), forms a covalent bond with Cys145 of SARS-CoV-2 nsp5. To explore NIR resistance we designed mutations to impair binding of NIR over substrate. Using 12 Omicron (BA.1) and WA.1 SARS-CoV-2 replicons, cell-based complementation and enzymatic assays, we showed that in both strains, E166V imparted high NIR resistance (~55-fold), with major decrease in WA1 replicon fitness (~20-fold), but not BA.1 (~2-fold). WA1 replicon fitness was restored by L50F. These differences may contribute to a potentially lower barrier to resistance in Omicron than WA1. E166V is rare in untreated patients, albeit more prevalent in paxlovid-treated EPIC-HR clinical trial patients. Importantly, NIR-resistant replicons with E166V or E166V/L50F remained susceptible to a) the flexible GC376, and b) PF-00835231, which forms additional interactions. Molecular dynamics simulations show steric clashes between the rigid and bulky NIR t-butyl and {beta}-branched V166 distancing the NIR warhead from its Cys145 target. In contrast, GC376, through-wiggling and jiggling- accommodates V166 and still covalently binds Cys145. PF-00835231 uses its strategically positioned methoxy-indole to form a beta-sheet and overcome E166V. Drug design based on strategic flexibility and main chain-targeting may help develop second-generation nsp5-targeting antivirals efficient against NIR-resistant viruses.

Pathways to Creative Learning and Teaching Online: An Ecological Model

Higher education practitioners may find that conceptualising and developing an online course is challenging at the best of times. Given the context of the Covid-19 pandemic and the recent accompanying changes to educational provision, more than ever we need assistance in envisaging and creatively shaping our pedagogical approaches for the online learning environment. Models that help us visualise learning designs, support us as creative teachers and contribute to our continuing professional learning and development needs (CPLD) may be particularly useful. Much can be learnt from the creative approaches of exemplary practitioners in the field. Examples from practice, CPLD principles, and adaptable learning designs are all useful tools to support praxis and enrich experience. In this chapter, I share an ecological model for designing for creative online learning that can also be used as a prompt for CPLD activities. The model is derived from lessons learned from practitioners in Australian higher education and illustrated with international examples of online adaptations implemented during the Covid-19 health emergency. © 2022, The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

Multistate Modeling of Clinical Trajectories and Outcomes in the ICU: A Proof-of-Concept Evaluation of Acute Kidney Injury Among Critically Ill Patients With COVID-19

IMPORTANCE: Multistate models yield high-fidelity analyses of the dynamic state transition and temporal dimensions of a clinical condition’s natural history, offering superiority over aggregate modeling techniques for addressing these types of problems. OBJECTIVES: To demonstrate the utility of these models in critical care, we examined acute kidney injury (AKI) development, progression, and outcomes in COVID-19 critical illness through multistate analyses. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at an urban tertiary-care academic hospital in the United States. All patients greater than or equal to 18 years in an ICU with COVID-19 in 2020, excluding patients with preexisting end-stage renal disease. MAIN OUTCOMES AND MEASURES: Using electronic health record data, we determined AKI presence/stage in discrete 12-hour time windows and fit multistate models to determine longitudinal transitions and outcomes. RESULTS: Of 367 encounters, 241 (66%) experienced AKI (maximal stages: 88 stage-1, 49 stage-2, 104 stage-3 AKI [51 received renal replacement therapy (RRT), 53 did not]). Patients receiving RRT overwhelmingly received invasive mechanical ventilation (IMV) (n = 60, 95%) compared with the AKI-without-RRT (n = 98, 53%) and no-AKI groups (n = 39, 32%;p < 0.001), with similar mortality patterns (RRT: n = 36, 57%;AKI: n = 74, 40%;non-AKI: n = 23, 19%;p < 0.001). After 24 hours in the ICU, almost half the cohort had AKI (44.9%;95% CI, 41.6–48.2%). At 7 days after stage-1 AKI, 74.0% (63.6–84.4) were AKI-free or discharged. By contrast, fewer patients experiencing stage-3 AKI were recovered (30.0% [24.1–35.8%]) or discharged (7.9% [5.2–10.7%]) after 7 days. Early AKI occurred with similar frequency in patients receiving and not receiving IMV: after 24 hours in the ICU, 20.9% of patients (18.3–23.6%) had AKI and IMV, while 23.4% (20.6–26.2%) had AKI without IMV. CONCLUSIONS AND RELEVANCE: In a multistate analysis of critically ill patients with COVID-19, AKI occurred early and heterogeneously in the course of critical illness. Multistate methods are useful and underused in ICU care delivery science as tools for understanding trajectories, prognoses, and resource needs.

Psychological services to extend public health and disease management approaches in criminal justice settings: An introduction.

COVID-19 has brought renewed attention to the physical and mental health needs of underserved populations and the settings that assist them in receiving services. This introduction presents six articles of a special section on disease management approaches used within criminal justice settings to address such needs. Articles span a range of settings, including prisons, jails, mental health courts, forensic settings, and crisis units. Collectively, the articles in this special section discuss medical conditions, substance use, and mental health. They provide information on the diverse approaches taken across various settings in managing the physical and mental health challenges of those involved in the criminal justice system. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Responding to individuals and communities after disasters and other traumatic events: An introduction

Public service psychologists are often at the forefront of responding to communities affected by disasters, violence, and other traumatic events. Through prevention efforts, risk management and treatment response interventions practiced in prisons, military installations, law enforcement, Veterans Affairs (VA) centers, state hospitals, and schools, public service psychologists offer care to those impacted. This introduction provides an overview of articles culled from a call for papers focusing on theoretical and empirical explorations of organized responses to traumatic events. The thirteen papers presented here are organized into two sections of articles illustrating two broad groupings of response-those that are immediate and those produced through a lengthier evaluation process. Public sector psychologists are an innovative and nimble workforce who can immediately meet urgent service delivery needs. They are also well equipped to perform the lengthier research and evaluation tasks that can be used to benefit service delivery responses during future events. From across these two groupings, an array of papers are presented, from psychological and mental health first aid to other innovative programs that offer an organized response to individuals and communities after traumatic events, including the coronavirus disease (COVID-19) pandemic. The range of interventions offered by public service psychologists to individuals and communities in an increasing number of traumatic events suggests that the field is pacing itself to meet this growing need. (PsycInfo Database Record (c) 2022 APA, all rights reserved) Impact Statement Impact Statement-Organized responses to deliver psychological services during disasters and other traumatic events is a central aspect of public sector psychology. The 13 papers presented here illustrate a range of prevention and intervention efforts and illustrate the work of public sector psychologists with those impacted. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

The National COVID Cohort Collaborative: Analyses of original and computationally derived electronic health record data

Background: Computationally derived ("synthetic") data can enable the creation and analysis of clinical, laboratory, and diagnostic data as if they were the original electronic health record data. Synthetic data can support data sharing to answer critical research questions to address the COVID-19 pandemic. Objective: We aim to compare the results from analyses of synthetic data to those from original data and assess the strengths and limitations of leveraging computationally derived data for research purposes. Methods: We used the National COVID Cohort Collaborative's instance of MDClone, a big data platform with data-synthesizing capabilities (MDClone Ltd). We downloaded electronic health record data from 34 National COVID Cohort Collaborative institutional partners and tested three use cases, including (1) exploring the distributions of key features of the COVID-19-positive cohort;(2) training and testing predictive models for assessing the risk of admission among these patients;and (3) determining geospatial and temporal COVID-19-related measures and outcomes, and constructing their epidemic curves. We compared the results from synthetic data to those from original data using traditional statistics, machine learning approaches, and temporal and spatial representations of the data. Results: For each use case, the results of the synthetic data analyses successfully mimicked those of the original data such that the distributions of the data were similar and the predictive models demonstrated comparable performance. Although the synthetic and original data yielded overall nearly the same results, there were exceptions that included an odds ratio on either side of the null in multivariable analyses (0.97 vs 1.01) and differences in the magnitude of epidemic curves constructed for zip codes with low population counts. Conclusions: This paper presents the results of each use case and outlines key considerations for the use of synthetic data, examining their role in collaborative research for faster insights. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

The Use of Teledermatology in Medical Education.

Certain aspects of medical education have transitioned to virtual platforms since the start of the COVID-19 pandemic. This commentary explores advantages and barriers to teledermatology in medical education, which has the potential to reach an extensive pool of learners and preceptors but may be limited by logistical and security considerations of a virtual platform. Dermatology in particular lends itself to an online platform as a highly visual specialty, although clinical exam would be highly dependent on quality of images captured. With teledermatology, learners can begin developing an approach to delivering care remotely, and becoming accustomed to virtual platforms.

Estrogen hormone is an essential sex factor inhibiting inflammation and immune response in COVID-19.

Although vaccines have been evaluated and approved for SARS-CoV-2 infection prevention, there remains a lack of effective treatments to reduce the mortality of COVID-19 patients already infected with SARS-CoV-2. The global data on COVID-19 showed that men have a higher mortality rate than women. We further observed that the proportion of mortality of females increases starting from around the age of 55 significantly. Thus, sex is an essential factor associated with COVID-19 mortality, and sex related genetic factors could be interesting mechanisms and targets for COVID-19 treatment. However, the associated sex factors and signaling pathways remain unclear. Here, we propose to uncover the potential sex associated factors using systematic and integrative network analysis. The unique results indicated that estrogens, e.g., estrone and estriol, (1) interacting with ESR1/2 receptors, (2) can inhibit SARS-CoV-2 caused inflammation and immune response signaling in host cells; and (3) estrogens are associated with the distinct fatality rates between male and female COVID-19 patients. Specifically, a high level of estradiol protects young female COVID-19 patients, and estrogens drop to an extremely low level in females after about 55 years of age causing the increased fatality rate of women. In conclusion, estrogen, interacting with ESR1/2 receptors, is an essential sex factor that protects COVID-19 patients from death by inhibiting inflammation and immune response caused by SARS-CoV-2 infection. Moreover, medications boosting the down-stream signaling of ESR1/ESR2, or inhibiting the inflammation and immune-associated targets on the signaling network can be potentially effective or synergistic combined with other existing drugs for COVID-19 treatment.

Clinical and Financial Outcomes Associated With a Workplace Mental Health Program Before and During the COVID-19 Pandemic.

Importance: Investment in workplace wellness programs is increasing despite concerns about lack of clinical benefit and return on investment (ROI). In contrast, outcomes from workplace mental health programs, which treat mental health difficulties more directly, remain mostly unknown. Objective: To determine whether participation in an employer-sponsored mental health benefit was associated with improvements in depression and anxiety, workplace productivity, and ROI as well as to examine factors associated with clinical improvement. Design, Setting, and Participants: This cohort study included participants in a US workplace mental health program implemented by 66 employers across 40 states from January 1, 2018, to January 1, 2021. Participants were employees who enrolled in the mental health benefit program and had at least moderate anxiety or depression, at least 1 appointment, and at least 2 outcome assessments. Intervention: A digital platform that screened individuals for common mental health conditions and provided access to self-guided digital content, care navigation, and video and in-person psychotherapy and/or medication management. Main Outcomes and Measures: Primary outcomes were the Patient Health Questionnaire-9 for depression (range, 0-27) score and the Generalized Anxiety Disorder 7-item scale (range, 0-21) score. The ROI was calculated by comparing the cost of treatment to salary costs for time out of the workplace due to mental health symptoms, measured with the Sheehan Disability Scale. Data were collected through 6 months of follow-up and analyzed using mixed-effects regression. Results: A total of 1132 participants (520 of 724 who reported gender [71.8%] were female; mean [SD] age, 32.9 [8.8] years) were included. Participants reported improvements from pretreatment to posttreatment in depression (b = -6.34; 95% CI, -6.76 to -5.91; Cohen d = -1.11; 95% CI, -1.18 to -1.03) and anxiety (b = -6.28; 95% CI, -6.77 to -5.91; Cohen d = -1.21; 95% CI, -1.30 to -1.13). Symptom change per log-day of treatment was similar post-COVID-19 vs pre-COVID-19 for depression (b = 0.14; 95% CI, -0.10 to 0.38) and anxiety (b = 0.08; 95% CI, -0.22 to 0.38). Workplace salary savings at 6 months at the federal median wage was US $3440 (95% CI, $2730-$4151) with positive ROI across all wage groups. Conclusions and Relevance: Results of this cohort study suggest that an employer-sponsored workplace mental health program was associated with large clinical effect sizes for employees and positive financial ROI for employers.

Reliably Assessing Duration of Protection for Coronavirus Disease 2019 Vaccines.

Decision making about vaccination and boosting schedules for coronavirus disease 2019 (COVID-19) hinges on reliable methods for evaluating the longevity of vaccine protection. We show that modeling of protection as a piecewise linear function of time since vaccination for the log hazard ratio of the vaccine effect provides more reliable estimates of vaccine effectiveness at the end of an observation period and also detects plateaus in protective effectiveness more reliably than the standard method of estimating a constant vaccine effect over each time period. This approach will be useful for analyzing data pertaining to COVID-19 vaccines and other vaccines for which rapid and reliable understanding of vaccine effectiveness over time is desired.