Insights Derived From Text-Based Digital Media, in Relation to Mental Health and Suicide Prevention, Using Data Analysis and Machine Learning: Systematic Review.

BACKGROUND: Text-based digital media platforms have revolutionized communication and information sharing, providing valuable access to knowledge and understanding in the fields of mental health and suicide prevention. OBJECTIVE: This systematic review aimed to determine how machine learning and data analysis can be applied to text-based digital media data to understand mental health and aid suicide prevention. METHODS: A systematic review of research papers from the following major electronic databases was conducted: Web of Science, MEDLINE, Embase (via MEDLINE), and PsycINFO (via MEDLINE). The database search was supplemented by a hand search using Google Scholar. RESULTS: Overall, 19 studies were included, with five major themes as to how data analysis and machine learning techniques could be applied: (1) as predictors of personal mental health, (2) to understand how personal mental health and suicidal behavior are communicated, (3) to detect mental disorders and suicidal risk, (4) to identify help seeking for mental health difficulties, and (5) to determine the efficacy of interventions to support mental well-being. CONCLUSIONS: Our findings show that data analysis and machine learning can be used to gain valuable insights, such as the following: web-based conversations relating to depression vary among different ethnic groups, teenagers engage in a web-based conversation about suicide more often than adults, and people seeking support in web-based mental health communities feel better after receiving online support. Digital tools and mental health apps are being used successfully to manage mental health, particularly through the COVID-19 epidemic, during which analysis has revealed that there was increased anxiety and depression, and web-based communities played a part in reducing isolation during the pandemic. Predictive analytics were also shown to have potential, and virtual reality shows promising results in the delivery of preventive or curative care. Future research efforts could center on optimizing algorithms to enhance the potential of text-based digital media analysis in mental health and suicide prevention. In addressing depression, a crucial step involves identifying the factors that contribute to happiness and using machine learning to forecast these sources of happiness. This could extend to understanding how various activities result in improved happiness across different socioeconomic groups. Using insights gathered from such data analysis and machine learning, there is an opportunity to craft digital interventions, such as chatbots, designed to provide support and address mental health challenges and suicide prevention.

Coproduction of accessible digital mental health supports in partnership with young people from marginalised backgrounds: a scoping review protocol.

INTRODUCTION: Despite the evidence supporting the value of digital supports for enhancing youth mental health services, there is a lack of guidance on how best to engage with young people in coproduction processes during the design and evaluation of these technologies. User input is crucial in digital mental health, especially for disadvantaged, vulnerable and marginalised young people as they are often excluded from coproduction. A scoping review of international literature written in English will explore the coproduction processes with marginalised young people in digital mental health supports, from mental health promotion to targeted interventions. The review is guided by the research question: what are the most appropriate coproduction processes for engaging young people, especially marginalised young people, in the different stages of designing and evaluating digital mental health supports? The review aims to map and summarise the evidence, inform the overall research project and address the knowledge gaps. METHODS AND ANALYSIS: The scoping review uses Arksey and O'Malley's framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols Extension for Scoping Reviews. From 22-24 October 2023, PubMed, Scopus, EBSCO, ASSIA, Web of Science, Ovid MEDLINE, Cochrane database, Embase, Google Scholar, ProQuest, OAIster and BASE will be systematically searched. Papers from 2021 onwards with a range of study designs and evidence that illustrate engagement with marginalised young people (aged 16-25) in the design, implementation and evaluation of digital technologies for young people's mental health will be considered for inclusion. At least two reviewers will screen full texts and chart data. The results of this review will be summarised quantitatively through numerical counts of included literature and qualitatively through a narrative synthesis. ETHICS AND DISSEMINATION: Ethical approval is not required. Results will be disseminated through publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: This scoping review protocol has been registered with the Open Science Framework (https://osf.io/9xhgv).

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy and the role of advanced practice providers and pharmacists.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a severe and potentially life-threatening complication. HSCT-TMA is often underdiagnosed due to multifactorial pathophysiology and a historic lack of standard diagnostic criteria. Identification of the multi-hit hypothesis and the key role of the complement system, particularly the lectin pathway of complement, has led to development of treatments targeting the underlying pathogenesis of HSCT-TMA. Additional research is ongoing to investigate the efficacy and safety of these targeted therapies in patients with HSCT-TMA. Advanced practice providers (APPs; nurse practitioners and physician assistants) and pharmacists are critical members of the multidisciplinary HSCT team and ensure management of patients throughout the continuum of care. Additionally, pharmacists and APPs can improve patient care through medication management of complex regimens; transplant education for patients, staff, and trainees; evidence-based protocol and clinical guideline development; assessment and reporting of transplant-related outcomes; and quality improvement initiatives to improve outcomes. Understanding the presentation, prognosis, pathophysiology, and treatment options for HSCT-TMA can improve each of these efforts. Collaborative practice model for monitoring and care of HSCT-TMA. Advanced practice providers and pharmacists contribute to many aspects of patient care in transplant centers, including medication management for complex regimens; transplant education for patients, staff, and trainees; evidence-based protocol and clinical guideline development; assessment and reporting of transplant-related outcomes; and quality improvement initiatives. HSCT-TMA is a severe and potentially life-threatening complication that is often underdiagnosed. The collaboration of a multidisciplinary team of advanced practice providers, pharmacists, and physicians can optimize recognition, diagnosis, management, and monitoring of patients with HSCT-TMA, thereby improving outcomes for these patients.

Implementation and results of a standardized process for identifying ambulatory pharmacy clinical outcome measures.

PURPOSE: Given the variation in clinical practice, a clinician-centric, standardized process to implement and validate clinical pharmacy outcome measures was developed. SUMMARY: Four specialty clinics with embedded clinic-based pharmacists underwent an iterative process to define, refine, and implement the build of electronic health record functionality for outcome measure data collection and reporting. Starting with a list of identified measures, clinic workgroups met to discuss each measure and identify gaps in measure implementation. Information technology experts created electronic documentation forms with discrete data and reports based on criteria specified by the clinic workgroups. Of 32 outcome measures identified as priorities for demonstrating pharmacists' impact in previous research, 29 were implemented for routine monitoring through this project. Implementation strategies included identification through existing reporting, development of discrete documentation tools within the electronic health record, and development of new reporting tools from available discrete data fields. Time to implementation decreased from the first to the last pilot clinic implementation, as demonstrated through a 9-day reduction in electronic documentation form development and 31-day reduction in report development turnaround time. CONCLUSION: A standardized and reproducible process was developed for the implementation of clinical pharmacy outcomes measures for 4 specialty clinics. The process was successfully utilized to develop measurable outputs for a variety of oncology and nononcology specialty disease states based upon multidisciplinary stakeholder input.

The impact of systemic racism on health outcomes among Black women: Recommendations for change.

ABSTRACT: Black women suffer disproportionately from healthcare inequities in comparison to their White counterparts. Using the Public Health Critical Race framework, this article explores the lasting effects of systemic racism on the health outcomes of Black women across the lifespan. A case study and specific strategies are presented to examine how clinicians, educators, and policymakers can work with Black women to mitigate and eliminate health inequities.

Can Diffusion Tensor Imaging Apparent Diffusion Coefficient Diagnose Carpal Tunnel Syndrome? A Systematic Review and Meta-Analysis.

Magnetic resonance diffusion tensor imaging (DTI) can detect microstructural changes in peripheral nerves. Studies have reported that the median nerve apparent diffusion coefficient (ADC), a quantification of water molecule diffusion direction, is sensitive in diagnosing carpal tunnel syndrome (CTS). Five databases were searched for studies using ADC to investigate CTS. Apparent diffusion coefficient (measured in mm2/s) were pooled in random-effects meta-analyses. Twenty-two studies met criteria yielding 592 patients with CTS and 414 controls. Median nerve ADC were measured at the level of the distal radioulnar joint (CTS ADC: 1.11, 95% CI: 1.07-1.15, I2 = 54%; control ADC: 1.04, 95% CI: 1.01-1.07, I2 = 57%), pisiform (CTS ADC: 1.39, 95% CI: 1.37-1.42, I2 = 0%; control ADC: 1.27, 95% CI: 1.23-1.31, I2 = 59%), hamate (CTS ADC: 1.40, 95% CI: 1.36-1.43, I2 = 58%; control ADC: 1.27, 95% CI: 1.25-1.28, I2 = 47%), and as an combination of several measurements (CTS ADC: 1.40, 95% CI: 1.37-1.47, I2 = 100%; control ADC: 1.39, 95% CI: 1.24-1.53, I2 = 100%). Median nerve ADC is decreased in individuals with CTS compared to controls at the levels of the hamate and pisiform. ADC cut-offs to diagnose CTS should be established according to these anatomic levels and can be improved through additional studies that include use of a wrist coil.

Development and implementation of a standardized process for identifying ambulatory pharmacy clinical outcomes measures.

PURPOSE: There is minimal available guidance on the process for selection of clinical outcomes measures to demonstrate the impact of clinic-based pharmacists (CBPs) despite an increased need and desire for outcomes data. The overall aims of this project were to (1) develop a standardized process for identifying clinical outcomes measures impacted by CBPs and (2) identify and prioritize potential clinical outcomes measures to track for CBPs within 4 specialty clinic pilot sites. METHODS: To develop a standardized process for identification and prioritization of measures, 4 consecutive Plan-Do-Study-Act (PDSA) cycles were performed with 4 different specialty clinics serving as pilot sites. Following each pilot cycle, rapid cycle improvements were implemented. A modified Delphi methodology served as the framework for measure selection and included gathering expert stakeholder insights regarding importance, feasibility, and validity of potential measures. Measures were identified via environmental scan of existing validated quality metrics, clinical guidelines, and other relevant literature. RESULTS: The primary outcome for this project was the development and refinement of a standardized process for measure identification and prioritization. The secondary outcome was narrowed and ranked lists of stakeholder-prioritized measures for 4 CBP-embedded pilot specialty clinics. These lists included 12 cardiothoracic transplant, 6 breast oncology, 9 neurology, and 7 gynecologic oncology measures. CONCLUSION: The measure identification and prioritization process developed was successfully utilized to identify and prioritize outcomes measures to track for 4 CBP-embedded specialty clinics. Due to the successful use of the process in a variety of specialty clinics, the standardized process has significant potential for expansion.

Digital transformation of mental health services.

This paper makes a case for digital mental health and provides insights into how digital technologies can enhance (but not replace) existing mental health services. We describe digital mental health by presenting a suite of digital technologies (from digital interventions to the application of artificial intelligence). We discuss the benefits of digital mental health, for example, a digital intervention can be an accessible stepping-stone to receiving support. The paper does, however, present less-discussed benefits with new concepts such as 'poly-digital', where many different apps/features (e.g. a sleep app, mood logging app and a mindfulness app, etc.) can each address different factors of wellbeing, perhaps resulting in an aggregation of marginal gains. Another benefit is that digital mental health offers the ability to collect high-resolution real-world client data and provide client monitoring outside of therapy sessions. These data can be collected using digital phenotyping and ecological momentary assessment techniques (i.e. repeated mood or scale measures via an app). This allows digital mental health tools and real-world data to inform therapists and enrich face-to-face sessions. This can be referred to as blended care/adjunctive therapy where service users can engage in 'channel switching' between digital and non-digital (face-to-face) interventions providing a more integrated service. This digital integration can be referred to as a kind of 'digital glue' that helps join up the in-person sessions with the real world. The paper presents the challenges, for example, the majority of mental health apps are maybe of inadequate quality and there is a lack of user retention. There are also ethical challenges, for example, with the perceived 'over-promotion' of screen-time and the perceived reduction in care when replacing humans with 'computers', and the trap of 'technological solutionism' whereby technology can be naively presumed to solve all problems. Finally, we argue for the need to take an evidence-based, systems thinking and co-production approach in the form of stakeholder-centred design when developing digital mental health services based on technologies. The main contribution of this paper is the integration of ideas from many different disciplines as well as the framework for blended care using 'channel switching' to showcase how digital data and technology can enrich physical services. Another contribution is the emergence of 'poly-digital' and a discussion on the challenges of digital mental health, specifically 'digital ethics'.

Effect of Relative Humidity on Transfer of Aerosol-Deposited Artificial and Human Saliva from Surfaces to Artificial Finger-Pads.

Surface to hand transfer of viruses represents a potential mechanism for human exposure. An experimental process for evaluating the touch transfer of aerosol-deposited material is described based on controlling surface, tribological, and soft matter components of the transfer process. A range of high-touch surfaces were evaluated. Under standardized touch parameters (15 N, 1 s), relative humidity (RH) of the atmosphere around the contact transfer event significantly influenced transfer of material to the finger-pad. At RH < 40%, transfer from all surfaces was <10%. Transfer efficiency increased markedly as RH increased, reaching a maximum of approximately 50%. The quantity of material transferred at specific RHs above 40% was also dependent on roughness of the surface material and the properties of the aerosol-deposited material. Smooth surfaces, such as melamine and stainless steel, generated higher transfer efficiencies compared to those with textured roughness, such as ABS pinseal and KYDEX® plastics. Pooled human saliva was transferred at a lower rate compared to artificial saliva, indicating the role of rheological properties. The artificial saliva data were modeled by non-linear regression and the impact of environmental humidity and temperature were evaluated within a Quantitative Microbial Risk Assessment model using SARS-CoV-2 as an example. This illustrated that the trade-off between transfer efficiency and virus survival may lead to the highest risks of fomite transmissions in indoor environments with higher humidity.

Plerixafor strategies for autologous hematopoietic cell transplant mobilization: A comparison of efficacy and cost.

Addition of plerixafor (P) to granulocyte colony stimulating factor (G-CSF) during peripheral blood mobilization of hematopoietic stem cells (HSC) increases the number of patients meeting collection goals prior to autologous stem cell transplant (aSCT). However, use of P is not universal among transplant centers due to cost. This study aims to compare clinical and financial impacts of using an algorithm-based P mobilization strategy versus use in all patients. This was a single center, retrospective analysis of adult patients with myeloma or amyloidosis receiving aSCT who received apheresis of their HSC between 3/1/2017 and 3/1/2019. Patients prior to 3/1/2018 were classified as receiving P "per algorithm" and those after this date were classified as "up-front" P. For the per-algorithm group, P was given for a pre-apheresis CD34+ cell count of <20 cells/µL on mobilization day 5 and patients returned on day 6 for apheresis. Of the 129 patients included, 55 received P per-algorithm and 74 received up-front P. There was a reduction in median number of apheresis days (1.5 vs 1 day, p < 0.001) and an increase in median number of CD34+ cells collected (6.6 vs 8.5 × 106 cells/kg, p < 0.001) with up-front P. Up-front P increased drug cost but reduced apheresis costs, which resulted in a net savings of $121 per patient in total mobilization costs. These findings suggest that use of up-front P for mobilization significantly reduces apheresis days and increases HSC collection yield without increasing overall cost per patient.

Upper Limb Position Tracking with a Single Inertial Sensor Using Dead Reckoning Method with Drift Correction Techniques.

Inertial sensors are widely used in human motion monitoring. Orientation and position are the two most widely used measurements for motion monitoring. Tracking with the use of multiple inertial sensors is based on kinematic modelling which achieves a good level of accuracy when biomechanical constraints are applied. More recently, there is growing interest in tracking motion with a single inertial sensor to simplify the measurement system. The dead reckoning method is commonly used for estimating position from inertial sensors. However, significant errors are generated after applying the dead reckoning method because of the presence of sensor offsets and drift. These errors limit the feasibility of monitoring upper limb motion via a single inertial sensing system. In this paper, error correction methods are evaluated to investigate the feasibility of using a single sensor to track the movement of one upper limb segment. These include zero velocity update, wavelet analysis and high-pass filtering. The experiments were carried out using the nine-hole peg test. The results show that zero velocity update is the most effective method to correct the drift from the dead reckoning-based position tracking. If this method is used, then the use of a single inertial sensor to track the movement of a single limb segment is feasible.

An Efflux Pumps Inhibitor Significantly Improved the Antibacterial Activity of Botanicals from Plectranthus glandulosus towards MDR Phenotypes.

Bacterial multidrug resistance causes many therapeutic failures, making it more difficult to fight against bacterial diseases. This study aimed to investigate the antibacterial activity of extract, fractions, and phytochemicals from Plectranthus glandulosus (Lamiaceae) against multidrug-resistant (MDR) Gram-negative phenotypes expressing efflux pumps. The crude extract after extraction was subjected to column chromatography, and the structures of the isolated compounds were determined using spectrometric and spectroscopic techniques. Antibacterial assays of samples alone and in the presence of an efflux pump inhibitor (phenylalanine-arginine ß-naphthylamide, PAßN) were carried out using the broth microdilution method. The phytochemical study of P. glandulosus plant extract afforded seven major fractions (A-G) which lead to the isolation of seventeen known compounds. The ethanol extract of P. glandulosus was not active at up to 1024 µg/mL, whereas its fractions showed MICs varying from 32 to 512 µg/mL on the studied bacteria. Fraction C of P. glandulosus showed the lowest MIC (32 µg/mL) on E. coli ATCC8739 strain. Fraction D presented the highest activity spectrum by inhibiting the growth of 90% (9/10) of the studied bacteria. The presence of PAßN has improved the activity of extract and all fractions. Overall, the tested phytochemicals showed low activity against the studied bacteria. The overall results obtained in this study show that some fractions from P. glandulosus, mainly fractions C and D, should be investigated more for their possible use to fight against MDR bacteria.

Ethical Issues in Democratizing Digital Phenotypes and Machine Learning in the Next Generation of Digital Health Technologies.

Digital phenotyping is the term given to the capturing and use of user log data from health and wellbeing technologies used in apps and cloud-based services. This paper explores ethical issues in making use of digital phenotype data in the arena of digital health interventions. Products and services based on digital wellbeing technologies typically include mobile device apps as well as browser-based apps to a lesser extent, and can include telephony-based services, text-based chatbots, and voice-activated chatbots. Many of these digital products and services are simultaneously available across many channels in order to maximize availability for users. Digital wellbeing technologies offer useful methods for real-time data capture of the interactions of users with the products and services. It is possible to design what data are recorded, how and where it may be stored, and, crucially, how it can be analyzed to reveal individual or collective usage patterns. The paper also examines digital phenotyping workflows, before enumerating the ethical concerns pertaining to different types of digital phenotype data, highlighting ethical considerations for collection, storage, and use of the data. A case study of a digital health app is used to illustrate the ethical issues. The case study explores the issues from a perspective of data prospecting and subsequent machine learning. The ethical use of machine learning and artificial intelligence on digital phenotype data and the broader issues in democratizing machine learning and artificial intelligence for digital phenotype data are then explored in detail.

Sequence and Properties of Cagein, a Coiled-Coil Scaffold Protein Linking Basal Bodies in the Polykinetids of the Ciliate Euplotes aediculatus.

In the hypotrich ciliate Euplotes, many individual basal bodies are grouped together in tightly packed clusters, forming ventral polykinetids. These groups of basal bodies (which produce compound ciliary organelles such as cirri and oral membranelles) are cross-linked into ordered arrays by scaffold structures known as "basal-body cages." The major protein comprising Euplotes cages has been previously identified and termed "cagein." Screening a E. aediculatus cDNA expression library with anti-cagein antisera identified a DNA insert containing most of a putative cagein gene; standard PCR techniques were used to complete the sequence. Probes designed from this gene identified a macronuclear "nanochromosome" of ca. 1.5 kb in Southern blots against whole-cell DNA. The protein derived from this sequence (463 residues) is predicted to be hydrophilic and highly charged; however, the native cage structures are highly resistant to salt/detergent extraction. This insolubility could be explained by the coiled-coil regions predicted to extend over much of the length of the derived cagein polypeptide. One frameshift sequence is found within the gene, as well as a short intron. BLAST searches find many ciliates with evident homologues to cagein within their derived genomic sequences.

Anti-inflammatory effects of haptoglobin on LPS-stimulated macrophages: Role of HMGB1 signaling and implications in chronic wound healing.

Nonhealing wounds possess elevated numbers of pro-inflammatory M1 macrophages, which fail to transition to anti-inflammatory M2 phenotypes that promote healing. Hemoglobin (Hb) and haptoglobin (Hp) proteins, when complexed (Hb-Hp), can elicit M2-like macrophages through the heme oxygenase-1 (HO-1) pathway. Despite the fact that nonhealing wounds are chronically inflamed, previous studies have focused on non-inflammatory systems, and do not thoroughly compare the effects of complexed vs individual proteins. We aimed to investigate the effect of Hb/Hp treatments on macrophage phenotype in an inflammatory, lipopolysaccharide (LPS)-stimulated environment, similar to chronic wounds. Human M1 macrophages were cultured in vitro and stimulated with LPS. Concurrently, Hp, Hb, or Hb-Hp complexes were delivered. The next day, 27 proteins related to inflammation were measured in the supernatants. Hp treatment decreased a majority of inflammatory factors, Hb increased many, and Hb-Hp had intermediate trends, indicating that Hp attenuated overall inflammation to the greatest extent. From this data, Ingenuity Pathway Analysis software identified high motility group box 1 (HMGB1) as a key canonical pathway-strongly down-regulated from Hp, strongly up-regulated from Hb, and slightly activated from Hb-Hp. HMGB1 measurements in macrophage supernatants confirmed this trend. In vivo results in diabetic mice with biopsy punch wounds demonstrated accelerated wound closure with Hp treatment, and delayed wound closure with Hb treatment. This work specifically studied Hb/Hp effects on macrophages in a highly inflammatory environment relevant to chronic wound healing. Results show that Hp-and not Hb-Hp, which is known to be superior in noninflammatory conditions-reduces inflammation in LPS-stimulated macrophages, and HMGB1 signaling is also implicated. Overall, Hp treatment on M1 macrophages in vitro reduced the inflammatory secretion profile, and also exhibited benefits in in silico and in vivo wound-healing models.

Why do people call crisis helplines? Identifying taxonomies of presenting reasons and discovering associations between these reasons.

The objective of this study is to identify the most common reasons for contacting a crisis helpline through analysing a large call log data set. Two taxonomies were identified within the call log data from a Northern Ireland telephone crisis helpline (Lifeline), categorising the cited reason for each call. One taxonomy categorised the reasons at a fine granular level; the other taxonomy used the relatively coarser International Classification of Diseases-10. Exploratory data analytic techniques were applied to discover insights into why individuals contact crisis helplines. Risk ratings of calls were also compared to assess the associations between presenting issue and of risk of suicide as assessed. Reasons for contacting the service were assessed across geolocations. Association rule mining was used to identify associations between the presenting reasons for client's calls. Results demonstrate that both taxonomies show that calls with reasons relating to suicide are the most common reasons for contacting Lifeline and were a prominent feature of the discovered association rules. There were significant differences between reasons in both taxonomies concerning risk ratings. Reasons for calling helplines that are associated with higher risk ratings include those calling with a personality disorder, mental disorders, delusional disorders and drugs (legal). In conclusion, employing two differing taxonomy approaches to analyse call log data reveals the prevalence of main presenting reasons for contacting a crisis helpline. The association rule mining using each taxonomy provided insights into the associations between presenting reasons. Practical and research applications are discussed.

Evaluation of mobilization efficacy with an extended interval following plerixafor administration.

Plerixafor is a hematopoietic stem cell mobilizing agent used in combination with granulocyte-colony stimulating factor to improve collection for autologous stem cell transplantation. Despite a recommendation for administration 11 h prior to apheresis per package labeling, logistical challenges lead many institutions to administer plerixafor at an extended interval. The purpose of this study was to determine if plerixafor effectively and efficiently mobilizes CD34+ cells when given at an extended interval prior to apheresis. This was a retrospective evaluation of adult patients who received plerixafor based on an algorithm reserving daily plerixafor only for patients with a pre-apheresis CD34+ count of < 20 cells/µL (pre-apheresis plerixafor) or with a low CD34+ yield after the first apheresis session (rescue plerixafor). The primary outcome was achievement of a disease-specific collection goal of ≥ 6 ×106 CD34+ cells/kg for multiple myeloma and ≥ 4 ×106 CD34+ cells/kg for lymphoma. The mean interval between plerixafor administration and apheresis was 17 h in this study. Despite this extended interval, 64% of patients met their disease-specific collection goal. A minimum collection goal of ≥ 2 ×106 CD34+ cells/kg was achieved by 95% of patients. Mobilization remained efficient with a median of two days to complete collection. Based on this data, plerixafor effectively and efficiently mobilizes CD34+ cells when given at an extended interval prior to apheresis.

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

Drug-Drug Interaction Between Isavuconazole and Tacrolimus: Is Empiric Dose Adjustment Necessary?

A paucity of data currently exists regarding drug-drug interaction (DDI) with tacrolimus and isavuconazole coadministration. Current literature provides conflicting recommendations on whether an empiric tacrolimus dose reduction is necessary when coadministered with isavuconazole. A 47-year-old African American female with acute lymphoblastic leukemia underwent an allogenic stem cell transplant (alloSCT) and was subsequently placed on routine posttransplant therapy including tacrolimus for immunosuppression and posaconazole for antifungal prophylaxis. Tacrolimus was empirically dose reduced due to the expected DDI with posaconazole based on current recommendations. Due to a persistently prolonged QTc interval and need for mold coverage, antifungal prophylaxis was ultimately changed to isavuconazole at standard recommended dosing. Tacrolimus was empirically dose reduced by 40% based on limited available literature at the time; however, tacrolimus trough concentrations subsequently declined, requiring an increase in tacrolimus dose to maintain therapeutic trough concentrations. Adequate isavuconazole absorption was documented through pharmacokinetic and pharmacodynamic data by measuring an isavuconazole trough concentration and directly observing isavuconazole's shortening effect on the QTc interval, respectively. Our experience in an alloSCT patient suggests that an empiric tacrolimus dose reduction is not required when isavuconazole is initiated, but close tacrolimus therapeutic drug monitoring should rather be performed to guide tacrolimus dosing.