Administration Guidelines Research Articles

Cryotherapy-Induced Iatrogenic Frostbite on Distal Digit: Case Report and Review of Management Strategies.

Cryotherapy is a widely utilized topical treatment for various dermatological conditions. While generally safe and effective, it carries potential risks, such as frostbite injury. Frostbite, a vascular condition causing skin and tissue freezing, is usually associated with prolonged exposure to freezing environments. Certain populations, like military personnel navigating frigid terrains, face an increased risk of frostbite and other cold-weather injuries. In this case, we present an unusual instance of iatrogenic frostbite in a 23-year-old active duty United States Navy Sailor. The patient required a diverse range of treatment modalities, including pain management, sildenafil, nitroglycerine paste, and hyperbaric oxygen therapy. The implemented treatment regimen resulted in significant clinical improvements with minimal long-term structural damage. This case underscores the clinical value of establishing clear management guidelines for cryotherapy administration in cutaneous conditions. Such guidelines are essential to ensure optimal dosing, minimize adverse sequelae, and improve overall prognosis.

Withholding Tax and Equity-Linked Financial Contracts: Has France Taken A Step Closer to Section 871(m) of the US Internal Revenue Code?

On 15 February 2023, the French tax authorities adopted an unprecedented interpretation of article 119 bis(2) of the French Tax Code, permitting its application to certain equity-linked financial contracts entered into by French banks in a cross-border context. The French Supreme Administrative Court ruled that the administrative guidelines were unlawful. In the authors’ opinion, that is fortunate given the doubts surrounding the legality and the relevance of these guidelines. The only way forward might be for the legislator to intervene.

Postoperative Radiotherapy and Survival in Oral Cavity Squamous Cell Carcinoma With Mandibulectomy

Oral cavity squamous cell carcinoma (SCC) tumors with mandibular invasion are upstaged to pT4a regardless of their size. Even small tumors with boney invasion, which would otherwise be classified as pT1-2, are recommended for the locally advanced treatment pathway to receive administration of postoperative radiotherapy (PORT). To evaluate the association of PORT with overall survival according to tumor size among patients who received mandibulectomy for pT4aN0 oral cavity SCC. This was a retrospective analysis using data from the US National Cancer Database from January 1, 2004, through December 31, 2019. All patients who received mandibulectomy for treatment-naive pT4aN0 oral cavity SCC with negative surgical margins were included. Data analyses were performed in January 2023 and finalized in July 2023. PORT vs no PORT. Entropy balancing was used to balance covariate moments between treatment groups. Weighted multivariable Cox proportional hazards regression was used to measure the association of PORT with overall survival associated with tumor size. Among 3268 patients with pT4aN0 oral cavity SCC (mean [SD] age, 65.9 [12.1] years; 2024 [61.9%] male and 1244 [38.1%] female), 1851 (56.6%) received PORT and 1417 (43.4%) did not receive PORT. On multivariable analysis was adjusted for age, insurance status, Charlson Comorbidity Index score, tumor site, tumor grade, tumor size, and PORT. Findings indicated that PORT was associated with improved overall survival and that this relative survival advantage trended upwards with increasing tumor size. That is, the larger the tumor, the greater the survival advantage associated with the use of PORT. For the 1068 patients with tumors greater than 4 cm, the adjusted hazard ratio (aHR) in favor of PORT was 0.63 (95% CI, 0.48-0.82); for the 1774 patients with tumors greater than 2 cm but less than or equal to 4 cm, the aHR was 0.76 (95% CI, 0.62-0.93); and for 426 patients with tumors less than 2 cm, the aHR was 0.81 (95% CI, 0.57-1.15). In this retrospective analysis of patients who received mandibulectomy for pT4aN0 oral cavity SCC, PORT was associated with improved overall survival, the benefit of which improved relatively with increasing tumor size. These findings suggest that tumor size should be considered in guidelines for PORT administration in this patient population.

Guidelines for outpatient administration of naxitamab: Experience from Atrium Health Levine Children's Hospital.

In this publication, we will share our experience of AE management, provide guidance for appropriate staffing, and the discuss the importance of patient education when treating patients with R/R HR neuroblastoma using naxitamab. Approved treatments for patients with refractory and/or relapsed (R/R) high-risk (HR) neuroblastoma are limited, and there is a high unmet need for new treatment combinations. Naxitamab is a disialoganglioside 2 (GD2)-binding antibody that was approved by the United States Food and Drug Administration in 2020 for use in combination with granulocyte-macrophage colony-stimulating factor for the treatment of patients with R/R HR neuroblastoma in the bone and/or bone marrow and who have demonstrated a partial response, minor response, or stable disease with prior therapy. The pediatric oncology team at Atrium Health Levine Children's Hospital has successfully treated several patients with naxitamab both alone and in combination with chemotherapy, with no patients requiring unplanned overnight hospitalization and few severe adverse events (AEs). To accomplish this, the team at Levine Children's Hospital established standard operating procedures for naxitamab, a therapy defined as high acuity due to the potential for acute AEs with rapid onset and that benefits from continuous monitoring by a nursing team and a dedicated provider. This will provide a practical guide for institutions offering naxitamab to their patients, and ensure successful administration of this high acuity treatment in the outpatient setting.

Association of Calcium and Vitamin D Supplements with Fractures in Persons with a Traumatic SCI.

Osteoporotic fractures occur in almost half of patients with a spinal cord injury (SCI) and are associated with significant morbidity and excess mortality. Paralyzed Veterans Administration (PVA) guidelines suggest that adequate calcium and vitamin D intake is important for skeletal health, however, the association of these supplements with osteoporotic fracture risk is unclear. To determine the association of filled prescriptions for calcium and vitamin D with fracture risk in Veterans with an SCI. The 5897 persons with a traumatic SCI of at least 2 years' duration (96% male; 4% female) included in the VSSC SCI/D Registry in FY2014 were followed from FY2014 to FY2020 for incident upper and lower extremity fractures. Filled daily prescriptions for calcium or vitamin D supplements for ≥6 months with an adherence ≥80% were examined. Filled prescriptions for calcium (hazard ratio [HR] 0.65; 95% CI, 0.54-0.78) and vitamin D (HR 0.33; 95% CI, 0.29-0.38) supplements were associated with a significantly decreased risk for incident fractures. Calcium and vitamin D supplements are associated with decreased risk of fracture, supporting PVA guidelines that calcium and vitamin D intake are important for skeletal health in persons with an SCI.

Innovative Genoceuticals in Human Gene Therapy Solutions: Challenges and Safe Clinical Trials of Orphan Gene Therapy Products.

The success of gene therapy attempts is controversial and inconclusive. Currently, it is popular among the public, the scientific community, and manufacturers of Gene Therapy Medical Products. In the absence of any remedy or treatment options available for untreatable inborn metabolic orphan or genetic diseases, cancer, or brain diseases, gene therapy treatment by genoceuticals and T-cells for gene editing and recovery remains the preferred choice as the last hope. A new concept of "Genoceutical Gene Therapy" by using orphan 'nucleic acid-based therapy' aims to introduce scientific principles of treating acquired tissue damage and rare diseases. These Orphan Genoceuticals provide new scope for the 'genodrug' development and evaluation of genoceuticals and gene products for ideal 'gene therapy' use in humans with marketing authorization application (MAA). This perspective study focuses on the quality control, safety, and efficacy requirements of using 'nucleic acid-based and human cell-based new gene therapy' genoceutical products to set scientific advice on genoceutical-based 'orphan genodrug' design for clinical trials as per Western and European guidelines. The ethical Western FDA and European EMA guidelines suggest stringent legal and technical requirements on genoceutical medical products or orphan genodrug use for other countries to frame their own guidelines. The introduction section proposes lessknown 'orphan drug-like' properties of modified RNA/DNA, human cell origin gene therapy medical products, and their transgene products. The clinical trial section explores the genoceutical sources, FDA/EMA approvals for genoceutical efficacy criteria with challenges, and ethical guidelines relating to gene therapy of specific rare metabolic, cancer and neurological diseases. The safety evaluation of approved genoceuticals or orphan drugs is highlighted with basic principles and 'genovigilance' requirements (to observe any adverse effects, side effects, developed signs/symptoms) to establish their therapeutic use. Current European Union and Food and Drug Administration guidelines continuously administer fast-track regulatory legal framework from time to time, and they monitor the success of gene therapy medical product efficacy and safety. Moreover, new ethical guidelines on 'orphan drug-like genoceuticals' are updated for biodistribution of the vector, genokinetics studies of the transgene product, requirements for efficacy studies in industries for market authorization, and clinical safety endpoints with their specific concerns in clinical trials or public use.

An Empirical Survey on the Adaption of Neoadjuvant Chemotherapy in Bladder Cancer

Introduction: The aim of the study was to determine the adaption of neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) in Germany, Austria, and Switzerland and especially underlying reasons for potential low adherence to guidelines. Methods: We conducted a non-validated survey among 336 urologic departments in Germany, Austria, and Switzerland. RedCap questionnaires were electronically distributed and included 23 items concerning the general NAC administration standards and guideline compliance in patient counseling regarding the actual treatment. Results: The return rate of the questionnaire was 19.1% (63/336). Although 45 departments (71.4%) claim to perform NAC as the standard of care, only 49% of eligible patients actually receive NAC. An advanced disease stage (≥cT3) and a high tumor volume were mentioned to support the application of NAC, whereas 35% of responders worry about deterioration of patients’ preoperative status due to NAC. Furthermore, 26.7% of respondents are concerned about the low extent of survival benefit. Conclusion: Application of NAC in eligible MIBC patients in Germany, Austria, and Switzerland remains low. Although the majority of urologic departments discuss NAC and acknowledge the need for intensified treatment in advanced disease stages, not all eligible patients will actually receive NAC before radical cystectomy.

Liquid chromatography-tandem mass spectrometry determination of bumetanide in human plasma and application to a clinical pharmacokinetic study.

Determining a drug's bioavailability and bioequivalence is important for developing and approving a drug product. The procedure supports applications for generic drug products and novel therapeutic substances, makes important decisions regarding safety and efficacy, and measures a drug's concentration in biological matrices. This study aimed to develop and validate a specific, simple, sensitive, and accurate method using liquid chromatography-tandem mass spectrometry (LC-MS) for measuring bumetanide (BUM) in human plasma. Chromatographic separation was achieved using a Hypurity C18 column (4.6× 50 mm, 5μm) under isocratic conditions, and LC-MS detected positive ionization acquisition modes. Protonated precursor to product ion transitions were observed at m/z 365.08 → 240.10 and 370.04 → 244.52 for BUM and internal standard, respectively. The linear range of BUM in plasma samples was 3.490-401.192 ng/mL. The inter-precision value ranged from 1.76% to 4.75%. The inter-accuracy value ranged from 96.46% to 99.95%. The method was adequately validated per the U.S. Food and Drug Administration guidelines, and the results were within permissible bounds. The Cmax and Tmax values were ~53.097 ± 13.537 ng/mL and 1.25 (0.67-5.00)h, respectively. The new approach showed satisfactory results for studying BUM in human plasma with potential use in pharmacokinetic and bioequivalence investigations.

Digital Therapeutics for Improving Effectiveness of Pharmaceutical Drugs and Biological Products: Preclinical and Clinical Studies Supporting Development of Drug + Digital Combination Therapies for Chronic Diseases.

Limitations of pharmaceutical drugs and biologics for chronic diseases (e.g., medication non-adherence, adverse effects, toxicity, or inadequate efficacy) can be mitigated by mobile medical apps, known as digital therapeutics (DTx). Authorization of adjunct DTx by the US Food and Drug Administration and draft guidelines on "prescription drug use-related software" illustrate opportunities to create drug + digital combination therapies, ultimately leading towards drug-device combination products (DTx has a status of medical devices). Digital interventions (mobile, web-based, virtual reality, and video game applications) demonstrate clinically meaningful benefits for people living with Alzheimer's disease, dementia, rheumatoid arthritis, cancer, chronic pain, epilepsy, depression, and anxiety. In the respective animal disease models, preclinical studies on environmental enrichment and other non-pharmacological modalities (physical activity, social interactions, learning, and music) as surrogates for DTx "active ingredients" also show improved outcomes. In this narrative review, we discuss how drug + digital combination therapies can impact translational research, drug discovery and development, generic drug repurposing, and gene therapies. Market-driven incentives to create drug-device combination products are illustrated by Humira® (adalimumab) facing a "patent-cliff" competition with cheaper and more effective biosimilars seamlessly integrated with DTx. In conclusion, pharma and biotech companies, patients, and healthcare professionals will benefit from accelerating integration of digital interventions with pharmacotherapies.

Implementasi kebijakan disiplin Pegawai Negeri Sipil di Kabupaten Minahasa

The aim of this research is to analyze the implementation of Civil Servant Discipline Policy in Minahasa Regency based on Government Regulation Number 94 of 2021 concerning Civil Servant Discipline. The research location is the Minahasa Regency Women's Empowerment and Child Protection Service. This research uses a qualitative method. The research results show that the work discipline of civil servants in the Minahasa Regency Women's Empowerment and Child Protection Service isn't yet ideal since there are still representatives who disregard the standards as per the appropriate arrangements in regards to limits on beginning and leaving available time. There are still employees who do not comprehend the Job Description in light of the Main Duties and Functions, they put off doing the work that is assigned to them, and their supervisors do not discipline them. Factors that ruin government employee discipline are administration endlessly factors from the actual workers as representative quality and mindset and absence of socialization of the execution of these administration guidelines.

Assessment and predictors of inappropriate dose of direct oral anticoagulants

Direct-Acting Oral Anticoagulants (DOACs) have revolutionized the management of Atrial Fibrillation (AF) and Venous Thromboembolism (VTE). However, recent audits reveal a significant burden of inappropriate dosages in the prescribing of direct-acting oral anticoagulants. Our aim is to identify the prevalence and predictors of such inappropriate dosing in our patients. This retrospective study was conducted from June 2016 to January 2018. Patients who received dabigatran, rivaroxaban, or apixaban for treatment of venous thromboembolism or atrial fibrillation were included. Appropriateness of direct-acting oral anticoagulants dosing was assessed using US Food and Drug Administration guidelines. Data was analyzed using IBM® SPSS Version 26. 337 patients were included, with a mean age of 62.9±18.7 years. The majority were female (196, 58.3%). Of the patients, 194 (57.6%) received apixaban, 99 (29.4%) received rivaroxaban, and 44 (13.1%) received dabigatran. A total of 242 (71.8%) patients were prescribed direct-acting oral anticoagulants appropriately. Under-dosing and over-dosing were identified in 74 (22%) and 21 (6.2%) patients, respectively. Predictors of inappropriate dosing were age greater than 75 years (OR: 2.76, 95% CI: 1.67-4.56, p<0.001) and creatinine clearance less than 50 ml/minute (OR: 0.38, 95% CI: 0.19-0.74, p: 0.005). Inappropriate dosing was significantly associated with mortality (p=0.010).One-third of our patients received an inappropriate dose of direct-acting oral anticoagulants, mostly from underdosing. Elderly age and low creatinine clearance are significant predictors of inappropriate dose administration.

Requesting conflicts of interest declarations from the European Medicines Agency: 3-year follow-up status.

We have previously described the European Medicines Agency's (EMA) and the US Food and Drug Administration's guidelines, each for a specific psychiatric indication, on how to design pivotal drug trials used in new drug applications. Here, we report on our efforts over 3years to retrieve conflicts of interest declarations from EMA. We wanted to assess potential internal industry influence judged as the proportion of guideline committee members with industry conflicts of interest. We submitted Freedom of Information requests in February 2020 to access EMA's lists of committee members (and their declared conflicts of interest) involved in drafting the 13 'Clinical efficacy and safety' guidelines available on EMA's website pertaining to psychiatric indications. In our request, we did not specify the exact EMA committees. Here, we describe the received documents and report the proportion of members with industry interests (i.e.defined as any financial industry relationship). It is a follow-up paper to our first report (http://doi.org/10.1017/S2045796021000147). After 2years and 9months (November 2022), the EMA sent us member lists and corresponding conflicts of interest declarations from the Committee for Medicinal Products for Human use (CHMP) from 2012, 2013 and 2017. These member lists pertained to 3 of the 13 requested guidelines (schizophrenia, depression and autism spectrum disorder). The 10 remaining guidelines were published before 2011 and EMA stated that they needed to require permission from their expert members (with unknown retrieval rate) and foresaw excessive workload and long wait. Therefore, we withdrew our request. The CHMPs from 2012, 2013 and 2017 had from 34 to 36 members; 39%-44% declared any interests and we judged 14%-18% as having industry interests. For the schizophrenia guideline, we identified two members with industry interests to companies who submitted feedback on the guideline. We did not receive declarations from the Central Nervous System (CNS) Working Party, the CHMP appointed expert group responsible for drafting and incorporating feedback into the guidelines. After almost 3years, we received information, which only partly addressed our request. We recommend EMA to improve transparency by publishing the author names and their corresponding conflicts of interest declarations directly in the 'Clinical efficacy and safety' guidelines and to not remove conflicts of interest declarations after 1year from their website to reduce the risk of stealth corporate influence during the development of these influential guidelines.

Barriers and facilitators for adherence to antiretroviral therapy, and strategies to address the barriers in key populations, Mumbai-A qualitative study.

Even though quantitative studies have described barriers to anti-retroviral therapy (ART), a more exploratory approach will provide in-depth information on these issues, and potential suggestions to address these issues at individual as well as structural level. We designed this qualitative study to examine the barriers and facilitators for antiretroviral therapy adherence in key population (KP) in Mumbai, India. We also wanted to understand the strategies adopted by these groups and get suggestions to improve adherence to ART. This is a qualitative analysis of seven focus group discussions (FGDs) conducted with four KP subgroups in Mumbai. We conducted two FGDs each with female sex workers (FSW), men who have sex with men (MSM), male-to-female transgendered people/Hijras (TGH) each, and one FGD with people who inject drugs (IDU). We transcribed the audio-recorded electronic records of these FGDs. We also added the notes of the observers on the group dynamics to the transcribed data. We used the Framework Approach to analyse these data. Some experiences-such as side effects to ART medicines-were common across groups. However, incarceration as a reason for stopping ART was reported by FSWs but not by other KPs. Friends and family (including Guru) are important support systems for HIV infected individuals and adherence to ART. Stigma and discrimination by community members and general community prevent regular access of ART centres and other health care facilities. Additional factors which led to missed doses were mental health issues, alcohol use, and misplacing the ART tablets during police raids or during robbery attempts at the cruising sites. Since a common source of discrimination among peers and the community was the presence of 'Green book' (or their treatment book); the key population wanted the AIDS program to change it to digital cards so that labelling one as 'HIV positive' for being seen with the book can be avoided. The qualitative study helped us explore the barriers to ART among key population and the community provided specific suggestions to address them. In addition to Key Population centric enhanced adherence counselling, some administrative guidelines and procedures may need to be altered to improve adherence to ART in these populations.

The patronage of religious tourism seen from its motivations that predict satisfaction and loyalty: The Virgin of Chaguaya in Bolivia.

This study focused on pilgrimages as part of religious tourism and aimed to achieve the following objectives: identify the main motivational factors of religious tourism focused on pilgrimages; analyze the motivational dimensions that predict satisfaction in religious tourism focused on pilgrimages; analyze the motivational dimensions that predict loyalty in religious tourism focused on pilgrimages. The study was conducted during the pilgrimage to the Virgin of Chaguaya in Bolivia. The sample consisted of 384 tourists who were surveyed on-site. The statistical techniques used included factor analysis and multiple regression. The results revealed four motivational dimensions: Tourism and Escape, Religious Experience, Belief Experience, and Shopping. Additionally, specific motivations that influence the satisfaction and loyalty of attendees at religious events such as pilgrimages have been identified, among them the "Religious Experience" and the "Belief Experience" motivational dimensions. The findings will contribute to planning and management guidelines for religious event administrators and provide information to academic literature.

Development of Root Caries Associated With the Use of Sugar‐Free Nicotine Lozenges: A Long‐Term Case Report

The authors present a case concerning an adult male patient who developed multiple sites of root caries adjacent to the area where he habitually held a sugar‐free nicotine lozenge that contained mannitol and maltodextrin. The root caries occurred despite the patient’s excellent oral hygiene, exemplary dietary habits, and clinically normal salivary flow. Between 1999 and 2008, he had only required two restorations to repair carious lesions. This patient had a 20+‐year habit of using smokeless tobacco before switching to a cessation aid nicotine lozenge in May of 2008. A full‐mouth series of radiographs taken in November 2009 revealed carious lesions on virtually every posterior tooth. The nicotine lozenge’s principal ingredients were mannitol (75.7%) and maltodextrin. According to the United States’ current Food and Drug Administration (FDA) guidelines, manufacturers can advertise these lozenges as sugar‐free. Thus, it is assumed by the public that these types of products are incapable of “causing a cavity.” However, this case report presents evidence suggesting that frequent use of sugar‐free nicotine lozenges may be associated with dental caries.

Determination of a robust headspace GC-MS/MS method for analysis of ethyl alcohol and acetaldehyde: clinical application to pharmacokinetics study.

Due to the forensic aspects of drinking and exposure to toxic substances, more sophisticated quantitative technology is needed to quantify the concentration of ethyl alcohol and acetaldehyde in the blood. In this study, we developed a headspace gas chromatography tandem mass spectrometry method that could simultaneously detect ethyl alcohol and acetaldehyde in human plasma. Through a simple preparation process, ethyl alcohol and acetaldehyde were quickly detected within 4 min, and a lower limit of quantification (LLOQ) (20 and 0.2 µg/mL) was obtained; these results confirmed the suitability of the system. According to Food and Drug Administration guidelines, the linearity (correlation coefficient > 0.9996), intraday and intraday accuracy, precision, and both short- and long-term stability and freeze-thaw stability satisfied the evaluation criteria (within 100.0 ± 15.0% and 20.0% of the LLOQ). Carryover and batch size assessment for the evaluation of the sample influence during analysis also satisfied the evaluation criteria. A valid method was applied to the pharmacokinetics study, and the plasma from 43 subjects after oral administration of the placebo or HK-GCM-H01 was analyzed. The developed analysis method for ethyl alcohol and acetaldehyde in blood could be used in various fields, such as forensics and those requiring precise quantification.

Neural tissue tolerance to synthetic dural mater graft implantation in a rabbit durotomy model.

In neurosurgical interventions, effective closure of the dura mater is essential to prevent cerebrospinal fluid leakage and minimize post-operative complications. Biodegradable synthetic materials have the potential to be used as dura mater grafts owing to their regenerative properties and low immunogenicity. This study evaluated the safety of ArtiFascia, a synthetic dura mater graft composed of poly(l-lactic-co-caprolactone acid) and poly(d-lactic-co-caprolactone acid), in a rabbit durotomy model. Previously, ArtiFascia demonstrated positive local tolerance and biodegradability in a 12-month preclinical trial. Here, specialized stains were used to evaluate potential brain damage associated with ArtiFascia use. Histochemical and immunohistochemical assessments included Luxol Fast Blue, cresyl Violet, Masson's Trichrome, neuronal nuclei,, Glial Fibrillary Acidic Protein, and ionized calcium-binding adaptor molecule 1 stains. The stained slides were graded based on the brain-specific reactions. The results showed no damage to the underlying brain tissue for either the ArtiFascia or control implants. Neither inflammation nor neuronal loss was evident, corroborating the safety of the ArtiFascia. This approach, combined with previous histopathological analyses, strengthens the safety profile of ArtiFascia and sets a benchmark for biodegradable material assessment in dura graft applications. This study aligns with the Food and Drug Administration guidelines and offers a comprehensive evaluation of the potential neural tissue effects of synthetic dura mater grafts.

Perioperative fluid and electrolyte management in surgical neonates

Neonates with surgical conditions may experience significant electrolyte abnormalities and dehydration of varying degrees. Increased awareness of perioperative hyponatremia and its associated morbidity has led to a shift in Pediatric fluid guidelines favoring the use of isotonic fluids. However, there is a lack of evidence-based guidelines for neonatal perioperative fluid administration, resulting in the extrapolation of fluid management principles from adults and children. This article reviews perioperative neonatal fluid management.

Empowering the Future: Innovative Education Strategies for Global Skills in the Context of the Golden Generation 2045

This research aims to explore the development of 21st century skills in a global context for the 2045 generation through innovative educational strategies. The study used descriptive qualitative research methods and included in-depth interviews with teachers, classroom observations and document analyses. The uniqueness of this study lies in the comprehensive mapping of the implementation of innovative strategies in a multicultural and international education environment. The results of this study highlight the success of student-centred learning approaches, integration of advanced technologies and curriculum design linked to 21st century skills. These findings contribute significantly to a deeper understanding of how innovative education can address the global challenges of the 2045 generation. In addition, this research provides a concrete picture of the dynamics and success of implementing this strategy in an international context. The novelty of this research lies in the combination of a qualitative descriptive approach and global impact, which makes a valuable contribution to the textbook literature. The practical implications of this research include specific guidelines for policy makers, administrators and education professionals who want to prepare students for a challenging future in the globalised era of 2045.

Trends in co-prescribed opioids and benzodiazepines, non-prescribed opioids and benzodiazepines, and schedule-I drugs in the United States, 2013 to 2019

Concurrent opioid and benzodiazepine users are at increased risk of overdose death, compared to opioid-only users.The objective of this study was to understand recent time trends in opioid and benzodiazepine concurrent use, misuse, and schedule-I drug use, and how these differ by age, sex and geographic region. Commercial, United States medical insurance claims data and urine drug test results from 2013 to 2019 were used to study the outcomes of concurrent use (n = 756,258), schedule-I drug use (n = 746,672) and prescription misuse (n = 452,523). Drug use outcomes were studied at quarterly time points for each year.Data analysis included joinpoint regression models to estimate quarterly drug use rates, determined by positive urine tests for corresponding drug categories, and was conducted from November 2021 through January 2022. Concurrent use decreased from 19.3% to 9.8%, misuse generally decreased from 75.6% to 55.1%, and schedule-I use increased from 8.9% to 13.8%, from 2013 to 2019. Concurrent use decreased at greater rates after 2016, after the Centers for Disease Control and Food and Drug Administration guidelines against concurrent use were released, while schedule-I use increased, notably after the 2014 hydrocodone reschedule. This indicates a potential shift from prescription use to non-prescribed drug use, where most affected groups included males, younger individuals, and those residing in Northeastern regions.Study results support public health initiatives focused on policy that increases access to multimodal pain management and substance use disorder management programs—critical steps in preventing patients from seeking non-prescribed drugs for self- medicating due to pain or addiction.