Vitamin K2 Supplementation in Hospitalised COVID-19 Patients: A Randomised Controlled Trial.

Background: In observational studies, high levels of desphospho-uncarboxylated matrix gla protein (dp-ucMGP) that result from vitamin K deficiency were consistently associated with poor clinical outcomes during COVID-19. Vitamin K-activated matrix gla protein (MGP) is required to protect against elastic fibre degradation, and a deficiency may contribute to pathology. However, intervention trials assessing the effects of vitamin K supplementation in COVID-19 are lacking. Methods: This is a single-centre, phase 2, double-blind, randomised, placebo-controlled trial investigating the effects of vitamin K2 supplementation in 40 hospitalised COVID-19 patients requiring supplemental oxygen. Individuals were randomly assigned in a 1:1 ratio to receive 999 mcg of vitamin K2-menaquinone-7 (MK-7)-or a placebo daily until discharge or for a maximum of 14 days. Dp-ucMGP, the rate of elastic fibre degradation quantified by desmosine, and hepatic vitamin K status quantified by PIVKA-II were measured. Grade 3 and 4 adverse events were collected daily. As an exploratory objective, circulating vitamin K2 levels were measured. Results: Vitamin K2 was well tolerated and did not increase the number of adverse events. A linear mixed model analysis showed that dp-ucMGP and PIVKA-II decreased significantly in subjects that received supplementation compared to the controls (p = 0.008 and p = 0.0017, respectively), reflecting improved vitamin K status. The decrease in dp-ucMGP correlated with higher plasma MK-7 levels (p = 0.015). No significant effect on desmosine was found (p = 0.545). Conclusions: These results demonstrate that vitamin K2 supplementation during COVID-19 is safe and decreases dp-ucMGP. However, the current dose of vitamin K2 failed to show a protective effect against elastic fibre degradation.

The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients.

OBJECTIVE: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine. METHODS: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity. RESULTS: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms. CONCLUSIONS: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.

The European List of Key Medicines for Medical Education: A Modified Delphi Study.

Rational prescribing is essential for the quality of health care. However, many final-year medical students and junior doctors lack prescribing competence to perform this task. The availability of a list of medicines that a junior doctor working in Europe should be able to independently prescribe safely and effectively without supervision could support and harmonize teaching and training in clinical pharmacology and therapeutics (CPT) in Europe. Therefore, our aim was to achieve consensus on such a list of medicines that are widely accessible in Europe. For this, we used a modified Delphi study method consisting of three parts. In part one, we created an initial list based on a literature search. In part two, a group of 64 coordinators in CPT education, selected via the Network of Teachers in Pharmacotherapy of the European Association for Clinical Pharmacology and Therapeutics, evaluated the accessibility of each medicine in his or her country, and provided a diverse group of experts willing to participate in the Delphi part. In part three, 463 experts from 24 European countries were invited to participate in a 2-round Delphi study. In total, 187 experts (40%) from 24 countries completed both rounds and evaluated 416 medicines, 98 of which were included in the final list. The top three Anatomical Therapeutic Chemical code groups were (1) cardiovascular system (n = 23), (2) anti-infective (n = 21), and (3) musculoskeletal system (n = 11). This European List of Key Medicines for Medical Education could be a starting point for country-specific lists and could be used for the training and assessment of CPT.

Supporting antidepressant discontinuation using mindfulness plus monitoring versus monitoring alone: A cluster randomized trial in general practice.

Discontinuing antidepressant medication (ADM) can be challenging for patients and clinicians. In the current study we investigated if Mindfulness-Based Cognitive Therapy (MBCT) added to supported protocolized discontinuation (SPD) is more effective than SPD alone to help patients discontinue ADM. This study describes a prospective, cluster-randomized controlled trial (completed). From 151 invited primary care practices in the Netherlands, 36 (24%) were willing to participate and randomly allocated to SPD+MBCT (k = 20) or SPD (k = 16). Adults using ADM > 9 months were invited by GPs to discuss tapering, followed by either MBCT+SPD, or SPD alone. Exclusion criteria included current psychiatric treatment; substance use disorder; non-psychiatric indication for ADM; attended MBCT within past 5 years; cognitive barriers. From the approximately 3000 invited patients, 276 responded, 119 participated in the interventions and 92 completed all assessments. All patients were offered a decision aid and a personalized tapering schedule (with GP). MBCT consisted of eight group sessions of 2.5 hours and one full day of practice. SPD was optional and consisted of consultations with a mental health assistant. Patients were assessed at baseline and 6, 9 and 12 months follow-up, non-blinded. In line with our protocol, primary outcome was full discontinuation of ADM within 6 months. Secondary outcomes were depression, anxiety, withdrawal symptoms, rumination, well-being, mindfulness skills, and self-compassion. Patients allocated to SPD + MBCT (n = 73) were not significantly more successful in discontinuing (44%) than those allocated to SPD (n = 46; 33%), OR 1.60, 95% CI 0.73 to 3.49, p = .24, number needed to treat = 9. Only 20/73 allocated to MBCT (27%) completed MBCT. No serious adverse events were reported. In conclusion, we were unable to demonstrate a significant benefit of adding MBCT to SPD to support discontinuation in general practice. Actual participation in patient-tailored interventions was low, both for practices and for patients. (Trial registration: ClinicalTrials.gov PRS ID: NCT03361514 registered December 2017).

External validity of an automated delirium prediction model (DEMO) and comparison to the manual VMS-questions: a retrospective cohort study.

BACKGROUND: It is estimated that one-third of delirium cases in hospitals could be prevented with appropriate interventions. In Dutch hospitals a manual instrument (VMS-questions) is used to identify patients at-risk for delirium. Delirium Model (DEMO) is an automated model which could support delirium prevention more efficiently. However, it has not been validated beyond the hospital it was developed in. AIM: To externally validate the DEMO and compare its performance to the VMS-questions. METHOD: A retrospective cohort study between July and December 2018 was conducted. Delirium cases were identified through a chart review, and the VMS-questions were extracted from the electronic health records. The DEMO was validated in patients ≥ 60 years, and a comparison with the VMS-questions was made in patients ≥ 70 years. RESULTS: In total 1,345 admissions were included. The DEMO predicted 59 out of 75 delirium cases (sensitivity 0.79, 95% CI = 0.68-0.87; specificity 0.75, 95% CI = 0.72-0.77). Compared to the VMS-questions, the DEMO showed a lower specificity (0.64 vs. 0.72; p < 0.001) and a comparable sensitivity (0.83 vs. 0.80; p = 0.56). The VMS-questions were missing in 20% of admissions, in which the DEMO correctly predicted 10 of 12 delirium cases. CONCLUSION: The DEMO showed acceptable performance for delirium prediction. Overall the DEMO predicted more delirium cases because the VMS-questions were missing in 20% of admissions. This study shows that automated instruments such as DEMO could play a key role in the efficient and timely deployment of measures to prevent delirium.

The impact of a summative national prescribing assessment and curriculum type on the development of the prescribing competence of junior doctors.

PURPOSE: The primary aim of this study was to investigate the effect of including the Dutch National Pharmacotherapy Assessment (DNPA) in the medical curriculum on the level and development of prescribing knowledge and skills of junior doctors. The secondary aim was to evaluate the relationship between the curriculum type and the prescribing competence of junior doctors. METHODS: We re-analysed the data of a longitudinal study conducted in 2016 involving recently graduated junior doctors from 11 medical schools across the Netherlands and Belgium. Participants completed three assessments during the first year after graduation (around graduation (+ / - 4 weeks), and 6 months, and 1 year after graduation), each of which contained 35 multiple choice questions (MCQs) assessing knowledge and three clinical case scenarios assessing skills. Only one medical school used the DNPA in its medical curriculum; the other medical schools used conventional means to assess prescribing knowledge and skills. Five medical schools were classified as providing solely theoretical clinical pharmacology and therapeutics (CPT) education; the others provided both theoretical and practical CPT education (mixed curriculum). RESULTS: Of the 1584 invited junior doctors, 556 (35.1%) participated, 326 (58.6%) completed the MCQs and 325 (58.5%) the clinical case scenarios in all three assessments. Junior doctors whose medical curriculum included the DNPA had higher knowledge scores than other junior doctors (76.7% [SD 12.5] vs. 67.8% [SD 12.6], 81.8% [SD 11.1] vs. 76.1% [SD 11.1], 77.0% [12.1] vs. 70.6% [SD 14.0], p < 0.05 for all three assessments, respectively). There was no difference in skills scores at the moment of graduation (p = 0.110), but after 6 and 12 months junior doctors whose medical curriculum included the DNPA had higher skills scores (both p < 0.001). Junior doctors educated with a mixed curriculum had significantly higher scores for both knowledge and skills than did junior doctors educated with a theoretical curriculum (p < 0.05 in all assessments). CONCLUSION: Our findings suggest that the inclusion of the knowledge focused DNPA in the medical curriculum improves the prescribing knowledge, but not the skills, of junior doctors at the moment of graduation. However, after 6 and 12 months, both the knowledge and skills were higher in the junior doctors whose medical curriculum included the DNPA. A curriculum that provides both theoretical and practical education seems to improve both prescribing knowledge and skills relative to a solely theoretical curriculum.

Opioid Analgesics after Bariatric Surgery: A Scoping Review to Evaluate Physiological Risk Factors for Opioid-Related Harm.

The persisting use of opioids following bariatric surgery has emerged as a prevalent complication, heightening the probability of opioid-related harm (ORM), such as opioid-related fatalities and prescription opioid use disorder (OUD). A comprehensive review of PubMed literature from 1990 to 2023 was conducted to pinpoint physiological influences on postoperative ORM. As a result, we found that patients undertaking bariatric operations often exhibit an inherently higher risk for substance use disorders, likely attributable to genetic predisposition and related neurobiological changes that engender obesity and addiction-like tendencies. Furthermore, chronic pain is a common post-bariatric surgery complaint, and the surgical type impacts opioid needs, with increased long-term opioid use after surgeries. Additionally, the subjective nature of pain perception in patients with obesity can distort pain reporting and the corresponding opioid prescription both before and after surgery. Furthermore, the postoperative alterations to the gastrointestinal structure can affect the microbiome and opioid absorption rates, resulting in fluctuating systemic exposure to orally ingested opioids. The prospect of ORM development post-bariatric surgery appears amplified due to a preexisting susceptibility to addictive habits, surgically induced pain, modified gut-brain interaction and pain management and the changed pharmacokinetics post-surgery. Further research is warranted to clarify these potential risk variables for ORM, specifically OUD, in the bariatric population.

[A DNA medication pass for everyone?] / Iedereen een DNA-medicatiepas?

Pharmacogenetics holds the promise of personalized medicine, resulting in higher effectiveness and fewer adverse effects. Yet, the clinical benefit of a pre-emptive pharmacogenetic test has not been demonstrated rigorously. Recently an open-label real-world implementation study has been published, in which patients were randomized to either genotype-informed treatment (based on a 12-gene pharmacogenetic panel) or standard treatment. The study shows that genotype-informed prescription of different types of medication, i.e., opioids, anticoagulants and antidepressants, leads to a 30% reduction of clinically relevant adverse effects. This result is promising and indicates that genotype-informed treatment improves medication safety. Unfortunately, the influence of genotype-informed treatment on the balance between effectiveness and adverse effects could not be assessed and cost-effectiveness data are pending. Hence, a pharmacogenetic panel and a DNA medication pass for everyone are on the horizon, but not yet there.

Inhaled Δ9-tetrahydrocannabinol does not enhance oxycodone-induced respiratory depression: randomised controlled trial in healthy volunteers.

BACKGROUND: In humans, the effect of cannabis on ventilatory control is poorly studied, and consequently, the effect of Δ9-tetrahydrocannabinol (THC) remains unknown, particularly when THC is combined with an opioid. We studied the effect of THC on breathing without and with oxycodone pretreatment. We hypothesised that THC causes respiratory depression, which is amplified when THC and oxycodone are combined. METHODS: In this randomised controlled crossover trial, healthy volunteers were administered inhaled Bedrocan® 100 mg (Bedrocan International B.V., Veendam, The Netherlands), a pharmaceutical-grade high-THC cannabis variant (21.8% THC; 0.1% cannabidiol), after placebo or oral oxycodone 20 mg pretreatment; THC was inhaled 1.5 and 4.5 h after placebo or oxycodone intake. The primary endpoint was isohypercapnic ventilation at an end-tidal Pco2 of 55 mm Hg or 7.3 kPa (VE55), measured at 1-h intervals for 7 h after placebo/oxycodone intake. RESULTS: In 18 volunteers (age 22 yr [3]; 9 [50%] female), oxycodone produced a 30% decrease in VE55, whereas placebo was without effect on VE55. The first cannabis inhalation resulted in VE55 changing from 20.3 (3.1) to 23.8 (2.4) L min-1 (P=0.06) after placebo, and from 11.8 (2.8) to 13.0 (3.9) L min-1 (P=0.83) after oxycodone. The second cannabis inhalation also had no effect on VE55, but slightly increased sedation. CONCLUSIONS: In humans, THC has no effect on ventilatory control after placebo or oxycodone pretreatment. CLINICAL TRIAL REGISTRATION: 2021-000083-29 (EU Clinical Trials Register.).

Are psychedelics the answer to chronic pain: A review of current literature.

AIMS: We aim to provide an evidence-based overview of the use of psychedelics in chronic pain, specifically LSD and psilocybin. CONTENT: Chronic pain is a common and complex problem, with an unknown etiology. Psychedelics like lysergic acid diethylamide (LSD) and psilocybin, may play a role in the management of chronic pain. Through activation of the serotonin-2A (5-HT2A) receptor, several neurophysiological responses result in the disruption of functional connections in brain regions associated with chronic pain. Healthy reconnections can be made through neuroplastic effects, resulting in sustained pain relief. However, this process is not fully understood, and evidence of efficacy is limited and of low quality. In cancer and palliative related pain, the analgesic potential of psychedelics was established decades ago, and the current literature shows promising results on efficacy and safety in patients with cancer-related psychological distress. In other areas, patients suffering from severe headache disorders like migraine and cluster headache who have self-medicated with psychedelics report both acute and prophylactic efficacy of LSD and psilocybin. Randomized control trials are now being conducted to study the effects in cluster headache Furthermore, psychedelics have a generally favorable safety profile especially when compared to other analgesics like opioids. In addition, psychedelics do not have the addictive potential of opioids. IMPLICATIONS: Given the current epidemic use of opioids, and that patients are in desperate need of an alternative treatment, it is important that further research is conducted on the efficacy of psychedelics in chronic pain conditions.

Cannabis-opioid interaction in the treatment of fibromyalgia pain: an open-label, proof of concept study with randomization between treatment groups: cannabis, oxycodone or cannabis/oxycodone combination-the SPIRAL study.

BACKGROUND: Opioids continue to be widely prescribed for chronic noncancer pain, despite the awareness that opioids provide only short-time pain relief, lead to dose accumulation, have numerous adverse effects, and are difficult to wean. As an alternative, we previously showed advantages of using pharmaceutical-grade cannabis in a population of chronic pain patients with fibromyalgia. It remains unknown whether combining an opioid with pharmaceutical-grade cannabis has advantages, such as fewer side effects from lesser opioid consumption in chronic pain. METHODS: Trial design: a single-center, randomized, three-arm, open-label, exploratory trial. Trial population: 60 patients with fibromyalgia according to the 2010 definition of the American College of Rheumatologists. INTERVENTION: Patients will be randomized to receive up to 4 daily 5 mg oral oxycodone sustained release (SR) tablet, up to 5 times 150 mg inhaled cannabis (Bediol®, containing 6.3% Δ9-tetrahydrocannabinol and 8% cannabidiol), or the combination of both treatments. Treatment is aimed at self-titration with the daily maximum doses given. Treatment will continue for 6 weeks, after which there is a 6-week follow-up period. Main trial endpoint: The number of side effects observed during the course of treatment using a composite adverse effect score that includes the following 10 symptoms: dizziness (when getting up), sleepiness, insomnia, headache, nausea, vomiting, constipation, drug high, hallucinations, and paranoia. Secondary and tertiary endpoints include pain relief and number of oxycodone doses and cannabis inhalations. DISCUSSION: The trial is designed to determine whether self-titration of oxycodone and cannabis will reduce side effects in chronic pain patients with fibromyalgia. TRIAL REGISTRATION {2A AND 2B}: EU trial register 2019-001861-33, URL https://www.clinicaltrialsregister.eu , on July 17, 2019; World Health Organization International Clinical Trials Research Platform NL7902, URL https://trialsearch.who.int , on July 26, 2019.

The Dutch list of essential drugs for undergraduate medical education: A modified Delphi study.

AIMS: Prescribing errors among junior doctors are common in clinical practice because many lack prescribing competence after graduation. This is in part due to inadequate education in clinical pharmacology and therapeutics (CP&T) in the undergraduate medical curriculum. To support CP&T education, it is important to determine which drugs medical undergraduates should be able to prescribe safely and effectively without direct supervision by the time they graduate. Currently, there is no such list with broad-based consensus. Therefore, the aim was to reach consensus on a list of essential drugs for undergraduate medical education in the Netherlands. METHODS: A two-round modified Delphi study was conducted among pharmacists, medical specialists, junior doctors and pharmacotherapy teachers from all eight Dutch academic hospitals. Participants were asked to indicate whether it was essential that medical graduates could prescribe specific drugs included on a preliminary list. Drugs for which ≥80% of all respondents agreed or strongly agreed were included in the final list. RESULTS: In all, 42 (65%) participants completed the two Delphi rounds. A total of 132 drugs (39%) from the preliminary list and two (3%) newly proposed drugs were included. CONCLUSIONS: This is the first Delphi consensus study to identify the drugs that Dutch junior doctors should be able to prescribe safely and effectively without direct supervision. This list can be used to harmonize and support the teaching and assessment of CP&T. Moreover, this study shows that a Delphi method is suitable to reach consensus on such a list, and could be used for a European list.

Teaching resources for the European Open Platform for Prescribing Education (EurOP2E)-a nominal group technique study.

The European Open Platform for Prescribing Education (EurOP2E) seeks to improve and harmonize European clinical pharmacology and therapeutics (CPT) education by facilitating international collaboration and sharing problem-based, online, open educational resources. The COVID-19 pandemic forced teachers to switch to virtual modalities, highlighting the need for high-quality online teaching materials. The goal of this study was to establish the online problem-based teaching resources needed to sustain prescribing education during the pandemic and thereafter. A nominal group technique study was conducted with prescribing teachers from 15 European countries. Results were analyzed through thematic analysis. In four meetings, 20 teachers from 15 countries proposed and ranked 35 teaching materials. According to the participants, the most necessary problem-based-online teaching materials related to three overarching themes. Related to learning outcomes for CPT, participants proposed creating prescription scenarios, including materials focusing on background knowledge and resources on personalized medicine and topical/ethical issues such as the prescription's impact on planetary health. Second, related to teaching, they proposed online case discussions, gamification and decision support systems. Finally, in relation to faculty development, they recommend teacher courses, a repository of reusable exam questions and harmonized formularies. Future work will aim to collaboratively produce such materials.

Buprenorphine/naloxone versus methadone opioid rotation in patients with prescription opioid use disorder and chronic pain: study protocol for a randomized controlled trial.

BACKGROUND: Opioids are effective in pain-management, but long-term opioid users can develop prescription opioid use disorder (OUD). One treatment strategy in patients with OUD is rotating from a short-acting opioid to a long-acting opioid (buprenorphine/naloxone (BuNa) or methadone). Both BuNa and methadone have been shown to be effective strategies in patients with OUD reducing opioid misuse, however data on head-to-head comparison in patients with chronic non-malignant pain and prescription OUD are limited. METHODS: This two-armed open-label, randomized controlled trial aims to compare effectiveness between BuNa and methadone in patients with chronic non-malignant with prescription OUD (n = 100). Participants receive inpatient rotation to either BuNa or methadone with a flexible dosing regimen. The primary outcome is opioid misuse 2 months after rotation. Secondary outcomes include treatment compliance, side effects, analgesia, opioid craving, quality of life, mood symptoms, cognitive and physical functioning over 2- and 6 months follow-up. Linear mixed model analysis will be used to evaluate change in outcome parameters over time between the treatment arms. DISCUSSION: This is one of the first studies comparing buprenorphine/naloxone and methadone for treating prescription OUD in a broad patient group with chronic non-malignant pain. Results may guide future treatment for patients with chronic pain and prescription OUD. Trial registration https://www.trialregister.nl/ , NL9781.

Polypharmacy, comorbidity and frailty: a complex interplay in older patients at the emergency department.

PURPOSE: Older adults at the emergency department (ED) with polypharmacy, comorbidity, and frailty are at risk of adverse health outcomes. We investigated the association of polypharmacy with adverse health outcomes, in relation to comorbidity and frailty. METHODS: This is a prospective cohort study in ED patients ≥ 70 years. Non-polypharmacy was defined as 0-4 medications, polypharmacy 5-9 and excessive polypharmacy ≥ 10. Comorbidity was classified by the Charlson comorbidity index (CCI). Frailty was defined by the Identification of Seniors At Risk-Hospitalized Patients (ISAR-HP) score. The primary outcome was 3-month mortality. Secondary outcomes were readmission to an ED/hospital ward and a self-reported fall < 3 months. The association between polypharmacy, comorbidity and frailty was analyzed by logistic regression. RESULTS: 881 patients were included. 43% had polypharmacy and 18% had excessive polypharmacy. After 3 months, 9% died, 30% were readmitted, and 21% reported a fall. Compared with non-polypharmacy, the odds ratio (OR) for mortality ranged from 2.62 (95% CI 1.39-4.93) in patients with polypharmacy to 3.92 (95% CI 1.95-7.90) in excessive polypharmacy. The OR weakened after adjustment for comorbidity: 1.80 (95% CI 0.92-3.52) and 2.32 (95% CI 1.10-4.90). After adjusting for frailty, the OR weakened to 2.10 (95% CI 1.10-4.00) and OR 2.40 (95% CI 1.15-5.02). No significant association was found for readmission or self-reported fall. CONCLUSIONS: Polypharmacy is common in older patients at the ED. Polypharmacy, and especially excessive polypharmacy, is associated with an increased risk of mortality. The observed association is complex given the confounding effect of comorbidity and frailty.

Do we become better prescribers after graduation: A 1-year international follow-up study among junior doctors.

AIM: The aim of this study was to investigate how the prescribing knowledge and skills of junior doctors in the Netherlands and Belgium develop in the year after graduation. We also analysed differences in knowledge and skills between surgical and nonsurgical junior doctors. METHODS: This international, multicentre (n = 11), longitudinal study analysed the learning curves of junior doctors working in various specialties via three validated assessments at about the time of graduation, and 6 months and 1 year after graduation. Each assessment contained 35 multiple choice questions (MCQs) on medication safety (passing grade ≥85%) and three clinical scenarios. RESULTS: In total, 556 junior doctors participated, 326 (58.6%) of whom completed the MCQs and 325 (58.5%) the clinical case scenarios of all three assessments. Mean prescribing knowledge was stable in the year after graduation, with 69% (SD 13) correctly answering questions at assessment 1 and 71% (SD 14) at assessment 3, whereas prescribing skills decreased: 63% of treatment plans were considered adequate at assessment 1 but only 40% at assessment 3 (P < .001). While nonsurgical doctors had similar learning curves for knowledge and skills as surgical doctors (P = .53 and P = .56 respectively), their overall level was higher at all three assessments (all P < .05). CONCLUSION: These results show that junior doctors' prescribing knowledge and skills did not improve while they were working in clinical practice. Moreover, their level was under the predefined passing grade. As this might adversely affect patient safety, educational interventions should be introduced to improve the prescribing competence of junior doctors.

Corrigendum: Effects of Vitamin D and K on Interleukin-6 in COVID-19.

[This corrects the article DOI: 10.3389/fnut.2021.761191.].