Original COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters.

Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.

Immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV in the Netherlands.

OBJECTIVE: We evaluated the immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV (PWH). DESIGN: Prospective observational cohort study. METHODS: PWH aged ≥45 years received Wuhan-BA.1 mRNA-1273.214 and those < 45 years Wuhan-BA.1 BNT162b2. Participants were propensity score-matched 1:2 to people without HIV (non-PWH) by age, primary vaccine platform (mRNA-based or vector-based), number of prior COVID-19 boosters and SARS-CoV-2 infections, and spike (S1)-specific antibodies on the day of booster administration. The primary endpoint was the geometric mean ratio (GMR) of ancestral S1-specific antibodies from day 0 to 28 in PWH compared to non-PWH. Secondary endpoints included humoral responses, T-cell responses, and cytokine responses up to 180 days post-vaccination. RESULTS: Forty PWH received mRNA-1273.214 (N = 35) or BNT162b2 (N = 5) following mRNA-based (N = 29) or vector-based (N = 11) primary vaccination. PWH were predominantly male (87% vs 26% of non-PWH) and median 57 years (interquartile range [IQR] 53-59). Their median CD4+ T-cell count was 775 (IQR 511-965) and the plasma HIV-RNA load was < 50 copies/mL in 39/40. The GMR of S1-specific antibodies by 28 days post-vaccination was comparable between PWH (4.48, 95% confidence interval [CI] 3.24-6.19) and non-PWH (4.07, 95% CI 3.42-4.83). S1-specific antibody responses were comparable between PWH and non-PWH up to 180 days, and T-cell responses up to 90 days post-vaccination. IFN-γ, IL-2, and IL-4 cytokine concentrations increased 28 days post-vaccination in PWH. CONCLUSION: A bivalent BA.1 booster vaccine was immunogenic in well-treated PWH, eliciting comparable humoral responses to non-PWH. However, T-cell responses waned faster after 90 days in PWH compared to non-PWH.

Human resource management at the intensive care unit: A pragmatic review and future research agenda for building a learning health system.

Recently, the importance of efficient and effective health care has been recognized, especially during the acute phase of the Coronavirus Disease-2019 (COVID-19) pandemic. Intensive care units (ICUs) have faced an immense workload, with massive numbers of patients being treated in a very short period of time. In general, ICUs are required to deliver high-quality care at all times during the year. At the same time, high-quality organizational goals may not be aligned with the interests, motivation, and development of individual staff members (eg, nurses, and doctors). For management of the ICU, it is important to balance the organizational goals and development of the staff members ("their human capital"), usually referred to as human resource management. Although many studies have considered this area, no holistic view of the topic has been presented. Such a holistic view may help leadership and/or other stakeholders at the ICU to design a better learning health system. This pragmatic review aims to provide a conceptual model for the management of ICUs. Future research may also use this conceptual model for studying important factors for designing and understanding human resources in an ICU.

Prices of Orphan Drugs in Four Western European Countries Before and After Market Exclusivity Expiry: A Cross-Country Comparison of List Prices and Purchase Prices.

BACKGROUND: Increasing pharmaceutical expenditure challenges the sustainability and accessibility of healthcare systems across Europe. Confidentiality restraints hinder assessment of actual prices of Orphan Medicinal Products (OMPs). Hence, we assessed the real prices of brand-name OMPs around market exclusivity expiry (MEE). OBJECTIVE: We aimed to explore developments in published list prices (LPs) and confidential hospital purchase prices (PPs) of brand-name OMPs relative to their market exclusivity status in Western European countries with similar GDPs. METHODS: We analyzed LPs and PPs of 13 selected OMPs purchased by university hospitals in Western European countries between 2000 and 2020. For confidentially reasons, proportions were used, with the Dutch LPs of the selected OMPs at the year of MEE serving as reference values. PPs included pre-purchase discounts. Rebates were not considered. RESULTS: Data were analyzed from hospitals in Denmark (DK) (n = 1), France (FR) (n = 1), Germany (DE) (n = 2), and the Netherlands (NL) (n = 1). Average LPs and PPs of included OMPs dropped gradually but limited over time, with no explicit price drop after MEE. LP levels differed more per country than PP levels: LP range before MEE was 164% (DE)-101% (FR) and after MEE was 135% (DE)-82% (FR); PP range before MEE was 150% (DE)-102% (FR) and after MEE was 107% (DE)-80% (FR). Overall differences between LPs and PPs were < 3% in all countries, except for Denmark. CONCLUSION: No evident price drops of included brand-name OMPs were observed around MEE and differences in purchase prices are modest in the selected Western European countries. Results were not subject to significance testing. More robust data are needed to strengthen negotiations with suppliers.

Immunogenicity of bivalent omicron (BA.1) booster vaccination after different priming regimens in health-care workers in the Netherlands (SWITCH ON): results from the direct boost group of an open-label, multicentre, randomised controlled trial.

BACKGROUND: Bivalent mRNA-based COVID-19 vaccines encoding the ancestral and omicron spike (S) protein were developed as a countermeasure against antigenically distinct SARS-CoV-2 variants. We aimed to assess the (variant-specific) immunogenicity and reactogenicity of mRNA-based bivalent omicron (BA.1) vaccines in individuals who were primed with adenovirus-based or mRNA-based vaccines encoding the ancestral spike protein. METHODS: We analysed results of the direct boost group of the SWITCH ON study, an open-label, multicentre, randomised controlled trial. Health-care workers from four academic hospitals in the Netherlands aged 18-65 years who had completed a primary COVID-19 vaccination regimen and received one booster of an mRNA-based vaccine, given no later than 3 months previously, were eligible. Participants were randomly assigned (1:1) using computer software in block sizes of 16 and 24 to receive an omicron BA.1 bivalent booster straight away (direct boost group) or a bivalent omicron BA.5 booster, postponed for 90 days (postponed boost group), stratified by priming regimen. The BNT162b2 OMI BA.1 boost was given to participants younger than 45 years, and the mRNA-1273.214 boost was given to participants 45 years or older, as per Dutch guidelines. The direct boost group, whose results are presented here, were divided into four subgroups for analysis: (1) Ad26.COV2.S (Johnson & Johnson) prime and BNT162b2 OMI BA.1 (BioNTech-Pfizer) boost (Ad/P), (2) mRNA-based prime and BNT162b2 OMI BA.1 boost (mRNA/P), (3) Ad26.COV2.S prime and mRNA-1273.214 (Moderna) boost (Ad/M), and (4) mRNA-based prime and mRNA-1273.214 boost (mRNA/M). The primary outcome was fold change in S protein S1 subunit-specific IgG antibodies before and 28 days after booster vaccination. The primary outcome and safety were assessed in all participants except those who withdrew, had a SARS-CoV-2 breakthrough infection, or had a missing blood sample at day 0 or day 28. This trial is registered with ClinicalTrials.gov, NCT05471440. FINDINGS: Between Sept 2 and Oct 4, 2022, 219 (50%) of 434 eligible participants were randomly assigned to the direct boost group; 187 participants were included in the primary analyses; exclusions were mainly due to SARS-CoV-2 infection between days 0 and 28. From the 187 included participants, 138 (74%) were female and 49 (26%) were male. 42 (22%) of 187 participants received Ad/P and 44 (24%) mRNA/P (those aged <45 years), and 45 (24%) had received Ad/M and 56 (30%) mRNA/M (those aged ≥45 years). S1-specific binding antibody concentrations increased 7 days after bivalent booster vaccination and remained stable over 28 days in all four subgroups (geometric mean ratio [GMR] between day 0 and day 28 was 1·15 [95% CI 1·12-1·19] for the Ad/P group, 1·17 [1·14-1·20] for the mRNA/P group, 1·20 [1·17-1·23] for the Ad/M group, and 1·16 [1·13-1·19] for the mRNA/M group). We observed no significant difference in the GMR between the Ad/P and mRNA/P groups (p=0·51). The GMR appeared to be higher in the Ad/M group than in the mRNA/M group, but was not significant (p=0·073). Most side-effects were mild to moderate in severity and resolved within 48 h in most individuals. INTERPRETATION: Booster vaccination with mRNA-1273.214 or BNT162b2 OMI BA.1 in adult healthcare workers resulted in a rapid recall of humoral and cellular immune responses independent of the priming regimen. Monitoring of SARS-CoV-2 immunity at the population level, and simultaneously antigenic drift at the virus level, remains crucial to assess the necessity and timing of COVID-19 variant-specific booster vaccinations. FUNDING: The Netherlands Organization for Health Research and Development (ZonMw).

Digital Outcome Measurement to Improve Care for Patients With Immune-Mediated Inflammatory Diseases: Protocol for the IMID Registry.

BACKGROUND: Despite enormous clinical improvements, due to better management strategies and the availability of biologicals, immune-mediated inflammatory diseases (IMIDs) still have a significant impact on patients' lives. To further reduce disease burden, provider- as well as patient-reported outcomes (PROs) should be taken into account during treatment and follow-up. Web-based collection of these outcomes generates valuable repeated measurements, which could be used (1) in daily clinical practice for patient-centered care, including shared decision-making; (2) for research purposes; and (3) as an essential step toward the implementation of value-based health care (VBHC). Our ultimate goal is that our health care delivery system is completely aligned with the principles of VBHC. For aforementioned reasons, we implemented the IMID registry. OBJECTIVE: The IMID registry is a digital system for routine outcome measurement that mainly includes PROs to improve care for patients with IMIDs. METHODS: The IMID registry is a longitudinal observational prospective cohort study within the departments of rheumatology, gastroenterology, dermatology, immunology, clinical pharmacy, and outpatient pharmacy of the Erasmus MC, the Netherlands. Patients with the following diseases are eligible for inclusion: inflammatory arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, uveitis, Behçet disease, sarcoidosis, and systemic vasculitis. Generic and disease-specific (patient-reported) outcomes, including adherence to medication, side effects, quality of life, work productivity, disease damage, and activity, are collected from patients and providers at fixed intervals before and during outpatient clinic visits. Data are collected and visualized through a data capture system, which is linked directly to the patients' electronic health record, which not only facilitates a more holistic care approach, but also helps with shared decision-making. RESULTS: The IMID registry is an ongoing cohort with no end date. Inclusion started in April 2018. From start until September 2022, a total of 1417 patients have been included from the participating departments. The mean age at inclusion was 46 (SD 16) years, and 56% of the patient population is female. The average percentage of filled out questionnaires at baseline is 84%, which drops to 72% after 1 year of follow-up. This decline may be due to the fact that the outcomes are not always discussed during the outpatient clinic visit or because the questionnaires were sometimes forgotten to set out. The registry is also used for research purposes and 92% of the patients with IMIDs gave informed consent to use their data for that. CONCLUSIONS: The IMID registry is a web-based digital system that collects provider- and PROs. The collected outcomes are used to improve care for the individual patient with an IMID and facilitate shared decision-making, and they are also used for research purposes. The measurement of these outcomes is an essential step toward the implementation of VBHC. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/43230.

Clinical Decision Support Systems in Hospitalized Older Patients: An Exploratory Analysis in a Real-Life Clinical Setting.

BACKGROUND: Inappropriate prescribing is associated with negative patient outcomes. In hospitalized patients, the use of Clinical Decision Support Systems (CDSSs) may reduce inappropriate prescribing and thereby improve patient-related outcomes. However, recently published large clinical trials (OPERAM and SENATOR) have shown negative results on the use of CDSSs and patient outcomes and strikingly low acceptance of recommendations. OBJECTIVE: The purpose of the present study was to investigate the use of a CDSS in a real-life clinical setting of hospitalized older patients. As such, we report on the real-life pattern of this in-hospital implemented CDSS, including (i) whether generated alerts were resolved; (ii) whether a recorded action by the pharmacist led to an improved number of resolved alerts; and (iii) the natural course of generated alerts, in particular of those in the non-intervention group; as these data are largely lacking in current studies. METHODS: Hospitalized patients, aged 60 years and older, admitted to Zuyderland Medical Centre, the Netherlands, in 2018 were included. The evaluation of the CDSS was investigated using a database used for standard care. Alongside demographic and clinical data, we also collected the total numbers of CDSS alerts, the number of alerts 'handled' by the pharmacist, those that resulted in an action by the pharmacist, and finally the outcome of the alerts at day 1 and day 3 after the alert was generated. RESULTS: A total of 3574 unique hospitalized patients, mean age 76.7 (SD 8.3) years and 53% female, were included. From these patients, 8073 alerts were generated, of which 7907 (97.9% of total) were handled by the pharmacist (day 1). In 51.6% of the alerts handled by the pharmacist, an action was initiated, resulting in 36.1% of the alerts resolved after day 1, compared with 27.3% if the pharmacist did not perform an action (p < 0.001). On day 3, in 52.6% of the alerts an action by the pharmacist was initiated, resulting in 62.4% resolved alerts, compared with 48.0% when no action was performed (p < 0.001). In the category renal function, the percentages differed significantly between an action versus no action of the pharmacist at day 1 and at day 3 (16.6% vs 10.6%, p < 0.001 [day 1]; 29.8% vs 19.4%, p < 0.001 [day 3]). CONCLUSION: This study demonstrates the pattern and natural course of clinical alerts of an in-hospital implemented CDSS in a real-life clinical setting of hospitalized older patients. Besides the already known beneficial effect of actions by pharmacists, we have also shown that many alerts become resolved without any specific intervention. As such, our study provides an important insight into the spontaneous course of resolved alerts, since these data are currently lacking in the literature.

Impact of the First SARS-CoV-2 Lockdown on Adherence to Biological Treatment in Patients with Immune-Mediated Inflammatory Diseases in the Netherlands.

Purpose: During the SARS-CoV-2 pandemic, national and international societies have recommended continuing biological agents in patients with immune-mediated inflammatory diseases (IMID) in the absence of SARS-CoV-2 symptoms. However, adherence to biological treatment might decrease, because these recommendations contradict patients' beliefs. Especially an increased concern about side effects could have influenced the adherence to biological treatment during the first lockdown. The primary objective was to investigate the impact of the first SARS-CoV-2 lockdown on adherence to biological treatment in IMID patients. Patients and Methods: In this prospective cohort study, IMID patients who received a biological agent before and during the first SARS-CoV-2 lockdown (March 2020- June 2020) were included. Patients were excluded if they did not complete the medication adherence report scale-5 (MARS-5) questionnaire at ≥1 visit before the lockdown and ≥1 visit during the lockdown. Adherence to biological treatment was measured with the MARS-5 and Medication Possession Ratio (MPR). Results: We included 157 IMID patients. The percentage of adherent patients, defined as MARS-5 score >21, was significantly lower during the lockdown compared to the period before the lockdown (88.5% vs 84.1%, p<0.001). Additionally, the overall percentage of adherent patients during the lockdown based on the MPR ≥90% was significantly lower compared to adherence based upon the MARS-5 (65.1% vs 84.1%, p<0.001). Conclusion: This study showed that the first SARS-CoV-2 lockdown negatively impacts adherence to biological treatment in IMID patients. Therefore, treating physicians should be aware of this problem to minimize the potential harmful effects of non-adherence.

Durability of Immune Responses After Boosting in Ad26.COV2.S-Primed Healthcare Workers.

The emergence of SARS-CoV-2 variants raised questions regarding the durability of immune responses after homologous or heterologous boosters after Ad26.COV2.S-priming. We found that SARS-CoV-2-specific binding antibodies, neutralizing antibodies, and T cells are detectable 5 months after boosting, although waning of antibodies and limited cross-reactivity with Omicron BA.1 was observed.

Ad26.COV2.S priming provided a solid immunological base for mRNA-based COVID-19 booster vaccination.

The emergence of novel SARS-CoV-2 variants led to the recommendation of booster vaccinations after Ad26.COV2.S priming. It was previously shown that heterologous booster vaccination induces high antibody levels, but how heterologous boosters affect other functional aspects of the immune response remained unknown. Here, we performed immunological profiling of Ad26.COV2.S-primed individuals before and after homologous or heterologous (mRNA-1273 or BNT162b2) booster. Booster vaccinations increased functional antibodies targeting ancestral SARS-CoV-2 and emerging variants. Especially heterologous booster vaccinations induced high levels of functional antibodies. In contrast, T-cell responses were similar in magnitude following homologous or heterologous booster vaccination and retained cross-reactivity towards variants. Booster vaccination led to a minimal expansion of SARS-CoV-2-specific T-cell clones and no increase in the breadth of the T-cell repertoire. In conclusion, we show that Ad26.COV2.S priming vaccination provided a solid immunological base for heterologous boosting, increasing humoral and cellular responses targeting emerging variants of concern.

Divergent SARS-CoV-2 Omicron-reactive T and B cell responses in COVID-19 vaccine recipients.

The severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is spreading rapidly, even in vaccinated individuals, raising concerns about immune escape. Here, we studied neutralizing antibodies and T cell responses targeting SARS-CoV-2 D614G [wild type (WT)] and the Beta, Delta, and Omicron variants of concern in a cohort of 60 health care workers after immunization with ChAdOx-1 S, Ad26.COV2.S, mRNA-1273, or BNT162b2. High binding antibody levels against WT SARS-CoV-2 spike (S) were detected 28 days after vaccination with both mRNA vaccines (mRNA-1273 or BNT162b2), which substantially decreased after 6 months. In contrast, antibody levels were lower after Ad26.COV2.S vaccination but did not wane. Neutralization assays showed consistent cross-neutralization of the Beta and Delta variants, but neutralization of Omicron was significantly lower or absent. BNT162b2 booster vaccination after either two mRNA-1273 immunizations or Ad26.COV2 priming partially restored neutralization of the Omicron variant, but responses were still up to 17-fold decreased compared with WT. SARS-CoV-2-specific T cells were detected up to 6 months after all vaccination regimens, with more consistent detection of specific CD4+ than CD8+ T cells. No significant differences were detected between WT- and variant-specific CD4+ or CD8+ T cell responses, including Omicron, indicating minimal escape at the T cell level. This study shows that vaccinated individuals retain T cell immunity to the SARS-CoV-2 Omicron variant, potentially balancing the lack of neutralizing antibodies in preventing or limiting severe COVID-19. Booster vaccinations are needed to further restore Omicron cross-neutralization by antibodies.

Barriers to patient enrolment in phase III cancer clinical trials: interviews with clinicians and pharmaceutical industry representatives.

OBJECTIVES: Phase III cancer clinical trials are expensive and time-consuming phases in drug development. Effective patient enrolment can reduce delays and save costs, offering patients an opportunity to benefit from innovative treatments. However, the current evidence base does not fully explain the persistence of barriers to patient enrolment in phase III cancer clinical trials. The aim was to explore clinicians' and pharmaceutical representatives' views on these barriers. DESIGN: A qualitative study was performed. In-depth information was collected from 15 experts in the field of oncology clinical trials, in particular clinical oncologists acting as principal investigators (PIs) and clinical research associates. By means of semistructured interviews, based on a questionnaire derived from our newly developed conceptual framework, they were asked to identify barriers to patient enrolment they had experienced and comment on barriers identified in literature. FINDINGS: Existing knowledge on barriers to patient enrolment was confirmed by all interviewees. Two new key barriers to patient enrolment were identified, that is, insufficient attention to the importance of clinical trial-based research in medical training and a trust gap between PIs and pharmaceutical representatives. A third important barrier was increasingly narrow patient inclusion criteria. CONCLUSIONS: The success rate of patient enrolment in phase III cancer clinical trials highly depends on the clinicians' willingness to take part in clinical trials. Raising awareness of the importance of clinical trials in medical training and among practising oncologists is recommended. Furthermore, to reduce barriers to patient enrolment, it is essential that both clinicians and pharmaceutical representatives acknowledge each other's expertise, become acquainted with each other's procedures and regulations, and work on building trust relationships. Finally, in accordance with our key findings, we propose to add two new barriers to our newly developed conceptual framework; insufficient attention to clinical trial research in medical training and trust gap.

Immunogenicity and Reactogenicity of Vaccine Boosters after Ad26.COV2.S Priming.

BACKGROUND: The Ad26.COV2.S vaccine, which was approved as a single-shot immunization regimen, has been shown to be effective against severe coronavirus disease 2019. However, this vaccine induces lower severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S)-specific antibody levels than those induced by messenger RNA (mRNA)-based vaccines. The immunogenicity and reactogenicity of a homologous or heterologous booster in persons who have received an Ad26.COV2.S priming dose are unclear. METHODS: In this single-blind, multicenter, randomized, controlled trial involving health care workers who had received a priming dose of Ad26.COV2.S vaccine, we assessed immunogenicity and reactogenicity 28 days after a homologous or heterologous booster vaccination. The participants were assigned to receive no booster, an Ad26.COV2.S booster, an mRNA-1273 booster, or a BNT162b2 booster. The primary end point was the level of S-specific binding antibodies, and the secondary end points were the levels of neutralizing antibodies, S-specific T-cell responses, and reactogenicity. A post hoc analysis was performed to compare mRNA-1273 boosting with BNT162b2 boosting. RESULTS: Homologous or heterologous booster vaccination resulted in higher levels of S-specific binding antibodies, neutralizing antibodies, and T-cell responses than a single Ad26.COV2.S vaccination. The increase in binding antibodies was significantly larger with heterologous regimens that included mRNA-based vaccines than with the homologous booster. The mRNA-1273 booster was most immunogenic and was associated with higher reactogenicity than the BNT162b2 and Ad26.COV2.S boosters. Local and systemic reactions were generally mild to moderate in the first 2 days after booster administration. CONCLUSIONS: The Ad26.COV2.S and mRNA boosters had an acceptable safety profile and were immunogenic in health care workers who had received a priming dose of Ad26.COV2.S vaccine. The strongest responses occurred after boosting with mRNA-based vaccines. Boosting with any available vaccine was better than not boosting. (Funded by the Netherlands Organization for Health Research and Development ZonMw; SWITCH ClinicalTrials.gov number, NCT04927936.).

Intranasal treatment of vitamin B12 deficiency in children.

Vitamin B12 deficiency is traditionally treated with intramuscular injections of cobalamin, which are stressful events for children. In adults, studies have shown adequate absorption of intranasally administered vitamin B12. To date, data concerning efficacy of intranasal administration of vitamin B12 in children are lacking. We report on ten cases of children with vitamin B12 deficiency who were successfully treated with intranasal administration of a spray containing hydroxocobalamin. The mean baseline vitamin B12 concentration increased from 126.3 pmol/l (SD 55.4) to 1914.7 pmol/l (SD 1509.7). No side effects were reported.Conclusion: In children, intranasal application of vitamin B12 seems a safe and effective alternative to intramuscular injections, leading to higher compliance and less burden to patients.What is Known:• Children with vitamin B12deficiency are traditionally treated with intramuscular cobalamin injections, which are costly and painful.• Studies in adults showed that intranasal application of hydroxocobalamin leads to normalisation of vitamin B12levels.What is New:• The intranasal application of vitamin B12resulted in a substantial increase of the mean baseline vitamin B12levels without any side effect.• These data encourage a systematic evaluation of intranasal treatment of vitamin B12deficiency in order to define safety, optimal dosage and administration frequency.

No advantage of adrenaline in the local infiltration analgesia mixture during total knee arthroplasty.

PURPOSE: Local infiltration analgesia (LIA) is widely applied in patients undergoing total knee arthroplasty (TKA). In daily practice, adrenaline is added to the LIA mixture to achieve vasoconstriction. However, adrenaline has some possible negative side effects (e.g. tissue necrosis). This trial investigated whether ropivacaine alone is at least as effective for postoperative pain relief after LIA. METHODS: Fifty patients scheduled for primary TKA were included in this prospective randomized, double-blind, controlled pilot study receiving high-volume (150 mL) single-shot intra-capsular LIA with ropivacaine (2 %) with (Ropi+) or without (Ropi-) adrenaline (0.01 %). All patients received the same pre-, peri- and postoperative care with multimodal oral pain protocol. Postoperative pain was assessed before and after the first mobilization and during the first 48 h postoperative using the visual analogue scale (VAS). Secondary outcomes were rescue medication use, early mobilization, length of hospital stay, adverse events (AE's) and readmission rates. Patient reported outcomes measures (PROMS); Oxford Knee Score and WOMAC, were obtained preoperative and 3 months postoperative. RESULTS: VAS scores were not significantly different before (n.s.) and after the first mobilization (n.s.), neither over the first 48 h postoperative (n.s.). Patients who needed rescue medication (n.s.), who mobilized <6 h postoperative (n.s.), who were discharged before postoperative day 3 (n.s.), AE's and readmission rate (n.s.) were comparable between both groups. At 3-month follow-up, PROMS significantly improved within both groups. CONCLUSION: To prevent possible negative side effects (e.g. tissue necrosis), adrenaline should be omitted from the LIA mixture. Single-shot LIA with ropivacaine alone results in clinical acceptable adequate pain control and can be used in daily TKA practice. LEVEL OF EVIDENCE: Randomized, double-blind, prospective clinical trial, Level I.

Patient selection criteria for outpatient joint arthroplasty.

PURPOSE: General consensus of patient selection criteria for outpatient joint arthroplasty is lacking, which is paramount to prevent prolonged hospital stay, adverse events and/or readmissions. This review highlights patient selection criteria for OJA based on the current literature and expert opinion. METHODS: A search of the English and International electronic healthcare databases including MEDLINE/PubMed, EMBASE, AMED and the Cochrane library was performed in November 2015 to include studies published during the last 10 years. Furthermore, a survey of physicians from different specialties was performed. RESULTS: Fourteen studies described results regarding outpatient joint arthroplasty. Studies on outpatient hip and/or knee arthroplasty resulted in similar outcome in preselected patients. Patients who are able and willing to participate, with a low ASA classification (II), bleeding disorders, poorly controlled and/or severe cardiac (e.g. heart failure, arrhythmia) or pulmonary (e.g. embolism, respiratory failure) comorbidities, uncontrolled DM (type I or II), a high BMI (>30 m2/kg), chronic opioid consumption, functional neurological impairments, dependent functional status, chronic/end-stage renal disease and/or reduced preoperative cognitive capacity should be excluded from outpatient joint arthroplasty. The expert opinion-based selection criteria were comparable to literature with a further extension of exclusion for patients with practical issue's, urologic medical history and/or severe mobility disorders. CONCLUSION: Based on the current literature, the presented patient selection criteria provide a basis for outpatient joint arthroplasty and can be useful when selecting patients. Together with a change in mindset, a multidisciplinary approach and literature-based protocols, outpatient joint arthroplasty can be applied in daily orthopaedic practice while ensuring patients' safety. LEVEL OF EVIDENCE: Clinical review, Level III.

Long QTc interval and torsade de pointes caused by fluconazole.

OBJECTIVE: To describe a patient who developed torsade de pointes while being treated with fluconazole. CASE SUMMARY: A 33-year-old woman with a 5 year history of systemic lupus erythematosus was admitted to the intensive care unit because of respiratory insufficiency due to Candida albicans pneumonia. Therapy with intravenous fluconazole 200 mg/day, with dose later adjusted according to her renal function, was started. Prolongation of the QTc interval and torsade de pointes occurred. Initially, domperidone, which had been initiated the day before fluconazole, was suspected as the possible cause and was discontinued; ultimately, both drugs were discontinued. However, torsade de pointes recurred several weeks later when the patient was treated with fluconazole for a second time and disappeared again on withdrawal of the drug. According to the Naranjo probability scale, this adverse reaction was highly probable. DISCUSSION: The risk of torsade de pointes does not correlate in a linear fashion with prolongation of the QTc interval, but an interval beyond 500 msec is considered a significant risk factor. Given that both fluconazole and domperidone are metabolized by the cytochrome P450 system, they may intensify each other's proarrhythmic effects, particularly in patients with concurrent renal dysfunction. These risks are of particular concern in patients whose baseline QTc interval is prolonged for any reason. CONCLUSIONS: From the case history, as well as use of the Naranjo scale, we concluded that fluconazole was the highly probable cause of the development of torsade de pointes in our patient.

The relationship between reticulocyte hemoglobin content with C-reactive protein and conventional iron parameters in dialysis patients.

Adequate iron stores are a prerequisite for successful erythropoietin (EPO) therapy in hemodialysis (HD) patients. Nevertheless, iron status estimation in HD patients remains problematic, as most parameters are influenced by inflammation. The reticulocyte hemoglobin content (CHr) has recently been proposed as a useful tool in iron status assessment. However, the effect of inflammation on CHr remains unstudied. This study aimed to assess the relationship between CHr with other parameters of iron status as well as with C-reactive protein (CRP). This relationship was studied in all the patients (n=61) at our dialysis unit. CHr was significantly and positively related to transferrin saturation (TS) (rho=0.26; p<0.05) and inversely to the percentage of hypochromic red blood cells (%Hypo) (rho=-0.63; p<0.0001), but not to serum ferritin. CHr was strongly and inversely related to log CRP (rho=-0.50; p<0.0001). Despite the use of maintenance intravenous (i.v.) iron doses and relatively high serum ferritin levels, a large percentage of patients were in a state of functional iron deficiency (%Hypo > or = 6 in 41% of patients and CHr < or = 29 pg in 13% of patients). This percentage was far lower in patients with CRP levels below the detection limit (2 mg/L) (26% and 0%, respectively). In conclusion, CHr is related to both TS and %Hypo, but not to serum ferritin, and is strongly influenced by the presence of inflammation (as determined by CRP). In patients with elevated CRP levels, it is very difficult to reach target iron status levels without exceeding the upper limits for serum ferritin.