Higher Initial Dose Research Articles

Complication comparison in intermediate-to-high risk venous thromboembolism patients, treated with high vs standard dose apixaban and rivaroxaban after low molecular weight heparin

Abstract Background In patients with intermediate-to-high risk venous thromboembolism (VTE), current guidelines recommend initial treatment with low molecular weight heparin (LMWH), followed by an oral anticoagulant. However, the studies supporting these guidelines have only focused on the use of Edoxaban and Dabigatran after 5 days of LMWH treatment. To date there are no studies supporting similarly implemented guidelines for Apixaban and Rivaroxaban. Purpose To investigate the incidence of bleeding complications and thrombosis in intermediate-to-high risk VTE patients, when treated with either lead-in high or standard dose Rivaroxaban or Apixaban, following initial LMWH treatment. Methods Through a real-life retrospective study of 844 intermediate-to-high risk VTE patients, 584 were initially treated with LMWH and subsequently Apixaban or Rivaroxaban and divided into two groups. The first group of 514 patients, received high dose Apixaban or Rivaroxaban (10mg x 2 for 7 days and 15mg x 2 for 21 days respectively) before being reduced to their standard doses. The remaining 70 patients, instead transitioned directly to the standard doses (5mg x 2 and 20mg x 1 respectively) from LMWH. All patients started treatment between 2018 and 2023, and all complications were recorded until one year following initiation of treatment. Treatment complications include recurrent VTE, separated into deep vein thrombosis and pulmonary embolism, and bleeding complications in the form of fatal, non-fatal, minor and a drop in haemoglobin. The recurrence of VTE and incidence of bleeding complications were evaluated as the primary efficacy outcome and safety outcome respectively. Results Overall, 4.7% of patients treated with initial high dose Apixaban or Rivaroxaban suffered major bleeding complications as opposed to 2.9% treated with the standard dose (p=<0.05). Out of all complications, 5 were fatal, all of which were part of the high dose group and included 3 cerebral and 2 gastrointestinal bleeds. However, minor bleeding complications were more frequent in the standard dose group, presenting in 26.1% of patients, while, paradoxically, the high dose group had similar complications in only 15.8% of patients (p=<0.05). Although treated with a higher dose, 6/478 (1,26%) incurred a recurrent thrombus within a year of treatment, while the standard dose group had no cases of recurrence, though this was not a statistically significant result. Conclusion Directly transitioning from LMWH to standard dose Apixaban/Rivaroxaban in intermediate-to-high risk VTE, leads to a statistically significant reduced incidence of major bleeding complications, without an increased risk of recurrent thrombosis.

The Jyndevad Experiment: Revealing long-term interactions between liming and phosphorus fertilization in a coarse sand soil

The Jyndevad field experiment, initiated in 1942 on a coarse sand soil in South of Denmark, explores the effect of four liming levels (0, 4, 8 and 12 Mg lime ha−1). These were in 1944 combined with two levels of mineral phosphorus (P) fertilizer (0 and 15.6 kg P ha−1 year−1), with or without a high initial dose of 156 kg mineral P ha−1. This study assesses interactions between liming and P fertilization on soil pH, Olsen-P contents and barley yields covering the last three decades. Annual P application improved barley yield regardless of liming, but the optimal liming level differed from year to year. This emphasizes the need for long-term field experiments to detect the complex interactions between liming and P availability on crop performance. The initial high P dose in 1944 and annual P fertilization increased Olsen-P contents in soil. The unlimed soil with pH(CaCl2) values below 4 had the highest Olsen-P content. The Jyndevad Experiment now harbors wide gradients in soil P (Olsen-P contents: 9–82 mg P kg−1 soil) and pH (3.6–6.9), providing a unique research platform for future studies on interactions between liming and P fertilization on coarse sand soils. We present a selection of studies that have used the Jyndevad Experiment to illustrate the research potential of the experiment.

Impact of Dexmedetomidine Dosing and Timing on Acute Kidney Injury and Renal Outcomes After Cardiac Surgery: A Meta-Analytic Approach.

Acute kidney injury (AKI) is a common and serious complication following cardiac surgery. Dexmedetomidine, a highly selective α2-adrenergic agonist, has shown potential renoprotective effects, but previous studies have yielded conflicting results. This meta-analysis aimed to evaluate the efficacy and safety of dexmedetomidine in preventing AKI and reducing postoperative serum creatinine levels in adult patients undergoing cardiac surgery. We comprehensively searched 5 databases for randomized controlled trials comparing dexmedetomidine with control groups in adult cardiac surgery patients. The main outcomes were the incidence of AKI and change in postoperative serum creatinine levels. Meta-analyses were conducted using RevMan 5.4 models, and subgroup analyses were performed based on dexmedetomidine dosing and timing of administration. Continuous outcomes were combined and analyzed using either mean difference (M.D.), while dichotomous outcomes were analyzed using risk ratio (RR) with 95% confidence intervals (CI). Our study included a total of 14 trials involving 2744 patients. Dexmedetomidine administration significantly reduced the incidence of AKI compared to control groups (RR = 0.54, 95% CI: 0.41-0.70, P < 0.00001). Postoperative serum creatinine levels were also lower with dexmedetomidine (MD = -0.14 mg/dL, 95% CI: -0.28 to -0.001, P =0.04). Subgroup analyses revealed that higher initial doses (>0.5 μg/kg) and administration during intraoperative and postoperative periods were associated with more pronounced renoprotective effects. Dexmedetomidine did not significantly affect mortality but reduced the duration of the length of hospital stay and mechanical ventilation. This meta-analysis demonstrates that dexmedetomidine administration, particularly at higher doses and during both intraoperative and postoperative periods, reduces the risk of AKI in adults undergoing cardiac surgery. These findings support the use of dexmedetomidine as a preventive strategy to enhance renal outcomes in this population.

Somapacitan-induced reversible lipoatrophy in an adult woman with hypopituitarism

BackgroundLipoatrophy is rare adverse event (AE) in daily recombinant human growth hormone (rhGH). Data on lipoatrophy in newly developed long-acting GH (LAGH) are scarce. We report the first case of lipoatrophy in adult patient treated with LAGH somapacitan.Case presentationA 38-year-old woman with congenital panhypopituitarism was transitioned from daily rhGH 0.4 mg QD to somapacitan dose 4 mg QW due to non-adherence to daily rhGH. Despite adequate education and regular changing of injection sites, the patient reported reduced subcutaneous tissue at all four injection sites, after the 4th application of somapacitan. Somapacitan was discontinued at patient preference and lipoatrophy completely reversed after 3 months.ConclusionsLipoatrophy caused by somapacitan was completely reversible. We speculate that high initial dose and volume of somapacitan caused delayed diffusion and a direct local lipolytic effect in our patient. Although, titration of somapacitan was initiated as previously reported in REAL2 study protocol, recent clinical guidelines advise more gradual increase of somapacitan dose also in women on oral estogens that are switched from daily rhGH. Importantly, our case and the two previously described cases in children in the REAL 3 study showed that lipoatrophy caused by somapacitan was transient and completely reversible, and that discontinuation of the drug is not always mandatory.

A high-throughput focused collimator for OAR-sparing preclinical proton FLASH studies: commissioning and validation

Objective. To fabricate and validate a novel focused collimator designed to spare normal tissue in a murine hemithoracic irradiation model using 250 MeV protons delivered at ultra-high dose rates (UHDRs) for preclinical FLASH radiation therapy (FLASH-RT) studies. Approach. A brass collimator was developed to shape 250 MeV UHDR protons from our Varian ProBeam. Six 13 mm apertures, of equivalent size to kV x-ray fields historically used to perform hemithorax irradiations, were precisely machined to match beam divergence, allowing concurrent hemithoracic irradiation of six mice while sparing the contralateral lung and abdominal organs. The collimated field profiles were characterized by film dosimetry, and a radiation survey of neutron activation was performed to ensure the safety of staff positioning animals. Main results. The brass collimator produced 1.2 mm penumbrae radiation fields comparable to kV x-rays used in preclinical studies. The penumbrae in the six apertures are similar, with full-width half-maxima of 13.3 mm and 13.5 mm for the central and peripheral apertures, respectively. The collimator delivered a similar dose at an average rate of 52 Gy s−1 for all apertures. While neutron activation produces a high (0.2 mSv h−1) initial ambient equivalent dose rate, a parallel work-flow in which imaging and setup are performed without the collimator ensures safety to staff. Significance. Scanned protons have the greatest potential for future translation of FLASH-RT in clinical treatments due to their ability to treat deep-seated tumors with high conformality. However, the Gaussian distribution of dose in proton spots produces wider lateral penumbrae compared to other modalities. This presents a challenge in small animal pre-clinical studies, where millimeter-scale penumbrae are required to precisely target the intended volume. Offering high-throughput irradiation of mice with sharp penumbrae, our novel collimator-based platform serves as an important benchmark for enabling large-scale, cost-effective radiobiological studies of the FLASH effect in murine models.

Biotransformation of ferulic acid into vanillyl alcohol and vanillic acid employing thermophilic bacterium Caldimonas thermodepolymerans

Caldimonas thermodepolymerans, a Gram-negative, moderately thermophilic bacterium, exhibits a remarkable biotechnological potential. Given the presence of genes in its genome dedicated to the metabolization of ferulic acid (FA), this study aimed to explore the bacterium's capability for biotransforming FA into high-value metabolites. The results unequivocally demonstrate the bacterium's proficiency in the efficient and rapid conversion of FA into vanillyl alcohol (VOH) and vanillic acid (VA). By manipulating key cultivation parameters, such as adjusting initial FA doses and varying cultivation periods, the product profile can be tailored. Higher initial doses and shorter cultivation periods favor the production of VOH, while lower FA doses and extended cultivation periods lead to the predominant formation of VA. Furthermore, the process can be operated in a repeated-batch scenario. This underscores the potential of C. thermodepolymerans for industrial biotransformation of FA, presenting a promising avenue for leveraging its capabilities in practical applications.

Machine learning identifies risk factors associated with long-term opioid use in fibromyalgia patients newly initiated on an opioid

ObjectivesFibromyalgia is frequently treated with opioids due to limited therapeutic options. Long-term opioid use is associated with several adverse outcomes. Identifying factors associated with long-term opioid use is the first...

Quantification and Potential Viability of Human Noroviruses in Final Effluent from Wastewater Treatment Works in Pretoria, South Africa

Growing global concerns over water scarcity, worsened by climate change, drive wastewater reclamation efforts. Inadequately treated wastewater presents significant public health risks. Previous studies in South Africa (SA) have reported high norovirus levels in final effluent and sewage-polluted surface water, indicating pathogen removal inefficiency. However, the viability of these virions was not explored. This study assessed human norovirus viability in final effluent from wastewater treatment works (WWTWs) in Pretoria, SA. Between June 2018 and August 2020, 200 samples were collected from two WWTWs, including raw sewage and final effluent. Norovirus concentrations were determined using in-house RNA standards. Viability of noroviruses in final effluent was assessed using viability RT-qPCR (vPCR) with PMAxx™-Triton X-100. There was no significant difference in GI concentrations between raw sewage (p = 0.5663) and final effluent (p = 0.4035) samples at WWTW1 and WWTW2. WWTW1 had significantly higher GII concentrations in raw sewage (p < 0.001) compared to WWTW2. No clear seasonal pattern was observed in norovirus concentrations. At WWTW1, 50% (7/14) of GI- and 64.9% (24/37) of GII-positive final effluent samples had no quantifiable RNA after vPCR. At WWTW2, the majority (92.6%, 25/27) of GII-positive final effluent samples showed a 100% RNA reduction post vPCR. PMAxx™-Triton X-100 vPCR provides a more accurate reflection of discharge of potentially viable noroviruses in the environment than standard RT-qPCR. Despite significant reductions in potentially viable noroviruses after wastewater treatment, the levels of potentially viable viruses in final effluent are still of concern due to the high initial load and low infectious dose of noroviruses.

Association Between Initial Corticosteroid Regimen and Treatment Response Time in Acetylcholine Receptor Antibody–Positive Myasthenia Gravis

Background: Corticosteroids remain the cornerstone in the management of myasthenia gravis (MG). Initiation of corticosteroid treatment at a high dose and subsequently decreasing the dose or gradual escalation from a low dose is recommended. We aimed to investigate the association between the initial corticosteroid regimen and treatment response.Methods: A retrospective study was conducted on 234 acetylcholine receptor (AChR) antibody (Ab)–positive MG patients who visited our institution between January 2010 and February 2023. Patients were grouped based on prednisolone dosages received: initial high (IH, ≥50 mg/day) or initial low (IL, ≤20 mg/day). Time to initial improvement and the achievement of minimal manifestation (MM) status were the main outcomes.Results: Of the 234 patients, 135 were classified as IH and 99 as IL group. The IH group demonstrated a faster onset of improvement compared with the IL group (20.0 [16.0–29.0] vs. 40.0 [27.0–84.0] days), with the IH group being a significant prognostic factor for initial improvement (HR, 2.44; 95% CI, 1.76–3.39). However, the IH group had a higher incidence of steroid‐induced exacerbation (51.9% vs. 2.0%, p &lt; 0.001). No significant difference between the IH and IL groups was found in terms of the proportion of patients achieving MM or the time to achieve MM within the first year after treatment initiation.Conclusion: While an initial high dose of corticosteroid treatment accelerated the onset of therapeutic responses in patients with AChR Ab–positive MG, it was associated with a higher cumulative steroid dose and an increased risk of steroid‐induced exacerbations.

Narrow-band UVB phototherapy in patients with atopic dermatitis: analysis of the factors determining treatment efficacy

Background. Efficacy the narrow-band UVB phototherapy in patients with atopic dermatitis varies greatly. An important condition for achieving optimal therapeutic effect is the identification of factors that can impact on the efficacy of therapy and considering their influence when prescribing treatment.&#x0D; Aims. The present study aimed to identify the factors which affect the efficacy of narrow-band phototherapy in patients with atopic dermatitis&#x0D; Methods. A prospective, open-label trial was conducted to evaluate the efficacy and safety of narrow-band UVB phototherapy for patients with moderate-to-severe atopic dermatitis. All patients were treated with narrow-band UVB phototherapy four times weekly for 5 weeks. Disease severity was evaluated by SCORing of the Atopic Dermatitis Index (SCORAD) and Eczema Area and Severity Index (EASI). Distribution of patients by the severity of therapeutic effect was evaluated. To compare the efficacy of therapy depending on initial atopic dermatitis severity, initial and cumulative irradiation doses, skin phototype, and smoking status patients were divided into subgroups.&#x0D; Results. 40 patients with moderate-to-severe atopic dermatitis received course of narrow-band UVB phototherapy. After NB-UVB therapy SCORAD and EASI scores reduced from 45.6 ± 11.4 at baseline to 22.6 ± 12.4 (p 0,05) and from 14.4 ± 7.2 at baseline to 4.1 ± 3.9 (p 0,05) respectively demonstrating the efficacy of narrow-band UVB phototherapy in patients with atopic dermatitis. Our investigation showed that tobacco smokers had definitely lower efficacy of NB-UVB phototherapy in comparison with non-smokers. Narrow-band UVB phototherapy had definitely higher efficacy when it is started with an initial dose 0.2–0.3 J/cm2 chosen in compliance with results of MED determing in comparison with an initial dose 0.05–0.15 J/cm2 selected according to skin phototype.&#x0D; Conclusions. Factors that impact on the efficacy of narrow-band UVB phototherapy in patients with atopic dermatitis were identified. It was determined that using higher initial dose is associated with higher efficacy of therapy. The obtained data suggest the opportunity of decrease in efficacy of therapy in smokers with atopic dermatitis.

Patient Outcomes after Initial High Dose Versus Low Dose Romiplostim for Inpatient Management of Immune Thrombocytopenia

Introduction: Romiplostim is a thrombopoietin receptor agonist approved by the US FDA for chronic immune thrombocytopenia (ITP) in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The recommended dose is 1 mcg/kg/week subcutaneously, escalated weekly by increments of 1 mcg/kg to achieve and maintain a platelet count of 50 x 10 9 /L g ( Kuter et al 2021). It has been postulated that starting at the maximum recommended dose of 10 mcg/kg/week in patients with severe bleeding may swiftly increase platelets and minimize bleeding ( Roumier et al 2021). However, this approach may also increase the risk of major thrombotic events (TE). It is unclear if the more aggressive dosing strategy results in more rapid, robust responses and a tolerable safety profile compared to the FDA approved approach. Methods: This retrospective chart review included adult patients who initiated romiplostim while admitted for ITP at a Mayo Clinic Enterprise site from May 2018 to May 2022. Outcomes included rate of TE at 30 days and 90 days and time to first TE in patients receiving initial romiplostim doses of &amp;lt; 5 mcg/kg (low dose, LD) and &amp;gt; 5 mcg/kg (high dose, HD), median time to platelet response (defined as platelets &amp;gt; 30 x10 9/L and &amp;gt; 50 x10 9/L on 2 separate checks) in LD vs HD, and cost to the institution comparing LD to HD. Outcomes were summarized using descriptive statistics. Statistical analysis was done using BlueSky. Fischer's exact test and chi-squared were performed for categorical data, and Wilcoxon rank sum test were done for continuous variables. Results: Forty-five patients met eligibility criteria: 33 (73%) received initial romiplostim doses &amp;lt; 5 mcg/kg and 12 (27%) received doses &amp;gt; 5 mcg/kg. The majority of patients (43/45 (96%)) presented with platelets &amp;lt; 50 x 10 9/L. The median age was 65 years (68 in LD vs 57 HD). There were 24 (73%) males in the LD group vs five (42%) in the HD group. At baseline, 64% (n = 21) of LD patients and 75% (n = 9) of HD patients presented with bleeding. Major bleeding (defined by 2019 ASH ITP guidelines) was present in 21% (n= 7) vs 17% (n = 2) of patients, LD versus HD, respectively ( Neunert et al 2019). The overall incidence of TE in this study was 24% (n = 11): LD 5 (15%) and HD 6 (50%) (p = 0.044) at 90 days. Median days to TE was 21 days, 12 days in LD group (range 5-21) vs 24.5 days (range 14-58) in HD group (p = 0.067). TE included deep vein thrombosis (DVT, n = 6), DVT with pulmonary embolism (n = 1), portal vein thrombus (n = 1), multiple brain infarcts (n = 1), splenic vein thrombus (n = 1), and left atrial appendage thrombus (n = 1). The median platelet count at the time of TE was 304 x 10 9/L, 415 x 10 9/L (range 58-900) in the LD group vs 323 x 10 8/L (range 33-1427) in the HD group (p = 0.79). Thirty-two (71%) out of 45 patients had a response to romiplostim: 22 in the LD group (71%) vs 10 (83.3%) in the HD group (p = 0.698). Of the patients that responded, the median time to response was 6 days in the LD group vs 11.5 days in the HD group (p = 0.09) The median dose at time of initial response was 2 mcg/kg in the LD group and 6 mcg/kg in the HD group. Wholesale Acquisition Cost (WAC) was used to determine the cost per dose, rounded to the nearest vial size. The average WAC for the initial dose in LD patients was $1806.80 compared to $6061.79 in HD patients. Conclusion:There was a significantly increased incidence of thrombosis in patients admitted with ITP that received initial romiplostim doses &amp;gt; 5 mcg/kg, with no differences in the time to platelet response. Careful consideration of risks versus benefits should be given prior to initiating romiplostim at doses higher than recommended doses.

The HEPDOSE pilot study: the use of the PRODOSE algorithm to reverse the effects of the administration of initial high dose unfractionated heparin.

The HEPDOSE pilot study: the use of the PRODOSE algorithm to reverse the effects of the administration of initial high dose unfractionated heparin.

P11.80.A DOUBLE BLIND RANDOMISED TRIAL WITH ADD-ON OF VALGANCICLOVIR OR PLACEBO TO STANDARD THERAPY OF NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND The origin of glioblastoma is not known. Our earlier and other groups research have shown the presence of cytomegalovirus in glioblastoma, but not in adjacent tumor-free tissue. Furthermore there is a significant correlation between the amount of virus proteins in the tumor and prognosis, patients with low tumoral load have longer survival compared to patient with hogh tumoral viral load. In a retrospective study with 100 newly diagnosed patients with glioblastoma we showed tha the addition of valganciclovir yielded a median survival of 25 months as compared to 13 months for contemporary controls from the same institution. In the case of maximal surgical resection, the median survival reached 29 months. We therefore aimed to run a randomised doule blind study in newly diagnosed glioblastoma. MATERIAL AND METHODS The study started in September 2019, and has the goal to recruit 220 patients, 110 in the valganciclovir group and 110 in the placebo. A macroscopic surgery (at least 90% resection of contrast enhancing tumor on post op MRI), followed by radiation and chemotherapy with temozolomide. Patients receive the study drug, 900mg twice daily during the first 6 weeks, followed by maintenance 450mg twice daily for 2 years. There is no cross-over. The use of Optune is allowed. There is a stratification for MGMT methylation status. Only IDH1 wt tumors can be included, and the randomization has to take place within 10 weeks from surgery. The primary outcome is overall survival, secondary endpoints are the proportion surviving at 2 years and quality of life. 20 patients who fullfilled inclusions criteria have not been randomised. RESULTS since September 2019, 120 patients have been included at Karolinska Hospital in Stockholm. The oncology clinics in Oslo and Stavanger started including patients in September 2022, and have so far included 20 patients. At Karolinska there are 47 MGMT methylated and 73 unmethylated. Nineteen deceased patients and 45 deceased respectively. The median survival is 22 and 14 months respectively. Forteen patients with MGMT methyl completed the study (24 months and 6 months follow-up) versus 8 in the unmethylated. The survival of 20 patients not randomised was 18 months. Five patients showed reversibel hematological side effects grade 3-4, always with the initial high dose and concomittant to radiochemotherapy. No patient stopped the study due to side effects. CONCLUSION the is an ongoing trial, that has recruited about 35 patients per year at the main center, even during the 2 years of pandemics. about half of newly diagnosed patients are eligible for this study, and more than 80% of eligible patients are randomized which is remarkable for this category of patients. There may be a trend as a group for positive survival results, but we need to wait the final results, which may be available in 2-3 years. The study wil recruit until December 2024.

Clinical efficacy of angiotensin receptor-neprilysin inhibitor in de novo heart failure with reduced ejection fraction.

We aimed to analyze the efficacy of angiotensin receptor-neprilysin inhibitor (ARNI) by the disease course of heart failure (HF). We evaluated 227 patients with HF in a multi-center retrospective cohort that included those with left ventricular ejection fraction (LVEF) ≤ 40% undergoing ARNI treatment. The patients were divided into patients with newly diagnosed HF with ARNI treatment initiated within 6 months of diagnosis (de novo HF group) and those who were diagnosed or admitted for HF exacerbation for more than 6 months prior to initiation of ARNI treatment (prior HF group). The primary outcome was a composite of cardiovascular death and worsening HF, including hospitalization or an emergency visit for HF aggravation within 12 months. No significant differences in baseline characteristics were reported between the de novo and prior HF groups. The prior HF group was significantly associated with a higher primary outcome (23.9 vs. 9.4%) than the de novo HF group (adjusted hazard ratio 2.52, 95% confidence interval 1.06-5.96, p = 0.036), although on a higher initial dose. The de novo HF group showed better LVEF improvement after 1 year (12.0% vs 7.4%, p = 0.010). Further, the discontinuation rate of diuretics after 1 year was numerically higher in the de novo group than the prior HF group (34.4 vs 18.5%, p = 0.064). The de novo HF group had a lower risk of the primary composite outcome than the prior HF group in patients with reduced ejection fraction who were treated with ARNI.

Macrophage-Targeted Lipid Nanoparticle Delivery of microRNA-146a to Mitigate Hemorrhagic Shock-Induced Acute Respiratory Distress Syndrome.

The pro-inflammatory response of alveolar macrophages to injurious physical forces during mechanical ventilation is regulated by the anti-inflammatory microRNA, miR-146a. Increasing miR-146a expression to supraphysiologic levels using untargeted lipid nanoparticles reduces ventilator-induced lung injury but requires a high initial dose of miR-146a making it less clinically applicable. In this study, we developed mannosylated lipid nanoparticles that can effectively mitigate lung injury at the initiation of mechanical ventilation with lower doses of miR-146a. We used a physiologically relevant humanized in vitro coculture system to evaluate the cell-specific targeting efficiency of the mannosylated lipid nanoparticle. We discovered that mannosylated lipid nanoparticles preferentially deliver miR-146a to alveolar macrophages and reduce force-induced inflammation in vitro. Our in vivo study using a clinically relevant mouse model of hemorrhagic shock-induced acute respiratory distress syndrome demonstrated that delivery of a low dose of miR-146a (0.1 nmol) using mannosylated lipid nanoparticles dramatically increases miR-146a levels in mouse alveolar macrophages and decreases lung inflammation. These data suggest that mannosylated lipid nanoparticles may have the therapeutic potential to mitigate lung injury during mechanical ventilation.

Lessons about Botulinum Toxin A Therapy from Cervical Dystonia Patients Drawing the Course of Disease: A Pilot Study.

To compare the course of severity of cervical dystonia (CD) before and after long-term botulinum toxin (BoNT) therapy to detect indicators for a good or poor clinical outcome. A total of 74 outpatients with idiopathic CD who were continuously treated with BoNT and who had received at least three injections were consecutively recruited. Patients had to draw the course of severity of CD from the onset of symptoms until the onset of BoNT therapy (CoDB graph), and from the onset of BoNT therapy until the day of recruitment (CoDA graph) when they received their last BoNT injection. Mean duration of treatment was 9.6 years. Three main types of CoDB and four main types of CoDA graphs could be distinguished. The demographic and treatment-related data of the patients were extracted from the patients' charts. The best outcome was observed in those patients who had experienced a clear, rapid response in the beginning. These patients had been treated with the lowest doses and with a low number of BoNT preparation switches. The worst outcome was observed in those 17 patients who had drawn a good initial improvement, followed by a secondary worsening. These secondary nonresponders had been treated with the highest initial and actual doses and with frequent BoNT preparation switches. A total of 12 patients were primary nonresponders and did not experience any improvement at all. No relation between the CoDB and CoDA graphs could be detected. Primary and secondary nonresponses were observed for all three CoDB types. The use of initial high doses as a relevant risk factor for the later development of a secondary nonresponse was confirmed. Patients' drawings of their course of disease severity helps to easily detect "difficult to treat" primary and secondary nonresponders to BoNT on the one hand, but also to detect "golden responders" on the other hand.

Interventions for dialysis patients with hepatitis C virus (HCV) infection.

Interventions for dialysis patients with hepatitis C virus (HCV) infection.

Effects of dosage in new users of lamotrigine inducing epidermal necrolysis: Results of the German Registry of Severe Skin Reactions.

This study was undertaken to determine the impact of dosage in new users of lamotrigine (LTG) and the concomitant intake of valproic acid (VPA) on epidermal necrolysis (EN). A total of 102 EN cases with exposure to LTG were identified (1992-2018) in the German Registry of Severe Skin Reactions. All cases are validated by an independent expert committee. Six cases were excluded due to lack of exposure in the relevant time frame. Causality assessment was performed with ALDEN (Algorithm for Assessment of Drug Causality in EN) on definite/probable cases (≥12 years; n= 84). Evaluation of dosing regimen was restricted to cases with complete LTG dosing history (n= 74). Demography showed a mean age of 42.4 years, female predominance (69%), and low mortality (7.3%). Epilepsy was the indication for use in 87.5%. LTG was the very probable cause in 71.4% and probable cause in 28.6%. On average, one additional antiseizure medication was taken, most frequently VPA (43/84). Combined LTG/VPA treatment showed no statistically significant difference in morbidity or mortality. Mean time latency from initiation of LTG to reaction onset was 24.2 days, varying between 21 days with high initial dose and 29.2 days with low initial dose. Low initial LTG dose (n= 9) revealed higher mortality (22.2%) and higher severity (5/9) than high initial dose (n= 35, mortality=14.3%, 14/35 higher severity). No patient died when the starting dose was as recommended. The highest mortality (25%) was found in patients with no dose increase (n= 8), which correlated with higher age. Despite the recommended or low initial dose, 52.7% of patients developed EN, in contrast to 39.2% with a slow, recommended, or no dose escalation. Neither the initial dose, dose escalation, nor the combination with VPA seems to influence the general occurrence of EN. However, EN patients with the recommended starting dose and the recommended dose escalation had the best outcome in terms of clinical severity and mortality.

DO HIGHER DOSES OF NALOXONE INCREASE THE RISK OF PULMONARY COMPLICATIONS?

Background: Although naloxone has proven to be an effective opioid reversal agent, concern that high doses of naloxone can cause pulmonary edema may prevent health care providers from administering it in initial high doses. Objective: Our aim was to determine whether increased doses of naloxone are correlated with an increase in pulmonary complications in patients presenting to the emergency department (ED) after an opioid overdose. Methods: This was a retrospective study of patients treated with naloxone by emergency medical services (EMS) or in the ED at an urban level I trauma center and three associated freestanding EDs. Data were queried from EMS run reports and the medical record and included demographic characteristics, naloxone dosing, administration route, and pulmonary complications. Patients were grouped by naloxone dose received, defined as low (≤ 2 mg), moderate (> 2 mg to ≤ 4 mg), and high (> 4 mg). Results: Of the 639 patients included, 13 (2.0%) were diagnosed with a pulmonary complication. There was no difference in the development of pulmonary complications across groups (p = 0.676). There was no difference in pulmonary complications based on the route of administration (p = 0.342). The administration of higher doses of naloxone was not associated with longer hospital stays (p = 0.0327). Conclusions: Study results suggest that the reluctance of many health care providers to administer larger doses of naloxone on initial treatment may not be warranted. In this investigation, there were no poor outcomes associated with an increase in naloxone administration. Further investigation in a more diverse population is warranted.

An alternative dosing strategy for ropeginterferon alfa-2b may help improve outcomes in myeloproliferative neoplasms: An overview of previous and ongoing studies with perspectives on the future.

Ropeginterferon alfa-2b is a novel, long-acting mono-pegylated proline-IFN-alpha-2b approved for treatment of polycythemia vera in adults, regardless of thrombotic risk level or treatment history. Clinical trial data indicate the dose and titration of ropeginterferon alfa-2b is safe and effective. However, additional studies may provide rationale for an amended, higher initial dosage and rapid titration. This article is an overview of current and upcoming studies of ropeginterferon alfa-2b in myeloproliferative neoplasms that support the exploration of an amended dosing scheme in order to optimize patient tolerability and efficacy outcomes.