Continuous Therapy Research Articles

Effect of Interrupting Prolonged Sitting with Frequent Activity Breaks on Postprandial Glycemia and Insulin Sensitivity in Adults with Type 1 Diabetes on Continuous Subcutaneous Insulin Infusion Therapy: A Randomized Crossover Pilot Trial.

Objective: This study examined acute effects of interrupting prolonged sitting with short activity breaks on postprandial glucose/insulin responses and estimations of insulin sensitivity in adults with type 1 diabetes (T1D). Method: In a randomized crossover trial, eight adults (age = 46 ± 14 years [mean ± SD], body mass index [BMI] = 27.2 ± 3.8 kg/m2) receiving continuous subcutaneous insulin infusion (CSII) therapy completed two 6-h conditions as follows: uninterrupted sitting (SIT) and sitting interrupted with 3-min bouts of simple resistance activities (SRAs) every 30 min. Basal and bolus insulin were standardized across conditions except in cases of hypoglycemia. Postprandial responses were assessed using incremental area-under-the-curve (iAUC) and total AUC (tAUC) from half-hourly venous sampling. Meal-based insulin sensitivity determined from glucose sensor and insulin pump (SiSP) was assessed from flash continuous glucose monitor and insulin pump data. Outcomes were analyzed using mixed models adjusted for sex, BMI, treatment order, and preprandial values. Results: Glucose iAUC did not differ by condition (SIT: 19.8 ± 3.0 [estimated marginal means ± standard error] vs. SRA: 14.4 ± 3.0 mmol.6 h.L-1; P = 0.086). Despite CSII being standardized between conditions, insulin iAUC was higher in SRA compared to SIT (137.1 ± 22.7 vs. 170.9 ± 22.7 mU.6 h.L-1; P < 0.001). This resulted in a lower glucose response relative to the change in plasma insulin in SRA (tAUCglu/tAUCins: 0.32 ± 0.02 vs. 0.40 ± 0.02 mmol.mU-1; P = 0.03). SiSP was also higher at dinner following the SRA condition, with no between-condition differences at breakfast or lunch. Conclusion: Regularly interrupting prolonged sitting in T1D may increase plasma insulin and improve insulin sensitivity when meals and CSII are standardized. Future studies should explore underlying mechanistic determinants and the applicability of findings to those on multiple daily injections. Trial Registration: Australian and New Zealand Clinical Trial Registry Identifier-ACTRN12618000126213 (www.anzctr.org.au).

Albumin and platelet loss during the application of CytoSorb® in critically ill patients: a post-hoc analysis of the Cyto-SOLVE trial

Introduction: Adsorption devices like CytoSorb® (CS) are increasingly used in critically ill patients. However, potential adverse effects have not been sufficiently investigated. The aim of this post-hoc analysis of the monocentric prospective Cyto-SOLVE study was to examine albumin concentration and platelet count during the application of CS in intensive care unit (ICU) patients with different indications for CS therapy. Methods: 29 Adult ICU patients receiving continuous kidney replacement therapy and CS application for 12 hours were included. Albumin concentration and platelet count were measured before, during, and after application. Changes in albumin concentration and platelet count were investigated. Since 10/29 patients were substituted with platelets during CS therapy and 20/29 received albumin, subgroup analysis was performed in patients receiving no platelet concentrate and &lt;20g albumin substitution during CS application. The dependent sample t-test was used to detect significant (p&lt;0.05) changes over time and multivariate models were investigated. Results: We observed a significant reduction in platelets (p=0.005, mean 14 G/l, 95% confidence interval (CI) 4 - 23G/l) during CS therapy with an even more pronounced drop in those 19 patients without platelet substitution (p=0.001, mean 22G/l, 95% CI 10 – 34). No significant change was detected in the albumin concentration of all patients. However, a significant albumin decrease was observed in those 17 patients with less than 20g albumin substitution during CS therapy (p=0.007, mean 0.17g/dL, 95% CI 0.05 – 0.29). No other potential covariates for the decrease could be identified in a multivariate model. Conclusion: Since a drop in albumin and platelets occurred during the use of CS, an increased substitution might be necessary. Knowledge of potential side effects is of great importance to prevent harm during the use of extracorporeal procedures. This knowledge should be considered for a reliable risk-benefit assessment in the future.

Analysis of treatment-free remission outcomes in patients with chronic myeloid leukemia who received sequential nilotinib therapy after achieving deep molecular response to imatinib

Objective: To analyze the treatment-free remission (TFR) outcomes in patients with chronic myeloid leukemia (CML) treated sequentially with nilotinib (NIL) after achieving deep molecular response (DMR) to imatinib (IM). Methods: Retrospectively enrolled 103 CML patients from 6 hematological centers in Henan Province who chose sequential NIL therapy or continued IM therapy after achieving DMR to first-line IM from June 2, 2013 to August 30, 2022. Among them, 42 cases were treated with sequential NIL and 61 cases continued IM therapy. The 42 patients in the sequential NIL group were further divided into 3 subgroups based on the duration of DMR at switching to sequential NIL therapy: Group 1 (17 cases): DMR duration<12 months at switching to sequential NIL therapy; Group 2 (8 cases): DMR duration≥12 months to<24 months at switching to sequential NIL therapy; Group 3 (17 cases): DMR duration≥24 months at switching to sequential NIL therapy. Follow-up ended on January 9, 2024, with a median follow-up of 40 (16, 91) months for the sequential NIL group and 49 (21, 123) months for the continuous IM group. Survival curves were plotted using the Kaplan-Meier method and the log-rank test was performed to compare the TFR rates between groups. Results: There were 19 males and 23 females with a median age [M (Q1, Q3)] of 43 (31, 50) years in the sequential NIL group. There were 32 males and 29 females with a median age of 41 (31, 50) years in the continuous IM group. Kaplan-Meier survival curve analysis showed that the TFR rate was higher in the sequential NIL group than in the continuous IM group (88.1% vs 63.9%, P=0.005). The results of subgroup analysis showed that the TFR rates in Group 1, Group 2 and Group 3 were 94.1%, 87.5% and 82.4%, respectively, with no statistically significant differences (all P>0.05).The TFR rate in Group 1 was higher than in the continued IM group (P=0.017), and there were no statistically significant differences in Group 2 and Group 3 compared with the continuous IM group(all P>0.05). Conclusion: Sequential NIL therapy after achieving DMR with IM therapy can improve the TFR rate in CML patients, especially in those with DMR duration<12 months before switching to sequential NIL therapy.

Safety of and chorioretinal circulation during repeated low-level red-light therapy for myopic children.

To evaluate the safety of repeated low-level red-light (RLRL) therapy in children, and the dynamic evolution of choroidal and retinal blood flow. This is a single-centre, randomised, single-blind, parallel-group clinical trial. Seventy myopic children were randomly assigned to either the intervention group [receiving RLRL therapy plus single-vision spectacle (SVS)] or the control group (wearing SVS). Participants underwent comprehensive ophthalmic examinations following their first irradiation, 9 months continuous RLRL therapy and stop of treatment. Quantitative analyses of choroidal and retinal microcirculation were analysed via optical coherence tomography angiography. Over 9 months of treatment, while the RLRL treatment demonstrated significantly less increases in refractive error and axial length compared with the SVS treatment (ps < 0.05), no abnormalities in fundus structure or visual function (mfERG, VEP and microperimetry) were detected (ps > 0.05). A single red-light exposure did not exert a significant influence on choroidal thickness (ps > 0.05). Upon continuous treatment, the RLRL group achieved peak values in these circulations at 9 months (ps < 0.05). Following cessation of exposure, all circulations exhibited a declining trend, reaching similar levels in both groups (ps > 0.05). As the frequency of red-light exposures intensified, there was a consistent surge in these circulations (ps < 0.05). Nine months of continuous RLRL exposure does not cause toxic side effects on retinal or optic nerve functions, and there is a time-dependent cumulative response in choroidal and retinal circulation.

Successful treatment of refractory interstitial lung disease with cyclophosphamide and pirfenidone in a new onset of juvenile SLE: a case report

Introduction and importance: Systemic lupus erythematosus (SLE) is a systemic immune disease, presented with a broad spectrum of clinical manifestations. The occurrence of interstitial lung disease (ILD) as the initial manifestation of SLE is very rare. Case presentation: The authors present the case of a 6-year-old girl who presented with symptoms of fatigue, fever, oral ulcers, and dry cough with difficulty breathing. On physical examination, the patient had fever and oral ulcers, in addition of acute phase reactant analysis, positive ANA, and double-stranded DNA. Chest computed tomography images showed nonspecific interstitial pneumonia + organizing pneumonia pattern, leading to the diagnosis of onset of SLE with ILD. The patient was treated with steroids and azathioprine for 1 year, and the radiological and immunological resolution was noted. However, the patient continued to cough, have difficulty breathing, and was readmitted to the hospital due to SLE recurrence after 1 year of follow-up. Despite continued corticosteroid therapy and monthly administration of steroids and cyclophosphamide for 6 months, the patient’s respiratory symptoms and chest radiography results did not improve significantly. The patient was then prescribed a daily regimen of cyclophosphamide and pirfenidone, which was found to be effective in reducing the steroid dose and achieving remission after 1 year of follow-up. Clinical discussion: Treatment of connective tissue disease-associated ILD is difficult due to a lack of treatment data. Conclusion: This case provided evidence of the efficacy of combination therapy of pirfenidone and cyclophosphamide for refractory connective tissue disease-associated ILD in young children.

Omparative Study Between Pulsed and Continuous Itraconazole for the Treatment of Onychomycosis

Objective: To compare efficacy of pulsed versus continuous daily oral Itraconazole in the treatment of onychomycosis. Study Design: Randomized Control Trial (ClinicalTrials.gov: NCT05567484). Place and Duration of Study: Department of Dermatology, Combined Military Hospital, Abbottabad, Pakistan, from May to Dec 2021. Methodology: We enrolled 60 patients whose toenails showed signs of onychomycosis (crumbling nail plates, thicker nail beds, and yellowing). They were randomly divided into Group-A and Group-B, with 30 patients each. Group -A (Pulse Therapy) took two capsules of oral Itraconazole 100 mg twice weekly for one week every month for three months while Group-B (Continuous Therapy) received continuous oral 100 mg of Itraconazole once daily for 12 weeks continuously. Patients were subjected to an Onychomycosis Severity Index-based clinical evaluation. Results: In Group-A (Pulse Therapy), 25(83.3%) patients showed mycological cure whereas in Group-B (Continuous Therapy), 23(76.7%) patients showed mycological cure but difference in the efficacy of both drugs was not statistically significant (p-value=0.519). Conclusion: Pulsed therapy with Itraconazole and continuous Itraconazole therapy have comparable efficacies in treating dermatophyte toenail onychomycosis.

Clinical characteristics and outcomes of cerebral venous sinus thrombosis in patients with antiphospholipid syndrome.

Cerebral venous sinus thrombosis (CVST) is a rare but serious manifestation of venous thrombosis in patients with antiphospholipid syndrome (APS). This study investigated the risk factors, clinical characteristics and prognosis of CVST in APS patients. This retrospective cohort study included all thrombotic APS (tAPS) patients from Peking Union Medical College Hospital (PUMCH) from April 2005 to August 2023. Demographic characteristics, laboratory data and thrombotic risk factors were compared between tAPS-CVST group and tAPS-non-CVST group. Kaplan-Meier survival analysis was utilized to compare the recanalization rate and the recurrence rate. A total of 453 APS patients were enrolled, and 40 (8.8%) APS patients were with CVST. The median age of the APS-CVST patients was 27 (21.25, 32.75) years, and 72.5% were females. In 50% of these patients, CVST was the initial symptom of APS, with headache being the most prevalent clinical symptom (95%). Involvement of more than two venous sinuses were observed in 79.5% of patients, with the transverse sinus (79.5%) and sigmoid sinus (74.4%) being the most commonly affected sites. Oral contraceptives, intracranial infections and malignancy were identified as risk factors of APS-CVST. There were no statistically significant differences in baseline characteristics or the distribution of antiphospholipid antibodies profiles between the two groups. After a median follow-up of 24 (12, 52) months, 21 patients (52.5%) experienced recanalization, and 13 patients (32.5%) had a thrombotic recurrence. Survival analysis indicated that adequate anticoagulant therapy significantly contributed to recanalization (HR 6.27, 95% CI 2.616-15.02, P = 0.003), while continuous anticoagulant therapy was highly effective in reducing the recurrence of thrombotic events (HR 0.14, 95% CI 0.0447-0.4328, P = 0.0007). CVST should be considered in APS patients who experience sudden onset headaches, particularly those with thrombotic risk factors, such as the use of oral contraceptives, intracranial infections and malignancy. Continuous and adequate anticoagulant therapy is pivotal and beneficial for achieving recanalization and prevention of recurrence. Key Points • The prevalence of CVST in patients with APS may be underestimated. • APS-CVST is associated with special risk factors, including pregnancy, intracranial infection, oral contraceptives and tumors. • Long-term and adequate anticoagulation therapy can increase the vascular recanalization rate and reduce thrombosis recurrence.

Cardiovascular effects of obstructive sleep apnoea and effects of continuous positive airway pressure therapy: evidence from different study models

INTRODUCTIONCardiovascular consequences of obstructive sleep apnoea (OSA) and the effects of continuous positive airway pressure (CPAP) therapy on blood pressure, endothelial dysfunction, and MACE (major adverse cardiovascular events) have been studied over decades using different study designs. However, clinical findings from different study models on cardiovascular outcomes are sometimes contradictory.METHODSA literature search was conducted in PubMed for randomised controlled trials, meta-analyses, population-based epidemiological studies and OSA cohort studies up to September 2023 investigating the cardiovascular effect of OSA and CPAP in adults with OSA on the following cardiovascular endpoints: blood pressure, arterial hypertension, endothelial function, and MACE (myocardial infarction, stroke, transient ischemic attack, cardiovascular death). The level of evidence for these outcomes was discussed on the basis of different study models.RESULTS AND CONCLUSIONSThere is high-level evidence of a causal relationship between OSA and arterial hypertension and endothelial dysfunction, as well as on higher MACE incidence among subgroups of patients with untreated OSA. The cardiovascular effects of OSA depend on the severity of OSA, symptoms, phenotype, and comorbidities. The blood pressure-lowering effect of CPAP is mainly observed in uncontrolled and treatment-resistant hypertension. The MACE risk reduction in OSA depends on good long-term CPAP adherence. Younger, sleepy patients with more severe OSA, higher hypoxaemic burden and without overt cardiovascular end-organ disease may particularly benefit from CPAP treatment in terms of cardiovascular risk reduction. Randomised controlled trials of CPAP or other effective OSA treatments in primary cardiovascular prevention and in patients at highest risk are lacking.

Potential Risks Associated With Long-term Use of Proton Pump Inhibitors and the Maintenance Treatment Modality for Patients With Mild Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) significantly affects the health-related quality of life and healthcare costs. The prevalence of this disease is increasing in Asia, leading to a rapid increase in the demand of proton pump inhibitors (PPIs). Despite effective symptom management during initial treatment, relapse rates after PPI cessation remain high in patients with GERD, warranting longterm maintenance therapy. Concerns regarding potential side effects related to the long-term use of PPIs are escalating with increased usage. Studies have reported diverse side effects of PPIs, such as increased fracture risk, cardiovascular concerns, enteric infections, neurological diseases, and potential associations with gastric cancer. However, definitive causal relationships remain unclear. This review comprehensively summarizes the latest knowledge on the potential risks associated with long-term use of PPIs. Continuous or noncontinuous therapy can be used as a maintenance treatment modality for GERD. For patients with mild GERD, including those with nonerosive and mildly erosive reflux disease, on-demand therapy following a sufficient period of continuous maintenance therapy is recommended as a long-term maintenance treatment option.

Endocrine disorders in Kearns-Sayre syndrome with different severity of symptoms: two case reports and a literature review.

Kearns-Sayre Syndrome (KSS) is a variant of mitochondrial disorder caused by a Mitochondrial Deoxyribonucleic Acid (mtDNA) deletion. Clinical manifestations of KSS can include different organ and system involvement. Different organ malfunctions, more often cardiac dysfunction, can lead to death. No effective treatment of this condition exists to date. Here, we report two patients with KSS. Female patient with a large-scale deletion of 7,020 base pairs (bp) suffered from hypogonadism, diabetes mellitus with fluctuating glucose levels, and had poor general health. A male patient with a common 4,977 bp deletion did not have diabetes mellitus but had impaired glucose tolerance. He also had a higher level of general health than our female patient. Both patients had reduced Bone Mineral Density (BMD). In female patients, calcium and vitamin D supplementation combined with metabolic therapy and nutritional drink supplements helped increase BMD (up to 32% in L1-L4). Comparing these two patients suggests that the larger the mtDNA deletion is, the more severe the course of the disease is. Not only does the size of the mtDNA deletion probably determine the severity of the disease, but also such factors as mtDNA heteroplasmy level, presence of mtDNA duplications, and pleioplasmy. Moreover, continuous nonconsecutive metabolic therapy and nutritional supplements are helpful in the prevention of deterioration of symptoms and general health.

Dysphasia: metastatic prostate cancer to the leptomeninges: a case report

BackgroundLeptomeningeal metastasis occurs in 5% of patients with prostate cancer and indicates a very poor prognosis.Case presentationA 60-year-old Caucasian male patient diagnosed with metastatic castration-resistant prostate cancer with sclerotic bone metastases and soft tissue metastases underwent multiple courses of chemotherapy and hormone therapy. The diagnosis of prostate cancer is based on elevated prostate-specific antigen levels and tissue biopsy. He subsequently presented with expressive aphasia. Nonspecific, diffuse irregular dural/pachymeningeal thickening enhancement was noted on magnetic resonance imaging. Upon evaluation by neurology, electroencephalogram was negative for an epileptiform correlate. The workup included a lumbar puncture to rule out infectious etiology. The patient’s neurological status stabilized, and he was discharged home with a plan for continued therapy with abiraterone and prednisone. Due to advanced malignancy, the patient enrolled in hospice and died 3 weeks after hospital discharge.ConclusionsCentral nervous system metastasis occurs very rarely in prostate cancer. With the increase in life expectancy and advances in oncologic therapy for prostate cancer, physicians should be aware of and consider central nervous system metastasis in men aged 50 years and above.

Safety of beta-blocker discontinuation in patients after acute coronary syndromes and preserved left ventricular ejection fraction: long-term clinical outcomes from the SPUM-ACS cohort

Abstract Background While beta-blockers have been shown to improve outcomes after acute coronary syndromes (ACS), most trials predate the advent of reperfusion therapy and modern secondary prevention. Recent trial data in the reperfusion era found no all-cause or cardiovascular mortality benefit in patients with a left ventricular ejection fraction (LVEF) &amp;gt;40%, while myocardial infarction and angina were reduced. We hypothesized that, in patients who receive optimal contemporary treatment following ACS and who have an LVEF &amp;gt;40%, beta-blocker discontinuation within 1 year after ACS is safe and non-inferior to beta-blocker continuation in terms of the 5-year incidence of major adverse cardiovascular events (MACE). Purpose We assessed the safety of beta-blocker discontinuation within 12 months following ACS in patients with an LVEF &amp;gt;40% at discharge, compared to continued long-term beta-blocker therapy, with respect to the 5-year incidence of MACE. Methods Data was derived from the Swiss Special Program University Medicine – Inflammation in ACS (SPUM-ACS) cohort (N=3,762), a multicenter prospective cohort of patients hospitalized for invasive management of ACS between 2009-2017. We included patients with an LVEF &amp;gt;40%, beta-blockers at discharge, and who completed the 5-year follow-up. Patients who continued beta-blockers at one year were compared with those who discontinued beta-blockers at any time throughout the first year after ACS using a target trial emulation design. Adjusted hazard ratios (aHR) were obtained with a Cox model using an inverse probability weighting adjustment for baseline characteristics including demographic parameters, comorbidities, and concomitant medication. The primary endpoint was 5-year MACE (cardiovascular death, myocardial infarction, stroke or transient ischemic attack, unplanned coronary revascularization, and hospitalization for unstable angina). Results Of 2,077 patients with an LVEF &amp;gt;40% and beta-blockers at discharge, 1,758 (85%) continued beta-blockers and 319 (15%) had discontinued beta-blocker therapy at one year. The 5-year risk between the discontinuation and continuation group was similar for the primary endpoint (14.5% vs 14.3%, respectively, aHR 1.00, 95%CI 0.73-1.36, p=0.98). All-cause mortality (aHR 1.08, 95%CI, 0.64-1.81, p=0.79) did not differ between both groups. In a subgroup analysis, there was no effect modification by LVEF, but some evidence for a higher risk of primary endpoint with beta-blocker discontinuation in STEMI (aHR 1.50, 95%CI 1.02-2.21) compared with NSTEMI (aHR 0.69, 95%CI 0.40-1.19, P interaction = 0.022). Conclusion Beta-blocker discontinuation within 12 months following ACS in patients with an LVEF &amp;gt;40% was not associated with an increased risk of MACE at 5 years, compared to long-term continuation of beta-blocker therapy. In the absence of a dedicated randomized controlled trial, beta-blocker discontinuation may be safe, especially after NSTEMI.Kaplan-Meier plot: probability of MACE

Fluid Overload in Children Following Hematopoietic Cell Transplant: A Comprehensive Review

Fluid overload significantly increases morbidity and mortality in critically ill children. Following hematopoietic cell transplant (HCT), children are at a high risk of fluid accumulation due to essential increased fluid intake for nutrition, blood products, and antimicrobials. In addition, many complications predispose these children to capillary leak and fluid overload (FO), such as sinusoidal obstruction syndrome, engraftment syndrome, sepsis, and acute kidney injury (AKI). FO &gt; 10% occurs in nearly half of children following HCT and is associated with a lower PICU survival rate. In addition, in children with acute respiratory failure post HCT, each 1% increase in cumulative fluid balance on d 3 increases the odds of PICU mortality by 3%. Furthermore, FO worsens AKI. Tools such as the renal angina index and urinary biomarkers such as neutrophil gelatinase-associated lipocalin can help identify patients at risk of AKI and FO. Early detection, prevention, and intervention are crucial to improving outcomes in this population. Management strategies include fluid restriction, diuretics, and continuous kidney replacement therapy (CKRT) when FO exceeds 10% and other measures have failed.

Avatrombopag for the treatment of patients with chemotherapy-induced thrombocytopenia: A case series.

Management of chemotherapy-induced thrombocytopenia (CIT) is challenging, often resulting in chemotherapy treatment delays, dose reduction, and treatment interruption. Randomized trials support the potential efficacy and safety of thrombopoietin receptor agonists in CIT management. A phase III trial of avatrombopag (AVA) demonstrated increased platelet counts (PC) in patients with solid tumours experiencing CIT. To complement those findings, this case series of six patients with solid tumours and CIT is presented. Results from these cases support the clinical benefit of AVA in improving PC and reducing the impact of CIT on tumour treatment, allowing continued therapy without dose reduction or treatment interruption.

Using technology to support diabetes care in hospital: Guidelines from the Joint British Diabetes Societiesfor Inpatient Care (JBDS-IP) group and Diabetes Technology Network (DTN) UK.

This article summarises the Joint British Diabetes Societies for Inpatient Care (JBDS-IP) Group guidelines on the use of technology to support diabetes care in hospital. The guideline incorporates two main areas: (i) use of wearable technology devices to improve diabetes management in hospital (including continuous glucose monitoring and insulin pump therapy) and (ii) information technology. Although it is reasonable to extrapolate from the evidence available, that devices developed to enhance diabetes care outside hospital will show similar benefits, there are challenges posed within the inpatient setting in hospital. This guidance provides a pragmatic approach to supporting self-management in individuals using wearable technology admitted to hospital. Furthermore, it also aims to provide a best practice guide for using information technology to monitor diabetes care and communicate between health professionals.

Intensive care unit continuous kidney replacement therapy: time to change dosage recommendations?

Continuous kidney replacement therapy (CKRT) is the predominant form of acute kidney support used for hemodynamically unstable adult ICU patients with severe AKI (KDIGO stage 3). The success of CKRT depends on the achieved doses. Practice patterns worldwide are highly variable. A contemporary understanding of treatment adequacy is essential. The KDIGO AKI clinical guidelines recommend delivering effluent volumes of 20-25ml/kg/hour for CKRT in the ICU setting, with the caveat that higher prescribed doses (25-30ml(kg/h) may be necessary to achieve adequate delivered CKRT doses. The reference landmark trials provide definitive evidence that increases of delivered CKRT doses beyond the recommended dose are not beneficial for unselected ICU patients with severe AKI. However, the minimum delivered CKRT intensity at which underdosing becomes harmful remains unknown. The answer to this question has clinical relevance (dosing of critically ill patients with obesity or Covid-19 disease, minimizing adverse effects of CKRT) and a relevant impact on the costs of CKRT. The delivered dose of CKRT for Japanese ICU patients with severe AKI has been generally smaller (median 15ml/h/kg) than the recommended delivered KDIGO dose. The most recently published retrospective cohort study by Okamoto et al. demonstrated that low delivered CKRT doses were associated with a higher mortality among critically ill patients with severe AKI. These data challenge the nation-wide accepted hypothesis that a lower limit of delivered CKRT (< 20ml/ kg/h) may adequately control uremia/volume overload. Thus, there is an unmet clinical need for prospective randomized trials defining the minimal effective dose of CKRT. Given the dynamic nature of the precipitating critical illness and the natural course of most episodes of AKI, CKRT dose targets are likely to vary. Doses should be tailored to the needs of the individual patient within the limits of the KDIGO guideline recommendations. The Japanese experience with low-dose CKRT is not practice changing.

Nocturnal continuous subcutaneous infusion of apomorphine in advanced Parkinson's disease: a series of 37 cases

Multiple factors can cause sleep disturbances in Parkinson's disease. The quality of sleep and therefore of life is usually improved with continuous dopaminergic stimulation therapies, such as continuous subcutaneous infusion of apomorphine. We present an observational retrospective study of patients at our centre with advanced Parkinson's disease, treated with continuous infusion of apomorphine, with treatment extended to nights, between 2011 and 2022. We collected data from 37 patients, and evaluated the indication for nocturnal treatment, efficacy, safety and reasons for withdrawal. Fifty percent of patients began nocturnal treatment for motor complications, 19% for non-motor complications and 31% for both. The most common non-motor symptoms were sleep fragmentation and disturbances, neuropathic pain, psychiatric symptoms and intense nocturia. Twenty of the 37 patients (54%) were continuing treatment at the end of the study follow-up, 16 (43%) discontinued the infusion, and one (3%) was lost to follow-up. The adverse reactions that led to termination of the infusion were severe nodules (two), dopaminergic psychosis (one) and a positive Coombs test with/without anaemia (one). Four patients terminated the nocturnal infusions while continuing the daytime infusions due to suboptimal adaptation to the device. Patients whose symptoms improved without any significant adverse effects continued the treatment. Continuous infusion of apomorphine during the night was an effective and safe treatment in our series.

Use of continuous glucose monitoring and hybrid closed-loop therapy in pregnancy.

Continuous glucose monitoring (CGM) has led to a paradigm shift in the management of pregnant women with type 1 diabetes (T1D), with improved glycaemic control, less hypoglycaemia and fewer pregnancy complications. Data on CGM use in pregnant women with type 2 diabetes (T2D) are limited. A large randomized controlled trial (RCT) on CGM use in people with T2D in pregnancy is ongoing. Small studies on CGM use in women with gestational diabetes (GDM) have suggested improved glycaemic control and better qualification when insulin is needed. However, none of these studies was powered to evaluate pregnancy outcomes. Several large RCTs are ongoing in women with GDM. In addition to CGM, other technologies, such as advanced hybrid closed-loop (AHCL) systems have further improved glycaemic management in people with T1D. AHCL therapy adapts insulin delivery via a predictive algorithm integrated with CGM and an insulin pump. A large RCT with the AHCL CamAPS® FX demonstrated a 10% increase in time in range compared to standard insulin therapy in a pregnant population with T1D. Recently, an RCT of an AHCL system not approved for use in pregnancy (780G MiniMed) has also demonstrated additional benefits of AHCL therapy compared to standard insulin therapy, with improved time in range overnight, less hypoglycaemia and improved treatment satisfaction. More evidence is needed on the impact of AHCL therapy on maternal and neonatal outcomes and on which glycaemic targets with CGM should be used in pregnant women with T2D and GDM. We review the current evidence on the use of CGM and AHCL therapy in pregnancy.

Plasma sphingomyelin levels were negatively correlated with ferritin levels in splenectomized thalassemia patients

Abstract Beta thalassemia results from decreased production of beta chains due to either mutations or deletions in the beta-globin gene, leading to impaired production of hemoglobin A. Thalassemia patients take frequent blood transfusions to compensate for hemolytic anemia and iron overload. Iron overload is monitored by serum ferritin levels in these patients. Extra-medullary hematopoiesis in beta thalassemia major leads to hypersplenism which often necessitates splenectomy to increase red cell life span and decrease transfusion need. Sphingomyelin is the second most abundant phospholipid in human plasma after phosphatidylcholine. In contrast to the well-defined roles of sphingolipids in cell membranes, their possible physiological role in lipoprotein metabolism has recently gained attention. Increased circulating levels of sphingomyelins and ceramides were observed in obesity, diabetes, and cardiovascular diseases. Although lipid abnormalities such as hypocholesterolemia and relatively increased triglycerides were reported in beta-thalassemia patients, there is no study investigating sphingolipid levels in thalassemia. Therefore, we investigate certain long chain and very long chain sphingomyelins and ceramides in beta-thalassemia patients who are under routine follow-up in our hospital. Thalassemia major patients who applied to the hospital for regular blood transfusion and gave consent were included in the study. Blood samples were obtained before transfusion. Plasma sphingomyelin (C16, C18 and C24) and ceramide (C16, C18, C20, C22, C24) species were measured by triple quadruple LC-ESI-MS/MS (Shimadzu, Japan). D-erythrosphingosine-D9 (Matreya) was used as an internal standard, all other lipid standards were from Avanti. Body iron stores of the patients were monitored by serum ferritin levels. A total of thirty patients were included in the study. All patients typically received regular erythrocyte suspension transfusions every three weeks and continuous oral iron chelation therapy. Twenty of the patients had a previous splenectomy. The mean age was 34.5 ±8.1 years in the splenectomy group and 32.8 ±8 years in the group without splenectomy. Mean ferritin levels were not different between the groups, being 1073.2±563.5 µg/L in splenectomy and 1709 ±1660.4 µg/L in non-splenectomy groups. All measured sphingolipid levels were similar between splenectomy and non-splenectomy groups. When correlation analysis was performed between measured sphingolipid and ferritin levels, significant negative correlations were found between sphingomyelin C16 (r= -0.591 p&amp;lt;0.006) and C18 (r= -0.594 p&amp;lt;0.006) with ferritin levels in the splenectomy group. However, this negative correlation was absent in the non-splenectomy group. In conclusion, we found that iron overload is associated with lower plasma sphingomyelin levels in splenectomized thalassemia patients. We have been working on the lipidomic analysis of the plasma and erythrocytes of thalassemia patients and other hemolytic anemias. The results may further help to get a better picture of lipid metabolism in thalassemia.

Monte Carlo simulations of cefepime in children receiving continuous kidney replacement therapy support continuous infusions for target attainment

BackgroundSepsis is a leading cause of acute kidney injury requiring continuous kidney replacement therapy (CKRT) and CKRT can alter drug pharmacokinetics (PK). Cefepime is used commonly in critically ill children and is cleared by CKRT, yet data regarding cefepime PK and pharmacodynamic (PD) target attainment in children receiving CKRT are scarce, so we performed Monte Carlo simulations (MCS) of cefepime dosing strategies in children receiving CKRT.MethodsWe developed a CKRT “module” in the precision dosing software Edsim++. The module was added into a pediatric cefepime PK model. 1000-fold MCS were performed using six dosing strategies in patients aged 2–25 years and ≥ 10 kg with differing residual kidney function (estimated glomerular filtration rate of 5 vs 30 mL/min/1.73 m2), CKRT prescriptions, (standard-dose total effluent flow of 2500 mL/h/1.73 m2 vs high-dose of 8000 mL/h/1.73 m2), and fluid accumulation (0–30%). Probability of target attainment (PTA) was defined by percentage of patients with free concentrations exceeding bacterial minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT > 1xMIC) and 4xMIC using an MIC of 8 mg/L for Pseudomonas aeruginosa.ResultsAssuming standard-dose dialysis and minimal kidney function, > 90% PTA was achieved for 100% fT > 1x MIC with continuous infusions (CI) of 100–150 mg/kg/day (max 4/6 g) and 4-h infusions of 50 mg/kg (max 2 g), but > 90% PTA for 100% fT > 4x MIC was only achieved by 150 mg/kg CI. Decreased PTA was seen with less frequent dosing, shorter infusions, higher-dose CKRT, and higher residual kidney function.ConclusionsOur new CKRT-module was successfully added to an existing cefepime PK model for MCS in young patients on CKRT. When targeting 100% fT > 4xMIC or using higher-dose CKRT, CI would allow for higher PTA than intermittent dosing.