Intravenous immunoglobulin alteration in response to adverse reactions in neurological conditions: A retrospective cohort study.

INTRODUCTION: Intravenous immunoglobulin (IVIg) is an important treatment in a range of neurological conditions. There is currently limited evidence regarding the frequency and management of IVIg-associated adverse reactions (AR) in neurological disorders. METHODS: A single-centre 18-month retrospective cohort study was conducted for all patients at a single tertiary hospital receiving IVIg as an inpatient or the medical day unit. Electronic medical record AR and alerts were reviewed for entries relating to IVIg, and prescribing records associated with recent IVIg administration were reviewed for the use of premedications. Case note review was undertaken to identify AR associated with alterations in IVIg treatment (such as reduction in rate, use of premedications or cessation of IVIg). Demographic, patient, and treatment factors were analysed for associations with AR necessitating alteration in IVIg treatment. RESULTS: This study included 98 individuals who received IVIg during the study period. Of these, 12 (12.1%) patients required an alteration in their IVIg treatment. In total, 3 (3.1%) of the 98 included patients required a reduced rate of IVIg, and 10 (10.2%) patients received premedication. The most common premedications were normal saline at the time of the infusion, cetirizine, and hydrocortisone. No demographic factors, indications or comorbidities were found to be associated with an increased likelihood of AR. However, an IVIg daily dose of >35 g and >45 g were associated with an increased likelihood of requiring IVIg treatment alteration due to AR. CONCLUSIONS: Alterations to IVIg treatment due to AR are commonly required in neurology patients, and may be associated with higher daily doses of IVIg.

Isopropyl alcohol inhalation versus 5-HT3 antagonists for treatment of nausea: a meta-analysis of randomised controlled trials.

PURPOSE: Nausea is a common and unpleasant sensation for which current therapies such as serotonin (5-HT3) antagonists are often ineffective, while also conferring a risk of potential adverse events. Isopropyl alcohol (IPA) has been proposed as a treatment for nausea. We aimed to compare IPA with 5-HT3 antagonists for the treatment of nausea across all clinical settings. METHODS: MEDLINE, EMBASE, PubMed, CENTRAL and CINAHL were searched from inception to 17 July 2023 for randomised controlled trials (RCTs) comparing inhaled IPA and a 5-HT3 antagonist for treatment of nausea. Severity and duration of nausea, rescue antiemetic use, adverse events and patient satisfaction were the outcomes sought. Risk of bias (RoB) was assessed using Cochrane RoB 2. Random-effects model was used for meta-analysis. Combination of meta-analyses and narrative review was used to synthesise findings. The evidence was appraised using GRADE. RESULTS: From 1242 records, 4 RCTs were included with 382 participants. Participants receiving IPA had a significantly lower mean time to 50% reduction in nausea (MD - 20.06; 95% CI - 26.26, - 13.85). Nausea score reduction at 30 min was significantly greater in the IPA group (MD 21.47; 95% CI 15.47, 27.47). IPA led to significantly reduced requirement for rescue antiemetics (OR 0.60; 95% CI 0.37, 0.95; p = 0.03). IPA led to no significant difference in patient satisfaction when compared with a 5-HT3 antagonist. The overall GRADE assessment of evidence quality ranged from very low to low. CONCLUSION: IPA may provide rapid, effective relief of nausea when compared with 5-HT3 antagonists.

Adverse Reactions Associated with Intravenous Immunoglobulin Administration in the Treatment of Neurological Disorders: A Systematic Review.

Intravenous immunoglobulin (IVIg), which is used to treat multiple neurological conditions, may be associated with serious adverse reactions. The individual neurological disease characteristics associated with adverse reactions, along with strategies to prevent and treat adverse reactions, are uncertain. A systematic review was conducted of the databases PubMed, Embase, and Cochrane Library to summarise studies that report adverse reactions of IVIg therapy in patients with neurological disease. There were 65 studies included in the review. The reported rates of adverse reactions vary widely, but the best evidence suggests rates between 25 and 34% per patient. Common adverse reactions include headache and laboratory abnormalities. Less common but serious adverse reactions included thromboembolic complications and anaphylaxis. Overall, there is a lack of high-quality comparative data to definitively determine if any specific neurological indications are associated with a higher risk of adverse reactions. However, individual neurological disease characteristics possibly associated with an increased likelihood of adverse reactions include limited mobility (as in certain neuromuscular conditions), paraproteinaemia (as in certain peripheral neuropathies), and cardiomyopathy (as in certain myopathies). There is limited evidence to support the effectiveness of prevention and treatment strategies, which may include modification to dose, reduced infusion rate, and premedication. Further studies regarding methods to prevent and treat IVIg-ARs in neurology patients are required.

Association of physiological reserve measures with adverse outcomes following liver transplantation.

BACKGROUND AND AIM: The comparative utility of physiological reserve measures in predicting important clinical outcomes following liver transplantation (LT) requires further study. The aim of this work was therefore to compare the utility of physiological reserve measures in predicting early adverse clinical outcomes post-LT. METHODS: A single-center, retrospective cohort study of LT patients consecutively recruited between 1 January 2015, and 31 August 2020. Outcomes measured were sepsis and death within 12 months of LT, hospital length of stay (LOS), and intensive care LOS. Physiological reserve measures were handgrip strength, mid-arm muscle circumference, and cardiopulmonary exercise testing (CPET) measures. Analysis was performed using univariate and multivariate logistic regression for sepsis and death, and univariate and multivariate Cox regression for hospital and intensive care LOS. RESULTS: Data were obtained for 109 subjects. Patients were predominantly (64%) male with a median (interquartile range [IQR]) age of 57 (49-63) and median (IQR) Model for End-Stage Liver Disease score of 16 (11-21). In multivariate analysis, the odds of sepsis were lower in patients in the highest versus lowest tertile (odds ratio = 0.004; 95% confidence interval [CI] 0.00-0.13; P = 0.002). Hospital LOS was linearly associated with handgrip strength (hazard ratio [HR] = 1.03; 95% CI 1.00-1.06; P = 0.03) in multivariate analysis. Intensive care LOS was associated with peak VO2 (HR 1.83; 95% CI 1.06-3.16; P = 0.03) and VE/VCO2 slope (HR 0.71; 95% CI 0.58-0.88; P = 0.002) in multivariate analysis. CONCLUSION: Handgrip strength and CPET both identify candidates at high risk of adverse outcomes after LT.

Continuous mixing technology: Validation of a DEM model.

Continuous powder mixing is an important technology used in the development and manufacturing of solid oral dosage forms. Since critical quality attributes of the final product greatly depend on the performance of the mixing step, an analysis of such a process using the Discrete Element Method (DEM) is of crucial importance. On one hand, the number of expensive experimental runs can be reduced dramatically. On the other hand, numerical simulations can provide information that is very difficult to obtain experimentally. In order to apply such a simulation technology in product development and to replace experimental runs, an intensive model validation step is required. This paper presents a DEM model of the vertical continuous mixing device termed CMT (continuous mixing technology) and an extensive validation workflow. First, a cohesive contact model was calibrated in two small-scale characterization experiments: a compression test with spring-back and a shear cell test. An improved, quicker calibration procedure utilizing the previously calibrated contact models is presented. The calibration procedure is able to differentiate between the blend properties caused by different API particle sizes in the same formulation. Second, DEM simulations of the CMT were carried out to determine the residence time distribution (RTD) of the material inside the mixer. After that, the predicted RTDs were compared with the results of tracer spike experiments conducted with two blend material properties at two mass throughputs of 15 kg/h and 30 kg/h. Additionally, three hold-up masses (500, 730 and 850 g) and three impeller speeds (400, 440 and 650 rpms) were considered. Finally, both RTD datasets from DEM and tracer experiments were used to predict the damping behavior of incoming feeder fluctuations and the funnel of maximum duration and magnitude of incoming deviations that do not require a control action. The results for both tools in terms of enabling a control strategy (the fluctuation damping and the funnel plot) are in excellent agreement, indicating that DEM simulations are well suited to replace process-scale tracer spike experiments to determine the RTD.

Continuous Mixing Technology: Characterization of a Vertical Mixer Using Residence Time Distribution.

Continuous powder mixing technology (CMT) application during continuous direct compression has emerged as a leading technology used in the development and manufacture of solid oral dosage forms. The critical quality attributes of the final product are heavily dependent on the performance of the mixing step as the quality of mixing directly influences the drug product quality attributes. This study investigates the impact of blend material properties (bulk density, API particle size distribution) and process parameters (process throughput, hold up mass and impeller speed) on the mixing performance. Mixing of the blend was characterized using the Residence Time Distribution (RTD) of the process by trending the outlet stream of the mixer using a near-infrared (NIR) probe after the injection of a small mass of tracer at the inlet stream. The outcomes of this study show that the RTDs of the mixer with throughput ranging between 15 and 30 kg/h; impeller speed ranging between 400 and 600 rpm and hold up mass (HUM) ranging between 500 and 850 g can be described by a series of two ideal Continuous Stirred Tank Reactors (CSTRs) with different volumes, and correspondingly, different mean residence times. It is also observed that the mixing is mainly occurring in the lower chamber of the CMT and the normalized RTDs of the mixer are similar across the range of process conditions and material attributes studied. The results also showed that the formulation blend with different API particle sizes and bulk properties, like bulk density and flowability, provide insignificant impact on the mixing performance. The CMT allows independent selection of target set points for HUM, impeller rotational speed and line throughput and it shows great robustness and flexibility for continuous blending in solid oral dose manufacturing.

Young-onset colorectal cancer is associated with a personal history of type 2 diabetes.

BACKGROUND: Colorectal cancer (CRC) is rising in incidence in young adults, and this observation is currently unexplained. We investigated whether having a personal history of type 2 diabetes mellitus (T2D) was a potential risk factor for young-onset colorectal cancer (YOCRC). METHODS: The South Australian Young Onset (SAYO) CRC study is a series of young adults with CRC below age 55. Ninety unrelated YOCRC cases were recruited to the study. Personal history and detailed family history of T2D were obtained at face-to-face interview and confirmed from medical records. Whole exome sequencing was conducted on germline DNA from each CRC case. Controls for personal history studies of T2D were 240 patients with proven clear colonoscopies and no known CRC predispositions. RESULTS: The median age of YOCRC cases was 44 years (18-54) and of controls was 45 years (18-54), and 53% of both cases and controls were females (P = 0.99). Left-sided (distal) CRC was seen in 67/89 (75%) of cases. A personal history of T2D was confirmed in 17/90 (19%) YOCRC patients compared with controls (12/240, 5%; P < 0.001; odds ratio = 4.4; 95% confidence interval, 2.0-9.7). YOCRC patients frequently reported at least one first-degree relative with T2D (32/85, 38%). Ten of 87 (12%) of YOCRC cases had CRC-related pathogenic germline variants, however, no pathogenic variants in familial diabetes-associated genes were seen. CONCLUSIONS: Though the mechanism remains unclear, our observations suggest that there is enrichment for personal history of T2D in YOCRC patients. IMPACT: A diagnosis of T2D could therefore potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate.

Pacemaker Implantation in Patient With Persistent Left Superior Vena Cava and Absent Right Superior Vena Cava.

Persistent left superior vena cava (LSVC) is an asymptomatic congenital heart disease. It is usually found incidentally on imaging, during central line placements or while undergoing electrophysiological procedures. We present a case of a 91-year-old female who initially presented with seizures and was diagnosed with tachy-brady syndrome. She was planned to undergo dual-chamber permanent pacemaker placement. However, during the procedure, she was incidentally found to have an LSVC without a right superior vena cava. Due to challenging anatomy, her pacemaker was changed to a single-chamber atrial lead pacemaker. This case highlights the clinical implications of this unusual structural anomaly, technical difficulties that arise alongside and solutions on how to overcome these issues in the context of pacemaker implantation.

The Disappearing Murmur: Systolic Anterior Motion of the Mitral Valve Leaflet in a Non-hypertrophic Cardiomyopathy Patient.

Systolic anterior motion (SAM) of the mitral valve is a well-known phenomenon associated with left ventricular outflow tract obstruction and hemodynamic compromise. This finding may occur in patients with or without hypertrophic cardiomyopathy. In this report, a patient with no prior medical history presented to the hospital with left-sided chest pain and high-risk echocardiogram (ECG) findings. Left heart catheterization with coronary angiography was negative for coronary artery disease. His initial examination was significant for a systolic murmur due to the underlying SAM, as demonstrated by transthoracic echocardiogram. During his hospitalization, he developed acute heart failure syndrome as a result of dynamic outflow tract obstruction. He was treated with fluid resuscitation with a resolution of his hemodynamic compromise. On a follow-up examination, there was no murmur and SAM was no longer present on echocardiogram. This case demonstrates the importance of recognizing the clinical manifestations of SAM as well as its role in maintaining an appropriate hemodynamic status.

Syncopal Episodes of Arrhythmogenic Right Ventricular Cardiomyopathy in a Patient with Pre-existing Seizure Disorder.

Arrhythmogenic right ventricular cardiomyopathy (ARVC), is a heritable condition that is an important, and under-recognized cause of sudden cardiac death. Microscopically, it is represented by fibrofatty replacement of myocardium involving the right ventricular inflow area, apex, and infundibulum. Common clinical manifestations of ARVC include palpitations, syncope, chest pain, dyspnea, and sudden cardiac death. This is a case of a 25-year-old male with a history of thalassemia, and tonic-clonic seizure status post head trauma with cystic encephalomalacia in left parietal lobe who described recurrent syncope. He was followed by neurology and maintained only on Lamotrigine. Episodes occurred within the span of four weeks and were without prodrome, lasting only a few seconds. On evaluation, blood pressure was 123/69 mmHg. Neurologic exam was grossly normal. Heart was regular rate and rhythm without gallops, murmur, or rub. An EKG showed normal sinus rhythm with an incomplete right bundle branch block and Epsilon waves in leads V1 and V2 without evidence of Brugada syndrome. The patient was admitted and had a 24-hour electroencephalogram that showed no seizure activity. A 2D Echo showed normal left ventricular function and no valvular disease. Eventual cardiac magnetic resonance imaging (MRI) showed small focal outpouchings of the right ventricular free wall. A diagnosis of ARVC was achieved, and the patient underwent electrophysiology (EP) study and successful implantation of a dual-chamber cardioverter defibrillator.