Large Bolus Research Articles

The role of anti-osteoporosis drugs in fall risk

Osteoporosis is a common skeletal disease characterized by reduced bone mass and micro-architectural deterioration, which leads to an increased risk of fractures. A significant concern associated with osteoporosis is the risk of falls, which can result in fractures and other related complications. This review examines the role of anti-osteoporosis drugs in the prevention of falls, focusing on pharmacological interventions that have shown promise in reducing the incidence of falls in osteoporotic patients. Falls in older people often lead to fractures, decreased mobility and reduced quality of life. Given that individuals with osteoporosis are more susceptible to fractures, it is essential to explore therapeutic strategies aimed at mitigating fall risk in this population. Anti-osteoporosis drugs have been developed primarily to improve bone mineral density and strength. The most extensively explored in this sense is probably vitamin D. Several meta-analyses have indicated that vitamin D could reduce the risk of falling compared with placebo. For this nutrient, important in vitro and experimental research data are available showing, overall, a positive effect on muscle. However, there is emerging evidence that large bolus doses and/or high levels of vitamin D may increase the risk of falls. Denosumab, a monoclonal antibody against RANKL (receptor activator of nuclear factor-кB ligand), is widely used to treat osteoporosis, and its influence on falls, although supported by a recent systematic review, is currently under investigation. Understanding the relationship between anti-osteoporosis medications and fall prevention is critical in comprehensive management of osteoporosis. Although these drugs are primarily used to improve bone health, their influence on falls is an intriguing topic. KEY WORDS: Falls, denosumab, vitamin D, romosozumab.

Association between Self-Perception of Chewing, Chewing Behavior, and the Presence of Gastrointestinal Symptoms in Candidates for Bariatric Surgery.

Given the changes in the digestive tract post-bariatric surgery, adapting to a new pattern of eating behavior becomes crucial, with special attention to the specifics of chewing mechanics. This study aimed to investigate the association between self-perception of chewing, chewing behavior, and the presence of gastrointestinal symptoms in preoperative patients undergoing bariatric surgery. Sixty adult candidates for bariatric surgery at a public hospital in Belém (Brazil) were analyzed. Participants predominantly exhibited unilateral chewing patterns (91.6%), a fast chewing rhythm (73.3%), a large food bolus (80%), liquid intake during meals (36.7%), and 41.7% reported that chewing could cause some issue. Significant associations were found between the perception of causing problems and chewing scarcity (p = 0.006), diarrhea (p = 0.004), absence of slow chewing (p = 0.048), and frequent cutting of food with front teeth (p = 0.034). These findings reveal a relationship between the perception of chewing problems and chewing scarcity, presence of diarrhea, and fast chewing.

Levosimendan and Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials.

Atrial fibrillation (AF) is a prevalent complication associated with levosimendan; however, it remains uncertain whether there are any disparities in the effects of levosimendan on non-postoperative and postoperative AF. This study aimed to evaluate the levosimendan effect on non-postoperative and postoperative AF by conducting a meta-analysis of randomized control trials (RCTs). PubMed, Embase, Cochrane Library, and other databases were searched. Pairs of reviewers identified RCTs that compared levosimendan and placebo or other therapies, and the results reported AF events data. Random effects models were used (at a significance level of 5%). Twenty-nine eligible trials comprising 6550 participants were included, eleven of which evaluated the non-postoperative AF incidence, and 18 included postoperative AF. The analysis revealed that levosimendan elevated the AF risk significantly in the non-postoperative group (OR, 1.62; 95% CI: 1.19-2.20; p=0.002) and reduced the AF incidence in the postoperative group (OR, 0.65; 95% CI: 0.44-0.96; p=0.03). AF occurrence decreased more significantly in patients who used levosimendan after cardiac surgery (OR, 0.53; 95% CI: 0.32-0.88; p=0.02) than in patients who used levosimendan before cardiac surgery (OR, 0.67; 95% CI: 0.42-1.06; p=0.09). Moreover, The AF risk was significantly elevated by levosimendan large bolus dose (bolus dose≥12 μg/kg) (OR, 1.44; 95% CI: 1.10-1.88; p=0.004) and decreased by small bolus dose of levosimendan (bolus dose<12 μg/kg) (OR, 0.64; 95% CI: 0.34-1.20; p=0.16). Levosimendan was linked to an increased non-postoperative AF incidence. The employment of levosimendan was effective in preventing postoperative AF.

Levosimendana e Fibrilação Atrial: Uma Metanálise de Ensaios Clínicos Randomizados

Abstract Background Atrial fibrillation (AF) is a prevalent complication associated with levosimendan; however, it remains uncertain whether there are any disparities in the effects of levosimendan on non-postoperative and postoperative AF. Objectives This study aimed to evaluate the levosimendan effect on non-postoperative and postoperative AF by conducting a meta-analysis of randomized control trials (RCTs). Methods PubMed, Embase, Cochrane Library, and other databases were searched. Pairs of reviewers identified RCTs that compared levosimendan and placebo or other therapies, and the results reported AF events data. Random effects models were used (at a significance level of 5%). Results Twenty-nine eligible trials comprising 6550 participants were included, eleven of which evaluated the non-postoperative AF incidence, and 18 included postoperative AF. The analysis revealed that levosimendan elevated the AF risk significantly in the non-postoperative group (OR, 1.62; 95% CI: 1.19-2.20; p=0.002) and reduced the AF incidence in the postoperative group (OR, 0.65; 95% CI: 0.44-0.96; p=0.03). AF occurrence decreased more significantly in patients who used levosimendan after cardiac surgery (OR, 0.53; 95% CI: 0.32-0.88; p=0.02) than in patients who used levosimendan before cardiac surgery (OR, 0.67; 95% CI: 0.42-1.06; p=0.09). Moreover, The AF risk was significantly elevated by levosimendan large bolus dose (bolus dose≥12 μg/kg) (OR, 1.44; 95% CI: 1.10-1.88; p=0.004) and decreased by small bolus dose of levosimendan (bolus dose&lt;12 μg/kg) (OR, 0.64; 95% CI: 0.34-1.20; p=0.16). Conclusion Levosimendan was linked to an increased non-postoperative AF incidence. The employment of levosimendan was effective in preventing postoperative AF.

The anabolic response to protein ingestion during recovery from exercise has no upper limit in magnitude and duration in vivo in humans

The belief that the anabolic response to feeding during postexercise recovery is transient and has an upper limit and that excess amino acids are being oxidized lacks scientific proof. Using a comprehensive quadruple isotope tracer feeding-infusion approach, we show that the ingestion of 100g protein results in a greater and more prolonged (>12 h) anabolic response when compared to the ingestion of 25g protein. We demonstrate a dose-response increase in dietary-protein-derived plasma amino acid availability and subsequent incorporation into muscle protein. Ingestion of a large bolus of protein further increases whole-body protein net balance, mixed-muscle, myofibrillar, muscle connective, and plasma protein synthesis rates. Protein ingestion has a negligible impact on whole-body protein breakdown rates or amino acid oxidation rates. These findings demonstrate that the magnitude and duration of the anabolic response to protein ingestion is not restricted and has previously been underestimated invivo in humans.

A Receptor Story: Insulin Resistance Pathophysiology and Physiologic Insulin Resensitization's Role as a Treatment Modality.

Physiologic insulin secretion consists of an oscillating pattern of secretion followed by distinct trough periods that stimulate ligand and receptor activation. Apart from the large postprandial bolus release of insulin, β cells also secrete small amounts of insulin every 4-8 min independent of a meal. Insulin resistance is associated with a disruption in the normal cyclical pattern of insulin secretion. In the case of type-2 diabetes, β-cell mass is reduced due to apoptosis and β cells secrete insulin asynchronously. When ligand/receptors are constantly exposed to insulin, a negative feedback loop down regulates insulin receptor availability to insulin, creating a relative hyperinsulinemia. The relative excess of insulin leads to insulin resistance (IR) due to decreased receptor availability. Over time, progressive insulin resistance compromises carbohydrate metabolism, and may progress to type-2 diabetes (T2D). In this review, we discuss insulin resistance pathophysiology and the use of dynamic exogenous insulin administration in a manner consistent with more normal insulin secretion periodicity to reverse insulin resistance. Administration of insulin in such a physiologic manner appears to improve insulin sensitivity, lower HgbA1c, and, in some instances, has been associated with the reversal of end-organ damage that leads to complications of diabetes. This review outlines the rationale for how the physiologic secretion of insulin orchestrates glucose metabolism, and how mimicking this secretion profile may serve to improve glycemic control, reduce cellular inflammation, and potentially improve outcomes in patients with diabetes.

Mechanistic approaching study in COVID-19 patients treated with high doses of vitamin D

Aim: To evaluate angiotensin II (Ang II) and Ang-(1-7) levels and the cytokine profile in patients hospitalized with mild coronavirus disease 2019 (COVID-19) and contrast them with patients with identical clinical conditions but treated with high doses of vitamin D (vitD). Methods: From the 218 patients recruited (ClinicalTrials.gov NCT04411446), 16 participated in this sub-study and were randomized to a single oral dose of 500,000 IU vitD (n = 10) or placebo (n = 6). Plasmatic Ang II and Ang-(1-7) levels were determined by radioimmunoassay and interleukins (ILs) 1, 6, 8, and 10 and tumor necrosis factor alpha (TNF-α) by enzyme-linked immunosorbent assay before and after treatment. Parallel, serum 25-hydroxyvitamin D3 (25-OH vitD) concentrations as vitD status was measured by a chemiluminescence immunoassay. Results: A trend towards an increase in Ang-(1-7) and a decrease in Ang II levels were observed in placebo- and vitD-treated COVID-19 patients compared to baseline values. There was no difference in Ang II and Ang-(1-7) levels between placebo- and vitD-treated COVID-19 patients. Similar results were obtained with ILs profile. COVID-19 patients showed an increase in the protective component of the RAS which was not improved by vitD treatment. Conclusions: VitD did not improve RAS disbalance in COVID-19. Notwithstanding, the authors visualize that acute treatment with high doses of vitD may show a trend to a decline in inflammatory ILs and an increase in protective markers. Finally, the authors would like to highlight the limitations of this preliminary study, namely the small number of patients and the use of a large single bolus dose of vitD rather than lower daily doses for extended periods with prolonged follow-up times. All these factors need special consideration in the designs of new vitD supplementation trials. All these factors need special consideration in the designs of new vitD supplementation trials (ClinicalTrials.gov identifier: NCT04411446).

Effect of Glycerol-Induced Hyperhydration on a 5-kilometer Running Time-Trial Performance in the Heat in Recreationally Active Individuals.

Maximal oxygen consumption (V˙O2max) is a major determinant of 5-km running time-trial (TT) performance. Glycerol-induced hyperhydration (GIH) could improve V˙O2max in recreationally active persons through an optimal increase in plasma volume. Moreover, ingestion of a large bolus of cold fluid before exercise could decrease thermal stress during exercise, potentially contributing to improved performance. We determined the effect of GIH on 5-km running TT performance in 10 recreationally active individuals (age: 24 ± 4 years; V˙O2max: 48 ± 3 mL/kg/min). Using a randomized and counterbalanced protocol, participants underwent two, 120-min hydration protocols where they ingested a 1) 30 mL/kg fat-free mass (FFM) of cold water (~4 °C) with an artificial sweetener + 1.4 g glycerol/kg FFM over the first 60 min (GIH) or 2) 7.5 mL/kg FFM of cold water with an artificial sweetener over the first 20 min (EUH). Following GIH and EUH, participants underwent a 5-km running TT at 30 °C and 50% relative humidity. After 120 min, GIH was associated with significantly greater fluid retention (846 ± 415 mL) and plasma volume changes (10.1 ± 8.4%) than EUH, but gastrointestinal (GI) temperature did not differ. During exercise, 5-km running TT performance (GIH: 22.95 ± 2.62; EUH: 22.52 ± 2.74 min), as well as heart rate, GI temperature and perceived exertion did not significantly differ between conditions. This study demonstrates that the additional body water and plasma volume gains provided by GIH do not improve 5-km running TT performance in the heat in recreationally active individuals.

Vitamin D in the older population: a consensus statement.

BackgroundThis paper reports results from the 5th International Conference “Controversies in Vitamin D” that was held in Stresa, Italy, 15–18 September 2021. The conference is part of this series that started in 2017 and has been conducted annually since. The objective of these conferences is to identify timely and controversial topics related to Vitamin D. Dissemination of the results of the conference through publications in peer-reviewed journals is an important means by which the most up to date information can be shared with physicians, investigators, and other health care professionals. Vitamin D and aging, the subject of this paper was featured at the conference.MethodsParticipants were selected to review available literature on assigned topics related to vitamin D and aging and to present their findings with illustrative material, the intent of which was to stimulate discussion and to arrive at a consensus. The presentations were directed towards the following areas: impact of aging on vitamin D production and levels; skeletal effects of vitamin D deficiency in the older population; falls and vitamin D in the aging; potential extra skeletal effects of vitamin D; and strategies to prevent vitamin D deficiency. A final topic was related to how vitamin D might influence the efficacy of vaccines for Covid-19.ResultsHypovitaminosis D can lead to several skeletal and extra-skeletal outcomes. Older adults are at risk for vitamin D deficiency as both production and metabolism of vitamin D change with aging due to factors, such as reduced sun exposure and reduced production capacity of the skin. Skeletal consequences of these age-related changes can include reduced bone mineral density, osteomalacia and fractures. Potential extra-skeletal effects can include added risks for falls, reduced muscle strength, diabetes, cancer, and cardiovascular disease. Strategies to avoid these vitamin D deficiency-related negative outcomes include sun exposure, food fortification, and supplementation. While aging does not diminish sufficient reserve capacity for cutaneous vitamin D production, concerns about skin cancers and practical matters for the institutionalized elderly limit this option. Supplementation with vitamin D is the best option either pharmacologically or through food fortification. Regardless of treatment strategies, interventions to restore sufficient vitamin D status will show positive results only in those who are truly deficient. Thus, treatment goals should focus on avoiding 25(OH)D serum levels <30 nmol/l, with a goal to reach levels >50 nmol/l.ConclusionsThe results of this conference has led to consensus on several issues. Vitamin D supplementation should be combined with calcium to reduce fractures in the older population. The goal for adequate Vitamin D status should be to reach a serum level of 25(OH)D >50 nmol/l. It appears that daily low-dose vitamin D regimens reduce the risk of falling, especially in the elderly, compared with infrequent, large bolus doses that may increase it. The role of Vitamin D supplementation on muscle strength remains to be clarified. On the other hand, supplementation decreases the risk of progression to T2D from prediabetes among those who are Vitamin Ddeficient. Of three possible strategies to establish vitamin D sufficiency – sunshine exposure, food fortification, and supplementation – the latter seems to be the most effective and practical in the aging population.

Contrast Beware! Single-Institution Experience Contra-Indicating the Use of Contrast-Enhanced Simulation CT Images for Online Adaptive Treatment Planning

<h3>Purpose/Objective(s)</h3> Online adaptive radiotherapy is in its nascent years of clinical implementation. Recently, a dedicated CBCT-based adaptive radiotherapy delivery system was cleared by the FDA for clinical use. While academic institutions have seen rapid adoption of these systems, established clinical guidelines may not be reproducible in the adaptive environment. Here we share our clinical experience on the use of intravenous (IV) contrast during CT simulation for a patient to be treated with CBCT-based adaptive therapy. <h3>Materials/Methods</h3> Recently, our institution simulated a candidate for lung SBRT with an upper left lobe mass. The intent for this treatment was to deliver 52.5 Gy to the GTV using the treatment delivery system. Per institutional protocol, all thoracic SBRT cases are simulated acquiring a free-breathing CT scan which is then followed by the acquisition of a 4DCT scan. As part of this protocol, IV-iodine contrast is applied during 4DCT acquisition for improved ITV definition. CT scans are acquired on a scanner using 120 kVp, 1400 mAs, and an IMR reconstruction filter. CT slice thickness is set to 2 mm and pixel spacing is 1.11 mm. A maximum intensity projection (MIP) and average (AVG) scans are derived from the 4DCT scan for target delineation and planning, respectively. <h3>Results</h3> As physics began planning, it was noticed that a large bolus of IV contrast remained clustered at the junction of the left subclavian and left internal jugular veins, which was located very near (< 4 cm) to the intended target volume. Furthermore, the bolus of contrast was in a position that occluded radiation entry to the target from angles anterior through the patient's left side. By design, the treatment delivery system only provides limited options for density overrides of volumes (water, bone, or titanium). Even with careful determination and assignment of materials to contoured "artifact" volumes in a planning CT scan, these density override assignments are carried over in dose calculation of online adaptive sessions. In addition, since the treatment delivery system uses deformable image registration to map the planning CT with the daily CBCT to improve the accuracy of online adaption dose calculation, errors in registration caused by the lack of presence of iodine contrast during CBCT acquisition could result in increased dose uncertainties on the order of approximately 5-7%. Based on these estimates, this case was re-planned prior to treatment delivery using the free-breathing CT scan. <h3>Conclusion</h3> Due to the treatment delivery system online adaptive methodology, errors that propagate from a bolus of contrast in proximity to the target need to be prospectively estimated using an emulator. At a minimum, planning for Ethos should be done on non-contrast scans to better represent the daily CBCT that is used for deformation.

Vitamin D Status and Fracture Healing: A Systematic Review of 63 Studies

Category: Other Introduction/Purpose: There is little consensus on the effects of vitamin D on fracture healing. This review aims to clarify that effect in addition to determining trends in the classification of deficiency and supplementation. Methods: This systematic review searched Pubmed, Embase, and Web of Science for manuscripts related to vitamin D status/deficiency and fracture healing. Two independent reviewers screened articles, graded evidence quality, and extracted data. A total of 38 human studies, 11 in vivo studies and 14 systematic reviews were analyzed. Results: The median vitamin D deficiency prevalence reported amongst the human studies was 41.2% which is comparable to subset of patients with deficiency defined as &lt;20 ng/mL, 43.3%. Amongst the 9 human studies reporting vitamin D supplementation, the exact dosage varied greatly. No RCTs reported any radiographic evidence of increased fracture union with any form of supplementation. Several RCTs reported reduction in pain with smaller daily supplementation compared to placebo or single large boluses. Animal studies reported mixed results, with some showing no significant effects of vitamin D status on the biomechanical properties of bone, while others demonstrated a correlation between supplementation improved biomechanical stiffness. Furthermore, the metabolite 24,25D may be a mediator in Vitamin D's probable osteoprotective effects. Conclusion: While the role of vitamin D in fracture healing appears to be osteoprotective in animal models, the degree and significance of its effects on human fracture healing and prevention remains inconclusive. We recommend standardizing the definitions for vitamin D deficiency to be &lt;20 ng/mL for deficiency and &gt;30 ng/mL for sufficiency. Although there is no radiographic evidence, daily smaller doses of vitamin D supplementation seem to have a stronger impact on clinical fracture healing than large boluses.

S2403 A Rare Case of Lymphocytic Esophagitis Presenting With Food Impaction

Introduction: Lymphocytic esophagitis (LyE) was first described in the literature in 2006 and remains a very rare diagnosis, with diagnostic criteria being met in only 0.1% of esophageal biopsies. LyE shares features with GERD and eosinophilic esophagitis and is often misdiagnosed. It is most common in middle-aged women and presents with very nonspecific symptoms, most commonly dysphagia. Esophageal biopsy is the gold standard for diagnosis and LyE is currently defined solely on histological criteria. Treatment options are limited, with proton-pump inhibitors (PPIs) being the first line treatment. Case Description/Methods: A 71-year-old male with a past medical history of hypertension and tobacco and alcohol use disorder presented after experiencing an episode of acute dysphagia to solids and liquids. Urgent EGD was performed, which showed a large food bolus at the distal esophagus/gastroesophageal junction. This was fragmented and pushed distally into the stomach by an endoscopic retrieval device. Several ulcers were present in the lower esophagus and biopsies taken showed mild erosive gastropathy and duodenitis. Repeat EGD was performed 8 weeks later, and a distal esophageal stricture was noted and was dilated with a balloon dilator to 15mm. Biopsies taken of the proximal and distal esophagus showed squamous mucosa with >20 intraepithelial lymphocytes per high-power field with rare neutrophils and rare eosinophils with associated patchy, peripapillary lymphocytic infiltrates, consistent with LyE. Patient was placed on a proton-pump inhibitor twice daily with reported improvement of symptoms and resolution of dysphagia at follow-up. Discussion: Lymphocytic esophagitis (LyE) is a very rare cause of esophagitis and is often misdiagnosed due to its variable symptoms and nonspecific gross appearance on endoscopy. Diagnosis can only be made with biopsy, specifically the presence of >20 intraepithelial lymphocytes per high-power field. Food impaction is a rare presentation of LyE and has only been shown in around 9% of cases. Although the pathogenesis remains unknown, inflammation has been associated with the development of this condition. LyE was diagnosed in this male patient after endoscopic removal of food impaction, resulting in stricture. This could support the theory that inflammation due esophageal trauma/injury could be associated with the development of LyE. This diagnosis is important to keep on the differential for causes of esophagitis.

Vitamin D and COVID-19-Revisited.

Vitamin D, when activated to 1,25‐dihydroxyvitamin D, is a steroid hormone that induces responses in several hundred genes, including many involved in immune responses to infection. Without supplementation, people living in temperate zones commonly become deficient in the precursor form of vitamin D, 25‐hydroxyvitamin D, during winter, as do people who receive less sunlight exposure or those with darker skin pigmentation. Studies performed pre‐COVID‐19 have shown significant but modest reduction in upper respiratory infections in people receiving regular daily vitamin D supplementation. Vitamin D deficiency, like the risk of severe COVID‐19, is linked with darker skin colour and also with obesity. Greater risk from COVID‐19 has been associated with reduced ultraviolet exposure. Various studies have examined serum 25‐hydroxyvitamin D levels, either historical or current, in patients with COVID‐19. The results of these studies have varied but the majority have shown an association between vitamin D deficiency and increased risk of COVID‐19 illness or severity. Interventional studies of vitamin D supplementation have so far been inconclusive. Trial protocols commonly allow control groups to receive low‐dose supplementation that may be adequate for many. The effects of vitamin D supplementation on disease severity in patients with existing COVID‐19 are further complicated by the frequent use of large bolus dose vitamin D to achieve rapid effects, even though this approach has been shown to be ineffective in other settings. As the pandemic passes into its third year, a substantial role of vitamin D deficiency in determining the risk from COVID‐19 remains possible but unproven.

Corpus Alienum captured in Post Mortem Computed Tomography, death due to an accidental ingestion of “Momos (Dumpling)”

• The authors have analyzed the risk factors in this case and also compared the common sites of retrieval of the corpus alienum in choking deaths. • The novelty in this case is to increase the awareness of the forensic experts, that a non-radiopaque foreign body can be well interpreted in PMCT. This could be easily missed if the history and the circumstantial evidences are not clear. • An inexperienced forensic pathologist may not suspect the hidden cause of death and easily miss the finding, if thorough dissection is not done. : Choking is a condition where there is obstruction in the airway at any place between pharynx and bifurcation of trachea. The choking is caused by internal and external blockage. A corpus alienum or a foreign body is any object originating from outside the body. If this is too large to gain access into the trachea, then it will lodge in the posterior hypopharynx, resulting in blockage of the respiratory tract. Sudden unexpected deaths due to blockage of the airway by a large bolus of food are not very common. The incidence of asphyxia by food is found to cause 0.66 fatalities per 100,000 of the general population every year. : Here, the authors are reporting a case, where the deceased lost his life suddenly when he was munching a momo (dumpling). India is in the initial stages of virtual autopsy and has only been started in the premier Institute of the country, All Indian Institute of Medical Sciences (AIIMS), New Delhi. : This case report will help the forensic experts in interpretation and will supplement the medical literature regarding detection of foreign body lodged in upper airway using Post Mortem Computed Tomography (PMCT), and so helps in concluding the cause of death.

Crosstalk between adenine nucleotide transporter and mitochondrial swelling: experimental and computational approaches.

Mitochondrial metabolism and function are modulated by changes in matrix Ca2+. Small increases in the matrix Ca2+ stimulate mitochondrial bioenergetics, whereas excessive Ca2+ leads to cell death by causing massive matrix swelling and impairing the structural and functional integrity of mitochondria. Sustained opening of the non-selective mitochondrial permeability transition pores (PTP) is the main mechanism responsible for mitochondrial Ca2+ overload that leads to mitochondrial dysfunction and cell death. Recent studies suggest the existence of two or more types of PTP, and adenine nucleotide translocator (ANT) and FOF1-ATP synthase were proposed to form the PTP independent of each other. Here, we elucidated the role of ANT in PTP opening by applying both experimental and computational approaches. We first developed and corroborated a detailed model of the ANT transport mechanism including the matrix (ANTM), cytosolic (ANTC), and pore (ANTP) states of the transporter. Then, theANT model was incorporated into a simple, yet effective, empirical model of mitochondrial bioenergetics to ascertain the point when Ca2+ overload initiates PTP opening via an ANT switch-like mechanism activated by matrix Ca2+ and is inhibited by extra-mitochondrial ADP. We found that encoding a heterogeneous Ca2+ response of at least three types of PTPs, weakly, moderately, and strongly sensitive to Ca2+, enabled the model to simulate Ca2+ release dynamics observed after large boluses were administered to a population of energized cardiac mitochondria. Thus, this study demonstrates the potential role of ANT in PTP gating and proposes a novel mechanism governing the cryptic nature of the PTP phenomenon.

Insulin sensitivity and kinetics in African American and White people with obesity: Insights from different study protocols.

Studies that used an intravenous glucose tolerance test (IVGTT) have suggested that race is an important modulator of insulin sensitivity, β-cell function, and insulin clearance. However, the validity of the IVGTT has been challenged. This study assessed insulin sensitivity and insulin kinetics in non-Hispanic White (NHW, n = 29) and African American (AA, n = 14) people with obesity by using a hyperinsulinemic-euglycemic pancreatic clamp with glucose tracer infusion, an oral glucose tolerance test (OGTT), and an IVGTT. Hepatic insulin sensitivity was better in AA participants than in NHW participants. Muscle insulin sensitivity, insulin secretion in relation to plasma glucose during the OGTT, and insulin clearance during basal conditions during the hyperinsulinemic-euglycemic pancreatic clamp and during the OGTT were not different between AA participants and NHW participants. The acute insulin response to the large glucose bolus administered during the IVGTT was double in AA participants compared with NHW participants because of increased insulin secretion and reduced insulin clearance. AA individuals are not more insulin resistant than NHW individuals, and the β-cell response to glucose ingestion and postprandial insulin clearance are not different between AA individuals and NHW individuals. However, AA individuals have greater insulin secretory capacity and reduced insulin clearance capacity than NHW individuals and might be susceptible to hyperinsulinemia after consuming very large amounts of glucose.

A novel EndoFLIP marker during hiatal hernia repair is associated with short-term postoperative dysphagia.

Endoluminal functional lumen imaging probe (EndoFLIP) provides an objective measure of the distensibility index (DI) during different parts of hiatal hernia repair. However, the absolute DI measure above a cut-off after creating a barrier alone has not shown a relationship to dysphagia after surgery. We wanted to determine if the change in DI with volume change is associated with dysphagia. We included patients who had hiatal hernia repair with EndoFLIP values, including two values taken at the end of the surgical case with different volumes of fluid in the balloon (30mL and 40mL). We compared the absolute and change in DI during hiatal hernia repair and performed an analysis to determine if there was a correlation with short-term clinical outcomes. A total of 103 patients met the inclusion and exclusion criteria. Most of the patients underwent Toupet fundoplication (n = 56, 54%), followed by magnetic sphincter augmentation (LINX, n = 28, 27%) and Nissen fundoplication (n = 19, 18%). There was a significant reduction in the DI from the initial DI taken after mobilization of the hiatus (3 mm2/mmHg) and after the creation of the barrier (1.4 mm2/mmHg, p < 0.001). A minority of patients had a decrease or no change in the DI with an increase in balloon volume increased from 30 to 40mL (n = 37, 36%). Overall, after 1month, there was a significant decrease in the GERD-HRQL score from 23 to 4 (p < 0.001) and bloat score from 3 to 2 (p = 0.003) with a non-significant decrease in the dysphagia score from 1 to 0 (p = 0.11). Patients who had a decreased or unchanged DI with an increase in the balloon volume from 30 to 40mL had a significant decrease in their dysphagia score by 2 points (p = 0.04). The decreased or unchanged DI with an increase in the balloon volume on EndoFLIP is associated with a significant reduction in dysphagia after surgery. The decrease in DI denotes the esophagus's ability to create higher pressure relative to the change in the cross-sectional area with a larger bolus across the gastroesophageal junction. This measure may be a new marker that can predict short-term outcomes in patients undergoing hiatal hernia repair.

Clinical experience with titrating doses of digoxin antibodies in acute digoxin poisoning. (ATOM-6)

Introduction For acute digoxin poisoning, it has been recommended to give bolus doses of 10–20 vials or potentially larger than needed doses calculated from dose ingested or the measured concentration. However, a recent revision of internal Poisons Information Centre guidelines prompted a change of our recommendations, specifically instead of large boluses, to use titrating repeated low doses of digoxin antibodies(Digoxin-Fab) based on bedside assessment of cardiac toxicity. Methods This is a prospective observational study of patients with acute digoxin poisoning identified through two Poisons Information Centres and three toxicology units. Patient demographics, signs and symptoms of digoxin toxicity, doses and response to Digoxin-Fab, free and bound serum digoxin concentrations. Outcomes were recorded and analysed. Results From September 2013 to September 2020, 23 patients with 25 presentations (median age 56 years, females 56%) were recruited. Median dose ingested was 13 mg(IQR: 9.5–25). Median heart rate (HR) was 41 beats/min before treatment. Initial median digoxin and potassium concentrations were 14.5 nmol/L (IQR: 10.9–20) [11.2 µg/L(IQR: 8.4–15.4)] and 5 mmol/L (IQR: 4.5–5.4 mmol/L), respectively. Gastrointestinal symptoms and acute kidney injury were present in 22 patients (88%) and 5 patients (20%), respectively. Four patients received an initial bolus dose of Digoxin-Fab of 5–20 vials. Twenty-one patients received repeated titrated doses (1–2 vials) of Digoxin-Fab and the median total dose was 4 vials (IQR: 2–7.5). Median maximal change in HR post-Digoxin-Fab was 19 beats/min. The median potassium concentration decrease post-Digoxin-Fab was 0.3 mmol/L. Total dose used in the titration group was 25% and 35% of the predicted doses based on the amount of digoxin ingested or measured serum concentration, respectively. Twelve had free digoxin concentrations measured. Free digoxin concentrations dropped to almost zero after any dose of Digoxin-Fab. Ten patients had a rebound of digoxin >2.6 nmol/L (2 µg/L). There were no deaths from acute digoxin toxicity. Conclusions The new practice of using small, titrated doses of Digoxin-Fab led to a considerable reduction in total usage and major savings. The clinical response to titrated doses was safe and acceptable in acute digoxin poisoning.

Continuous Platelet Transfusion As a Potential Desensitization Regimen in HLA Class I Alloimmune-Mediated Platelet Refractoriness

Background: The development of HLA antibodies is responsible for 4-8% of platelet transfusion refractoriness (PTR). The presence of HLA antibodies is a clinical complication that is generally managed by the selection of products that are negative for the antigens cognate to the patient's antibodies. Often, this selection is facilitated by targeted recruitment of donors with known HLA types. However, for very broadly HLA-alloimmunized patients, compatible products may be exceedingly scarce or completely unavailable, precluding the ability to consistently provide products the patient will likely increment to and benefit from. Here we describe a case of a patient with severe aplastic anemia (platelet count chronically <1 K/uL) and platelet transfusion refractoriness secondary to broad HLA-alloimmunization (98% PRA). HLA compatible products were unavailable due to the patient's rare HLA type and breadth of antibodies, and attempts at procuring compatible products via multiple national agency searches were unsuccessful. Thus, the patient could only be supplied with HLA incompatible products, which yielded insufficient post-transfusion platelet corrected-count increments (CCI). Her course was eventually complicated by multifocal intracranial hemorrhages, necessitating ICU admission with aggressive platelet transfusion support, immune-targeting therapy consisting of IVIg, and aminocaproic acid and recombinant activated factor VIIa.Methods: A continuous platelet infusion, or “platelet drip,” was employed in order to provide platelet transfusion support in the face of her severe thrombocytopenia with profound refractoriness. This consisted of consecutive transfusions of 4-6 equivalent unit apheresis platelet products (“doses”) transfused over 4 hours with a 15 minute post-transfusion CBC obtained from Q8 to Q12 hours to assess platelet increments. This ultimately resulted in 24-30 equivalent unit platelet product infusions/day.Results: Two days into the continuous platelet infusion, the patient began incrementing appropriately to occasional platelet products (CCI>>5) and, consequently, the infusions were able to sustain a platelet count >10K/uL, with a range of 20-70 K/uL, over the subsequent week. The improved counts, along with the patient's improved clinical condition and stable imaging findings showing resolving intracranial hemorrhages, allowed the transfusion support to be goal-directed targeting a prophylactic platelet threshhold of 10K/uL. Continued monitoring of the patient's CCIs enabled the identification of permissive antigens (i.e., allogeneic platelets with HLA antigens predicted to be incompatible with the patient's serum by solid-phase testing but were found to result in satisfactory increments); this knowledge allowed progressive widening of her permissive donor pool and enabled continued prophylactic support as needed. After three weeks the patient was able to be discharged from the ICU.Subsequent HLA class I antibody screens using flow-cytometry based single antigen bead (SAB) technology revealed progressive decrease in the patient's mean fluorescence intensity for most of her antibody specificities, with the majority of her class I A antibodies falling to undetectable or near-undetectable levels (while previously >5000 MFI). Simple regression analysis (RStudio 1.0.153, R version 3.4.1) was used to test to how level of exposure to individual HLA platelet antigens (as measured by the number of doses with a given antigen) affected subsequent MFI levels. The results of the regression indicate that pre MFI and exposure explain 70.6% of the variance (R2=0.706, F(2,78)=93.7, p=<2.2e-16). It was found that exposure is a significant predictor of decreased MFI (b=-107.20, p=0.01422). High initial MFI was strongly associated with high subsequent MFI (b=0.75, p= <2.2e-16).Conclusions: This data raises the possibility that large bolus platelet infusions could not only be of immediate therapeutic benefit in patients with HLA-alloimmune-mediated platelet refractoriness, but may also accelerate the evanescence of the responsible antibodies. Further research is warranted to explore this possibility, and to ascertain the potential magnitude of this effect in comparison to competing factors such as natural evanescence and/or B-cell immunosuppressive or immunomodulatory therapies. DisclosuresNo relevant conflicts of interest to declare.

Individualizing Therapy in CIDP: A Mini-Review Comparing the Pharmacokinetics of Ig With SCIg and IVIg.

Immunoglobulin (Ig) therapy is a first-line treatment for CIDP, which can be administered intravenously (IVIg) or subcutaneously (SCIg) and is often required long term. The differences between these modes of administration and how they can affect dosing strategies and treatment optimization need to be understood. In general, the efficacy of IVIg and SCIg appear comparable in CIDP, but SCIg may offer some safety and quality of life advantages to some patients. The differences in pharmacokinetic (PK) profile and infusion regimens account for many of the differences between IVIg and SCIg. IVIg is administered as a large bolus every 3–4 weeks resulting in cyclic fluctuations in Ig concentration that have been linked to systemic adverse events (AEs) (potentially caused by high Ig levels) and end of dose “wear-off” effects (potentially caused by low Ig concentration). SCIg is administered as a smaller weekly, or twice weekly, volume resulting in near steady-state Ig levels that have been linked to continuously maintained function and reduced systemic AEs, but an increase in local reactions at the infusion site. The reduced frequency of systemic AEs observed with SCIg is likely related to the avoidance of high Ig concentrations. Some small studies in immune-mediated neuropathies have focused on serum Ig data to evaluate its potential use as a biomarker to aid clinical decision-making. Analyzing dose data may help understand how establishing and monitoring patients' Ig concentration could aid dose optimization and the transition from IVIg to SCIg therapy.