Extracorporeal membrane oxygenation in South Africa: Experience from a single centre in the private sector.

Background: Extracorporeal membrane oxygenation (ECMO) is an advanced, resource-intensive technology used in a limited capacity in South Africa (SA). Minimal data on the use of ECMO in SA are available. Objectives: To describe the indications, early outcome and comorbidities of patients placed on ECMO in the highest-volume ECMO centre in SA. Methods: We performed a single-centre retrospective review of all adult patients supported with any form of ECMO from August 2016 to December 2018. Operative and clinical records were reviewed. The primary objective of this study was to review the outcome of patients placed on ECMO in the form of survival to hospital discharge. The secondary objectives were to identify population-specific comorbidities and indications for ECMO that could be associated with non-survival and to compare outcome with known risk scores in the form of the Respiratory ECMO Survival Prediction (RESP) and Survival After Venoarterial ECMO (SAVE) scores. Results: One hundred and seven patients were identified. The primary indication for ECMO was respiratory support in 78 patients and cardiac support in 29 patients. Forty-seven patients were discharged from hospital, with a 44.0% overall survival rate. Gender (p=0.039), age (p=0.019) and hypertension (p=0.022) were associated with death in univariate logistic regression analysis. However, after adjusting for potential confounding in multivariate logistic regression analysis, the association was no longer significant. In the all respiratory support group, patients in risk class IV had better than predicted survival according to the RESP score, while risk classes I, II and III had worse than predicted survival. In the circulatory support group, all risk classes had worse than predicted survival according to the SAVE score. Conclusion: We report ECMO outcomes in SA for the first time. We identified very high mortality rates for patients transferred on ECMO from other facilities and for patients converted from venovenous ECMO to venoarterial ECMO. Although our outcomes were comparable in some of the risk classes, further external validation of the SAVE and RESP scores will be needed to compare our outcomes with these scores. Study synopsis: What the study adds. We report on extracorporeal membrane oxygenation (ECMO) outcomes in South Africa for the first time. We identified a high mortality rate in patients transferred on ECMO from other facilities, and in patients converted from venovenous ECMO to venoarterial ECMO.Implications of the findings. Transferred patients had a high mortality rate. The reason for this should be further investigated and may highlight the need for possible protocols to assist with appropriate timing of patient transfers and possible earlier intervention or transfer.

Recommendations for the diagnosis and management of vaccine-induced immune thrombotic thrombocytopenia.

There have recently been safety concerns regarding an increased risk of vaccine-induced immune thrombotic thrombocytopenia (VITT) following administration of SARS-CoV-2 adenoviral vector vaccines. The Southern African Society of Thrombosis and Haemostasis reviewed the emerging literature on this idiosyncratic complication. A draft document was produced and revised by consensus agreement by a panel of professionals from various specialties. The recommendations were adjudicated by independent international experts to avoid local bias. We present concise, practical guidelines for the clinical management of VITT.

Assurance for Endurance? Introducing a Novel Ergonomics Curriculum to Reduce Pain and Enhance Physical Well-Being Among GI Fellows.

Musculoskeletal pain and injuries (MSKPI) are common among gastroenterologists (GI) and GI fellows. Common areas of pain include the back, neck, hands/fingers, shoulders, and elbows. Although the prevalence of career-related pain and injuries among GIs is high, few endoscopists receive training in how to prevent MSKPI. We developed an ergonomics curriculum for our GI fellows that consisted of two modules that were led by physical therapists. Twelve out of 15 GI fellows, and one out of two hepatology fellows, participated in Module 1. Prior to the first module, 77% of participants reported pain in one or more body parts. Of those who reported pain, 100% of the fellows stated that this pain occurred during procedures, and 50% indicated this pain was performance-limiting. After completing Module 1, 100% of fellows reported that this was a valuable topic and 100% of the participants felt that this information would both help them feel and perform better. All fellows stated they had an immediate decrease in physical discomfort after engaging in the exercises that were included in Module 1. Eight fellows participated in Module 2. At the end of this module, 100% of fellows reported that this ergonomics training would likely help them to "physically perform better during procedures" and 100% of fellows indicated a reduction of physical discomfort (pain, aching) immediately after completing these exercises. Preliminary data indicated that this novel curriculum was perceived as valuable by GI fellows and that practicing these exercises reduced pain, particularly in the neck and the lower back.

Lung transplantation in South Africa: Indications, outcomes and disease-specific referral guidelines.

Lung transplantation (LT) is a robust therapy for advanced lung disease, which offers recipients extended and good-quality survival. In South Africa (SA), patients have historically had limited access to this therapy, particularly if unfunded. LT has been used as a successful therapeutic intervention for a wide variety of end-stage pulmonary parenchymal and vascular diseases, but the most common diseases that lead to LT are chronic obstructive pulmonary disease, interstitial lung disease, cystic fibrosis, alpha-1-antitrypsin deficiency and pulmonary arterial hypertension. Timing of referral for LT can be challenging and is disease specific, influenced by the rate of progression of the disease, the development of associated comorbidities, and access and response to advanced therapies. Advances in recipient and donor selection, surgical technique and postoperative management have improved early survival, but mortality remains higher than for other solid organ transplants. Rejection and infection remain major causes of early posttransplant death, while chronic rejection is the major cause of death after the first year. Survival is heavily influenced by the underlying lung disease. In this review, we summarise the indications and contraindications for LT, remind pulmonologists of the availability of this therapy in SA and offer guidelines for the timely referral of suitable candidates.

USPIO-related T1 and T2 mapping MRI of cartilage in a rabbit model of blood-induced arthritis: a pilot study.

Ultrasmall paramagnetic iron oxide (USPIO)-enhanced MRI is promising for evaluating inflammation. The aims of this study were to investigate the effect of USPIO on cartilage T1 and T2 mapping, and to evaluate a proposed rapid vs. conventional T2 map method for imaging cartilage in a blood-induced arthritis model. Knees of nine arthritic (induction by intra-articular autologous blood injection) and six control rabbits were imaged over time (baseline, weeks 1, 5, 10) by 1.5 T MRI. All rabbits had USPIO (35-75 µmol Fe/kg)-enhanced MRI at each time point. T1 and T2 (conventional and rapid) maps and signal-to-noise ratios (SNR) were obtained pre- and post-USPIO administration. Cartilage biochemistry and histology were compared with MRI. Excellent correlations were noted between T1 map values and histologic scores at week 10 pre-USPIO (medial, r = 0.93, P = 0.0007; lateral, r = 0.87, P = 0.005) in the arthritic group, but not between T2 map and histology. Marginally and significant differences were observed between pre- and post-USPIO T2 values at weeks 5 (P = 0.06) and 10 (P = 0.02), but only with the administration of high USPIO doses in the arthritic group using the conventional method. No significant differences were noted between pre- and post-USPIO T1 values at any imaging time points. Cartilage T2 maps with short-TR and conventional protocols provided similar T2 values [(decreased trend)] (P > 0.05). Concomitant use of USPIO to T1 and T2 mapping of cartilage would not impair the identification of interval changes of T1 and T2 maps. Rapid T2 map provides similar results compared to conventional method, but its validation warrants further investigation.

Operating on penetrating trauma to the mediastinal vessels.

BACKGROUND AND AIMS: Patients with penetrating trauma of the major vessels of the chest are infrequently encountered. This is due to the fact that the majority of these patients die on scene, as well as due to the overall dramatic decline in the incidence of penetrating trauma in the Western world. A certain proportion of survivors are physiologically stable and can be transferred to adequate care. Patients who are physiologically unstable must be dealt with by the surgeons available without delay. Rapid diagnosis and operation can salvage patients who would otherwise be lost, and all general surgeons should be capable of recognizing these injuries and intervening if a trauma and/or cardiothoracic surgeon is not immediately available. MATERIAL AND METHODS: Technical description of practical emergency surgery approaches to patients bleeding to death from penetrating mediastinal vessel injuries. RESULTS: The scope of this review familiarizes the "uninitiated" surgeon with the operative management of this rare and lethal type of injuries. Technical aspects are described, and pitfalls as well as tips and tricks of the trade are discussed. CONCLUSIONS: Patients with penetrating injuries to the mediastinal vessels can be saved by swift and knowing operative management of this rare and lethal type of injuries, even if a trauma and/or cardiothoracic surgeon is not immediately available.

Assessing analytical variability of measurement of vitamin A in corn-soy blend.

Two multilaboratory investigations were conducted by SUSTAIN to assess variability in the measurement of vitamin A, the marker used to verify levels of vitamin premix addition to enriched/fortified food aid products, including the widely distributed corn-soy blend (CSB). CSB specifications identify AACC Approved Method 86-06 or equivalent methods for vitamin A analysis, however there is no requirement to demonstrate equivalency. CSB samples with known and blinded levels of vitamin A and a reference standard were analyzed by 16 laboratories using their respective methods. Calculated coefficients of variation across all laboratories and methods for unknown samples and reference standard were 35 and 7.1%, respectively, suggesting the largest source of variation is the vitamin extraction procedure. Laboratories generally overestimated low levels and underestimated high levels of vitamin A within the range of 6000 and 16 000 IU/lb. Only two laboratories demonstrated excellent internal precision (+/- 300 IU vitamin A/lb) and reported values within 95% confidence interval for all blinded samples. Results of this study have implications both for quality control in food aid products (due to the use of vitamin A as a marker) and for regulatory oversight of vitamin A content in commercial food products.

Strategies of hip management in neuromuscular disorders: Duchenne Muscular Dystrophy, Spinal Muscular Atrophy, Charcot-Marie-Tooth Disease and Arthrogryposis Multiplex Congenita.

Joint contractures, subluxation and dislocation are common problem in children with neuromuscular disorders. Medical, surgical and rehabilitative approaches can be used to maintain patient function and comfort. Contracture release, hip dysplasia correction and procedures to address or prevent hip subluxation or dislocation, are not always necessary since patients can be asymptomatic and surgical treatment will not always be successful in maintaining a reduced hip. In fact, controversy surrounds the management of hip disorder in children with Duchenne Muscular Dystrophy, Spinal Muscular Atrophy, Charcot-Marie-Tooth Disease and Arthrogryposis Multiplex Congenita. Patients with neuromuscular disorders also frequently develop a progressive scoliosis with pelvic obliquity which may affect sitting balance and become painful. Most subluxations and dislocations have the tendency to occur on the high side of a tilted pelvis. Spinal stabilisation is sometimes necessary to improve the pelvic tilt and to prevent further increase. The present article provides an overview of the current strategies of hip management in neuromuscular disorders.

Kinetics of the translocation and phosphorylation of alphaB-crystallin in mouse heart mitochondria during ex vivo ischemia.

alphaB-crystallin (alphaBC) is a small heat shock protein expressed at high levels in the myocardium where it protects from ischemia-reperfusion damage. Ischemia-reperfusion activates p38 MAP kinase, leading to the phosphorylation of alphaBC on serine 59 (P-alphaBC-S59), enhancing its ability to protect myocardial cells from damage. In the heart, ischemia-reperfusion also causes the translocation of alphaBC from the cytosol to other cellular locations, one of which was recently shown to be mitochondria. However, it is not known whether alphaBC translocates to mitochondria during ischemia-reperfusion, nor is it known whether alphaBC phosphorylation takes place before or after translocation. In the present study, analyses of mitochondrial fractions isolated from mouse hearts subjected to various times of ex vivo ischemia-reperfusion showed that alphaBC translocation to mitochondria was maximal after 20 min of ischemia and then declined steadily during reperfusion. Phosphorylation of mitochondrial alphaBC was maximal after 30 min of ischemia, suggesting that at least in part it occurred after alphaBC association with mitochondria. Consistent with this was the finding that translocation of activated p38 to mitochondria was maximal after only 10 min of ischemia. The overexpression of alphaBC-AAE, which mimics alphaBC phosphorylated on serine 59, has been shown to stabilize mitochondrial membrane potential and to inhibit apoptosis. In the present study, infection of neonatal rat cardiac myocytes with adenovirus-encoded alphaBC-AAE decreased peroxide-induced mitochondrial cytochrome c release. These results suggest that during ischemia alphaBC translocates to mitochondria, where it is phosphorylated and contributes to modulating mitochondrial damage upon reperfusion.

Quantitative MR imaging evaluation of the cartilage thickness and subchondral bone area in patients with ACL-reconstructions 7 years after surgery.

OBJECTIVE: To evaluate the cartilage thickness (ThC) and subchondral bone area (tAB) of the operated and contra-lateral non-operated (healthy) knees in patients with anterior cruciate ligament (ACL)-reconstruction 7 years after surgery using a quantitative and regional cartilage MR imaging (qMRI) technique. METHODS: Charts of 410 patients with ACL-reconstructions were retrospectively reviewed. Fifty-two patients (male/female, 28/24; mean age, 33.3 years) were included. Patients underwent KT-1000 testing and qMRI of both knees using coronal fat-saturated 3D spoiled gradient-recalled echo (SPGR) sequences (TR/TE, 44/4 ms) at 1.5 T. Quantitative analyses of ThC and tAB in the femoro-tibial cartilage plates were performed using a subregional approach. In addition, qualitative and quantitative assessment of femoral condyle shapes was performed. t tests with Bonferroni corrections were used for statistical analysis of side-to-side differences between the operated and non-operated knees. RESULTS: KT-1000 testing was abnormal in 3/52 patients (6%). Lateral femoral tAB was significantly lower (-9.2%), and medial tibial tAB was significantly larger (+2%) in the operated vs non-operated knee (P<0.001). Regional and subregional ThC side-to-side differences were less than 0.1mm and, except for the external lateral femoral subregion, they were not statistically significant. Flattened and broader shapes of medial femoral condyles (P<0.001) were found in operated knees. No significant association of presence of cartilage or meniscus lesions at surgery with ThC 7 years post-operatively was found (P=0.06-0.98). CONCLUSION: There is evidence for changes in the tAB and femoral shape 7 years post-ACL-reconstruction, but no side-to-side differences in subregional ThC were found between the operated and contra-lateral non-operated knees.

A new temperature-sensitive contrast mechanism for MRI: Curie temperature transition-based imaging.

A temperature-sensitive MRI contrast mechanism is proposed based on the physical property, the Curie temperature (T(c)), at which a ferromagnetic material transitions to paramagnetic state and vice versa. To evaluate the feasibility of this new contrast mechanism, experiments were performed with solid gadolinium metal, which has a T(c) of 20 degrees C. In phantom and ex vivo experiments, the magnetic susceptibility artifact area decreased with increasing temperature transitioning across T(c) (p < 0.05). Similar results would be expected for a variety of ferromagnetic substances with substance-specific T(c) values. Temperature-sensitive MRI contrast agents harnessing this mechanism may be used to (1) indicate regional attainment of specific temperatures in thermotherapy, (2) render an accumulated contrast agent more or less visible by the external application of appropriate heating or cooling, or (3) quantify tissue temperature based on MR image characteristics and magnetic susceptibility artifact caused by a ferromagnetic-paramagnetic transitioning substance.

Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.

BACKGROUND: The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence. OBJECTIVE: To review available evidence on corticosteroid treatment of boys with Duchenne dystrophy. METHODS: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification, and areas for future research are defined. RESULTS: Seven class I studies and numerous less rigorous trials all demonstrated that corticosteroid treatment for 6 months with prednisone (0.75 or 1.5 mg/kg/day) increased muscle strength, performance, and pulmonary function and significantly slowed the progression of weakness. Two class I trials examined the effect of lower dosage of prednisone (0.30 and 0.35 mg/kg/day), demonstrated lesser but similar benefits, and showed a lower frequency of side effects (e.g., weight gain). The only significant side effects in all class I trials were weight gain and development of a cushingoid facial appearance. One longer-term trial of daily prednisone (0.3 to 0.7 mg/kg/day), a class III study, showed prolongation of functional ability and slower progression of weakness in patients during 3 years of treatment. One class IV, open trial of alternate-day prednisone (2 mg/kg for 2 months, then two-thirds dose every other day) extended ambulation by approximately 2 years in treated compared with untreated patients. Deflazacort, a corticosteroid similar in structure to prednisone, produced similar improvement in muscle strength and function with a similar side effect profile. CONCLUSIONS: Prednisone has been demonstrated to have a beneficial effect on muscle strength and function in boys with Duchenne dystrophy and should be offered (at a dose of 0.75 mg/kg/day) as treatment. If side effects require a decrease in prednisone, tapering to dosages as low as 0.3 mg/kg/day gives less robust but significant improvement. Deflazacort (0.9 mg/kg/day) can also be used for the treatment of Duchenne dystrophy in countries in which it is available. Benefits and side effects of corticosteroid therapy need to be monitored. The offer of treatment with corticosteroids should include a balanced discussion of potential risks.

Ischemic mitral valve reconstruction and replacement: comparison of long-term survival and complications.

OBJECTIVE: This study reviews the 223 consecutive mitral valve operations for ischemic mitral insufficiency performed at New York University Medical Center between January 1976 and January 1996. The results for mitral valve reconstruction are compared with those for prosthetic mitral valve replacement. METHODS: From January 1976 to January 1996, 223 patients with ischemic mitral insufficiency underwent mitral valve reconstruction (n = 152) or prosthetic mitral valve replacement (n = 71). Coronary artery bypass grafting was performed in 89% of cases of mitral reconstruction and 80% of cases of prosthetic replacement. In the group undergoing reconstruction, 77% had valvuloplasty with a ring annuloplasty and 23% had valvuloplasty with suture annuloplasty. In the group undergoing prosthetic replacement, 82% of patients received bioprostheses and 18% received mechanical prostheses. RESULTS: Follow-up was 93% complete (median 14.6 mo, range 0-219 mo). Thirty-day mortality was 10% for mitral reconstruction and 20% for prosthetic replacement. The short-term mortality was higher among patients in New York Heart Association functional class IV than among those in classes I to III (odds ratio 5.75, confidence interval 1.25-26.5) and was reduced among patients with angina relative to those without angina (odds ratio 0.26, confidence interval 0.05-1.2). The 30-day death or complication rate was similarly elevated among patients in functional class IV (odds ratio 5.53; confidence interval 1.23-25.04). Patients with mitral valve reconstruction had lower short-term complication or death rates than did patients with prosthetic valve replacement (odds ratio 0.43, confidence interval 0.20-0.90). Eighty-two percent of patients with mitral valve reconstruction had no insufficiency or only trace insufficiency during the long-term follow-up period. Five-year complication-free survivals were 64% (confidence interval 54%-74%) for patients undergoing mitral valve reconstruction and 47% (confidence interval 33%-60%) for patients undergoing prosthetic valve replacement. Results of a series of statistical analyses suggest that outcome was linked primarily to preoperative New York Heart Association functional class. CONCLUSIONS: Initial mortalities were similar among patients undergoing prosthetic replacement and valve reconstruction. Poor outcome was primarily related to preexisting comorbidities. Patients undergoing valve reconstruction had fewer valve-related complications. Valve reconstruction resulted in excellent durability and freedom from complications. These findings suggest that mitral valve reconstruction should be considered for appropriate patients with ischemic mitral insufficiency.

Functions of AKT1 and AKT2 potassium channels determined by studies of single and double mutants of Arabidopsis.

A reverse genetic strategy was used to isolate Arabidopsis plants containing "knockout" mutations in AKT1 and AKT2, two members of a K+ channel gene family. Comparative studies of growth and membrane properties in wild-type and mutant seedlings were performed to investigate the physiological functions of these two related channels. The growth rates of plants supplied with rate-limiting concentrations of K+ depended on the presence of AKT1 but not AKT2 channels. This result indicates that AKT1 but not AKT2 mediates growth-sustaining uptake of K+ into roots, consistent with the expression patterns of these two genes. K+ -induced membrane depolarizations were measured with microelectrodes to assess the contribution each channel makes to the K+ permeability of the plasma membrane in three different organs. In apical root cells, AKT1 but not AKT2 contributed to the K+ permeability of the plasma membrane. In cotyledons, AKT1 was also the principal contributor to the K+ permeability. However, in the mesophyll cells of leaves, AKT2 accounted for approximately 50% of the K+ permeability, whereas AKT1 unexpectedly accounted for the remainder. The approximately equal contributions of AKT1 and AKT2 in leaves detected by the in vivo functional assay employed here are not in agreement with previous RNA blots and promoter activity studies, which showed AKT2 expression to be much higher than AKT1 expression in leaves. This work demonstrates that comparative functional studies of specific mutants can quantify the relative contributions of particular members of a gene family, and that expression studies alone may not reliably map out distribution of gene functions.

Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia.

Mutations in the cartilage oligomeric matrix protein (COMP) gene result in pseudoachondroplasia (PSACH), which is a chondrodysplasia characterized by early-onset osteoarthritis and short stature. COMP is a secreted pentameric glycoprotein that belongs to the thrombospondin family of proteins. We have identified a novel missense mutation which substitutes a glycine for an aspartic acid residue in the thrombospondin (TSP) type 3 calcium-binding domain of COMP in a patient diagnosed with PSACH. Immunohistochemistry and immunoelectron microscopy both show abnormal retention of COMP within characteristically enlarged rER inclusions of PSACH chondrocytes, as well as retention of fibromodulin, decorin and types IX, XI and XII collagen. Aggrecan and types II and VI collagen were not retained intracellularly within the same cells. In addition to selective extracellular matrix components, the chaperones HSP47, protein disulfide isomerase (PDI) and calnexin were localized at elevated levels within the rER vesicles of PSACH chondrocytes, suggesting that they may play a role in the cellular retention of mutant COMP molecules. Whether the aberrant rER inclusions in PSACH chondrocytes are a direct consequence of chaperone-mediated retention of mutant COMP or are otherwise due to selective intracellular protein interactions, which may in turn lead to aggregation within the rER, is unclear. However, our data demonstrate that retention of mutant COMP molecules results in the selective retention of ECM molecules and molecular chaperones, indicating the existence of distinct secretory pathways or ER-sorting mechanisms for matrix molecules, a process mediated by their association with various molecular chaperones.

Sarcoplasmic reticulum Ca(2+) atpase (SERCA) 1a structurally substitutes for SERCA2a in the cardiac sarcoplasmic reticulum and increases cardiac Ca(2+) handling capacity.

Ectopic expression of the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA) 1a pump in the mouse heart results in a 2.5-fold increase in total SERCA pump level. SERCA1a hearts show increased rates of contraction/relaxation and enhanced Ca(2+) transients; however, the cellular mechanisms underlying altered Ca(2+) handling in SERCA1a transgenic (TG) hearts are unknown. In this study, using confocal microscopy, we demonstrate that SERCA1a protein traffics to the cardiac SR and structurally substitutes for the endogenous SERCA2a isoform. SR Ca(2+) load measurements revealed that TG myocytes have significantly enhanced SR Ca(2+) load. Confocal line-scan images of field-stimulated SR Ca(2+) release showed an increased rate of Ca(2+) removal in TG myocytes. On the other hand, ryanodine receptor binding activity was decreased by approximately 30%. However, TG myocytes had a greater rate of spontaneous ryanodine receptor opening as measured by spark frequency. Whole-cell L-type Ca(2+) current density was reduced by approximately 50%, whereas the time course of inactivation was unchanged in TG myocytes. These studies provide important evidence that SERCA1a can substitute both structurally and functionally for SERCA2a in the heart and that SERCA1a overexpression can be used to enhance SR Ca(2+) transport and cardiac contractility.