Toward an integrated multi-gigahertz ionizing particle diagnostic.

Needs arising at both current and future accelerator facilities call for the development of radiation-hardened position-sensing diagnostics that can operate with multi-GHz repetition rates. Such instruments are likely to also have applications in the diagnosis of rapid plasma behavior. Building on the recent work of our Advanced Accelerator Diagnostics Collaboration, we are exploring the development of integrated multi-GHz ionizing particle detection systems based on chemical-vapor deposition diamond sensors, with the initial goal of producing a quadrant detector that can determine the intensity and centroid position of a particle beam at a repetition rate between 5 and 10 GHz. Results from our initial high-speed characterization work are presented, including those from a single-channel sensor with a GHz response. Approaches to achieving multi-GHz (5-10 GHz) rate capability, including the design of a dedicated Application Specific Integrated Circuit and the use of 3D RF-solver computer aided design software, are presented and discussed in more detail. 3D RF simulations suggest clean pulses of duration less than 250 ps (FWHM less than 125 ps) can be achieved with the approaches developed by this work.

A Longitudinal Study of Thrombosis and Bleeding Outcomes With Thromboprophylaxis in Pregnant Women at Intermediate and High Risk of VTE.

BACKGROUND: The efficacy and safety of thromboprophylaxis in pregnancy at intermediate to high risk of venous thrombo-embolism (VTE) is an area of ongoing research. AIM: This study aimed to assess thrombosis and bleeding outcomes associated with thromboprophylaxis in women at risk of VTE. METHODS: A cohort of 129 pregnancies, who received thromboprophylaxis for the prevention of VTE, were identified from a specialist obstetric clinic in Johannesburg, South Africa. Intermediate-risk pregnancies, with medical comorbidities or multiple low risks, were managed with fixed low-dose enoxaparin antepartum and for a median (interquartile range) of 4 (4) weeks postpartum. High-risk pregnancies, with a history of previous VTE, were managed with anti-Xa adjusted enoxaparin antepartum and for a median of 6 (0) weeks postpartum. Pregnancy-related VTE was objectively confirmed. Major bleeding, clinically relevant nonmajor bleeding (CRNMB) and minor bleeding were defined according to the International Society on Thrombosis and Hemostasis Scientific Subcommittee. RESULTS: Venous thrombo-embolism occurred antepartum in 1.4% (95% CI: 0.04-7.7) of intermediate and 3.4% (95% CI: 0.4-11.7) of high-risk pregnancies. Bleeding events occurred in 7.1% (95% CI: 2.4-15.9) of intermediate and 8.5% (95% CI: 2.8-18.7) of high-risk pregnancies. Of these bleeding events, 3.1% (95% CI: 1.0-8.0) were classified as major bleeding. On univariate analysis, no independent predictors of bleeding were identified. CONCLUSION: The rates of thrombosis and bleeding in this predominantly African population were consistent with similar studies and can be used to inform pregnant women of the benefits of anticoagulation and the risks of potential bleeding.

Pathophysiology of Influenza D Virus Infection in Specific-Pathogen-Free Lambs with or without Prior Mycoplasma ovipneumoniae Exposure.

Polymicrobial pneumonias occur frequently in cattle, swine, and sheep, resulting in major economic losses. Individual pathogens comprising these complex infections may be mild on their own but can instead exhibit synergism or increase host susceptibility. Two examples of such pathogens, Mycoplasma ovipneumoniae (M. ovipneumoniae) and influenza D viruses (IDVs), naturally infect domestic sheep. In sheep, the role of M. ovipneumoniae in chronic nonprogressive pneumonia is well-established, but the pathogenesis of IDV infection has not previously been studied. We utilized a specific-pathogen-free sheep flock to study the clinical response to IDV infection in naïve vs. M. ovipneumoniae-exposed lambs. Lambs were inoculated intranasally with M. ovipneumoniae or mock infection, followed after four weeks by infection with IDV. Pathogen shedding was tracked, and immunological responses were evaluated by measuring acute phase response and IDV-neutralizing antibody titers. While lamb health statuses remained subclinical, M. ovipneumoniae-exposed lambs had significantly elevated body temperatures during IDV infection compared to M. ovipneumoniae-naïve, IDV-infected lambs. Moreover, we found a positive correlation between prior M. ovipneumoniae burden, early-infection IDV shedding, and IDV-neutralizing antibody response. Our findings suggest that IDV infection may not induce clinical symptoms in domestic sheep, but previous M. ovipneumoniae exposure may promote mild IDV-associated inflammation.

Baseline characteristics of 32 patients with Gaucher disease who were treated with imiglucerase: South African data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry.

BACKGROUND: Gaucher disease (GD) is a rare inherited autosomal recessive metabolic disorder with a prevalence in the general population of ~1 per 100 000. To optimise the recognition, diagnosis and management of patients with GD in South Africa (SA), it is important to have an understanding of local patterns of presentation of the disease. OBJECTIVES: To describe the baseline pretreatment characteristics of the SA cohort of patients enrolled into the International Collaborative Gaucher Group (ICGG) Gaucher Registry whowere treated with imiglucerase (Cerezyme; Sanofi Genzyme). METHODS: The ICGG Gaucher Registry is an observational, longitudinal, international database that tracks the clinical, demographic, genetic, biochemical and therapeutic characteristics of patients with GD globally, irrespective of disease severity, treatment status or treatment choice. The study population included all SA patients reported in the ICGG Gaucher Registry as of 1 May 2020. RESULTS: The registry included 49 SA GD patients, of whom 32 received imiglucerase as first primary GD therapy. All the patients had GD type 1, 59.4% were female, and mean and median ages at diagnosis were 14.7 and 9.8 years, respectively. The most common genotype was N370S/N370S (37.5%). At treatment initiation, 30.0% of patients had been splenectomised. Among patients for whom data were available, anaemia was present in one-third of non-splenectomised patients and 12.5% of those with splenectomy, and moderate or severe thrombocytopenia was reported in two-thirds of non-splenectomised patients. Bone pain was present in 30.8% and 57.1% of non- splenectomised and splenectomised patients, respectively. No bone crises were reported, and data relating to other bone complications were available for only ≤3 patients. CONCLUSIONS: Haematological findings and bone pain in this group are similar to those in the global ICGG Gaucher Registry cohort. Lack of baseline data for other bone complications limits interpretation in that regard. Clinicians who treat patients with GD are encouraged to submit accurate, complete and up-to-date information so that comprehensive data for the subset of SA GD patients can be maintained to improve recognition and diagnosis, and guide appropriate and effective use of treatment for SA patients.

Experimental infection of specific-pathogen-free domestic lambs with Mycoplasma ovipneumoniae causes asymptomatic colonization of the upper airways that is resistant to antibiotic treatment.

Mycoplasma ovipneumoniae (M. ovipneumoniae) is a respiratory pathogen associated with mild to moderate respiratory disease in domestic lambs and severe pneumonia outbreaks in wild ruminants such as bighorn sheep. However, whether M. ovipneumoniae by itself causes clinical respiratory disease in domestic sheep in the absence of secondary bacterial pathogens is still unclear. The goal of our study was to better understand the role of M. ovipneumoniae as a respiratory pathogen in domestic sheep and to explore potential antibiotic treatment approaches. Therefore, we inoculated four 4-month-old, specific-pathogen-free lambs with fresh nasal wash fluids from M. ovipneumoniae-infected sheep. The lambs were monitored for M. ovipneumoniae colonization, M. ovipneumoniae-specific antibodies, clinical signs, and cellular and molecular correlates of lung inflammation for eight weeks. All lambs then were treated with gamithromycin and observed for an additional four weeks. M. ovipneumoniae inoculation resulted in stable colonization of the upper respiratory tract in all M. ovipneumoniae-inoculated, but in none of the four mock-infected control lambs. All M. ovipneumoniae-infected lambs developed a robust antibody response to M. ovipneumoniae within 2 weeks. However, we did not observe significant signs of respiratory disease, evidence of lung damage or inflammation in any of the infected lambs. Interestingly, treatment with gamithromycin, which blocked growth of the M. ovipneumoniae in vitro, failed to reduce M. ovipneumoniae colonization. These observations indicate that, in the absence of co-infections, M. ovipneumoniae caused asymptomatic colonization of the upper respiratory tract that was resistant to clearance by the host immune response and by gamithromycin treatment.

Heparin-induced thrombocytopenia: An update for the COVID-19 era.

The increased use of heparin during the current COVID-19 pandemic has highlighted the risk of a rare but potentially serious complication of heparin therapy, viz. heparin-induced thrombocytopenia (HIT). This is a short review on the pharmacology of heparin and its derivatives, and the pathophysiology of HIT. Guidance on laboratory testing for and clinical management of HIT is presented in accordance with international guidelines. There are important similarities and differences between HIT and the new entity of vaccine-induced immune thrombotic thrombocytopenia, also known as thrombosis with thrombocytopenia syndrome, which clinicians need to be aware of.

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.

The Novel Coronavirus and Haemostatic Abnormalities: Pathophysiology, Clinical Manifestations, and Treatment Recommendations.

The COVID-19 pandemic, caused by the SARS-C0V-2 virus, was initially considered and managed in a similar manner to the previous SARS epidemic as they are both caused by coronaviruses. What has now become apparent is that a major cause of morbidity and mortality in COVID-19 is abnormal thrombosis. This thrombosis occurs on a macro- and microvascular level and is unique to this disease. The virus has been demonstrated in the endothelium of the pulmonary alveoli and as such is thought to contribute to the devastating respiratory complications encountered. D-dimer concentrations are frequently raised in COVID to levels not frequently seen previously. The optimal anticoagulation treatment in COVID remains to be determined, and the myriad of pathophysiologic effects caused by this virus in the human host have also yet to be fully elucidated.

An Assessment of the Accuracy of Creatinine Measurements in Guyana

ABSTRACT Background: The incidence of chronic kidney disease (CKD) is relatively high in Guyana. Estimated glomerular filtration rate (eGFR) reporting allows for early-stage CKD identification when therapeutic interventions can prevent CKD progression. Accurate creatinine measurements are essential for valid eGFR calculations. Objective: This study was undertaken to assess the accuracy of creatinine measurements in Guyana prior to implementing routine eGFR reporting. Methods: Sixteen Guyanese laboratories participated in this study. Each laboratory received a common set of blinded human serum samples (n = 3) containing clinically relevant creatinine concentrations, assigned by an international reference method (ID-GCMS). Laboratories performed repeated measurements of creatinine in each sample. These data were used to calculate bias, precision and total error (TE) for each creatinine method. Linear regression was used to compare measured creatinine results to assigned reference sample values and to post-analytically correct calibration bias, a priori, for recent patient results from each laboratory. Patient eGFR profiles were compared before and after bias correction. Results: The mean across samples CV and bias for all labs were 9% (range 2.5%-39.3%) and 11% positive (range 0.4%-29.1%), respectively. The mean TE was 28.6%. If the mean TE from a subset of the better performing laboratories (CV < 7%) was to apply nationally, an 'all stage' eGFR misclassification rate of 36% would result. Conclusion: There is a pressing need to improve the accuracy of creatinine measurements in Guyana as, at this time, routine reporting of eGFR by Guyanese laboratories cannot be recommended based on the accuracy data presented in this study.

Accurate and confident prediction of electron beam longitudinal properties using spectral virtual diagnostics.

Longitudinal phase space (LPS) provides a critical information about electron beam dynamics for various scientific applications. For example, it can give insight into the high-brightness X-ray radiation from a free electron laser. Existing diagnostics are invasive, and often times cannot operate at the required resolution. In this work we present a machine learning-based Virtual Diagnostic (VD) tool to accurately predict the LPS for every shot using spectral information collected non-destructively from the radiation of relativistic electron beam. We demonstrate the tool's accuracy for three different case studies with experimental or simulated data. For each case, we introduce a method to increase the confidence in the VD tool. We anticipate that spectral VD would improve the setup and understanding of experimental configurations at DOE's user facilities as well as data sorting and analysis. The spectral VD can provide confident knowledge of the longitudinal bunch properties at the next generation of high-repetition rate linear accelerators while reducing the load on data storage, readout and streaming requirements.

A high-power, high-repetition-rate THz source for pump-probe experiments at Linac Coherent Light Source II.

Experiments using a THz pump and an X-ray probe at an X-ray free-electron laser (XFEL) facility like the Linac Coherent Light Source II (LCLS II) require frequency-tunable (3 to 20 THz), narrow bandwidth (∼10%), carrier-envelope-phase-stable THz pulses that produce high fields (>1 MV cm-1) at the repetition rate of the X-rays and are well synchronized with them. In this paper, a two-bunch scheme to generate THz radiation at LCLS II is studied: the first bunch produces THz radiation in an electromagnet wiggler immediately following the LCLS II undulator that produces X-rays from the second bunch. The initial time delay between the two bunches is optimized to compensate for the path difference in THz transport. The two-bunch beam dynamics, the THz wiggler and radiation are described, as well as the transport system bringing the THz pulses from the wiggler to the experimental hall.

A case series of Factor V Leiden mutation in pregnancy

Background. Pregnant patients with Factor V Leiden (FVL) mutation are at an increased risk of venous thromboembolic disease (VTED) and placental-mediated complications. Thromboprophylaxis with low-molecular-weight heparin (LMWH) can potentially mitigate these risks. Objective. To describe the clinical course of a cohort of patients with FVL mutation with different underlying genotypes.Methods. The pregnancy outcomes, occurrence of VTED events and laboratory test results of pregnant women with FVL mutation managed at a quaternary medical centre over a period of 18 years in Johannesburg, South Africa, were analysed. Results. Over the period of analysis, 25 pregnant women with FVL mutation were referred to the haematology department for management. Ten patients (40%) had a family history, and 15 patients (60%) a personal history of VTED. The majority of provoked VTED events (90%) were secondary to combined oral contraceptive exposure. Previous pregnancy loss occurred in 4 (16%) patients, of whom 3 (75%) suffered recurrent losses. All women received prophylactic anti-Factor Xa (anti-FXa) dose-adjusted LMWH during ante- and postnatal periods. All pregnancies resulted in live births with 1 VTED event recorded. Conclusion. Patients with FVL mutation show phenotypical heterogeneity in terms of pregnancy outcomes, VTED events and placental-mediated complications. Confounders contributing to the heterogeneity are not completely defined and deciding on appropriate treatment is not fully standardised but the live birth rate is encouraging

The benefit of pharmacological venous thromboprophylaxis in foot and ankle surgery.

BACKGROUND: Ten percent of patients with a deep-vein thrombosis (DVT) will develop a fatal pulmonary embolism (PE), often initially asymptomatic. The risks and benefits of pharmacological thromboprophylaxis are well documented in respect of total joint arthroplasty and hip fractures, but little is understood about the incidence of venous thromboembolism (VTE) or the potential risks and benefits of chemoprophylaxis in foot and ankle surgery. OBJECTIVE: To determine whether prophylactic chemoprophylaxis had any impact on the prevention of VTE in a cohort of foot and ankle surgical patients requiring the combination of below-knee cast immobilisation and non-weightbearing for ≥4 weeks. METHODS: Between March 2014 and April 2015, a prospective cohort study of 142 patients was performed. All completed a thrombosis risk assessment form prior to surgery and were commenced on rivaroxaban (Xarelto) 10 mg/d postoperatively. The primary outcome measure was clinical VTE confirmed by compression ultrasonography (DVT) or a ventilation/perfusion scan (PE). RESULTS: Three patients (2.1%) developed a clinical DVT. Two did so well beyond the immobilisation and anticoagulation period, and one was non-compliant with therapy. The average risk factor score in this subgroup was 7. No patient had a DVT while on the prescribed regimen of anticoagulant therapy. Five patients (3.5%) developed wound breakdown, two requiring surgical debridement with local skin flap closure. One case of menorrhagia that may have been linked to the anticoagulant therapy was reported. When compared with a previous study, pharmacological thromboprophylaxis significantly reduced VTE risk (p=0.02). CONCLUSIONS: Oral pharmacological thromboprophylaxis significantly reduces the risk of VTE in patients requiring cast immobilisation and non-weightbearing following foot and ankle surgery. The risk/benefit ratio favours this treatment as opposed to the treatment of major morbidity following non-fatal VTE.

Correlation between rivaroxaban (Xarelto) plasma activity, patient clinical variables and outcomes in a South African centre.

BACKGROUND: Low-molecular-weight heparin and vitamin K antagonists such as warfarin are the gold standard for prohylaxis and treatment of venous thromboembolic disease (VTED). Direct oral anticoagulants (DOACs) result in predictable anticoagulation with significantly reduced inter- and intra-patient variability. DOAC absorption is rapid, with a short half-life and relatively few drug interactions. DOACs are effective and safe at fixed doses without activity monitoring. However, specific situations may require assessment of accurate drug activity. Rivaroxaban, a DOAC targeting activated coagulation factor X (FXa), is registered for the prevention and treatment of VTED in South Africa. OBJECTIVES: To establish a prophylactic rivaroxaban activity level range and determine any associations with clinical complications, viz. haemorrhage and/or thrombosis. METHODS: Samples from 115 orthopaedic patients were tested 3 hours after a prophylactic oral dose of 10 mg rivaroxaban with STAGO rivaroxaban anti-FXa reagent on an automated coagulation analyser. Patient demographics and clinical outcomes were documented. RESULTS: The mean rivaroxaban anti-FXa level was 105.7 ng/mL. Two patients developed adverse events on therapy. One patient had minor bleeding (menorrhagia) (drug activity level 288.7 ng/mL) and another a deep-vein thrombosis (drug activity level 34.7 ng/mL). Statistical analysis demonstrated an association between drug activity and advancing age (p=0.008), most apparent among those aged ≥65 years. CONCLUSIONS: Measuring rivaroxaban activity levels reduces uncertainty if treatment failure and complications occur. Patients aged ≥65 years should be closely monitored. A local rivaroxaban activity level for patients on rivaroxaban prophylaxis has been established.

Histopathological changes and mRNA expression in lungs of horses after inhalation anaesthesia with different ventilation strategies.

Inappropriate mechanical ventilation can lead to ventilator-induced lung injury (VILI). Aim of this study was to evaluate the effects of inhalation anaesthesia and ventilation with and without recruitment (RM) and PEEP titration on alveolar integrity in horses. Twenty-three horses were divided into 4 groups (group OLC ventilated with OLC, group IPPV ventilated with intermittent positive pressure ventilation, group NV non-ventilated, and group C non-anaesthetized control group). After sedation with xylazine and induction with diazepam and ketamine anaesthetized horses were under isoflurane anaesthesia for 5.5h. The horses were euthanized and tissue samples of the dependent and non-dependent lung areas were collected. Histopathological examinations of the lung tissue as well as relative quantification of mRNA of IL-1ß, IL-6, iNOS, MMP1 and MMP9 by PCR were performed. Horses of group OLC had significantly less alveolar congestion and atelectasis but greater alveolar overdistension compared to groups NV and IPPV. In groups OLC and group IPPV an increase in IL-1ß/6 and MMP1/9 was detected compared to groups NV and C. In conclusion, in breathing spontaneously or IPPV-ventilated horses a higher degree of atelectasis was detected, whereas in OLC-ventilated horses a higher degree of overdistention was present. Elevated levels in IL and MMP might be early signs of VILI in ventilated horses.

Validation of the CoaguChek XS international normalised ratio point-of-care analyser in patients at Charlotte Maxeke Johannesburg Academic Hospital, South Africa.

BACKGROUND: Measurement of the international normalised ratio (INR) is essential in the management of patients on long-term warfarin therapy. The CoaguChek XS portable coagulometer is a point-of-care test for INR measurement. It offers the advantage of improved patient accessibility, particularly in peripheral clinics. OBJECTIVES: To evaluate the clinical utility of the CoaguChek XS for monitoring of patients on standard warfarin therapy (INR 2 - 3) as well as those with mechanical heart valve replacements (INR 2.5 - 3.5). METHODS: We compared the performance of the CoaguChek XS device with that of the STAGO laboratory analyser with regard to accuracy and precision in 304 patients referred for routine testing. RESULTS: The mean INR value of the CoaguChek XS of 2.75 (standard deviation (SD) 1.18) was comparable to that of the STAGO (2.65 (SD 1.04)). The Bland-Altman difference plot revealed good agreement. Bias between the two methods was small, and the imprecision was within acceptable limits. Within the target range (2.0 - 3.5), 93.9% of the CoaguChek XS INR readings were within 0.5 units of the standard laboratory method result. There was, however, an increase in the variability of the differences between the two test methods when the INR was >3.6. CONCLUSION: The CoaguChek XS point-of-care device can be used to provide accurate and precise INR measurements over a wide range for monitoring of valvular and non-valvular patients on long-term warfarin therapy.

EFFECT OF ENERGY DRINKS ON SELECTED FINE MOTOR TASKS.

This study assessed the effect of energy shots on selected fine motor tasks. The participants were college-age male (n=19; M age=20.5 yr., SD=0.7) and female (n=21; M age=21.1 yr., SD=0.7) volunteers who were assessed on hand steadiness, choice reaction time, rotary pursuit, and simple reaction time. The energy shots group scored significantly poorer on the hand steadiness tests and significantly better on choice reaction time and simple reaction time tests. The enhanced reaction time and disruption in hand steadiness afforded by energy shots would not be apparent in many gross motor activities, but it is possible that reaction time improvement could be beneficial in sports that require quick, reflexive movements. However, the potential adverse psychological and physiological effects warrant discretionary use of such products.

Antisense oligonucleotide targeting eukaryotic translation initiation factor 4E reduces growth and enhances chemosensitivity of non-small-cell lung cancer cells.

Elevated levels of eukaryotic translation initiation factor 4E (eIF4E) enhance translation of many malignancy-related proteins, such as vascular endothelial growth factor (VEGF), c-Myc and osteopontin. In non-small-cell lung cancer (NSCLC), levels of eIF4E are significantly increased compared with normal lung tissue. Here, we used an antisense oligonucleotide (ASO) to inhibit the expression of eIF4E in NSCLC cell lines. eIF4E levels were significantly reduced in a dose-dependent manner in NSCLC cells treated with eIF4E-specific ASO (4EASO) compared with control ASO. Treatment of NSCLC cells with the 4EASO resulted in decreased cap-dependent complex formation, decreased cell proliferation and increased sensitivity to gemcitabine. At the molecular level, repression of eIF4E with ASO resulted in decreased expression of the oncogenic proteins VEGF, c-Myc and osteopontin, whereas expression of ß-actin was unaffected. Based on these findings, we conclude that eIF4E-silencing therapy alone or in conjunction with chemotherapy represents a promising approach deserving of further investigation in future NSCLC clinical trials.