Internal border zone injury predicts the functional outcome of acute MCA stroke patients.

BACKGROUND AND PURPOSE: Classification of deep (D), superficial (S) MCA territories and their junctional vascular area (the internal border zone, IBZ) can help to identify patients most likely to benefit from aggressive reperfusion therapy after stroke. We tested the prognostic value of an IBZ injury compared to DWI-ASPECTS and infarct volume. MATERIALS AND METHODS: DW lesions of 168 patients with acute (4.2±6.5 h) MCA strokes were retrospectively examined and manually delineated. Patients with haemorrhagic transformation or other neurological diseases were excluded. Clinical data were recorded within 24 h following symptom onset and 48 h for patients who benefited from reperfusion therapy. The occurrence of an IBZ injury was determined using a standardized stereotaxic atlas. Performance to predict a good outcome (mRS<3 at 3 months) was estimated through ROC curves for DWI-ASPECTS≤6, lesion volume≥100 mL and IBZ injury. Logistic regression models were performed to estimate independent outcomes for infarct volume and IBZ injury. RESULTS: Infarcts involving the IBZ were larger (94.9±98.8 mL vs. 30.2±31.3 mL), had higher NIHSS (13.8±7.2 vs. 7.2±5.7), more frequent MCA occlusions (64.9% vs. 28.3%), and worse outcomes (mRS 3.0±1.8 vs. 1.9±1.7), and were less responsive to IVtPA (34±47% vs. 55±48% of NIHSS improvement). The area under the ROC curves was comparable between the occurrence of IBZ injury (0.651), ASPECTS≤6 (0.657) and volume≥100 mL (0.629). Logistic regression analyses showed an independent effect of an IBZ injury, especially for superficial MCA strokes and for patients who benefited from reperfusion therapy. CONCLUSION: An IBZ injury is an early and independent marker of stroke severity, functional prognosis and treatment responsiveness.

Biliary atresia: The profile, management and outcome of patients treated at a tertiary hospital in central South Africa.

BACKGROUND: Biliary atresia (BA) is an obstructive inflammatory disease of the bile ducts. Without intervention, the disease rapidly progresses to liver cirrhosis and fibrosis, with end-stage liver failure and death occurring within the first 3 years of life. It is the most common indication for liver transplantation (LT) in the paediatric population. The management of BA in South Africa (SA) faces multiple challenges, such as late referrals and socioeconomic burdens, with suboptimal outcomes. OBJECTIVES: To determine risk factors and shortcomings that are detrimental to the outcome of the paediatric patient population by reviewing the profile, management and outcome of patients with BA treated at Universitas Academic Hospital Complex (UAHC), Bloemfontein, SA. METHODS: This was a retrospective analytical record review of all patients diagnosed with BA and treated at UAHC from 1 January 2009 to 31 December 2019. RESULTS: In total, 67 patients were included; 74.6% were female, and 86.6% were black Africans. Most (62.7%) had isolated BA. A Kasai portoenterostomy (KPE) was performed in 32 patients (47.8%). Of 5 patients referred for LT evaluation, 2 received a transplant. Of 55 patients with known outcomes, 5.5% (n=3) survived and 94.5% (n=52) died after receiving a KPE or palliative treatment. Of the 3 patients who were alive at the end of the study period, 1 had a KPE and 2 had LTs. CONCLUSION: Late presentation, cholangitis and cessation of bile flow after an initial successful KPE, and socioeconomic challenges are issues of concern and had a detrimental influence on the outcome of BA in our study population. Implementing screening measures and education programmes at the primary healthcare level is essential to diagnose and refer BA patients timeously. Establishing support systems to assist socioeconomically disadvantaged patients will enable them to qualify for LT.

Spinal Arachnoid Web: A didactic report of two cases with clinical, radiological, surgical and pathological correlations.

BACKGROUND: Arachnoid web (AW) is a rare but probably underestimated cause of spinal cord injury that is complex to diagnose due to subtle MRI findings and similarities to other better-known diseases such as arachnoid cyst (AC) or transdural spinal cord herniation (TSCH). Increased recognition of AW is mandatory since delay in diagnosis can lead to potentially serious neurological sequelae. CASE PRESENTATIONS: We report two additional cases of AW for didactic purposes, with special emphasis on the distinctive MRI and intraoperative findings. Both patients presented with progressively worsening neurological symptoms, including proprioceptive ataxia, motor weakness, numbness and neuropathic pain. The diagnosis of AW was suspected on the basis of specific MRI criteria, especially the so-called "scalpel sign". Formal confirmation of the diagnosis was obtained in two patients that were managed surgically. Postoperative follow-up demonstrated significant functional recovery. DISCUSSION: There is a need for better recognition of AW by the medical community. Careful analysis of MRI semiology is crucial for the distinction between AW, AC and TSCH. Prompt and accurate diagnosis is mandatory to conserve functional prognosis, since appropriate surgical treatment with AW resection is curative, halting or even resolving the neurological symptoms.

Covid-19 severe hypoxemic pneumonia: A clinical experience using high-flow nasal oxygen therapy as first-line management.

PURPOSE: To report a French experience in patients admitted to Intensive Care Unit (ICU) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requiring high fractional concentration of inspired oxygen supported by high flow nasal cannula (HFNC) as first-line therapy. METHODS: Retrospective cohort study conducted in two ICUs of a French university hospital. All consecutive patients admitted during 28-days after the first admission for SARS-CoV-2 pneumonia were screened. Demographic, clinical, respiratory support, specific therapeutics, ICU length-of-stay and survival data were collected. RESULTS: Data of 43 patients were analyzed: mainly men (72%), median age 61 (51-69) years, median body mass index of 28 (25-31) kg/m2, median simplified acute physiology score (SAPS II) of 29 (22-37) and median PaO2/fraction of inspired oxygen (FiO2) (P/F) ratio of 146 (100-189) mmHg. HFNC was initiated at ICU admission in 76% of patients. Median flow was 50 (45-50) L/min and median FiO2 was 0.6 (0.5-0.8). 79% of patients presented at least one comorbidity, mainly hypertension (58%). At day (D) 28, 32% of patients required invasive mechanical ventilation, 3 patients died in ICU. Risk factors for intubation were diabetes (10% vs. 43%, P=0.04) and extensive lesions on chest computed tomography (CT) (P=0.023). Patients with more than 25% of lesions on chest CT were more frequently intubated during ICU stay (P=0.012). At ICU admission (D1), patients with higher SAPS II and Sequential Organ Failure Assessment (SOFA) scores (respectively 39 (28-50) vs. 27 (22-31), P=0.0031 and 5 (2-8) vs. 2 (2-2.2), P=0.0019), and a lower P/F ratio (98 (63-109) vs. 178 (126-206), P=0.0005) were more frequently intubated. Among non-intubated patients, the median lowest P/F was 131 (85-180) mmHg. Four caregivers had to stop working following coronavirus 2 contamination, but did not require hospitalization. CONCLUSION: Our clinical experience supports the use of HFNC as first line-therapy in patients with SARS-COV-2 pneumonia for whom face mask oxygen does not provide adequate respiratory support.

[Venous thrombo-embolism during immune-mediated thrombotic thrombocytopenic purpura is prevalent in patients with a prolonged treatment with therapeutic plasma exchange]. / La maladie thrombo-embolique veineuse au cours du purpura thrombotique thrombocytopénique autoimmun est associée à un traitement prolongé par échanges plasmatiques.

INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) is a devastating disease characterized by disseminated microvascular thrombosis. Despite pro-thrombotic predisposing conditions, the prevalence of macrovascular venous thrombosis event (VTE) in immune-mediated TTP (iTTP) has rarely been assessed. METHODS: We reviewed data of all iTTP patients of the French reference Center for thrombotic microangiopathies registry prospectively enrolled through a 10-year period, between 2008 and 2018. Venous thrombosis included either thrombosis of central venous catheter, symptomatic deep venous thrombosis of the limbs or pulmonary embolism. RESULTS: Forty-eight (12.7%) VTE were diagnosed. VTE was diagnosed after a median time of 7 [IQR, 3-16] days following the first therapeutic plasma exchange (TPE) and consisted mainly in catheter-related thrombosis (73%), and to a lesser extend symptomatic deep venous thrombosis (16%), proximal pulmonary embolism (8%) and splanchnic vein thrombosis (2%). Cases with VTE (VTE+ cases), required more TPE to achieve remission (P < 0.01), and the total volume of plasma required to achieve remission was larger (P < 0.01) than for VTE- cases. There was also a trend for more rituximab use in the VTE+ cases as compared to the VTE- cases (47% vs 33%; respectively; P = 0.07). Curative anticoagulation was started in 38 cases (79%), while 6 VTE cases did not receive any antithrombotic agents, and catheter was systematically removed when catheter-related thrombosis was diagnosed. VTE+ cases had a higher number of inserted central venous catheters than VTE- cases (P < 0.05). CONCLUSION: VTE is a frequent condition occurring during iTTP management and is observed when patients require a prolonged treatment with daily TPE and multiple catheter insertions. Therapeutic strategies aimed at reducing the duration of TPE treatment in iTTP should substantially reduce this complication.

Use of a dense monitoring network of low-cost instruments to observe local changes in the diurnal ozone cycles as marine air passes over a geographically isolated urban centre.

Ozone (O3) concentrations in urban areas are spatially and temporally variable, influenced by chemical production, depletion through deposition and chemical titration processes and dispersion. To date, analysis of intra-urban variability of O3 concentrations, and the influence of local controls on production and depletion rates, has been limited due to the low spatial and/or temporal resolution of measurements. We demonstrate that measurements made using a carefully managed multi-sensor network of low-cost gas-sensitive semiconductor instruments are sufficiently precise to resolve subtle but significant variations in ozone concentration across a region. Ozone was measured at 12 sites in the isolated subtropical city of Auckland, New Zealand. Overall O3 concentrations in the Auckland region were low (annual mean: 19ppb) across all seasons, with a minimum in summer. Higher O3 concentrations (max. 57ppb) were observed when wind speeds were >5ms-1 and from the W/SW, and were associated with maritime air masses. Ozone formation in the Auckland region is low, which is attributed to a combination of the low O3 background concentrations, the negligible contribution of long-range transport and the effect of NOx titration. Intra-urban variability showed that the lowest O3 concentrations were measured at the residential sites, particularly at night and during rush hours. Ozone depletion from reaction with traffic-generated NO explains the rush-hour minima but did not fully account for the low night-time values. The results suggest that night-time depletion may result from other processes such as the reaction of ozone with nitrite on surfaces such as concrete, pointing towards the need for further studies concerning the rate and mechanism of dry deposition at night in urban areas.

[The revolution of monoclonal antibodies in the treatment of thrombotic microangiopathy]. / La révolution des anticorps monoclonaux dans la prise en charge des microangiopathies thrombotiques.

Thrombotic microangiopathies (TMA) define a syndrome characterized by the association of microangiopathic haemolytic anaemia with schistocytes, peripheral thrombocytopenia, and organ injury of variable severity. Thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uremic syndrome (HUS) are the main forms of TMA. Recent advances in the pathophysiology of those two diseases, which include in HUS the identification of a deregulation of the alternative complement pathway, and in TTP a severe deficiency in ADAMTS-13, allowed to develop specific, pathophysiology-based therapies. Therefore, rituximab and eculizumab tends to be increasingly used, and there is an urgent need to define consensual modes of administration at the international level, as well as common definitions of response evaluation and follow-up explorations.

Prevalence and consequences of delayed diagnosis of anterior cruciate ligament ruptures.

PURPOSE: Rupture of the anterior cruciate ligament (ACL) is a common injury, often presenting with a typical injury pattern. Historically, the literature indicates that the accuracy of diagnosis of ACL ruptures is poor at the initial medical consultation. The aims of this study were to determine: the mechanism of injury; changes in accuracy of diagnosis of ACL ruptures at initial presentation over the last decade; and the effect of subsequent delay in diagnosis and definitive treatment. METHODS: A prospective cohort of one hundred and thirty-two consecutive patients who underwent ACL reconstruction between 2005 and 2009 were analysed. The median age of the patients was 18 years (12-57). Sixteen patients were excluded due to chronic ACL injury. RESULTS: One hundred and sixteen patients (117 ACL ruptures) were included in the analysis. A typical injury pattern was documented in 87 (74.4 %) of cases. The most common sporting activities associated with an ACL injury were football (35.3 %), skiing (21.6 %) and rugby (10.3 %). The majority of patients (67.5 %) sought medical attention within 1 week from time of injury. The correct diagnosis of an ACL rupture was made in 33 cases (28.2 %) at the initial medical consultation. The diagnosis was made following medical consultation in 13 (11.1 %) of cases with the use of magnetic resonance imaging and 6 (5.1 %) cases at arthroscopy. The median time to diagnosis was 6 weeks (0-192), and the median time to ACL reconstruction was 24 weeks (1-240). A delay in diagnosis of >6 months was associated with a medial meniscal tear rate of 72.2 % compared to 23.1 % if the diagnosis was made within 4 months of the injury (p < 0.05). CONCLUSIONS: Despite a 'typical' mechanism of injury leading to ACL rupture, the rate of initial diagnosis in the UK still remains poor. This often leads to an unnecessary delay in the diagnosis and subsequent treatment and increases the risk of secondary injury to the knee. A delay in diagnosis of >6 months was associated with an increased medial meniscal tear rate. Patients who present with a 'typical' injury pattern should therefore be referred for further assessment by a knee specialist within 6 weeks. LEVEL OF EVIDENCE: IV.

Abortion-prone mating influences placental antioxidant status and adversely affects placental and foetal development.

Oxidative stress is associated with decreased female fertility and adversely affects prenatal development. Mammalian cells have developed a network of enzymatic and non-enzymatic antioxidant defence systems to prevent oxidative stress. Little attention has been paid to the antioxidative pathways in placentas of normal and disturbed pregnancies, leaving a gap in our knowledge about the role of antioxidants in the control of foeto-placental development. The challenges in studying early human pregnancy can partly be overcome by designing animal models of abnormal pregnancy. We aimed to determine whether the antioxidant status of placentas from the CBA/J × DBA/2 abortion-prone pregnant mice differed from that of normal pregnant mice. The foetal/placental weight ratio was lower in abortion-prone matings compared with that in non-abortion-prone matings. The increased placental malondialdehyde (MDA) content, the end products of lipid peroxidation, with concomitants alterations in placental antioxidants, namely copper-zinc containing superoxide dismutase (SOD1), manganese containing (SOD2), glutathione peroxidases (GPX), glutathione reductase (GR) and catalase (CAT) activities may be involved in placental and foetal growth restriction. We show that placental oxidative stress is linked with poor prenatal development and pregnancy losses in CBA/J × DBA/2 mice matings. This animal model may be useful in the evaluation of nutritional antioxidant therapies for oxidative stress and associated prenatal developmental disorders.

"When can I return to driving?": a review of the current literature on returning to driving after lower limb injury or arthroplasty.

Clinicians are often asked by patients, "When can I drive again?" after lower limb injury or surgery. This question is difficult to answer in the absence of any guidelines. This review aims to collate the currently available evidence and discuss the factors that influence the decision to allow a patient to return to driving. Medline, Web of Science, Scopus, and EMBASE were searched using the following terms: 'brake reaction time', 'brake response time', 'braking force', 'brake pedal force', 'resume driving', 'rate of application of force', 'driving after injury', 'joint replacement and driving', and 'fracture and driving'. Of the relevant literature identified, most studies used the brake reaction time and total brake time as the outcome measures. Varying recovery periods were proposed based on the type and severity of injury or surgery. Surveys of the Driver and Vehicle Licensing Agency, the Police, insurance companies in the United Kingdom and Orthopaedic Surgeons offered a variety of opinions. There is currently insufficient evidence for any authoritative body to determine fitness to drive. The lack of guidance could result in patients being withheld from driving for longer than is necessary, or returning to driving while still unsafe.

Thorough QT/QTc study of tocilizumab after single-dose administration at therapeutic and supratherapeutic doses in healthy subjects.

OBJECTIVES: The study was intended to determine whether tocilizumab has a threshold pharmacologic effect on cardiac repolarization as detected by QT/QTc prolongation on 12-lead electrocardiograms (ECGs) in healthy subjects. METHODS: This was a multicenter, double-blind, placebo- and active-controlled, parallel group study. Healthy subjects received either an intravenous infusion of tocilizumab 10 mg/kg (n = 30) or 20 mg/kg (n = 31), oral moxifloxacin 400 mg (n = 31), or placebo (n = 29). Triplicate ECGs were obtained at predose, 2 h postdose on Day 1, and on Days 8, 15, and 29. Blood samples for pharmacokinetic analyses were collected at predose and up to 28 days postdose. Adverse events and laboratory safety tests were assessed throughout the study. RESULTS: Estimated mean study-specific, heart rate-corrected QT interval change from time-matched baseline versus placebo was negative at all time points (range -5.4 to -1.0 ms); the associated upper bound of the 1-sided 95% confidence limit was below threshold (10 ms). No clinically significant abnormalities in other electrocardiographic parameters were detected. No electrocardiographic abnormalities constituted an adverse event. After tocilizumab dosing, median time to maximum serum concentration was 2 h postdose; mean apparent terminal half-life was 9.3 ± 1.2 (10 mg/kg) and 12.1 ± 1.5 (20 mg/kg) days. Tocilizumab was well tolerated. Neutrophil counts decreased after tocilizumab administration, reaching a nadir 2 to 5 days after infusion. Mean neutrophil counts returned to baseline in the 10-mg/kg group and were near baseline in the 20-mg/kg group at the follow-up visit (Day 50 ± 2). CONCLUSIONS: There was no QT prolongation effect of clinical concern by tocilizumab at both the therapeutic (10 mg/kg) and the supratherapeutic (20 mg/kg) dose in healthy subjects.

Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis.

In rheumatoid arthritis (RA), interleukin-6 (IL-6) concentration is elevated, which may cause reduced cytochrome P450 (CYP) activity and increased exposure (peak plasma concentration and area under the plasma concentration-vs.-time curve (AUC)) to certain drugs. Tocilizumab may reverse IL-6-induced suppression of CYP3A4 activity. In this study, exposure to simvastatin was significantly reduced at 1 and 5 weeks after tocilizumab infusion in 12 patients with RA. The mean effect ratio for simvastatin AUC(last) was 43% (90% confidence interval (CI), 34-55%) at 1 week after tocilizumab infusion (day 15) and 61% (90% CI, 47-78%) at 5 weeks after tocilizumab infusion, as compared with baseline (day 1); both ratios were significantly lower than the bioequivalence boundary (80-125%). Mean plasma C-reactive protein (CRP) levels normalized within 1 week after tocilizumab was initiated; the time course of tocilizumab's CRP-reducing effect paralleled that of simvastatin pharmacokinetics. The study findings suggest that caution should be exercised when starting tocilizumab in RA patients who are taking simvastatin.

Voluntary intake and digestibility in horses: effect of forage quality with emphasis on individual variability.

Food intake is a key biological process in animals, as it determines the energy and nutrients available for the physiological and behavioural processes. In herbivores, the abundance, structure and quality of plant resources are known to influence intake strongly. In ruminants, as the forage quality declines, digestibility and total intake decline. Equids are believed to be adapted to consume high-fibre low-quality forages. As hindgut fermenters, it has been suggested that their response to a reduction in food quality is to increase intake to maintain rates of energy and nutrient absorption. All reviews of horse nutrition show that digestibility declines with forage quality; for intake, however, most studies have found no significant relationship with forage quality, and it has even been suggested that horses may eat less with declining forage quality similarly to ruminants. A weakness of these reviews is to combine data from different studies in meta-analyses without allowing the differences between animals and diets to be controlled for. In this study, we analysed a set of 45 trials where intake and digestibility were measured in 21 saddle horses. The dataset was analysed both at the group (to allow comparisons with the literature) and at the individual levels (to control for individual variability). As expected, dry matter digestibility declined with forage quality in both analyses. Intake declined slightly with increasing fibre contents at the group level, and there were no effects of crude protein or dry matter digestibility on intake. Overall, the analysis for individual horses showed a different pattern: intake increased as digestibility and crude protein declined, and increased with increasing fibre. Our analysis at the group level confirms previous reviews and shows that forage quality explains little of the variance in food intake in horses. For the first time, using mixed models, we show that the variable 'individual' clarifies the picture, as the horses showed different responses to a decrease in forage quality: some compensated for the low nutritional value of the forages by increasing intake, few others responded by decreasing intake with declining forage quality, but not enough to cause any deficit in their energy and protein supplies. On the whole, all the animals managed to meet their maintenance requirements. The individual variability may be a by-product of artificial selection for performance in competition in saddle horses.

A non-contact mouse for surgeon-computer interaction.

We have developed a system that uses computer vision to replace standard computer mouse functions with hand gestures. The system is designed to enable non-contact human-computer interaction (HCI), so that surgeons will be able to make more effective use of computers during surgery. In this paper, we begin by discussing the need for non-contact computer interfaces in the operating room. We then describe the design of our non-contact mouse system, focusing on the techniques used for hand detection, tracking, and gesture recognition. Finally, we present preliminary results from testing and planned future work.

A haptic guidance tool for CT-directed percutaneous interventions.

We have developed a new navigation approach for computer-assisted interventional radiology. Our system combines a virtual reality display with high-fidelity haptic rendering to provide assistance and guidance of the medical gesture. Specifically, the system is designed to improve the accuracy of blind needle placement within tissues. The proposed technique actively helps the surgeon while keeping him in control of the procedure. We have recently developed an experimental setup for CT-guided biopsy. The setup features a high-precision haptic device connected to the biopsy needle, combined with a graphical interface. The haptic system guides the surgeon's hand to the target tissue based on CT data, whereas a real-time, graphical visualization of the tool trajectory provides navigation information. The setup requires rigid registration of the patient with respect to the haptic interface. Tests have been performed in the presence of radiologists to validate the proposed concept, and early results show that the system is easy to use and requires little training. We are planning to conduct clinical testing in the near future to quantitatively assess system performance.

Postmortem findings in the Coffin-Lowry Syndrome.

The Coffin-Lowry Syndrome (CLS) is a congenital disorder that can be recognized by retarded growth and development, the characteristic appearance of the face and hands, and often by the typical deformities of the back and chest; there are many other anomalies. The history of the syndrome is reviewed, noting the x-linked semidominant pattern of inheritance, and two autopsies are presented and compared with the three autopsy reports that have been published previously. The five young patients died at ages between 18 to 28 years of advancing pneumonia, aspiration of food into the trachea, or postoperative complications. There were lesions or abnormalities in the heart, brain, lungs, liver, skeleton, kidneys, intestines, and other organs. Molecular geneticists have located the CLS gene or Rsk-2 gene at Xp22.2 and demonstrated that it works by influencing the activation of other genes. The "monopolygenic" pattern may help to explain the large number of seemingly unrelated abnormalities that make up this syndrome.

A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats.

PURPOSE: To study the PK interaction of L-dopa/benserazide in rats. METHODS: Male rats received a single oral dose of 80 mg/kg L-dopa or 20 mg/kg benserazide or 80/20 mg/kg L-dopa/benserazide. Based on plasma concentrations the kinetics of L-dopa, 3-O-methyldopa (3-OMD), benserazide, and its metabolite Ro 04-5127 were characterized by noncompartmental analysis and a compartmental model where total L-dopa clearance was the sum of the clearances mediated by amino-acid-decarboxylase (AADC), catechol-O-methyltransferase and other enzymes. In the model Ro 04-5127 inhibited competitively the L-dopa clearance by AADC. RESULTS: The coadministration of L-dopa/benserazide resulted in a major increase in systemic exposure to L-dopa and 3-OMD and a decrease in L-dopa clearance. The compartmental model allowed an adequate description of the observed L-dopa and 3-OMD concentrations in the absence and presence of benserazide. It had an advantage over noncompartmental analysis because it could describe the temporal change of inhibition and recovery of AADC. CONCLUSIONS: Our study is the first investigation where the kinetics of benserazide and Ro 04-5127 have been described by a compartmental model. The L-dopa/benserazide model allowed a mechanism-based view of the L-dopa/benserazide interaction and supports the hypothesis that Ro 04-5127 is the primary active metabolite of benserazide.