Association between tocilizumab treatment of hyperinflammatory patients with COVID-19 in a critical care setting and elevated incidence of hospital-acquired bacterial and invasive fungal infections.

BACKGROUND: Tocilizumab is an interleukin-6 inhibitor that reduces mortality and the need for invasive mechanical ventilation, while increasing the possibility of successful hospital discharge for hyperinflammatory patients with severe coronavirus disease 2019 (COVID-19). No increase in adverse events or serious infections has been reported previously. AIM: To describe the characteristics and outcomes of patients with severe COVID-19 in critical care who received tocilizumab, and to compare mortality and length of hospital stay for patients who received tocilizumab (N=41) with those who did not (N=33). METHODS: Retrospective review of data related to patients with COVID-19 who received tocilizumab in a critical care setting from 1st January to 31st December 2021. FINDINGS: Amongst COVID-19 survivors, those who had received tocilizumab had longer intensive care unit (ICU) stays (median length 21 vs 9 days) and hospital stays (45 vs 34 days) compared with those who had not received tocilizumab. Thirty-day mortality (29% vs 36%; P=0.5196) and 60-day mortality (37% and 42%; P=0.6138) were not significantly lower in patients who received tocilizumab. Serious bacterial and fungal infections occurred at higher frequency amongst patients who received tocilizumab [odds ratio (OR) 2.67, 95% confidence interval (CI) 1.04-6.86; P=0.042], and at significantly higher frequency than in non-COVID-19 ICU admissions (OR 5.26, 95% CI 3.08-9.00; P<0.0001). CONCLUSIONS: In this single-centre study, patients in critical care with severe COVID-19 who received tocilizumab had a greater number of serious bacterial and fungal infections, but this may not have been a direct effect of tocilizumab treatment.

Photosynthesis in response to salinity and submergence in two Rhizophoraceae mangroves adapted to different tidal elevations.

Mangrove ecosystems are vulnerable to rising sea levels. When the sea level rises, the plants are exposed to increased salinity and tidal submergence. In Taiwan, the mangrove species Kandelia obovata and Rhizophora stylosa grow in different habitats and at different elevations. To understand the response of photosynthesis to salinity and submergence in mangroves adapted to different tidal elevations, gas exchange and chlorophyll fluorescence parameters were measured in K. obovata and R. stylosa under different salinity (20 and 40‰) and submergence treatments. The period of light induction of photosynthesis for the two mangrove species was >60 min. In the induction process, the increase in photosystem efficiency was faster than the increase in stomatal opening, but CO2 fixation efficiency was restricted by stomatal conductance. The constraint of stomatal opening speed is related to the conservative water-use strategy developed in response to mangrove environments. Submergence increased the photosynthetic rate of K. obovata, but not that of R. stylosa. Although R. stylosa was more salt tolerant than K. obovata, R. stylosa was not submergence tolerant in a high-salinity environment, which may be the reason for the higher intertidal elevations observed for R. stylosa in comparison with K. obovata. The photosynthetic rate and energy-dependent quenching (qE) of the two mangroves presented a negative relationship with photoinhibition, and high-salt treatment simultaneously reduced photosynthetic rate and qE. A decrease in the photosynthetic rate increased excess energy, whereas a decrease in qE decreased photoprotection; both increased photoinhibition. As the degree of photoinhibition can be easily measured in the field, it is a useful ecological monitoring index that provides a suitable reference for mangrove restoration, habitat construction and ecological monitoring.

Retrospective Planning Study of Patients with Superior Sulcus Tumours Comparing Pencil Beam Scanning Protons to Volumetric-Modulated Arc Therapy.

AIMS: Twenty per cent of patients with non-small cell lung cancer present with stage III locally advanced disease. Precision radiotherapy with pencil beam scanning (PBS) protons may improve outcomes. However, stage III is a heterogeneous group and accounting for complex tumour motion is challenging. As yet, it remains unclear as to whom will benefit. In our retrospective planning study, we explored if patients with superior sulcus tumours (SSTs) are a select cohort who might benefit from this treatment. MATERIALS AND METHODS: Patients with SSTs treated with radical radiotherapy using four-dimensional planning computed tomography between 2010 and 2015 were identified. Tumour motion was assessed and excluded if greater than 5 mm. Photon volumetric-modulated arc therapy (VMAT) and PBS proton single-field optimisation plans, with and without inhomogeneity corrections, were generated retrospectively. Robustness analysis was assessed for VMAT and PBS plans involving: (i) 5 mm geometric uncertainty, with an additional 3.5% range uncertainty for proton plans; (ii) verification plans at maximal inhalation and exhalation. Comparative dosimetric and robustness analyses were carried out. RESULTS: Ten patients were suitable. The mean clinical target volume D95 was 98.1% ± 0.4 (97.5-98.8) and 98.4% ± 0.2 (98.1-98.9) for PBS and VMAT plans, respectively. All normal tissue tolerances were achieved. The same four PBS and VMAT plans failed robustness assessment. Inhomogeneity corrections minimally impacted proton plan robustness and made it worse in one case. The most important factor affecting target coverage and robustness was the clinical target volume entering the spinal canal. Proton plans significantly reduced the mean lung dose (by 21.9%), lung V5, V10, V20 (by 47.9%, 36.4%, 12.1%, respectively), mean heart dose (by 21.4%) and thoracic vertebra dose (by 29.2%) (P < 0.05). CONCLUSIONS: In this planning study, robust PBS plans were achievable in carefully selected patients. Considerable dose reductions to the lung, heart and thoracic vertebra were possible without compromising target coverage. Sparing these lymphopenia-related organs may be particularly important in this era of immunotherapy.

Modified Delphi study of decision-making around treatment sequencing in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Existing effectiveness models of disease-modifying drugs (DMDs) for relapsing-remitting multiple sclerosis (RRMS) evaluate a single line of treatment; however, RRMS patients often receive more than one lifetime DMD. To develop treatment sequencing models grounded in clinical reality, a detailed understanding of the decision-making process regarding DMD switching is required. Using a modified Delphi approach, this study attempted to reach consensus on modelling assumptions. METHODS: A modified Delphi technique was conducted based on three rounds of discussion amongst an international group of 10 physicians with expertise in RRMS. RESULTS: The panel agreed that the expected time from disease onset to Expanded Disability Status Scale 6.0 is a proxy for disease severity as well as suitable for classifying severity into three groups. A modelled clinical decision rule regarding the timing of switching should contain at least the time between relapses, magnetic resonance imaging outcomes and the occurrence/risk of adverse events. The experts agreed that the assessment of adverse event risk for a DMD is dependent on disease severity, with more risks accepted when the patient's disease is more severe. The effectiveness of DMDs conditional on their position in a sequence and/or disease duration was discussed: there was consensus on some statements regarding this topic but these were accompanied by a high degree of uncertainty due to considerable knowledge gaps. CONCLUSION: Useful insights into the medical decision-making process regarding treatment sequencing in RRMS were obtained. The knowledge gained has been used to validate the main modelling concepts and to further generate clinically meaningful results.

Multi-disciplinary Psychiatric Case Management Model in Hong Kong: Service Coverage and Risk Stratification.

INTRODUCTION: Community mental health services in Hong Kong follow a multi-disciplinary case management model. We investigated whether at-risk patients received higher intensity care and whether risk stratification concorded between personalised care programmes and integrated community centres of mental wellness. METHODS: Records of all patients in North Lantau and Mongkok districts who received case management services (from personalised care programmes and/or integrated community centres of mental wellness) between 1 April 2014 and 30 June 2015 were reviewed. Patients' levels of risk, demographic data, and clinical characteristics were analysed. RESULTS: Identified at-risk patients received high-intensity care from personalised care programmes and integrated community centres of mental wellness. Case management was coordinated between the Hospital Authority and non-government organisations. However, risk stratification did not correlate with assessment rating scores of psychopathology or psychosocial functioning. Assessment rating scales appear unsuitable to provide any optimal cut-off scores for risk stratification. CONCLUSIONS: Risk stratification should be a structured clinical judgement based on comprehensive and accurate information of protective and risk factors, rather than relying on cut-off scores of assessment rating scales.

Dedifferentiated endometrioid adenocarcinoma of the uterus: A case series and review of literature.

Introduction Dedifferentiated endometrioid adenocarcinoma (DEAC) was first described in 2007. However, it has only been recognised as a distinct subtype of endometrioid adenocarcinoma in the last 1-2 years. DEAC is a more aggressive histological subtype and carries a poorer prognosis. Patients with DEAC tend to present with advanced disease compared the other endometrioid adenocarcinomas. Methodology The study is a retrospective review of patients with DEAC diagnosed in two institutions in Singapore between January 2012 and October 2017. Results 7 patients were diagnosed with DEAC. The mean age was 56.4 years. All patients presented with either abnormal uterine bleeding or post menopausal bleeding. Out of the 7 patients, one was diagnosed with Stage 2 disease, 5 were diagnosed with Stage 3 disease and 1 was diagnosed with Stage 4 disease. One patient had neoadjuvant chemotherapy, followed by surgery, and completion chemotherapy post surgery. The other 6 patients (87.5%) underwent primary debulking surgery. Out of these 6 patients, 5 patients had adjuvant chemotherapy post surgery and one patient had both adjuvant chemotherapy and radiotherapy. Lymphovascular invasion was found in 71.4% of the cases. Conclusion DEAC is a more aggressive histological subtype of endometrioid adenocarcinomas. Better awareness of this condition can lead to proper diagnosis and treatment.

The Landmark Series: Randomized Trials Examining Surgical Margins for Cutaneous Melanoma.

Between 1980 and 2004, six randomized, controlled trials (RCTs) have been performed to evaluate the width of surgical margin excision for primary cutaneous melanoma and its influence on recurrence and survival. These trials have led to the current recommendation of not more than a 2-cm margin excision and have allowed reduced morbidity of surgery for primary melanoma. Long-term follow-up data has been published which has led to impactful knowledge of the natural history of this disease, yet controversy remains for 1- to 2-mm thickness melanomas. Interpretation of these trials must be done in light of them enrolling patients before the use of sentinel node biopsy and contemporary immunotherapy regimens. These RCTs as well as a contemporary, actively enrolling trial are summarized and discussed in this review.

Meta-analysis of completion lymph node dissection in sentinel lymph node-positive melanoma.

BACKGROUND: The role of completion lymph node dissection (CLND) in patients with sentinel lymph node (SLN)-positive melanoma continues to be debated. This systematic review and meta-analysis evaluated survival and recurrence rate in these patients who underwent CLND, compared with observation. METHODS: A comprehensive MEDLINE and Embase database search was performed for cohort studies and RCTs published between January 2000 and June 2017 that assessed the outcomes of CLND compared with observation in patients with SLN-positive melanoma. The primary outcome was survival and the secondary outcome was recurrence rate. Studies were assessed for quality using the Cochrane risk-of-bias tool for RCTs and Newcastle-Ottawa Scale for cohort studies. Pooled relative risk or hazard ratio with 95 per cent confidence intervals were calculated for each outcome. The extent of heterogeneity between studies was assessed with the I2 test. The protocol was registered in PROSPERO (CRD42017070152). RESULTS: Fifteen studies (13 cohort studies with 7868 patients and 2 RCTs with 2228 patients) were identified for qualitative synthesis. Thirteen studies remained for quantitative meta-analysis. Survival was similar in patients who underwent CLND and those who were observed (risk ratio (RR) for death 0·85, 95 per cent c.i. 0·71 to 1·02). The recurrence rate was also similar (RR 0·91, 0·79 to 1·05). CONCLUSION: Patients with SLN-positive melanoma do not have a significant benefit in survival or recurrence rate if they undergo CLND rather than observation.

Safety and pharmacodynamics of venetoclax (ABT-199) in a randomized single and multiple ascending dose study in women with systemic lupus erythematosus.

Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18-65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials). Results All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets. Conclusions Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells. Registration ClinicalTrials.gov: NCT01686555.

Economic costs of recorded reasons for cow mortality and culling in a pasture-based dairy industry.

The objective of this study was to determine the economic costs associated with different reasons for cow culling or on-farm mortality in a pasture-based seasonal system. A bioeconomic model was developed to quantify costs associated with the different farmer-recorded reasons and timing of cow wastage. The model accounted for the parity and stage of lactation at which the cows were removed as well as the consequent effect on the replacement rate and average age structure of the herd. The costs and benefits associated with the change were quantified, including animal replacement cost, cull salvage value, milk production loss, and the profitability of altered genetic merit based on industry genetic trends for each parity. The total cost of cow wastage was estimated to be NZ$23,628/100 cows per year (NZ$1 = US$0.69) in a pasture-based system. Of this total cost, NZ$14,300/100 cows worth of removals were for nonpregnancy and unknown reasons, and another NZ$3,631/100 cows was attributed to low milk production, mastitis, and udder problems. The total cost for cow removals due to farmer-recorded biological reasons (excluding unknown, production, and management-related causes) was estimated to be NZ$13,632/100 cows per year. Of this cost, an estimated NZ$10,286/100 cows was attributed to nonpregnancy, mastitis, udder problems, calving trouble, and injury or accident. There is a strong economic case for the pasture-based dairy industries to invest in genetic, herd health, and production management research focused on reducing animal wastage due to reproductive failure, mastitis, udder problems, injuries or accidents, and calving difficulties.

Pyrolysis of low density polyethylene waste in subcritical water optimized by response surface methodology.

Pyrolysis of low density polyethylene (LDPE) waste from local waste separation company in subcritical water was conducted to investigate the effect of reaction time, temperature, as well as the mass ratio of water to polymer on the liquid yield. The data obtained from the study were used to optimize the liquid yield using response surface methodology. The range of reaction temperature used was 162-338°C, while the reaction time ranged from 37 min to 143 min, and the ratio of water to polymer ranged from 1.9 to 7.1. It was found that pyrolysis of LDPE waste in subcritical water produced hydrogen, methane, carbon monoxide and carbon dioxide, while the liquid product contained alkanes and alkenes with 10-50 carbons atoms, as well as heptadecanone, dichloroacetic acid and heptadecyl ester. The optimized conditions were 152.3°C, reaction time of 1.2 min and ratio of water solution to polymer of 32.7, with the optimum liquid yield of 13.6 wt% and gases yield of 2.6 wt%.

Impermeable barrier films and protective coatings based on reduced graphene oxide.

Flexible barrier films preventing permeation of gases and moistures are important for many industries ranging from food to medical and from chemical to electronic. From this perspective, graphene has recently attracted particular interest because its defect-free monolayers are impermeable to all atoms and molecules. However, it has been proved to be challenging to develop large-area defectless graphene films suitable for industrial use. Here we report barrier properties of multilayer graphitic films made by gentle chemical reduction of graphene oxide laminates with hydroiodic and ascorbic acids. They are found to be highly impermeable to all gases, liquids and aggressive chemicals including, for example, hydrofluoric acid. The exceptional barrier properties are attributed to a high degree of graphitization of the laminates and little structural damage during reduction. This work indicates a close prospect of graphene-based flexible and inert barriers and protective coatings, which can be of interest for numerous applications.

Twist-controlled resonant tunnelling in graphene/boron nitride/graphene heterostructures.

Recent developments in the technology of van der Waals heterostructures made from two-dimensional atomic crystals have already led to the observation of new physical phenomena, such as the metal-insulator transition and Coulomb drag, and to the realization of functional devices, such as tunnel diodes, tunnel transistors and photovoltaic sensors. An unprecedented degree of control of the electronic properties is available not only by means of the selection of materials in the stack, but also through the additional fine-tuning achievable by adjusting the built-in strain and relative orientation of the component layers. Here we demonstrate how careful alignment of the crystallographic orientation of two graphene electrodes separated by a layer of hexagonal boron nitride in a transistor device can achieve resonant tunnelling with conservation of electron energy, momentum and, potentially, chirality. We show how the resonance peak and negative differential conductance in the device characteristics induce a tunable radiofrequency oscillatory current that has potential for future high-frequency technology.

Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development.

BACKGROUND: A growing health problem, venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), requires refined diagnostic and therapeutic approaches. Neutrophils contribute to thrombus initiation and development in experimental DVT. Recent animal studies recognized neutrophil extracellular traps (NETs) as an important scaffold supporting thrombus stability. However, the hypothesis that human venous thrombi involve NETs has not undergone rigorous testing. OBJECTIVE: To explore the cellular composition and the presence of NETs within human venous thrombi at different stages of development. PATIENTS AND METHODS: We examined 16 thrombi obtained from 11 patients during surgery or at autopsy using histomorphological, immunohistochemical and immunofluorescence analyses. RESULTS: We classified thrombus regions as unorganized, organizing and organized according to their morphological characteristics. We then evaluated them, focusing on neutrophil and platelet deposition as well as micro-vascularization of the thrombus body. We observed evidence of NET accumulation, including the presence of citrullinated histone H3 (H3Cit)-positive cells. NETs, defined as extracellular diffuse H3Cit areas associated with myeloperoxidase and DNA, localized predominantly during the phase of organization in human venous thrombi. CONCLUSIONS: NETs are present in organizing thrombi in patients with VTE. They are associated with thrombus maturation in humans. Dissolution of NETs might thus facilitate thrombolysis. This finding provides new insights into the clinical development and pathology of thrombosis and provides new perspectives for therapeutic advances.

Pedometer-determined physical activity and body composition in Chinese working adults.

PURPOSE: Overweight and obesity are prevalent public health problems in many developed and developing regions. Despite extensive documentation on the health benefits of physical activities, little is known about the level of physical activity in the Hong Kong Chinese population. Working adults, in particular, deserve primary attention because they account for the largest proportion of Hong Kong society. The purposes of this study were to investigate pedometer-determined physical activity and examine the associations between physical activity and body composition variables among Chinese working adults in Hong Kong. DESIGN: This study adopted a descriptive cross-sectional design. METHODS: A quota sample of 913 working adults from nine major occupational categories was recruited. Demographic characteristics and body composition parameters (weight, height, and waist and hip circumferences) were assessed. Body mass index and waist-to-hip ratio were then calculated. Physical activity was measured in terms of daily walking steps using a pedometer over 1 week. Participants were then categorized as "inactive,""somewhat active," or "regularly active." Descriptive and inferential statistics (analysis of variance, t test, and χ(2) test) were used appropriately. FINDINGS: Of the 913 participants, 893 returned complete step count records. The completion rate was 97.8%. Participants on average walked 8,661 steps per day, suggesting a "somewhat active" populace. Significant differences were found between the group "regularly active" and "inactive" in most of the body composition parameters. However, a significant weak correlation was found between physical activity and body mass index (r= 0.12, p= .001). Such findings deserve further investigation. CONCLUSIONS: The Chinese working adults in Hong Kong were found to be somewhat active in physical activity. CLINICAL RELEVANCE: Findings pose implications for healthcare professionals who are responsible for health promotion in the Asian community setting. Leisure-type physical activity, such as walking, can be incorporated into daily routines.

Cryptococcal osteomyelitis of the femur: a case report and review of literature.

Fungal osteomyelitis is a rare opportunistic infection. It exhibits some clinical and radiological similarities to several other bone pathologies. A diagnostic delay may result in significant increase in morbidity. We report a case of a 37-year-old man with underlying hypogammaglobulinaemia presented with isolated cryptococcal osteomyelitis of the femur.

A new mathematical model for irradiance field prediction of upper-room ultraviolet germicidal systems.

There has been an increasing interest in the use of upper-room ultraviolet germicidal irradiation (UVGI) system because of its proven disinfection effect for airborne microorganisms. To better design and explore further potential applications of UVGI systems, it is of critical importance to predict the spatial UV intensity in enclosures. In this paper, we developed a new mathematical model to predict spatial radiation intensity for upper-room ultraviolet germicidal irradiation systems. The detail geometries of the lamp and the reflector were removed and replaced by introducing a fictitious irradiation surface near louver slots. The view factor approach was applied to evaluate the UV irradiance in a three-dimensional space with different louver configurations. With this approach no detail meshing of the fixture is required and this leads to significant simplification of the entire systems from modeling perspectives. To validate the model, experiments were performed in a full-scale environmental controlled chamber in which one UVGI fixture was mounted on a sidewall. The UV irradiance was measured by a radiometer. The results predicted by the present model agree very well with the experimental measurements. Factors affect the accuracy of the model was also discussed.

Children with learning disabilities in the paediatric clinic, Hospital Tuanku Ja'afar Seremban: an overview.

The aim of the study was to document the prevalence of learning disability among the children attending the Paediatric Clinic in Hospital Tuanku Ja'afar Seremban. The demographic distribution of these patients; the age of detection of the problem; the associated medical conditions and types of intervention received by these patients were documented. Patients who were between the ages of five to twelve years were included in the study. Learning disability was divided into three categories: speech and articulation problems, academic skills disorder and other categories which included developmental delay. Children with cerebral palsy were excluded from the study. Out of 1320 patients screened, 355 were found to have learning disorders. Majority were Malays, with the male to female ratio of 1.9:1. Most of the patients stayed in Seremban. The learning problem was most commonly detected at the age of 4 years and below. The commonest type of learning disorder was developmental delay, followed by academic skills disorder, speech and academic skills problems and speech disorders. Problems that were detected early were speech problems and developmental delay. Majority of the children had associated medical conditions. Most of the patients received some form of intervention but 11.3% did not attend any intervention program at all. A strategy should be formulated and implemented to help this group of children.

Osteonecrosis of the jaw after oral bisphosphonate for osteoporosis.

Bisphosphonates are a common treatment for osteoporosis. Osteonecrosis of the jaw has been associated with the use of bisphosphonates, usually when they have been used parenterally to treat malignancies. Cases associated with oral bisphosphonate as a treatment for osteoporosis are less frequent. We describe two patients exhibiting the clinical manifestations of bisphosphonate-associated osteonecrosis of the jaw. A brief review of the literature on the incidence, possible risk factors, and practice guidelines is also presented.