Lower respiratory tract infection admissions and deaths among children under 5 years in public sector facilities in the Western Cape Province, South Africa, before and during the COVID-19 pandemic (2019 - 2021).

BACKGROUND: The COVID-19 pandemic resulted in the implementation of strict public health and social measures (PHSMs) (including mobility restrictions, social distancing, mask-wearing and hand hygiene), limitations on non-essential healthcare services, and public fear of COVID-19 infection, all of which potentially affected transmission and healthcare use for other diseases such as lower respiratory tract infections (LRTIs). OBJECTIVE: To determine changes in LRTI hospital admissions and in-facility mortality in children aged <5 years in the Western Cape Province during the pandemic. METHODS: We conducted a retrospective analysis of LRTI admissions and in-facility deaths from January 2019 to November 2021. We estimated changes in rates and trends of LRTI admissions during the pandemic compared with pre-pandemic period using interrupted time series analysis, adjusting for key characteristics. RESULTS: There were 36 277 children admitted for LRTIs during the study period, of whom 58% were male and 51% were aged 28 days - 1 year. COVID-19 restrictions were associated with a 13% step reduction in LRTI admissions compared with the pre-COVID-19 period (incidence rate ratio (IRR) 0.87, 95% confidence interval (CI)) 0.80 - 0.94). The average LRTI admission trend increased on average by 2% per month during the pandemic (IRR 1.02, 95% CI 1.02 - 1.04). CONCLUSIONS: The COVID-19 surges and their associated measures were linked to declining LRTI admissions and in-facility deaths, likely driven by a combination of reduced infectious disease transmission and reduced use of healthcare services, with effects diminishing over time. These findings may inform future pandemic response policies.

Comparison of paediatric infectious disease deaths in public sector health facilities using different data sources in the Western Cape, South Africa (2007-2021).

BACKGROUND: Routinely collected population-wide health data are often used to understand mortality trends including child mortality, as these data are often available more readily or quickly and for lower geographic levels than population-wide mortality data. However, understanding the completeness and accuracy of routine health data sources is essential for their appropriate interpretation and use. This study aims to assess the accuracy of diagnostic coding for public sector in-facility childhood (age < 5 years) infectious disease deaths (lower respiratory tract infections [LRTI], diarrhoea, meningitis, and tuberculous meningitis [TBM]) in routine hospital information systems (RHIS) through comparison with causes of death identified in a child death audit system (Child Healthcare Problem Identification Programme [Child PIP]) and the vital registration system (Death Notification [DN] Surveillance) in the Western Cape, South Africa and to calculate admission mortality rates (number of deaths in admitted patients per 1000 live births) using the best available data from all sources. METHODS: The three data sources: RHIS, Child PIP, and DN Surveillance are integrated and linked by the Western Cape Provincial Health Data Centre using a unique patient identifier. We calculated the deduplicated total number of infectious disease deaths and estimated admission mortality rates using all three data sources. We determined the completeness of Child PIP and DN Surveillance in identifying deaths recorded in RHIS and the level of agreement for causes of death between data sources. RESULTS: Completeness of recorded in-facility infectious disease deaths in Child PIP (23/05/2007-08/02/2021) and DN Surveillance (2010-2013) was 70% and 69% respectively. The greatest agreement in infectious causes of death were for diarrhoea and LRTI: 92% and 84% respectively between RHIS and Child PIP, and 98% and 83% respectively between RHIS and DN Surveillance. In-facility infectious disease admission mortality rates decreased significantly for the province: 1.60 (95% CI: 1.37-1.85) to 0.73 (95% CI: 0.56-0.93) deaths per 1000 live births from 2007 to 2020. CONCLUSION: RHIS had accurate causes of death amongst children dying from infectious diseases, particularly for diarrhoea and LRTI, with declining in-facility admission mortality rates over time. We recommend integrating data sources to ensure the most accurate assessment of child deaths.

A proposal for a new PhD level curriculum on quantitative methods for drug development.

This paper provides an overview of "Improving Design, Evaluation and Analysis of early drug development Studies" (IDEAS), a European Commission-funded network bringing together leading academic institutions and small- to large-sized pharmaceutical companies to train a cohort of graduate-level medical statisticians. The network is composed of a diverse mix of public and private sector partners spread across Europe, which will host 14 early-stage researchers for 36 months. IDEAS training activities are composed of a well-rounded mixture of specialist methodological components and generic transferable skills. Particular attention is paid to fostering collaborations between researchers and supervisors, which span academia and the private sector. Within this paper, we review existing medical statistics programmes (MSc and PhD) and highlight the training they provide on skills relevant to drug development. Motivated by this review and our experiences with the IDEAS project, we propose a concept for a joint, harmonised European PhD programme to train statisticians in quantitative methods for drug development.

Likely Transiting Exocomets Detected By Kepler.

We present the first good evidence for exocomet transits of a host star in continuum light in data from the Kepler mission. The Kepler star in question, KIC 3542116, is of spectral type F2V and is quite bright at Kp = 10. The transits have a distinct asymmetric shape with a steeper ingress and slower egress that can be ascribed to objects with a trailing dust tail passing over the stellar disk. There are three deeper transits with depths of ≃ 0.1% that last for about a day, and three that are several times more shallow and of shorter duration. The transits were found via an exhaustive visual search of the entire Kepler photometric data set, which we describe in some detail. We review the methods we use to validate the Kepler data showing the comet transits, and rule out instrumental artefacts as sources of the signals. We fit the transits with a simple dust-tail model, and find that a transverse comet speed of ∼35-50 km s-1 and a minimum amount of dust present in the tail of ∼ 1016 g are required to explain the larger transits. For a dust replenishment time of ∼10 days, and a comet lifetime of only ∼300 days, this implies a total cometary mass of ≳ 3 × 1017 g, or about the mass of Halley's comet. We also discuss the number of comets and orbital geometry that would be necessary to explain the six transits detected over the four years of Kepler prime-field observations. Finally, we also report the discovery of a single comet-shaped transit in KIC 11084727 with very similar transit and host-star properties.

Critical care in acute ischemic stroke.

Most ischemic strokes are managed on the ward or on designated stroke units. A significant proportion of patients with ischemic stroke require more specialized care. Several studies have shown improved outcomes for patients with acute ischemic stroke when neurocritical care services are available. Features of acute ischemic stroke patients requiring intensive care unit-level care include airway or respiratory compromise; large cerebral or cerebellar hemisphere infarction with swelling; infarction with symptomatic hemorrhagic transformation; infarction complicated by seizures; and a large proportion of patients require close management of blood pressure after thrombolytics. In this chapter, we discuss aspects of acute ischemic stroke care that are of particular relevance to a neurointensivist, covering neuropathology, neurodiagnostics and imaging, blood pressure management, glycemic control, temperature management, and the selection and timing of antithrombotics. We also focus on the care of patients who have received intravenous thrombolysis or mechanical thrombectomy. Complex clinical decision making in decompressive hemicraniectomy for hemispheric infarction and urgent management of basilar artery thrombosis are specifically addressed.

Design of structurally distinct proteins using strategies inspired by evolution.

Natural recombination combines pieces of preexisting proteins to create new tertiary structures and functions. We describe a computational protocol, called SEWING, which is inspired by this process and builds new proteins from connected or disconnected pieces of existing structures. Helical proteins designed with SEWING contain structural features absent from other de novo designed proteins and, in some cases, remain folded at more than 100°C. High-resolution structures of the designed proteins CA01 and DA05R1 were solved by x-ray crystallography (2.2 angstrom resolution) and nuclear magnetic resonance, respectively, and there was excellent agreement with the design models. This method provides a new strategy to rapidly create large numbers of diverse and designable protein scaffolds.

Advancing the framework for considering the effects of climate change on worker safety and health.

In 2009, a preliminary framework for how climate change could affect worker safety and health was described. That framework was based on a literature search from 1988-2008 that supported seven categories of climate-related occupational hazards: (1) increased ambient temperature; (2) air pollution; (3) ultraviolet radiation exposure; (4) extreme weather; (5) vector-borne diseases and expanded habitats; (6) industrial transitions and emerging industries; and (7) changes in the built environment. This article reviews the published literature from 2008-2014 in each of the seven categories. Additionally, three new topics related to occupational safety and health are considered: mental health effects, economic burden, and potential worker safety and health impacts associated with the nascent field of climate intervention (geoengineering). Beyond updating the literature, this article also identifies key priorities for action to better characterize and understand how occupational safety and health may be associated with climate change events and ensure that worker health and safety issues are anticipated, recognized, evaluated, and mitigated. These key priorities include research, surveillance, risk assessment, risk management, and policy development. Strong evidence indicates that climate change will continue to present occupational safety and health hazards, and this framework may be a useful tool for preventing adverse effects to workers.

Cortical EEG oscillations and network connectivity as efficacy indices for assessing drugs with cognition enhancing potential.

Synchronization of electroencephalographic (EEG) oscillations represents a core mechanism for cortical and subcortical networks, and disturbance in neural synchrony underlies cognitive processing deficits in neurological and neuropsychiatric disorders. Here, we investigated the effects of cognition enhancers (donepezil, rivastigmine, tacrine, galantamine and memantine), which are approved for symptomatic treatment of dementia, on EEG oscillations and network connectivity in conscious rats chronically instrumented with epidural electrodes in different cortical areas. Next, EEG network indices of cognitive impairments with the muscarinic receptor antagonist scopolamine were modeled. Lastly, we examined the efficacy of cognition enhancers to normalize those aberrant oscillations. Cognition enhancers elicited systematic ("fingerprint") enhancement of cortical slow theta (4.5-6 Hz) and gamma (30.5-50 Hz) oscillations correlated with lower activity levels. Principal component analysis (PCA) revealed a compact cluster that corresponds to shared underlying mechanisms as compared to different drug classes. Functional network connectivity revealed consistent elevated coherent slow theta activity in parieto-occipital and between interhemispheric cortical areas. In rats instrumented with depth hippocampal CA1-CA3 electrodes, donepezil elicited similar oscillatory and coherent activities in cortico-hippocampal networks. When combined with scopolamine, the cognition enhancers attenuated the leftward shift in coherent slow delta activity. Such a consistent shift in EEG coherence into slow oscillations associated with altered slow theta and gamma oscillations may underlie cognitive deficits in scopolamine-treated animals, whereas enhanced coherent slow theta and gamma activity may be a relevant mechanism by which cognition enhancers exert their beneficial effect on plasticity and cognitive processes. The findings underscore that PCA and network connectivity are valuable tools to assess efficacy of novel therapeutic drugs with cognition enhancing potential.

Strong absorption and selective emission from engineered metals with dielectric coatings.

We demonstrate strong-to-perfect absorption across a wide range of mid-infrared wavelengths (5-12µm) using a two-layer system consisting of heavily-doped silicon and a thin high-index germanium dielectric layer. We demonstrate spectral control of the absorption resonance by varying the thickness of the dielectric layer. The absorption resonance is shown to be largely polarization-independent and angle-invariant. Upon heating, we observe selective thermal emission from our materials. Experimental data is compared to an analytical model of our structures with strong agreement.

Reporter gene expression from LTR-circles as tool to identify HIV-1 integrase inhibitors.

Early HIV-1 integrase inhibitors, such as compounds containing a ß-diketo acid moiety, were identified by extensive high-throughput screening campaigns. Traditionally, in vitro biochemical assays, measuring the catalytic activities of integrase, have been used for this purpose. However, these assays are confounded by the absence of cellular processes or cofactors that play a role in the integration of HIV-1 DNA in the cellular genome. In contrast to regular cell-based virus inhibition assays, which targets all steps of the viral replication cycle, a novel cellular screening assays was developed to enable the specific identification of integrase inhibitors, employing a readout that is linked with the inhibition of integrase activity. Therefore, a HIV-1 lentiviral vector equipped with the enhanced green fluorescent protein (eGFP) reporter gene was used to detect expression from extrachromosomal viral DNA (1- or 2-long terminal repeat circles), formed when integration of vector DNA into the cellular genome is prevented by an integrase inhibitor. In this assay, eGFP expression from the low residual level of transcriptional activity of extrachromosomal DNA was measured via high-throughput flow cytometry. An algorithm for analysis of eGFP expression histograms enabled the specific identification of integrase inhibitors. This assay is amenable for high throughput screening to identify inhibitors of HIV-1 integrase.

Efficient control of Plasmodium yoelii infection in BALB/c and C57BL/6 mice with pre-existing Strongyloides ratti infection.

About 225 million malaria cases have been reported worldwide in 2009, and one-third of the world's population is infected with parasitic helminths. As helminths and Plasmodium are co-endemic, concurrent infections frequently occur. Helminths have been shown to modulate the host's immune response; therefore, pre-existing helminth infections may interfere with the efficient immune response to Plasmodium. To study the interaction between helminths and Plasmodium, we established a murine model of co-infection using the gastrointestinal nematode Strongyloides ratti and Plasmodium yoelii. We show that a pre-existing Strongyloides infection slightly enhanced peak parasitemia and weight loss in P. yoelii-infected BALB/c mice, while disease progression was not altered in co-infected C57BL/6 mice. The Plasmodium-induced IFN-γ production and final clearance of Plasmodium infection were not affected by S. ratti co-infection in both C57BL/6 and BALB/c mice. Interestingly, the T helper cell (Th) 2 response induced by S. ratti was significantly suppressed upon P. yoelii co-infection. This suppressed Th2 response, however, was still sufficient to allow expulsion of S. ratti parasitic adults. Taken together, we provide evidence that simultaneous presence of helminth and protist parasites does not interfere with efficient host defence in our co-infection model although changes in Th responses were observed.

Placental pathologic aberrations in cases of familial idiopathic spontaneous preterm birth.

OBJECTIVE: To test the hypothesis that placental histologic characteristics in familial spontaneous preterm birth (sPTB) differ by gestational age (GA) and reflect possible mechanisms of pathogenesis. STUDY DESIGN: Secondary analysis from prospective cohort study in women with sPTB <35 weeks and a first degree family member with PTB. Placental specimens (n = 79) were categorized by maternal and/or fetal inflammatory response (MIR, FIR) and compared among three preterm GA categories. RESULTS: Inflammatory changes were common. MIR was most frequent at the earliest GAs, 85% with PTB <28 weeks [(adj)OR 77.5 (95% CI 5, 1213.1)], and 57% at 28-32 weeks [(adj)OR 6.1 (0.8, 48.5)] compared to later PTBs occurring at 32-35 weeks (22%). FIR also occurred most frequently in the earliest cases of PTB <28 weeks. CONCLUSIONS: Placental inflammatory responses are common in women with familial sPTB. This data suggests that inflammation plays an important role in the onset of parturition in cases otherwise classified as idiopathic or spontaneous in nature, especially at the earliest GAs when neonatal outcomes are the poorest.

Studies on neuronal differentiation and signalling processes with a novel impedimetric biosensor.

The differentiation of neural cells is an important process during the development of the central nervous system. Studies on the mechanisms of the differentiation process is of special importance, e.g. in the field of regenerative medicine. In this contribution the cellular differentiation of gel matrix embedded neuronal cells was studied. The three-dimensional organization of neuronal cells represents a new cellular model system closer to the physiology than conventional two-dimensional cell cultures. Neuro2a (N2a) neuroblastoma cells were immobilized in different gel matrices and the grade of differentiation was compared. Furthermore, the impact of the cell number and selected differentiation factors were analyzed. Experimental results revealed that gel matrices based on collagen-laminin mixtures in contact with serum free medium enable neural differentiation. Therefore, collagen-laminin gels appear as a suitable three-dimensional model for drug screening in developmental neurobiology. Following optimization of the immobilization process, a novel impedimetric sensor and electrical impedance spectroscopy technique was applied to on-line monitor the differentiation process by means of changes in the dielectric and conductive properties. Experimental results showed an increase in the impedance magnitude that can be mainly attributed to differentiating cells accompanied by an increase in the specific resistivity of the bare gel mixture.

Anesthesia and perioperative management for a patient with Ullrich syndrome undergoing surgery for scoliosis.

Ullrich syndrome is a rare congenital hypotonic-sclerotic muscular disorder in which affected children develop a slowly progressive scoliosis and contractures and limpness of joints. The disease causes increasingly invalidating contractures and hardening of the muscles of the neck and trunk. While this neuromuscular type of scoliosis is progressive, patients rarely attain the point of surgery due to their compromised general medical condition. This may explain the current lack of outcome data and the paucity of information on perioperative management for patients with Ullrich syndrome undergoing major surgery. The purpose of this report was therefore to describe our first experience with the perioperative and anesthetic management of a 15-year-old boy presenting with Ullrich syndrome and a secondary invalidating scoliosis. The specific challenges of this condition characterized by severe restrictive lung disease and a challenging airway abnormality are discussed.

The peri-operative use of intra-articular local anesthetics: a review.

Acute and chronic pain are of major concern after orthopedic surgery. The increasing trend toward day case surgery induced the development of different techniques in postoperative pain control. One commonly used strategy in pain management after knee and shoulder joint surgery is the intra-articular (IA) use of local anesthetics (LA). Recent attention has been drawn to the possible toxicity on chondrocytes of local anesthetics. The aim of this manuscript is to evaluate and compare through literature review the existing evidence on the clinical use and possible adverse effects of intra-articular injection of local anesthetics peri-operatively.

Liposome-encapsulated antigens induce a protective CTL response against Listeria monocytogenes independent of CD4+ T cell help.

Protection against intracellular pathogens is usually mediated by cytotoxic T lymphocytes (CTL). Induction of a protective CTL response for vaccination purposes has proven difficult because of the limited access of protein antigens or attenuated pathogens to the MHC class I presentation pathway. We show here that pH-sensitive PE/CHEMS liposomes can be used as a vehicle to efficiently deliver intact proteins for presentation by MHC class I. Mice immunized with listerial proteins encapsulated in such liposomes launched a strong CTL response and were protected against a subsequent challenge with L. monocytogenes. Remarkably, the CTL response was induced independently of detectable CD4(+) T cell help.

[Interdisciplinary diagnosis of and therapy for cholangiocarcinoma]. / Interdisziplinäre Diagnostik und Therapie von Gallengangskarzinomen.

The diagnosis of and therapy for cholangiocarcinomas still remains an interdisciplinary challenge. For diagnostic and therapeutic purposes intra- and extrahepatic cholangiocarcinomas need to be distinguished. Multiple imaging tools such as sonography, multidetector computer tomography, magnetic resonance tomography as well as endoscopic ultrasound and endoscopic retrograde cholangiography for the diagnosis and localisation of these tumours are available. To date, surgical resection is the only curative treatment. At the time of diagnosis, most of the tumours are advanced. Therefore, only a small percentage of patients are suitable for curative surgery. Infiltration of the portal vein no longer constitutes a contraindication for surgery. Liver transplantation is not a reasonable option for intrahepatic cholangiocarcinomas but may be of advantage for perihilar Klatskin tumours. Severe cholangitis is the main cause of death of patients with obstructive cholangiocarcinomas. Drainage of the biliary tree system or surgery with construction of a biliary-digestive anastomosis is often necessary. If possible, a photodynamic therapy (PDT) should be performed in addition to biliary drainage. PDT has been shown to facilitate biliary drainage and to improve survival. The value of radiologist-assisted interventional procedures as well as percutaneous ablation and radiochemotherapy is not well established. In addition, so far, there is no standardised chemotherapy in a palliative situation established but there is some evidence for a benefit of gemcitabine-based chemotherapy. For the best care and treatment of patients with cholangiocarcinomas an interdisciplinary approach is required and to achieve progress in the therapy patients should be included in prospective clinical trials to test new approaches.

Augmented serum lactic acid combined with metabolic alkalosis: a case report.

Lactic acidosis is a common problem in the peri-operative period. During extensive surgery we frequently have an augmentation of lactic acid most often on the basis of hypoperfusion. Normally, a rise in serum lactate level causes a fall in blood pH, and this metabolic acidosis is accompanied by a high anion gap. In this case report a perioperative rise in lactic acid and an elevation in serum pH in a patient during meningeal tumour surgery is presented.