9 research outputs found
Deep brain stimulation in Parkinson’s disease: Looking back, looking forward
No full textPatients with Parkinson’s disease (PD) may present with prodromal (e.g. hyposmia, sleep disorders, constipation), motor (e.g. tremors, rigidity, bradykinesia, postural dysfunction) and non-motor (e.g. cognitive dysfunction, depression) symptoms.1 Treatment is symptomatic, targeting motor and non-motor manifestations, but there is presently no effective disease modifying treatment.1 Although PD therapies have primarily been focused on supplementing dopamine, which has improved survival and quality of life of PD patients,1-3 other neurotransmitter systems (e.g. serotonergic, cholinergic and noradrenergic) are also dysfunctional, especially for the non-motor symptoms.1,4,5 By the time patients reach the later stages of PD, many of them would have developed significant gait and balance difficulties, dysarthria, dysphagia and motor fluctuations like wearing off and levodopa-induced dyskinesias (LID), as well as non-motor symptoms such as orthostasis, depression, dementia and psychosis.1,2,6,
Putting ethics on the spot in neurology
No full text10.1038/ncpneuro1000Nature Clinical Practice Neurology53136-13
Repurposing povidone-iodine to reduce the risk of SARS-CoV-2 infection and transmission: a narrative review
No full textBACKGROUND: Accumulating data suggest antiviral effects of povidone-iodine against the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This narrative review aims to examine the antiviral mechanisms of povidone-iodine, efficacy of povidone-iodine against the SARS-CoV-2 virus, and safety of povidone-iodine to human epithelial cells and thyroid function. METHODS: We searched the electronic databases PubMed, Embase, Cochrane Library, ClinicalTrials.gov and World Health Organization’s International Clinical Trials Registry Platform for articles containing the keywords “povidone-iodine”, “SARS-CoV-2” and “COVID-19” from database inception till 3 June 2021. RESULTS: Despite in vitro data supporting the anti-SARS-CoV-2 effects of povidone-iodine, findings from clinical studies revealed differences in treatment response depending on study settings (healthy vs. hospitalized individuals), treatment target (nasal vs. oral vs. pharynx), method of administration (oral rinse vs. gargle vs. throat spray) and choice of samples used to measure study endpoints (nasopharyngeal vs. saliva). One large-scale clinical trial demonstrated reduction in the incidence of SARS-CoV-2 infection among participants who administered povidone-iodine 3 times daily during an active outbreak. Povidone-iodine is also used to disinfect the oro-pharyngeal space prior to dental or otolaryngology procedures. Although existing data suggest minimal impact of povidone-iodine on thyroid function, high-quality safety data are presently lacking. CONCLUSIONS: Povidone-iodine application to the oropharyngeal space could complement existing non-pharmacological interventions to reduce SARS-CoV-2 infection especially in high exposure settings. KEY MESSAGES: Accumulating data suggest antiviral effects of povidone-iodine against the SARS-CoV-2 virus. Findings from clinical studies reveal differences in treatment response depending on study settings, treatment target, method of administration and choice of samples used to measure study endpoints. One large-scale clinical trial observed reduction in the incidence of SARS-CoV-2 infection among participants who administered povidone-iodine 3 times daily during an active outbreak. Povidone-iodine application to the oropharyngeal space could complement existing non-pharmacological interventions to reduce SARS-CoV-2 infection especially in high exposure settings
Estimating transmission dynamics of SARS-CoV-2 at different intraspatial levels in an institutional outbreak
No full textINTRODUCTION: Large, localised outbreaks of COVID-19 have been repeatedly reported in high-density residential institutions. Understanding the transmission dynamics will inform outbreak response and the design of living environments that are more resilient to future outbreaks. METHODS: We developed an individual-based, multilevel transmission dynamics model using case, serology and symptom data from a 60-day cluster randomised trial of prophylaxes in a densely populated foreign worker dormitory in Singapore. Using Bayesian data augmentation, we estimated the basic reproduction number and the contribution that within-room, between-level and across-block transmission made to it, and the prevalence of infection over the study period across different spatial levels. We then simulated the impact of changing the building layouts in terms of floors and blocks on outbreak size. RESULTS: We found that the basic reproduction number was 2.76 averaged over the different putative prophylaxes, with substantial contributions due to transmission beyond the residents’ rooms. By the end of ~60 days of follow up, prevalence was 64.4 % (95 % credible interval 64.2–64.6 %). Future outbreak sizes could feasibly be halved by reducing the density to include additional housing blocks, or taller buildings, while retaining the overall number of men in the complex. DISCUSSION: The methods discussed can potentially be utilised to estimate transmission dynamics at any high-density accommodation site with the availability of case and serology data. The restructuring of infrastructure to reduce the number of residents per room can dramatically slow down epidemics, and therefore should be considered by policymakers as a long-term intervention
Long-term outcomes of ischaemic stroke patients with diabetes in a multi-ethnic cohort in Singapore
No full text10.47102/annals-acadmedsg.2020105ANNALS ACADEMY OF MEDICINE SINGAPORE50116-2
Augmentation of 5-lipoxygenase activity and expression during dengue serotype-2 infection
No full textpublished_or_final_versio
Neutropenia in cancer patients, risk prediction models of neutropenia, and supportive measures
No full textEpidemiology studies the causes and distribution of population health and disease conditions in defined populations. It identifies risk factors for disease which may help to prevent disease and promote health.
Each year, the American Cancer Society describes the epidemiology of cancer in the USA. Breast cancer and CLL are the most common cancers in women and adults, respectively. European data for CLL are limited. For both cancers, chemotherapy is an important treatment option. But side effects such as neutropenia and infections remain the principal dose-limiting toxicities, which may affect the effectiveness of cancer chemotherapy. Several studies evaluated risk factors for chemotherapy-induced neutropenia (CIN; absolute neutrophil count [ANC] <1.5x10^9/L) and febrile neutropenia (FN; ANC <0.5x10^9/L and oral temperature =38° for more than 1 hour): e.g. older age, recent infection, prior chemotherapy, and planned relative dose intensity greater than 85% of standard chemotherapy dosing. The prophylactic use of granulocyte colony-stimulating factors (G-CSFs) has been shown to be protective.
Based on the above mentioned risk factors, a number of risk prediction models have been developed over the years. Very often, the risk prediction models considered patient-related, tumour-related, treatment-related, or genetic factors. The majority of these models are not validated using an independent dataset. Systematic reviews of G-CSFs to prevent neutropenia are available, but do not include new long-acting G-CSFs or observational study designs.
To address the epidemiology of CLL, the incidence and risk factors of CIN and FN, and to develop and externally validate a risk prediction model for the occurrence of FN including a broad range of risk factors, three quantitative studies were conducted and published. The fourth published study summarised the efficacy, effectiveness and safety of G-CSFs for the prevention of CIN and FN.
For the first study, the author conducted a cohort analysis of the UK Clinical Practice Research Datalink (CPRD) to identify the epidemiology of CLL, the incidence of neutropenia, and changes in medical resource utilisation of CLL patients. Due to limited data regarding the incidence of neutropenia, the study focused on the epidemiology of CLL and medical resource utilisation of CLL patients. The incidence of CLL was 6.2 per 100’000 person-years and remained stable between 2006 and 2011. Medical resource utilisation in CLL patients increased over the time period from 2000 to 2012. Primary care data from the UK CPRD seemed to be valid to determine the incidence of CLL. These data may not reflect the total of medical resource use in CLL patients as chemotherapy and treatment of related complications such as infections and neutropenia are mainly performed in secondary or tertiary care.
The second study addressed the identification of risk factors and the development of a risk prediction model for FN in a hospital-based breast cancer cohort. Risk factors for FN were lower platelet count and haemoglobin, higher alanine aminotransferase (ALT), and specific allele variants of two single nucleotide polymorphisms (SNPs) in a gene involved in multidrug resistance. Genetic testing beforehand might be helpful to identify patients at a very high risk of FN. Predictive performance of the model was improved by adding genetic information but overall remained limited.
The third study used an available risk prediction model for FN in Non-Hodgkin lymphoma (NHL) patients and applied its prediction rules to an independent dataset of NHL patients. Age, weight, baseline white blood cell count, and planned chemotherapy dose were confirmed to predict the risk of FN. However, there was a decrease of the predictive performance in the independent validation dataset. This limits its use in clinical practice. But if successful risk prediction models are developed and externally validated, these may help to optimally target prophylaxis with G-CSFs to those patients at high risk of FN.
Finally, a systematic literature review was conducted to identify studies evaluating the efficacy, effectiveness and safety of G-CSFs in the prevention of CIN and FN. Most studies showed better efficacy and effectiveness for the long-acting pegfilgrastim than daily filgrastim. Efficacy and safety profiles of new long-acting G-CSFs such as lipegfilgrastim and balugrastim were comparable to pegfilgrastim. In times of increasing health care costs and scarce resources, the cost-efficient use of supportive measures is necessary.
The studies this work is based on showed that the availability of and access to appropriate data sources are necessary to develop and systematically validate risk prediction models. The findings contribute to the development of an evidence-based, efficient and cost-efficient approach to prevent neutropenia in cancer patients
Stem cell expansion and bioreactor development
No full textPhDA major challenge to the clinical success of cell-based tissue engineering strategies is the ability to obtain sufficient numbers of cells within an acceptable time frame. The expansion of cells on microcarriers within spinner flask bioreactor has shown promise in meeting that challenge. Spinner flask microcarrier technology is space-saving and media utilisation efficient. However, further optimisation in terms of, for example, seeding efficiency, expansion rates and harvest efficiency is necessary to realise the clinical potential of this technology. The present work is designed to improve cell expansion rates. It involves investigation of microcarrier composition and surface structure and spinner flask shear stress on cell growth.
BMSC growth on PHBV microcarriers was superior to PCL and PLGA microcarriers and comparable to Cytodex 1 microcarriers. Lower density PHBV microcarriers showed promise as a superior alternative to Cytodex 1. Two different impeller designs employed in the w/o/w method of microcarrier synthesis resulted in smoother and rougher PCL microcarriers with Ra = 1.77 ± 0.42 μm to 6.4 ± 1.48 μm respectively. Superior BMSC growth was observed on the rougher PCL microcarriers. Differentiation potential along the osteogenic and adipogenic lineages of BMSCs expanded on the microcarrier types was retained.
Particle Image Velocimetry was used to quantify shear stress within a spinner flask bioreactor. It was found that 80% of the shear stress was localised within the impeller region which occupied 55% of the bioreactor working volume. Shear stress increased as Cytodex 1 microcarrier concentration and impeller rotational speed increased. Superior BMSC growth rates on microcarriers were observed for the lowest shear stress experimental group (3.4 x 10-3 N/m2 ≤ impeller region mean shear stress ≤ 4.6 x 10-3 N/m2) as compared to the three higher shear stress groups (5.5 x 10-3 N/m2 ≤ mean shear stress ≤ 1.3 x 10-2 N/m2). Expanded BMSCs on the cytodex 1 microcarriers retained multipotentiality for the range of shear stresses investigated
Targeting DNA damage response and replication stress in pancreatic cancer
No full textBackground and aims:
Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC.
Methods:
We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids.
Results:
Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency.
Conclusions:
Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy
