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1.
Water Res ; 256: 121527, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38685173

ABSTRACT

For real-time control to become a standard measure for upgrading urban drainage systems, control potential screenings need to be easily integrated into the early planning processes that already take place. However, current screening methods are either not aligned with the present planning process, unrelatable for water managers or too time-consuming. We therefore developed an automated screening methodology through a co-design process with six Danish utilities. The process started out from a literature review, included interviews and workshops, and resulted in the control potential screening tool COPOTO. In the co-design process, utilities generally responded that indicators based solely on an assessment of static system attributes are insufficient. Thus, COPOTO instead post-processes the results of urban drainage simulation models that are commonly available. The decision context considered in initial planning phases was found to include environmental, economic, social and technical objectives that were highly case-dependent. When presenting CSO reduction potentials, the utilities therefore generally preferred interactive, spatially explicit visualisations that link the CSO reduction at a particular location to the storages and actuators that need to be activated. This enables water managers to discuss, for example, operational constraints of a considered control location. COPOTO provides such assessments with very limited manual and computational effort and thus facilitates the integration of real-time control into standard planning workflows of utilities.


Subject(s)
Sewage , Automation , Denmark , Models, Theoretical , Waste Disposal, Fluid/methods , Drainage, Sanitary
3.
Nat Aging ; 3(9): 1144-1166, 2023 09.
Article in English | MEDLINE | ID: mdl-37563227

ABSTRACT

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.


Subject(s)
DNA Methylation , Epigenesis, Genetic , Humans , Mice , Animals , DNA Methylation/genetics , Aging/genetics , Longevity/genetics , Mammals/genetics
4.
Clin Radiol ; 76(11): 862.e19-862.e28, 2021 11.
Article in English | MEDLINE | ID: mdl-34261595

ABSTRACT

AIM: To quantify the real-world clinical and cost impact of computed tomography (CT) coronary angiography (CTCA)-derived fractional flow reserve (FFRCT) in the National Health Service (NHS). MATERIALS AND METHODS: Consecutive clinical CTCA examinations from September to December 2018 with ≥1 stenosis of ≥25% underwent FFRCT analysis. The Heart Team reviewed clinical data and CTCA findings, blinded to FFRCT values, and documented hypothetical consensus management. FFRCT results were then unblinded and hypothetical consensus management re-recorded. Diagnostic waiting times for management pathways were estimated. A per-patient cost analysis for diagnostic certainty regarding coronary artery disease (CAD) management was performed using 2014-2020 NHS tariffs for pre- and post-FFRCT pathways. RESULTS: Two hundred and fifty-one CTCAs were performed during the study period. Fifty-seven percent (145/251) had no CAD or stenosis <25%. One study was non-diagnostic. Of the remaining 42% (105/251), two were ineligible for FFRCT and there was a 5% (5/103) failure rate. FFRCT led to a change in hypothetical management in 65% (64/98; p<0.001) patients with a functional imaging test cancelled in 17% (17/98) and a diagnostic angiogram cancelled in 47% (46/98). FFRCT-guided management had a reduced mean time to definitive investigation compared with CTCA alone (28 ± 4 versus 44 ± 4 days; p=0.004). Using the proposed 2020/21 tariff, CTCA + FFRCT for stenosis ≥50% resulted in a diagnostic pathway £44.97 more expensive per patient than usual care without FFRCT. CONCLUSIONS: In the real-world NHS setting, FFRCT-guided management has the potential to rationalise patient management, accelerate diagnostic pathways, and depending on the stenosis severity modelled, may be cost-effective.


Subject(s)
Computed Tomography Angiography/economics , Computed Tomography Angiography/methods , Coronary Angiography/economics , Coronary Angiography/methods , Coronary Stenosis/diagnostic imaging , Costs and Cost Analysis/methods , Fractional Flow Reserve, Myocardial/physiology , Coronary Stenosis/economics , Coronary Stenosis/physiopathology , Costs and Cost Analysis/statistics & numerical data , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Severity of Illness Index , State Medicine , United Kingdom
5.
Injury ; 52(10): 3139-3142, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33894990

ABSTRACT

BACKGROUND: Falanga is a punishment that involves hitting the bare soles of a person's feet. The consequences of this punishment may be limb and life-threatening. Post-traumatic acute kidney injury (AKI) secondary to rhabdomyolysis is a well-documented complication. Patients often require prompt surgical intervention and renal replacement therapy (RRT). The clinical and biochemical presentation of these patients and subsequent outcomes are poorly understood. AIMS: This prospective observational study describes the clinical presentation and effects of foot whipping on patient outcomes. METHODOLOGY: Prospective data were collected over a one-year period for 135 patients presenting following blunt force assault admitted to a single centre. Presenting clinical characteristics and patient outcomes were recorded and correlations between presenting clinical characteristics and surgical and clinical outcomes were assessed. RESULTS: Of 138 patients presenting following blunt force assault 96% were male with a mean age of 28.8 ± 8.01. Thirty-six out of the 138 patients presenting following blunt force assault had received foot-whipping only (falanga group, FG). Ten of these 36 patients in the FG group required surgical intervention, with one requiring a below knee amputation, compared with only two patients who required surgical intervention in the group who experienced blunt force trauma not restricted to foot whipping (Sjambok group). Average length of stay was 4 days (range 2-38) in FG group compared with 5 (range 1-21) in SG group, with no mortalities in either group. For patients in the FG, Hb was higher at presentation compared to patients in the SG group (135.2 33.7 vs 124.2 21.3, p = 0.03) and correlated positively with the need for surgical intervention (r = 0.6, p < 0.01). In this same group, the presenting characteristics of CK (4251.3 3087.4, p = 0.1 vs 7422.6 12347.7, p = 0.1) and urine output (0.95 0.4 vs 0.7 0.4) positively correlated with RRT [CK r = 0.6, p < 0.01, UO r = 0.46, p < 0.01]. CONCLUSION: Patients who present following falanga frequently require surgical intervention and the related healthcare utilisation and morbidity is high. Clinical indicators of a greater systemic injury at presentation may correlate with an increased likelihood of requiring surgical intervention or RRT.


Subject(s)
Acute Kidney Injury , Renal Replacement Therapy , Foot , Humans , Male , Prospective Studies , Treatment Outcome
6.
BMC Nephrol ; 22(1): 92, 2021 03 15.
Article in English | MEDLINE | ID: mdl-33722189

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) is a common manifestation among patients critically ill with SARS-CoV-2 infection (Coronavirus 2019) and is associated with significant morbidity and mortality. The pathophysiology of renal failure in this context is not fully understood, but likely to be multifactorial. The intensive care unit outcomes of patients following COVID-19 acute critical illness with associated AKI have not been fully explored. We conducted a cohort study to investigate the risk factors for acute kidney injury in patients admitted to and intensive care unit with COVID-19, its incidence and associated outcomes. METHODS: We reviewed the medical records of all patients admitted to our adult intensive care unit suffering from SARS-CoV-2 infection from 14th March 2020 until 12th May 2020. Acute kidney injury was defined using the Kidney Disease Improving Global Outcome (KDIGO) criteria. The outcome analysis was assessed up to date as 3rd of September 2020. RESULTS: A total of 81 patients admitted during this period. All patients had acute hypoxic respiratory failure and needed either noninvasive or invasive mechanical ventilatory support. Thirty-six patients (44%) had evidence of AKI (Stage I-33%, Stage II-22%, Renal Replacement Therapy (RRT)-44%). All patients with AKI stage III had RRT. Age, diabetes mellitus, immunosuppression, lymphopenia, high D-Dimer levels, increased APACHE II and SOFA scores, invasive mechanical ventilation and use of inotropic or vasopressor support were significantly associated with AKI. The peak AKI was at day 4 and mean duration of RRT was 12.5 days. The mortality was 25% for the AKI group compared to 6.7% in those without AKI. Among those received RRT and survived their illness, the renal function recovery is complete and back to baseline in all patients. CONCLUSION: Acute kidney injury and renal replacement therapy is common in critically ill patients presenting with COVID-19. It is associated with increased severity of illness on admission to ICU, increased mortality and prolonged ICU and hospital length of stay. Recovery of renal function was complete in all survived patients.


Subject(s)
Acute Kidney Injury/etiology , COVID-19/complications , APACHE , Acute Kidney Injury/epidemiology , Acute Kidney Injury/mortality , Acute Kidney Injury/therapy , COVID-19/epidemiology , Cohort Studies , Critical Illness , Female , Hospital Mortality , Humans , Incidence , Intensive Care Units , Male , Middle Aged , Organ Dysfunction Scores , Recovery of Function , Renal Replacement Therapy/statistics & numerical data , Respiration, Artificial/adverse effects , Risk Factors , Water-Electrolyte Balance
8.
Philos Trans A Math Phys Eng Sci ; 378(2168): 20190201, 2020 Apr 03.
Article in English | MEDLINE | ID: mdl-32063172

ABSTRACT

This paper presents a novel interdisciplinary and catchment-based approach for exploring urban flood resilience. Our research identified and developed a diverse set of adaptation measures for Elwood, a suburb in Melbourne, Australia, that is vulnerable to pluvial and coastal flooding. We drew on methods from social science, urban design and environmental engineering to gain integrated insights into the opportunities for Elwood to increase its flood resilience and urban liveability. Results showed that an appropriate balance of social, infrastructural and urban design responses would be required to retreat from, accommodate and protect against flood risk. These would also deliver broader benefits such as securing water supplies through harvested stormwater and mitigating extreme heat through greener landscapes. Our interdisciplinary approach demonstrated the value of (i) engaging with the community to understand their concerns, aspirations and adaptation ideas, (ii) exploring design measures that densify and use urban forms in ways that implement adaptation measures while responding to local context, (iii) adopting modelling techniques to test the performance, robustness and economic viability of possible adaptation solutions, and (iv) innovating governance arrangements and principles needed to improve flood resilience in the Elster Creek catchment. Our research also provided valuable insight on how to operationalize interdisciplinary work in practice, highlighting the importance of sharing an impact agenda, taking a place-based approach, developing a common conceptual framework, and fostering a constructive team culture. This article is part of the theme issue 'Urban flood resilience'.

9.
Lab Chip ; 17(24): 4265-4272, 2017 12 05.
Article in English | MEDLINE | ID: mdl-29090716

ABSTRACT

Measuring small changes in refractive index can provide both sensitive and contactless information on molecule concentration or process conditions for a wide range of applications. However, refractive index measurements are easily perturbed by non-specific background signals, such as temperature changes or non-specific binding. Here, we present an optofluidic device for measuring refractive index with direct background subtraction within a single measurement. The device is comprised of two interdigitated arrays of nanofluidic channels designed to form an optical grating. Optical path differences between the two sets of channels can be measured directly via an intensity ratio within the diffraction pattern that forms when the grating is illuminated by a collimated laser beam. Our results show that no calibration or biasing is required if the unit cell of the grating is designed with an appropriate built-in asymmetry. In proof-of-concept experiments we attained a noise level equivalent to ∼10-5 refractive index units (30 Hz sampling rate, 4 min measurement interval). Furthermore, we show that the accumulation of biomolecules on the surface of the nanochannels can be measured in real-time. Because of its simplicity and robustness, we expect that this inherently differential measurement concept will find many applications in ultra-low volume analytical systems, biosensors, and portable devices.


Subject(s)
Biosensing Techniques/instrumentation , Microfluidic Analytical Techniques/instrumentation , Refractometry/instrumentation , Signal Processing, Computer-Assisted
10.
Vet Comp Oncol ; 15(3): 775-784, 2017 Sep.
Article in English | MEDLINE | ID: mdl-27001443

ABSTRACT

To describe the results of electrochemotherapy (ECT) in dogs with mast cell tumours (MCTs) either as first line therapy or as an adjuvant to surgery. The treatment combines administration of low dose chemotherapeutic drugs with the application of microsecond electric pulses, which cause the temporary permeabilization and increased porosity of the tumour cell membranes. The design of this study is a retrospective case series. A total of 51 dogs with MCTs were included and classified according to ECT procedure into 4 groups (ECT only, 15 cases, intra-surgery ECT, 11, ECT Adjuvant to surgery, 14, Surgery followed by ECT, 11). The four groups (staged with location, size and grade) were evaluated to assess complete or partial remission, disease free interval, overall survival time and local toxicity. In this case series, Boxers, mixed breed and Labrador Retrievers, male dogs, between 4 and 9 years old were more represented. MCTs were predominantly grade 2 (Patnaik) and T stage 0-1, I-1 (World Health Organization). Treated lesions were most commonly identified on the hindlimb and head where curative surgery would involve cosmetic or functional compromise. The intra-surgery group of dogs showed the best disease free interval with Kaplan-Meyer analysis. Local toxicity induced by ECT ranged mostly from 1 to 4 in a 5-point arbitrary scale with 0 - no toxicity to 5 - highest toxicity. In this study, ECT can be applied successfully as an exclusive therapy in smaller MCTs as an alternative to surgery. ECT can be combined with surgery either intra-operatively or post operatively for larger lesions without significant toxicity.


Subject(s)
Dog Diseases/therapy , Electrochemotherapy/veterinary , Mastocytosis, Cutaneous/veterinary , Skin Neoplasms/veterinary , Animals , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/therapeutic use , Bleomycin/administration & dosage , Bleomycin/therapeutic use , Combined Modality Therapy/veterinary , Dog Diseases/drug therapy , Dogs , Electrochemotherapy/methods , Female , Male , Mastocytosis, Cutaneous/drug therapy , Mastocytosis, Cutaneous/therapy , Retrospective Studies , Skin Neoplasms/drug therapy , Skin Neoplasms/therapy
11.
BMJ Open ; 6(11): e011768, 2016 Nov 23.
Article in English | MEDLINE | ID: mdl-27881521

ABSTRACT

OBJECTIVES: Famine exposure in utero can 'programme' an individual towards type 2 diabetes and obesity in later life. We sought to identify, (1) whether Bangladeshis exposed to famine during developmental life are programmed towards diabetes and obesity, (2) whether this programming was specific to gestational or postnatal exposure windows and (3) whether epigenetic differences were associated with famine exposure. DESIGN: A historical cohort study was performed as part of a wider cross-sectional survey. Exposure to famine was defined through birth date and historical records and participants were selected according to: (A) exposure to famine in postnatal life, (B) exposure to famine during gestation and (C) unexposed. SETTING: Matlab, a rural area in the Chittagong division of Bangladesh. PARTICIPANTS: Young adult men and women (n=190) recruited to a historical cohort study with a randomised subsample included in an epigenetic study (n=143). OUTCOME MEASURES: Primary outcome measures of weight, body mass index and oral glucose tolerance tests (0 and 120 min glucose). Secondary outcome measures included DNA methylation using genome-wide and targeted analysis of metastable epialleles sensitive to maternal nutrition. RESULTS: More young adults exposed to famine in gestation were underweight than those postnatally exposed or unexposed. In contrast, more young adults exposed to famine postnatally were overweight compared to those gestationally exposed or unexposed. Underweight adults exposed to famine in gestation in utero were hyperglycaemic following a glucose tolerance test, and those exposed postnatally had elevated fasting glucose, compared to those unexposed. Significant differences in DNA methylation at seven metastable epialleles (VTRNA2-1, PAX8, PRDM-9, near ZFP57, near BOLA, EXD3) known to vary with gestational famine exposure were identified. CONCLUSIONS: Famine exposure in developmental life programmed Bangladeshi offspring towards diabetes and obesity in adulthood but gestational and postnatal windows of exposure had variable effects on phenotype. DNA methylation differences were replicated at previously identified metastable epialleles sensitive to periconceptual famine exposure.


Subject(s)
DNA Methylation , Diabetes Mellitus, Type 2/epidemiology , Maternal Nutritional Physiological Phenomena , Obesity/epidemiology , Starvation , Adult , Bangladesh , Body Mass Index , Body Weight , Cross-Sectional Studies , Female , Genome-Wide Association Study , Glucose Tolerance Test , Humans , Longitudinal Studies , Male , Middle Aged , Pregnancy , Prenatal Exposure Delayed Effects/genetics , Regression Analysis , Rural Population
14.
J Forensic Leg Med ; 40: 34-9, 2016 May.
Article in English | MEDLINE | ID: mdl-27010493

ABSTRACT

INTRODUCTION: Human bite marks are often sustained during sexual, domestic or child abuse. Currently, analysis of these marks involves digital photography techniques along with an expert forensic odontologist opinion. Photographs often focus closely on the bite mark and give little context to the anatomical location of the injury. Due to variation in camera models and expertise of the photographer, photograph quality can affect its interpretation. Additionally, it can sometimes be days between injury and examination, allowing the injury pattern and colour to alter, making it harder to analyse. AIM: To investigate if a 3D imaging technique, creating a time-lapse image of a bite mark in three dimensions, can provide context to the injury in terms of nature and location, and also allow analysis of the change in appearance of a bite mark over time. METHOD: Participants had an experimental bite mark produced on their forearm by dental casts mounted on a dental articulator. The forearms were photographed immediately following the bite, and at intervals of 3, 6, 24, 48, 72 and 96 h. A DI3D(®) (Dimensional Imaging 3D) photogrammetry system and Autodesk Maya 2015(®) software was used to create a 3D animation from the images obtained. The clearest, long lasting bite mark injuries were selected for animation, enabling the 3D imaging technique to be used optimally. RESULTS: 3D time-lapse animations were successfully created with the ability to be viewed on most electronic devices. With further refinement this technique could be valuable in a number of areas. We anticipate animations produced in this way to have significant benefit to the presentation of photographic evidence in a court setting, and in age estimation of injuries.


Subject(s)
Bites, Human/diagnostic imaging , Forearm Injuries/diagnostic imaging , Imaging, Three-Dimensional , Female , Forensic Dentistry , Healthy Volunteers , Humans , Image Processing, Computer-Assisted , Male , Models, Dental , Photogrammetry , Software , Time Factors
15.
Spinal Cord ; 52(12): 911-8, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25330938

ABSTRACT

STUDY DESIGN: A descriptive audit. OBJECTIVES: To audit the participation and satisfaction in a Massive Open Online Course (MOOC) for teaching physiotherapy students and physiotherapists about spinal cord injuries. SETTING: Global and online. METHODS: A 5-week MOOC about the physiotherapy management of spinal cord injuries was hosted by Physiopedia and run in partnership with the International Spinal Cord Society. The MOOC was based on the physiotherapy-specific module of www.elearnSCI.org, and also involved extra readings, activities and online discussion through a closed Facebook group. Participation and satisfaction was quantified through a pre- and post-MOOC knowledge assessment and an online course evaluation. Participation was also gauged through Facebook activity and internet-based usage statistics. RESULTS: Three thousand five hundred and twenty-three people from 108 countries registered for the MOOC and 2527 joined the Facebook group. One thousand one hundred and twenty-one completed the pre- and post-MOOC knowledge assessments, with more completing one or the other. The median (interquartile range) results for those who completed the pre and post-MOOC knowledge assessments were 70% (60-80%) and 90% (80-95%), respectively. One thousand and twenty-nine completed the online course evaluation, with more than 80% agreeing or strongly agreeing with 12 of the 13 positive statements posed to them about the course. CONCLUSION: Most participants who completed the MOOC performed well on the post-MOOC knowledge assessment and enjoyed the learning experience. However, these results may be biased if those who did not complete the MOOC were dissatisfied and/or did not sit the post-MOOC knowledge assessment.


Subject(s)
Physical Therapists/education , Physical Therapy Specialty/education , Spinal Cord Injuries/therapy , Curriculum , Educational Measurement , Humans , International Cooperation , Internet , Management Audit , Online Systems , Personal Satisfaction , Social Media , Students
16.
Poult Sci ; 93(8): 2060-8, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24902702

ABSTRACT

Several studies illustrated that the structure of feed, i.e., the particle size, particle-size distribution, and the physical form of the diet, affects the avian gastrointestinal function and health leading to changes in productive performance. However, investigations concerning the effects of feeding differently processed diets on laying hens are limited and primarily concentrated on bird performance. The current study examines the effect of feed processing on the gastrointestinal morphology and on the jejunal glucose transport of laying hens. In 8 replicates, a total of 384 hens (Lohmann Brown) aged 20 wk were randomly allocated to 8 different groups and fed over a period of 21 d in a 3-factorial design. Diets differed in 1) grinding method, either hammer or roller mill; 2) physical form, either mash or expandate; and 3) particle size, either coarsely or finely ground. During the experimental trial, the laying performance of each feeding group was recorded daily and the feed intake and BW determined weekly. After slaughtering, the weights of the pancreas, proventriculus, gizzard, and small intestine were measured. Villus lengths and crypt depths of the duodenum, jejunum, and ileum were determined. The jejunal electrogenic glucose transport was studied in Ussing chambers. Hens that received mash instead of expandate had higher proventriculus (P = 0.011), gizzard (P < 0.001), and pancreas (P = 0.019) weights, whereas the feeding of coarsely instead of finely ground diets led to higher gizzard weights (P < 0.001). Mash-fed hens showed longer duodenal (P < 0.001) and shorter ileal villi (P = 0.047) and increased duodenal villus height-to-crypt depth ratios (P < 0.001) than those given the expandate. Mash-fed hens had higher glucose transport rates than expandate-fed hens (P < 0.001). In conclusion, the feeding of coarsely ground as well as mash diets had stimulating effects on the development of the gastrointestinal organs. Moreover, the feeding of mash influenced the intestinal microstructure of the epithelium that was accompanied by higher glucose transport capacities.


Subject(s)
Animal Feed/analysis , Chickens/anatomy & histology , Chickens/metabolism , Food Handling , Gastrointestinal Tract/cytology , Glucose/metabolism , Jejunum/metabolism , Animals , Diet/veterinary , Female , Particle Size , Random Allocation , Reproduction/physiology
17.
Genes Immun ; 15(3): 137-44, 2014.
Article in English | MEDLINE | ID: mdl-24500400

ABSTRACT

Activation-induced CD154 expression on CD4 T cells is prolonged in systemic lupus erythematosus, but the mechanism(s) for its dysregulation are unknown. The studies reported herein demonstrate that interleukin-15 (IL-15) is capable of prolonging CD154 expression on phytohemagglutinin (PHA)-activated CD4 T cells. As IL-15 signals through signal transducer and activator of transcription 5 (STAT5), predicted STAT5 binding sites in the human CD154 transcriptional promoter were identified, and STAT5 binding to the proximal CD154 promoter in vitro and in vivo following primary CD4 T-cell activation was demonstrated. Moreover, overexpression of wild-type STAT5 in primary human CD4 T cells augmented CD154 transcription, whereas overexpression of a dominant-negative (DN) STAT5 protein inhibited CD154 transcription. Mutation of the most proximal STAT5 binding site in the CD154 promoter resulted in diminished DNA binding and reduced CD154 transcriptional activity. Interestingly, STAT5-specific small interfering RNA inhibited CD154 surface expression at 48 but not 24 h after T-cell activation. Thus, these findings provide some of the first evidence to support a possible mechanistic link to explain how the overexpression of IL-15 observed in lupus patients may be involved in the prolonged expression of CD154 that has also been observed on lupus CD4 T cells.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , CD40 Ligand/genetics , Interleukin-15/metabolism , Promoter Regions, Genetic , STAT5 Transcription Factor/metabolism , Transcriptional Activation , Adolescent , Binding Sites , CD4-Positive T-Lymphocytes/drug effects , CD40 Ligand/metabolism , Case-Control Studies , Child , Female , Gene Expression Regulation/drug effects , Genes, Reporter , Humans , Interleukin-15/pharmacology , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Mutation , Protein Binding , RNA Interference , STAT5 Transcription Factor/genetics , Transcription, Genetic , Transcriptional Activation/drug effects , Up-Regulation
18.
Int J Clin Pract ; 66(8): 800-812, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22805272

ABSTRACT

Aims: The aim of this analysis was to assess the overall safety and tolerability profiles of various statins + ezetimibe vs. statin monotherapy and to explore tolerability in sub-populations grouped by age, race, and sex. Methods: Study-level data were combined from 27 double-blind, placebo-controlled or active-comparator trials that randomized adult hypercholesterolemic patients to statin or statin + ezetimibe for 6-24 weeks. In the full cohort, % patients with AEs within treatment groups (statin: N = 10,517; statin + ezetimibe: N = 11,714) was assessed by logistic regression with terms for first-/second-line therapy (first line = drug-naïve or rendered drug-naïve by washout at study entry; second line = ongoing statin at study entry or statin run-in), trial within first-/second-line therapy, and treatment. The same model was fitted for age (< 65, ≥ 65 years), sex, race (white, black, other) and first-/second-line subgroups with additional terms for subgroup and subgroup-by-treatment interaction. Results: In the full cohort, the only significant difference between treatments was consecutive AST or ALT elevations ≥ 3 × upper limit of normal (ULN) (statin: 0.35%, statin + ezetimibe: 0.56%; p = 0.017). Significantly more subjects reported ≥ 1 AE; drug-related, hepatitis-related and gastrointestinal-related AEs; and CK elevations ≥ 10 × ULN (all p ≤ 0.008) in first-line vs. second-line therapy studies with both treatments. AEs were generally similar between treatments in subgroups, and similar rates of AEs were reported within age and race subgroups; however, women reported generally higher AE rates. Conclusions: In conclusion, in second-line studies, ongoing statin treatment at study entry likely screened out participants for previous statin-related AEs and tolerability issues. These results describe the safety profiles of widely used lipid-lowering therapies and encourage their appropriate and judicious use in certain subpopulations.

19.
Pregnancy Hypertens ; 2(3): 193-4, 2012 07.
Article in English | MEDLINE | ID: mdl-26105246

ABSTRACT

INTRODUCTION: Pre-eclampsia is the second leading cause of maternal mortality in low and middle income countries (LMIC). Pharmacological management of pre-eclampsia has five major components including antihypertensive therapy for severe and non-severe hypertension, magnesium sulphate for prevention or treatment of eclampsia, treatment of pre-eclampsia-related end-organ complications, antenatal corticosteroids for acceleration of fetal pulmonary maturity given iatrogenic preterm delivery for maternal and/or fetal indications, and labour induction for such indicated deliveries. Essential medicines are defined by the World Health Organization (WHO) as "drugs that satisfy the health care needs of the majority of the population". Essential Medicines Lists (EMLs) detail these essential medicines within an individual country and support the argument that the medication should be routinely available. OBJECTIVES: To determine how many drugs required for comprehensive pre-eclampsia management are listed in national EMLs of LMIC. METHODS: We conducted a descriptive analysis of relevant drug prevalence on identified EMLs. We searched for the national EMLs of the 144 LMIC identified by the World Bank. EMLs were collected by broad based internet searches and in collaboration with the WHO. The EMLs were surveyed for therapies for the different aspects of pre-eclampsia management: hypertension (non-severe and severe with oral or parenteral agents), eclampsia, pre-eclampsia complications (e.g., pulmonary oedema, thrombosis), preterm birth, and labour induction. RESULTS: EMLs were located and reviewed for 58(40.3%) of LMIC. One or more parenteral antihypertensive agents were listed in 51(87.9%) EMLs. The most common agents were: hydralazine (67.2%), verapamil (58.6%), propranolol (39.7%) and sodium nitroprusside (37.9%); parenteral labetalol was listed by only 19.0% of EMLs. The most prevalent oral antihypertensive therapies listed were: nifedipine (96.6%, usually 10 or 20mg intermediate-acting tablets), methyldopa (94.8%), propranolol (89.7%), and atenolol (87.9%). Captopril, enalapril, hydrochlorothiazide and spironolactone were commonly listed. Magnesium sulphate for prevention and management of eclampsia was present in 86.2% of EMLs (and its antidote, calcium gluconate in 82.8%). To manage complications of pre-eclampsia, oral frusemide was listed in 94.8% of EMLs and parenteral heparin in 91.4%. Most EMLs listed parenteral dexamethasone (91.4%) for acceleration of fetal pulmonary maturity and oxytocin (98.3%) or a prostanoid (usually misoprostol, 39.7%) for labour induction. CONCLUSION: EMLs of LMIC provide comprehensive coverage of all aspects of recommended pre-eclampsia pharmacotherapy. These EMLs may be used as advocacy tools to ensure the availability of these therapies within each country.

20.
Brain Inj ; 25(4): 426-32, 2011.
Article in English | MEDLINE | ID: mdl-21323415

ABSTRACT

BACKGROUND: Assessment of awareness in patients with severe brain injury remains subjective, although patients with even limited awareness (e.g. minimal conscious state, MCS) have different prognoses and treatment than those in vegetative state (VS). Recently, task appropriate differential regional activation in VS has been reported using fMRI during mental imagery. PRIMARY OBJECTIVE: Demonstration of conscious awareness in reproducible differential EEG source localization images in a VS patient reflecting requested mental imagery was performed. METHODS: A VS patient (with re-test) and a normal control were requested to imagine singing and to mentally perform serial subtraction, while EEG was recorded. QEEG source localization was performed to identify regions of brain activation in response to tasks. RESULTS: Replicable distinctive activation of brain areas appropriate for each task was seen in the VS patient and control. Frequency spectra shifted to beta, with significant source activation in regions including the bilateral anterior cingulate, insula, left caudate and dorsolateral pre-frontal cortex to singing and the putamen, insula, left pre-frontal cortex and right temporal gyrus to subtraction by 7's. CONCLUSIONS: Results from this single case suggests the potential utility of QEEG source localization images to detect awareness in patients clinically diagnosed as being in VS. This indicates the possibility that EEG may serve as an important adjunct to the assessment of awareness in patients with disorders of consciousness in the clinical setting.


Subject(s)
Awareness/physiology , Brain Injuries/physiopathology , Electroencephalography/methods , Magnetic Resonance Imaging/methods , Persistent Vegetative State/physiopathology , Brain Injuries/rehabilitation , Consciousness/physiology , Humans , Male , Middle Aged , Persistent Vegetative State/diagnosis , Persistent Vegetative State/rehabilitation
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