Machine learning methods for detecting urinary tract infection and analysing daily living activities in people with dementia.

Dementia is a neurological and cognitive condition that affects millions of people around the world. At any given time in the United Kingdom, 1 in 4 hospital beds are occupied by a person with dementia, while about 22% of these hospital admissions are due to preventable causes. In this paper we discuss using Internet of Things (IoT) technologies and in-home sensory devices in combination with machine learning techniques to monitor health and well-being of people with dementia. This will allow us to provide more effective and preventative care and reduce preventable hospital admissions. One of the unique aspects of this work is combining environmental data with physiological data collected via low cost in-home sensory devices to extract actionable information regarding the health and well-being of people with dementia in their own home environment. We have worked with clinicians to design our machine learning algorithms where we focused on developing solutions for real-world settings. In our solutions, we avoid generating too many alerts/alarms to prevent increasing the monitoring and support workload. We have designed an algorithm to detect Urinary Tract Infections (UTI) which is one of the top five reasons of hospital admissions for people with dementia (around 9% of hospital admissions for people with dementia in the UK). To develop the UTI detection algorithm, we have used a Non-negative Matrix Factorisation (NMF) technique to extract latent factors from raw observation and use them for clustering and identifying the possible UTI cases. In addition, we have designed an algorithm for detecting changes in activity patterns to identify early symptoms of cognitive decline or health decline in order to provide personalised and preventative care services. For this purpose, we have used an Isolation Forest (iForest) technique to create a holistic view of the daily activity patterns. This paper describes the algorithms and discusses the evaluation of the work using a large set of real-world data collected from a trial with people with dementia and their caregivers.

Health management and pattern analysis of daily living activities of people with dementia using in-home sensors and machine learning techniques.

The number of people diagnosed with dementia is expected to rise in the coming years. Given that there is currently no definite cure for dementia and the cost of care for this condition soars dramatically, slowing the decline and maintaining independent living are important goals for supporting people with dementia. This paper discusses a study that is called Technology Integrated Health Management (TIHM). TIHM is a technology assisted monitoring system that uses Internet of Things (IoT) enabled solutions for continuous monitoring of people with dementia in their own homes. We have developed machine learning algorithms to analyse the correlation between environmental data collected by IoT technologies in TIHM in order to monitor and facilitate the physical well-being of people with dementia. The algorithms are developed with different temporal granularity to process the data for long-term and short-term analysis. We extract higher-level activity patterns which are then used to detect any change in patients' routines. We have also developed a hierarchical information fusion approach for detecting agitation, irritability and aggression. We have conducted evaluations using sensory data collected from homes of people with dementia. The proposed techniques are able to recognise agitation and unusual patterns with an accuracy of up to 80%.

Acute Molecular Changes in Synovial Fluid Following Human Knee Injury: Association With Early Clinical Outcomes.

OBJECTIVE: To investigate whether molecules found to be up-regulated within hours of surgical joint destabilization in the mouse are also elevated in the analogous human setting of acute knee injury, how this molecular response varies between individuals, and whether it is related to patient-reported outcomes in the 3 months after injury. METHODS: Seven candidate molecules were analyzed in blood and synovial fluid (SF) from 150 participants with recent structural knee injury at baseline (<8 weeks from injury) and in blood at 14 days and 3 months following baseline. Knee Injury and Osteoarthritis Outcome Score 4 (KOOS4 ) was obtained at baseline and 3 months. Patient and control samples were compared using Meso Scale Discovery platform assays or enzyme-linked immunosorbent assay. RESULTS: Six of the 7 molecules were significantly elevated in human SF immediately after injury: interleukin-6 (IL-6), monocyte chemotactic protein 1, matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), activin A, and tumor necrosis factor-stimulated gene 6 (TSG-6). There was low-to-moderate correlation with blood measurements. Three of the 6 molecules were significantly associated with baseline KOOS4 (those with higher SF IL-6, TIMP-1, or TSG-6 had lower KOOS4 ). These 3 molecules, MMP-3, and activin A were all significantly associated with greater improvement in KOOS4 over 3 months, after adjustment for other relevant factors. Of these, IL-6 alone significantly accounted for the molecular contribution to baseline KOOS4 and change in KOOS4 over 3 months. CONCLUSION: Our findings validate relevant human biomarkers of tissue injury identified in a mouse model. Analysis of SF rather than blood more accurately reflects this response. The response is associated with patient-reported outcomes over this early period, with SF IL-6 acting as a single representative marker. Longitudinal outcomes will determine if these molecules are biomarkers of subsequent disease risk.

Human replication protein A melts a DNA triple helix structure in a potent and specific manner.

Alternate DNA structures other than double-stranded B-form DNA can potentially impede cellular processes such as transcription and replication. The DNA triplex helix and G4 tetraplex structures that form by Hoogsteen hydrogen bonding are two examples of alternate DNA structures that can be a source of genomic instability. In this study, we have examined the ability of human replication protein A (RPA), a single-stranded DNA binding protein that is implicated in all facets of DNA metabolism, to destabilize DNA triplexes and tetraplexes. Biochemical studies demonstrate that RPA efficiently melts an intermolecular DNA triple helix consisting of a pyrimidine motif third strand annealed to a 4 kb duplex DNA fragment at protein concentrations equimolar to the triplex substrate. Heterologous single-stranded DNA binding proteins ( Escherichia coli SSB, T4 gene 32) melt the triplex substrate very poorly or not at all, suggesting that the triplex destabilizing effect of RPA is specific. In contrast to the robust activity on DNA triplexes, RPA does not melt intermolecular G4 tetraplex structures. Cellular assays demonstrated increased triplex DNA content when RPA is transiently repressed, suggesting that RPA melting of triple helical structures is physiologically important. On the basis of our results, we suggest that the abundance of RPA known to exist in vivo is likely to be a strong deterrent to the stability of triplexes that can potentially form from human genomic DNA sequences.

FANCJ (BACH1) helicase forms DNA damage inducible foci with replication protein A and interacts physically and functionally with the single-stranded DNA-binding protein.

The BRCA1 associated C-terminal helicase (BACH1, designated FANCJ) is implicated in the chromosomal instability genetic disorder Fanconi anemia (FA) and hereditary breast cancer. A critical role of FANCJ helicase may be to restart replication as a component of downstream events that occur during the repair of DNA cross-links or double-strand breaks. We investigated the potential interaction of FANCJ with replication protein A (RPA), a single-stranded DNA-binding protein implicated in both DNA replication and repair. FANCJ and RPA were shown to coimmunoprecipitate most likely through a direct interaction of FANCJ and the RPA70 subunit. Moreover, dependent on the presence of BRCA1, FANCJ colocalizes with RPA in nuclear foci after DNA damage. Our data are consistent with a model in which FANCJ associates with RPA in a DNA damage-inducible manner and through the protein interaction RPA stimulates FANCJ helicase to better unwind duplex DNA substrates. These findings identify RPA as the first regulatory partner of FANCJ. The FANCJ-RPA interaction is likely to be important for the role of the helicase to more efficiently unwind DNA repair intermediates to maintain genomic stability.

Safety and efficacy of hydromorphone as an analgesic alternative to morphine in acute pain: a randomized clinical trial.

STUDY OBJECTIVE: We compare a standard weight-based dose of intravenous hydromorphone (Dilaudid) to a standard weight-based dose of intravenous morphine in adults presenting to the ED with acute severe pain. METHODS: This was a prospective, randomized, double-blind, clinical trial conducted in an academic medical center. Of the 198 adult patients presenting to the ED with acute severe pain who were randomized to receive either intravenous hydromorphone at 0.015 mg/kg or intravenous morphine at 0.1 mg/kg, 191 patients had sufficient data for analysis. The main outcome measure was the difference between the 2 groups in pain reduction at 30 minutes as measured on a validated numeric rating scale. Adverse effects, pain reduction at 5 minutes and 2 hours postbaseline, and additional analgesics and antiemetics were tracked as secondary outcome measures. RESULTS: The mean change of pain from baseline to 30 minutes postbaseline in patients allocated to intravenous hydromorphone was -5.5 numeric rating scale units versus -4.1 in patients allocated to intravenous morphine (difference -1.3; 95% confidence interval -2.2 to -0.5). Adverse effects were similar in both groups, with the exception of pruritus, which did not occur in patients receiving hydromorphone (0% versus 6% [difference -6%; 95% confidence interval -11% to -1%]). No patient required naloxone. CONCLUSION: For the treatment of acute, severe pain in the emergency department, intravenous hydromorphone at 0.015 mg/kg represents a feasible alternative to intravenous morphine at 0.1 mg/kg.

Intravenous morphine at 0.1 mg/kg is not effective for controlling severe acute pain in the majority of patients.

STUDY OBJECTIVE: The objective was to quantify the analgesic effect of a dose of intravenous morphine, 0.1 mg/kg, to emergency department (ED) patients presenting in acute, severe pain. METHODS: This was a prospective convenience cohort of patients aged 21 to 65 years and presenting to an academic urban ED with acute, severe pain. Patients rated their pain intensity on a validated 11-point verbal numeric rating scale ranging from 0, "no pain," to 10, "worst possible pain," immediately before they received 0.1 mg of intravenous morphine per kilogram of body weight and 30 minutes later. The main outcome was proportion of patients whose pain decreased by less than 50% during the 30-minute interval. RESULTS: Of 119 patients who received intravenous morphine at 0.1 mg/kg, the average age was 42 years (SD=11 years), 55% were female patients, 65% were Hispanic, 28% were black, and 7% were classified as other. The median numeric rating scale pain score at baseline was 10 (interquartile range 9 to 10). Sixty-seven percent (95% confidence interval 58% to 76%) of the patients receiving intravenous morphine at 0.1 mg/kg reported a less than 50% decrease in pain. No patient required an opioid antagonist at any time during or after the study period. CONCLUSION: The data suggest that a 0.1 mg/kg dose of morphine may be too low to adequately control acute severe pain.

Physical and functional mapping of the replication protein a interaction domain of the werner and bloom syndrome helicases.

The single-stranded DNA-binding protein replication protein A (RPA) interacts with several human RecQ DNA helicases that have important roles in maintaining genomic stability; however, the mechanism for RPA stimulation of DNA unwinding is not well understood. To map regions of Werner syndrome helicase (WRN) that interact with RPA, yeast two-hybrid studies, WRN affinity pull-down experiments and enzyme-linked immunosorbent assays with purified recombinant WRN protein fragments were performed. The results indicated that WRN has two RPA binding sites, a high affinity N-terminal site, and a lower affinity C-terminal site. Based on results from mapping studies, we sought to determine if the WRN N-terminal region harboring the high affinity RPA interaction site was important for RPA stimulation of WRN helicase activity. To accomplish this, we tested a catalytically active WRN helicase domain fragment (WRN(H-R)) that lacked the N-terminal RPA interaction site for its ability to unwind long DNA duplex substrates, which the wild-type enzyme can efficiently unwind only in the presence of RPA. WRN(H-R) helicase activity was significantly reduced on RPA-dependent partial duplex substrates compared with full-length WRN despite the presence of RPA. These results clearly demonstrate that, although WRN(H-R) had comparable helicase activity to full-length WRN on short duplex substrates, its ability to unwind RPA-dependent WRN helicase substrates was significantly impaired. Similarly, a Bloom syndrome helicase (BLM) domain fragment, BLM(642-1290), that lacked its N-terminal RPA interaction site also unwound short DNA duplex substrates similar to wild-type BLM, but was severely compromised in its ability to unwind long DNA substrates that full-length BLM helicase could unwind in the presence of RPA. These results suggest that the physical interaction between RPA and WRN or BLM helicases plays an important role in the mechanism for RPA stimulation of helicase-catalyzed DNA unwinding.

p53 modulates RPA-dependent and RPA-independent WRN helicase activity.

Werner syndrome is a hereditary disorder characterized by the early onset of age-related symptoms, including cancer. The absence of a p53-WRN helicase interaction may disrupt the signal to direct S-phase cells into apoptosis for programmed cell death and contribute to the pronounced genomic instability and cancer predisposition in Werner syndrome cells. Results from coimmunoprecipitation studies indicate that WRN is associated with replication protein A (RPA) and p53 in vivo before and after treatment with the replication inhibitor hydroxyurea or gamma-irradiation that introduces DNA strand breaks. Analysis of the protein interactions among purified recombinant WRN, RPA, and p53 proteins indicate that all three protein pairs bind with similar affinity in the low nanomolar range. In vitro studies show that p53 inhibits RPA-stimulated WRN helicase activity on an 849-bp M13 partial duplex substrate. p53 also inhibited WRN unwinding of a short (19-bp) forked duplex substrate in the absence of RPA. WRN unwinding of the forked duplex substrate was specific, because helicase inhibition mediated by p53 was retained in the presence of excess competitor DNA and was significantly reduced or absent in helicase reactions catalyzed by a WRN helicase domain fragment lacking the p53 binding site or the human RECQ1 DNA helicase, respectively. p53 effectively inhibited WRN helicase activity on model DNA substrate intermediates of replication/repair, a 5' ssDNA flap structure and a synthetic replication fork. Regulation of WRN helicase activity by p53 is likely to play an important role in genomic integrity surveillance, a vital function in the prevention of tumor progression.

Specific stimulation of human apurinic/apyrimidinic endonuclease by heat shock protein 70.

We previously demonstrated the stimulation of human apurinic/apyrimidinic endonuclease 1 (HAP1) by heat shock protein 70 (HSP70). In this work, we further defined the functional interaction between these proteins. Digestion of HSP70 by trypsin released 48 and 43 kDa amino terminal fragments that retained the ability to stimulate HAP1. In agreement with this result, an HSP70 N-terminal deletion mutant protein containing amino acids 1-385 was comparable to the full-length protein in its ability to enhance HAP1 activity. HSP70 mutants containing carboxy terminal amino acids 386-640 stimulated HAP1 only slightly, as did unrelated proteins. These results implicate the amino terminal portion of HSP70 in stimulating the activity of HAP1.