PCOM Library / Hot Topics in Research / Archive for "Internal Medicine"

Category: Internal Medicine

Hot Topics: Metabolite Constellation Predicts Chronic Fatigue Syndrome

katheride Hot Topics in Research, Rheumatology

Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics
Nagy-Szakal D, Barupal DK, Lee B, et al. Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. Scientific Reports. 2018;8(1):10056. https://doi.org/10.1038/s41598-018-28477-9.
The pathogenesis of ME/CFS, a disease characterized by fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, irritable bowel syndrome (IBS), and lymphadenopathy, is poorly understood. We report biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS patients and 50 healthy controls. We confirm reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide. Integration of fecal metagenomic and plasma metabolomic data resulted in a stronger predictive model of ME/CFS (cross-validated AUC = 0.836) than either metagenomic (cross-validated AUC = 0.745) or metabolomic (cross-validated AUC = 0.820) analysis alone. Our findings may provide insights into the pathogenesis of ME/CFS and its subtypes and suggest pathways for the development of diagnostic and therapeutic strategies.

Hot Topics: New Technology Could Allow Dementia Patients to Live Alone Longer

katheride Dementia, Hot Topics in Research, Neurology

Health management and pattern analysis of daily living activities of people with dementia using in-home sensors and machine learning techniques
Enshaeifar S, Zoha A, Markides A, et al. Health management and pattern analysis of daily living activities of people with dementia using in-home sensors and machine learning techniques. PLOS ONE. 2018;13(5):e0195605. https://doi.org/10.1371/journal.pone.0195605.
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%.

Hot Topics: New Drug Improves Bladder Function After Spinal Cord Injury

katheride Hot Topics in Research, Neurology, Pharmaceutical Sciences

Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury
Ryu JC, Tooke K, Malley SE, et al. Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury. J Clin Invest. 2018;128(5):1772-1786. https://doi.org/10.1172/JCI97837
Loss of bladder control is a challenging outcome facing patients with spinal cord injury (SCI). We report that systemic blocking of pro–nerve growth factor (proNGF) signaling through p75 with a CNS-penetrating small-molecule p75 inhibitor resulted in significant improvement in bladder function after SCI in rodents. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase–positive fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompany SCI were largely prevented. Urothelial cell loss that precedes hyperplasia was dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and the ensuing hyperplastic response were beneficial to functional recovery. Deleting p75 from the urothelium prevented urothelial death, but resulted in reduction in overall voiding efficiency after SCI. These results unveil a dual role of proNGF/p75 signaling in bladder function under pathological conditions with a CNS effect overriding the peripheral one.

Hot Topics: Childhood Cancer Tumor Pathway Discovered Through Zebrafish

katheride Hot Topics in Research, Oncology, Pediatrics

PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis
Kendall GC, Watson S, Xu L, et al. PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis. eLife. 2018;7:e33800. https://doi.org/10.7554/eLife.33800.
Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human PAX3-FOXO1 -driven zebrafish models of tumorigenesis and found that PAX3-FOXO1 exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6–19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this PAX3-FOXO1 transgenic zebrafish model to study how PAX3-FOXO1 leverages early developmental pathways for oncogenesis and found that her3 is a unique target. Ectopic expression of the her3 human ortholog, HES3, inhibits myogenesis in zebrafish and mammalian cells, recapitulating the arrested muscle development characteristic of rhabdomyosarcoma. In patients, HES3 is overexpressed in fusion-positive versus fusion-negative tumors. Finally, HES3 overexpression is associated with reduced survival in patients in the context of the fusion. Our novel zebrafish rhabdomyosarcoma model identifies a new PAX3-FOXO1 target, her3/HES3, that contributes to impaired myogenic differentiation and has prognostic significance in human disease.

Hot Topics: Opioids Overprescribed After Joint and Spine Surgery

katheride Hot Topics in Research, Pharmaceutical Sciences, Rheumatology, Surgery

Opioid Oversupply After Joint and Spine Surgery: A Prospective Cohort Study
Bicket MC, White E, Pronovost PJ, Wu CL, Yaster M, Alexander GC. Opioid oversupply after joint and spine surgery: A prospective cohort study. Anesth Analg. 2018. doi: 10.1213/ANE.0000000000003364.
BACKGROUND: Many patients receive prescription opioids at hospital discharge after surgery, yet little is known regarding how often these opioids go unused. We estimated the prevalence of unused opioids, use of nonopioid analgesics, and storage and disposal practices after same-day and inpatient surgery.
METHODS: In this prospective cohort study at a large, inner-city tertiary care hospital, we recruited individuals ≥18 years of age undergoing elective same-day or inpatient joint and spine surgery from August to November 2016. Using patient surveys via telephone calls, we assessed patient-reported outcomes at 2-day, 2-week, 1-month, and 6-month intervals, including: (1) stopping opioid treatment and in possession of unused opioid pills (primary outcome), (2) number of unused opioid tablets reported after stopping opioids, (3) use of nonopioid pain treatments, and (4) knowledge and practice regarding safe opioid storage and disposal.
RESULTS: Of 141 eligible patients, 140 (99%) consented (35% taking preoperative opioids; mean age 56 years [standard deviation 16 years]; 47% women). One- and 6-month follow-up was achieved for 115 (82%) and 110 patients (80%), respectively. Among patients who stopped opioid therapy, possession of unused opioids was reported by 73% (95% confidence intervals, 62%-82%) at 1-month follow-up and 34% (confidence interval, 24%-45%) at 6-month follow-up. At 1 month, 46% had ≥20 unused pills, 37% had ≥200 morphine milligram equivalents, and only 6% reported using multiple nonopioid adjuncts. Many patients reported unsafe storage and failure to dispose of opioids at both 1-month (91% and 96%, respectively) and 6-month (92% and 47%, respectively) follow-up.
CONCLUSIONS: After joint and spine surgery, many patients reported unused opioids, infrequent use of analgesic alternatives, and lack of knowledge regarding safe opioid storage and disposal. Interventions are needed to better tailor postoperative analgesia and improve the safe storage and disposal of prescription opioids.

Hot Topics: Palliative Care Lowers Overall Hospital Costs

katheride Critical Care, Geriatrics

Economics of Palliative Care for Hospitalized Adults With Serious Illness: A Meta-analysis
May P, Normand C, Cassel J, et a. Economics of palliative care for hospitalized adults with serious illness: A meta-analysis. JAMA Internal Medicine. 2018. doi: 10.1001/jamainternmed.2018.0750.
Importance  Economics of care for adults with serious illness is a policy priority worldwide. Palliative care may lower costs for hospitalized adults, but the evidence has important limitations.
Objective  To estimate the association of palliative care consultation (PCC) with direct hospital costs for adults with serious illness.
Data Sources  Systematic searches of the Embase, PsycINFO, CENTRAL, PubMed, CINAHL, and EconLit databases were performed for English-language journal articles using keywords in the domains of palliative care (eg, palliative, terminal) and economics (eg, cost, utilization), with limiters for hospital and consultation. For Embase, PsycINFO, and CENTRAL, we searched without a time limitation. For PubMed, CINAHL, and EconLit, we searched for articles published after August 1, 2013. Data analysis was performed from April 8, 2017, to September 16, 2017.
Study Selection  Economic evaluations of interdisciplinary PCC for hospitalized adults with at least 1 of 7 illnesses (cancer; heart, liver, or kidney failure; chronic obstructive pulmonary disease; AIDS/HIV; or selected neurodegenerative conditions) in the hospital inpatient setting vs usual care only, controlling for a minimum list of confounders.
Data Extraction and Synthesis  Eight eligible studies were identified, all cohort studies, of which 6 provided sufficient information for inclusion. The study estimated the association of PCC within 3 days of admission with direct hospital costs for each sample and for subsamples defined by primary diagnoses and number of comorbidities at admission, controlling for confounding with an instrumental variable when available and otherwise propensity score weighting. Treatment effect estimates were pooled in the meta-analysis.
Main Outcomes and Measures  Total direct hospital costs.
Results  This study included 6 samples with a total 133 118 patients (range, 1020-82 273), of whom 93.2% were discharged alive (range, 89.0%-98.4%), 40.8% had a primary diagnosis of cancer (range, 15.7%-100.0%), and 3.6% received a PCC (range, 2.2%-22.3%). Mean Elixhauser index scores ranged from 2.2 to 3.5 among the studies. When patients were pooled irrespective of diagnosis, there was a statistically significant reduction in costs (−$3237; 95% CI, −$3581 to −$2893; P < .001). In the stratified analyses, there was a reduction in costs for the cancer (−$4251; 95% CI, −$4664 to −$3837; P < .001) and noncancer (−$2105; 95% CI, −$2698 to −$1511; P < .001) subsamples. The reduction in cost was greater in those with 4 or more comorbidities than for those with 2 or fewer.

Hot Topics: Gut Bacteria May Change Course of Atherosclerosis

katheride Cardiology, Hot Topics in Research

Metabolic Products of the Intestinal Microbiome and Extremes of Atherosclerosis
Bogiatzi C, Gloor G, Allen-Vercoe E, et al. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis. 2018;273:91-97. doi: https://doi.org/10.1016/j.atherosclerosis.2018.04.015.
Background and aims
There is increasing awareness that the intestinal microbiome plays an important role in human health. We investigated its role in the burden of carotid atherosclerosis, measured by ultrasound as total plaque area.
Methods
Multiple regression with traditional risk factors was used to identify three phenotypes among 316/3056 patients attending vascular prevention clinics. Residual score (RES; i.e. the distance off the regression line, similar to standard deviation) was used to identify the 5% of patients with much less plaque than predicted by their risk factors (Protected, RES <−2), the 90% with about as much plaque as predicted (Explained, RES -2 to 2), and the 5% with much more plaque than predicted (Unexplained RES >2). Metabolic products of the intestinal microbiome that accumulate in renal failure – gut-derived uremic toxins (GDUT) – were assayed in plasma by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.
Results
Plasma levels of trimethylamine n-oxide (TMAO), p-cresyl sulfate, p-cresyl glucuronide, and phenylacetylglutamine were significantly lower among patients with the Protected phenotype, and higher in those with the Unexplained phenotype, despite no significant differences in renal function or in dietary intake of nutrient precursors of GDUT. In linear multiple regression with a broad panel of risk factors, TMAO (p = 0.011) and p-cresyl sulfate (p = 0.011) were significant independent predictors of carotid plaque burden.
Conclusions
The intestinal microbiome appears to play an important role in atherosclerosis. These findings raise the possibility of novel approaches to treatment of atherosclerosis such as fecal transplantation and probiotics.

Hot Topics: Animal Model May Show How to Reduce Chemotherapy Pain

katheride Hot Topics in Research, Oncology, Pharmaceutical Sciences

Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms
Wahlman C, Doyle TM, Little JW, et al. Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms. Pain. doi: 10.1097/j.pain.0000000000001177
Development of chemotherapy-induced neuropathic pain (CINP) compromises the use of chemotherapy and greatly impacts thousands of lives. Unfortunately, there are no Food and Drug Administration–approved drugs to prevent or treat CINP. Neuropathological changes within CNS, including neuroinflammation and increased neuronal excitability, are driven by alterations in neuro-glia communication; but, the molecular signaling pathways remain largely unexplored. Adenosine is a potent neuroprotective purine nucleoside released to counteract the consequences of these neuropathological changes. Adenosine signaling at its adenosine receptors (ARs) is dictated by adenosine kinase (ADK) in astrocytes, which provides a cellular sink for the removal of extracellular adenosine. We now demonstrate that chemotherapy (oxaliplatin) in rodents caused ADK overexpression in reactive astrocytes and reduced adenosine signaling at the A3AR subtype (A3AR) within the spinal cord. Dysregulation of ADK and A3AR signaling was associated with increased proinflammatory and neuroexcitatory interleukin-1β expression and activation of nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome, but not putative oxaliplatin-associated GSK3β transcriptional regulation. Intrathecal administration of the highly selective A3AR agonist MRS5698 attenuated IL-1β production and increased the expression of potent anti-inflammatory and neuroprotective IL-10. The effects of MRS5698 were blocked by attenuating IL-10 signaling in rats with intrathecal neutralizing IL-10 antibody and in IL-10−/− knockout mice. These findings provide new molecular insights implicating astrocyte-based ADK-adenosine axis and nucleotide-binding oligomerization domain-like receptor protein 3 in the development of CINP and IL-10 in the mechanism of action of A3AR agonists. These findings strengthen the pharmacological rationale for clinical evaluation of A3AR agonists already in advanced clinical trials as anticancer agents as an adjunct to chemotherapy.

Hot Topics: Treating Depression May Counteract Cognitive Impairments

katheride Alzheimer Disease, Geriatrics, Hot Topics in Research, Mood Disorders

Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment
Sugarman MA, Alosco ML, Tripodis Y, Steinberg EG, Stern RA. Neuropsychiatric symptoms and the diagnostic stability of mild cognitive impairment. Journal of Alzheimer’s Disease. 2018:1-15. doi: 10.3233/JAD-170527.
Background:
Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer’s disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses.
Objective:
The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses.
Method:
The sample included 6,763 participants from the National Alzheimer’s Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15).
Results:
1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia.
Discussion:
The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults.
 
 
 

Hot Topics: NIH Releases Big Data for Brain Development Research

katheride Hot Topics in Research, Neurology, Pediatrics, Psychology and Psychiatry

NIH releases first dataset from unprecedented study of adolescent brain development
National Institutes of Health. (2018, February 13). NIH releases first dataset from unprecedented study of adolescent brain development [Press release]. Retrieved from https://www.nih.gov/news-events/news-releases/nih-releases-first-dataset-unprecedented-study-adolescent-brain-development.
The National Institutes of Health Tuesday released to the scientific community an unparalleled dataset from the Adolescent Brain Cognitive Development (ABCD) study. To date, more than 7,500 youth and their families have been recruited for the study, well over half the participant goal.  Approximately 30 terabytes of data (about three times the size of the Library of Congress collection), obtained from the first 4,500 participants, will be available to scientists worldwide to conduct research on the many factors that influence brain, cognitive, social, and emotional development. The ABCD study is the largest long-term study of brain development and child health in the United States.