Telemedicine Critical Care-Mediated Mortality Reductions in Lower-Performing Patient Diagnosis Groups: A Prospective, Before and After Study

OBJECTIVES: Studies evaluating telemedicine critical care (TCC) have shown mixed results. We prospectively evaluated the impact of TCC implementation on risk-adjusted mortality among patients stratified by pre-TCC performance. DESIGN: Prospective, observational, before and after study. SETTING: Three adult ICUs at an academic medical center. PATIENTS: A total of 2,429 patients in the pre-TCC (January to June 2016) and 12,479 patients in the post-TCC (January 2017 to June 2019) periods. INTERVENTIONS: TCC implementation which included an acuity-driven workflow targeting an identified “lower-performing” patient group, defined by ICU admission in an Acute Physiology and Chronic Health Evaluation diagnoses category with a pre-TCC standardized mortality ratio (SMR) of greater than 1.5. MEASUREMENTS AND MAIN RESULTS: The primary outcome was risk-adjusted hospital mortality. Risk-adjusted hospital length of stay (HLOS) was also studied. The SMR for the overall ICU population was 0.83 pre-TCC and 0.75 post-TCC, with risk-adjusted mortalities of 10.7% and 9.5% (p = 0.09). In the identified lower-performing patient group, which accounted for 12.6% (n = 307) of pre-TCC and 13.3% (n = 1671) of post-TCC ICU patients, SMR decreased from 1.61 (95% CI, 1.21–2.01) pre-TCC to 1.03 (95% CI, 0.91–1.15) post-TCC, and risk-adjusted mortality decreased from 26.4% to 16.9% (p \u3c 0.001). In the remaining (“higher-performing”) patient group, there was no change in pre- versus post-TCC SMR (0.70 [0.59–0.81] vs 0.69 [0.64–0.73]) or risk-adjusted mortality (8.5% vs 8.4%, p = 0.86). There were no pre- to post-TCC differences in standardized HLOS ratio or risk-adjusted HLOS in the overall cohort or either performance group. CONCLUSIONS: In well-staffed and overall higher-performing ICUs in an academic medical center, Acute Physiology and Chronic Health Evaluation granularity allowed identification of a historically lower-performing patient group that experienced a striking TCC-associated reduction in SMR and risk-adjusted mortality. This study provides additional evidence for the relationship between pre-TCC performance and post-TCC improvement

Searching for Novel Biomarkers Using a Mouse Model of CLN3-Batten Disease

CLN3-Batten disease is a rare, autosomal recessive disorder involving seizures, visual, motor and cognitive decline, and premature death. The Cln3Δex7/8 mouse model recapitulates several phenotypic characteristics of the most common 1.02kb disease-associated deletion. Identification of reproducible biomarker(s) to facilitate longitudinal monitoring of disease progression and provide readouts for therapeutic response has remained elusive. One factor that has complicated the identification of suitable biomarkers in this mouse model has been that variations in animal husbandry appear to significantly influence readouts. In the current study, we cross-compared a number of biological parameters in blood from Cln3Δex7/8 mice and control, non-disease mice on the same genetic background from multiple animal facilities in an attempt to better define a surrogate marker of CLN3-Batten disease. Interestingly, we found that significant differences between Batten and non-disease mice found at one site were generally not maintained across different facilities. Our results suggest that colony variation in the Cln3Δex7/8 mouse model of CLN3-Batten disease can influence potential biomarkers of the disease

Assessment, Quantification, and Management of Fracture Pain: from Animals to the Clinic

Purpose of review: Fractures are painful and disabling injuries that can occur due to trauma, especially when compounded with pathologic conditions, such as osteoporosis in older adults. It is well documented that acute pain management plays an integral role in the treatment of orthopedic patients. There is no current therapy available to completely control post-fracture pain that does not interfere with bone healing or have major adverse effects. In this review, we focus on recent advances in the understanding of pain behaviors post-fracture. Recent findings: We review animal models of bone fracture and the assays that have been developed to assess and quantify spontaneous and evoked pain behaviors, including the two most commonly used assays: dynamic weight bearing and von Frey testing to assess withdrawal from a cutaneous (hindpaw) stimulus. Additionally, we discuss the assessment and quantification of fracture pain in the clinical setting, including the use of numeric pain rating scales, satisfaction with pain relief, and other biopsychosocial factor measurements. We review how pain behaviors in animal models and clinical cases can change with the use of current pain management therapies. We conclude by discussing the use of pain behavioral analyses in assessing potential therapeutic treatment options for addressing acute and chronic fracture pain without compromising fracture healing. There currently is a lack of effective treatment options for fracture pain that reliably relieve pain without potentially interfering with bone healing. Continued development and verification of reliable measurements of fracture pain in both pre-clinical and clinical settings is an essential aspect of continued research into novel analgesic treatments for fracture pain

Cyclin D2-knock-out mice with attenuated dentate gyrus neurogenesis have robust deficits in long-term memory formation.

Neurobehavioral studies have produced contradictory findings concerning the function of neurogenesis in the adult dentate gyrus. Previous studies have proved inconsistent across several behavioral endpoints thought to be dependent on dentate neurogenesis, including memory acquisition, short-term and long-term retention of memory, pattern separation, and reversal learning. We hypothesized that the main function of dentate neurogenesis is long-term memory formation because we assumed that a newly formed and integrated neuron would have a long-term impact on the local neural network. We used a cyclin D2-knock-out (cyclin D2-/-) mouse model of endogenously deficient dentate neurogenesis to test this hypothesis. We found that cyclin D2-/- mice had robust and sustained loss of long-term memory in two separate behavioral tasks, Morris water maze (MWM) and touchscreen intermediate pattern separation. Moreover, after adjusting for differences in brain volumes determined by magnetic resonance (MR) imaging, reduced dentate neurogenesis moderately correlated with deficits in memory retention after 24 hours. Importantly, cyclin D2-/- mice did not show deficits in learning acquisition in a touchscreen paradigm of intermediate pattern separation or MWM platform location, indicating intact short-term memory. Further evaluation of cyclin D2-/- mice is necessary to confirm that deficits are specifically linked to dentate gyrus neurogenesis since cyclin D2-/- mice also have a reduced size of the olfactory bulb, hippocampus, cerebellum and cortex besides reduced dentate gyrus neurogenesis

No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing

Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their pain-promoting effects. Finally, further examination of protein-sequestering antibodies and/or small molecule agonists and antagonists may lead to new therapies that can decrease the rate of delayed union/nonunion outcomes and fracture-associated pain

Dementia risk and dynamic response to exercise: A non-randomized clinical trial

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Background Physical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the Apolipoprotein epsilon 4 (APOE4) allele, a genetic risk factor for developing Alzheimer’s. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers. Methods Sixty-two older adults (73±5 years old, 41 female [67%]) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change in cortical gray matter cerebral blood flow in cortical gray matter measured by magnetic resonance imaging (MRI) arterial spin labeling (ASL), defined as the total perfusion (area under the curve, AUC) following exercise. Secondary outcomes were changes in blood neurotrophin concentrations of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF). Results Genotyping failed in one individual (n = 23 APOE4 carriers and n = 38 APOE4 non-carriers) and two participants could not complete primary outcome testing. Cerebral blood flow AUC increased immediately following exercise, regardless of APOE4 carrier status. In an exploratory regional analyses, we found that cerebral blood flow increased in hippocampal brain regions, while showing no change in cerebellum across both groups. Among high inter-individual variability, there were no significant changes in any of the 3 neurotrophic factors for either group immediately following exercise. Conclusions Our findings show that both APOE4 carriers and non-carriers show similar effects of exercise-induced increases in cerebral blood flow and neurotrophic response to acute aerobic exercise. Our results provide further evidence that acute exercise-induced increases in cerebral blood flow may be regional specific, and that exercise-induced neurotrophin release may show a differential effect in the aging cardiovascular system. Results from this study provide an initial characterization of the acute brain blood flow and neurotrophin responses to a bout of exercise in older adults with and without this known risk allele for cardiovascular disease and Alzheimer’s disease

A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome

A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Na(v)1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9a(N641Y/N641Y) knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p.N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Na(v)1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Na(v)1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations

Prevalence of unrecognised myocardial infarction in a low-intermediate risk asymptomatic cohort and its relation to systemic atherosclerosis

The study was funded by the Souter Charitable Foundation and the Chest, Heart and Stroke Scotland Charity. J.R.W.M. is supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (grant no. WT 085664) in the form of a clinical research fellowship.Aims :  Unrecognized myocardial infarctions (UMIs) have been described in 19-30% of the general population using late gadolinium enhancement (LGE) on cardiac magnetic resonance. However, these studies have focused on an unselected cohort including those with known cardiovascular disease (CVD). The aim of the current study was to ascertain the prevalence of UMIs in a non-high-risk population using magnetic resonance imaging (MRI). Methods and Results :  A total of 5000 volunteers aged >40 years with no history of CVD and a 10-year risk of CVD of <20%, as assessed by the ATP-III risk score, were recruited to the Tayside Screening for Cardiac Events study. Those with a B-type natriuretic peptide (BNP) level greater than their gender-specific median were invited for a whole-body MR angiogram and cardiac MR including LGE assessment. LGE was classed as absent, UMI, or non-specific. A total of 1529 volunteers completed the imaging study; of these, 53 (3.6%) were excluded because of either missing data or inadequate LGE image quality. Ten of the remaining 1476 (0.67%) displayed LGE. Of these, three (0.2%) were consistent with UMI, whereas seven were non-specific occurring in the mid-myocardium (n = 4), epicardium (n = 1), or right ventricular insertion points (n = 2). Those with UMI had a significantly higher BNP [median 116 (range 31-133) vs. 22.6 (5-175) pg/mL, P = 0.015], lower ejection fraction [54.6 (36-62) vs. 68.9 (38-89)%, P = 0.007], and larger end-systolic volume [36.3 (27-61) vs. 21.7 (5-65) mL/m(2), P = 0.014]. Those with non-specific LGE had lower diastolic blood pressure [68 (54-70) vs. 72 (46-98) mmHg, P = 0.013] but no differences in their cardiac function. Conclusion :  Despite previous reports describing high prevalence of UMI in older populations, in a predominantly middle-aged cohort, those who are of intermediate or low cardiovascular risk have a very low risk of having an unrecognized myocardial infarct.Publisher PDFPeer reviewe

A Small Conductance Calcium-Activated K⁺ Channel in C. elegans, KCNL-2, Plays a Role in the Regulation of the Rate of Egg-Laying

In the nervous system of mice, small conductance calcium-activated potassium (SK) channels function to regulate neuronal excitability through the generation of a component of the medium afterhyperpolarization that follows action potentials. In humans, irregular action potential firing frequency underlies diseases such as ataxia, epilepsy, schizophrenia and Parkinson's disease. Due to the complexity of studying protein function in the mammalian nervous system, we sought to characterize an SK channel homologue, KCNL-2, in C. elegans, a genetically tractable system in which the lineage of individual neurons was mapped from their early developmental stages. Sequence analysis of the KCNL-2 protein reveals that the six transmembrane domains, the potassium-selective pore and the calmodulin binding domain are highly conserved with the mammalian homologues. We used widefield and confocal fluorescent imaging to show that a fusion construct of KCNL-2 with GFP in transgenic lines is expressed in the nervous system of C. elegans. We also show that a KCNL-2 null strain, kcnl-2(tm1885), demonstrates a mild egg-laying defective phenotype, a phenotype that is rescued in a KCNL-2-dependent manner. Conversely, we show that transgenic lines that overexpress KCNL-2 demonstrate a hyperactive egg-laying phenotype. In this study, we show that the vulva of transgenic hermaphrodites is highly innervated by neuronal processes and by the VC4 and VC5 neurons that express GFP-tagged KCNL-2. We propose that KCNL-2 functions in the nervous system of C. elegans to regulate the rate of egg-laying. © 2013 Chotoo et al