The prevalence of hypertension in multiple sclerosis based on 37 million electronic health records from the United States.

BACKGROUND AND PURPOSE: Hypertension (HTN) is a common comorbidity in multiple sclerosis (MS), and it significantly contributes to adverse outcomes. Unfortunately, the distribution of HTN in persons with MS has not been well characterized, and prior estimates have primarily relied on modest sample sizes. The objective of this study was to robustly describe the distribution of HTN in the MS population in comparison to the non-MS population with considerations for age, sex, and race. To date, this is the largest investigation of its kind. METHODS: We conducted a cross-sectional study of 37 million unique electronic health records available in the IBM Explorys Enterprise Performance Management: Explore database (Explorys) spanning the United States. This resource has previously been validated for use in MS. We evaluated the prevalence of HTN in MS (N = 122 660) and non-MS (N = 37 075 350) cohorts, stratifying by age, sex, and race. RESULTS: The prevalence of HTN was significantly greater among those with MS than among those without MS across age, sex, and race subpopulations, even after adjusting for age and sex. HTN was 25% more common in MS. In both MS and non-MS cohorts, the prevalence of HTN progressively increased with age and was higher in Black Americans and in males. DISCUSSION: This study demonstrated that HTN is significantly more common in the MS population compared to the non-MS population, irrespective of sex and race. Because HTN is the leading global risk factor for disability and death, these results emphasize the need for aggressive screening for, and management of, HTN in the MS population.

Development of a Telehealth Intervention to Improve Access to Live Donor Kidney Transplantation.

BACKGROUND: Live donor kidney transplantation (LDKT) is underutilized by patients with end-stage kidney disease due to knowledge, communication, and logistical barriers. MATERIAL AND METHODS: The Talking About Live Kidney Donation Social Worker Intervention (TALK-SWI) is a previously validated intervention demonstrated to improve patients' access to and pursuit of LDKT through in-person delivery of education and social support. To help overcome logistical barriers to LDKT, we adapted TALK-SWI into a telehealth intervention employing digital (ie, tablet, smartphone) and telephone technologies. We studied the usability and acceptability of both the mobile device and telephone counseling portions of the intervention among people with kidney disease. For the digital portion, we assessed critical (ie, inability to complete a task) and non-critical (ie, ability to complete a task utilizing an alternative method) errors participants encountered when using the program and their preferences regarding digital materials. Simultaneously, we assessed participants' satisfaction with telephone-adapted counseling compared to the original, in-person counseling. RESULTS: The 15 participants testing the digital technology made 25 critical errors and 29 non-critical errors, while they easily completed 156 tasks (out of 210). A majority of participants (73%) preferred the tablet/smart phone education application over traditional materials, and most (80%) indicated they would be more likely to utilize the mobile platform over traditional materials. Participants testing the telephone-adapted (n = 45) and in-person (n = 125) social worker counseling all reported high satisfaction with the intervention. CONCLUSION: We successfully adapted a validated educational and behavioral intervention to improve access to LDKT into a usable and acceptable telehealth intervention.

Metabolome-based signature of disease pathology in MS.

BACKGROUND: Diagnostic delays are common for multiple sclerosis (MS) since diagnosis typically depends on the presentation of nonspecific clinical symptoms together with radiologically-determined central nervous system (CNS) lesions. It is important to reduce diagnostic delays as earlier initiation of disease modifying therapies mitigates long-term disability. Developing a metabolomic blood-based MS biomarker is attractive, but prior efforts have largely focused on specific subsets of metabolite classes or analytical platforms. Thus, there are opportunities to interrogate metabolite profiles using more expansive and comprehensive approaches for developing MS biomarkers and for advancing our understanding of MS pathogenesis. METHODS: To identify putative blood-based MS biomarkers, we comprehensively interrogated the metabolite profiles in 12 non-Hispanic white, non-smoking, male MS cases who were drug naïve for 3 months prior to biospecimen collection and 13 non-Hispanic white, non-smoking male controls who were frequency matched to cases by age and body mass index. We performed untargeted two-dimensional gas chromatography and time-of-flight mass spectrometry (GCxGC-TOFMS) and targeted lipidomic and amino acid analysis on serum. 325 metabolites met quality control and supervised machine learning was used to identify metabolites most informative for MS status. The discrimination potential of these select metabolites were assessed using receiver operator characteristic curves based on logistic models; top candidate metabolites were defined as having area under the curves (AUC) >80%. The associations between whole-genome expression data and the top candidate metabolites were examined, followed by pathway enrichment analyses. Similar associations were examined for 175 putative MS risk variants and the top candidate metabolites. RESULTS: 12 metabolites were determined to be informative for MS status, of which 6 had AUCs >80%: pyroglutamate, laurate, acylcarnitine C14:1, N-methylmaleimide, and 2 phosphatidylcholines (PC ae 40:5, PC ae 42:5). These metabolites participate in glutathione metabolism, fatty acid metabolism/oxidation, cellular membrane composition, and transient receptor potential channel signaling. Pathway analyses based on the gene expression association for each metabolite suggested enrichment for pathways associated with apoptosis and mitochondrial dysfunction. Interestingly, the predominant MS genetic risk allele HLA-DRB1×15:01 was associated with one of the 6 top metabolites. CONCLUSION: Our analysis represents the most comprehensive description of metabolic changes associated with MS in serum, to date, with the inclusion of genomic and genetic information. We identified atypical metabolic processes that differed between MS patients and controls, which may enable the development of biological targets for diagnosis and treatment.

Putting patients at the center of kidney care transitions: PREPARE NOW, a cluster randomized controlled trial.

Care for patients transitioning from chronic kidney disease to kidney failure often falls short of meeting patients' needs. The PREPARE NOW study is a cluster randomized controlled trial studying the effectiveness of a pragmatic health system intervention, 'Patient Centered Kidney Transition Care,' a multi-component health system intervention designed to improve patients' preparation for kidney failure treatment. Patient-Centered Kidney Transition Care provides a suite of new electronic health information tools (including a disease registry and risk prediction tools) to help providers recognize patients in need of Kidney Transitions Care and focus their attention on patients' values and treatment preferences. Patient-Centered Kidney Transition Care also adds a 'Kidney Transitions Specialist' to the nephrology health care team to facilitate patients' self-management empowerment, shared-decision making, psychosocial support, care navigation, and health care team communication. The PREPARE NOW study is conducted among eight [8] outpatient nephrology clinics at Geisinger, a large integrated health system in rural Pennsylvania. Four randomly selected nephrology clinics employ the Patient Centered Kidney Transitions Care intervention while four clinics employ usual nephrology care. To assess intervention effectiveness, patient reported, biomedical, and health system outcomes are collected annually over a period of 36 months via telephone questionnaires and electronic health records. The PREPARE NOW Study may provide needed evidence on the effectiveness of patient-centered health system interventions to improve nephrology patients' experiences, capabilities, and clinical outcomes, and it will guide the implementation of similar interventions elsewhere. TRIAL REGISTRATION: NCT02722382.

Annotation of functional variation within non-MHC MS susceptibility loci through bioinformatics analysis.

There is a strong and complex genetic component to multiple sclerosis (MS). In addition to variation in the major histocompatibility complex (MHC) region on chromosome 6p21.3, 110 non-MHC susceptibility variants have been identified in Northern Europeans, thus far. The majority of the MS-associated genes are immune related; however, similar to most other complex genetic diseases, the causal variants and biological processes underlying pathogenesis remain largely unknown. We created a comprehensive catalog of putative functional variants that reside within linkage disequilibrium regions of the MS-associated genic variants to guide future studies. Bioinformatics analyses were also conducted using publicly available resources to identify plausible pathological processes relevant to MS and functional hypotheses for established MS-associated variants.

Monitoring of International Diabetes Federation-recommended Clinical Diabetes Indicators in a Public Health Centre in Southwest Trinidad.

OBJECTIVES: To examine availability of International Diabetes Federation (IDF)-recommended diabetes indicators in the medical charts of patients in active care at a public health centre in southwest Trinidad and Tobago, and to determine clinical status of the patient population according to Caribbean Health Research Council/Pan American Health Organization (CHRC/PAHO) guidelines for disease control. METHODS: Data were extracted from the medical records of consecutive patients with diagnosed diabetes who presented for routine care at the health centre over a seven-month period. The three most recent dates and results for the following clinical indicators were extracted: glycated haemoglobin (HbA1c), blood pressure, lipid panel, random blood sugar and weight. RESULTS: Data were extracted from 486 patient medical records (91% of patients who presented for care). The majority of records, 366 (76%), had one of three recommended IDF indicators of HbA1c, blood pressure or low-density lipoprotein (LDL) in the past year, 58 (12%) had two, 55 (11%) had three and seven (1%) had no indicators recorded. Random blood sugar and blood pressure were recorded in 93% of records, while only 20% had an HbA1c reported in the past year. The vast majority of patients did not meet guidelines for control of blood sugar, blood pressure or cholesterol. Due to a non-standardized HbA1c assay, rate of controlled HbA1c, based on CHRC/PAHO clinical guidelines, could not be determined. CONCLUSIONS: Although availability of indicators suggests an increase from prior audits reported in the literature, current reporting patterns challenge optimal patient management and future systematic evaluation of trends in diabetes care and outcomes.

Glycated haemoglobin and cognitive decline: the Atherosclerosis Risk in Communities (ARIC) study.

AIMS/HYPOTHESIS: This study aimed to examine the association between diabetes and hyperglycaemia-assessed by HbA(1c)-and change in cognitive function in persons with and without diabetes. METHODS: This was a prospective cohort study of 8,442 non-diabetic and 516 diabetic participants in the Atherosclerosis Risk in Communities (ARIC) study. We examined the association of baseline categories of HbA(1c) with 6 year change in three measures of cognition: the digit symbol substitution test (DSST); the delayed word recall test (DWRT); and the word fluency test (WFT). Our primary outcomes were the quintiles with the greatest annual cognitive decline for each test. Logistic regression models were adjusted for demographic (age, sex, race, field centre, education, income), lifestyle (smoking, drinking) and metabolic (adiposity, blood pressure, cholesterol) factors. RESULTS: The mean age was 56 years. Women accounted for 56% of the study population and 21% of the study population were black. The mean HbA(1c) was 5.7% overall: 8.5% in persons with and 5.5% in persons without diabetes. In adjusted logistic regression models, diagnosed diabetes was associated with cognitive decline on the DSST (OR 1.42, 95% CI 1.14-1.75, p = 0.002), but HbA(1c) was not a significant independent predictor of cognitive decline when stratifying by diabetes diagnosis (diabetes, p trend = 0.320; no diabetes, p trend = 0.566). Trends were not significant for the DWRT or WFT in either the presence or the absence of diabetes. CONCLUSIONS/INTERPRETATION: Hyperglycaemia, as measured by HbA(1c), did not add predictive power beyond diabetes status for 6 year cognitive decline in this middle-aged population. Additional work is needed to identify the non-glycaemic factors by which diabetes may contribute to cognitive decline.

Supervised machine learning and logistic regression identifies novel epistatic risk factors with PTPN22 for rheumatoid arthritis.

Investigating genetic interactions (epistasis) has proven difficult despite the recent advances of both laboratory methods and statistical developments. With no 'best' statistical approach available, combining several analytical methods may be optimal for detecting epistatic interactions. Using a multi-stage analysis that incorporated supervised machine learning and methods of association testing, we investigated epistatic interactions with a well-established genetic factor (PTPN22 1858T) in a complex autoimmune disease (rheumatoid arthritis (RA)). Our analysis consisted of four principal stages: Stage I (data reduction)-identifying candidate chromosomal regions in 292 affected sibling pairs, by predicting PTPN22 concordance using multipoint identity-by-descent probabilities and a supervised machine learning algorithm (Random Forests); Stage II (extension analysis)-testing detailed genetic data within candidate chromosomal regions for epistasis with PTPN22 1858T in 677 cases and 750 controls using logistic regression; Stage III (replication analysis)-confirmation of epistatic interactions in 947 cases and 1756 controls; Stage IV (combined analysis)-a pooled analysis including all 1624 RA cases and 2506 control subjects for final estimates of effect size. A total of seven replicating epistatic interactions were identified. SNP variants within CDH13, MYO3A, CEP72 and near WFDC1 showed significant evidence for interaction with PTPN22, affecting susceptibility to RA.

Constraints on changes in fundamental constants from a cosmologically distant OH absorber or emitter.

We have detected the four 18 cm OH lines from the z approximaetely 0.765 gravitational lens toward PMN J0134-0931. The 1612 and 1720 MHz lines are in conjugate absorption and emission, providing a laboratory to test the evolution of fundamental constants over a large lookback time. We compare the HI and OH main line absorption redshifts of the different components in the z approximately 0.765 absorber and the z approximately 0.685 lens toward B0218 + 357 to place stringent constraints on changes in F triple-bond g(p)[alpha(2)/mu](1.57). We obtain [DeltaF/F] = (0.44 +/- 0.36(stat) +/- 1.0(sys)t) x 10(-5), consistent with no evolution over the redshift range 0 < z < or = 0.7. The measurements have a 2sigma sensitivity of [Deltaalpha/alpha] < 6.7 x 10(-6) or [Deltamu/mu] < 1.4 x 10(-5) to fractional changes in alpha and mu over a period of approximately 6.5 G yr, half the age of the Universe. These are among the most sensitive constraints on changes in mu.

Layer-specific input to distinct cell types in layer 6 of monkey primary visual cortex.

Layer 6 of monkey V1 contains a physiologically and anatomically diverse population of excitatory pyramidal neurons. Distinctive arborization patterns of axons and dendrites within the functionally specialized cortical layers define eight types of layer 6 pyramidal neurons and suggest unique information processing roles for each cell type. To address how input sources contribute to cellular function, we examined the laminar sources of functional excitatory input onto individual layer 6 pyramidal neurons using scanning laser photostimulation. We find that excitatory input sources correlate with cell type. Class I neurons with axonal arbors selectively targeting magnocellular (M) recipient layer 4Calpha receive input from M-dominated layer 4B, whereas class I neurons whose axonal arbors target parvocellular (P) recipient layer 4Cbeta receive input from P-dominated layer 2/3. Surprisingly, these neuronal types do not differ significantly in the inputs they receive directly from layers 4Calpha or 4Cbeta. Class II cells, which lack dense axonal arbors within layer 4C, receive excitatory input from layers targeted by their local axons. Specifically, type IIA cells project axons to and receive input from the deep but not superficial layers. Type IIB neurons project to and receive input from the deepest and most superficial, but not middle layers. Type IIC neurons arborize throughout the cortical layers and tend to receive inputs from all cortical layers. These observations have implications for the functional roles of different layer 6 cell types in visual information processing.

Astronomical constraints on the cosmic evolution of the fine structure constant and possible quantum dimensions.

We present measurements of absorption by the 21 cm hyperfine transition of neutral hydrogen toward radio sources at substantial look-back times. These data are used in combination with observations of rotational transitions of common interstellar molecules to set limits on the evolution of the fine structure constant: alpha/ alpha<3.5x10(-15) yr(-1), to a look-back time of 4.8 Gyr. In the context of string theory, the limit on the secular evolution of the scale factor of the compact dimensions, R, is &Rdot/ R<10(-15) yr(-1). Including terrestrial and other astronomical measurements places 2sigma limits on slow oscillations of R from the present to the epoch of cosmic nucleosynthesis, just seconds after the big bang, of DeltaR /R<10(-5).

Salbutamol and the conditioning of latissimus dorsi for cardiomyoplasty.

BACKGROUND: Cardiomyoplasty is a new surgical alternative therapy for CHF. Although conditioning of muscle for cardiomyoplasty has a positive effect on fatigue resistance it also produces negative effects. In this study we assessed the effect of salbutamol, a beta2-agonist, on both the positive and the negative effects of conditioning. METHODS: In a control group of six animals one latissimus dorsi was subject to chronic, 1 Hz, low-frequency stimulation (CLFS) while the other served as a control. The experimental group of seven dogs received a continuous SC infusion of salbutamol and one latissimus dorsi was subjected to CLFS. The other muscle demonstrated the effects of salbutamol per se. After 42 days the animals were anesthetized and fatigue resistance, muscle mass, and mechanical properties of the muscles were evaluated. RESULTS: Salbutamol increased muscle mass, tetanic tension, and rate of rise and fall of tetanic tension. It diminished fatigue resistance and had no effect on shortening velocity. Chronic stimulation decreased muscle mass, tetanic tension, rate of rise and fall of tetanic tension, and muscle shortening velocity in both groups of dogs. Salbutamol diminished the declines in muscle mass, rate of tension development, and rate of muscle shortening due to CLFS, but did not change the effects of CLFS on tetanic tension and the rate of fall of tetanic tension. Salbutamol did not alter the increase in fatigue resistance induced by CLFS. CONCLUSIONS: The favorable effect of CLFS on fatigue resistance was unaffected by salbutamol. The unfavorable effects of CLFS on loss of muscle mass, rate of tension development, and decline in shortening velocity were partially blocked by salbutamol, improving the ability of the latissimus dorsi to augment cardiac systole.

The beta2-agonist salbutamol affects the expression of phospholamban and both isoforms of SERCA in canine skeletal muscle and blocks changes in these induced by neuromuscular stimulation.

Chronic administration of salbutamol induced expression of hybrid fibers in canine skeletal muscles. Fast-twitch fibers expressed SERCA2a (the slow-twitch isoform of sarcoplasmic reticulum Ca2+-ATPase) and slow-twitch fibers expressed SERCA1 (the fast-twitch isoform of the Ca2+-ATPase). The proportion of fibers that became hybrid increased from a small percentage in the control muscles to 30% in the predominantly fast-twitch latissimus dorsi and to 45% in the predominantly slow-twitch vastus intermedius. In contrast to this response by the SERCA genes the phospholamban gene response was muscle specific. The fraction of fibers that expressed phospholamban decreased slightly in the latissimus dorsi while increasing moderately in the vastus intermedius. The effects of chronic neurostimulation of the latissimus dorsi on SERCA1, SERCA2a and phospholamban levels were mostly blocked by salbutamol. While 100% of fibers from neurostimulated muscles expressed phospholamban, only 51% of the fibers from the neurostimulated and salbutamol-treated muscles expressed it. In the neurostimulated muscle, very few muscle fibers expressed SERCA1a while 61% of the fibers that received salbutamol expressed it, albeit as hybrid fibers. The levels of SERCA2a in response to these interventions were just the opposite. In the neurostimulated muscle 37.5% of fibers were hybrid and 62.5% expressed SERCA2a only. With co-administration of neurostimulation and salbutamol, 61.3% of fibers were hybrid and 38.7% expressed SERCA2a only.

Transcription rates of SERCA and phospholamban genes change in response to chronic stimulation of skeletal muscle.

Chronic low frequency stimulation of predominantly fast-twitch skeletal muscles decrease the levels of SERCA1 (fast-twitch sarco(endo)plasmic reticulum Ca2+-ATPase) mRNA, and increase the levels of SERCA2 (slow-twitch sarco(endo)plasmic reticulum Ca2+-ATPase) and phospholamban mRNAs. To assess the role of transcription in these changes in mRNA levels, nuclei were isolated from chronically stimulated canine latissimus dorsi muscles and transcription rates were estimated by nuclear run-on assays. Decreases in the rates of SERCA1 gene transcription matched the fall in its mRNA level and increases in the rates of SERCA2 and phospholamban gene transcription matched the increases in their mRNAs.

Oligomerization is an intrinsic property of calsequestrin in normal and transformed skeletal muscle.

In skeletal muscle fibers, the high-capacity medium-affinity Ca(2+)-binding protein calsequestrin functions as the major Ca(2+)-reservoir of the sarcoplasmic reticulum. To determine the oligomeric status of calsequestrin, immunoblotting of microsomal proteins following chemical crosslinking was performed. Diagonal non-reducing/reducing two-dimensional gel electrophoresis was employed to unequivocally differentiate between cross-linked species of 63 kDa calsequestrin and calsequestrin-like proteins of higher relative molecular mass. Since chronic low-frequency stimulation has a profound effect on the expression of many muscle-specific protein isoforms, we investigated normal and conditioned muscle fibers. Calsequestrin was found to exist in a wide range of high-molecular-mass clusters in normal and chronically stimulated skeletal muscle fibers. Hence, oligomerization is an intrinsic property of this important Ca(2+)-binding protein and does not appear to be influenced by the fast-to-slow transformation process. Although fiber-type specific differences exist in the physiology of the skeletal muscle Ca(2+)-regulatory system, oligomerization of calsequestrin seems to be essential for proper functioning.

Correlations between MyoD, myogenin, SERCA1, SERCA2 and phospholamban transcripts during transformation of type-II to type-I skeletal muscle fibers.

Canine latissimus dorsi, composed predominantly of fast-twitch muscle fibers, were subjected to chronic 1 Hz neuromuscular stimulation for periods up to 42 days to induce changes in gene expression. This produced down regulation of SERCA1 (fast-twitch isoform of sarco(endo)plasmic reticulum Ca2+-ATPase), a gene product of fast-twitch muscle, and up regulation fo SERCA2 (slow-twitch isoform of sarco(endo)plasmic reticulum Ca2+-ATPase) and phospholamban, products of genes expressed by slow-twitch muscles. To assess the involvement of MyoD and myogenin in the regulation of the expression of these genes their levels were measured during the stimulation period. The prompt, at 7 days, fall in SERCA1 mRNA preceded the fall in MyoD by about 7 days, suggesting that the decline in MyoD was not causally related to the decline in SERCA1. The prompt rise in SERCA2 mRNA at 7 days preceded the rise in myogenin by 14 days. The rise in myogenin at 21 days did correlate with the similar rise in phospholamban mRNA.

Fast- and slow-twitch isoforms (SERCA1 and SERCA2a) of sarcoplasmic reticulum Ca-ATPase are expressed simultaneously in chronically stimulated muscle fibers.

Using an immunohistochemical double-labeling technique, we observed that different isoforms of sarcoplasmic reticulum Ca-ATPase are co-expressed in single fibers of canine fast-twitch skeletal muscles stimulated chronically at low frequency. By 7 days of neuromuscular stimulation, the population of hybrid fibers expressing both SERCA1 and SERCA2a [fast- and slow-twitch isoforms of sarco(endo)plasmic reticulum Ca(2+)-ATPase] had increased from 1.5% to 9.2% of fibers. By 14 days of stimulation 90% of the pure fast-twitch fibers (expressing only SERCA1) were replaced by hybrid fibers. An additional 28 days of stimulation caused all fast-twitch fibers to express SERCA2a at the same level as found in nonstimulated slow-twitch fibers (expressing only SERCA2a). At this time, one-half of the previously hybrid fibers had become pure-slow-twitch fibers. The remaining one-half of the hybrid fibers expressed SERCA1 at a very low level. Extending stimulation to 70 days did not further change the percentage of fibers that were slow-twitch or hybrid. Immunoblot studies at the whole-muscle level confirmed that changes in SERCA expression at 42 days of neuromuscular stimulation were complete. Immunohistochemical analysis of longitudinal sections of muscle showed that the changes in SERCA protein were uniform along the length of the muscle fiber, indicating that nuclei along its length responded equally to chronic stimulation.

Induction of molecular and mechanical transformations in canine skeletal muscle by chronic neuromuscular stimulation.

The canine latissimus dorsi was stimulated at 1 Hz via the thoracodorsal nerve for 70 days. Seven days of muscle stimulation caused muscle mass, fibre cross-sectional areas, and tetanic tensions to decrease. Fourteen days of stimulation produced marked decreases in Ca(2+)-uptake rates in a membrane fraction containing sarcoplasmic reticulum. At this time there was a decline in fusion frequency, but no statistically significant changes in time-to-peak tension, total contraction times, or half-relaxation times. With 42 days of stimulation a switch from the fast-twitch to the slow-twitch phenotype was indicated by elevations in the levels of expression of the slow-twitch isoforms of sarco(endo)plasmic reticulum Ca(2+)-ATPase and myosin heavy chain-I, and increases in half-relaxation times, total contraction times and time-to-peak tensions. Decreases in muscle shortening velocity correlated negatively with increases in myosin heavy chain-I levels. Up-regulation of the slow-twitch isoforms of sarco(endo)plasmic reticulum Ca(2+)-ATPase increases in half-relaxation times. The changes in the slow-twitch isoform of sarco(endo)plasmic reticulum Ca(2+)-ATPase and myosin heavy chain-I levels indicated coordinate expression of these two proteins in chronically stimulated muscles.