North Florida/South Georgia Veterans Health System

Effective rehabilitative therapies are needed for patients with long-term deficits after stroke.In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks.At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], -0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, -0.14 points; 95% CI, -2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, -8.10 seconds; 95% CI, -13.61 to -2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported.In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.)

Because hemiinattention is most commonly caused by right parietal lesions, it is possible that the left hemisphere attends to contralateral stimuli whereas the right attends to both contralateral and ipsilateral stimuli. We gave lateralized visual stimuli to 12 normal subjects and recorded the electroencephalograms. Desynchronization was determined by comparing the alpha power 1 second before and 1 second after a lateralized visual stimulus. Although the left parietal lobe desynchronized most after right-sided stimuli, the right parietal lobe desynchronized equally after right or left stimuli. These findings support the hypothesis that the right hemisphere is dominant for attention.

Online support groups are expanding as the general public becomes more comfortable using computer-mediated communication technology. These support groups have certain benefits for users who may not be able to or do not have the desire to attend face-to-face sessions. Online support groups also present challenges when compared to traditional face-to-face group communication. Communication difficulties may arise resulting from lack of visual and aural cues found in traditional face-to-face communication. Online support groups have emerged within health care as a result of the need individuals have to know more about health conditions they are confronting. The proliferation of these online communities may provide an opportunity for health educators to reach target populations with specific messages. This paper reviews the development of health-related online support groups, examines research conducted within these communities, compares their utility with traditional support groups and discusses the implications of these groups for health education.

Abstract This paper is devoted to the development of a composite model of limb praxis processing that is supported by a series of dissociations noted in the performance of apraxic patients. These dissociations include die separability of praxis production from praxis reception, the selectivity of input modalities, an “assembled” route of praxis imitation, and the possible fragmentation of semantics into an action and a nonaction system.

The current paper provides a brief overview of research on the effects of race and ethnicity on pain. More specifically, the article reviews the utility of the concepts of race and ethnicity for pain research, suggests operational definitions of race and ethnicity, reviews the literature on the effects of race and ethnicity on laboratory and clinical pain, and provides suggestions for future research.

Artificial intelligence (AI) has shown promise for diagnosing prostate cancer in biopsies. However, results have been limited to individual studies, lacking validation in multinational settings. Competitions have been shown to be accelerators for medical imaging innovations, but their impact is hindered by lack of reproducibility and independent validation. With this in mind, we organized the PANDA challenge-the largest histopathology competition to date, joined by 1,290 developers-to catalyze development of reproducible AI algorithms for Gleason grading using 10,616 digitized prostate biopsies. We validated that a diverse set of submitted algorithms reached pathologist-level performance on independent cross-continental cohorts, fully blinded to the algorithm developers. On United States and European external validation sets, the algorithms achieved agreements of 0.862 (quadratically weighted κ, 95% confidence interval (CI), 0.840-0.884) and 0.868 (95% CI, 0.835-0.900) with expert uropathologists. Successful generalization across different patient populations, laboratories and reference standards, achieved by a variety of algorithmic approaches, warrants evaluating AI-based Gleason grading in prospective clinical trials.

Renal nitrogen metabolism primarily involves urea and ammonia metabolism, and is essential to normal health. Urea is the largest circulating pool of nitrogen, excluding nitrogen in circulating proteins, and its production changes in parallel to the degradation of dietary and endogenous proteins. In addition to serving as a way to excrete nitrogen, urea transport, mediated through specific urea transport proteins, mediates a central role in the urine concentrating mechanism. Renal ammonia excretion, although often considered only in the context of acid-base homeostasis, accounts for approximately 10% of total renal nitrogen excretion under basal conditions, but can increase substantially in a variety of clinical conditions. Because renal ammonia metabolism requires intrarenal ammoniagenesis from glutamine, changes in factors regulating renal ammonia metabolism can have important effects on glutamine in addition to nitrogen balance. This review covers aspects of protein metabolism and the control of the two major molecules involved in renal nitrogen excretion: urea and ammonia. Both urea and ammonia transport can be altered by glucocorticoids and hypokalemia, two conditions that also affect protein metabolism. Clinical conditions associated with altered urine concentrating ability or water homeostasis can result in changes in urea excretion and urea transporters. Clinical conditions associated with altered ammonia excretion can have important effects on nitrogen balance.

BACKGROUND: Effective communication of risks and benefits to patients is critical for shared decision making. PURPOSE: To review the comparative effectiveness of methods of communicating probabilistic information to patients that maximize their cognitive and behavioral outcomes. DATA SOURCES: PubMed (1966 to March 2014) and CINAHL, EMBASE, and the Cochrane Central Register of Controlled Trials (1966 to December 2011) using several keywords and structured terms. STUDY SELECTION: Prospective or cross-sectional studies that recruited patients or healthy volunteers and compared any method of communicating probabilistic information with another method. DATA EXTRACTION: Two independent reviewers extracted study characteristics and assessed risk of bias. DATA SYNTHESIS: Eighty-four articles, representing 91 unique studies, evaluated various methods of numerical and visual risk display across several risk scenarios and with diverse outcome measures. Studies showed that visual aids (icon arrays and bar graphs) improved patients' understanding and satisfaction. Presentations including absolute risk reductions were better than those including relative risk reductions for maximizing accuracy and seemed less likely than presentations with relative risk reductions to influence decisions to accept therapy. The presentation of numbers needed to treat reduced understanding. Comparative effects of presentations of frequencies (such as 1 in 5) versus event rates (percentages, such as 20%) were inconclusive. LIMITATION: Most studies were small and highly variable in terms of setting, context, and methods of administering interventions. CONCLUSION: Visual aids and absolute risk formats can improve patients' understanding of probabilistic information, whereas numbers needed to treat can lessen their understanding. Due to study heterogeneity, the superiority of any single method for conveying probabilistic information is not established, but there are several good options to help clinicians communicate with patients. PRIMARY FUNDING SOURCE: None.

Automaticity is a hallmark feature of walking in adults who are healthy and well-functioning. In the context of walking, "automaticity" refers to the ability of the nervous system to successfully control typical steady state walking with minimal use of attention-demanding executive control resources. Converging lines of evidence indicate that walking deficits and disorders are characterized in part by a shift in the locomotor control strategy from healthy automaticity to compensatory executive control. This is potentially detrimental to walking performance, as an executive control strategy is not optimized for locomotor control. Furthermore, it places excessive demands on a limited pool of executive reserves. The result is compromised ability to perform basic and complex walking tasks and heightened risk for adverse mobility outcomes including falls. Strategies for rehabilitation of automaticity are not well defined, which is due to both a lack of systematic research into the causes of impaired automaticity and to a lack of robust neurophysiological assessments by which to gauge automaticity. These gaps in knowledge are concerning given the serious functional implications of compromised automaticity. Therefore, the objective of this article is to advance the science of automaticity of walking by consolidating evidence and identifying gaps in knowledge regarding: (a) functional significance of automaticity; (b) neurophysiology of automaticity;

Through a community-driven competition, the PANDA challenge provides a curated diverse dataset and a catalog of models for prostate cancer pathology, and represents a blueprint for evaluating AI algorithms in digital pathology.Artificial intelligence (AI) has shown promise for diagnosing prostate cancer in biopsies. However, results have been limited to individual studies, lacking validation in multinational settings. Competitions have been shown to be accelerators for medical imaging innovations, but their impact is hindered by lack of reproducibility and independent validation. With this in mind, we organized the PANDA challenge-the largest histopathology competition to date, joined by 1,290 developers-to catalyze development of reproducible AI algorithms for Gleason grading using 10,616 digitized prostate biopsies. We validated that a diverse set of submitted algorithms reached pathologist-level performance on independent cross-continental cohorts, fully blinded to the algorithm developers. On United States and European external validation sets, the algorithms achieved agreements of 0.862 (quadratically weighted kappa, 95% confidence interval (CI), 0.840-0.884) and 0.868 (95% CI, 0.835-0.900) with expert uropathologists. Successful generalization across different patient populations, laboratories and reference standards, achieved by a variety of algorithmic approaches, warrants evaluating AI-based Gleason grading in prospective clinical trials.

Patients with hemispatial neglect perform activities poorly in the hemispace contralateral to the lesion. We postulate that hemispatial neglect induced by right hemisphere lesions may be associated with a directional hypokinesia: initiation of movements toward the hemispace contralateral to the lesion is affected more than movements toward the lesion. We tested 6 patients with hemispatial neglect caused by right hemisphere damage, 7 with left hemisphere damage and no neglect, and 12 controls. Patients with left hemispatial neglect initiated responses to left hemispace more slowly than toward right hemispace.

The major murine systemic lupus erythematosus (SLE) susceptibility locus Sle1 is syntenic to a chromosomal region linked with SLE susceptibility in multiple human studies. Congenic analyses have shown that Sle1 breaks tolerance to chromatin, a necessary step for full disease induction that can be suppressed by specific modifier loci. In the present study, our fine mapping analysis of the location of Sle1 has determined that three loci within this congenic interval, termed Sle1a, Sle1b, and Sle1c, can independently cause a loss of tolerance to chromatin. Each displays a distinctive profile of serological and cellular characteristics, with T and B cell functions being more affected by Sle1a and Sle1b, respectively. The epistatic interactions of Sle1 with other susceptibility loci to cause severe nephritis cannot be accounted, however, by these three loci alone, suggesting the existence of an additional locus, termed Sle1d. These findings indicate that the potent autoimmune phenotype caused by the Sle1 genomic interval reflects the combined impact of four, separate, susceptibility genes. This level of genetic complexity, combined with similar findings in other systems, supports the possibility that many complex trait loci reflect the impact of polymorphisms in linked clusters of genes with related functions.

BACKGROUND AND PURPOSE: Residual disability after stroke presents a major economic and humanistic burden. To quantify disability in patients, activities of daily living (ADL; Barthel Index [BI], and motor component of Functional Independence Measure [M-FIM]) and categorical disability measures (Modified Rankin Scale [MRS]) are used. The purpose of this study is to examine the predicting ability of ADL measures to global disability scale. METHODS: Kansas City Stroke Study data were used for the present study. Correlation coefficient, Kruskal-Wallis test, and polytomous logistic regression analysis were applied to examine the relationship between the ADL measure and global disability scale. Model fit statistics were examined to verify logistic regression appropriateness. A categorization scheme, which minimized the false-positive response rate, was selected as the optimal categorizing system. RESULTS: The 3 measures were highly correlated. Both BI and M-FIM differentiated disability better in lower than higher disability. In logistic regression, BI differentiated 4 disability levels; M-FIM differentiated 3 levels in MRS. However, on the basis of results of the Kruskal-Wallis and multiple comparison tests, we suspect that M-FIM may have the potential to predict MRS categories better with a different model. CONCLUSIONS: The proposed categorization scheme can serve as a translation between measures. However, because of the ceiling effect of BI and M-FIM, the translation could not be completed for all 6 levels of MRS. No apparent variation over time in the categorization scheme was observed. Further research needs to be conducted to develop better prediction models explaining the relationship between M-FIM and MRS.

BACKGROUND: For clinical trials in stroke rehabilitation, self-selected walking speed has been used to stratify persons to predict functional walking status and to define clinical meaningfulness of changes. However, this stratification was validated primarily using self-report questionnaires. OBJECTIVE: This study aims to validate the speed-based classification system with quantitative measures of walking performance. METHODS: A total of 59 individuals who had hemiparesis for more than 6 months after stroke participated in this study. Spatiotemporal and kinetic measures included the percentage of total propulsion generated by the paretic leg (Pp), the percentage of the stride length accounted for by the paretic leg step length (PSR), and the percentage of the gait cycle spent in paretic preswing (PPS). Additional measures included the synergy portion of the Fugl-Meyer Assessment and the average number of steps/day in the home and community measured with a step activity monitor. Participants were stratified by self-selected gait speed into 3 groups: household (<0.4 m/s), limited community (0.4-0.8 m/s), and community (>0.8 m/s) ambulators. Group differences were analyzed using a Kruskal-Wallis H test with rank sums test post hoc analyses. RESULTS: Analyses demonstrated a main effect in all measures, but only steps/day and PPS demonstrated a significant difference between all 3 groups. CONCLUSIONS: Classifying individuals poststroke by self-selected walking speed is associated with home and community-based walking behavior as quantified by daily step counts. In addition, PPS distinguishes all 3 groups. Pp differentiates the moderate from the fast groups and may represent a contribution to mechanisms of increasing walking speed. Speed classification presents a useful yet simple mechanism to stratify subjects poststroke and may be mechanically linked to changes in PPS.

BACKGROUND: Excess iron has been implicated in cancer risk through increased iron-catalyzed free radical-mediated oxidative stress. METHODS: A multicenter randomized, controlled, single-blinded clinical trial (VA Cooperative Study #410) tested the hypothesis that reducing iron stores by phlebotomy would influence vascular outcomes in patients with peripheral arterial disease. Patients without a visceral malignancy in the last 5 years (n = 1277) were randomly assigned to control (n = 641) or iron reduction (n = 636). Occurrence of new visceral malignancy and cause-specific mortality data were collected prospectively. Cancer and mortality outcomes in the two arms were compared using intent-to-treat analysis with a Cox proportional hazards regression model. Statistical tests were two-sided. RESULTS: Patients were followed up for an average of 4.5 years. Ferritin levels were similar in both groups at baseline but were lower in iron reduction patients than control patients across all 6-month visits (mean = 79.7 ng/mL, 95% confidence interval [CI] = 73.8 to 85.5 ng/mL vs 122.5 ng/mL, 95% CI = 115.5 to 129.5 ng/mL; P < .001). Risk of new visceral malignancy was lower in the iron reduction group than in the control group (38 vs 60, hazard ratio [HR] = 0.65, 95% CI = 0.43 to 0.97; P = .036), and, among patients with new cancers, those in the iron reduction group had lower cancer-specific and all-cause mortality (HR = 0.39, 95% CI = 0.21 to 0.72; P = .003; and HR = 0.49, 95% CI = 0.29 to 0.83; P = .009, respectively) than those in the control group. Mean ferritin levels across all 6-monthly visits were similar in patients in the iron reduction and control groups who developed cancer but were lower among all patients who did not develop cancer than among those who did (76.4 ng/mL, 95% CI = 71.4 to 81.4 ng/mL, vs 127.1 ng/mL, 95% CI = 71.2 to 183.0 ng/mL; P = .017). CONCLUSIONS: Iron reduction was associated with lower cancer risk and mortality. Further studies are needed to define the role of body iron in cancer risk.

OBJECTIVE: The purpose of this pilot study was to test constraint-induced movement therapy for chronic upper-limb stroke hemiparesis and to investigate the neural correlates of recovery with functional magnetic resonance imaging (MRI) in two subjects. Both subjects had been discharged from traditional therapy because no further improvement was anticipated. DESIGN: Constraint-induced movement therapy consisted of 6 hr of daily upper-limb training for 2 wk; a restrictive mitt was worn on the nonparetic limb during waking hours. Functional MRI was performed on a 1.5-T MRI with echo-planar imaging; at the same time, the subjects attempted sequential finger-tapping. RESULTS: Compared with baseline, performance time improved an average of 24% immediately after training and also continued to improve up to 33% 3 mo after training. Lift, grip strength, and Motor Activity Log scores likewise improved. Initially, on functional MRI, subject 1 activated scattered regions in the ipsilateral posterior parietal and occipital cortices. Subject 2 showed almost no areas of significant activation. After training, subject 1 showed activity bordering the lesion, bilateral activation in the association motor cortices, and ipsilateral activation in the primary motor cortex. Subject 2 showed activation near the lesion site. CONCLUSION: Constraint-induced movement therapy produced significant functional improvement and resulted in plasticity as demonstrated by functional MRI.

OBJECTIVE: Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA. METHODS: We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. RESULTS: One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. INTERPRETATION: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225.

The plasma potassium level is normally maintained within narrow limits by multiple mechanisms. This article reviews the mechanisms that regulate potassium homeostasis and describes the important role that the circadian clock exerts on these processes.

Increased consumption of fructose may play an important role in the epidemic of metabolic syndrome and may presage the development of diabetes, cardiovascular disease, and chronic kidney disease. Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through xanthine oxidoreductase (XOR). This study aimed to examine the direct effects of fructose in human kidney proximal tubular cells (HK-2) and whether they are mediated by the fructose metabolism via KHK. At a similar concentration to that observed in peripheral blood after a meal, fructose induced production of monocyte chemotactic protein 1 (MCP-1) and reactive oxygen species in HK-2 cells. Knockdown of KHK by stable transfection with small hairpin RNA demonstrated that these processes were KHK dependent. Several antioxidants, including specific inhibitors of NADPH oxidase and XOR, prevented MCP-1 secretion. We detected XOR mRNA in HK-2 cells and confirmed its activity by identifying uric acid by mass spectrometry. Fructose increased intracellular uric acid, and uric acid induced production of MCP-1 as well. In summary, postprandial concentrations of fructose stimulate redox- and urate-dependent inflammatory mediators in proximal tubular cells.

Previous experiments found that placebos produced small decreases in neural activity of pain-related areas of the brain, yet decreases were only statistically significant after termination of stimuli and in proximity to when subjects rated them. These changes could reflect report bias rather than analgesia. This functional magnetic resonance imaging (fMRI) study examined whether placebo analgesia is accompanied by reductions in neural activity in pain-related areas of the brain during the time of stimulation. Brain activity of irritable bowel syndrome patients was measured in response to rectal distension by a balloon barostat. Large reductions in pain and in brain activation within pain-related regions (thalamus, somatosensory cortices, insula, and anterior cingulate cortex) occurred during the placebo condition. Results indicate that decreases in activity were related to placebo suggestion and a second factor (habituation/attention/conditioning). Although many factors influence placebo analgesia, it is accompanied by reduction in pain processing within the brain in clinically relevant conditions.