EMPOWER-H (Engaging and Motivating Patients Online With Enhanced Resources-Hypertension) is a personalized-care model facilitating engagement in hypertension self-management utilizing an interactive Web-based disease management system integrated with the electronic health record. The model is designed to support timely patient-provider interaction by incorporating decision support technology to individualize care and provide personalized feedback for patients with chronic disease. Central to this process were patient-generated health data, including blood pressure (BP), weight, and lifestyle behaviors, which were uploaded using a smartphone.The aim of this study was to evaluate the program among patients within primary care already under management for hypertension and with uncontrolled BP.Using a 6-month pre-post design, outcome measures included office-measured and home-monitored BP, office-measured weight, intervention contacts, diet, physical activity, smoking, knowledge, and health-related quality of life.P<.001) and 86.0% achieved clinically meaningful reduction in office BP (reduction in systolic BP [SBP] ≥5 mm Hg or diastolic BP [DBP] ≥3 mm Hg). At baseline, 25.2% of participants met home BP goals (<135/85 mm Hg), and this percentage significantly increased to 71.4% (P<.001) at 6 months. EMPOWER-H also significantly reduced both office and home SBP and DBP, decreased office-measured weight and consumption of high-salt and high-fat foods , and increased intake of fruit and vegetables, minutes of aerobic exercise, and hypertension knowledge . Patients with higher home BP upload frequencies had significantly higher odds of achieving home BP goals. Patients receiving more total intervention, behavioral, pharmaceutical contacts had significantly lower odds of achieving home BP goals but higher improvements in office BP .At 6 months, 55.9% of participants (N=149) achieved office BP goals (<140/90 mm Hg; EMPOWER-H significantly improved participants’ office-measured and home-monitored BP, weight, and lifestyle behaviors, suggesting that technologically enabled BP home-monitoring, with structured use of patient-generated health data and a personalized care-plan facilitating patient engagement, can support effective clinical management. The experience gained in this study provides support for the feasibility and value of using carefully managed patient-generated health data in the day-to-day clinical management of patients with chronic conditions. A large-scale, real-world study to evaluate sustained effectiveness, cost-effectiveness, and scalability is warranted. Hypertension is a major risk factor for cardiovascular disease (CVD), with an estimated annual cost of US $46 billion in the United States ,2. In naHealth policies have begun to shift away from episodic management of individual patients toward managing and paying for ongoing health care services that drive engagement and achieve valuable outcomes for groups of patients . PopulatThe Engaging and Motivating Patients Online With Enhanced Resources (EMPOWER) program is an innovative care delivery model for chronic disease management utilizing an interactive Web-based system integrated with the electronic health record (EHR). The model is designed to support timely patient-provider interaction by incorporating decision support technology to individualize care. The program also supports patient self-management and engagement by providing real-time feedback on progress against clinical goals to facilitate care-plan engagement. The model is designed to be generalizable to any chronic condition where behavior change has a direct impact on health outcomes. In this pilot study, we sought to evaluate the EMPOWER-Hypertension (EMPOWER-H) program among patients with uncontrolled BP in the context of primary care, using data from home BP monitoring as a major input to clinical decision making.We evaluated the EMPOWER-H intervention using a pre-post design. An institutional review board of Palo Alto Medical Foundation (PAMF), an affiliate of Sutter Health, approved the study. All participants provided written informed consent.Participants were recruited (March 2012 to June 2012) from two clinical sites at PAMF, a large ambulatory health care system. Patients were eligible to participate in the pilot study if they were in the age range of 35 to 75 years, had uncontrolled BP, and had been treated within PAMF during the previous 6 months. Participants were considered to have uncontrolled BP if (1) the average of 2 BP readings taken within 6 months of the study start date and separated by at least 2 weeks was 140 mm Hg to 175 mm Hg for SBP or 90 mm Hg to 110 mm Hg for DBP or both and (2) BP was within this same range when taken by the research staff during an in-person baseline visit. Exclusion criteria included having serious medical conditions , requiring management of psychiatric issues, being under primary care management for a diagnosis of hypertension for less than 6 months, participating in other research projects, or having special life circumstances . Of the 1467 patients contacted for recruitment, 527 patients declined participation, 142 were ineligible, 584 were not contactable or nonresponsive, 62 were interested but not enrolled as the study reached full enrollment before their initial study visit, and 3 consented but did not complete baseline home BP measurement or nurse care managers’ (NCMs) visit (first in-person intervention visit). This process yielded the target enrollment of 149 eligible and consenting participants .Recruitment began by querying the EHR to identify patients who met the inclusion criteria. Upon identification, a clinical study coordinator conducted chart reviews to verify BP readings during the previous 6 months, as well as other exclusion criteria. A list of potentially eligible patients was provided to primary care physicians (PCPs) for final approval. After approval, PCPs contacted their eligible patients either via a secure Web-based patient portal  message, or by letter and encouraged them to participate in the study. The Web-based patient portal is an integral part of the PAMF EHR. Patients can log in to message their medical providers, view lab results, and receive information about appointments. The initial communication included instructions on accessing the study enrollment site where the patient could read a description of the study, provide consent online, complete a self-screening questionnaire  and, if eligible, complete a baseline questionnaire.For patients who were eligible per the initial Web-based screening, trained research staff arranged an in-person baseline visit where written consent was attained, and BP was measured in the office using the patient’s home BP monitor according to standardized protocols  to confiEMPOWER-H was a 6-month intervention delivered by a care team, including 2 NCMs, a registered dietitian (RD), and a pharmacist for consultation. The intervention was based on theoretical constructs such as perceived severity of a health threat; relevant values; self-efficacy; perceived barriers to action, as described in the theory of planned behavior ; health At the baseline visit, research staff provided eligible patients with their study tools as described above, including the BP monitor with appropriate sized cuff, a pedometer, and a smartphone, along with instructions for use. Research staff also introduced patients to their personal dashboard and provided educational handouts and actions to take in case of very high or very low BP measurements. Patients were instructed to measure and upload BP readings in the morning and evening at regular times or events  for at least 3 days a week over the following 7 days (baseline home BP monitoring) and to continue the same pattern of uploading during the entire 6-month intervention. They were also encouraged to use their pedometer and upload daily step count. A scale that allowed wireless upload of weight was provided to selected patients at a later visit, based on clinical indications determined by an RD.Participants had a first in-person visit with an NCM as soon as possible after the 7-day baseline home BP collection period. This visit included the following activities: (1) addressing participants’ questions; (2) providing education about cardiovascular risks; (3) reviewing how to use study tools; (4) setting 2 to 3 small attainable goals utilizing motivational interviewing techniques; (5) visiting the Web-based dashboard, entering the personalized goals, and showing patients how to enter and view their data; and (6) developing a personalized BP management plan  informed by the 7-day baseline home BP. Home BP goals were set at American Heart Association’s (AHA) recommended levels of <135 mm Hg for SBP and <85 mm Hg for DBP . The NCMThe NCM contacted each patient via EHR secure messaging or telephone or both as soon as possible 1 week after the first visit to assess engagement, challenges with both the technology and clinical management, as well as to check BP control and modify the BP management plan if needed.During the 6-month intervention, patients were monitored daily using a provider dashboard which used both a 14-day average of home BP data and frequency of BP uploading (as a measure of engagement) to prioritize patients into high-risk (red), medium-risk (yellow), or low-risk (green) category . The dasAn NCM or RD had a library of Web-based education handouts and feedback message nuggets  that could be sent via secure messaging on the Web-based patient portal throughout the intervention. NCMs and RD primarily used secure messaging to provide regular pertinent electronic messages and timely feedback about participants’ clinical variables . In addition to these Web-based learning opportunities, participants were invited to participate in other engagement activities throughout the intervention, including healthy shopping tours and cooking classes at a grocery store, educational and interactive webinars on behavioral change, a pedometer challenge, and a healthy recipe challenge.The 149 enrolled participants were assessed at baseline and 147 (98.7%) were assessed at 6 months . All outWe assessed the effectiveness of the intervention using BP measurements taken in the office by trained research staff (office BP) and taken at home by the patient (home BP) as part of self-monitoring for the intervention. Office BP was measured by trained research staff according to standardized protocols . The priOther secondary outcomes included number of participants meeting weekly home BP monitoring frequency target (upload twice a day and 3 days in a week), body mass index (BMI), weight, dietary intake, physical activity, smoking status, hypertension knowledge, as well as health-related quality of life (HRQoL). Home-monitored BP data were extracted from the EHR that pulled data from the Numera database. Indicators of dietary intake included frequency of consuming fruit and vegetables, high-salt food, and high-fat food measured by scales adapted from the validated Block food screeners ,26. PhysIndicators of engagement in the intervention included total number of times patients uploaded BP measurement, pedometer step data, weight, stress , and medication  to the Numera and EMPOWER-H apps. Other indicators of intervention engagement included participation in 6 additional activities designed to support education and motivation .In addition, we tracked the number of intervention contacts .Participant activation was measured by the 13-item Patient Activation Measure (PAM) assessing patient’s knowledge, skill, and confidence for self-management ,33. PAM t tests for continuous outcomes and McNemar tests on paired proportions for categorical outcomes. McNemar exact tests were performed for the outcomes with small counts within certain categories . We used mixed model growth curve analysis for all available home-monitored BP during the study period and plotted the results according to time. We analyzed SBP and DBP as an outcome in two separate models; each included random intercept and random and fixed effects of slope and quadratic term of days from start. The quadratic term of days was removed in the final model for both home-monitored SBP and DBP because it was not significant. We used logistic regression and regression models to examine the bivariate associations of indicators of intervention engagement with the categorical and continuous BP outcomes, respectively.To examine our primary outcome, we used a one sample proportion test to compare the percentage of participants achieving office BP goals (<140 mm Hg for SBP and <90 mm Hg for DBP) at 6 months with the 0% who were meeting goals at baseline. As supplementary analyses, we compared the percentage of participants achieving office BP goals at 6 months with the percentage of patients who achieved normal BP with usual care alone in the same clinics during a similar period (30%). Frequencies and percentages were calculated for categorical variables, and means and standard deviations (SD) were calculated for continuous variables. Study outcomes at baseline and 6 months were compared using paired P<.05 (two-tailed). We powered this study on the primary outcome of percentage of participants achieving office BP goals (<140 mm Hg for SBP and <90 mm Hg for DBP) at 6 months. A sample of 149 had 80% power to detect at least 40% of participants achieving office BP goals at 6 months at alpha=.05 (two-sided), assuming at least 90% retention at 6 months based on our prior experiences. We based our estimates on the 30% transition rate from abnormal BP to normal BP without intervention using patient data from our EHR assessed from 2009 to 2010.All analyses were conducted in Statistical Analysis System (SAS) version 9.3 (SAS Institute Inc). Statistical significance was set at 2, SBP was 149.8 (9.8) mm Hg, DBP was 91.0 (8.0) mm Hg, and PAM score was 43.1 (6.1).Participants had a mean (SD) age of 62.2 (9.5) years, 51% were female, 73% were married or lived with partner, and 76% were non-Hispanic white . Most paP<.001). Additionally, this was also significantly higher than 30%, which was achieved with usual care alone based on 2009-2010 patient data in EHR (P<.001). Paired t test results show that mean (SD) systolic office BP was significantly reduced from 149.8 (9.8) to 134.4 (14.0) mm Hg and mean (SD) diastolic office BP from 91.0 (8.0) to 84.5 (8.6) mm Hg (both P<.001). At 6 months, 86% of participants achieved clinically meaningful reduction in office BP (reduction in SBP ≥5 mm Hg or reduction in SBP ≥3 mm Hg).P<.001), with a mean (SD) reduction of 11.7 (11.5) mm Hg for systolic and 6.1 (6.5) mm Hg for diastolic home BP . Of 132 participants with both baseline and 6-month home BP measurements, 27 (20%) started and stayed within the home BP goal at 6 months, 67 (51%) were not at goal at baseline and were meeting goal at 6 months, 6 (5%) started within goal but were above goal at 6 months, and 32 (24%) started and stayed outside goal at 6 months (data not shown). Comparison between office and home BP shows that change in office and home BP at 6 months was significantly correlated .Home-monitored BP measurements show that percent of participants achieving home BP goals (<135 mm Hg for SBP and <85 mm Hg for DBP) significantly increased from 25.2% to 71.4% Compared with baseline, participants’ BMI and body weight were significantly reduced (P=.01) and reduced consumption frequency of high-salt and high-fat foods , whereas minutes of stretching or strengthening remained the same (P=.91). Participants’ hypertension knowledge also significantly improved (P<.001); however, smoking status and HRQoL measured by VR-12 remained unchanged  of participants did at least one of the 6 additional activities designed to support sustained program engagement . None of the intervention engagement measures  were associated with achieving office BP goals or clinically meaningful office BP improvement at 6 months . HoweverP=.02); however, a higher number of total intervention, behavioral, pharmaceutical contacts were significantly associated with lower odds of achieving home BP goals . None of the intervention engagement measures was associated with improvements in values of home BP.The number of participants meeting home BP monitoring frequency target (uploading twice a day and 3 days in a week) gradually decreased during the course of the intervention . Table 5Additionally, none of the office and home BP outcomes were associated with baseline and change in participant activation, as measured by the PAM score (data not shown).This pre-post pilot study evaluated the EMPOWER-H program, a new personalized care delivery model utilizing an interactive Web-based disease management system integrated with the EHR for hypertension management. Compared with baseline, participants significantly reduced office-measured and home-monitored BP at 6 months, with 55.9% of the participants achieving office BP goals, 71.4% achieving home BP goals, and 86.0% achieving clinically meaningful reduction in office BP. The EMPOWER-H program also significantly decreased participants’ body weight; increased consumption frequency of fruit and vegetables, minutes of aerobic exercise, and knowledge; and reduced consumption frequency of high-salt and high-fat foods.The findings of this study are consistent with previous studies showing that technology-assisted clinical tools and approaches hold great promise in improving the quality of hypertension management in the real world. The EMPOWER-H program led to a greater or similar reduction in systolic and diastolic office BP at 6 months compared with the amount of within-group reductions at 6 or 12 months achieved in previous information technology-supported interventions in primary care settings -39. The The number of intervention contacts showed contrasting associations for office and home BP outcomes. Greater improvement in systolic or diastolic office BP was significantly associated with more intervention contacts, reflecting higher levels of clinical management. In contrast, higher odds of achieving home BP goals were significantly associated with fewer intervention contacts, reflecting lower levels of clinical management. We hypothesize that these results may be because of the clinical management challenges of different subsets of patients. Observation identified that some patients were highly motivated and able to meet their home BP goals independently, using their home BP data and adjustments in personal behavior. Other patients were less motivated, requiring significant clinical attention and more intervention contacts but achieving only moderate improvement in BP as manifested in office BP results. The contrasting results may also be partially explained by changes in the need for intervention contact over time, with more contacts needed in the beginning of the study and less contacts needed once some improvement was seen in home BP values.Technology-assisted interventions in primary care are well aligned with a population health management strategy. About 90% of the American adults with poorly controlled hypertension have health insurance coverage and have received health care in the past year , suggestHowever, a number of barriers to wider use exist, and this study provides some insight into how these barriers may be overcome. In this study, whereas the primary outcome measure was office-measured BP, home-monitored values became the primary metric for day-to-day clinical management decisions. Using AHA recommended normal levels for home-monitored BP values provided clinical validity. The fact that patients could not alter the BP measurements allowed practitioners to build trust in the data over time. In addition, regular uploads showing patterns of BP changes, including insights to BP variability by time-of-day , presented new opportunities for personalized management. Although it is accepted that targets for home-monitored BP are lower than office-measured BP targets ,45, therThe EMPOWER-H technology can be categorized as a population health software system. These systems are of increasing importance to health providers and payers to support the delivery of value-based care. A diverse range of information systems have been identified as supporting population health and subcategorization based on differentiation of features , and funOur study has some methodological limitations such as small sample size, short intervention and follow-up duration, and lack of a control group. Furthermore, this study used a pre-post design, making it hard to discern whether the observed significant improvements were because of the EMPOWER-H intervention or the usual care treatments. Previous randomized controlled trials evaluated the primary care–based interventions that achieved less or similar amount of reduction in systolic and diastolic office BP compared with EMPOWER-H against a usual care condition -39. The Future studies are needed to answer the following questions: (1) What are the long-term effects of this kind of information technology–assisted interventions on clinical outcomes? (2) How could the approaches be further integrated into standard clinic workflows and the EHR, potentially relying more on patient-generated health data for routine care and reducing the need for office visits? (3) How could the approaches be automated , supporting patients to effectively self-manage their condition with lifestyle changes, to allow cost savings, and further transfer to the whole health care system at a scalable level? (4) How can these methods be applied to other clinical situations ? and (5) What is the cost-effectiveness and economic sustainability of such interventions when delivered at large scale?This study demonstrates that a Web-based system for BP management, with a focus on home BP monitoring driving personalized feedback and care-plan engagement, can be integrated with the EHR and can improve BP among adult patients with poorly controlled hypertension. Furthermore, this study provides insight to the feasibility and value of using patient-generated health data in the day-to-day management of chronic conditions. Questions about generalizability, scalability, and economic sustainability remain, and therefore, a large-scale pragmatic study with a longer follow-up period is warranted. If future studies show that these questions can be addressed, the program has the potential for widespread positive impact through implementation in primary care settings.


Anhedonia, the reduced ability to experience pleasure in response to otherwise rewarding stimuli, is a core symptom of major depressive disorder (MDD). Although the posterior ventromedial prefrontal cortex (pVMPFC) and its functional connections have been consistently implicated in MDD, their roles in anhedonia remain poorly understood. Furthermore, it is unknown whether anhedonia is primarily associated with intrinsic ‘resting-state' pVMPFC functional connectivity or an inability to modulate connectivity in a context-specific manner. To address these gaps, a pVMPFC region of interest was first identified using activation likelihood estimation meta-analysis. pVMPFC connectivity was then examined in relation to anhedonia and general distress symptoms of depression, using both resting-state and task-based functional magnetic resonance imaging involving pleasant music, in current MDD and healthy control groups. In MDD, pVMPFC connectivity was negatively correlated with anhedonia but not general distress during music listening in key reward- and emotion-processing regions, including nucleus accumbens, ventral tegmental area/substantia nigra, orbitofrontal cortex and insula, as well as fronto-temporal regions involved in tracking complex sound sequences, including middle temporal gyrus and inferior frontal gyrus. No such dissociations were observed in the healthy controls, and resting-state pVMPFC connectivity did not dissociate anhedonia from general distress in either group. Our findings demonstrate that anhedonia in MDD is associated with context-specific deficits in pVMPFC connectivity with the mesolimbic reward system when encountering pleasurable stimuli, rather than a static deficit in intrinsic resting-state connectivity. Critically, identification of functional circuits associated with anhedonia better characterizes MDD heterogeneity and may help track of one of its core symptoms. Our primary goal was to investigate the specificity of neurofunctional pathways associated with anhedonia by conducting differential circuit analysis with task-based and resting-state functional magnetic resonance imaging (fMRI) in individuals with MDD. Our second goal was to examine whether connectivity patterns related to anhedonia are specific to distinct anatomical ventromedial prefrontal cortex (VMPFC) subregions. A third goal of this study was to investigate whether anhedonia-specific pathways observed in MDD are also present in healthy controls.Little is known about the neural underpinnings of individual symptoms of major depressive disorder (MDD), such as anhedonia, as the disorder has been primarily examined as a unitary construct. However, the research domain criteria framework highlights the growing recognition that complex psychiatric disorders such as MDD need to be more fully characterized by identifying potentially distinct neurobiological mechanisms associated with individual symptom clusters.3 Recent estimates suggest that approximately 37% of individuals with MDD experience clinically significant anhedonia.4 Anhedonia involves specific impairments in motivation and reward-based decision-making,6 and is linked to abnormal activity in the brain regions important for reward processing.9 Anhedonia is also a predictor of poor treatment response in MDD,10 and is especially difficult to treat both pharmacologically and psychosocially.19 Given the significance of anhedonia in MDD and its relationship with reward-processing deficits, it is critical to identify the brain regions and functional circuits that are specifically associated with this symptom in affected individuals.A clinical diagnosis of MDD requires the presence of at least one of two symptoms: depressed mood and anhedonia, defined as diminished interest or pleasure in response to rewarding stimuli.22 Furthermore, the posterior VMPFC (pVMPFC) has been consistenty implicated in MDD in previous neuroimaging studies,27 as well as findings from psychopharmacology,28 psychotherapy29 and deep-brain stimulation treatments.31 Indeed, the pVMPFC is thought to be central to the pathophysiology of depression.32 However, the unique effects of anhedonia on the pVMPFC circuits are currently unknown.There have been relatively few neuroimaging studies examining anhedonia in MDD and fewer still have disentangled anhedonia from depression severity. Emerging evidence suggests that anhedonia is characterized by reduced activity in subcortical and ventromedial prefrontal cortex regions involved in reward processing and monitoring.34 In addition, the pVMPFC has connections to limbic structures that are central to emotion-processing and hypothalamic regions that modulate autonomic reactivity.33 The animal models of depression have shown that optogenetic stimulation of medial prefrontal cortex cells that terminate in the NAc elicits antidepressant effects in mice,35 and these tracks are implicated in appetitive conditioning and reward-related hedonic behavior.36 To date, however, no study has examined the functional connectivity of this network in humans or determined whether its dysfunction is related to individual MDD symptoms. Furthermore, a critical question that has not yet been addressed is whether specific clinical symptoms are associated with intrinsic resting-state brain connectivity or an inability to modulate brain responses in a context-specific manner.Understanding the pathophysiology of psychiatric disorders such as MDD requires better characterization of underlying task-modulated and intrinsic resting-state functional circuits. A network of brain regions that includes the pVMPFC, specifically its BA25/32pl subdivision, is particularly relevant to MDD. Anatomical tracing studies have identified pVMPFC projections to regions in the mesolimbic reward system, including the nucleus accumbens (NAc).41 Thus, it is unknown whether anhedonia in MDD is related to aberrant intrinsic (resting-state) functional circuits or an inability to engage reward- and emotion-related networks in a contextually appropriate manner. It is also unknown whether such deficits are specific to anhedonia, rather than general depressive symptoms. Here, we investigate the relationship of anhedonia with task-modulated and resting-state pVMPFC connectivity in current MDD patients and healthy controls. To assess the specificity of these relationships with anhedonia, we also examined general distress, which is common across anxiety and mood disorders and is associated with elevated negative affect, poor outcome and abnormalities in threat-related neural circuitry.43 Given the anatomical connections of pVMPFC to reward-related regions and the close relationship of anhedonia to reward processing, we hypothesized that weakened pVMPFC connectivity with reward-related brain regions would be related to anhedonia but not general distress. By assessing both anhedonia and general distress, as well as including task- and resting-state fMRI, we are able to characterize functional brain circuits uniquely associated with anhedonia.Previous studies of brain networks in MDD have separately focused on either task-modulated connectivity or resting-state connectivity.32 Critically, this allowed for an unbiased and theoretically motivated selection of the pVMPFC region most frequently implicated in mood and anxiety disorders. Our meta-analysis also identified a perigenual VMPFC region, which was used to examine the anatomical specificity of our pVMPFC findings. We used task-based fMRI with pleasant music and control stimuli because music is an ecologically relevant stimulus that is capable of evoking strong emotions45 and feelings of pleasure.47 Music reliably activates the brain's reward circuits,54 as well as superior temporal sulcus and auditory regions45 that send auditory and polymodal outputs to the VMPFC.56 A passive music-listening task also facilitates a more direct comparison of pVMPFC connectivity differences between task and rest states without the potentially confounding effects of performance, decision-making and action. In summary, we used both resting-state and task-based fMRI to probe pVMPFC, and secondarily perigenual VMPFC, connectivity in relation to anhedonia and general distress symptoms of depression in MDD patients. We also investigated whether similar dissociations between anhedonia and general distress are seen in healthy controls despite constricted range on clinical measures.We first identified a pVMPFC region of interest (ROI) by performing a meta-analysis based on voxels identified in a recent review of mood and anxiety disorders.χ2=0.56, P>0.45, but did significantly differ in age, t(41)=3.02, P=0.004  and 22 healthy controls  were included in the final analyses after excluding participants for outlier data and excessive motion (>3 mm) during the fMRI scan. The resting-state connectivity analyses included 17 patients as three patients did not complete the resting-state scan and one patient had outlier data, as well as 16 healthy controls as three participants did not complete the resting-state scan and three participants had excessive motion during the scan. The depressed and control groups did not significantly differ in gender,  P=0.004 . Thus, g57 except for two patients who completed the Mini International Neuropsychiatric Interview (MINI);58 one patient completed the Mini International Neuropsychiatric Interview outside of the 30-day time window, but a current major depressive episode was confirmed at the time of testing using the mood module only. All the participants also completed the 24-item Hamilton Rating Scale for Depression (HDRS).59 All the patients met DSM-IV criteria for current major depressive episode and all the healthy controls were free of Axis I or Axis II disorders. The eligible participants completed the scan within 30 days of the interview and the majority completed the scan within 2 weeks. Before scanning, all the participants were re-interviewed using the HDRS59 and completed the Mood and Anxiety Symptom Questionnaire (MASQ) 62-item Short Form.61The exclusion criteria for both the groups included history of seizures, major medical illnesses, head trauma, neurological illnesses, pregnancy, current or recent (last 6 months) substance abuse, current or recent smoking habits and any metal in the body that precluded MRI. All the participants completed the Structured Clinical Interview for the DSM-IV,63 (3) general distress anxious symptoms, which assesses negative affect related to anxiety and (4) anxious arousal, which is specific to anxiety.61 The MASQ-AD can be further decomposed into a reverse-scored 14-item high positive affect factor, assessing anhedonia and an eight-item depressive/low positive affect factor.64 To assess anhedonia independently of negative emotionality, we used the high positive affect factor of the MASQ-AD (MASQ-AD-PA) and the MASQ-GDD to probe anhedonia and depression symptoms, respectively. The MASQ consists of four scales: (1) general distress depressive symptoms (MASQ-GDD), which measures overall negative affect related to depression, (2) anhedonic depression (MASQ-AD), which assesses high and low positive affect,48 and consisted of three classical musical pieces that were likely familiar and three that were likely unfamiliar (stimuli available at http://www.scsnl.stanford.edu). The Music and Scrambled stimuli were each presented for 22 to 28 s, followed by a 22-s rest epoch. The Scrambled pieces controlled for low-level acoustic features and attention to complex auditory events, and thus served as the control for the Music pieces. Additional details are available in The participants listened and responded with a button press at the start and end of each music epoch. Stimuli were chosen on the basis of a previously published studyFor the resting-state fMRI scan, the participants were instructed to keep their eyes closed and remain still for the duration of an 8-min scan (one patient completed a 9-min 4-s scan).Following the fMRI session, the participants listened to the music epochs again and rated the Music and Scrambled pieces on a nine-point Likert scale (−4 to +4) on 10 different bipolar semantic differentials: exciting–calm, unpleasant–pleasant, tense–relaxed, annoying–unannoying, dissonant–consonant, angry–peaceful, happy–sad, moving–unmoving, boring–interesting and unfamiliar–familiar . The ratThe acquisition and preprocessing details of both task and resting-state fMRI data are described in We first confirmed that reward-related regions showed expected task-related brain activation during music listening. Details are available in 67 performed on the studies described in the review article by Myers-Schulz and Koenigs.32 Six-millimeter spherical ROIs were created around the peak foci obtained from the GingerALE meta-analysis that was within the pVMPFC  coordinates: −2, 24, −14) and the perigenual VMPFC  regions outlined in Myers-Schulz32 and Ongur.55 Perigenual VMPFC control analyses highlighted the specificity of results to the pVMPFC  pVMPFC seed only to examine connectivity main effects, (2) pVMPFC seed with a MASQ-AD-PA covariate and (3) pVMPFC seed with a MASQ-GDD covariate. Significant activation clusters were assessed using a voxel-wise statistical height threshold of P<0.01, with family-wise error correction at the cluster level P<0.01 (k=128 voxels) as determined by Monte Carlo simulations.69For group-level analyses, individual psychophysiological interaction contrast images were entered into three separate two-sample Regional time series within the seed ROI were extracted from bandpass filtered resting-state fMRI data (0.008–0.10 Hz). Each time series was then submitted into an individual-level fixed-effects analysis under the general linear model framework. A global signal regressor and six motion parameters for each participant were included as covariates of no interest in the model to account for physiological noise and movement-related artifacts.t-test. Significant activation clusters were assessed using a voxel-wise statistical height threshold of P<0.01, with family-wise error correction at the cluster level P<0.01.The relation between anhedonia and pVMPFC resting-state connectivity at the whole-brain level with age as a covariate of no interest was examined using a two-sample P<0.05 with FDR correction for multiple comparisons.To confirm the robustness of the findings, we further examined the regions that showed a significant relationship between task-modulated pVMPFC connectivity and MASQ-AD-PA and MASQ-GDD scores  in MDD and healthy control groups. In these regions, both parameter estimates from task-modulated and resting-state connectivity analyses were extracted for each participant. MASQ-AD-PA partial correlations controlling for age, MASQ-GDD partial correlations controlling for age, partial correlations of MASQ-AD-PA controlling for age and MASQ-GDD, as well as partial correlations of MASQ-GDD controlling for age and MASQ-AD-PA were assessed for significance at t(40)=10.09, P<0.001) and general distress (t(40)=11.727, P<0.001) than healthy controls. The MDD patients had a mean±s.d. HDRS score of 26.57±7.12 with all but four participants in the moderately or severely depressed range, a mean±s.d. MASQ-AD-PA score of 61.81±4.77 (range: 49 to 69), and a mean±s.d. MASQ-GDD score of 38.62±9.38 (range 20 to 54). Healthy controls had a mean±s.d. HDRS score of 0.68±1.32, a mean±s.d. MASQ-AD-PA score of 39.27±9.11 (range: 26 to 57) and a mean±s.d. MASQ-GDD score of 13.95±2.06 (range 12 to 20).The MDD patients had significantly more severe anhedonia , all P-values >0.56.All the patients had a primary diagnosis of current MDD. Seven of 21 patients had a current comorbid Axis I disorder . Those with comorbid diagnoses were equivalent to those without comorbidities on HDRS,59 MASQ-AD-PA and MASQ-GDD,61 all P-values >0.24. Furthermore, one-way analyses of variance showed that HDRS, MASQ-AD-PA and MASQ-GDD did not differ depending in medication type, HDRS: P=0.08, MASQ-AD-PA: P=0.65, MASQ-GDD: P=0.30. Additional analyses controlling for comorbidity status and medication use are in Eight patients were not currently taking psychiatric medication and 13 were taking medications . Those on medication were equivalent to those off medication in HDRS,F=1.070, P>0.30. Follow-up paired t-tests on the significant main effects of rating and stimulus type showed that participants found the Music stimuli to be less annoying and more pleasant, calm, relaxed, consonant, peaceful, happy, moving, interesting and familiar in comparison with Scrambled music pieces  confirmed that participants found the Music stimuli to be pleasant, not annoying, exciting, consonant, peaceful, happy, moving and interesting, all P-values <0.001.A repeated-measures analysis of variance with group as a between-participant factor and the 10 ratings for Music and Scrambled pieces as within-subject factors showed that MDD and healthy controls did not significantly differ in ratings for Music and Scrambled pieces, c pieces . One-samr=−0.515, P=0.017, but not in MDD patients, P>0.44. No such relations were detected for MASQ-GDD in either group, all P-values >0.75.MASQ-AD-PA was negatively correlated with Music pleasantness ratings in healthy controls, 8 pleasant Music compared with Scrambled stimuli evoked significant activation in reward- and emotion-related regions including left orbitofrontal cortex BA47, left amygdala/parahippocampal gyrus and bilateral VMPFC  and right NAc , defined using previous meta-analyses.71 We found significant activation of the right (t(42)=2.396, P=0.02), but not left NAc (P>0.64). Scrambled stimuli evoked greater activation in bilateral superior temporal gyrus, right inferior frontal gyrus (IFG) and right inferior parietal lobule when compared with Music . We then performed a partial correlation analysis controlling for the effects of age and MASQ-GDD, and found that pVMPFC connectivity with all reward-related and auditory-processing regions except right caudate showed significant relations to anhedonia in MDD patients ; pVMPFC connectivity was not correlated with MASQ-GDD in any of these regions (P>0.05, FDR corrected; In healthy controls, only pVMPFC connectivity with left supplementary motor cortex and left supramarginal gyrus was correlated with MASQ-AD-PA after controlling for age and MASQ-GDD (P<0.05, FDR corrected; A significant interaction between general distress depressive symptoms, group and pVMPFC connectivity was observed and driven by both positive and negative correlations between MASQ-GDD and pVMPFC connectivity in MDD, and only negative correlations in healthy controls . In MDD In the MDD group, MASQ-AD-PA was not positively or negatively correlated with pVMPFC resting-state connectivity in any brain region. In the healthy controls, the MASQ-AD-PA was positively correlated with pVMPFC resting-state connectivity in fronto-temporal cortex . HoweverP>0.05, FDR corrected; We also conducted targeted analyses to investigate whether the brain areas that showed a relationship between task-modulated pVMPFC connectivity and MASQ-AD-PA also showed impairments in resting-state functional connectivity. No significant relationship between MASQ-AD-PA and resting-state pVMPFC connectivity was observed in either MDD or healthy control groups (P>0.05, FDR corrected; Similar analyses were conducted for the regions that showed significant task-modulated relationships between pVMPFC connectivity and MASQ-GDD in MDD and healthy controls. After controlling for age and MASQ-AD-PA, no significant relationship between MASQ-GDD and resting-state pVMPFC connectivity was observed in either group (32 To examine the anatomical specificity of our pVMPFC findings related to anhedonia and general distress, we investigated perigenual VMPFC connectivity in MDD and healthy controls (The perigenual subdivision of the VMPFC has also been implicated in depression and anhedonia.controls . In contcontrols , Table 2controls . CrucialThe primary goal of this study was to investigate the differential relationships of anhedonia and general distress symptoms with task-modulated and resting-state pVMPFC functional connectivity in current MDD patients. We also investigated whether these differential relationships can be detected in healthy controls as a secondary aim. Our study demonstrates that in MDD patients, anhedonia, but not general distress, is associated with weak communication between pVMPFC and multiple brain regions important for reward, emotion and auditory processing. In contrast, pVMPFC resting-state connectivity was not associated with anhedonia in current MDD patients. Thus, the dissociation between anhedonia and general distress in pVMPFC connectivity is specific to the context of processing pleasant stimuli and does not appear to be a general feature of intrinsic resting-state brain connectivity in MDD. In addition, these pVMPFC dissociations were specific to current MDD patients and were not seen in the healthy controls. Our findings provide important new insights into the neurobiological basis of anhedonia in affected individuals and highlight its unique relationship with reward- and emotion-related functional circuits.75 and has dense reciprocal connections to the NAc.76 The NAc is essential for detecting and modulating responses to rewarding stimuli77 and has been implicated in both ‘liking' and ‘wanting' components of reward.79 Connectivity between the pVMPFC and orbitofrontal cortex, a region important for the hedonic experience of reward, also showed a negative relationship with anhedonia in current MDD patients. The orbitofrontal cortex has dense reciprocal connections with the VMPFC80 and is involved in reward value prediction and integration of reward cues.81 Crucially, these effects were specific to anhedonia—general distress was not correlated with pVMPFC connectivity with reward-related brain regions, and in fact had minimal impact on pVMPFC connectivity overall. In sum, anhedonia is specifically associated with aberrant functional links that span multiple regions of the mesolimbic reward system and its cortical projections. More generally, our results suggest that distinct abnormalities in functional connectivity underlie anhedonia symptoms in MDD.Our findings suggest that anhedonia is characterized by a lack of engagement between the pVMPFC and reward-related functional circuits while processing pleasant stimuli. We found that pVMPFC connectivity with core nodes of the mesolimbic reward system is negatively correlated with anhedonia during music listening in current MDD patients. In MDD patients, greater anhedonia was associated with weaker pVMPFC connectivity with the ventral tegmental area/substantia nigra and NAc. The ventral tegmental area/substantia nigra contains dopamine neurons that are central to the reward response,82 tonal structure83 melodies84 and the structural elements of music over time,85 these fronto-temporal regions also interact with the mesolimbic reward system.86 A study that required neurotypical adults to determine the subjective reward value of individual musical stimuli demonstrated that aesthetic aspects of reward processing result from interactions between the mesolimbic system and secondary auditory cortex.54 Furthermore, we previously demonstrated that in neurotypical adults, trait anhedonia is modulated by functional connectivity between core mesolimbic regions and auditory cortex regions.8 Taken together, our findings suggest that anhedonia may disrupt the ability to experience pleasure from positive auditory stimuli like music, which requires successful integration of sensory perception with reward-related cognitive and evaluative processes. The relation between anhedonia and the extended reward network observed in our study likely reflects an inability to engage with positively valenced music stimuli, as both groups were able to rate the music stimuli as pleasant. Consistent with this view, anhedonia was negatively correlated with pleasantness ratings in healthy controls, but not in patients. Taken together with our brain imaging findings, these results suggest that while MDD patients are not impaired at rating the pleasantness of musical stimuli, they may experience pleasurable stimuli differently. Further research is needed to examine this question and determine whether the deficits identified here reflect apathy87 or reduced interest or motivation to engage with pleasant stimuli.In addition to reward-related regions, anhedonia was also negatively correlated with task-modulated pVMPFC connectivity to fronto-temporal areas involved in processing musical structure, including bilateral IFG pars triangularis and pars opercularis as well as bilateral middle temporal gyrus/superior temporal sulcus in those with current MDD. Besides tracking prosodic information,An important question that has not yet been addressed in depression research is whether anhedonia is associated with resting-state brain connectivity or an inability to appropriately modulate brain responses when encountering pleasurable stimuli. Two findings from our study suggest that the effects of anhedonia are task or context specific. First, anhedonia was differentially associated with pVMPFC connectivity when processing pleasant musical stimuli but not during rest. Second, these relations were specific to music stimuli and were not detected when processing scrambled music, the control stimuli used in the task-based fMRI investigation. Thus, anhedonia reflects a lack of engagement between the pVMPFC and reward-related functional circuits when encountering pleasurable stimuli, rather than a constant static deficit in connectivity. Our findings and approach here suggest that longitudinally tracking both task-induced and resting-state changes has the potential to inform how deficits in functional organization might result in aberrant reward processing and anhedonia.45 Finally, studies distinguishing different anhedonia subtypes89 are important for refining our understanding of how different anhedonia phenotypes are represented in the brain.Although our study represents an important step towards the identification of anhedonia-related functional circuits in MDD, several limitations are important to note. First, the current MDD and the healthy control groups significantly differed in age. However, our analyses were primarily focused on the MDD group and we included age as a covariate of no interest in all the analyses; including this covariate did not affect the task-based connectivity results within either group. Second, although anhedonia was negatively correlated with pleasantness ratings in healthy controls but not in patients, there were no significant differences in music stimulus ratings across groups. Further research is needed to examine how pVMPFC connectivity is differentially related to anhedonia, pleasantness ratings and hedonic value. Third, our sample size was modest so analyses testing the potentially confounding effects of medication status and comorbidity may be underpowered. Finally, including sad stimuli would enable the investigation of differential relationships between pVMPFC-NAc circuits involved in the experience of positively valenced rewarding stimuli versus pVMPFC-amygdala circuits implicated in processing negatively valenced stimuli. In this context, auditory stimuli could have a distinct advantage over the more widely used visual stimuli.1 our study provides new insights into the neurobiological basis of anhedonia and highlights its unique relationship with emotion- and reward-processing systems. More specifically, we show that anhedonia in MDD is associated with disrupted communication between the pVMPFC and reward- and emotion-related regions during the processing of positively valenced stimuli. Our results also indicate that in adults with MDD, anhedonia reflects a lack of engagement between the pVMPFC and reward-related functional circuits when contextually appropriate, rather than a constant deficit in connectivity. Thus, probing resting-state connectivity of the pVMPFC may be inadequate for assessing anhedonia-specific effects. Our findings also support the notion that specific psychiatric symptoms in MDD can be linked to distinct neurophysiological pathways.1 Finally, our results show that connectivity patterns related to anhedonia and general distress vary between VMPFC subregions, demonstrating the importance of anatomical specificity. In summary, the identification of specific anhedonia-related circuits can facilitate a better understanding of psychopathology and heterogeneity in MDD, as well as more effective tracking of one of the core MDD symptoms.Consistent with the goals of the research domain criteria initiative,


Cryptococcal disease remains a significant source of global morbidity and mortality for people living with HIV, especially in resource-limited settings. The recently updated estimate of cryptococcal disease revealed a global incidence of 223,100 cases annually with 73% of these cases being diagnosed in sub-Saharan Africa. Furthermore, 75% of the estimated 181,100 deaths associated with cryptococcal disease occur in sub-Saharan Africa. Point-of-care diagnostic assays have revolutionised the diagnosis of this deadly opportunistic infection. The theory of asymptomatic cryptococcal antigenaemia as a forerunner to symptomatic meningitis and death has been conclusively proven. Thus, cryptococcal antigenaemia screening coupled with pre-emptive antifungal therapy has been demonstrated as a cost-effective strategy with survival benefits and has been incorporated into HIV national guidelines in several countries. However, this is yet to be implemented in a number of other high HIV burden countries. Flucytosine-based combination therapy during the induction phase is associated with improved survival, faster cerebrospinal fluid sterilisation and fewer relapses. Flucytosine, however, is unavailable in many parts of the world. Studies are ongoing on the efficacy of shorter regimens of amphotericin B. Early diagnosis, proactive antifungal therapy with concurrent management of raised intracranial pressure creates the potential to markedly reduce mortality associated with this disease. Cryptococcus remains one of the most important opportunistic fungal pathogens worldwide . It. It48]. Induction therapy with amphotericin B plus flucytosine is associated with improved survival among patients with cryptococcal meningitis, as compared to amphotericin B alone or amphotericin B plus fluconazole . HoweverC. gattii. Recent data from a phase II randomized controlled non-inferiority trial from Tanzania showed that single dose 10 mg/kg of liposomal amphotericin B is well-tolerated with a non-inferior early fungicidal activity (EFA) compared to 14-day courses of 3 mg/kg liposomal amphotericin B in the treatment of HIV-associated cryptococcal meningitis [Lipid formulations of amphotericin B  can be used in place of conventional amphotericin B and are less nephrotoxic, although not more effective. They are preferred for cryptococcal meningitis in patients who are immunosuppressed through organ transplantation, who do not tolerate conventional amphotericin B well. Amphotericin B-based induction is often prolonged beyond two weeks in these cases, and in the non-HIV, non-transplant patient group, including those who are immune-competent and those infected with ningitis . The indningitis . Long-teningitis .In search for a novel agents for treating cryptococcal meningitis, a recent study in Tanzania has shown that the antidepressant drug sertraline in combination with fluconazole improves the two-week CSF fungal clearance rate and clinical outcomes and is superior to fluconazole monotherapy or short course amphotericin B therapy .The Infectious Diseases Society of America (IDSA) clinical guideline for the management of cryptococcal meningitis recommends initiation of ART 2–10 weeks after the commencement of the initial antifungal treatment, based on earlier studies . HoweverRaised intracranial pressure (ICP) is very common, occurring in up to over 60% of patients with cryptococcal meningitis  and is aIn resource-limited settings, the tools for repeated lumbar punctures and manometry are not available, or they exist in such limited supply as to impede the provision of optimal care for the majority of persons with HIV-associated cryptococcal meningitis. In addition to these economic barriers, there are also cultural barriers to care; for example, permission for additional lumbar punctures for the management of increased intracranial pressure is often denied by patients or their families due to misunderstanding and fear .Occasional patients have persistently raised CSF pressure, despite three or four lumbar punctures and good antifungal therapy. The best option for most of these patients is the insertion of a lumbar drain. An alternative is the insertion of a ventricular drain, either directly draining externally or a ventriculo-peritoneal shunt ,69.Other measures to reduce raised CSF pressure are ineffective or harmful. The controversial role of corticosteroid in the management of cryptococcal meningitis has recently been laid to rest. A double-blind, randomized, placebo-controlled trial, that recruited 451 adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi did not show any survival benefit in using adjunctive dexamethasone, but rather adverse events and disability in patients that received it .Cryptococcal meningitis accounts for up to 15% of HIV-related deaths . It is oWithout consolidation and maintenance antifungal therapy, recurrence is very common occurring in up to 40–50% of the patients after a successful induction antifungal therapy . The diaC-IRIS is an emerging problem in resource-limited settings. It can present any time after initiation of ART and can present as late as two years, and this can be explained from the persistence of CrAg in the systemic circulation ,81. The Visual loss is the major complication of sustained high ICP in cryptococcal meningitis . It has Antifungal prophylaxis is one of the key components of the comprehensive care for HIV-infected persons who are at risk of developing cryptococcal meningitis or patients who have had a recent episode of cryptococcal disease .In the early 2000s, a multicenter, randomized, double-blind, placebo-controlled trial of fluconazole for primary cryptococcal meningitis prophylaxis in HIV-infected patients with a CD4+ T-cell count < 100 cells/µL showed that patients in the placebo group were 4.3 times more likely to die than those in the fluconazole group . This isIn a recent two-year prospective observational cohort study conducted by Sungkanuparph et al.  in ThailCryptococcus species from clinical isolates, and this could be attributed to the use of these agents for in primary prophylaxis or primary therapy for cryptococcosis [In developed countries such as Europe and the USA, with a wide availability of ART, the low burden of HIV-related cryptococcosis and very low prevalence of cryptococcal antigenaemia, primary antifungal prophylaxis for cryptococcosis is not routinely recommended in HIV-infected patients ,88. A recoccosis .This is also known as maintenance or suppressive therapy. The relapse rate for cryptococcal meningitis in persons with AIDS is more than 50% within the first year ,90. It i3 are at the highest risk for developing cryptococcal disease. Cryptococcus spp. shed their polysaccharide capsular antigens very early into the bloodstream during systemic dissemination i.e., between five and 234 (median 22) days before the development of clinical cryptococcal disease; a clinical phenomenon now described “asymptomatic antigenaemia” [As mentioned before, HIV-infected individuals with CD4 counts < 100 cells/mmenaemia” . The undenaemia” . The clienaemia” .In 2012, Jarvis et al.  proposedscreen and treat” strategy in ARV-naïve patients with CD4 counts < 100 cells/µL have been conducted in various settings, including South Africa, Uganda, Vietnam and Cambodia [In 2015, South Africa established a national cryptococcal antigenaemia screening policy targeting at ART naïve HIV-infected patients with CD4+ T-cell counts < 100 cells/µL. Two screening strategies are included in their national guidelines: reflex screening, where a CrAg test is performed on remnant blood samples from CD4 testing; and provider-initiated screening, where providers order a CrAg test after a patient returns for CD4 test results. CrAg screening before the initiation of ART was shown to potentially reduce the incidence of cryptococcal meningitis and save lives. Reflex screening compared to provider-initiated screening had more survival benefits and cost-effectiveness by reducing additional costs per additional year of life saved ,97. In sCambodia ,100,101.Cambodia .prevention is better than cure”. The burden of HIV-associated cryptococcal disease remains high, especially in resource-limited settings. We advocate for routine CrAg screening and pre-emptive antifungal therapy, especially in settings with a limited availability of ART, high levels of antiretroviral drug resistance, and a high burden of cryptococcal disease. This is a cost-effective public health intervention associated with reduced mortality by decreasing the incidence of cryptococcal meningitis among HIV-infected patients, especially in a population with a high prevalence (>3%) of cryptococcal antigenaemia. However, on the other hand, timely diagnosis and early treatment of an acute episode of cryptococcal meningitis and its associated complications  is associated with better clinical outcomes. However, the time old adage still stands that “


Moreover, the localization of SGPG-immunoreactivity on the motor neurons of rat spinal cord and a mouse motor neuronal cell line, NSC-34 was observed by an immunofluorescence method. These data suggest that SGPG could represent a specific pathogenic antigen in those ALS patients. The presence of anti-SGPG antibodies in the serum of ALS patients should represent a diagnostic biomarker of ALS, and it could reflect the severity of the disease.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. Although the etiology of ALS is obscure, genetic studies of familiar ALS suggest a multifactorial etiology for this condition. Similarly, there probably are multiple causes for sporadic ALS. Autoimmune-mediated motor neuron dysfunction is one proposed etiology for sporadic ALS. In the present study, anti-glycolipid antibodies including GM1, GD1b, GD3, and sulfoglucuronosyl paragloboside (SGPG) were investigated in the sera of a large number of patient samples, including 113 ALS patients and 50 healthy controls, by means of enzyme-linked immunosorbent assay with affinity parametric complex criterion evaluation and thin-layer chromatography immunooverlay (immuno-TLC). Anti-SGPG antibodies were found in the sera of 13.3% ALS patients (15 out of 113). The highest titer reached 1:1600. The presence of anti-SGPG antibodies in the serum samples was also confirmed by immuno-TLC. Importantly, a multiple logistic regression analysis showed that the presence of anti-SGPG antibody was positively correlated with age ( Amyotrophic lateral sclerosis (ALS) is a progressive neurologic disorder causing loss of motor neurons in the motor cortex, brain stem, and spinal cord, resulting in atrophy and weakness of skeletal muscles along with corticospinal tract dysfunction . Most ALSulfoglucuronosyl paragloboside (SGPG) is one of the glycolipid target antigens in various peripheral neuropathies . Anti-SGSGPG is also located in the microvessels of adult rat brain, which suggests the reaction of circulating anti-SGPG antibodies with SGPG on the microvessels may potentially cause the breakdown of the blood–brain barrier or blood–nerve barrier, resulting in the penetration of these antibodies to target the antigenic sites on the nervous tissues for degeneration . Since AIn the present study, anti-glycolipid antibodies including GM1, GD1b, GD3, and SGPG were investigated in the sera of 113 ALS patients as well as 50 healthy controls by means of an enzyme-linked immunosorbent assay (ELISA) with affinity parametric complex criterion (APCC) evaluation. The presence of these anti-glycolipid antibodies in serum samples was confirmed by immuno-thin-layer chromatography (immuno-TLC). The relationships of age, gender, race, clinic symptoms, forced vital capacity (FVC), as well as Functional Rating Scale (ALSFRS) scores with the presence of anti-glycolipid antibodies, were also assessed. An immunofluorescence method was used to confirm the localization of SGPG-immunoreactivity on the motor neurons of rat spinal cord and a mouse motor neuron cell line, NSC-34, which is a hybrid cell line produced by fusion of motor neuron enriched, embryonic mouse spinal cord cells with mouse neuroblastoma .One hundred and thirteen (113) ALS patient serum samples received from the ALS Clinic at the Medical College of Georgia, Augusta University, and 50 healthy male and nonpregnant female subjects were enrolled in the study. All ALS patients were examined in the AUHealth ALS clinic and met the El-Escorial criteria for possible, probable, or definite ALS. Demographic characteristics such as age, gender, and race as well as clinical symptoms, FVC and ALSFRS scores were collected.The presence of anti-glycolipid  antibodies was first screened by means of ELISA. We used 25 ng each of GM1, GD1b, GD3, and SGPG, dissolved in methanol, as the antigens to coat the wells of the ELISA plate. The solvent in each well was dried in air. Nonspecific bindings were blocked by incubation of each well with 1% bovine serum albumin in phosphate-buffered saline (PBS) for 30 min. Serum samples were diluted 1:400 and added in duplicate onto the plate followed by incubation at room temperature overnight. Commercial normal human serum  was treated as control. Horseradish peroxidase-conjugated anti-human IgG or IgM was used as the secondary antibody. After addition of the secondary antibody, the plate was developed with o-phenylenediamine dihydrochloride  peroxidase substrate solution. The optical density (OD) value of each well was measured at 492 nm with a microplate spectrophotometer.The P/N ratio was calculated by dividing the OD value of test serum by the OD value of the normal control. Samples with a P/N ratio > 2.1 were regarded as positive.false positives). Anti-glycolipid antibody titers were assigned as the highest dilution at which the adjusted OD value  was ≧0.1. Specific antibody binding activity was evaluated by APCC value calculated according to our previous report . Since we had frequently encountered serum samples that presented high background OD values, the serially diluted serum samples were compared using glycolipid-coated and noncoated ELISA plate wells to avoid the high background values which could be misinterpreted as positives . After the plate was dried in air, it was dipped in 0.25% poly-isobutyl-methyl acrylate in n-hexane, which was used as the coating agent. Nonspecific bindings were blocked by incubation with 1% bovine serum albumin in PBS for 30 min. The TLC plate was incubated with the serum sample (1:50) overnight. Horseradish peroxidase-conjugated anti-human IgG or IgM was used as the secondary antibody enhanced chemiluminescent blotting kit  for X-ray film was used for revealing the positive bands.The presence of anti-glycolipid antibodies in the serum samples was also confirmed by immuno-TLC. Briefly, 300 ng of an antigen  was spotted on each lane of a TLC plate. The TLC plate was then developed with the solvent of chloroform: methanol: 0.25% CaClNSC-34 cells were cultured on poly-D-ornithine-coated glass coverslips in Dulbecco's Modified Eagle's Medium (DMEM) plus 10% fetal bovine serum for 3 days, and then the fetal bovine serum was removed for further differentiation. Cells were fixed in 4% paraformaldehyde in PBS for 30 min and stored in PBS at 4℃ for immunofluorescence staining.Normal rats were anesthetized by intramuscular injection of ketamine hydrochloride (40 mg/kg body weight) and xylazine hydrochloride (4 mg/kg body weight), then perfused with 4% paraformaldehyde in PBS. After perfusion, lumbar spinal cords were removed and postfixed for 4 hr at 4℃ in the same 4% paraformaldehyde solution. The blocks were then equilibrated in sucrose (30% in PBS) and sectioned (35 µm).Cells and sections were washed three times in PBS and incubated in 1% bovine serum albumin (containing 1% Triton X-100 in PBS) for 30 min prior to overnight incubation at 4℃ with the primary monoclonal antibody specific for the sulfoglucuronosyl epitope of SGPG .Statistical analyses were performed using the SPSS 16.0 version software program. The association between age, gender, race, clinic symptoms, FVC, as well as ALSFRS score and the presence of anti-glycolipid antibody were evaluated using multiple logistic regression analysis. A Demographic characteristics of the subjects recruited in the present study are shown in The presence of anti-SGPG IgG or IgM activities was confirmed in the positive samples by means of immuno-TLC. Anti-GM1 IgM was also confirmed similarly in one of the samples .Figure p < .01) and negatively correlated with ALSFRS score (p < .05). Gender, race, FCV level, and other clinical symptoms such as tongue atrophy and fasiculations as well as other bulbar-related symptoms were not significantly related to the presence of anti-SGPG antibody  motor neurons . Due to In the present study, anti-SGPG antibodies were found in the sera of 13.3% ALS patients (15 out of 113) by means of ELISA. The presence of anti-SGPG antibodies in the serum samples was also confirmed by immuno-TLC. Age and ALSFRS scores were found for the first time to be correlated with the presence of anti-SGPG antibodies. Most interestingly, we also showed that the localization of SGPG on the motor neurons of NSC-34 cells as well as rat spinal cord, consistent with the notion that these glycolipids may represent the target antigens underlying the pathogenic mechanisms of motor neuron disease.The identification of anti-SGPG antibodies in a significant proportion (13.3%) of a large patient population with ALS is noteworthy and consistent with our previous studies . But theIt should be mentioned that SGPG and its homolog, sulfoglucuronosyl lactosaminyl paragloboside have been reported to be present in cancer cells of neuroectodermal origin; anti-SGPG antibodies have also been detected in sera of patients with metastatic neural tumors but not in healthy controls . This maAnti-GM1 antibodies were also found in 6.2% (7 out of 113) of the ALS samples, but the positive rate was much lower than those in other neurological diseases, such as Guillain-Barré syndrome . TherefoIt is interesting that the presence of anti-SGPG antibody was correlated with age and negatively correlated ALSFRS score. The ALSFRS provides an estimate of the patient’s degree of functional impairment . The preALS is associated with the selective loss of motor neurons in the motor cortex, spinal cord, and brain stem. The presence of anti-SGPG antibodies in ALS patient serum suggests that motor neurons may bear specific target antigen(s), such as SGPG and sulfoglucuronosyl lactosaminyl paragloboside, responsible for the immune attack. Therefore, it is necessary to detect the presence of SGPG on motor neurons. Since the human spinal cord sample is unavailable at the moment, we performed immunofluorescence staining to detect the localization of SGPG in NSC-34 cells and rat spinal cord. The results confirmed that the motor neurons do contain SGPG. Interestingly, most of the immunopositivity appears to be associated with α motor neurons. For this reason, the presence of anti-SGPG antibodies in the serum of this subgroup of ALS patients may initiate motor neuron degeneration by targeting SGPG on α motor neurons.To study the pathogenic role of SGPG in ALS, we have carried a preliminary study by sensitizing Lewis rats with SGPG. All rats sensitized with SGPG developed high titers of anti-SGPG antibodies, and 50% animals developed mild to moderate neurological symptoms, such as distal tail tone loss . HoweverSGPG was reported to react with anti-ELEC-39, HNK-1, and NC-1 antibodies as well as anti-voltage-gated calcium channel antibodies . It is sIn conclusion, our present study suggests that SGPG and/or an sulfoglucuronosyl epitope bearing molecule is a target antigen in a significant number of patients diagnosed as having ALS. We can safely conclude that anti-SGPG antibody can be used as a serum biomarker of ALS, and this antibody may be useful for presymptomatic diagnosis and therapeutic monitoring of new therapeutic strategies.


Many senior medical students lack simple surgical and procedural skills such as knot tying.The aim of this study was to determine whether viewing a Web-based expert knot-tying training video, in addition to the standard third-year medical student curriculum, will result in more proficient surgical knot tying.At the start of their obstetrics and gynecology clerkship, 45 students were videotaped tying surgical knots for 2 minutes using a board model. Two blinded female pelvic medicine and reconstructive surgery physicians evaluated proficiency with a standard checklist (score range 0-16) and anchored scoring scale (range 0-20); higher numbers represent better skill. Students were then randomized to either (1) expert video (n=26) or (2) nonvideo (n=24) groups. The video group was provided unlimited access to an expert knot-tying instructional video. At the completion of the clerkship, students were again videotaped and evaluated.P=.90, respectively). Postclerkship scores improved in both the nonvideo and video groups . Increased knot board practice was significantly correlated with higher postclerkship scores on the knot-tying task, but only in the video group .At initial evaluation, preclerkship cumulative scores (range 0-36) on the standard checklist and anchored scale were not significantly different between the nonvideo and video groups (mean 20.3, SD 7.1 vs mean 20.2, SD 9.2, The addition of a Web-based expert instructional video to a standard curriculum, coupled with knot board practice, appears to have a positive impact on medical student knot-tying proficiency. Many senior medical students lack simple surgical and procedural skills such as knot tying . InitiatThere is no standardized method of teaching medical students knot-tying skills and several curricula have been proposed -11. GersAdditionally, if medical students cannot tie surgical knots, they are often marginalized in the operating room. DiMaggio et al  demonstrOverall, in our practice, we have noted that third-year medical students participating in their obstetrics and gynecology clerkship have a dearth of knot-tying experience. Using a prospective, randomized controlled study design, we sought to determine whether having access to an expert knot-tying training video would result in more proficient surgical knot tying.Between November 2015 and March 2016, 55 third-year medical students were approached at the start of their obstetrics and gynecology clerkships for inclusion in this Institutional Review Board-exempt study. As this was an educational intervention, the trial did not require prospective registration. As part of the standard curriculum at Northwestern University’s Feinberg School of Medicine in Chicago, IL, all medical students underwent a 1-hour knot-tying education session on the first day of their clerkship. This session involved both didactics and a hands-on knot-tying workshop led by an attending physician. Participating medical students were then randomized to either the standard curriculum (“no video” group) or to the “video” group. Students in the video group received unlimited access to a Web-based expert instructional video on surgical knot tying (courtesy of Dr John OL DeLancey). Students in both groups received access to a knot-tying board for home practice for the duration of their clerkship. At the conclusion of their clerkship, all students received access to the expert knot-tying video.On the second day of their clerkship, students in both groups were videotaped tying as many square, two-handed knots as they could on a knot-tying board in 2 minutes. Students in both groups also provided demographic  and prior experience information , family members in medicine, and if they were anticipating entering a surgical career. At the conclusion of their 4-week clerkship, students were again videotaped completing the knot-tying task and a satisfaction survey was administered . Students also self-reported the number of times they had viewed the expert video and practiced knot tying outside of the clinical setting using their knot board.t tests, Student t tests, Fisher exact, and Pearson correlations were calculated.Videos of students performing the knot-tying tasks were viewed by two blinded female pelvic medicine and reconstructive surgery physicians who evaluated medical student proficiency using a standard knot-tying checklist (score range 0-16) and an anchored scale range 0-20). The standard knot-tying checklist responses were 1=yes and 2=no on eight knot-tying metrics, including the following: sutures start crossed, index finger lifts suture to form loop, fingers pinch together, push suture through and grasp/tighten, hook thumb under suture, form loop, fingers pinch together, and push suture through and grasp/tighten. The anchored scale was based on a modified objective structured assessment of technical skill scale, which assigned scores from 1 to 5 on four separate procedure domains: respect for tissue, time and motion, instrument handling, and flow of operation and forward planning [. The staOf the initial 55 medical students approached for the study, 3 students declined to participate and 2 transferred from the clerkship. Of the remaining 50 students, 26 students were randomized to the video group and 24 to the nonvideo group. In total, 5 students were lost to follow up and did not complete either of the videotaped tasks. Ultimately, a total of 45 medical students completed both preclerkship and postclerkship knot-tying videotaped tasks and were included in the final analysis: 22 students in the video and 23 students in the nonvideo group .P=.46) or gender  or median comfort level with knot tying at the start of the rotation (P=.55). Participants in the nonvideo and video groups did not differ in age . Additionally, preclerkship standard checklist and anchored scale scores on the knot-tying task were not significantly different (P=.90) between the two groups.Thirteen of 45 students (29%) in the entire cohort reported having family members who were physicians and 10 students (22%) reported planning on entering surgical fields; this did not differ between groups (P=.66); it was median 5 (range 0-20) in the nonvideo group and median 3 (range 0-20) in the video group. Student performance on the knot-tying tasks as evaluated by the standard checklist and anchored scale improved significantly through the course of the rotation in both groups . When stratified by access to the knot-tying video, increased knot board practice was significantly correlated with higher postclerkship scores on the knot-tying task, but only in the video group  compared to the nonvideo group . Interrater scoring reliability was high . Both the nonvideo and video groups reported high rates of satisfaction with their knot-tying educational experiences .For the entire cohort, increased knot board practice was not correlated with higher postclerkship scores on the knot-tying task (In this prospective, randomized controlled study, addition of an expert instructional video to a standard curriculum, coupled with knot board practice, appears to have a positive impact on medical student knot-tying proficiency. These findings suggest that self-directed learning is more effective when augmented with an instructional video. The basic tenants of self-directed medical student learning include diagnosing needs, formulating goals, identifying resources, implementing appropriate activities, and evaluating outcomes . In thisSelf-directed learning is a critical component of modern medical student education. Technical skills, such as knot tying, are increasingly being taught in a simulated environment but additional practice, usually at home, is necessary to achieve task competency. Green et al  recentlyOur study has several strengths and limitations. We performed a randomized controlled trial to evaluate the role of an expert educational video in medical student knot-tying proficiency. Our study population included medical students who had completed variable amounts of surgical clerkships. Additionally, knot-tying proficiency was evaluated by blinded trained gynecologists in a structured fashion with excellent interrater reliability. Limitations of our study include a relatively small sample size and its focus on a single institution. Because students were asked to record how many times they both viewed the expert video and practiced using the knot board at the conclusion of the rotation, recall bias may be a factor in students’ responses. Future studies may benefit from implementing a logging methodology in which medical students can report their knot board and video use in an ongoing fashion. Additionally, although medical students were advised to not view the video if they were randomized to the nonvideo group, inadvertent crossover may have occurred between the groups.Based on our analysis, Web-based video instruction appears to be a valuable adjunct to a standard knot-tying medical student curriculum. Additional prospective studies are necessary with focus on addressing the role of knot-tying practice outside of the clinical setting and the availability of practice materials, such as knot-tying boards and instructional videos.


Aim. This study aimed to assess clinical impact of hepatitis C viral load on the development of hepatocellular carcinoma (HCC) and liver-related mortality in HCV-infected patients. Methods. A total of 111 subjects with chronic HCV infection who were available for serum quantitation of HCV RNA were recruited in this retrospective cohort. Cox-proportional hazards models were used to calculate hazard ratio (HR) of developing HCC and liver-related mortality according to serum HCV RNA titers. Results. HCC was developed in 14 patients during follow-up period. The cumulative risk of HCC development was higher in subjects with high HCV RNA titer (log HCV RNA IU/mL > 6) than subjects with low titer (log HCV RNA IU/mL ≦ 6) , giving an incidence rate of 474.1 and 111.5 per 10,000 person-years, respectively. Old age , accompanying cirrhosis , and low platelet count  were other independent risk factors for the development of HCC. Liver-related death occurred in 7 patients. Accompanying cirrhosis  and low albumin level , but not HCV RNA titer, were significant risk factors related to liver-related mortality. Conclusion. Serum HCV RNA titer may be considered an independent risk factor for the development of HCC but not liver-related mortality. Hepatitis C virus (HCV) infection is one of the leading causes of chronic hepatitis worldwide and is also a major risk factor for the disease progression to advanced entities such as liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) , 2. AccoThis study was retrospectively conducted by reviewing medical records. We identified 266 patients seropositive for anti-HCV antibody between January 2003 and June 2009 at Dankook University Hospital in Korea. Among them, 155 patients were excluded under the following exclusion criteria: (1) 105 patients whose quantitative tests of serum HCV RNA were not evaluated, (2) 8 patients who were coinfected with HBV, (3) 33 patients who were not followed up regularly for at least 3 years, and (4) 9 patients initially presenting with HCC. Ultimately, a total of 111 HCV-infected patients who had available data of serum HCV RNA quantitation were recruited in this retrospective cohort. The schematic flow for the enrollment of study participants is shown in Anti-HCV antibodies were detected using an immunoradiometric assay  based on recombinant proteins from the HCV genome, which showed a sensitivity of 98.5% and a specificity of 99.7%. Serum HCV RNA titers were quantitatively determined by real-time polymerase chain reaction (PCR) using COBAS TaqMan HCV quantitative test, version 2.0  with a linear range from 43 to 69,000,000 IU/mL. In the present study, we classified patients into two groups with high or low viral load based on the serum HCV RNA level at study entry. The cut-off log titer of HCV RNA levels was 6: (1) high viral load > 6 log titer of HCV RNA IU/mL and (2) low viral load ≦ 6 log titer of HCV RNA IU/mL. HCV genotyping was performed by reverse transcription PCR and sequencing analysis using ABI PRISM 3130 Genetic Analyzer .α-fetoprotein level ≧ 400 ng/mL [Hepatocellular carcinoma was confirmed by histology. Cases not available for histologic evaluation were diagnosed by applying nonhistologic criteria, mainly depending on the radiologic imaging on the base of chronic liver diseases. The radiologic findings typical of HCC diagnosis are an enhancement of a liver nodule on the arterial phase with a washout on the portal or delayed venous phase. Nonhistologic criteria of the HCC diagnosis were adopted by two dynamic image modalities  suitable to radiologic findings of HCC mentioned above, or by one imaging modality appropriate to HCC plus a serum 00 ng/mL . In high00 ng/mL . Liver-r P < 0.05 were considered as a significant value.Cumulative incidence rates of HCC and liver-related death were calculated by the Kaplan-Meier method with a log-rank test to verify the significance. Person-years of follow-up for each subject were calculated as the time period from the date of clinical baseline survey at study enrollment to the date of HCC diagnosis, the date of death, or the date of last follow-up or at least June 30, 2012, whichever occurred first. Cox proportional-hazards regression was used for univariate analysis and multivariate analysis to determine the most significant and independent variables related to the development of HCC and liver-related mortality. Hazard ratios (HR) and corresponding 95% confidence intervals (95% CI) were calculated to estimate the degree of association between risk variables and the development of HCC or liver-related death. Statistical analyses were performed using SPSS Statistics version 18.0.The clinical characteristics of 111 HCV-infected patients  are listed in 3), and low serum albumin level (<3.0 g/dL) were significant risk factors associated with the development of HCC. Clinical factors with P value less than 0.05 on the univariate analysis were incorporated into a multivariate analysis. The risk of HCC development was higher in subjects with high viral load of HCV RNA than subjects with low viral load  ( P = 0.014), initial presence of cirrhosis , and low platelet count  were other independent risk factors for the cumulative incidence of HCC , initial presence of cirrhosis, high viral load of serum HCV RNA (>6 log titer of HCV RNA IU/mL), low platelet count  . The fiv= 0.032) . Old agee of HCC .  Table 3), and low serum albumin level (<3.0 g/dL) were significant risk factors associated with liver-related mortality on univariate analysis. However, the viral load of serum HCV RNA was not significant. Multivariate analysis with Cox-proportional hazards models finally indicated initial presence of cirrhosis  and low serum albumin level  as significant risk factors for liver-related death  at the study entry were based on classifying study participants into subjects with high viral load or low viral load [5 copies/mL) and low (<105 copies/mL) viral load [It is an important matter to determine the threshold value of viral load associated with an increased risk of long-term adverse outcomes in HCV-infected patients. Currently, clinical studies for cut-off serum level of hepatitis C viral load relevant to the development of HCV-related HCC are rare. In one study, the median detectable serum HCV RNA levels . This result should be further evaluated because HCV genotypes in our study were examined in a small proportion of study subjects who were in need of anti-HCV therapy. A meta-analysis of controlled trials has shown that antiviral therapy reduced the rate of HCC development in patients with type C liver cirrhosis [In addition to HCV RNA viral load, in the present study, old age, low platelet count, and the presence of cirrhosis were found to be significant and independent risk factors for the development of HCC. Although the patient age ≧ 50 at the study entry was associated with HCC development, the period from the diagnosis of HCV infection would be more important than the patient age at the study recruitment, as shown in case of HBV infection. However, it was difficult to know exactly the time period from HCV infection to study recruitment of subjects because of the innate limitation of this retrospective study. Several studies demonstrated that HCV genotype 1b was more closely related to the development of HCC than the genotype non-1b , 21–24, irrhosis . Previouirrhosis –31. Receirrhosis –34. In tSVR is known to be associated with not only the inhibition of HCC development, but also the control of all-cause mortality and liver-related mortality in chronically HCV-infected patients , 36; furThere were several limitations that could not be averted in this study. First, this is a single-center, hospital-based cohort study with a small sample size and relatively short follow-up duration. So, multicenter, population-based long-term follow-up data are needed to strengthen and generalize the study results. Second, because the study was retrospective in nature, we could not escape unmeasured or unrecorded clinical data conducting the statistical analyses. Third, we could not consider suggestive baseline characteristics, such as body mass index, amount of alcohol consumption, or presence of diabetes mellitus, which are considered to be significant risk factors predicting the development of HCC in patients with chronic HCV infection. Fourth, the serum level of HCV RNA is a dynamic parameter in patients with chronic hepatitis C; however, we presented the measurement of viral load from a study entry point in time, which could not give the complete picture of the association of the severity of the liver disease based on the serologic fluctuation of viral load. Although the influence of these limitations on our results would not be substantial, these considerations indicate the need for care in interpretation of these results.This retrospective cohort study demonstrated that the serum HCV RNA titer may be considered to be an independent risk factor affecting the development of HCC but not liver-related mortality in HCV-infected patients. Although any interpretation of these results requires careful consideration, the establishment of risk factors for HCC, such as hepatitis C viral load, may be useful in determining a follow-up strategy in HCV-infected patients. Furthermore, large-scaled long-term follow-up studies to assess whether the present results can be generalized or are representative of other populations are needed.