Comparison of 6 tests for diagnosing minimal hepatic encephalopathy and predicting clinical outcome: A prospective, observational study.

BACKGROUND AND AIMS: Current guidelines recommend the assessment for minimal HE in patients with liver cirrhosis. Various efforts were made to find tools that simplify the diagnosis. Here, we compare the 6 most frequently used tests for their validity and their predictive value for overt hepatic encephalopathy (oHE), rehospitalization, and death. APPROACH AND RESULTS: One hundred thirty-two patients with cirrhosis underwent the Portosystemic Encephalopathy-Syndrome-Test yielding the psychometric hepatic encephalopathy score (PHES), Animal Naming Test (ANT), Critical Flicker Frequency (CFF), Inhibitory Control Test (ICT), EncephalApp (Stroop), and Continuous Reaction Time Test (CRT). Patients were monitored for 365 days regarding oHE development, rehospitalization, and death. Twenty-three patients showed clinical signs of HE grade 1-2 at baseline. Of the remaining 109 neurologically unimpaired patients, 35.8% had abnormal PHES and 44% abnormal CRT. Percentage of abnormal Stroop (79.8% vs. 52.3%), ANT (19.3% vs. 51.4%), ICT (28.4% vs. 36.7%), and CFF results (18.3% vs. 25.7%) changed significantly when adjusted norms were used for evaluation instead of fixed cutoffs. All test results correlated significantly with each other ( p <0.05), except for CFF. During follow-up, 24 patients developed oHE, 58 were readmitted to the hospital, and 20 died. Abnormal PHES results were linked to oHE development in the multivariable model. No other adjusted test demonstrated predictive value for any of the investigated endpoints. CONCLUSIONS: Where applicable, the diagnosis of minimal HE should be made based on adjusted norm values for the tests, exclusively. The minimal HE tests cannot be equated with one another and have an overall limited value in predicting clinical outcomes.

Understanding COVID-19 impact on cervical, breast, and colorectal cancer screening among federally qualified healthcare centers participating in "Back on track with screening" quality improvement projects.

The COVID-19 pandemic has contributed to decreases in breast, colorectal, and cervical cancer screenings between 86 and 94% compared to three-year averages. These postponed screenings have created backlogs that systems will need to address as healthcare facilities re-open for preventive care. The American Cancer Society is leading a 17-month intervention with 22 federally qualified health centers (FQHCs) across the United States aimed at reducing cancer incidence and mortality disparities and alleviating additional strain caused by COVID-19. This study describes COVID-related cancer screening service disruptions reported by participating FQHCs. Selected FQHCs experienced service disruptions and/or preventive care cancellations due to COVID-19 that varied in severity and duration. Fifty-nine percent stopped cancer screenings completely. Centers transitioned to telehealth visits or rescheduled for the future, but the impact of these strategies may be limited by continued pandemic-related disruptions and the inability to do most screenings at home; colon cancer screening being the exception. Most centers have resumed in-person screening, but limited in person appointments and high levels of community transmission may reduce FQHC abilities to provide catch-up services. FQHCs provide critical cancer prevention services to vulnerable populations. The delivery of culturally competent, high-quality healthcare can mitigate and potentially reverse racial and ethnic disparities in cancer prevention testing and treatment. Ensuring and expanding access to care as we move out of the pandemic will be critical to preventing excess cancer incidence and mortality in vulnerable populations.

A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor.

BACKGROUND: Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor. METHODS: We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). RESULTS: Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. CONCLUSIONS: MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).

A prospective trial of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: Results at the 2-year follow-up.

OBJECTIVE: Magnetic resonance guided focused ultrasound (MRgFUS) has recently been investigated as a new treatment modality for essential tremor (ET), but the durability of the procedure has not yet been evaluated. This study reports results at a 2- year follow-up after MRgFUS thalamotomy for ET. METHODS: A total of 76 patients with moderate-to-severe ET, who had not responded to at least two trials of medical therapy, were enrolled in the original randomized study of unilateral thalamotomy and evaluated using the clinical rating scale for tremor. Sixty-seven of the patients continued in the open-label extension phase of the study with monitoring for 2 years. Nine patients were excluded by 2 years, for example, because of alternative therapy such as deep brain stimulation (n = 3) or inadequate thermal lesioning (n = 1). However, all patients in each follow-up period were analyzed. RESULTS: Mean hand tremor score at baseline (19.8 ± 4.9; 76 patients) improved by 55% at 6 months (8.6 ± 4.5; 75 patients). The improvement in tremor score from baseline was durable at 1 year (53%; 8.9 ± 4.8; 70 patients) and at 2 years (56%; 8.8 ± 5.0; 67 patients). Similarly, the disability score at baseline (16.4 ± 4.5; 76 patients) improved by 64% at 6 months (5.4 ± 4.7; 75 patients). This improvement was also sustained at 1 year (5.4 ± 5.3; 70 patients) and at 2 years (6.5 ± 5.0; 67 patients). Paresthesias and gait disturbances were the most common adverse effects at 1 year-each observed in 10 patients with an additional 5 patients experiencing neurological adverse effects. None of the adverse events worsened over the period of follow-up, and 2 of these resolved. There were no new delayed complications at 2 years. INTERPRETATION: Tremor suppression after MRgFUS thalamotomy for ET is stably maintained at 2 years. Latent or delayed complications do not develop after treatment. Ann Neurol 2018;83:107-114.

Long-Term Outcomes of Bilateral Pallidal Deep Brain Stimulation for X-Linked Dystonia and Parkinsonism.

BACKGROUND: X-linked dystonia parkinsonism (XDP) causes adult-onset progressive dystonia and parkinsonism, which may not respond to pharmacotherapy. OBJECTIVE: Previous case reports have reported beneficial effects from bilateral pallidal (GPi) deep brain stimulation (DBS). Here, we report the long-term clinical outcomes of 3 patients treated at our center. METHODS: All patients presented with medication refractory dystonia and parkinsonism. They were followed prospectively. Clinical evaluations included the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS). Adverse events were recorded. RESULTS: The average length of follow-up was 45.7 months. No serious adverse events occurred. All patients experienced an immediate and sustained improvement in dystonia. Mean percentage improvement in motor subscores of BFMDRS was 63.5% at the last follow-up visit. Parkinsonism was less responsive to neuromodulation, with a mean improvement in UPDRS-III of 39.5%. Standard pallidal stimulation parameters were used. Freezing of gait developed after DBS therapy in 2 patients, stimulation-induced in one and due to disease progression in the other. CONCLUSION: Bilateral pallidal DBS resulted in significant and sustained improvement in dystonia and moderate improvement in parkinsonism. Pallidal DBS represents an important treatment option for XPD for the management of motor symptoms.

Predictive factors of outcome in primary cervical dystonia following pallidal deep brain stimulation.

BACKGROUND: Improvement after bilateral globus pallidus internus deep brain stimulation (DBS) in primary generalized dystonia has been negatively associated with disease duration and age, but no predictive factors have been identified in primary cervical dystonia (CD). METHODS: Patients treated with bilateral globus pallidus internus DBS for primary CD from 2 DBS centers with preoperative and postoperative Toronto Western Spasmodic Torticollis Rating Scales (TWSTRS) were studied retrospectively to explore possible predictors of response. RESULTS: Patients showed significantly improved TWSTRS total and severity scores (n = 28, mean 55.6% and 50.8%, respectively, both P < .001). Patients with lateral shift at baseline had less improvement in TWSTRS severity subscores (P = .02). No correlations between outcomes and disease duration, age at dystonia onset or surgery, baseline scores, or other included variables were found. CONCLUSIONS: Although this is the largest study supporting efficacy of bilateral pallidal DBS in primary CD, no major clinical predictive outcomes of surgical benefit were identified.

Rivastigmine is associated with restoration of left frontal brain activity in Parkinson's disease.

The objective of this study was to investigate how acetylcholinesterase inhibitor (ChEI) treatment affects brain function in Parkinson's disease (PD). Twelve patients with PD and either dementia or mild cognitive impairment underwent task-free functional magnetic resonance imaging before and after 3 months of ChEI treatment and were compared with 15 age- and sex-matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low-frequency fluctuations. At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (eg, caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (eg, lateral prefrontal cortex), and episodic memory (eg, precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased posttreatment compared with baseline and was no longer different from controls. Treatment-related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention. PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared with controls, and rivastigmine is associated with performance-related normalization in the left frontal cortex function.

Use of pallidal deep brain stimulation in postinfarct hemidystonia.

BACKGROUND/AIMS: Reports of outcomes in treating dystonia secondary to stroke with deep brain stimulation (DBS) are limited. We report our experience with 3 patients, all with infarcts involving the striatum, who developed hemidystonia and were treated with unilateral globus pallidus interna DBS. METHODS: Case series describing characteristics and outcomes based on the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores before and after DBS at 3, 6 and at least 12 months. RESULTS: All patients reported subjective improvements after surgery. At 1 year or more after surgery, none of the 3 patients displayed a measureable improvement in the BFMDRS movement score. CONCLUSION: Our findings are consistent with previous reports of limited benefits from pallidal DBS in secondary dystonia. Future work should focus on predictive factors for DBS outcomes and the development of more sensitive assessment tools specifically for secondary dystonias as well as the exploration of alternative brain targets for stimulation.

Age nine is possible: Improving age 9 HPV initiation through a national quality improvement initiative during the COVID-19 pandemic.

The American Cancer Society collaborated with a range of healthcare partners in 2020-2022 to implement quality improvement clinical interventions with the goal of improving HPV vaccination rates among adolescents' ages 9-13. 2020 was the first cohort for which partners had been asked to submit HPV rate data for patients' ages 9-12. At least 80% of the partners across all reported project years were able and willing to report HPV rates for these ages. Partners submitted HPV initiation rates at the beginning and end of the 12-month project year along with project activities, including evidence-based interventions (EBIs) implemented. Mean initiation rates for ages 9-10 significantly increased 4.1% during 2020 compared to non-significant rate increases of 2.6% and 2.0% for ages 11-12 and age 13, respectively. In 2021, ages 9-10 initiation saw a non-significant increase of 2.2%, whereas ages 11-12 and age 13 decreased non-significantly by 0.3% and 0.1%, respectively. The 2022 cohort saw significant initiation rate increases of at least 4% across all ages, potentially a promising result of the myriad back on track HPV vaccination campaigns designed to reverse the damage of the COVID-19 pandemic on adolescent immunizations. These findings demonstrate an effective adaptation of quality improvement in increasing HPV vaccination coverage among younger ages even during a national pandemic.

TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide. In mice and humans, NAFLD progression is characterized by the appearance of TREM2-expressing macrophages in the liver. However, their mechanistic contributions to disease progression have not been completely elucidated. Here, we show that TREM2+ macrophages prevent the generation of a pro-inflammatory response elicited by LPS-laden lipoproteins in vitro. Further, Trem2 expression regulates bone-marrow-derived macrophages (BMDMs) and Kupffer cell capacity to phagocyte apoptotic cells in vitro, which is dependent on CD14 activation. In line with this, loss of Trem2 resulted in an increased pro-inflammatory response, which ultimately aggravated liver fibrosis in murine models of NAFLD. Similarly, in a human NAFLD cohort, plasma levels of TREM2 were increased and hepatic TREM2 expression was correlated with higher levels of liver triglycerides and the acquisition of a fibrotic gene signature. Altogether, our results suggest that TREM2+ macrophages have a protective function during the progression of NAFLD, as they are involved in the processing of pro-inflammatory lipoproteins and phagocytosis of apoptotic cells and, thereby, are critical contributors for the re-establishment of liver homeostasis.

Predicting overt hepatic encephalopathy after TIPS: Value of three minimal hepatic encephalopathy tests.

Background & Aims: Hepatic encephalopathy (HE) is a frequent and severe complication in patients after transjugular intrahepatic portosystemic shunt (TIPS) insertion. However, risk factors for post-TIPS HE remain poorly defined. Minimal HE (mHE) is a well-known risk factor for overt HE in patients with cirrhosis without TIPS. We aimed to evaluate three tools frequently used for diagnosing mHE for their dynamic changes and their predictive value for overt HE after TIPS. Methods: We prospectively recruited 84 consecutive patients before TIPS insertion and monitored them for 180 days for post-TIPS HE. Before TIPS insertion, the patients underwent the portosystemic encephalopathy (PSE) syndrome test, the animal naming test (ANT), and the critical flicker frequency (CFF). Patients were retested after TIPS insertion. Results: The majority of patients were male (67.9%), and the predominant indication for TIPS was refractory ascites (75%). Median age was 59 years, model for end-stage liver disease score was 12, and 66.3%, 64.6%, and 28.4% patients had evidence for mHE according to the PSE syndrome test, ANT, and CFF, respectively. Overall, 25 patients developed post-TIPS HE within 180 days after TIPS insertion. Post-TIPS incidence of overt HE was 22.2, 28.6, 45.5, and 55.6% in those with no, one, two, and three pathological tests at baseline, respectively. However, none of the three tests was significantly associated with post-TIPS HE. Of note, mean performance in all tests remained stable over time after TIPS insertion. Conclusions: PSE syndrome test, ANT and CFF, which are frequently used for diagnosing mHE have limited value for predicting HE after TIPS insertion. We could not find evidence that TIPS insertion leads to a psychometric decline in the long term. Impact and implications: This prospective observational study compared three diagnostic tests for mHE and showed the limited value of these tests for predicting overt HE in patients with cirrhosis undergoing TIPS insertion. In addition, the results suggest that cognitive performance generally remains stable after TIPS insertion. These results are important for physicians and researchers involved in the management of patients with cirrhosis undergoing TIPS procedures. The study's findings serve as a starting point for further investigations on the development of more effective strategies for predicting and managing post-TIPS HE. Clinical trial number: ClinicalTrials.gov NCT04801290.

An update on gene therapy in Parkinson's disease.

Gene therapy for Parkinson's disease (PD) may offer an alternative to current pharmacologic and surgical treatments; the former are limited by motor complications and non-motor adverse effects, and both by lack of neuroprotection. Three main strategies under investigation using gene transfer for targeted protein expression include improving availability of dopamine to the striatum with more continuous delivery, reducing activity in the subthalamic nucleus by locally inducing γ-aminobutyric acid expression, or protecting and restoring nigrostriatal neuronal function with trophic factor expression. This review summarizes the components of gene therapy for PD, the preclinical rationale for each strategy, data from the most recently published clinical trials using four different vector-gene agents, and challenges in moving gene therapy forward. Thus far, safety data from phase 1 trials have been encouraging for all four agents and one phase 2 trial suggests modest symptomatic efficacy, but definitive conclusions on efficacy cannot yet be drawn.

Depression and Anxiety Management in Parkinson Disease.

ABSTRACT: BACKGROUND: Depression and anxiety are common but underrecognized and undertreated nonmotor symptoms of Parkinson disease (PD) due to their diagnostic criteria overlapping with other PD symptoms, limited randomized controlled studies in this specific population, and the need for multidisciplinary expertise. The purpose of this article is to offer evidence-based solutions for managing comorbid depression and anxiety in patients with PD through a case study analysis. CASE STUDY: A case study is used to illustrate the somatic manifestations of anxiety in PD that leads to diagnostic challenge and multidisciplinary management. MANAGEMENT CONSIDERATIONS: The appropriate use of screening tools, pharmacological and nonpharmacological management, and education are important interventions to consider when treating depression and anxiety in PD. CONCLUSION: Effective management requires accurate assessments, individualized treatment modalities, and patient education. Nurses who are knowledgeable about the effects and management of mood disorders in PD can play an integral role in the multidisciplinary team approach for assessment, patient and caregiver education, and treatment plan implementation.

Impact of a Multilevel Quality Improvement Intervention Using National Partnerships on Human Papillomavirus Vaccination Rates.

OBJECTIVE: To evaluate the effectiveness of a multilevel intervention using national partnerships on human papillomavirus (HPV) vaccination rates. METHODS: The American Cancer Society's Vaccinate Adolescents against Cancer program is a multilevel intervention focusing on systems and providers. The 2017 cohort introduced national partnerships to deliver intervention elements and Maintenance of Certification and continuing medical education credits for physicians. Eleven federally qualified health center (FQHC) systems completed interventions in 2017. Interventions included provider training and ≥1 other evidence-based systems improvement. We compared adolescent vaccination rates in the preintervention period (2016) and intervention period (2017) among adolescents who turned 13 during the calendar year. Intervention effectiveness was assessed using repeated measures paired t tests and Cohen's d effect size for vaccination rate change. RESULTS: All FQHC systems implemented provider training plus an average of 2.3 additional systems improvements. Series initiation increased by an average of 23.6 percentage points (47.2%-70.8%). HPV completion rates increased by an average of 22.7 percentage points (24.6%-46.3%). Meningococcal and Tdap vaccination rates increased by 23.3 and 25.9 percentage points respectively (47.9%-71.2% and 48.8%-74.7%). All changes were statistically significant (all P < .05) and indicated large effect sizes (Cohen's d3 1.15). Among clinicians completing postintervention surveys, 90% reported making changes to their health care system or direct patient care based on what they had learned. CONCLUSIONS: Multilevel interventions focusing on provider training and systems changes can substantially improve on-time adolescent vaccination coverage and can be successfully performed using national partnerships and a train-the-trainer model.

Three-year follow-up of prospective trial of focused ultrasound thalamotomy for essential tremor.

OBJECTIVE: To test the hypothesis that transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) thalamotomy is effective, durable, and safe for patients with medication-refractory essential tremor (ET), we assessed clinical outcomes at 3-year follow-up of a controlled multicenter prospective trial. METHODS: Outcomes were based on the Clinical Rating Scale for Tremor, including hand combined tremor-motor (scale of 0-32), functional disability (scale of 0-32), and postural tremor (scale of 0-4) scores, and total scores from the Quality of Life in Essential Tremor Questionnaire (scale of 0-100). Scores at 36 months were compared with baseline and at 6 months after treatment to assess for efficacy and durability. Adverse events were also reported. RESULTS: Measured scores remained improved from baseline to 36 months (all p < 0.0001). Range of improvement from baseline was 38%-50% in hand tremor, 43%-56% in disability, 50%-75% in postural tremor, and 27%-42% in quality of life. When compared to scores at 6 months, median scores increased for hand tremor (95% confidence interval [CI] 0-2, p = 0.0098) and disability (95% CI 1-4, p = 0.0001). During the third follow-up year, all previously noted adverse events remained mild or moderate, none worsened, 2 resolved, and no new adverse events occurred. CONCLUSIONS: Results at 3 years after unilateral tcMRgFUS thalamotomy for ET show continued benefit, and no progressive or delayed complications. Patients may experience mild degradation in some treatment metrics by 3 years, though improvement from baseline remains significant. CLINICALTRIALSGOV IDENTIFIER: NCT01827904. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with severe ET, unilateral tcMRgFUS thalamotomy provides durable benefit after 3 years.

DM9 Domain Containing Protein Functions As a Pattern Recognition Receptor with Broad Microbial Recognition Spectrum.

DM9 domain was first identified in Drosophila melanogaster, and it was subsequently found to integrate with or without other protein domains across a wide range of invertebrates and vertebrates. In the present study, a member of DM9 domain containing protein (DM9CP) family from marine invertebrate Crassostrea gigas (designated CgDM9CP-1), which was only composed of two DM9 domains, was taken as a protein model to study the biological functions of DM9 domain and its molecular determinants. CgDM9CP-1 was found to exhibit high binding specificity and avidity toward d-mannose residue. It served as a pattern recognition receptor (PRR) with a broad range of recognition spectrum to various pathogen-associated molecular patterns, including lipopolysaccharide, peptidylglycan, mannan, and ß-1, 3-glucan in a d-mannose-dependent manner, as well as bacteria and fungi. In order to reveal the molecular mechanism underlying its pattern recognition activity, the crystal structures of wild-type and loss-of-function mutants were solved, and Asp22 and Lys43 were found to be the critical residues for ligand recognition. Moreover, CgDM9CP-1 protein was found to mainly distribute on the surface of C. gigas hemocytes, and it could be translocated into cytoplasm and colocalized with the engulfed microbes during hemocyte phagocytosis. The present result clearly indicated that CgDM9CP-1 was a PRR, and it provided an important clue for the better understanding of DM9CP function.

Early death and late morbidity after blood transfusion of injured children: a pilot study.

BACKGROUND/PURPOSE: Early postinjury death after packed red blood cell (pRBC) transfusion is attributed to uncontrolled hemorrhage and coagulopathy. The adverse immunomodulatory effects of blood transfusion are implicated in subsequent morbidity. We hypothesized that injured children requiring pRBC transfusion demonstrate patterns in outcome similar to those observed in adults. METHODS: Our prospectively collected trauma registry was queried for demographics, treatment, and outcome (2006-2009). Outcomes of children who received pRBC transfusion were compared with those of age- and Injury Severity Score (ISS)-matched children who did not receive pRBC transfusion by both univariate and multivariable analysis. RESULTS: Eight percent (43/512) of injured children received a pRBC transfusion: 20 early and 23 late. The likelihood of pRBC transfusion increased with increasing ISS (ISS <15, 2%; ISS 16-25, 17%; ISS >25, 72%). One-half of injured children who received an early pRBC transfusion died; however, most deaths were because of central nervous system injury. Both ventilator and intensive care unit days were increased in children who received pRBC transfusion as compared with those who did not. CONCLUSION: Early pRBC transfusion is associated with a high mortality in children. Late blood transfusion is associated with worse outcomes, although this relationship may not be causal. This pilot study provides evidence of an association between pRBC transfusion, morbidity, and mortality among injured children that warrants refinement in larger, prospective investigations.