Network Medicine for Alzheimer's Disease and Traditional Chinese Medicine.

Alzheimer's Disease (AD) is a neurodegenerative condition that currently has no known cure. The principles of the expanding field of network medicine (NM) have recently been applied to AD research. The main principle of NM proposes that diseases are much more complicated than one mutation in one gene, and incorporate different genes, connections between genes, and pathways that may include multiple diseases to create full scale disease networks. AD research findings as a result of the application of NM principles have suggested that functional network connectivity, myelination, myeloid cells, and genes and pathways may play an integral role in AD progression, and may be integral to the search for a cure. Different aspects of the AD pathology could be potential targets for drug therapy to slow down or stop the disease from advancing, but more research is needed to reach definitive conclusions. Additionally, the holistic approaches of network pharmacology in traditional Chinese medicine (TCM) research may be viable options for the AD treatment, and may lead to an effective cure for AD in the future.

Risk stratification based on thyroid cytology: can we rely on national data?

PURPOSE: Determine correlation of malignancy rates between fine needle aspiration (FNA) biopsy and surgical specimen in an urban academic environment. METHODS: Retrospective review at an academic medical center of fine needle aspiration biopsies and surgical specimens in a head and neck otolaryngology practice between 2000 and 2012. RESULTS: Of the 74 biopsies diagnosed as follicular lesion, 34 (45.9%) were malignant. Of the 45 biopsies diagnosed as follicular neoplasm, 22 (48.9%) were malignant. These results are significantly higher than the average risk of malignancy cited by the American Thyroid Association of 5%-10% and 20%-30% for follicular lesions and neoplasms respectively. CONCLUSIONS: The rate of malignancy based on a FNA diagnosis of indeterminate cytology (follicular lesion or follicular neoplasm) can vary greatly among different institutions. Thyroid surgeons should be aware of their local pathology practices to better guide therapy and counsel patients.

Benralizumab in Severe Eosinophilic Asthma and Chronic Rhinosinusitis with Nasal Polyps: The Real-World, Multi-Country RANS Observational Study.

Purpose: Real-world evidence of benralizumab effectiveness on nasal polyps (NP) and asthma outcomes in patients with severe eosinophilic asthma (SEA) and comorbid chronic rhinosinusitis with NP are limited. The objective of this study was to assess NP and asthma outcomes in benralizumab-treated patients with SEA and comorbid NP in a real-world setting. Patients and Methods: RANS was a retrospective, multi-country observational study (ClinicalTrials.gov: NCT05180357) using medical chart reviews of adults with SEA and comorbid NP. Total NP Score (NPS), SinoNasal Outcome Test-22 (SNOT-22) total score, annualized exacerbation rate (AER), and 6-item Asthma Control Questionnaire (ACQ-6) and Asthma Control Test (ACT) scores during the 12 months pre-index (baseline) and post-index (follow-up) were measured. Clinically meaningful improvement from baseline following treatment, in terms of total NPS (≥1-point reduction), SNOT-22 total (≥8.9-point reduction), ACQ-6 (≥0.5-point reduction) or ACT (≥3-point increase) scores, were reported. Results: A total of 233 patients were included. Baseline mean (standard deviation [SD]) NPS and SNOT-22 total scores were 3.8 (2.4) and 47.5 (22.6), respectively. The mean change (95% confidence interval [CI]) from baseline was -1.2 (-1.7, -0.6) for NPS, and -19.8 (-23.6, -15.9) for SNOT-22. The AER (95% CI) was 1.2 (0.96, 1.41) at baseline and 0.2 (0.13, 0.28) at follow-up. Mean (SD) ACQ-6 and ACT scores were 1.6 (1.3) and 15.0 (5.2) at baseline and 0.8 (1.0) and 22.0 (3.9) at follow-up, respectively. The proportion of patients who achieved clinically meaningful improvements in NPS, SNOT-22 total, ACQ-6, and ACT scores was 49.1%, 67.6%, 56.6%, and 81.1%, respectively. Conclusion: In this real-world study, improvements in NP and asthma outcomes in patients with SEA and comorbid NP were observed during the 12 months following benralizumab initiation.

Understanding Shield Laws.

In anticipation of extraterritorial application of antiabortion laws, many states have enacted laws that attempt to shield abortion providers, helpers, and patients from civil, professional, or criminal liability associated with legal abortion care. This essay analyzes and compares the statutory schemes of the seven early adopting shield states: California, Connecticut, Delaware, Illinois, Massachusetts, New Jersey, and New York. After describing what the laws do and how they operate, we offer reflections on coming disputes, areas of legal uncertainty, and ways to improve future shield laws.

Abortion Shield Laws.

Abortion Shield LawsThe overturning of Roe v. Wade has created new obstacles for physicians providing reproductive health care. Cohen et al. review the new development of abortion shield laws, which some abortion-supportive states have passed to protect physicians from attempts by states with abortion bans to enforce their laws beyond their borders.

An Updated Patient-Centered Sialadenitis Instrument: The Obstructive Salivary Problem Impact Test (SPIT).

OBJECTIVE: The Chronic Obstructive Sialadenitis Symptoms questionnaire (COSS) was created to assess chronic sialadenitis symptoms and treatment response, but its development lacked patient input and validation. We analyzed COSS responses and feedback from sialadenitis patients and physician experts to create the novel obstructive Salivary Problem Impact Test (SPIT), a new standardized measure of sialadenitis-associated symptoms. METHODS: We analyzed COSS responses via exploratory factor analysis (EFA) to identify essential symptom domains and reduce overlap in questions. Sialadenitis patients evaluated the significance of index symptoms identified from the literature review. Expert physicians rated symptom relevance in clinical assessment. An updated questionnaire (SPIT) was piloted with both patient and expert interviews to optimize structure and readability. The SPIT was assessed for internal consistency, construct validity, and test-retest stability. RESULTS: EFA of 310 COSS responses demonstrated 3 main symptom domains (functional impact, pain, swelling) that explained 58.4% of response variance. Results were not statistically different when collapsing from 11 to 5 question response options. Experts (n = 5) ranked gland swelling, mealtime pain, and foul taste as most clinically important, while patients (n = 12) ranked swelling, non-mealtime pain, and difficulty eating as most bothersome. Most patients experienced sialadenitis-related functional or psychosocial impairment. Following interviews for question refinement, a 25-question survey was finalized. SPIT responses from 50 sialadenitis patients demonstrated internal consistency (Cronbach's alpha = 0.96), 14-day stability (p < 0.001), and agreement with Oral Health Impact Profile-14 scores (p < 0.0001). CONCLUSIONS: We developed the SPIT instrument to improve usability and content validity in chronic sialadenitis evaluation. The psychometric assessment demonstrated high construct validity and test-retest reliability. Further work will assess longitudinal changes with treatment. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:539-546, 2023.

Perioperative Analgesia for Thyroid and Parathyroid Surgery: A Review of Current Practices.

This article discusses the algorithms and published practice patterns on perioperative analgesia for thyroid and parathyroid surgery. This includes medications and techniques used for general anesthesia, local anesthesia including nerve block methods, and oral medication used for postoperative pain control. The authors also discuss multimodality pain control and the increased trend to reduce opioid analgesics without inadequate pain control or patient satisfaction.

Contextualizing Medicaid reimbursement rates for abortion procedures.

OBJECTIVE: Low Medicaid reimbursement rates have been cited as a key threat to abortion clinic sustainability in the United States. This study examines differences between Medicaid and Medicare reimbursements for abortion and miscarriage management procedures under a fee-for-service (FFS) model. STUDY DESIGN: Using 2017 Medicaid and Medicare Physician fee schedules, we extracted reimbursement data for the two most commonly-billed abortion procedures and two miscarriage management procedures for 45 states and the District of Columbia (DC). We compared Medicaid and Medicare reimbursement rates for each procedure by state. RESULTS: Medicaid reimbursement rates for both procedures varied widely across the states. Medicaid rates for second-trimester abortion procedures had the widest range; $79-$626. Median Medicaid reimbursement rates were lower than median Medicare rates for first- and second-trimester abortion procedures. Median reimbursement rates for first-trimester induced abortion were lower than median reimbursement rates for miscarriage management for both Medicaid and Medicare. CONCLUSION: Our findings indicate that Medicaid reimbursement rates for abortion are low; the median patient cost for a first- and second-trimester abortion have been reported as $490 and $750, respectively. Median Medicaid reimbursement rates for a first- and second-trimester abortion covers approximately 37% and 41% of patient costs for a first- and second-trimester abortion. Further, while induced abortion procedures are similar to miscarriage management procedures, Medicaid and Medicare reimbursement rates are lower for first- and second-trimester abortion procedures. IMPLICATION STATEMENT: Ensuring reimbursement rates are closely aligned with procedural costs bolsters provider willingness to accept Medicaid. Data that highlights the potential impact of fee-for-service reimbursement rates on healthcare provision and ultimately patient access can help inform healthcare policies. This is especially important as more states consider expanding Medicaid coverage of abortion.

Deep learning-based classification of multi-categorical Alzheimer's disease data.

It is urgent to find the appropriate technology for the early detection of Alzheimer's disease (AD) due to the unknown AD etiopathologies that bring about serious social problems. Early detection of mild cognitive impairment (MCI) has pivotal importance in delaying or preventing the AD onset. Herein, we utilize deep learning (DL) techniques for the purpose of multiclass classification between normal control, MCI, and AD subjects. We used multi-categorical data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) including brain imaging measurements, cognitive test results, cerebrospinal fluid measures, ApoE4 status, and age. We achieved an overall accuracy of 87.197% for our artificial neural network classifier and a similar overall accuracy of 88.275% for our 1D convolutional neural network classifier. We conclude that DL-based techniques are powerful tools in analyzing ADNI data although further method refinements are needed.

Blockchain in Healthcare: A Patient-Centered Model.

A blockchain is a system for storing and sharing information that is secure because of its transparency. Each block in the chain is both its own independent unit containing its own information, and a dependent link in the collective chain, and this duality creates a network regulated by participants who store and share the information, rather than a third party. Blockchain has many applications in healthcare, and can improve mobile health applications, monitoring devices, sharing and storing of electronic medical records, clinical trial data, and insurance information storage. Research about blockchain and healthcare is currently limited, but blockchain is on the brink of transforming the healthcare system; through its decentralized principles, blockchain can improve accessibility and security of patient information, and can therefore overturn the healthcare hierarchy and build a new system in which patients manage their own care.

Alzheimer's Pathogenesis, Metal-Mediated Redox Stress, and Potential Nanotheranostics.

Alzheimer's disease (AD) characterized by insoluble amyloid-ß (Aß) deposits, neurofibrillary tangles (NFTs), and neuronal demise. The influence of environmental and genetic factors on AD progression remains elusive, however evidence suggests biometal dyshomeostasis elicits neuronal death, neuroinflammation, and accumulated oxidative damages in AD brain. As such, three pathways have been identified that result from abnormal biometal accumulation and increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in AD brain parenchyma: (1) the damage caused by direct oxidation of cellular components such as DNA and proteins; (2) the oligomerization of Aß and NFTs, and (3) the promotion of apoptosis through NF-κB signaling pathway. Finally, given recent developments in nanotechnology, we have briefly reviewed potential nanotheranostic agents as potential AD theranostics.

Modulation of SPARC/Hevin Proteins in Alzheimer's Disease Brain Injury.

Alzheimer's disease (AD) is an age-related progressive form of dementia that features neuronal loss, intracellular tau, and extracellular amyloid-ß (Aß) protein deposition. Neurodegeneration is accompanied by neuroinflammation mainly involving microglia, the resident innate immune cell population of the brain. During AD progression, microglia shift their phenotype, and it has been suggested that they express matricellular proteins such as secreted protein acidic and rich in cysteine (SPARC) and Hevin protein, which facilitate the migration of other immune cells, such as blood-derived dendritic cells. We have detected both SPARC and Hevin in postmortem AD brain tissues and confirmed significant alterations in transcript expression using real-time qPCR. We suggest that an infiltration of myeloid-derived immune cells occurs in the areas of diseased tissue. SPARC is highly expressed in AD brain and collocates to Aß protein deposits, thus contributing actively to cerebral inflammation and subsequent tissue repair, and Hevin may be downregulated in the diseased state. However, further research is needed to reveal the exact roles of SPARC and Hevin proteins and associated signaling pathways in AD-related neuroinflammation. Nevertheless, normalizing SPARC/Hevin protein expression such as interdicting heightened SPARC protein expression may confer a novel therapeutic opportunity for modulating AD progression.

Rethinking Malignancy Risk in Indeterminate Thyroid Nodules with Positive Molecular Studies: Southern California Permanente Experience.

OBJECTIVES: To recognize that thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS; Bethesda III) have different risks of malignancy based on genetic mutation and to consider molecular testing of nodules with AUS/FLUS to help avoid unnecessary morbidity or cost. STUDY DESIGN: Retrospective cohort study. SETTING: Multiple locations within Southern California Permanente Medical Group. SUBJECTS AND METHODS: Patients included those with indeterminate thyroid nodules and AUS/FLUS on 2 separate fine-needle aspirations with positive ThyGenX testing from 2014 to 2017 who underwent thyroid surgery. Patients were classified as having benign or malignant disease. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features was considered benign. RESULTS: A total of 231 patients had repeat AUS/FLUS with positive molecular testing and surgery. The most frequent type of malignancy was papillary carcinoma, followed by follicular carcinoma. The overall prevalence of malignancy in nodules with mutations was 74.0%, although there was considerable variation: BRAF = 100%, RET = 100%, PAX8-PPARγ = 84.6%, HRAS = 70.7%, NRAS = 63.4%, and KRAS = 33%-a statistically significant finding (P < .001). CONCLUSIONS: Not all molecular mutations in thyroid nodules with AUS/FLUS have a high risk of malignancy. Of note, patients with BRAF and RET mutations in our population had a 100% risk of malignancy. Patients with PAX, HRAS, or NRAS mutations had a high risk of malignancy, while patients with KRAS mutations had a lower risk of malignancy. Further studies are needed to determine if the presence of certain molecular mutations can help personalize care and aid in the decision for thyroid surgery.

Identification and Analysis of Alzheimer's Candidate Genes by an Amplitude Deviation Algorithm.

BACKGROUND: Alzheimer's disease (AD) is the most common form of senile dementia. However, its pathological mechanisms are not fully understood. In order to comprehend AD pathological mechanisms, researchers employed AD-related DNA microarray data and diverse computational algorithms. More efficient computational algorithms are needed to process DNA microarray data for identifying AD-related candidate genes. METHODS: In this paper, we propose a specific algorithm that is based on the following observation: When an acrobat walks along a steel-wire, his/her body must have some swing; if the swing can be controlled, then the acrobat can maintain the body balance. Otherwise, the acrobat will fall. Based on this simple idea, we have designed a simple, yet practical, algorithm termed as the Amplitude Deviation Algorithm (ADA). Deviation, overall deviation, deviation amplitude, and 3δ are introduced to characterize ADA. RESULTS: 52 candidate genes for AD have been identified via ADA. The implications for some of the AD candidate genes in AD pathogenesis have been discussed. CONCLUSIONS: Through the analysis of these AD candidate genes, we believe that AD pathogenesis may be related to the abnormality of signal transduction (AGTR1 and PTAFR), the decrease in protein transport capacity (COL5A2 (221729_at), COL5A2 (221730_at), COL4A1), the impairment of axon repair (CNR1), and the intracellular calcium dyshomeostasis (CACNB2, CACNA1E). However, their potential implication for AD pathology should be further validated by wet lab experiments as they were only identified by computation using ADA.

Alzheimer's Disease and Its Potential Alternative Therapeutics.

Alzheimer's Disease (AD) is a chronic neurodegenerative disease that affects over 5 million individuals in the United States alone. Currently, there are only two kinds of pharmacological interventions available for symptomatic relief of AD; Acetyl Cholinesterase Inhibitors (AChEI) and N-methyl-D-aspartic Acid (NMDA) receptor antagonists and these drugs do not slow down or stop the progression of the disease. Several molecular targets have been implicated in the pathophysiology of AD, such as the tau (τ) protein, Amyloid-beta (Aß), the Amyloid Precursor Protein (APP) and more and several responses have also been observed in the advancement of the disease, such as reduced neurogenesis, neuroinflammation, oxidative stress and iron overload. In this review, we discuss general features of AD and several small molecules across different experimental AD drug classes that have been studied for their effects in the context of the molecular targets and responses associated with the AD progression. These drugs include: Paroxetine, Desferrioxamine (DFO), N-acetylcysteine (NAC), Posiphen/-(-)Phenserine, JTR-009, Carvedilol, LY450139, Intravenous immunoglobulin G 10%, Indomethacin and Lithium Carbonate (Li2CO3).

Deep learning and virtual drug screening.

Current drug development is still costly and slow given tremendous technological advancements in drug discovery and medicinal chemistry. Using machine learning (ML) to virtually screen compound libraries promises to fix this for generating drug leads more efficiently and accurately. Herein, we explain the broad basics and integration of both virtual screening (VS) and ML. We then discuss artificial neural networks (ANNs) and their usage for VS. The ANN is emerging as the dominant classifier for ML in general, and has proven its utility for both structure-based and ligand-based VS. Techniques such as dropout, multitask learning and convolution improve the performance of ANNs and enable them to take on chemical meaning when learning about the drug-target-binding activity of compounds.

Expression of Oligodendrocyte Marker during Peripheral-Central Transitional Zone Formation of the Postnatal Mouse Cochlear Nerve.

Objective To better understand oligodendrocyte protein expression along the mouse cochlear nerve in postnatal mice. Study Design In vivo murine study. Setting Research laboratory. Subjects and Methods Swiss Webster mice used at multiple postnatal days (0, 1, 3, 5, 7, 8, 10, 14, 30, and 60). There were 5 replicates at each postnatal day. Cryosection was done to produce sections that included the cochlear nucleus, cochlear nerve, and cochlea in a single sample. Differential interference contrast (DIC) microscopy and immunofluorescence with antibodies specific to the oligodendrocyte protein Olig2 were used to study the cochlear nerve of Swiss Webster mice at postnatal days. Results The myelination of central nervous system projections initiates in close proximity to the peripheral nervous system-central nervous system transitional zone (PCTZ), and oligodendrocytes in neonatal mice are seen with immunohistochemistry peripheral to the DIC-PCTZ interface. Conclusions As the PCTZ migrates from the brain to the cochlea, oligodendrocytes are a part of peripheral extension of central nervous system tissue along the cochlear nerve. Expression of oligodendrocyte marker Oligo2 was observed peripherally to the formation of PCTZ, as determined by DIC microscopy.

Facial Nerve Schwannomas Mimicking as Vestibular Schwannomas.

Objective The objective of this study was to identify preoperative and intraoperative findings that may aid in distinguishing facial nerve schwannomas (FNS) from vestibular schwannomas (VSs), particularly in cases limited to the internal auditory canal (IAC) and cerebellopontine angle (CPA). Study Design This was a retrospective study. Setting This study was set at a Tertiary Referral Center. Patients Seventeen cases from October 2002 to July 2015 with an IAC/CPA mass presumed to be a VS who were found to have a FNS intraoperatively. Main Outcome Measures The main outcome measures included preoperative presentation, intraoperative findings, and subsequent intervention. Results Preoperative hearing loss and imbalance were seen in 70.5 and 64.7%, respectively. Suspicious intraoperative findings included: facial nerve incorporated intimately with the tumor capsule in 12 cases; spontaneous action potentials noted while drilling the bony IAC in 3 cases; and action potentials noted on stimulation of the entire tumor capsule in 10 cases. The mean long-term facial function was House-Brackmann grade II and the mean length of follow-up was 4.86 years. Conclusion FNSs are rare and may be difficult to distinguish from VS preoperatively. Surgical findings that should raise concern include spontaneous action potentials during drilling the bony IAC, absence of a plane of dissection between the facial nerve and tumor, or stimulation of the tumor capsule.

Classification of MRI and psychological testing data based on support vector machine.

Alzheimer's disease (AD) is a progressive, and often fatal, brain disease that causes neurodegeneration, resulting in memory loss as well as other cognitive and behavioral problems. Here, we propose a novel multimodal method combining independent components from MRI measures and clinical assessments to distinguish Alzheimer's patients or mild cognitive impairment (MCI) subjects from healthy elderly controls. 70 AD subjects (mean age: 77.15 ± 6.2 years), 98 MCI subjects (mean age: 76.91 ± 5.7 years), and 150 HC subjects (mean age: 75.69 ± 3.8 years) were analyzed. Our method includes the following steps: pre-processing, estimating the number of independent components from the MR image data, extracting effective voxels for classification, and classification using a support vector machine (SVM)-based classifier. As a result, with regards to classifying AD from healthy controls, we achieved a classification accuracy of 97.7%, sensitivity of 99.2%, and specificity of 96.7%; for differentiating MCI from healthy controls, we achieved a classification accuracy of 87.8%, a sensitivity of 86.0%, and a specificity of 89.6; these results are better than those obtained with clinical measurements alone (accuracy of 79.5%, sensitivity of 74.0%, and specificity of 85.1%). We found that (1) both AD patients and MCI subjects showed brain tissue loss, but the volumes of gray matter loss in MCI subjects was far less, supporting the notion that MCI is a prodromal stage of AD; and (2) combining gray matter features from MRI and three commonly used measures of mental status, cognitive function improved classification accuracy, sensitivity, and specificity compared with classification using only independent components or clinical measurements.

Outcomes of nonsurgical management of locally advanced carcinomas of the sinonasal cavity.

OBJECTIVE: To determine the outcome of definitive concurrent chemoradiation with platinum for locally advanced sinonasal carcinomas. STUDY DESIGN: Retrospective cohort. METHODS: Twenty-three nonsurgically and definitively treated patients diagnosed between July 1998 and February 2009 were analyzed. Patients with adenoid cystic carcinoma or adenocarcinoma were treated with photons and neutrons; the other histologies received photons alone. The vast majority received chemotherapy. Descriptive statistics were utilized, and Kaplan-Meier estimates were computed. RESULTS: Female (57%) and Caucasian (74%) preponderance were observed. Eighty-seven percent were unresectable; the maxillary and nasoethmoid sites were equally prevalent. Intensity-modulated radiation therapy (IMRT) and photons alone were utilized in 74% and 70%, respectively. Platinum agents were given in 95% of chemotherapy patients. Complete response was observed in 64% of patients. Median progression-free survival (PFS) and overall survival (OS) were 28.8 and 65.3 months, respectively. Three-year PFS and OS rates were 44% and 72%, respectively; 5-year PFS and OS rates were 30% and 60%, respectively. Intensity-modulated radiation therapy and a maxillary site of origin showed a trend toward superior PFS; higher-dose regimens were associated with somewhat shorter PFS. Relapse was observed in 59% of patients, predominantly local. There were few unanticipated adverse effects, and no grade IV/V events were reported. CONCLUSION: Advanced sinonasal carcinomas are chemoradiosensitive tumors, albeit with a high propensity for local relapse. There is a definite indication for IMRT and a potential curative role of platinum-based chemoradiation regimens. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:855-861, 2017.