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Neuroinflammation is believed to be a key process in Alzheimer’s disease (AD) pathogenesis. Recently, the neutrophil-to-lymphocyte (NLR) and lymphocyte-to-monocyte ratios (LMR) have been proposed to be useful peripheral markers of inflammation. However, it is unclear how these inflammatory ratios relate to AD pathology, such as β-amyloid (Aβ) plaques and tau tangles. Using 18 F-florbetapir and 18 F-flortaucipir positron emission tomography (PET), we sought to determine how the NLR and LMR are associated with AD pathology both cross-sectionally and longitudinally. We further evaluated associations between the NLR and LMR and longitudinal cognitive decline. Using data from the Alzheimer’s Disease Neuroimaging Initiative, we analyzed blood, PET, and cognitive data from 1544 subjects—405 cognitively normal, 838 with mild cognitive impairment (MCI), and 301 with AD. Associations between the NLR and LMR and Aβ and tau on PET were assessed using ordinary least-squares and mixed-effects regression models, while adjusting for age, sex, years of education, and apolipoprotein E ε2 or ε4 carrier status. Associations between the NLR and LMR and cognitive function, as measured by the AD Assessment Scale-Cognitive Subscale, 13-item version, were also assessed. MCI and AD subjects had higher NLR ( p  = 0.017, p  < 0.001, respectively) and lower LMR ( p  = 0.013, p  = 0.023). The NLR, but not the LMR, was significantly associated with Aβ ( p  = 0.028), suggesting that higher NLR was associated with greater Aβ deposition in the brain. Neither the NLR nor the LMR was associated with tau deposition ( p  > 0.05). A higher NLR was associated with greater longitudinal cognitive decline ( p  < 0.001). A higher ratio of peripheral neutrophils to lymphocytes, possibly reflecting an imbalance in innate versus adaptive immunity, is related to greater Aβ deposition and longitudinal cognitive decline. As the field moves toward blood-based biomarkers of AD, the altered balance of innate versus adaptive immunity could be a useful biomarker of underlying pathology and may also serve as a potential therapeutic target.

While ventricular shunts are the main treatment for adult hydrocephalus, shunt malfunction remains a common problem that can be challenging to diagnose. Computer vision-derived algorithms present a potential solution. We designed a feasibility study to see if such an algorithm could automatically predict ventriculomegaly indicative of shunt failure in a real-life adult hydrocephalus population. We retrospectively identified a consecutive series of adult shunted hydrocephalus patients over an eight-year period. Associated computed tomography scans were extracted and each scan was reviewed by two investigators. A machine learning algorithm was trained to identify the lateral and third ventricles, and then applied to test scans. Results were compared to human performance using Sørensen–Dice coefficients, calculated total ventricular volumes, and ventriculomegaly as documented in the electronic medical record. 5610 axial images from 191 patients were included for final analysis, with 52 segments (13.6% of total data) reserved for testing. Algorithmic performance on the test group averaged a Dice score of 0.809 ± 0.094. Calculated total ventricular volumes did not differ significantly between computer-derived volumes and volumes marked by either the first reviewer or second reviewer ( p  > 0.05). Algorithm detection of ventriculomegaly was correct in all test cases and this correlated with correct prediction of need for shunt revision in 92.3% of test cases. Though development challenges remain, it is feasible to create automated algorithms that detect ventriculomegaly in adult hydrocephalus shunt malfunction with high reliability and accuracy.

Purpose of Review Almost half of people diagnosed with diabetes mellitus will develop painful diabetic neuropathy (PDN), a condition greatly impacting quality of life with complicated pathology. While there are different FDA approved forms of treatment, many of the existing options are difficult to manage with comorbities and are associated with unwanted side effects. Here, we summarize the current and novel treatments for PDN. Recent Findings Current research is exploring alternative pain management treatments from the first line options of pregabalin, gabapentin, duloxetine, and amitriptyline which often have side effects. The use of FDA approved capsaicin and spinal cord stimulators (SCS) has been incredibly beneficial in addressing this. In addition, new treatments looking at different targets, such as NMDA receptor and the endocannabinoid system, show promising results. Summary There are several treatment options that have been shown to be successful in helping treat PDN, but often require adjunct treatment or alterations due to side effects. While there is ample research for standard medications, treatments such as palmitoylethanolamide and endocannabinoid targets have extremely limited clinical trials. We also found that many studies did not evaluate additional variables other than pain relief, such as functional changes nor were there consistent measurement methods. Future research should continue trials comparing treatment efficacies along with more quality of life measures.

Purpose of Review Patients diagnosed with Ehlers–Danlos syndromes (EDS), and especially those with the hypermobility subtype, often experience a diverse range of acute and chronic pain conditions throughout their lifetime. These can present in a variety of different phenotypes and comorbidities, making it difficult to develop structured treatment protocols. This review seeks to summarize the current literature to address old and novel treatments for EDS. Recent Findings Historically, medications and surgery have been used to treat patients with EDS but with low efficacy. Newer therapies that have shown promising effects for both decreasing pain and increasing quality of life include physical/occupational therapy, transcutaneous electrical nerve stimulation units, trigger point injections, low-dose naltrexone, and laser therapy. In addition, addressing the psychosocial aspects of pain with EDS through methods like cognitive behavioral therapy and patient education has shown to be vital in minimizing pain. Most research also emphasizes that pain management should not only focus on pain reduction, but on helping reduce symptoms of hypermobility, central sensitization, and fatigue to make an impactful difference. Summary Research on pain in EDS is still limited with good clinical practice guidelines often limited by poor sample size and lack of clinical studies. Treatment options should be structured based on the specific type of pain pathology and presenting symptoms of each patient and their comorbidities. Future research should attempt to prioritize larger sample sizes, clear definitions of EDS subtypes, randomized trials for treatment efficacy, and more studies dedicated to non-musculoskeletal forms of pain.

Caveolin-1 (cav-1), an integral protein of the membrane microdomains caveolae, is required for synthesis of matrix proteins by glomerular mesangial cells (MC). Previously, we demonstrated that the antifibrotic protein follistatin (FST) is transcriptionally upregulated in cav-1 knockout MC and that its administration is protective against renal fibrosis. Here, we screened cav-1 wild-type and knockout MC for FST-targeting microRNAs in order to identity novel antifibrotic therapeutic targets. We identified that miR299a-5p was significantly suppressed in cav-1 knockout MC, and this was associated with stabilization of the FST 3′UTR. Overexpression and inhibition studies confirmed the role of miR299a-5p in regulating FST expression. Furthermore, the profibrotic cytokine TGFβ1 was found to stimulate the expression of miR299a-5p and, in turn, downregulate FST. Through inhibition of FST, miR299a-5p overexpression augmented, while miR299a-5p inhibition diminished TGFβ1 profibrotic responses, whereas miR299a-5p overexpression re-enabled cav-1 knockout MC to respond to TGFβ1. In vivo, miR299a-5p was upregulated in the kidneys of mice with chronic kidney disease (CKD). miR299a-5p inhibition protected these mice against renal fibrosis and CKD severity. Our data demonstrate that miR299a-5p is an important post-transcriptional regulator of FST, with its upregulation an important pathogenic contributor to renal fibrosis. Thus, miR299a-5p inhibition offers a potential novel therapeutic approach for CKD.

Physician reviews influence how patients seek care, but dishonest reviews can be detrimental to a physician practice. It is unclear if reviews can be challenged, and processes differ and are not readily apparent. The objective of this observational study was to determine the ability to challenge dishonest negative reviews online. Commonly used websites for physician reviews as of August 2021 were utilized: Healthgrades, Vitals, RateMDs, Zocdoc, Yelp, and Google Business. Each review platform’s website was tested for leaving a physician review and process of appeal and possible removal of a negative review. The process for appeal and the steps involved in posting and appealing a review were determined, whether individuals are verified patients and criteria for verification, how physicians can respond, and the process of appealing false or defamatory reviews.Any individual can leave reviews by searching for a physician’s name or practice and visiting their profile page and can then provide a rating and written review of their experience with the physician. Many require verification to prevent suspicious activity but not proof of a medical visit, allowing significant potential for inaccurate review postings. Posting a review can be done by anyone without verification of a visit. It is challenging for physicians to remove negative online reviews, as most review platforms have strict policies against. This review concludes that physicians should be aware of their online presence and the steps that can be taken to address issues to mitigate adverse effects on their practices.

Ideally, a physical or chemical nonsurgical neurolytic procedure provides targeted neurolysis to relieve pain for a suitable length of time without causing complications. This narrative review focuses on five nonsurgical neurolytic procedures that are well-established and well-documented in the literature for the treatment of refractory neuropathic pain and peripheral neuropathies, in particular: two physical nonsurgical neurolytic techniques (cryoablation and radiofrequency ablation) and three chemoneurolytic agents (alcohol injection, phenol injection, and a high-concentration capsaicin 8% topical system). Using the definition of nonsurgical physical and chemical neurolytic procedures for neuropathic pain, a focused literature search of the PubMed database for English-language, human studies published through July 2024 included, but was not limited to, the following search terms: \"neuropathic pain\" AND \"cryoablation\", \"cryoneurolysis\", \"radiofrequency ablation\", \"alcohol neurolysis\", \"alcohol injection\", \"phenol neurolysis\", \"phenol injection\", \"chemoneurolysis\", \"topical capsaicin\", and \"TRPV1.\" While attempts were made to identify prospective clinical trials for each type of neurolytic procedure, information regarding the conduct and safety and efficacy of some of these nonsurgical neurolytic procedures was primarily limited to case studies and anecdotal evidence. The risk benefit basis of each technique is discussed, and recommendations for proper use based on the literature are summarized. Most techniques require ultrasound or fluoroscopy guidance. Pain relief typically ranges from 3 to 12 months, with repeat neurolytic procedures often required to maintain suitable levels of pain relief. The authors provide their insights as to the best utilization of these identified nonsurgical physical and chemoneurolytic procedures for the treatment of refractory neuropathic pain in different patient populations based on neural targets. Together, these five nonsurgical neurolytic techniques provide patients and physicians with a variety of options for the treatment of refractory neuropathic pain.

Reduced cerebrospinal fluid (CSF) clearance is a suggested pathological feature of Alzheimer's disease (AD). There is increasing evidence from non-human studies that the nasal mucosa may serve as a CSF drainage site, particularly through the cribriform plate into the nose. We explored this pathway using dynamic PET with [1-11C]-Butanol, a radiotracer with high permeability and minimal brain binding, to examine the relationship between egress from the brain and the nasal turbinates, particularly in the context of amyloid pathology. Cognitively normal subjects (n = 24; 65+ years) underwent 60 minutes of dynamic PET [1-11C]Butanol imaging. The cohort consisted of 8 amyloid PET Aβ+ and 16 amyloid PET Aβ- participants. Regions of interest (ROI) included the lateral orbitofrontal cortex (LOF), cribriform plate, and the superior, middle and inferior nasal turbinates. Time-activity curves were analyzed to model tracer influx, egress, and area under the curve (AUC) to assess drainage kinetics. Substantial positive correlations were observed between tracer kinetics in the LOF and turbinates (Spearman correlation r = 0.658, p < 0.001), indicating a functional connection between brain and nasal clearance pathways. In subjects with amyloid positivity, tracer input into and egress from the nasal turbinates were significantly reduced, as indicated by time-activity curves (TACs) from [1-11C]-Butanol administration. More specifically, there was a significant main effect of Aβ subgroup (F(1,22) = 4.641, p =  0.0424) on egress from the LOF, as well as input into (F(1,22) = 10.24, p =  0.0041) and egress out of (F(1,22) = 11.36, p =  0.0028) the turbinates, by Repeated Measures Two-Way ANOVA, such that Aβ+ individuals had less influx and slower clearance across time. The findings suggest that the nasal pathway may serve as a viable route for CSF drainage in humans, with brain amyloid deposition impairing the drainage efficiency. These results provide novel insights into the relationship between brain amyloid pathology and the nasal clearance mechanism, warranting further investigation into the role of peripheral neurovascular pathways as potential biomarkers for AD. Understanding these mechanisms could pave the way for developing innovative interventions aimed at enhancing drainage pathways and mitigating the impact of amyloid burden on neurodegenerative processes.

Purpose of Review The objective of this systematic review is to present the available evidence for the utilization of the atypical opioids tapentadol, buprenorphine, and levorphanol for the treatment of neuropathic pain. Recent Findings In total, 1619 articles were retrieved of which 10 studies were included. Of 5 included studies pertaining to tapentadol, 4 studies show tapentadol monotherapy to be effective for the treatment of diabetic peripheral neuropathy or chronic, radiating low back pain. Of the 3 studies included for buprenorphine, only one was a randomized controlled trial found not to have a statistically significant reduction in pain with TD buprenorphine likely due to very high withdrawal rates during the trial. Only 2 case reports were included from the available literature for levorphanol providing low-quality anecdotal evidence. Summary The role of tapentadol, buprenorphine, and levorphanol for neuropathic pain conditions requires robust research including randomized controlled trials to evaluate their efficacy and safety.