Applications of functional magnetic resonance imaging to the study of functional connectivity and activation in neurological disease: a scoping review of the literature.

BACKGROUND: Functional magnetic resonance imaging (fMRI) has transformed our understanding of brain's functional architecture, providing critical insights into neurological diseases. This scoping review synthesizes the current landscape of fMRI applications across various neurological domains, elucidating the evolving role of both task-based and resting-state fMRI in different settings. METHODS: We conducted a comprehensive scoping review following the Preferred Reporting Items for Systematic Review and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. Extensive searches in Medline/PubMed, Embase, and Web of Science were performed, focusing on studies published between 2003 and 2023 that utilized fMRI to explore functional connectivity and regional activation in adult patients with neurological conditions. Studies were selected based on predefined inclusion and exclusion criteria, with data extracted. RESULTS: We identified 211 studies, covering a broad spectrum of neurological disorders including mental health, movement disorders, epilepsy, neurodegeneration, traumatic brain injury, cerebrovascular accidents, vascular abnormalities, neurorehabilitation, neuro-critical care, and brain tumors. The majority of studies utilized resting-state fMRI, underscoring its prominence in identifying disease-specific connectivity patterns. Results highlight the potential of fMRI to reveal the underlying pathophysiological mechanisms of various neurological conditions, facilitate diagnostic processes, and potentially guide therapeutic interventions. CONCLUSIONS: fMRI serves as a powerful tool for elucidating complex neural dynamics and pathologies associated with neurological diseases. Despite the breadth of applications, further research is required to standardize fMRI protocols, improve interpretative methodologies, and enhance the translation of imaging findings to clinical practice. Advances in fMRI technology and analytics hold promise for improving the precision of neurological assessments and interventions.

TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus.

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly, is one of the most common reasons for pediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate CH risk gene, however, TRIM71 variants have not been systematically examined in a large patient cohort or conclusively linked with an OMIM syndrome. Through cross-sectional analysis of the largest assembled cohort of patients with cerebral ventriculomegaly, including neurosurgically-treated CH (totaling 2,697 parent-proband trios and 8,091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, CH, developmental delay, dysmorphic features, and other structural brain defects including corpus callosum dysgenesis and white matter hypoplasia. Eight unrelated patients were found to harbor arginine variants, including two recurrent missense DNVs, at homologous positions in RPXGV motifs of different NHL domains. Seven additional patients with rare, damaging, unphased or transmitted variants of uncertain significance were also identified. NHL-domain variants of TRIM71 exhibited impaired binding to the canonical TRIM71 target CDKN1A; other variants failed to direct the subcellular localization of TRIM71 to processing bodies. Single-cell transcriptomic analysis of human embryos revealed expression of TRIM71 in early first-trimester neural stem cells of the brain. These data show TRIM71 is essential for human brain morphogenesis and that TRIM71 mutations cause a novel neurodevelopmental syndrome featuring ventriculomegaly and CH.

Biomechanical instability of the brain-CSF interface in hydrocephalus.

Hydrocephalus, characterized by progressive expansion of the cerebrospinal fluid (CSF)-filled ventricles (ventriculomegaly), is the most common reason for brain surgery. "Communicating" (i.e., non-obstructive) hydrocephalus is classically attributed to a primary derangement in CSF homeostasis, such as choroid plexus-dependent CSF hypersecretion, impaired cilia-mediated CSF flow currents, or decreased CSF reabsorption via the arachnoid granulations or other pathways. Emerging data suggest abnormal biomechanical properties of the brain parenchyma are an underappreciated driver of ventriculomegaly in multiple forms of communicating hydrocephalus across the lifespan. We discuss recent evidence from human and animal studies that suggests impaired neurodevelopment in congenital hydrocephalus, neurodegeneration in elderly normal pressure hydrocephalus, and, in all age groups, inflammation-related neural injury post-infectious and post-hemorrhagic hydrocephalus, can result in loss of stiffness and viscoelasticity of the brain parenchyma. Abnormal brain biomechanics creates barrier alterations at the brain-CSF interface that pathologically facilitates secondary enlargement of the ventricles, even at normal or low intracranial pressures. This "brain-centric" paradigm has implications for the diagnosis, treatment, and study of hydrocephalus from womb to tomb.

Evaluation of the safety, accuracy, and helpfulness of the GPT-4.0 Large Language Model in neurosurgery.

BACKGROUND: Although prior work demonstrated the surprising accuracy of Large Language Models (LLMs) on neurosurgery board-style questions, their use in day-to-day clinical situations warrants further investigation. This study assessed GPT-4.0's responses to common clinical questions across various subspecialties of neurosurgery. METHODS: A panel of attending neurosurgeons formulated 35 general neurosurgical questions spanning neuro-oncology, spine, vascular, functional, pediatrics, and trauma. All questions were input into GPT-4.0 with a prespecified, standard prompt. Responses were evaluated by two attending neurosurgeons, each on a standardized scale for accuracy, safety, and helpfulness. Citations were indexed and evaluated against identifiable database references. RESULTS: GPT-4.0 responses were consistent with current medical guidelines and accounted for recent advances in the field 92.8 % and 78.6 % of the time respectively. Neurosurgeons reported GPT-4.0 responses providing unrealistic information or potentially risky information 14.3 % and 7.1 % of the time respectively. Assessed on 5-point scales, responses suggested that GPT-4.0 was clinically useful (4.0 ± 0.6), relevant (4.7 ± 0.3), and coherent (4.9 ± 0.2). The depth of clinical responses varied (3.7 ± 0.6), and "red flag" symptoms were missed 7.1 % of the time. Moreover, GPT-4.0 cited 86 references (2.46 citations per answer), of which only 50 % were deemed valid, and 77.1 % of responses contained at least one inappropriate citation. CONCLUSION: Current general LLM technology can offer generally accurate, safe, and helpful neurosurgical information, but may not fully evaluate medical literature or recent field advances. Citation generation and usage remains unreliable. As this technology becomes more ubiquitous, clinicians will need to exercise caution when dealing with it in practice.

[1-11C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects.

BACKGROUND: Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. METHODS: 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aß+) and 16 Aß- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. RESULTS: LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aß+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. CONCLUSION: The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

Potential Mechanisms of Precision Nutrition-Based Interventions for Managing Obesity.

Precision nutrition (PN) considers multiple individual-level and environmental characteristics or variables to better inform dietary strategies and interventions for optimizing health, including managing obesity and metabolic disorders. Here, we review the evidence on potential mechanisms-including ones to identify individuals most likely to respond-that can be leveraged in the development of PN interventions addressing obesity. We conducted a review of the literature and included laboratory, animal, and human studies evaluating biochemical and genetic data, completed and ongoing clinical trials, and public programs in this review. Our analysis describes the potential mechanisms related to 6 domains including genetic predisposition, circadian rhythms, physical activity and sedentary behavior, metabolomics, the gut microbiome, and behavioral and socioeconomic characteristics, i.e., the factors that can be leveraged to design PN-based interventions to prevent and treat obesity-related outcomes such as weight loss or metabolic health as laid out by the NIH 2030 Strategic Plan for Nutrition Research. For example, single nucleotide polymorphisms can modify responses to certain dietary interventions, and epigenetic modulation of obesity risk via physical activity patterns and macronutrient intake have also been demonstrated. Additionally, we identified limitations including questions of equitable implementation across a limited number of clinical trials. These include the limited ability of current PN interventions to address systemic influences such as supply chains and food distribution, healthcare systems, racial or cultural inequities, and economic disparities, particularly when designing and implementing PN interventions in low- and middle-income communities. PN has the potential to help manage obesity by addressing intra- and inter-individual variation as well as context, as opposed to "one-size fits all" approaches though there is limited clinical trial evidence to date.

Elevated risk of recurrence and retreatment for silent pituitary adenomas.

PURPOSE: Pituitary adenomas are the most common tumor of the pituitary gland and comprise nearly 15% of all intracranial masses. These tumors are stratified into functional or silent categories based on their pattern of hormone expression and secretion. Preliminary evidence supports differential clinical outcomes between some functional pituitary adenoma (FPA) subtypes and silent pituitary adenoma (SPA) subtypes. METHODS: We collected and analyzed the medical records of all patients undergoing resection of SPAs or FPAs from a single high-volume neurosurgeon between 2007 and 2018 at Brigham and Women's Hospital. Descriptive statistics and the Mantel-Cox log-rank test were used to identify differences in outcomes between these cohorts, and multivariate logistic regression was used to identify predictors of radiographic recurrence for SPAs. RESULTS: Our cohort included 88 SPAs and 200 FPAs. The majority of patients in both cohorts were female (48.9% of SPAs and 63.5% of FPAs). SPAs were larger in median diameter than FPAs (2.1 cm vs. 1.2 cm, p < 0.001). The most frequent subtypes of SPA were gonadotrophs (55.7%) and corticotrophs (30.7%). Gross total resection (GTR) was achieved in 70.1% of SPA resections and 86.0% of FPA resections (p < 0.001). SPAs had a higher likelihood of recurring (hazard ratio [HR] 3.2, 95% confidence interval [95%CI] 1.6-7.2) and a higher likelihood of requiring retreatment for recurrence (HR 2.5; 95%CI 1.0-6.1). Subset analyses revealed that recurrence and retreatment were more both likely for subtotally resected SPAs than subtotally resected FPAs, but this pattern was not observed in SPAs and FPAs after GTR. Among SPAs, recurrence was associated with STR (odds ratio [OR] 9.3; 95%CI 1.4-64.0) and younger age (OR 0.92 per year; 95%CI 0.88-0.98) in multivariable analysis. Of SPAs that recurred, 12 of 19 (63.2%) were retreated with repeat surgery (n = 11) or radiosurgery (n = 1), while the remainder were observed (n = 7).There were similar rates of recurrence across different SPA subtypes. CONCLUSION: Patients undergoing resection of SPAs should be closely monitored for disease recurrence through more frequent clinical follow-up and diagnostic imaging than other adenomas, particularly among patients with STR and younger patients. Several patients can be observed after radiographic recurrence, and the decision to retreat should be individualized. Longitudinal clinical follow-up of SPAs, including an assessment of symptoms, endocrine function, and imaging remains critical.

Applications of Cryoneurolysis in Chronic Pain Management: a Review of the Current Literature.

PURPOSE OF REVIEW: The purpose of this review is to evaluate and summarize the literature investigating cryoneurolysis in the treatment of various chronic pain pathologies. RECENT FINDINGS: There is an increasing amount of interest in the use of cryoneurolysis in chronic pain, and various studies have investigated its use in lumbar facet joint pain, SI joint pain, post-thoracotomy syndrome, temporomandibular joint pain, chronic knee pain, phantom limb pain, neuropathic pain, and abdominal pain. Numerous retrospective studies and a more limited number of prospective, sham-controlled prospective studies suggest the efficacy of cryoneurolysis in managing these chronic pain pathologies with a low complication rate. However, more blinded, controlled, prospective studies comparing cryoneurolysis to other techniques are needed to clarify its relative risks and advantages.

Utility of cortical tissue analysis in normal pressure hydrocephalus.

Clinical improvement following neurosurgical cerebrospinal fluid shunting for presumed idiopathic normal pressure hydrocephalus is variable. Idiopathic normal pressure hydrocephalus patients may have undetected Alzheimer's disease-related cortical pathology that confounds diagnosis and clinical outcomes. In this study, we sought to determine the utility of cortical tissue immuno-analysis in predicting shunting outcomes in idiopathic normal pressure hydrocephalus patients. We performed a pooled analysis using a systematic review as well as analysis of a new, original patient cohort. Of the 2707 screened studies, 3 studies with a total of 229 idiopathic normal pressure hydrocephalus patients were selected for inclusion in this meta-analysis alongside our original cohort. Pooled statistics of shunting outcomes for the 229 idiopathic normal pressure hydrocephalus patients and our new cohort of 36 idiopathic normal pressure hydrocephalus patients revealed that patients with Aß + pathology were significantly more likely to exhibit shunt nonresponsiveness than patients with negative pathology. Idiopathic normal pressure hydrocephalus patients with Alzheimer's disease -related cortical pathology may be at a higher risk of treatment facing unfavorable outcomes following cerebrospinal fluid shunting. Thus, cortical tissue analysis from living patients may be a useful diagnostic and prognostic adjunct for patients with presumed idiopathic normal pressure hydrocephalus and potentially other neurodegenerative conditions affecting the cerebral cortex.

The "microcephalic hydrocephalus" paradox as a paradigm of altered neural stem cell biology.

Characterized by enlarged brain ventricles, hydrocephalus is a common neurological disorder classically attributed to a primary defect in cerebrospinal fluid (CSF) homeostasis. Microcephaly ("small head") and hydrocephalus are typically viewed as two mutually exclusive phenomenon, since hydrocephalus is thought of as a fluid "plumbing" disorder leading to CSF accumulation, ventricular dilatation, and resultant macrocephaly. However, some cases of hydrocephalus can be associated with microcephaly. Recent work in the genomics of congenital hydrocephalus (CH) and an improved understanding of the tropism of certain viruses such as Zika and cytomegalovirus are beginning to shed light into the paradox "microcephalic hydrocephalus" by defining prenatal neural stem cells (NSC) as the spatiotemporal "scene of the crime." In some forms of CH and viral brain infections, impaired fetal NSC proliferation leads to decreased neurogenesis, cortical hypoplasia and impaired biomechanical interactions at the CSF-brain interface that collectively engender ventriculomegaly despite an overall and often striking decrease in head circumference. The coexistence of microcephaly and hydrocephalus suggests that these two phenotypes may overlap more than previously appreciated. Continued study of both conditions may be unexpectedly fertile ground for providing new insights into human NSC biology and our understanding of neurodevelopmental disorders.

Dishonest Physician Reviews: Challenging Physician Online Reviews and the Appeals Process.

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.

Characterizing complications associated with skull clamps: A review of the manufacturer and user facility device experience database.

OBJECTIVE: Head immobilization with skull clamps is a prerequisite of many neurosurgical procedures. Adverse events relating to the use of skull clamps have been reported, however, given the paucity of published reports, we sought to conduct a more comprehensive analysis using the Manufacturer and User Facility Device Experience (MAUDE) database. METHODS: The MAUDE database was queried for neurosurgical skull clamp events over a 10-year period between January 2013 and December 2022. Reports were qualitatively analyzed and categorically assigned by the study authors as 'mechanical failure,' 'slippage,' 'contamination,' 'insufficient information,' and 'other.' Patient injury reports were also classified as 'abrasion,' 'laceration,' 'hematoma,' 'fracture,' 'intracranial hemorrhage (ICH),' 'other,' 'insufficient information,' and 'death.' RESULTS: Of 3672 reports retrieved, 2689 (73.2%) were device malfunctions, with mechanical failure (50.7%) and slippage (47.7%) being the most common causes. There were 983 reports (26.8%) involving patient injury which included lacerations (n = 776, 78.9%), fractures (n = 24, 2.4%), abrasions (n = 23, 2.3%), hematomas (n = 7, 0.71%), ICH (n = 3, 0.31%), and other causes (n = 6, 0.61%). Five (0.1%) deaths due to skull clamp related complications were also reported. CONCLUSIONS: This study provides a more comprehensive picture of adverse events in neurosurgical procedures relating to the use of skull clamps. Mechanical failures of device parts were the most common device-related complication, and lacerations the most common adverse patient-related event. While more severe patient-related events were reported, they are relatively rare. The MAUDE database is useful for characterizing underreported device-related and patient-related adverse events.

A systematic review of the impacts of post-harvest handling on provitamin A, iron and zinc retention in seven biofortified crops.

Post-harvest handling can affect micronutrient retention in biofortified crops through to the point of consumption. Here we conduct a systematic review identifying 67 articles examining the retention of micronutrients in conventionally bred biofortified maize, orange sweet potato, cassava, pearl millet, rice, beans and wheat. Provitamin A crops maintain high amounts compared with non-biofortified counterparts. Iron and zinc crops have more variability in micronutrient retention dependent on processing method; for maximum iron and zinc content, whole grain product consumption such as whole wheat flour or only slightly milled brown rice is beneficial. We offer preliminary suggestions for households, regulatory bodies and programme implementers to increase consumer awareness on best practices for preparing crops to maximize micronutrient content, while highlighting gaps in the literature. Our online, interactive Micronutrient Retention Dashboard ( https://www.cpnh.cornell.edu/mn-retention-db ) offers an at-a-glance view of the compiled minimum and maximum retention found, organized by processing method.

Molecular Diagnostic Yield of Exome Sequencing in Patients With Congenital Hydrocephalus: A Systematic Review and Meta-Analysis.

Importance: Exome sequencing (ES) has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as global developmental delay and autism spectrum disorder; however, current recommendations are not specific to or inclusive of congenital hydrocephalus (CH). Objective: To determine the diagnostic yield of ES in CH and whether ES should be considered as a first line diagnostic test for CH. Data Sources: PubMed, Cochrane Library, and Google Scholar were used to identify studies published in English between January 1, 2010, and April 10, 2023. The following search terms were used to identify studies: congenital hydrocephalus, ventriculomegaly, cerebral ventriculomegaly, primary ventriculomegaly, fetal ventriculomegaly, prenatal ventriculomegaly, molecular analysis, genetic cause, genetic etiology, genetic testing, exome sequencing, whole exome sequencing, genome sequencing, microarray, microarray analysis, and copy number variants. Study Selection: Eligible studies included those with at least 10 probands with the defining feature of CH and/or severe cerebral ventriculomegaly that had undergone ES. Studies with fewer than 10 probands, studies of mild or moderate ventriculomegaly, and studies using genetic tests other than ES were excluded. A full-text review of 68 studies was conducted by 2 reviewers. Discrepancies were resolved by consensus. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-Analysis of Observational Studies in Epidemiology guidelines were used by 2 reviewers to extract data. Data were synthesized using a random-effects model of single proportions. Data analysis occurred in April 2023. Main Outcomes and Measures: The primary outcome was pooled diagnostic yield. Additional diagnostic yields were estimated for specific subgroups on the basis of clinical features, syndromic presentation, and parental consanguinity. For each outcome, a 95% CI and estimate of interstudy heterogeneity (I2 statistic) was reported. Results: From 498 deduplicated and screened records, 9 studies with a total of 538 CH probands were selected for final inclusion. The overall diagnostic yield was 37.9% (95% CI, 20.0%-57.4%; I2 = 90.1). The yield was lower for isolated and/or nonsyndromic cases (21.3%; 95% CI, 12.8%-31.0%; I2 = 55.7). The yield was higher for probands with reported consanguinity (76.3%; 95% CI, 65.1%-86.1%; I2 = 0) than those without (16.2%; 95% CI, 12.2%-20.5%; I2 = 0). Conclusions and Relevance: In this systematic review and meta-analysis of the diagnostic yield of ES in CH, the diagnostic yield was concordant with that of previous recommendations for other neurodevelopmental disorders, suggesting that ES should also be recommended as a routine diagnostic adjunct for patients with CH.

Impact of Patient Subgroups on the Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients with Advanced Illness.

Purpose: We evaluated the impact of baseline patient characteristics on safety and efficacy of methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, in patients with advanced illness with opioid-induced constipation (OIC). Patients and Methods: This analysis pooled data from 2 randomized, double-blind, placebo-controlled studies (study 302: NCT00402038; study 4000: NCT00672477) in patients with advanced illness, including cancer, and OIC. Patients were randomized to receive subcutaneous methylnaltrexone (study 302: 0.15 mg/kg; study 4000: 8 or 12 mg based on weight) or placebo every other day for 2 weeks. The proportions of patients achieving rescue-free laxation within 4 or 24 hours after the first dose of study drug were assessed in patient subgroups stratified by baseline age, Eastern Cooperative Oncology Group (ECOG) performance status, cancer status, laxative type, and opioid requirement. Treatment-emergent adverse events (TEAEs) were evaluated. Results: Overall, 363 patients were included in this analysis (methylnaltrexone, 178; placebo, 185). Mean (SD) age was 66.3 (13.7) years and 48.5% were men overall. A significantly greater proportion of patients receiving methylnaltrexone versus placebo achieved rescue-free laxation within 4 hours (111/178 [62.4%] vs 31/185 [16.8%]; P<0.0001) and 24 hours (135/178 [75.8%] vs 81/185 [43.8%]; P<0.0001) of the first dose. These trends were consistent across all subgroups. Most patients experienced ≥1 TEAE in the overall population (methylnaltrexone, 82.1%; placebo, 76.2%), which remained consistent when stratified by baseline characteristics. More than half of TEAEs were gastrointestinal in nature. Abdominal pain was more common in patients receiving methylnaltrexone than placebo across baseline characteristic subgroups. Conclusion: Methylnaltrexone treatment was superior to placebo in achieving rescue-free laxation within 4 and 24 hours after the first dose, irrespective of patients' cancer status, baseline ECOG performance status, or baseline opioid or laxative use. The methylnaltrexone safety profile remained consistent across baseline characteristic subgroups.

Human genetics and molecular genomics of Chiari malformation type 1.

Chiari malformation type 1 (CM1) is the most common structural brain disorder involving the craniocervical junction, characterized by caudal displacement of the cerebellar tonsils below the foramen magnum into the spinal canal. Despite the heterogeneity of CM1, its poorly understood patho-etiology has led to a 'one-size-fits-all' surgical approach, with predictably high rates of morbidity and treatment failure. In this review we present multiplex CM1 families, associated Mendelian syndromes, and candidate genes from recent whole exome sequencing (WES) and other genetic studies that suggest a significant genetic contribution from inherited and de novo germline variants impacting transcription regulation, craniovertebral osteogenesis, and embryonic developmental signaling. We suggest that more extensive WES may identify clinically relevant, genetically defined CM1 subtypes distinguished by unique neuroradiographic and neurophysiological endophenotypes.

Cases of familial idiopathic normal pressure hydrocephalus implicate genetic factors in disease pathogenesis.

Idiopathic normal pressure hydrocephalus is a disorder of unknown pathophysiology whose diagnosis is paradoxically made by a positive response to its proposed treatment with cerebrospinal fluid diversion. There are currently no idiopathic normal pressure hydrocephalus disease genes or biomarkers. A systematic analysis of familial idiopathic normal pressure hydrocephalus could aid in clinical diagnosis, prognosis, and treatment stratification, and elucidate disease patho-etiology. In this 2-part analysis, we review literature-based evidence for inheritance of idiopathic normal pressure hydrocephalus in 22 pedigrees, and then present a novel case series of 8 familial idiopathic normal pressure hydrocephalus patients. For the case series, demographics, familial history, pre- and post-operative symptoms, and cortical pathology were collected. All novel familial idiopathic normal pressure hydrocephalus patients exhibited improvement following shunt treatment and absence of neurodegenerative cortical pathology (amyloid-beta and hyperphosphorylated tau), in contrast to many sporadic cases of idiopathic normal pressure hydrocephalus with variable clinical responses. Analysis of the 30 total familial idiopathic normal pressure hydrocephalus cases reported herein is highly suggestive of an autosomal dominant mechanism of inheritance. This largest-ever presentation of multiply affected idiopathic normal pressure hydrocephalus pedigrees provides strong evidence for Mendelian inheritance and autosomal dominant transmission of an idiopathic normal pressure hydrocephalus trait in a subset of patients that positively respond to shunting and lack neurodegenerative pathology. Genomic investigation of these families may identify the first bona fide idiopathic normal pressure hydrocephalus disease gene.

The Efficacy of Endoscopic Third Ventriculostomy for Idiopathic Normal Pressure Hydrocephalus.

Recently, intervention with endoscopic third ventriculostomy (ETV) for patients with idiopathic normal pressure hydrocephalus (iNPH) has emerged as a potential minimally invasive alternative to traditional treatments (ventriculoperitoneal shunting). The clinical response to these interventions is variable and unclear. The objective of this review was to assess the efficacy of endoscopic third ventriculostomy in treating patients with iNPH. A systematic review of PubMed, Web of Science, and Google Scholar was conducted using search terms relevant to ETV and iNPH. Included studies met consistent, predetermined diagnostic criteria for iNPH, implemented ETV in subjects greater than 40 years of age, and assessed all 3 components of Hakim's triad (gait impairment, dementia, and incontinence). Data extraction included dichotomization of successful ETV clinical outcomes and a subgroup meta-analysis of ETV success rates across binarized age groups. Meta-analysis was conducted using a Mantel-Haenszel fixed-effects model. The outcomes presented include generalized ETV success rates across all 12 studies. Age-specific individual data was measured with odds ratios, with a pooled statistic measured using the Mantel-Haenszel test. Overall, 2294 studies were identified in this search, of which 12 were selected for inclusion in this systematic review. Of these, 3 studies were utilized for age-specific meta-analyses. Preliminary synthesis of ETV clinical outcomes across all 12 studies revealed a success rate of 60.2%. Additionally, meta-analysis revealed that iNPH patients younger than or equal to 65 years of age were significantly more likely to respond successfully to ETV intervention. Heterogeneity was inconsequential in this analysis.

Sensory acceptability of biofortified foods and food products: a systematic review.

CONTEXT: It is important to understand the sensory acceptability of biofortified food products among target population groups if biofortification is to be realized as a sustainable strategy for mitigation of micronutrient deficiencies, able to be scaled up and applied through programs. OBJECTIVE: This systemic review aims to summarize and synthesize the sensory acceptability of conventionally bred iron-, zinc-, and provitamin A-biofortified food products. DATA SOURCES: MEDLINE (PubMed), AGRICOLA, AgEcon, CABI Abstracts (Web of Science), and organizational websites (eg, those of HarvestPlus and CGIAR and their partners) were searched for relevant articles. No access to any market research that may have been internally conducted for the commercial biofortified food products was available. DATA EXTRACTION: This review identified articles measuring the sensory acceptability of conventionally bred biofortified food products. Extraction of the hedonic ratings of food products was performed. DATA ANALYSIS: An "Acceptability Index %" was defined based on hedonic scoring to determine an overall rating, and used to categorize biofortified food products as "acceptable" (≥70%) or "not acceptable" (<70%). Additionally, this review narratively synthesized studies using methods other than hedonic scoring for assessing sensory acceptability. CONCLUSIONS: Forty-nine studies assessed the acceptability of 10 biofortified crops among children and adults, in mostly rural, low-income settings across Africa, Latin America, and India; food products made from mineral and provitamin A-biofortified food products were generally acceptable. Compared with studies on provitamin-A biofortified food products, few studies (1 to 2 each) on mineral-enhanced crops such as rice, cowpeas, lentils, and wheat were found, limiting the generalizability of the findings. Similarly, few studies examined stored biofortified food products. Few commercial food products have so far been developed, although new varieties of crops are being continuously tested and released globally. Certain crop varieties were found to be acceptable while others were not, suggesting that particular varieties should be prioritized for scale-up. Determining sensory acceptability of biofortified food products is important for informing programmatic scale-up and implementation across diverse populations and settings.

Preclinical Development and Characterization of Novel Adeno-Associated Viral Vectors for the Treatment of Lipoprotein Lipase Deficiency.

Lipoprotein lipase deficiency (LPLD) results from mutations within the lipoprotein lipase (LPL) gene that lead to a complete lack of catalytically active LPL protein. Glybera was one of the first adeno-associated virus (AAV) gene replacement therapy to receive European Medicines Agency regulatory approval for the treatment of LPLD. However, Glybera is no longer marketed potentially due to a combination of economical, manufacturing, and vector-related issues. The aim of this study was to develop a more efficacious AAV gene therapy vector for LPLD. Following preclinical biodistribution, efficacy and non-Good Laboratory Practice toxicity studies with novel AAV1 and AAV8-based vectors in mice, we identified AAV8 pVR59. AAV8 pVR59 delivered a codon-optimized, human gain-of-function hLPLS447X transgene driven by a CAG promoter in an AAV8 capsid. AAV8 pVR59 was significantly more efficacious, at 10- to 100-fold lower doses, compared with an AAV1 vector based on Glybera, when delivered intramuscularly or intravenously, respectively, in mice with LPLD. Efficient gene transfer was observed within the injected skeletal muscle and liver following delivery of AAV8 pVR59, with long-term correction of LPLD phenotypes, including normalization of plasma triglycerides and lipid tolerance, for up to 6 months post-treatment. While intramuscular delivery of AAV8 pVR59 was well tolerated, intravenous administration augmented liver pathology. These results highlight the feasibility of developing a superior AAV vector for the treatment of LPLD and provide critical insight for initiating studies in larger animal models. The identification of an AAV gene therapy vector that is more efficacious at lower doses, when paired with recent advances in production and manufacturing technologies, will ultimately translate to increased safety and accessibility for patients.