A rare case of angioinvasive aspergillosis aortic graft infection causing peripheral thromboembolism.

Angioinvasive aspergillosis is a fungal infection that rarely involves vascular grafts. This case illustrates a patient with a history of aortic arch Dacron graft reconstruction presenting with acute bilateral lower extremity ischemia. The patient underwent emergent open thromboembolectomy. The intraluminal contents had an atypical appearance for thromboembolism, and histologic examination was consistent with aspergillosis. Cardiac computed tomography and transesophageal echocardiography showed an aortic arch graft vegetation. Aortic graft excision and reconstruction were performed for control of the fungal source. Investigation into the etiology of thromboembolism should include consideration for septic emboli in patients with indwelling vascular grafts. When suspected, graft excision should be considered for definitive management.

Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force.

Timely and accurate diagnosis of Alzheimer's disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

Tackling a Major Deficiency of Diversity in Alzheimer's Disease Therapeutic Trials: An CTAD Task Force Report.

As the last opportunity to assess treatment effect modification in a controlled setting prior to formal approval, clinical trials are a critical tool for understanding the safety and efficacy of new treatments in diverse populations. Recruitment of diverse participants in Alzheimer's Disease (AD) clinical trials are therefore essential to increase the generalizability of study results, with diversity broadly described to be representative and inclusive. This representation of study participants is equally critical in longitudinal cohort (observational) studies, which will be key to understanding disease disparities and are often used to design adequately powered AD clinical trials. New and innovative recruitment initiatives and enhanced infrastructure facilitate increased participant diversity in AD clinical studies.

The Future of AD Clinical Trials with the Advent of Anti-Amyloid Therapies: An CTAD Task Force Report.

BACKGROUND: Aducanumab (ADUHELMTM) was approved for the treatment of Alzheimer's disease (AD) in the US. This approval was supported by an effect on the cerebral amyloid plaque load and evidence of cognitive efficacy to be confirmed in post-marketing trials. Other anti-amyloid antibodies are under investigation in phase III (donanemab, lecanemab, gantenerumab) and have shown preliminary evidence of a cognitive benefit in phase II trials. Although these agents target a small segment of patients with mild cognitive impairment due to AD or mild AD dementia, their advent will change the design of future clinical trials both for anti-amyloid and non-amyloid drugs. These changes will promote the selection of patients in clinical trials by amyloid and tau biomarkers that identify patients with appropriate biology and may follow the treatment response to approved amyloid antibodies. The use of these agents creates the opportunity to test combined drug therapies and to conduct comparative assessments with innovative therapies and newly approved drugs available in clinical practice. Blood-based AD biomarkers should be implemented in research and could facilitate the recruitment into clinical trials. Anti-amyloid antibodies will have positive (e.g., more early diagnosis) and negative impacts (some subjects will be reluctant to participate in trials and risk assignment to placebo) on AD trials in the immediate future. We present the results of the CTAD Task Force on this topic, in Boston, November 6, 2021.

Aducanumab: Appropriate Use Recommendations Update.

Aducanumab (Aduhelm) is approved in the United States for the treatment of patients with mild cognitive impairment due to Alzheimer's disease or mild AD dementia. Aducanumab Appropriate Use Recommendations (AURs) have been published and have helped guide best practices for use of aducanumab. As real-world use has occurred and more information has accrued, the AURs require refinement. We update the AURs to better inform appropriate patient selection and improve shared decision-making, safety monitoring, and risk mitigation in treated patients. Based on evolving experience we emphasize the importance of detecting past medical conditions that may predispose to amyloid related imaging abnormalities (ARIA) or may increase the likelihood of ARIA complications including autoimmune or inflammatory conditions, seizures, or disorders associated with extensive white matter pathology. The apolipoprotein E ε4 (APOE4) genotype is strongly associated with ARIA and exhibits a gene dose effect. We recommend that clinicians perform APOE genotyping to better inform patient care decisions, discussions regarding risk, and clinician vigilance concerning ARIA. As most ARIA occurs during the titration period of aducanumab, we suggest performing MRI before the 5th, 7th, 9th, and 12th infusions to improve detection. Uncommonly, ARIA may be recurrent or serious; we suggest additional parameters for treatment discontinuation taking these observations into account. It is important to continue to learn from the real-world use of aducanumab and the AURs will continue to evolve as new information becomes available. This AUR update does not address efficacy, price, or insurance coverage and is provided to assist clinicians to establish best practices for use of aducanumab in the treatment of patients with mild cognitive impairment and mild Alzheimer's dementia.

Using Black Bone Magnetic Resonance Imaging for Fibula Free Flap Surgical Planning: A Means to Reduce Radiation Exposure with Accurate Surgical Outcomes.

SUMMARY: Advances in virtual surgical planning and three-dimensionally-printed guides have enabled increased precision in vascularized free fibula flap reconstruction of the mandible and valuable preoperative planning. However, virtual surgical planning currently requires high-resolution computed tomographic scans, exposing patients to ionizing radiation. The aim of this study was to determine whether black bone magnetic resonance imaging can be used for accurate surgical planning and three-dimensionally-printed guide creation, thus reducing patient radiation exposure. This study included 10 cadaver heads and 10 cadaver lower extremities. A mock fibula free flap for mandible reconstruction was performed. Five operations were planned with guides created using black bone magnetic resonance imaging, whereas the other five were planned and performed using guides created with computed tomographic scan data. All specimens underwent a postoperative computed tomographic scan, and three-dimensional reconstruction of scans was performed and surgical accuracy to the planned surgery was assessed. Guides created from black bone magnetic resonance imaging demonstrated high accuracy to the surgical plan. There was no statistically significant difference in postoperative deviation from the plan when black bone magnetic resonance imaging versus computed tomographic scanning was used for virtual surgical planning and guide creation. Both modalities led to a postoperative positive or negative deviation from the virtual plan within 0.8 mm. This study demonstrates that virtual surgical planning and three-dimensionally-printed guide creation for free fibula flaps for mandible reconstruction can be performed using black bone magnetic resonance imaging with comparable accuracy to computed tomographic scanning. This could reduce radiation exposure for patients and enable a more streamlined imaging process for head and neck cancer patients.

Diagnosis of Early Alzheimer's Disease: Clinical Practice in 2021.

Alzheimer's disease is a progressive, irreversible neurodegenerative disease impacting cognition, function, and behavior. Alzheimer's disease progresses along a continuum from preclinical disease, to mild cognitive and/or behavioral impairment and then Alzheimer's disease dementia. Recently, clinicians have been encouraged to diagnose Alzheimer's earlier, before patients have progressed to Alzheimer's disease dementia. The early and accurate detection of Alzheimer's disease-associated symptoms and underlying disease pathology by clinicians is fundamental for the screening, diagnosis, and subsequent management of Alzheimer's disease patients. It also enables patients and their caregivers to plan for the future and make appropriate lifestyle changes that could help maintain their quality of life for longer. Unfortunately, detecting early-stage Alzheimer's disease in clinical practice can be challenging and is hindered by several barriers including constraints on clinicians' time, difficulty accurately diagnosing Alzheimer's pathology, and that patients and healthcare providers often dismiss symptoms as part of the normal aging process. As the prevalence of this disease continues to grow, the current model for Alzheimer's disease diagnosis and patient management will need to evolve to integrate care across clinical disciplines and the disease continuum, beginning with primary care. This review summarizes the importance of establishing an early diagnosis of Alzheimer's disease, related practical 'how-to' guidance and considerations, and tools that can be used by healthcare providers throughout the diagnostic journey.

Examining the Role of Microbiota in Emotional Behavior: Antibiotic Treatment Exacerbates Anxiety in High Anxiety-Prone Male Rats.

Intestinal microbiota are essential for healthy gastrointestinal function and also broadly influence brain function and behavior, in part, through changes in immune function. Gastrointestinal disorders are highly comorbid with psychiatric disorders, although biological mechanisms linking these disorders are poorly understood. The present study utilized rats bred for distinct emotional behavior phenotypes to examine relationships between emotionality, the microbiome, and immune markers. Prior work showed that Low Novelty Responder (LR) rats exhibit high levels of anxiety- and depression-related behaviors as well as myriad neurobiological differences compared to High Novelty Responders (HRs). Here, we hypothesized that the divergent HR/LR phenotypes are accompanied by changes in fecal microbiome composition. We used next-generation sequencing to assess the HR/LR microbiomes and then treated adult HR/LR males with an antibiotic cocktail to test whether it altered behavior. Given known connections between the microbiome and immune system, we also analyzed circulating cytokines and metabolic factors to determine relationships between peripheral immune markers, gut microbiome components, and behavioral measures. There were no baseline HR/LR microbiome differences, and antibiotic treatment disrupted the microbiome in both HR and LR rats. Antibiotic treatment exacerbated aspects of HR/LR behavior, increasing LRs' already high levels of anxiety-like behavior while reducing passive stress coping in both strains. Our results highlight the importance of an individual's phenotype to their response to antibiotics, contributing to the understanding of the complex interplay between gut microbes, immune function, and an individual's emotional phenotype.

Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

Relationship of amyloid beta and neurofibrillary tau deposition in Neurodegeneration in Aging Down Syndrome (NiAD) study at baseline.

IMPORTANCE: Adults with Down syndrome (DS) are at high-risk of revealing Alzheimer's disease (AD) pathology, in part due to the triplication of chromosome 21 encoding the amyloid precursor protein. Adults with DS are uniformly affected by AD pathology by their 30's and have a 70% to 80% chance of clinical dementia by their 60's. Our previous studies have assessed longitudinal changes in amyloid beta (Aß) accumulation in DS. OBJECTIVE: The goal of the present study was to assess the presence of brain tau using [18F]AV-1451 positron emission tomography (PET) in DS and to assess the relationship of brain tau pathology to Aß using Pittsburgh Compound B (PiB)-PET. DESIGN: Cohort study. SETTING: Multi-center study. PARTICIPANTS: Participants consisted of a sample of individuals with DS and sibling controls recruited from the community; exclusion criteria included contraindications for magnetic resonance imaging (MRI) and/or a medical or psychiatric condition that impaired cognitive functioning. EXPOSURES: PET brain scans to assess Aß ([11C]PiB) and tau ([18F]AV-1451) burden. MAIN OUTCOMES AND MEASURES: Multiple linear regression models (adjusted for chronological age, sex and performance site) were used to examine associations between regional [18F]AV-1451 standard uptake value ratio (SUVR) (based on regions associated with Braak stages 1-6) and global [11C]PiB SUVR (as both a continuous and dichotomous variable). RESULTS: A cohort of 156 participants (mean age = 39.05, SD(8.4)) were examined. These results revealed a significant relationship between in vivo Aß and tau pathology in DS. As a dichotomous variable, [18F]AV-1451 retention was higher in each Braak region in PiB(+) participants. We also found, based on our statistical models, starting with the Braak 3 region of interest (ROI), an acceleration of [18F]AV-1451 SUVR deposition with [11C]PiB SUVR increases.

Complex Microsurgical Reconstruction After Tumor Resection in the Trunk and Extremities.

Reconstruction of soft tissue defects following tumor ablation procedures in the trunk and extremities can challenge the microsurgeon. The goal is not just to provide adequate soft tissue coverage but also to restore form and function and minimize donor site morbidity. Although the principles of the reconstructive ladder still apply in the trunk and extremities, free tissue transfer is used in many cases to optimally restore form and function. Microsurgery has changed the practice in soft tissue tumors, and amputation is less frequently necessary.

Non-Amyloid Approaches to Disease Modification for Alzheimer's Disease: An EU/US CTAD Task Force Report.

While amyloid-targeting therapies continue to predominate in the Alzheimer's disease (AD) drug development pipeline, there is increasing recognition that to effectively treat the disease it may be necessary to target other mechanisms and pathways as well. In December 2019, The EU/US CTAD Task Force discussed these alternative approaches to disease modification in AD, focusing on tau-targeting therapies, neurotrophin receptor modulation, anti-microbial strategies, and the innate immune response; as well as vascular approaches, aging, and non-pharmacological approaches such as lifestyle intervention strategies, photobiomodulation and neurostimulation. The Task Force proposed a general strategy to accelerate the development of alternative treatment approaches, which would include increased partnerships and collaborations, improved trial designs, and further exploration of combination therapy strategies.

Rationale for Early Diagnosis of Mild Cognitive Impairment (MCI) Supported by Emerging Digital Technologies.

Disease-modifying pharmacotherapies for Alzheimer's Disease (AD) are currently in late-stage clinical development; once approved, new healthcare infrastructures and services, including primary healthcare, will be necessary to accommodate a huge demand for early and large-scale detection of AD. The increasing global accessibility of digital consumer electronics has opened up new prospects for early diagnosis and management of mild cognitive impairment (MCI) with particular regard to AD. This new wave of innovation has spurred research in both academia and industry, aimed at developing and validating a new "digital generation" of tools for the assessment of the cognitive performance. In light of this paradigm shift, an international working group (the Global Advisory Group on Future MCI Care Pathways) convened to elaborate on how digital tools may be optimally integrated in screening-diagnostic pathways of AD The working group developed consensus perspectives on new algorithms for large-scale screening, detection, and diagnosis of individuals with MCI within primary medical care delivery. In addition, the expert panel addressed operational aspects concerning the implementation of unsupervised at-home testing of cognitive performance. The ultimate intent of the working group's consensus perspectives is to provide guidance to developers of cognitive tests and tools to facilitate the transition toward globally accessible cognitive screening aimed at the early detection, diagnosis, and management of MCI due to AD.

Early Detection of Mild Cognitive Impairment (MCI) in Primary Care.

Mild cognitive impairment (MCI) is significantly misdiagnosed in the primary care setting due to multi-dimensional frictions and barriers associated with evaluating individuals' cognitive performance. To move toward large-scale cognitive screening, a global panel of clinicians and cognitive neuroscientists convened to elaborate on current challenges that hamper widespread cognitive performance assessment. This report summarizes a conceptual framework and provides guidance to clinical researchers and test developers and suppliers to inform ongoing refinement of cognitive evaluation. This perspective builds upon a previous article in this series, which outlined the rationale for and potentially against efforts to promote widespread detection of MCI. This working group acknowledges that cognitive screening by default is not recommended and proposes large-scale evaluation of individuals with a concern or interest in their cognitive performance. Such a strategy can increase the likelihood to timely and effective identification and management of MCI. The rising global incidence of AD demands innovation that will help alleviate the burden to healthcare systems when coupled with the potentially near-term approval of disease-modifying therapies. Additionally, we argue that adequate infrastructure, equipment, and resources urgently should be integrated in the primary care setting to optimize the patient journey and accommodate widespread cognitive evaluation.

Early Detection of Mild Cognitive Impairment (MCI) in an At-Home Setting.

Emerging digital tools have the potential to enable a new generation of qualitative and quantitative assessment of cognitive performance. Moreover, the ubiquity of consumer electronics, such as smartphones and tablets, can be harnessed to support large-scale self-assessed cognitive screening with benefit to healthcare systems and consumers. A wide variety of apps, wearables, and new digital technologies are either available or in development for the detection of mild cognitive impairment (MCI), a risk factor for dementia. Two categories of novel methodologies may be considered: passive technologies (which monitor a user's behavior without active user input) and interactive assessments (which require active user input). Such examinations can be self-administered, supervised by a caregiver, or conducted by an informant at home or outside of a clinical setting. These direct-to-consumer tools have the potential to sidestep barriers associated with cognitive evaluation in primary care, thus improving access to cognitive assessments. Although direct-to-consumer cognitive assessment is associated with its own barriers, including test validation, user experience, and technological concerns, it is conceivable that these issues can be addressed so that a large-scale, self-assessed cognitive evaluation that would represent an initial cognitive screen may be feasible in the future.

The Turkey Digit: A New Training Model for Digit Replantation.

PURPOSE: Replant survival rates have reportedly declined over the past decade. Although this problem is multifactorial, 1 potential solution may include the development of a relevant teaching model. The development of an in vivo animal model that can be used for surgical training could enhance surgeon and resident experience and potentially improve outcomes. Here, we present a novel training model for digit replantation using turkey digits. METHODS: Six mature male Bourbon Red turkeys were included in this study. With the animal under general anesthesia, the third digit on either the left or the right foot was randomly selected and amputated. The medial and lateral digital neurovascular bundles were dissected on both sides and the digit was replanted. Perfusion was confirmed prior to skin closure. The foot was casted prior to extubating the turkeys. Turkeys were then placed in a non-weight-bearing sling. Digit status was evaluated twice daily. RESULTS: All 6 replanted digits were viable immediately after surgery and for at least 24 hours after surgery. The average digit survival was 6 days with a maximum survival of 15 days. All digits were eventually lost owing to a variety of reasons including infection and arterial thrombosis. CONCLUSIONS: The turkey digit proved to be a successful short-term animal training model for digit replantation. Future studies are needed to determine optimum standard surgical procedure and postoperative care to maximize the educational benefits of this training model. CLINICAL RELEVANCE: To establish an animal model that can simulate digital replantation.

Postoperative Management After Total Pharyngolaryngectomy Using the Free Ileocolon Flap: A 5-Year Surgical Intensive Care Unit Experience.

INTRODUCTION: Management after total pharyngolaryngectomy with free ileocolon flaps can be challenging. Adequate postoperative surgical guidelines are essential to avoid complications. Factors, such as agitation, hypotension, or prolonged mechanical ventilation, might compromise final outcomes. Herein, we describe our experience in the early postoperative care of patients after total pharyngolaryngectomy with immediate reconstruction using the free ileocolon flap. METHODS: This is a retrospective review of all patients who underwent total pharyngolaryngectomy and immediate reconstruction using the free Ileocolon flap. Demographics, etiology of resection, neoadjuvant therapy, surgical time, method of sedation, postoperative use of vasopressors, length of intensive care unit (ICU) stay, time of discontinuation of mechanical ventilation, and complications were recorded and analyzed. RESULTS: Between 2010 and 2015, a total of 34 patients underwent total pharyngolaryngectomy and immediate reconstruction using the free Ileocolon flap. The most common cause of total pharyngolaryngectomy was cancer. Twenty-eight patients had neoadjuvant therapy (radiation). The average surgical time was 11.5 hours (range, 8-14.5 hours), average length of ICU stay was 3 days (range, 2-15 days) with an average time for mechanical ventilation cessation of 3 days (range, 1-20 days). Midazolam and dexmedetomidine were the most common sedatives used during surgery and in the ICU period. Three patients required vasopressors due to hypotension, 2 had unplanned self-extubation from the tracheostomy site, 2 experienced postoperative bleeding, 1 had pneumonia, 4 required unplanned return to the operating room, 2 had partial flap loss, and 1 had complete flap loss. CONCLUSIONS: Overall, a majority of patients recovered well postoperatively with minimal complications and low rate of reoperation. Our research provides a foundation to develop a risk-stratified approach to determine the need for an ICU admission or early transfer to floor care.

Technique for Open Posterior Cervical Foraminotomy: 2-Dimensional Operative Video.

Foraminal stenosis is an important cause of cervical radiculopathy, which can be treated with an anterior or posterior approach, depending on a number of factors. These include the etiology of the foraminal stenosis, individual patient risk factors, and surgeon preference. We provide a step-by-step technique guide for performing an open posterior cervical foraminotomy on a 33-yr-old male with a history of left-sided pain radiating down the medial aspect of his left arm and left triceps weakness. Magnetic resonance imaging demonstrated a left-sided C6-7 disc herniation causing foraminal stenosis. Guidance on positioning, relevant anatomy, and appropriately planning the extent of bony decompression is also provided in this video. The patient, who consented to the recording of this surgical video, tolerated the procedure without complication, and upon follow-up had a significant improvement in his symptoms.