Myalgic Encephalomyelitis-Chronic Fatigue Syndrome Common Data Element item content analysis.

INTRODUCTION: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem chronic disease estimated to affect 836,000-2.5 million individuals in the United States. Persons with ME/CFS have a substantial reduction in their ability to engage in pre-illness levels of activity. Multiple symptoms include profound fatigue, post-exertional malaise, unrefreshing sleep, cognitive impairment, orthostatic intolerance, pain, and other symptoms persisting for more than 6 months. Diagnosis is challenging due to fluctuating and complex symptoms. ME/CFS Common Data Elements (CDEs) were identified in the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) Common Data Element Repository. This study reviewed ME/CFS CDEs item content. METHODS: Inclusion criteria for CDEs (measures recommended for ME/CFS) analysis: 1) assesses symptoms; 2) developed for adults; 3) appropriate for patient reported outcome measure (PROM); 4) does not use visual or pictographic responses. Team members independently reviewed CDEs item content using the World Health Organization International Classification of Functioning, Disability and Health (ICF) framework to link meaningful concepts. RESULTS: 119 ME/CFS CDEs (measures) were reviewed and 38 met inclusion criteria, yielding 944 items linked to 1503 ICF meaningful concepts. Most concepts linked to ICF Body Functions component (b-codes; n = 1107, 73.65%) as follows: Fatiguability (n = 220, 14.64%), Energy Level (n = 166, 11.04%), Sleep Functions (n = 137, 9.12%), Emotional Functions (n = 131, 8.72%) and Pain (n = 120, 7.98%). Activities and Participation concepts (d codes) accounted for a smaller percentage of codes (n = 385, 25.62%). Most d codes were linked to the Mobility category (n = 69, 4.59%) and few items linked to Environmental Factors (e codes; n = 11, 0.73%). DISCUSSION: Relatively few items assess the impact of ME/CFS symptoms on Activities and Participation. Findings support development of ME/CFS-specific PROMs, including items that assess activity limitations and participation restrictions. Development of psychometrically-sound, symptom-based item banks administered as computerized adaptive tests can provide robust assessments to assist primary care providers in the diagnosis and care of patients with ME/CFS.

Altered Plasma Mitochondrial Metabolites in Persistently Symptomatic Individuals after a GBCA-Assisted MRI.

Despite the impressive safety of gadolinium (Gd)-based contrast agents (GBCAs), a small number of patients report the onset of new, severe, ongoing symptoms after even a single exposure-a syndrome termed Gadolinium Deposition Disease (GDD). Mitochondrial dysfunction and oxidative stress have been repeatedly implicated by animal and in vitro studies as mechanisms of Gd/GBCA-related toxicity, and as pathogenic in other diseases with similarities in presentation. Here, we aimed to molecularly characterize and explore potential metabolic associations with GDD symptoms. Detailed clinical phenotypes were systematically obtained for a small cohort of individuals (n = 15) with persistent symptoms attributed to a GBCA-enhanced MRI and consistent with provisional diagnostic criteria for GDD. Global untargeted mass spectroscopy-based metabolomics analyses were performed on plasma samples and examined for relevance with both single marker and pathways approaches. In addition to GDD criteria, frequently reported symptoms resembled those of patients with known mitochondrial-related diseases. Plasma differences compared to a healthy, asymptomatic reference cohort were suggested for 45 of 813 biochemicals. A notable proportion of these are associated with mitochondrial function and related disorders, including nucleotide and energy superpathways, which were over-represented. Although early evidence, coincident clinical and biochemical indications of potential mitochondrial involvement in GDD are remarkable in light of preclinical models showing adverse Gd/GBCA effects on multiple aspects of mitochondrial function. Further research on the potential contributory role of these markers and pathways in persistent symptoms attributed to GBCA exposure is recommended.

Safety analysis and complications of condylar screws in a single-surgeon series of 250 occipitocervical fusions.

OBJECTIVE: Condylar screw fixation is a rescue technique and an alternative to the conventional configuration of occipitocervical fusion. Condylar screws are utilized when previous surgical bone removal along the supraocciput has occurred which makes anchoring of a traditional barplate technically difficult or impossible. However, the challenging dissection of C0-1 necessary for condylar screw fixation and the concerns about possible complications have, thus far, prevented the acquisition of large surgical series utilizing occipital condylar screws. In the largest case series to date, this paper aims to evaluate the safety profile and complications of condylar screw fixation for occipitocervical fusion. METHODS: A retrospective safety and complication-based analysis of occipitocervical fusion via condylar screws fixation was performed. RESULTS: A total of 250 patients underwent occipitocervical fusions using 500 condylar screws between September 2012 and September 2018. No condylar screw pullouts, or vertebral artery impingements were observed in this series. The sacrifice of condylar veins during the dissection at C0-1 did not cause any venous stroke. Hypotrophic condyles were found in 36.4% (91 of the 250) cases and did not prevent the insertion of condylar screws. Two transient hypoglossal deficits occurred at the beginning of this surgical series and were followed by recovery a few months later. Corrective strategies were effective in preventing further hypoglossal injuries. CONCLUSIONS: This surgical series suggests that the use of condylar screws fixation is a relatively safe and reliable option for OC fusion in both adult and pediatric patients. Methodical dissection of anatomical landmarks, intraoperative imaging, and neurophysiologic monitoring allowed the safe execution of the largest series of condylar screws reported to date. Separate contributions will follow in the future to provide details about the long-term clinical outcome of this series.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management.

Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.

Diagnosis of mast cell activation syndrome: a global "consensus-2".

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of "mast cell activation syndrome" (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a "consensus" (re-termed here as "consensus-1"). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as "consensus-2"), resembling "consensus-1" in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by "consensus-2" criteria has potential to be problematic, but underdiagnosis by "consensus-1" criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.

PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature.

BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

The genetics of Leigh syndrome and its implications for clinical practice and risk management.

Leigh syndrome, also referred to as subacute necrotizing encephalomyelopathy, is a severe, early-onset neurodegenerative disorder that is relentlessly progressive and devastating to both the patient and the patient's family. Attributed to the ultimate failure of the mitochondrial respiratory chain, once it starts, the disease often results in the regression of both mental and motor skills, leading to disability and rapid progression to death. It is a mitochondrial disorder with both phenotypic and genetic heterogeneity. The cause of death is most often respiratory failure, but there are a whole host of complications, including refractory seizures, that may further complicate morbidity and mortality. The symptoms may develop slowly or with rapid progression, usually associated with age of onset. Although the disease is usually diagnosed within the first year of life, it is important to note that recent studies reveal phenotypic heterogeneity, with some patients having evidence of in utero presentation and others having adult-onset symptoms.

Cystathionine beta-synthase deficiency heralded by cerebral sinus venous thrombosis and stroke.

BACKGROUND: Elevated plasma homocysteine is a risk factor for arterial and venous thromboses in adults. Homocysteine is increased in cystathionine beta-synthase deficiency, a treatable amino acid metabolic disorder that may be missed on newborn screening placing children at risk of thrombosis and strokes. PATIENT: We present a 3-year-old girl with normal newborn screening for cystathionine beta-synthase deficiency who developed a symptomatic cerebral venous sinus thrombosis. Subsequent testing revealed marked hyperhomocystinemia and genetic testing confirmed cystathionine beta-synthase deficiency. CONCLUSIONS: Current newborn screening is limited in its ability to detect cystathionine beta-synthase deficiency and although postanalytical interpretation may provide increased sensitivity, a normal newborn screening result should not replace the importance of physician surveillance.

Lower-dose prescribing: minimizing "side effects" of pharmaceuticals on society and the environment.

The prescribed use of pharmaceuticals can result in unintended, unwelcomed, and potentially adverse consequences for the environment and for those not initially targeted for treatment. Medication usage frequently results in the collateral introduction to the environment (via excretion and bathing) of active pharmaceutical ingredients (APIs), bioactive metabolites, and reversible conjugates. Imprudent prescribing and non-compliant patient behavior drive the accumulation of unused medications, which pose major public health risks from diversion as well as risks for the environment from unsound disposal, such as flushing to sewers. The prescriber has the unique wherewithal to reduce each of these risks by modifying various aspects of the practice of prescribing. By incorporating consideration of the potential for adverse environmental impacts into the practice of prescribing, patient care also could possibly be improved and public health better protected. Although excretion of an API is governed by its characteristic pharmacokinetics, this variable can be somewhat controlled by the prescriber in selecting APIs possessing environment-friendly excretion profiles and in selecting the lowest effective dose. This paper presents the first critical examination of the multi-faceted role of drug dose in reducing the ambient levels of APIs in the environment and in reducing the incidence of drug wastage, which ultimately necessitates disposal of leftovers. Historically, drug dose has been actively excluded from consideration in risk mitigation strategies for reducing ambient API levels in the environment. Personalized adjustment of drug dose also holds the potential for enhancing therapeutic outcomes while simultaneously reducing the incidence of adverse drug events and in lowering patient healthcare costs. Optimizing drug dose is a major factor in improving the sustainability of health care. The prescriber needs to be cognizant that the "patient" encompasses the environment and other "bystanders," and that prescribed treatments can have unanticipated, collateral impacts that reach far beyond the healthcare setting.

Green pharmacy and pharmEcovigilance: prescribing and the planet.

Active pharmaceutical ingredients (APIs) are ubiquitous environmental contaminants, resulting primarily from excretion and bathing and from disposal of leftover drugs by consumers and healthcare facilities. Although prudent disposal of leftover drugs has attracted the most attention for reducing API levels in the aquatic environment, a more effective approach would prevent the generation of leftover drugs in the first place. Many aspects of the practice of medicine and pharmacy can be targeted for reducing environmental contamination by APIs. These same modifications--focused on treating humans and the environment as a single, integral patient--could also have collateral outcomes with improved therapeutic outcomes, and with a reduced incidence of unintended poisonings, drug interactions and drug diversion, and lower consumer costs.

Environmental footprint of pharmaceuticals: the significance of factors beyond direct excretion to sewers.

The combined excretion of active pharmaceutical ingredients (APIs) via urine and feces is considered the primary route by which APIs from human pharmaceuticals enter the environment. Disposal of unwanted, leftover medications by flushing into sewers has been considered a secondary route-one that does not contribute substantially to overall environmental loadings. The present study presents the first comprehensive examination of secondary routes of API release to the environment and for direct but unintentional human exposure. These include bathing, washing, and laundering, all of which release APIs remaining on the skin from the use of high-content dermal applications or from excretion to the skin via sweating, and disposal of unused and partially used high-content devices. Also discussed are the health hazards associated with: partially used devices, medication disposal practices of consumers, and interpersonal dermal transfer of API residues. Understanding these secondary routes is important from the perspective of pollution prevention, because actions can be designed more easily for reducing the environmental impact of APIs compared with the route of direct excretion (via urine and feces), for reducing the incidence of unintentional and purposeful poisonings of humans and pets, and for improving the quality and cost-effectiveness of health care. Overall, unintentional exposure to APIs for humans via these routes is possibly more important than exposure to trace residues recycled from the environment in drinking water or foods.

Disposal practices for unwanted residential medications in the United States.

The occurrence of trace levels of prescription and over-the-counter pharmaceuticals in the environment began to receive concerted attention nearly two decades ago. The public's growing awareness and concern over the presence of these chemicals, especially in drinking water, has served to catalyze considerable discussion and debate regarding the best practices for disposal of unused or unwanted medications. In the United States, the first federal guidance for consumers was issued in 2007. It recommends discarding unused pharmaceuticals to household trash, after taking precautions to mix the pharmaceuticals with an inert substance and conceal the contents from view. Providing the consumer with additional options for conscientious disposal are various community, city, and state collection events, ongoing programs, and government-funded pilot projects. These strategies include the opportunity to mail or bring unused medications to various collection points, such as pharmacies, for eventual destruction. All of these approaches to medication disposal play roles in reducing the introduction of pharmaceuticals to the environment.

The afterlife of drugs and the role of pharmEcovigilance.

The prescribing and usage of medications (for both humans and domestic animals) have ramifications extending far beyond the traditional objectives of conventional medical care. The healthcare industry has an environmental footprint that includes the active pharmaceutical ingredients (APIs) from medications, residues of which can establish themselves as environmental pollutants. This occurs by a variety of routes, but primarily from excretion, bathing and disposal. Many parallels exist between healthcare and the protection and remediation of the environment, spanning the stages from symptomology and diagnosis to treatment. The critical role played by pharmacovigilance in healthcare has a counterpart with the ecological environment. The term ecopharmacovigilance has been used with respect to the unforeseen consequences APIs can have once they enter the environment. We propose that conventional pharmacovigilance could be expanded to encompass environmental concerns--a concept we term pharmEcovigilance--as a way to unify the parallel but interconnected needs for protecting both human and ecological health.To convey the scope of a pharmEcovigilance programme, we provide an overview of the occurrence of APIs as environmental pollutants, their ramifications for human health and the environment and some of the ways in which their impact could be reduced or minimized. The major areas discussed include: (i) the routes by which APIs become contaminants in the environment; (ii) the hazards of leftover drugs as a result of stockpiling and from disposal to sewage, which can also eventually contribute to the contamination of drinking water; (iii) why drugs accumulate unused; and (iv) the benefits for humans and the environment that could accrue from reducing the accumulation of leftover drugs and the subsequent introduction of APIs into the environment. A broad spectrum of actions could be taken by prescribers (including veterinarians) and the healthcare industry at large (including manufacturers and insurers) to reduce the release or introduction of APIs to the environment. Most significantly, however, a major reason to consider implementing a pharmEcovigilance programme--beyond reducing the environmental footprint of healthcare--is the previously unforeseen collateral benefit in making further progress in optimizing the delivery, effectiveness, outcomes and cost of healthcare, as well as improving safety for humans, pets and wildlife. For this reason, the relationships that healthcare professionals and patients have with medications might also include consideration of pharmEcovigilance. Like any profession that deals with chemicals, perhaps a major challenge to be faced is how to ensure the sustainability (and minimize the life cycle exposure hazards) of a chemical-based, chemical-centric society in the most cost-effective and safest manner. Given that the medical community is a major source of numerous 'exotic' chemical pollutants in the environment (with thousands of chemically distinct APIs in current use), albeit at very low levels, an imperative could be created for designing and implementing approaches for reducing and controlling this source of pollution. With reduced wastage of medications, in part driven by appropriate or rational prescribing and dispensing, the ecological footprint of medicine could be greatly reduced, with concomitant improvements in many aspects of healthcare.

Beyond the medicine cabinet: an analysis of where and why medications accumulate.

Active pharmaceutical ingredients (APIs) from medications can enter the environment as trace contaminants, at individual concentrations generally below a part per billion (microg/L). APIs enter the environment primarily via the discharge of raw and treated sewage. Residues of unmetabolized APIs from parenteral and enteral drugs are excreted in feces and urine, and topically applied medications are washed from skin during bathing. These trace residues may pose risks for aquatic life and cause concern with regard to subsequent human exposure. APIs also enter the environment from the disposal of unwanted medications directly to sewers and trash. The relative significance of this route compared with excretion and bathing is poorly understood and has been subject to much speculation. Two major aspects of uncertainty exist: the percentage of any particular API in the environment originating from disposal is unknown, and disposal undoubtedly occurs from a variety of dispersed sources. Sources of disposal, along with the types and quantities of APIs resulting from each source, are important to understand so that effective pollution prevention approaches can be designed and implemented. Accumulation of leftover, unwanted drugs poses three major concerns: (i) APIs disposed to sewage or trash compose a diverse source of potential chemical stressors in the environment. (ii) Accumulated drugs represent increased potential for drug diversion, with its attendant risks of unintentional poisonings and abuse. (iii) Leftover drugs represent wasted healthcare resources and lost opportunities for medical treatment. This paper has four major purposes: (1) Define the processes, actions, and behaviors that control and drive the consumption, accumulation, and need for disposal of pharmaceuticals. (2) Provide an overview of the diverse locations where drugs are used and accumulate. (3) Present a summary of the first cataloging of APIs disposed by a defined subpopulation. (4) Identify opportunities for pollution prevention and source reduction.

Types and quantities of leftover drugs entering the environment via disposal to sewage--revealed by coroner records.

Pharmaceuticals designed for humans and animals often remain unused for a variety of reasons, ranging from expiration to a patient's non-compliance. These leftover, accumulated drugs represent sub-optimal delivery of health care and the potential for environmentally unsound disposal, which can pose exposure risks for humans and wildlife. A major unknown with respect to drugs as pollutants is what fractions of drug residues occurring in the ambient environment result from discarding leftover drugs. To gauge the significance of leftover drugs as potential pollutants, data are needed on the types, quantities, and frequencies with which drugs accumulate. Absence of this data has prevented assessments of the significance of drug accumulation and disposal as a contributing source of drug residues in the environment. One particular source of drug accumulation is those drugs that become "orphaned" by the death of a consumer. A new approach to acquiring the data needed to assess the magnitude and extent of drug disposal as a source of environmental pollution is presented by using the inventories of drugs maintained by coroner offices. The data from one metropolitan coroner's office demonstrates proof of concept. Coroner data on leftover drugs are useful for measuring the types and amounts of drugs accumulated by consumers. This inventory also provides an accurate measure of the individual active ingredients actually disposed into sewage by coroners. The types of questions these data can address are presented, and the possible uses of these data for deriving estimates of source contributions from the population at large are discussed. The approach is proposed for nationwide implementation (and automation) to better understand the significance of consumer disposal of medications.