Nutritional care pathways in cancer patients with malignant bowel obstruction: A retrospective multi-centre study.

INTRODUCTION: Variation in access to parenteral nutrition (PN) in patients with intestinal failure secondary to malignant bowel obstruction (MBO) exists due to differing practice, beliefs and resource access. We aimed to examine differences in nutritional care pathways and outcomes, by referral to nutrition team for PN in patients with MBO. METHODS: This is a retrospective cohort study of MBO adults admitted to eight UK hospitals within a year and 1 year follow-up. Demographic, nutritional and medical data were analysed by comparing patients referred (R) or not referred (NR) for PN. Differences between groups were tested by Kruskal-Wallis, Chi-Squared tests and multi-level regression and survival using Cox regression. RESULTS: 232 patients with 347 MBO admissions [median 66yr, (IQR: 55-74yrs), 67 % female], 79/232 patients were referred for PN (R group). Underlying primary malignancies of gynaecological and gastrointestinal origin predominated (71 %) and 78 % with metastases. Those in the NR group were found to be older, weigh more on admission, and more likely to be treated conservatively compared to those in the R group. For 123 (35 %) admissions, patients were referred to a nutrition team, and for 204 (59 %) admissions, patients were reviewed by a dietician. Multi-disciplinary team discussion and dietetic contact were more likely to occur in the R group-123/347 admissions (R vs NR group: 27 % vs. 7 %, P = 0.001; 95 % vs 39 %, P < 0.0001). Median admission weight loss was 8 % (IQR: 0 to 14). 43/123 R group admissions received inpatient PN only, with 32 patients discharged or already established on home parenteral nutrition. Overall survival was 150 days (126-232) with no difference between R/NR groups. CONCLUSION: In this multi-centre study evaluating nutritional care management of patients with malignant bowel obstruction, only 1 in 3 admissions resulted in a referral to the nutrition team for PN, and just over half were reviewed by a dietician. Further prospective research is required to evaluate possible consequences of these differential care pathways on clinical outcomes and quality of life.

Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson's.

Ca2+ entry into nigrostriatal dopamine (DA) neurons and axons via L-type voltage-gated Ca2+ channels (LTCCs) contributes, respectively, to pacemaker activity and DA release and has long been thought to contribute to vulnerability to degeneration in Parkinson's disease. LTCC function is greater in DA axons and neurons from substantia nigra pars compacta than from ventral tegmental area, but this is not explained by channel expression level. We tested the hypothesis that LTCC control of DA release is governed rather by local mechanisms, focussing on candidate biological factors known to operate differently between types of DA neurons and/or be associated with their differing vulnerability to parkinsonism, including biological sex, α-synuclein, DA transporters (DATs) and calbindin-D28k (Calb1). We detected evoked DA release ex vivo in mouse striatal slices using fast-scan cyclic voltammetry and assessed LTCC support of DA release by detecting the inhibition of DA release by the LTCC inhibitors isradipine or CP8. Using genetic knockouts or pharmacological manipulations, we identified that striatal LTCC support of DA release depended on multiple intersecting factors, in a regionally and sexually divergent manner. LTCC function was promoted by factors associated with Parkinsonian risk, including male sex, α-synuclein, DAT and a dorsolateral co-ordinate, but limited by factors associated with protection, that is, female sex, glucocerebrosidase activity, Calb1 and ventromedial co-ordinate. Together, these data show that LTCC function in DA axons and isradipine effect are locally governed and suggest they vary in a manner that in turn might impact on, or reflect, the cellular stress that leads to parkinsonian degeneration.

Utility of pharmacogenetic testing to optimise antidepressant pharmacotherapy in youth: a narrative literature review.

Pharmacogenetics (PGx) is the study and application of how interindividual differences in our genomes can influence drug responses. By evaluating individuals' genetic variability in genes related to drug metabolism, PGx testing has the capabilities to individualise primary care and build a safer drug prescription model than the current "one-size-fits-all" approach. In particular, the use of PGx testing in psychiatry has shown promising evidence in improving drug efficacy as well as reducing toxicity and adverse drug reactions. Despite randomised controlled trials demonstrating an evidence base for its use, there are still numerous barriers impeding its implementation. This review paper will discuss the management of mental health conditions with PGx-guided treatment with a strong focus on youth mental illness. PGx testing in clinical practice, the concerns for its implementation in youth psychiatry, and some of the barriers inhibiting its integration in clinical healthcare will also be discussed. Overall, this paper provides a comprehensive review of the current state of knowledge and application for PGx in psychiatry and summarises the capabilities of genetic information to personalising medicine for the treatment of mental ill-health in youth.

Dental Bite-Sized Bits: A Module for Teaching Common Oral Health Conditions to Multidisciplinary Students.

The Surgeon General's report in the year 2000 highlighted the association between chronic diseases and oral health infections. Current healthcare education programs, regrettably, report only 1 to 3 h of oral health instruction within curricula. In the years 2020-2022, as part of their respective oral health curricula, 278 first-year physician assistant and 12 pre-clinical second-year pharmacy students were invited to participate in a voluntary survey examining the effectiveness of animated succinct, online video-based oral health units. Among all student responses for the post-use survey, respondents "strongly agreed" or "agreed" that learning objectives of the unit(s) were achieved after reviewing the videos. Of the participants, 97% "strongly agreed" or "agreed" that the videos helped them understand information of which they had no prior knowledge. Similarly, 98% "strongly agreed" or "agreed" the information was appropriate for their level of knowledge. Most students, 93%, "strongly agreed" or "agreed" the exercise was a valuable learning experience. Regarding the importance of future interprofessional collaboration pertaining to a mutual patient's oral health, 95% of participants "strongly agreed" or "agreed" that they would be likely to collaborate. This study demonstrates the importance of oral health as a critical area of focus in healthcare education. The study also confirms the hypothesis that Dental Bite-Sized Bits units deliver engaging, valuable oral health education for preclinical healthcare learners, incorporating interprofessional perspectives from the disciplines of dental, pharmacy, and physician assistant.

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. This review endeavours to capture the scope of literature regarding the aetiology and development of ALS and its commonalities with "synucleinopathy disorders". We will discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.

Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2.

The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties, and whether they have similar or distinct functions is unknown. Here, we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. Disruption of both mTOR complexes leads to pronounced deficits in dopamine release demonstrating the importance of balanced mTORC1 and mTORC2 signaling for dopaminergic function.

Dopamine Release in Nucleus Accumbens Is under Tonic Inhibition by Adenosine A1 Receptors Regulated by Astrocytic ENT1 and Dysregulated by Ethanol.

Striatal adenosine A1 receptor (A1R) activation can inhibit dopamine release. A1Rs on other striatal neurons are activated by an adenosine tone that is limited by equilibrative nucleoside transporter 1 (ENT1) that is enriched on astrocytes and is ethanol sensitive. We explored whether dopamine release in nucleus accumbens core is under tonic inhibition by A1Rs, and is regulated by astrocytic ENT1 and ethanol. In ex vivo striatal slices from male and female mice, A1R agonists inhibited dopamine release evoked electrically or optogenetically and detected using fast-scan cyclic voltammetry, most strongly for lower stimulation frequencies and pulse numbers, thereby enhancing the activity-dependent contrast of dopamine release. Conversely, A1R antagonists reduced activity-dependent contrast but enhanced evoked dopamine release levels, even for single optogenetic pulses indicating an underlying tonic inhibition. The ENT1 inhibitor nitrobenzylthioinosine reduced dopamine release and promoted A1R-mediated inhibition, and, conversely, virally mediated astrocytic overexpression of ENT1 enhanced dopamine release and relieved A1R-mediated inhibition. By imaging the genetically encoded fluorescent adenosine sensor [GPCR-activation based (GRAB)-Ado], we identified a striatal extracellular adenosine tone that was elevated by the ENT1 inhibitor and sensitive to gliotoxin fluorocitrate. Finally, we identified that ethanol (50 mm) promoted A1R-mediated inhibition of dopamine release, through diminishing adenosine uptake via ENT1. Together, these data reveal that dopamine output dynamics are gated by a striatal adenosine tone, limiting amplitude but promoting contrast, regulated by ENT1, and promoted by ethanol. These data add to the diverse mechanisms through which ethanol modulates striatal dopamine, and to emerging datasets supporting astrocytic transporters as important regulators of striatal function.SIGNIFICANCE STATEMENT Dopamine axons in the mammalian striatum are emerging as strategic sites where neuromodulators can powerfully influence dopamine output in health and disease. We found that ambient levels of the neuromodulator adenosine tonically inhibit dopamine release in nucleus accumbens core via adenosine A1 receptors (A1Rs), to a variable level that promotes the contrast in dopamine signals released by different frequencies of activity. We reveal that the equilibrative nucleoside transporter 1 (ENT1) on astrocytes limits this tonic inhibition, and that ethanol promotes it by diminishing adenosine uptake via ENT1. These findings support the hypotheses that A1Rs on dopamine axons inhibit dopamine release and, furthermore, that astrocytes perform important roles in setting the level of striatal dopamine output, in health and disease.

Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling.

Striatal dopamine (DA) release is critical for motivated actions and reinforcement learning, and is locally influenced at the level of DA axons by other striatal neurotransmitters. Here, we review a wealth of historical and more recently refined evidence indicating that DA output is inhibited by striatal γ-aminobutyric acid (GABA) acting via GABAA and GABAB receptors. We review evidence supporting the localisation of GABAA and GABAB receptors to DA axons, as well as the identity of the striatal sources of GABA that likely contribute to GABAergic modulation of DA release. We discuss emerging data outlining the mechanisms through which GABAA and GABAB receptors inhibit the amplitude as well as modulate the short-term plasticity of DA release. Furthermore, we highlight recent data showing that DA release is governed by plasma membrane GABA uptake transporters on striatal astrocytes, which determine ambient striatal GABA tone and, by extension, the tonic inhibition of DA release. Finally, we discuss how the regulation of striatal GABA-DA interactions represents an axis for dysfunction in psychomotor disorders associated with dysregulated DA signalling, including Parkinson's disease, and could be a novel therapeutic target for drugs to modify striatal DA output.

GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model.

Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.

CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.

Parkinson's disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation.

Prevalence and dental professional awareness of antibiotic self-medication among older adults: Implications for dental education.

OBJECTIVE: Antibiotic stewardship has been recognized as an essential component of dental education. A notable threat to stewardship is the growing trend toward self-medication with nonprescribed antibiotics (SMNPA), particularly among older adults who may be at increased risk for adverse outcomes. This study aimed to assess the need to incorporate SMNPA into dental education by researching (1) professional awareness and (2) self-medication behaviors among older adults. METHODS: A SMNPA awareness survey was administered to dentists in Arizona with 148 respondents including general dentists, dental school faculty, and public health clinicians. A second survey was distributed to 410 households in an independent and assisted living facility. RESULTS: The dentists were aware of sources of SMNPA such as friends/family, leftover prescriptions, as well as sources outside of the United States; however, most (>80%) were not aware that ornamental fish antibiotics could be obtained online or in pet stores. The survey response rate for the older adults was 46.3%, of which 68.3% reported antibiotic use within the past 2 years (several for dental premedication) and 6.4% (n = 12) admitted to SMNPA for treating cold symptoms or pain. The main reason given for self-treatment was the belief that antibiotics had resolved similar symptoms in the past. One-third of the older adult respondents were unaware that antibiotics only treat bacterial infections. CONCLUSION: Approximately 1 in 16 older adults surveyed reported SMNPA. Dental professionals reported some knowledge of SMNPA but were unaware of all sources. This study highlights the need for SMNPA education, awareness, and implementation within dental curricula.

Practice management curricular changes may lead to enhanced preparedness for practice.

PURPOSE: The 2018 American Dental Education Association Survey of Dental School Seniors showed that 62.5% of graduates felt prepared in practice administration compared to 49.5% in 2013. The aim of this study was to survey and Internet search U.S. Dental Schools' Practice Management curriculum (PMC) to assess if and what changes, made in the past 5 years, may account for the continued increase in dental graduates' perception of preparedness for practice METHODS: An electronic survey was emailed to 64 dental schools querying factors for changes in PMC, updates in instructors, instructional methods, technology, topics, hours, and content enhancements. In addition, if a dual degree in business administration was developed or planned in the future. RESULTS: Twenty-three schools responded for a 36.0% response rate. All participants (100.0%) indicated PMC changes, 73.9% responded that changes were motivated by student interest, and 60.9% planned future PMC improvements. All respondents (100.0%) updated subject matter and 52.2% had added technology, including Web-based business model and simulation courses. Two schools added dual degree MBA programs in 2017 due to student interest in entrepreneurship and administrative goals. CONCLUSION: The study showed that upgrades in topics and teaching methods with Web-based technology, dual degrees, and additional focus on PMC hours, sequence, and number of practice administration courses in D1 and D2 years may be contributory factors for the development of enhanced skills and enhanced attitudes of graduates for practice readiness. Future study is needed to assess if these PMC improvements and advanced business courses have been successful in practicing dentists' careers.

Plasticity in striatal dopamine release is governed by release-independent depression and the dopamine transporter.

Mesostriatal dopaminergic neurons possess extensively branched axonal arbours. Whether action potentials are converted to dopamine output in the striatum will be influenced dynamically and critically by axonal properties and mechanisms that are poorly understood. Here, we address the roles for mechanisms governing release probability and axonal activity in determining short-term plasticity of dopamine release, using fast-scan cyclic voltammetry in the ex vivo mouse striatum. We show that brief short-term facilitation and longer short term depression are only weakly dependent on the level of initial release, i.e. are release insensitive. Rather, short-term plasticity is strongly determined by mechanisms which govern axonal activation, including K+-gated excitability and the dopamine transporter, particularly in the dorsal striatum. We identify the dopamine transporter as a master regulator of dopamine short-term plasticity, governing the balance between release-dependent and independent mechanisms that also show region-specific gating.

Ensemble encoding of action speed by striatal fast-spiking interneurons.

Striatal fast-spiking interneurons (FSIs) potently inhibit the output neurons of the striatum and, as such, powerfully modulate action learning. Through electrical synaptic coupling, FSIs are theorized to temporally coordinate their activity. This has important implications for their ability to temporally summate inhibition on downstream striatal projection neurons. While some in vivo single-unit electrophysiological recordings of putative FSIs support coordinated firing, others do not. Moreover, it is unclear as to what aspect of action FSIs encode. To address this, we used in vivo calcium imaging of genetically identified FSIs in freely moving mice and applied machine learning analyses to decipher the relationship between FSI activity and movement. We report that FSIs exhibit ensemble activity that encodes the speed of action sub-components, including ambulation and head movements. These results suggest FSI population dynamics fit within a Hebbian model for ensemble inhibition of striatal output guiding action.

TrkB-dependent disinhibition of the nucleus accumbens is enhanced by ethanol.

The nucleus accumbens is a critical integration center for reward-related circuitry and is comprised primarily of medium spiny projection neurons. The dynamic balance of excitation and inhibition onto medium spiny neurons determines the output of this structure. While nucleus accumbens excitatory synaptic plasticity is well-characterized, inhibitory synaptic plasticity mechanisms and their potential relevance to shaping motivated behaviors is poorly understood. Here we report the discovery of long-term depression of inhibitory synaptic transmission in the mouse nucleus accumbens core. This long-term depression is postsynaptically expressed, tropomyosin kinase B (TrkB) receptor-mediated, and augmented in the presence of ethanol. Our findings support the emerging view that TrkB signaling regulates inhibitory synaptic plasticity and suggest this mechanism in the nucleus accumbens as a target for ethanol modulation of reward.

Activation of the Rostral Intralaminar Thalamus Drives Reinforcement through Striatal Dopamine Release.

Glutamatergic projections of the thalamic rostral intralaminar nuclei of the thalamus (rILN) innervate the dorsal striatum (DS) and are implicated in dopamine (DA)-dependent incubation of drug seeking. However, the mechanism by which rILN signaling modulates reward seeking and striatal DA release is unknown. We find that activation of rILN inputs to the DS drives cholinergic interneuron burst-firing behavior and DA D2 receptor-dependent post-burst pauses in cholinergic interneuron firing. In vivo, optogenetic activation of this pathway drives reinforcement in a DA D1 receptor-dependent manner, and chemogenetic suppression of the rILN reduces dopaminergic nigrostriatal terminal activity as measured by fiber photometry. Altogether, these data provide evidence that the rILN activates striatal cholinergic interneurons to enhance the pursuit of reward through local striatal DA release and introduce an additional level of complexity in our understanding of striatal DA signaling.

Dental Students' Use of Student-Managed Google Docs and Other Technologies in Collaborative Learning.

Textbooks, once the standard of education, now have competition when students prefer the Internet and digital technology. The aim of this research study was to survey dental students at one dental school about their use of student-managed Google Docs and other online technologies in collaborative e-learning. All dental students in all four classes at Midwestern University College of Dental Medicine-Arizona were invited to participate in online surveys in 2015 and 2017. The average class size was 140 (n=560 for all four years) for each survey. The 2015 survey focused on the emerging use of Google Docs in collaborative learning. The 2017 study asked not only about Google Docs but how students were using other e-learning technologies and textbooks. In 2015, 282 students responded, for a 50.4% response rate; in 2017, 129 students responded, for a 23% response rate. The 2017 survey showed a 36% increase (p<0.0001) in the use of Google Docs in all dental classes over use in 2015, and a 67% increase (p<0.0001) in respondents' reporting they had used Google Docs during their undergraduate education. Google Docs, Blackboard, and collaboration with peers were the most popular study choices in 2017. The results showed a decline in respondents' reported use of hard copy textbooks from 24.5% in 2015 to 14.8% in 2017 (p=0.0405). Future studies are needed to increase dental educators' understanding of the ways their students are using collaborative technologies in learning and to define ways to overcome challenges posed by these technologies identified in our study.

Inhibition of Nigrostriatal Dopamine Release by Striatal GABAA and GABAB Receptors.

Nigrostriatal dopamine (DA) is critical to action selection and learning. Axonal DA release is locally influenced by striatal neurotransmitters. Striatal neurons are principally GABAergic projection neurons and interneurons, and a small minority of other neurons are cholinergic interneurons (ChIs). ChIs strongly gate striatal DA release via nicotinic receptors (nAChRs) identified on DA axons. Striatal GABA is thought to modulate DA, but GABA receptors have not been documented conclusively on DA axons. However, ChIs express GABA receptors and are therefore candidates for potential mediators of GABA regulation of DA. We addressed whether striatal GABA and its receptors can modulate DA release directly, independently from ChI regulation, by detecting DA in striatal slices from male mice using fast-scan cyclic voltammetry in the absence of nAChR activation. DA release evoked by single electrical pulses in the presence of the nAChR antagonist dihydro-ß-erythroidine was reduced by GABA or agonists of GABAA or GABAB receptors, with effects prevented by selective GABA receptor antagonists. GABA agonists slightly modified the frequency sensitivity of DA release during short stimulus trains. GABA agonists also suppressed DA release evoked by optogenetic stimulation of DA axons. Furthermore, antagonists of GABAA and GABAB receptors together, or GABAB receptors alone, significantly enhanced DA release evoked by either optogenetic or electrical stimuli. These results indicate that striatal GABA can inhibit DA release through GABAA and GABAB receptors and that these actions are not mediated by cholinergic circuits. Furthermore, these data reveal that there is a tonic inhibition of DA release by striatal GABA operating through predominantly GABAB receptors.SIGNIFICANCE STATEMENT The principal inhibitory transmitter in the mammalian striatum, GABA, is thought to modulate striatal dopamine (DA) release, but definitive evidence for GABA receptors on DA axons is lacking. Striatal cholinergic interneurons regulate DA release via axonal nicotinic receptors (nAChRs) and also express GABA receptors, but they have not been eliminated as potentially critical mediators of DA regulation by GABA. Here, we found that GABAA and GABAB receptors inhibit DA release without requiring cholinergic interneurons. Furthermore, ambient levels of GABA inhibited DA release predominantly through GABAB receptors. These findings provide further support for direct inhibition of DA release by GABA receptors and reveal that striatal GABA operates a tonic inhibition on DA output that could critically influence striatal output.

Characterizing classes of fibromyalgia within the continuum of central sensitization syndrome.

BACKGROUND: While fibromyalgia (FM) is characterized by chronic widespread pain and tenderness, its presentation among patients as a continuum of diseases rather than a single disease contributes to the challenges of diagnosis and treatment. The purpose of this analysis was to distinguish and characterize classes of FM within the continuum using data from chronic pain patients. METHODS: FM patients were identified from administrative claims data from the ProCare Systems' network of Michigan pain clinics between January 1999 and February 2015. Identification was based on either use of traditional criteria (ie, ICD-9 codes) or a predictive model indicative of patients having FM. Patients were classified based on similarity of comorbidities (symptom severity), region of pain (widespread pain), and type and number of procedures (treatment intensity) using unsupervised learning. Text mining and a review of physician notes were conducted to assist in understanding the FM continuum. RESULTS: A total of 2,529 FM patients with 79,570 observations or clinical visits were evaluated. Four main classes of FM patients were identified: Class 1) regional FM with classic symptoms; Class 2) generalized FM with increasing widespread pain and some additional symptoms; Class 3) FM with advanced and associated conditions, increasing widespread pain, increased sleep disturbance, and chemical sensitivity; and Class 4) FM secondary to other conditions. CONCLUSION: FM is a disease continuum characterized by progressive and identifiable classifications. Four classes of FM can be differentiated by pain and symptom severity, specific comorbidities, and use of clinical procedures.

Anterior Cingulate Cortex Input to the Claustrum Is Required for Top-Down Action Control.

Cognitive abilities, such as volitional attention, operate under top-down, executive frontal cortical control of hierarchically lower structures. The circuit mechanisms underlying this process are unresolved. The claustrum possesses interconnectivity with many cortical areas and, thus, is hypothesized to orchestrate the cortical mantle for top-down control. Whether the claustrum receives top-down input and how this input may be processed by the claustrum have yet to be formally tested, however. We reveal that a rich anterior cingulate cortex (ACC) input to the claustrum encodes a preparatory top-down information signal on a five-choice response assay that is necessary for optimal task performance. We further show that ACC input monosynaptically targets claustrum inhibitory interneurons and spiny glutamatergic projection neurons, the latter of which amplify ACC input in a manner that is powerfully constrained by claustrum inhibitory microcircuitry. These results demonstrate ACC input to the claustrum is critical for top-down control guiding action.