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Genomic tumor testing (GTT) is an emerging technology aimed at identifying variants in tumors that can be targeted with genomically matched drugs. Due to limited resources, rural patients receiving care in community oncology settings may be less likely to benefit from GTT. We analyzed GTT results and observational clinical outcomes data from patients enrolled in the Maine Cancer Genomics Initiative (MCGI), which provided access to GTTs; clinician educational resources; and genomic tumor boards in community practices in a predominantly rural state. 1603 adult cancer patients completed enrollment; 1258 had at least one potentially actionable variant identified. 206 (16.4%) patients received a total of 240 genome matched treatments, of those treatments, 64% were FDA-approved in the tumor type, 27% FDA-approved in a different tumor type and 9% were given on a clinical trial. Using Inverse Probability of Treatment Weighting to adjust for baseline characteristics, a Cox proportional hazards model demonstrated that patients who received genome matched treatment were 31% less likely to die within 1 year compared to those who did not receive genome matched treatment (HR: 0.69; 95% CI: 0.52-0.90; p-value: 0.006). Overall, GTT through this initiative resulted in levels of genome matched treatment that were similar to other initiatives, however, clinical trials represented a smaller share of treatments than previously reported, and "off-label" treatments represented a greater share. Although this was an observational study, we found evidence for a potential 1-year survival benefit for patients who received genome matched treatments. These findings suggest that when disseminated and implemented with a supportive infrastructure, GTT may benefit cancer patients in rural community oncology settings, with further work remaining on providing genome-matched clinical trials., (© 2024. The Author(s).)

Purpose: The Maine Cancer Genomics Initiative (MCGI) aimed to overcome patient- and provider-level barriers to using genomic tumor testing (GTT) in rural practices by providing genomic tumor boards (GTBs), clinician education, and access to comprehensive large-panel next-generation sequencing to all patients with cancer in Maine. This paper describes the successful implementation of the initiative and three key services made operative between 2016 and 2020., Methods: A community-inclusive, hub-and-spoke approach was taken to implement the three program components: (1) a centralized GTB program; (2) a modular online education program, designed using an iterative approach with broad clinical stakeholders; and (3) GTT free of charge to clinicians and patients. Implementation timelines, participation metrics, and survey data were used to describe the rollout., Results: The MCGI was launched over an 18-month period at all 19 oncology practices in the State. Seventy-nine physicians (66 medical oncologists, 5 gynecologic oncologists, 1 neuro-oncologist, and 7 pediatric oncologists) enrolled on the study, representing 100% of all practicing oncologists in Maine. Between July 2017 and September 2020, 1610 patients were enrolled. A total of 515 cases were discussed by 47 (73%) clinicians in 196 GTBs. Clinicians who participated in the GTBs enrolled significantly more patients on the study, stayed in Maine, and reported less time spent in clinical patient care., Conclusion: The MCGI was able to engage geographically and culturally disparate cancer care practices in a precision oncology program using a hub-and-spoke model. By facilitating access to GTT, structured education, and GTBs, we narrowed the gap in the implementation of precision oncology in one of the most rural states in the country.

During REM sleep, skeletal muscles are paralyzed in one moment but twitch and jerk in the next. REM sleep twitches are traditionally considered random motor events that result from momentary lapses in REM sleep paralysis [1-3]. However, recent evidence indicates that twitches are not byproducts of REM sleep, but are in fact self-generated events that could function to promote motor learning and development [4-6]. If REM twitches are indeed purposefully generated, then they should be controlled by a coordinated and definable mechanism. Here, we used behavioral, electrophysiological, pharmacological, and neuroanatomical methods to demonstrate that an inhibitory drive onto skeletal motoneurons produces a temporally coordinated pattern of muscle twitches during REM sleep. First, we show that muscle twitches in adult rats are not uniformly distributed during REM sleep, but instead follow a well-defined temporal trajectory. They are largely absent during REM initiation but increase steadily thereafter, peaking toward REM termination. Next, we identify the transmitter mechanism that controls the temporal nature of twitch activity. Specifically, we show that a GABA and glycine drive onto motoneurons prevents twitch activity during REM initiation, but progressive weakening of this drive functions to promote twitch activity during REM termination. These results demonstrate that REM twitches are not random byproducts of REM sleep, but are instead rather coherently generated events controlled by a temporally variable inhibitory drive., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is a progressive neurodegenerative disorder typified by the presence of intraneuronal inclusions containing aggregated alpha synuclein (αsyn). The progression of parkinsonian pathology and clinical phenotype has been broadly demonstrated to follow a specific pattern, most notably described by Braak and colleagues. In more recent times it has been hypothesized that αsyn itself may be a critical factor in mediating transmission of disease pathology from one brain area to another. Here we investigate the growing body of evidence demonstrating the ability of αsyn to spread transcellularly and induce pathological aggregation affecting neurons by permissive templating and provide a critical analysis of some irregularities in the hypothesis that the progression of PD pathology may be mediated by such a prion-like process. Finally we discuss some key questions that remain unanswered which are vital to determining the potential contribution of a prion-like process to the pathogenesis of PD.

CR1 is a novel Alzheimer's disease (AD) gene identified by genome-wide association studies (GWAS). Recently, we showed that AD risk could be explained by an 18-kilobase insertion responsible for the complement component (3b/4b) receptor 1 (CR1)-S isoform. We investigated the relevance of the CR1 isoforms to AD in a Canadian dataset. Also, we genotyped rs4844610 tagging the GWAS-significant CR1 single nucleotide polymorphisms. Individuals with F/S genotype had a 1.8 times increased risk for AD compared with F/F genotype (p-adjusted = 0.003), while rs4844610 was only marginally significant (p-adjusted = 0.024). The analyses of brain samples demonstrated that the CR1-S isoform is expressed at lower protein levels than CR1-F (p < 0.0001) hence likely associated with increased complement activation. Intriguingly, our neuropathological results show that the pattern of CR1 expression in neurons is different between the F/F and F/S genotypes (filiform vs. vesicular-like profiles). Furthermore, double labeling studies supported a differential distribution of CR1 in neurons (endoplasmic reticulum intermediate compartment vs. lysosomes). These observations indicate that the CR1-S and CR1-F isoforms could be processed in different ways in neurons. In conclusion, our results support that the CR1-S isoform explains the GWAS signals and open a novel prospect for the investigation of CR1-related disease mechanisms., (Copyright © 2012 Elsevier Inc. All rights reserved.)

During REM sleep the CNS is intensely active, but the skeletal motor system is paradoxically forced into a state of muscle paralysis. The mechanisms that trigger REM sleep paralysis are a matter of intense debate. Two competing theories argue that it is caused by either active inhibition or reduced excitation of somatic motoneuron activity. Here, we identify the transmitter and receptor mechanisms that function to silence skeletal muscles during REM sleep. We used behavioral, electrophysiological, receptor pharmacology and neuroanatomical approaches to determine how trigeminal motoneurons and masseter muscles are switched off during REM sleep in rats. We show that a powerful GABA and glycine drive triggers REM paralysis by switching off motoneuron activity. This drive inhibits motoneurons by targeting both metabotropic GABA(B) and ionotropic GABA(A)/glycine receptors. REM paralysis is only reversed when motoneurons are cut off from GABA(B), GABA(A) and glycine receptor-mediated inhibition. Neither metabotropic nor ionotropic receptor mechanisms alone are sufficient for generating REM paralysis. These results demonstrate that multiple receptor mechanisms trigger REM sleep paralysis. Breakdown in normal REM inhibition may underlie common sleep motor pathologies such as REM sleep behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a neurological disease characterized by loss of normal REM motor inhibition and subsequent dream enactment. RBD is clinically relevant because it predicts neurodegenerative disease onset (e.g., Parkinson's disease) and is clinically problematic because it disrupts sleep and results in patient injuries and hospitalization. Even though the cause of RBD is unknown, multiple lines of evidence indicate that abnormal inhibitory transmission underlies the disorder. Here, we show that transgenic mice with deficient glycine and GABA transmission have a behavioral, motor, and sleep phenotype that recapitulates the cardinal features of RBD. Specifically, we show that mice with impaired glycine and GABA(A) receptor function exhibit REM motor behaviors, non-REM muscle twitches, sleep disruption, and EEG slowing--the defining disease features. Importantly, the RBD phenotype is rescued by drugs (e.g., clonazepam and melatonin) that are routinely used to treat human disease symptoms. Our findings are the first to identify a potential mechanism for RBD--we show that deficits in glycine- and GABA(A)-mediated inhibition trigger the full spectrum of RBD symptoms. We propose that these mice are a useful resource for investigating in vivo disease mechanisms and developing potential therapeutics for RBD.

The aim of this study was to determine if GABA(B) receptors play a role in suppressing upper airway muscle tone in rapid eye movement (REM) sleep. The results reported herein indicate that GABA(B) receptors, acting in concert with GABA(A) and glycine receptors, play a role in mediating REM sleep atonia.

A hallmark of rapid eye movement (REM) sleep is a potent suppression of postural muscle tone. Motor control in REM sleep is unique because it is characterized by flurries of intermittent muscle twitches that punctuate muscle atonia. Because somatic motoneurons are bombarded by strychnine-sensitive IPSPs during REM sleep, it is assumed that glycinergic inhibition underlies REM atonia. However, it has never been determined whether glycinergic inhibition of motoneurons is indeed responsible for triggering the loss of postural muscle tone during REM sleep. Therefore, we used reverse microdialysis, electrophysiology, and pharmacological and histological methods to determine whether glycinergic and/or GABA(A)-mediated neurotransmission at the trigeminal motor pool mediates masseter muscle atonia during REM sleep in rats. By antagonizing glycine and GABA(A) receptors on trigeminal motoneurons, we unmasked a tonic glycinergic/GABAergic drive at the trigeminal motor pool during waking and non-rapid eye movement (NREM) sleep. Blockade of this drive potently increased masseter muscle tone during both waking and NREM sleep. This glycinergic/GABAergic drive was immediately switched-off and converted into a phasic glycinergic drive during REM sleep. Blockade of this phasic drive potently provoked muscle twitch activity in REM sleep; however, it did not prevent or reverse REM atonia. Muscle atonia in REM even persisted when glycine and GABA(A) receptors were simultaneously antagonized and trigeminal motoneurons were directly activated by glutamatergic excitation, indicating that a powerful, yet unidentified, inhibitory mechanism overrides motoneuron excitation during REM sleep. Our data refute the prevailing hypothesis that REM atonia is caused by glycinergic inhibition. The inhibitory mechanism mediating REM atonia therefore requires reevaluation.

Male Djungarian hamsters, Phodopus campbelli, are highly parental and experience a late-afternoon prolactin surge before the birth that is not seen in a closely related species, P. sungorus, which lacks paternal care. At the same stage, female prolactin is needed for later maternal behavior. Male prolactin was suppressed in first-time fathers before the birth of the litter using two different dopamine agonists, bromocriptine mesylate and cabergoline. Plasma prolactin concentration confirmed the efficacy of each treatment. Paternal responsiveness was quantified using three variations on a pup-displacement paradigm. No adverse effects of either treatment were seen. Across four experiments, there was no decrease in paternal retrieval or in retrieval latency in response to male prolactin suppression. In addition, there was no decrease in litter growth or survival, nor was there an increase in maternal investment to compensate for a deficit in paternal care. As cabergoline suppression of prolactin persisted after the birth without behavioral deficits, prolactin after the birth was also not required for the expression of paternal behavior. In spite of an extensive literature supporting an association between prolactin and natural paternal behavior, we conclude that dopamine-mediated prolactin release into peripheral plasma is not essential for paternal responsiveness in P. campbelli.

A patient presented with the Lambert-Eaton syndrome and small cell anaplastic carcinoma of the lung was subsequently diagnosed. Treatment with cytotoxic chemotherapy and radiotherapy resulted in remission of both the cancer and the neuromuscular disorder. This case represents the first documented remission of the Lambert-Eaton syndrome following nonoperative treatment of the primary malignancy and emphasizes the therapeutic value of early diagnosis of this disorder.

Identification of open set words, by an experienced normal hearing subject using the tactile vocoder developed at Queen's University, was examined. The tactile vocoder filters and processes the acoustic waveform into 16 filter channels, each of which controls a vibrator on the skin surface. After acquiring a 250-word vocabulary through the tactile vocoder, the subject was presented with three sets of 1000 different open set words in three reception conditions. The percentages of words correctly identified in the tactile vocoder (TV), lipreading (L), and lipreading plus tactile vocoder (L + TV) conditions were 8.8, 39.4, and 68.7 percent respectively. Phonemic analysis of stimulus/response pairs revealed that 36.7, 64.9 and 85.5 percent of the phonemes were correctly identified in TV, L, and L + TV conditions, respectively, indicating that incorrect-response words often contained many correct phonemes. Also, syllabic stress of stimulus and response words was identical 88 percent of the time in the TV condition. Important information about speech was transmitted through the tactile vocoder.

Normal subjects learned to identify words through a tactile vocoder. The vocoder employed 16 filter channels, each with a bandwidth of 1/3 octave, with center frequencies ranging from 200-8000 Hz. The output of each filter was detected and after logarithmic amplification the resulting outputs were transmitted to a 16-channel solenoid array placed on the subject's ventromedial forearm. Words, spoken "live voice," were used as stimuli; the subject was able to feel both the vocalization of the reader and herself and, most importantly, extensive training was provided. In 40.5 h one subject learned 70 words and a second subject reached criterion on 150 words in the comparatively short time of 55 h. Words that were poorly identified initially were identified more readily with increased experience. Phonetic identification tests showed that the features of voicing, nasality, and frication were reliably recognized, indicating the tactile vocoder will be useful in providing information to complement lipreading. Finally, subjects learned rapidly to generalize word-learning to unfamiliar readers.

Identification of open set words by an experienced normal hearing subject using the tactile vocoder developed at Queen's University was examined. The tactile vocoder filters and processes the acoustic waveform into 16 filter channels each of which activates a vibrator on the skin surface. After acquiring a 250-word vocabulary through the tactile vocoder, the subject was presented with 1000 different open set sentences in two reception conditions. The percentages of words correctly identified within the sentences in the lipreading (L) and lipreading plus tactile vocoder (L + TV) conditions were 57.8 percent and 79.6 percent, respectively. After two presentations of the stimulus sentences, the number of sentences repeated verbatim in the L + TV condition was 58.4 percent, which was 27.8 percent higher than scores obtained in the L condition. Performance on the tactile vocoder was also evaluated using the "tracking procedure," in which phrases of text are read to the subject who attempts to repeat the material verbatim. The final tracking rate obtained using lipreading was 15.3 words per minute, which was considerably lower than the L + TV tracking rate of 49.3 words per minute. The tactile vocoder provided valuable information which improved the subject's lipreading ability.

The experiments described are part of an ongoing evaluation of the Queen's University Tactile Vocoder, a device that allows the acoustic waveform to be felt as a vibrational pattern on the skin. Two prelingually profoundly deaf teenagers reached criterion on a 50-word vocabulary (live voice, single speaker) using information obtained solely from the tactile vocoder with 28.5 and 24.0 hours of training. Immediately following word-learning experiments, subjects were asked to place 16 CVs into five phonemic categories (voiced & unvoiced stops, voiced & unvoiced fricatives, approximants). Average accuracy was 84.5%. Similar performance (89.6%) was obtained for placement of 12 VCs into four phonemic categories. Subjects were able to acquire some general rules about voicing and manner of articulation cues.

In a previous experiment [P. L. Scilley, "Evaluation of a vibrotactile auditory prosthetic device for the profoundly deaf," unpublished Masters thesis, Queen's University, Kingston, Canada (1980)] two normal subjects learned to identify 70 and 150 words, respectively, using the Queen's Tactile Vocoder. In the present experiment, the most advanced subject continued word learning until a tactile vocabulary of 250 words was acquired. At this point randomized tests were given to obtain an indication of final performance level. From these data conditional probabilities of correct response for each stimulus word and significant confusions were obtained, which provides insight into the advantages and present limitations of the tactile vocoder.