Clinical, Biomarker, and Research Tests Among US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: Since 2015, US government and related personnel have reported dizziness, pain, visual problems, and cognitive dysfunction after experiencing intrusive sounds and head pressure. The US government has labeled these anomalous health incidents (AHIs). Objective: To assess whether participants with AHIs differ significantly from US government control participants with respect to clinical, research, and biomarker assessments. Design, Setting, and Participants: Exploratory study conducted between June 2018 and July 2022 at the National Institutes of Health Clinical Center, involving 86 US government staff and family members with AHIs from Cuba, Austria, China, and other locations as well as 30 US government control participants. Exposures: AHIs. Main Outcomes and Measures: Participants were assessed with extensive clinical, auditory, vestibular, balance, visual, neuropsychological, and blood biomarkers (glial fibrillary acidic protein and neurofilament light) testing. The patients were analyzed based on the risk characteristics of the AHI identifying concerning cases as well as geographic location. Results: Eighty-six participants with AHIs (42 women and 44 men; mean [SD] age, 42.1 [9.1] years) and 30 vocationally matched government control participants (11 women and 19 men; mean [SD] age, 43.8 [10.1] years) were included in the analyses. Participants with AHIs were evaluated a median of 76 days (IQR, 30-537) from the most recent incident. In general, there were no significant differences between participants with AHIs and control participants in most tests of auditory, vestibular, cognitive, or visual function as well as levels of the blood biomarkers. Participants with AHIs had significantly increased fatigue, depression, posttraumatic stress, imbalance, and neurobehavioral symptoms compared with the control participants. There were no differences in these findings based on the risk characteristics of the incident or geographic location of the AHIs. Twenty-four patients (28%) with AHI presented with functional neurological disorders. Conclusions and Relevance: In this exploratory study, there were no significant differences between individuals reporting AHIs and matched control participants with respect to most clinical, research, and biomarker measures, except for objective and self-reported measures of imbalance and symptoms of fatigue, posttraumatic stress, and depression. This study did not replicate the findings of previous studies, although differences in the populations included and the timing of assessments limit direct comparisons.

Neuroimaging Findings in US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: US government personnel stationed internationally have reported anomalous health incidents (AHIs), with some individuals experiencing persistent debilitating symptoms. Objective: To assess the potential presence of magnetic resonance imaging (MRI)-detectable brain lesions in participants with AHIs, with respect to a well-matched control group. Design, Setting, and Participants: This exploratory study was conducted at the National Institutes of Health (NIH) Clinical Center and the NIH MRI Research Facility between June 2018 and November 2022. Eighty-one participants with AHIs and 48 age- and sex-matched control participants, 29 of whom had similar employment as the AHI group, were assessed with clinical, volumetric, and functional MRI. A high-quality diffusion MRI scan and a second volumetric scan were also acquired during a different session. The structural MRI acquisition protocol was optimized to achieve high reproducibility. Forty-nine participants with AHIs had at least 1 additional imaging session approximately 6 to 12 months from the first visit. Exposure: AHIs. Main Outcomes and Measures: Group-level quantitative metrics obtained from multiple modalities: (1) volumetric measurement, voxel-wise and region of interest (ROI)-wise; (2) diffusion MRI-derived metrics, voxel-wise and ROI-wise; and (3) ROI-wise within-network resting-state functional connectivity using functional MRI. Exploratory data analyses used both standard, nonparametric tests and bayesian multilevel modeling. Results: Among the 81 participants with AHIs, the mean (SD) age was 42 (9) years and 49% were female; among the 48 control participants, the mean (SD) age was 43 (11) years and 42% were female. Imaging scans were performed as early as 14 days after experiencing AHIs with a median delay period of 80 (IQR, 36-544) days. After adjustment for multiple comparisons, no significant differences between participants with AHIs and control participants were found for any MRI modality. At an unadjusted threshold (P < .05), compared with control participants, participants with AHIs had lower intranetwork connectivity in the salience networks, a larger corpus callosum, and diffusion MRI differences in the corpus callosum, superior longitudinal fasciculus, cingulum, inferior cerebellar peduncle, and amygdala. The structural MRI measurements were highly reproducible (median coefficient of variation <1% across all global volumetric ROIs and <1.5% for all white matter ROIs for diffusion metrics). Even individuals with large differences from control participants exhibited stable longitudinal results (typically, <±1% across visits), suggesting the absence of evolving lesions. The relationships between the imaging and clinical variables were weak (median Spearman ρ = 0.10). The study did not replicate the results of a previously published investigation of AHIs. Conclusions and Relevance: In this exploratory neuroimaging study, there were no significant differences in imaging measures of brain structure or function between individuals reporting AHIs and matched control participants after adjustment for multiple comparisons.

Systematic Review of Interventions to Reduce Suicide Risk in Transgender and Gender Diverse Youth.

Transgender youth experience high rates of suicidal ideation and suicide attempts. This systematic review sought to examine interventions for suicide prevention in transgender children and adolescents. Literature related to suicide in the transgender population was systematically collected in accordance with PRISMA criteria. Searches identified studies with at least one suicide prevention method for participants ages 24 years or younger with gender identity and sex clearly defined. Primary outcomes include suicide-related thoughts and behaviors. A total of 1558 citations were identified with 17 articles meeting inclusion criteria. Interventions with potential effectiveness included a gender-affirming crisis hotline, medical care via interdisciplinary gender clinics, online media-based outreach, safety and connectedness in schools, and family system-based interventions. In the included studies, the overall quality of evidence was low and the risk of bias high. Further high-quality studies are needed.

A novel variant affecting the cytoplasmic tail of the FAT1 protocadherin causing coloboma and renal failure: A case report.

BACKGROUND: Variations in the protocadherin gene FAT1 have recently been associated with a syndrome that includes coloboma, facial dysmorphism, renal failure, syndactyly, and other developmental defects. MATERIALS AND METHODS: Detailed medical and family history, physical examination, and molecular analysis. RESULTS: This non-dysmorphic, intellectually normal 51-year-old woman presented with bilateral colobomata and renal failure of unclear etiology, and asymmetric sensorineural hearing loss. Family history was notable for multiple family members with various forms of cancer. Whole exome sequencing revealed a homozygous frame shift variant in FAT1, predicted to truncate the FAT1 protein at the furthest position in the protein structure published to date in a patient with coloboma. CONCLUSIONS: This case provides further evidence of the pleiotropic effects of FAT1 in optic fissure closure and kidney function. Also, because this variant is in the last exon, it would be anticipated to escape nonsense-mediated decay, opening the possibility that the protein is made and expressed, but not completely functional, as its intracellular domain is truncated.

"Everything That's Hard Got Harder": Preservice Teachers' Attempts at Rigorous and Responsive Instruction During Pedagogical Rehearsals in the COVID Pandemic.

At the onset of the COVID-19 pandemic, our teacher preparation program shifted to an online setting, disrupting a key feature of practice-based teacher preparation: preservice science teachers' (PSTs) approximation of rigorous and responsive instruction during extended pedagogical rehearsals, called macroteaching. Given this unplanned shock to their preparation, we examined how PSTs viewed macroteaching and their evolving participation in the teaching rehearsal. Using a situative perspective, we collected multiple forms of data. We found that although PSTs wanted to enact rigorous and responsive instruction, their participation was deeply affected by the sudden shift to an online setting. Our analysis of video-recorded lessons confirmed PSTs' observations that their instruction became less rigorous and responsive over time. We conclude with questions about teacher preparation during the pandemic.

Increased muscle activity during sleep and more RBD symptoms in H1N1-(Pandemrix)-vaccinated narcolepsy type 1 patients compared with their non-narcoleptic siblings.

STUDY OBJECTIVES: Narcolepsy type 1 (NT1) is characterized by unstable sleep-wake and muscle tonus regulation during sleep. We characterized dream enactment and muscle activity during sleep in a cohort of post-H1N1 NT1 patients and their siblings, and analyzed whether clinical phenotypic characteristics and major risk factors are associated with increased muscle activity. METHODS: RBD symptoms and polysomnography m. tibialis anterior electromyographical signals [long (0.5-15 s); short (0.1-0.49 s)] were compared between 114 post-H1N1 NT1 patients and 89 non-narcoleptic siblings. Association sub-analyses with RBD symptoms, narcoleptic symptoms, CSF hypocretin-1 levels, and major risk factors [H1N1-(Pandemrix)-vaccination, HLA-DQB1*06:02-positivity] were performed. RESULTS: RBD symptoms, REM and NREM long muscle activity indices and REM short muscle activity index were significantly higher in NT1 patients than siblings (all p < 0.001). Patients with undetectable CSF hypocretin-1 levels (<40 pg/ml) had significantly more NREM periodic long muscle activity than patients with low but detectable levels (40-150 pg/ml) (p = 0.047). In siblings, REM and NREM sleep muscle activity indices were not associated with RBD symptoms, other narcolepsy symptoms, or HLA-DQB1*06:02-positivity. H1N1-(Pandemrix)-vaccination status did not predict muscle activity indices in patients or siblings. CONCLUSION: Increased REM and NREM muscle activity and more RBD symptoms is characteristic of NT1, and muscle activity severity is predicted by hypocretin deficiency severity but not by H1N1-(Pandemrix)-vaccination status. In the patients' non-narcoleptic siblings, neither RBD symptoms, core narcoleptic symptoms, nor the major NT1 risk factors is associated with muscle activity during sleep, hence not indicative of a phenotypic continuum.

Audiometric and Otologic Findings in Children and Young Adults with Neurofibromatosis Type 1 and Plexiform Neurofibromas.

OBJECTIVES: To characterize otologic and audiologic manifestations in our NF1 cohort and explore the relationship between otologic and audiologic findings in a subset of patients with ear-related plexiform neurofibromas (PNs). METHODS: Audiologic and otologic clinical evaluations were conducted on 102 patients with NF1 in a natural history study (5-45 years; M = 14.4 years; Mdn = 14). Testing included pure tone and speech audiometry, middle ear function, neurodiagnostic auditory brainstem response (ABR), auditory processing, and MRIs of the head and neck region. Patients referred to this study had an overall higher incidence and burden of PNs than the overall NF1 population. RESULTS: The majority of subjects in this cohort had normal hearing sensitivity (81%) and normal middle ear function (78%). Nineteen participants had hearing loss that ranged in degree from mild to profound, with the majority in the mild range. Hearing loss was twice as likely to be conductive than sensorineural. In patients with ear-related PNs (n = 12), hearing loss was predominantly conductive (60%). Seventy-five percent of ears with PNs had atypical tympanometric tracings that could not be characterized by the classic categories. In all 20 patients with a PN in the temporal bone, the ear canal was affected, and the PNs often extended to the surrounding soft tissue regions. CONCLUSIONS: People with NF1-related PNs in the temporal bone and adjacent skull base should have audiometric and otologic monitoring. Addressing hearing concerns should be part of routine clinical evaluations in patients with NF1. Magnetic resonance imaging (MRI) should be performed in patients with NF1 who have hearing loss. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2770-2778, 2023.

To treat or not to treat? High-potency benzodiazepine use in a case of comorbid hallucinogen persisting perception disorder and alcohol use disorder.

Hallucinogen persisting perception disorder (HPPD) is characterized by visual disturbances that resemble psychedelic intoxication and linger after use has ceased. The most common substances precipitating HPPD, lysergic acid diethylamide (LSD) and psilocybin, are posited to do so via damage to serotonergic neurons involved in vision. Mr. N is a 37-year-old with a history of alcohol, cannabis, LSD, cocaine, and nicotine use disorders who described visual distortions that resolved when he drank heavily or received benzodiazepines for withdrawal. He did not appear psychotic. Over 20 years after his last LSD use, he continued to experience illusions of halos around objects, moving walls, and figures appearing cartoonish. He understood that his perceptual disturbances were not reality based. During hospitalization for suicidal ideation, laboratory tests, head computed tomography (CT), and electroencephalogram (EEG) studies offered no explanation for his visual disturbances other than HPPD. The visual distortions remitted with scheduled clonazepam treatment, although chemical dependency treatment programs were hesitant to accept him while on a benzodiazepine. This case emphasizes the importance of diagnostic clarification when patients present with perceptual disturbances that do not fit typical psychotic presentations. Our discussion will distinguish misperceptions from hallucinations and review the pathophysiology of HPPD. Last, we will discuss management strategies for patients with co-occurring HPPD and substance use disorders. It is necessary to discern the correct cause of visual disturbances in order to provide proper treatment. The risks and benefits of long-term benzodiazepine use must be weighed when deciding whether to prescribe them for patients with comorbid HPPD and alcohol use disorder. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

ASPHALT II: Study Protocol for a Multi-Method Evaluation of a Comprehensive Peer-Led Youth Community Sport Programme Implemented in Low Resource Neighbourhoods.

To reduce inequalities in children's sport participation, studies are needed to explore ways in which children from low resource neighbourhoods can be engaged and retained in sport. GAME Community is a peer-led community sport programme which aims to promote physical activity through participation in inclusive street sports activities targeting 8-15-year-old children living in low resource neighbourhoods. The GAME Community intervention is implemented by the non-profit street sport organisation GAME. Five components support the implementation of GAME Community: (1) training of peer leaders; (2) a focus on inclusion of inactive girls; (3) parental involvement; (4) community engagement; (5) strengthened organisational support to peer leaders. In the ASPHALT II study, we aim to evaluate GAME Community and hence contribute to understanding how children growing up in low resource neighbourhoods can be engaged and retained in physical activity through participation in peer-led, community-based sport and to generate new understandings on the scale up of community interventions. The primary objective of the evaluation is to investigate the implementation of GAME Community and the programme's reach, and to establish the functioning and mechanisms of the programme. The secondary objective is to establish the health enhancing potential of the programme. The evaluation of GAME Community involves three linked but independent studies that investigate (1) the functioning (i.e., mechanisms and processes), (2) reach, and (3) outcomes. The functioning of the five intervention components is investigated using qualitative methodologies. Programme reach will be investigated based on participant registrations. Systematic observations using a novel combination of validated tools will provide information on outcomes (physical activity level and social behaviour) during GAME Community activities. Investigating functioning, reach, and outcomes of the GAME Community intervention by using multiple methods is a strength, as different data complement and inform each other. This study will provide in-depth insights into if and how children living in low resource neighbourhoods can be engaged and retained in physical activity through participation in peer-led, community-based sport. Contributions of this evaluation include new understanding of the mechanisms and scalability of a community-based street sport intervention.

Activating the 'peerness' of youth leaders in a community sports programme through techne and phronesis.

Peer-to-peer approaches engage groups of people considered to share one or more characteristics that identify them as peers and draw on rationales of credibility, identification and role modelling in peer-to-peer interactions. Despite the popularity of the approach, the ways in which the peer leadership component specifically contributes to health promotion is not thoroughly understood. We suggest that a first step for making use of peer leader characteristics is to make explicit what the peer leadership component is expected to bring to a programme. To approach such an understanding, we investigated how peer leaders can be supported in activating their 'peerness' in health promotion programmes, using as a case the peer leader education of a youth-led, peer-to-peer community sports programme, implemented by the non-profit street sports organization, GAME. We analysed the peer leader training programme's learning objectives and field notes from observations of the training programme. The empirical material was analysed using an abductive approach by drawing upon contemporary interpretations of two forms of knowledge originally proposed by Aristotle. In so doing, this article explores how the development of techne (practical knowledge) and phronesis (practical wisdom) was supported in a peer leader training programme for young people. Findings suggest that supporting the development of both these types of knowledge can strengthen programme planners' attention to the contribution of peers. Concurrently, an emphasis on promoting phronesis in peer leader training can support and encourage peer leaders in activating their 'peerness' in peer-to-peer health promotion programmes.

Peer-to-peer approaches are commonly used in the health promotion. Peer-led programmes engage groups of people considered to share one or more characteristics that identify them as peers. Peer leaders are suggested to be credible sources of information and provide identification and role modelling to their peers. However, despite the popularity of the approach, the ways in which peer leaders specifically contribute to health promotion are not thoroughly understood. It is thus unclear how the 'peerness' of peer leaders is activated in health promotion programmes. In this study, we investigated how peer leaders can be supported in activating their 'peerness' during peer-led activities. To do so, we observed and analysed the peer leader training programme of a youth-led community sport programme, implemented by the non-profit organization, GAME. As a theoretical framework, we employed two forms of knowledge originally proposed by Aristotle; namely, techne (practical knowledge) and phronesis (practical wisdom). Our results suggest that supporting the development of both these types of knowledge can strengthen programme planners' attention to the contribution of peers. Concurrently, an emphasis on promoting phronesis in peer leader training can support and encourage peer leaders in activating their 'peerness' in peer-to-peer health promotion programmes.

Changes in quality of life 6 months after parathyroidectomy for primary hyperparathyroidism.

Objective: The extent of symptoms due to primary hyperparathyroidism (PHPT) depends on the population being studied. PHPT is mainly discovered incidentally through routine laboratory findings. Less is known about patient-experienced improvement following successful parathyroidectomy. The aim of our study was to assess the changes in the quality of life (QoL) after successful surgery using an SF-36 questionnaire. Design: This is a prospective cohort study based on questionnaires. Methods: Forty consecutive patients diagnosed with PHPT were prospectively administered an SF-36 questionnaire before and 6 months after successful parathyroidectomy. A subgroup of 18 patients answered the questionnaire at 1 and 3 months after surgery. Successful surgery was based on biochemistry and pathology reports as confirmed by an endocrinologist. Results of each SF-36 subcategory were compared to the results at baseline in order to detect changes in patient-reported QoL after successful surgery. Results: There were significant improvements in six of eight SF-36 subcategories: vitality (P = 0.0001), physical functioning (P = 0.04), general health perception (P = 0.004), physical role functioning (P = 0.04), social role functioning (P = 0.004), and mental health perception (P = 0.0001). Changes appeared within a month after surgery with no further significant changes at later time points. Conclusions: Parathyroidectomy significantly improves QoL as measured by a decrease in SF-36 scores as early as 1 month after successful parathyroidectomy. The SF-36 QoL questionnaire is suitable for monitoring changes in patient well-being after successful parathyroidectomy.

Preoperative imaging in primary hyperparathyroidism: Are 11 C-Choline PET/CT and 99m Tc-MIBI/123 Iodide subtraction SPECT/CT interchangeable or do they supplement each other?

OBJECTIVE: Preoperative location of hyperfunctioning parathyroid glands (HPGs) is vital when planning minimally invasive surgery in patients with primary hyperparathyroidism (PHPT). Dual-isotope subtraction scintigraphy with 99m Tc-MIBI/123 Iodide using SPECT/CT and planar pinhole imaging (Di-SPECT) has shown high sensitivity, but is challenged by high radiation dose, time consumption and cost. 11 C-Choline PET/CT (faster with a lower radiation dose) is non-inferior to Di-SPECT. We aim to clarify to what extent the two are interchangeable and how often there are discrepancies. DESIGN: This is a prospective, GCP-controlled cohort study. PATIENTS AND MEASUREMENTS: One hundred patients diagnosed with PHPT were included and underwent both imaging modalities before parathyroidectomy. Clinical implications of differences between imaging findings and negative imaging results were assessed. Surgical findings confirmed by biochemistry and pathology served as reference standard. RESULTS: Among the 90 patients cured by parathyroidectomy, sensitivity was 82% (95% confidence interval [CI]: 74%-88%) and 87% (95% CI: 79%-92%) for Choline PET and Di-SPECT, respectively, p = .88. In seven cases at least one imaging modality found no HPG. Of these, neither modality found any true HPGs and only two were cured by surgery. When a positive finding in one modality was incorrect, the alternative modality was correct in approximately half of the cases. CONCLUSION: Choline PET and Di-SPECT performed equally well and are both appropriate as first-line imaging modalities for preoperative imaging of PHPT. When the first-line modality fails to locate an HPG, additional preoperative imaging with the alternate modality offers no benefit. However, if parathyroidectomy is unsuccessful, additional imaging with the alternate modality has merit before repeat surgery.

Audiologic and Otologic Clinical Manifestations of Loeys-Dietz Syndrome: A Heritable Connective Tissue Disorder.

OBJECTIVE: Loeys-Dietz syndrome (LDS) is a rare genetic connective tissue disorder resulting from TGF-ß signaling pathway defects and characterized by a wide spectrum of aortic aneurysm, arterial tortuosity, and various extravascular abnormalities. This study describes the audiologic, otologic, and craniofacial manifestations of LDS. STUDY DESIGN: Consecutive cross-sectional study. SETTING: Tertiary medical research institute. METHODS: Audiologic and clinical evaluations were conducted among 36 patients (mean ± SD age, 24 ± 17 years; 54% female) with genetically confirmed LDS. Cases were categorized into genetically based LDS types 1 to 4 (TGFBR1, TGFBR2, SMAD3, TGFB2, respectively). Audiometric characteristics included degree and type of hearing loss: subclinical, conductive, mixed, and sensorineural. RESULTS: LDS types 1 to 4 included 11, 13, 5, and 7 patients, respectively. In LDS-1, 27% had bilateral conductive hearing loss; 9%, unilateral mixed; and 36%, subclinical. In LDS-2, 38% had conductive hearing loss and 38% subclinical. In LDS-3 and LDS-4, 40% and 43% had bilateral sensorineural hearing loss, respectively. Degree of hearing loss ranged from mild to moderate. Bifid uvula was observed only in LDS-1 (55%) and LDS-2 (62%). Submucosal/hard cleft palates were primarily in LDS-1 and LDS-2. Posttympanostomy tympanic membrane perforations occurred in 45% (10/22 ears) of LDS-1 and LDS-2. There were 4 cases of cholesteatoma: 3 middle ear (LDS-1 and LDS-2) and 1 external ear canal (LDS-3). CONCLUSION: Conductive hearing loss, bifid uvula/cleft palate, and posttympanostomy tympanic membrane perforation are more common in LDS-1 and LDS-2 than LDS-3 and LDS-4, while sensorineural hearing loss was present only in LDS-3 and LDS-4. These LDS-associated key clinical presentations may facilitate an early diagnosis of LDS and thus prompt intervention to prevent related detrimental outcomes.

Video-polysomnography procedures for diagnosis of rapid eye movement sleep behavior disorder (RBD) and the identification of its prodromal stages: guidelines from the International RBD Study Group.

Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible.

Locating hyperfunctioning parathyroid glands using 11C-Choline PET/CT: an inter- and intra-observer variation study.

BACKGROUND: Use of 11C-Choline PET/CT is gaining ground in detecting hyperfunctioning parathyroid glands in primary hyperparathyroidism. The purpose of this study was to evaluate the robustness of 11C-Choline PET/CT by assessing intra- and inter-observer agreement to determine whether the method was reader sensitive and therefore should only be performed at highly specialised sites with a high number of cases. PET/CT images of 40 patients diagnosed with primary hyperparathyroidism were anonymised and evaluated three times by three readers: an expert reader and two non-experts (non-experts were experienced in PET/CT imaging, but not in 11C-Choline PET/CT in the setting of primary hyperparathyroidism). Number of hyperfunctioning parathyroid glands, location relative to the thyroid gland and confidence of each assessment (low, moderate or high) were noted, and intra- and inter-observer agreement calculated using Fleiss' kappa method. Sensitivities and specificities of the non-experts were calculated using the expert reader as gold standard. RESULTS: Intra-observer agreement was 'good' to 'near perfect' for all readers. Inter-observer agreement was good between non-experts and the expert, with kappa values ≥ 0.74. Sensitivities between non-experts and the expert were high, > 81%, when assessing which side and 75% when assessing thyroid quadrant. All specificities were > 94%. Reader certainties were 'high' in > 80% of cases for the expert and > 70% and > 65%, respectively for the two non-experts. CONCLUSION: 11C-Choline PET/CT is not reader sensitive for the localisation of hyperfunctioning parathyroid glands and may therefore be safely implemented at sites that have a moderate number of cases. Access to a cyclotron laboratory is, however, a necessity for the production of 11C-Choline. The study was conducted in accordance with the Helsinki 2 declaration and The International Council for Harmonisation Guideline for Good Clinical Practice (ICH_GCP) clinical trial, approved by the Research Ethics Committee of the Capital Region of Denmark (Journal-nr.:H-18012490, date of approval: 18 June 2018) and the Danish Medicines Agency (EudraCT no. 2018-000726-63, date of approval: 6 June 2018). The GCP unit in Eastern Denmark has carried out regular monitoring of the trial according to GCP (ID: 2018-1050).

The levels of the serine protease HTRA1 in cerebrospinal fluid correlate with progression and disability in multiple sclerosis.

BACKGROUND: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease. OBJECTIVE: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue. METHODS: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map. RESULTS: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons. CONCLUSION: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.

Association of neurocognitive functioning with sleep stage dissociation and REM sleep instability in medicated patients with schizophrenia.

Many patients with schizophrenia present with impaired cognitive functioning and sleep disturbances. Dissociated stages of sleep represent instability within distinct sleep regulatory cerebral networks. Previous studies found increased rates of rapid eye movement (REM) sleep abnormalities in patients with schizophrenia and a positive association with psychopathology. In this study, we examined if sleep stage dissociation and REM sleep instability was associated with neurocognitive functioning in a sample of medicated patients with schizophrenia. The analyses were performed on 31 baseline polysomnographic recordings as well as baseline data on neurocognitive performance. Regression models were built with the cognitive composite score as primary dependent variable and measures of sleep stage dissociation, including REM sleep without atonia (RSWA), REM sleep without eye movements, non-REM sleep with eye movements, REM sleep percentage in REM periods and REM sleep stability as independent variables. Analyses were adjusted for age, gender, total antipsychotic dose, total benzodiazepine dose, and symptom severity. After correction for multiple testing, we found that the neurocognitive composite score was inversely associated with the degree of RSWA. Exploratory analyses with the cognitive sub scores as dependent variables showed that RSWA was associated with cognitive performance across several sub domains. Dissociated sleep stages, specifically the RSWA feature, might represent a new treatment target for improving cognitive impairment in patients with schizophrenia.