AMEERA-4: a randomized, preoperative window-of-opportunity study of amcenestrant versus letrozole in early breast cancer.

BACKGROUND: Window-of-opportunity (WOO) studies provide insights into the clinical activity of new drugs in breast cancer. METHODS: AMEERA-4 (NCT04191382) was a WOO study undertaken to compare the pharmacodynamic effects of amcenestrant, a selective estrogen receptor degrader, with those of letrozole in postmenopausal women with newly diagnosed, operable estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. Women were randomized (1:1:1) to receive amcenestrant 400 mg, amcenestrant 200 mg, or letrozole 2.5 mg once daily for 14 days before breast surgery. The primary endpoint was change in Ki67 between baseline and Day 15 (i.e., day of surgery). RESULTS: Enrollment was stopped early because of slow recruitment, in the context of the COVID-19 pandemic. The modified intent-to-treat population consisted of 95 study participants with baseline and post-treatment Ki67 values, whereas the safety population included 104 participants who had received at least one dose of study medication. Relative change from baseline in Ki67 was - 75.9% (95% confidence interval [CI] - 81.9 to - 67.9) for amcenestrant 400 mg, - 68.2% (- 75.7 to - 58.4) for amcenestrant 200 mg, and - 77.7% (- 83.4 to - 70.0) for letrozole (geometric least-squares mean [LSM] estimates). Absolute change in ER H-score from baseline (LSM estimate) was - 176.7 in the amcenestrant 400 mg arm, - 202.9 in the amcenestrant 200 mg arm, and - 32.5 in the letrozole arm. There were no Grade ≥ 3 treatment-related adverse events. CONCLUSIONS: Both amcenestrant and letrozole demonstrated antiproliferative activity in postmenopausal women with previously untreated, operable ER+/HER2- breast cancer and had good overall tolerability. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04191382 https://clinicaltrials.gov/ct2/show/NCT04191382 . Registered 9 December 2019.

Development of a core outcome set for traumatic brachial plexus injury.

The aim of the present study was to reach international consensus on the minimum set of outcomes to measure and report in adult traumatic brachial plexus injury care and research. This would facilitate comparison of outcomes from different centres and meta-analysis in research. A list of outcomes was developed from a systematic review (n = 54) and patient interviews (n = 12). The outcomes were rated in a three-round online Delphi survey completed by international surgeons, patients and therapists. Two online consensus meetings with patients and clinicians ratified the final core outcome set. A total of 72 people (20 surgeons, 21 patients, 31 therapists) from 19 countries completed all survey rounds. Thirty-eight people from nine countries attended separate patient (n = 13) and clinician consensus (n = 25) meetings. Outcomes were included if recommended by more than 85% of contributors. Pain, voluntary movement and carrying out a daily routine are the core outcome domains that should be assessed and reported when treating and researching adults with a traumatic brachial plexus injury. LEVEL OF EVIDENCE: V.

Autobiographical memory in chronic schizophrenia: A follow-up study.

Chronic schizophrenia is a very disabling disease and patient's social integration remains difficult. One important aspect is autobiographical memory (AM) as it is impaired in schizophrenia and highly correlated to patient's outcome, since its closely linked to self and identity. Reduced specificity and lack of details are characteristics of patients' AM, but its longitudinal course in schizophrenia remains unclear. We examined 21 patients who underwent our protocol twice with an interval of 7 years. AM was assessed using a semi-structured interview, covering four periods of life and addressing semantic knowledge and autobiographical episodes as well as their details. The results can be divided into three parts, separating semantic memories, specific autobiographical memories and details describing the latter. While a significant deterioration of semantic AM over time could be revealed, the specificity of the free recalled autobiographical episodes remained rather stable - albeit on a low level. In contrast, unique events were remembered with significantly less details at follow-up than at the first examination. While floor-effects given a relatively small number of unique events have to be considered, semantic AM and episodic details seem to be a valuable target for AM remediation given their further deterioration over time.

Structural brain networks in schizophrenia based on nonnegative matrix factorization.

Schizophrenia is a severe mental disease with significant morphometric reductions in gray matter volume and cortical thickness in a variety of brain regions. However, most studies only focused on the voxel level alterations in specific cerebral regions and ignored the spatial relationship between voxels. In the present study, we used a novel, data-driven technique-nonnegative matrix factorization (NMF) to group voxels with similar information into a network, and studied the structural covariance at the network level in schizophrenia. Our sample included 36 patients with schizophrenia and 21 healthy controls. Compared with healthy controls, patients with schizophrenia showed significant gray matter volume reductions in six structural covariance networks (dorsal striatum, thalamus, hippocampus-parahippocampus, supplementary motor area-fusiform, middle/inferior temporal network, frontal-parietal-occipital network). Our findings confirmed the assumption of a disturbance in the cortical-subcortical circuit in schizophrenia and suggested that NMF is a useful multivariate method to identify brain networks, which provides a new perspective to study the neural mechanism in schizophrenia.

Adjuvant endocrine therapy uptake, toxicity, quality of life, and prediction of early discontinuation.

BACKGROUND: Many patients receiving adjuvant endocrine therapy (ET) for breast cancer experience side effects and reduced quality of life (QoL) and discontinue ET. We sought to describe these issues and develop a prediction model of early discontinuation of ET. METHODS: Among patients with hormone receptor-positive and HER2-negative stage I-III breast cancer of the Cancer Toxicities cohort (NCT01993498) who were prescribed adjuvant ET between 2012 and 2017, upon stratification by menopausal status, we evaluated adjuvant ET patterns including treatment change and patient-reported discontinuation and ET-associated toxicities and impact on QoL. Independent variables included clinical and demographic features, toxicities, and patient-reported outcomes. A machine-learning model to predict time to early discontinuation was trained and evaluated on a held-out validation set. RESULTS: Patient-reported discontinuation rate of the first prescribed ET at 4 years was 30% and 35% in 4122 postmenopausal and 2087 premenopausal patients, respectively. Switching to a new ET was associated with higher symptom burden, poorer QoL, and higher discontinuation rate. Early discontinuation rate of adjuvant ET before treatment completion was 13% in postmenopausal and 15% in premenopausal patients. The early discontinuation model obtained a C index of 0.62 in the held-out validation set. Many aspects of QoL, most importantly fatigue and insomnia (European Organization for Research and Treatment of Cancer QoL questionnaire 30), were associated with early discontinuation. CONCLUSION: Tolerability and adherence to ET remains a challenge for patients who switch to a second ET. An early discontinuation model using patient-reported outcomes identifies patients likely to discontinue their adjuvant ET. Improved management of toxicities and novel more tolerable adjuvant ETs are needed for maintaining patients on treatment.

Structural and cross-cultural validity of the Afrikaans for the Western Cape Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire.

BACKGROUND: The Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire has been translated and cross-culturally adapted to Afrikaans for the Western Cape, within the public health service context of South Africa. The aim of this study was to evaluate structural validity, internal consistency, and cross-cultural validity/measurement invariance of this new translation to increase applicability and clinical utility in a public health service context. METHODS: During this cross-sectional study, exploratory factor analysis (EFA) was conducted with parallel analysis and oblimin rotation. Confirmatory factor analysis (CFA) and multiple group confirmatory factor analysis (MGCFA) to assess cross-cultural validity/measurement invariance, was employed to test model fit with X2 goodness-of-fit statistic, root mean square error of approximation (RMSEA), standardized root mean square residual (SRMR) and comparative fit index (CFI). Internal consistency was calculated using Cronbach's alpha. RESULTS: 109 women and 110 men (n = 219) completed the Afrikaans for the Western Cape and the South African English DASH questionnaire, used during the analysis. Unidimensionality of the Afrikaans for the Western Cape DASH questionnaire was not supported in the 218 questionnaires eligible for inclusion in the analysis [X2 (df) = 1799.10 (405); p value = < 0.01; RMSEA (90% CI) = 0.126 (0.120-0.132); SRMR = 0.09 and CFI = 0.984]. EFA revealed a two-factor structure with Eigenvalues exceeding one explaining 55% and 7% of the variance. The two-factor structure of the Afrikaans for the Western Cape DASH questionnaire was supported during CFA. Cronbach's alpha revealed good internal consistency of both factors [factor 1 = 0.97 (0.96, 0.97) and factor 2 = 0.92 (0.90, 0.94)]. MGCFA conducted between 218 Afrikaans for the Western Cape DASH and 219 South African English DASH questionnaires (N = 437) revealed that the data supports configural, metric and scalar invariance models during initial model fit assessment. Subsequent hypotheses testing comparing the nested models revealed that scalar invariance holds. CONCLUSION: The Afrikaans for the Western Cape DASH questionnaire revealed a two-factor structure with good internal consistency across the two factors and demonstrated measurement invariance with the South African English DASH questionnaire.

Neurological soft signs and structural network changes: a longitudinal analysis in first-episode schizophrenia.

BACKGROUND: Neurological soft signs (NSS) are often reported in patients with schizophrenia and may vary with psychopathological symptoms during the course of disease. Many cross-sectional neuroimaging studies have shown that NSS are associated with disturbed network connectivity in schizophrenia. However, it remains unclear how these associations change over time during the course of disorder. METHODS: In present study, 20 patients with first-episode schizophrenia and 20 controls underwent baseline structural magnetic resonance imaging (MRI) scan and at one-year follow-up. Structural network characteristics of patients and controls were analyzed using graph theoretical approach based on MRI data. NSS were assessed using the Heidelberg scale. RESULTS: At baseline, patients demonstrated significant changes of the local network properties mainly involving regions of the cortical-subcortical-cerebellar circuits compared to healthy controls. For further analysis, the whole patient group was dichotomized into a NSS-persisting and NSS-decreasing subgroup. After one-year follow-up, the NSS-persisting subgroup showed decreased betweenness in right inferior opercular frontal cortex, left superior medial frontal cortex, left superior temporal cortex, right putamen and cerebellum vermis and increased betweenness in right lingual cortex. However, the NSS-decreasing subgroup exhibited only localized changes in right middle temporal cortex, right insula and right fusiform with decreased betweenness, and in left lingual cortex with increased betweenness. CONCLUSIONS: These findings provide evidence for brain network reorganization subsequent to clinical disease manifestation in patients with first-episode schizophrenia, and support the hypothesis that persisting NSS refer to progressive brain network abnormalities in patients with schizophrenia. Therefore, NSS could help to establish a better prognosis in first-episode schizophrenia patients.

Brachial plexus injury: living with uncertainty.

PURPOSE: A traumatic brachial plexus injury (BPI) has life-changing consequences for patients and their families. Despite advancements in treatments final outcome is unpredictable depending on factors including time to treatment, injury severity, neural regeneration, and available interventions. The final outcome may not be seen for up to four years. This study aimed to explore the impact of uncertainty on people with a traumatic BPI. METHODS: Secondary qualitative analysis was conducted on data from a study exploring outcomes important to patients with a traumatic BPI. Data from semi-structured interviews with adult traumatic BPI patients (n = 13) were analyzed using reflexive thematic analysis. RESULTS: Three major themes were identified in the qualitative data: (i) "I don't know what happened to me," focused on uncertainty in diagnosis. (ii) "I went to work one day… and then it all changed" centered around uncertainty in the future. (iii) Coping with uncertainty. CONCLUSION: The results illustrate that people with a traumatic BPI face uncertainty regarding diagnosis, prognosis, and surrounding their roles in the future. Individuals respond to uncertainty in different ways and this needs to be understood by health care professionals. IMPLICATIONS FOR REHABILITATIONHealth professionals should consider uncertainty in all their contacts with people who have experienced a traumatic brachial plexus injury.People with a traumatic brachial plexus injury experience uncertainty in different ways therefore education and information given may be optimized if tailored to the individual rather than generic.Increasing awareness of the injury and its presentation in non-specialist acute care clinicians may accelerate diagnosis and reduce initial uncertainty.Acknowledging the presence of uncertainty is important during the shared decision-making in brachial plexus injuries.

Autobiographical memory impairment in chronic schizophrenia: Significance and clinical correlates.

Previous studies of autobiographical memory (AM) in schizophrenia yielded a reduction of specificity, richness of details and conscious recollection, which indicate both, quantitative and qualitative AM changes. However, their associations with psychopathological symptoms and neuropsychological deficits were not resolved. Therefore, we sought to investigate AM with respect to psychopathology and neuropsychology in patients with chronic schizophrenia to rule out the influence of different courses of the disease. AM of four lifetime periods was examined in 75 patients and 50 healthy controls by using a semi-structured interview. The recalled episodes were rated for memory specificity. Subsequently, one single event of each period of life was rated for details and experiential aspects of reliving (originality, vividness/visual imagery, emotional re-experiencing and emotional valence). When contrasted with healthy controls, patients recalled a significantly reduced number of episodes and personal semantic facts; moreover, memory specificity of AM was significantly lower in patients than controls. While the richness of details calculated for single events showed only minor, non-significant group differences, vividness and emotional re-experiencing were significantly less pronounced in the patient group. Along with this, AM performance correlated significantly with negative symptoms including apathy as well as verbal memory and executive functions. Our results underline the significance of overgenerality as a key feature of AM in schizophrenia as well as a dissociation between intact number of details of single events and reduced vividness and emotional re-experiencing. The extent of negative symptoms including apathy and impairments of verbal memory/executive functions may explain AM deficits in chronic schizophrenia.

Morphology, biochemistry and connectivity of Cluster N and the hippocampal formation in a migratory bird.

The exceptional navigational capabilities of migrating birds are based on the perception and integration of a variety of natural orientation cues. The "Wulst" in the forebrain of night-migratory songbirds contains a brain area named "Cluster N", which is involved in processing directional navigational information derived from the Earth´s magnetic field. Cluster N is medially joined by the hippocampal formation, known to retrieve and utilise navigational information. To investigate the connectivity and neurochemical characteristics of Cluster N and the hippocampal formation of migratory birds, we performed morphological and histochemical analyses based on the expression of calbindin, calretinin, parvalbumin, glutamate receptor type 1 and early growth response protein-1 in the night-migratory Garden warbler (Sylvia borin) and mapped their mutual connections using neuronal tract tracing. The resulting expression patterns revealed regionally restricted neurochemical features, which mapped well onto the hippocampal and hyperpallial substructures known from other avian species. Magnetic field-induced neuronal activation covered caudal parts of the hyperpallium and the medially adjacent hippocampal dorsomedial/dorsolateral subdivisions. Neuronal tract tracings revealed connections between Cluster N and the hippocampal formation with the vast majority originating from the densocellular hyperpallium, either directly or indirectly via the area corticoidea dorsolateralis. Our data indicate that the densocellular hyperpallium could represent a central relay for the transmission of magnetic compass information to the hippocampal formation where it might be integrated with other navigational cues in night-migratory songbirds.

Regional Patterning of Adult Neurogenesis in the Homing Pigeon's Brain.

In the avian brain, adult neurogenesis has been reported in the telencephalon of several species, but the functional significance of this trait is still ambiguous. Homing pigeons (Columba livia f.d.) are well-known for their navigational skills. Their brains are functionally adapted to homing with, e.g., larger hippocampi. So far, no comprehensive mapping of adult neuro- and gliogenesis or studies of different developmental neuronal stages in the telencephalon of homing pigeons exists, although comprehensive analyses in various species surely will result in a higher understanding of the functional significance of adult neurogenesis. Here, adult, free flying homing pigeons were treated with 5-bromo-deoxyuridine (BrdU) to label adult newborn cells. Brains were dissected and immunohistochemically processed with several markers (GFAP, Sox2, S100ß, Tbr2, DCX, Prox1, Ki67, NeuN, Calbindin, Calretinin) to study different stages of adult neurogenesis in a quantitative and qualitative way. Therefore, immature and adult newborn neurons and glial cells were analyzed along the anterior-posterior axis. The analysis proved the existence of different neuronal maturation stages and showed that immature cells, migrating neurons and adult newborn neurons and glia were widely and regionally unequally distributed. Double- and triple-labelling with developmental markers allowed a stage classification of adult neurogenesis in the pigeon brain (1: continuity of stem cells/proliferation, 2: fate specification, 3: differentiation/maturation, 4: integration). The most adult newborn neurons and glia were found in the intercalated hyperpallium (HI) and the hippocampal formation (HF). The highest numbers of immature (DCX+) cells were detected in the nidopallium (N). Generally, the number of newborn glial cells exceeded the number of newborn neurons. Individual structures (e.g., HI, N, and HF) showed further variations along the anterior-posterior axis. Our qualitative classification and the distribution of maturing cells in the forebrain support the idea that there is a functional specialization, respectively, that there is a link between brain-structure and function, species-specific requirements and adult neurogenesis. The high number of immature neurons also suggests a high level of plasticity, which points to the ability for rapid adaption to environmental changes through additive mechanisms. Furthermore, we discuss a possible influence of adult neurogenesis on spatial cognition.

Behavioral Training Related Neurotransmitter Receptor Expression Dynamics in the Nidopallium Caudolaterale and the Hippocampal Formation of Pigeons.

Learning and memory are linked to dynamic changes at the level of synapses in brain areas that are involved in cognitive tasks. For example, changes in neurotransmitter receptors are prerequisite for tuning signals along local circuits and long-range networks. However, it is still unclear how a series of learning events promotes plasticity within the system of neurotransmitter receptors and their subunits to shape information processing at the neuronal level. Therefore, we investigated the expression of different glutamatergic NMDA (GRIN) and AMPA (GRIA) receptor subunits, the GABAergic GABARG2 subunit, dopaminergic DRD1, serotonergic 5HTR1A and noradrenergic ADRA1A receptors in the pigeon's brain. We studied the nidopallium caudolaterale, the avian analogue of the prefrontal cortex, and the hippocampal formation, after training the birds in a rewarded stimulus-response association (SR) task and in a simultaneous-matching-to-sample (SMTS) task. The results show that receptor expression changed differentially after behavioral training compared to an untrained control group. In the nidopallium caudolaterale, GRIN2B, GRIA3, GRIA4, DRD1D, and ADRA1A receptor expression was altered after SR training and remained constantly decreased after the SMTS training protocol, while GRIA2 and DRD1A decreased only under the SR condition. In the hippocampal formation, GRIN2B decreased and GABARG2 receptor expression increased after SR training. After SMTS sessions, GRIN2B remained decreased, GABARG2 remained increased if compared to the control group. None of the investigated receptors differed directly between both conditions, although differentially altered. The changes in both regions mostly occur in favor of the stimulus response task. Thus, the present data provide evidence that neurotransmitter receptor expression dynamics play a role in the avian prefrontal cortex and the hippocampal formation for behavioral training and is uniquely, regionally and functionally associated to cognitive processes including learning and memory.

Neurological soft signs and brain morphology in people living with HIV.

Neurological soft signs (NSS) are a common feature of severe psychiatric disorders such as schizophrenia but are also prevalent in organic brain diseases like HIV-associated neurocognitive disorder (HAND) or Alzheimer's disease. While distinct associations between NSS, neurocognition, and cerebral regions were demonstrated in schizophrenia, these associations still have to be elucidated in HIV. Therefore, we investigated 36 persons with HIV of whom 16 were neurocognitively healthy and 20 were diagnosed with HAND. NSS were assessed using the Heidelberg scale. NSS scores were correlated with gray matter (GM) using whole brain voxel-based morphometry. Results showed significantly elevated NSS in the HAND group when compared to the neurocognitively healthy with respect to NSS total score and the subscores "orientation" and "complex motor tasks". While the two groups showed only minor, non-significant GM differences, higher NSS scores (subscales "motor coordination", "orientation") were significantly correlated with GM reduction in the right insula and cerebellum (FWE-corrected). Our results corroborate elevated NSS in HIV+ patients with HAND in contrast to cognitively unimpaired patients. In addition, cerebral correlates of NSS with GM reductions in insula and cerebellum were revealed. Taken together, NSS in this patient group could be considered a marker of cerebral damage and neurocognitive deficits.

A pilot single-blind parallel randomised controlled trial comparing kinesiology tape to compression in the management of subacute hand oedema after trauma.

BACKGROUND: Hand oedema is a common consequence of hand trauma or surgery. There are numerous methods to reduce hand oedema but lack high-quality evidence to support best practice. The primary objective of this pilot trial was to assess study feasibility when comparing treatments for subacute hand oedema after trauma. METHODS: A parallel two-arm pilot randomised controlled trial was conducted in the hand therapy department at a regional hospital in Norfolk between October 2017 and July 2018. Patients were eligible if 18 years or over, referred to hand therapy with subacute hand oedema. Randomisation was on a 1:1 basis to treatment as usual (TAU) (compression, elevation and massage) or trial treatment (TT) (kinesiology tape, elevation and massage). One blinded assessor completed all assessments (prior to randomisation, 4 and 12 weeks later). Data on study feasibility, adherence and acceptability of treatments were collected. The primary outcome measure was hand volume (volumetry). Patient-rated severity (0-5 Likert scale), hand health profile of the Patient Evaluation Measure (PEM) and quality of life (EQ-5D-5L) were also recorded. RESULTS: Forty-five patients were screened for eligibility and 26 consented and were randomised with 13 patients in each treatment arm. Twelve participants were lost to follow-up leaving 7 participants in each group included in the analysis. Assessor blinding was maintained in 64% of participants (9/14). Total mean acceptability scores, out of 100, were higher for TAU (87.9) than TT (76.1). Health resource use results showed TT was marginally cheaper (~£2 per patient) than TAU. Individual adherence ranged between 39 and 100%, with higher levels of overall adherence seen in the TAU group. Four participants (28%) reported adverse effects (TT group n = 3, TAU group n = 1). CONCLUSION: This pilot trial has identified that modifications are required in order to make a full-scale trial feasible. They include a formal assessment of treatment fidelity, research staff assisting with screening and recruitment of participants and multiple blinded assessors at each study site. Whilst not designed as an efficacy trial, it should be acknowledged that the small sample size and high loss to follow-up meant very small numbers were included in the final analysis resulting in wide confidence intervals and therefore low precision in parameter estimates. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: 94083271 . Date of registration 16th August 2017. TRIAL FUNDING: National Institute for Health Research Trainees Co-ordinating Centre (TCC); Grant Codes: CDRF-2014-05-064.

How should interventions to treat hand oedema be delivered? An online Delphi Consensus Method.

Introduction: Hand oedema (swelling) is a common consequence of hand trauma or surgery, but there is little agreement on how interventions to treat hand oedema should be delivered in practice. The purpose of this study was to engage a group of self-identified hand therapy experts to develop consensus on how four commonly used oedema management treatments should be implemented, which could be used in clinical practice or future clinical trials. Method: A web-based Delphi study was conducted with eight volunteer hand therapists who met the pre-defined eligibility criteria for an 'expert' and were members of the British Association of Hand Therapists (BAHT). An a priori level of agreement was set at 75%. Interventions requiring consensus were decided on as a result of a previous national survey of practice and consisted of compression, elevation, massage and kinesiology tape. Results: A total of 25 items were discussed across 3 rounds. This ranged from 23 items in round 1, to three items in round 3. In round 1, consensus was reached on 7/23 (30%) items. The required 75% consensus was reached on 14 items in round 2 and 1/3 items achieved consensus in round 3. Massage was the only treatment that required a third round. Discussion: Consensus was reached on intervention description for three of the four modalities including the materials used (what), method of application including duration and frequency (when and how much) and tailoring or modifications. Two questions relating to massage did not reach the required consensus threshold and a majority agreement was accepted. The small panel size is a limitation and may affect the credibility of the consensus reached.

Factors Associated with the Development, Progression, and Outcome of Dupuytren Disease Treatment: A Systematic Review.

BACKGROUND: The factors typically considered to be associated with Dupuytren disease have been described, such as those in the "Dupuytren diathesis." However, the quality of studies describing them has not been appraised. This systematic review aimed to analyze the evidence for all factors investigated for potential association with the development, progression, outcome of treatment, or recurrence of Dupuytren disease. METHODS: A systematic review of the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and Cumulative Index to Nursing and Allied Health Literature databases was conducted using a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant methodology up to September of 2019. Articles were screened in duplicate. Prognostic studies were quality assessed using the Quality in Prognosis Study tool. RESULTS: This study identified 2301 records; 51 met full inclusion criteria reporting data related to 54,491 patients with Dupuytren disease. In total, 46 candidate factors associated with the development of Dupuytren disease were identified. There was inconsistent evidence between the association of Dupuytren disease and the presence of "classic" diathesis factors. The quality of included studies varied, and the generalizability of studies was low. There was little evidence describing the factors associated with functional outcome. CONCLUSIONS: This systematic review challenges conventional notions of diathesis factors. Traditional diathesis factors are associated with disease development and recurrence, although they are not significantly associated with poor outcome following intervention based on the current evidence.

Neural Correlates of Autobiographical Memory: Evidence From a Positron Emission Tomography Study in Patients With Mild Cognitive Impairment and Alzheimer's Disease.

Background: Autobiographical memory (AM) changes are the hallmark of Alzheimer's disease (AD) and mild cognitive impairment (MCI). In recent neuroimaging studies, AM changes have been associated with numerous cerebral sites, such as the frontal cortices, the mesial temporal lobe, or the posterior cingulum. Regional glucose uptake in these sites was investigated for underlying subdimensions using factor analysis. Subsequently, the factors were examined with respect to AM performance in a subgroup of patients. Methods: Data from 109 memory clinic referrals, who presented with MCI (n = 60), mild AD (n = 49), or were cognitively intact, were analyzed. The glucose metabolic rates determined by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in 34 cerebral sites important for AM were investigated for underlying subdimensions by calculating factor analysis with varimax rotation. Subsequently, the respective factor scores were correlated with the episodic and semantic AM performance of 22 patients, which was measured with a semi-structured interview assessing episodic memories (characterized by event-related emotional, sensory, contextual, and spatial-temporal details) and personal semantic knowledge from three periods of life (primary school, early adulthood, and recent years). Results: Factor analysis identified seven factors explaining 69% of the variance. While patients with MCI and AD showed lower values than controls on the factors frontal cortex, mesial temporal substructures, and occipital cortex, patients with MCI presented with increased values on the factors posterior cingulum and left temporo-prefrontal areas. The factors anterior cingulum and right temporal cortex showed only minor, non-significant group differences. Solely, the factor mesial temporal substructures was significantly correlated with both episodic memories (r = 0.424, p < 0.05) and personal semantic knowledge (r = 0.547, p < 0.01) in patients with MCI/AD. Conclusions: The factor structure identified corresponds by large to the morphological and functional interrelations of the respective sites. While reduced glucose uptake on the factors frontal cortex, mesial temporal substructures, and occipital cortex in the patient group may correspond to neurodegenerative changes, increased values on the factors posterior cingulum and left temporo-prefrontal areas in MCI may result from compensatory efforts. Interestingly, changes of the mesial temporal substructures were correlated with both semantic and episodic AM. Our findings suggest that AM deficits do not only reflect neurodegenerative changes but also refer to compensatory mechanisms as they involve both quantitative losses of specific memories and qualitative changes with a semantization of memories.

Developing a core outcome set for traumatic brachial plexus injuries: a systematic review of outcomes.

OBJECTIVE: To identify what outcomes have been assessed in traumatic brachial plexus injury (TBPI) research to inform the development of a core outcome set for TBPI. DESIGN: Systematic review. METHOD: Medline (OVID), EMBASE, CINAHL and AMED were systematically searched for studies evaluating the clinical effectiveness of interventions in adult TBPIs from January 2013 to September 2018 updated in May 2021. Two authors independently screened papers. Outcome reporting bias was assessed. All outcomes were extracted verbatim from studies. Patient-reported outcomes or performance outcome measures were extracted directly from the instrument. Variation in outcome reporting was determined by assessing the number of unique outcomes reported across all included studies. Outcomes were categorised into domains using a prespecified taxonomy. RESULTS: Verbatim outcomes (n=1491) were extracted from 138 studies including 32 questionnaires. Unique outcomes (n=157) were structured into 4 core areas and 11 domains. Outcomes within the musculoskeletal domain were measured in 86% of studies, physical functioning in 25%, emotional functioning in 25% and adverse events in 33%. We identified 63 different methods for measuring muscle strength, 16 studies for range of movement and 63 studies did not define how they measured movement. More than two-thirds of the outcomes were incompletely reported in prospective studies. CONCLUSION: This review of outcome reporting in TBPI research demonstrated an impairment focus and heterogeneity. A core outcome set would ensure standardised and relevant outcomes are reported to facilitate future systematic review and meta-analysis. PROSPERO REGISTRATION NUMBER: CRD42018109843.

The Neurotransmitter Receptor Architecture of the Mouse Olfactory System.

The uptake, transmission and processing of sensory olfactory information is modulated by inhibitory and excitatory receptors in the olfactory system. Previous studies have focused on the function of individual receptors in distinct brain areas, but the receptor architecture of the whole system remains unclear. Here, we analyzed the receptor profiles of the whole olfactory system of adult male mice. We examined the distribution patterns of glutamatergic (AMPA, kainate, mGlu2/3, and NMDA), GABAergic (GABAA, GABAA(BZ), and GABAB), dopaminergic (D1/5) and noradrenergic (α1 and α2) neurotransmitter receptors by quantitative in vitro receptor autoradiography combined with an analysis of the cyto- and myelo-architecture. We observed that each subarea of the olfactory system is characterized by individual densities of distinct neurotransmitter receptor types, leading to a region- and layer-specific receptor profile. Thereby, the investigated receptors in the respective areas and strata showed a heterogeneous expression. Generally, we detected high densities of mGlu2/3Rs, GABAA(BZ)Rs and GABABRs. Noradrenergic receptors revealed a highly heterogenic distribution, while the dopaminergic receptor D1/5 displayed low concentrations, except in the olfactory tubercle and the dorsal endopiriform nucleus. The similarities and dissimilarities of the area-specific multireceptor profiles were analyzed by a hierarchical cluster analysis. A three-cluster solution was found that divided the areas into the (1) olfactory relay stations (main and accessory olfactory bulb), (2) the olfactory cortex (anterior olfactory cortex, dorsal peduncular cortex, taenia tecta, piriform cortex, endopiriform nucleus, entorhinal cortex, orbitofrontal cortex) and the (3) olfactory tubercle, constituting its own cluster. The multimodal receptor-architectonic analysis of each component of the olfactory system provides new insights into its neurochemical organization and future possibilities for pharmaceutic targeting.