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.

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.

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.

New boundaries and dissociation of the mouse hippocampus along the dorsal-ventral axis based on glutamatergic, GABAergic and catecholaminergic receptor densities.

In rodents, gene-expression, neuronal tuning, connectivity and neurogenesis studies have postulated that the dorsal, the intermediate and the ventral hippocampal formation (HF) are distinct entities. These findings are underpinned by behavioral studies showing a dissociable role of dorsal and ventral HF in learning, memory, stress and emotional processing. However, up to now, the molecular basis of such differences in relation to discrete boundaries is largely unknown. Therefore, we analyzed binding site densities for glutamatergic AMPA, NMDA, kainate and mGluR2/3 , GABAergic GABAA (including benzodiazepine binding sites), GABAB , dopaminergic D1/5 and noradrenergic α1 and α2 receptors as key modulators for signal transmission in hippocampal functions, using quantitative in vitro receptor autoradiography along the dorsal-ventral axis of the mouse HF. Beside general different receptor profiles of the dentate gyrus (DG) and Cornu Ammonis fields (CA1, CA2, CA3, CA4/hilus), we detected substantial differences between dorsal, intermediate and ventral subdivisions and individual layers for all investigated receptor types, except GABAB . For example, striking higher densities of α2 receptors were detected in the ventral DG, while the dorsal DG possesses higher numbers of kainate, NMDA, GABAA and D1/5 receptors. CA1 dorsal and intermediate subdivisions showed higher AMPA, NMDA, mGluR2/3 , GABAA , D1/5 receptors, while kainate receptors are higher expressed in ventral CA1, and noradrenergic α1 and α2 receptors in the intermediate region of CA1. CA2 dorsal was distinguished by higher kainate, α1 and α2 receptors in the intermediate region, while CA3 showed a more complex dissociation. Our findings resulted not only in a clear segmentation of the mouse hippocampus along the dorsal-ventral axis, but also provides insights into the neurochemical basis and likely associated physiological processes in hippocampal functions. Therein, the presented data has a high impact for future studies modeling and investigating dorsal, intermediate and ventral hippocampal dysfunction in relation to neurodegenerative diseases or psychiatric disorders.

Is it time to revisit the Boston Carpal Tunnel Questionnaire? New insights from a Rasch model analysis.

BACKGROUND: The Boston Carpal Tunnel Questionnaire (BCTQ) is a patient-reported outcome measure (PROM) used to measure symptom severity and function in carpal tunnel syndrome (CTS). Despite its wide use, investigation of its measurement properties using modern psychometric methodologies is limited. METHODS: Completed BCTQ data collected routinely in the Canterbury carpal tunnel clinic was used to investigate the structural validity and measurement properties of the BCTQ through application of a Rasch model analytic approach. RESULTS: A total of 600 patients with electrodiagnostically confirmed CTS in their right hand were randomly selected from the database and analyzed. Mean age was 48.8 y, and 73% were women. Initial analysis showed that the 19 items could not be reliably added up to form a single linear construct. All subsequent analyses were done by subscale only. The Symptom Severity Subscale (SSS) displayed a large amount of local dependence. This could be accommodated through the creation of four clinically derived testlets, allowing for the ordinal SSS raw score to be transformed to a linear measure. The Functional Status Subscale (FSS) displayed a number of issues regarding its psychometric integrity. These include scale and item fit, targeting, differential item functioning, and dimensionality. CONCLUSIONS: This study shows that a single total score generated across all BCTQ items is not psychometrically valid, and that the SSS and FSS subscales should be treated separately. We propose a modified scoring system for the SSS, resulting in a linear measure that can be used in the analysis of future and existing datasets.

Neurological soft signs and cognition in the late course of chronic schizophrenia: a longitudinal study.

Neurological soft signs (NSS) are minor ('soft') neurological abnormalities in sensory and motor performances, which are frequently reported in patients with schizophrenia at any stage of their illness. It has been demonstrated that NSS vary in the clinical course of the disorder: longitudinally NSS decrease in parallel with remission of psychopathological symptoms, an effect which mainly applies to patients with a remitting course. These findings are primarily based on patients with a first episode of the disorder, while the course of NSS in patients with chronic schizophrenia and persisting symptoms is rather unknown. Therefore, we investigated NSS twice in 21 patients with chronic schizophrenia (initial mean duration of illness: 23 ± 11 years) with a mean follow-up interval of 7 years. NSS were evaluated by the Heidelberg Scale, established instruments were used to rate neuropsychological performance and psychopathological symptoms. NSS showed significant increases on the subscales "motor coordination" and "integrative functions", while positive and negative symptoms, including apathy, showed only minor, non-significant changes. Verbal memory, verbal fluency, and cognitive flexibility along with severity of global cognitive deficits demonstrated a significant deterioration. Regression analyses identified executive dysfunction (cognitive flexibility and verbal fluency) at baseline as significant predictors of NSS increase at follow-up. Our findings indicate that NSS deteriorate in the long-term course of chronic schizophrenia. This effect may be accounted for by a decrease of executive functions and logical memory, which can be attributed to premature brain aging.

Prognostic factors for response to treatment by corticosteroid injection or surgery in carpal tunnel syndrome (palms study): A prospective multicenter cohort study.

INTRODUCTION: Studies of prognosis for surgery and corticosteroid injection for carpal tunnel syndrome (CTS) have considered only a limited range of explanatory variables for outcome. METHODS: Data were prospectively collected on patient-reported symptoms, physical and psychological functioning, comorbidity, and quality of life at baseline and every 6 months for up to 2 years. Outcomes were patient-rated change over a 6-month period and symptom-severity score at 18 months. RESULTS: In total, 754 patients with CTS completed baseline questionnaires, and 626 (83%) completed follow-up to 18 months. Multivariable modeling identified, independent of symptom severity at outset, higher health utility, fewer comorbidities, and lower anxiety as significant predictors of better outcome from surgery. In patients treated by steroid injection, independent of symptom severity at outset, shorter duration of symptoms and having no prior injection were significant predictors of better outcome. DISCUSSION: These multivariable models of outcome may inform shared decision making about treatment for CTS. Muscle Nerve, 2019.

Self-efficacy and risk of persistent shoulder pain: results of a Classification and Regression Tree (CART) analysis.

OBJECTIVES: To (i) identify predictors of outcome for the physiotherapy management of shoulder pain and (ii) enable clinicians to subgroup people into risk groups for persistent shoulder pain and disability. METHODS: 1030 people aged ≥18 years, referred to physiotherapy for the management of musculoskeletal shoulder pain were recruited. 810 provided data at 6 months for 4 outcomes: Shoulder Pain and Disability Index (SPADI) (total score, pain subscale, disability subscale) and Quick Disability of the Arm, Shoulder and Hand (QuickDASH). 34 potential prognostic factors were used in this analysis. RESULTS: Four classification trees (prognostic pathways or decision trees) were created, one for each outcome. The most important predictor was baseline pain and/or disability: higher or lower baseline levels were associated with higher or lower levels at follow-up for all outcomes. One additional baseline factor split participants into four subgroups. For the SPADI trees, high pain self-efficacy reduced the likelihood of continued pain and disability. Notably, participants with low baseline pain but concomitant low pain self-efficacy had similar outcomes to patients with high baseline pain and high pain self-efficacy. Cut-off points for defining high and low pain self-efficacy differed according to baseline pain and disability. In the QuickDASH tree, the association between moderate baseline pain and disability with outcome was influenced by patient expectation: participants who expected to recover because of physiotherapy did better than those who expected no benefit. CONCLUSIONS: Patient expectation and pain self-efficacy are associated with clinical outcome. These clinical elements should be included at the first assessment and a low pain self-efficacy response considered as a target for treatment intervention.

Learning to live with a hand nerve disorder: A constructed grounded theory.

STUDY DESIGN: Grounded theory. INTRODUCTION: The broader perspective of health offered by the World Health Organization's International Classification of Functioning, Disability and Health has had a significant bearing on how we view the measurement of health outcomes after surgical or therapy interventions for peripheral nerve disorders affecting the hand. The value of the patient's perspective is now recognized and outcomes which reflect this are being advocated in the clinical management and support of this population. PURPOSE OF THE STUDY: This qualitative study sought to explore the lived experience of a hand nerve disorder and in particular the impact on body structure/function, activities, and participation. METHODS: In depth, one-to-one interviews with 14 people with a range of hand nerve disorders were conducted. Constructivist grounded theory methods were used to collect and analyze the data. Patients were also given the option of taking photographs to visually represent what it is like to live with a nerve disorder, to bring with them for discussion during the interview. RESULTS: The impact of hand nerve disorders forms part of a wider narrative on adaptation. A process of "struggling" and then "overcoming" was experienced. This was followed by an interior aspect of adaptation described as "accepting." This gave rise to participants "transforming," being changed as a result of the journey that they had been on. CONCLUSIONS: This study provides an explanatory theory on the adaptive process following a hand nerve disorder which may inform future patient-therapist interactions.

An evaluation of the structural validity of the shoulder pain and disability index (SPADI) using the Rasch model.

PURPOSE: The shoulder pain and disability index (SPADI) has been extensively evaluated for its psychometric properties using classical test theory (CTT). The purpose of this study was to evaluate its structural validity using Rasch model analysis. METHODS: Responses to the SPADI from 1030 patients referred for physiotherapy with shoulder pain and enrolled in a prospective cohort study were available for Rasch model analysis. Overall fit, individual person and item fit, response format, dependence, unidimensionality, targeting, reliability and differential item functioning (DIF) were examined. RESULTS: The SPADI pain subscale initially demonstrated a misfit due to DIF by age and gender. After iterative analysis it showed good fit to the Rasch model with acceptable targeting and unidimensionality (overall fit Chi-square statistic 57.2, p = 0.1; mean item fit residual 0.19 (1.5) and mean person fit residual 0.44 (1.1); person separation index (PSI) of 0.83. The disability subscale however shows significant misfit due to uniform DIF even after iterative analyses were used to explore different solutions to the sources of misfit (overall fit (Chi-square statistic 57.2, p = 0.1); mean item fit residual 0.54 (1.26) and mean person fit residual 0.38 (1.0); PSI 0.84). CONCLUSIONS: Rasch Model analysis of the SPADI has identified some strengths and limitations not previously observed using CTT methods. The SPADI should be treated as two separate subscales. The SPADI is a widely used outcome measure in clinical practice and research; however, the scores derived from it must be interpreted with caution. The pain subscale fits the Rasch model expectations well. The disability subscale does not fit the Rasch model and its current format does not meet the criteria for true interval-level measurement required for use as a primary endpoint in clinical trials. Clinicians should therefore exercise caution when interpreting score changes on the disability subscale and attempt to compare their scores to age- and sex-stratified data.

Psychological factors are associated with the outcome of physiotherapy for people with shoulder pain: a multicentre longitudinal cohort study.

BACKGROUND/AIM: Shoulder pain is a major musculoskeletal problem. We aimed to identify which baseline patient and clinical characteristics are associated with a better outcome, 6 weeks and 6 months after starting a course of physiotherapy for shoulder pain. METHODS: 1030 patients aged ≥18 years referred to physiotherapy for the management of musculoskeletal shoulder pain were recruited and provided baseline data. 840 (82%) provided outcome data at 6 weeks and 811 (79%) at 6 months. 71 putative prognostic factors were collected at baseline. Outcomes were the Shoulder Pain and Disability Index (SPADI) and Quick Disability of the Arm, Shoulder and Hand Questionnaire. Multivariable linear regression was used to analyse prognostic factors associated with outcome. RESULTS: Parameter estimates (ß) are presented for the untransformed SPADI at 6 months, a negative value indicating less pain and disability. 4 factors were associated with better outcomes for both measures and time points: lower baseline disability (ß=-0.32, 95% CI -0.23 to -0.40), patient expectation of 'complete recovery' compared to 'slight improvement' as 'a result of physiotherapy' (ß=-12.43, 95% CI -8.20 to -16.67), higher pain self-efficacy (ß=-0.36, 95% CI -0.50 to -0.22) and lower pain severity at rest (ß=-1.89, 95% CI -1.26 to -2.51). CONCLUSIONS: Psychological factors were consistently associated with patient-rated outcome, whereas clinical examination findings associated with a specific structural diagnosis were not. When assessing people with musculoskeletal shoulder pain and considering referral to physiotherapy services, psychosocial and medical information should be considered. STUDY REGISTRATION: Protocol published at http://www.biomedcentral.com/1471-2474/14/192.

The validity and clinical utility of the Disabilities of the Arm Shoulder and Hand questionnaire for hand injuries in developing country contexts: A systematic review.

STUDY DESIGN: Systematic review. INTRODUCTION: The Disabilities of the Arm Shoulder and Hand Questionnaire has multiple language versions from many countries around the world. In addition there is extensive research evidence of its psychometric properties. PURPOSE OF THE STUDY: The purpose of this study was to systematically review the evidence available on the validity and clinical utility of the Disabilities of the Arm Shoulder and Hand as a measure of activity and participation in patients with musculoskeletal hand injuries in developing country contexts. METHODS: We registered the review with international prospective register of systematic reviews prior to conducting a comprehensive literature search and extracting descriptive data. Two reviewers independently assessed methodological quality with the Consensus-Based Standards for the Selection of Health Measurement Instruments critical appraisal tool, the checklist to operationalize measurement characteristics of patient-rated outcome measures and the multidimensional model of clinical utility. RESULTS: Fourteen studies reporting 12 language versions met the eligibility criteria. Two language versions (Persian and Turkish) had an overall rating of good, and one (Thai) had an overall rating of excellent for cross-cultural validity. The remaining 9 language versions had an overall poor rating for cross-cultural validity. Content and construct validity and clinical utility yielded similar results. DISCUSSION/CONCLUSIONS: Poor quality ratings for validity and clinical utility were due to insufficient documentation of results and inadequate psychometric testing. With the increase in migration and globalization, hand therapists are likely to require a range of culturally adapted and translated versions of the Disabilities of the Arm Shoulder and Hand. Recommendations include rigorous application and reporting of cross-cultural adaptation, appropriate psychometric testing, and testing of clinical utility in routine clinical practice.

Effectiveness of edema management techniques for subacute hand edema: A systematic review.

STUDY DESIGN: Systematic review. INTRODUCTION: Prolonged hand edema can have detrimental effects on range of motion and function. There is no consensus on how best to manage traumatic subacute edema. This is the first systematic review which examines the clinical effectiveness of edema treatments on hand volume. PURPOSE OF THE STUDY: The purpose of this systematic review was to examine the evidence of effectiveness of treatments for sub-acute hand edema. METHODS: A literature search of AMED, CINAHL, Embase, and OVID MEDLINE (from inception to August 2015) was undertaken. Studies were selected if they met the following inclusion criteria: randomized controlled or controlled trials in adults who have subacute swelling after a recent upper limb musculoskeletal trauma or cerebral vascular attack or after surgery. Two independent assessors rated study quality and risk of bias using the 24-point MacDermid Structured Effectiveness Quality Evaluation Scale (SEQES). RESULTS: Ten studies met the inclusion criteria. Study quality ranged from 23 to 41 out of 48 points on the SEQES. A total of 16 edema interventions were evaluated across the studies. Due to heterogeneity of the patient characteristics, interventions, and outcomes assessed, it was not possible to pool the results from all studies. Therefore, a narrative best evidence synthesis was undertaken. There is low to moderate quality evidence with limited confidence in the effect estimate to support the use of manual edema mobilization methods in conjunction with standard therapy to reduce problematic hand edema. CONCLUSION: Manual edema mobilization techniques should be considered in conjunction with conventional therapies, in cases of excessive edema or when the edema has not responded to conventional treatment alone; however, manual edema mobilization is not advocated as a routine intervention. LEVEL OF EVIDENCE: 2b.

Cervical cancer control in Latin America: A call to action.

Cervical cancer (CC) is second most common cause of cancer in Latin America and is a leading cause of cancer mortality among women. In 2015, an estimated 74,488 women will be diagnosed with CC in Latin America and 31,303 will die of the disease. CC mortality is projected to increase by 45% by 2030 despite human papillomavirus (HPV) vaccination and screening efforts. In this setting, the goal was of the current study was to examine CC control efforts in Latin America and identify deficiencies in these efforts that could be addressed to reduce CC incidence and mortality. The authors found that HPV vaccination has been introduced in the majority of Latin American countries, and there is now a need to monitor the success (or shortcomings) of these programs and to ensure that these programs are sustainable. This topic was also reviewed in light of emerging data demonstrating that visual inspection with acetic acid and HPV DNA testing without Papanicolaou tests have efficacy from a screening perspective and are good alternatives to cytology-based screening programs. Overall, there is a need to build capacity for CC control in Latin America and the best strategy will depend on the country/region and must be tailored to meet the needs of the population as well as available resources.

Early-Stage Breast Cancer in the Octogenarian: Tumor Characteristics, Treatment Choices, and Clinical Outcomes.

BACKGROUND: Nodal staging with sentinel node biopsy (SLNB), post-lumpectomy radiotherapy (RT), and endocrine therapy (ET) for estrogen receptor-positive (ER+) tumors is valuable in the treatment of early-stage (stages 1 or 2) breast cancer but used less often for elderly women. METHODS: This retrospective study investigated women referred for surgical evaluation of biopsy-proven primary early-stage invasive breast cancer from January 2001 to December 2010. Clinicopathologic features, treatment course, and outcomes for women ages 80-89 years and 50-59 years were compared. RESULTS: The study identified 178 eligible women ages 80-89 years and 169 women ages 50-59 years. The elderly women more often had grade 1 or 2 disease (p = 0.003) and ER+ tumors (p = 0.007) and less frequently had undergone adjuvant therapies (all p ≤ 0.001). Lumpectomy was performed more commonly for the elderly (92 vs. 83 %, p = 0.02), and axillary surgery was less commonly performed (46 vs. 96 %; p < 0.001). Fewer elderly women had undergone post-lumpectomy RT (42 vs. 89 %; p < 0.001) and ET for ER+ tumors (72 vs. 95 %; p < 0.001). During the median follow-up period of 56 months for the 80- to 89-year old group and 98 months for the 50- to 59-year-old group, death from breast cancer was similar (4 vs. 5 %; p = 0.5). The two groups respectively experienced 7 versus 6 locoregional recurrences and 11 versus 13 distant recurrences. CONCLUSIONS: The octogenarians had disease survivorship similar to that of the younger women despite less frequent use of adjuvant therapies, likely reflecting lower-risk disease features. Whether increased use of axillary surgery, post-lumpectomy RT, and/or ET for ER+ tumors would further improve outcomes is an important area for further study, but treatment should not be deferred solely on the basis of age.

Neurocognitive Deficits and Effects of Cognitive Reserve in Mild Cognitive Impairment.

BACKGROUND/AIMS: Mild cognitive impairment (MCI) is a frequent syndrome in the older population, which involves an increased risk to develop Alzheimer's disease (AD). The latter can be modified by the cognitive reserve, which can be operationalized by the length of school education. MCI can be differentiated into four subtypes according to the cognitive domains involved: amnestic MCI, multiple-domain amnestic MCI, non-amnestic MCI and multiple-domain non-amnestic MCI. While neurocognitive deficits are a constituent of the diagnosis of these subtypes, the question of how they refer to the cognitive reserve still needs to be clarified. METHODS: We examined neuropsychological deficits in healthy controls, patients with MCI and patients with mild AD (n = 485) derived from a memory clinic. To reduce the number of neuropsychological variables, a factor analysis with varimax rotation was calculated. In a second step, diagnostic groups including MCI subtypes were compared with respect to their clinical and neuropsychological characteristics including cognitive reserve. RESULTS: Most MCI patients showed the amnestic multiple-domain subtype followed by the pure amnestic subtype, while the non-amnestic subtypes were rare. The amnestic subtype displayed a significantly higher level of cognitive reserve and higher MMSE scores than the amnestic multiple-domain subtype, which was in most cases characterized by additional psychomotor and executive deficits. CONCLUSIONS: These findings confirm earlier reports revealing that the amnestic multiple-domain subtype is the most frequent one and indicating that a high cognitive reserve may primarily prevent psychomotor and executive deficits in MCI.

The maturation of research into the avian hippocampal formation: Recent discoveries from one of the nature's foremost navigators.

For more than 30 years, a growing number of researchers have been attracted to the challenge of understanding the neurobiological organization of the avian hippocampal formation (HF) and its relationship to the remarkable spatial cognitive abilities of birds. In this selective review, we highlight recent anatomical and developmental findings that reveal a HF design that defies any simple comparison to the mammalian hippocampus and leaves unanswered the seemingly enduring question of whether a dentate gyrus homologue is to be found in HF. From a functional perspective, we highlight the recent discoveries that implicate HF in the use of space for memory pattern segregation and continued interest in the role HF neurogenesis may play in supporting memory function and its relationship to memory decline in aging birds. We also summarize data that nurture a fundamental reinterpretation of the role of HF in spatial cognition by suggesting HF involvement in spatial perception antecedent to any memory formation. Given the disproportionate adaptive significance of space for birds, which has led to the evolution of their exceptional navigational and memory abilities, there is little doubt that the avian HF will continue to provide important and unexpected insights into the neural basis of spatial cognition.

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

BACKGROUND: Next-generation sequencing (NGS) allows for simultaneous sequencing of multiple cancer susceptibility genes and, for an individual, may be more efficient and less expensive than sequential testing. The authors assessed the frequency of deleterious germline mutations among individuals with breast cancer who were referred for BRCA1 and BRCA2 (BRCA1/2) gene testing using a panel of 25 genes associated with inherited cancer predisposition. METHODS: This was a cross-sectional study using NGS in 2158 individuals, including 1781 who were referred for commercial BRCA1/2 gene testing (cohort 1) and 377 who had detailed personal and family history and had previously tested negative for BRCA1/2 mutations (cohort 2). RESULTS: Mutations were identified in 16 genes, most frequently in BRCA1, BRCA2, CHEK2, ATM, and PALB2. Among the participants in cohort 1, 9.3% carried a BRCA1/2 mutation, 3.9% carried a mutation in another breast/ovarian cancer susceptibility gene, and 0.3% carried an incidental mutation in another cancer susceptibility gene unrelated to breast or ovarian cancer. In cohort 2, the frequency of mutations in breast/ovarian-associated genes other than BRCA1/2 was 2.9%, and an additional 0.8% had an incidental mutation. In cohort 1, Lynch syndrome-related mutations were identified in 7 individuals. In contrast to BRCA1/2 mutations, neither age at breast cancer diagnosis nor family history of ovarian or young breast cancer predicted for other mutations. The frequency of mutations in genes other than BRCA1/2 was lower in Ashkenazi Jews compared with non-Ashkenazi individuals (P=.026). CONCLUSIONS: Using an NGS 25-gene panel, the frequency of mutations in genes other than BRCA1/2 was 4.3%, and most mutations (3.9%) were identified in genes associated with breast/ovarian cancer.

Association of cortical thickness and neurological soft signs in patients with chronic schizophrenia and healthy controls.

BACKGROUND: Neurological soft signs (NSS), i.e. subtle neurological abnormalities, have been frequently found in schizophrenia. Neuroimaging studies in schizophrenia have shown abnormal cortical thickness changes across the cortical mantle. However, few studies have examined relationships between NSS and cortical thickness abnormalities in schizophrenia. METHOD: A sample of 18 patients with chronic schizophrenia and 20 age-matched healthy controls were included. Cortical thickness was assessed on high-resolution 3-tesla magnetic resonance imaging by using FreeSurfer software and NSS were rated on the Heidelberg Scale. RESULTS: Significant negative correlations between NSS and cortical thickness were found in the prefrontal, inferior temporal, superior parietal, postcentral, and supramarginal cortices in the schizophrenia patients. In the controls, however, this negative correlation was found in the anterior cingulate, pericalcarine and superior/middle temporal regions. CONCLUSION: Our results not only confirmed the association between NSS and cortical thickness in chronic schizophrenia but also indicated that patients and controls have different anatomical substrates of NSS.