Early Consolidation Research Articles

Twice Weekly Induction with Ixazomib-Lenalidomide-Dexamethasone (IRd) Combination Followed By Extended IRD Consolidation and Lenalidomide Maintenance in Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM): A Phase 2 Study from the Intergroupe Francophone Du Myelome (IFM 2014-03)

Twice Weekly Induction with Ixazomib-Lenalidomide-Dexamethasone (IRd) Combination Followed By Extended IRD Consolidation and Lenalidomide Maintenance in Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM): A Phase 2 Study from the Intergroupe Francophone Du Myelome (IFM 2014-03)

Pro-cognitive effect of upregulating cyclic guanosine monophosphate signalling during memory acquisition or early consolidation is mediated by increased AMPA receptor trafficking.

Background:Episodic memory consists of different mnemonic phases, including acquisition and early and late consolidation. Each of these phases is characterised by distinct molecular processes. Although both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are implicated in the acquisition phase, early consolidation only depends on cGMP, whereas late consolidation is mediated by cAMP. Accordingly, the cGMP-selective phosphodiesterase 5 (PDE5) inhibitor vardenafil or the cAMP-selective PDE4 inhibitor rolipram can improve memory acquisition or consolidation when applied during their respective time windows.Aims:Considering the important role of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) during normal memory function, we aimed to investigate whether the differential actions of these PDE inhibitors are mediated through AMPAR dynamics.Methods:For biochemical analysis, mice were treated with either vardenafil or rolipram and sacrificed shortly after injection. For the behavioural studies, mice received either of the inhibitors during the different mnemonic phases, while their spatial memory was tested using the object location task, and they were sacrificed 24 hours later.Results:Administration of either vardenafil or rolipram causes rapid changes in AMPARs. Moreover, treatment with vardenafil during the acquisition or early consolidation of spatial memory resulted in increased surface levels of AMPARs which were still augmented 24 hours after learning. Membrane levels of AMPARs were not affected anymore 24 hours after learning when rolipram was administrated at either the acquisition or late consolidation phase.Conclusions:These results suggest that dissociative molecular mechanisms could mediate the pro-cognitive function of different classes of PDE inhibitors, and in the case of vardenafil, this phenomenon could be explained by changes in AMPAR dynamics.

Acute exercise and mindfulness meditation on learning and memory: randomized controlled intervention.

Background: The purpose of this experiment was to evaluate the potential combined effects of acute exercise and mindfulness mediation on episodic memory. Methods: All data collection occurred in the authors’ laboratory (January to May of 2019). In this three-arm, within-subject design, participants (N=20; Mage=21.6 years) completed three counterbalanced laboratory visits, including Exercise Only, Exercise + Meditation and Control. Learning and memory were assessed from a word-list task. A one-factor repeated-measures ANOVA was computed for two memory outcomes, including the learning outcome (average performance across the 6 trials) and the long-term memory recall (10-minute delay). Results: The exercise conditions had a greater learning effect when compared to the Control visit, Mdiff = 0.68 (95% CI: 0.10, 1.25), P = 0.02. The Exercise + Memory visit had better longterm memory when compared to Exercise Only, Mdiff = 0.95 (95% CI: 0.07, 1.83), P = 0.03. Conclusion: The present experiment provides suggestive evidence that acute exercise may enhance learning and, when coupling acute exercise prior to encoding with meditation during early consolidation, long-term memory may be enhanced.

Prior Knowledge Predicts Early Consolidation in Second Language Learning.

Language learning occurs in distinct phases. Whereas some improvement is evident during training, offline memory consolidation processes that take place after the end of training play an important role in learning of linguistic information. The timing of offline consolidation is thought to depend on the type of task, with generalization of implicit knowledge suggested to take more time and sleep to consolidate. The current study aims to investigate individual differences in the timing of consolidation following learning of morphological inflections in a novel language in typical adults. Participants learned to make plural inflections in an artificial language, where inflection was based on morpho-phonological regularities. Participants were trained in the evening, and consolidation was measured after two intervals: 12 h (one night) and 36 h (two nights) post training. We measured both inflection of trained items, which may rely on item-specific learning, and generalization to new untrained items, which requires extraction of morpho-phonological regularities. The results for both trained and un-trained items showed two patterns of consolidation: early versus late, that is while some participants improved during the first night, others, who deteriorated in performance during the first night, improved in the later consolidation interval. Importantly, phonological awareness in L1 predicted early consolidation for trained items. Furthermore, there was no association between participants’ consolidation trajectory in trained and untrained items. Our results suggest that consolidation timing depends on the interaction between task characteristics and individual abilities. Moreover, the results show that prior meta-linguistic knowledge predicts the quality of early consolidation processes. These results are consistent with studies in rodents and humans, showing that prior knowledge accelerates consolidation of newly learnt episodic memory. Finally, the rate of consolidation across exposures to the language might explain some of the variability found in the attained level of second language proficiency.

A single high-intensity exercise bout during early consolidation does not influence retention or relearning of sensorimotor locomotor long-term memories.

A single exercise bout has been found to improve the retention of a skill-based upper extremity motor task up to a week post-practice. This effect is the greatest when exercise intensity is high and exercise is administered immediately after motor practice (i.e., early in consolidation). Whether exercise can affect other motor learning types (e.g., sensorimotor adaptation) and tasks (e.g., walking) is still unclear as previous studies have not optimally refined the exercise parameters and long-term retention testing. Therefore, we investigated whether a single high-intensity exercise bout during early consolidation would improve the long-term retention and relearning of sensorimotor adaptation during split-belt treadmill walking. Twenty-six neurologically intact adults attended three sessions; sessions 2 and 3 were 1day and 7days after session 1, respectively. Participants were allocated either to Rest (REST) or to Exercise (EXE) group. In session 1, all groups walked on a split-belt treadmill in a 2:1 speed ratio (1.5:0.75m/s). Then, half of the participants exercised for 5min (EXE), while the other half rested for 5min (REST). A short exercise bout during early consolidation did not improve retention or relearning of locomotor memories one or seven days after session 1. This result reinforces previous findings that the effect of exercise on motor learning may differ between sensorimotor locomotor adaptation and skilled-based upper extremity tasks; thus, the utility of exercise as a behavioral booster of motor learning may depend on the type of motor learning and task.

Autologous stem cell transplantation may be curative for patients with follicular lymphoma with early therapy failure without the need for immunotherapy

Objective/BackgroundPatients with follicular lymphoma (FL) with early therapy failure (ETF) within 2 years of frontline therapy have poor overall survival (OS). We recently reported the results of autologous stem cell transplantation (ASCT) in patients from the Grupo Español de Linfomas y Trasplantes de Médula Ósea (GELTAMO) registry treated with rituximab prior to ASCT and with ETF after first-line immunochemotherapy, leading to 81% 5-year OS since ASCT. We explored whether ASCT is also an effective option in the pre-rituximab era—that is, in patients treated in induction and rescued only with chemotherapy. MethodsETF was defined as relapse/progression within 2 years of starting first-line therapy. We identified two groups: the ETF cohort (n = 87) and the non-ETF cohort (n = 47 patients receiving ASCT but not experiencing ETF following first-line therapy). ResultsThere was a significant difference in 5-year progression-free survival between the ETF and non-ETF cohorts (43% vs. 57%, respectively; p = .048). Nevertheless, in patients with ETF with an interval from first relapse after primary treatment to ASCT of <1 year, no differences were observed in 5-year progression-free survival (48% vs. 66%, respectively; p = .44) or in 5-year OS (69% vs. 77%, p = .4). Patients in the ETF cohort transplanted in complete remission showed a plateau in the OS curves, at 56%, beyond 13.7 years of follow-up. ConclusionASCT may be a curative option for ETF in patients who respond to rescue chemotherapy, without the need for immunotherapy or other therapies, and should be considered as an early consolidation, especially in patients with difficult access to rituximab.

The Cahokian Crucible: Burning Ritual and the Emergence of Cahokian Power in the Mississippian Midwest

Much of what is known about the Indigenous city of Cahokia, located in and influential on the North American midcontinent during the eleventh through fourteenth centuries AD, derives from decades of salvage, research, and CRM excavations in the surrounding American Bottom region. We use this robust dataset to explore patterns of building conflagration that suggest these practices of burning were part of pre-Mississippian traditions that were bundled into new Cahokian landscapes during the early consolidation of the city. These bundled practices entangled sources of power that were at once political and religious, thus transforming the practices and meanings associated with terminating building use via fire.

Early soil consolidation from magnetic extensometers and full resolution SAR interferometry over highly decorrelated reclaimed lands

Reclaimed lands account for a large portion of the developable territories in Hong Kong. Towards better construction planning for the follow-up civil works, stability monitoring is usually required at these artificial sites. The Synthetic Aperture Radar Interferometry (InSAR) technique can provide bi-weekly updates of high resolution (up to 1 m) and high precision (millimeter level) ground motion maps at low costs, which overcomes the limitations of ground-based instruments. However, rapid settlement during the early stage of soil consolidation can result in significant temporal decorrelation to phase signals and impact InSAR detection, especially over newly reclaimed areas. Here, we give a first demonstration on how the introduction of in-situ extensometer measurements can help improve InSAR capabilities for signal recovery of the early consolidation process. We integrate persistent scatterers (PS) and distributed scatterers (DS) in our processing chain to establish a two-tier monitoring network. Magnetic extensometers are used to estimate local consolidation models, which are then utilized to replace the linear part in the conventional functional phase model. For nonlinear deformation, both hyperbolic and exponential models were considered. The proposed method was applied to 61 TerraSAR-X images covering the Penny's Bay Reclamation Stage 2 (PBR2) in Hong Kong. The consolidation history of the new reclamation site has been successfully extracted, with cumulative subsidence exceeding 1.6 m between May 2008 and Dec. 2011. Approximately 84% of the settlement of the non-dredged region was found to be from compaction of underlying soft marine deposits, not the filling materials. In addition to highlighting the spatiotemporal characteristics of the deformation, InSAR also helps reveal the compaction evolution of the underlying deposit. The results benefit our understanding of the early consolidation process in PBR2 and inform extra reinforcement plans if necessary.

Explaining divergent transformation paths in Tunisia and Egypt: The role of inter-elite trust

ABSTRACT This article analyses why the political transformations following the Arab Spring took different paths in Egypt and Tunisia. Based on data from field interviews conducted between 2012 and 2018 as well as press analyses, we argue that a strong factor why Tunisia was more successful in establishing democracy is that it had a higher level of inter-elite trust. Moreover, we show that the establishment of inter-elite trust depends on the presence of functioning trust-building arenas during the transition and the early democratic consolidation period. To investigate the role of inter-elite trust, we develop a theoretical-analytical framework, drawing on Arab Spring literature, transition theory, scholarship on democratic consolidation, and research on trust.

Feasibility of brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in children and adolescents (&lt; 18 years) with early relapse Hodgkin lymphoma.

e19012 Background: High-dose therapy followed by autologous stem-cell transplantation (ASCT) is standard of care for patients with relapsed Hodgkin lymphoma (HL). Approximately 50% of relapsed HL patients are cured after ASCT. However, most patients with unfavorable risk factors (refractory disease, early relapse &lt; 12 months and extranodal involvement prior to ASCT) progress after ASCT. Brentuximab Vedotin (BV) improves progression-free survival (PFS) when given as early consolidation after ASCT in adults. In pediatrics, the use of consolidative BV for relapsed HL has not been studied. Methods: Retrospective review of relapsed HL patients who received post ASCT consolidative BV from January 2016 to January 2017. We evaluated time of relapse, sites of involvement, presence of extranodal disease, clinical response after salvage therapy, response, PFS and BV toxicity. Results: During the study period 6 patients (age 12 -18 years) had relapsed HL. Of those, five had high risk (IIIB n = 1 , IVA n = 2, IVB n = 2) and one intermediate risk (IIA) disease. All had disease progression 0 – 3 months after completion of frontline therapy. High risk patients received ABVE-PC regimen and intermediate risk received Stanford V. Four patients received radiation therapy (RT) based on anatomical response as per protocol. Following relapse, 2 cycles of salvage Gemcitabine and Vinorelbine was given to 5 patients. Due to partial response, two of these patients received 2 additional cycles of BV-Bendamustine. One patient was re-induced with BV-Gemcitabine. FDG-PET/CT status prior to ASCT was negative for all 6 patients (Deauville score equal to or less than 3). High dose therapy prior to ASCT consisted of BEAM or BEC. Four patients received additional RT. All patients received consolidative BV every 3 weeks up to 16 cycles. Two patients experienced grade 3 motor and sensorial neuropathy and discontinued BV after 12 cycles. Two patients experienced grade 3 neutropenia. At present the PFS for the six patients is 12, 16, 23, 24, 28 and 30 months. Conclusions: Early consolidation with BV after ASCT is feasible in patients less than 18 years of age. Toxicity included grade 3 peripheral neuropathy and neutropenia. Larger studies are needed to determined safety and efficacy of consolidative BV post ASCT.

The Temporal Effects of Acute Exercise on Episodic Memory Function: Systematic Review with Meta-Analysis.

Background: Accumulating research demonstrates that the timing of exercise plays an important role in influencing episodic memory. However, we have a limited understanding as to the factors that moderate this temporal effect. Thus, the purpose of this systematic review with meta-analysis was to evaluate the effects of study characteristics (e.g., exercise modality, intensity and duration of acute exercise) and participant attributes (e.g., age, sex) across each of the temporal periods of acute exercise on episodic memory (i.e., acute exercise occurring before memory encoding, and during memory encoding, early consolidation, and late consolidation). Methods: The following databases were used for our computerized searches: Embase/PubMed, Web of Science, Google Scholar, Sports Discus and PsychInfo. Studies were included if they: (1) Employed an experimental design with a comparison to a control group/visit, (2) included human participants, (3) evaluated exercise as the independent variable, (4) employed an acute bout of exercise (defined as a single bout of exercise), (5) evaluated episodic memory as the outcome variable (defined as the retrospective recall of information either in a spatial or temporal manner), and (6) provided sufficient data (e.g., mean, SD, and sample size) for a pooled effect size estimate. Results: In total, 25 articles met our inclusionary criteria and were meta-analyzed. Acute exercise occurring before memory encoding (d = 0.11, 95% CI: −0.01, 0.23, p = 0.08), during early memory consolidation (d = 0.47, 95% CI: 0.28, 0.67; p < 0.001) and during late memory consolidation (d = 1.05, 95% CI: 0.32, 1.78; p = 0.005) enhanced episodic memory function. Conversely, acute exercise occurring during memory encoding had a negative effect on episodic memory (d = −0.12, 95% CI: −0.22, −0.02; p = 0.02). Various study designs and participant characteristics moderated the temporal effects of acute exercise on episodic memory function. For example, vigorous-intensity acute exercise, and acute exercise among young adults, had greater effects when the acute bout of exercise occurred before memory encoding or during the early memory consolidation period. Conclusions: The timing of acute exercise plays an important role in the exercise-memory interaction. Various exercise- and participant-related characteristics moderate this temporal relationship.

Post-Encoding Amygdala-Visuosensory Coupling Is Associated with Negative Memory Bias in Healthy Young Adults.

The amygdala is well documented as the critical nexus of emotionally enhanced memory, yet its role in the creation of negative memory biases, better memory for negative compared with positive stimuli, has not been clarified. Although prior work suggests valence-specific effects at the moment of "online" encoding and retrieval, with enhanced visuosensory processes supporting negative memories in particular, here we tested the novel hypothesis that the amygdala engages with distant cortical regions after encoding in a manner that predicts inter-individual differences in negative memory biases in humans. Twenty-nine young adults (males and females) were scanned while they incidentally encoded negative, neutral, and positive scenes, each preceded by a line-drawing sketch of the scene. Twenty-four hours later, participants were scanned during an Old/New recognition memory task with only the line-drawings presented as retrieval cues. We replicated and extended our prior work, showing that enhanced online visuosensory recapitulation supports negative memory. Critically, resting-state scans flanked the encoding task, allowing us to show for the first time that individual differences in "off-line" increases in amygdala resting-state functional connectivity (RSFC) immediately following encoding relate to negative and positive memory bias at test. Specifically, post-encoding increases in amygdala RSFC with visuosensory and frontal regions were associated with the degree of negative and positive memory bias, respectively. These findings provide new evidence that valence-specific negative memory biases can be linked to the way that sensory processes are integrated into amygdala-centered emotional memory networks.SIGNIFICANCE STATEMENT Decades of research has placed the amygdala at the center of the emotional memory network. Despite the clinical importance of disproportionate memory for negative compared with positive events, it is not known whether post-encoding increases in amygdala-cortical coupling, possibly reflective of early consolidation processes, bear any influence on the degree or direction of such emotional memory biases. We demonstrate that, across participants, increases in post-encoding amygdala coupling with visuosensory and frontal regions are associated with more pronounced negative and positive memory biases, respectively. These findings provide the first evidence linking post-encoding amygdala modulation to the degree of negative or positive memory bias, emphasizing the need for valence-based accounts of the amygdala's role in emotional memory.

Clinical Outcomes of Newly Diagnosed Multiple Myeloma Patients with Elevated Lactate Dehydrogenase Who Underwent Autologous Hematopoietic Stem Cell Transplantation

Background Multiple Myeloma (MM) is a malignant disorder of clonal plasma cells. Elevated Lactate Dehydrogenase (LDH) has been shown to be an independent prognostic marker associated with shorter survival. Methods Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database, we identified patients with baseline LDH values (>4.68 microkatals/liter). We compared baseline characteristics and outcomes with autologous stem cell transplant (ASCT), based on LDH as categorical variable. Results We identified 871 patients with NDMM who had baseline LDH values. 385 patients underwent ASCT (High LDH N=44; Normal LDH N=341). Those with high LDH had an inferior OS when compared with those with normal LDH (median OS 800.5 vs 878.8 days, p=0.019). Of the 44 patients with high LDH who underwent ASCT, median age was 60 years and ECOG performance status was 1. 61.36% were females, 77% were Caucasian, 11% were African American. Induction therapy consisted of 4 drugs or more in 16%, 3 drugs in 61%, and 2 drugs in 23%. Bortezomib and immune modulating agents (IMIDS) were combined in 72%. In those who did not receive an IMID, a bortezomib-based induction was used in 16% and carfilzomib-based induction was used in 11%. 93.18% underwent transplant in the consolidative setting with a median time to transplant was 178 days. 21 of the 44 patients (47.72%) received post-transplant maintenance. 10/21(48%) patients received triplet, 8/21 (38%) patients received lenalidomide alone. The median duration of maintenance was 217 days. Of the 341 patients with normal LDH who underwent ASCT, the median age was age 61 years, ECOG performance status was 1. 41.34% were females, 79% were Caucasian, 13% African American. Induction therapy consisted of 4 drugs in 8%, 3 drugs in 64%, 2 drugs in 24%. Combined Bortezomib-IMID in 76.24%, carfilzomib-IMID based therapy in 6%, and bortezomib-non-IMID based in 9.67%. 94.7% underwent an upfront consolidative with median time to transplant 164 days. Post-transplant maintenance was given in 213/341 (62.4%) of patients, in whom triplet therapy was given to 41/213 (19.2%), doublet therapy to 34/213 (16%), 130/213 (61%) received single agent. Median duration of maintenance 266 days. There was no statistically significant difference in race, performance status, drug class and number of drugs used in induction therapy, time to transplant, whether or not patients received maintenance as well as maintenance duration between the groups when stratified by LDH. Female gender was enriched in the high LDH group (p=0.009). Conclusion Elevated LDH was confirmed as a poor prognostic factor in MMRF CoMMpass cohort. ASCT did not abrogate the poor prognosis associated with high LDH. Since clinical outcomes remain poor despite the use of novel effective therapies and early consolidation with AHCT in patients with high baseline LDH, this group represents an unmet need for alternative therapy.

Hippocampus and Prefrontal Cortex Modulation of Contextual Fear Memory Is Dissociated by Inhibiting De Novo Transcription During Late Consolidation

To uncover the factors that dictate the persistence of a memory, it is critical to determine the molecular basis of consolidation. Here, we submitted male adult C57/BL6 mice to contextual fear conditioning using 1US (US: foot-shock, 0.7mA, 2s) or 5US, to generate recent (24 to 48h) and remote (30days) memories, respectively. To access the functional role of de novo transcription, we injected actinomycin D (ActD: 2.5ng/side) directly into the dorsal hippocampus (HIP) or dorsomedial prefrontal cortex (dmPFC), 0 (early consolidation) or 12h (late consolidation) after training. Our results showed that de novo transcription at 0h was required for recent and remote memories. However, 12h was a critical time point to memory persistence. In the dHIP, de novo transcription at 12h post-training differentiated the recent memory from the remote. In the dmPFC, ActD affected memory formation depending on the training intensity (1 or 5US). Specifically, freezing was amplified after 5US conditioning. Furthermore, inhibiting de novo transcription at 12h post-training in the dmPFC rapidly increased c-Fos expression in the amygdala. Altogether, our results indicate that contextual fear memory duration is particularly sensitive to de novo transcription in the dHIP and dmPFC, at a specific time point of late consolidation.

Structuration and Learning in a Software Firm

This case study presents the evolution of a software firm from startup into early internationalization. Building on a structuration theory, the case is framed within a conceptual model that illustrates the way skills and routines co-evolve both at the level of the founding entrepreneur (agency) and of the firm (structure). As such, this article contributes to an emergent structurational view of technology-based entrepreneurship. Such views places emphasis on learning both at the individual and collective level, in terms of software engineering, commercial, managerial and strategic capabilities. In addition, it supports a dynamic perspective of entrepreneurship in the software industry by covering not only the startup phase but also early growth and consolidation of the firm.

"Teaching old dogs new tricks": targeting neural extracellular matrix for normal and pathological aging-related cognitive decline.

Cognitive decline is a feature of normal and pathological aging. As the proportion of the global aged population continues to grow, it is imperative to understand the molecular and cellular substrates of cognitive aging for therapeutic discovery. This review focuses on the critical role of neural extracellular matrix in the regulation of neuroplasticity underlying learning and memory in another under-investigated “critical period”: the aging process. The fascinating ideas of neural extracellular matrix forming a synaptic cradle in the tetrapartite synapse and possibly serving as a substrate for storage of very long-term memories will be introduced. We emphasize the distinct functional roles of diffusive neural extracellular matrix and perineuronal nets and the advantage of the coexistence of two structures for the adaptation to the ever-changing external and internal environments. Our study of striatal neural extracellular matrix supports the idea that chondroitin sulfate proteoglycan-associated extracellular matrix is restrictive on synaptic neuroplasticity, which plays important functional and pathogenic roles in early postnatal synaptic consolidation and aging-related cognitive decline. Therefore, the chondroitin sulfate proteoglycan-associated neural extracellular matrix can be targeted for normal and pathological aging. Future studies should focus on the cell-type specificity of neural extracellular matrix to identify the endogenous, druggable targets to restore juvenile neuroplasticity and confer a therapeutic benefit to neural circuits affected by aging.

A combined score of clinical factors and serum proteins can predict time to recurrence in high grade serous ovarian cancer

ObjectiveTo investigate the utility of a combined panel of protein biomarkers and clinical factors to predict recurrence in serous ovarian cancer patients. MethodsWomen at Augusta University diagnosed with ovarian cancer were enrolled between 2005 and 2015 (n = 71). Blood was drawn at enrollment and follow-up visits. Patient serum collected at remission was analyzed using the SOMAscan array (n = 35) to measure levels of 1129 proteins. The best 26 proteins were confirmed using Luminex assays in the same 35 patients and in an additional 36 patients (ntotal = 71) as orthogonal validation. The data from these 26 proteins was combined with clinical factors using an elastic net multivariate model to find an optimized combination predictive of progression-free survival (PFS). ResultsOf the 26 proteins, Brain Derived Neurotrophic Factor and Platelet Derived Growth Factor molecules were significant for predicting PFS on both univariate and multivariate analyses. All 26 proteins were combined with clinical factors using the elastic net algorithm. Ten components were determined to predict PFS (HR of 6.55, p-value 1.12 × 10−6, CI 2.57–16.71). This model was named the serous high grade ovarian cancer (SHOC) score. ConclusionThe SHOC score can predict patient prognosis in remission. This tool will hopefully lead to early intervention and consolidation therapy strategies in remission patients destined to recur.

Transcranial static magnetic stimulation over the primary motor cortex alters sequential implicit motor learning

Transcranial static magnetic stimulation (tSMS) is a recently introduced noninvasive brain stimulation technique that can modulate brain excitability. Here, we investigated a hypothesis that motor learning would be altered by tSMS applied to the primary motor cortex (M1). For motor task, we chose a serial reaction time task consisting of sequential trials and random trials in which the visual cue doesn’t play out a repeating pattern of positions to evaluate an implicit motor learning, where the M1 is a key structure for skill acquisition and early consolidation. Forty-four healthy right-handed volunteers participated in the present study. TSMS was placed over the right M1 or dorsolateral prefrontal cortex (DLPFC). The control group received Sham stimulation over the right M1. Reaction times (RTs) of left hand were analyzed before (Pre session) and after (Post session) practice to examine online learning, and were also assessed 24 h later to examine offline learning (Cons session). The results showed that the RTs became faster in Post than Pre session regardless of the stimulation location. Interestingly, the RTs were significantly faster with the M1 stimulation than the DLPFC or Sham stimulation in Cons session. There was not significant difference in error rate among sessions or stimulation locations. These findings suggest that the modulation of the M1 using tSMS can enhance offline motor learning in an implicit task.

Uninterrupted Infant Sleep, Development, and Maternal Mood.

Contrary to the importance of total sleep duration, the association between sleeping through the night and development in early infancy remains unclear. Our aims were to investigate the proportion of infants who sleep through the night (6- or 8-hour sleep blocks) at ages 6 and 12 months in a longitudinal cohort and to explore associations between sleeping through the night, mental and psychomotor development, maternal mood, and breastfeeding. At 6 and 12 months of age, maternal reports were used to assess the longest period of uninterrupted infant sleep and feeding method (n = 388). Two different criteria were used to determine if infants slept through the night: 6 and 8 hours of uninterrupted sleep. Mental and psychomotor developmental indices (Bayley Scales of Infant Development II) and maternal mood (Center for Epidemiologic Studies Depression Scale) were measured at 6, 12, and 36 months of age. Using a definition of either 6 or 8 hours of uninterrupted sleep, we found that 27.9% to 57.0% of 6- and 12-month-old infants did not sleep through the night. Linear regressions revealed no significant associations between sleeping through the night and concurrent or later mental development, psychomotor development, or maternal mood (P > .05). However, sleeping through the night was associated with a much lower rate of breastfeeding (P < .0001). Considering that high proportions of infants did not sleep through the night and that no associations were found between uninterrupted sleep, mental or psychomotor development, and maternal mood, expectations for early sleep consolidation could be moderated.

Clinical Outcomes of Newly Diagnosed Multiple Myeloma Patients with Elevated Lactate Dehydrogenase Who Underwent Autologous Hematopoietic Stem Cell Transplantation

BackgroundMultiple Myeloma (MM) is a clinically heterogeneous disorder of clonal plasma cells. Elevated Lactate Dehydrogenase (LDH) has been shown to be an independent prognostic marker associated with drug resistance and shorter survival.MethodsUtilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA12) which includes over 1000 newly-diagnosed MM (NDMM) patients with enriched tumor and matched constitutional samples analyzed using whole genome/exome and RNA sequencing, we identified patients with baseline LDH values. High LDH was defined as LDH greater than the upper limit of normal, (>4.68 microkatals/liter). We compared baseline characteristics and outcomes with autologous stem cell transplant (ASCT), based on LDH as categorical variable. We sought to determine if there is enrichment of high and standard risk cytogenetic changes when stratified by LDH.ResultsWe identified 871 patients with NDMM who had baseline LDH values. 143 patients had high LDH and 728 patients had a normal baseline LDH. Consistent with prior reports, high LDH was associated with shortened survival, 660 days vs 795 days (p=0.02852) in patients with normal LDH.385 patients underwent ASCT (High LDH N=44; Normal LDH N=341). Those with high LDH had an inferior OS when compared with those with normal LDH (median OS 800.5 vs 878.8 days, p=0.019).In order to understand this difference, we examined baseline characteristics. Of the 44 patients with high LDH who underwent ASCT, median age was 60 years and ECOG performance status was 1. 61.36% were females, 77% were Caucasian, 11% were African American. Induction therapy consisted of 4 drugs or more in 16%, 3 drugs in 61%, and 2 drugs in 23%. Bortezomib and immune modulating agents (IMIDS) were combined in 72%. In those who did not receive an IMID, a bortezomib-based induction was used in 16% and carfilzomib-based induction was used in 11%. 93.18% underwent transplant in the consolidative setting with a median time to transplant was 178 days. 21 of the 44 patients (47.72%) received post-transplant maintenance. 10/21(48%) patients received triplet therapy (5/10 - lenalidomide, bortezomib, dexamethasone), 8/21 (38%) patients received lenalidomide alone. The median duration of maintenance was 217 days.Of the 341 patients with normal LDH who underwent ASCT, the median age was age 61 years, ECOG performance status was 1. 41.34% were females, 79% were Caucasian, 13% African American. Induction therapy consisted of 4 drugs in 8%, 3 drugs in 64%, 2 drugs in 24%. Combined Bortezomib-IMID in 76.24%, carfilzomib-IMID based therapy in 6%, and bortezomib-non-IMID based in 9.67%. 94.7% underwent an upfront consolidative with median time to transplant 164 days. Post-transplant maintenance was given in 213/341 (62.4%) of patients, in whom triplet therapy was given to 41/213 (19.2%), doublet therapy to 34/213 (16%), 130/213 (61%) received single agent. 107/213 (50%) received lenalidomide alone and 19/213 (6%) received bortezomib alone. Median duration of maintenance 266 days.There was no statistically significant difference in race, performance status, drug class and number of drugs used in induction therapy, time to transplant, whether or not patients received maintenance as well as maintenance duration between the groups when stratified by LDH. Female gender was enriched in the high LDH group (hypergeometric test, p=0.009).We used hypergeometric tests to assess for enrichment of high and standard risk cytogenetic changes. Del(17p13) was significantly enriched (p=0.011) in the high LDH subset where there were no statistically significant difference in the presence of t(4;14) (p=0.16) and t(14;16) (p=0.21). There was no difference in good risk hyperdiploid structural changes between the 2 groups.ConclusionElevated LDH was confirmed as a poor prognostic factor in MMRF CoMMpass cohort. Among patients who underwent ASCT, those with high LDH have inferior survival, possibly driven by the presence of del(17p13). Since clinical outcomes remain poor despite the use of novel effective therapies and early consolidation with AHCT in patients with high baseline LDH, this group represents an unmet need for alternative therapy. DisclosuresNo relevant conflicts of interest to declare.