Interpreting life-history traits, seasonal cycles, and coastal climate from an intertidal mussel species: Insights from 9000 years of synthesized stable isotope data.

Understanding past coastal variability is valuable for contextualizing modern changes in coastal settings, yet existing Holocene paleoceanographic records for the North American Pacific Coast commonly originate from offshore marine sediments and may not represent the dynamic coastal environment. A potential archive of eastern Pacific Coast environmental variability is the intertidal mussel species Mytilus californianus. Archaeologists have collected copious stable isotopic (δ18O and δ13C) data from M. californianus shells to study human history at California's Channel Islands. When analyzed together, these isotopic data provide windows into 9000 years of Holocene isotopic variability and M. californianus life history. Here we synthesize over 6000 δ18O and δ13C data points from 13 published studies to investigate M. californianus shell isotopic variability across ontogenetic, geographic, seasonal, and millennial scales. Our analyses show that M. californianus may grow and record environmental information more irregularly than expected due to the competing influences of calcification, ontogeny, metabolism, and habitat. Stable isotope profiles with five or more subsamples per shell recorded environmental information ranging from seasonal to millennial scales, depending on the number of shells analyzed and the resolution of isotopic subsampling. Individual shell profiles contained seasonal cycles and an accurate inferred annual temperature range of ~ 5°C, although ontogenetic growth reduction obscured seasonal signals as organisms aged. Collectively, the mussel shell record reflected millennial-scale climate variability and an overall 0.52‰ depletion in δ18Oshell from 8800 BP to the present. The archive also revealed local-scale oceanographic variability in the form of a warmer coastal mainland δ18Oshell signal (-0.32‰) compared to a cooler offshore islands δ18Oshell signal (0.33‰). While M. californianus is a promising coastal archive, we emphasize the need for high-resolution subsampling from multiple individuals to disentangle impacts of calcification, metabolism, ontogeny, and habitat and more accurately infer environmental and biological patterns recorded by an intertidal species.

Proopiomelanocortin (POMC) and psychodermatology.

Psychodermatology is the crossover discipline between Dermatology and Clinical Psychology and/or Psychiatry. It encompasses both Psychiatric diseases that present with cutaneous manifestations (such as delusional infestation) or more commonly, the psychiatric or psychological problems associated with skin disease, such as depression associated with psoriasis. These problems may be the result either of imbalance in or be the consequence of alteration in the homoeostatic endocrine mechanisms found in the systemic hypothalamic-pituitary-adrenal axis or in the local cutaneous corticotrophin-releasing factor-proopiomelanocortin-corticosteroid axis. Alteration in either of these systems can lead to immune disruption and worsening of immune dermatoses and vice-versa. These include diseases such as psoriasis, atopic eczema, acne, alopecia areata, vitiligo and melasma, all of which are known to be linked to stress. Similarly, stress and illnesses such as depression are linked with many immunodermatoses and may reflect alterations in the body's central and peripheral neuroendocrine stress pathways. It is important to consider issues pertaining to skin of colour, particularly with pigmentary disorders.

Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate Cancer.

Androgen receptor (AR)-castrate-resistant prostate cancer (CRPC) is an aggressive form of prostate cancer that does not have clinically approved targeted treatment options. To this end, the cytotoxic potential of raloxifene and the synthetic curcumin derivative 2,6-bis (pyridin-4-ylmethylene)-cyclohexanone (RL91) was examined in AR-(PC3 and DU145) cells and AR+ (LnCaP) CRPC cells. The results showed that both raloxifene and RL91 elicited significant cytotoxicity across three cell lines with the lowest EC50 values in PC3 cells. Additionally, the two drugs were synergistically cytotoxic toward the PC3, DU-145 and LNCaP cell lines. To determine the effect of the drug combination in vivo, an orthotopic model of CRPC was used. Male mice were injected with PC3 prostate cancer cells and then treated with vehicle (5 mL/kg), raloxifene (8.5 mg/kg, po), RL91 (8.5 mg/kg, po) or a combination of raloxifene and RL91 for six weeks. Sham animals were subjected to the surgical procedure but were not implanted with PC3 cells. The results showed that raloxifene decreased tumor size and weight as well as metastasis to renal lymph nodes. However, combination treatment reversed the efficacy of raloxifene as tumor volume and metastasis returned to control levels. The results suggest that raloxifene has tumor suppressive and anti-metastatic effects and has potential for further clinical use in AR-CRPC.

Network-based rTMS to modulate working memory: The difficult choice of effective parameters for online interventions.

BACKGROUND: Online repetitive transcranialmagnetic stimulation (rTMS) has been shown to modulate working memory (WM) performance in a site-specific manner, with behavioral improvements due to stimulation of the dorsolateral prefrontal cortex (DLPFC), and impairment from stimulation to the lateral parietal cortex (LPC). Neurobehavioral studies have demonstrated that subprocesses of WM allowing for the maintenance and manipulation of information in the mind involve unique cortical networks. Despite promising evidence of modulatory effects of rTMS on WM, no studies have yet demonstrated distinct modulatory control of these two subprocesses. The current study therefore sought to explore this possibility through site-specific stimulation during an online task invoking both skills. METHODS: Twenty-nine subjects completed a 4-day protocol, in which active or sham 5Hz rTMS was applied over the DLPFC and LPC in separate blocks of trials while participants performed tasks that required either maintenance alone, or both maintenance and manipulation (alphabetization) of information. Stimulation targets were defined individually based on fMRI activation and structural network properties. Stimulation amplitude was adjusted using electric field modeling to equate induced current in the target region across participants. RESULTS: Despite the use of advanced techniques, no significant differences or interactions between active and sham stimulation were found. Exploratory analyses testing stimulation amplitude, fMRI activation, and modal controllability showed nonsignificant but interesting trends with rTMS effects. CONCLUSION: While this study did not reveal any significant behavioral changes in WM, the results may point to parameters that contribute to positive effects, such as stimulation amplitude and functional activation.

Developing Expert Gaze Pattern in Laparoscopic Surgery Requires More than Behavioral Training.

Expertise in laparoscopic surgery is realized through both manual dexterity and efficient eye movement patterns, creating opportunities to use gaze information in the educational process. To better understand how expert gaze behaviors are acquired through deliberate practice of technical skills, three surgeons were assessed and five novices were trained and assessed in a 5-visit protocol on the Fundamentals of Laparoscopic Surgery peg transfer task. The task was adjusted to have a fixed action sequence to allow recordings of dwell durations based on pre-defined areas of interest (AOIs). Trained novices were shown to reach more than 98% (M = 98.62%, SD = 1.06%) of their behavioral learning plateaus, leading to equivalent behavioral performance to that of surgeons. Despite this equivalence in behavioral performance, surgeons continued to show significantly shorter dwell durations at visual targets of current actions and longer dwell durations at future steps in the action sequence than trained novices (ps ≤ .03, Cohen's ds > 2). This study demonstrates that, while novices can train to match surgeons on behavioral performance, their gaze pattern is still less efficient than that of surgeons, motivating surgical training programs to involve eye tracking technology in their design and evaluation.

Movement form of the overarm throw for children at 6, 10 and 14 years of age.

This study investigated overarm throwing technique at different developmental ages in children from the perspective of three distinct, though potentially complementary, approaches to motor skill acquisition. Children at 6, 10, and 14 years of age (N = 18), completed dominant overarm throws during which whole-body kinematic data were collected. Firstly, application of Newell's ([1985]. Coordination, control and skill. In Advances in Psychology (Vol. 27, pp. 295-317). North-Holland.) stages of learning identified three distinct age-related coupling modes between forward motion of the centre-of-mass (CoM) and the wrist, which demonstrated a greater range of couplings for older children. Secondly, in line with Bernstein's ([1967]. The coordination and regulation of movement. London: Pergamon Press.) hypothesis of freezing before freeing degrees of freedom, a significantly smaller range of motion (ROM) at the ankle and knee joints, but greater ROM at the hip and upper limb joints was found for the 6 year old group compared to the 10 and 14 year old groups. Thirdly, based on the components model (Roberton & Halverson [1984]. Developing children-their changing movement: A guide for teachers. Lea & Febiger.), the overarm throws demonstrated by 6 year olds were characterised as primitive to intermediate, where 10 and 14 year old's throws were characterised by the penultimate action level for each component. Characteristics of CoM-wrist coupling more clearly identify children's age-related technique and highlight the importance of posture-ball release dynamics. The posture-ball dynamics were supported by changes in ROM and the components model, revealing the complementary nature of the three approaches to the analysis of age-related differences in overarm throwing action.

Extensive morphological variability in asexually produced planktic foraminifera.

Marine protists are integral to the structure and function of pelagic ecosystems and marine carbon cycling, with rhizarian biomass alone accounting for more than half of all mesozooplankton in the oligotrophic oceans. Yet, understanding how their environment shapes diversity within species and across taxa is limited by a paucity of observations of heritability and life history. Here, we present observations of asexual reproduction, morphologic plasticity, and ontogeny in the planktic foraminifer Neogloboquadrina pachyderma in laboratory culture. Our results demonstrate that planktic foraminifera reproduce both sexually and asexually and demonstrate extensive phenotypic plasticity in response to nonheritable factors. These two processes fundamentally explain the rapid spatial and temporal response of even imperceptibly low populations of planktic foraminifera to optimal conditions and the diversity and ubiquity of these species across the range of environmental conditions that occur in the ocean.

Intensity- and timing-dependent modulation of motion perception with transcranial magnetic stimulation of visual cortex.

Despite the widespread use of transcranial magnetic stimulation (TMS) in research and clinical care, the dose-response relations and neurophysiological correlates of modulatory effects remain relatively unexplored. To fill this gap, we studied modulation of visual processing as a function of TMS parameters. Our approach combined electroencephalography (EEG) with application of single pulse TMS to visual cortex as participants performed a motion perception task. During each participants' first visit, motion coherence thresholds, 64-channel visual evoked potentials (VEPs), and TMS resting motor thresholds (RMT) were measured. In second and third visits, single pulse TMS was delivered at one of two latencies, either 30 ms before the onset of motion or at the onset latency of the N2 VEP component derived from the first session. TMS was delivered at 0%, 80%, 100%, or 120% of RMT over the site of N2 peak activity, or at 120% over vertex. Behavioral results demonstrated a significant main effect of TMS timing on accuracy, with better performance when TMS was applied at the N2-Onset timing versus Pre-Onset, as well as a significant interaction, indicating that 80% intensity produced higher accuracy than other conditions at the N2-Onset. TMS effects on the P3 VEP showed reduced amplitudes in the 80% Pre-Onset condition, an increase for the 120% N2-Onset condition, and monotonic amplitude scaling with stimulation intensity. The N2 component was not affected by TMS. These findings reveal the influence of TMS intensity and timing on visual perception and electrophysiological responses, with optimal facilitation at stimulation intensities below RMT.

Structural Controllability Predicts Functional Patterns and Brain Stimulation Benefits Associated with Working Memory.

The brain is an inherently dynamic system, and much work has focused on the ability to modify neural activity through both local perturbations and changes in the function of global network ensembles. Network controllability is a recent concept in network neuroscience that purports to predict the influence of individual cortical sites on global network states and state changes, thereby creating a unifying account of local influences on global brain dynamics. While this notion is accepted in engineering science, it is subject to ongoing debates in neuroscience as empirical evidence linking network controllability to brain activity and human behavior remains scarce. Here, we present an integrated set of multimodal brain-behavior relationships derived from fMRI, diffusion tensor imaging, and online repetitive transcranial magnetic stimulation (rTMS) applied during an individually calibrated working memory task performed by individuals of both sexes. The modes describing the structural network system dynamics showed direct relationships to brain activity associated with task difficulty, with difficult-to-reach modes contributing to functional brain states in the hard task condition. Modal controllability (a measure quantifying the contribution of difficult-to-reach modes) at the stimulated site predicted both fMRI activations associated with increasing task difficulty and rTMS benefits on task performance. Furthermore, fMRI explained 64% of the variance between modal controllability and the working memory benefit associated with 5 Hz online rTMS. These results therefore provide evidence toward the functional validity of network control theory, and outline a clear technique for integrating structural network topology and functional activity to predict the influence of stimulation on subsequent behavior.SIGNIFICANCE STATEMENT The network controllability concept proposes that specific cortical nodes are able to steer the brain into certain physiological states. By applying external perturbation to these control nodes, it is theorized that brain stimulation is able to selectively target difficult-to-reach states, potentially aiding processing and improving performance on cognitive tasks. The current study used rTMS and fMRI during a working memory task to test this hypothesis. We demonstrate that network controllability correlates with fMRI modulation because of working memory load and with the behavioral improvements that result from a multivisit intervention using 5 Hz rTMS. This study demonstrates the validity of network controllability and offers a new targeting approach to improve efficacy.

Application of long-interval paired-pulse transcranial magnetic stimulation to motion-sensitive visual cortex does not lead to changes in motion discrimination.

The perception of visual motion is dependent on a set of occipitotemporal regions that are readily accessible to neuromodulation. The current study tested if paired-pulse Transcranial Magnetic Stimulation (ppTMS) could modulate motion perception by stimulating the occipital cortex as participants viewed near-threshold motion dot stimuli. In this sham-controlled study, fifteen subjects completed two sessions. On the first visit, resting motor threshold (RMT) was assessed, and participants performed an adaptive direction discrimination task to determine individual motion sensitivity. During the second visit, subjects performed the task with three difficulty levels as TMS pulses were delivered 150 and 50 ms prior to motion stimulus onset at 120% RMT, under the logic that the cumulative inhibitory effect of these pulses would alter motion sensitivity. ppTMS was delivered at one of two locations: 3 cm dorsal and 5 cm lateral to inion (scalp-based coordinate), or at the site of peak activation for "motion" according to the NeuroSynth fMRI database (meta-analytic coordinate). Sham stimulation was delivered on one-third of trials by tilting the coil 90°. Analyses showed no significant active-versus-sham effects of ppTMS when stimulation was delivered to the meta-analytic (p = 0.15) or scalp-based coordinates (p = 0.17), which were separated by 29 mm on average. Active-versus-sham stimulation differences did not interact with either stimulation location (p = 0.12) or difficulty (p = 0.33). These findings fail to support the hypothesis that long-interval ppTMS recruits inhibitory processes in motion-sensitive cortex but must be considered within the limited parameters used in this design.

Site-Specific Effects of Online rTMS during a Working Memory Task in Healthy Older Adults.

The process of manipulating information within working memory is central to many cognitive functions, but also declines rapidly in old age. Improving this process could markedly enhance the health-span in older adults. The current pre-registered, randomized and placebo-controlled study tested the potential of online repetitive transcranial magnetic stimulation (rTMS) applied at 5 Hz over the left lateral parietal cortex to enhance working memory manipulation in healthy elderly adults. rTMS was applied, while participants performed a delayed-response alphabetization task with two individually titrated levels of difficulty. Coil placement and stimulation amplitude were calculated from fMRI activation maps combined with electric field modeling on an individual-subject basis in order to standardize dosing at the targeted cortical location. Contrary to the a priori hypothesis, active rTMS significantly decreased accuracy relative to sham, and only in the hardest difficulty level. When compared to the results from our previous study, in which rTMS was applied over the left prefrontal cortex, we found equivalent effect sizes but opposite directionality suggesting a site-specific effect of rTMS. These results demonstrate engagement of cortical working memory processing using a novel TMS targeting approach, while also providing prescriptions for future studies seeking to enhance memory through rTMS.

Utilizing transcranial direct current stimulation to enhance laparoscopic technical skills training: A randomized controlled trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that delivers constant, low electrical current resulting in changes to cortical excitability. Prior work suggests it may enhance motor learning giving it the potential to augment surgical technical skill acquisition. OBJECTIVES: The aim of this study was to test the efficacy of tDCS, coupled with motor skill training, to accelerate laparoscopic skill acquisition in a pre-registered (NCT03083483), double-blind and placebo-controlled study. We hypothesized that relative to sham tDCS, active tDCS would accelerate the development of laparoscopic technical skills, as measured by the Fundamentals of Laparoscopic Surgery (FLS) Peg Transfer task quantitative metrics. METHODS: In this study, sixty subjects (mean age 22.7 years with 42 females) were randomized into sham or active tDCS in either bilateral primary motor cortex (bM1) or supplementary motor area (SMA) electrode configurations. All subjects practiced the FLS Peg Transfer Task during six 20-min training blocks, which were preceded and followed by a single trial pre-test and post-test. The primary outcome was changes in laparoscopic skill performance over time, quantified by group differences in completion time from pre-test to post-test and learning curves developed from a calculated score accounting for errors. RESULTS: Learning curves calculated over the six 20-min training blocks showed significantly greater improvement in performance for the bM1 group than the sham group (t = 2.07, p = 0.039), with the bM1 group achieving approximately the same amount of improvement in 4 blocks compared to the 6 blocks required of the sham group. The SMA group also showed greater mean improvement than sham, but exhibited more variable learning performance and differences relative to sham were not significant (t = 0.85, p = 0.400). A significant main effect was present for pre-test versus post-test times (F = 133.2, p < 0.001), with lower completion times at post-test, however these did not significantly differ for the training groups. CONCLUSION: Laparoscopic skill training with active bilateral tDCS exhibited significantly greater learning relative to sham. The potential for tDCS to enhance the training of surgical skills, therefore, merits further investigation to determine if these preliminary results may be replicated and extended.

Pressure promoted low-temperature melting of metal-organic frameworks.

Metal-organic frameworks (MOFs) are microporous materials with huge potential for chemical processes. Structural collapse at high pressure, and transitions to liquid states at high temperature, have recently been observed in the zeolitic imidazolate framework (ZIF) family of MOFs. Here, we show that simultaneous high-pressure and high-temperature conditions result in complex behaviour in ZIF-62 and ZIF-4, with distinct high- and low-density amorphous phases occurring over different regions of the pressure-temperature phase diagram. In situ powder X-ray diffraction, Raman spectroscopy and optical microscopy reveal that the stability of the liquid MOF state expands substantially towards lower temperatures at intermediate, industrially achievable pressures and first-principles molecular dynamics show that softening of the framework coordination with pressure makes melting thermodynamically easier. Furthermore, the MOF glass formed by melt quenching the high-temperature liquid possesses permanent, accessible porosity. Our results thus imply a route to the synthesis of functional MOF glasses at low temperatures, avoiding decomposition on heating at ambient pressure.

Low- and High-Frequency Repetitive Transcranial Magnetic Stimulation Effects on Resting-State Functional Connectivity Between the Postcentral Gyrus and the Insula.

The insular cortex supports the conscious awareness of physical and emotional sensations, and the ability to modulate the insula could have important clinical applications in psychiatry. Repetitive transcranial magnetic stimulation (rTMS) uses transient magnetic fields to induce electrical currents in the superficial cortex. Given its deep location in the brain, the insula may not be directly stimulated by rTMS; however, rTMS may modulate the insula via its functional connections with superficial cortical regions. Furthermore, low- versus high-frequency rTMS is thought to have opposing effects on cortical excitability, and the present study investigated these effects on brain activity and functional connectivity with the insula. Separate groups of healthy participants (n = 14 per group) received low (1 Hz)- or high (10 Hz)-frequency rTMS in five daily sessions to the right postcentral gyrus, a superficial region known to be functionally connected to the insula. Resting-state functional connectivity (RSFC) was measured pre- and post-rTMS. Both 1 and 10 Hz rTMS increased RSFC between the right postcentral gyrus and the left insula. These results suggest that low- and high-frequency rTMS has similar long-term effects on brain activity and RSFC. However, given the lack of difference, we cannot exclude the possibility that these effects are simply due to a nonspecific effect. Given this limitation, these unexpected results underscore the need for acoustic- and stimulation-matched sham control conditions in rTMS research.

Qualitative and quantitative change in the kinematics of learning a non-dominant overarm throw.

This study investigated changes in non-dominant overarm throw technique over practice from the perspective of three distinct though potentially complementary approaches to motor skill acquisition. Ten participants (mean ±â€¯SD age 22 ±â€¯2 yrs, stature 1.71 ±â€¯0.60 m, mass 73 ±â€¯14 kg) completed 9-practice sessions (each 10 trials), during which whole-body kinematic data were collected. In line with the motor learning model of Newell (1985), we examined changes in the coupling between the centre-of-mass (CoM) and wrist motion. During initial practice, coupling was initially in-phase moving to wrist-led coupling with whole-body motion. With practice a more complex backwards wrist-led coupling that progressed to forward wrist-led coupling was observed. Secondly, in line with Bernstein's (1967) notion of freezing before freeing degrees of freedom; a significant increase in joint angle range of motion (ROM) at the lower limb joints and shoulder, and significant decrease in elbow and wrist ROM was observed. Thirdly, ROM changes coincided with the time course of changes in the four components of technique change in overarm throwing action proposed by Robertson and Halverson (1984). Participants began in mid to high action levels for the torso/arm components, while the step component progressed to higher action levels with practice. Common practice induced changes in the collective posture-ball release dynamics and were supported by individual strategies at the joint ROM level revealing the complementarity nature of the three approaches and their key dependent variables to the analysis of learning to throw.

Validation of a model to predict the risk of nephrotoxicity in patients receiving colistin.

Despite concerns about its nephrotoxicity, colistin often remains the only effective agent for treating multidrug-resistant Gram-negative infections. Published studies have reported a wide range of nephrotoxicity risk factors. To assess the clinical utility of various models, we compared their performances for predicting the risk of nephrotoxicity. We identified a model demonstrating reasonable overall risk assessment, with an observed/expected ratio of 1.29 (95% confidence interval [CI], 0.68 to 1.90) and a positive predictive value of 87.5% for identifying patients at high risk of developing nephrotoxicity.

Healthcare resource utilization for recurrent Clostridium difficile infection in a large university hospital in Houston, Texas.

BACKGROUND: There are limited data examining healthcare resource utilization in patients with recurrent Clostridium difficile infection (CDI). METHODS: Patients with CDI at a tertiary-care hospital in Houston, TX, were prospectively enrolled into an observational cohort study. Recurrence was assessed via follow-up phone calls. Patients with one or more recurrence were included in this study. The location at which healthcare was obtained by patients with recurrent CDI was identified along with hospital length of stay. CDI-attributable readmissions, defined as a positive toxin test within 48 hours of admission and a primary CDI diagnosis, were also assessed. RESULTS: 372 primary cases of CDI were identified of whom 64 (17.2%) experienced at least one CDI recurrence. Twelve of 64 patients experienced 18 further episodes of CDI recurrence. Of these 64 patients, 33 (50.8%) patients with recurrent CDI were readmitted of which 6 (18.2%) required ICU care, 29 (45.3%) had outpatient care only, and 2 (3.1%) had an ED visit. Nineteen (55.9%) readmissions were defined as CDI-attributable. For patients with CDI-attributable readmission, the average length of stay was 6 ± 6 days. CONCLUSION: Recurrent CDI leads to significant healthcare resource utilization. Methods of reducing the burden of recurrent CDI should be further studied.

Clinical practice patterns in hospitalized patients at risk for invasive candidiasis: role of antifungal stewardship programs in an era of rapid diagnostics.

BACKGROUND: Rapid diagnostic tests for Candida are becoming available that may supplement traditional microbiological identification. OBJECTIVE: Assess clinical practice patterns in patients with or at risk of candidiasis who may benefit from the use of rapid diagnostic tests. METHODS: This was a prospective cohort study of patients with candidemia or receiving systemic antifungals conducted at a university-affiliated tertiary care hospital. Time to initiation of therapy, Candida species, time to identification, and indications for antifungal use were assessed. RESULTS: A total of 162 patients with candidemia aged 58 ± 17 years were identified. Average time to yeast identification yeast was 2.2 ± 1.3 days and varied by Candida species (range = 0.6-7.9 days). Average time for patient to start antifungal therapy was 3.5 ± 2.1 days. In Monte Carlo simulations, average time to initiation of antifungal therapy was 0.6 ± 0.2 days for T2Candida, 2.6 ± 1.3 days for PNA-FISH (fluorescence in situ hybridization using peptide nucleic acid probes), and 2.5 ± 1.4 days for MALDI-TOF (matrix-assisted laser desorption/ionization time of flight). Use of T2Candida on the day of the blood culture collection resulted in 3136 to 6078 fewer doses of echinocandins annually per 5000 patients. CONCLUSION: Many interventions are possible for antifungal stewardship programs to improve care of patients at risk for systemic candidiasis, including rapid identification of yeast species and limiting unnecessary antifungal agents. Technology enabling rapid diagnosis of Candida will be paramount to appropriate, cost-effective treatment of patients with or at risk for candidiasis.