Miracle-dz/UniFAR-FTUs huggingface dataset:
Risk factors for severe acute pain and persistent pain after surgery for breast cancer: a prospective observational study

Background and objectives There are few prospective studies providing comprehensive assessment of risk factors for acute and persistent pain after breast surgery. This prospective observational study assessed patient-related, perioperative, and genetic risk factors for severe acute pain and persistent pain following breast cancer surgery. Methods Women presenting for elective breast cancer surgery completed State Trait Anxiety Inventory, Beck Depression Inventory, and Pain Catastrophizing Scale questionnaires preoperatively. Diffuse noxious inhibitory control and mechanical temporal summation were assessed. A blood sample was obtained for genetic analysis. Analgesic consumption and pain scores were collected in the post-anesthesia care unit, and at 24 and 72 hours. Patients were contacted at 1, 3, 6, and 12 months to assess persistent pain. Primary outcome was maximum acute pain score in first 72 hours and secondary outcome was persistent pain. Results One hundred twenty-four patients were included in analysis. Increased duration of surgery, surgeon, and higher pain catastrophizing scores were associated with increased severity of acute pain, while preoperative radiotherapy was associated with reduced severity. Persistent pain was reported by 57.3% of patients. Postdischarge chemotherapy (OR 2.52, 95% CI 1.13 to 5.82), postdischarge radiation (OR 3.39, 95% CI 1.24 to 10.41), severe acute pain (OR 5.39, 95% CI 2.03 to 15.54), and moderate acute pain (OR 5.31, 95% CI 1.99 to 15.30) were associated with increased likelihood of persistent pain. Conclusions Increased duration of surgery, higher pain catastrophizing score, and surgeon were associated with increased severity of acute pain. Preoperative radiation was associated with lower acute pain scores. Postsurgery radiation, chemotherapy, and severity of acute pain were associated with increased likelihood of persistent pain. Trial registration NCT03307525.
Connectivity and Dynamics Underlying Synaptic Control of the Subthalamic Nucleus

Adaptive motor control critically depends on the interconnected nuclei of the basal ganglia in the CNS. A pivotal element of the basal ganglia is the subthalamic nucleus (STN), which serves as a therapeutic target for deep brain stimulation (DBS) in movement disorders, such as Parkinson's disease. The functional connectivity of the STN at the microcircuit level, however, still requires rigorous investigation. Here we combine multiple simultaneous whole-cell recordings with extracellular stimulation and post hoc neuroanatomical analysis to investigate intrinsic and afferent connectivity and synaptic properties of the STN in acute brain slices obtained from rats of both sexes. Our data reveal an absence of intrinsic connectivity and an afferent innervation with low divergence, suggesting that STN neurons operate as independent processing elements driven by upstream structures. Hence, synchrony in the STN, a hallmark of motor processing, exclusively depends on the interactions and dynamics of GABAergic and glutamatergic afferents. Importantly, these inputs are subject to differential short-term depression when stimulated at high, DBS-like frequencies, shifting the balance of excitation and inhibition toward inhibition. Thus, we present a mechanism for fast yet transient decoupling of the STN from synchronizing afferent control. Together, our study provides new insights into the microcircuit organization of the STN by identifying its neurons as parallel processing units and thus sets new constraints for future computational models of the basal ganglia. The observed differential short-term plasticity of afferent inputs further offers a basis to better understand and optimize DBS algorithms. SIGNIFICANCE STATEMENT The subthalamic nucleus (STN) is a pivotal element of the basal ganglia and serves as target for deep brain stimulation, but information on the functional connectivity of its neurons is limited. To investigate the STN microcircuitry, we combined multiple simultaneous patch-clamp recordings and neuroanatomical analysis. Our results provide new insights into the synaptic organization of the STN identifying its neurons as parallel processing units and thus set new constraints for future computational models of the basal ganglia. We further find that synaptic dynamics of afferent inputs result in a rapid yet transient decoupling of the STN when stimulated at high frequencies. These results offer a better understanding of deep brain stimulation mechanisms, promoting the development of optimized algorithms.
Accommodation and near visual function in children with albinism

Albinism degrades visual function due to developmental disorders of the eye and visual pathways, larger refractive errors, absent binocularity and poor fixation control. Reading spectacles is commonly prescribed in our clinic and well tolerated. The purpose was to evaluate whether the accommodative response is typical or affected in comparison to a reference group.
The Two Prevalent Genotypes of an Emerging Infectious Disease, Deformed Wing Virus, Cause Equally Low Pupal Mortality and Equally High Wing Deformities in Host Honey Bees

Deformed wing virus (DWV) is an emerging infectious disease of the honey bee (Apis mellifera) that is considered a major cause of elevated losses of honey bee colonies. DWV comprises two widespread genotypes: the originally described genotype A, and genotype B. In adult honey bees, DWV-B has been shown to be more virulent than DWV-A. However, their comparative effects on earlier host developmental stages are unknown. Here, we experimentally inoculated honey bee pupae and tested for the relative impact of DWV-A versus DWV-B on mortality and wing deformities in eclosing adults. DWV-A and DWV-B caused similar, and only slightly elevated, pupal mortality (mean 18% greater mortality than control). Both genotypes caused similarly high wing deformities in eclosing adults (mean 60% greater wing deformities than control). Viral titer was high in all of the experimentally inoculated eclosing adults, and was independent of wing deformities, suggesting that the phenotype ‘deformed wings’ is not directly related to viral titer or viral genotype. These viral traits favor the emergence of both genotypes of DWV by not limiting the reproduction of its vector, the ectoparasitic Varroa destructor mite, in infected pupae, and thereby facilitating the spread of DWV in honey bees infested by the mite.
Working Time Society consensus statements: Prescriptive rule sets and risk management-based approaches for the management of fatigue-related risk in working time arrangements

Traditionally, working time arrangements to limit fatigue-related risk have taken a prescriptive approach, which sets maximum shift durations in order to prevent excessive buildup of fatigue (and the associated increased risk) within shifts and sets minimum break durations to allow adequate time for rest and recovery within and/or between shifts. Prescriptive rule sets can be successful when, from a fatigue-related risk standpoint, they classify safe work hours as permitted and unsafe work hours as not permitted. However, prescriptive rule sets ignore important aspects of the biological factors (such as the interaction between circadian and homeostatic processes) that drive fatigue, which are critical modulators of the relationship between work hours and fatigue-related risk. As such, in around-the-clock operations when people must work outside of normal daytime hours, the relationship between regulatory compliance and safety tends to break down, and thus these rule sets become less effective. To address this issue, risk management-based approaches have been designed to regulate the procedures associated with managing fatigue-related risk. These risk management-based approaches are suitable for nighttime operations and a variety of other non-standard work schedules, and can be tailored to the particular job or industry. Although the purpose of these fatigue risk management approaches is to curb fatigue risk, fatigue risk cannot be measured directly. Thus, the goal is not on regulating fatigue risk per se, but rather to put in place procedures that serve to address fatigue before, during, and after potential fatigue-related incidents. Examples include predictive mathematical modeling of fatigue for work scheduling, proactive fatigue monitoring in the workplace, and reactive post-incident follow-up. With different risks and different needs across industries, there is no “one size fits all” approach to managing fatigue-related risk. However, hybrid strategies combining prescriptive rule sets and risk management-based approaches can create the flexibility necessary to reduce fatigue-related risk based on the specific needs of different work environments while maintaining appropriate regulatory oversight.
Characterization of Host and Bacterial Contributions to Lung Barrier Dysfunction Following Co-infection with 2009 Pandemic Influenza and Methicillin Resistant Staphylococcus aureus

Influenza viruses are a threat to global public health resulting in ~500,000 deaths each year. Despite an intensive vaccination program, influenza infections remain a recurrent, yet unsolved public health problem. Secondary bacterial infections frequently complicate influenza infections during seasonal outbreaks and pandemics, resulting in increased morbidity and mortality. Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), is frequently associated with these co-infections, including the 2009 influenza pandemic. Damage to alveolar epithelium is a major contributor to severe influenza-bacterial co-infections and can result in gas exchange abnormalities, fluid leakage, and respiratory insufficiency. These deleterious manifestations likely involve both pathogen- and host-mediated mechanisms. However, there is a paucity of information regarding the mechanisms (pathogen- and/or host-mediated) underlying influenza-bacterial co-infection pathogenesis. To address this, we characterized the contributions of viral-, bacterial-, and host-mediated factors to the altered structure and function of alveolar epithelial cells during co-infection with a focus on the 2009 pandemic influenza (pdm2009) and MRSA. Here, we characterized pdm2009 and MRSA replication kinetics, temporal host kinome responses, modulation of MRSA virulence factors, and disruption of alveolar barrier integrity in response to pdm2009-MRSA co-infection. Our results suggest that alveolar barrier disruption during co-infection is mediated primarily through host response dysregulation, resulting in loss of alveolar barrier integrity.
Group I p21-Activated Kinases (PAKs) Promote Tumor Cell Proliferation and Survival through the AKT1 and Raf–MAPK Pathways

Group I p21–activated kinases (PAK) are important effectors of the small GTPases Rac and Cdc42, which regulate cell motility/migration, survival, proliferation, and gene transcription. Hyperactivation of these kinases have been reported in many tumor types, making PAKs attractive targets for therapeutic intervention. PAKs are activated by growth factor–mediated signaling and are negatively regulated by the tumor suppressor neurofibromatosis type 2 (NF2)/Merlin. Thus, tumors characterized by NF2 inactivation would be expected to show hyperactivated PAK signaling. On the basis of this rationale, we evaluated the status of PAK signaling in malignant mesothelioma, an aggressive neoplasm that is resistant to current therapies and shows frequent inactivation of NF2. We show that group I PAKs are activated in most mesotheliomas and mesothelioma cell lines and that genetic or pharmacologic inhibition of PAKs is sufficient to inhibit mesothelioma cell proliferation and survival. We also identify downstream effectors and signaling pathways that may contribute mechanistically to PAK-related tumorigenesis. Specifically, we show that inhibition of PAK results in attenuation of AKT and Raf–MAPK signaling and decreased tumor cell viability. Collectively, these data suggest that pharmacologic inhibition of group I PAKs may have therapeutic efficacy in tumors characterized by PAK activation. Mol Cancer Res; 10(9); 1178–88. ©2012 AACR.
The Enterococcus: a Model of Adaptability to Its Environment

The genus Enterococcus comprises a ubiquitous group of Gram-positive bacteria that are of great relevance to human health for their role as major causative agents of health care-associated infections. The enterococci are resilient and versatile species able to survive under harsh conditions, making them well adapted to the health care environment. SUMMARY The genus Enterococcus comprises a ubiquitous group of Gram-positive bacteria that are of great relevance to human health for their role as major causative agents of health care-associated infections. The enterococci are resilient and versatile species able to survive under harsh conditions, making them well adapted to the health care environment. Two species cause the majority of enterococcal infections: Enterococcus faecalis and Enterococcus faecium. Both species demonstrate intrinsic resistance to common antibiotics, such as virtually all cephalosporins, aminoglycosides, clindamycin, and trimethoprim-sulfamethoxazole. Additionally, a remarkably plastic genome allows these two species to readily acquire resistance to further antibiotics, such as high-level aminoglycoside resistance, high-level ampicillin resistance, and vancomycin resistance, either through mutation or by horizontal transfer of genetic elements conferring resistance determinants.
Caregiver Burden and Desire for Institutional Placement—The Roles of Positive Aspects of Caregiving and Religious Coping

Based on stress coping theory, this study investigated whether and how positive aspects of caregiving (PAC) and religiosity buffered the association between caregiving burden and desire to institutionalize (DTI). Secondary data (N = 637) were drawn from the baseline assessment of the Resources for Enhancing Alzheimer’s Caregiver Health II project. Descriptive analysis, bivariate correlation, and multiple linear regressions were conducted. The results indicated that higher levels of caregiver burden, daily care bother, and Revised Memory and Behavioral Problem Checklist bother were all significantly associated with higher level of DTI. Both PAC and religious coping were negatively associated with DTI; however, only PAC was significant. Only the interaction between daily care bother and religious coping was significant, which indicated that the harmful effect of daily care bother on DTI was significantly buffered among those who have religiosity. Study findings have important implications for policy makers and for providers who serve dementia family caregivers.
The droplet size of intraduodenal fat emulsions influences antropyloroduodenal motility, hormone release, and appetite in healthy males.

BACKGROUND The presence of fat in the small intestine modulates gastrointestinal motility, stimulates plasma cholecystokinin and peptide YY release, and suppresses appetite and energy intake. These effects are dependent on the lipolysis of fat. OBJECTIVE Our aim was to evaluate the hypothesis that increasing the droplet size of a fat emulsion would attenuate these effects. DESIGN Ten healthy, lean males were studied on 4 separate occasions in single-blind randomized order. Antropyloroduodenal pressures, plasma triglycerides, cholecystokinin, peptide YY, and appetite were measured during 120-min intraduodenal infusions of fat emulsions comprising 3 different droplet sizes: 1) 0.26 microm (LE-0.26), 2) 30 microm (LE-30), and 3) 170 microm (LE-170) in addition to saline (control). Energy intake at a buffet lunch was quantified immediately after the infusions. RESULTS Increasing the droplet size of the lipid emulsion was associated with diminished suppression of antral (r = 0.75, P < 0.01) and duodenal (r = 0.80, P < 0.01) pressure waves and with stimulation of isolated (r = -0.72, P < 0.01) and basal (r = -0.83, P < 0.01) pyloric pressures. Increasing the droplet size was also associated with attenuation of the stimulation of plasma triglycerides (r = -0.73, P < 0.001), cholecystokinin (r = -0.73, P < 0.001), and peptide YY (r = -0.83, P < 0.001) as well as with reductions in the suppression of hunger (r = 0.75, P < 0.01) and energy intake (r = 0.66, P < 0.001). CONCLUSIONS The acute effects of intraduodenal fat emulsions on gastrointestinal function and appetite are dependent on fat droplet size. These observations have implications for the design of functional foods to maximize effects on those gut functions that are involved in the suppression of appetite.
Diet‐Induced Obesity in Cannabinoid‐2 Receptor Knockout Mice and Cannabinoid Receptor 1/2 Double‐Knockout Mice

Evidence suggests that cannabinoid‐1 receptor (CB1R) activation is associated with increased food intake and body weight gain. Human epidemiological studies, however, show decreased prevalence of obesity in cannabis users. Given the overlapping and complementary functions of the cannabinoid receptors (CB1R and CB2R), mice lacking CB2R and mice lacking both CB1R and CB2R were studied.
Subthalamic Nucleus and Sensorimotor Cortex Activity During Speech Production

The sensorimotor cortex is somatotopically organized to represent the vocal tract articulators such as lips, tongue, larynx, and jaw. How speech and articulatory features are encoded at the subcortical level, however, remains largely unknown. We analyzed LFP recordings from the subthalamic nucleus (STN) and simultaneous electrocorticography recordings from the sensorimotor cortex of 11 human subjects (1 female) with Parkinson's disease during implantation of deep-brain stimulation (DBS) electrodes while they read aloud three-phoneme words. The initial phonemes involved either articulation primarily with the tongue (coronal consonants) or the lips (labial consonants). We observed significant increases in high-gamma (60–150 Hz) power in both the STN and the sensorimotor cortex that began before speech onset and persisted for the duration of speech articulation. As expected from previous reports, in the sensorimotor cortex, the primary articulators involved in the production of the initial consonants were topographically represented by high-gamma activity. We found that STN high-gamma activity also demonstrated specificity for the primary articulator, although no clear topography was observed. In general, subthalamic high-gamma activity varied along the ventral–dorsal trajectory of the electrodes, with greater high-gamma power recorded in the dorsal locations of the STN. Interestingly, the majority of significant articulator-discriminative activity in the STN occurred before that in sensorimotor cortex. These results demonstrate that articulator-specific speech information is contained within high-gamma activity of the STN, but with different spatial and temporal organization compared with similar information encoded in the sensorimotor cortex. SIGNIFICANCE STATEMENT Clinical and electrophysiological evidence suggest that the subthalamic nucleus (STN) is involved in speech; however, this important basal ganglia node is ignored in current models of speech production. We previously showed that STN neurons differentially encode early and late aspects of speech production, but no previous studies have examined subthalamic functional organization for speech articulators. Using simultaneous LFP recordings from the sensorimotor cortex and the STN in patients with Parkinson's disease undergoing deep-brain stimulation surgery, we discovered that STN high-gamma activity tracks speech production at the level of vocal tract articulators before the onset of vocalization and often before related cortical encoding.
Conditional BDNF Delivery from Astrocytes Rescues Memory Deficits, Spine Density, and Synaptic Properties in the 5xFAD Mouse Model of Alzheimer Disease

It has been well documented that neurotrophins, including brain-derived neurotrophic factor (BDNF), are severely affected in Alzheimer's disease (AD), but their administration faces a myriad of technical challenges. Here we took advantage of the early astrogliosis observed in an amyloid mouse model of AD (5xFAD) and used it as an internal sensor to administer BDNF conditionally and locally. We first demonstrate the relevance of BDNF release from astrocytes by evaluating the effects of coculturing WT neurons and BDNF-deficient astrocytes. Next, we crossed 5xFAD mice with pGFAP:BDNF mice (only males were used) to create 5xFAD mice that overexpress BDNF when and where astrogliosis is initiated (5xF:pGB mice). We evaluated the behavioral phenotype of these mice. We first found that BDNF from astrocytes is crucial for dendrite outgrowth and spine number in cultured WT neurons. Double-mutant 5xF:pGB mice displayed improvements in cognitive tasks compared with 5xFAD littermates. In these mice, there was a rescue of BDNF/TrkB downstream signaling activity associated with an improvement of dendritic spine density and morphology. Clusters of synaptic markers, PSD-95 and synaptophysin, were also recovered in 5xF:pGB compared with 5xFAD mice as well as the number of presynaptic vesicles at excitatory synapses. Additionally, experimentally evoked LTP in vivo was increased in 5xF:pGB mice. The beneficial effects of conditional BDNF production and local delivery at the location of active neuropathology highlight the potential to use endogenous biomarkers with early onset, such as astrogliosis, as regulators of neurotrophic therapy in AD. SIGNIFICANCE STATEMENT Recent evidence places astrocytes as pivotal players during synaptic plasticity and memory processes. In the present work, we first provide evidence that astrocytes are essential for neuronal morphology via BDNF release. We then crossed transgenic mice (5xFAD mice) with the transgenic pGFAP-BDNF mice, which express BDNF under the GFAP promoter. The resultant double-mutant mice 5xF:pGB mice displayed a full rescue of hippocampal BDNF loss and related signaling compared with 5xFAD mice and a significant and specific improvement in all the evaluated cognitive tasks. These improvements did not correlate with amelioration of β amyloid load or hippocampal adult neurogenesis rate but were accompanied by a dramatic recovery of structural and functional synaptic plasticity.