Nobel and novice: Author prominence affects peer review.

Peer review is a well-established cornerstone of the scientific process, yet it is not immune to biases like status bias, which we explore in this paper. Merton described this bias as prominent researchers getting disproportionately great credit for their contribution, while relatively unknown researchers get disproportionately little credit [R. K. Merton, Science 159, 56-63 (1968)]. We measured the extent of this bias in the peer-review process through a preregistered field experiment. We invited more than 3,300 researchers to review a finance research paper jointly written by a prominent author (a Nobel laureate) and by a relatively unknown author (an early career research associate), varying whether reviewers saw the prominent author's name, an anonymized version of the paper, or the less-well-known author's name. We found strong evidence for the status bias: More of the invited researchers accepted to review the paper when the prominent name was shown, and while only 23% recommended "reject" when the prominent researcher was the only author shown, 48% did so when the paper was anonymized, and 65% did when the little-known author was the only author shown. Our findings complement and extend earlier results on double-anonymized vs. single-anonymized review [R. Blank, Am. Econ. Rev. 81, 1041-1067 (1991); M. A. Ucci, F. D'Antonio, V. Berghella, Am. J. Obstet. Gynecol. MFM 4, 100645 (2022)].

Electrophysiological markers of memory consolidation in the human brain when memories are reactivated during sleep.

Human accomplishments depend on learning, and effective learning depends on consolidation. Consolidation is the process whereby new memories are gradually stored in an enduring way in the brain so that they can be available when needed. For factual or event knowledge, consolidation is thought to progress during sleep as well as during waking states and to be mediated by interactions between hippocampal and neocortical networks. However, consolidation is difficult to observe directly but rather is inferred through behavioral observations. Here, we investigated overnight memory change by measuring electrical activity in and near the hippocampus. Electroencephalographic (EEG) recordings were made in five patients from electrodes implanted to determine whether a surgical treatment could relieve their seizure disorders. One night, while each patient slept in a hospital monitoring room, we recorded electrophysiological responses to 10 to 20 specific sounds that were presented very quietly, to avoid arousal. Half of the sounds had been associated with objects and their precise spatial locations that patients learned before sleep. After sleep, we found systematic improvements in spatial recall, replicating prior results. We assume that when the sounds were presented during sleep, they reactivated and strengthened corresponding spatial memories. Notably, the sounds also elicited oscillatory intracranial EEG activity, including increases in theta, sigma, and gamma EEG bands. Gamma responses, in particular, were consistently associated with the degree of improvement in spatial memory exhibited after sleep. We thus conclude that this electrophysiological activity in the hippocampus and adjacent medial temporal cortex reflects sleep-based enhancement of memory storage.

Depth versus surface: A critical review of subdural and depth electrodes in intracranial electroencephalographic studies.

Intracranial electroencephalographic (IEEG) recording, using subdural electrodes (SDEs) and stereoelectroencephalography (SEEG), plays a pivotal role in localizing the epileptogenic zone (EZ). SDEs, employed for superficial cortical seizure foci localization, provide information on two-dimensional seizure onset and propagation. In contrast, SEEG, with its three-dimensional sampling, allows exploration of deep brain structures, sulcal folds, and bihemispheric networks. SEEG offers the advantages of fewer complications, better tolerability, and coverage of sulci. Although both modalities allow electrical stimulation, SDE mapping can tessellate cortical gyri, providing the opportunity for a tailored resection. With SEEG, both superficial gyri and deep sulci can be stimulated, and there is a lower risk of afterdischarges and stimulation-induced seizures. Most systematic reviews and meta-analyses have addressed the comparative effectiveness of SDEs and SEEG in localizing the EZ and achieving seizure freedom, although discrepancies persist in the literature. The combination of SDEs and SEEG could potentially overcome the limitations inherent to each technique individually, better delineating seizure foci. This review describes the strengths and limitations of SDE and SEEG recordings, highlighting their unique indications in seizure localization, as evidenced by recent publications. Addressing controversies in the perceived usefulness of the two techniques offers insights that can aid in selecting the most suitable IEEG in clinical practice.

In-vivo testing of a novel wireless intraspinal microstimulation interface for restoration of motor function following spinal cord injury.

BACKGROUND: Spinal cord injury causes a drastic loss in motor and sensory function. Intraspinal microstimulation (ISMS) is an electrical stimulation method developed for restoring motor function by activating the spinal networks below the level of injury. Current ISMS technology uses fine penetrating microwires to stimulate the ventral horn of the lumbar enlargement. The penetrating wires traverse the dura mater through a transdural conduit that connects to an implantable pulse generator. OBJECTIVE: A wireless, fully intradural ISMS implant was developed to mitigate the potential complications associated with the transdural conduit, including tethering and leakage of cerebrospinal fluid. METHODS: Two wireless floating microelectrode array (WFMA) devices were implanted in the lumbar enlargement of an adult domestic pig. Voltage transients were used to assess the electrochemical stability of the interface. Manual flexion and extension movements of the spine were performed to evaluate the mechanical stability of the interface. Post-mortem 9T MRI imaging was used to confirm the location of the electrodes. RESULTS: The WFMA-based ISMS interface successfully evoked extension and flexion movements of the hip joint. Stimulation thresholds remained stable following manual extension and flexion of the spine. CONCLUSION: The preliminary results demonstrate the surgical feasibility as well as the functionality of the proposed wireless ISMS system.

Visual cortex responds to sound onset and offset during passive listening.

Sounds enhance our ability to detect, localize, and respond to co-occurring visual targets. Research suggests that sounds improve visual processing by resetting the phase of ongoing oscillations in visual cortex. However, it remains unclear what information is relayed from the auditory system to visual areas and if sounds modulate visual activity even in the absence of visual stimuli (e.g., during passive listening). Using intracranial electroencephalography (iEEG) in humans, we examined the sensitivity of visual cortex to three forms of auditory information during a passive listening task: auditory onset responses, auditory offset responses, and rhythmic entrainment to sounds. Because some auditory neurons respond to both sound onsets and offsets, visual timing and duration processing may benefit from each. In addition, if auditory entrainment information is relayed to visual cortex, it could support the processing of complex stimulus dynamics that are aligned between auditory and visual stimuli. Results demonstrate that in visual cortex, amplitude-modulated sounds elicited transient onset and offset responses in multiple areas, but no entrainment to sound modulation frequencies. These findings suggest that activity in visual cortex (as measured with iEEG in response to auditory stimuli) may not be affected by temporally fine-grained auditory stimulus dynamics during passive listening (though it remains possible that this signal may be observable with simultaneous auditory-visual stimuli). Moreover, auditory responses were maximal in low-level visual cortex, potentially implicating a direct pathway for rapid interactions between auditory and visual cortices. This mechanism may facilitate perception by time-locking visual computations to environmental events marked by auditory discontinuities.NEW & NOTEWORTHY Using intracranial electroencephalography (iEEG) in humans during a passive listening task, we demonstrate that sounds modulate activity in visual cortex at both the onset and offset of sounds, which likely supports visual timing and duration processing. However, more complex auditory rate information did not affect visual activity. These findings are based on one of the largest multisensory iEEG studies to date and reveal the type of information transmitted between auditory and visual regions.

Visual speech differentially modulates beta, theta, and high gamma bands in auditory cortex.

Speech perception is a central component of social communication. Although principally an auditory process, accurate speech perception in everyday settings is supported by meaningful information extracted from visual cues. Visual speech modulates activity in cortical areas subserving auditory speech perception including the superior temporal gyrus (STG). However, it is unknown whether visual modulation of auditory processing is a unitary phenomenon or, rather, consists of multiple functionally distinct processes. To explore this question, we examined neural responses to audiovisual speech measured from intracranially implanted electrodes in 21 patients with epilepsy. We found that visual speech modulated auditory processes in the STG in multiple ways, eliciting temporally and spatially distinct patterns of activity that differed across frequency bands. In the theta band, visual speech suppressed the auditory response from before auditory speech onset to after auditory speech onset (-93 to 500 ms) most strongly in the posterior STG. In the beta band, suppression was seen in the anterior STG from -311 to -195 ms before auditory speech onset and in the middle STG from -195 to 235 ms after speech onset. In high gamma, visual speech enhanced the auditory response from -45 to 24 ms only in the posterior STG. We interpret the visual-induced changes prior to speech onset as reflecting crossmodal prediction of speech signals. In contrast, modulations after sound onset may reflect a decrease in sustained feedforward auditory activity. These results are consistent with models that posit multiple distinct mechanisms supporting audiovisual speech perception.

Exosomes released from Shiga toxin 2a-treated human macrophages modulate inflammatory responses and induce cell death in toxin receptor expressing human cells.

Shiga toxins (Stxs) produced by Stx-producing Escherichia coli are the primarily virulence factors of hemolytic uremic syndrome and central nervous system (CNS) impairment. Although the precise mechanisms of toxin dissemination remain unclear, Stxs bind to extracellular vesicles (EVs). Exosomes, a subset of EVs, may play a key role in Stx-mediated renal injury. To test this hypothesis, we isolated exosomes from monocyte-derived macrophages in the presence of Stx2a or Stx2 toxoids. Macrophage-like differentiated THP-1 cells treated with Stxs secreted Stx-associated exosomes (Stx-Exo) of 90-130 nm in diameter, which induced cytotoxicity in recipient cells in a toxin receptor globotriaosylceramide (Gb3 )-dependent manner. Stx2-Exo engulfed by Gb3 -positive cells were translocated to the endoplasmic reticulum in the human proximal tubule epithelial cell line HK-2. Stx2-Exo contained pro-inflammatory cytokine mRNAs and proteins and induced more severe inflammation than purified Stx2a accompanied by greater death of target cells such as human renal or retinal pigment epithelial cells. Blockade of exosome biogenesis using the pharmacological inhibitor GW4869 reduced Stx2-Exo-mediated human renal cell death. Stx2-Exo isolated from human primary monocyte-derived macrophages activated caspase 3/7 and resulted in significant cell death in primary human renal cortical epithelial cells. Based on these results, we speculate that Stx-containing exosomes derived from macrophages may exacerbate cytotoxicity and inflammation and trigger cell death in toxin-sensitive cells. Therapeutic interventions targeting Stx-containing exosomes may prevent or ameliorate Stx-mediated acute vascular dysfunction.

The First of Two One-Year, Multicenter, Open-Label, Repeat-Dose, Phase II Safety Studies of PrabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult Patients.

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin type A produced by Clostridium botulinum. OBJECTIVES: The authors sought to investigate the safety of prabotulinumtoxinA for treatment of glabellar lines. METHODS: This was a multicenter, open-label, repeat-dose, 1-year phase II safety study. Adults with moderate to severe glabellar lines at maximum frown, as assessed by the investigator on the validated 4-point photonumeric Glabellar Line Scale (0 = no lines, 1 = mild, 2 = moderate, 3 = severe), were enrolled. On day 0, patients received an initial treatment of 20 U prabotulinumtoxinA (4 U/0.1 mL freeze-dried formulation injected into 5 target glabellar sites). On and after day 90, patients received a repeat treatment (RT) if their Glabellar Line Scale score was ≥2 at maximum frown by investigator assessment. Safety was evaluated throughout the study. RESULTS: The 352 study patients received a median total dose of 60 U, that is, 3 treatments per year. Fifty-one patients (14.5%) experienced adverse events (AEs) assessed as possibly study drug related; 11.1% experienced study drug-related AEs after the initial treatment. With each RT, progressively lower percentages of patients experienced study drug-related AEs. Six patients (1.7%) experienced study drug-related AEs of special interest: 3 eyelid ptosis (0.9%), 2 speech disorder (0.6%), and 1 blepharospasm (0.3%). Seven patients (2.0%) experienced serious AEs; none were study drug related. Of the 2393 samples tested, 2 patients (0.6%) tested positive for antibotulinum toxin antibodies at a single postbaseline visit. CONCLUSIONS: The safety of RTs of 20 U of prabotulinumtoxinA for moderate to severe glabellar lines was first established in this early phase II study based on a broad range of outcomes.

Immunoglobulin free light chains as an inflammatory biomarker of heart failure with myocarditis.

BACKGROUND: In this study, we measured immunoglobulin free light chains (FLC), a biomarker of inflammation in the sera of patients with heart failure due to myocarditis. METHODS: FLC kappa and FLC lambda were assayed in stored serum samples from patients with heart failure with myocarditis from the US myocarditis treatment trial by a competitive-inhibition multiplex Luminex® assay. RESULTS: The median concentration of circulating FLC kappa/lambda ratio was significantly lower in the sera from patients with heart failure with myocarditis than in healthy controls, and FLC kappa/lambda ratio had good diagnostic ability for identification of heart failure with myocarditis. Further, FLC kappa/lambda ratio was an independent prognostic factor for overall survival, and allowed creation of three prognostic groups by combining with N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: This study suggests that FLC kappa/lambda ratio is a promising biomarker of heart failure with myocarditis.

Joint Encoding of Auditory Timing and Location in Visual Cortex.

Co-occurring sounds can facilitate perception of spatially and temporally correspondent visual events. Separate lines of research have identified two putatively distinct neural mechanisms underlying two types of crossmodal facilitations: Whereas crossmodal phase resetting is thought to underlie enhancements based on temporal correspondences, lateralized occipital evoked potentials (ERPs) are thought to reflect enhancements based on spatial correspondences. Here, we sought to clarify the relationship between these two effects to assess whether they reflect two distinct mechanisms or, rather, two facets of the same underlying process. To identify the neural generators of each effect, we examined crossmodal responses to lateralized sounds in visually responsive cortex of 22 patients using electrocorticographic recordings. Auditory-driven phase reset and ERP responses in visual cortex displayed similar topography, revealing significant activity in pericalcarine, inferior occipital-temporal, and posterior parietal cortex, with maximal activity in lateral occipitotemporal cortex (potentially V5/hMT+). Laterality effects showed similar but less widespread topography. To test whether lateralized and nonlateralized components of crossmodal ERPs emerged from common or distinct neural generators, we compared responses throughout visual cortex. Visual electrodes responded to both contralateral and ipsilateral sounds with a contralateral bias, suggesting that previously observed laterality effects do not emerge from a distinct neural generator but rather reflect laterality-biased responses in the same neural populations that produce phase-resetting responses. These results suggest that crossmodal phase reset and ERP responses previously found to reflect spatial and temporal facilitation in visual cortex may reflect the same underlying mechanism. We propose a new unified model to account for these and previous results.

Stereotactic EEG-guided laser interstitial thermal therapy for mesial temporal lobe epilepsy.

OBJECTIVE: To determine the outcomes of combined stereo-electroencephalography-guided and MRI-guided stereotactic laser interstitial thermal therapy (LITT) in the treatment of patients with drug-resistant mesial temporal lobe epilepsy (mTLE). METHODS: We prospectively assessed the surgical and neuropsychological outcomes in 21 patients with medically refractory mTLE who underwent LITT at the University of Chicago Medical Center. We further compared the surgical outcomes in patients with and without mesial temporal sclerosis (MTS). RESULTS: Of the 21 patients, 19 (90%) underwent Invasive EEG study and 11 (52%) achieved freedom from disabling seizures with a mean duration of postoperative follow-up of 24±11 months after LITT. Eight (73%) of 11 patients with MTS achieved freedom from disabling seizures, whereas 3 (30 %) of 10 patients without MTS achieved freedom from disabling seizures. Patients with MTS were significantly more likely to become seizure-free, as compared with those without MTS (P=0.002). There was no significant difference in total ablation volume and the percentage of the ablated amygdalohippocampal complex between seizure-free and non-seizure-free patients. Presurgical and postsurgical neuropsychological assessments were obtained in 10 of 21 patients. While there was no group decline in any neuropsychological assessment, a significant postoperative decline in verbal memory and confrontational naming was observed in individual patients. CONCLUSIONS: MRI-guided LITT is a safe and effective alternative to selective amygdalohippocampectomy and anterior temporal lobectomy for mTLE with MTS. Nevertheless, its efficacy in those without MTS seems modest. Large multicentre and prospective studies are warranted to further determine the efficacy and safety of LITT.

Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy.

Glutamic acid decarboxylase (GAD) antibody-associated encephalitis causes both acute seizures and chronic epilepsy with predominantly temporal lobe onset. This condition is challenging in diagnosis and management, and the incidence of GAD antibody (Ab)-related epilepsy could be much higher than commonly believed. Imaging and CSF evidence of inflammation along with typical clinical presentations, such as adult onset temporal lobe epilepsy (TLE) with unexplained etiology, should prompt testing for the diagnostic antibodies. High serum GAD Ab titer (≥2000U/mL or ≥20nmol/L) and evidence of intrathecal anti-GAD Ab synthesis support the diagnosis. Unlike other immune-mediated epilepsies, antiglutamic acid decarboxylase 65 (GAD65) antibody-mediated epilepsy is often poorly responsive to antiepileptic drugs (AEDs) and only moderately responsive to immune therapy with steroids, intravenous immunoglobulin (IVIG), or plasma exchange (PLEX). Long-term treatment with more aggressive immunosuppressants such as rituximab (RTX) and/or cyclophosphamide is often necessary and may be more effective than current immunosuppressive approaches. The aim of this review is to review the physiology, pathology, clinical presentation, related ancillary tests, and management of GAD Ab-associated autoimmune epilepsy by searching the keywords and to promote the recognition and the initiation of proper therapy for this condition.

Retrading, production, and asset market performance.

Prior studies have shown that traders quickly converge to the price-quantity equilibrium in markets for goods that are immediately consumed, but they produce speculative price bubbles in resalable asset markets. We present a stock-flow model of durable assets in which the existing stock of assets is subject to depreciation and producers may produce additional units of the asset. In our laboratory experiments inexperienced consumers who can resell their units disregard the consumption value of the assets and compete vigorously with producers, depressing prices and production. Consumers who have first participated in experiments without resale learn to heed their consumption values and, when they are given the option to resell, trade at equilibrium prices. Reproducibility is therefore the most natural and most effective treatment for suppression of bubbles in asset market experiments.

Cervical Cancer Screening.

Screening in women has decreased the incidence and mortality of cervical cancer. Precancerous cervical lesions (cervical intraepithelial neoplasias) and cervical carcinomas are strongly associated with sexually-transmitted high-risk human papillomavirus (HPV) infection, which causes more than 99% of cervical cancers. Screening methods include cytology (Papanicolaou test) and HPV testing, alone or in combination. The American Academy of Family Physicians and the U.S. Preventive Services Task Force recommend starting screening in immunocompetent, asymptomatic women at 21 years of age. Women 21 to 29 years of age should be screened every three years with cytology alone. Women 30 to 65 years of age should be screened every five years with cytology plus HPV testing or every three years with cytology alone. Screening is not recommended for women younger than 21 years or in women older than 65 years with an adequate history of negative screening results. The U.S. Preventive Services Task Force is in the process of updating its guidelines. In 2015, the American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology published interim guidance for the use of primary HPV testing.

Intermuscular coherence in amyotrophic lateral sclerosis: A preliminary assessment.

INTRODUCTION: Simple laboratory tests of upper motor neuron involvement in amyotrophic lateral sclerosis (ALS) are not available. Intermuscular coherence has been shown to distinguish patients with primary lateral sclerosis, a pure upper motor neuron disorder, from normal subjects, suggesting it could be useful for assessing ALS. We aimed to determine whether intermuscular coherence can distinguish ALS patients from normal subjects. METHODS: We measured biceps brachii and brachioradialis activity using surface electromyography while subjects held the elbow at flexion and the forearm in semipronation. Intermuscular coherence was calculated at between 20 and 40 Hz in 15 ALS patients and 15 normal subjects. RESULTS: On average, intermuscular coherence was 3.8-fold greater in normal subjects than in ALS patients (P < 0.01), and it distinguished ALS patients from normal subjects with a sensitivity of 87% and specificity of 87%. CONCLUSION: Intermuscular coherence measurement is a rapid, painless method that may detect upper motor neuron dysfunction in ALS. Muscle Nerve 55: 862-868, 2017.

Infancy and pediatric cancer: an exploratory study of parent psychological distress.

BACKGROUND: Research on the psychological experiences of parents of infants within pediatric oncology is sparse. This study examined rates and indicative risk factors for psychological distress in parents where there is either an infant patient or infant sibling of a patient. METHODS: Participants were mothers (n = 41) and fathers (n = 25) of infants under 2 years who either had a cancer diagnosis (n = 37; infant patients) or was an infant sibling of an older child with cancer (n = 29; infant siblings) recruited from a single oncology center. There were 21 couple dyads. Parents completed the Depression Anxiety Stress Scales short form and the Posttraumatic Stress Disorder Checklist. RESULTS: Mothers (47.5%) and fathers (37.5%) reported elevated, cancer-related posttraumatic stress symptoms. Rates of depression (12.2% of mothers and 12.0% of fathers) and anxiety symptoms (17.1% of mothers and 8.0% of fathers) were lower. Compared with parents of infant patients, parents of infant siblings reported significantly higher rates of depressive symptoms and trends toward higher rates of posttraumatic stress symptoms and anxiety symptoms. Parent anxiety was higher with increased time post diagnosis. No demographic or illness-related variables were associated with psychological distress, with the exception of the number of children in the family. CONCLUSIONS: Parent-child relationships are of fundamental importance during infancy. This study provides novel data highlighting the psychological impact for parents when a cancer diagnosis is made during this critical developmental period, including the contribution of family structure to parental distress. Results provide further support for applying a traumatic stress framework when exploring parent experiences of pediatric cancer. Copyright © 2016 John Wiley & Sons, Ltd.

Association of sleep with sudden unexpected death in epilepsy.

OBJECTIVE: The objective of this study was to determine the association of sleep with sudden unexpected death in epilepsy (SUDEP). METHODS: We conducted a systematic review and meta-analysis based on literature search from databases PubMed, Web of Science, and Scopus using keywords "SUDEP", or "sudden unexpected death in epilepsy", or "sudden unexplained death in epilepsy". Sudden unexpected death in epilepsy was considered to occur during sleep if the patient was found in bed, if the SUDEP cases were documented as in sleep, or if the patient was found at bedside on the bedroom floor. RESULTS: Circadian pattern was documented in 880 of the 1025 SUDEP cases in 67 studies meeting the inclusion and exclusion criteria. Of the 880 SUDEP cases, 69.3% occurred during sleep and 30.7% occurred during wakefulness. Sudden unexpected death in epilepsy was significantly associated with sleep as compared to wakefulness (P<0.001). In the subgroup of 272 cases in which circadian pattern and age were documented, patients 40years old or younger were more likely to die in sleep than those older than 40years (OR: 2.0; 95% CI=1.0, 3.8; P=0.05). In the subgroup of 114 cases in which both circadian pattern and body position at the time of death were documented, 87.6% (95% CI=81.1%, 94.2%) of patients who died during sleep were in the prone position, whereas 52.9% (95% CI=24.7%, 81.1%) of patients who died during wakefulness were in the prone position. Patients with nocturnal seizures were 6.3 times more likely to die in a prone position than those with diurnal seizures (OR: 6.3; 95% CI=2.0, 19.5; P=0.002). CONCLUSIONS: There is a strong association of SUDEP with sleep, suggesting that sleep is a significant risk factor for SUDEP. Although the risks of SUDEP associated with sleep are unknown and likely multifactorial, the prone position might be an important contributory factor.

Forests, fields, and the edge of sustainability at the ancient Maya city of Tikal.

Tikal has long been viewed as one of the leading polities of the ancient Maya realm, yet how the city was able to maintain its substantial population in the midst of a tropical forest environment has been a topic of unresolved debate among researchers for decades. We present ecological, paleoethnobotanical, hydraulic, remote sensing, edaphic, and isotopic evidence that reveals how the Late Classic Maya at Tikal practiced intensive forms of agriculture (including irrigation, terrace construction, arboriculture, household gardens, and short fallow swidden) coupled with carefully controlled agroforestry and a complex system of water retention and redistribution. Empirical evidence is presented to demonstrate that this assiduously managed anthropogenic ecosystem of the Classic period Maya was a landscape optimized in a way that provided sustenance to a relatively large population in a preindustrial, low-density urban community. This landscape productivity optimization, however, came with a heavy cost of reduced environmental resiliency and a complete reliance on consistent annual rainfall. Recent speleothem data collected from regional caves showed that persistent episodes of unusually low rainfall were prevalent in the mid-9th century A.D., a time period that coincides strikingly with the abandonment of Tikal and the erection of its last dated monument in A.D. 869. The intensified resource management strategy used at Tikal-already operating at the landscape's carrying capacity-ceased to provide adequate food, fuel, and drinking water for the Late Classic populace in the face of extended periods of drought. As a result, social disorder and abandonment ensued.

Shiga Toxins Activate the NLRP3 Inflammasome Pathway To Promote Both Production of the Proinflammatory Cytokine Interleukin-1ß and Apoptotic Cell Death.

Shiga toxin (Stx)-mediated immune responses, including the production of the proinflammatory cytokines tumor necrosis-α (TNF-α) and interleukin-1ß (IL-1ß), may exacerbate vascular damage and accelerate lethality. However, the immune signaling pathway activated in response to Stx is not well understood. Here, we demonstrate that enzymatically active Stx, which leads to ribotoxic stress, triggers NLRP3 inflammasome-dependent caspase-1 activation and IL-1ß secretion in differentiated macrophage-like THP-1 (D-THP-1) cells. The treatment of cells with a chemical inhibitor of glycosphingolipid biosynthesis, which suppresses the expression of the Stx receptor globotriaosylceramide and subsequent endocytosis of the toxin, substantially blocked activation of the NLRP3 inflammasome and processing of caspase-1 and IL-1ß. Processing and release of both caspase-1 and IL-1ß were significantly reduced or abolished in Stx-intoxicated D-THP-1 cells in which the expression of NLRP3 or ASC was stably knocked down. Furthermore, Stx mediated the activation of caspases involved in apoptosis in an NLRP3- or ASC-dependent manner. In Stx-intoxicated cells, the NLRP3 inflammasome triggered the activation of caspase-8/3, leading to the initiation of apoptosis, in addition to caspase-1-dependent pyroptotic cell death. Taken together, these results suggest that Stxs trigger the NLRP3 inflammasome pathway to release proinflammatory IL-1ß as well as to promote apoptotic cell death.

Comorbidities associated with HIV and antiretroviral therapy (clinical sciences): a workshop report.

In the era of combination antiretroviral therapy (ART), parsing out the effects of HIV vs ART on health outcomes is challenging. Nadir CD4 count, a marker of the extent of immunosuppression, has significant long-term impact on an array of disease states in HIV+ persons; however, in the dental literature, reporting of pre-ART exposure to immunosuppression has largely been ignored and this limits the validity of previous studies. In Workshop A1, we explain fully the importance of nadir CD4, pre-ART immunosuppression, and identify a need to include specific variables in future research. The questions posed herein are challenging, typically not neatly addressed by any one study and require integration of the latest evidence from the wider medical literature. We consider topics beyond the confines of the oral cavity and examine oral health in the complex context of ART era HIV immunopathophysiology. We depict how variability in geographic setting and time period (pre- and post-ART era) can impact oral conditions - influencing when HIV infection was detected (at what CD4 count), the type and timing of ART as well as social determinants such as strong stigma and limited access to care. We hope our Workshop will stir debate and energize a rigorous focus on relevant areas of future research in HIV/AIDS.