Geometrical frustration versus Kitaev interactions in BaCo2(AsO4)2.

Recently, Co-based honeycomb magnets have been proposed as promising candidate materials to host the Kitaev spin liquid (KSL) state. One of the front-runners is BaCo2(AsO4)2 (BCAO), where it was suggested that the exchange processes between Co2+ ions via the surrounding edge-sharing oxygen octahedra could give rise to bond-dependent Kitaev interactions. In this work, we present and analyze a comprehensive inelastic neutron scattering (INS) study of BCAO with fields in the honeycomb plane. Combining the constraints from the magnon excitations in the high-field polarized state and the inelastic spin structure factor measured in zero magnetic field, we examine two leading theoretical models: the Kitaev-type [Formula: see text] model and the XXZ[Formula: see text]model. We show that the existing experimental data can be consistently accounted for by the XXZ[Formula: see text]model but not by the [Formula: see text] model, and we discuss the implications of these results for the realization of a spin liquid phase in BCAO and more generally for the realization of the Kitaev model in cobaltates.

Role of STIM1 in stretch-induced signaling in human airway smooth muscle.

Alteration in the normal mechanical forces of breathing can contribute to changes in contractility and remodeling characteristic of airway diseases, but the mechanisms that mediate these effects in airway cells are still under investigation. Airway smooth muscle (ASM) cells contribute to both contractility and extracellular matrix (ECM) remodeling. In this study, we explored ASM mechanisms activated by mechanical stretch, focusing on mechanosensitive piezo channels and the key Ca2+ regulatory protein stromal interaction molecule 1 (STIM1). Expression of Ca2+ regulatory proteins, including STIM1, Orai1, and caveolin-1, mechanosensitive ion channels Piezo-1 and Piezo-2, and NLRP3 inflammasomes were upregulated by 10% static stretch superimposed on 5% cyclic stretch. These effects were blunted by STIM1 siRNA. Histamine-induced [Ca2+]i responses and inflammasome activation were similarly blunted by STIM1 knockdown. These data show that the effects of mechanical stretch in human ASM cells are mediated through STIM1, which activates multiple pathways, including Piezo channels and the inflammasome, leading to potential downstream changes in contractility and ECM remodeling.NEW & NOTEWORTHY Mechanical forces on the airway can contribute to altered contractility and remodeling in airway diseases, but the mechanisms are not clearly understood. Using human airway smooth muscle cells exposed to cyclic forces with static stretch to mimic breathing and static pressure, we found that the effects of stretch are mediated through STIM1, resulting in the activation of multiple pathways, including Piezo channels and the inflammasome, with potential downstream influences on contractility and remodeling.

Piezo channels modulate human lung fibroblast function.

Bronchial airways and lung parenchyma undergo both static and dynamic stretch in response to normal breathing as well as in the context of insults such as mechanical ventilation (MV) or in diseases such as asthma and chronic obstructive pulmonary disease (COPD) which lead to airway remodeling involving increased extracellular matrix (ECM) production. Here, the role of fibroblasts is critical, but the relationship between stretch- and fibroblast-induced ECM remodeling under these conditions is not well-explored. Piezo (PZ) channels play a role in mechanotransduction in many cell and organ systems, but their role in mechanical stretch-induced airway remodeling is not known. To explore this, we exposed human lung fibroblasts to 10% static stretch on a background of 5% oscillations for 48 h, with no static stretch considered controls. Collagen I, fibronectin, alpha-smooth muscle actin (α-SMA), and Piezo 1 (PZ1) expression was determined in the presence or absence of Yoda1 (PZ1 agonist) or GsMTx4 (PZ1 inhibitor). Collagen I, fibronectin, and α-SMA expression was increased by stretch and Yoda1, whereas pretreatment with GsMTx4 or knockdown of PZ1 by siRNA blunted this effect. Acute stretch in the presence and absence of Yoda1 demonstrated activation of the ERK pathway but not Smad. Measurement of [Ca2+]i responses to histamine showed significantly greater responses following stretch, effects that were blunted by knockdown of PZ1. Our findings identify an essential role for PZ1 in mechanical stretch-induced production of ECM mediated by ERK phosphorylation and Ca2+ influx in lung fibroblasts. Targeting PZ channels in fibroblasts may constitute a novel approach to ameliorate airway remodeling by decreasing ECM deposition.NEW & NOTEWORTHY The lung is an inherently mechanosensitive organ that can respond to mechanical forces in adaptive or maladaptive ways, including via remodeling resulting in increased fibrosis. We explored the mechanisms that link mechanical forces to remodeling using human lung fibroblasts. We found that mechanosensitive Piezo channels increase with stretch and mediate extracellular matrix formation and the fibroblast-to-myofibroblast transition that occurs with stretch. Our data highlight the importance of Piezo channels in lung mechanotransduction toward remodeling.

Detecting adolescent depression through passive monitoring of linguistic markers in smartphone communication.

BACKGROUND: Cross sectional studies have identified linguistic correlates of major depressive disorder (MDD) in smartphone communication. However, it is unclear whether monitoring these linguistic characteristics can detect when an individual is experiencing MDD, which would facilitate timely intervention. METHODS: Approximately 1.2 million messages typed into smartphone social communication apps (e.g. texting, social media) were passively collected from 90 adolescents with a range of depression severity over a 12-month period. Sentiment (i.e. positive vs. negative valence of text), proportions of first-person singular pronouns (e.g. 'I'), and proportions of absolutist words (e.g. 'all') were computed for each message and converted to weekly aggregates temporally aligned with weekly MDD statuses obtained from retrospective interviews. Idiographic, multilevel logistic regression models tested whether within-person deviations in these linguistic features were associated with the probability of concurrently meeting threshold for MDD. RESULTS: Using more first-person singular pronouns in smartphone communication relative to one's own average was associated with higher odds of meeting threshold for MDD in the concurrent week (OR = 1.29; p = .007). Sentiment (OR = 1.07; p = .54) and use of absolutist words (OR = 0.99; p = .90) were not related to weekly MDD. CONCLUSIONS: Passively monitoring use of first-person singular pronouns in adolescents' smartphone communication may help detect MDD, providing novel opportunities for early intervention.

Neurophysiological responses to emotional faces predict dynamic fluctuations in affect in adolescents.

The ability to accurately identify and interpret others' emotions is critical for social and emotional functioning during adolescence. Indeed, previous research has identified that laboratory-based indices of facial emotion recognition and engagement with emotional faces predict adolescent mood states. Whether socioemotional information processing relates to real-world affective dynamics using an ecologically sensitive approach, however, has rarely been assessed. In the present study, adolescents (N = 62; ages 13-18) completed a Facial Recognition Task, including happy, angry, and sad stimuli, while EEG data were acquired. Participants also provided ecological momentary assessment (EMA) data probing their current level of happiness, anger, and sadness for 1-week, resulting in indices of emotion (mean-level, inertia, instability). Analyses focused on relations between (1) accuracy for and (2) prolonged engagement with (LPP) emotional faces and EMA-reported emotions. Greater prolonged engagement with happy faces was related to less resistance to changes in happiness (i.e., less happiness inertia), whereas greater prolonged engagement with angry faces associated with more resistance to changes in anger (i.e., greater anger inertia). Results suggest that socioemotional processes captured by laboratory measures have real-world implications for adolescent affective states and highlight potentially actionable targets for novel treatment approaches (e.g., just-in-time interventions). Future studies should continue to assess relations among socioemotional informational processes and dynamic fluctuations in adolescent affective states.

Artificial Intelligence and Virtual Reality in Headache Disorder Diagnosis, Classification, and Management.

PURPOSE OF REVIEW: This review provides an overview of the current and future role of artificial intelligence (AI) and virtual reality (VR) in addressing the complexities inherent to the diagnosis, classification, and management of headache disorders. RECENT FINDINGS: Through machine learning and natural language processing approaches, AI offers unprecedented opportunities to identify patterns within complex and voluminous datasets, including brain imaging data. This technology has demonstrated promise in optimizing diagnostic approaches to headache disorders and automating their classification, an attribute particularly beneficial for non-specialist providers. Furthermore, AI can enhance headache disorder management by enabling the forecasting of acute events of interest, such as migraine headaches or medication overuse, and by guiding treatment selection based on insights from predictive modeling. Additionally, AI may facilitate the streamlining of treatment efficacy monitoring and enable the automation of real-time treatment parameter adjustments. VR technology, on the other hand, offers controllable and immersive experiences, thus providing a unique avenue for the investigation of the sensory-perceptual symptomatology associated with certain headache disorders. Moreover, recent studies suggest that VR, combined with biofeedback, may serve as a viable adjunct to conventional treatment. Addressing challenges to the widespread adoption of AI and VR in headache medicine, including reimbursement policies and data privacy concerns, mandates collaborative efforts from stakeholders to enable the equitable, safe, and effective utilization of these technologies in advancing headache disorder care. This review highlights the potential of AI and VR to support precise diagnostics, automate classification, and enhance management strategies for headache disorders.

Diabetic Neuropathy: A Guide to Pain Management.

PURPOSE OF REVIEW: Diabetic neuropathy is a common complication of diabetes mellitus (DM) and can affect up to 50% of DM patients during their lifetime. Patients typically present with numbness, tingling, pain, and loss of sensation in the extremities. Since there is no treatment targeting the underlying mechanism of neuropathy, strategies focus on preventative care and pain management. RECENT FINDINGS: Up to 69% of patients with diabetic neuropathy receive pharmacological treatment for neuropathic pain. The United States Food and Drug Administration (FDA) confirmed four drugs for painful diabetic neuropathy (PDN): pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch. Nonpharmacological treatments such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS) both show promise in reducing pain in DM patients. Despite the high burden associated with PDN, effective management remains challenging. This update covers the background and management of diabetic neuropathy, including its epidemiology, pathogenesis, preventative care, and current therapeutic strategies.

Removal of the Metaphyseal Screw From Tension Band Constructs After Hemiepiphysiodesis: High Rates of Physeal Tethering and Subsequent Implant Removal.

BACKGROUND: Removal of the metaphyseal screw from tension band plate constructs after correction of angular deformity in patients treated with hemiepiphysiodesis has been suggested as an alternative to removing the plate and both screws. While this has the potential benefit of easier implant removal and reinsertion in the event of rebound, there is debate in the literature regarding the benefits and risks of leaving the epiphyseal screw and plate in place. METHODS: Patients treated with hemiepiphysiodesis at the distal femur and/or proximal tibia with tension band plates and screws who underwent subsequent removal of the metaphyseal screw after correction were included. Charts and radiographs were reviewed for the need for metaphyseal screw reinsertion, subsequent removal of deep implants, and evidence of physeal tethering. Tethering was defined as progressive overcorrection in the treated bone segment after removal of the metaphyseal screw with the mechanical axis moving one full mechanical axis zone or more. Patients with tethering were compared with those without. RESULTS: A total of 215 patients with 387 limbs treated met inclusion criteria. Of those, 175 patients were treated for idiopathic genu valgum, while 40 were treated for other conditions. Fifty-nine individuals (27%) underwent replacement of the metaphyseal screw for repeat angular correction. Fifty-one percent of patients underwent secondary procedures for reasons other than metaphyseal screw reinsertion (74 symptomatic implant removal, 7 elective implant removal, 29 due to tethering). There were 44 cases of tethering in 36 patients (17%). In cases of tethering, 7 patients were treated with observation, 11 with implant removal only, 16 with hemiepiphysiodesis on the opposite side, and 2 with osteotomy. Patients with tethering were significantly younger, more likely to be male, and more likely to have had the metaphyseal screw removed more than once (P < 0.05). CONCLUSION: Removal of only the metaphyseal screw after hemiepiphysiodesis has high rates of tethering and further surgery for iatrogenic deformity correction and implant removal. This technique is not recommended. LEVEL OF EVIDENCE: Therapeutic Level III, case-control study.

Screw Diameter and Use of a Washer Affect Symptomatic Implant Removal Rates in Pediatric Medial Epicondyle Fractures.

OBJECTIVE: Medial epicondyle fractures are a common pediatric injury. When operative, cannulated partially threaded screws, with or without a washer, are commonly utilized. These implants may need to be removed after full healing if symptomatic. There is mixed evidence regarding the influence of a washer on rates of implant removal, and the influence of screw size has not been studied. We aim to determine the rate of symptomatic deep implant removal for each fixation type and identify factors associated with the need for removal. METHODS: This was an IRB-reviewed, retrospective, case-cohort study. Patients treated at our institution between January 1, 2004 and December 31, 2019, age 18 years old or younger, with a medial epicondyle fracture managed operatively with 4.0 or 4.5 mm cannulated screws with or without washers were included. Patients with multiple operative ipsilateral elbow fractures and those who underwent implant removal for reasons other than pain or irritation were excluded. Removal rates were compared between screw sizes (4.0 vs 4.5 mm), as well as with and without a washer using a Cox proportional hazards model. RESULTS: In total, 151 patients met the inclusion criteria, 54 with symptomatic hardware removed and 97 without symptomatic hardware removed. A significantly higher number of patients treated with 4.5 mm screws compared with 4.0 mm screws underwent removal of symptomatic deep implants (50% vs 30%, P = 0.033). In a multivariable Cox regression model adjusting for age and ulnar nerve status, when no washer was used, the hazard ratio (HR) for symptomatic hardware removal for 4.5 mm screws was 2.92 times the HR for 4.0 mm screws (95% CI: 1.35-6.29). When a 4.0 mm screw was used, the HR for symptomatic hardware removal for a washer was 3.24 times the HR without a washer (95% CI: 1.53-6.84). CONCLUSION: Implant removal rates are influenced by screw size and the use of a washer. These results may help guide implant choice and counsel families regarding the rate of symptomatic implant removal. LEVEL OF EVIDENCE: Level III-therapeutic level, case-control study.

Piezo channels in stretch effects on developing human airway smooth muscle.

The use of respiratory support strategies such as continuous positive airway pressure in premature infants can substantially stretch highly compliant perinatal airways, leading to airway hyperreactivity and remodeling in the long term. The mechanisms by which stretch detrimentally affects the airway are unknown. Airway smooth muscle cells play a critical role in contractility and remodeling. Using 18-22-wk gestation human fetal airway smooth muscle (fASM) as an in vitro model, we tested the hypothesis that mechanosensitive Piezo (PZ) channels contribute to stretch effects. We found that PZ1 and PZ2 channels are expressed in the smooth muscle of developing airways and that their expression is influenced by stretch. PZ activation via agonist Yoda1 or stretch results in significant [Ca2+]i responses as well as increased extracellular matrix production. These data suggest that functional PZ channels may play a role in detrimental stretch-induced airway changes in the context of prematurity.NEW & NOTEWORTHY Piezo channels were first described just over a decade ago and their function in the lung is largely unknown. We found that piezo channels are present and functional in the developing airway and contribute to intracellular calcium responses and extracellular matrix remodeling in the setting of stretch. This may improve our understanding of the mechanisms behind development of chronic airway diseases, such as asthma, in former preterm infants exposed to respiratory support, such as continuous positive airway pressure (CPAP).

Functional α7 nicotinic receptors in human airway smooth muscle increase intracellular calcium concentration and contractility in asthmatics.

Although nicotinic acetylcholine receptors (nAChRs) are commonly associated with neurons in the brain and periphery, recent data indicate that they are also expressed in non-neuronal tissues. We recently found the alpha7 (α7nAChR) subunit is highly expressed in human airway smooth muscle (hASM) with substantial increase in asthmatics, but their functionality remains unknown. We investigated the location and functional role of α7nAChRs in hASM cells from normal versus mild-moderate asthmatic patients. Immunostaining and protein analyses showed α7nAChR in the plasma membrane including in asthmatics. In asthmatic hASM, patch-clamp recordings revealed significantly higher functional homomeric α7nAChR channels. Real-time fluorescence imaging showed nicotine, via α7nAChR, increases intracellular Ca2+ ([Ca2+]i) independent of ACh effects, particularly in asthmatic hASM, while cellular traction force microscopy showed nicotine-induced contractility including in asthmatics. These results indicate functional homomeric and heteromeric nAChRs that are increased in asthmatic hASM, with pharmacology that likely differ owing to different subunit interfaces that form the orthosteric sites. nAChRs may represent a novel target in alleviating airway hyperresponsiveness in asthma.NEW & NOTEWORTHY Cigarette smoking and vaping exacerbate asthma. Understanding the mechanisms of nicotine effects in asthmatic airways is important. This study demonstrates that functional alpha7 nicotinic acetylcholine receptors (α7nAChRs) are expressed in human airway smooth muscle, including from asthmatics, and enhance intracellular calcium and contractility. Although a7nAChRs are associated with neuronal pathways, α7nAChR in smooth muscle suggests inhaled nicotine (e.g., vaping) can directly influence airway contractility. Targeting α7nAChR may represent a novel approach to alleviating airway hyperresponsiveness in asthma.

Utilization of carbonated calcium phosphate cement for contouring cranioplasty in patients with syndromic craniosynostosis.

PURPOSE: Carbonated calcium phosphate (CCP) cement is an alloplastic material which has been increasingly utilized for cranioplasty reconstruction; however, there is a paucity of data investigating its use in patients with syndromic craniosynostosis. The purpose of this study was to characterize our institutional experience with CCP cement for secondary contouring cranioplasty in these patients to establish safety and aesthetic efficacy. METHODS: Patients with syndromic craniosynostosis undergoing cranioplasty with CCP cement from 2009 to 2022 were retrospectively reviewed for prior medical and surgical history, cranioplasty size, cement usage, and postoperative complications. Aesthetic ratings of the forehead region were quantified using the Whitaker scoring system at three timepoints: preoperative (T1), < 6 months postoperative (T2), and > 1 year postoperative (T3). RESULTS: Twenty-one patients were included. Age at surgery was 16.2 ± 2.8 years, forehead cranioplasty area was 135 ± 112 cm2, and mass of cement was 17.2 ± 7.8 g. Patients were followed for 3.0 ± 3.1 years. Whitaker scores decreased from 1.9 ± 0.4 at T1 to 1.4 ± 0.5 at T2 (p = 0.005). Whitaker scores at T2 and T3 were not significantly different (p = 0.720). Two infectious complications (9.5%) were noted, one at 4.5 months postoperatively and the other at 23 months, both requiring operative removal of CCP cement. CONCLUSION: Our results suggest that aesthetic forehead ratings improve after CCP contouring cranioplasty and that the improvement is sustained in medium-term follow-up. Complications were uncommon, suggesting that CCP is relatively safe though longer-term follow-up is needed before reaching definitive conclusions.

Functional neuroanatomy of craving in heroin use disorder: voxel-based meta-analysis of functional magnetic resonance imaging (fMRI) drug cue reactivity studies.

Background: The neuroanatomy of craving, typically investigated using the functional magnetic resonance imaging (fMRI) drug cue reactivity (FDCR) paradigm, has been shown to involve the mesocorticolimbic, nigrostriatal, and corticocerebellar systems in several substances. However, the neuroanatomy of craving in heroin use disorder is still unclear.Objective: The current meta-analysis examines previous research on the neuroanatomy of craving in abstinent individuals with opioid use disorder (OUD).Method: Seven databases were searched for studies comparing abstinent OUD versus healthy controls on drug > neutral contrast interaction at the whole-brain level. Voxel-based meta-analysis was performed using seed-based d mapping with permuted subject images (SDM-PSI). Thresholds were set at a family-wise error rate of less than 5% with the default pre-processing parameters of SDM-PSI.Results: A total of 10 studies were included (296 OUD and 187 controls). Four hyperactivated clusters were identified with Hedges' g of peaks that ranged from 0.51 to 0.82. These peaks and their associated clusters correspond to the three systems identified in the previous literature: a) mesocorticolimbic, b) nigrostriatal, and c) corticocerebellar. There were also newly revealed hyperactivation regions including the bilateral cingulate, precuneus, fusiform gyrus, pons, lingual gyrus, and inferior occipital gyrus. The meta-analysis did not reveal areas of hypoactivation.Conclusion: Recommendations based on the functional neuroanatomical findings of this meta-analysis include pharmacological interventions such as buprenorphine/naloxone and cognitive-behavioral treatments such as cue-exposure combined with HRV biofeedback. In addition, research should utilize FDCR as pre- and post-measurement to determine the effectiveness and mechanism of action of such interventions.

Hemiepiphysiodesis for Lower Extremity Coronal Plane Angular Correction in the Distal Femur and Proximal Tibia in Children With Achondroplasia.

BACKGROUND: Achondroplasia is the most prevalent form of skeletal dysplasia, affecting more than 250,000 individuals. Lower extremity angular deformities, particularly genu varum, are common in children with achondroplasia, often resulting in pain and limitation of function. The authors aim to determine the utility of lower extremity growth modulation with hemiepiphysiodesis in children with achondroplasia for correction of coronal plane deformities about the knee. METHODS: The authors performed a retrospective chart review of a single center from 1/1/2000 to 12/31/2020 to identify pediatric patients with achondroplasia treated with hemiepiphysiodesis as their initial procedure at the distal femur and/or proximal tibia. Patients with adequate records and who had completed their treatment were included. Data collected included duration of treatment, complications, need for osteotomy, and radiographic measurements including initial and final mechanical axis deviation, knee mechanical axis zone, mechanical lateral distal femoral angle and medial proximal tibia angle. RESULTS: Ten patients with 17 limbs met our criteria. Nine patients (15 limbs) were treated for genu varum and 1 patient (2 limbs) was treated for genu valgum. Prior to treatment, the mechanical axis fell in zone 3 in 59% of limbs and zone 2 in 41%. Average correction in mechanical axis deviation was 26.1 mm. Average change in mechanical lateral distal femoral angle was 10.3 degrees per limb, and average change in medial proximal tibia angle was 7.1 degrees per limb. Average treatment duration was 909 days. At final follow up, 81% (14/17) of limbs had the mechanical axis in zone 1, with the remaining 18% (3/17) in zone 2. No patient/limb underwent subsequent distal femur or proximal tibia osteotomy for coronal plane alignment. CONCLUSIONS: Children with achondroplasia can successfully be treated with hemiepiphysiodesis to correct coronal plane deformities at the distal femur and proximal tibia. Using this technique, no patient in our series required an osteotomy for genu varum/valgum. LEVEL OF EVIDENCE: Therapeutic level IV, Case series.

Patient and Clinician Satisfaction with the Early Implementation of Telemental Health Services in an Urban Behavioral Health Clinic During the COVID-19 Pandemic.

Objective: The COVID-19 pandemic served as an impetus for the rapid expansion of telehealth. In this study, we examined the experience of rapid transition to telemental health (TMH) within The Family Health Centers at NYU Langone, a large, urban, Federally Qualified Health Center, in the 3 months after the onset of the COVID-19 pandemic. Methods: We administered surveys to clinicians and patients who utilized TMH between March 16, 2020 and July 16, 2020. Patients were sent a web-based survey via email or received a phone survey (for those without email) with four languages choices: English, Spanish, Traditional Chinese, or Simplified Chinese. Results: The majority (79%) of clinicians (n = 83) rated the experience of TMH as "excellent" or "good," and felt that they could establish and maintain the patient relationship through TMH. Four thousand seven hundred seventy-two survey invitations were sent out to patients, and 654 (13.7%) responded. Ninety percent reported that they were satisfied with the service they received and rated TMH as better or the same as in-person care (81.6%) with a high mean satisfaction score (4.5 out of 5). Patients were more likely to rate TMH as better or the same as in-person care relative to the clinicians. Conclusions: These results are consistent with several recent studies that have explored patient satisfaction with TMH during the COVID-19 pandemic and demonstrate that both clinicians and patients experienced a high degree of satisfaction with mental health care delivered virtually compared with face-to-face encounters.

HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis.

BACKGROUND & AIMS: There is controversy regarding the overall value of hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis given the lack of data from randomized-controlled trials. To address this issue, we conducted a systematic review and meta-analysis of cohort studies evaluating the benefits and harms of HCC surveillance in patients with cirrhosis. METHODS: We performed a search of the Medline and EMBASE databases and national meeting abstracts from January 2014 through July 2020 for studies reporting early-stage HCC detection, curative treatment receipt, or overall survival, stratified by HCC surveillance status, among patients with cirrhosis. Pooled risk ratios (RRs) and hazard ratios, according to HCC surveillance status, were calculated for each outcome using the DerSimonian and Laird method for random effects models. RESULTS: We identified 59 studies including 145,396 patients with HCC, which was detected by surveillance in 41,052 (28.2%) cases. HCC surveillance was associated with improved early-stage detection (RR 1.86, 95% CI 1.73-1.98; I2 = 82%), curative treatment receipt (RR 1.83, 95% CI 1.69-1.97; I2 = 75%), and overall survival (hazard ratio 0.67, 95% CI 0.61-0.72; I2 = 78%) after adjusting for lead-time bias; however, there was notable heterogeneity in all pooled estimates. Four studies examined surveillance-related physical harms due to false positive or indeterminate surveillance results, but no studies examined potential financial or psychological harms. The proportion of patients experiencing surveillance-related physical harms ranged from 8.8% to 27.5% across studies, although most harms were mild in severity. CONCLUSION: HCC surveillance is associated with improved early detection, curative treatment receipt, and survival in patients with cirrhosis, although there was heterogeneity in pooled estimates. Available data suggest HCC surveillance is of high value in patients with cirrhosis, although continued rigorous studies evaluating benefits and harms are still needed. LAY SUMMARY: There has been ongoing debate about the overall value of hepatocellular carcinoma (HCC) screening in patients with cirrhosis given the lack of data from randomized-controlled trials. In a systematic review of contemporary cohort studies, we found that HCC screening is associated with improved early detection, curative treatment receipt, and survival in patients with cirrhosis, although there were fewer data quantifying potential screening-related harms. Available data suggest HCC screening is of high value in patients with cirrhosis, although continued studies evaluating benefits and harms are still needed.

Uncovering Footprints of Dipolar-Octupolar Quantum Spin Ice from Neutron Scattering Signatures.

Recent experiments on Ce_{2}Zr_{2}O_{7} suggest that this material may host a novel form of quantum spin ice, a three-dimensional quantum spin liquid with an emergent photon. The Ce^{3+} local moments on the pyrochlore lattice are described by pseudospin-1/2 degrees of freedom, whose components transform as dipolar and octupolar moments under symmetry operations. In principle, there exist four possible quantum spin ice regimes, depending on whether the Ising component is in the dipolar or octupolar channel, and two possible flux configurations of the emergent gauge field. In this Letter, using exact diagonalization and molecular dynamics, we investigate the equal-time and dynamical spin structure factors in all four quantum spin ice regimes using quantum and classical calculations. Contrasting the distinct signatures of quantum and classical results for the four possible quantum spin ice regimes and elucidating the role of quantum fluctuations, we show that the quantum structure factor computed for the π-flux octupolar quantum spin ice regime is most compatible with the neutron scattering results on Ce_{2}Zr_{2}O_{7}.

PS1 FAD mutants decrease ephrinB2-regulated angiogenic functions, ischemia-induced brain neovascularization and neuronal survival.

Microvascular pathology and ischemic lesions contribute substantially to neuronal dysfunction and loss that lead to Alzheimer disease (AD). To facilitate recovery, the brain stimulates neovascularization of damaged tissue via sprouting angiogenesis, a process regulated by endothelial cell (EC) sprouting and the EphB4/ephrinB2 system. Here, we show that in cultures of brain ECs, EphB4 stimulates the VE-cadherin/Rok-α angiogenic complexes known to mediate sprouting angiogenesis. Importantly, brain EC cultures expressing PS1 FAD mutants decrease the EphB4-stimulated γ-secretase cleavage of ephrinB2 and reduce production of the angiogenic peptide ephrinB2/CTF2, the VE-cadherin angiogenic complexes and EC sprouting and tube formation. These data suggest that FAD mutants may attenuate ischemia-induced brain angiogenesis. Supporting this hypothesis, ischemia-induced VE-cadherin angiogenic complexes, levels of neoangiogenesis marker Endoglin, vascular density, and cerebral blood flow recovery, are all decreased in brains of mouse models expressing PS1 FAD mutants. Ischemia-induced brain neuronal death and cognitive deficits also increase in these mice. Furthermore, a small peptide comprising the C-terminal sequence of peptide ephrinB2/CTF2 rescues angiogenic functions of brain ECs expressing PS1 FAD mutants. Together, our data show that PS1 FAD mutations impede the EphB4/ephrinB2-mediated angiogenic functions of ECs and impair brain neovascularization, neuronal survival and cognitive recovery following ischemia. Furthermore, our data reveal a novel brain angiogenic mechanism targeted by PS1 FAD mutants and a potential therapeutic target for ischemia-induced neurodegeneration. Importantly, FAD mutant effects occur in absence of neuropathological hallmarks of AD, supporting that such hallmarks may form downstream of mutant effects on neoangiogenesis and neuronal survival.

Probing growth of metal-organic frameworks with X-ray scattering and vibrational spectroscopy.

Nucleation and crystallization arising from liquid to solid phase are involved in a multitude of processes in fields ranging from materials science to biology. Controlling the thermodynamics and kinetics of growth is advantageous to help tune the formation of complex morphologies. Here, we harness wide-angle X-ray scattering and vibrational spectroscopy to elucidate the mechanism for crystallization and growth of the metal-organic framework Co-MOF-74 within microscopic volumes enclosed in a capillary and an attenuated total reflection microchip reactor. The experiments reveal molecular and structural details of the growth processes, while the results of plane wave density functional calculations allow identification of lattice and linker modes in the formed crystals. Synthesis of the metal-organic framework with microscopic volumes leads to monodisperse and micron-sized crystals, in contrast to those typically observed under bulk reaction conditions. Reduction in the volume of reagents within the microchip reactor was found to accelerate the reaction rate. The coupling of spectroscopy with scattering to probe reactions in microscopic volumes promises to be a useful tool in the synthetic chemist's kit to understand chemical bonding and has potential in designing complex materials.

Clonal Vγ6+Vδ4+ T cells promote IL-17-mediated immunity against Staphylococcus aureus skin infection.

T cell cytokines contribute to immunity against Staphylococcus aureus, but the predominant T cell subsets involved are unclear. In an S. aureus skin infection mouse model, we found that the IL-17 response was mediated by γδ T cells, which trafficked from lymph nodes to the infected skin to induce neutrophil recruitment, proinflammatory cytokines IL-1α, IL-1ß, and TNF, and host defense peptides. RNA-seq for TRG and TRD sequences in lymph nodes and skin revealed a single clonotypic expansion of the encoded complementarity-determining region 3 amino acid sequence, which could be generated by canonical nucleotide sequences of TRGV5 or TRGV6 and TRDV4 However, only TRGV6 and TRDV4 but not TRGV5 sequences expanded. Finally, Vγ6+ T cells were a predominant γδ T cell subset that produced IL-17A as well as IL-22, TNF, and IFNγ, indicating a broad and substantial role for clonal Vγ6+Vδ4+ T cells in immunity against S. aureus skin infections.