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Abstract Background Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer’s disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy. Methods Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers. Results In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks. Conclusions These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD. Trial registration Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.clinicaltrials.gov/study/NCT03635047 .

IntroductionThe phenotypic expression of mental health (MH) conditions among people with HIV (PWH) in Uganda and worldwide are heterogeneous. Accordingly, there has been a shift toward identifying MH phenotypes using data-driven methods capable of identifying novel insights into mechanisms of divergent MH phenotypes among PWH. We leverage the analytic strengths of machine learning combined with inferential methods to identify novel MH phenotypes among PWH and the underlying explanatory features.MethodsA total of 277 PWH (46% female, median age = 44; 93% virally suppressed [ 33). Clusters 2 (n = 32; anxiety phenotype) and 3 (n = 130; mixed anxiety/depression phenotype) reported minimal PTSD symptoms, with modest BAI (Cluster 2) and PHQ-9 (Cluster 3) elevations. Cluster 4 (n = 39; minimal symptom phenotype) reported no clinical MH symptom elevations. Comparisons revealed higher rates of sexual abuse during childhood among the PTSD phenotype vs. the minimal symptom phenotype (p = 0.03).DiscussionWe identified unique MH phenotypes among PWH and confirmed the importance of early life adversity as an early risk determinant for unfavorable MH among PWH in adulthood.

Cognitive-experiential self-theory is a unique model for exploring restaurant patrons’ decision making. Fear and its impact on diners’ decision making, particularly related to specific dining contexts (dine-in, takeout, and delivery), are limited in their representation in the literature. The COVID-19 pandemic provided an instance where a single fear could be explored universally for dining patrons. This study explores how fear influences diners’ perception of risk, antipathy, and avoidance toward restaurant dining and how these factors impact their intention to dine in a restaurant. Furthermore, it investigates how those constructs influence diner decision making regarding the selection of one of the identified dining contexts. Online survey data (n = 1225) of diners were analyzed using SEM. The research finds that fear impacts dining contexts differentially. Additionally, environmental control is identified as a valuable tool in the mitigation of diners’ fear. The pandemic had devastating impacts on the restaurant industry, partly due to the lack of research into fear, particularly in dining contexts. This research helps to fill the important research gap through the findings and theoretical and managerial implications provided.

Abstract Background Heterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN. Methods In vitro characterization studies were first performed to assess the mechanism of action of latozinemab. After the in vitro studies, a series of in vivo studies were performed to assess the efficacy of a mouse-cross reactive anti-sortilin antibody and the pharmacokinetics, pharmacodynamics, and safety of latozinemab in nonhuman primates and humans. Results In a mouse model of FTD-GRN, the rodent cross-reactive anti-sortilin antibody, S15JG, decreased total sortilin levels in white blood cell (WBC) lysates, restored PGRN to normal levels in plasma, and rescued a behavioral deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in WBCs and concomitantly increased plasma and cerebrospinal fluid (CSF) PGRN by 2- to threefold. Finally, in a first-in-human phase 1 clinical trial, a single infusion of latozinemab caused a reduction in WBC sortilin, tripled plasma PGRN and doubled CSF PGRN in healthy volunteers, and restored PGRN to physiological levels in asymptomatic GRN mutation carriers. Conclusions These findings support the development of latozinemab for the treatment of FTD-GRN and other neurodegenerative diseases where elevation of PGRN may be beneficial. Trial registration ClinicalTrials.gov, NCT03636204. Registered on 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03636204 .

Objective: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)—a densely innervated tissue layer covering the calvarial skull—has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. Methods: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. Results: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model—an effect that was preventable by the administration of an OTR antagonist. Conclusion: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.

Abstract INTRODUCTION Heterozygous mutations in the GRN gene lead to reduced progranulin (PGRN) levels in plasma and cerebrospinal fluid (CSF) and are causative of frontotemporal dementia (FTD) with > 90% penetrance. Latozinemab is a human monoclonal immunoglobulin G1 antibody that is being developed to increase PGRN levels in individuals with FTD caused by heterozygous loss‐of‐function GRN mutations. METHODS A first‐in‐human phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple‐dose intravenous administration of latozinemab in eight symptomatic participants with FTD caused by a heterozygous loss‐of‐function GRN mutation (FTD‐GRN). RESULTS Latozinemab demonstrated favorable safety and PK/PD profiles. Multiple‐dose administration of latozinemab increased plasma and CSF PGRN levels in participants with FTD‐GRN to levels that approximated those seen in healthy volunteers. DISCUSSION Data from the first‐in‐human phase 1 study support further development of latozinemab for the treatment of FTD‐GRN. Highlights GRN mutations decrease progranulin (PGRN) and cause frontotemporal dementia (FTD). Latozinemab is being developed as a PGRN‐elevating therapy. Latozinemab demonstrated a favorable safety profile in a phase 1 clinical trial. Latozinemab increased PGRN levels in the CNS of symptomatic FTD‐GRN participants.

Purpose: Post acute sequelae of SARS-CoV-2 infection are defined by persistence or re-occurrence of symptoms six to 12 weeks after SARS-CoV-2 infections. Methods: Twice vaccinated hospital employees after mild to moderate post-vaccination SARS-CoV-2 infection completed a questionnaire on the incidence of general, respiratory, neuropsychiatric, dermatological and gastrointestinal symptoms, experienced during their acute infection and eight weeks after recovery. Post acute sequelae of SARS-CoV-2 infection were analysed in relation to socio-demographic-, health-, virus- and acute infection-related characteristics. Results: 73 participants, 25 women and 48 men with a mean age of 40.9 years, with a post-vaccination SARS-CoV-2 infection completed the survey. Out of these 93 % reported at least one symptom at time of initial SARS-CoV-2 infection, 31.5 %, predominantly women, reported post acute sequelae at least eight weeks after the acute infection stage. Fatigue, dysgeusia and dysosmia, headache or difficulty concentrating and shortness of breath during acute infection, BMI> 25 and pre-existing pulmonary disorders were associated with post acute sequelae of SARS-CoV-2 infection. Participants with initially more than five symptoms were four times more likely to report post acute sequelae. Conclusion: It is suggested that the multiplicity of symptoms during acute SARS-CoV-2 infections increases the risk for post acute symptoms.

Summary: Background: The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019. Methods: We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends. Findings: In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of −0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC = −0.41), inflammatory bowel disease (AAPC = −0.72), multiple sclerosis (AAPC = −0.26), psoriasis (AAPC = −0.77), and atopic dermatitis (AAPC = −0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR. Interpretation: The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively. Funding: The Global Burden of Disease Study is funded by the Bill and Melinda Gates Foundation. The project funded by Scientific Research Fund of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (2022QN38).

Background:. Seroma, along with other complications, occurs as a result of poor wound healing following breast reconstructive surgery. The Interi System was developed to address the need for more effective approaches to close internal dead space and evacuate postsurgical fluid. Interi is an internal negative pressure delivery system with a unique branching manifold for broad coverage of internal tissue planes. Initial experience in a small cohort undergoing prepectoral breast reconstruction showed a clinical and statistically significant reduction in seroma and any complication versus standard drains. The purpose of this study is to report on the safety and effectiveness of Interi, compared with standard drains, in a larger patient population followed up over a longer period than our initial study. Methods:. Data on demographics, mastectomy and reconstructive variables, postoperative complications, and manifold/drain duration were retrieved from patient records and compared between the two groups. Results:. Interi was used in 100 patients (170 breasts) and standard drains in 100 patients (166 breasts). Groups were well matched in demographic, reconstructive, and mastectomy variables. Interi was removed significantly earlier than drains (16.5 versus 19.6 days; P < 0.0001) and was associated with a significantly lower incidence of seroma (4.1% versus 22.9%, P < 0.00001), flap revision (10.6% versus 21.7%, P = 0.006), and any complication (23.5% versus 44.0%, P = 0.0001). Conclusions:. Interi effectively reduced dead space and evacuated fluid from internal tissue planes, thereby decreasing seroma and other complications after prepectoral breast reconstruction. As a viable alternative to standard drains, it could significantly improve patient outcomes.

Precise and prompt predictions of crop yields are crucial for optimising farm management, post-harvest operations, and marketing strategies within the agricultural sector. While various machine learning approaches have been employed to forecast crop yield, their application to grain quality, particularly head rice yield (HRY), is less explored. This research collated crop-level HRY data across four seasons (2017/18–2020/21) from Australia’s rice-growing region. Models were developed using the XGBoost algorithm trained at varying time steps up to 16 weeks pre-harvest. The study compared the accuracy of models trained on datasets with climate data alone or paired with vegetative indices using two- and four-week aggregations. The results suggest that model accuracy increases as the harvest date approaches. The dataset combining climate and vegetative indices aggregated over two weeks surpassed industry benchmarks early in the season, achieving the highest accuracy two weeks before harvest (LCCC = 0.65; RMSE = 6.43). The analysis revealed that HRY correlates strongly with agroclimatic conditions nearer harvest, with the significance of vegetative indices-based features increasing as the season progresses. These features, indicative of crop and grain maturity, could aid growers in determining optimal harvest timing. This investigation offers valuable insights into grain quality forecasting, presenting a model adaptable to other regions with accessible climate and satellite data, consequently enhancing farm- and industry-level decision-making.

Abstract Background Zika virus (ZIKV) is a mosquito-transmitted flavivirus that affects many regions of the world. Infection, in utero, causes microcephaly and later developmental and neurologic impairments. The impact of ZIKV infection on neurocognition in adults has not been well described. The objective of the study was to assess the neurocognitive impact of ZIKV infection in adult rhesus macaques. Methods Neurocognitive assessments were performed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) via a touch screen and modified Brinkman Board before and after subcutaneous ZIKV inoculation. Immune activation markers were measured in the blood and cerebral spinal fluid (CSF) by multiplex assay and flow cytometry. Results All animals (N = 8) had detectable ZIKV RNA in plasma at day 1 post-inoculation (PI) that peaked at day 2 PI (median 5.9, IQR 5.6–6.2 log10 genome equivalents/mL). In all eight animals, ZIKV RNA became undetectable in plasma by day 14 PI, but persisted in lymphoid tissues. ZIKV RNA was not detected in the CSF supernatant at days 4, 8, 14 and 28 PI but was detected in the brain of 2 animals at days 8 and 28 PI. Elevations in markers of immune activation in the blood and CSF were accompanied by a reduction in accuracy and reaction speed on the CANTAB in the majority of animals. Conclusions The co-occurrence of systemic and CSF immune perturbations and neurocognitive impairment establishes this model as useful for studying the impact of neuroinflammation on neurobehavior in rhesus macaques, as it pertains to ZIKV infection and potentially other pathogens.

Gasperini syndrome (GS), a rare brainstem syndrome, is featured by ipsilateral cranial nerves (CN) V–VIII dysfunction with contralateral hemibody hypoesthesia. While there have been 18 reported cases, the GS definition remains ambiguous. We report a new case and reviewed the clinical features of this syndrome from all published reports to propose a new definition. A 57-year-old man with acute brainstem stroke had right CN V–VIII and XII palsies, left body hypoesthesia and ataxia. Brain MRI showed an acute stroke in the right caudal pons and bilateral cerebellum. After a systematic review, we classified the clinical manifestations into core and associate features based on the frequencies of occurring neurological deficits. We propose that a definitive GS requires the presence of ipsilateral CN VI and VII palsies, plus one or more of the other three core features (ipsilateral CN V, VIII palsies and contralateral hemibody hemihypalgesia). Additionally, GS, similar to Wallenberg’s syndrome, represents a spectrum that can have other associated neurological features. The revised definition presented in this study may enlighten physicians with the immediate recognition of the syndrome and help improve clinical localization of the lesions and its management.

Purpose – There has been significant growth in entrepreneurship research over the past several decades. Yet with all of the knowledge gained and presumably improved training of would-be entrepreneurs, firm failure rates remain persistently high. It is argued here that the historical and continued research focus on successful entrepreneurs has limited the field. Entrepreneurs are often considered to possess uniquely positive capabilities relative to the general population; this paper explores the possibility that the majority of entrepreneurs suffer from overconfidence and that this leads most entrepreneurs to make “bad bets” that result in underperformance and firm failure. Design/methodology/approach – In this paper, a qualitative review of the literature was performed. Findings – Based on the literature review, three formal propositions are developed. The first two suggest that the majority of entrepreneurs are overconfident in their personal capabilities and the prospects for their new ventures. It is then proposed that this overconfidence leads to errors in judgment that results in financial underperformance and failure found among most new ventures. Originality/value – This paper makes an important contribution to the entrepreneurship literature by arguing that overconfidence negatively impacts pre-founding decision-making such that entrepreneurs pursue flawed opportunities. Studying the issues raised in this paper may spur new lines of research and knowledge that lead to better entrepreneurial outcomes.

Context: Wind tunnels are essential devices in the study of flow properties through objects and scaled prototypes. This work presents a numerical study to characterize an existing wind tunnel, proposing modifications with the aim to improve the quality of the flow in the test chamber. Method: Experimental measurements of the inlet velocity and pressure distribution of a wind tunnel are nperformed. These empirical values are used as parameters to define boundary conditions in simulations. The Finite Element Method (FEM) at low speeds is implemented to determine the stream function by using a standard Galerkin method. Polynomial interpolations are employed to modify the contraction section design, and numerical simulations are performed in order to compare the numerical results of the flow for the existing and the modified wind tunnels. Results: Experimental measurements of the flow at the wind tunnel entrance are presented. The velocity field and distribution of thermodynamic variables inside the tunnel are numerically determined. This computations are useful since it is experimentally difficult to make measurements inside the channel. Additionally, numerical calculations of these variables are presented under modifications in the tunnel geometry. Conclusions: A comparison between these simulations show that laminar flow at low velocities can be modeled as incompressible and irrotational fluid under a bidimensional approximation along its longitudinal section. It is observed that modifications in the geometry of the tunnel can improve the flow in the test section of the wind tunnel in the laminar regime.

Background:. Seroma remains a common complication after breast surgery, despite meticulous surgical technique to obliterate dead space and use of standard postsurgical drains for fluid evacuation. Therefore, novel approaches are needed. The Interi System is an internal, negative-pressure delivery system consisting of a manifold that is a silicone tubing with a central trunk and three peel-apart channeled branches connected to an external therapy unit, which simultaneously delivers continuous negative pressure of 125 mm Hg and removes excess fluid from internal tissue planes. This retrospective study evaluated the safety and effectiveness of Interi compared with standard drains in consecutive patients undergoing immediate, prepectoral, acellular dermal matrix-assisted, and implant-based breast reconstruction. Methods:. Patient records were reviewed, and data on demographics, mastectomy, and reconstructive variables, postoperative complications, fluid output volume, and manifold/drain duration were retrieved and compared between the two groups. Results:. Interi was used in 23 patients (38 breasts) and standard drains in 23 patients (39 breasts). Patients in both groups were well matched in all demographic, reconstructive, and mastectomy variables. Interi duration was significantly shorter than drains (16.7 versus 19.7 days; P = 0.020). There were no instances of seroma formation after removal of the manifold, edematous flap, or reconstructive failure with Interi. Seroma rate was 20.5% after drain removal (P = 0.005). All other complications were similar between the two groups. Conclusion:. Interi effectively removed excess fluid from internal tissue compartments in prepectoral breast reconstruction and may offer significant improvement over current standards of care for seroma prevention in this procedure.

Resting-state functional connectivity has been used to study Alzheimer's disease, revealing underlying differences between groups of individuals at different levels of cognitive impairment, or groupwise changes over time. Most of these studies have employed a single scanner and/or a single scan per subject. In this study, we used data collected from a substudy to two randomized clinical trials in patients with mild-to-moderate Alzheimer's Disease to investigate the robustness of functional connectivity in a multicenter, longitudinal setting. This substudy was not powered to detect drug treatment effects. With a basic imaging charter for inter-site acquisition standardization, we found no changes to functional connectivity over time in the placebo group, despite observable changes in clinical test scores and regional brain atrophy. We infer that functional connectivity, as implemented in our study, is not sensitive enough to detect disease progression in our patients. Using an 8-week interval between scans (in both treatment and placebo groups), we found that our test-retest reproducibility was comparable with other published results. We also found that the dominant source of measurement variability was within individuals over time, compared with variability between subjects and sites. Finally, we propose a simple method of visual inspection to identify scans that should be excluded from longitudinal analysis.

BackgroundAlthough there has been an increase in the number of randomized controlled trials evaluating treatment efficacy for hidradenitis suppurativa (HS), instrument measurements of disease severity and quality of life (QoL) are varied, making the compilation of data and comparisons between studies a challenge for clinicians. ObjectiveWe aimed to perform a systematic literature search to examine the recent trends in the use of disease severity and QoL outcome instruments in randomized controlled trials that have been conducted on patients with HS. MethodsA scoping review was conducted in February 2021. The PubMed, Embase, Web of Science, and Cochrane databases were used to identify all articles published from January 1964 to February 2021. In total, 41 articles were included in this systematic review. ResultsThe HS Clinical Response (HiSCR) score (18/41, 44%) was the most commonly used instrument for disease severity, followed by the Sartorius and Modified Sartorius scales (combined: 16/41, 39%). The Dermatology Life Quality Index (18/41, 44%) and visual analogue pain scales (12/41, 29%) were the most commonly used QoL outcome instruments in HS research. ConclusionsRandomized controlled trials conducted from 2013 onward commonly used the validated HiSCR score, while older studies were more heterogeneous and less likely to use a validated scale. A few (6/18, 33%) QoL measures were validated instruments but were not specific to HS; therefore, they may not be representative of all factors that impact patients with HS. Trial RegistrationNational Institute of Health Research PROSPERO CRD42020209582; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020209582

There is significant evidence to support the notion that glial cells can modulate the strength of synaptic connections between nerve cells, and it has further been suggested that alterations in intracellular calcium are likely to play a key role in this process. However, the molecular mechanism(s) by which glial cells modulate neuronal signaling remains contentiously debated. Recent experiments have suggested that alterations in extracellular H+ efflux initiated by extracellular ATP may play a key role in the modulation of synaptic strength by radial glial cells in the retina and astrocytes throughout the brain. ATP-elicited alterations in H+ flux from radial glial cells were first detected from Müller cells enzymatically dissociated from the retina of tiger salamander using self-referencing H+-selective microelectrodes. The ATP-elicited alteration in H+ efflux was further found to be highly evolutionarily conserved, extending to Müller cells isolated from species as diverse as lamprey, skate, rat, mouse, monkey and human. More recently, self-referencing H+-selective electrodes have been used to detect ATP-elicited alterations in H+ efflux around individual mammalian astrocytes from the cortex and hippocampus. Tied to increases in intracellular calcium, these ATP-induced extracellular acidifications are well-positioned to be key mediators of synaptic modulation. In this article, we examine the evidence supporting H+ as a key modulator of neurotransmission, review data showing that extracellular ATP elicits an increase in H+ efflux from glial cells, and describe the potential signal transduction pathways involved in glial cell—mediated H+ efflux. We then examine the potential role that extracellular H+ released by glia might play in regulating synaptic transmission within the vertebrate retina, and then expand the focus to discuss potential roles in spreading depression, migraine, epilepsy, and alterations in brain rhythms, and suggest that alterations in extracellular H+ may be a unifying feature linking these disparate phenomena.

Digital technology has been an integral part of transforming educational resources for students in recent decades, however, the fallout of the COVID-19 pandemic has focused education on infusion of digital technologies throughout programs to better meet students' needs. School districts have benefited from the American Rescue Plan Act funding and the surge of new or re-envisioned resources and tools launched in the aftermath of the pandemic's influence on school environments. Through this phenomenon, new opportunities have become particularly accessible to students with disabilities, and educators are in a new position to collaboratively consult to ensure resource availability. This paper discusses implications of the progressing landscape of technology in schools for providing mental health services. Using a fictional district-wide memo it illustrates how collaborative consultation can guide practitioners to use ethical considerations and ideal practices in technology integration and collaboration to meet the needs of students with disabilities.

Abstract In recent years, nickel (Ni) deficiency symptoms has been observed in commercial pecan [Carya illinoinensis (Wangenh.) K. Koch.] orchards in New Mexico. Nickel deficiency can cause a reduction in lignin formation, which could affect the risk for breakage on pecan tree shoots. Ni deficiency might furthermore disrupt ureide catabolism in pecan and, therefore, could negatively affect nitrogen (N) nutrition in the plant. The objective of this study was to identify the effects of Ni and N fertilizer applications, at two rates, on net photosynthesis (Pn), leaf greenness (SPAD), and branch lignin concentration in New Mexico’s nonbearing pecan trees. Sixty trees for year 2012 (Pawnee and Western cultivars) and 40 trees for year 2013 (Pawnee cultivar) were used at two New Mexico locations (Artesia and Las Cruces) to evaluate the effects of Ni and N on tree measures. Treatments were as follows: (1) High N plus Ni (+Ni); (2) Low N no Ni (−Ni); (3) High N −Ni; and (4) Low N +Ni. In 2012 and 2013, there was an increase in leaf greenness for each location and cultivar (tree group) through time (June to September). Photosynthesis measures in 2012 differed between tree group, time in the season, and N and Ni treatments. In 2013, Pn was influenced by tree group and time (P < 0.0001), but N and Ni interaction did not present a significant effect related to Ni benefits. Photosynthesis varied over time in 2012 and 2013, with an inconsistent pattern. In this study, Ni application at the high N rate had a negative effect on ‘Pawnee’ Pn early in the season at the Artesia site, but this application had a positive effect for ‘Western’ from Artesia at the low N level, also early in the season. Lignin content varied between tree groups only. The application of N and Ni did not affect lignin in pecan shoots. The results show an inconsistent pattern regarding the benefits of Ni on nonbearing pecan orchards for leaf greenness, Pn, and lignin content during the 2-year study. Future studies on Ni should focus on pecan trees exhibiting leaf Ni deficiency symptoms or on soils with less than 0.14 mg·kg−1 of DTPA extractable Ni, as well as the long-term effect of Ni on pecan growth and development to optimize the addition of Ni into an efficient fertilization program.

Abstract Introduction Dolutegravir (DTG)-based antiretroviral therapy (ART) is currently the first-line treatment for people living with HIV. Neuropsychiatric adverse events (NP-AEs) have been reported with DTG but neuropsychiatric symptoms have not been systemically quantified using structured scales. This study examined mood and cognitive parameters before and after a planned transition from non-DTG to DTG-based ART within a longitudinal study of acute HIV infection (AHI). Methods RV254 AHI cohort participants on ≥ 24 weeks of ART initiated at AHI underwent sequential assessments before and after the switch including: (1) Patient Health Questionnaire-9 (PHQ-9), a 9-item survey (scores 0–27) that evaluates somatic and affective/cognitive symptoms of depression; (2) a 2-Questions screening that has been validated locally for depression; (3) Distress Thermometer (scores 0–10); and 4) administration of a 4-test neurocognitive battery sensitive to HIV. Results 254 individuals (95% male, median age 30) switched to a DTG-based regimen after a median 144 weeks of ART. Serial assessments were completed at a median of 19 weeks before and 37 weeks after DTG. There was a modest but statistically significant increase in PHQ-9 scores after DTG (pre-switch: 5 [IQR 1–7] vs. Post-switch: 5 [IQR 2–8], p = 0.009). The percentage of participants with at least moderate depression (PHQ-9 ≥ 10) increased from 10 to 16% (p = 0.006), but the frequency of moderate-severe depression (PHQ-9 ≥ 15) remained unchanged (3%). No volunteer reported NP-AEs within the study period. Somatic symptoms of depression increased more than cognitive/affective symptoms. Plasma viral suppression (HIV-1 RNA

Health emerges from coordinated psychobiological processes powered by mitochondrial energy transformation. But how do mitochondria regulate the multisystem responses that shape resilience and disease risk across the lifespan? The Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study was established to address this question and determine how mitochondria influence the interconnected neuroendocrine, immune, metabolic, cardiovascular, cognitive, and emotional systems among individuals spanning the spectrum of mitochondrial energy transformation capacity, including participants with rare mitochondrial DNA (mtDNA) lesions causing mitochondrial diseases (MitoDs). This interdisciplinary effort is expected to generate new insights into the pathophysiology of MitoDs, provide a foundation to develop novel biomarkers of human health, and integrate our fragmented knowledge of bioenergetic, brain-body, and mind-mitochondria processes relevant to medicine and public health.

HIV-1 disrupts the host epigenetic landscape with consequences for disease pathogenesis, viral persistence, and HIV-associated comorbidities. Here, we examined how soon after infection HIV-associated epigenetic changes may occur in blood and whether early initiation of antiretroviral therapy (ART) impacts epigenetic modifications. We profiled longitudinal genome-wide DNA methylation in monocytes and CD4+ T lymphocytes from 22 participants in the RV254/SEARCH010 acute HIV infection (AHI) cohort that diagnoses infection within weeks after estimated exposure and immediately initiates ART. We identified monocytes harbored 22,697 differentially methylated CpGs associated with AHI compared to 294 in CD4+ T lymphocytes. ART minimally restored less than 1% of these changes in monocytes and had no effect upon T cells. Monocyte DNA methylation patterns associated with viral load, CD4 count, CD4/CD8 ratio, and longitudinal clinical phenotypes. Our findings suggest HIV-1 rapidly embeds an epigenetic memory not mitigated by ART and support determining epigenetic signatures in precision HIV medicine. Trial Registration: NCT00782808 and NCT00796146.

Background: clinically relevant methods to identify individuals at risk for impaired daily living abilities secondary to neurocognitive impairment (ADLs) remain elusive. This is especially true for complex clinical conditions such as HIV-Associated Neurocognitive Disorders (HAND). The aim of this study was to identify novel and modifiable factors that have potential to improve diagnostic accuracy of ADL risk, with the long-term goal of guiding future interventions to minimize ADL disruption. Methods: study participants included 79 people with HIV (PWH; mean age = 63; range = 55–80) enrolled in neuroHIV studies at University California San Francisco (UCSF) between 2016 and 2019. All participants were virally suppressed and exhibited objective evidence of neurocognitive impairment. ADL status was defined as either normative (n = 39) or at risk (n = 40) based on a task-based protocol. Gradient boosted multivariate regression (GBM) was employed to identify the combination of variables that differentiated ADL subgroup classification. Predictor variables included demographic factors, HIV disease severity indices, brain white matter integrity quantified using diffusion tensor imaging, cognitive test performance, and health co-morbidities. Model performance was examined using average Area Under the Curve (AUC) with repeated five-fold cross validation. Findings: the univariate GBM yielded an average AUC of 83% using Wide Range Achievement test 4 (WRAT-4) reading score, self-reported thought confusion and difficulty reading, radial diffusivity (RD) in the left external capsule, fractional anisotropy (FA) in the left cingulate gyrus, and Stroop performance. The model allowing for two-way interactions modestly improved classification performance (AUC of 88%) and revealed synergies between race, reading ability, cognitive performance, and neuroimaging metrics in the genu and uncinate fasciculus. Conversion of Neuropsychological Assessment Battery Daily Living Module (NAB-DLM) performance from raw scores into T scores amplified differences between White and non-White study participants. Interpretation: demographic and sociocultural factors are critical determinants of ADL risk status among older PWH who meet diagnostic criteria for neurocognitive impairment. Task-based ADL assessment that relies heavily on reading proficiency may artificially inflate the frequency/severity of ADL impairment among diverse clinical populations. Culturally relevant measures of ADL status are needed for individuals with acquired neurocognitive disorders, including HAND.

Small alterations in the level of extracellular H+ can profoundly alter neuronal activity throughout the nervous system. In this study, self-referencing H+-selective microelectrodes were used to examine extracellular H+ fluxes from individual astrocytes. Activation of astrocytes cultured from mouse hippocampus and rat cortex with extracellular ATP produced a pronounced increase in extracellular H+ flux. The ATP-elicited increase in H+ flux appeared to be independent of bicarbonate transport, as ATP increased H+ flux regardless of whether the primary extracellular pH buffer was 26 mM bicarbonate or 1 mM HEPES, and persisted when atmospheric levels of CO2 were replaced by oxygen. Adenosine failed to elicit any change in extracellular H+ fluxes, and ATP-mediated increases in H+ flux were inhibited by the P2 inhibitors suramin and PPADS suggesting direct activation of ATP receptors. Extracellular ATP also induced an intracellular rise in calcium in cultured astrocytes, and ATP-induced rises in both calcium and H+ efflux were significantly attenuated when calcium re-loading into the endoplasmic reticulum was inhibited by thapsigargin. Replacement of extracellular sodium with choline did not significantly reduce the size of the ATP-induced increases in H+ flux, and the increases in H+ flux were not significantly affected by addition of EIPA, suggesting little involvement of Na+/H+ exchangers in ATP-elicited increases in H+ flux. Given the high sensitivity of voltage-sensitive calcium channels on neurons to small changes in levels of free H+, we hypothesize that the ATP-mediated extrusion of H+ from astrocytes may play a key role in regulating signaling at synapses within the nervous system.

Abstract Background Cognitive and behavioral impairment are common in children living with perinatally acquired HIV (pHIV) and children exposed to HIV in utero but uninfected (HEU). Methods We sought to determine the prevalence of adverse behavioral symptomatology using a Thai-translated and validated version of the SNAP-IV questionnaire and assess cognitive function utilizing the Children's Color Trails Test, Delis-Kaplan Executive Function System, and the Wechsler Intelligence Scales, in our cohort of Thai adolescents (10–20 years old) with well-controlled pHIV compared to HEU and HIV-unexposed, uninfected youth. We then evaluated the interaction between HIV status, behavioral impairment, and executive function outcomes independent of demographic variables. Results After controlling for demographic factors of age and household income, adolescents with pHIV had higher inattentive symptomatology and poorer neuropsychological test scores compared to uninfected controls. Significant interactions were found between inattention and executive function across multiple neurocognitive tests. Conclusions Behavioral impairment and poor executive functioning are present in adolescents with well-controlled pHIV compared to HIV-uninfected matched peers. The SNAP-IV questionnaire may be a useful tool to identify those with attentional impairment who may benefit from further cognitive testing in resource-limited settings.

Introduction: Magnetic Resonance Imaging (MRI) documented abnormal brain structure in methamphetamine abusers with inconsisting results. It is likely that this discrepency could be from different analysis methods for example absolute volume analysis method and intracranial volume(ICV) normalization. Objectives: To compare the effect of analysis method between absolute volume analysis and normalized volume with ICV analysis among methamphetamine abusers (MA) and healthy controls (HC) groups. Materials and methods: Ten MAs and 14 HCs with gender and age matched were recruited. MRI of brain were acquired on 1.5 Tesla MR Scanner (Achieva, Philips, Netherland). Axial T1-weighted images with 3D FFE pulse sequence were used for MRI acquisition with the following data acquisition parameters: TE/TR =4.6/20 ms, FOV = 24 cm, 256x128 imaging matrix and 120 slices. Measurement of brain volume were performed with Freesurfer (FS) version 5.3. Absolute volume and normalized volume with ICV between HCs and MAs groups were compared. Pearson correlation was used to find the correlation of the brain volume between the two methods. Results: In absolute volume analysis method, we observed consistent significant larger brain volumes in HCs compared to MAs. A positive correlation in most parts of brains was observed between absolute volume analysis method and ICV in HCs and MAs group. In contrast, negative correlation in most parts f brains was observed between ICV normalized volume method and ICV between HC and MA. The different of correlation for each brain region between HCs and MAs could be associated with the effect of methamphetamine. Conclusion: The difference of the two analysis methods give similar results but varied in different brain regions. The choice of analysis method should be carefully selected in brain imaging study.

Purpose - Given the growing number of immigrant entrepreneurs in the USA, the purpose of this paper is to better understand the behaviors of this subgroup of entrepreneurs. Specifically, the paper aims to understand the unique challenges faced by immigrant entrepreneurs and how environmental challenges affect decisions to grow or abandon their ventures. Design/methodology/approach - To make the theoretical arguments in this conceptual paper, the authors draw on the theory of planned behavior developed by Ajzen (1985), which suggests that a person’s behavior is predicted by their intention, and intentions are predicted by one’s attitudes, subjective norm and perceived behavioral control. Findings - The paper provides theoretical insights on the effect of demands of immigration on the intentions of immigrant entrepreneurs to engage in three specific entrepreneurial behaviors: new venture formation, growth and abandonment. The authors propose that immigrant entrepreneurs deal with increased stress yet continue to maintain higher intentions to found new ventures compared to non-immigrants. Contrastingly, the authors also propose that the stress and obstacles immigrant entrepreneurs face reduce their intentions to grow their firms and increase their intentions to abandon their firms. The authors also explore entrepreneurial resilience as a possible moderating factor between stress and entrepreneurial intentions of immigrant entrepreneurs. Research limitations/implications - First, the authors do not distinguish between immigrants from different nations or parts of the world or having different backgrounds. Second, the authors do not fully develop or incorporate the element of coping. Also, our paper is limited to behaviors of immigrant entrepreneurs with micro- and small-businesses. Practical implications Venture capitalists could benefit from empirical results of these propositions as funding decisions may need to include consideration of the proposed effects of stress and demands of immigration. Originality/value - This paper meets an identified need to examine the effects of immigrant-specific issues such as the demands of immigration on the behaviors of this growing group of entrepreneurs.

Abstract Background We investigated the effect of crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer’s disease (AD). Methods This double-blind, placebo-controlled, randomized phase II study enrolled patients with mild-to-moderate AD and a Mini-Mental State Examination (MMSE) score of 18–26. In part 1 of the study, patients were 2:1 randomized to receive low-dose subcutaneous (SC) 300 mg crenezumab every 2 weeks (q2w) or placebo for 68 weeks; in part 2, patients were 2:1 randomized to receive high-dose intravenous (IV) 15 mg/kg crenezumab every 4 weeks (q4w) or placebo for 68 weeks. The primary endpoint was change in amyloid burden from baseline to week 69 assessed by florbetapir positron emission tomography (PET) in the modified intent-to-treat population. Secondary endpoints were change from baseline to week 69 in cerebrospinal fluid (CSF) biomarkers and fluorodeoxyglucose PET, and change from baseline to week 73 in 12-point Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog12) and Clinical Dementia Rating Sum of Boxes (CDR-SB). Safety was assessed in patients who received at least one dose of study treatment. Results From August 2011 to September 2012, 91 patients were enrolled and randomized (low-dose SC cohort: crenezumab (n = 26) or placebo (n = 13); high-dose IV cohort: crenezumab (n = 36) or placebo (n = 16)). The primary endpoint was not met using a prespecified cerebellar reference region to calculate standard uptake value ratios (SUVRs) from florbetapir PET. Exploratory analyses using subcortical white matter reference regions showed nonsignificant trends toward slower accumulation of plaque amyloid in the high-dose IV cohort. In both cohorts, a significant mean increase from baseline in CSF Aβ(1–42) levels versus placebo was observed. Nonsignificant trends toward ADAS-Cog12 and CDR-SB benefits were identified in a mild (MMSE 20–26) subset of the high-dose IV cohort. No amyloid-related imaging abnormalities due to edema/effusion were observed. Conclusion The primary endpoint was not met. Exploratory findings suggest potential Aβ target engagement with crenezumab and possible slower accumulation of plaque amyloid. Studies investigating the effects of higher doses of crenezumab on amyloid load and disease progression are ongoing. Trial registration ClinicalTrials.gov, NCT01397578. Registered on 18 July 2011.

In this manuscript a review of the prevalence of trauma among students in the United States and its impact on child development and the educational environment is conducted. Case vignettes are used to highlight the impact of trauma present in schools and a framework for implementing trauma-informed care (TIC) in special education is explored. The Missouri Model for Trauma Informed Schools, an existing trauma-informed schools model, is used as a guide throughout the manuscript to highlight principles of TIC and explore the collaborative partnerships needed for TIC, particularly those between special education teachers and school counselors. Finally, indicators for TIC and resources for school personnel are provided.