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Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to

BackgroundInjectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study.MethodsThe HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094.FindingsOf the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation.InterpretationLong-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance.FundingDivision of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

Abstract Arterial thrombosis is a leading cause of death and disability worldwide with no effective bioassay for clinical prediction. As a symbolic feature of arterial thrombosis, severe stenosis in the blood vessel creates a high-shear, high-gradient flow environment that facilitates platelet aggregation towards vessel occlusion. Here, we present a thrombus profiling assay that monitors the multi-dimensional attributes of thrombi forming in such biomechanical conditions. Using this assay, we demonstrate that different receptor–ligand interactions contribute distinctively to the composition and activation status of the thrombus. Our investigation into hypertensive and older individuals reveals intensified biomechanical thrombogenesis and multi-dimensional thrombus profile abnormalities, endorsing the diagnostic potential of the assay. Furthermore, we identify the hyperactivity of GPIbα-integrin αIIbβ3 mechanosensing axis as a molecular mechanism that contributes to hypertension-associated arterial thrombosis. By studying drug-disease interactions and inter-individual variability, our work reveals a need for personalized anti-thrombotic drug selection that accommodates each patient’s pathological profile.

Abstract We bootstrap the Veneziano superstring amplitude in 10 dimensions from the bottom-up. Starting with the most general maximally supersymmetric Yang-Mills EFT, we input information about the lowest-lying massive states, which we assume contribute via tree-level exchanges to the 4-point amplitude. We show the following: (1) if there is only a single state at the lowest mass, it must be a scalar. (2) Assuming a string-inspired gap between the mass of this scalar and any other massive states, the allowed region of Wilson coefficients has a new sharp corner where the Veneziano amplitude is located. (3) Upon fixing the next massive state to be a vector, the EFT bounds have a one-parameter family of corners; these would correspond to models with linear Regge trajectories of varying slopes, one of which is the open superstring. (4) When the ratio between the massive scalar coupling and the trF 4 coefficient is fixed to its string value, the spin and mass of the second massive state is determined by the bootstrap and the Veneziano amplitude is isolated on a small island in parameter space. Finally, we compare with other recent bootstraps approaches, both the pion model and imposing Regge-inspired maximal spin constraints.

The article is devoted to the history of the oldest Russian sect of Hristovovery or Khlysty on the territory of Ukraine during Soviet times. The purpose of the work is to explore the existence of the Khlysty sect in the Ukrainian SSR, to consider some of the features of the spread of the sect and the details of its rituals. The source base of the research was unpublished operational documents of Ukrainian archives. Special studies devoted to the sect of Christ-believers in Ukraine during the Soviet period were not found. The article applies a materialistic understanding of history, which requires consideration of historical phenomena in development, in the unity of the logical and historical, i.e. in the unity of material and spiritual factors. In the course of the work, it was established that the Khlysty sect was recorded on the territory of the future Ukraine from the first half of the 18th century and spreads across those regions where the Great Russian population lived compactly: in Old Believer settlements in Starodubye (the future Chernigov region), in the Azov region. West of the Dnieper, the sect of Christian believers is not fixed. In Soviet times, state security agencies regularly reported the existence of Christian believers in the same areas where they existed in the pre-revolutionary period. A feature of the Christian faith in Soviet times was the merger of the sect with Orthodox movements that were in opposition to both the Soviet regime and the official Russian Orthodox Church.

Abstract The effects of heat exposure on negative affect are thought to be central to the observed relationships between hot summer days and deleterious outcomes, such as violent crime or mental health crises. As these relationships are likely to be magnified by the effects of climate change, a better understanding of how consistent or variable the effects of hot weather on affective states is required. The current work combines data gathered from an ecological momentary assessment (EMA) study on individuals’ thermal perceptions, comfort, and affective states in outdoor environments during their daily lives with high spatiotemporal resolution climate-modeled weather variables. Using these data, associations between objective weather variables (temperature, humidity, etc.), perceived heat (thermal perception and comfort), and affective states are examined. Overall, objective weather data reasonably predicted perception and comfort, but only comfort predicted negative affective states. The variance explained across individuals was generally very low in predicting negative affect or comfort, but within-person variance explained was high. In other words, while there may be a relatively consistent relationship between temperature and psychological experience for any given person, there are significant individual differences across people. Age and gender were examined as moderators of these relationships, and while gender had no impact, participant age showed several significant interactions. Specifically, while older adults tended to experience more thermal discomfort and perceived higher temperatures as hotter, the relationship between discomfort and negative affect was lower in older adults. Taken together, these results emphasize the importance of thermal discomfort specifically in predicting negative affect, as well as the high inter-individual variability in thermal perceptions and comfort for the same ambient temperatures.

In response to a globalised education context that places increasing pressure on higher education institutions for pedagogical innovation and reform, universities are attempting to carve out more meaningful identities through reimagining campus design. As universities introduce more decentralised spaces, from strictly learning environments to a more collaborative organisation, the boundaries between these and other spaces become more fluid, redefining universities as learning environments. The concept of the Sticky Campus has been gaining currency recently. Emulating trends in 'third places' and popular urban co-working spaces, a Sticky Campus blurs the boundaries between study and living by incorporating areas for relaxation, social interaction, group learning, eating or study. Moreover, Sticky Campuses offer opportunities for shared meaning-making amongst faculty, students and the broader community. This paper introduces the contemporary concept of the Sticky Campus and explores its viability in Japanese institutional settings. Given the Sticky Campus concept has emerged from a predominantly Western lens, this paper provides a commentary on whether the concept is transferable into non-Western cultural settings such as Japan. Such a discussion is crucial for Japanese university transformations in the twenty-first century, as the higher education sector considers its options in transitioning to post-COVID conditions.

This article leverages existing literature around the use of telepresence robots to provide a conceptualisation of virtual inclusion. Telepresence involves the use of mediating technology to generate connection with others in a remote context. Recent developments have seen telepresence robots used to create a sense of 'being there' when the person's physical presence is not possible. Telepresence robots can provide children with the capability to maintain an embodied experience in schooling locations when they are absent due to chronic illness. Through building their knowledge of integrating this technology into their pedagogy, teachers can support students to engage in classroom activities through real-time virtual communication. The article extends what is known about how telepresence robots can be used for virtual inclusion and what the challenges and considerations are for the use of telepresence robots in schools. Technological, physical, social and pedagogical aspects of telepresence robots use for virtual inclusion are detailed with heuristic for introducing them into schools.

The research question studied in this paper is how teachers' task designing can be enhanced in professional development. We show that this can be done by scaffolding. Scaffolding is used in problem solving and we apply it by considering designing a task as a problem. In the paper, we describe a professional development of four teachers led by a mathematics educator. The professional development consisted of 10 meetings. The teachers were first exposed to a well-designed task in geometry as learners and then were asked to design new geometry tasks for their students. The mathematics educator helped them by supplying scaffolds such as modelling, reflection, articulation and worked examples. The data consisted of video-recordings of the workshops and a semi-structured interview with each of the teachers at the end of the project. The data analysis shows how the use of particular scaffolds was helpful while preserving the teachers' autonomy as task designers.

Objective: To evaluate how access to an office-based laboratory (OBL) and ambulatory surgery center (ASC) impacted vascular care during the Coronavirus Disease 2019 (COVID-19) pandemic. Methods: Vascular procedures performed by our group during the 6-week period before COVID-19 restrictions (group 1) and in the first 6-week period during the COVID-19 restrictions (group 2) were reviewed. The number of procedures performed was categorized as hospital inpatient (HIP), hospital outpatient (HOP), OBL, ASC, and vein center (VC). The procedures were also grouped by type: aneurysm (AAA), carotid (CAR), peripheral arterial disease (PAD), amputation/wound care (AMP), vascular access (VA), deep vein thrombosis (DVT), and venous reflux (CVI). The number of healthcare provider contact points for each patient undergoing care at the HOP, OBL, and ASC were also collected and compared between groups 1 and 2. Differences between groups were determined using the two-way ANOVA. Results: There were no statistically significant differences between groups 1 and 2 for procedure location or type of procedure (p > 0.05). Patient contact with healthcare providers decreased between groups 1 and 2 for ambulatory care. However, projecting the number of contacts for patients in group 2 if they had to have ambulatory care in the HOP setting (913) compared to contacts in the OBL and ASC setting (588) was statistically significant (p < 0.05). No patient or staff member at the OBL or ASC developed COVID-19 infection because of the care received at these venues. Conclusions: The ability to provide essential care for patients in an ambulatory environment was enhanced using our OBL and ASC without compromising safety, efficacy, or transmission of the virus to patients or staff during the height of the COVID-19 pandemic and limited their contact with healthcare workers and therefore reduced the consumption of personal protective equipment by healthcare personnel.

Approximately 5% of Alzheimer's disease cases have an early age at onset (

PURPOSE: To characterize the recovery of diagnostic cardiovascular procedure volumes in U.S. and non-U.S. facilities in the year following the initial COVID-19 outbreak. MATERIALS AND METHODS: The International Atomic Energy Agency (IAEA) coordinated a worldwide study called the IAEA Noninvasive Cardiology Protocols Study of COVID-19 2 (INCAPS COVID 2), collecting data from 669 facilities in 107 countries, including 93 facilities in 34 U.S. states, to determine the impact of the pandemic on diagnostic cardiovascular procedure volumes. Participants reported volumes for each diagnostic imaging modality used at their facility for March 2019 (baseline), April 2020, and April 2021. This secondary analysis of INCAPS COVID 2 evaluated differences in changes in procedure volume between U.S. and non-U.S. facilities and among U.S. regions. Factors associated with return to prepandemic volumes in the United States were also analyzed in a multivariable regression analysis. RESULTS: Reduction in procedure volumes in April 2020 compared with baseline was similar for U.S. and non-U.S. facilities (-66% vs -71%, P = .27). U.S. facilities reported greater return to baseline in April 2021 than did all non-U.S. facilities (4% vs -6%, P = .008), but there was no evidence of a difference when comparing U.S. facilities with non-U.S. high-income country (NUHIC) facilities (4% vs 0%, P = .18). U.S. regional differences in return to baseline were observed between the Midwest (11%), Northeast (9%), South (1%), and West (-7%, P = .03), but no studied factors were significant predictors of 2021 change from prepandemic baseline. CONCLUSION: The reductions in cardiac testing during the early pandemic have recovered within a year to prepandemic baselines in the United States and NUHICs, while procedure volumes remain depressed in lower-income countries.Keywords: SPECT, Cardiac, Epidemiology, Angiography, CT Angiography, CT, Echocardiography, SPECT/CT, MR Imaging, Radionuclide Studies, COVID-19, Cardiovascular Imaging, Diagnostic Cardiovascular Procedure, Cardiovascular Disease, Cardiac Testing Supplemental material is available for this article. © RSNA, 2023.

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lees scale), clinical grading of spasm intensity (Chens scale), and a modified version of the Abnormal Involuntary Movement Scale (Tuncs scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from poor to moderate; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lees, Chens, and Tuncs scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tuncs scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tuncs scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training.

Foraging behavior requires weighing costs of time to decide when to leave one reward patch to search for another. Computational and animal studies suggest that striatal dopamine is key to this process; however, the specific role of dopamine in foraging behavior in humans is not well characterized. We use positron emission tomography (PET) imaging to directly measure dopamine synthesis capacity and D1 and D2/3 receptor availability in 57 healthy adults who complete a computerized foraging task. Using voxelwise data and principal component analysis to identify patterns of variation across PET measures, we show that striatal D1 and D2/3 receptor availability and a pattern of mesolimbic and anterior cingulate cortex dopamine function are important for adjusting the threshold for leaving a patch to explore, with specific sensitivity to changes in travel time. These findings suggest a key role for dopamine in trading reward benefits against temporal costs to modulate behavioral adaptions to changes in the reward environment critical for foraging.

IntroductionThe National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis.MethodsThe cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated.ResultsWe observed a significant difference in Aβ42/40 after 12 months in the A+T- group. Post mortem neuropathologic analyses indicated that most of the p-Tau 181 positive (T+) cases also had a high Braak stage.DiscussionThis suggests that DLB patients who are A+ but T- may need to be monitored to determine whether they remain A+ or ever progress to T positivity.HighlightsSome A+T- DLB subjects transition from A+ to negative after 12-months. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Monitoring of the A+T- sub-type of DLB may be necessary.

Coral nurseries and associated techniques are the most common and widespread reef restoration methods worldwide. Due to the rapid decline of coral reefs, coral nurseries need to be eco-friendlier and adapted for effective upscaling to support large restoration projects. We suggest new design and fabrication processes associated with coral gardening and transplantation with 3D printing technology to offer a beneficial solution for growing coral fragments in on-land and underwater nurseries. We describe multiple combinations of building nurseries through the integration of biomimetic substrates and novel solutions for attaching coral fragments. Our methods are supported with supplemental testing of two hybrid substrate designs and coral mounting structures, building upon previous studies in the Gulf of Eilat/Aqaba (GoE/A), Red Sea. We identified and quantified marine invertebrates colonizing the surfaces of our substrates with environmental DNA (eDNA) by targeting the mitochondrial COI gene. We evaluated our coral fragments with and without our mounting structures to obtain an indication of total protein as a proxy for tissue health. We demonstrate the ability to design hybrid nurseries with custom mounting structures using biomimetic substrates, such as large ceramic artificial reefs, or with an interlocking mesh for holding numerous fragments to maximize out-planting efforts. We propose several methods for both land and underwater nurseries catered to various restoration initiatives for cost-effective up-scaling to meet the demands of global reef restoration.

OBJECTIVE: The effectiveness of coronary artery calcification (CAC) for risk stratification in obesity, in which imaging is often limited because of a reduced signal to noise ratio, has not been well studied. METHODS: Data from 9334 participants (mean age: 53.3 ± 9.7 years; 67.9% men) with BMI ≥ 30 kg/m2 from the CAC Consortium, a retrospectively assembled cohort of individuals with no prior cardiovascular diseases (CVD), were used. The predictive value of CAC for all-cause and cause-specific mortality was evaluated using multivariable-adjusted Cox proportional hazards and competing-risks regression. RESULTS: Mean BMI was 34.5 (SD 4.4) kg/m2 (22.7% Class II and 10.8% Class III obesity), and 5461 (58.5%) had CAC. Compared with CAC = 0, those with CAC = 1-99, 100-299, and ≥300 Agatston units had higher rates (per 1000 person-years) of all-cause (1.97 vs. 3.5 vs. 5.2 vs. 11.3), CVD (0.4 vs. 1.1 vs. 1.5 vs. 4.2), and coronary heart disease (CHD) mortality (0.2 vs. 0.6 vs. 0.6 vs. 2.5), respectively, after mean follow-up of 10.8 ± 3.0 years. After adjusting for traditional cardiovascular risk factors, CAC ≥ 300 was associated with significantly higher risk of all-cause (hazard ratio [HR]: 2.05; 95% CI: 1.49-2.82), CVD (subdistribution HR: 3.48; 95% CI: 1.81-6.70), and CHD mortality (subdistribution HR: 5.44; 95% CI: 2.02-14.66), compared with CAC = 0. When restricting the sample to individuals with BMI ≥ 35 kg/m2 , CAC ≥ 300 remained significantly associated with the highest risk. CONCLUSIONS: Among individuals with obesity, including moderate-severe obesity, CAC strongly predicts all-cause, CVD, and CHD mortality and may serve as an effective cardiovascular risk stratification tool to prioritize the allocation of therapies for weight management.