Reversible Chemical Modification of Antibody Effector Function Mitigates Unwanted Systemic Immune Activation.

Antibody effector functions including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) are mediated through the interaction of the antibody Fc region with Fcγ receptors present on immune cells. Several approaches have been used to modulate antibody Fc-Fcγ interactions with the goal of driving an effective antitumor immune response, including Fc point mutations and glycan modifications. However, robust antibody-Fcγ engagement and immune cell binding of Fc-enhanced antibodies in the periphery can lead to the unwanted induction of systemic cytokine release and other dose-limiting infusion-related reactions. Creating a balance between effective engagement of Fcγ receptors that can induce antitumor activity without incurring systemic immune activation is an ongoing challenge in the field of antibody and immuno-oncology therapeutics. Herein, we describe a method for the reversible chemical modulation of antibody-Fcγ interactions using simple poly(ethylene glycol) (PEG) linkers conjugated to antibody interchain disulfides with maleimide attachments. This method enables dosing of a therapeutic with muted Fcγ engagement that is restored in vivo in a time-dependent manner. The technology was applied to an effector function enhanced agonist CD40 antibody, SEA-CD40, and experiments demonstrate significant reductions in Fc-induced immune activation in vitro and in mice and nonhuman primates despite showing retained efficacy and improved pharmacokinetics compared to the parent antibody. We foresee that this simple, modular system can be rapidly applied to antibodies that suffer from systemic immune activation due to peripheral FcγR binding immediately upon infusion.

Surgical arrest of post-tonsillectomy haemorrhage: hospital episode statistics 2016-2022.

INTRODUCTION: Return to theatre for arrest of post-tonsillectomy haemorrhage represents a significant complication of a commonly performed Ear, Nose and Throat procedure. We used Hospital Episode Statistics data to quantify this risk. This method has been used previously for data from 2002-2004 and again for 2010-2016. In this article, coblation tonsillectomy was considered separately as it had not been analysed in previous studies. METHODS: We used Hospital Episode Statistics data provided by the Department of Health to determine the risk of return to theatre for patients undergoing tonsillectomy between 2016 and 2022. Adults and children were analysed separately. RESULTS: Between 1 April 2016 and 30 April 2022, 179,172 tonsillectomies were performed (not including coblation tonsillectomy), 4,311 (2.41%) of which returned to theatre for control of postoperative bleeding. In children, 1.16% returned to theatre, whereas in adults, 3.80% returned (p<0.05). When including coblation tonsillectomy, the return to theatre rate was 0.82% in children, 3.46% in adults and 1.92% overall. CONCLUSIONS: This study shows that adults remain more than three times more likely than children to require a return to theatre for arrest of haemorrhage following tonsillectomy. The rates of post-tonsillectomy haemorrhage decrease when coblation tonsillectomies are added to the analysis. The rate of return to theatre for post-tonsillectomy haemorrhage seems to have stabilised compared with previous work carried out. The authors recommend further work to assess the complication rate of tonsillectomy in the UK and to compare coblation tonsillectomy with other techniques.

Disparities in the accuracy of reporting opioid overdoses to 9-1-1 by race and sex of overdose victim, Marion County, Indiana, 2011-2020.

OBJECTIVES: To assess the prevalence of emergency medical incidents wherein naloxone was administered but overdose was not described as the chief complaint during the 9-1-1 call, including differences by overdose victim race/ethnicity and sex. METHODS: We computed the percentage of 9-1-1 calls in Marion County, Indiana, from 2011 to 2020, wherein naloxone was administered but the caller did not describe overdose as the chief complaint. We estimated a logistic regression to examine the associations between reporting of overdose as the chief complaint and race and sex of the overdose victim. RESULTS: Almost one-fifth of 9-1-1 calls preceding naloxone administration did not describe overdose as the chief complaint. 9-1-1 callers were more likely to describe a non-overdose as the chief complaint when the overdose victim was Black or female. CONCLUSION: 9-1-1 callers are less likely to use terminology describing overdose when the overdose victim is female or Black, than when the victim is male or White. Inaccurate terminology when calling 9-1-1 could delay naloxone administration, thereby increasing risk of overdose death and hypoxic brain injury. Some 9-1-1 callers may be avoiding overdose terminology to prevent a police response, or due to lack of knowledge about overdose identification, but further research is needed to determine the mechanisms underlying these findings.

A National Survey of Problem-Solving Court Staff Perceptions of In-Person versus Virtual Hearings.

During the COVID-19 pandemic, problem-solving courts adopted virtual hearings. We conducted an online nationwide survey with a convenience sample of court staff to elicit their perceptions of court participants' attendance, engagement, willingness to talk, and ability to form connection with judges during in-person versus virtual hearings. Sign tests compared ordinal ratings for perceptions of court participant outcomes during in-person versus virtual hearing modalities, and for audiovisual technology versus audio-only technology. The final analysis included 146 staff. Staff felt that during in-person hearings judges could form closer relationships with participants, quality of information exchanged was higher, and participants were more willing to talk. Staff rated attendance as high regardless of the modality. Staff felt participant engagement was higher with audiovisual technology than audio-only technology. Our results suggest that staff have concerns about effects of virtual hearings on court participant engagement and ability to form relationships with judges. Courts should address these potential negative effects of virtual hearings. We are concerned that staff perceived participants more negatively when participants used audio-only versus audiovisual technology, because technology access could be associated with participant demographic characteristics. Further research is needed to examine court participant perceptions and outcomes.

Exotic Dark Matter Search with the Majorana Demonstrator.

With excellent energy resolution and ultralow-level radiogenic backgrounds, the high-purity germanium detectors in the Majorana Demonstrator enable searches for several classes of exotic dark matter (DM) models. In this work, we report new experimental limits on keV-scale sterile neutrino DM via the transition magnetic moment from conversion to active neutrinos ν_{s}→ν_{a}. We report new limits on fermionic dark matter absorption (χ+A→ν+A) and sub-GeV DM-nucleus 3→2 scattering (χ+χ+A→ϕ+A), and new exclusion limits for bosonic dark matter (axionlike particles and dark photons). These searches utilize the (1-100)-keV low-energy region of a 37.5-kg y exposure collected by the Demonstrator between May 2016 and November 2019 using a set of ^{76}Ge-enriched detectors whose surface exposure time was carefully controlled, resulting in extremely low levels of cosmogenic activation.

Sitting Less for Success: Reducing Sedentary Behaviors to Increase Kindergarten Achievement.

BACKGROUND: Physical activity (PA) improves outcomes, but disadvantaged children typically experience more sedentary behavior (SB). This study explored movement, executive function (EF) health, and academic achievement (AA) for economically disadvantaged kindergarteners. METHODS: Children in 2 classrooms (n = 16; n = 7) wore wrist-based accelerometers to assess PA/SB during the school day. Independent t-tests and analysis of variance analyzed mean group differences in PA/SB and EF/AA, and correlations explored AA and EF associations. RESULTS: The movement-based class spent significantly less time in SB compared to the contemporary class (t = 2.552, g = 1.115), made greater reading (t = -2.611) and math (t = .967) gains, and had better EF (t = .012). There were significant negative correlations between SB and math (r = -.534) and reading (r = -.592), but no significant relationships with EF. IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: Schools should consider methods to decrease time spent in SB at lower-SES schools, which is financially feasible and less time-consuming than programs to increase PA. CONCLUSION: Decreased SB time was associated with better AA. More research is needed to determine whether interventions to decrease time spent in SB at school improve academic outcomes in disadvantaged children.

Multi-omics for studying and understanding polar life.

Polar ecosystems are experiencing amongst the most rapid rates of regional warming on Earth. Here, we discuss 'omics' approaches to investigate polar biodiversity, including the current state of the art, future perspectives and recommendations. We propose a community road map to generate and more fully exploit multi-omics data from polar organisms. These data are needed for the comprehensive evaluation of polar biodiversity and to reveal how life evolved and adapted to permanently cold environments with extreme seasonality. We argue that concerted action is required to mitigate the impact of warming on polar ecosystems via conservation efforts, to sustainably manage these unique habitats and their ecosystem services, and for the sustainable bioprospecting of novel genes and compounds for societal gain.

Constraints on the Decay of

^{180m}Ta is a rare nuclear isomer whose decay has never been observed. Its remarkably long lifetime surpasses the half-lives of all other known ß and electron capture decays due to the large K-spin differences and small energy differences between the isomeric and lower-energy states. Detecting its decay presents a significant experimental challenge but could shed light on neutrino-induced nucleosynthesis mechanisms, the nature of dark matter, and K-spin violation. For this study, we repurposed the Majorana Demonstrator, an experimental search for the neutrinoless double-beta decay of ^{76}Ge using an array of high-purity germanium detectors, to search for the decay of ^{180m}Ta. More than 17 kg, the largest amount of tantalum metal ever used for such a search, was installed within the ultralow-background detector array. In this Letter, we present results from the first year of Ta data taking and provide an updated limit for the ^{180m}Ta half-life on the different decay channels. With new limits up to 1.5×10^{19} yr, we improved existing limits by 1-2 orders of magnitude which are the most sensitive searches for a single ß and electron capture decay ever achieved. Over all channels, the decay can be excluded for T_{1/2}<0.29×10^{18} yr.

Implant-Abutment Connections and Their Effect on Implant Survival Rates and Changes in Marginal Bone Levels (Δ): A Systematic Review and Meta-Analysis of 45,347 Oral Implants.

Purpose: To quantify the cumulative oral implant survival rates and changes in radiographic bone levels based on the configuration of the implant-abutment connection type over time. Materials and Methods: An electronic literature search was conducted in four databases (PubMed/MEDLINE, Cochrane Library, Web of Science, and Embase), and records were refereed by two independent reviewers based on the inclusion criteria. Data from included articles were grouped by implant-abutment connection type into four categories ([1] external hex; [2] bone level, internal, narrow cone < 45 degrees; [3] bone level, internal wide cone ≥ 45 degrees or flat; and [4] tissue level) and duration of follow-up (short-term 1 to 2 years, mid-term 2 to 5 years, and long-term > 5 years). Meta-analyses were performed for cumulative survival rate (CSR) and changes in marginal bone level (ΔMBL) from baseline (loading) to last reported follow-up. Studies were split or merged as appropriate based on the implants and follow-up duration in the study and trial design. The study was compiled under PRISMA 2020 guidelines and registered in the PROSPERO database. Results: A total of 3,082 articles were screened. Full-text review of 465 articles resulted in a total of 270 articles (representing 16,448 subjects with 45,347 implants) included for quantitative synthesis and analysis. Mean ΔMBL (95% CI) was as follows: short-term external hex = 0.68 mm (0.57, 0.79); short-term bone level, internal, narrow cone < 45 degrees = 0.34 mm (0.25, 0.43); short-term bone level, internal wide cone ≥ 45 degrees = 0.63 mm (0.52, 0.74); short-term tissue level = 0.42 mm (0.27, 0.56); mid-term external hex = 1.03 mm (0.72, 1.34); mid-term bone level, internal, narrow cone < 45 degrees = 0.45 mm (0.34, 0.56); mid-term bone level, internal wide cone ≥ 45 degrees = 0.73 mm (0.58, 0.88); mid-term tissue level = 0.4 mm (0.21, 0.61); long-term external hex = 0.98 mm, 0.70, 1.25); long-term bone level, internal, narrow cone < 45 degrees = 0.44 mm (0.31, 0.57); long-term bone level, internal wide cone ≥ 45 degrees = 0.95 mm (0.68, 1.22); and long-term tissue level = 0.43 mm (0.24, 0.61). CSRs (95% CI) were: short-term external hex = 97% (96%, 98%); short-term bone level, internal, narrow cone < 45 degrees = 99% (99%, 99%); short-term bone level, internal wide cone ≥ 45 degrees = 98% (98%, 99%); short-term tissue level = 99% (98%, 100%); mid-term external hex = 97% (96%, 98%); mid-term bone level, internal, narrow cone < 45 degrees = 98% (98%, 99%); mid-term bone level, internal wide cone ≥ 45 degrees = 99% (98%, 99%); mid-term tissue level = 98% (97%, 99%); long-term external hex = 96% (95%, 98%); long-term bone level, internal, narrow cone < 45 degrees = 98% (98%, 99%); long-term bone level, internal wide cone ≥ 45 degrees = 99% (98%, 100%); and long-term tissue level = 99% (98%, 100%). Conclusion: The configuration of the implant-abutment interface has a measurable effect on the ΔMBL over time. These changes can be observed over a period of at least 3 to 5 years. At all measured time intervals, similar ΔMBL was noted for external hex and internal wide cone ≥ 45-degree connections, as were internal, narrow cone < 45-degree and tissue-level connections.

Searching for Heavy Dark Matter near the Planck Mass with XENON1T.

Multiple viable theoretical models predict heavy dark matter particles with a mass close to the Planck mass, a range relatively unexplored by current experimental measurements. We use 219.4 days of data collected with the XENON1T experiment to conduct a blind search for signals from multiply interacting massive particles (MIMPs). Their unique track signature allows a targeted analysis with only 0.05 expected background events from muons. Following unblinding, we observe no signal candidate events. This Letter places strong constraints on spin-independent interactions of dark matter particles with a mass between 1×10^{12} and 2×10^{17} GeV/c^{2}. In addition, we present the first exclusion limits on spin-dependent MIMP-neutron and MIMP-proton cross sections for dark matter particles with masses close to the Planck scale.

Can patients detect peri­implant mucosal inflammation? Results from a multicentre randomized trial.

PURPOSE: The objective of this study was to compare patient-reported outcomes (PROs) of peri­implant soft tissue inflammation and aesthetics around single-tooth implants in the anterior maxillary region with three different implant-abutment interface designs. METHODS: Participants were randomized to one of three different types of implant-abutment interface designs [Conical (CI), flat-to-flat (FI), and Platform Switched (PS)]. Implants and provisional crowns with prefabricated titanium abutments were placed 5 months following extraction and/or ridge augmentation. Permanent ceramic crowns with zirconia abutments were placed after 12 weeks. To assess PROs, appearance and inflammation questionnaires were completed from provisional crown placement to the 3-year follow-up. RESULTS: Tooth appearance at the 3-year follow-up revealed a difference amongst CI, FI and PS implants (p=0.049; Kruskal-Wallis test). PS was rated better than FI (p=0.047) at 1 year for appearance of soft-tissue and satisfaction with colour. There were no differences for self-consciousness, smile and pain/discomfort while eating/hard food items. CONCLUSIONS: Although participants tended to rate the health of mucosa around PS implants as slighty better than the other two implant systems, the differences were minimal and inconsistent. Thus, patient satisfaction in terms self-perceived gingival health and esthetics was high for all 3 systems tested, suggesting that patients are unable to detect mucosal inflammation. CLINICAL SIGNIFICANCE: Patients find it difficult to perceive mucosal inflammation; hence, it is recommended that patients attend implant follow-up visits, even if they do not perceive inflammation. The study suggests that there is a relationship between the PROs and the clinical outcomes of tested implants.

Erratum: Search for Spontaneous Radiation from Wave Function Collapse in the Majorana Demonstrator [Phys. Rev. Lett. 129, 080401 (2022)].

This corrects the article DOI: 10.1103/PhysRevLett.129.080401.

Nature-positive goals for an organization's food consumption.

Organizations are increasingly committing to biodiversity protection targets with focus on 'nature-positive' outcomes, yet examples of how to feasibly achieve these targets are needed. Here we propose an approach to achieve nature-positive targets with respect to the embodied biodiversity impacts of an organization's food consumption. We quantify these impacts using a comprehensive database of life-cycle environmental impacts from food, and map exploratory strategies to meet defined targets structured according to a mitigation and conservation hierarchy. By considering the varying needs and values across the organization's internal community, we identify a range of targeted approaches towards mitigating impacts, which balance top-down and bottom-up actions to different degrees. Delivering ambitious nature-positive targets within current constraints will be challenging, particularly given the need to mitigate cumulative impacts. Our results evidence that however committed an organization is to being nature positive in its food provision, this is unachievable in the absence of systems change.

Individualized diet conversation in primary care: A pilot intervention.

BACKGROUND: Most primary care providers do not routinely discuss nutrition and diet with their patients, largely due to lack of time, inadequate resources, and perceived complexity of the topic. This article describes development and implementation of a brief protocol for systematically assessing and discussing diet during routine primary care visits to increase the frequency of these conversations and improve patient health outcomes. METHODS: The authors developed a protocol for assessing both nutrition and stage of change as well as a guide for engaging in patient-led conversations about nutrition. The protocol was modeled after Screening, Brief Intervention, and Referral to Treatment and informed by the Dietary Guidelines for Americans, the Transtheoretical Model of Behavior Change, and principles of motivational interviewing. It was implemented over three months at a rural health clinic staffed by one NP. RESULTS: The protocol and conversation guide were easy to use with minimal training and seamlessly incorporated into clinic workflow. The likelihood of making diet changes increased significantly following the diet conversation, with persons who initially scored lower in readiness to change ultimately reporting significantly greater increases. CONCLUSION: A protocol for assessing diet and engaging patients in a stage of change-appropriate diet conversation can be efficiently integrated into a single primary care visit and increase patients' intent to change their diet. Further investigation is needed to evaluate the protocol more completely and in multiple clinics.

Systematic review with meta-analysis: Current and emerging models of preoperative psychological preparation for individuals undergoing stoma surgery.

OBJECTIVE: Stoma surgery is a profoundly life changing event that can result in a range of negative psychological and mental health outcomes, often requiring significant postoperative adaption. While postoperative avenues of support to address these outcomes exist, there remains a lack of preoperative psychological preparation for surgical candidates in standard models of care. The present systematic review and meta-analysis aims to examine the current and emerging models of psychological preparation available to stoma surgery candidates during the preoperative period. METHODS: A systematic search of PubMed, Embase, Emcare, PsycINFO, CINAHL, and SCOPUS was conducted. All studies examining the effects of preoperative psychological interventions targeting postoperative psychological adjustment and/or mental health outcomes for individuals planning to undergo or who had undergone stoma surgery were included. RESULTS: Overall, 15 publications meeting inclusion criteria were identified, encompassing 1565 total participants. Intervention types ranged from psychoeducational, counselling, and practical based skills, examining the postoperative outcomes of anxiety, depression, quality of life, adjustment, self-efficacy, and systematic improvements to standard models of care. Five studies examining postoperative anxiety were included for meta-analysis, demonstrating an overall significant effect (SMD = -1.13, 95% CI -1.96 to -0.30, p = .008). Due to the high level of heterogeneity between remaining studies, articles examining postoperative outcomes other than anxiety were synthesised in narrative form. CONCLUSION: Despite some promising advancements in the field, there remains insufficient evidence to judge the overall effectiveness of current and emerging models of preoperative psychological preparation on postoperative psychological outcomes for individuals facing stoma surgery.

Perceptions of vaccine safety and hesitancy among incarcerated adults and correctional staff in the rural midwest.

Objectives: This project assessed vaccine hesitancy among staff and incarcerated adults in one rural medium-security prison in the Midwestern United States and identified differences in hesitancy across sociodemographic and work-related variables. Methods: 610 prison staff and people incarcerated completed a cross-sectional survey in May 2021. The vaccine hesitancy scale (VHS) identified perceived risk and confidence in vaccination. A single item assessed whether people typically follow public health protocols in the prison. A combination of analyses was utilized, including ANOVA, Chi-Square, and Pearson's correlation. Results: Vaccine hesitancy was moderate to high for both populations. Incarcerated people had more confidence in vaccination than staff; differences did not reach statistical significance. Incarcerated people had statistically significantly higher perceptions of risk compared to staff. Both populations reported doing their best to follow public health protocols. For both populations, vaccine hesitancy varied by education and veteran status. Among staff, hesitancy varied by gender and political beliefs. For people incarcerated, it varied by pre-incarceration income and visit frequency. Conclusions: Results support the need for public health policy and procedural interventions to reduce hesitancy towards vaccination in correctional settings.