Apoptotic cells promote circulating tumor cell survival and metastasis.

During tumor progression and especially following cytotoxic therapy, cell death of both tumor and stromal cells is widespread. Despite clinical observations that high levels of apoptotic cells correlate with poorer patient outcomes, the physiological effects of dying cells on tumor progression remain incompletely understood. Here, we report that circulating apoptotic cells robustly enhance tumor cell metastasis to the lungs. Using intravenous metastasis models, we observed that the presence of apoptotic cells, but not cells dying by other mechanisms, supports circulating tumor cell (CTC) survival following arrest in the lung vasculature. Apoptotic cells promote CTC survival by recruiting platelets to the forming metastatic niche. Apoptotic cells externalize the phospholipid phosphatidylserine to the outer leaflet of the plasma membrane, which we found increased the activity of the coagulation initiator Tissue Factor, thereby triggering the formation of platelet clots that protect proximal CTCs. Inhibiting the ability of apoptotic cells to induce coagulation by knocking out Tissue Factor, blocking phosphatidylserine, or administering the anticoagulant heparin abrogated the pro-metastatic effect of apoptotic cells. This work demonstrates a previously unappreciated role for apoptotic cells in facilitating metastasis by establishing CTC-supportive emboli, and suggests points of intervention that may reduce the pro-metastatic effect of apoptotic cells.

Pulmonary responses following cardiac rehabilitation and the relationship with functional outcomes in children and young adults with heart disease.

Introduction: Patients with congenital heart disease (CHD) often have pulmonary abnormalities and exercise intolerance following cardiac surgery. Cardiac rehabilitation (CR) improves exercise capacity in patients with CHD, but minimal study has been performed to see if resting and dynamic pulmonary performance improves following CR in those with prior cardiac surgery. Methods: This was a retrospective cohort study of all patients who completed ≥12 weeks of CR from 2018 through 2022. Demographic, cardiopulmonary exercise test (CPET), spirometry, 6-minute walk, functional strength measures, and outcomes data were collected. Data are presented as median[IQR]. A Student's t-test was used for comparisons between groups and serial measurements were measured with a paired t-test. A p < 0.05 was considered significant. Results: There were a total of 37 patients [age 16.7 (14.2-20.1) years; 46% male] included. Patients with prior surgery (n = 26) were more likely to have abnormal spirometry data than those without heart disease (n = 11) (forced vital capacity [FVC] 76.7 [69.1-84.3]% vs. 96.4 [88.1-104.7]%, p = 0.002), but neither group experienced a significant change in spirometry. On CPET, peak oxygen consumption increased but there was no change in other pulmonary measures during exercise. Percent predicted FVC correlated with hand grip strength (r = 0.57, p = 0.0003) and percent predicted oxygen consumption (r = 0.43, p = 0.009). The number of prior sternotomies showed negative associations with both percent predicted FVC (r = -0.43, p = 0.04) and FEV1 (r = -0.47, p = 0.02). Discussion: Youth and young adults with a prior history of cardiac surgery have resting and dynamic pulmonary abnormalities that do not improve following CR. Multiple sternotomies are associated with worse pulmonary function.

Deaf/hard of hearing students' experiences with higher education's real-time captioning services.

Real-time captions appear to be an effective tool in assisting deaf and hard of hearing (DHH) college students' access information and communication in certain classroom settings. However, there is limited knowledge of DHH students' direct experiences with real-time captioning services. In this study, we gathered narratives from 15 DHH college students across the United States about their experiences with real-time captioning services in college. We analyzed the stories using thematic narrative analysis and uncovered 4 types that students told about their experiences. The story types were (a) stories of overcoming obstacles, (b) stories of resignation, (c) pragmatic stories, and (d) stories of personal connection. These story types reveal that although many students eventually experience effective communication access through real-time captioning services, they can initially struggle to overcome barriers to using the services successfully. Making time and space to listen to DHH students' narratives can teach educators and professionals how to support these students and resolve barriers before they arise.

Switching to Dolutegravir/Lamivudine Two-Drug Regimen: Durability and Virologic Outcomes by Age, Sex, and Race in Routine US Clinical Care.

Purpose: Two-drug regimens (2DR) may address drug-drug interactions and toxicity concerns. Dolutegravir/lamivudine (DTG/3TC) 2DR was approved in the US for both treatment-naïve and treatment-experienced individuals with a viral load <50 copies/mL. This study describes real-world DTG/3TC 2DR treatment outcomes among treatment-experienced individuals, stratified by age, sex, and race. Methods: From the OPERA® cohort, people with HIV with a viral load <50 copies/mL who switched from a commonly used three-drug regimen to DTG/3TC 2DR as per the label between April 8, 2019 and April 30, 2021 were included. Incidence rates (Poisson regression) for loss of virologic control (first viral load ≥50 copies/mL), confirmed virologic failure (2 viral loads ≥200 copies/mL or discontinuation after 1 viral load ≥200 copies/mL), and DTG/3TC 2DR discontinuation were estimated overall and stratified by age, sex, and race. Results: The 787 individuals included were followed for a median of 13.6 months (IQR: 8.2, 22.3). Confirmed virologic failure occurred in ≤5 individuals. Loss of virologic control occurred at a rate of 14.0 per 100 person-years (95% CI: 11.7, 16.8). DTG/3TC 2DR discontinuation occurred at a rate of 17.5 per 100 person-years (95% CI: 15.0, 20.3); 4% discontinued for treatment-related reasons (viremia, adverse diagnosis, side effect, lab abnormality). For all outcomes, incidence rates were comparable across strata of age, sex, and race. Conclusion: This descriptive study demonstrates that DTG/3TC 2DR is an effective and well-tolerated treatment option for people with HIV with a viral load <50 copies/mL at switch, regardless of their age, sex, or race.

Ecological correlates of three-dimensional muscle architecture within the dietarily diverse Strepsirrhini.

Analysis of muscle architecture, traditionally conducted via gross dissection, has been used to evaluate adaptive relationships between anatomical form and behavioral function. However, gross dissection cannot preserve three-dimensional relationships between myological structures for analysis. To analyze such data, we employ diffusible, iodine-based contrast-enhanced computed tomography (DiceCT) to explore the relationships between feeding ecology and masticatory muscle microanatomy in eight dietarily diverse strepsirrhines: allowing, for the first time, preservation of three-dimensional fascicle orientation and tortuosity across a functional comparative sample. We find that fascicle properties derived from these digital analyses generally agree with those measured from gross-dissected conspecifics. Physiological cross-sectional area was greatest in species with mechanically challenging diets. Frugivorous taxa and the wood-gouging species all exhibit long jaw adductor fascicles, while more folivorous species show the shortest relative jaw adductor fascicle lengths. Fascicle orientation in the parasagittal plane also seems to have a clear dietary association: most folivorous taxa have masseter and temporalis muscle vectors that intersect acutely while these vectors intersect obliquely in more frugivorous species. Finally, we observed notably greater magnitudes of fascicle tortuosity, as well as greater interspecific variation in tortuosity, within the jaw adductor musculature than in the jaw abductors. While the use of a single specimen per species precludes analysis of intraspecific variation, our data highlight the diversity of microanatomical variation that exists within the strepsirrhine feeding system and suggest that muscle architectural configurations are evolutionarily labile in response to dietary ecology-an observation to be explored across larger samples in the future.

A Novel Tissue-Specific Insight into Sex Steroid Fluctuations Throughout the Murine Estrous Cycle.

Serum sex steroid levels fluctuate throughout the reproductive cycle. However, the degree to which sex steroid tissue content mimics circulating content is unknown. Understanding the flux and physiological quantity of tissue steroid content is imperative for targeted hormonal therapy development. Utilizing a gold-standard ultrasensitive liquid chromatography-mass spectrometry (LC/MS) method we determined sex steroid (17ß-estradiol [E2], testosterone, androstenedione, and progesterone) fluctuations in serum and in 15 tissues throughout the murine estrous cycle (proestrus, estrus, and diestrus I) and in ovariectomized (OVX) mice. We observed dynamic fluctuations in serum and tissue steroid content throughout the estrous cycle with proestrus generally presenting the highest content of E2, testosterone, and androstenedione, and lowest content of progesterone. In general, the trend in circulating steroid content between the stages of the estrous cycle was mimicked in tissue. However, the absolute amounts of steroid levels when normalized to tissue weight were found to be significantly different between the tissues with the serum steroid quantity often being significantly lower than the tissue quantity. Additionally, we found that OVX mice generally displayed a depletion of all steroids in the various tissues assessed, except in the adrenal glands which were determined to be the main site of peripheral E2 production after ovary removal. This investigation provides a comprehensive analysis of steroid content throughout the estrous cycle in a multitude of tissues and serum. We believe this information will help serve as the basis for the development of physiologically relevant, tissue-specific hormonal therapies.

Impact of ligand chlorination and counterion tuning on high-field spin relaxation in a series of V(IV) complexes.

Methods of controlling spin coherence by molecular design are essential to efforts to develop molecular qubits for quantum information and sensing applications. In this manuscript, we perform the first studies of how arrangements of 35/37Cl nuclear spins in the ligand shell and counterion selection affect the coherent spin dynamics of V(IV) complexes at a high magnetic field. We prepared eight derivatives of the vanadium triscatecholate complex with varying arrangements of 35/37Cl substitution on the catechol backbone and R3NH+ counterions (R = Et, n-Bu, n-Hex) and investigated these species via structural and spectroscopic methods. Hahn-echo pulsed electron paramagnetic resonance (EPR) experiments at high-frequency (120 GHz) and field (ca. 4.4 T) were used to extract the phase-memory relaxation time (Tm) and spin-lattice relaxation (T1) times of the series of complexes. We found Tm values ranging from 4.8 to 1.1 µs in the temperature range of 5 to 40 K, varying by approximately 20% as a function of substitutional pattern. In-depth analysis of the results herein and comparison with related studies of brominated analogues disproves multiple hypothesized mechanisms for Tm control. Ultimately, we propose that more specific properties of the halogen atoms, e.g. the chemical shift, V⋯Cl hyperfine coupling, and quadrupolar coupling, could be contributing to the V(IV) Tm time.

Gait Variability Structure Linked to Worse Cartilage Composition Post-ACL Reconstruction.

INTRODUCTION: Aberrant gait variability has been observed after anterior cruciate ligament reconstruction (ACLR), yet it remains unknown if gait variability is associated with early changes in cartilage composition linked to osteoarthritis development. Our purpose was to determine the association between femoral articular cartilage T1ρ magnetic resonance imaging relaxation times and gait variability. METHODS: T1ρ magnetic resonance imaging and gait kinematics were collected in 22 ACLR participants (13 women; 21 ± 4 yr old; 7.52 ± 1.43 months post-ACLR). Femoral articular cartilage from the ACLR and uninjured limbs were segmented into anterior, central, and posterior regions from the weight-bearing portions of the medial and lateral condyles. Mean T1ρ relaxation times were extracted from each region and interlimb ratios (ILR) were calculated (i.e., ACLR/uninjured limb). Greater T1ρ ILR values were interpreted as less proteoglycan density (worse cartilage composition) in the injured limb compared with the uninjured limb. Knee kinematics were collected at a self-selected comfortable walking speed on a treadmill with an eight-camera three-dimensional motion capture system. Frontal and sagittal plane kinematics were extracted, and sample entropy was used to calculate kinematic variability structure (KV structure ). Pearson's product-moment correlations were conducted to determine the associations between T1ρ and KV structure variables. RESULTS: Lesser frontal plane KV structure was associated with greater mean T1ρ ILR in the anterior lateral ( r = - 0.44, P = 0.04) and anterior medial condyles ( r = - 0.47, P = 0 .03). Lesser sagittal plane KV structure was associated with greater mean T1ρ ILR in the anterior lateral condyle ( r = - 0.47, P = 0.03). CONCLUSIONS: The association between less KV structure and worse femoral articular cartilage proteoglycan density suggests a link between less variable knee kinematics and deleterious changes joint tissue changes. The findings suggest that less knee kinematic variability structure is a mechanism linking aberrant gait to early osteoarthritis development.

Muscarinic receptor activation overrides boundary conditions on memory updating in a calcium/calmodulin-dependent manner.

Long-term memory storage is a dynamic process requiring flexibility to ensure adaptive behavioural responding in changing environments. Indeed, it is well established that memory reactivation can "destabilize" consolidated traces, leading to various forms of updating. However, the neurobiological mechanisms rendering long-term memories labile and modifiable remain poorly described. Moreover, boundary conditions, such as the age or strength of the memory, can reduce the likelihood of this destabilization; yet, intuitively, these most behaviourally influential of memories should also be modifiable under appropriate conditions. Here, we provide evidence that salient novelty at the time of memory reactivation promotes integrative updating of resistant object memories in rats. Furthermore, blockade of muscarinic acetylcholine receptors (mAChRs; with pirenzepine) or disruption of calcium/calmodulin (Ca2+/CaM) with KN-93, a Ca2+/CaM-binding molecule that inhibits calcium/calmodulin-dependent protein kinase II (CaMKII) activation, in perirhinal cortex (PRh) prevented novelty-induced destabilization and updating of resistant object memories. Finally, PRh M1 mAChR activation (with CDD-0102A) was sufficient to destabilize resistant object memories for updating, and this effect was blocked by KN-93, possibly via inhibition of CaMKII activity. Thus, mAChRs and activation of CaMKII appear to interact as part of a mechanism to override boundary conditions on resistant object memories to ensure integrative modification with novel information. These findings therefore have important implications for understanding the dynamic nature of long-term memory storage and potential treatments for conditions characterized by maladaptive and inflexible memories.

Heavily treatment-experienced people living with HIV in the OPERA® cohort: population characteristics and clinical outcomes.

BACKGROUND: Multi-class resistance, intolerance, and drug-drug interactions can result in unique antiretroviral (ART) combinations for heavily treatment-experienced (HTE) people living with HIV (PLWH). We aimed to compare clinical outcomes between HTE and non-HTE PLWH. METHODS: Eligible ART-experienced PLWH in care in the OPERA® Cohort were identified in a cross-sectional manner on December 31, 2016 and observed from the date of initiation of the ART regimen taken on December 31, 2016 until loss to follow up, death, study end (December 31, 2018), or becoming HTE (non-HTE group only). In the absence of resistance data, HTE was defined based on the ART regimens used (i.e., exposed to ≥ 3 core agent classes or regimen suggestive of HTE). Time to virologic undetectability, failure, and immunologic preservation were assessed using Kaplan-Meier methods; cumulative probabilities were compared between the two groups. Regimen changes, incident morbidities, and death were described. RESULTS: A total of 24,183 PLWH (2277 HTE PLWH, 21,906 non-HTE) were followed for a median of 28 months (IQR 21, 38). Viremic HTE PLWH (viral load [VL] ≥ 50 copies/mL) were less likely to achieve undetectability (VL < 50 copies/mL; 24-month cumulative probability: 80% [95% Confidence Interval 77-82]) than their non-HTE counterparts (85% [84-86]). No difference was observed in the probability of maintaining VLs < 200 copies/mL over the first 48 months after achieving suppression (< 50 copies/mL). HTE PLWH were less likely than non-HTE PLWH to maintain CD4 cell counts ≥ 200 cells/µL (24-month cumulative probability: 95% HTE [91-93]; 97% non-HTE [97-97]), and more likely to change regimens (45% HTE; 41% non-HTE). Incident non-AIDS defining event (ADE) morbidities were common in both populations, though more likely among HTE PLWH (45%) than non-HTE PLWH (35%). Incident ADE morbidities and deaths were uncommon among HTE (ADEs 5%; deaths 2%) and non-HTE (ADEs 2%; deaths 1%) PLWH. CONCLUSIONS: HTE PLWH were at greater risk of unfavorable treatment outcomes than non-HTE PLWH, suggesting additional therapeutic options are needed for this vulnerable population.

Real-Time Suicide Surveillance: Comparison of International Surveillance Systems and Recommended Best Practice.

OBJECTIVE: Some countries have implemented systems to monitor suicides in real-time. These systems differ because of the various ways in which suicides are identified and recorded. The main objective of this study was to conduct an international comparison of major real-time suicide mortality surveillance systems to identify joint strengths, challenges, and differences, and thereby inform best-practice criteria at local, national, and international levels. METHODS: Five major real-time suicide mortality surveillance systems of various coverage levels were identified and selected for review via an internet-based scoping exercise and prior knowledge of existing systems. Key information including the system components and practices was collated from those organizations that developed and operate each system using a structured template. The information was narratively and critically synthesized to determine similarities and differences between the systems. RESULTS: The comparative review of the five established real-time suicide surveillance systems revealed more commonalities than differences overall. Commonalities included rapid, routine surveillance based on minimal, provisional data to facilitate timely intervention and postvention efforts. Identified differences include the timeliness of case submission and system infrastructure. CONCLUSION: The recommended criteria could promote replicable components and practices in real-time suicide surveillance while offering flexibility in adapting to regional/local circumstances and resource availability.HIGHLIGHTSEvidence-informed recommendations for current best practice in real-time suicide surveillance.Proposed comprehensive framework can be adapted based on available resources and capacity.Real-time suicide mortality data facilitates rapid data-driven decision-making in suicide prevention.

Dissociating the involvement of muscarinic and nicotinic cholinergic receptors in object memory destabilization and reconsolidation.

The content of long-term memory is neither fixed nor permanent. Reminder cues can destabilize consolidated memories, rendering them amenable to change before being reconsolidated. However, not all memories destabilize following reactivation. Characteristics of a memory, such as its age or strength, impose boundaries on destabilization. Previously, we demonstrated that presentation of salient novel information at the time of reactivation can readily destabilize resistant object memories in rats and this form of novelty-induced destabilization is dependent upon acetylcholine (ACh) activity at muscarinic receptors (mAChRs). In the present study, we sought to determine if this same mechanism for initiating destabilization of resistant object memories is present in mice and further expand our understanding of the mechanisms through which ACh modulates object memory destabilization by investigating the role of nicotinic receptors (nAChRs). We provide evidence that in mice mAChRs are necessary for destabilizing object memories that are readily destabilized and those that are resistant to destabilization. Conversely, nAChRs were found to be necessary only when memories are readily destabilized. We then investigated the role of both receptors in the reconsolidation of destabilized object memory traces and determined that nAChRs, but not mAChRs, are necessary for object memory reconsolidation. Together, these results suggest that nAChRs may play a more selective role in the re-storage of object memories following destabilization and that ACh acts through mAChRs to act as an override signal to initiate destabilization of resistant object memories following reactivation with novelty. These findings expand our current understanding of the role of ACh in the dynamic storage of long-term memory.

The development and validation of a dashboard prototype for real-time suicide mortality data.

Introduction/Aim: Data visualisation is key to informing data-driven decision-making, yet this is an underexplored area of suicide surveillance. By way of enhancing a real-time suicide surveillance system model, an interactive dashboard prototype has been developed to facilitate emerging cluster detection, risk profiling and trend observation, as well as to establish a formal data sharing connection with key stakeholders via an intuitive interface. Materials and Methods: Individual-level demographic and circumstantial data on cases of confirmed suicide and open verdicts meeting the criteria for suicide in County Cork 2008-2017 were analysed to validate the model. The retrospective and prospective space-time scan statistics based on a discrete Poisson model were employed via the R software environment using the "rsatscan" and "shiny" packages to conduct the space-time cluster analysis and deliver the mapping and graphic components encompassing the dashboard interface. Results: Using the best-fit parameters, the retrospective scan statistic returned several emerging non-significant clusters detected during the 10-year period, while the prospective approach demonstrated the predictive ability of the model. The outputs of the investigations are visually displayed using a geographical map of the identified clusters and a timeline of cluster occurrence. Discussion: The challenges of designing and implementing visualizations for suspected suicide data are presented through a discussion of the development of the dashboard prototype and the potential it holds for supporting real-time decision-making. Conclusions: The results demonstrate that integration of a cluster detection approach involving geo-visualisation techniques, space-time scan statistics and predictive modelling would facilitate prospective early detection of emerging clusters, at-risk populations, and locations of concern. The prototype demonstrates real-world applicability as a proactive monitoring tool for timely action in suicide prevention by facilitating informed planning and preparedness to respond to emerging suicide clusters and other concerning trends.

Impact of COVID-19 on the Incidence and Severity of Obstetric and Gynecologic Emergency Department Visits in an Integrated Health Care System.

OBJECTIVE: COVID-19 has had an unprecedented impact on medical care use and delivery, including stark reductions in emergency department (ED) volume. The aim of this study was to assess changes in incidence of OB/GYN ED visits and disease severity at time of presentation during the COVID-19 pandemic. STUDY DESIGN: We conducted a multicenter retrospective study of OB/GYN-related ED visits before and during the COVID-19 pandemic. Incidence rates (IRs) and severity measures were compared across time periods and years. RESULTS: A total of 18,668 OB/GYN ED encounters occurred between January 1 and December 31, 2020, compared to 21,014 encounters between January 1 and December 31, 2019. During shelter-in-place, visits decreased by 41% compared to the pre-pandemic period in 2020 before returning to typical rates (incidence rate ratio (IRR) = 0.98 in fall/winter). We found a similar proportion of patients with hemoglobin < 7 g/dL for diagnoses associated with bleeding and patients with white blood cell count > 12,000 per µL in the setting of infection comparing corresponding time periods in 2019 and 2020. There were fewer formal OB/GYN consults, hospital admissions at time of presentation, and urgent surgical procedures performed across all periods in 2020; however, hospitalization within 7 days substantially increased in the first half of 2020. CONCLUSION: The incidence of OB/GYN ED visits declined substantially between March and August 2020 but then returned to pre-pandemic levels by fall/winter 2020. The decreased incidence was not accompanied by an increase in severity of presentation.

The evidence for and against reactivation-induced memory updating in humans and nonhuman animals.

Systematic investigation of reactivation-induced memory updating began in the 1960s, and a wave of research in this area followed the seminal articulation of "reconsolidation" theory in the early 2000s. Myriad studies indicate that memory reactivation can cause previously consolidated memories to become labile and sensitive to weakening, strengthening, or other forms of modification. However, from its nascent period to the present, the field has been beset by inconsistencies in researchers' abilities to replicate seemingly established effects. Here we review these many studies, synthesizing the human and nonhuman animal literature, and suggest that these failures-to-replicate reflect a highly complex and delicately balanced memory modification system, the substrates of which must be finely tuned to enable adaptive memory updating while limiting maladaptive, inaccurate modifications. A systematic approach to the entire body of evidence, integrating positive and null findings, will yield a comprehensive understanding of the complex and dynamic nature of long-term memory storage and the potential for harnessing modification processes to treat mental disorders driven by pervasive maladaptive memories.

T cell activation and IFNγ modulate organ dysfunction in LPS-mediated inflammation.

LPS challenge is used to model inflammation-induced organ dysfunction. The effects of T cell activation on LPS-mediated organ dysfunction and immune responses are unknown. We studied these interactions through in vivo administration of anti-CD3ε (CD3) T cell activating antibody and LPS. Mortality in response to high-dose LPS (LPSHi; 600 µg) was 60%; similar mortality was observed with a 10-fold reduction in LPS dose (LPSLo; 60 µg) when administered with CD3 (CD3LPSLo). LPSHi and CD3LPSLo cohorts suffered severe organ dysfunction. CD3LPSLo led to increased IFNγ and IL12p70 produced by T cells and dendritic cells (cDCs) respectively. CD3LPSLo caused cDC expression of CD40 and MHCII and prevented PD1 expression in response to CD3. These interactions led to the generation of CD4 and CD8 cytolytic T cells. CD3LPSLo responded to IFNγ or IL12p40 blockade, in contrast to LPSHi. The combination of TCR activation and LPS (CD3LPSLo) dysregulated T cell activation and increased LPS-associated organ dysfunction and mortality through T cell and cDC interactions.

The role of ATXR6 expression in modulating genome stability and transposable element repression in Arabidopsis.

ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) AND ATXR6 are required for the deposition of H3K27me1 and for maintaining genomic stability in Arabidopsis Reduction of ATXR5/6 activity results in activation of DNA damage response genes, along with tissue-specific derepression of transposable elements (TEs), chromocenter decompaction, and genomic instability characterized by accumulation of excess DNA from heterochromatin. How loss of ATXR5/6 and H3K27me1 leads to these phenotypes remains unclear. Here we provide extensive characterization of the atxr5/6 hypomorphic mutant by comprehensively examining gene expression and epigenetic changes in the mutant. We found that the tissue-specific phenotypes of TE derepression and excessive DNA in this atxr5/6 mutant correlated with residual ATXR6 expression from the hypomorphic ATXR6 allele. However, up-regulation of DNA damage genes occurred regardless of ATXR6 levels and thus appears to be a separable process. We also isolated an atxr6-null allele which showed that ATXR5 and ATXR6 are required for female germline development. Finally, we characterize three previously reported suppressors of the hypomorphic atxr5/6 mutant and show that these rescue atxr5/6 via distinct mechanisms, two of which involve increasing H3K27me1 levels.

Real-time suicide surveillance supporting policy and practice.

Suicide mortality rates are a strong indicator of population mental-health and can be used to determine the efficacy of prevention measures. Monitoring suicide mortality rates in real-time provides an evidence-base to inform targeted interventions in a timely manner and accelerate suicide prevention responses. This paper outlines the importance of real-time suicide surveillance in the context of policy and practice, with a particular focus on public health and humanitarian crises.

Feasibility and Enjoyment of Exercise Video Games in Older Adults.

Introduction: Several interventions have been developed to enhance social connectedness among older adults. However, little research has demonstrated their performance in a social distancing environment. Exergames are not only beneficial to older adults' physical and cognitive health, but they also allow players to interact with each other at a distance, which can reduce loneliness and increase social connection. The aim of this pilot study was to investigate older adults' perceptions of two commercially available exergames. Methods: Twenty healthy community-dwelling older adults (M age = 73.30, SD = 5.95, range = 65-84 years, 80% women) were recruited in this pilot study between July 2019 and February 2020. They were asked to play two exergames for 10 min each on the Xbox One with Kinect console: Just Dance and Kinect Sports Rivals. After gameplay, they provided both quantitative and qualitative feedback on these games. Results: Participants reported an average rating for exergame enjoyment. Greater enjoyment was significantly related with younger age and greater extraversion but not gender. Participants were highly motivated to do well on the games but reported lower scores for likelihood of playing these games in the future. Greater likelihood of future play was associated with younger age but not gender or extraversion. "Not aerobic or strengthen enough; not enough exertion," and "slower movements, repetition, clear purpose of doing the exercise" were some factors that would influence their decision to buy and play these games. Discussion: The preliminary results of this pilot study suggest that exergames may help address social isolation and loneliness-particularly during times of social distancing. Before applying exergames as a social isolation or loneliness intervention for older adults, study replication in larger representative studies and future work that examines important design issues related to older adults' experiences with these games is needed.

FDA-approved bone grafts and bone graft substitute devices in bone regeneration.

To induce bone regeneration there is a complex cascade of growth factors. Growth factors such as recombinant BMP-2, BMP-7, and PDGF are FDA-approved therapies in bone regeneration. Although, BMP shows promising results as being an alternative to autograft, it also has its own downfalls. BMP-2 has many adverse effects such as inflammatory complications such as massive soft-tissue swelling that can compromise a patient's airway, ectopic bone formation, and tumor formation. BMP-2 may also be advantageous for patients not willing to give up smoking as it shows bone regeneration success with smokers. BMP-7 is no longer an option for bone regeneration as it has withdrawn off the market. PDGF-BB grafts in studies have shown PDGF had similar fusion rates to autologous grafts and fewer adverse effects. There is also an FDA-approved bioactive molecule for bone regeneration, a peptide P-15. P-15 was found to be effective, safe, and have similar outcomes to autograft at 2 years post-op for cervical radiculopathy due to cervical degenerative disc disease. Growth factors and bioactive molecules show some promising results in bone regeneration, although more research is needed to avoid their adverse effects and learn about the long-term effects of these therapies. There is a need of a bone regeneration method of similar quality of an autograft that is osteoconductive, osteoinductive, and osteogenic. This review covers all FDA-approved bone regeneration therapies such as the "gold standard" autografts, allografts, synthetic bone grafts, and the newer growth factors/bioactive molecules. It also covers international bone grafts not yet approved in the United States and upcoming technologies in bone grafts.