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Abstract Introduction In emergency medicine, triage encompasses more than the initial prioritization of treatment; it also includes decisions about the most suitable level of care and disposition for each patient. However, the increasing use of mobile technology by patients in the emergency department (ED) introduces a new factor. This study aims to explore the relationship between patients’ cellphone use at the time of initial assessment and final disposition in the ED. Methods A prospective, cross-sectional study was conducted on 292 patients who presented to the ED between 9/1/2021 and 8/9/2022. Patients were stratified into two cohorts based on their behavior during the initial assessment: actively using a cell phone (n = 32) or not using a cell phone (n = 259). Final disposition was dichotomously recorded as admission or discharge. Hospital admission, hospital observation, and admission to the ED observation unit were consolidated into the combined category of admission. Results Patients not actively using their cell phone on initial assessment exhibited a discharge rate of 64%, while those engaged with their cellphones displayed notably higher dismissal rates at 94%. The calculated odds ratio (OR) of 8.4 (95% confidence interval: 1.96-36.0, p = 0.004) underscores a significantly heightened likelihood of dismissal among individuals actively using their cellphones, suggesting a potential association between cellphone use and a reduced probability of hospital admission. Conclusion The study suggests an association between cellphone use during initial ED assessment and higher discharge rates. While this introduces a novel concept, the study’s potential contribution to more informed and efficient triage decisions warrants careful consideration in future research and clinical applications.

Abstract Aims Intra‐aortic balloon pump (IABP) devices are commonly used in patients with heart failure related cardiogenic shock (HF‐CS), including those with out‐of‐proportion right ventricular (RV) dysfunction. Pulmonary artery pulsatility index (PAPi) is a haemodynamic surrogate for RV performance. We aimed to assess short‐term haemodynamic changes in patients with HF‐CS following IABP support stratified by baseline PAPi. Methods and results This is a single‐centre study of 67 consecutive patients with HF‐CS who underwent IABP placement between 2020 and 2022. The primary aim was haemodynamic changes of specific variables on pulmonary artery catheter monitoring over 72 h following IABP placement. Secondary aims were clinically significant changes in diuretic regimens, changes in inotropes or vasopressors at 72 h following IABP, along with clinical outcomes. Prior to IABP placement, 57% of the total cohort (median age 59 years [48, 69], 31% female) had Society of Cardiovascular Angiography and Interventions Stage C HF‐CS. Thirty‐eight (56%) patients had a PAPi

Abstract Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell’s protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal delivery of surface and extracellular targets while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer.

Abstract Modulating inflammation is critical to enhance nerve regeneration after injury. However, clinically applicable regenerative therapies that modulate inflammation have not yet been established. Here, we demonstrate synergistic effects of the combination of an HMG-CoA reductase inhibitor, statin/fluvastatin and critical components of the extracellular matrix, Matrix-Bound Nanovesicles (MBV) to enhance axon regeneration and neuroprotection after mouse optic nerve injury. Mechanistically, co-intravitreal injections of fluvastatin and MBV robustly promote infiltration of monocytes and neutrophils, which lead to RGC protection and axon regeneration. Furthermore, monocyte infiltration is triggered by elevated expression of CCL2, a chemokine, in the superficial layer of the retina after treatment with a combination of fluvastatin and MBV or IL-33, a cytokine contained within MBV. Finally, this therapy can be further combined with AAV-based gene therapy blocking anti-regenerative pathways in RGCs to extend regenerated axons. These data highlight novel molecular insights into the development of immunomodulatory regenerative therapy.

Abstract Background Two-drug regimens (2DRs) have been introduced in recent years to potentially reduce antiretroviral therapy (ART) toxicities and drug-drug interactions while demonstrating comparable efficacy to three-drug regimens (3DRs) for people with HIV (PWH). The objective of this study was to compare the real-world effectiveness and durability of a single-tablet 2DR of dolutegravir/lamivudine (DTG/3TC) with that of commonly prescribed 3DRs in ART-experienced, virologically suppressed PWH during the first 24 months of DTG/3TC availability in the United States. Methods Virologically suppressed (viral load [VL]

Background: Current treatment guidelines for infective endocarditis focus on left-sided infective endocarditis. Because right-sided infective endocarditis has different presentations and outcomes, it is crucial to further delineate surgical outcomes for isolated tricuspid valve endocarditis (TVE). Methods: This retrospective study reviewed 374 surgically treated patients with isolated TVE from January 2012 through April 2022 who underwent isolated tricuspid valve surgical procedures. Primary outcomes were in-hospital mortality, permanent pacemaker need, and postsurgical inotropic support. Results: The in-hospital mortality was 4% (n = 15). Patients with liver disease had 3.81-times higher odds of death vs no liver disease (odds ratio [OR], 3.81; 95% CI, 1.22-12.17). A pacemaker was required in 17% of patients without a prior pacemaker, which was 4.07 times the odds with tricuspid valve replacement (OR, 4.07; 95% CI, 1.72-11.60) vs tricuspid valve repair. Each yearly increase in patient age demonstrated lower odds of permanent pacemaker requirement by 7% (OR, 0.93; 95% CI, 0.89-0.97). The odds for postoperative inotropic support increased 2.55-times higher in patients receiving preoperative inotropic agents (OR, 2.55; 95% CI, 1.29-5.05), 2.27-times higher with renal failure (OR, 2.27; 95% CI, 1.38-3.74), and 86% higher in patients administered preoperative heparin (OR, 1.86; 95% CI, 1.14-3.02). Conclusions: Mortality of surgical treatment for TVE was 4%, with higher risks with liver disease. Tricuspid valve replacement was associated with higher odds for permanent pacemaker vs repair. Renal failure, preoperative inotropic support, and preoperative heparin were associated with higher odds for postoperative inotropic support. These findings further illustrate surgical outcomes with TVE.

Abstract Background The field of long COVID research is rapidly evolving, however, tools to assess and monitor symptoms and recovery of the disease are limited. The objective of the present study was to develop a new patient-reported outcomes instrument, the Symptoms Evolution of Long COVID‑19 (SE-LC19), and establish its content validity. Methods The 40-item SE-LC19 instrument was developed based on patient-relevant empirical evidence from scientific literature and clinical guidelines that reported symptoms specific to long COVID. A 2-part mixed-method approach was employed. Part 1: Qualitative interviews with a purposive sample of 41 patients with confirmed long COVID were conducted for the content validation of SE-LC19. During cognitive debriefing interviews, patients were asked to describe their understanding of the instrument’s instructions, specific symptoms, response options, and recall period to ensure its relevance and comprehensiveness. Five clinicians of different medical specialties who regularly treated patients with long COVID were also interviewed to obtain their clinical expert opinions on SE-LC19. Part 2: Exploratory Rasch Measurement Theory (RMT) analysis was conducted to evaluate the psychometric properties of the SE-LC19 data collected during the interviews. Results Overall, patients reported that the instructions, questions, recall period, and response options for SE-LC19 were comprehensive and relevant. Minor conceptual gaps reported by patients captured nuances in the experience of some symptoms that could be considered in future studies. Some patients suggested a revision of the recall period from 24 h to 7 days to be able to capture more symptoms given the waxing and waning nature of some symptoms. Clinicians found the instrument comprehensive with minimal suggestions regarding its content. Exploratory RMT analyses provided evidence that the SE-LC19 questionnaire performed as intended. Conclusion The present mixed-methods study in patients with confirmed long COVID supports the content validity and applicability of the SE-LC19 instrument to evaluate the symptoms of patients with long COVID. Further research is warranted to explore the psychometric properties of the instrument and refine a meaningful and robust patient-relevant endpoint for use in different settings such as clinical trials and clinical practice to track the onset, severity, and recovery of long COVID.

Submarine groundwater discharge (SGD) is a recognized contributor to the hydrological and biogeochemical functioning of coral reef ecosystems located along coastlines. However, the distribution, size, and thermal properties of SGD remain poorly understood at most land–reef margins. We developed, deployed, and demonstrated an operational method for airborne detection and mapping of SGD using the 200 km coastline of western Hawai‘i Island as a testing and analysis environment. Airborne high spatial resolution (1 m) thermal imaging produced relative sea surface temperature (SST) maps that aligned geospatially with boat-based transects of SGD presence–absence. Boat-based SST anomaly measurements were highly correlated with airborne SST anomaly measurements (R2 = 0.85; RMSE = 0.04 °C). Resulting maps of the relative difference in SST inside and outside of SGD plumes, called delta-SST, revealed 749 SGD plumes in 200 km of coastline, with nearly half of the SGD plumes smaller than 0.1 ha in size. Only 9% of SGD plumes were ≥1 ha in size, and just 1% were larger than 10 ha. Our findings indicate that small SGD is omnipresent in the nearshore environment. Furthermore, we found that the infrequent, large SGD plumes (>10 ha) displayed the weakest delta-SST values, suggesting that large discharge plumes are not likely to provide cooling refugia to warming coral reefs. Our operational approach can be applied frequently over time to generate SGD information relative to terrestrial substrate, topography, and pollutants. This operational approach will yield new insights into the role that land-to-reef interactions have on the composition and condition of coral reefs along coastlines.

Biological invasions can disrupt the close and longstanding coevolved relationships between host and parasites. At the same time, the shifting selective forces acting on demography during invasion can result in rapid evolution of traits in both host and parasite. Hosts at the invasion front may reduce investment into costly immune defences and redistribute those resources to other fitness-enhancing traits. Parasites at the invasion front may have reduced pathogenicity because traits that negatively impact host dispersal are left behind in the expanding range. The host’s immune system is its primary arsenal in the coevolutionary ‘arms race’ with parasites. To assess the effects of invasion history on immune responses to parasite infection, we conducted a cross-infection experiment which paired common-garden reared cane toads and lungworm parasites originating from various sites in their invaded range across northern Australia. Infected toads had larger spleens and higher concentrations of eosinophils than did uninfected toads. Infected toads also exhibited lower bacteria-killing ability, perhaps reflecting a trade-off of resources towards defences that are more specifically anthelminthic. The impact of infection intensity on multiple immune measures differed among toads and parasites from different parts of the invasion trajectory, supporting the hypothesis that invasion has disrupted patterns of local adaptation.

IntroductionNon-typhoidal Salmonella enterica (NTS) are leading bacterial agents of foodborne illnesses and a global concern for human health. While there are over 2,600 different serovars of NTS, epidemiological data suggests that certain serovars are better at causing disease than others, resulting in the majority of reported human illnesses in the United States. To improve food safety, there is a need to rapidly detect these more pathogenic serovars to facilitate their removal from the food supply.MethodsAddressing this need, we conducted a comparative analysis of 23 closed Salmonella genomic sequences of five serotypes. The analysis pinpointed eight genes (sseK2, sseK3, gtgA/gogA, avrA, lpfB, SspH2, spvD, and invA) that in combination, identify 7 of the 10 leading Salmonella serovars attributed to human illnesses in the US each year (i.e., Serovars of Concern or SoC). A multiplex PCR assay was developed to detect the presence of these genes, with strains amplifying five or more targets designated Highly Pathogenic Salmonella, or HPS. The utility of the resulting HPS assay for identifying SoC was examined in silico, using BLAST to determine the distribution of gene targets among closed Salmonella genome sequences in GenBank (n = 2,192 representing 148 serotypes) and by assaying 1,303 Salmonella (69 serotypes), isolated from FSIS regulatory samples.Results and discussionComparison of serotypes identified by the assay as HPS, with those identified as SoC, produced an Area Under the Curve (AUC) of 92.2% with a specificity of 96% and a positive predictive value of 97.4%, indicating the HPS assay has strong ability to identify SoC. The data presented lay the groundwork for development of rapid commercial assays for the detection of SoC.

ABSTRACT We studied a population of large varanid lizards (yellow‐spotted monitors Varanus panoptes) on a floodplain in tropical Australia. Growth records from radio‐tracked lizards show that despite their large adult body sizes (to > 7 kg in males), these lizards attained sexual maturity at less than 1 year of age and rarely lived for more than 2 years (females) or 4 years (males), even before mortality increased due to the arrival of toxic cane toads (Rhinella marina). This is a “faster” life history than has been reported for other species of large monitors. Growth was especially rapid in males during the wet season. The low survivorship prior to toad invasion was due to predation by pythons; communal nesting by female varanids may render them especially vulnerable. The life history of yellow‐spotted monitors requires high feeding rates, favouring the evolution of “risky” tactics such as consuming novel prey items (such as cane toads); and the combination of high abundance (> 20 adult lizards per square kilometre) and high feeding rates (> 9.9 kg of prey per lizard per annum) means that these giant lizards play a critical role in energy and nutrient flow within the floodplain ecosystem. As a result, foodwebs with the yellow‐spotted monitor as an apex predator are more vulnerable to disruption by cane toads than is the case in other parts of the toad's invasive range, where the varanid species affected by toads have “slower” life histories.

Category: Ankle; Midfoot/Forefoot Introduction/Purpose: In the United States, there has been a substantial rise in podiatrists to address the increasing prevalence of foot and ankle pathologies. Although this may improve accessibility to foot and ankle care, there may be differences in the quality of care delivered by podiatrists compared to orthopedic surgeons. Some studies have found that patients treated by podiatrists have higher postoperative complication rates and length of hospital stay. With a growing emphasis on patient-centered care, there is a need for research investigating these differences so patients can make informed decisions when selecting providers. The purpose of our study is to compare postoperative complications in common foot and ankle procedures performed by orthopedic surgeons and podiatrists. Methods: A national database was queried to identify patients 18 years and older who underwent forefoot surgery (including fusion and bunionectomy), hindfoot or midfoot fusion, rotational ankle fracture fixation, ankle arthrodesis, or ankle arthroplasty from 2009-2022. Provider variable codes were then utilized to identify patients who underwent the corresponding procedures by orthopedic surgeons and podiatrists. Univariate analyses and multivariate logistic regressions were performed to compare 90-day rates of medical and surgical complications between the two provider categories for each procedure while controlling for age, sex, diabetes, smoking, and obesity. Results: Overall, 34,807 patients underwent foot and ankle (F&A) procedures by an orthopedic surgeon and 43,787 patients by a podiatric surgeon. Orthopedic patients were older (51.77 versus 50.79; p< 0.001), had a higher comorbidity index (Charlson Comorbidity Score 1.13 versus 0.97; p< 0.001), and were more likely to undergo surgery from an inpatient facility (16.18% versus 2.18%; p< 0.001). Comparing 90-day complication rates, podiatry patients exhibited higher rates of complications, including neuritis, nonunion, prosthetic complications, and wound debridement across various procedures when compared to orthopedic surgeons. Conclusion: Common foot and ankle procedures performed by podiatrists may be associated with higher postoperative complications affecting quality of care which could be attributed to differences in training, case volume and variety, and surgical techniques between orthopedic surgeons and podiatrists. Although access to foot and ankle procedures has improved, these data raise questions about the safety of procedures performed by podiatrists. Thus, additional highly powered studies are needed to investigate these postoperative differences to ensure that patients have all the information necessary to make informed decisions regarding their care.

BackgroundGiant cell arteritis (GCA) is the most common vasculitis in patients older than 50 years and is considered a “do not miss” diagnosis. However, it remains a diagnostic challenge given overlapping clinical syndromes such as non-arteritic anterior ischemic optic neuropathy (NAION) and poorly explored imaging findings.Materials and methodsIn this retrospective study between the time period of January 2013 and December 2021, a total of 13 consecutive patients with a pathological diagnosis of GCA and 8 patients with clinical diagnosis of NAION were isolated. Demographic and clinical data for each patient were collected, including pertinent laboratory data. Pertinent physical exam data was also collected, including fundoscopic exam and visual acuity. Two neuroradiologist assessed the orbital MRI imaging findings of GCA and NAION for the presence and characterization of imaging abnormalities. Assessment for potential relationship between GCA orbital findings, laboratory and visual outcomes was performed. Finally, comparison between GCA and NAION imaging findings was performed.Results13 GCA patients were assessed. 9 patients had abnormal orbital findings. Of these 8 patients had bilateral orbital involvement The most common imaging findings was perineuritis of the optic nerve sheath, present in 7 patients. In total, 8 NAION patients were assessed. All patients demonstrate optic nerve involvement. The Snellen test was converted to logmar, and visual acuity was assessed for both NAION and GCA for each eye at diagnosis and at the last follow-up. There was no statistical significance for either eye for both GCA and NAION at initial diagnosis and final follow-up. In the 4 GCA patients with normal MRI findings and 9 GCA patients with abnormal MRI findings, there was no statistical significance between initial presentation and final follow-up visual acuity.ConclusionGCA and NAION are potentially overlapping clinical syndromes with different treatment approach and poorly explored imaging findings. Our case series assesses the orbital imaging findings of both syndromes while noting different imaging pattern of both on MRI, which can serve as a potential tool to aid in diagnosis of both.

Category: Hindfoot; Other Introduction/Purpose: There are few comparative studies between the traditional triple arthrodesis and the commonly performed modified procedure in which the calcaneocuboid joint is spared. Earlier investigations proposed that stiffening the lateral column of the hindfoot can increase lateral plantar pressures, potentially precipitating lateral column pain. We used a cadaver model to quantify the potential for reduced lateral column overload achieved by sparing the calcaneocuboid joint in a cadaveric model of triple arthrodesis simulating standing on both a neutral and sloping surface. Methods: Nine fresh-frozen, thawed cadaver legs were tested in 2 positions of the loaded surface: neutral and 10 degrees of eversion. Tendon loading and axial pressure was applied according to standard cadaveric models. Medial and lateral forefoot pressures were recorded using a pressure-sensitive plate (F-scan). The data were normalized as a percentage of the native state. Results: In neutral loading, the mean contact pressures under the fifth metatarsal head increased dramatically compared to the native state in both the standard (76.3%, p

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: Minimally invasive surgery (MIS) techniques have largely focused on first metatarsal osteotomies in hallux valgus correction, but have also been used for joint preparation in foot and ankle surgery. Concurrently, new fixation methods allow early weightbearing protocols with the open Lapidus procedure, with nonunion rates comparable to those of more traditional protocols requiring prolonged nonweightbearing. We aimed to assess the nonunion rate and clinical results of a percutaneous modified Lapidus (PML) technique with axial nail fixation (Phantom Lapidus Intramedullary Nail: Paragon28, Englewood, CO USA) and early weightbearing. Methods: A retrospective chart review was performed for a consecutive series of 88 feet in 70 patients who underwent the PML technique from June 2018 to January 2023 by two fellowship-trained orthopedic foot and ankle surgeons. Indications for surgery included moderate to severe hallux valgus deformity with or without first tarsometatarsal joint (TMT) instability, first TMT arthritis, adolescent bunion, and failed prior surgery. All patients initiated weightbearing in a controlled ankle motion (CAM) boot within 12 days from surgery. Nonunion rate was defined as a symptomatic nonunion (confirmed with CT scan) that underwent revision surgery. Patients were also sent follow-up questionnaires to obtain postoperative visual analog scale (VAS) pain scores, Patient-Reported Measurement Information System (PROMIS) Physical Function scores, PROMIS Pain Interference scores, and ability to return to work. Results: Overall nonunion rate was 9.1%. All nonunions were successfully treated with nail retention, medial plate augmentation and bone grafting. There was a 15.9% all-cause reoperation rate on the 1st ray. There were 3 minor wound complications (3.4%). Average tourniquet time for the PML technique (cases performed in isolation) was 65 minutes. Survey response rate was 50%. Average follow-up time from surgery to survey response was 3.4 years (SD 1.3, range 1.2 - 5.7). VAS scores improved from 3.5 (SD 2.6) preoperatively to 0.7 (SD 1.1, range 0 – 5). Mean postoperative PROMIS Physical Function and Pain Interference scores were 56.1 (SD 6.8) and 43.6 (SD 6.6), respectively. All patients who were employed within 6 months prior to surgery were able to return to work. Conclusion: The PML technique combined with early weightbearing yields low rate of wound complications and nonunion rates comparable to historical cohorts using prolonged weightbearing protocols. For the patient, this technique additionally provides improved cosmesis and accelerated rehabilitation.

Category: Hindfoot; Other Introduction/Purpose: The Evans osteotomy is a lateral column lengthening procedure of the calcaneus that is commonly used in the correction of flexible flatfoot deformities. Currently, there is no consensus on whether fixation is necessary when performing this osteotomy. The primary aim of this study was to determine the nonunion rate of an unfixed Evans osteotomy with use of an allograft wedge performed in patients undergoing flexible flatfoot reconstruction. The secondary aim was to report on the incidence and magnitude of calcaneocuboid (CC) joint subluxation. Methods: a retrospective chart review was done for a consecutive series of 145 feet in 137 patients who underwent Evans osteotomy as part of a flatfoot reconstruction with allogenic bone graft between January 2013 and October 2017, by a single fellowship-trained foot and ankle surgeon. Of those, 118 cases were available for analysis at a mean follow up of 62.5 weeks (SD 56.9). No fixation was used in any case. Time to union, estimated by clinical and plane radiographic evaluation was recorded, along with standard measures of deformity correction and CC joint subluxation. Results: There was only one nonunion 1/118 (0.84%) at final follow up. The mean time to union was 10.9 weeks (SD 1.56). Postoperative calcaneocuboid joint subluxation occurred in 50.8% of feet, with a mean of 1.51 mm, SD 2.3 mm and no correlation with wedge size (r=0.05, p=0.55). The mean wedge size was 7.1 mm , SD 1.4 mm (range, 5-12 mm). There was no correlation between wedge size and change in lateral column length (r=0.13, p=0.16). There was significant change between pre and postoperative calcaneal pitch, talonavicular uncoverage percentage, anteroposterior and lateral talo-first metatarsal angle, medial and lateral column height, and lateral column length (p < 0.05). Conclusion: Evans osteotomy without fixation for symptomatic flatfoot deformity resulted in an exceptionally low nonunion rate. CC joint subluxation occurred frequently but was small in magnitude, a finding that may be related to the relatively small size of the wedges used.

Category: Midfoot/Forefoot; Other Introduction/Purpose: The development of adjacent joint arthritis following arthrodesis is a universal concern in orthopaedic surgery. Arthrodesis of the hallux metatarsophalangeal (MTP) joint is an effective and commonly performed treatment for first MTP arthritis and other conditions. Despite its widespread use, the risk of symptomatic degeneration at the interphalangeal joint remains undetermined and is a common question from patients considering the procedure. This study investigated the rate of subsequent hallux interphalangeal joint (IPJ) fusion following arthrodesis of the first MTP joint using a large commercial database. Methods: Patients who underwent hallux interphalangeal arthrodesis after hallux metatarsophalangeal arthrodesis were identified from a large national commercial insurance database using CPT code identification (PearlDiver). The Kaplan-Meier curve for survivorship free of subsequent interphalangeal fusion was generated covering 10 years from the index operation. Results: Of 87,890 patients who had first metatarsophalangeal arthrodesis, 808 patients (0.91%) subsequently underwent subsequent hallux interphalangeal joint arthrodesis within 10 years. Because CPT codes were reported without laterality, it is possible that a small subset of patients may have undergone a subsequent contralateral IP fusion, and therefore this result should be regarded as an upper limit of the possible rate. Conclusion: This is the first large-scale data to address the common patient concern of subsequent degeneration of the interphalangeal joint following metatarsophalangeal fusion. The rate of subsequent fusion is less than 1%, a result that highlights the durability of the clinical result of the first MTP fusion and should reassure patients and surgeons considering the procedure relative to motion-sparing alternatives.

Background: Patients with recent acute coronary syndrome (ACS) commonly experience chest pain, which affects quality of life even when not due to recurrence of ACS. This post hoc analysis of ODYSSEY OUTCOMES assessed the effect of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, on the incidence of chest pain not due to recurrent ACS. Methods: Patients with recent ACS (n = 18,894) and elevated atherogenic lipoprotein levels despite optimized statin therapy were randomized to subcutaneous alirocumab or matching placebo every 2 weeks. Alirocumab dose was adjusted to target low-density lipoprotein cholesterol (LDL-C) 25–50 mg/dL (0.6–1.3 mmol/L) and to avoid consecutive LDL-C

Background: Pain associated with osteoarthritis (OA) is frequently disabling; treatments are often ineffective or intolerable. Fasinumab selectively inhibits nerve-growth factor and has shown efficacy for the management of OA pain. Methods: In this randomized, double-blind, phase III safety study, patients with moderate-to-severe OA pain and history of inadequate pain relief received placebo or fasinumab (at 1, 3, 6, and 9 ​mg every 4 weeks [Q4W] and 1 and 6 ​mg every 8 weeks [Q8W] for 52 weeks). Primary safety endpoints included adverse events, adjudicated arthropathies (AAs), and joint replacements (JRs). Co-primary endpoints of an efficacy sub-study were change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores. During the study, higher fasinumab doses were discontinued for safety; 1 ​mg doses continued. Results: Of 13,945 patients screened, 5331 were randomized; 1074 were included in the efficacy sub-study. AAs and JRs occurred in all groups. Increased severity of disease at baseline was associated with higher rates of AAs and JRs. A dose-dependent risk of AA or JR was observed for fasinumab; in the 1 ​mg groups, only a small percentage of patients with JR had prior AA. Fasinumab significantly improved WOMAC pain and physical function scores compared with placebo; least squares mean differences versus placebo were −1.22 and ​−1.20 for 1 ​mg Q4W and −0.73 and ​−0.74 for 1 ​mg Q8W, respectively (P

Heterochromatin is an organizational property of eukaryotic chromosomes, characterized by extensive DNA and histone modifications, that is associated with the silencing of transposable elements and repetitive sequences. Maintaining heterochromatin is crucial for ensuring genomic integrity and stability during the cell cycle. During meiosis, heterochromatin is important for homologous chromosome synapsis, recombination, and segregation, but our understanding of meiotic heterochromatin formation and condensation is limited. In this review, we focus on the dynamics and features of heterochromatin and how it condenses during meiosis in plants. We also discuss how meiotic heterochromatin influences the interaction and recombination of homologous chromosomes during prophase I.

Background Nearly half of active duty Royal Canadian Mounted Police (RCMP) officers report experiencing current chronic pain (43%; i.e. pain lasting longer than 3 months). Most RCMP officers who report chronic pain indicate that the pain started after working as RCMP officers (91%). Baseline data on chronic pain prevalence among RCMP cadets has not been available.Aims The current study was designed to provide cross-sectional estimates of chronic pain prevalence among RCMP cadets starting the Cadet Training Program and to assess for sociodemographic differences among participants.Methods The RCMP Study uses a longitudinal prospective sequential experimental cohort design to create a clustered randomized trial that engages individual participants for 5.5 years. The current article provides cross-sectional associations between chronic pain prevalence and sociodemographic characteristics. Participants were RCMP cadets starting the Cadet Training Program (n = 770). Location, intensity (on a 0–10 scale and days per week experienced), and duration (number of months) of chronic pain were reported. Differences across sociodemographic characteristics were examined.Results Few RCMP cadets reported experiencing chronic pain (10%); lower back pain was rated as the most severe in terms of intensity and duration and second most frequently reported in number of days experienced per week. Prevalence of chronic pain was lower among RCMP cadets than among RCMP officers.Conclusions Chronic pain prevalence among active duty RCMP officers may result from or be moderated by operational duties, as well as routine aging. Future researchers could examine ways to mitigate chronic pain development during RCMP officer careers.

Muskrat (Ondatra zibethicus) populations are declining in North America. The exact cause of these declines is largely unknown. Along a similar timeframe, wetlands have been experiencing an invasion of cattail (Typha) throughout the continent. Specifically, T. x glauca, a hybrid of native T. latifolia and non-native T. angustifolia, has been increasing in range and abundance. This hybrid is associated with many negative impacts on wetland ecosystems, including reductions in biodiversity, open water habitat, and interspersion of water and emergent vegetation, the latter of which is an important habitat feature for muskrats. We sought to determine the impact of invasive T. x glauca on muskrat populations. We sampled 39 Typha-dominated marshes in southern Ontario, Canada to test the hypotheses that muskrats are declining in North America due to: (1) the increased relative abundance of T. x glauca in marshes, and (2) reduced wetland interspersion, which is associated with T. x glauca invasions. We estimated muskrat population density using house counts, sampled Typha communities to determine the relative abundance of T. x glauca, and measured interspersion using remote sensing techniques. We found that muskrat population density was positively associated with interspersion, but not associated with the relative abundance of T. x glauca. However, most sites were highly dominated by T. x glauca, limiting our inference. Our findings suggest that changing wetland structure may be contributing to muskrat population declines in North America, but more research is needed to determine the full impact of T. x glauca invasions on muskrat population declines.

What is this summary about? This plain language summary shares results from a clinical study called INTEGRIS-IPF that was published in the American Journal of Respiratory and Critical Care Medicine in 2024. This study looked at a medicine called bexotegrast (beck-so-teh-grast) as a possible treatment for idiopathic pulmonary fibrosis (i-dee-uh-pa-thick pul-muh-ner-ee fie-bro-sis; IPF). Bexotegrast is an investigational medicine, which means that it is being studied and has not yet been approved by the US Food and Drug Administration (FDA), for people with IPF to take as a treatment. IPF is a chronic, progressive lung disease that makes it hard to breathe and gets worse over time. There is no cure for IPF, treatment includes symptom management and consideration for the use of nintedanib or pirfenidone , which may decrease the pace of disease progression. The study compared bexotegrast to a placebo (a treatment that looks identical to the medicine but has no medicinal effect) to look at how well it works and how safe it is in treating people with IPF. Most people in the study also took one of two medicines that are already approved by the FDA for IPF, pirfenidone or nintedanib .

Abstract Introduction This study aimed to assess the effects of a monoclonal antibody (mAb) combination on symptoms, daily function, and overall health-related quality of life. Methods We analyzed patient-reported outcomes data from symptomatic outpatients in a phase 1/2/3 trial. Patients with confirmed SARS-CoV-2 infection and ≥ 1 risk factor for severe COVID-19 received mAb treatment (casirivimab plus imdevimab 1200 mg) or placebo. Prespecified exploratory assessments included time to sustained symptoms resolution, usual health, and return to usual activities (assessed daily for 29 days). The trial was conducted from September 2020 to February 2021, prior to widespread COVID-19 vaccination programs and Omicron-lineage variants against which casirivimab + imdevimab is not active. Results In this analysis 736 outpatients received mAb and 1341 received placebo. Median time to sustained symptoms resolution was consistently shorter with mAb versus placebo (≥ 2 consecutive days: 14 vs 17 days, [nominal p = 0.0017]; ≥ 3 consecutive days: 17 vs 21 days, [nominal p = 0.0046]). Median time to sustained return to usual health and usual activities were both consistently shorter with mAb versus placebo (≥ 2 consecutive days: 12 vs 15 days [nominal p = 0.0001] and 9 vs 11 days [nominal p = 0.0001], respectively; ≥ 3 consecutive days: 14 vs 18 days [nominal p = 0.0003] and 10 vs 13 days [nominal p = 0.0041], respectively). Conclusions mAb treatment against susceptible SARS-CoV-2 strains improved how patients feel and function, as evidenced by shortened time to sustained symptoms resolution and return to usual health and activities. Future studies are warranted to assess the patient experience with next generation mAbs. ClinicalTrials.gov Registration number, NCT04425629; Submission date June 11, 2020.

Introduction:. The orthopaedic surgery physician workforce is predominately White and male and has been identified as the least diverse medical specialty. Increasing efforts toward diversification within orthopaedic surgery are underway. Evaluating the effectiveness of these programs requires a thorough understanding of the current demographic profile of the profession. Methods:. The American Board of Orthopaedic Surgery (ABOS) is the leading board certification organization for orthopaedic surgeons in the United States. The ABOS began collecting self-reported race/ethnicity and sex/gender data of its examinees and diplomates in 2017. This new data set of ABOS was analyzed to describe both the current demographic profile of orthopaedic surgery and trends over time. Underrepresented minority (URM) was defined as a group that is less well represented in orthopaedic surgery than in US census data and includes female, American Indian or Alaska Native, Black or African American, Hispanic/Latino, and Native Hawaiian or Other Pacific Islander categories. Results:. Of the 21,025 currently practicing ABOS diplomates with time-limited ABOS certificates (issued since 1986), 19,912 (94.7%) provided sex/gender data, and 19,876 (94.5%) provided race/ethnicity data. Approximately 84.78% selected male and 8.43% female. The majority identified as White (73.67%), whereas 16.35% selected a URM race/ethnicity category. There have been significant increases in the proportions of female (odds ratio [OR] = 4.72, 95% confidence interval [CI] = 3.64-6.11, p < 0.001) and URM (OR = 2.31, 95% CI = 1.80-2.96, p < 0.0001). Diplomates among orthopaedic surgeons attaining ABOS board Diplomates from 1989 to present. Among the subspecialties, pediatric orthopaedics reported the highest percentage of females (30.4%). Spine had both the lowest percentage of females (2.63%) and the highest percentage of URMs (8.97%). Sports had the lowest percentage of URMs at 5.63%. Conclusion:. Orthopaedic surgery in 2023 remains largely White and male. However, there have been promising trends toward diversification of orthopaedic surgery both in terms of gender and race/ethnicity. Specialties within orthopaedics have a wide variety of demographic profiles. Level of Evidence:. Level IV Retrospective Cohort Study. See Instructions for Authors for a complete description of levels of evidence.

Auditory hallucinations (AH) are the most common symptom of psychosis. The voices people hear make comments that are benign or even encouraging, but most often voices are threatening and derogatory. Negative AH are often highly distressing and contribute to suicide risk and violent behavior. Biological mechanisms underlying the valence of voices (i.e., positive, negative, neutral) are not well delineated. In the current study, we examined whether AH voice valence was associated with increased activation of the Defensive Motivational System, as indexed by central and autonomic system response to unpleasant stimuli. Data were evaluated from two studies that used a common symptom rating instrument, the Psychotic Symptom Rating Scale (PSY-RATS), to measure AH valence. Participants included outpatients diagnosed with SZ. Tasks included: Study 1: Trier Social Stress Task while heart rate was recorded via electrocardiography (N = 27); Study 2: Passive Viewing Task while participants were exposed to pleasant, unpleasant, and neutral images from the International Affective Picture System (IAPS) library while eye movements, pupil dilation, and electroencephalography were recorded (N = 25). Results indicated that negative voice content was significantly associated with: 1) increased heart rate during an acute social stressor, 2) increased pupil dilation to unpleasant images, 3) higher neural reactivity to unpleasant images, and 4) a greater likelihood of having bottom-up attention drawn to unpleasant stimuli. Findings suggest that negative AH are associated with greater Defensive Motivational System activation in terms of central and autonomic nervous system response.

Objectives: Greener neighbourhoods may support physical activity; however, it is also important to consider whether greener neighbourhoods are walkable. We assessed whether neighbourhood greenness and walkability were independently and jointly associated with transportational (PATRA) and recreational (PAREC) physical activity among a nationally representative sample of urban-dwelling youth and adults in Canada. Methods: We analyzed repeated cross-sectional data from 132,927 urban-dwelling youth (12–17 years) and adults (≥18 years) who participated in the Canadian Community Health Survey (2015–2018). To derive an indicator of neighbourhood greenness, for each survey year, we aggregated mean Normalized Difference Vegetation Index (NDVI) values within 2016 dissemination areas. As a proxy for neighbourhood walkability, we used 2016 Canadian Active Living Environments (Can-ALE) metrics. We used weighted linear regressions to examine whether, and the extent to which, neighbourhood NDVI and the Can-ALE index were independently and jointly associated with self-reported and log-transformed PATRA and PAREC, while adjusting for individual and neighbourhood characteristics. Results: Among adults, but not youth, higher NDVI was independently associated with higher PATRA (β = 0.2, 95 % CI 0.02, 0.36) and PAREC (β = 0.3, 95 % CI 0.14, 0.47). Among both youth (β = 0.4, 95 % CI 0.21, 0.66) and adults (β = 0.3, 95 % CI 0.22, 0.35), NDVI and Can-ALE were jointly associated with PATRA. Conclusion: Living in a neighbourhood that is both greener and more walkable was more strongly associated with higher transportational, but not recreational, physical activity, than either feature alone. These novel findings highlight the importance of designing cities that are both greener and more walkable to promote active living.

Suprascapular nerve (SSN) entrapment is a rare but significant cause of posterior shoulder pain and weakness. Compression of the nerve at the level of the spinoglenoid notch leads to weakness and atrophy of the infraspinatus. A detailed history and physical examination along with appropriate workup are paramount to arrive at this diagnosis. Surgical decompression is indicated in cases refractory to conservative management. In this Technical Note, we describe our technique for open decompression of the SSN at the spinoglenoid notch. This approach permits direct visualization of the SSN and allows for a safe, reliable, and thorough decompression.

Background Prematurely born adults have increased risk for cardiovascular disease. There are limited cardiac data on US‐born preterm individuals. We aimed to determine whether adolescents and adults born prematurely have altered left ventricular (LV) structure and function, and to interrogate diastolic function using isometric handgrip exercise. Methods and Results Adolescents and adults born moderately to extremely preterm (≤32 weeks gestation or

Abstract Biogenic organic compounds in the surface ocean may significantly alter the cloud‐forming ability of sea spray aerosol and thereby affect the amount of solar radiation reaching the ocean surface. Estimates of the organic mass fraction of sea spray vary widely, and some results show a significant dependence on biological activity in the source seawater. We present airborne observations of the organic mass fraction of individual sea spray particles measured using the Particle Analysis by Laser Mass Spectrometry (PALMS) instrument during the Atmospheric Tomography (ATom) mission, which sampled a wide range of latitudes and altitudes over the remote Atlantic and Pacific Oceans across four seasons, from the marine boundary layer to the upper troposphere. The measured sea spray particles of about 0.15–0.7 μm dry diameter showed higher average organic mass fractions at smaller sizes, but values were low overall, with regional integrated submicron means almost always

Purpose: To compare the biomechanical performance of a suture with proposed dynamic self-tensioning properties with that of commonly used high-tensile sutures by evaluating suture loop length changes, responses to cyclic loading, and failure testing with intermittent saline soaks. Methods: Six knots each of 4 different sutures were studied: 3 high-tensile sutures (ORTHOCORD, FiberWire, and ETHIBOND), and a dynamically self-tensioning suture (DYNACORD). After we measured loop length, knots were soaked in 37°C saline for 24 hours. Loop lengths were remeasured and tensile testing was performed. Cyclic elongation, first-cycle excursion, and elongation amplitude were recorded. Knots were then resoaked and retested. Finally, knots were pulled to failure, and peak load and stiffness were measured. Values were compared using nonparametric statistical tests. Results: DYNACORD loop length decreased by 27% after the first soak (P = .002), whereas the other sutures demonstrated no length change (P > .05). Although DYNACORD loop length increased during cyclic load testing (P = .009), it was still significantly reduced after the second saline soak compared with its initial length (P = .002), whereas all other suture loops had elongated. ETHIBOND (P = .004) and ORTHOCORD (P = .002) had significantly less cyclic elongation from cycle I to cycle II testing compared with the other sutures. ETHIBOND had the lowest peak load at failure (P = .002). FiberWire had the greatest stiffness (P = .006). Conclusions: Compared with other suture types, the self-tensioning suture showed dynamic properties, demonstrating a decrease in loop length when soaked in a saline bath. This length was maintained after a second soak despite increased loop length during interval cyclic loading. Clinical Relevance: Knot and loop security are of paramount importance to arthroscopic soft-tissue procedures. The ability for a suture to self-tension has implications for how it may interact with tissues in vivo to increase construct stability after arthroscopic soft tissue repair procedures.

Abstract Background The field of Artificial Intelligence (AI) holds transformative potential in medicine. However, the lack of universal reporting guidelines poses challenges in ensuring the validity and reproducibility of published research studies in this field. Methods Based on a systematic review of academic publications and reporting standards demanded by both international consortia and regulatory stakeholders as well as leading journals in the fields of medicine and medical informatics, 26 reporting guidelines published between 2009 and 2023 were included in this analysis. Guidelines were stratified by breadth (general or specific to medical fields), underlying consensus quality, and target research phase (preclinical, translational, clinical) and subsequently analyzed regarding the overlap and variations in guideline items. Results AI reporting guidelines for medical research vary with respect to the quality of the underlying consensus process, breadth, and target research phase. Some guideline items such as reporting of study design and model performance recur across guidelines, whereas other items are specific to particular fields and research stages. Conclusions Our analysis highlights the importance of reporting guidelines in clinical AI research and underscores the need for common standards that address the identified variations and gaps in current guidelines. Overall, this comprehensive overview could help researchers and public stakeholders reinforce quality standards for increased reliability, reproducibility, clinical validity, and public trust in AI research in healthcare. This could facilitate the safe, effective, and ethical translation of AI methods into clinical applications that will ultimately improve patient outcomes.

Despite the limited coverage of coral reefs in the world’s oceans, they play a crucial role in global marine biodiversity and providing essential ecosystem services. This study explores the influence of chlorophyll-a (Chl-a) concentration in the water column on the estimation of bottom reflectance (rb) in coral reefs monitored by the Allen Coral Atlas coral reef monitoring system, using satellite imagery from a Sentinel-2 MSI sensor. We conducted a comprehensive analysis, considering Chl-a global distribution and variability, and its combined effect with water column depth over rb calculation. Our results demonstrated that the impact of Chl-a on rb estimation becomes significant when the water column depth exceeds 3 m. While suggesting the optionality of using regional Chl-a values, our study highlights potential overestimations of Chl-a in optically complex environments, such as along the Brazilian coast. This research contributes to refining coral reef monitoring systems and underscores the importance of accurate Chl-a assessments for robust environmental evaluations.

In recent years, the sports communication landscape has seen changes in terms of who occupies the role of sports reporter. In-house reporters, or sports communicators employed by specific clubs, teams, or leagues, now contribute content to the sports media landscape. This study explores the complicated relationship between in-house reporters’ self-perceived professional identities and in-houses reporters’ perceptions of their audiences through the lens of Bourdieusian field theory. As such, it sees in-house reporters as peripheral actors negotiating the boundaries of the sports journalism field. Through semi-structured interviews with 28 in-house sports reporters from the United States and Austria, our findings suggest that in-house reporters conceive of themselves both in relation to professional journalism and as members of the sports establishment. Furthermore, they note an ambiguous relationship to their audience, which is both reliant upon the reporters’ work, and, at times, highly critical of it.

High-resolution water quality maps derived from imaging spectroscopy provide valuable insights for environmental monitoring and management, but the processing of all pixels of large datasets is extremely computationally intensive and limits the speed of map production. We demonstrate a superpixel approach to accelerating water quality parameter inversion on such data to considerably reduce time and resource needs. Neighboring pixels were clustered into spectrally similar superpixels, and bio-optical inversions were performed at the superpixel level before a nearest-neighbor interpolation of the results back to pixel resolution. We tested the approach on five example airborne imaging spectroscopy datasets from Hawaiian coastal waters, comparing outputs to pixel-by-pixel inversions for three water quality parameters: suspended particulate matter, chlorophyll-a, and colored dissolved organic matter. We found significant reduction in computational time, ranging from 38 to 2625 times faster processing for superpixel sizes of 50 to 5000 pixels (200 to 20,000 m2). Using 1000 paired output values from each example image, we found minimal reduction in accuracy (as decrease in R2 or increase in RMSE) of the model results when the superpixel size was less than 750 2 m × 2 m resolution pixels. Such results mean that this methodology could reduce the time needed to produce regional- or global-scale maps and thereby allow environmental managers and other stakeholders to more rapidly understand and respond to changing water quality conditions.

Background: Age-related macular degeneration (AMD) is the most common cause of vision loss in people above the age of 50, affecting approximately 10% of the population worldwide and the incidence is rising. Hyperreflective foci (HRF) are a major predictor of AMD progression. The purpose of this study was to use the sodium iodate mouse model to study HRF formation in retinal degeneration. Methods: Sodium iodate (NaIO3) treated rodents were studied to characterize HRF. 3-month-old male wild-type (WT) C57Bl/6J mice were injected with phosphate-buffered saline (PBS) or varying doses of NaIO3 (15–60 mg/kg). Optical Coherence Tomography (OCT) images were collected at baseline and several days post-NaIO3 injection. Retinal thicknesses were measured using Bioptigen software. Seven days post-injection, eyes were prepared for either transmission electron microscopy (TEM), Hematoxylin & Eosin (H&E), or immunofluorescence. Results: OCT imaging of the mice given higher doses of NaIO3 revealed HRF formation in the neural retina (n = 4). The amount of HRF correlated with the degree of retinal tissue loss. H&E and TEM imaging of the retinas seven days post-NaIO3 injection revealed several pigmented bodies in multiple layers of the retina (n = 3–5). Immunofluorescence revealed that some pigmented bodies were positive for macrophage markers and an epithelial-to-mesenchymal transition marker, while all were retinal pigment epithelium (RPE) 65-negative (n = 4). Conclusions: The data suggest that NaIO3 induces the formation of HRF in the outer retina and their abundance correlates with retinal tissue loss. The experiments in this study highlight NaIO3 as a clinically relevant model of intermediate AMD that can be used to study HRF formation and to discover new treatment targets.

Abstract Grabens, or valleys formed during extensional tectonic events, are common but rarely observed during formation. In November 2023, inelastic surface deformation formed abruptly along Iceland's plate boundary in Grindavík. We documented graben formation in real‐time through satellite mapping (InSAR), seismicity, GNSS data, repeated lidar surveys, and field mapping. Five normal faults and ∼12 fissures ruptured the surface delineating two grabens separated by a horst, a context not present in other contemporary case studies. The graben normal faults slipped rapidly (over hours) and maximum surface motions coincided with the occurrence of turbulent seismic swarms in both space and time. Although 3 eruptions took place ∼15 km northeast of Grindavík from 2021 to 2023, attributed to magma intrusions (i.e., dikes), none of these also formed grabens. Thus, the Grindavík grabens shows evidence for tectonic origins. Real‐time monitoring of these phenomena provide insight into graben formation on Earth and potentially on other planets.

Objectives: In the United States, a federal emergency program has made SARS-CoV-2 self-test kits available at no cost. It is unclear how widely free tests are preferred. We conducted a survey to estimate the proportion of respondents who do not prefer a free test. We hypothesized that free tests would not be preferred universally, and that a preference for paying would be more common among those with conservative politics than with liberal politics, regardless of income. Design: Observational study design. Methods: A national sample of US adults completed an online survey. To reduce potential enrollment bias, the survey’s focus was not specified beforehand. To prioritize a high-risk group, participation was limited to those who were unvaccinated or were incompletely vaccinated in the primary series against COVID-19. Participants reported their testing preferences and socio-demographic characteristics, including political affiliation. The main outcome assessed if a participant preferred to pay for a self-test or receive a free one (subsidized by the US government). Results: Among 1215 participants, (73%, n = 886) preferred free self-testing, while 27% (n = 329) preferred to pay for the same testing. After adjusting for income, the odds of preferring to pay for self-testing were 66% higher in “strong” Republicans compared to “strong” Democrats (odds ratio = 1.66, 95% confidence interval = 1.07–2.62). Conclusions: More than a quarter of individuals preferred paying for these tests. This preference was more likely among those with right-wing politics. Policy implications are discussed, along with future research directions.

Conservation paleobiology is a cross-disciplinary field that utilizes the geohistorical record of past life on Earth to inform present-day decisions in conservation and restoration and assist in planning for future natural resource management. However, information on how past ecosystems and species responded to environmental change over decadal to millennial timescales is rarely incorporated into conservation and restoration decision-making. To heighten awareness among conservation and restoration practitioners of the relevance of geohistorical data and to bridge the gap between research and implementation in conservation paleobiology, we proposed a Research Topic titled “Integrating Conservation Biology and Paleobiology to Manage Biodiversity and Ecosystems in a Changing World”. The 21 articles subsequently published demonstrate the diversity and breadth of geohistorical information available to resource management and the challenges of translating these results into conservation practice and policy. Here we discuss the lessons we learned from editing the Research Topic and suggest a pathway forward for conservation paleobiologists who aspire to generate actionable research results to solve current problems in biodiversity conservation and ecological restoration.

The purpose of this study was to identify major characteristics of children and youth with mental health problems who have contact with police officers and to determine which variables lead to the highest probability of police intervention and if there are differences between children and youth compared to adults. Two samples were taken from data obtained from the use of a new police brief mental health screener (interRAI BMHS) in a large southwestern Ontario city between April 2016 and April 2019: 619 cases under age 18 and 4,084 cases over age 18. Univariate and bivariate analysis revealed that all 23 variables on the BMHS were significantly associated with police intervention except for intoxication by drugs or alcohol, squalid home environment, and refusal to take prescribed medication. Variables with the highest odds of police intervention included hallucinations, diminished cognitive skills for daily decision-making, and family or others concerned for potential self-harm. Logistic regression analysis indicated that the variables most predictive of police intervention were hallucinations, lack of insight into their own mental health problems, violent ideation, violence to others, self-injurious attempt in the last 7 days, suicide plan, diminished cognitive skills for daily decision-making, and family or others concerned for self-harm. As to the differences between under and over age 18, adults had higher frequencies of intoxication, hallucinations, delusions, pressured speech, and abnormal thoughts, while under age 18 had slightly higher frequency of socially inappropriate/disruptive behaviour. Risk of harm variables were high in both groups; however, they were clearly higher in the under age 18 group, in particular self-injurious attempt in the last 7 days. The results of this study indicate that there are distinct differences between why police officers intervene with children and youth as opposed to adults which should be reflected in police training and intervention policy.

Background Extracellular microRNAs (miRNAs) are a class of noncoding RNAs that remain stable in the extracellular milieu, where they contribute to various physiological and pathological processes by facilitating intercellular signaling. Previous studies have reported associations between miRNAs and cardiovascular diseases (CVDs); however, the plasma miRNA signatures of CVD and its risk factors have not been fully elucidated at the population level. Methods and Results Plasma miRNA levels were measured in 4440 FHS (Framingham Heart Study) participants. Linear regression analyses were conducted to test the cross‐sectional associations of each miRNA with 8 CVD risk factors. Prospective analyses of the associations of miRNAs with new‐onset obesity, hypertension, type 2 diabetes, CVD, and all‐cause mortality were conducted using proportional hazards regression. Replication was carried out in 1999 RS (Rotterdam Study) participants. Pathway enrichment analyses were conducted and target genes were predicted for miRNAs associated with ≥5 risk factors in the FHS. In the FHS, 6 miRNAs (miR‐193b‐3p, miR‐122‐5p, miR‐365a‐3p, miR‐194‐5p, miR‐192‐5p, and miR‐193a‐5p) were associated with ≥5 risk factors. This miRNA signature was enriched for pathways associated with CVD and several genes annotated to these pathways were predicted targets of the identified miRNAs. Furthermore, miR‐193b‐3p, miR‐194‐5p, and miR‐193a‐5p were each associated with ≥2 risk factors in the RS. Prospective analysis revealed 8 miRNAs associated with all‐cause mortality in the FHS. Conclusions These findings highlight associations between miRNAs and CVD risk factors that may provide valuable insights into the underlying pathogenesis of CVD.

Objectives: To report the safety and side effects associated with taking verapamil for beta-cell preservation in children with newly-diagnosed T1D. Research Design and Methods: Eighty-eight participants aged 8.5 to 17.9 years weighing ≥ 30 kg were randomly assigned to verapamil (N = 47) or placebo (N = 41) within 31 days of T1D diagnosis and followed for 12 months from diagnosis, main CLVer study. Drug dosing was weight-based with incremental increases to full dosage. Side effect monitoring included serial measurements of pulse, blood pressure, liver enzymes, and electrocardiograms (ECGs). At study end, participants were enrolled in an observational extension study (CLVerEx), which is ongoing. No study drug is provided during the extension, but participants may use verapamil if prescribed by their diabetes care team. Results: Overall rates of adverse events were low and comparable between verapamil and placebo groups. There was no difference in the frequency of liver function abnormalities. Three CLVer participants reduced or discontinued medication due to asymptomatic ECG changes. One CLVerEx participant (18 years old), treated with placebo during CLVer, who had not had a monitoring ECG, experienced complete AV block with a severe hypotensive episode 6 weeks after reaching his maximum verapamil dose following an inadvertent double dose on the day of the event. Conclusions: The use of verapamil in youth newly-diagnosed with T1D appears generally safe and well tolerated with appropriate monitoring. We strongly recommend monitoring for potential side effects including an ECG at screening and an additional ECG once full dosage is reached.ClinicalTrials.gov number: NCT04233034.

Ambitious biodiversity goals to protect 30% or more of the Earth’s surface by 2030 (30x30) require strategic near-term targets. To define areas that must be protected to prevent the most likely and imminent extinctions, we propose Conservation Imperatives—16,825 unprotected sites spanning ~164 Mha of the terrestrial realm that harbor rare and threatened species. We estimate that protecting the Conservation Imperatives would cost approximately US$169 billion (90% probability: US$146—US$228 billion). Globally, 38% of the 16,825 sites are either adjacent to or within 2.5 km of an existing protected area, potentially reducing land acquisition and management costs. These sites should be prioritized for conservation action over the next 5 years as part of a broader strategy to expand the global protected area network. The expansion of global protected areas between 2018 and 2023 incorporated only 7% of sites harboring range-limited and threatened species, highlighting a renewed urgency to conserve these habitats. Permanently protecting only 0.74% of land found in the tropics, where Conservation Imperatives are concentrated, could prevent the majority of predicted near-term extinctions once adequately resourced. We estimate this cost to be from US$29 billion to US$46 billion per year over the next 5 years. Multiple approaches will be required to meet long-term protection goals: providing rights and titles to Indigenous Peoples and Local Communities (IPLCs) conserving traditional lands, government designation of new protected areas on federal and state lands, and land purchase or long-term leasing of privately held lands.

Plasma lipid levels are modulated by systemic infection and inflammation; it is unknown whether these changes reflect inflammatory responses or caused directly by pathogen presence. We explored the hypothesis that anti-inflammatory intervention via interleukin 6 receptor (IL-6R) blockade would influence plasma lipid levels during severe infection and evaluated the association of plasma lipid changes with clinical outcomes. Sarilumab (monoclonal antibody blocking IL-6R) efficacy was previously assessed in patients with coronavirus disease 2019 (COVID-19) (NCT04315298). This analysis determined whether strong inflammatory reduction by sarilumab in patients with COVID-19 pneumonia of increasing severity (severe, critical, multisystem organ dysfunction) affected plasma lipid changes between day 1 and day 7 of study therapy. Baseline lipid levels reflected the presence of acute systemic infection, characterized by very low HDL-C, low LDL-C, and moderately elevated triglycerides (TGs). Disease severity was associated with progressively more abnormal lipid levels. At day 7, median lipid levels increased more in the sarilumab versus placebo group (HDL-C +10.3%, LDL-C +54.7%, TG +32% vs. HDL-C +1.7%, LDL-C +15.4%, TG +8.8%, respectively). No significant association between lipid changes and clinical outcomes was observed. In conclusion, severe-to-critical COVID-19 pneumonia causes profound HDL-C depression that is only modestly responsive to strong anti-IL-6R inflammatory intervention. Conversely, LDL-C depression is strongly responsive to IL-6R blockade, with LDL-C levels likely returning to the predisease set point. These results advance our understanding of the complex relationship between serum lipids and infection/inflammation and suggest that HDL-C depression during acute contagious disease is driven by infection and not IL-6–mediated inflammation.

ObjectiveThe Royal Canadian Mounted Police (RCMP) Study includes longitudinal multimodal assessments of RCMP cadets from pre-training (i.e., starting the Cadet Training Program [CTP]) to post-deployment and for five years thereafter. The data allow for investigating the multidimensionality of volitional participation in digital health data collection frameworks within serial data collection platforms and the impact of participation inequalities by classifying cadets using the 90–9-1 rule. By classifying cadets as Lurkers, Contributors, and Superusers formally described by the 90–9-1 rule, where 90% of actors do not participate, 9% seldom contribute, and 1% contribute substantially allows for the assessing of relationships between participation inequalities in self-monitoring behaviors as well as whether mental health disorder symptoms at pre-training (i.e., starting the CTP) were associated with subsequent participation.MethodsParticipants were asked to complete a Full Assessment prior to their training at CTP, as well as short daily surveys throughout their training. Participation frequency was described using a process where participants were rank ordered by the number of daily surveys completed and classified into one of three categories. Full assessment surveys completed prior to their training at CTP included screening tools for generalized anxiety disorder (GAD), major depressive disorder (MDD), posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and panic disorder (PD). The Kruskal-Wallis H test was used to assess differences in participation rates between mental health disorder symptom screening groups for each measure at pre-training, and Spearman’s Rho was used to test for associations amongst self-reported Full Assessment screening tool responses and the number of daily surveys completed during CTP.ResultsThere were 18557 daily survey records collected from 772 participants. The rank-ordering of cadets by the number of daily surveys completed produced three categories in line with the 90–9-1 rule: Superusers who were the top 1% of cadets (n=8) and produced 6.4% of all recordings; Contributors who were the next 9% of cadets (n=68) and produced 49.2% of the recordings; and Lurkers who were the next 90% of cadets (n=695) and produced 44.4% of daily survey recordings. Lurkers had the largest proportion of positive screens for self-reported mental health disorders at pre-training.ConclusionThe creation of highly individualized, population-based mental health injury programs has been limited by an incomplete understanding of the causal relationships between protective factors and mental health. Disproportionate rates of disengagement from persons who screen positive for mental health disorders further compounds the difficulty in understanding the relationships between training programs and mental health. The current results suggest persons with mental health challenges may be less likely to engage in some forms of proactive mental health training. The current results also provide useful information about participation, adherence, and engagement that can be used to inform evidence-based paradigm shifts in health-related data collection in occupational populations.