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Cancer enhances the risk of venous thromboembolism, but a hypercoagulant microenvironment also promotes cancer progression. Although anticoagulants have been suggested as a potential anticancer treatment, clinical studies on the effect of such modalities on cancer progression have not yet been successful for unknown reasons. In normal physiology, complex formation between the subendothelial-expressed tissue factor (TF) and the blood-borne liver-derived factor VII (FVII) results in induction of the extrinsic coagulation cascade and intracellular signaling via protease-activated receptors (PARs). In cancer, TF is overexpressed and linked to poor prognosis. Here, we report that increased levels of FVII are also observed in breast cancer specimens and are associated with tumor progression and metastasis to the liver. In breast cancer cell lines, tumor-expressed FVII drives changes reminiscent of epithelial-to-mesenchymal transition (EMT), tumor cell invasion, and expression of the prometastatic genes, SNAI2 and SOX9. In vivo, tumor-expressed FVII enhanced tumor growth and liver metastasis. Surprisingly, liver-derived FVII appeared to inhibit metastasis. Finally, tumor-expressed FVII-induced prometastatic gene expression independent of TF but required a functional endothelial protein C receptor, whereas recombinant activated FVII acting via the canonical TF:PAR2 pathway inhibited prometastatic gene expression. Here, we propose that tumor-expressed FVII and liver-derived FVII have opposing effects on EMT and metastasis.

Single-arm trials (SATs) may be used to support regulatory submissions in settings where there is a high unmet medical need and highly promising early efficacy data undermine the equipoise needed for randomization. In this context, patient-level real-world data (RWD) may be used to create an external control arm (ECA) to contextualize the SAT results. However, naive comparisons of the SAT with its ECA will yield biased estimates of causal effects if groups are imbalanced with regards to (un)measured prognostic factors. Several methods are available to adjust for measured confounding, but the interpretation of such analyses is challenging unless the causal question of interest is clearly defined, and the estimator is aligned with the estimand. Additional complications arise when patients in the ECA are eligible for the SAT at multiple timepoints. In this paper, we use a case-study of a pivotal SAT of a novel CAR-T therapy for heavily pre-treated patients with follicular lymphoma to illustrate how a combination of the target trial and the ICH E9(R1) estimand frameworks can be used to define the target estimand and avoid common methodological pitfalls related to the design of the ECA and comparisons with the SAT. We also propose an approach to address the challenge of how to define an appropriate time zero for external controls who meet the SAT inclusion/exclusion criteria at several timepoints. Use of the target trial and estimand frameworks facilitates discussions amongst internal and external stakeholders, as well as an early assessment of the adequacy of the available RWD.

Rates of reported cases of syphilis have steadily increased since 2000 in the United States. However, despite the increase in cases, mortality from 2000–2014 declined. The following study examines the latest trends in syphilis-related deaths using 2015–2020 Multiple Cause of Death data. A total of 925 syphilis-related deaths were identified during the study period, 30% of which listed syphilis as the underlying cause of death. On average, age-adjusted syphilis mortality increased by 9.51% annually (95% CI = 5.41%–13.77%). Study findings indicate a marked increase in deaths attributed to syphilis, underscoring the need to more systematically and comprehensively address the growing sexually transmitted infection epidemic in the United States.

Lisa V Doan,1 Anna Li,1 Lee Brake,1 Deborah Ok,1 Hyun Jung Jee,1 Hyung Park,2 Randy Cuevas,1 Steven Calvino,1 Amber Guth,3 Freya Schnabel,3 Karen Hiotis,3 Deborah Axelrod,3 Jing Wang1,4 1Department of Anesthesiology, Perioperative Care and Pain Medicine, New York University Grossman School of Medicine, New York, NY, USA; 2Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA; 3Department of Surgery, New York University Grossman School of Medicine, New York, NY, USA; 4Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, USACorrespondence: Lisa V Doan, Department of Anesthesiology, Perioperative Care and Pain Medicine, New York University Grossman School of Medicine, 240 E 38th St, 14th Floor, New York, NY, 10016, USA, Tel +1 212201-1004, Email Lisa.Doan@nyulangone.orgBackground and Objectives: Perioperative ketamine has been shown to reduce opioid consumption and pain after surgery. Ketamine is most often given as an infusion, but an alternative is single-dose ketamine. Single-dose ketamine at up to 1 mg/kg has been shown to reduce symptoms of depression, and a wide range of dosages has been used for pain in the emergency department. However, limited data exists on the tolerability and efficacy of a single-dose of ketamine at 0.6 mg/kg for pain when administered immediately after surgery. We conducted a pilot study of single-dose ketamine in patients undergoing mastectomy with reconstruction, hypothesizing that a single-dose of ketamine is well tolerated and can relieve postoperative pain and improve mood and recovery.Methods: This is a randomized, single-blind, placebo-controlled, two-arm parallel, single-center study. Thirty adult women undergoing mastectomy with reconstruction for oncologic indication received a single-dose of ketamine (0.6mg/kg) or placebo after surgery in the post-anesthesia care unit (PACU). Patients were followed through postoperative day (POD) 7. The primary outcome was postoperative pain measured by the Brief Pain Inventory (BPI) pain subscale on POD 1 and 2. Secondary outcomes include effects on opioid use, PROMIS fatigue and sleep, mood, Quality of Recovery-15, and the Breast Cancer Pain Questionnaire.Results: Side effects were minor and not significantly different in frequency between groups. The ketamine group reported lower scores on the BPI pain severity subscale, especially at POD 7; however, the difference was not statistically significant. There were no statistically significant differences between ketamine and placebo groups for the secondary outcomes.Conclusion: A single-dose of ketamine at 0.6mg/kg administered postoperatively in the PACU is well tolerated in women undergoing mastectomy and may confer better pain control up to one week after surgery. Future studies with larger sample sizes are necessary to adequately characterize the effect of postoperative single-dose ketamine on pain control in this population.Keywords: postoperative pain, non-opioid, analgesia

Episodic failures of ice-dammed lakes have produced some of the largest floods in history, with disastrous consequences for communities in high mountains1–7. Yet, estimating changes in the activity of ice-dam failures through time remains controversial because of inconsistent regional flood databases. Here, by collating 1,569 ice-dam failures in six major mountain regions, we systematically assess trends in peak discharge, volume, annual timing and source elevation between 1900 and 2021. We show that extreme peak flows and volumes (10 per cent highest) have declined by about an order of magnitude over this period in five of the six regions, whereas median flood discharges have fallen less or have remained unchanged. Ice-dam floods worldwide today originate at higher elevations and happen about six weeks earlier in the year than in 1900. Individual ice-dammed lakes with repeated outbursts show similar negative trends in magnitude and earlier occurrence, although with only moderate correlation to glacier thinning8. We anticipate that ice dams will continue to fail in the near future, even as glaciers thin and recede. Yet widespread deglaciation, projected for nearly all regions by the end of the twenty-first century9, may bring most outburst activity to a halt., Nature, 614 (7949), ISSN:0028-0836, ISSN:1476-4687

This study examined the feasibility of implementing the Screening Tool for Autism in Toddlers, an interactive Level-2 screen for autism spectrum disorder, within Part C Early Intervention settings. Participants included 69 Early Intervention providers ( M age = 43.3 years, 93.7% females, 92.4% Whites) from nine programs who attended a one-day Screening Tool for Autism in Toddlers training workshop. Half of the providers reported using the Screening Tool for Autism in Toddlers, and reported it to be feasible and effective. Regardless of Screening Tool for Autism in Toddlers use, providers reported increased knowledge about recognizing the early signs of autism spectrum disorder following the workshop. Provider-reported self-efficacy regarding skills related to autism spectrum disorder screening increased significantly from baseline to the 18-month follow-up. Providers also described the facilitators (e.g. promotes communication with families) and barriers (e.g. certification process), that influenced their adoption. Results highlight the potential use of the Screening Tool for Autism in Toddlers within Early Intervention settings to identify autism spectrum disorder, and suggest an implementation model in which specific providers serve as a screening “point-person,” rather than expecting it to be used by all providers. Future research should aim to identify characteristics of agencies or providers that might facilitate Screening Tool for Autism in Toddlers use, as well as specific implementation plans and strategies that might promote long-term sustainability of Level-2 screening practices. This study was registered on ClinicalTrials.gov before the time of the first study enrollee. Registration number: NCT02409303; URL: https://clinicaltrials.gov/ct2/show/NCT02409303 Lay abstract The early detection of autism spectrum disorder can lead to access to autism spectrum disorder-specific services that have been shown to have a large impact on a child’s overall development. Although a stable diagnosis of autism spectrum disorder can be made by age 2 years, most children are not diagnosed until much later. To address this issue, this study examined the effectiveness of training Part C Early Intervention providers to use an interactive autism spectrum disorder screening tool, the Screening Tool for Autism in Toddlers. Sixty-nine providers attended a 1-day training workshop on the use of the Screening Tool for Autism in Toddlers. After the workshop, providers reported increased knowledge about recognizing the early signs of autism spectrum disorder, and about 45% of the providers reported using the Screening Tool for Autism in Toddlers with families in their caseloads 18 months after the training. These results suggest that the Screening Tool for Autism in Toddlers is feasible for use within Early Intervention settings. In addition, they suggest that specific providers might serve as a screening “point-person,” rather than expecting the Screening Tool for Autism in Toddlers to be used by all providers. Future research should aim to identify specific characteristics of agencies or providers that might be best suited for using the Screening Tool for Autism in Toddlers.

Purpose A cancer diagnosis poses unique challenges for moms with young children who must balance illness-management alongside existing paid (e.g., employment) and unpaid (e.g., domestic/caregiving) work. The goal of this study was to improve understanding of the support needs of mothers living with cancer and their experiences receiving psychosocial and childcare support from a community organization, the Nanny Angel Network (NAN). Methods Mothers who accessed NAN services during their cancer treatment and/or recovery (N = 20) participated in qualitative semi-structured interviews. Thematic analysis was used to inductively and deductively identify emerging patterns in the data and theoretical abduction was applied to further interpret participants’ accounts using a feminist political economy framework. Results Participants expressed how balancing the demands of patienthood and parenthood was challenging and how cancer treatment created new needs for support with care work. Mothers explained that NAN offered indispensable family-centered support largely missing from the health care system, promoting improved physical, psychosocial, and relational health for them and their families. While accessible from a cost-perspective, participants identified different pathways, including awareness, cross-system collaboration, and stable funding, that limited timely access to NAN. Conclusion Access to family-centered care, such as that offered through NAN, was vital to the health and healing of the study participants and their families. Improved collaboration with and investment in community organizations like NAN that have a strong infrastructure to support moms living with cancer offers a practical, feasible, and immediate solution to help address some of the distinct challenges this population faces.

The Screening Tool for Autism in Toddlers (STAT) is a validated stage-2 autism spectrum disorder (ASD) screening measure that takes 20 minutes to administer and comprises 12 play-based items that are scored according to specific criteria. This study examines an expanded version (STAT-E) that includes the examiner's subjective ratings of children's social engagement (SE) and atypical behaviors (AB) in the scoring algorithm. The sample comprised 238 children who were 24-35 months old. The STAT-E assessors had limited ASD experience to mimic its use by community-based non-specialists, and were trained using a scalable web-based platform. A diagnostic evaluation was completed by clinical experts who were blind to the STAT-E results. Logistic regression, ROC curves, and classification matrices and metrics were used to determine the screening properties of STAT-E when scored using the original STAT scoring algorithm versus a new algorithm that included the SE and AB ratings. Inclusion of the SE and AB ratings improved positive risk classification appreciably, while the specificity declined. These results suggest that the STAT-E using the original STAT scoring algorithm optimizes specificity, while the STAT-E scoring algorithm with the two new ratings optimizes the positive risk classification. Using multiple scoring algorithms on the STAT may provide improved screening accuracy for diverse contexts, and a scalable web-based tutorial may be a pathway for increasing the number of community providers who can administer the STAT and contribute toward increased rates of autism screening.

Research suggests that individuals with Huntington's disease (HD) perform better than individuals with Alzheimer's disease (AD) on the California Verbal Learning Test (CVLT) Yes/No Recognition trial. However, those with HD have been shown to have deficits comparable to those with AD on the Source Recognition Discriminability (RD) index (which assesses the ability to distinguish between List A targets and List B distractors), suggesting that HD may involve selective impairment in aspects of yes/no recognition that rely on source memory. However, whether individuals with HD and AD show comparable deficits on Source RD across stages of dementia severity has not been adequately investigated. We examined performance on the CVLT-3 List A vs. List B RD index in individuals with HD or AD and mild or moderate dementia. Among individuals with mild dementia, scores were higher in the HD versus AD group, whereas among individuals with moderate dementia, scores were comparable between the HD and AD groups; this corresponded to differential performance across dementia stages among individuals with HD, but not AD. The present findings suggest that, relative to AD, HD may be associated with disproportionate decline in aspects of yes/no recognition that rely on source memory.

The Patient Reported Outcomes Measurement Information System (PROMIS ® ) is a validated tool used to evaluate different domains of function in patients with chronic health conditions. This tool has not been validated in children with unilateral congenital below elbow deficiency (UCBED). The purpose of this study was to determine whether PROMIS discerns functional impairment for children with UCBED and whether children with UCBED differ from the general population with respect to PROMIS outcomes. We hypothesized that children with UCBED report mild impairment in upper extremity function but normal mobility, pain interference and peer relations.A retrospective chart review of children aged 5 to 17 years with a diagnosis of UCBED who completed a PROMIS questionnaire at their clinic visit at the [blinded locations] was conducted between April 1, 2017 and March 31, 2020. The mean PROMIS scores of UCBED patients were compared with that of the general reference population. Mann Whitney and ANOVA tests were used to explore the differences across the PROMIS upper extremity function domain by arm length and prosthesis use.Fifty-five children (28 boys) with a mean age of 11±3.6 years met the inclusion criteria. Children with UCBED had similar PROMIS scores as the reference population in mobility (51.9±6.2), peer relations (53.5±9.4), and pain interference (40.1±7.2), with mild impairment in the upper extremity function (44.3±10.7). Compared with the 8 to 17-year-old cohort, the parent-proxy (5 to 7-year-old group) reported significantly more upper extremity function impairment (31.3±5.9) vs (48.0±8.8) ( P =0.000). The two age groups did not differ with respect to mobility, pain interference and peer relations.Our study confirms previous findings that children with UCBED report upper extremity function, peer relationships, pain interference, and mobility, similar to the reference population. In addition, parents of younger children with UCBED report more upper extremity functional impairment than is self-reported by older children with UCBED.Prognostic Level III (comparison with reference population).

Vaccinating homebound individuals during the COVID-19 pandemic presented several challenges, including time and cost of engaging this group. In Los Angeles County, the departments of Public Health and Aging and Disabilities turned to home delivered meals programs (HDMs) for help with this public health priority. A mixed-method organizational assessment of 34 HDMs was conducted during March-April 2022 to describe these efforts. Most HDMs were nonprofit (67.6%) and had

High-risk patients—those patients with complex health care needs who are most likely to face hospitalization or death in the following two years—are most often initially seen in the primary care setting. This small group of patients uses a disproportionate amount of care resources. Contributing to the challenges of care planning for this population is that individuals are highly heterogeneous; no two patients present the same set of symptoms, diagnoses, and challenges related to social determinants of health (SDOH). Methods for early identification of these high-risk patients—and their care needs—have raised the possibility of timely enhanced care. In this study, the authors conduct a scoping review to identify existing measures of care quality; assessment and screening guidelines; and tools that (1) assess social support, the need for caregiver support, and the need for referral to social services and (2) screen for cognitive impairment (CI). Evidence-based screening guidelines define who and what should be assessed—and how often—to enhance care quality and improve health outcomes, whereas measures permit ascertainment that this assessment is occurring. Evidence-based guidelines and measures—those that are found to lead to better health care outcomes—would be candidates for inclusion in a measure dashboard for high-risk patients in primary care settings.

The study of spinning bodies moving in curved spacetime has relevance to binary black hole systems with large mass ratios, as well as being of formal interest. At zeroth order in a binary's mass ratio, the smaller body moves on a geodesic of the larger body's spacetime. Post-geodesic corrections describing forces driving the small body's worldline away from geodesics must be incorporated to model the system accurately. An important post-geodesic effect is the gravitational self-force, which describes the small body's interaction with its own spacetime curvature. This effect includes the backreaction due to gravitational-wave emission that leads to the inspiral of the small body into the black hole. When a spinning body orbits a black hole, its spin couples to spacetime curvature. This introduces another post-geodesic correction known as the spin-curvature force. An osculating geodesic integrator that includes both the backreaction due to gravitational waves and spin-curvature forces can be used to generate a spinning-body inspiral. In this paper, we use an osculating geodesic integrator to combine the leading backreaction of gravitational waves with the spin-curvature force. Our analysis only includes the leading orbit-averaged dissipative backreaction, and examines the spin-curvature force to leading order in the small body's spin. This is sufficient to build generic inspirals of spinning bodies, and serves as a foundation for further work examining how to include secondary spin in large-mass-ratio waveform models., 23 pages, 8 figures, submitted to Physical Review D

Studies of health care access and use among historically resilient populations, while common, often field a limited sample size and rarely ask the groups most impacted by health inequities to weigh in. This is especially so for research and programs that focus on the American Indian and Alaska Native (AIAN) population. The present study addresses this gap by examining data from a cross-sectional survey of AIANs in Los Angeles County. To better interpret project findings and generate culturally relevant contexts, qualitative feedback was gathered at a community forum held in Spring 2018. Because recruitment of AIANs has historically been challenging, purposive sampling was employed to strategically identify a larger eligible pool. Among those who were eligible, 94% completed the survey (n = 496). AIANs who were enrolled in a tribe were 32% more likely to use the Indian Health Service (IHS), compared with those who were not enrolled (95% CI: 20.4%, 43.2%; p < .0001). In multivariable modeling, the strongest factors influencing IHS access and use were: tribal enrollment, preference for culturally-specific health care, proximity of the services to home or work, having Medicaid, and having less than a high school education. Feedback from the community forum indicated cost and trust (of a provider) were important considerations for most AIANs. Study findings reveal heterogeneous patterns of health care access and use in this population, suggesting a need to further improve the continuity, stability, and the image of AIANs' usual sources of care (e.g., IHS, community clinics).

Pharmaceutical companies regularly need to make decisions about drug development programs based on the limited knowledge from early stage clinical trials. In this situation, eliciting the judgements of experts is an attractive approach for synthesising evidence on the unknown quantities of interest. When calculating the probability of success for a drug development program, multiple quantities of interest—such as the effect of a drug on different endpoints—should not be treated as unrelated. We discuss two approaches for establishing a multivariate distribution for several related quantities within the SHeffield ELicitation Framework (SHELF). The first approach elicits experts' judgements about a quantity of interest conditional on knowledge about another one. For the second approach, we first elicit marginal distributions for each quantity of interest. Then, for each pair of quantities, we elicit the concordance probability that both lie on the same side of their respective elicited medians. This allows us to specify a copula to obtain the joint distribution of the quantities of interest. We show how these approaches were used in an elicitation workshop that was performed to assess the probability of success of the registrational program of an asthma drug. The judgements of the experts, which were obtained prior to completion of the pivotal studies, were well aligned with the final trial results.

OBJECTIVE: To determine whether an intervention addressing both logistical and knowledge barriers to early screening for autism spectrum disorder (ASD) increases evidence-based screening during 18-month well-child visits and PCPs’ perceived self-efficacy in caring for children with ASD. METHODS: Forty-six primary care providers (PCPs) from 10 diverse practices across four counties in Washington State participated. PCPs attended a two-hour training workshop on early recognition and care for toddlers with ASD and use of a REDCap-based version of the Modified Checklist for Autism in Toddlers–Revised with Follow-up (webM-CHAT-R/F) that provided automated presentation and scoring of follow-up questions. Data were collected at baseline and six-months following each county’s training window. PCPs’ screening methods and rates and perceived self-efficacy regarding ASD care were measured by self-report and webM-CHAT-R/F use was measured via REDCap records. RESULTS: At follow-up, 8 of the 10 practices were using the webM-CHAT-R/F routinely at 18-month visits. The proportion of PCPs reporting routine M-CHAT screening increased from 82% at baseline to 98% at follow-up (16% increase, 95% CI 3%–28%; McNemar exact p=.02). The proportion using the M-CHAT-R/F follow-up interview questions increased from 33% to 82% (49% increase, 95% CI 30%–68%, exact McNemar test, p

Introduction The Veterans Health Administration (VA) Primary Care-Mental Health Integration (PC-MHI) initiative targets depression (MDD), anxiety/posttraumatic stress disorder (PTSD) and alcohol misuse (AM) for care improvement. In primary care, case finding often relies on depression screening. Whereas clinical practice guidelines solely inform management of depression, minimal information exists to guide treatment when psychiatric symptom clusters coexist. We provide descriptive clinical information for care planners about VA PC patients with depression alone, depression plus alcohol misuse, and depression with complex psychiatric comorbidities (PTSD and/or probable bipolar disorder). Method We examined data from a VA study that used a visit-based sampling procedure to screen 10,929 VA PC patients for depression; 761 patients with probable major depression completed baseline measures of health and care engagement. Follow-up assessments were completed at 7 months. Results At baseline, 53% of patients evidenced mental health conditions in addition to depression; 10% had concurrent AM, and 43% had psychiatrically complex depression (either with or without AM). Compared with patients with depression alone or depression with AM, those with psychiatrically complex depression evinced longer standing and more severe mood disturbance, higher likelihood of suicidal ideation, higher unemployment, and higher levels of polypharmacy. Baseline depression complexity predicted worse mental health status and functioning at follow-up. Discussion A substantial proportion of VA primary care patients with depression presented with high medical multimorbidity and elevated safety concerns. Psychiatrically complex depression predicted lower treatment effectiveness, suggesting that PC-MHI interventions should co-ordinate and individualize care for these patients. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

To describe alcohol use among younger military active duty service members and veterans (SMVs) in the first 5 years after traumatic brain injury (TBI) and examine whether differential alcohol use patterns emerge as a function of brain injury severity and active duty service at time of injury.Veterans Affairs (VA) Polytrauma Rehabilitation Centers (PRCs).In total, 265 SMVs enrolled in the VA Traumatic Brain Injury Model Systems (TBIMS) PRC national database. Participants sustained a TBI of any severity level; received inpatient care at a PRC within 1 year of injury; were younger than 40 years; and completed survey interviews or questionnaires regarding their pre- and postinjury alcohol use for at least 3 of 4 time points (preinjury, postinjury years 1, 2, and 5).Self-reported alcohol use, defined as amount of weekly consumption and endorsement of binge drinking. Participant information related to demographics, injury, TBI severity, active duty status, mental health treatment, and FIM (Functional Independence Measure) total scores was also obtained to examine impact of these as covariates in the analyses.Alcohol use generally increased following an initial period of reduced consumption for SVMs with moderate-to-severe TBI. Individuals with mild TBI showed an opposite trend, with an initial period of increased use, followed by a decline and return to baseline levels in the long term. However, alcohol use did not significantly differ over time within this subsample after adjusting for covariates.The current study identified longitudinal alcohol use among a young, military/veteran cohort with a history of TBI, an at-risk population for problematic alcohol use. Patterns of self-reported alcohol consumption suggest the time frame of 2 to 5 years postinjury may be a critical window of opportunity for further intervention to maintain lowered levels of alcohol use, particularly among SVMs with moderate-to-severe TBI.

Enterohemorrhagic Escherichia coli (EHEC) is a major cause of severe bloody diarrhea, with potentially lethal complications, such as hemolytic uremic syndrome. In humans, EHEC colonizes the colon, which is also home to a diverse community of trillions of microbes known as the gut microbiota. Although these microbes and the metabolites that they produce represent an important component of EHEC's ecological niche, little is known about how EHEC senses and responds to the presence of gut microbiota metabolites. In this study, we used a combined RNA-Seq and Tn-Seq approach to characterize EHEC's response to metabolites from an in vitro culture of 33 human gut microbiota isolates (MET-1), previously demonstrated to effectively resolve recurrent Clostridioides difficile infection in human patients. Collectively, the results revealed that EHEC adjusts to growth in the presence of microbiota metabolites in two major ways: by altering its metabolism and by activating stress responses. Metabolic adaptations to the presence of microbiota metabolites included increased expression of systems for maintaining redox balance and decreased expression of biotin biosynthesis genes, reflecting the high levels of biotin released by the microbiota into the culture medium. In addition, numerous genes related to envelope and oxidative stress responses (including cpxP, spy, soxS, yhcN, and bhsA) were upregulated during EHEC growth in a medium containing microbiota metabolites. Together, these results provide insight into the molecular mechanisms by which pathogens adapt to the presence of competing microbes in the host environment, which ultimately may enable the development of therapies to enhance colonization resistance and prevent infection.

This study focuses on future seasonal changes in daily precipitation using Regional Climate Models (RCMs) from the Coordinated Regional Climate Downscaling Experiments-Southeast Asia ensemble (CORDEX-SEA). Projections using this RCM ensemble generally show a larger inter-model spread in winter than in summer, with higher significance and model agreement in summer over most land areas. We evaluate how well the RCMs simulate climatological precipitation using two skill metrics. To extract reliable projections, two sub-ensembles of ‘better’ and ‘worse’ performing models are selected and their respective projections compared. We find projected intensification of summer precipitation over northern SEA, which is robust across RCMs. On the contrary, in the southern part of SEA, the ‘worse’ ensemble projects a significant and widespread decrease in summer rainfall intensity whereas a slight intensification is projected by the ‘better’ ensemble. Further exploration of inter-model differences in future changes reveals that these are mainly explained by changes in moisture supply from large-scale sources (i.e., moisture convergence) with enhanced effects from local sources (i.e., evapotranspiration). The ‘worse’ models project greater changes in atmospheric circulation compared with the ‘better’ models, which can explain part of the uncertainty in projections for daily precipitation over the CORDEX-SEA domain. Hence, our findings might help assess more reliable projections over the SEA region by selecting models based on a two-step model evaluation: the ability of models to simulate historical daily precipitation and their performance in reproducing key physical processes of the regional climate.

Background: Aloe ferox is an indigenous medicinal plant that is widely used for its various medicinal and pharmacological properties. Despite the medicinal importance and various applications of the species, it is surprising that little is known about the extent of geographical differences in its major chemical compounds. Also, the correlation between different geographic regions and variations in plant phytochemicals has received less attention.Aim: This study sought to investigate the presence of biologically active compounds in the leaf extracts of A. ferox from different geographical regions across South Africa.Setting: This study was set in different regions within South Africa.Methods: Phytochemical screening was performed qualitatively using established standard procedures involving chemical reagents such as hexane, chloroform and methanol and a series of reactions to determine the presence of phytocompounds of biological importance.Results: The study revealed that A. ferox leaves possess several classes of phytocompounds such as alkaloids, tannins, terpenoids, glycosides, phenolics, flavonoids, saponins and fixed oils and fats across various samples. Mucilage was absent across the samples.Conclusion: The study revealed eight classes of phytochemical compounds present on A. ferox leaves in three different geographic regions, which is consistent with the previous studies; however, further research is needed to enhance the study through qualitative research, gas chromatography–mass spectrometry and high-performance liquid chromatography analyses to validate phytochemical variations and their therapeutic effects.Contribution: This study contributes to the existing knowledge of the therapeutic Aloe genus.

We present a hybrid-integrated extended cavity diode laser tunable around 637 mn, with a total tuning range of 8 nm, allowing to address the zero-phonon line of nitrogen vacancy centers. The laser provides wide mode-hop free tuning over 43.6 GHz and a narrow intrinsic linewidth below 10 kHz. The maximum output power is 2.5 mW in a single-mode fiber, corresponding to an on-chip power of 4.0 mW. The laser is assembled in a standard laser housing and fiber-pigtailed.

Probabilistic models to inform landslide early warning systems often rely on rainfall totals observed during past events with landslides. However, these models are generally developed for broad regions using large catalogs, with dozens, hundreds, or even thousands of landslide occurrences. This study evaluates strategies for training landslide forecasting models with a scanty record of landslide-triggering events, which is a typical limitation in remote, sparsely populated regions. We train and evaluate 136 statistical models with a rainfall dataset with five landslide-triggering rainfall events recorded near Sitka, Alaska, USA, as well as >6,000 days of non-triggering rainfall (2002–2020). We use Akaike, Bayesian, and leave-one-out information criteria to compare models trained on cumulative precipitation at timescales ranging from 1 hour to 2 weeks, using both frequentist and Bayesian methods to estimate the daily probability and intensity of potential landslide occurrence (logistic regression and Poisson regression). We evaluate the best-fit models using leave-one-out validation as well as with testing a subset of the data. Despite this sparse landslide inventory, we find that probabilistic models can effectively distinguish days with landslides from days without. Although frequentist and Bayesian inference produce similar estimates of landslide hazard, they do have different implications for use and interpretation: frequentist models are familiar and easy to implement, but Bayesian models capture the rare-events problem more explicitly and allow for better understanding of parameter uncertainty given the available data. Three-hour precipitation totals are the best predictor of elevated landslide hazard, and adding antecedent precipitation (days to weeks) did not improve model performance. This relatively short timescale combined with the limited role of antecedent conditions reflects the rapid draining of porous colluvial soils on very steep hillslopes around Sitka. We use the resulting estimates of daily landslide probability to establish two decision boundaries for three levels of warning. With these decision boundaries, the frequentist logistic regression model incorporates National Weather Service quantitative precipitation forecasts into a real-time landslide early warning “dashboard” system (sitkalandslide.org). This dashboard provides accessible and data-driven situational awareness for community members and emergency managers.

SUMMARYBrainstem olivocochlear neurons (OCNs) modulate the earliest stages of auditory processing through feedback projections to the cochlea and have been shown to influence hearing and protect the ear from sound-induced damage through unclear mechanisms. Here, we used single-nucleus sequencing, anatomical reconstructions, and electrophysiology to characterize OCNs during postnatal development and after sound exposure. We identified markers for known OCN subtypes, medial (MOC) and lateral (LOC) OCNs, and show that they express distinct cohorts of physiologically relevant genes that change over development. In addition, we discovered a neuropeptide-enriched LOC subtype that produces Neuropeptide Y along with other neurotransmitters. Throughout the cochlea, both LOC subtypes extend arborizations over wide frequency domains. Moreover, LOC neuropeptide expression is strongly upregulated days after acoustic trauma, potentially providing a sustained protective signal to the cochlea. OCNs are therefore poised to have diffuse, dynamic effects on early auditory processing over timescales ranging from milliseconds to days.

ObjectiveAssessing one’s functional capacity—in addition to neuropsychological performance—is essential for determining neurocognitive status, and functional assessment is often provided via informant report. Although informant characteristics have been shown to influence reports of participant functioning, the degree to which they moderate relationships between reported functioning and participant performance on neuropsychological testing is unclear. Moreover, associations among informant characteristics, reported functioning, and neuropsychological performance have not been adequately examined with non-Hispanic Black (NHB) samples, despite this population’s disproportionately high risk of Alzheimer’s disease and related dementias.MethodIn this cross-sectional observational study, we examined the influence of informant characteristics on informant reports of participant functioning (assessed via the Functional Activities Questionnaire [FAQ]) and associations between reported functioning and participant performance on neuropsychological testing, among NHB adult participants in the National Alzheimer’s Coordinating Center cohort (n = 1024).ResultsInformants who were younger, female, more educated, knew participants longer, or lived with participants reported poorer participant functioning (p ConclusionsWithin the context of neurocognitive evaluations of NHB participants, informant characteristics may influence subjective reports of participants’ functioning and the extent to which reported functioning corroborates objective participant performance on neuropsychological testing.

Colloidal quantum-dots (cQDs) are finding increasingly widespread application in photonics and optoelectronics, providing high brightness and record-wide colour gamuts. However, the external quantum efficiencies in thin-film device architectures are still limited due to losses into waveguide modes and different strategies are being explored to promote the outcoupling of emission. Here we use a template-stripping-based direct-patterning strategy to fabricate linear gratings at the surface of cQD thin films. The linear gratings enhance optical outcoupling through Bragg scattering, yielding bright emission with a strong degree of linear polarization. By patterning linear gratings with different periodicities and orientations onto a film of mixed-colour cQDs, we demonstrate polarization-based active colour tuning of the thin-film emission. ISSN:2040-3364 ISSN:2040-3372

The point at which clinical development programs transition from early-phase to pivotal trials is a critical milestone. Substantial uncertainty about the outcome of pivotal trials may remain even after seeing positive early-phase data, and companies may need to make difficult prioritization decisions for their portfolio. The probability of success (PoS) of a program, a single number expressed as a percentage reflecting the multitude of risks that may influence the final program outcome, is a key decision making tool. Despite its importance, companies often rely on crude industry benchmarks that may be "adjusted" by experts based on undocumented criteria and which are typically misaligned with the definition of success used to drive commercial forecasts, leading to overly optimistic expected net present value calculations. We developed a new framework to assess the PoS of a program before pivotal trials begin. Our definition of success encompasses the successful outcome of pivotal trials, regulatory approval, and meeting the requirements for market access as outlined in the target product profile. The proposed approach is organized in four steps and uses an innovative Bayesian approach to synthesize all relevant evidence. The new PoS framework is systematic and transparent. It will help organizations to make more informed decisions. In this paper, we outline the rationale and elaborate on the structure of the proposed framework, provide examples, and discuss the benefits and challenges associated with its adoption.

We congratulate the authors of this landscape assessment on a comprehensive and stimulating article which carefully reviews many important biostatistical issues related to the use of real-world dat...

BACKGROUND Deciding on a disease modifying therapy (DMT) for the treatment of pediatric onset multiple sclerosis (POMS) often presents a challenge to families. Parents are often overwhelmed by DMT choices, but they desire to be an integral part of the decision making process for their child. There is no standard approach for how best to involve families in this process. The aim of this study was to describe the experience of decision making related to the use of disease modifying therapy in parents of children and adolescents with POMS. METHODS The research aim was addressed using a descriptive survey design. Participants were recruited from the Pediatric MS and Related Disorders Program at Boston Children's Hospital as well as from the Pediatric Multiple Sclerosis Alliance online Facebook group. RESULTS Overall, fewer than half of parents felt very satisfied with the DMT they chose for their child with POMS (44%). Parental satisfaction with the decision making process increased with a high level of control of the process (p

Modern genomic sequencing tests often interrogate large numbers of genes. Identification of appropriate reference materials for development, validation studies, and quality assurance of these tests poses a significant challenge for laboratories. It is difficult to develop and maintain expert knowledge to identify all variants that must be validated to ensure analytic and clinical validity. Additionally, it is usually not possible to procure appropriate and characterized genomic DNA reference materials containing the number and scope of variants required. To address these challenges, the Centers for Disease Control and Prevention's Genetic Testing Reference Material Program (GeT-RM) has partnered with the Clinical Genome Resource (ClinGen) to develop a publicly available list of expert curated, clinically important variants. ClinGen Variant Curation Expert Panels nominated 546 variants found in 84 disease-associated genes, including common pathogenic and difficult-to-detect variants. Variant types nominated included 346 single nucleotide variants, 104 deletions, 37 copy number variants, 25 duplications, 18 deletion-insertions, 5 inversions, 4 insertions, 2 complex rearrangements, 3 difficult-to-sequence regions, and 2 fusions. This expert-curated variant list is a resource that provides a foundation for designing comprehensive validation studies and for creating in silico reference materials for clinical genomic test development and validation.

Supplemental Material for An Organizational Assessment of 34 Home Delivered Meals Programs that Engaged and Assisted Homebound Individuals With Obtaining the COVID-19 Vaccine During the Pandemic by Dana Guglielmo, Jennifer Cloud, Laura Trejo, Chris Baca, Lisa V. Smith, Rashmi Shetgiri, and Tony Kuo; Homebound Data Workgroup in Journal of Applied Gerontology

This comprehensive scoping review will describe and compare the options for prosthetic hand replacements available on the market that are distal to the wrist, both surgical and non-surgical. Given the diversity of available prosthetics, we aim to fill the knowledge gap on prosthetics by synthesizing the available options and characterizing them to provide rapid evidence-based literature for clinicians and users alike. We will also highlight emerging prosthetic innovations to highlight the future directions of upper limb treatment. By doing so, clinicians and consumers can make informed decisions about their prosthetic choice that is optimized to complete their activities of daily living (ADL) and instrumental activities of daily living (IADL).

This work provides gravitational wave energy and angular momentum asymptotic fluxes from a spinning body moving on generic orbits in a Kerr spacetime up to linear in spin approximation. To achieve this, we have developed a new frequency domain Teukolsky equation solver that calculates asymptotic amplitudes from generic orbits of spinning bodies with their spin aligned with the total orbital angular momentum. However, the energy and angular momentum fluxes from these orbits in the linear in spin approximation are appropriate for adiabatic models of extreme mass ratio inspirals even for spins non-aligned to the orbital angular momentum. To check the newly obtained fluxes, they were compared with already known frequency domain results for equatorial orbits and with results from a time domain Teukolsky equation solver called Teukode for off-equatorial orbits. The spinning body framework of our work is based on the Mathisson-Papapetrou-Dixon equations under the Tulczyjew-Dixon spin supplementary condition., Comment: 19 pages, 8 figures

Hybrid integrated diode lasers based on combining semiconductor optical amplifiers with low-loss Si3N4-based feedback circuits enable great laser performance for advanced photonic circuits. In particular, using high-Q Si3N4 ring resonators for frequency-selective feedback provides wide spectral coverage, mode-hop free tuning, and high frequency stability on short timescales, showing as ultra-narrow intrinsic linewidths. However, many applications also require long-term stability, which can be provided by locking the laser frequency to a suitable reference. We present the stabilization of a hybrid-integrated laser, which is widely tunable around the central wavelength of 1550 nm, to a fiber-based optical frequency discriminator (OFD) and to an acetylene absorption line. By locking the laser to the OFD, the laser's fractional frequency stability is improved down to 2.1$\cdot$10$^{-12}$ over an averaging time of 0.5 ms. For absolute stability over longer times of several days, we successfully lock the laser frequency to an acetylene absorption line. This limits the frequency deviations of the laser to a range of less than 12 MHz over 5 days., Comment: 12 pages, 6 figures

ObjectiveGiven that several non-cognitive factors can contribute to difficulties with everyday functioning, examining the extent to which cognition is associated with brain-related changes in everyday functioning is critical to accurate characterization of cognitive disorders. In this study, we examined neuropsychological correlates of the shared variance between everyday functioning and pathological indicators of cognitive aging using MRI brain volumetrics.Participants and methodsParticipants were 600 adults aged 55 and older without dementia [432 cognitively normal; 168 mild cognitive impairment (MCI)] from the National Alzheimer’s Coordinating Center cohort who underwent neuropsychological testing, informant-rated everyday functioning, and brain MRI scanning at baseline. The shared variance between everyday functioning and brain volumetrics (i.e., hippocampal volume, white matter hyperintensity volume) was extracted using the predicted value from multiple regression. The shared variance was used as an indicator of pathological everyday functional impairment. The residual variance from the regression analysis was used to examine functional reserve.ResultsLarger white matter hyperintensity volumes (p = 0.002) and smaller hippocampal volumes (p p = 0.013) and category fluency (p = 0.012) were significantly correlated with pathological functional impairment in multiple regression analysis. In the cognitively normal group, only worse auditory working memory (i.e., digit span backward; p = 0.025) significantly correlated with pathological functioning. Functional reserve was inversely related to anxiety (p p = 0.003) and apathy (p ConclusionSubtle brain-related everyday functioning difficulties are evident in MCI and track with expected preclinical Alzheimer’s disease cognitive phenotypes in this largely amnestic sample. Our findings indicate that functional changes occur early in the disease process and that interventions to target neuropsychiatric symptoms may help to bolster functional reserve in those at risk.