Granzyme B-activated IL18 potentiates αß and γδ CAR T-cell immunotherapy in a tumor-dependent manner.

Interleukin (IL)18 is a potent pro-inflammatory cytokine that is activated upon caspase 1 cleavage of the latent precursor, pro-IL18. Therapeutic T-cell armoring with IL18 promotes autocrine stimulation and positive modulation of the tumor microenvironment (TME). However, existing strategies are imperfect since they involve constitutive/ poorly regulated activity, or fail to modify the TME. Here, we have substituted the caspase 1 cleavage site within pro-IL18 with that preferred by granzyme B, yielding GzB-IL18. We demonstrate that GzB-IL18 is constitutively released but remains functionally latent unless CAR T-cells are activated, owing to concomitant granzyme B release. Armoring with GzB-IL18 enhances cytolytic activity, proliferation, IFN-γ release and anti-tumor efficacy by a similar magnitude to constitutively active IL18. We also demonstrate that GzB-IL18 provides a highly effective armoring strategy for γδ CAR T-cells, leading to enhanced metabolic fitness and significant potentiation of therapeutic activity. Finally, we show that constitutively active IL18 can unmask CAR T-cell-mediated cytokine release syndrome in immunocompetent mice. By contrast, GzB-IL18 promotes anti-tumor activity and myeloid cell re-programming without inducing such toxicity. Using this stringent system, we have tightly coupled the biological activity of IL18 to the activation state of the host CAR T-cell, favoring safer clinical implementation of this technology.

Inaccuracy of Initial Clinical Mobility Assessment in Venous Thromboembolism Risk Stratification.

BACKGROUND: Venous thromboembolism risk increases in hospitals due to reduced patient mobility. However, initial mobility evaluations for thromboembolism risk are often subjective and lack standardization, potentially leading to inaccurate risk assessments and insufficient prevention. METHODS: A retrospective study at a quaternary academic hospital analyzed patients using the Padua risk tool, which includes a mobility question, and the Johns Hopkins-Highest Level of Mobility (JH-HLM) scores to objectively measure mobility. Reduced mobility was defined as JH-HLM scores ≤3 over ≥3 consecutive days. The study evaluated the association between reduced mobility and hospital-acquired venous thromboembolism using multivariable logistic regression, comparing admitting health care professional assessments with JH-HLM scores. Symptomatic, hospital-acquired thromboembolisms were diagnosed radiographically by treating providers. RESULTS: Of 1715 patients, 33 (1.9%) developed venous thromboembolisms. Reduced mobility, as determined by the JH-HLM scores, showed a significant association with thromboembolic events (adjusted OR: 2.53, 95%CI:1.23-5.22, P=0.012). In contrast, the initial Padua assessment of expected reduced mobility at admission did not. The JH-HLM identified 19.1% of patients as having reduced mobility versus 6.5% by admitting health care professional, suggesting 37 high-risk patients were misclassified as low risk and were not prescribed thrombosis prophylaxis; 4 patients developed thromboembolic events. JH-HLM detected reduced mobility in 36% of thromboembolic cases, compared to 9% by admitting health care professionals. CONCLUSION: Initial mobility evaluations by admitting health care professionals during venous thromboembolism risk assessment may not reflect patient mobility over their hospital stay. This highlights the need for objective measures like JH-HLM in risk assessments to improve accuracy and potentially reduce thromboembolism incidents.

Non-destructive Raman Method Development for Quantifying Active Pharmaceutical Ingredient in an Oral Suspension Through Plastic Dosing Syringes.

For liquid drug products, e.g., solutions or suspensions for oral or parenteral dosing, stability needs to be demonstrated in primary packaging during storage and in dosing devices during in-use periods per quality guidelines from the International Conference on Harmonisation (ICH) and the European Agency for the Evaluation of Medicinal Products (EMEA). One aspect of stability testing for liquid drug products is in-use stability, which typically includes transferring the liquid samples into another container for further sample preparation with extraction diluent and necessary agitation. Samples are then analyzed with traditional chromatography methods, which are laborious, prone to human errors, and time-consuming, especially when this process needs to be repeated multiple times during storage and in-use periods. Being able to analyze the liquid samples non-destructively would significantly improve testing efficiency. We investigated different Raman techniques, including transmission Raman (TRS) and back scatter Raman with a non-contact optic (NCO) probe, as alternative non-destructive tools to the UHPLC method for API quantitation in in-use liquid samples pulled into plastic dosing syringes. The linearity of the chemometric methods for these two techniques was demonstrated by cross-validation sample sets at three levels over an API concentration range of 60 to 80 mg/mL. The accuracy of the chemometric models was demonstrated by the accurate prediction of the API concentrations in independent samples from four different pilot plant batches manufactured at different sites. Both techniques were successful in measuring a signal through a plastic oral dosing syringe, and predicting the suspension API concentration to within 4% of the UHPLC-measured value. For future work, there are opportunities to improve the methodology by exploring additional probes or to expand the range of applications by using different sample presentations (such as prefilled syringes) or formulation matrices for solutions and suspensions.

Participant retention in follow-up studies of intensive care unit survivors - A scoping review.

OBJECTIVE: To synthesize participant retention data and related reporting in studies evaluating post-hospital outcomes of survivors of critical illness after an intensive care unit (ICU) stay. REVIEW METHOD USED: A synthesis of literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist. DATA SOURCES: PubMed, EMBASE, PsycINFO, Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Controlled Trials Registry. Hand searched reference lists and personal files of relevant narrative and systematic review articles. REVIEW METHODS: Articles were screened by pairs of independent reviewers. Similarly, data were abstracted by pairs of data collectors, with conflicts resolved by consensus or by a third reviewer. RESULTS: We included 243 publications, from 225 unique studies of 87,602 participants. Participant retention could not be calculated for any time-points in 13% of studies nor in 22% of all follow-up time-points. Retention ranged from 18-100%. When compared to follow-up before 1-month, retention at each later timepoint was not significantly different. Age and sex were not associated with retention and more recent studies had decreased retention (odds ratio: 0.94 [95% confidence interval: 0.92-0.96; p < 0.001]). Reporting of retention-related study methodology was inconsistent. CONCLUSION: Retention rate could not be calculated for 22% of study follow-up time-points, with retention at the remaining time-points generally being high (≥85%), but with high variability (18% - 100%). ICU survivorship research could be improved via: (i) more detailed guidance on reporting participant retention, and (ii) use of existing resources and best practices to facilitate better study design and to improve participant retention to preserve statistical power and reduce selection bias.

Exploring the relationship between AM-PAC scores and mobility components in falls and pressure injury risk assessment tools: A pathway to improve nursing clinical efficiency.

BACKGROUND: Nurses routinely perform multiple risk assessments related to patient mobility in the hospital. Use of a single mobility assessment for multiple risk assessment tools could improve clinical documentation efficiency, accuracy and lay the groundwork for automated risk evaluation tools. PURPOSE: We tested how accurately Activity Measure for Post-Acute Care (AM-PAC) mobility scores predicted the mobility components of various fall and pressure injury risk assessment tools. METHOD: AM-PAC scores along with mobility and physical activity components on risk assessments (Braden Scale, Get Up and Go used within the Hendrich II Fall Risk Model®, Johns Hopkins Fall Risk Assessment Tool (JHFRAT) and Morse Fall Scale) were collected on a cohort of hospitalised patients. We predicted scores of risk assessments based on AM-PAC scores by fitting of ordinal logistic regressions between AM-PAC scores and risk assessments. STROBE checklist was used to report the present study. FINDINGS: AM-PAC scores predicted the observed mobility components of Braden, Get Up and Go and JHFRAT with high accuracy (≥85%), but with lower accuracy for the Morse Fall Scale (40%). DISCUSSION: These findings suggest that a single mobility assessment has the potential to be a good solution for the mobility components of several fall and pressure injury risk assessments.

Engineering a Dual Specificity γδ T-Cell Receptor for Cancer Immunotherapy.

γδ T-cells provide immune surveillance against cancer, straddling both innate and adaptive immunity. G115 is a clonal γδ T-cell receptor (TCR) of the Vγ9Vδ2 subtype which can confer responsiveness to phosphoantigens (PAgs) when genetically introduced into conventional αß T-cells. Cancer immunotherapy using γδ TCR-engineered T-cells is currently under clinical evaluation. In this study, we sought to broaden the cancer specificity of the G115 γδ TCR by insertion of a tumour-binding peptide into the complementarity-determining region (CDR) three regions of the TCR δ2 chain. Peptides were selected from the foot and mouth disease virus A20 peptide which binds with high affinity and selectivity to αvß6, an epithelial-selective integrin that is expressed by a range of solid tumours. Insertion of an A20-derived 12mer peptide achieved the best results, enabling the resulting G115 + A12 T-cells to kill both PAg and αvß6-expressing tumour cells. Cytolytic activity of G115 + A12 T-cells against PAg-presenting K562 target cells was enhanced compared to G115 control cells, in keeping with the critical role of CDR3 δ2 length for optimal PAg recognition. Activation was accompanied by interferon (IFN)-γ release in the presence of either target antigen, providing a novel dual-specificity approach for cancer immunotherapy.

Chewing through challenges: Exploring the evolutionary pathways to wood-feeding in insects.

Decaying wood, while an abundant and stable resource, presents considerable nutritional challenges due to its structural rigidity, chemical recalcitrance, and low nitrogen content. Despite these challenges, certain insect lineages have successfully evolved saproxylophagy (consuming and deriving sustenance from decaying wood), impacting nutrient recycling in ecosystems and carbon sequestration dynamics. This study explores the uneven phylogenetic distribution of saproxylophagy across insects and delves into the evolutionary origins of this trait in disparate insect orders. Employing a comprehensive analysis of gut microbiome data, from both saproxylophagous insects and their non-saproxylophagous relatives, including new data from unexplored wood-feeding insects, this Hypothesis paper discusses the broader phylogenetic context and potential adaptations necessary for this dietary specialization. The study proposes the "Detritivore-First Hypothesis," suggesting an evolutionary pathway to saproxylophagy through detritivory, and highlights the critical role of symbiotic gut microbiomes in the digestion of decaying wood.

Revision of Eupyrochroa Blair, 1914 (Coleoptera: Pyrochroidae) based on morphological comparison and molecular phylogenetics.

Eupyrochroa Blair, 1914 is a small genus of fire-colored beetles (Coleoptera: Pyrochroidae) with two putative species recorded from limited historical distributions in China. The two species, E. insignita (Fairmaire, 1894) and E. limbaticollis (Pic, 1909), have been distinguished on the basis of color differences in the pronotum and scutellum, characters now known to exhibit significant variability. In the present study, adult morphology of the two species was compared, and partial fragments of cytochrome c oxidase subunit I (COI) from 36 samples representing 14 pyrochroid species were obtained by extraction and a GenBank search. Nucleotide composition, genetic distance, and phylogeny were analyzed. The results of morphological and molecular analyses indicate consistency, suggesting that the two species are indistinguishable by any significant measure. Therefore, Eupyrochroa limbaticollis (Pic, 1909) is proposed as a junior synonym of E. insignita (Fairmaire, 1894). The species is also redescribed and illustrated, including both adults and larvae.

Dynamic Prediction of Post-Acute Care Needs for Hospitalized Medicine Patients.

OBJECTIVES: Use patient demographic and clinical characteristics at admission and time-varying in-hospital measures of patient mobility to predict patient post-acute care (PAC) discharge. DESIGN: Retrospective cohort analysis of electronic medical records. SETTING AND PARTICIPANTS: Patients admitted to the two participating Hospitals from November 2016 through December 2019 with ≥72 hours in a general medicine service. METHODS: Discharge location (PAC vs home) was the primary outcome, and 2 time-varying measures of patient mobility, Activity Measure for Post-Acute Care (AM-PAC) Mobility "6-clicks" and Johns Hopkins Highest Level of Mobility, were the primary predictors. Other predictors included demographic and clinical characteristics. For each day of hospitalization, we predicted discharge to PAC using the demographic and clinical characteristics and most recent mobility data within a random forest (RF) for survival, longitudinal, and multivariate (RF-SLAM) data. A regression tree for the daily predicted probabilities of discharge to PAC was constructed to represent a global summary of the RF. RESULTS: There were 23,090 total patients and compared to PAC, those discharged home were younger (64 vs 71), had shorter length of stay (5 vs 8 days), higher AM-PAC at admission (43 vs 32), and average AM-PAC throughout hospitalization (45 vs 35). AM-PAC was the most important predictor, followed by age, and whether the patient lives alone. The area under the hospital day-specific receiver operating characteristic curve ranged from 0.76 to 0.79 during the first 5 days. The global summary tree explained 75% of the variation in predicted probabilities for PAC from the RF. Sensitivity (75%), specificity (70%), and accuracy (72%) were maximized at a PAC probability threshold of 40%. CONCLUSIONS AND IMPLICATIONS: Daily assessment of patient mobility should be part of routine practice to help inform care planning by hospital teams. Our prediction model could be used as a valuable tool by multidisciplinary teams in the discharge planning process.

Guided Online Mindfulness-Based Intervention for Community Residents with Emotional Distress during the COVID-19 Pandemic.

This study aimed to assess the efficacy of a guided online mindfulness-based intervention (iMBI) for community residents experiencing emotional distress during the COVID-19 pandemic in Hong Kong. In a randomized controlled trial, 64 participants were recruited from collaborating community-based mental health service units in Hong Kong and assigned to either the treatment (n = 32) or control (n = 32) groups. The treatment group received a guided iMBI consisting of 16 online modules, weekly telephone counseling, and two half-day online workshops on mindfulness practice. In contrast, the waitlist control group did not receive any intervention during the initial stage. Using a 2 (two groups) × time (pre versus post) repeated measures linear mixed model and one-way analysis of variance, authors demonstrated that the treatment group experienced a significantly larger reduction in anxiety and depressive symptoms with a large effect size compared with the control group. Additionally, the treatment group showed a significantly greater improvement in mindfulness with a moderate effect size. The findings support the effectiveness of guided iMBI for community residents experiencing emotional distress during the COVID-19 pandemic in Hong Kong.

Repetitive head impacts among professional fighters: a pilot study evaluating Traumatic Encephalopathy Syndrome and postural balance.

OBJECTIVES: Clinical criteria for Traumatic Encephalopathy Syndrome (ccTES) were developed for research purposes to reflect the clinical symptoms of Chronic Traumatic Encephalopathy (CTE). The aims of this study were to 1) determine whether there was an association between the research diagnosis of TES and impaired postural balance among retired professional fighters, and 2) determine repetitive head impacts (RHI) exposure thresholds among both TES positive and TES negative groups in retired professional fighters when evaluating for balance impairment. METHODS: This was a pilot study evaluating postural balance among participants of the Professional Athletes Brain Health Study (PABHS). Among the cohort, 57 retired professional fighters met the criteria for inclusion in this study. A generalized linear model with generalized estimating equations was used to compare various balance measures longitudinally between fighters with and without TES. RESULTS: A significant association was observed between a TES diagnosis and worsening performance on double-leg balance assessments when stratifying by RHI exposure thresholds. Additionally, elevated exposure to RHI was significantly associated with increased odds of developing TES; The odds for TES diagnosis were 563% (95% CI = 113, 1963; p-value = 0.0011) greater among athletes with 32 or more professional fights compared to athletes with less than 32 fights when stratifying by balance measures. Likewise, the odds for TES diagnosis were 43% (95% CI = 10, 102; p-value = 0.0439) greater with worsening double leg stance balance in athletes exposed to 32 or more fights. CONCLUSION: This pilot study provides preliminary evidence of a relationship between declining postural balance and a TES diagnosis among retired professional fighters with elevated RHI exposure. Further research exploring more complex assessments such as the Functional Gait Assessment may be of benefit to improve clinical understanding of the relationship between TES, RHI, and balance.

Oblatopyrochroabellula, an enigmatic new genus and species of Pyrochroinae (Coleoptera, Pyrochroidae) from Xizang, China.

Oblatopyrochroabellula, a new genus and species of Pyrochroinae Latreille, 1807 from Xizang, China, is described and illustrated. The antennae, cranial apparatus, and genitalia of the new genus form a truly unique set of characters not observed in any other pyrochroid genus. The taxonomic position and phylogenetic relationships of Oblatopyrochroagen. nov. are also discussed but appear difficult to resolve.

Integrating lesbian, gay, bisexual, transgender, and queer (LGBTQ) competency into the dental school curriculum.

BACKGROUND: Decreasing healthcare disparities in marginalized communities requires healthcare providers who understand and appreciate social, economic, and cultural backgrounds. This includes care and education focused on individuals who identify as lesbian, gay, bisexual, transgender, or queer (LGBTQ). METHODS: This study examined dental students' and residents' self-reported clinical preparedness, prejudicial attitudes (implicit and explicit), and knowledge of health disparities that exist in the LGBTQ community using the Lesbian, Gay, Bisexual, Transgender Development of Clinical Skills Scale (LGBT-DOCSS) prior to and after the presentation of an LGBTQ competency course. RESULTS: A total of 178 dental students at a private US dental school ranging from D1 to first-year postdoctoral residency participated in the course and completed both pre-course survey and post-course survey. Sixty-seven percent of the students reported having formal training in LGBTQ competency prior to completing the pre-training survey. The results of the LGBT-DOCSS in this population following intervention training revealed an increased feeling of clinical preparedness in treating LGBTQ patients, decreased bias toward LGBTQ, and increased knowledge of health disparities in the LGBTQ community. A more significant percentage of male respondents self-reported prejudicial beliefs. Knowledge of LGBTQ health issues increased significantly among pre-clinical students. CONCLUSION: Introducing an early intervention LGBTQ competency course in the dental curriculum is an effective method of improving students' awareness and self-confidence in working with LGBTQ patients while decreasing biases that may have existed prior to a training course.

Artificial Intelligence to derive aligned strain in cine CMR to detect patients with myocardial fibrosis: an open and scrutinizable approach.

Cine Cardiac Magnetic Resonance (CMR) is the gold standard for cardiac function evaluation, incorporating ejection fraction (EF) and strain as vital indicators of abnormal deformation. Rare pathologies like Duchenne muscular dystrophies (DMD) are monitored with repeated late gadolinium-enhanced (LGE) CMR for identification of myocardial fibrosis. However, it is judicious to reduce repeated gadolinium exposure and rather employ strain analysis from cine CMR. This solution is limited so far since full strain curves are not comparable between individual cardiac cycles and current practice mainly neglects diastolic deformation patterns. Our novel Deep Learning-based approach derives strain values aligned by key frames throughout the cardiac cycle. In a reproducibility scenario (57+82 patients), our results reveal five times more significant differences (22 vs. 4) between patients with scar and without, enhancing scar detection by +30%, improving detection of patients with preserved EF by +61%, with an overall sensitivity/specificity of 82/81%.

The effect of post-acute rehabilitation setting on 90-day mobility after stroke: A difference-in-difference analysis.

Background: After discharged from the hospital for acute stroke, individuals typically receive rehabilitation in one of three settings: inpatient rehabilitation facilities (IRFs), skilled nursing facilities (SNFs), or home with community services (i.e., home health or outpatient clinics). The initial setting of post-acute care (i.e., discharge location) is related to mortality and hospital readmission; however, the impact of this setting on the change in functional mobility at 90-days after discharge is still poorly understood. The purpose of this work was to examine the impact of discharge location on the change in functional mobility between hospital discharge and 90-days post-discharge. Methods: In this retrospective cohort study, we used the electronic health record to identify individuals admitted to Johns Hopkins Medicine with an acute stroke and who had measurements of mobility [Activity Measure for Post Acute Care Basic Mobility (AM-PAC BM)] at discharge from the acute hospital and 90-days post-discharge. Individuals were grouped by discharge location (IRF=190 [40%], SNF=103 [22%], Home with community services=182 [(38%]). We compared the change in mobility from time of discharge to 90-days post-discharge in each group using a difference-in-differences analysis and controlling for demographics, clinical characteristics, and social determinants of health. Results: We included 475 individuals (age 64.4 [14.8] years; female: 248 [52.2%]). After adjusting for covariates, individuals who were discharged to an IRF had a significantly greater improvement in AM-PAC BM from time of discharge to 90-days post-discharge compared to individuals discharged to a SNF or home with community services (ß=-3.5 (1.4), p=0.01 and ß=-8.2 (1.3), p=<0.001, respectively). Conclusions: These findings suggest that the initial post-acute rehabilitation setting impacts the magnitude of functional recovery at 90-days after discharge from the acute hospital. These findings support the need for high-intensity rehabilitation and for policies that facilitate the delivery of high-intensity rehabilitation after stroke.

Association of Longitudinal Mobility Levels in the Hospital and Injurious Inpatient Falls.

ABSTRACT: Falls are one of the most common adverse events in hospitals, and patient mobility is a key risk factor. In hospitals, risk assessment tools are used to identify patient-centered fall risk factors and guide care plans, but these tools have limitations. To address these issues, we examined daily patient mobility levels before injurious falls using the Johns Hopkins Highest Level of Mobility, which quantifies key patient mobility milestones from low-level to community distances of walking. We aimed to identify longitudinal characteristics of patient mobility before a fall to help identify fallers before the event. Conducting a retrospective matched case-control analysis, we compared mobility levels in the days leading up to an injurious fall between fallers and nonfallers. We observed that patients who experienced an injurious fall, on average, spent 28% of their time prefall at a low mobility level (Johns Hopkins Highest Level of Mobility levels 1-4), compared with nonfallers who spent 19% of their time at a low mobility level (mean absolute difference, 9%; 95% confidence interval, 1%-16%; P = 0.026; relative difference, 44%). This suggests that assessing a patient's mobility levels over time can help identify those at an increased risk for falls and enable hospitals to manage mobility problems more effectively.

Assessing burnout among early career faculty in US dental schools.

BACKGROUND: Burnout is a condition characterized by emotional exhaustion, low personal accomplishment, and feelings of depersonalization that may evolve as a result of chronic occupational stress. Our goal for the study was to measure the degree of burnout among US dental school faculty with less than 10 years in academia. MATERIALS AND METHODS: A mixed method approach to data collection was utilized for the study and included: A. A 15-items demographics survey B. Maslach Burnout Inventory (MBI) combined with the Area-Work life Scale (AWS) C. A survey open-ended response to respondent's general feelings about work environment. RESULTS: MBI results from the data collected from 52 respondents indicate 7 or 13.46% of respondents are categorized with a 'burnout' profile. The most abundant categories recognized among this group are feelings of being "overextended" (34.62%) while 32.69% of the respondents self-report signs of being engaged. The results from this population indicate higher emotional exhaustion while levels of depersonalization are lower. The Area-Work life Scale (AWS) for this group indicates a higher sense of reward and control, while a lower frequency of workload balance and fairness are recognized. The data collected from the sample population suggest increased higher feelings of burnout at the 9-year mark, with increased administrative duties, and age range over 44 years. CONCLUSION: Identifying factors in workload, work environment, and influences in the home that lead to burnout early in a faculty member's tenure and introducing reduction mechanisms are key to enhancing faculty production, satisfaction, and retention.

Low-intensity online mindfulness-based intervention for university students with anxiety during the COVID-19 pandemic-A randomized controlled trial with 3-month follow-up.

Objective: This study investigated the effectiveness of a low-intensity online mindfulness-based Intervention (iMBI) for alleviating anxiety in university students during the COVID-19 pandemic. Methods: In a randomized controlled trial involving 134 participants from a local university in Hong Kong, subjects were randomly assigned to either the intervention group (n = 67) or the inactive control group (n = 67). The intervention group participated in a low-intensity iMBI comprising 16 online modules and two half-day online mindfulness workshops over an eight-week period. Outcomes were measured via an online platform using standardized assessment scales, including the Beck Anxiety Inventory and the Chinese Five Facets Mindfulness Questionnaire, at three different time points: pre-intervention, post-intervention and at a three-month follow-up. Results: Intent-to-treat analysis using 2 (group) × 3 (time) repeated measures of covariance (ANCOVA) showed that the intervention group, compared to the control group, showed a significant reduction in anxiety symptoms with a medium effect size (Cohen's d = 0.5) and a significant improvement in mindfulness skills with a medium effect size (Cohen's d = 0.5) at post-intervention. The effects of the intervention in reducing anxiety and improving mindfulness persisted at the three-month follow-up. Conclusion: The results of this study demonstrate the effectiveness of the low-intensity iMBI in alleviating anxiety among university students.

Activities of Daily Living Assessment Early in Hospitalization Is Associated With Key Outcomes.

IMPORTANCE: Assessing patients' activities of daily living (ADLs) function early in hospitalization may help identify patients at risk for poor outcomes. OBJECTIVE: To investigate the association between patients' ADL function at hospital admission and length of stay, inpatient falls, hospital-acquired pressure injuries, and discharge disposition. DESIGN: Retrospective cohort study using scores collected on the Activity Measure for Post-Acute Care Inpatient Activity Short Form (AM-PAC IASF) in routine care at admission. SETTING: Two inpatient units at the Johns Hopkins Hospital. PARTICIPANTS: Hospitalized patients with various diagnoses, including neurosurgical, stroke, and general neurology (N = 1,899). RESULTS: People with lower AM-PAC scores (every 10-point difference) had increased odds (odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.4-1.8) of being in the highest length-of-stay quartile (≥8 days), having an injurious fall (OR = 1.7; 95% CI = 1.3-2.2), acquiring a pressure injury (OR = 2.7; 95% CI = 1.5-5.3), and being discharged to a postacute care facility (OR = 3.02; 95% CI = 2.1-2.7). CONCLUSIONS AND RELEVANCE: Greater functional impairments in ADLs, measured with the AM-PACS IASF, were significantly associated with worse outcomes. AM-PAC IASF scores may be useful in identifying patients with ADL deficits and targeting occupational therapy services for patients who are at higher risk for negative outcomes. What This Article Adds: Early assessment of ADL function in routine care of hospitalized patients may aid in treatment and care plan decisions, particularly for inpatients who may be at higher risk for adverse outcomes.

Membrane procoagulation and N­terminomics/TAILS profiling in Montreal platelet syndrome kindred with VWF p.V1316M mutation.

BACKGROUND: The Montreal platelet syndrome kindred (MPS) with VWF p.V1316M mutation (2B-VWDMPS) is an extremely rare disorder. It has been associated with macrothrombocytopenia, spontaneous platelet clumping, mucocutaneous, and other bleeding, which can be largely prevented by von Willebrand factor (VWF) concentrate infusion. However, supplemental platelet transfusion has been required on occasion, particularly for severe gastrointestinal bleeds. This raised the question of whether a previously uncharacterized platelet dysfunction contributes to bleeding diathesis in 2B-VWDMPS patients. We have previously shown that membrane ballooning, a principal part of the platelet procoagulant membrane dynamics (PMD) after collagen stimulation, is driven by the influx of Na+ and Cl-, followed by the entry of water. METHODS: We study two members (mother and daughter) of the MPS kindred with severe bleeding phenotype and address this question by coupling quantitative platelet shotgun proteomics and validating biochemical assays, with the systematic analysis of platelet procoagulant membrane dynamics (PMD). Using N-terminomics/TAILS (terminal amine isotopic labeling of substrates), we compare changes in proteolysis between healthy and 2B-VWDMPS platelets. RESULTS: Here, we report in 2B-VWDMPS platelets, the loss of the transmembrane chloride channel-1 (CLIC1), and reduced chloride ion influx after collagen stimulation. This was associated with diminished membrane ballooning, phosphatidylserine externalization, and membrane thrombin formation, as well as a distinct phenotypic composition of platelets over fibrillar collagen. We also identify processing differences of VWF, fibronectin (FN1), and Crk-like protein (CRKL). 2B-VWDMPS platelets are shown to be basally activated, partially degranulated, and have marked loss of regulatory, cytoskeletal, and contractile proteins. CONCLUSIONS: This may account for structural disorganization, giant platelet formation, and a weakened hemostatic response.

The Montreal platelet syndrome (MPS) is a very rare genetic illness caused by a specific modification in a protein called von Willebrand factor (VWF). VWF circulates in the blood and works with platelets to stop blood from escaping when blood vessels are injured. People with MPS have a bleeding problem, as they have decreased circulating VWF activity and platelets that also don't function as expected. Here, we studied a mother and a daughter who live with this condition to better understand if there are other reasons behind the bleeding issues in this family. These participants had low levels of several other proteins, and their platelets did not gather as usual to arrest bleeding. They also did not undergo the usual changes in shape. These changes could contribute to the bleeding problems reported in this family.