In-cell Catalysis by Tethered Organo-Osmium Complexes Generates Selectivity for Breast Cancer Cells.

Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi-targeting strategy to overcome drug resistance. Nonetheless, many in-cell catalysts in development are hindered by deactivation by endogenous nucleophiles. We have synthesised a highly potent, stable Os-based 16-electron half-sandwich ('piano stool') catalyst by introducing a permanent covalent tether between the arene and chelated diamine ligand. This catalyst exhibits antiproliferative activity comparable to the clinical drug cisplatin towards triple-negative breast cancer cells and can overcome tamoxifen resistance. Speciation experiments revealed Os to be almost exclusively albumin-bound in the extracellular medium, while cellular accumulation studies identified an energy-dependent, protein-mediated Os accumulation pathway, consistent with albumin-mediated uptake. Importantly, the tethered Os complex was active for in-cell transfer hydrogenation catalysis, initiated by co-administration of a non-toxic dose of sodium formate as a source of hydride, indicating that the Os catalyst is delivered to the cytosol of cancer cells intact. The mechanism of action involves the generation of reactive oxygen species (ROS), thus exploiting the inherent redox vulnerability of cancer cells, accompanied by selectivity for cancerous cells over non-tumorigenic cells.

A Photodynamic and Photochemotherapeutic Platinum-Iridium Charge-Transfer Conjugate for Anticancer Therapy.

The novel hetero-dinuclear complex trans,trans,trans-[PtIV(py)2(N3)2(OH)(µ-OOCCH2CH2CONHCH2-bpyMe)IrIII(ppy)2]Cl (Pt-Ir), exhibits charge transfer between the acceptor photochemotherapeutic Pt(IV) (Pt-OH) and donor photodynamic Ir(III) (Ir-NH2) fragments. It is stable in the dark, but undergoes photodecomposition more rapidly than the Pt(IV) parent complex (Pt-OH) to generate Pt(II) species, an azidyl radical and 1O2. The Ir(III)* excited state, formed after irradiation, can oxidise NADH to NAD⋅ radicals and NAD+. Pt-Ir is highly photocytotoxic towards cancer cells with a high photocytotoxicity index upon irradiation with blue light (465 nm, 4.8 mW/cm2), even with short light-exposure times (10-60 min). In contrast, the mononuclear Pt-OH and Ir-NH2 subunits and their simple mixture are much less potent. Cellular Pt accumulation was higher for Pt-Ir compared to Pt-OH. Irradiation of Pt-Ir in cancer cells damages nuclei and releases chromosomes. Synchrotron-XRF revealed ca. 4× higher levels of intracellular platinum compared to iridium in Pt-Ir treated cells under dark conditions. Luminescent Pt-Ir distributes over the whole cell and generates ROS and 1O2 within 1 h of irradiation. Iridium localises strongly in small compartments, suggestive of complex cleavage and excretion via recycling vesicles (e.g. lysosomes). The combination of PDT and PACT motifs in one molecule, provides Pt-Ir with a novel strategy for multimodal phototherapy.

A scoping review of web-based, interactive, personalized decision-making tools available to support breast cancer treatment and survivorship care.

PURPOSE: We reviewed existing personalized, web-based, interactive decision-making tools available to guide breast cancer treatment and survivorship care decisions in clinical settings. METHODS: The study was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). We searched PubMed and related databases for interactive web-based decision-making tools developed to support breast cancer treatment and survivorship care from 2013 to 2023. Information on each tool's purpose, target population, data sources, individual and contextual characteristics, outcomes, validation, and usability testing were extracted. We completed a quality assessment for each tool using the International Patient Decision Aid Standard (IPDAS) instrument. RESULTS: We found 54 tools providing personalized breast cancer outcomes (e.g., recurrence) and treatment recommendations (e.g., chemotherapy) based on individual clinical (e.g., stage), genomic (e.g., 21-gene-recurrence score), behavioral (e.g., smoking), and contextual (e.g., insurance) characteristics. Forty-five tools were validated, and nine had undergone usability testing. However, validation and usability testing included mostly White, educated, and/or insured individuals. The average quality assessment score of the tools was 16 (range: 6-46; potential maximum: 63). CONCLUSIONS: There was wide variation in the characteristics, quality, validity, and usability of the tools. Future studies should consider diverse populations for tool development and testing. IMPLICATIONS FOR CANCER SURVIVORS: There are tools available to support personalized breast cancer treatment and survivorship care decisions in clinical settings. It is important for both cancer survivors and physicians to carefully consider the quality, validity, and usability of these tools before using them to guide care decisions.

A Scoping Review of Personalized, Interactive, Web-Based Clinical Decision Tools Available for Breast Cancer Prevention and Screening in the United States.

Introduction. Personalized web-based clinical decision tools for breast cancer prevention and screening could address knowledge gaps, enhance patient autonomy in shared decision-making, and promote equitable care. The purpose of this review was to present evidence on the availability, usability, feasibility, acceptability, quality, and uptake of breast cancer prevention and screening tools to support their integration into clinical care. Methods. We used the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews Checklist to conduct this review. We searched 6 databases to identify literature on the development, validation, usability, feasibility, acceptability testing, and uptake of the tools into practice settings. Quality assessment for each tool was conducted using the International Patient Decision Aid Standard instrument, with quality scores ranging from 0 to 63 (lowest-highest). Results. We identified 10 tools for breast cancer prevention and 9 tools for screening. The tools included individual (e.g., age), clinical (e.g., genomic risk factors), and health behavior (e.g., alcohol use) characteristics. Fourteen tools included race/ethnicity, but no tool incorporated contextual factors (e.g., insurance, access) associated with breast cancer. All tools were internally or externally validated. Six tools had undergone usability testing in samples including White (median, 71%; range, 9%-96%), insured (99%; 97%-100%) women, with college education or higher (60%; 27%-100%). All of the tools were developed and tested in academic settings. Seven (37%) tools showed potential evidence of uptake in clinical practice. The tools had an average quality assessment score of 21 (range, 9-39). Conclusions. There is limited evidence on testing and uptake of breast cancer prevention and screening tools in diverse clinical settings. The development, testing, and integration of tools in academic and nonacademic settings could potentially improve uptake and equitable access to these tools. Highlights: There were 19 personalized, interactive, Web-based decision tools for breast cancer prevention and screening.Breast cancer outcomes were personalized based on individual clinical characteristics (e.g., age, medical history), genomic risk factors (e.g., BRCA1/2), race and ethnicity, and health behaviors (e.g., smoking). The tools did not include contextual factors (e.g., insurance status, access to screening facilities) that could potentially contribute to breast cancer outcomes.Validation, usability, acceptability, and feasibility testing were conducted mostly among White and/or insured patients with some college education (or higher) in academic settings. There was limited evidence on testing and uptake of the tools in nonacademic clinical settings.

Modeling Fatigue in Manual and Robot-Assisted Work for Operator 5.0.

Fatigue, and many other human performance factors, impact worker wellbeing, and thus production quality and efficiency. Adopting the Industry 5.0 perspective, we propose that integrating human performance models into wider industrial system models can improve modeling accuracy and lead to superior outcomes. Integrating our Worker Fatigue Model as part of their industrial system architect model allowed Airbus, a leading aircraft manufacturer, to more accurately predict system performance as a function of the workforce makeup, which could be a combination of human workers and robots, or a combination of highly experienced and less experienced workers. Our approach demonstrates the importance and value of including human performance models in trade studies for introducing robots on the shop floor, and can be used to include various aspects of human performance in industrial system models to address specific task requirements or different levels of automation.

Alzheimer's Disease-associated Region-specific Decrease of Vesicular Glutamate Transporter Immunoreactivity inthe Medial Temporal Lobe and Superior Temporal Gyrus.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are very limited treatment options. Dysfunction of the excitatory neurotransmitter system is thought to play a major role in the pathogenesis of this condition. Vesicular glutamate transporters (VGLUTs) are key to controlling the quantal release of glutamate. Thus, expressional changes in disease can have implications for aberrant neuronal activity, raising the possibility of a therapeutic target. There is no information regarding the expression of VGLUTs in the human medial temporal lobe in AD, one of the earliest and most severely affected brain regions. This study aimed to quantify and compare the layer-specific expression of VGLUT1 and VGLUT2 between control and AD cases in the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus. Free-floating fluorescent immunohistochemistry was used to label VGLUT1 and VGLUT2 in the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus. Sections were imaged using laser-scanning confocal microscopy and transporter densitometric analysis was performed. VGLUT1 density was not significantly different in AD tissue, except lower staining density observed in the dentate gyrus stratum moleculare (p = 0.0051). VGLUT2 expression was not altered in the hippocampus and entorhinal cortex of AD cases but was significantly lower in the subiculum (p = 0.015) and superior temporal gyrus (p = 0.0023). This study indicates a regionally specific vulnerability of VGLUT1 and VGLUT2 expression in the medial temporal lobe and superior temporal gyrus in AD. However, the causes and functional consequences of these disturbances need to be further explored to assess VGLUT1 and VGLUT2 as viable therapeutic targets.

Prospective evaluation of sexual health following radical cystectomy due to bladder cancer.

Background: There is a lack of data concerning sexual health following open radical cystectomy (RC), especially in elderly patients and women. Aim: To describe sexual health and its impact on general health as well as survival in patients undergoing standard open RC for the treatment of bladder cancer (BC). Due to limited data, subgroup analysis for elderly patients and women was performed. Methods: A prospective noninterventional clinical study was performed evaluating sexual health in RC with any kind of urinary diversion due to BC with a follow-up of 12 months after RC. The study was approved by the local ethics review board (A 2021-0175) and was registered at the German Clinical Trial Register (DRKS00026255). Assessment of sexual health was done with the following validated questionnaires: EORTC QLQ-C30 (for quality of life; European Organisation for Research and Treatment of Cancer), EORTC SH22 (for sexual health), and IIEF-5 (5-item International Index of Erectile Function). Outcomes: The standard measurements of EORTC QLQ-C30, EORTC SH22, and IIEF-5 as well as overall survival. Results: Thirty-two patients participated in the study with a mean age of 71.5 years (SD, 9.7): 25 (78.1%) were male and 7 (21.9%) were female. Overall there is a heterogenic picture for sexual health in the study population, but sexual satisfaction is significantly higher prior to surgery while the importance of a sex life stays high and stable. Interestingly, the general health score is significantly correlated to sexual satisfaction (Pearson's correlation; r = 0.522, P = .002) preoperatively but not following surgery: r = 0.103 (P = .665) after 3 months, r = 0.478 (P = .052) after 6 months, r = 0.276 (P = .302) after 9 months, and r = 0.337 (P = .202) after 12 months. The importance of a sex life is still essential for the patients, especially when recovering from RC; nearly the same can be reported for elderly patients. Unfortunately, the data for women are too limited to report robust results. Clinical Implications: Evaluation, advice, and monitoring of sexual health must be integrated into clinical practice, particularly in women. Strengths and Limitations: At least to our knowledge, this is the first systematic prospective evaluation of sexual health in patients with BC receiving RC. Due to the small sample size, there is a risk of selection bias. Conclusion: Sexual health is important for patients with BC receiving RC, and it is an essential part of quality of life, especially in elderly patients.

Simulation of the effects of molecular urine markers in follow-up of patients with high-risk non-muscle invasive bladder cancer.

A plethora of urine markers for the management of patients with bladder cancer has been developed and studied in the past. However, the clinical impact of urine testing on patient management remains obscure. The goal of this manuscript is to identify scenarios for the potential use of molecular urine markers in the follow-up of patients with high-risk non-muscle-invasive BC (NMIBC) and estimate potential risks and benefits. Information on the course of disease of patients with high-risk NMIBC and performance data of a point-of-care test (UBC rapid™), an MCM-5 directed ELISA (ADXBLADDER™), and 2 additional novel assays targeting alterations of mRNA expression and DNA methylation (Xpert bladder cancer monitor™, Epicheck™) were retrieved from high-quality trials and/or meta-analyses. In addition, the sensitivity of white light cystoscopy (WLC) and the impact of a urine marker result on the performance of WLC were estimated based on fluorescence cystoscopy data and information from the CeFub trial. This information was applied to different scenarios in patient follow-up and sensitivity, estimated number of cystoscopies, and the numbers needed to diagnose were calculated. The sensitivity of guideline-based regular follow-up (SOC) at 1 year was calculated at 96%. For different marker-supported strategies sensitivities ranging from 77% to 97.9% were estimated. Calculations suggest that several strategies are effective for the SOC. While for the SOC 24.6 WLCs were required to diagnose 1 tumor recurrence (NND), this NND dropped below 5 in some marker-supported strategies. Based on the results of this simulation, a marker-supported follow-up of patients with HR NMIBC is safe and offers the option to significantly reduce the number of WLCs. Further research focusing on prospective randomized trials is needed to finally find a way to implement urine markers into clinical decision-making.

Guidelines for Neuroprognostication in Critically Ill Adults with Moderate-Severe Traumatic Brain Injury.

BACKGROUND: Moderate-severe traumatic brain injury (msTBI) carries high morbidity and mortality worldwide. Accurate neuroprognostication is essential in guiding clinical decisions, including patient triage and transition to comfort measures. Here we provide recommendations regarding the reliability of major clinical predictors and prediction models commonly used in msTBI neuroprognostication, guiding clinicians in counseling surrogate decision-makers. METHODS: Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, we conducted a systematic narrative review of the most clinically relevant predictors and prediction models cited in the literature. The review involved framing specific population/intervention/comparator/outcome/timing/setting (PICOTS) questions and employing stringent full-text screening criteria to examine the literature, focusing on four GRADE criteria: quality of evidence, desirability of outcomes, values and preferences, and resource use. Moreover, good practice recommendations addressing the key principles of neuroprognostication were drafted. RESULTS: After screening 8125 articles, 41 met our eligibility criteria. Ten clinical variables and nine grading scales were selected. Many articles varied in defining "poor" functional outcomes. For consistency, we treated "poor" as "unfavorable". Although many clinical variables are associated with poor outcome in msTBI, only the presence of bilateral pupillary nonreactivity on admission, conditional on accurate assessment without confounding from medications or injuries, was deemed moderately reliable for counseling surrogates regarding 6-month functional outcomes or in-hospital mortality. In terms of prediction models, the Corticosteroid Randomization After Significant Head Injury (CRASH)-basic, CRASH-CT (CRASH-basic extended by computed tomography features), International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT)-core, IMPACT-extended, and IMPACT-lab models were recommended as moderately reliable in predicting 14-day to 6-month mortality and functional outcomes at 6 months and beyond. When using "moderately reliable" predictors or prediction models, the clinician must acknowledge "substantial" uncertainty in the prognosis. CONCLUSIONS: These guidelines provide recommendations to clinicians on the formal reliability of individual predictors and prediction models of poor outcome when counseling surrogates of patients with msTBI and suggest broad principles of neuroprognostication.

Weight Stigma in Latin America, Asia, the Middle East, and Africa: A Scoping Review.

INTRODUCTION: Being stigmatized because of one's weight can pose physical, mental, and social challenges. While weight stigma and its consequences are established throughout Europe, North America, and Australasia, less is known about weight stigma in other regions. The objective of this study was to identify the extent and focus of weight stigma research in Latin America, Asia, the Middle East, and Africa. METHODS: A scoping review of weight stigma research in Latin America, Asia, the Middle East, and Africa was conducted. SCOPUS and PsychINFO databases were searched, and weight stigma experts were contacted to identify relevant literature. Sources were classified based on country/region, population, setting, and category of weight stigma researched. RESULTS: A total of 130 sources were identified from 33 countries and territories. Results indicate that weight stigma has been investigated across populations and settings, mainly focusing on manifestations of weight stigma through experiences, practices, drivers, and personal outcomes of these manifestations. CONCLUSIONS: Weight stigma is a developing global health concern not restricted to Europe, North America, and Australasia. The extent and focus of weight stigma research in Latin America, Asia, the Middle East, and Africa vary between countries and regions leaving several research gaps that require further investigation.

Accelerated Lung Function Decline and Mucus-Microbe Evolution in Chronic Obstructive Pulmonary Disease.

RATIONALE: Progressive lung function loss is recognized in COPD; however, no study concurrently evaluates how accelerated lung function decline relates to mucus properties and the microbiome in COPD. OBJECTIVE: Longitudinal assessment of mucus and microbiome changes accompanying accelerated lung function decline in COPD patients. METHODS: Prospective, longitudinal assessment of the London COPD cohort exhibiting the greatest FEV1 decline (n=30; "accelerated decline"; 156 mL/year FEV1 loss) and with no FEV1 decline (n=28; "non-decline"; 49 mL/year FEV1 gain) over time. Lung microbiomes from "paired" sputum (total 116 specimens) were assessed by shotgun metagenomics and corresponding mucus profiles evaluated for biochemical and biophysical properties. RESULTS: Biochemical and biophysical mucus properties are significantly altered in the accelerated decline group. Unsupervised principal component analysis showed clear separation, with mucus biochemistry associated with accelerated decline, while biophysical mucus characteristics contributed to inter-individual variability. When mucus and microbes are considered together, an accelerated decline mucus-microbiome association emerges, characterized by increased mucin (MUC5AC and MUC5B) concentration and the presence of Achromobacter and Klebsiella. As COPD progresses, mucus-microbiome shifts occur, initially characterized by low mucin concentration and transition from viscous to elastic dominance accompanied by the commensals Veillonella, Gemella, Rothia and Prevotella (GOLD A and B) before transition to increased mucus viscosity, mucins, and DNA concentration along with the emergence of pathogenic microorganisms including Haemophilus, Moraxella and Pseudomonas (GOLD E). CONCLUSION: Mucus-microbiome associations evolve over time with accelerated lung function decline, symptom progression and exacerbations affording fresh therapeutic opportunities for early intervention. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Reassessment of the enigmatic "Prestosuchus" loricatus (Archosauria: Pseudosuchia) from the Middle-Late Triassic of southern Brazil.

Our knowledge of the diversity and evolution of South American Triassic pseudosuchians has greatly improved in the past 15 years, due to new discoveries, but also to the revision of several historically important specimens. One of the earliest descriptions of pseudosuchians from the Triassic of Brazil stems from the classic work of Huene from the first half of the 20th century, who described several species, including such influential taxa as Rauisuchus tiradentes or Prestosuchus chiniquensis, which have recently been reviewed. The more poorly known proposed second species of Prestosuchus, P. loricatus, is the focus of the present work. The original material included some elements of the axial skeleton (cervical and caudal vertebrae, ribs, osteoderms) and the hindlimb (ischia, calcaneum, metatarsus), collected from the Dinodontosaurus Assemblage Zone of the Chiniquá area, west of São Pedro do Sul. "Prestosuchus" loricatus shows numerous differences to P. chiniquensis, including the shape of cervical neural spines, presence of epipophyses on the cervical vertebrae, presence of a pit in the iliac articulation of the ischium, lack of longitudinal furrows in the dorsolateral surface of the ischial shafts, the more slender calcaneal tuber and a less pronounced ventral pit in the calcaneum, and is thus referred to a new genus, Schultzsuchus gen. nov. Phylogenetic analysis indicates an early branching position within Poposauroidea for Schultzsuchus, making it the oldest known member of this clade in South America.

Impact of palladium/palladium hydride conversion on electrochemical CO2 reduction via in-situ transmission electron microscopy and diffraction.

Electrochemical conversion of CO2 offers a sustainable route for producing fuels and chemicals. Pd-based catalysts are effective for converting CO2 into formate at low overpotentials and CO/H2 at high overpotentials, while undergoing poorly understood morphology and phase structure transformations under reaction conditions that impact performance. Herein, in-situ liquid-phase transmission electron microscopy and select area diffraction measurements are applied to track the morphology and Pd/PdHx phase interconversion under reaction conditions as a function of electrode potential. These studies identify the degradation mechanisms, including poisoning and physical structure changes, occurring in PdHx/Pd electrodes. Constant potential density functional theory calculations are used to probe the reaction mechanisms occurring on the PdHx structures observed under reaction conditions. Microkinetic modeling reveals that the intercalation of *H into Pd is essential for formate production. However, the change in electrochemical CO2 conversion selectivity away from formate and towards CO/H2 at increasing overpotentials is due to electrode potential dependent changes in the reaction energetics and not a consequence of morphology or phase structure changes.

Mouse model of radiation retinopathy reveals vascular and neuronal injury.

PURPOSE: To characterize the neuronal and vascular pathology in vivo and in vitro in a mouse model of radiation retinopathy. METHODS: C57Bl/6J mice underwent cranial irradiation with 12 Gy and in vivo imaging by optical coherence tomography and of relative blood flow velocity by laser speckle flowgraphy for up to 3-6 months after irradiation. Retinal architecture, vascular density and leakage and apoptosis were analyzed by histology and immunohistochemistry before irradiation or at 10, 30, 240, and 365 days after treatment. RESULTS: The vascular density decreased in the plexiform layers starting at 30 days after irradiation. No impairment in retinal flow velocity was seen. Subtle perivascular leakage was present at 10 days, in particular in the outer plexiform layer. This corresponded to increased width of this layer. However, no significant change in the retinal thickness was detected by OCT-B scans. At 365 days after irradiation, the nuclear density was significantly reduced compared to baseline. Apoptosis was detected at 30 days and less prominent at 365 days. CONCLUSIONS: By histology, vascular leakage at 10 days was followed by increased neuronal apoptosis and loss of neuronal and vascular density. However, in vivo imaging approaches that are commonly used in human patients did not detect pathology in mice.

Marsupials have monoallelic MEST expression with a conserved antisense lncRNA but MEST is not imprinted.

The imprinted isoform of the Mest gene in mice is involved in key mammalian traits such as placental and fetal growth, maternal care and mammary gland maturation. The imprinted isoform has a distinct differentially methylated region (DMR) at its promoter in eutherian mammals but in marsupials, there are no differentially methylated CpG islands between the parental alleles. Here, we examined similarities and differences in the MEST gene locus across mammals using a marsupial, the tammar wallaby, a monotreme, the platypus, and a eutherian, the mouse, to investigate how imprinting of this gene evolved in mammals. By confirming the presence of the short isoform in all mammalian groups (which is imprinted in eutherians), this study suggests that an alternative promoter for the short isoform evolved at the MEST gene locus in the common ancestor of mammals. In the tammar, the short isoform of MEST shared the putative promoter CpG island with an antisense lncRNA previously identified in humans and an isoform of a neighbouring gene CEP41. The antisense lncRNA was expressed in tammar sperm, as seen in humans. This suggested that the conserved lncRNA might be important in the establishment of MEST imprinting in therian mammals, but it was not imprinted in the tammar. In contrast to previous studies, this study shows that MEST is not imprinted in marsupials. MEST imprinting in eutherians, therefore must have occurred after the marsupial-eutherian split with the acquisition of a key epigenetic imprinting control region, the differentially methylated CpG islands between the parental alleles.

Guidelines for Neuroprognostication in Critically Ill Adults with Intracerebral Hemorrhage.

BACKGROUND: The objective of this document is to provide recommendations on the formal reliability of major clinical predictors often associated with intracerebral hemorrhage (ICH) neuroprognostication. METHODS: A narrative systematic review was completed using the Grading of Recommendations Assessment, Development, and Evaluation methodology and the Population, Intervention, Comparator, Outcome, Timing, Setting questions. Predictors, which included both individual clinical variables and prediction models, were selected based on clinical relevance and attention in the literature. Following construction of the evidence profile and summary of findings, recommendations were based on Grading of Recommendations Assessment, Development, and Evaluation criteria. Good practice statements addressed essential principles of neuroprognostication that could not be framed in the Population, Intervention, Comparator, Outcome, Timing, Setting format. RESULTS: Six candidate clinical variables and two clinical grading scales (the original ICH score and maximally treated ICH score) were selected for recommendation creation. A total of 347 articles out of 10,751 articles screened met our eligibility criteria. Consensus statements of good practice included deferring neuroprognostication-aside from the most clinically devastated patients-for at least the first 48-72 h of intensive care unit admission; understanding what outcomes would have been most valued by the patient; and counseling of patients and surrogates whose ultimate neurological recovery may occur over a variable period of time. Although many clinical variables and grading scales are associated with ICH poor outcome, no clinical variable alone or sole clinical grading scale was suggested by the panel as currently being reliable by itself for use in counseling patients with ICH and their surrogates, regarding functional outcome at 3 months and beyond or 30-day mortality. CONCLUSIONS: These guidelines provide recommendations on the formal reliability of predictors of poor outcome in the context of counseling patients with ICH and surrogates and suggest broad principles of neuroprognostication. Clinicians formulating their judgments of prognosis for patients with ICH should avoid anchoring bias based solely on any one clinical variable or published clinical grading scale.

Age-dependent effects of the ß3 adrenoceptor agonist CL316,243 on human and rat detrusor muscle strips.

Motility of detrusor smooth muscle includes adrenergic relaxation and cholinergic contraction. Since the latter may be deregulated in overactive bladder (OAB) pathophysiology, anticholinergics are the standard therapy but occasionally less tolerated due to side effects such as dry mouth and constipation. ß3 adrenoceptor agonists also alleviate OAB symptoms by relaxing the detrusor muscle. Their age dependence, however, is far from understood. To address this issue, we induced contractions with KCl (60 mM) and carbachol (from 10 nM to 100 µM) in the presence of the ß3 adrenoceptor agonist CL316,243 (from 0.1 to 10 µM) in both human and rat muscle strips. Our results confirmed that both contractions were attenuated by ß3 adrenoceptor activation in both species, but with differing age dependence. In humans, specimens from mid-life subjects showed a significantly more pronounced effect of CL316,243 in attenuating carbachol-induced contractions than those from aged subjects (Cohen's d of maximal attenuation: 1.82 in mid-life versus 0.13 in aged) without altering EC50. Conversely, attenuation of KCl responses by CL316,243 increased during ageing (Spearman correlation coefficient = -0.584, P<0.01). In rats, both KCl- and carbachol-induced contractions were significantly more attenuated by CL316,243 in samples from adolescent as compared to aged samples. Immunohistochemistry in human detrusor sections proved ß3 adrenoreceptor abundance to remain unaltered during ageing. In conclusion, our findings suggest differential age-dependent changes in human ß3 adrenoceptor-dependent attenuation of detrusor contraction in terms of electromechanical versus pharmacomechanical coupling; they may help understand the differential responsiveness of OAB patients to ß3 agents.

Benefits and Harms of Mammography Screening in 75 + Women to Inform Shared Decision-making: a Simulation Modeling Study.

BACKGROUND: Guidelines recommend shared decision-making (SDM) around mammography screening for women ≥ 75 years old. OBJECTIVE: To use microsimulation modeling to estimate the lifetime benefits and harms of screening women aged 75, 80, and 85 years based on their individual risk factors (family history, breast density, prior biopsy) and comorbidity level to support SDM in clinical practice. DESIGN, SETTING, AND PARTICIPANTS: We adapted two established Cancer Intervention and Surveillance Modeling Network (CISNET) models to evaluate the remaining lifetime benefits and harms of screening U.S. women born in 1940, at decision ages 75, 80, and 85 years considering their individual risk factors and comorbidity levels. Results were summarized for average- and higher-risk women (defined as having breast cancer family history, heterogeneously dense breasts, and no prior biopsy, 5% of the population). MAIN OUTCOMES AND MEASURES: Remaining lifetime breast cancers detected, deaths (breast cancer/other causes), false positives, and overdiagnoses for average- and higher-risk women by age and comorbidity level for screening (one or five screens) vs. no screening per 1000 women. RESULTS: Compared to stopping, one additional screen at 75 years old resulted in six and eight more breast cancers detected (10% overdiagnoses), one and two fewer breast cancer deaths, and 52 and 59 false positives per 1000 average- and higher-risk women without comorbidities, respectively. Five additional screens over 10 years led to 23 and 31 additional breast cancer cases (29-31% overdiagnoses), four and 15 breast cancer deaths avoided, and 238 and 268 false positives per 1000 average- and higher-risk screened women without comorbidities, respectively. Screening women at older ages (80 and 85 years old) and high comorbidity levels led to fewer breast cancer deaths and a higher percentage of overdiagnoses. CONCLUSIONS: Simulation models show that continuing screening in women ≥ 75 years old results in fewer breast cancer deaths but more false positive tests and overdiagnoses. Together, clinicians and 75 + women may use model output to weigh the benefits and harms of continued screening.

Guidelines for neuroprognostication in adults with traumatic spinal cord injury.

BACKGROUND: Traumatic spinal cord injury (tSCI) impacts patients and their families acutely and often for the long term. The ability of clinicians to share prognostic information about mortality and functional outcomes allows patients and their surrogates to engage in decision-making and plan for the future. These guidelines provide recommendations on the reliability of acute-phase clinical predictors to inform neuroprognostication and guide clinicians in counseling adult patients with tSCI or their surrogates. METHODS: A narrative systematic review was completed using Grading of Recommendations Assessment, Development, and Evaluation methodology. Candidate predictors, including clinical variables and prediction models, were selected based on clinical relevance and presence of an appropriate body of evidence. The Population/Intervention/Comparator/Outcome/Timing/Setting question was framed as "When counseling patients or surrogates of critically ill patients with traumatic spinal cord injury, should < predictor, with time of assessment if appropriate > be considered a reliable predictor of < outcome, with time frame of assessment >?" Additional full-text screening criteria were used to exclude small and lower quality studies. Following construction of an evidence profile and summary of findings, recommendations were based on four Grading of Recommendations Assessment, Development, and Evaluation criteria: quality of evidence, balance of desirable and undesirable consequences, values and preferences, and resource use. Good practice recommendations addressed essential principles of neuroprognostication that could not be framed in the Population/Intervention/Comparator/Outcome/Timing/Setting format. Throughout the guideline development process, an individual living with tSCI provided perspective on patient-centered priorities. RESULTS: Six candidate clinical variables and one prediction model were selected. Out of 11,132 articles screened, 369 met inclusion criteria for full-text review and 35 articles met eligibility criteria to guide recommendations. We recommend pathologic findings on magnetic resonance imaging, neurological level of injury, and severity of injury as moderately reliable predictors of American Spinal Cord Injury Impairment Scale improvement and the Dutch Clinical Prediction Rule as a moderately reliable prediction model of independent ambulation at 1 year after injury. No other reliable or moderately reliable predictors of mortality or functional outcome were identified. Good practice recommendations include considering the complete clinical condition as opposed to a single variable and communicating the challenges of likely functional deficits as well as potential for improvement and for long-term quality of life with SCI-related deficits to patients and surrogates. CONCLUSIONS: These guidelines provide recommendations about the reliability of acute-phase predictors of mortality, functional outcome, American Spinal Injury Association Impairment Scale grade conversion, and recovery of independent ambulation for consideration when counseling patients with tSCI or their surrogates and suggest broad principles of neuroprognostication in this context.

Weighty words: exploring terminology about weight among samples of physicians, obesity specialists, and the general public.

BACKGROUND: The words used to refer to weight and individuals with large bodies can be used to reinforce weight stigma. Given that most previous research has examined preferred terminology within homogenous groups, this research sought to examine terminology preferences across populations. METHODS: This paper reports on data gathered with the general public, family physicians, and obesity researchers/practitioners. Participants were asked about the words they commonly: (1) used to refer to people with large bodies (general public); (2) heard in their professional contexts (physicians and obesity specialists); and (3) perceived to be the most socially or professionally acceptable (all samples). RESULTS: Similarities and differences were evident between samples, especially related to weight-related clinical terms, the word fat, and behavioral stereotypes. CONCLUSION: The results provide some clarity into the differences between populations and highlight the need to incorporate use of strategies that may move beyond person-first language to humanize research and clinical practice with people with large bodies.