Stored platelet hemostatic phenotype and function is not altered when donors are on testosterone replacement therapy.

BACKGROUND: Critical shortages in the national blood supply have led to a re-evaluation of previously overlooked donor sources for blood products. As a part of that effort, red blood cells collected from therapeutic phlebotomy of donors on testosterone replacement therapy (TRT) have been conditionally approved for transfusion. However, platelets from TRT donors are not currently approved for use due to limited data on effects of supraphysiologic testosterone on recipient safety and platelet function. The objective of this study was to provide a comprehensive profile of phenotype and function in platelets from TRT and control donors. STUDY DESIGN AND METHODS: Platelets in plasma were collected from TRT and control donors (N = 10 per group; age- and sex-matched) and stored at room temperature for 7 days. On storage Day 1 (D1) and Day 7 (D7), platelet products were analyzed for platelet count, metabolic parameters (i.e., glucose, lactate, mitochondrial function), surface receptor expression, aggregation, thrombin generation, and thrombus formation under physiological flow conditions. RESULTS: TRT donor platelets were not significantly different than control donor platelets in terms of count, surface phenotype, metabolic function, ability to aggregate, thrombin generation, or ability to form occlusive thrombus under arterial flow regimes. Both groups were similar to each other by D7, but had significantly lost hemostatic function compared to D1. DISCUSSION: Platelets derived from donors undergoing TRT have similar phenotypic and functional profiles compared to those derived from control donors. This suggests that therapeutic phlebotomy of TRT donors may provide a useful source for platelet products.

High cannabigerol hemp extract moderates colitis and modulates the microbiome in an inflammatory bowel disease model.

Cannabis sativa L. has a long history of medicinal use, particularly for gastrointestinal diseases. Patients with inflammatory bowel disease (IBD) report using cannabis to manage their symptoms, despite little data to support the use of cannabis or cannabis products to treat the disease. In this study, we utilize the well-described dextran sodium sulfate (DSS) model of colitis in mice to assess the impact of commercially available, non-euphorigenic, high cannabigerol (CBG) hemp extract (20 mg/mL cannabigerol, 20.7 mg/mL cannabidiol, 1 mg/mL cannabichromene) on IBD activity and the colonic microbiome. Mice were given 2% DSS in drinking water for 5 days, followed by 2 days of regular drinking water. Over the 7 days, mice were dosed daily with either high CBG hemp extract or matched vehicle control. Daily treatment with high CBG hemp extract dramatically reduces the severity of disease at the histological and organismal levels as measured by decreased disease activity index, increased colon length, and decreases in percent colon tissue damage. 16S rRNA gene sequencing of the fecal microbiota reveals high CBG hemp extract treatment results in alterations in the microbiota, that may be beneficial for colitis. Finally, using metabolomic analysis of fecal pellets, we find that mice treated with high CBG hemp extract have a normalization of several metabolic pathways, including those involved in inflammation. Taken together these data suggest that high CBG hemp extracts may offer a novel treatment option for patients. Significance Statement Using the DSS model of colitis, we show that treatment with high CBG hemp extract reduces the severity of symptoms associated with colitis. Additionally, we show that treatment modulates both the fecal microbiota and metabolome with potential functional significance.

Effects of cannabidiol, with and without ∆9-tetrahydrocannabinol, on anxiety-like behavior following alcohol withdrawal in mice.

Introduction: Alcohol use disorder (AUD) is commonly associated with anxiety disorders and enhanced stress-sensitivity; symptoms that can worsen during withdrawal to perpetuate continued alcohol use. Alcohol increases neuroimmune activity in the brain. Our recent evidence indicates that alcohol directly modulates neuroimmune function in the central amygdala (CeA), a key brain region regulating anxiety and alcohol intake, to alter neurotransmitter signaling. We hypothesized that cannabinoids, such as cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC), which are thought to reduce neuroinflammation and anxiety, may have potential utility to alleviate alcohol withdrawal-induced stress-sensitivity and anxiety-like behaviors via modulation of CeA neuroimmune function. Methods: We tested the effects of CBD and CBD:THC (3:1 ratio) on anxiety-like behaviors and neuroimmune function in the CeA of mice undergoing acute (4-h) and short-term (24-h) withdrawal from chronic intermittent alcohol vapor exposure (CIE). We further examined the impact of CBD and CBD:THC on alcohol withdrawal behaviors in the presence of an additional stressor. Results: We found that CBD and 3:1 CBD:THC increased anxiety-like behaviors at 4-h withdrawal. At 24-h withdrawal, CBD alone reduced anxiety-like behaviors while CBD:THC had mixed effects, showing increased center time indicating reduced anxiety-like behaviors, but increased immobility time that may indicate increased anxiety-like behaviors. These mixed effects may be due to altered metabolism of CBD and THC during alcohol withdrawal. Immunohistochemical analysis showed decreased S100ß and Iba1 cell counts in the CeA at 4-h withdrawal, but not at 24-h withdrawal, with CBD and CBD:THC reversing alcohol withdrawal effects.. Discussion: These results suggest that the use of cannabinoids during alcohol withdrawal may lead to exacerbated anxiety depending on timing of use, which may be related to neuroimmune cell function in the CeA.

Systematic review of drug-drug interactions of delta-9-tetrahydrocannabinol, cannabidiol, and Cannabis.

Background: The recent exponential increase in legalized medical and recreational cannabis, development of medical cannabis programs, and production of unregulated over-the-counter products (e.g., cannabidiol (CBD) oil, and delta-8-tetrahydrocannabinol (delta-8-THC)), has the potential to create unintended health consequences. The major cannabinoids (delta-9-tetrahydrocannabinol and cannabidiol) are metabolized by the same cytochrome P450 (CYP) enzymes that metabolize most prescription medications and xenobiotics (CYP3A4, CYP2C9, CYP2C19). As a result, we predict that there will be instances of drug-drug interactions and the potential for adverse outcomes, especially for prescription medications with a narrow therapeutic index. Methods: We conducted a systematic review of all years to 2023 to identify real world reports of documented cannabinoid interactions with prescription medications. We limited our search to a set list of medications with predicted narrow therapeutic indices that may produce unintended adverse drug reactions (ADRs). Our team screened 4,600 reports and selected 151 full-text articles to assess for inclusion and exclusion criteria. Results: Our investigation revealed 31 reports for which cannabinoids altered pharmacokinetics and/or produced adverse events. These reports involved 16 different Narrow Therapeutic Index (NTI) medications, under six drug classes, 889 individual subjects and 603 cannabis/cannabinoid users. Interactions between cannabis/cannabinoids and warfarin, valproate, tacrolimus, and sirolimus were the most widely reported and may pose the greatest risk to patients. Common ADRs included bleeding risk, altered mental status, difficulty inducing anesthesia, and gastrointestinal distress. Additionally, we identified 18 instances (58%) in which clinicians uncovered an unexpected serum level of the prescribed drug. The quality of pharmacokinetic evidence for each report was assessed using an internally developed ten-point scale. Conclusion: Drug-drug interactions with cannabinoids are likely amongst prescription medications that use common CYP450 systems. Our findings highlight the need for healthcare providers and patients/care-givers to openly communicate about cannabis/cannabinoid use to prevent unintended adverse events. To that end, we have developed a free online tool (www.CANN-DIR.psu.edu) to help identify potential cannabinoid drug-drug interactions with prescription medications.

Correlating Severity of Pulmonary Hypertension by Echocardiogram with Mortality in Premature Infants with Bronchopulmonary Dysplasia.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth. Infants with BPD are at increased risk for pulmonary hypertension (PH). Cardiac catheterization is the gold standard for diagnosing PH, but cardiac catheterization is challenging to perform in small, sick, premature infants. The utility of echocardiography for diagnosing PH and predicting outcomes in extremely premature infants has not been clearly defined. Therefore, we sought to use predefined criteria to diagnose PH by echocardiogram and relate PH severity to mortality in extremely premature infants with BPD. STUDY DESIGN: Echocardiograms from 46 infants born ≤28 weeks' postmenstrual age with a diagnosis of BPD were assessed for PH by three pediatric cardiologists using predefined criteria, and survival times among categories of PH patients were compared. A total of 458 echocardiograms were reviewed, and 15 (33%) patients were found to have at least moderate PH. Patients with at least moderate PH had similar demographic characteristics to those with no/mild PH. RESULTS: Ninety percent of infants without moderate to severe PH survived to hospital discharge, compared with 67% of infants with at least moderate PH (p = 0.048). Patients with severe PH had decreased survival to hospital discharge (38%) compared with moderate (100%) and no/mild PH (90%) groups. Kaplan-Meier survival curves also differed among PH severity groups (Wilcoxon p < 0.001). CONCLUSION: Using predefined criteria for PH, premature infants with BPD can be stratified into PH severity categories. Patients diagnosed with severe PH by echocardiogram have significantly reduced survival. KEY POINTS: · A composite score definition of PH by echocardiogram showed high inter- and intrarater reliability.. · Infants with severe PH by echocardiogram had decreased survival rates.. · Early diagnosis of PH by echocardiogram dictates treatment which may improve outcomes..

Origins and Importance of Intragranular Cracking in Layered Lithium Transition Metal Oxide Cathodes.

Li-ion batteries have a pivotal role in the transition toward electric transportation. Ni-rich layered transition metal oxide (LTMO) cathode materials promise high specific capacity and lower cost but exhibit faster degradation compared with lower Ni alternatives. Here, we employ high-resolution electron microscopy and spectroscopy techniques to investigate the nanoscale origins and impact on performance of intragranular cracking (within primary crystals) in Ni-rich LTMOs. We find that intragranular cracking is widespread in charged specimens early in cycle life but uncommon in discharged samples even after cycling. The distribution of intragranular cracking is highly inhomogeneous. We conclude that intragranular cracking is caused by local stresses that can have several independent sources: neighboring particle anisotropic expansion/contraction, Li- and TM-inhomogeneities at the primary and secondary particle levels, and interfacing of electrochemically active and inactive phases. Our results suggest that intragranular cracks can manifest at different points of life of the cathode and can potentially lead to capacity fade and impedance rise of LTMO cathodes through plane gliding and particle detachment that lead to exposure of additional surfaces to the electrolyte and loss of electrical contact.

The Potential of Cannabichromene (CBC) as a Therapeutic Agent.

There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa The two most abundant cannabinoids (Δ9-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). While the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials. In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC. Significance Statement Cannabichromene (CBC) has been suggested to have disparate therapeutic benefits such as anti-inflammatory, anticonvulsant, antibacterial, and antinociceptive effects. Most of the focus on the medical benefits of cannabinoids has been focused on THC and CBD. The preliminary studies on CBC indicate that this phytocannabinoid may have unique therapeutic potential that warrants further investigation. Following easier access to hemp, CBC products are commercially available over-the-counter and are being widely utilized with little or no evidence of their safety or efficacy.

Interstitial keratitis presenting as the ocular manifestation of undiagnosed hidradenitis suppurativa.

Interstitial keratitis is defined as nonulcerative inflammation of the corneal stroma resulting from a bacterial or viral infection, parasitic antigen, or autoimmune response. Hidradenitis suppurativa is an inflammatory skin condition that presents with painful and inflamed boils in apocrine gland-bearing regions of the body, typically with onset around puberty, and ocular comorbidities exist in only a small percentage of these patients. Herein, we describe a unique ocular presentation of hidradenitis suppurativa including pronounced bilateral interstitial keratitis and association with high titer c-ANCA (antineutrophil cytoplasmic antibodies).

Co-relation of Portal Vein Tumour Thrombus Response With Survival Function Following Robotic Radiosurgery in Vascular Invasive Hepatocellular Carcinoma.

Background/aims: The aim of this study was to prospectively evaluate stereotactic body radiotherapy (SBRT) with robotic radiosurgery in hepatocellular carcinoma patients with macrovascular invasion (HCC-PVT). Materials and methods: Patients with inoperable HCC-PVT, good performance score (PS0-1) and preserved liver function [up to Child-Pugh (CP) B7] were accrued after ethical and scientific committee approval [Clinical trial registry-India (CTRI): 2022/01/050234] for treatment on robotic radiosurgery (M6) and planned with Multiplan (iDMS V2.0). Triple-phase contrast computed tomography (CT) scan was performed for contouring, and gross tumour volume (GTV) included contrast-enhancing mass within main portal vein and adjacent parenchymal disease. Dose prescription was as per risk stratification protocol (22-50 Gy in 5 fractions) while achieving the constraints of mean liver dose <15 Gy, 800 cc liver <8 Gy and the duodenum max of <24 Gy). Response assessment was done at 2 months' follow-up for recanalization. Patient- and treatment-related factors were evaluated for influence in survival function. Results: Between Jan 2017 and May 2022, 318 consecutive HCC with PVT patients were screened and 219 patients were accrued [male 92%, CP score: 5-7 90%, mean age: 63 years (38-85 yrs), Cancer of the Liver Italian Program <3: 84 (40%), 3-6117 (56%), infective aetiology 9.5%, performance status (PS): 0-37%; 1-56%]. Among 209 consecutive patients accrued for SBRT treatment (10 patients were excluded after accrual due to ascites and decompensation), 139 were evaluable for response assessment (>2 mo follow-up). At mean follow-up of 12.21 months (standard deviation: 10.66), 88 (63%) patients expired and 51 (36%) were alive. Eighty-two (59%) patients had recanalization of PVT (response), 57 (41%) patients did not recanalize and 28 (17%) had progressive/metastatic disease prior to response evaluation (<2 months). Mean overall survival (OS) in responders and non-responders were 18.4 [standard error (SE): 2.52] and 9.34 month (SE 0.81), respectively (P < 0.001). Mean survival in patients with PS0, PS1 and PS2 were 17, 11.7 and 9.7 months (P = 0.019), respectively. OS in partial recanalization, bland thrombus and complete recanalization was 12.4, 14.1 and 30.3 months, respectively (P-0.002). Adjuvant sorafenib, Barcelona Clinic Liver Classification stage, gender, age and RT dose did not influence response to treatment. Recanalization rate was higher in good PS patients (P-0.019). OS in patients with response to treatment, in those with no response to treatment, in those who are fit but not accrued and in those who are not suitable were 18.4, 9.34, 5.9 and 2.6 months, respectively (P-<0.001). Thirty-six of 139 patients (24%) had radiation-induced liver disease (RILD) [10 (7.2%) had classic RILD & 26 (19%) had non-classic RILD]. Derangement in CP score (CP score change) by more than 2 was seen in 30 (24%) within 2-month period after robotic radiosurgery. Eighteen (13%) had unplanned admissions, two patients required embolization due to fiducial-related bleeding and 20 (14%) had ascites, of which 9 (6%) patients required abdominocentesis. Conclusion: PVT response or recanalization after SBRT is a statistically significant prognostic factor for survival function in HCC-PVT.

Racial/ethnic differences in the association between transgender-related U.S. state policies and self-rated health of transgender women.

BACKGROUND: Policy protections for transgender adults in the United States are consistently associated with positive health outcomes. However, studies over-represent non-Latinx White transgender people and obscure variation in policies' intended goals. This study examined racial differences in the relationship between transgender-related policies and transgender women's self-rated health. Guided by Critical Race Theory, we hypothesized that policies conferring access to resources (e.g., healthcare) would be associated with better self-rated health among all participants while policies signifying equality (e.g., nondiscrimination laws) would be associated with better self-rated health only for White participants. METHODS: Using cross-sectional data collected between March 2018-December 2020 from 1566 transgender women, we analyzed 7 state-level 'access policies,' 5 'equality policies,' and sum indices of each. Participants represented 29 states, and 54.7% were categorized as people of color. We fit a series of multilevel ordinal regression models predicting self-rated health by each policy. Multivariate models were adjusted for relevant covariates at the individual- and state-level. We then tested moderation by race/ethnicity using interaction terms and generated stratified predicted probability plots. RESULTS: In bivariate models, 4 access policies, 2 equality policies, and both indices were associated with better self-rated health, but associations did not persist in adjusted models. Results from the multivariable models including interaction terms indicated that policies concerning private insurance coverage of gender-affirming care, private insurance nondiscrimination, credit nondiscrimination, and both indices were statistically significantly associated with better self-rated health for White participants and worse self-rated health for participants of color. CONCLUSIONS: The policies included in this analysis do not mitigate racism's effects on access to resources, indicating they may be less impactful for transgender women of color than White transgender women. Future research and policy advocacy efforts promoting transgender women's health must center racial equity as well as transgender people of color's priorities.

Assessing corn recovery from early season nutrient stress under different soil moisture regimes.

Corn (Zea mays) biomass accumulation and nutrient uptake by the six-leaf collar (V6) growth stage are low, and therefore, synchronizing nutrient supply with crop demand could potentially minimize nutrient loss and improve nutrient use efficiency. Knowledge of corn's response to nutrient stress in the early growth stages could inform such nutrient management. Field studies were conducted to assess corn recovery from when no fertilizer application is made until the V6 growth stage, and thereafter, applying fertilizer rates as those in non-stressed conditions. The early season nutrient stress and non-stress conditions received the same amount of nutrients. As the availability of nutrients for plant uptake is largely dependent on soil moisture, corn recovery from the early season nutrient stress was assessed under different soil moisture regimes induced via irrigation scheduling at 50% and 80% field capacity under overhead and subsurface drip irrigation (SSDI) systems. Peanut (Arachis hypogaea) was the previous crop under all conditions, and the fields were under cereal rye (Secale cereale) cover crop prior to planting corn. At the V6 growth stage, the nutrient concentrations of the early season-stressed crops, except for copper, were above the minimum threshold of sufficiency ranges reported for corn. However, the crops showed poor growth, with biomass accumulation being reduced by over 50% compared to non-stressed crops. Also, the uptake of all nutrients was significantly lower under the early season nutrient stress conditions. The recovery of corn from the early season nutrient stress was low. Compared to non-stress conditions, the early season nutrient stress caused 1.58 Mg ha-1 to 3.4 Mg ha-1 yield reduction. The percent yield reduction under the SSDI system was 37.6-38.2% and that under the overhead irrigation system was 11.7-13%. The high yield reduction from the early season nutrient stress under the SSDI system was because of water stress conditions in the topsoil soil layer. The findings of the study suggest ample nutrient supply in the early season growth stage is critical for corn production, and thus, further studies are recommended to determine the optimum nutrient supply for corn at the initial growth stages.

Impact of Controlled Versus Uncontrolled mFI-5 Frailty on Perioperative Complications After Adult Spinal Deformity Surgery.

STUDY DESIGN: Retrospective review. OBJECTIVES: We substratified the mFI-5 frailty index to reflect controlled and uncontrolled conditions and assess their relationship to perioperative complications. SUMMARY OF BACKGROUND DATA: Risk assessment before adult spinal deformity (ASD) surgery is critical because the surgery is highly invasive with a high complication rate. Although frailty is associated with risk of surgical complications, current frailty measures do not differentiate between controlled and uncontrolled conditions. METHODS: Frailty was calculated using the mFI-5 index for 170 ASD patients with fusion of ≥5 levels. Uncontrolled frailty was defined as blood pressure >140/90 mm Hg, HbA1C >7% or postprandial glucose >180 mg/dL, or recent chronic obstructive pulmonary disease (COPD) exacerbation, while on medication. Patients were divided into nonfrailty, controlled frailty, and uncontrolled frailty cohorts. The primary outcome measure was perioperative major and wound complications. Bivariate analysis was performed. Multivariable analysis assessed the relationship between frailty and perioperative complications. RESULTS: The cohorts included 97 nonfrail, 54 controlled frail, and 19 uncontrolled frail patients. Compared with nonfrail patients, patients with uncontrolled frailty were more likely to have age older than 60 years (84% vs. 24%), hyperlipidemia (42% vs. 20%), and Oswestry Disability Index (ODI) score >42 (84% vs. 52%) (P<0.05 for all). Controlled frailty was associated with those older than 60 years (41% vs. 24%) and hyperlipidemia (52% vs. 20%) (P<0.05 for all). On multivariable regression analysis controlling for hyperlipidemia, functional independence, motor weakness, ODI>42, and age older than 60 years, patients with uncontrolled frailty had greater odds of major complications (OR 4.24, P=0.03) and wound complications (OR 9.47, P=0.046) compared with nonfrail patients. Controlled frailty was not associated with increased risk of perioperative complications (P>0.05 for all). CONCLUSIONS: Although patients with uncontrolled frailty had higher risk of perioperative complications compared with nonfrail patients, patients with controlled frailty did not, suggesting the importance of controlling modifiable risk factors before surgery. LEVEL OF EVIDENCE: 3.

Changes in opioid prescribing and prescription drug monitoring program utilization following electronic health record integration-Massachusetts, 2018.

OBJECTIVE: In this study, we explored key prescription drug monitoring program-related outcomes among clinicians from a broad cohort of Massachusetts healthcare facilities following prescription drug monitoring program (PDMP) and electronic health record (EHR) data integration. METHODS: Outcomes included seven-day rolling averages of opioids prescribed, morphine milligram equivalents (MMEs) prescribed, and PDMP queries. We employed a longitudinal study design to analyze PDMP data over a 15-month study period which allowed for six and a half months of pre- and post-integration observations surrounding a two-month integration period. We used longitudinal mixed effects models to examine the effect of EHR integration on each of the key outcomes. RESULTS: Following EHR integration, PDMP queries increased both through the web-based portal and in total (0.037, [95% CI = 0.017, 0.057] and 0.056, [95% CI = 0.035, 0.077]). Both measures of clinician opioid prescribing declined throughout the study period; however, no significant effect following EHR integration was observed. These results were consistent when our analysis was applied to a subset consisting only of continuous PDMP users. CONCLUSIONS: Our results support EHR integration contributing to PDMP utilization by clinicians but do not support changes in opioid prescribing behavior.

Inequities in the distribution of adverse childhood experiences and their association with health among transgender people of color.

BACKGROUND: Racism and cisgenderism expose transgender people of color to adversity across the life course. However, little is known about the prevalence of adverse childhood experiences (ACEs) in this population or their association with health in comparison to other groups. OBJECTIVE: Guided by the structural trauma framework, we examined race/ethnicity/gender group differences in the prevalence of ACEs and their association with adult mental and physical health. PARTICIPANTS AND SETTING: 2019-2021 Behavioral Risk Factor Surveillance Survey. METHODS: Transgender participants (n = 551) were matched with two cisgender men (n = 1102) and two cisgender women (n = 1102) on key covariates. We compared age-adjusted predicted probabilities of nine ACEs by race/ethnicity/gender group. We then fit adjusted logistic regression models predicting poor mental and physical health by each ACE and compared marginal effects between groups. RESULTS: Transgender people of color had higher age-adjusted probabilities of six ACEs than at least one other group; for example, household incarceration was 0.16 (95 % CI: 0.11-0.22) compared to 0.09 (95 % CI: 0.06-0.13) for cisgender men of color (p = 0.032). The relationship between five ACEs and poor mental health was greater for transgender people of color than at least one other group. For instance, the marginal effect of household alcoholism on poor mental health was 0.28 (95 % CI: 0.11-0.45) compared to 0.07 (0.01-0.14) for White cisgender men (p = 0.031). There were no statistically significant differences regarding effects on poor physical health. CONCLUSIONS: ACEs inequitably impact transgender people of color, reflecting the need to restructure the interlocking systems that drive adversity among transgender children of color and exacerbate ACEs' health effects among adults.

Empirical legal analysis simplified: reducing complexity through automatic identification and evaluation of legally relevant factors.

This paper investigates the potential for reducing the complexity of AI and Law and empirical legal studies projects through a novel annotation methodology that relies on GPT Family Models to assist human annotators. Improving the speed, cost and quality of annotation could greatly benefit such projects. In modelling types of legal claims, researchers in the fields of empirical legal studies and AI and Law have long relied on manually annotating factors in case texts. To demonstrate our methodology, we employ cases and factors regarding whether a police officer has constitutional authority to detain a motorist on the basis of the officer's suspicion that the motorist is trafficking drugs. Our results demonstrate how recent advances in text analytics can reduce the burden of identifying factors in large numbers of cases and improve machine learning models' predictions of case outcomes. This article is part of the theme issue 'A complexity science approach to law and governance'.

Beta-blocker adjunct therapy as a prospective anti-metastatic with cardio-oncologic regulation.

The prevailing treatment stratagem in cancer therapy still challenges the dilemma of a probable metastatic spread following an initial diagnosis. Including an anti-metastatic agent demands a significant focus to overrule the incidence of treatment failures. Adrenergic stimulation underlying the metastatic spread paved the way for beta blockers as a breakthrough in repurposing as an anti-metastatic agent. However, the current treatment approach fails to fully harness the versatile potential of the drug in inhibiting probable metastasis. The beta blockers were seen to show a myriad of grip over the pro-metastatic and prognostic parameters of the patient. Novel interventions in immune therapy, onco-hypertension, surgery-induced stress, induction of apoptosis and angiogenesis inhibition have been used as evidence to interpret our objective of discussing the potential adjuvant role of the drug in the existing anti-cancer regimens. Adding weight to the relative incidence of onco-hypertension as an unavoidable side effect from chemotherapy, the slot for an anti-hypertensive agent is necessitated, and we try to suggest beta-blockers to fill this position. However, pointing out the paucity in the clinical study, we aim to review the current status of beta blockers under this interest to state how the drug should be included as a drug of choice in every patient undergoing cancer treatment.

Individual herpes simplex virus 1 (HSV-1) particles exit by exocytosis and accumulate at preferential egress sites.

The human pathogen herpes simplex virus 1 (HSV-1) produces a lifelong infection in the majority of the world's population. While the generalities of alpha herpesvirus assembly and egress pathways are known, the precise molecular and spatiotemporal details remain unclear. In order to study this aspect of HSV-1 infection, we engineered a recombinant HSV-1 strain expressing a pH-sensitive reporter, gM-pHluorin. Using a variety of fluorescent microscopy modalities, we can detect individual virus particles undergoing intracellular transport and exocytosis at the plasma membrane. We show that particles exit from epithelial cells individually, not bulk release of many particles at once, as has been reported for other viruses. In multiple cell types, HSV-1 particles accumulate over time at the cell periphery and cell-cell contacts. We show that this accumulation effect is the result of individual particles undergoing exocytosis at preferential sites and that these egress sites can contribute to cell-cell spread. We also show that the viral membrane proteins gE, gI, and US9, which have important functions in intracellular transport in neurons, are not required for preferential egress and clustering in non-neuronal cells. Importantly, by comparing HSV-1 to a related alpha herpesvirus, pseudorabies virus, we show that this preferential exocytosis and clustering effect are cell type dependent, not virus dependent. This preferential egress and clustering appear to be the result of the arrangement of the microtubule cytoskeleton, as virus particles co-accumulate at the same cell protrusions as an exogenous plus end-directed kinesin motor.IMPORTANCEAlpha herpesviruses produce lifelong infections in their human and animal hosts. The majority of people in the world are infected with herpes simplex virus 1 (HSV-1), which typically causes recurrent oral or genital lesions. However, HSV-1 can also spread to the central nervous system, causing severe encephalitis, and might also contribute to the development of neurodegenerative diseases. Many of the steps of how these viruses infect and replicate inside host cells are known in depth, but the final step, exiting from the infected cell, is not fully understood. In this study, we engineered a novel variant of HSV-1 that allows us to visualize how individual virus particles exit from infected cells. With this imaging assay, we investigated preferential egress site formation in certain cell types and their contribution to the cell-cell spread of HSV-1.

Exceptional diversity of KIR and HLA class I in Egypt.

Genetically determined variation of killer cell immunoglobulin like receptors (KIR) and their HLA class I ligands affects multiple aspects of human health. Their extreme diversity is generated through complex interplay of natural selection for pathogen resistance and reproductive health, combined with demographic structure and dispersal. Despite significant importance to multiple health conditions of differential effect across populations, the nature and extent of immunogenetic diversity is under-studied for many geographic regions. Here, we describe the first high-resolution analysis of KIR and HLA class I combinatorial diversity in Northern Africa. Analysis of 125 healthy unrelated individuals from Cairo in Egypt yielded 186 KIR alleles arranged in 146 distinct centromeric and 79 distinct telomeric haplotypes. The most frequent haplotypes observed were KIR-A, encoding two inhibitory receptors specific for HLA-C, two that are specific for HLA-A and -B, and no activating receptors. Together with 141 alleles of HLA class I, 75 of which encode a KIR ligand, we identified a mean of six distinct interacting pairs of inhibitory KIR and HLA allotypes per individual. We additionally characterize 16 KIR alleles newly identified in the study population. Our findings place Egyptians as one of the most highly diverse populations worldwide, with important implications for transplant matching and studies of immune-mediated diseases.

How Have Patient Out-of-pocket Costs for Common Outpatient Orthopaedic Foot and Ankle Surgical Procedures Changed Over Time? A Retrospective Study From 2010 to 2020.

BACKGROUND: Out-of-pocket (OOP) costs can be substantial financial burdens for patients and may even cause patients to delay or forgo necessary medical procedures. Although overall healthcare costs are rising in the United States, recent trends in patient OOP costs for foot and ankle orthopaedic surgical procedures have not been reported. Fully understanding patient OOP costs for common orthopaedic surgical procedures, such as those performed on the foot and ankle, might help patients and professionals make informed decisions regarding treatment options and demonstrate to policymakers the growing unaffordability of these procedures. QUESTIONS/PURPOSES: (1) How do OOP costs for common outpatient foot and ankle surgical procedures for commercially insured patients compare between elective and trauma surgical procedures? (2) How do these OOP costs compare between patients enrolled in various insurance plan types? (3) How do these OOP costs compare between surgical procedures performed in hospital-based outpatient departments and ambulatory surgical centers (ASCs)? (4) How have these OOP costs changed over time? METHODS: This was a retrospective, comparative study drawn from a large, longitudinally maintained database. Data on adult patients who underwent elective or trauma outpatient foot or ankle surgical procedures between 2010 and 2020 were extracted using the MarketScan Database, which contains well-delineated cost variables for all patient claims, which are particularly advantageous for assessing OOP costs. Of the 1,031,279 patient encounters initially identified, 41% (427,879) met the inclusion criteria. Demographic, procedural, and financial data were recorded. The median patient age was 50 years (IQR 39 to 57); 65% were women, and more than half of patients were enrolled in preferred provider organization insurance plans. Approximately 75% of surgical procedures were classified as elective (rather than trauma), and 69% of procedures were performed in hospital-based outpatient departments (rather than ASCs). The primary outcome was OOP costs incurred by the patient, which were defined as the sum of the deductible, coinsurance, and copayment paid for each episode of care. Monetary data were adjusted to 2020 USD. A general linear regression, the Kruskal-Wallis test, and the Wilcoxon-Mann-Whitney test were used for analysis, as appropriate. Alpha was set at 0.05. RESULTS: For foot and ankle indications, trauma surgical procedures generated higher median OOP costs than elective procedures (USD 942 [IQR USD 150 to 2052] versus USD 568 [IQR USD 51 to 1426], difference of medians USD 374; p < 0.001). Of the insurance plans studied, high-deductible health plans had the highest median OOP costs. OOP costs were lower for procedures performed in ASCs than in hospital-based outpatient departments (USD 645 [IQR USD 114 to 1447] versus USD 681 [IQR USD 64 to 1683], difference of medians USD 36; p < 0.001). This trend was driven by higher coinsurance for hospital-based outpatient departments than for ASCs (USD 391 [IQR USD 0 to 1136] versus USD 337 [IQR USD 0 to 797], difference of medians USD 54; p < 0.001). The median OOP costs for common outpatient foot and ankle surgical procedures increased by 102%, from USD 450 in 2010 to USD 907 in 2020. CONCLUSION: Rapidly increasing OOP costs of common foot and ankle orthopaedic surgical procedures warrant a thorough investigation of potential cost-saving strategies and initiatives to enhance healthcare affordability for patients. In particular, measures should be taken to reduce underuse of necessary care for patients enrolled in high-deductible health plans, such as shorter-term deductible timespans and placing additional regulations on the implementation of these plans. Moreover, policymakers and physicians could consider finding ways to increase the proportion of procedures performed at ASCs for procedure types that have been shown to be equally safe and effective as in hospital-based outpatient departments. Future studies should extend this analysis to publicly insured patients and further investigate the health and financial effects of high-deductible health plans and ASCs, respectively. LEVEL OF EVIDENCE: Level III, economic and decision analysis.