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Goals/backgroundPain is common among cirrhosis patients, particularly those hospitalized with acute illness. Managing pain in this population is challenging due to concern for adverse events and lack of guidelines for analgesic use. We sought to characterize analgesic use among inpatients with cirrhosis compared with matched noncirrhosis controls, as well as hospital-level variation in prescribing patterns.MethodsWe utilized the Vizient Clinical Database, which includes clinical and billing data from hospitalizations at >500 US academic medical centers. We identified cirrhosis patients hospitalized in 2017-2018, and a matched cohort of noncirrhosis patients. Types of analgesic given-acetaminophen (APAP), nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and adjuvants (eg, gabapentinoids, antidepressants) were defined from inpatient prescription records. Conditional logistic regression was used to associate cirrhosis diagnosis with analgesic use.ResultsOf 116,363 cirrhosis inpatients, 83% received at least 1 dose of an analgesic and 58% had regular inpatient analgesic use, rates that were clinically similar to noncirrhosis controls. Cirrhosis inpatients were half as likely to receive APAP (26% vs. 42%, P

BACKGROUND: Documented symptomatic progression of a paraganglioma (PGL) over many years is unusual. Our objective is to report a young man with such an occurrence. CASE REPORT: A 27-year-old male presented with headache, sweating, and palpitation. He had a history of cyanotic congenital heart disease. Five years before presentation, he had 24-hour urine metanephrines 43 mcg/d (25-222), vanillylmandelic acid 3 mg/d (

Double-stranded RNA produced during viral replication and transcription activates both protein kinase R (PKR) and ribonuclease L (RNase L), which limits viral gene expression and replication through host shutoff of translation. In this study, we find that APOBEC3B forms a complex with PABPC1 to stimulate PKR and counterbalances the PKR-suppressing activity of ADAR1 in response to infection by many types of viruses. This leads to translational blockage and the formation of stress granules. Furthermore, we show that APOBEC3B localizes to stress granules through the interaction with PABPC1. APOBEC3B facilitates the formation of protein-RNA condensates with stress granule assembly factor (G3BP1) by protecting mRNA associated with stress granules from RNAse L-induced RNA cleavage during viral infection. These results not only reveal that APOBEC3B is a key regulator of different steps of the innate immune response throughout viral infection but also highlight an alternative mechanism by which APOBEC3B can impact virus replication without editing viral genomes.

BackgroundTo evaluate the anatomic site(s) of initial disease progression in patients with castration resistant metastatic prostate cancer (mCRPC) in the presence or absence of pre-treatment visceral metastases while on systemic therapy.MethodsThis is a retrospective cohort study of mCRPC patients who have baseline and at least one follow up bone scan and CT chest, abdomen and pelvis (CAP). Disease progression was determined by RECIST and/or ≥ 30% increase in automated bone scan lesion area score. Kaplan-Meier plot was used to estimate the median progression free survival and log-rank tests were used to compare anatomic sites.ResultsOf 203 patients, 61 (30%) had pre-treatment visceral metastases. Patients with baseline visceral disease were 1.5 times more likely to develop disease progression (HR = 1.53; 95% CI, 1.03-2.26). Disease progression was a result of worsening bone scan disease (42% (16/38)) versus visceral (32% (12/38)) or lymph node disease (3% (1/38)) by CT or a combination thereof (23% (9/38)). Median time to progression (TTP) did not differ by anatomic location of initial progression (p = 0.86). Development of new lesions occurred in 50% of those visceral patients with soft tissue only progression and was associated with a significantly longer TTP (3.1 months (2.8-4.3 months) than those with worsening of pre-existing lesions (1.8 months (1.6-2.7 months); p = 0.04.ConclusionsPatients with pre-treatment visceral metastases in mCRPC are more likely to experience disease progression of bone disease with the initial anatomic site of progression similar to those without baseline visceral involvement.

BackgroundMost HIV cure-related studies involve interrupting antiretroviral treatment to assess the efficacy of pharmacologic interventions - also known as analytical treatment interruptions (ATIs). ATIs imply the risk of passing HIV to sexual partners due to the loss of undetectable HIV status. There has been a notable lack of attention paid to perceptions of ATIs among racial, ethnic, sex and gender minorities, and HIV serodifferent couples. These populations are among those most impacted by HIV in the United States. Future HIV cure research paradigms should equitably include considerations from these groups.MethodsFrom August - October 2020, we conducted in-depth interviews with 10 racial, ethnic, sex, and gender minority HIV serodifferent couples in geographically diverse regions of the United States to understand their perspectives about ATIs and partner protection measures to prevent secondary HIV transmissions because of participation in ATI studies. We used framework analysis to analyze the qualitative data.ResultsOf the 10 couples recruited, four identified as a gay couple, two as a gay and bisexual couple, two as a heterosexual couple, one as a gay and queer couple, and one as a queer couple. We found that HIV serodifferent couples in our study viewed ATIs as contradicting HIV treatment adherence messages. Couples expressed discomfort around ATIs in HIV cure research. They were concerned with the return of HIV detectability and worried ATIs might result in secondary HIV transmission. Participants were strongly in favor of using a range of partner protection measures during ATIs that included PrEP, HIV risk reduction counseling, and alternatives for penetrative sex practices. Couples also recommended that sex partners be consulted or involved as part of ATI trials.ConclusionsOur findings highlight new potential opportunities and strategies to mitigate risk of HIV transmission during ATIs among key groups historically under-represented in HIV cure research. Findings also underscore the relational aspects of ATI trials. We provide preliminary considerations for planning ATI trials with diverse HIV serodifferent partners. Future studies should continue to explore these issues among other types of partnerships, cultures, and socio-cultural settings.

Abstract In this article I explore changing state-citizen relationships in Mauritius. To do so, 1 outline and provide analysis of the system through which this Indian Ocean island has historically [...]

Abstract Animal models of depression show that acute stress negatively impacts functioning in neural regions sensitive to reward and punishment, often manifesting as anhedonic behaviors. However, few human studies have probed stress-induced neural activation changes in relation to anhedonia, which is critical for clarifying risk for affective disorders. Participants (N = 85, 12–14 years-old, 53 female), oversampled for risk of depression, were administered clinical assessments and completed an fMRI guessing task during a baseline (no-stress) period to probe neural response to receipt of rewards and losses. After the initial task run of the fMRI guessing task, participants received an acute stressor and then, were re-administered the guessing task. Including baseline, participants provided up to 10 self-report assessments of life stress and symptoms over a 2 year period. Linear mixed-effects models estimated whether change in neural activation (post- vs. pre-acute stressor) moderated the longitudinal associations between life stress and symptoms. Primary analyses indicated that adolescents with stress-related reductions in right ventral striatum response to rewards exhibited stronger longitudinal associations between life stress and anhedonia severity (β = −0.06, 95%CI[−0.11, −0.02], p = 0.008, p FDR = 0.048). Secondary analyses showed that longitudinal positive associations between life stress and depression severity were moderated by stress-related increases in dorsal striatum response to rewards (left caudate β = 0.11, 95%CI[0.07,0.17], p

BACKGROUND: Health systems have developed automated telephone call programs to screen and triage patients post-hospital discharge issues and concerns. The aims of our study were to determine whether and how older adults engage with automated post-hospital discharge telephone programs and to describe the prevalence of patient-reported post-discharge issues. METHODS: We identified all telephone calls made by an urban academic medical center as part of a post-hospital discharge program between May 1, 2018 and April 30, 2019. The program used automated telephone outreach to patients or their caregivers that included 11 distinct steps 3 days post-discharge. All adults discharged home from the hospital, were included, and we categorized patients into ≤64 years, 65-84 years, and ≥85 years age groups. We then compared call reach rate, completeness of 11-step calls and patient-reported issues between age groups. RESULTS: Eighteen thousand and seventy six patients were included. More patients 65-84 years old were reached compared to patients ≤64 years old (84.3% vs. 78.9%, AME 5.52%; 95%CI: 3.58%-7.45%). Completion rates of automated calls for those ≥85 years old were also high. Patients ≥85 years old were more likely to have questions about their follow-up plans and need assistance scheduling appointments compared to those ≤64 years old (19.0% vs. 11.9%, AME 7.0% (95%CI: 2.7%-11.3%). CONCLUSION: Post-hospital automated telephone calls are feasible and effective at reaching older adults. Future work should focus on improving discharge communication to ensure older adults are aware of their follow-up plan and appointments.

In response to the record-breaking COVID19 recession, many governments have adopted unprecedented fiscal stimuli. While countercyclical fiscal policy is effective in fighting conventional recessions, little is known about the effectiveness of fiscal policy in the current environment with widespread shelter-in-place ("lockdown") policies and the associated considerable limits on economic activity. Using detailed regional variation in economic conditions, lockdown policies, and U.S. government spending, we document that the effects of government spending were stronger during the peak of the pandemic recession, but only in cities that were not subject to strong stay-at-home orders. We examine mechanisms that can account for our evidence and place our findings in the context of other recent evidence from microdata.

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.

Background: Among children who start antibiotics for suspected urinary tract infection (UTI) in emergency departments (EDs), 40-60% have negative urine cultures or other results inconsistent with UTI. Practices contributing to excess antibiotic exposure are not well understood. The goal of this study was to understand diagnostic and post-encounter follow-up processes in children who received antibiotics, in order to define targets for intervention. Methods: We identified encounters by children evaluated in two pediatric EDs, over 2 months in the first ED and 9 months in the second ED, to balance different visit volumes. Children 2 months-17 years old were included if they had a urinalysis (UA) and/or urine culture performed, were assigned a primary or secondary diagnosis code for UTI, and initiated antibiotics. Patients were excluded if they received antibiotics prior to the encounter, had prior urologic surgery or device placement, or were immunocompromised or pregnant. Data abstracted by chart review included demographics, documented symptoms, test results, and documented urine culture review and management. Possible UTI symptoms per pediatric criteria included fever, dysuria, urinary frequency, urgency, or hesitancy, suprapubic, abdominal or flank pain, foul smelling urine, or new urinary incontinence. In both EDs, nurses review urine cultures and document changes to treatment plans. Final urine culture results were considered inconsistent with UTI if there was 1) no growth or 2) only mixed growth reported with quantity < 1 00,000 colony forming units/ml. Results: Of 150 eligible children, 146 (97%) had at least one UTI symptom and 146 (97%) had abnormal UA Results: Urine cultures were not performed in 27 (18%) children. Of 123 encounters with urine cultures performed, 71 (58%) had results inconsistent with UTI. Though 67/71 cultures were marked as reviewed, 43/67 (64%) of the patients who could have stopped antibiotics per guideline recommendations did not have documented plans to stop. In those who had documented plans to stop antibiotics, nurses reached 20/23 (87%) caregivers by phone to communicate these recommendations. Conclusion: Many children suspected to have UTI at the time of ED evaluation do not meet criteria for UTI. We found that the most frequent departures from evidence-based practice recommendations were 1) not sending urine cultures, and 2) not stopping antibiotics when culture results did not support the suspected UTI diagnosis. Further investigation should explore barriers and facilitators to these evidence-based practices to develop population- and context-specific diagnostic stewardship strategies.

Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes (Acadm, Acox1, Cpt2, Cyp4a1-3) and downregulation of lipid transport genes (Apoa1, Apoa5, Pltp). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis (Pck1) and bile acid synthesis (Cyp7a1) were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis (Scd) showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFAS-induced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis.

Summary: Background: Human restricted genes contribute to human specific traits in the immune system. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR), the highest Ca2+ conductor of the ACh receptors implicated in innate immunity. Understanding the mechanism of how CHRFAM7A affects the immune system remains unexplored. Methods: Two model systems are used, human induced pluripotent stem cells (iPSC) and human primary monocytes, to characterize α7 nAChR function, Ca2+ dynamics and decoders to elucidate the pathway from receptor to phenotype. Findings: CHRFAM7A/α7 nAChR is identified as a hypomorphic receptor with mitigated Ca2+ influx and prolonged channel closed state. This shifts the Ca2+ reservoir from the extracellular space to the endoplasmic reticulum (ER) leading to Ca2+ dynamic changes. Ca2+ decoder small GTPase Rac1 is then activated, reorganizing the actin cytoskeleton. Observed actin mediated phenotypes include cellular adhesion, motility, phagocytosis and tissue mechanosensation. Interpretation: CHRFAM7A introduces an additional, human specific, layer to Ca2+ regulation leading to an innate immune gain of function. Through the actin cytoskeleton it drives adaptation to the mechanical properties of the tissue environment leading to an ability to invade previously immune restricted niches. Human genetic diversity predicts profound translational significance as its understanding builds the foundation for successful treatments for infectious diseases, sepsis, and cancer metastasis. Funding: This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti) and in part by NIH grant R01HL163168 (Yongho Bae).

Background: The HeartWare ventricular assist device (HVAD) was discontinued in July 2021. The study aims to describe the impact the discontinuation the HVAD had on pediatric ventricular assist device (VAD) utilization and outcomes. Methods: The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry was queried for type of VAD utilization and outcomes/adverse event rates in patients with a body surface area of 0.7 to 1.4 m2. Results were compared from before and after July 2021. All patients in the registry implanted with an HVAD were reported to determine overall outcomes of these patients and define who remains on the device. Results: The HeartMate 3 (HM3) primarily replaced the HVAD in pediatric patients increasing from 29 of 258 (11%) of implants before July 2021 to 31 of 109 (29%) of implants after. A small increase in the use of the Berlin Heart EXCOR (40 of 258, 16% before to 20 of 109, 18% after) and paracorporeal continuous flow devices (116 of 258, 45% before to 58 of 109, 53% after) was also observed. The rate of ischemic stroke increased in the overall population and a decrease in bleeding complications in the EXCOR group was observed. Of the 187 pediatric patients implanted with an HVAD in the registry, 7 patients remain supported, 1 patient transitioned from the HVAD to an HM3, and 6 patients were lost to follow-up. Conclusions: The HM3 has been the primary replacement for the HVAD in the medium-sized pediatric population. The rate of ischemic stroke was higher after July 2021.

The role of prostate-specific membrane antigen (PSMA)-targeted PET in comparison to multiparametric MRI (mpMRI) in the evaluation of intraprostatic cancer foci is not well defined. The aim of our study was to compare the diagnostic performance of 68Ga-PSMA-11 PET/CT (PSMA PET/CT), mpMRI, and PSMA PET/CT + mpMRI using 3 independent masked readers for each modality and with histopathology as the gold standard in the detection, intraprostatic localization, and determination of local extension of primary prostate cancer. Methods: Patients with intermediate- or high-risk prostate cancer who underwent PSMA PET/CT as part of a prospective trial (NCT03368547) and mpMRI before radical prostatectomy were included. Each imaging modality was interpreted by 3 independent readers who were unaware of the other modality result. A central majority rule was applied (2:1). Pathologic examination of whole-mount slices was used as the gold standard. Imaging scans and whole-mount slices were interpreted using the same standardized approach on a segment level and a lesion level. A "neighboring" approach was used to define imaging-pathology correlation for the detection of individual prostate cancer foci. Accuracy in determining the location, extraprostatic extension (EPE), and seminal vesicle invasion (SVI) of prostate cancer foci was assessed using receiver-operating-characteristic curve analysis. Interreader agreement was calculated using intraclass correlation coefficient analysis. Results: The final analysis included 74 patients (14 [19%] with intermediate risk and 60 [81%] with high risk). The cancer detection rate (lesion-based analysis) was 85%, 83%, and 87% for PSMA PET/CT, mpMRI, and PSMA PET/CT + mpMRI, respectively. The change in AUC was statistically significant between PSMA PET/CT + mpMRI and the 2 imaging modalities alone for delineation of tumor localization (segment-based analysis) (P < 0.001) but not between PSMA PET/CT and mpMRI (P = 0.093). mpMRI outperformed PSMA PET/CT in detecting EPE (P = 0.002) and SVI (P = 0.001). In the segment-level analysis, intraclass correlation coefficient analysis showed moderate reliability among PSMA PET/CT and mpMRI readers using a 5-point Likert scale (range, 0.53-0.64). In the evaluation of T staging, poor reliability was found among PSMA PET/CT readers and poor to moderate reliability was found for mpMRI readers. Conclusion: PSMA PET/CT and mpMRI have similar accuracy in the detection and intraprostatic localization of prostate cancer foci. mpMRI performs better in identifying EPE and SVI. For the T-staging evaluation of intermediate to high-risk prostate cancer, mpMRI should still be considered the imaging modality of reference. Whenever available, PSMA PET/MRI or the coregistration or fusion of PSMA PET/CT and mpMRI (PSMA PET/CT + mpMRI) should be used as it improves tumor extent delineation.

Higher education has increasingly been called upon to develop interdisciplinary programs -- particularly in STEM fields -- that prepare students to address multi-faceted, real world problems. While the tensions between disciplinary cultures and interdisciplinary programs have been previously studied, relatively little is known about the experiences of students in interdisciplinary programs. In this grounded theory study, we interviewed 45 STEM students and alumnx from an interdisciplinary program at a public research institution to examine how individuals understand and integrate interdisciplinary perspectives into their academic pathways. Our findings demonstrate that participants moved through stages of interdisciplinarity regarding choice, navigation, and integration.

Abstract The Hall coefficient of the strongly interacting square lattice Hubbard model is calculated for temperatures between the antiferromagnetic interaction and the Mott gap scales. The leading order thermodynamic formula is evaluated for all doping concentrations. Second-order corrections of the thermodynamic formula are calculated and found to be negligible. The Hall coefficient diverges toward the Mott insulator. Below 45% doping the Hall sign is reversed relative to band structure-based Boltzmann’s equation. These results elucidate the effects of the Mott insulator on the charge carriers and their non-Fermi liquid transport.

Abstract Background Anemia is a worldwide problem with iron deficiency being the most common cause. When anemia occurs in pregnancy, it increases the risk of adverse maternal, fetal, and postnatal outcomes. It induces preterm births and low birth weight (LBW) deliveries, long-term neurodevelopmental sequelae, and an increased risk of earlier onset of postnatal iron deficiency. Anemia rates are among the highest in South Asia, and India’s National Family Health Survey (NFHS-5) for 2019–2021 indicated that over half of pregnant women, and more than 65% of children, in the country are classified as anemic (Sciences IIfP, National Family Health Survey-5, 2019–21, India Fact Sheet). In 2021, the parent RAPIDIRON Trial (Derman et al., Trials 22:649, 2021) was initiated in two states in India, with the goal of assessing whether a dose of intravenous (IV) iron given to anemic women during early pregnancy results in a greater proportion of participants with normal hemoglobin concentrations in the third trimester and a lower proportion of participants with LBW deliveries compared to oral iron. As a follow-up to the RAPIDIRON Trial, the RAPIDIRON-KIDS Study will follow the offspring of previously randomized mothers to assess, neurobehavioral, hematological, and health outcomes. Methods This prospective observational cohort study will follow a subset of participants previously randomized as part of the RAPIDIRON Trial and their newborns. Study visits occur at birth, 6 weeks, 4 months, 12 months, 24 months, and 36 months and include blood sample collection with both maternal and infant participants and specific neurobehavioral assessments conducted with the infants (depending on the study visit). The primary outcomes of interest are (1) infant iron status as indicated by both hemoglobin and ferritin (a) at birth and (b) at 4 months of age and (2) the developmental quotient (DQ) for the cognitive domain of the Bayley Scales of Infant Development Version IV (BSID-IV) at 24 months of age. Discussion This RAPIDIRON-KIDS Study builds upon its parent RAPIDIRON Trial by following a subset of the previously randomized participants and their offspring through the first 3 years of life to assess neurodevelopmental and neurobehavioral (infants, children), hematological, and health outcomes. Trial registration ClinicalTrials.gov NCT05504863 , Registered on 17 August 2022. Clinical Trials Registry – India CTRI/2022/05/042933 . Registered on 31 May 2022.

Background: Documented symptomatic progression of a paraganglioma (PGL) over many years is unusual. Our objective is to report a young man with such an occurrence. Case Report: A 27-year-old male presented with headache, sweating, and palpitation. He had a history of cyanotic congenital heart disease. Five years before presentation, he had 24-hour urine metanephrines 43 mcg/d (25-222), vanillylmandelic acid 3 mg/d (