LANCL1, a cell surface protein, promotes liver tumor initiation through FAM49B-Rac1 axis to suppress oxidative stress.

BACKGROUND AND AIMS: HCC is an aggressive cancer with a poor clinical outcome. Understanding the mechanisms that drive tumor initiation is important for improving treatment strategy. This study aimed to identify functional cell membrane proteins that promote HCC tumor initiation. APPROACH AND RESULTS: Tailor-made siRNA library screening was performed for all membrane protein-encoding genes that are upregulated in human HCC (n = 134), with sphere formation as a surrogate readout for tumor initiation. Upon confirmation of membranous localization by immunofluorescence and tumor initiation ability by limiting dilution assay in vivo, LanC-like protein-1 (LANCL1) was selected for further characterization. LANCL1 suppressed intracellular reactive oxygen species (ROS) and promoted tumorigenicity both in vitro and in vivo. Mechanistically, with mass spectrometry, FAM49B was identified as a downstream binding partner of LANCL1. LANCL1 stabilized FAM49B by blocking the interaction of FAM49B with the specific E3 ubiquitin ligase TRIM21, thus protecting FAM49B from ubiquitin-proteasome degradation. The LANCL1-FAM49B axis suppressed the Rac1-NADPH oxidase-driven ROS production, but this suppression of ROS was independent of the glutathione transferase function of LANCL1. Clinically, HCCs with high co-expression of LANCL1 and FAM49B were associated with more advanced tumor stage, poorer overall survival, and disease-free survival. In addition, anti-LANCL1 antibodies targeting the extracellular N-terminal domain were able to suppress the self-renewal ability, as demonstrated by the sphere formation ability of HCC cells. CONCLUSIONS: Our data showed that LANCL1 is a cell surface protein and a key contributor to HCC initiation. Targeting the LANCL1-FAM49B-Rac1-NADPH oxidase-ROS signaling axis may be a promising therapeutic strategy for HCC.

Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma.

OBJECTIVE: Fat mass and obesity-associated protein (FTO), an eraser of N 6-methyadenosine (m6A), plays oncogenic roles in various cancers. However, its role in hepatocellular carcinoma (HCC) is unclear. Furthermore, small extracellular vesicles (sEVs, or exosomes) are critical mediators of tumourigenesis and metastasis, but the relationship between FTO-mediated m6A modification and sEVs in HCC is unknown. DESIGN: The functions and mechanisms of FTO and glycoprotein non-metastatic melanoma protein B (GPNMB) in HCC progression were investigated in vitro and in vivo. Neutralising antibody of syndecan-4 (SDC4) was used to assess the significance of sEV-GPNMB. FTO inhibitor CS2 was used to examine the effects on anti-PD-1 and sorafenib treatment. RESULTS: FTO expression was upregulated in patient HCC tumours. Functionally, FTO promoted HCC cell proliferation, migration and invasion in vitro, and tumour growth and metastasis in vivo. FTO knockdown enhanced the activation and recruitment of tumour-infiltrating CD8+ T cells. Furthermore, we identified GPNMB to be a downstream target of FTO, which reduced the m6A abundance of GPNMB, hence, stabilising it from degradation by YTH N 6-methyladenosine RNA binding protein F2. Of note, GPNMB was packaged into sEVs derived from HCC cells and bound to the surface receptor SDC4 of CD8+ T cells, resulting in the inhibition of CD8+ T cell activation. A potential FTO inhibitor, CS2, suppresses the oncogenic functions of HCC cells and enhances the sensitivity of anti-PD-1 and sorafenib treatment. CONCLUSION: Targeting the FTO/m6A/GPNMB axis could significantly suppress tumour growth and metastasis, and enhance immune activation, highlighting the potential of targeting FTO signalling with effective inhibitors for HCC therapy.

Midline 1 interacting protein 1 promotes cancer metastasis through FOS-like 1-mediated matrix metalloproteinase 9 signaling in HCC.

BACKGROUND AND AIMS: Understanding the mechanisms of HCC progression and metastasis is crucial to improve early diagnosis and treatment. This study aimed to identify key molecular targets involved in HCC metastasis. APPROACH AND RESULTS: Using whole-transcriptome sequencing of patients' HCCs, we identified and validated midline 1 interacting protein 1 (MID1IP1) as one of the most significantly upregulated genes in metastatic HCCs, suggesting its potential role in HCC metastasis. Clinicopathological correlation demonstrated that MID1IP1 upregulation significantly correlated with more aggressive tumor phenotypes and poorer patient overall survival rates. Functionally, overexpression of MID1IP1 significantly promoted the migratory and invasive abilities and enhanced the sphere-forming ability and expression of cancer stemness-related genes of HCC cells, whereas its stable knockdown abrogated these effects. Perturbation of MID1IP1 led to significant tumor shrinkage and reduced pulmonary metastases in an orthotopic liver injection mouse model and reduced pulmonary metastases in a tail-vein injection model in vivo . Mechanistically, SP1 transcriptional factor was found to be an upstream driver of MID1IP1 transcription. Furthermore, transcriptomic sequencing on MID1IP1-overexpressing HCC cells identified FOS-like 1 (FRA1) as a critical downstream mediator of MID1IP1. MID1IP1 upregulated FRA1 to subsequently promote its transcriptional activity and extracellular matrix degradation activity of matrix metalloproteinase MMP9, while knockdown of FRA1 effectively abolished the MID1IP1-induced migratory and invasive abilities. CONCLUSIONS: Our study identified MID1IP1 as a regulator in promoting FRA1-mediated-MMP9 signaling and demonstrated its role in HCC metastasis. Targeting MID1IP1-mediated FRA1 pathway may serve as a potential therapeutic strategy against HCC progression.

Utilizing synchronous care to improve cardiovascular and renal health among patients with type 2 diabetes: Proof-of-concept results from the DECIDE-CV clinical programme.

AIM: The management of patients with type 2 diabetes is asynchronous, i.e. not coordinated in time, resulting in delayed access to care and low use of guideline-directed medical therapy (GDMT). METHODS: We retrospectively analysed consecutive patients assessed in the 'synchronized' DECIDE-CV clinic. In this outpatient clinic, patients with type 2 diabetes and cardiovascular or chronic kidney disease are simultaneously assessed by an endocrinologist, cardiologist and nephrologist in the same visit. The primary outcome was use of GDMT before and after the assessment in the clinic, including sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, renin-angiotensin system blockers and mineralocorticoid receptor antagonists. Secondary outcomes included the baseline-to-last-visit change in surrogate laboratory biomarkers. RESULTS: The first 232 patients evaluated in the clinic were included. The mean age was 67 ± 12 years, 69% were men and 92% had diabetes. In total, 73% of patients had atherosclerotic cardiovascular disease, 65% heart failure, 56% chronic kidney disease and 59% had a urinary albumin-to-creatinine ratio ≥30 mg/g. There was a significant increase in the use of GDMT:sodium-glucose cotransporter 2 inhibitors (from 44% to 87% of patients), glucagon-like peptide 1 receptor agonists (from 8% to 45%), renin-angiotensin system blockers (from 77% to 91%) and mineralocorticoid receptor antagonists (from 25% to 45%) (p < .01 for all). Among patients with paired laboratory data, glycated haemoglobin, urinary albumin-to-creatinine ratio and N-terminal proB-type natriuretic peptide levels significantly dropped from baseline (p < .05 for all). CONCLUSIONS: Joint assessment of patients with diabetes in a synchronized cardiometabolic clinic holds promise for enhancing GDMT use and has led to significant reductions in surrogate cardiovascular and renal laboratory biomarkers.

Safety of fluconazole in kidney transplant recipients for prevention of coccidioidomycosis.

Coccidioides is an endemic fungus that causes infections ranging from mild respiratory illness to life-threatening disease, and immunocompromised hosts such as solid organ transplant recipients are at higher risk for disseminated infection and mortality. Our center administers fluconazole prophylaxis to kidney transplant recipients residing in geographic areas with higher incidences of coccidioidomycosis. However, because drug-drug interactions occur between triazoles and immunosuppressants used in transplant medicine, we undertook a study to ascertain whether fluconazole prophylaxis was associated with any important safety outcomes in kidney transplant recipients. This retrospective study evaluated patients who had undergone kidney transplantation between 2016 and 2019. Data on patient demographics, transplant-related clinical information, use of fluconazole prophylaxis (200 mg daily for 6-12 months post-transplant), and patient outcomes were obtained. The primary outcome was mean estimated glomerular filtration rate (eGFR) at 12 months, comparing those who received fluconazole prophylaxis to those who did not. Secondary outcomes included mean eGFR at 3 months, 6 months, and 9 months post-transplant, patient survival, biopsy-proven graft rejection, graft loss, or a new requirement for post-transplant dialysis, all within 12 months post-transplant. The mean eGFR at 12 months was similar between both groups, with 66.4 ml/min/1.73 m² in the fluconazole prophylaxis group vs. 64.3 ml/min/1.73 m² in the non-fluconazole prophylaxis group (P = 0.55). Secondary outcomes were similar across both groups. Multivariable linear regression found no significant association between fluconazole use and graft function. Fluconazole prophylaxis for prevention of coccidioidomycosis was not associated with adverse graft outcomes in kidney transplant recipients.

Solid organ transplant recipients can be highly immune suppressed, and infection with Coccidioides (valley fever) after transplant can lead to severe infections in these patients. Our study showed that fluconazole was safe and effective for preventing Coccidioides in kidney transplant recipients.

A language-matching model to improve equity and efficiency of COVID-19 contact tracing.

Contact tracing is a pillar of COVID-19 response, but language access and equity have posed major obstacles. COVID-19 has disproportionately affected minority communities with many non-English-speaking members. Language discordance can increase processing times and hamper the trust building necessary for effective contact tracing. We demonstrate how matching predicted patient language with contact tracer language can enhance contact tracing. First, we show how to use machine learning to combine information from sparse laboratory reports with richer census data to predict the language of an incoming case. Second, we embed this method in the highly demanding environment of actual contact tracing with high volumes of cases in Santa Clara County, CA. Third, we evaluate this language-matching intervention in a randomized controlled trial. We show that this low-touch intervention results in 1) significant time savings, shortening the time from opening of cases to completion of the initial interview by nearly 14 h and increasing same-day completion by 12%, and 2) improved engagement, reducing the refusal to interview by 4%. These findings have important implications for reducing social disparities in COVID-19; improving equity in healthcare access; and, more broadly, leveling language differences in public services.

The effects of plastisphere on the physicochemical properties of microplastics.

The plastisphere is the microbial communities that grow on the surface of plastic debris, often used interchangeably with plastic biofilm or biofouled plastics. It can affect the properties of the plastic debris in multiple ways. This review aims to present the effects of the plastisphere on the physicochemical properties of microplastics systematically. It highlights that the plastisphere modifies the buoyancy and movement of microplastics by increasing their density, causing them to sink and settle out. Smaller and film microplastics are likely to settle sooner because of larger surface areas and higher rates of biofouling. Biofouled microplastics may show an oscillating movement in waterbodies when settling due to diurnal and seasonal changes in the growth of the plastisphere until they come close to the bottom of the waterbodies and are entrapped by sediments. The plastisphere enhances the adsorption of microplastics for metals and organic pollutants and shifts the adsorption mechanism from intraparticle diffusion to film diffusion. The plastisphere also increases surface roughness, reduces the pore size, and alters the overall charge of microplastics. Charge alteration is primarily attributed to changes in the functional groups on microplastic surfaces. The plastisphere introduces carbonyl, amine, amide, hydroxyl, and phosphoryl groups to microplastics, causing an increase in their surface hydrophilicity, which could alter their adsorption behaviors for heavy metals. The plastisphere may act as a reactive barrier that enhances the leaching of polar additives. It may anchor bacteria that can break down plastic additives, resulting in decreased crystallinity of microplastics. This review contributes to a better understanding of how the plastisphere alters the fate, transport, and environmental impacts of microplastics. It points to the possibility of engineering the plastisphere to improve microplastic biodegradation.

Integrating water quality data with a Bayesian network model to improve spatial and temporal phosphorus attribution: Application to the Maumee River Basin.

Surface water nutrient pollution, the primary cause of eutrophication, remains a major environmental concern in Western Lake Erie despite intergovernmental efforts to regulate nutrient sources. The Maumee River Basin has been the largest nutrient contributor. The two primary nutrient sources are inorganic fertilizer and livestock manure applied to croplands, which are later carried to the streams via runoff and soil erosion. Prior studies of nutrient source attribution have focused on large watersheds or counties at annual time scales. Source attribution at finer spatiotemporal scales, which enables more effective nutrient management, remains a substantial challenge. This study aims to address this challenge by developing a generalizable Bayesian network model for phosphorus source attribution at the subwatershed scale (12-digit Hydrologic Unit Code). Since phosphorus release is uncertain, we combine excess phosphorus derived from manure and fertilizer application and crop uptake data, flow information simulated by the SWAT model, and in-stream water quality measurements using Approximate Bayesian Computation to derive a posterior that attributes phosphorus contributions to subwatersheds. Our results show significant variability in subwatershed-scale phosphorus release that is lost in coarse-scale attribution. Phosphorus contributions attributed to the subwatersheds are on average lower than the excess phosphorus estimated by the nutrient balance approach currently adopted by environmental agencies. Fertilizer contributes more soluble reactive phosphorus than manure, while manure contributes most of the unreactive phosphorus. While developed for the specific context of Maumee River Basin, our lightweight and generalizable model framework could be adapted to other regions and pollutants and could help inform targeted environmental regulation and enforcement.

Cellular heterogeneity and plasticity in liver cancer.

Hepatocarcinogenesis involves complex genetic and cellular dysregulations which drive the formation of hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, with extensive heterogeneity. In contrast to the broad spectrum of molecularly driven therapies available for defined patient groups in certain cancer types, unfortunately the treatment options for HCC are highly limited. The lack of representative molecular and cellular signatures in the heterogeneous HCC tumors that can effectively guide the choice of the most appropriate treatment among the patients unavoidably limits the treatment outcome. Advancement and wide availability of the next-generation sequencing technologies have empowered us to examine and capture not only the detailed genetic alterations of the HCC cells but also the precise composition of different cell types within the tumor microenvironment and their interactions with the HCC cells at an unprecedented level. The information generated has provided new insight and better defined the inter-patient intertumoral heterogeneity, intra-patient intratumoral heterogeneity as well as the plasticity of HCC cells. These collectively provide a robust scientific basis in guiding the development and use of targeted therapy and immunotherapy. To complement, liquid biopsy coupled with high-sensitivity sequencing could potentially be adopted as a more practical and safer approach to detect and reflect the tumor heterogeneity in HCC patients in guiding the choice of treatment and monitoring disease progression.

Dysregulation of RalA signaling through dual regulatory mechanisms exerts its oncogenic functions in hepatocellular carcinoma.

BACKGROUND AND AIMS: Ras-like (Ral) small guanosine triphosphatases (GTPases), RalA and RalB, are proto-oncogenes directly downstream of Ras and cycle between the active guanosine triphosphate-bound and inactive guanosine diphosphate-bound forms. RalGTPase-activating protein (RalGAP) complex exerts a negative regulation. Currently, the role of Ral up-regulation in cancers remains unclear. We aimed to examine the clinical significance, functional implications, and underlying mechanisms of RalA signaling in HCC. APPROACH AND RESULTS: Our in-house and The Cancer Genome Atlas RNA sequencing data and quantitative PCR data revealed significant up-regulation of RalA in patients' HCCs. Up-regulation of RalA was associated with more aggressive tumor behavior and poorer prognosis. Consistently, knockdown of RalA in HCC cells attenuated cell proliferation and migration in vitro and tumorigenicity and metastasis in vivo. We found that RalA up-regulation was driven by copy number gain and uncovered that SP1 and ETS proto-oncogene 2 transcription factor cotranscriptionally drove RalA expression. On the other hand, RalGAPA2 knockdown increased the RalA activity and promoted intrahepatic and extrahepatic metastasis in vivo. Consistently, we observed significant RalGAPA2 down-regulation in patients' HCCs. Intriguingly, HCC tumors showing simultaneous down-regulation of RalGAPA2 and up-regulation of RalA displayed a significant association with more aggressive tumor behavior in terms of more frequent venous invasion, more advanced tumor stage, and poorer overall survival. Of note, Ral inhibition by a Ral-specific inhibitor RBC8 suppressed the oncogenic functions in a dose-dependent manner and sensitized HCC cells to sorafenib treatment, with an underlying enhanced inhibition of mammalian target of rapamycin signaling. CONCLUSIONS: Our results provide biological insight that dysregulation of RalA signaling through dual regulatory mechanisms supports its oncogenic functions in HCC. Targeting RalA may serve as a potential alternative therapeutic approach alone or in combination with currently available therapy.

Synchronization of multiple rigid body systems: A survey.

The multi-agent system has been a hot topic in the past few decades owing to its lower cost, higher robustness, and higher flexibility. As a particular multi-agent system, the multiple rigid body system received a growing interest for its wide applications in transportation, aerospace, and ocean exploration. Due to the non-Euclidean configuration space of attitudes and the inherent nonlinearity of the dynamics of rigid body systems, synchronization of multiple rigid body systems is quite challenging. This paper aims to present an overview of the recent progress in synchronization of multiple rigid body systems from the view of two fundamental problems. The first problem focuses on attitude synchronization, while the second one focuses on cooperative motion control in that rotation and translation dynamics are coupled. Finally, a summary and future directions are given in the conclusion.

A novel nonsense variant in the NFE2L1 transcription factor in a patient with developmental delay, hypotonia, genital anomalies, and failure to thrive.

The NFE2L1 transcription factor (also known as Nrf1 for nuclear factor erythroid 2-related factor-1) is a broadly expressed basic leucine zipper protein that performs a critical role in the cellular stress response pathway. Here, we identified a heterozygous nonsense mutation located in the last exon of the gene that terminates translation prematurely, resulting in the production of a truncated peptide devoid of the carboxyl-terminal region containing the DNA-binding and leucine-zipper dimerization interface of the protein. Variant derivatives were well expressed in vitro, and they inhibited the transactivation function of wild-type proteins in luciferase reporter assays. Our studies suggest that this dominant-negative effect of truncated variants is through the formation of inactive heterodimers with wild-type proteins preventing the expression of its target genes. These findings suggest the potential role of diminished NFE2L1 function as an explanation for the developmental delay, hypotonia, hypospadias, bifid scrotum, and failure to thrive observed in the patient.

The deubiquitinating enzyme USP7 regulates the transcription factor Nrf1 by modulating its stability in response to toxic metal exposure.

The nuclear factor E2-related factor 1 (Nrf1) transcription factor performs a critical role in regulating cellular homeostasis as part of the cellular stress response and drives the expression of antioxidants and detoxification enzymes among many other functions. Ubiquitination plays an important role in controlling the abundance and thus nuclear accumulation of Nrf1 proteins, but the regulatory enzymes that act on Nrf1 are not fully defined. Here, we identified ubiquitin specific protease 7 (USP7), a deubiquitinating enzyme, as a novel regulator of Nrf1 activity. We found that USP7 interacts with Nrf1a and TCF11-the two long protein isoforms of Nrf1. Expression of wildtype USP7, but not its catalytically defective mutant, resulted in decreased ubiquitination of TCF11 and Nrf1a, leading to their increased stability and increased transactivation of reporter gene expression by TCF11 and Nrf1a. In contrast, knockdown or pharmacologic inhibition of USP7 dramatically increased ubiquitination of TCF11 and Nrf1a and reduction of their steady state levels. Loss of USP7 function attenuated the induction of Nrf1 protein expression in response to treatment with arsenic and other toxic metals, and inhibition of USP7 activity significantly sensitized cells to arsenic treatment. Collectively, these findings suggest that USP7 may act to modulate abundance of Nrf1 protein to induce gene expression in response to toxic metal exposure.

Ephrin-A3/EphA2 axis regulates cellular metabolic plasticity to enhance cancer stemness in hypoxic hepatocellular carcinoma.

BACKGROUND & AIMS: The highly proliferative nature of hepatocellular carcinoma (HCC) frequently results in a hypoxic intratumoural microenvironment, which creates a therapeutic challenge owing to a lack of mechanistic understanding of the phenomenon. We aimed to identify critical drivers of HCC development and progression in the hypoxic microenvironment. METHODS: We performed integrative analysis of multiple transcriptomic and genomic profiles specific for HCC and hypoxia and identified the Ephrin-A3/Eph receptor A2 (EphA2) axis as a clinically relevant and hypoxia-inducible signalling axis in HCC. The functional significance and mechanistic consequences of the Ephrin-A3/EphA2 axis were examined in EFNA3- and EPHA2- knockdown/overexpressing HCC cells. The potential downstream pathways were investigated by transcriptome sequencing, quantitative reverse-transcription PCR, western blotting analysis and metabolomics. RESULTS: EFNA3 was frequently upregulated in HCC and its overexpression was associated with more aggressive tumour behaviours. HIF-1α directly and positively regulated EFNA3 expression under hypoxia. EFNA3 functionally contributed to self-renewal, proliferation and migration in HCC cells. EphA2 was identified as a key functional downstream mediator of EFNA3. Functional characterisation of the Ephrin-A3/EphA2 forward-signalling axis demonstrated a promotion of self-renewal ability and tumour initiation. Mechanistically, the Ephrin-A3/EphA2 axis promoted the maturation of SREBP1 and expression of its transcriptional target, ACLY, was significantly associated with the expression of EFNA3 and hypoxia markers in clinical cohorts. The metabolic signature of EPHA2 and ACLY stable knockdown HCC cells demonstrated significant overlap in fatty acid, cholesterol and tricarboxylic acid cycle metabolite profiles. ACLY was confirmed to mediate the self-renewal function of the Ephrin-A3/EphA2 axis. CONCLUSIONS: Our findings revealed the novel role of the Ephrin-A3/EphA2 axis as a hypoxia-sensitive modulator of HCC cell metabolism and a key contributor to HCC initiation and progression. LAY SUMMARY: Hepatocellular carcinoma (HCC) is a fast-growing tumour; hence, areas of the tumour often have insufficient vasculature and become hypoxic. The presence of hypoxia within tumours has been shown to negatively impact on the survival of patients with tumours, including HCC. Herein, we identified the Ephrin-A3/EphA2 axis as a key functional driver of tumour initiation and progression in response to hypoxia. Additionally, we showed that SREBP1-ACLY-mediated metabolic rewiring was an important downstream effector that induced cancer stemness in response to Ephrin-A3/EphA2 forward-signalling.

Hepatitis B Virus-Telomerase Reverse Transcriptase Promoter Integration Harnesses Host ELF4, Resulting in Telomerase Reverse Transcriptase Gene Transcription in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) integrations are common in hepatocellular carcinoma (HCC). In particular, alterations of the telomerase reverse transcriptase (TERT) gene by HBV integrations are frequent; however, the molecular mechanism and functional consequence underlying TERT HBV integration are unclear. APPROACH AND RESULTS: We adopted a targeted sequencing strategy to survey HBV integrations in human HBV-associated HCCs (n = 95). HBV integration at the TERT promoter was frequent (35.8%, n = 34/95) in HCC tumors and was associated with increased TERT mRNA expression and more aggressive tumor behavior. To investigate the functional importance of various integrated HBV components, we employed different luciferase reporter constructs and found that HBV enhancer I (EnhI) was the key viral component leading to TERT activation on integration at the TERT promoter. In addition, the orientation of the HBV integration at the TERT promoter further modulated the degree of TERT transcription activation in HCC cell lines and patients' HCCs. Furthermore, we performed array-based small interfering RNA library functional screening to interrogate the potential major transcription factors that physically interacted with HBV and investigated the cis-activation of host TERT gene transcription on viral integration. We identified a molecular mechanism of TERT activation through the E74 like ETS transcription factor 4 (ELF4), which normally could drive HBV gene transcription. ELF4 bound to the chimeric HBV EnhI at the TERT promoter, resulting in telomerase activation. Stable knockdown of ELF4 significantly reduced the TERT expression and sphere-forming ability in HCC cells. CONCLUSIONS: Our results reveal a cis-activating mechanism harnessing host ELF4 and HBV integrated at the TERT promoter and uncover how TERT HBV-integrated HCCs may achieve TERT activation in hepatocarcinogenesis.

Science Translation During the COVID-19 Pandemic: An Academic-Public Health Partnership to Assess Capacity Limits in California.

On the basis of an extensive academic-public health partnership around COVID-19 response, we illustrate the challenge of science-policy translation by examining one of the most common nonpharmaceutical interventions: capacity limits. We study the implementation of a 20% capacity limit in retail facilities in the California Bay Area. Through a difference-in-differences analysis, we show that the intervention caused no material reduction in visits, using the same large-scale mobile device data on human movements (mobility data) originally used in the academic literature to support such limits. We show that the lack of effectiveness stems from a mismatch between the academic metric of capacity relative to peak visits and the policy metric of capacity relative to building code. The disconnect in metrics is amplified by mobility data losing predictive power after the early months of the pandemic, weakening the policy relevance of mobility-based interventions. Nonetheless, the data suggest that a better-grounded rationale for capacity limits is to reduce risk specifically during peak hours. To enhance the connection between science, policy, and public health in future times of crisis, we spell out 3 strategies: living models, coproduction, and shared metrics. (Am J Public Health. 2022;112(2):308-315. https://doi.org/10.2105/AJPH.2021.306576).

Patient-present teaching in the clinic: Effect on agency and professional behaviour.

BACKGROUND/PURPOSE: Although much has been written about the medical learning environment, the patient, who is the focus of care, is rarely the focus in this literature. The purpose of this study was to explore the role of the patient as an active participant with agency in the medical learning environment from the standpoint of the learner, the attending physician, and most importantly, the patient. We hoped to gain insights into the mechanisms that can reinforce professional values such as patient-centred and respectful behaviours in a patient-present learning environment. METHODS: We conducted this study in an ambulatory internal medicine clinic using 'patient-present' clinic visits. All case presentations occurred in examination rooms with the patient. We invited participants (attending physicians, undergraduate and postgraduate learners, patients and family members) to participate in semistructured interviews after each clinic visit to explore the impact of the patient-present learning environment. We recruited 34 participants in the study; 10 attending physicians, 12 learners, 10 patients and 2 family members. We analysed the data deductively using a conceptual framework of agency. SUMMARY/RESULTS: We identified three major insights: (1) Patients felt engaged and valued opportunities to be heard; (2) Attending physicians and learners reported a more respectful learning environment and a positive though challenging teaching and learning experience; and (3) A hidden curriculum emerged in a performance-based view of professional behaviour. CONCLUSIONS: Patient-present teaching engaged patients and enhanced their agency by recasting the patient as the central focus within the healthcare encounter. We identified a tension between performing and learning. This study adds new insights to the concept of patient centredness and professionalism from the perspectives of all participants in the medical teaching and learning environment.

Walking orientation randomness metric (WORM) score: pilot study of a novel gait parameter to assess walking stability and discriminate fallers from non-fallers using wearable sensors.

BACKGROUND: Musculoskeletal disorders can contribute to injurious falls and incur significant societal and healthcare burdens. Identification of fallers from non-fallers through wearable-based gait analysis can facilitate timely intervention to assist mobility and prevent falls whilst improving care and attention for high fall-risk patients. In this study, we use wearable sensor-based gait analysis to introduce a novel variable to assess walking stability in fallers and non-fallers - the Walking Orientation Randomness Metric. The WORM score quantifies the stability, or 'figure-of-eight' motion of a subject's trunk during walking as an indicator of a falls-predictive (pathological) gait. METHODS: WORM is calculated as the 'figure-of-eight' oscillation mapped out in the transverse-plane by the upper body's centre-point during a walking bout. A sample of patients presenting to the Prince of Wales Hospital (Sydney, Australia) with a primary diagnosis of "falls for investigation" and age-matched healthy controls (non-fallers) from the community were recruited. Participants were fitted at the sternal angle with the wearable accelerometer, MetaMotionC (Mbientlab Inc., USA) and walked unobserved (at self-selected pace) for 5-50 m along an obstacle-free, carpeted hospital corridor. RESULTS: Participants comprised of 16 fallers (mean age: 70 + 17) and 16 non-fallers (mean age: 70 + 9) based on a recent fall(s) history. The (median) WORM score was 17-fold higher (p < 0.001) in fallers (3.64 cm) compared to non-fallers (0.21 cm). ROC curve analyses demonstrate WORM can discriminate fallers from non-fallers (AUC = 0.97). Diagnostic analyses (cut-off > 0.51 cm) show high sensitivity (88%) and specificity (94%). CONCLUSION: In this pilot study we have introduced the WORM score, demonstrating its discriminative performance in a preliminary sample size of 16 fallers. WORM is a novel gait metric assessing walking stability as measured by truncal way during ambulation and shows promise for objective and clinical evaluation of fallers.

Bioremediation of perfluorochemicals: current state and the way forward.

Perfluorochemicals are widely found in the environment due to their versatile uses and persistent nature. Perfluorochemicals have also been detected in human and animals due to direct or indirect exposures, giving rise to health concerns. This review aims to examine the bioremediation of perfluorochemicals with plants, bacteria and fungi, including their efficiency and limitations. It also aims to propose the future prospects of bioremediation of perfluorochemicals. This review retrieved peer-reviewed journal articles published between 2010 and 2021 from journal databases consisting of Web of Science, Scopus and ScienceDirect. This review shows that multiple Pseudomonas species could degrade perfluorochemicals particularly perfluoroalkyl acids under aerobic condition. Acidimicrobium sp. degraded perfluoroalkyl acids anaerobically in the presence of electron donors. A mixed Pseudomonas culture was more effective than pure cultures. Multiple plants were found to bioconcentrate perfluorochemicals and many demonstrated the ability to hyperaccumulate perfluoroalkyl acids, particularly Festuca rubra, Salix nigra and Betula nigra. Fungal species, particularly Pseudeurotium sp. and Geomyces sp., have the potential to degrade perfluorooctanoic acid or perfluorooctane sulphonic acid. Perfluorochemicals bioremediation could be advanced with identification of more candidate species for bioremediation, optimization of bioremediation conditions, mixed culturing, experiments with environmental media and studies on the biochemical pathways of biotransformation. This review provides comprehensive insight into the efficiency of different bacterial, plant and fungal species in perfluorochemicals bioremediation under different conditions, their limitations and improvement.

The application of bioremediation in wastewater treatment plants for microplastics removal: a practical perspective.

Wastewater treatment plants (WWTPs) play the role of intercepting microplastics in the environment and provide a platform for bioremediation to remove microplastics. Despite, this opportunity has not been adequately studied. This paper shows the potential ways microplastics-targeted bioremediation could be incorporated into wastewater treatment through the review of relevant literature on bioaugmentation of water treatment processes for pollutants removal. Having reviewed more than 90 papers in this area, it highlights that bioremediation in WWTPs can be employed through bioaugmentation of secondary biological treatment systems, particularly the aerobic conventional activated sludge, sequencing batch reactor, membrane bioreactor and rotating biological contactor. The efficiency of microplastics removal, however, is influenced by the types and forms of microorganisms used, the polymer types and the incubation time (100% for polycaprolactone with Streptomyces thermoviolaceus and 0.76% for low-density polyethylene with Acinetobacter iwoffii). Bioaugmentation of anaerobic system, though possible, is constrained by comparatively less anaerobic microplastics-degrading microorganisms identified. In tertiary system, bioremediation through biological activated carbon and biological aerated filter can be accomplished and enzymatic membrane reactor can be added to the system for deployment of biocatalysts. During sludge treatment, bioaugmentation and addition of enzymes to composting and anaerobic digestion are potential ways to enhance microplastics breakdown. Limitations of bioremediation in wastewater treatment include longer degradation time of microplastics, incomplete biodegradation, variable efficiency, specific microbial activities and uncertainty in colonization. This paper provides important insight into the practical applications of bioremediation in wastewater treatment for microplastics removal.